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Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study

• Elena Elez 1 ,
• Antonio Cubillo 2 , 3 ,
• Pilar Garcia Alfonso 4 ,
• Mark R. Middleton 5 ,
• Ian Chau 6 ,
• Baha Alkuzweny 7 ,
• Ann Alcasid 8 ,
• Xiaosong Zhang 9 &
• Eric Van Cutsem 10  

BMC Cancer volume  24 , Article number:  446 ( 2024 ) Cite this article

Metrics details

In patients with previously treated RAS -mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti–PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4).

In phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1. During phase 2, participants were randomly assigned to Arm 2A (binimetinib MTD/RP2D plus nivolumab) or Arm 2B (binimetinib MTD/RP2D plus nivolumab and ipilimumab) to assess the safety and clinical activity of these combinations.

In phase 1b, 21 participants were randomized to Arm 1A or Arm 1B; during phase 2, 54 participants were randomized to Arm 2A or Arm 2B. The binimetinib MTD/RP2D was determined to be 45 mg BID. In phase 2, no participants receiving binimetinib plus nivolumab achieved a response. Of the 27 participants receiving binimetinib, nivolumab, and ipilimumab, the overall response rate was 7.4% (90% CI: 1.3, 21.5). Out of 75 participants overall, 74 (98.7%) reported treatment-related adverse events (AEs), of whom 17 (22.7%) reported treatment-related serious AEs.

Conclusions

The RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS -mutated MSS mCRC.

Trial registration

NCT03271047 (09/01/2017).

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Colorectal cancer (CRC) is the third most diagnosed cancer (10% of cancer cases) and the second leading cause of cancer-related deaths (9.4% of cancer deaths) worldwide [ 1 ]. Patients with early-stage CRC can usually be cured through surgical resection of the primary tumor, but patients with metastatic CRC (mCRC) have a 5-year survival rate of only 14% [ 2 , 3 ]. CRC is a highly heterogeneous disease with different tumor phenotypes, each with specific molecular and morphological characteristics [ 4 ]. Due to these specific characteristics, CRC can be divided into discrete subclasses based on integrated molecular and clinical studies.

Comprehensive sequencing and proteomic studies have helped to define molecular subclasses of CRC, including disease that is microsatellite stable (MSS) or microsatellite-instability-high (MSI-H) [ 4 , 5 , 6 ]. Data has shown that MSS mCRC tumors have a distinct etiology and treatment recommendations that differ from tumors classified as MSI-H mCRC [ 5 , 6 , 7 ]. In general, immune checkpoint inhibitors (ICIs) are effective for MSI-H but not for MSS mCRC tumors [ 8 ]. However, approximately 96% of patients with mCRC have tumors with an ICI monotherapy–resistant MSS phenotype [ 7 , 8 ]. Multifactorial mechanisms may contribute to the intrinsic resistance of MSS mCRC tumors to ICI therapy such as having a lower tumor mutational burden and being poorly immunogenic [ 9 ]. Furthermore, MSS mCRC tumors may have an immunosuppressive environment caused by increased levels of tumor-associated macrophages and regulatory T cells compared with MSI-H mCRC tumors [ 10 ].

In MSS mCRC, RAS mutations have been linked to more aggressive tumor biology and a shorter overall survival (OS) compared with RAS wild-type MSS mCRC [ 11 , 12 ]. RAS belongs to a family of small G proteins, including KRAS, NRAS, and HRAS, that is responsible for controlling signaling downstream of ligand-dependent receptor activation. In mCRC overall, KRAS and NRAS activating mutations are reported in 40% and 3% to 5% of cases, respectively; HRAS activating mutations have been reported in rare cases [ 7 , 13 ]. RAS mutations represent a clinical setting where MAPK pathway inhibition may positively modulate the efficacy of ICIs in patients with MSS mCRC. Several preclinical studies suggest that MAPK signaling may influence tumor immune escape mechanisms, including downregulation of major histocompatibility complex class 1 expression and upregulation of immunosuppressive cytokines and cell surface molecules, including PD-1 expression, which can increase T-cell infiltration into tumors and enhance the antitumor activity of PD-1 inhibitors [ 14 , 15 ]. Therefore, combining a MEK1/MEK2 inhibitor with ICI treatment might be a way to overcome the inherent resistance of MSS mCRC to ICI.

Binimetinib (also known as MEK162 or ARRY-438162) is a potent and selective allosteric, ATP-uncompetitive inhibitor of MEK1 and MEK2 [ 16 ]. In most cancers, the ERK pathway, including RAS, BRAF, CRAF, and MEK1 or MEK2, is hyperactive due to deregulation of receptor tyrosine kinases. MEK1 and MEK2 are uniquely positioned within the ERK pathway, where they process inputs from multiple upstream activating kinases following RAF activation, making them attractive drug targets. Binimetinib has been investigated both as a single agent and in combination with other agents in patients with selected advanced or metastatic CRC [ 16 , 17 ]. The first in-human trial of binimetinib identified 60 mg twice daily (BID) as the maximum tolerated dose (MTD) and 45 mg BID as the recommended phase 2 dose (RP2D) for binimetinib monotherapy in patients with BRAF-mutant CRC [ 16 ]. Preliminary results indicate that binimetinib treatment in combination with ICIs has encouraging activity and acceptable tolerability in patients with MSS mCRC [ 18 , 19 ].

Nivolumab is an ICI monoclonal antibody (mAb) that targets the PD-1 cell surface membrane receptor. Nivolumab monotherapy and nivolumab in combination with the ICI ipilimumab, a mAb that targets CTLA4, have been approved to treat patients with MSI-H/mismatch repair-deficient (dMMR) mCRC that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan [ 20 , 21 ]. MSS mCRC tumors generally have fewer infiltrative CD8+ T-cell populations than MSI-H tumors [ 22 ], and immuno-oncological approaches with checkpoint inhibition alone may be insufficient for patients with limited tumor immune cell infiltration. The combination of MEK inhibitors with PD-1 inhibitors and CTLA-4 inhibitors has synergically promoted durable tumor regression and longevity of tumor-infiltrating CD8+ T cells to provide additional efficacy in preclinical mouse models [ 14 , 15 ].

Given that MAPK pathway inhibition might overcome the resistance to ICI in patients with MSS mCRC harboring an activating RAS mutation, this multicenter, open-label, phase 1b and phase 2 trial was designed to determine the MTD, RP2D, and schedule of binimetinib treatment in combination with nivolumab with or without ipilimumab. This study was also designed to assess the safety and efficacy of binimetinib administered in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated MSS mCRC with a documented RAS mutation.

Study design and participants

ARRAY-162–202 (NCT03271047) is a multicenter, open-label, phase 1b/2 study to evaluate the safety and preliminary antitumor activity of binimetinib in combination with nivolumab or nivolumab and ipilimumab in adult participants with MSS mCRC and a documented RAS mutation who have received 1 or 2 prior lines of therapy. This study included a dose-finding phase 1b period to determine the MTD and RP2D of binimetinib, followed by a randomized phase 2 period to assess the antitumor activity of the combinations ( Fig.  1 ) . Both phases also assessed the safety, efficacy, and pharmacokinetics of binimetinib administered in combination with nivolumab or nivolumab and ipilimumab. Key eligibility criteria included participants who: (1) were ≥ 18 years of age, (2) had Eastern Cooperative Oncology Group performance status of 0 or 1, (3) had mCRC categorized as MSS by immunohistochemistry or polymerase chain reaction-based local assay at any time prior to screening or by the central laboratory, (4) had RAS mutation assessed per local assay at any time prior to screening or by the central laboratory, and (5) had received ≤ 2 prior lines of systemic therapy in the metastatic setting (maintenance therapy given in the metastatic setting was not considered a separate regimen). Key exclusion criteria included: (1) prior treatment with any MEK inhibitor; (2) prior treatment with an anti–PD-1, anti–PD-L1, anti–PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways; (3) any untreated central nervous system (CNS) lesions, unless all known CNS lesions had been treated with radiotherapy or surgery and participants remained without evidence of CNS disease progression ≥ 4 weeks after treatment, and participants must have been off corticosteroid therapy for ≥ 3 weeks; and (4) participants who had an active, known or suspected autoimmune disease.

Study designs and flowcharts of (A) phase 1b, to determine the MTD and RP2D of binimetinib in combination with nivolumab (Arm 1A [Doublet]) and binimetinib in combination with nivolumab and ipilimumab (Arm 1B [Triplet]) and (B) phase 2 to determine the safety and clinical activity of the RP2D of binimetinib in combination with nivolumab (Arm 2A [Doublet]) and binimetinib in combination with nivolumab and ipilimumab (Arm 2B [Triplet]). BID, twice daily; DLT, dose-limiting toxicity; I-D, intermittent dosing; RP2D, recommended phase 2 dose; Q4W, every 4 weeks; Q8W, every 8 weeks

*Three weeks on, one week off

Study objectives and endpoints

The objective of the phase 1b part was to determine the MTD and RP2D of binimetinib administered in combination with nivolumab or nivolumab and ipilimumab. The MTD was defined as the highest combination drug dosage not causing medically unacceptable dose-limiting toxicities (DLTs) in > 35% of treated participants in the first cycle of treatment, based on a modified toxicity probability interval (mTPI-2) design. Four dose levels were tested using the mTPI-2 design, a model-based approach that is guided by a prespecified decision matrix that recommends escalating, reducing, or maintaining the same dose, or stopping dose escalation based on the number of patients with DLTs observed in the dose level under evaluation. DLTs were defined as adverse events (AEs) or clinically significant abnormal laboratory values assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications that occurred within the first 28 days of treatment and resulted in the inability to tolerate 75% dose intensity ([administered dose in mg/planned dose in mg] × 100) of binimetinib. The primary endpoint of the phase 1b part was the incidence of DLTs resulting from binimetinib in combination with nivolumab or nivolumab and ipilimumab.

The objective of the phase 2 part was to assess the preliminary antitumor activity of the treatment combinations based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 with a primary endpoint of overall response rate (ORR) per RECIST 1.1. The secondary safety endpoints for both parts were the incidence and severity of AEs graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. The phase 1b secondary efficacy endpoint was ORR per RECIST 1.1. The phase 1b and phase 2 secondary efficacy endpoints were duration of response (DOR) and rate of complete response per RECIST 1.1.

Study treatment and procedures

In phase 1b, Arm 1A participants received a starting dose of binimetinib 45 mg BID plus nivolumab 480 mg once every 4 weeks (Q4W), the US Food and Drug Administration–approved doses of both agents at the time (Fig.  1 A). In phase 1b, Arm 1B participants received a starting dose of binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks (Q8W) (Fig.  1 A). In Arm 1A and Arm 1B, dose de-escalation was planned as needed until the MTD/RP2D was determined.

In phase 2, Arm 2A participants received the MTD/RP2D of binimetinib, as determined during phase 1b, plus nivolumab 480 mg Q4W (Fig.  1 B). In phase 2, Arm 2B participants received the MTD/RP2D of binimetinib, as determined during phase 1b, plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg Q8W (Fig.  1 B).

Tumor response was evaluated locally by the investigator according to RECIST 1.1, using computed tomography scans and/or magnetic resonance imaging with intravenous contrast. Scans were performed at screening/baseline and then every 8 weeks (two 28-day cycles) until disease progression.

Safety was assessed throughout the study, and AEs were coded using Medical Dictionary for Regulatory Activities, version 21.0, terminology. Toxicity was assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events 4.03. Participants continued treatment until disease progression, development of unacceptable toxicity, or withdrawal of informed consent.

Statistical analysis

The MTD/RP2D of the combination treatment was estimated based on the anticipated probability of DLTs in cycle 1 for participants in the dose-determining set, which consisted of all phase 1b participants who met specified minimum exposure criteria and had sufficient safety evaluations during cycle 1 or who discontinued earlier due to a DLT during cycle 1. Efficacy analyses included all participants who received at least one dose of study drug. The ORR was calculated within each treatment arm and with exact (Clopper-Pearson) 2-sided 90% and 95% confidence intervals (CIs). A similar analysis was provided for the rate of complete response. An estimate of the DOR was presented descriptively. For progression-free survival (PFS) and OS, the survival function was constructed using the Kaplan–Meier (product-limit) method. The 25%, median, and 75% PFS and OS (in months) were summarized along with 95% CIs. Kaplan–Meier estimates with 95% CIs at specific time points were summarized as well. The safety set, which consists of all participants who received ≥ 1 dose of any study drug, was used for summaries of safety data, except for DLTs for which the dose-determining set was used. Descriptive statistics were used to summarize safety data. Statistical analyses were done using SAS, version 9.4.

A total of 75 participants were enrolled and dosed in the study: 10 participants in Arm 1A (starting dose of binimetinib 45 mg BID plus nivolumab 480 mg Q4W), 11 participants in Arm 1B (starting dose of binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg Q8W), and 27 participants each in Arm 2A (MTD/RP2D of binimetinib plus nivolumab 480 mg Q4W) and Arm 2B (MTD/RP2D of binimetinib plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg Q8W) (Table  1 ). In the Doublet Arms (Arms 1A and 2A) the median age at enrollment was 60 years (range, 31–80 years) (Table  1 ). In the Triplet Arms (Arms 1B and 2B) the median age at enrollment was 59.5 years (range, 29 − 78 years) (Table  1 ). Participant demographics and baseline disease characteristics were generally similar across treatment groups in the phase 1b and phase 2 parts (Table  1 ).

In Arm 1A (Doublet), of the 9 participants (90.0%) evaluable for DLTs, 1 participant (11.1%) was reported to have grade 3 dermatitis acneiform. In Arm 1B (Triplet), 2 of 11 participants (18.2%) reported multiple DLTs. One participant had DLTs of grade 3 rash, grade 2 blurred vision, and grade 2 pneumonitis, all reported during the first treatment cycle. Another participant had a DLT of grade 3 colitis reported during the first treatment cycle. The MTD and RP2D of binimetinib were determined as 45 mg BID for both Arm 1A (Doublet) and Arm 2A (Triplet). Therefore, this dose was used in the phase 2 part of the study (Arm 1B and Arm 2B).

In the Doublet Arms, binimetinib and nivolumab exposure had a median duration of 3.1 months (range, 1.8–7.1 months) and 3.2 months (range, 1.8–7.6 months) in Arm 1A and 2.0 months (range, 0.03–23.8 months) and 2.0 months (range, 0.0–24.5 months) in Arm 2A. In the Triplet Arms, binimetinib and nivolumab exposure had a median duration of 2.8 months (range, 0.7–5.6 months) and 2.8 months (range, 0.9–6.3 months) in Arm 1B and 2.1 months (range, 0.4–17.5 months) and 2.8 months (range, 0.9–17.9) in Arm 2B. The median duration of ipilimumab exposure was 3.7 months (range, 1.8–6.2 months) in Arm 1B and 1.8 months (range, 1.8–18.9 months) in Arm 2B. The most frequently reported AEs are described in Table S1 .

In the Doublet Arms, the most frequently reported treatment-related AEs were dermatitis acneiform (51.4%), blood creatine phosphokinase increased (48.6%), diarrhea (45.9%), fatigue (29.7%), and edema peripheral (29.7%) (Table  2 ). The most frequently reported treatment-related AEs in the Triplet Arms were dermatitis acneiform (47.4%), blood creatine phosphokinase increased (39.5%), diarrhea (39.5%), rash (39.5%), fatigue (28.9%), nausea (28.9%), and vomiting (28.9%) (Table  2 ).

AEs related to binimetinib were observed including grade 3 exfoliative rash, grade 3 alanine aminotransferase increased, grade 2 cardiac failure congestive, and grade 1 ejection fraction decreased that were reported for one participant each. One participant reported AEs related to binimetinib, nivolumab, and ipilimumab of grade 2 maculopathy and grade 2 retinopathy. Serious AEs related to all 3 study drugs were also reported. One participant had a grade 3 skin reaction, grade 3 myocarditis, grade 2 pleurisy, and grade 2 pneumonitis related to nivolumab and ipilimumab. Another participant had grade 3 colitis and 1 participant had grade 3 pancreatitis and grade 3 transaminase increased related to binimetinib, nivolumab, and ipilimumab. Additionally, 1 serious AE related to binimetinib, nivolumab, and ipilimumab of grade 5 Pneumocystis jirovecii pneumonia occurred in Arm 1B (Triplet) and 1 serious AE of grade 5 empyema occurred in Arm 2B (Triplet).

All-causality immune-mediated AEs were reported for 22 participants (59.5%) in the Doublet Arms and 25 participants (65.8%) in the Triplet Arms. The most frequently (≥ 4 participants) reported all-causality immune-mediated AEs were diarrhea, fatigue, and dermatitis acneiform in the Doublet Arms, and diarrhea, fatigue, dermatitis acneiform, rash, and pruritus in the Triplet Arms.

A total of 16 participants (21.3%) reported AEs leading to discontinuation of any study drug. All-causality AEs leading to discontinuation of binimetinib were reported for 3 participants (8.1%) in the Doublet Arms and 13 participants (34.2%) in Triplet Arms. Two participants in the Doublet Arms permanently discontinued binimetinib due to the following all-causality AEs (reported for 1 participant each): an AE of grade 4 blood bilirubin increased that was not considered treatment related and a serious AE of grade 4 myocarditis that was considered related to nivolumab. There was also a serious AE of grade 5 acute coronary syndrome that was not considered treatment related. Thirteen participants (34.2%) in the Triplet Arms permanently discontinued binimetinib due to the following all-causality AEs (reported for 1 participant each): grade 4 bacterial sepsis, grade 4 pneumonia, and grade 3 abdominal infection. None of these events were considered treatment related.

Clinical activity

In the phase 1b part, no participants had a response to binimetinib in combination with nivolumab in Arm 1A (Doublet) or binimetinib in combination with nivolumab and ipilimumab in Arm 1B (Triplet). In Arm 1A, 6 participants (60%) had stable disease (SD), for a disease control rate (DCR) of 60% (95% CI: 26.2, 87.8), and in Arm 1B, 4 participants (36.4%) had SD, for a DCR of 36.4% (95% CI: 10.9, 69.2) (Table  3 ). In the phase 2 part (Arm 2A [Doublet] and Arm 2B [Triplet]), the confirmed ORR was 0% in Arm 2A and 7.4% (90% CI: 1.3, 21.5) in Arm 2B, with 2 participants having a confirmed partial response (Table  3 ). Furthermore, 11 participants (40.7%) in Arm 2A had SD, for a DCR of 40.7% (95% CI: 22.4, 61.2); 13 participants (48.1%) in Arm 2B had SD, for a DCR of 55.6% (95% CI: 35.3, 74.5) (Table  3 ). For the 2 participants in Arm 2B who had a partial response (Table  3 ) the DORs were 462 and 229 days.

In the Doublet Arms, the median PFS, defined as the time from start of treatment to the date of the first documented disease progression or death due to any cause, was 3.0 months (95% CI: 1.6, 3.7) in Arm 1A ( n  = 10) and 1.8 months (95% CI: 1.7, 3.7) in Arm 2A ( n  = 27). In the Triplet Arms, the median PFS was 2.4 months (95% CI: 1.7, 5.6) in Arm 1B ( n  = 11) and 3.0 months (95% CI: 1.8, 13.8) in Arm 2B ( n  = 27). The median OS, defined as the duration from the start of treatment to the time of death due to any cause, was 5.1 months (95% CI: 2.5, 22.0) in Arm 1A, 7.6 months (95% CI: 4.1, 10.6) in Arm 2A, 5.1 months (95% CI: 1.7, 16.7) in Arm 1B, and 12.0 months (95% CI: 8.3, 17.8) in Arm 2B.

Aside from chemotherapy, which has limited efficacy, treatment options are lacking for previously treated patients with RAS -mutated MSS mCRC. Therefore, we undertook this phase 1b/2 study to determine if the combination of binimetinib with nivolumab or nivolumab and ipilimumab could improve outcomes for these patients, as the combination of MEK inhibition with ICI therapy has shown evidence of tumor regression even where either agent alone was only modestly effective [ 14 , 23 , 24 , 25 ].

In this study, the safety profile of the RP2D triplet regimen of binimetinib, nivolumab, and ipilimumab was similar to the clinically accepted and approved doublet regimen of nivolumab and ipilimumab [ 20 , 26 , 27 ], indicating that these therapies can be given together [ 16 , 25 , 28 ]. Moreover, the observed AEs for binimetinib were consistent with those reported for other MEK1/2 inhibitors, which were reversible with appropriate supportive medical care or dose modifications [ 16 , 25 , 28 ]. However, based on the ORR results, adding binimetinib in combination with nivolumab in Arm 1A or Arm 2A (Doublet Arms) did not result in an additional clinical benefit. This was also the case when binimetinib was added to nivolumab and ipilimumab in Arm 1B or Arm 2B (Triplet Arms).

Even though this study was able to examine several combinations at once, data interpretation was limited due to the small number of participants in each arm of the phase 1B and phase 2 parts. Furthermore, while no tissue samples were collected to look at possible modes of action, it could be that the extent and duration of MAPK pathway inhibition was insufficient to alter the immune environment or that the preclinical data on which this study design was based was not as relevant in the real world in this patient population. Prior studies have highlighted the challenges associated with treating patients with MSS mCRC with ICI therapy [ 28 , 29 , 30 , 31 ]. The combination of MEK inhibition and ICI therapy might not be sufficient to overcome the “immune cold” nature of the tumor microenvironment associated with MSS mCRC [ 32 , 33 ]. In addition, alternative mechanisms that bypass the inhibition of the MAPK pathway by a MEK inhibitor in MSS mCRC could contribute to the lack of additional clinical benefit from adding binimetinib to ICI therapy [ 34 ]. Despite the lack of efficacy results in this study, MEK inhibitors still have promise in MSS mCRC and are currently being tested with broader inhibitors upstream of MEK1/2 in the RAS-regulated RAF–MEK1/2–ERK pathway, including drugs targeting SHP2 and SOS [ 35 , 36 ]. MEK inhibitors are also being tested with cell cycle inhibitors, such as drugs targeting CDK4/6, to determine their safety and effectiveness [ 37 ].

As there are currently approved therapies available for patients with previously treated MSS mCRC with RAS mutation that have demonstrated a survival benefit [ 38 , 39 ], the lack of clinical benefit with the doublet and triplet regimens in the current study does not justify further clinical development in patients with CRC. However, other ongoing MEK inhibitor combination studies may have promise for patients with RAS -mutated MSS CRC.

Availability of data and materials

Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

Abbreviations

Adverse event

Twice daily

Central nervous system

• Colorectal cancer

Disease control rate

Dose-limiting toxicity

Mismatch repair deficient

Duration of response

Immune checkpoint inhibitor

Monoclonal antibody

Metastatic colorectal cancer

Microsatellite instability high

Microsatellite stable

Maximum tolerable dose

Modified toxicity probability interval

Overall response rate

Overall survival

Progression-free survival

Every 4 weeks

Every 8 weeks

Response Evaluation Criteria in Solid Tumors

Recommended phase 2 dose

Stable disease

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

Article   PubMed   Google Scholar  

Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70:145–64.

Chakrabarti S, Peterson CY, Sriram D, Mahipal A. Early stage colon cancer: current treatment standards, evolving paradigms, and future directions. World J Gastrointest Oncol. 2020;12:808–32.

Article   PubMed   PubMed Central   Google Scholar  

Singh MP, Rai S, Pandey A, Singh NK, Srivastava S. Molecular subtypes of colorectal cancer: an emerging therapeutic opportunity for personalized medicine. Genes Dis. 2021;8:133–45.

Article   CAS   PubMed   Google Scholar  

Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.

Article   Google Scholar  

Zhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z, et al. Proteogenomic characterization of human colon and rectal cancer. Nature. 2014;513:382–7.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Serebriiskii IG, Connelly C, Frampton G, Newberg J, Cooke M, Miller V, et al. Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients. Nat Commun. 2019;10:3722.

Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.

Kim CW, Chon HJ, Kim C. Combination immunotherapies to overcome intrinsic resistance to checkpoint blockade in microsatellite stable colorectal cancer. Cancers (Basel). 2021;13:4906.

Giordano G, Parcesepe P, D’Andrea MR, Coppola L, Di Raimo T, Remo A, et al. JAK/Stat5-mediated subtype-specific lymphocyte antigen 6 complex, locus G6D (LY6G6D) expression drives mismatch repair proficient colorectal cancer. J Exp Clin Cancer Res. 2019;38:28.

Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007;67:2643–8.

Taieb J, Le Malicot K, Shi Q, Penault-Llorca F, Bouche O, Tabernero J, et al. Prognostic value of BRAF and KRAS mutations in MSI and MSS stage III colon cancer. J Natl Cancer Inst. 2016;109:djw272.

Dienstmann R, Connor K, Byrne AT, COLOSSUS Consortium. Precision therapy in RAS mutant colorectal cancer. Gastroenterology. 2020;158:806–11.

Ebert PJR, Cheung J, Yang Y, McNamara E, Hong R, Moskalenko M, et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity. 2016;44:609–21.

Liu L, Mayes PA, Eastman S, Shi H, Yadavilli S, Zhang T, et al. The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4. Clin Cancer Res. 2015;21:1639–51.

Bendell JC, Javle M, Bekaii-Saab TS, Finn RS, Wainberg ZA, Laheru DA, et al. A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. Br J Cancer. 2017;116:575–83.

Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381:1632–43.

Friedrich T, Blatchford PJ, Lentz RW, Davis SL, Kim SS, Leal AD, et al. A phase II study of pembrolizumab, binimetinib, and bevacizumab in patients with microsatellite-stable, refractory, metastatic colorectal cancer (mCRC). J Clin Oncol. 2022;40(4 suppl. Abstract):118.

Cherri S, Oneda E, Zanotti L, Zaniboni A. Optimizing the first-line treatment for metastatic colorectal cancer. Front Oncol. 2023;13:1246716.

Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair–deficient/microsatellite instability–high metastatic colorectal cancer. J Clin Oncol. 2018;36:773–9.

Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18:1182–91.

Chirica M, Le Bourhis L, Lehmann-Che J, Chardiny V, Bouhidel F, Foulboeuf L, et al. Phenotypic analysis of T cells infiltrating colon cancers: correlations with oncogenetic status. Oncoimmunology. 2015;4: e1016698.

Mimura K, Kua LF, Shiraishi K, Kee Siang L, Shabbir A, Komachi M, et al. Inhibition of mitogen-activated protein kinase pathway can induce upregulation of human leukocyte antigen class I without PD-L1-upregulation in contrast to interferon-gamma treatment. Cancer Sci. 2014;105:1236–44.

Le DT, Kim TW, Van Cutsem E, Geva R, Jager D, Hara H, et al. Phase II open-label study of pembrolizumab in treatment–refractory, microsatellite instability–high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol. 2020;38:11–9.

Dummer R, Lebbé C, Atkinson V, Mandala M, Nathan PD, Arance A, et al. Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i. Nat Med. 2020;26:1557–63.

Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.

Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–33.

Hellmann MD, Kim TW, Lee CB, Goh BC, Miller WH Jr, Oh DY, et al. Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors. Ann Oncol. 2019;30:1134–42.

Eng C, Kim TW, Bendell J, Argiles G, Tebbutt NC, Di Bartolomeo M, et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019;20:849–61.

Lin KX, Istl AC, Quan D, Skaro A, Tang E, Zheng X. PD-1 and PD-L1 inhibitors in cold colorectal cancer: challenges and strategies. Cancer Immunol Immunother. 2023;72:3875–93.

Johnson B, Haymaker CL, Parra ER, Soto LMS, Wang X, Thomas JV, et al. Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). J Immunother Cancer. 2022;10: e005332.

Ros J, Balconi F, Baraibar I, Saoudi Gonzalez N, Salva F, Tabernero J, et al. Advances in immune checkpoint inhibitor combination strategies for microsatellite stable colorectal cancer. Front Oncol. 2023;13:1112276.

Sahin IH, Ciombor KK, Diaz LA, Yu J, Kim R. Immunotherapy for microsatellite stable colorectal cancers: challenges and novel therapeutic avenues. Am Soc Clin Oncol Educ Book. 2022;42:1–12.

PubMed   Google Scholar  

Weng J, Li S, Zhu Z, Liu Q, Zhang R, Yang Y, Li X. Exploring immunotherapy in colorectal cancer. J Hematol Oncol. 2022;15:95.

Fedele C, Ran H, Diskin B, Wei W, Jen J, Geer MJ, et al. SHP2 inhibition prevents adaptive resistance to MEK inhibitors in multiple cancer models. Cancer Discov. 2018;8:1237–49.

Sheffels E, Kortum RL. Breaking oncogene addiction: getting RTK/RAS-mutated cancers off the SOS. J Med Chem. 2021;64:6566–8.

Sorokin AV, Kanikarla Marie P, Bitner L, Syed M, Woods M, Manyam G, et al. Targeting RAS mutant colorectal cancer with dual inhibition of MEK and CDK4/6. Cancer Res. 2022;82:3335–44.

Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303–12.

Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, et al. Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med. 2023;388:1657–67.

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Acknowledgements

The authors thank the participants and their families, as well as the participating study teams, for making this study possible. Medical writing and editorial assistance were provided by Michael J. Williams, PhD, and Blaise Low, PhD, of Nucleus Global, an Inizio company, and were funded by Pfizer.

This study was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019, in collaboration with Bristol Myers Squibb.

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Facultad HM Hospitales de Ciencias de La Salud UCJC, 28050, Madrid, Spain

Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Universidad Complutense, Madrid, Spain

Pilar Garcia Alfonso

Department of Oncology, NIHR Biomedical Research Centre, University of Oxford, Oxford, UK

Mark R. Middleton

Gastrointestinal Unit, Royal Marsden Hospital, London & Surrey, UK

Formerly Pfizer, Inc, San Diego, CA, USA

Baha Alkuzweny

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Ann Alcasid

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Contributions

Conceptualization: MM, PGA, EVC. Data curation: MM, PGA. Formal analysis: BA. Investigation: AC, EE, IC. Methodology: AC. Project administration: AC. Resources: EE. Software: BA. Supervision: XZ, PGA. Validation: EE. Visualization: EE. Writing—review and editing: XZ, AA, EE, BA, AC, IC, MM, PGA, EVC.

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The final protocol, any amendments, and informed consent documentation were reviewed and approved by the institutional review boards and independent ethics committees at each of the investigational centers participating in the study. Investigators were required to inform their institutional review boards or independent ethics committees of the study’s progress and occurrence of any serious and/or unexpected adverse events. This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good Clinical Practice Guidelines. In addition, all local regulatory requirements were followed, particularly those affording greater protection to the safety of trial participants. The study was approved by the independent ethics committees (Commissie Medische Ethiek—UZ KU Leuven/Onderzoek; METC AVL; CEIC del Hospital General Universitario Gregorio Marañon; East Midlands—Leicester South Research Ethics Committee; Health Research Authority; Schulman Associates IRB; Western Institutional Review Board; Advarra Institutional Review Board; Office of Regulatory Affairs of the University of Pennsylvania; University of Texas MD Anderson Cancer Center; Christiana Care Health System Institutional Review Board; Washington University in St. Louis; UCLA Office of the Human Research Protection Program) in accordance with the Declaration of Helsinki. According to the research ethics guide, all patient information was completely confidential and all stages of the research were performed with patient satisfaction. All experiments were performed in accordance with relevant guidelines and regulations. Informed consent was obtained from all participants before enrollment in the study.

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Competing interests

Elena Elez declares personal financial interest for consulting, advisory roles, honoraria, travel grants, and research grants from Amgen, Bayer, F. Hoffman-La Roche, Merck Serono, Sanofi, Pierre Fabre, MSD, Organon, Novartis, and Servier; institutional financial interest in the form of financial support for clinical trials or contracted research for Amgen, Array Biopharma, AstraZeneca Pharmaceuticals, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International, F. Hoffmann-La Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Janssen-Cilag, MedImmune, Menarini, Merck Health KGaA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, and Taiho Pharma USA.

Antonio Cubillo declares there are no competing interests.

Pilar Garcia Alfonso declares personal financial interest for consulting, advisory roles, honoraria, travel grants, and research grants from Amgen, F. Hoffman-La Roche, Merck Serono, Sanofi, Pierre Fabre, MSD, Organon, Novartis, and Servier.

Mark Middleton reports grants from Roche, grants from AstraZeneca, grants from GSK, personal fees and other from Novartis, grants, personal fees, and other from Immunocore, personal fees and other from BMS, other from Pfizer, personal fees and other from Merck/MSD, other from Regeneron, personal fees and other from BiolineRx, personal fees and non-financial support from Replimune, personal fees from Kineta, personal fees from Silicon Therapeutics, grants from GRAIL, outside the submitted work.

Ian Chau declares advisory roles for Eli Lilly, Bristol Meyers Squibb, MSD, Roche, Merck-Serono, AstraZeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astella, GSK, Sotio, Eisai, Daiichi-Sankyo, Taiho, Servier, Seagen, Turning Point Therapeutics, and Novartis. Research funding from Eli Lilly and Janssen-Cilag, and an honorarium from Eli Lilly, Eisai, Servier, and Roche.

Baha Alkuzweny was formerly an employee of Pfizer.

Ann Alcasid is an employee of Pfizer.

Xiaosong Zhang is an employee of Pfizer.

Eric Van Cutsem declares consulting or advisory roles for Array, AstraZeneca, Bayer, Biocartis, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, MSD, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex, and Taiho; and research funding from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck, Merck KGaA, Novartis, Roche, and Servier.

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Elez, E., Cubillo, A., Alfonso, P.G. et al. Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study. BMC Cancer 24 , 446 (2024). https://doi.org/10.1186/s12885-024-12153-5

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DOI : https://doi.org/10.1186/s12885-024-12153-5

Effect of the COVID-19 pandemic on utilization of essential health services in Iran evidence from an interrupted time series analysis

• Mohammad Ranjbar 1 ,
• Seyed Masood Mousavi 1 ,
• Farzan Madadizadeh 2 ,
• Nahid Hosseini Dargani 3 ,
• Samaneh Iraji 4 ,
• Blake Angell 5 &
• Yibeltal Assefa 6  

BMC Public Health volume  24 , Article number:  1006 ( 2024 ) Cite this article

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The COVID-19 disrupted the provision of essential health services in numerous countries, potentially leading to outbreaks of deadly diseases. This study aims to investigate the effect of the COVID-19 pandemic on the utilization of essential health services in Iran.

An analytical cross-sectional study was conducted using interrupted time series (ITS) analysis. Data about five indicators, including 'childhood vaccination, infant care, hypertension screening, diabetes screening, and breast cancer screening,' were obtained from the electronic health record System in two-time intervals: 15 months before (November 2018 to January 2020) and 15 months after (January 2020 to May 2021) the onset of the COVID-19 pandemic. The data were analyzed by utilizing ITS. In addition, a Poisson model was employed due to the usage of count data. The Durbin-Watson (DW) test was used to identify the presence of lag-1 autocorrelation in the time series data. All statistical analysis was performed using R 4.3.1 software, considering a 5% significance level.

The ITS analysis showed that the COVID-19 pandemic significantly affected the utilization of all essential health services ( P  <  0.0001 ). The utilization of hypertension screening (RR = 0.51, p  < 0.001), diabetes screening (RR = 0.884, p  < 0.001), breast cancer screening (RR = 0.435, p  < 0.001), childhood vaccination (IRR = 0.947, p  < 0.001), and infant care (RR = 1.666, p  < 0.001), exhibited a significant decrease in the short term following the pandemic ( P  <  0.0001 ). However, the long-term trend for all service utilization, except breast cancer screening (IRR = 0.952, p  < 0.001), demonstrated a significant increase.

Conclusions

The COVID-19 pandemic affected utilization of essential health care in Iran. It is imperative to utilize this evidence to develop policies that will be translated into targeted planning and implementation to sustain provision and utilization of essential health services during public health emergencies. It is also vital to raise awareness and public knowledge regarding the consequences of interruptions in essential health services. In addition, it is important to identify the supply- and demand-side factors contributing to these disruptions.

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Following the diagnosis of the first case of COVID-19 in Wuhan, China, in January 2020, the number of patients infected with the virus increased worldwide [ 1 ]. According to the World Health Organization's (WHO) report, as of April 2023, 763,740,140 people worldwide had been infected, and 6,908,554 had died from this disease [ 2 , 3 ]. In response to the COVID-19 pandemic, countries around the globe emphasized the importance of implementing public health measures, including social distancing, quarantines, hand hygiene, and contact tracing, to control the incidence of the disease and reduce mortality rates [ 4 ]. Additionally, the prevalence of COVID-19 presented significant challenges to healthcare systems worldwide [ 5 ]. These healthcare systems encompass formal and informal organizations with diverse objectives, methods, resources, and responsibilities at local, regional, or global levels [ 6 ]. In critical situations, healthcare systems have two critical tasks: responding to emergency needs and ensuring the continuous provision of high-quality healthcare services. Among these services, reproductive services, vaccination, child and maternal health, and counseling are considered the most essential. These services aim to reduce the prevalence and mortality of preventable and curable diseases in children, mothers, and families [ 7 ].

The interruption in the provision of essential health services can be attributed to various factors, including lockdowns, media warnings, public health actions, fear of COVID-19, changes in hospital policies, and public health authorities' recommendations to stay at home in order to reduce infections and alleviate the burden on hospitals [ 3 , 7 ]. According to the WHO, the COVID-19 pandemic disrupted the delivery of essential health services in nearly all countries [ 7 ].

Hung et al. (2022) reported that married women with higher education levels avoided seeking healthcare services due to concerns about COVID-19 infection. Hence, there is a pressing need for a responsive healthcare system and timely communication to prevent preventable deaths during critical events such as pandemics [ 8 ]. Doubova et al. (2021) demonstrated that the COVID-19 pandemic significantly impacted healthcare systems and preventive services, reducing utilization of services such as breast cancer screening, pregnancy prevention, vaccination, diabetes and hypertension counseling, and pre-pregnancy care. Notably, there was a two-thirds reduction in visits for breast screening counseling services and a one-third reduction for vaccination and diabetes and hypertension counseling services [ 7 ].

According to WHO estimates, 70% of this disruption primarily affected child vaccination services [ 9 ]. The interruption in the delivery of child vaccination services can decrease herd immunity and increase the risk of future outbreaks of infectious diseases, such as measles and polio [ 10 , 11 ]. The consequences of this disruption are particularly severe in low and middle-income countries [ 12 ].

Two crucial milestones in routine childhood immunization programs within primary care are universal vaccinations at 8 weeks of age, including the hexavalent vaccine, and vaccines administered at one year, which coincides with the first dose of the DPT vaccine [ 13 ].

The results of previous studies in Colombia and Pakistan indicated that, despite WHO recommendations to continue children's vaccination programs during the COVID-19 pandemic, vaccination services decreased by 14.4% in Colombia and 65% in Pakistan [ 11 , 12 ]. In 2021, Ota et al. conducted a review study evaluating the impact of the pandemic on global immunization activities. The results indicated that a higher number of unvaccinated vulnerable individuals could lead to the re-emergence of preventable diseases such as measles. Therefore, there is a need for guidelines and targeted vaccination operations during and after the pandemic, as well as extensive cooperation among stakeholders and frontline healthcare providers [ 9 ].

Additionally, the pandemic has disrupted the provision of screening services, treatment, and necessary measures for cancer patients, resulting in a poor prognosis for these individuals [ 14 ]. In a cross-sectional study, Yuan Li et al. (2021) investigated 4551 patients in Hong Kong using a survey form to collect information and facts. The study results revealed a correlation between reduced physician consultations and the fear of COVID-19, with a 10% decrease in medical consultations during the COVID-19 pandemic [ 15 ]. Another qualitative study by Akbari et al. (2021) examined the self-care status of these patients during the pandemic using semi-structured interviews. The findings indicated that patients did not maintain desirable self-care practices related to nutrition, mobility, exercise, and medication during the COVID-19 pandemic [ 16 ].

In Iran, the healthcare network, including health houses and comprehensive healthcare centers, was established to ensure equitable access to essential health services for all people in rural and urban areas. This network aims to improve public health, enhance the quality of life, and reduce health disparities across the country [ 17 ]. Following the onset of the COVID-19 pandemic in Iran, numerous plans were implemented for early diagnosis, treatment, hospitalization, and patient recovery. These measures included the establishment of a crisis team, the development of guidelines and protocols, and the screening of all households. As of April 2023, the number of confirmed COVID-19 cases in Iran reached 7,603,697, with 145,837 reported deaths [ 2 , 18 ].

One of Iran's initial responses to the pandemic was the complete evacuation of certain hospitals to admit COVID-19 patients, the closure of clinics and schools, travel restrictions, and an emphasis on hand hygiene and social distancing to curb the spread of the coronavirus [ 19 , 20 ]. Interrupted time series (ITS) analysis has been widely employed to assess the performance of essential health services during the COVID-19 pandemic. This method allows for integrating longitudinal data that cannot be incorporated using other approaches within a specified population and reports the results [ 21 ].

As far as we know, some studies in Iran regarding the impact of the COVID-19 pandemic on healthcare utilization have been conducted, but none of them have examined essential health services; rather, they have mostly studied utilization of hospital services during the pandemic. On the other hand, the existing challenges in the Iranian healthcare system, specific society needs, financial constraints and resources, and stimulation of the research system convinced researchers to conduct study related to people's utilization of essential health services within the Iranian healthcare system. Hence, this study seeks to assess the influence of the COVID-19 pandemic on the utilization of essential health services, with a focus on access to services like hypertension screening, diabetes screening, breast cancer screening, childhood vaccination, and infant care during the pandemic.

This analytical cross-sectional study aimed to examine the impact of the COVID-19 pandemic on the utilization of essential health services in Yazd, Iran. Yazd, with an area of 74,650 square kilometers, is located in the central part of Iran and has a population of approximately 1,138,533. Essential health services in Yazd province are provided to the entire population through rural and urban comprehensive health centers, and the services provided to the covered population are recorded in the Electronic Health Record system (EHR). EHR, developed by the Ministry of Health, and Medical Education (MOHME) in Iran, is an electronic system designed to collect, record, and manage the health information of citizens. This comprehensive system offers policy makers, healthcare professionals and healthcare facilities access to population health information. EHR acquires information through various means, including citizen registration, reports from physicians and healthcare centers, vaccination details, and prescribed medication records. By collecting this data, the EHR assist healthcare professionals and healthcare centers in providing the best health services to population. It also enables better management of treatment histories and tracing of improvement and changes in health status. the most important essential health services currently provided at EHR include breast cancer screening, hypertension screening, diabetes screening, infant care, and childhood vaccination for which information on the utilization of these services is available in EHR. we used interrupted time series analysis (ITS) to focus on five key health service indices: breast cancer screening, hypertension screening, diabetes screening, infant care, and childhood vaccination. ITS analysis is particularly suitable for studying the utilization of essential health services before and after the COVID-19 outbreak because it allows for studying trends over time, controls for pre-existing trends, seasonality, and confounders, identifies immediate effects, such as changes following the outbreak, provides statistical rigor with segmented regression, and its commonly used for policy evaluation, making it suitable for assessing the impact of the COVID-19 outbreak on healthcare utilization.

In the context of this research, ITS analysis can reveal how the pandemic affected essential healthcare utilization, including changes in rates, patterns, and disparities. This information is crucial for healthcare planning and policy development during and after a crisis.

Sampling and data collection

Our target population was all the registered population in EHR of Yazd province who were eligible to receive essential health services. We collected the recorded data related to all children under 18 months covered by the childhood vaccination program, all women aged 30 to 70 included in the breast cancer screening program, the population over 30 years old included in the diabetes screening program, the entire population over 18 years old included in the blood pressure screening program, and all infants under 28 days from EHR in 2023. Data was collected over a 30-month period, with 15 months before (November 2018 to January 2020) and after the start of the pandemic (January 2020 to May 2021).

Statistical analysis

Statistical analysis involved paired t-tests to compare annual averages and ITS analysis to assess changes in the indicators' levels and trends. The ITS model included variables for immediate effects, long-term trends, and continuous effects.

To estimate the ITS model, accounting for the use of time series data, we assessed the correlation between time series observations in the response variable using the Durbin-Watson test. Subsequently, we employed the following regression model for each index:

Where β 0 is pre-intervention initial level of outcomes. T refers to the time since the start of the observation, and β 1 represents is the time trend coefficient (the linear slope since the start of the intervention). D is the change variable in such a way that it is 0 before the intervention and 1 after the intervention. β 2 refers to the immediate effect of the intervention, and P indicates the time since the start of the intervention. Its value was zero before the intervention. β 3 refers to the continuous effects and the difference between the linear slopes before and after the intervention. ε is the model error. All statistical analysis was performed using R 4.3.1 software, considering a 5% significance level.

Table 1 displays essential health services indicators' mean and standard deviation before and after the COVID-19 Pandemic.

According to the findings presented in Table  1 , there was a notable decrease in the average utilization rates of breast cancer screening, hypertension screening, diabetes screening, and childhood vaccination services following the emergence of the COVID-19 pandemic ( p  < 0.0001). Conversely, there was an increase in the mean utilization of infant care services after the pandemic ( p  < 0.0001).

Before the onset of the pandemic, an average of 4,587 individuals underwent breast cancer screening. This number decreased significantly to 1,861 post-pandemic, marking a substantial reduction of 70%. Similarly, the average number of individuals utilizing hypertension screening services decreased from 2,219 before the pandemic to 776 after, representing a significant 54% decrease in utilization.

In terms of diabetes screening, the average number of individuals receiving these services dropped from 662 pre-pandemic to 313 post-pandemic, indicating a notable 47% decrease in utilization. Table 1 further indicates that the average number of children vaccinated decreased from 10,917 before the pandemic to 9,579 after, showing a significant 14% reduction.

On the contrary, there was a significant increase in the utilization of infant care services. Before the pandemic, an average of 60 infants received these services, which rose to 515 after the pandemic, reflecting an 85% increase in utilization.

Table 2  presents the interrupted time series results from Poisson modeling, illustrating the changes in the level and trend of essential health services utilization both before and after the COVID-19 pandemic.

Table 2  illustrates a noteworthy increase in the utilization of breast cancer screening services prior to the COVID-19 outbreak, indicated by an incidence rate ratio (RR) of 1.02 with a p  < 0.001. However, there was a significant decline shortly after the onset of the pandemic, with an RR of 0.435 and a p  < 0.001. This reduction in service utilization remained a significant long-term trend, with an RR of 0.952 and a p  < 0.001.

Moreover, the trend of hypertension screening, which had been decreasing before the pandemic (RR = 0.96, p  < 0.001), experienced a substantial short-term decrease following the outbreak (RR = 0.51, p  < 0.001). Nonetheless, after several months of the pandemic, there was a notable increase in the long-term trend of utilizing hypertension screening (RR = 1.016, p  < 0.001).

Before the pandemic, there was a significant decrease in diabetes screening (RR = 0.944, p  < 0.001), which further declined immediately after the pandemic (RR = 0.884, p  < 0.001). However, the long-term trend of utilizing this service saw a significant increase after several months of the pandemic (RR = 1.0366, p  < 0.001).

Similarly, childhood vaccination experienced a significant decrease both before (IRR = 0.994, p  < 0.001) and immediately after the pandemic (IRR = 0.947, p  < 0.001). However, the long-term trend of utilizing this service increased significantly after several months of the pandemic (IRR = 1.003, p  < 0.001).

In terms of infant care, there was a significant decrease in utilization before the pandemic (IRR = 0.987, p  < 0.001), and this decline continued immediately after the pandemic (IRR = 1.666, p  < 0.001). However, the long-term trend of utilizing this service showed a significant increase after several months of the pandemic (IRR = 1.199, p  < 0.001).

The trend of changes in selected indicators in the period before and after the COVID-19 pandemic are depicted in Fig.  1 .

The trend of changes in selected indicators in the period before and after the covid-19 pandemic

This study investigated the profound impact of the COVID-19 pandemic on the utilization of essential health services in Yazd, Iran, employing interrupted time series analysis. This methodological approach enabled us to evaluate both immediate and enduring changes in essential health service utilization simultaneously, taking into account the prevailing conditions during the COVID-19 pandemic. Our findings unequivocally demonstrate that the utilization of all essential health services was significantly affected by the COVID-19 outbreak.

Specifically, we noted substantial declines in the utilization of breast cancer screening, hypertension management, diabetes care, and childhood vaccination services in the short term following the onset of the COVID-19 pandemic compared to the pre-pandemic period. However, it is noteworthy that there was a significant increase in the utilization of infant care services. Over the long term, the utilization of all services, except for breast cancer screening, exhibited a significant increase. Based on our estimations, 5,850 residents in Yazd were deprived of essential health services during the pandemic, with proportions ranging from approximately 70% in breast cancer screening services to about 14% in vaccination services.

A study by Doubova et al. (2021) conducted in Mexico revealed alarming figures where among nine health services, a staggering 8,074,000 people were deprived of essential services during the COVID-19 pandemic. Approximately one-third of these cases were linked to vaccination, diabetes management, hypertension screening, and infant care services [ 7 ].

The emergence of the COVID-19 pandemic had the potential to rapidly unravel significant health progress achieved over the past two decades. This impact was particularly profound in cancer screening, which suffered severely during the pandemic, leading to delayed cancer diagnoses. The management of cancer cases in primary care, spanning from diagnosis to patient treatment and follow-up, was significantly compromised during the COVID-19 pandemic [ 22 ]. We found that there was an average 70% reduction in breast cancer screening services from February 22, 2020, to May 24, 2021, compared to the corresponding period in the previous year. In practical terms, this translates to an estimated 70,914 women aged 30 to 70 being deprived of essential breast cancer screening services. the substantial decline in breast cancer screening services during the pandemic period have significant clinical implications such as: delayed cancer diagnoses, compromised outcomes, increase in advanced cases, psychological impact, and healthcare system burden.

In the United States, a previous study reported an astonishing 94% decrease in breast and cervical cancer screening tests, with 285,000 breast cancer screening tests remaining unperformed during the COVID-19 pandemic [ 14 , 23 ].

The disruption of vaccination services due to the COVID-19 pandemic is a critical issue that has received inadequate attention [ 24 ]. Globally, vaccination programs have been significantly impacted by the pandemic [ 25 ]. Building on previous research, our findings reveal a substantial 14% decrease in the utilization of vaccination services for children under 18 months following the outbreak. This decline represents one of the most pronounced reductions during the pandemic, likely stemming from parental concerns regarding potential coronavirus exposure in healthcare settings. Moreno et al. (2021) also reported a comparable decline of approximately 14.4% in vaccination coverage in Colombia from 2019 to 2020, notably affecting children under 12 months receiving the pneumococcal vaccine [ 12 ]. Furthermore, within just one week of the WHO declaring the COVID-19 outbreak a global emergency, the United States witnessed a significant decrease in vaccinations for children under 2 years of age. The results of previous studies in Pakistan indicated that, despite WHO recommendations to continue children's vaccination programs during the COVID-19 pandemic, vaccination services decreased by 65% [ 11 ]. Lina et al. (2021) highlighted a staggering 37% interruption rate in vaccination services in Saudi Arabia, primarily driven by COVID-19 fears [ 26 ]. Similarly, Doubova et al. (2021) reported a 37% reduction in vaccination services for children under 5 years old in Mexico, estimating that this led to 180,070 children missing out on vital vaccines, resulting in a 10% to 45% monthly increase in child mortality rates [ 7 ]. According to a World Health Organization report, at least 80 million children under one year old are now at risk of preventable diseases such as polio, diphtheria, and measles due to COVID-19-related disruptions in vaccination servic24).)

The era of COVID-19 has presented significant challenges for diabetic patients, impeding their ability to maintain optimal self-care. Factors such as insulin medication unavailability, increased consumption of unhealthy foods, reduced physical activity due to lockdowns, and diminished social interactions have compounded these difficulties [ 27 , 28 ]. Diabetes stands out as a pivotal chronic disease, serving as a precursor to various other serious conditions such as heart disease, hypertension, vision impairments, kidney disease, and neurological disorders. Given the rising prevalence of diabetes and the tendency for many cases to remain asymptomatic for extended periods, early screening for diabetes becomes paramount [ 28 ]. Screening assumes even greater importance considering the escalating prevalence of asymptomatic diabetes cases that can lead to microvascular complications [ 28 ]. Abdi et al.'s (2020) study reveals that during the COVID-19 pandemic, a significant number of non-COVID-19 patients with pre-existing conditions like diabetes were left without necessary healthcare services. Furthermore, many individuals with diabetes experienced reduced physical activity due to global quarantines imposed by governments. These ramifications pose substantial risks, increasing the likelihood of infections, hospitalizations, amputations, and potentially fatal outcomes in diabetic patients [ 29 ]. Our study highlights a striking 47% decrease in public utilization of diabetes screening services, likely driven by pandemic-related apprehensions about visiting healthcare facilities. Consequently, remote screening methods such as phone consultations emerged as viable alternatives to traditional in-person health center visits.

Detecting hypertension promptly and managing it effectively are critical for achieving optimal control. the increasing prevalence of hypertendion is linked to more than 16 percent of the burden of coronary artery disease, 21 percent of peripheral vascular diseases, and 29 percent of strokes [ 30 ]. Our estimations indicate that approximately 54% of individuals aged 30 and above were unable to access hypertension screening services during the pandemic. Kiari et al. (2022) also reported a 10.4% reduction in hypertension screening at the outset of the pandemic [ 31 ]. Hypertension itself carries a two- to three-fold heightened risk of contracting COVID-19 or experiencing adverse outcomes, including severe infections and mortality [ 32 ].

Globally, about 16 percent of children face developmental delays, highlighting the crucial need for early identification to implement preventive interventions. Complications from prematurity stand as the primary cause of death among infants and children under 5 years old. Studies estimate that achieving 95 percent coverage of essential care for small and sick newborns could potentially save the lives of 750,000 infants by 2030 across 81 countries. A study conducted in Nepal during the COVID-19 quarantine reported a 52 percent decrease in births, a 20 percent increase in premature birth rates, and a threefold rise in infant mortality rates [ 33 ]. Additionally, studies during the coronavirus pandemic among pregnant women with COVID-19 revealed a threefold higher risk of premature birth compared to women without the disease. The escalating rates of premature births have far-reaching negative repercussions on infants, families, and healthcare systems worldwide. Small infants, especially premature ones, are particularly vulnerable to reduced healthcare coverage and diminished service quality [ 34 ].

On the other hand, concerning infant care, our study uncovered a notable increase in service utilization post-pandemic, although the exact reason for this trend remains elusive. Further investigations unveiled changes in the registration period for infant care, transitioning from 3–5 days to 3–10 days in the revised booklet distributed to health centers by the Iranian Ministry of Health and Medical Education (MOHME) in late 2020. This alteration resulted in a concurrent increase in recorded cases within the comprehensive health information system during the COVID-19 pandemic. Additionally, shifts in MOHME policies, coupled with heightened emphasis and monitoring of integrated care for healthy children in health centers during the pandemic, likely contributed to the uptick in recorded cases.

In a study by Ashish and colleagues (2020) in Nepal, the stillbirth rate rose from 14 per 1000 total births before the COVID-19 quarantine to 21 per 1000 total births, and neonatal mortality increased from 13 per 1000 live births to 40 per 1000 births [ 33 ]. Another recent study in 2022 indicates that access to and utilization of newborn care services in many countries have been impacted by reduced routine checks and preventive care for women and infants by healthcare facilities. Healthcare providers have noted a decrease in the number of women and infants using newborn care services [ 35 ]. Globally, studies suggest that around 16% of children experience developmental delays, underlining the critical importance of early diagnosis for timely preventive interventions [ 36 ].

Limitations of the study

Our research had a few limitations. Initially, it was carried out over a 15-month period following the onset of the Covid-19 pandemic, focusing on the rapid changes in usage indicators during this brief timeframe. A longer study duration, particularly during the peak periods of Covid-19 spread, would offer policymakers a more comprehensive understanding of how a crisis impacts healthcare utilization. Secondly, being retrospective, not all data required to fully illustrate these changes were gathered, leaving room for potential unknown factors aside from Covid-19 that may have affected the outcomes. Additionally, a national study could enhance the generalizability of the findings.

The COVID-19 pandemic disrupted the provision and use of health and medical services. This disruption in essential health services can lead to outbreaks of eliminated diseases and increase the mortality rate from preventable diseases. The primary drivers of this interruption are due to fear of contracting COVID-19, national quarantines, travel restrictions, limited access, and the heightened focus of managers and policymakers on COVID-19 control measures aimed at reducing its prevalence and associated mortality. It is imperative to utilize this evidence to develop policies that will be translated into targeted planning and implementation to sustain the provision and utilization of essential health services during public health emergencies. It is also vital to raise awareness and public knowledge regarding the consequences of interruptions in essential health services. In addition, it is important to identify the supply- and demand-side factors contributing to these disruptions.

Availability of data and materials

The data sets generated during the study are available from the corresponding author upon reasonable request.

Abbreviations

Health Word Organization

Interrupted time series

Relative risk

Electronic health record

Choi DH, Jung JY, Suh D, Choi JY, Lee SU, Choi YJ, et al. Impact of the COVID-19 Outbreak on trends in emergency department utilization in children: a multicenter retrospective observational study in Seoul metropolitan area, Korea. J Korean Med Sci. 2021;36(5):e44.

Article   CAS   PubMed   PubMed Central   Google Scholar  

https://covid19.who.int/ . WHO Coronavirus (COVID-19) Dashboard. 2023.

Bardin A, Buja A, BarbielliniAmidei C, Paganini M, Favaro A, Saia M, et al. Elderly people’s access to emergency departments during the covid-19 pandemic: results from a large population-based study in Italy. J Clin Med. 2021;10(23):5563.

Khatiwada AP, Maskey S, Shrestha N, Shrestha S, Khanal S, Kc B, et al. Impact of the first phase of COVID-19 pandemic on childhood routine immunisation services in Nepal: a qualitative study on the perspectives of service providers and users. Journal of Pharmaceutical Policy and Practice. 2021;14(1):79.

Article   PubMed   PubMed Central   Google Scholar  

Mulholland RH, Wood R, Stagg HR, Fischbacher C, Villacampa J, Simpson CR, et al. Impact of COVID-19 on accident and emergency attendances and emergency and planned hospital admissions in Scotland: an interrupted time-series analysis. J R Soc Med. 2020;113(11):444–53.

Bloom DE, Cadarette D. Infectious disease threats in the twenty-first century: strengthening the global response. Frontiers in Immunology. 2019;10:549.

Doubova S, Leslie H, Kruk M, Perez-Cuevas R, Arsenault C. Disruption in essential health services in Mexico during COVID-19: an interrupted time series analysis of health information system data. BMJ Glob Health. 2021;6:e006204.

Article   PubMed   Google Scholar  

Hung KK, Walline JH, Chan EYY, Huang Z, Lo ESK, Yeoh EK, et al. Health service utilization in Hong Kong during the COVID-19 pandemic – a cross-sectional public survey. Int J Health Policy Manag. 2022;11(4):508–13.

PubMed   Google Scholar  

Ota MOC, Badur S, Romano-Mazzotti L, Friedland LR. Impact of COVID-19 pandemic on routine immunization. Ann Med. 2021;53(1):2286–97. https://doi.org/10.1080/07853890.2021.2009128 .

Dabo M, Samah Y, Kande M, Sompare D, Camara A, Dian BM, et al. Early effect of the Covid-19 epidemic on vaccine coverage of major antigens in Guinea: an analysis of the interrupted time series of national immunization coverage. medRxiv. 2020:2020.09.11.20192161. https://doi.org/10.1101/2020.09.11.20192161 .

Rana MS, Ikram A, Salman M, Usman M, Umair M. Negative impact of the COVID-19 pandemic on routine childhood immunization: experience from Pakistan. Nat Rev Immunol. 2021;21(11):689–90.

Moreno-Montoya J, Ballesteros SM, Rojas Sotelo JC, Bocanegra Cervera CL, Barrera-López P, De la Hoz-Valle JA. Impact of the COVID-19 pandemic on routine childhood immunisation in Colombia. Arch Dis Child. 2022;107(3):e4.  https://doi.org/10.1136/archdischild-2021-321792 .

McDonald HI, Tessier E, White JM, Woodruff M, Knowles C, Bates C, et al. Early impact of the coronavirus disease (COVID-19) pandemic and physical distancing measures on routine childhood vaccinations in England, January to April 2020. Eurosurveillance. 2020;25(19):2000848.

Dhada S, Stewart D, Cheema E, Hadi MA, Paudyal V. Cancer Services During the COVID-19 Pandemic: Systematic Review of Patient's and Caregiver's Experiences. Cancer Manag Res. 2021;13:5875–87. https://doi.org/10.2147/CMAR.S318115 .

Lai AY, Sit SM, Wu SY, Wang MP, Wong BY, Ho SY, et al. Associations of delay in doctor consultation with COVID-19 related fear, attention to information, and fact-checking. Front Public Health. 2021;9:797814.

Aliakbari dehkordi M, Eisazadeh F, Monzavi chaleshtari A. Assessing the self-care status of patients with type 2 diabetes during the Covid-19 epidemic: a qualitative study. Iranian J Diab Lipid Disord. 2021;21(2):79–91.

Google Scholar  

Khayatan M, Nasiri Pour A, Amini M, Mohamad Nejad S. The Effective factors on recievers’ access to health care services in urban health care centers. Payavard. 2011;4(3 and 4):18–27.

. Covid's 19 crisis management: reengineering the health services system in Iran. J Med Counc Islam Repub Iran. 2020;38(1):0-0. Available from: https://sid.ir/paper/1113927/en .

Sarboozi Hosein Abadi T, Askari M, Miri K, Namazi Nia M. Depression, stress and anxiety of nurses in COVID-19 pandemic in Nohe-Dey Hospital in Torbat-e-Heydariyeh city, Iran. J Military Med. 2020;22(6):526–33.

Rezapour R, Dorosti AA, Farahbakhsh M, Azami-Aghdash S, Iranzad I. The impact of the Covid-19 pandemic on primary health care utilization: an experience from Iran. BMC Health Serv Res. 2022;22:404. https://doi.org/10.1186/s12913-022-07753-5 .

Bernal JL, Cummins S, Gasparrini A. Interrupted time series regression for the evaluation of public health interventions: a tutorial. Int J Epidemiol. 2017;46(1):348–55.

Tabrizi JS, Khosravi A, Raeesi A, Atai A, Atefi A, Farkhi B, et al. Providing basic health services during the Covid-19 epidemic in the Islamic Republic of Iran; The third step of the national mobilization against covid-19. Depiction Health. 2022;13(Suppl 1):75–87. https://doi.org/10.34172/doh.2022.18 .

Article   Google Scholar  

Haghighat S. COVID-19 and Breast Cancer. Iranian J Breast Dis. 2021;14(1):7–10.

Baghdadi LR, Younis A, Al Suwaidan HI, Hassounah MM, Al Khalifah R. Impact of the COVID-19 pandemic lockdown on routine childhood immunization: a Saudi nationwide cross-sectional study. Front Pediatr. 2021;9:692877.

Chiappini E, Parigi S, Galli L, Licari A, Brambilla I, Angela Tosca M, et al. Impact that the COVID-19 pandemic on routine childhood vaccinations and challenges ahead: a narrative review. Acta Paediatr. 2021;110(9):2529–35.

Lynn RM, Avis JL, Lenton S, Amin-Chowdhury Z, Ladhani SN. Delayed access to care and late presentations in children during the COVID-19 pandemic: a snapshot survey of 4075 paediatricians in the UK and Ireland. Arch Dis Child. 2021;106(2):e8-e.

Eisazadeh F. Assessing the self-care status of patients with type 2 diabetes during the COVID-19 epidemic: a qualitative study. Iranian Journal of Diabetes and Metabolism. 2021;21(2):79–91.

Jalali-Farahani S, Mahani F, Panahi R, Azizi F, Amiri P. Explanation of factors affecting self-care and diabetes management during the COVID-19 pandemic: a qualitative study. Iranian Journal of Endocrinology and Metabolism. 2022;24(3):196–207.

Abdi A, Jalilian M, Sarbarzeh PA, Vlaisavljevic Z. Diabetes and COVID-19: a systematic review on the current evidences. Diabetes Res Clin Pract. 2020;166:108347.

Neelakandan BV, Gopalakrishnan S, Ramachandran H, Anuradha R, Gopichandran V. Health beliefs regarding uptake of hypertension screening in an urban setting: a population segmentation strategy. Int J Med Public Health. 2018;8(1):11–7.

Kiarie H, Temmerman M, Nyamai M, Liku N, Thuo W, Oramisi V, et al. The COVID-19 pandemic and disruptions to essential health services in Kenya: a retrospective time-series analysis. Lancet Glob Health. 2022;10(9):e1257–67.

Peng M, He J, Xue Y, Yang X, Liu S, Gong Z. Role of Hypertension on the Severity of COVID-19: A Review. J Cardiovasc Pharmacol. 2021;78(5):e648.

Ashish K, Gurung R, Kinney MV, Sunny AK, Moinuddin M, Basnet O, et al. Effect of the COVID-19 pandemic response on intrapartum care, stillbirth, and neonatal mortality outcomes in Nepal: a prospective observational study. Lancet Glob Health. 2020;8(10):e1273–81.

Minckas N, Medvedev MM, Adejuyigbe EA, Brotherton H, Chellani H, Estifanos AS, et al. Preterm care during the COVID-19 pandemic: a comparative risk analysis of neonatal deaths averted by kangaroo mother care versus mortality due to SARS-CoV-2 infection. EClinicalMedicine. 2021;33:100733.

Semaan A, Dey T, Kikula A, Asefa A, Delvaux T, Langlois EV, et al. “Separated during the first hours”—Postnatal care for women and newborns during the COVID-19 pandemic: A mixed-methods cross-sectional study from a global online survey of maternal and newborn healthcare providers. PLOS Glob Public Health. 2022;2(4):e0000214.

Hung KK, Walline JH, Chan EYY, Huang Z, Lo ESK, Yeoh EK, et al. Health service utilization in Hong Kong during the COVID-19 pandemic–a cross-sectional public survey. Int J Health Policy Manag. 2022;11(4):508–13.

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Acknowledgements

This paper has been extracted from the MSc research thesis of Shahid Sadoughi University of medical sciences. We are thankful to all participants and who helped us in collecting data and giving information to enrich the content of the study.

We are grateful to Shahid Sadoughi University of Medical Sciences for supporting the study.

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Department of Health Management and Economics, Health Policy & Management Research Center, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

Mohammad Ranjbar & Seyed Masood Mousavi

Department of Biostatistics and Epidemiology, Center for Healthcare Data Modeling, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

Farzan Madadizadeh

Department of Health Management and Economics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

Nahid Hosseini Dargani

Yazd Health District, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

Samaneh Iraji

Centre for Health Systems Science, the George Institute for Global Health, University of New South Wales, Sydney, Australia

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M.R., SM.M., N.HD., and F.M. contributed to the conception and design of the study; N.HD., S.I., and M.R. collected the data; M.R., F.M., N.HD., and Y.A. analyzed and interpreted the data; M.R. wrote the first draft of the manuscript; SM.M., N.HD. S.I., and F.M. reviewed and wrote sections of the manuscript; and B.A., Y.A., SM.M., N.HD., and F.M. critically revised the manuscript. All authors read and approved the submitted version.

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Ranjbar, M., Mousavi, S.M., Madadizadeh, F. et al. Effect of the COVID-19 pandemic on utilization of essential health services in Iran evidence from an interrupted time series analysis. BMC Public Health 24 , 1006 (2024). https://doi.org/10.1186/s12889-024-18537-3

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Nian Wang said: "It's my great honor to receive this award. The image shows the complex 3D tubular structures of a mouse kidney. It was taken at the Center for In Vivo Microscopy (Directed by Prof. G. Allan Johnson), where our research focuses on developing novel MRI methods to detect tissue microstructures. The non-destructive nature of MRI and its ability to assess the renal microstructure in 3D make it a promising tool to understand the complex structures of the renal system."

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The runner up by An-Lun Chin, at the Brain Research Center, National Tsing Hua University, Taiwan, entitled 'Synchrotron x-ray tomographic 3D reconstruction of the Drosophila brain circuitry structure,' is a high-resolution 3D reconstruction of a Drosophila head, showing the nervous system, muscles, cuticles, and visual sensory system. Drosophila melanogaster is a species of fly, known generally as the common fruit fly. It is widely used for biological research.

Rachel Burley said: " Drosophila melanogaster will, of course, be familiar to researchers as a model organism and to people more generally as a common pest in homes, restaurants, and other places where food is served. Our judges felt that the image by An-Lun Chin shines a new light on this commonly known species by giving us a look inside its head."

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Exploring research progress in studying serum exosomal miRNA-21 as a molecular diagnostic marker for breast cancer

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• Published: 11 April 2024

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• Hang Li   ORCID: orcid.org/0009-0000-9518-732X 1   na1 &
• Xiao-jing Tie 2   na1  

Breast cancer is one of the most prevalent malignancies affecting women globally and poses a significant public health challenge. Early clinical detection plays a pivotal role in providing optimal treatment opportunities and favorable prognoses, crucial for reducing breast cancer mortality and enhancing patients’ quality of life. Therefore, the timely identification and diagnosis of breast cancer are imperative. Conventional tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA15-3), serve as reliable methods for actively monitoring disease progression and have become a routine auxiliary diagnostic approach in clinical settings. However, these biomarkers exhibit limitations in sensitivity and specificity, particularly in the early screening and diagnosis of tumors, often yielding results inconsistent with clinical manifestations. In recent years, research has increasingly focused on exosomes released by tumor cells as potential new biomarkers for early stage breast cancer screening. Exosomes carry various components, including tumor-derived proteins, nucleic acids, and lipids. This paper delves into the specific utilization of serum exosomal microRNA-21 (miR-21) as a biomarker for early detection and diagnosis of breast cancer, evaluating its efficacy within this framework.

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Abbreviations

Carcinoembryonic antigen

Carbohydrate antigen 15-3

Microribonucleic acid-21

Messenger RNAs

Non-coding RNAs

Long non-coding RNAs

B-cell lymphoma 2

Breast cancer susceptibility gene 1

Breast cancer susceptibility gene 2

Tumor suppressor protein p53

Diagnostic odds ratio

Negative likelihood of detection results ratio

Positive likelihood ratio

Confidence interval

Phosphatase and tensin homolog deleted on chromosome 10

The phosphoinositide 3-kinase

Phosphoinositide 3-kinase/v-akt murine thymoma viral oncogene/mammalian target of rapamycin

Michigan Cancer Foundation-7

Programmed cell death protein 4

Epithelial growth factor

Transforming growth factor β

Tumor suppressor gene tropomyosin 1

Mammary serine protease inhibitor

Liquid chromatography/mass spectrometry

Receptor protein against Pseudomonas MACULICOLA1

Human epidermal growth receptor 2

Breast cancer stem cells

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in185 countries. CA Cancer J Clin. 2021;71(3):209–49.

Article   PubMed   Google Scholar  

Rabbani F, Yazdiniapour Z, Ghanadian M, Zolfaghari B, Maleki M, Shafiee F. Cytotoxicity and apoptosis assay of novel cyclomyrsinol diterpenes against breast cancer cell lines. World J Tradit Chin Med. 2022;8:273–7.

Article   CAS   Google Scholar  

Tang Z, Xu L, Sun Z, Chen W, Li R. Differential diagnosis of benign and malignant breast lesions using mammography and 3.0T magnetic resonance imaging. Chin Med Equip. 2022;19(10):48–52.

Huang W-H, Chen I-W, Yang C-C, Wang T-Y. The sonography is a valuable tool for diagnosis of microcalcification in screening mammography. Ultrasound Med Biol. 2017;43:S28.

Article   Google Scholar  

Wang H, Song Q, Zheng G, Cao g. Study on the diagnosis of early breast cancer with molybdenum target and ultrasound Doppler combined with serum tumor markers. China Med Equip. 2024;21(1):82–7.

Google Scholar  

Li X, Xu Y, Zhang L. Serum CA153 as biomarker for cancer and noncancer diseases. Prog Mol Biol Transl Sci. 2019;162:265–76.

Article   CAS   PubMed   Google Scholar  

Jia L, Li G, Ma N, Zhang A, Zhou Y, Ren L, et al. Soluble POSTN is a novel biomarker complementing CA153 and CEA for breast cancer diagnosis and metastasis prediction. BMC Cancer. 2022;22(1):760.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Lin Z. Clinical significance of CA15-3, CA125 and CEA joint detection in the diagnosis of breast cancer. Exp Lab Med. 2009;27(3):261–2.

Tanman Ü, Yangın S, Cansaran-Duman D. Determination of dysregulated miRNA expression levels by qRT-PCR after the application of usnic acid to breast cancer. J Anticancer Agents Med Chem. 2020;20(5):548–58.

Ortega MA, Fraile-Martínez O, Guijarro LG, Casanova C, Coca S, Álvarez-Mon M, et al. The regulatory role of mitochondrial microRNAs (MitomiRs) in breast cancer: translational implications present and future. Cancers (Basel). 2020;12(9):2443.

Ren FL, Li P, Wang CM, Chen QH. Application of exosomes in cancer diagnosis and treatment and progress in isolation technology. J Chin Oncol. 2020;26(6):475–80.

Boriachek K, Islam MN, Möller A, Salomon C, Nguyen NT, Hossain MSA, et al. Biological functions and current advances in isolation and detection strategies for exosome nanovesicles. Small. 2018;14(6).

Lauretti E, Dabrowski K, Praticò D. The neurobiology of non-coding RNAs and Alzheimer’s disease pathogenesis: pathways, mechanisms and translational opportunities. Ageing Res Rev. 2021;71:101425.

Hill M, Tran N. miRNA interplay: mechanisms and consequences in cancer. Dis Model Mech. 2021;14(4):dmm047662.

Kim MW, Park S, Lee H, Gwak H, Hyun KA, Kim JY, et al. Multi-miRNA panel of tumor-derived extracellular vesicles as promising diagnostic biomarkers of early-stage breast cancer. Cancer Sci. 2021;112(12):5078–87.

Abdel-Hamid NR, Mohammed EA, Abbas AH, Badr FM. MicroRNA-21 expression in primary breast cancer tissue among Egyptian female patients and its correlation with chromosome 17 aneusomy. Mol Diagn Ther. 2015;19(6):365–73.

Shaaban NZ, Ibrahim NK, Saada HN, El-Rashidy FH, Shaaban HM, Elbakary NM, et al. The implication of microRNAs as non-invasive biomarkers in 179 Egyptian breast cancer female patients. Oncol Res. 2023;30(6):269–76.

Article   PubMed   PubMed Central   Google Scholar  

Wang M, Wang Y, Tian X, Wang Q, Huang H, Lu X, et al. Diagnostic and predictive value of liquid biopsy-derived exosome miR-21 for breast cancer: a systematic review and meta-analysis. Expert Rev Mol Diagn. 2023;23(4):315–24.

Yu X, Liang J, Xu J, Li X, Xing S, Li H, et al. Identification and validation of circulating microRNA signatures for breast cancer early detection based on large scale tissue-derived data. J Breast Cancer. 2018;21(4):363–70.

Liang Y, Hao M, Guo R, Li X, Li Y, Yu C, et al. Biomarkers for early screening and diagnosis of breast cancer: a review. Sheng Wu Gong Cheng Xue Bao. 2023;39(4):1425–44.

CAS   PubMed   Google Scholar  

García Z, Kumar A, Marqués M, Cortés I, Carrera AC. Phosphoinositide 3-kinase controls early and late events in mammalian cell division. EMBO J. 2006;25(4):655–61.

Asaga S, Kuo C, Nguyen T, Terpenning M, Giuliano AE, Hoon DS. Direct serum assay for microRNA-21 concentrations in early and advanced breast cancer. Clin Chem. 2011;57(1):84–91.

Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH. Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem. 2008;283(2):1026–33.

Han M, Wang F, Gu Y, Pei X, Guo G, Yu C, et al. MicroRNA- 21 induces breast cancer cell invasion and migration by suppressing smad7 via EGF and TGF-β pathways. Oncol Rep. 2016;35(1):73–80.

Wu MF, Yang J, Xiang T, Shi YY, Liu LJ. miR-21 targets Fas ligand-mediated apoptosis in breast cancer cell line MCF-7. J Huazhong Univ Sci Technol Med Sci. 2014;34(2):190–4.

Wang W, Li J, Zhu W, Gao C, Jiang R, Li W, et al. MicroRNA-21 and the clinical outcomes of various carcinomas: a systematic review and meta-analysis. BMC Cancer. 2014;14:819. https://doi.org/10.1186/1471-2407-14-819 .

Zhu W, Xu B. MicroRNA-21 identified as predictor of cancer outcome: a meta-analysis. PLoS One. 2014;9(8):103373.

Desouky EM, Khaliefa AK, Hozayen WG, Shaaban SM, Hasona NA. Signature of miR-21 and MEG-2 and their correlation with TGF-β signaling in breast cancer. Hum Exp Toxicol. 2023;42:9603271231159800.

El-Toukhy SE, El-Daly SM, Kamel MM, Nabih HK. The diagnostic significance of circulating miRNAs and metabolite profiling in early prediction of breast cancer in Egyptian women. J Cancer Res Clin Oncol. 2023;149(8):5437–51.

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Acknowledgements

We would like to acknowledge the hard and dedicated work of all the staff who implemented the intervention and evaluation components of the study.

No external funding received to conduct this study.

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Hang Li and Xiao-jing Tie have contributed equally to this work.

Authors and Affiliations

Department of Laboratory Medicine, Kaifeng Central Hospital, 85 HeDao Street, Kaifeng, 475000, China

Department of Oncology, Kaifeng Central Hospital, Kaifeng, 475000, China

Xiao-jing Tie

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Conception and design of the research: HL, XT. Acquisition of data: HL, XT. Analysis and interpretation of the data: HL. Statistical analysis: HL. Obtaining financing: None. Writing of the manuscript: HL. Critical revision of the manuscript for intellectual content: HL. All authors read and approved the final draft.

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Li, H., Tie, Xj. Exploring research progress in studying serum exosomal miRNA-21 as a molecular diagnostic marker for breast cancer. Clin Transl Oncol (2024). https://doi.org/10.1007/s12094-024-03454-z

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Understanding social needs screening and demographic data collection in primary care practices serving Maryland Medicare patients

• Claire M. Starling 1 ,
• Marjanna Smith 1 ,
• Sadaf Kazi 2 , 3 ,
• Arianna Milicia 3 ,
• Rachel Grisham 4 ,
• Emily Gruber 4 ,
• Joseph Blumenthal 5 &
• Hannah Arem 1 , 6  

BMC Health Services Research volume  24 , Article number:  448 ( 2024 ) Cite this article

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Health outcomes are strongly impacted by social determinants of health, including social risk factors and patient demographics, due to structural inequities and discrimination. Primary care is viewed as a potential medical setting to assess and address individual health-related social needs and to collect detailed patient demographics to assess and advance health equity, but limited literature evaluates such processes.

We conducted an analysis of cross-sectional survey data collected from n  = 507 Maryland Primary Care Program (MDPCP) practices through Care Transformation Requirements (CTR) reporting in 2022. Descriptive statistics were used to summarize practice responses on social needs screening and demographic data collection. A stepwise regression analysis was conducted to determine factors predicting screening of all vs. a targeted subset of beneficiaries for unmet social needs.

Almost all practices (99%) reported conducting some form of social needs screening and demographic data collection. Practices reported variation in what screening tools or demographic questions were employed, frequency of screening, and how information was used. More than 75% of practices reported prioritizing transportation, food insecurity, housing instability, financial resource strain, and social isolation.

Conclusions

Within the MDPCP program there was widespread implementation of social needs screenings and demographic data collection. However, there was room for additional supports in addressing some challenging social needs and increasing detailed demographics. Further research is needed to understand any adjustments to clinical care in response to identified social needs or application of data for uses such as assessing progress towards health equity and the subsequent impact on clinical care and health outcomes .

Peer Review reports

There is increasing attention on the impact of factors such as economic stability, education, neighborhood, and built environment on healthcare outcomes and, in particular, how primary care settings can assess and address individual level health-related social needs (HRSN) [ 1 , 2 ]. In turn, the American Academy of Pediatrics (AAP) and the American Academy of Family Physicians (AAFP) both recommend that primary care providers screen and address social needs as part of routine primary care visits [ 3 ]. Patients with unmet social needs are at a higher risk of missing appointments, frequent emergency room visits, and hospitalization and rehospitalization [ 4 , 5 ]. Identifying social needs and collecting detailed patient demographics in primary care can be used to tailor care, allocate resources effectively, and advocate for equitable policies, making these workflows a critical step towards advancing health equity [ 1 , 2 , 3 ].

Despite acknowledgement of the importance of integrating social care in clinical settings including a recent mandate by the Centers for Medicare and Medicaid services for screening in inpatient settings, the implementation of social needs screening and demographic data collection is complex and resource intensive [ 6 , 7 ]. Furthermore, patients who screen positive for social needs may decline assistance to address those needs. These occurrences may prove frustrating to those conducting screening if they lack sufficient training on delivering screening or assisting individuals with addressing social needs [ 8 ]. Additionally, while many practices already collect basic demographic data such as age, ethnicity, and race, demographic information is not always collected in a culturally sensitive or inclusive manner. Demographic data collection processes are not standardized, and many demographic fields (e.g., education level, sexual orientation, and disability status) are sometimes not asked at all. As part of a contract to provide technical assistance to Maryland Primary Care Program (MDPCP) practices to support social needs screening and demographic data collection, we explored collected survey data to understand current practices around social needs screening and demographic data collection as well as potential areas for growth in screening delivery.

Study population

MDPCP is a voluntary program for eligible primary care practices that provides funding and support for the delivery of advanced primary care for Medicare beneficiaries throughout Maryland. MDPCP supports the overall health care transformation process and allows primary care providers to play an increased role in disease prevention, management of chronic disease, and prevention of unnecessary hospital utilization [ 9 ]. The primary goal of MDPCP is the sustainable transformation of primary care across Maryland to include all the elements of advanced primary care to support the health needs of state residents [ 9 ]. MDPCP is co-administered by teams at the Maryland Department of Health and the Center for Medicare and Medicaid Innovation (CMMI). At the time of the survey, the MDPCP network included n  = 507 participating primary care practices representative of every county in Maryland.

MDPCP offers a combination of financial incentives and other supports tailored to primary care practices. These incentives encompass non-visit-based payments specifically designed for care coordination initiatives, as well as performance-based incentives, rewarding practices for achieving clinical quality, patient experience, and utilization benchmarks. In addition to financial incentives, MDPCP provides a variety of additional supports for care transformation MDPCP practices are paired with a Practice Transformation Coaches, who provide guidance, answer questions, and work directly with practices to improve processes that improve quality of care and decrease costs. In addition to Coaches, practices have access to the MDPCP Learning System encompassing a myriad of learning opportunities including User Groups, All-Practice Calls, and other collaborative forums for practices to learn from subject matter experts and fellow participants. Practices also have access to a handful of Guides including the Advancing Primary Care Guide, which provides information on MDPCP requirements, tactics for advancing the functions of primary care, and achieving care transformation. Additionally, practices have the option to partner with a Care Transformation Organization (CTO), who can assist with care management or other related patient services.

Data collection

Care transformation requirement (CTR) reporting questions ask MDPCP participants about progress on specific MDPCP requirements that span the five comprehensive primary care functions (Appendix 1 ). The five key functions of advanced primary care are care management, access and continuity, comprehensiveness, and coordination across the continuum of care, beneficiary and caregiver experience, and planned care for health outcomes. The questionnaire is developed by CMMI, and MDPCP participants respond in the online Centers for Medicare and Medicaid Services (CMS) program portal twice annually, as a requirement of program participation (Appendix 2 ). The survey used in this analysis was collected in the third quarter of 2022. This analysis was deemed exempt by the Georgetown/MedStar Institutional Review Board (Study 4698).

Statistical analysis

We used descriptive statistics to review social needs screening and demographic data collection responses from MDPCP practices . We conducted additional analysis to investigate responses by practice characteristics including practice size (small 1–2, medium 3–7, large 8 + providers) and hospital affiliation (yes or no). Further, a stepwise regression analysis was used to determine factors predicting the routine screening of beneficiaries for unmet social needs, comparing all beneficiaries to a specific targeted subsection. Variables used in the model were practice size, and hospital affiliation. 487 of the 507 records were used for regression analyses. We excluded practices if they did not report screening beneficiaries ( n  = 4), practice size ( n  = 1), or hospital affiliation status ( n  = 15). SAS 9.4 (Cary, NC) was used in all analyses.

Practice responses on social needs screening and referral processes are presented in Table  1 . Among the MDPCP practices, nearly all reported some form of social needs screening for all (63%) or at least some (36%) beneficiaries. Many practices reported utilizing a social needs screening tool developed by the practice or affiliated health system (32%). Other practices reported screening using standardized screening tools, including, an unspecified standardized tool (21%); EHR-specific tool (19%); Accountable Health Communities (14%); and PRAPARE (5%). There was substantial variation in EHR vendors, with 23% of practices using EPIC, 17% using eClinicalWorks, 14% using Cerner, and 11% using Athenahealth. Approximately half (49.5%) of the practices reported conducting social needs screening annually, while 18% of practices reported conducting screenings at every visit and 15% when indicated based on reason for visit. Just over a quarter (27%) of practices reported linking responses to discrete ICD-10 or Social Determinants of Health (SDOH) Z codes.

Survey responses revealed variability regarding which patients receive social needs screening, screening frequency, EHR integration and use of Z-codes based on practice characteristics (Appendix 3 ). In an exploratory multivariate logistic regression we found that practices with a hospital affiliation were more likely to screen a targeted population than all patients (OR = 1.54, 95% CI = 1.05–2.27) and practices that were small- (1–2 providers) or medium-sized (3–7 providers) were more likely to screen all patients. (OR = 0.46, 95% CI = 0.26–0.80; OR = 0.46, 95% CI = 0.27–0.78, respectively; data shown in text only). Practices had the opportunity to describe which beneficiaries were targeted. Responses included individuals at high risk ( n  = 67) or experiencing recent mental or clinical health events ( n  = 18), participants in care management or care coordination programs ( n  = 82), Health Equity Advancement Resource and Transformation (HEART) patients ( n  = 25), and attendees of annual wellness visits ( n  = 40).

When practices were asked to select social needs that they prioritize, common responses were transportation (93%), food insecurity (89%), housing instability (86%), financial resource strain (85%), and social isolation (84%) (Table  2 ). The least common needs prioritized were internet access (42%), phone access (46%), employment (48%), and language access (51%). Practices also reported which social needs were most challenging to support. The greatest challenges came with addressing housing instability (31%), internet access (31%), financial resource strain (30%), and medication affordability (30%).

Nearly all practices reported collecting patient demographics in some capacity (99%), with most practices reporting that demographic data are collected by a staff member (70%), collected at every visit (51%), annually (23%), or only at the patient’s initial visit (20%). Race and primary language were collected by nearly all practices (96%), gender identity was collected by 92%, relationship status by 87%, ethnicity by 87%, and employment status by 84% of practices. Other demographic factors were less commonly asked: only 49% of practices reported asking about sexual orientation, 48% asked about disability status, and 38% asked about highest level of education.

In this study we found that primary care practices participating in the MDPCP program overall had a high rate of social risk factor screening, with many using screeners that had been developed to meet individual practice needs. Commonly prioritized domains included transportation, food insecurity, housing instability, financial strain, and social isolation, the last being a commonly cited problem among older adults. Describing patterns of screening and demographics in this sample of practices across the state increase understanding of successes and challenges in real-world practice settings and informs potential future interventions.

Determining which patients should be screened and by whom in a busy primary care setting, as well as who can respond to identified needs, can be challenging. In our study there were differences both in which patients were screened and how often by practice [ 10 , 11 ]. Open ended responses suggested that among some MDPCP practices, screening was performed only for individuals who qualify for extra social assistance through the MDPCP program (i.e., those who qualify due to medical complexity and area deprivation index). Although we did not find other published literature focused specifically on Medicare patients at the state level, we found literature on programs focused on social needs screening among Medicaid populations in several states. Like Maryland practices, standardized measures and consistent approaches to measuring social needs have not been adopted or required in many states [ 12 , 13 , 14 ]. Further, a high percentage of the Maryland practices reported using home grown and standardized screening tools with additional questions to meet the practices’ needs. While the ability to aggregate social needs data across care settings can be challenging with different screeners, there is national movement to harmonize domains across various social risk factor screeners through the Gravity Project and the Office of the National Coordinator [ 12 , 15 ]. Notably, CMS has mandated social needs reporting in the inpatient setting beginning January 2024 for five specific domains, but has not specified a single tool or set of tools given that while there are some validated subsets of questions (e.g., Hunger Vital Signs), there is currently no gold standard tool [ 16 ]. Potential hurdles in requiring specific tools may include limitations on EHR technology, referral processes, and provider or staff level comfort and training in asking specific questions. Furthermore, implementing screening without supports for training the staff on trauma-informed approaches and how to respond to identified needs has the potential to cause more harm than benefit to patients. Thus, toolkits established by various professional societies and public health societies may be useful to determine which tools are most appropriate for a given practice and how to integrate them into care where practices have not yet started screening or encounter challenges [ 17 , 18 , 19 ].

Regarding practices with a hospital affiliation being more likely to screen a targeted population, one possibility is that practices affiliated with hospitals may have access to additional resources and supports that facilitate targeted screening efforts. Hospitals often have established practices including social risk factor screening for targeted subpopulations to address costly hospital readmissions, which may encourage affiliated practices to deliver more targeted screening practices. While it is unclear why small or medium-sized practices were more likely to screen all patients than a sub-population, it may have to do with more autonomy in workflow process, less customization of the EHR to target sub-populations, or differences in staffing and provider to patient ratios. While we cannot explain these differences from the survey alone, findings suggest that the size and affiliation of practices play a role in their screening practices, highlighting the importance of considering practice characteristics when designing specific supportive interventions or policies aimed at increasing screening rates.

It is important to highlight that MDPCP practices have achieved impressive levels of social needs screening and demographic data collection implementation. This success could be attributed largely to the program’s requirements and incentives to screen beneficiaries for social needs and collect demographic information. Additionally, the program provides technical support and resources to meet these requirements and to stand up social needs screening workflows if not already in place. By joining MDPCP, participating practices have demonstrated a commitment to advanced primary care, further indicating MDPCP participation may be associated with higher uptake of these workflows, as opposed to primary care practices who do not participate in similar value-based programs. Other states considering such programs may look to some of these supports when rolling out new requirements or incentives.

While the findings highlight the high level of social needs screening and demographic data collection, challenges in addressing identified needs may also be due to various factors including complexity of workflows and staffing, patients with social needs declining assistance, or limited local resource availability [ 20 ]. Previous research suggests patients may decline social needs assistance in healthcare settings if they do not feel like they need help, are confused about what is offered, are not confident that the assistance would be helpful, have experienced previous negative experiences, or feel fear and mistrust related to disclosing personal information [ 8 ]. In areas that posed the greatest referral challenges, policy efforts may be needed to deliver services and bridge the gaps to access. For example, the challenge of addressing housing needs is not newly identified; previous literature has shown increasing costs and declining supply have contributed to national housing availability and affordability challenges [ 21 , 22 ]. Medication cost continues to be a major problem cited in the literature, especially for older populations with a higher incidence of chronic diseases [ 23 , 24 ]. Financial strain among individuals often poses a challenge as financial needs fluctuate frequently, and changes can be dramatic; further, these changing needs over time are often not resolved by a one-time intervention and require long-term involvements [ 11 ]. Though research on the effects of internet access and health outcomes is still emerging, literature suggests investment in digital infrastructure by federal, state, and local governments is needed for further development of the internet as a means of addressing long-standing inequality in health [ 25 , 26 ]. While food insecurity and transportation were top needs prioritized within MDPCP practices, they did not present the same level of challenge to practices, perhaps due to wider availability of resources, partnerships, and supports such as transportation vouchers.

Although addressing connection to resources continues to be a challenge for practices, there are opportunities to leverage information from social needs screenings and demographic data collection in several other ways to improve care. Aggregate screening and demographic data can be used for quality improvement initiatives within primary care practices by analyzing trends and patterns in social needs data to help practices identify areas of unmet need, track outcomes, and update protocols for screening and referral processes. Additionally, data can be used to advocate for policy changes to address systemic issues affecting patients’ health outcomes. However, challenges in utilizing information from social needs screening and demographic data collection may still exist due to limited resources and capacity and lack of provider awareness and training availability.

Increased collection of detailed demographic data, particularly regarding sexual orientation, education level, and disability status presents an opportunity for improvement in primary care. Furthermore, collecting detailed demographic information can better allow practices to understand the need for targeted educational materials, track quality indicators, and address challenges faced by historically marginalized populations [ 26 , 27 ]. Still, even with good data collection approaches, some practices do not have the infrastructure or resources to analyze data to assess disparities in care or outcomes.

This study's strengths lie in its comprehensive analysis of a diverse range of primary care practices across Maryland. The inclusion of 507 practices with variations in size, location, and demographics enhances the representativeness of the findings and improves the generalizability of the results to a broader population. Consequently, the findings derived from studying a large population can contribute to a stronger evidence base for decision-making in healthcare and support the development of effective interventions and policies. A limitation of the study is the reliance on self-report, which may depend on the participants’ perspectives. Additionally, MDPCP practices meet eligibility criteria and voluntarily select to join the program, so these practices may be better equipped to join a value-based program that includes requirements or incentives to screen for social needs. Despite the limitations, our findings are novel in that few published studies highlight current practices at scale on social risk factor screening and referral in outpatient primary care settings for adults. Future research is warranted to show what strategies effectively increase uptake and drive meaningful change in social-needs responsive healthcare delivery.

MDPCP practices have demonstrated widespread adoption of social risk factor screenings and needs prioritization. While practices have implemented strategies to link patients to resources to address needs, challenges remain with providing social needs resources to beneficiaries from the primary care setting. Additionally, there is room for improvement in collecting certain demographic data fields within primary care practices. As the present analysis was based on cross-sectional data, future studies are needed to understand how to effect change in implementing or scaling social risk factor screening and detailed demographic data collection at the practice level. Additionally, future work is needed to understand how care is adjusted in response to identified social needs and how that impacts outcomes at the patient level.

Availability of data and materials

To access the datasets examined in this study, interested parties must follow the procedure outlined by the CMS. Requests should be submitted through the CMS website (cms.gov), and any queries can be directed to [email protected].

Abbreviations

Maryland Primary Care Program

Care Transformation Requirements

Center for Medicare and Medicaid Innovation

Centers for Medicare and Medicaid Services

Electronic Health Record

Social Determinants of Health

Social Determinants of Health. World Health Organization, 2023, at https://www.who.int/health-topics/social-determinants-of-health#tab=tab_1 . Accessed 9 Apr 2023.

DeVoe JE, Bazemore AW, Cottrell EK, et al. Perspectives in Primary Care: A Conceptual Framework and Path for Integrating Social Determinants of Health into Primary Care Practice. Ann Fam Med. 2016;14(2):104–8. https://doi.org/10.1370/afm.1917 .

Article   PubMed   PubMed Central   Google Scholar  

Lax Y, Bathory E, Braganza S. Pediatric primary care and subspecialist providers’ comfort, attitudes and practices screening and referring for social determinants of health. BMC Health Serv Res. 2021;21(1):956. https://doi.org/10.1186/s12913-021-06975-3 . PMID:34511119;PMCID:PMC8436516.

Andermann A; CLEAR Collaboration. Taking action on the social determinants of health in clinical practice: a framework for health professionals. CMAJ. 2016;188(17–18):E474–83. https://doi.org/10.1503/cmaj.160177 .

Article   Google Scholar  

Berkowitz SA, Seligman HK, Meigs JB, Basu S. Food insecurity, healthcare utilization, and high cost: a longitudinal cohort study. Am J Manag Care. 2018;24(9):399–404. https://pubmed.ncbi.nlm.nih.gov/33989068/ . PMID: 30222918; PMCID: PMC6426124.

PubMed   PubMed Central   Google Scholar  

McQueen A, Li L, Herrick CJ, Verdecias N, Brown DS, Broussard DJ, Smith RE, Kreuter M. Social Needs, Chronic Conditions, and Health Care Utilization among Medicaid Beneficiaries. Popul Health Manag. 2021;24(6):681–90. https://doi.org/10.1089/pop.2021.0065 . PMID: 33989068; PMCID: PMC8713253.

National Academies of Sciences, Engineering, and Medicine. Integrating Social Care into the Delivery of Health Care: Moving Upstream to Improve the Nation’s Health. Washington: The National Academies Press; 2019. https://doi.org/10.17226/25467 .

Book   Google Scholar  

Pfeiffer EJ, De Paula CL, Flores WO, Lavallee AJ. Barriers to Patients’ Acceptance of Social Care Interventions in Clinic Settings. Am J Prev Med. 2022;63(3 Suppl 2):S116–21. https://doi.org/10.1016/j.amepre.2022.03.035 . Epub 2022 Aug 17 PMID: 35987523.

Article   PubMed   Google Scholar  

Centers for Medicare and Medicaid Services, Centers for Medicare and Medicaid Innovation Sate Innovations Group. https://innovation.cms.gov/files/x/mdtcocm-rfa.pdf . Accessed 9 Apr 2023.

Sandhu S, Xu J, Eisenson H, Prvu Bettger J. Workforce Models to Screen for and Address Patients’ Unmet Social Needs in the Clinic Setting: A Scoping Review. J Prim Care Community Health. 2021;12:21501327211021020. https://doi.org/10.1177/21501327211021021 . PMID: 34053370; PMCID: PMC8772357.

Kreuter MW, Thompson T, McQueen A, Garg R. Addressing Social Needs in Health Care Settings: Evidence, Challenges, and Opportunities for Public Health. Annu Rev Public Health. 2021;42:329–44. https://doi.org/10.1146/annurev-publhealth-090419-102204 . Epub 2021 Dec 16. PMID: 33326298; PMCID: PMC8240195.

Measuring Social Determinants of Health among Medicaid Beneficiaries: Early State Lessons. Center for Health Care Strategies, Inc. 2016. https://www.chcs.org/media/CHCS-SDOH-Measures-Brief_120716_FINAL.pdf . Accessed 21 June 2023.

States Reporting Social Determinants of Health Related Policies Required in Medicaid Managed Care. Kaiser Family Foundation. 2022. https://www.kff.org/other/state-indicator/states-reporting-social-determinant-of-health-related-policies-required-in-medicaid-managed-care-contracts/?currentTimeframe=0&sortModel=%7B%22colId%22:%22Location%22,%22sort%22:%22asc%22%7D . Accessed 21 June 2023.

Social Determinants of Health Measurement Work Group: Final Report. Oregon Health Authority. 2021. https://www.oregon.gov/oha/HPA/ANALYTICS/SDOH%20Page%20Documents/SDOH%20final%20report%202_10_21.pdf . Accessed 21 June 2023.

The Gravity Project: Accelerating National Social Determinants of Health (SDOH) Data Standards. Gravity Project. 2022. https://confluence.hl7.org/download/attachments/46892727/Gravity%20Overview%20One%20Pager%2020220209.pdf?version=1&modificationDate=1644529823670&api=v2 . Accessed 21 June 2023.

Quality ID #487: Screening for Social Drivers of Health. Centers for Medicare & Medicaid Services. 2022. https://qpp.cms.gov/docs/QPP_quality_measure_specifications/CQM-Measures/2023_Measure_487_MIPSCQM.pdf . Accessed 21 June 2023.

Identifying and Addressing Social Needs in Primary Care Settings. Agency for Healthcare Research and Quality. 2021. https://www.ahrq.gov/sites/default/files/wysiwyg/evidencenow/tools-and-materials/social-needs-tool.pdf . Accessed 21 June 2023.

The Health Leads Social Health Data Toolkit. Health Leads. 2021. https://healthleadsusa.org/wp-content/uploads/2021/02/Health-Leads-Social-Health-Data-Toolkit.pdf . Accessed 21 June 2023.

A Guide to Using the Accountable Health Communities Health-Related Social Needs Screening Took: Promising Practices and Key Insights. Centers for Medicare & Medicaid Services. 2023. https://www.cms.gov/priorities/innovation/media/document/ahcm-screeningtool-companion . Accessed 21 June 2023.

Beidler LB, Razon N, Lang H, Fraze TK. “More than just giving them a piece of paper”: Interviews with Primary Care on Social Needs Referrals to Community-Based Organizations. J Gen Intern Med. 2022;37(16):4160–7. https://doi.org/10.1007/s11606-022-07531-3 . Epub 2022 Apr 14. PMID: 35426010; PMCID: PMC9708990.

Child Care and Housing: Big Expenses with Too Little Help Available. Center on Budget and Policy Priortities. 2019. https://www.cbpp.org/research/housing/child-care-and-housing-big-expenses-with-too-little-help-available . Accessed 13 July 2023.

Key facts about housing affordability in the U.S. Pew Research Center. 2022. https://www.pewresearch.org/short-reads/2022/03/23/key-facts-about-housing-affordability-in-the-u-s/ . Accessed 13 July 2023.

Soumerai SB, Pierre-Jacques M, Zhang F, et al. Cost-related medication nonadherence among elderly and disabled medicare beneficiaries: a national survey 1 year before the medicare drug benefit. Arch Intern Med. 2006;166(17):1829–35. https://doi.org/10.1001/archinte.166.17.1829 . PMID: 17000938.

Naci H, Soumerai SB, Ross-Degnan D, Zhang F, Briesacher BA, Gurwitz JH, Madden JM. Medication affordability gains following Medicare Part D are eroding among elderly with multiple chronic conditions. Health Aff (Millwood). 2014;33(8):1435–43. https://doi.org/10.1377/hlthaff.2013.1067 . PMID:25092846;PMCID:PMC4340076.

Studies and Data Analytics on Broadband and Health. Federal Communications Commision. 2022. https://www.fcc.gov/health/sdoh/studies-and-data-analytics . Accessed 13 July 2023.

Yu J, Meng S. Impacts of the Internet on Health Inequality and Healthcare Access: A Cross-Country Study. Front Public Health. 2022;9(10):935608. https://doi.org/10.3389/fpubh.2022.935608 . PMID:35757602;PMCID:PMC9218541.

Grasso C, McDowell MJ, Goldhammer H, Keuroghlian AS. Planning and implementing sexual orientation and gender identity data collection in electronic health records. J Am Med Inform Assoc. 2019;26(1):66–70. https://doi.org/10.1093/jamia/ocy137 . PMID:30445621;PMCID:PMC6657380.

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This study was supported by the Centers for Disease Control and Prevention’s National Initiative to Address COVID-19 Health Disparities Among Populations at High-Risk and Underserved, Including Racial and Ethnic Minority Populations and Rural Communities grant number OT21-2103 through the Maryland Department of Health.

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CMS and HA analyzed and interpreted the data and drafted the manuscript. MS, SK, AM, RG, EG, and JB contributed to revising the manuscript. All authors approved the version to be published and agreed to be accountable for the accuracy and integrity of the data.

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Starling, C.M., Smith, M., Kazi, S. et al. Understanding social needs screening and demographic data collection in primary care practices serving Maryland Medicare patients. BMC Health Serv Res 24 , 448 (2024). https://doi.org/10.1186/s12913-024-10948-7

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• Published: 08 April 2024

Accuracy of Genomic prediction for fleece traits in Inner Mongolia Cashmere goats

• Xiaochun Yan 1 ,
• Jinquan Li 1 , 2 , 3 , 4 ,
• Libing He 5 ,
• Oljibilig Chen 6 ,
• Na Wang 6 ,
• Shuai Wang 6 ,
• Xiuyan Wang 7 ,
• Zhiying Wang 1 &

BMC Genomics volume  25 , Article number:  349 ( 2024 ) Cite this article

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The fleece traits are important economic traits of goats. With the reduction of sequencing and genotyping cost and the improvement of related technologies, genomic selection for goats has become possible. The research collect pedigree, phenotype and genotype information of 2299 Inner Mongolia Cashmere goats (IMCGs) individuals. We estimate fixed effects, and compare the estimates of variance components, heritability and genomic predictive ability of fleece traits in IMCGs when using the pedigree based Best Linear Unbiased Prediction (ABLUP), Genomic BLUP (GBLUP) or single-step GBLUP (ssGBLUP). The fleece traits considered are cashmere production (CP), cashmere diameter (CD), cashmere length (CL) and fiber length (FL). It was found that year of production, sex, herd and individual ages had highly significant effects on the four fleece traits ( P  < 0.01). All of these factors should be considered when the genetic parameters of fleece traits in IMCGs are evaluated. The heritabilities of FL, CL, CP and CD with ABLUP, GBLUP and ssGBLUP methods were 0.26 ~ 0.31, 0.05 ~ 0.08, 0.15 ~ 0.20 and 0.22 ~ 0.28, respectively. Therefore, it can be inferred that the genetic progress of CL is relatively slow. The predictive ability of fleece traits in IMCGs with GBLUP (56.18% to 69.06%) and ssGBLUP methods (66.82% to 73.70%) was significantly higher than that of ABLUP (36.73% to 41.25%). For the ssGBLUP method is significantly (29% ~ 33%) higher than that with ABLUP, and which is slightly (4% ~ 14%) higher than that of GBLUP. The ssGBLUP will be as an superiors method for using genomic selection of fleece traits in Inner Mongolia Cashmere goats.

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Introduction

By the end of 2021, the number of goats in stock has been up to 133.32 million in China, and the cashmere yield was about 15,102.18 tons ( http://www.stats.gov.cn ). Inner Mongolia Cashmere goats (IMCGs) is an important breed of cashmere goats in China, which is famous with its high cashmere yield and excellence quality of cashmere. It is a dual-purpose breed producing cashmere and meat. Reducing cashmere diameter and increasing cashmere yield are the breeding objectives for IMCGs. With the development of quantitative genetics and molecular biology, the selection methods of livestock have been improved gradually[ 1 ]. A central methodology is the BLUP method proposed by Henderson in 1975 [ 2 ]. Here, genetics parameters can be estimated based on the so-called mixed model equations in which covariance matrices need to be defined. In the standard approach, the pedigree-based relationship matrix (A) is used and the method is referred to as ABLUP. Several studies have demonstrated that using BLUP method can achieve higher genetic gains in pigs compared to individual phenotype selection [ 3 , 4 ]. Using BLUP method to estimate the breeding value of litter size traits of Landrace pigs, which indicated that selection by BLUP method is feasible for the improvement of the litter size of swine [ 5 ]. Jang et al.(2019) assessed that the effect of progeny numbers and pedigree depth on the accuracy of the estimated breeding value (EBV) of Hanwoo beef using BLUP method, the results showed that EBV can show more precise outcome with more progenies [ 6 ].

In 2001, the idea of genomic selection (GS) was proposed by Meuwissen. The method can improve estimation accuracy of breeding value, increase genetic gain, in particular by shortening the generation interval and reduce breeding costs[ 7 , 8 , 9 , 10 ]. Genomic best linear unbiased prediction (GBLUP) utilizes genomic relationships to estimate the genetic merit of an individual [ 11 , 12 ]. The genomic relationship matrix ( G ) defines the covariance between individuals based on observed similarity at the genomic level, rather than on expected similarity A based on pedigree. Thus, more accurate predictions of merit can be obtained. The GBLUP method assigns the same variance to all loci and essentially treats them all as equally important. The single-step genomic BLUP (ssGBLUP) was provided by Legarra et al. [ 13 ]. The core idea of ssGBLUP method is to combine pedigree relationship matrix ( A ) and genomic relationship matrix ( G ) to reconstruct a new relationship matrix ( H ) [ 14 , 15 , 16 , 17 ]. Both, GBLUP as well as ssGBLUP use the same equations as ABLUP, but with different covariance, that is relationship matrices.

This approach is beneficial for traits that are difficult to measure and traits with low heritability. It has been successfully applied to other livestock, such as dairy cattle [ 18 ], beef [ 19 ], pigs [ 20 ], chickens [ 21 ], and sheep [ 22 ]. It demonstrated that accuracies of breeding values for milk fatty acid of dairy cattle were low to high, ranging from 0.13 to 0.72 and from 0.18 to 0.74 considering the pedigree and the genomic information, respectively. It was confirmed that the contribution of genomic information in milk yield is more accurate compared to the ABLUP methodology[ 18 ]. Zhao (2019) estimated genetic parameters and conducted genomic prediction for five types of sperm morphology abnormalities in a large Duroc boar population by using GBLUP and ssGBLUP method. It showed that the comparative predictive abilities of breeding values with ssGBLUP outperformed that with GBLUP method [ 20 ]. Zhu (2021) evaluated the effect of statistical model, heritability and marker density on genomic prediction of six wool traits of sheep. The results showed that the prediction ability of GBLUP model for traits with low heritability was better [ 22 ].Muir (2015) reported that the accuracy of GEBV was higher than that estimated by using ABLUP method with simulated data when the enough training generations were provided [ 23 ].

Genomic selection has been widely applied in animal breeding programs. However, due to the limitations of sequencing costs, and economic benefits, the application of genome selection for goats has not yet fully developed. With the construction of reference populations and the development of 70 K commercial SNP genotyping chips for goats, a routine application of GS is in sight. In this study, the records of phenotype, genotype, pedigree of 2299 IMCGs was used. Genomic prediction of fleece traits in Inner Mongolia Cashmere goats (IMCGs) using the pedigree based Best Linear Unbiased Prediction (BLUP), Genomic BLUP (GBLUP), single-step GBLUP (ssGBLUP) were performed. This study will provide a reference for genome selection breeding of Inner Mongolia Cashmere goats.

Materials and Methods

Phenotypic data.

The phenotypic data were collected from an Inner Mongolia YiWei White Cashmere Goat Limited Liability Company, Wulan Town, Etuoke Banner, Ordos City, Inner Mongolia Autonomous Region, China (39°12′N; 107°97′E). In this study, a total of 33,623 production performance records of fleece traits for 2256 individuals (372 males and 1884 females) at ages of 1 to 8 years old were collected from 2011 to 2021. All animal pedigree can be traced back three generations. The fleece traits included cashmere production (CP), cashmere diameter (CD) and cashmere length (CL), fiber length (FL). The basic statistics of phenotypic data were analyzed with Microsoft Excel 2021 ( https://www.microsoft.com/zh-cn/microsoft-365/excel ) and R4.2.2 ( https://www.r-project.org/ ).

Genotype data

The 2299 individuals were genotyped using the Illumina GGP_Goat_70K BeadChip (Illumina, San Diego, CA). Markers on the sex chromosome were discarded. SNPs were selected based on minor allele frequency (MAF > 0.05), proportion of missing genotypes (missing < 0.05), and Hardy Weinberg equilibrium (HWE > 10 –5 ). Unqualified SNPs were removed. Moreover, individuals with more than 10% missing genotypes were excluded. Use PLINK1.9 software to perform quality control on genotype data. The genotype data after quality control was utilized to draw the SNP density maps by CMplot packages in R language.

Estimation of genetic parameters and genomic breeding value

In this study, the fixed effects including sex, year of production, herd (1 to 11), individual age, dam age, birth type were determined by generalized linear model (GLM). The generalized linear model formula was as follow:

where \({{\varvec{y}}}_{{\varvec{i}}{\varvec{j}}{\varvec{k}}{\varvec{l}}{\varvec{m}}{\varvec{n}}{\varvec{o}}}\) is the vector of observations of the animal, \({\varvec{\mu}}\) is the mean value vector of the observations, \({{\varvec{S}}}_{{\varvec{i}}}\) is the effect of sex, \({{\varvec{Y}}}_{{\varvec{j}}}\) is the effect of year of production, \({{\varvec{H}}}_{{\varvec{k}}}\) is the effect of herd, \({{\varvec{I}}}_{{\varvec{l}}}\) is the effect of individual age, \({{\varvec{D}}}_{{\varvec{m}}}\) is the effect of dams of age, \({{\varvec{B}}}_{{\varvec{n}}}\) is the effect of birth type, \({{\varvec{e}}}_{{\varvec{i}}{\varvec{j}}{\varvec{k}}{\varvec{l}}{\varvec{m}}{\varvec{n}}{\varvec{o}}}\) is the effect of residual.

After determining the fixed effect, a repeatability animal model was used to estimate the genetic parameters and genomic breeding values with ABLUP, GBLUP and ssGBLUP methods. All methods were performed by the ASREML software [ 24 ].

In this study, the model was the same for ABLUP, GBLUP and ssGBLUP:

where \({\text{y}}\) is the vector of the observations, \(\mu\) is the mean value vector of the observations, \(b\) is the vector of fixed effects, \(a\) is a vector of additive genetic effects, \(c\) is a vector of permanent environmental effects and \(e\) is a vector of residual. The matrix \({\varvec{X}}\) is the incidence matrix for the fixed effects, \({\varvec{Z}}\) is the incidence matrix relating additive genetic effects and \({\varvec{W}}\) is the incidence matrix relating permanent environmental effects.

In ABLUP, additive genetic effects are sampled from distribution \(N(0,{\varvec{A}}{\sigma }_{a}^{2})\) ; \({{\varvec{\sigma}}}_{{\varvec{a}}}^{2}\) is the additive genetic variance and \({\varvec{A}}\) is the identity by descent (IBD) relationship matrix constructed from pedigree information. In GBLUP, the matrix relating to additive genetic effects for the genomic relationship matrix ( G ) [ 12 , 25 ]:

In ssGBLUP, the matrix relating additive genetic effects for H matrix:

Here,the individuals are divided into two parts: Part 1 contains the individuals whose genotype is not available and Part 2 consists of the phenotype individuals. Thus, \({\mathbf{A}}_{11}\) denotes the entries of \(\mathbf{A}\) that provide the relationships within Part 1, \({\mathbf{A}}_{12}\) and \({\mathbf{A}}_{21}\) the relationships between the individuals of the two parts, and \({\mathbf{A}}_{22}\) the pedigree relationships within Part 2. Moreover, \({\mathbf{A}}_{22}^{-1}\) denotes the inverse of \({\mathbf{A}}_{22}\) .

Construction of the inverse of H matrix for ssGBLUP:

where \({{\varvec{A}}}^{-1}\) is the inverse matrix of all pedigree relations, \({{\varvec{G}}}^{-1}\) is the inverse matrix of genome relationships, and \({{\varvec{A}}}_{22}^{-1}\) is the inverse matrix of pedigree relations for the genotype individuals.

Accuracy of genetic evaluation

In this study, five-fold cross-validation was used to evaluate the accuracy of genomic prediction. Firstly, the individuals were randomly divided into five groups, and then one group was selected as the validation population at each time, and the other four groups were used as the training population. The accuracy of genomic prediction is evaluated by calculating the correlation between the estimated phenotypic value and the true phenotypic value in the validation population divided by the square root of heritability. The formula was as follow:

The unbiased of genomic prediction is evaluated by the regression coefficient between the true phenotypic value and the estimated phenotypic value.

Basic statistical analysis of phenotypic data

Minimums (Min), mean, maximum (Max), standard deviation (SD) and coefficient of variation (CV) values of the fleece traits were presented in Table  1 . The averages values of four fleece traits including fiber length, cashmere length, cashmere production, cashmere diameter is 18.89 cm, 6.23 cm, 740.3 g and 15.23 μm, respectively. And the corresponding coefficient of variation were 25.94%, 17.60%, 29.07% and 5.32%. The four fleece traits approximately follow a normal distribution [See Additional file 1 , Figure S1].

Analysis of genotype data

The 43 individuals and 16,360 SNPs were deleted from the raw genotype data. Finally, 2256 individuals and 50,728 markers were used to analyze. The number of SNPs on each chromosome before and after quality control were shown in Fig.  1 . The SNP density after quality control were similar over 29 autosomes (Fig.  2 ).

Comparison of SNP numbers on each chromosome before and after quality control

The distribution of SNP density on each chromosome

Determination of fixed effects

The results demonstrated that year of production, sex, herd and individual ages had high significantly effect on the fleece traits ( P  <  0.01 ), however, birth type and dams of age had no effect on the fleece traits for FL, CL and CD ( P  >  0.05 ) (Table  2 ). Therefore, year, sex, herd and individual ages should be considered when the genetic parameters of fleece traits in IMCGs were evaluated.

Estimation of genetic parameters

The residual plots of fleece traits in each method were shown in Figure S2-S4 [See Additional file 1 , Figure S2, Figure S3, Figure S4]. All of these indicated that the models fit well. The variance components and genetic parameters of fleece traits in IMCGs were shown in Table  3 . The heritability of FL (fiber length), CL (cashmere length), CP (cashmere production) and CD (cashmere diameter) by using ABLUP method were 0.27, 0.06, 0.15 and 0.24 respectively, and the repeatability of FL, CL, CP and CD were 0.51, 0.08, 0.35 and 0.37 respectively. The heritability of FL (fiber length), CL (cashmere length), CP (cashmere production) and CD (cashmere diameter) by using GBLUP method were 0.31, 0.08, 0.20 and 0.28 respectively, and the repeatability of FL, CL, CP and CD were 0.48, 0.08, 0.34 and 0.36 respectively. The heritability of FL, CL, CP and CD by using ssGBLUP method were 0.26, 0.05, 0.15 and 0.22 respectively, and the repeatability of FL, CL, CP and CD were 0.39, 0.05, 0.26 and 0.24 respectively. Because genome information is considered, the heritability estimated by methods GBLUP is higher than that by ABLUP method, and the repeatability estimated is slightly lower. And the standard error of genomic based methods are lower than pedigree.

Accuracy of GEBV in each method

Akaike's An Information Criterion (AIC) and Schwarz's Bayesian criterion (BIC or SBC) are used to evaluate the effectiveness of model fitting. It was illustrated that the model by using ssGBLUP and GBLUP methods fitted better than that by using ABLUP methods [See Additional file 1 , Figure S5]. The accuracy of GEBV by using GBLUP and ssGBLUP methods were shown in Table  4 and Fig.  3 . The results demonstrated that the prediction accuracy of four fleece traits by using ssGBLUP and GBLUP were significantly higher than that using ABLUP. The range of predict ability of the fleece traits by using ABLUP, GBLUP and ssGBLUP range are 36.73% ~ 41.25%, 56.18% ~ 69.06%, 66.82% ~ 73.70%, respectively. There was no significant difference in prediction accuracy between the GBLUP and ssGBLUP methods for the other three personality traits, except for CL. Numerically speaking, the prediction accuracy of fleece traits in ssGBLUP method is slightly higher than that in GBLUP method.

Comparison of the accuracy of GEBV for fleece traits with three methods

In this study, the results that sex, year, herd and animal age had highly significant effect on the fleece traits in IMCGs, which is similar to the findings in most studies. Wang (2013) reported that the year of production, sex and herd had highly significant influences on all fleece traits [ 26 ]. Salehi (2010) was to evaluate effect of some environmental factors on fiber characteristics of Raeini Cashmere goats, and the results of this study indicated that the fixed effects including age and sex should be considered in the breeding programs[ 27 ]. It may be explained by differences in rearing conditions, rainfall, and quality of grassland. In this study, that the results demonstrated that dams of age and birth type had no significant effect on fleece traits of Inner Mongolia Cashmere goats. Newman (1996) found that the dams of age had no significant effect on cashmere diameter and cashmere length on New Zealand cashmere goats [ 28 ]. Snyman reported the non-genetic factors affecting the growth and fleece traits of Afrino sheep, in which the dams of age had no significant effect on fiber diameter [ 29 ]. Bromley used REML method to estimate the genetic parameters of prolificacy, weight and wool traits of Columbia, Polypay, Rambouillet and Targhee sheep, which illustrated that birth type had no significant effect on fleece traits [ 30 ]. However, Zhou reported that the birth type had significant impact on yearling cashmere length, but had no significant impact on cashmere diameter, it is inconsistent with our results [ 31 ]. This may be due to the data collection time and the size of the phenotypic data set. Therefore, year, sex, herd and individual ages should be considered when the genetic parameters of fleece traits in IMCGs were evaluated.

Many methods, including GBLUP, ssGBLUP and Bayesian methods, have been used to perform genomic selection in plants and animals. To some extent, the methods affected the accuracy of the prediction accuracy. The results in this study show that the estimation accuracy of ssGBLUP and GBLUP is significantly higher than that of ABLUP method. It is basically consistent with that in other studies [ 32 , 33 ]. Mrode (2021) reported that the estimates of heritability for daily milk yield from GBLUP and ssGBLUP were essentially the same [ 34 ], which is similar to this study. Lourenco reported that prediction accuracy of GEBV for growth traits and calving ease when using single-step genomic BLUP (ssGBLUP) in Angus cattle was higher than that in using BLUP [ 35 ]. Teissier (2019) illustrated that the accuracy of GEBV for milk production traits, udder type traits, and somatic cell scores in French dairy goats was higher than that using other methods. Similarly, the accuracy of GEBV in ssGBLUP for fiber diameter and live body weight was higher than that with other methods in our study [ 36 ]. Wei (2020) compared estimates of genetic parameters and the accuracy of breeding values for wool traits in Merino sheep between pedigree-based best linear unbiased prediction and single-step genomic best linear unbiased prediction, the results showed that the heritability of wool traits with ssGBLUP were slightly higher than those obtained with pedigree-based best linear unbiased prediction [ 37 ]. The accuracies of estimated breeding values were low to moderate, ranging from 0.362 to 0.573 for the whole population. Compared with ABLUP, GBLUP and ssGBLUP has relatively better prediction ability. Therefore, it is suggested to use ssGBLUP method for genome selection of goats. With the continuous progress of breeding work, more efficient and simple models will be optimized and developed. Applying these methods to perform genomic selection of important traits in livestock and poultry will inevitably accelerate the breeding process of population.

Conclusions

In this study, the genetic parameters and genomic breeding values of fleece traits in IMCGs were estimated by using ABLUP, GBLUP and ssGBLUP methods. Regardless of which method is used, the heritability of cashmere length is low, while the heritability of other three fleece traits are medium or low to medium. The prediction accuracy of GEBV for fleece traits by using GBLUP and ssGBLUP is significantly higher than that with ABLUP method. And the prediction accuracy of fleece traits in ssGBLUP method is slightly higher than that in GBLUP method. The accuracy of GEBV with ssGBLUP method for fleece traits ranged from 66.82% to 73.70%, which is 29.03%-33.97% higher than that with ABLUP method. Therefore, ssGBLUP is recommended as the method of genetic evaluation of fleece traits in IMCGs.

Availability of data and materials

The original contributions presented in the study are publicly available. Please refer to https://db.cngb.org/ , or email: [email protected] for detailed application guidance. The accession code CNP0005155 should be included in the application.

Rabier CE, Barre P, Asp T, Charmet G, Mangin B. On the accuracy of genomic selection. PLoS ONE. 2016;11: e0156086.

Article   PubMed   PubMed Central   Google Scholar  

Henderson CR. Best linear unbiased estimation and prediction under a selection model. Biometrics. 1975;31:423–47.

Article   CAS   PubMed   Google Scholar  

Belonsky GM, Kennedy BW. Selection on individual phenotype and best linear unbiased predictor of breeding value in a closed swine herd. J Anim Sci. 1988;66:1124–31. https://doi.org/10.2527/jas1988.6651124x .

Sorensen DA. Effect of selection index versus mixed model method of prediction of breeding value on response to selection in a simulated pig population. Livest Prod Sci. 1988;20:135–48.

Article   Google Scholar  

Ieiri T. The improvement of litter size and its genetic trend using animal model blup in pigs. Nihon Yoton Gakkaishi. 1999;36.

Jang S, Kim SY, Lee SH, Min GS, Kang J, Lee D, et al. The effect of progeny numbers and pedigree depth on the accuracy of the ebv with the blup method. Korean Journal of Agricultural Science. 2019;46.

Meuwissen TH, Hayes BJ, Goddard ME. Prediction of total genetic value using genome-wide dense marker maps. Genetics. 2001;157:1819–29.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Scott B, Haile-Mariam M, Cocks B, Pryce J. How genomic selection has increased rates of genetic gain and inbreeding in the australian national herd, genomic information nucleus, and bulls. J Dairy Sci. 2021;104:11832–49.

Song H, Hu H. Strategies to improve the accuracy and reduce costs of genomic prediction in aquaculture species. Evol Appl. 2021.

Kim EH, Kang HC, Sun DW, Myung CH, Kim JY, Lee DH, et al. Estimation of breeding value and accuracy using pedigree and genotype of hanwoo cows (korean cattle). J Anim Breed and Genet. 2022;139:281–91.

Habier D, Fernando RL, Dekkers JC. The impact of genetic relationship information on genome-assisted breeding values. Genetics. 2007;177:2389–97. https://doi.org/10.1534/genetics.107.081190 .

VanRaden P. Efficient methods to compute genomic predictions. J Dairy Sci. 2008;91:4414–23. https://doi.org/10.3168/jds.2007-0980 .

Legarra A, Aguilar I, Misztal I. A relationship matrix including full pedigree and genomic information. J Dairy Sci. 2009;92:4656–63.

Misztal I, Legarra A, Aguilar I. Computing procedures for genetic evaluation including phenotypic, full pedigree, and genomic information. J Dairy Sci. 2009;92:4648–55. https://doi.org/10.3168/jds.2009-2064 .

Aguilar I, Misztal I, Johnson DL, Legarra A, Tsuruta S, Lawlor TJ. Hot topic: a unified approach to utilize phenotypic, full pedigree, and genomic information for genetic evaluation of holstein final score. J Dairy Sci. 2010;93:743–52.

Christensen OF, Lund MS. Genomic prediction when some animals are not genotyped. Genet Sel Evol. 2010;42:2. https://doi.org/10.1186/1297-9686-42-2 .

Legarra A, Ducrocq V. Computational strategies for national integration of phenotypic, genomic, and pedigree data in a single-step best linear unbiased prediction. J Dairy Sci. 2012;95:4629–45.

Palombo V, Pegolo S, Conte G, Cesarani A, Macciotta NPP, Stefanon B, et al. Genomic prediction for latent variables related to milk fatty acid composition in holstein, simmental and brown swiss dairy cattle breeds. J Anim Breed Genet. 2021;138:389–402. https://doi.org/10.1111/jbg.12532 .

Liang M, Miao J, Wang X, Chang T, An B, Duan X, et al. Application of ensemble learning to genomic selection in chinese simmental beef cattle. J Anim Breed Genet. 2021;138:291–9. https://doi.org/10.1111/jbg.12514 .

Zhao Y, Gao N, Cheng J, El-Ashram S, Zhu L, Zhang C, et al. Genetic parameter estimation and genomic prediction of duroc boars' sperm morphology abnormalities. Animals (Basel). 2019;9. doi: https://doi.org/10.3390/ani9100710 .

Zhang J, Wang J, Li Q, Wang Q, Wen J, Zhao G. Comparison of the efficiency of blup and gblup in genomic prediction of immune traits in chickens. Animals (Basel). 2020;10. doi: https://doi.org/10.3390/ani10030419 .

Zhu S, Guo T, Yuan C, Liu J, Li J, Han M, et al. Evaluation of bayesian alphabet and gblup based on different marker density for genomic prediction in alpine merino sheep. G3 (Bethesda). 2021;11. doi: https://doi.org/10.1093/g3journal/jkab206 .

Muir WM. Comparison of genomic and traditional blup-estimated breeding value accuracy and selection response under alternative trait and genomic parameters. J Anim Breed Genet. 2015;124:342–55.

Butler DG, Cullis BR, Gilmour AR, Gogel BG, Thompson R. Asreml-r reference manual version 4. 2017.

Forni S, Aguilar I, Misztal I. Different genomic relationship matrices for single-step analysis using phenotypic, pedigree and genomic information. Genet Sel Evol. 2011;43:1. https://doi.org/10.1186/1297-9686-43-1 .

Wang Z, Wang R, Zhang W, Wang Z, Wang P, Liu H, et al. Estimation of genetic parameters for fleece traits in yearling inner mongolia cashmere goat. Small Rumin Res. 2013.

Salehi M, Aasadi FM, Mir HA. Enviromental factors affecting fleece traits in raeini down fibers goat. 2010.

Newman SAN, Paterson DJ. Estimates of environmental effects for liveweight and fleece characteristics of new zealand cashmere goats. N Z J Agric Res. 1996;39:379–86.

Snyman MA, Erasmus GJ, Wyk J. Non-genetic factors influencing growth and fleece traits in afrino sheep. S Afr J Anim Sci. 1995;25:70–4.

Google Scholar  

Bromley CM, Snowder GD, Van Vleck LD. Genetic parameters among weight, prolificacy, and wool traits of columbia, polypay, rambouillet, and targhee sheep. J Anim Sci. 2000;78:846–58. https://doi.org/10.2527/2000.784846x .

Zhou HM, Allain D, Li JQ, Zhang WG, Yu XC. Effects of non-genetic factors on production traits of inner mongolia cashmere goats in china. Small Rumin Res. 2003;47:85–9.

Afrazandeh M, Abdolahi-Arpanahi R, Abbasi MA, Kashan NEJ, Torshizi RV. Comparison of different response variables in genomic prediction using gblup and ssgblup methods in iranian holstein cattle. J Dairy Res. 2022:1–7. doi: https://doi.org/10.1017/s0022029922000395 .

Yan X, Zhang T, Liu L, Yu Y, Yang G, Han Y, et al. Accuracy of genomic selection for important economic traits of cashmere and meat goats assessed by simulation study. Front Vet Sci. 2022;9. doi: https://doi.org/10.3389/fvets.2022.770539 .

Mrode R, Ojango J, Ekine-Dzivenu C, Aliloo H, Gibson J, Okeyo MA. Genomic prediction of crossbred dairy cattle in tanzania: a route to productivity gains in smallholder dairy systems. J Dairy Sci. 2021;104:11779–89. https://doi.org/10.3168/jds.2020-20052 .

Lourenco D, Tsuruta S, Fragomeni BO, Masuda Y, Aguilar I, Legarra A, et al. Genetic evaluation using single-step genomic best linear unbiased predictor in american angus. J Anim Sci. 2015.

Teissier M, Larroque H, Robert-Granie C. Accuracy of genomic evaluation with weighted single-step genomic best linear unbiased prediction for milk production traits, udder type traits, and somatic cell scores in french dairy goats. J Dairy Sci. 2019.

Wei C, Luo H, Zhao B, Tian K, Huang X, Wang Y, et al. The effect of integrating genomic information into genetic evaluations of chinese merino sheep. Animals (Basel). 2020;10. doi: https://doi.org/10.3390/ani10040569 .

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The authors are grateful for the grants supported by National Key Research and Development Program of China [2022YFE0113300, 2022YFD1300201, 2022YFD1300204], Science and Technology Research Project of Inner Mongolia Autonomous Region [2021GG0086], "Youth Science and Technology Talent Support Plan" of colleges and universities in Inner Mongolia Inner Mongolia Autonomous Region[NJYT22038], Supported by Program for Innovative Research Team in Universities of Inner Mongolia Autonomous Region [NMGIRT2322], China Agriculture Research System of MOF and MARA [No. CARS-39], Inner Mongolia Autonomous Region Natural Science Foundation Project (2023LHMS03003), Inner Mongolia Agricultural University Outstanding Youth Science Fund Cultivation Project (BR230304); High level Achievement Cultivation Special Project of School of Animal Science, Inner Mongolia Agricultural University (GZL202204).

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Xiaochun Yan, Jinquan Li, Zhiying Wang & Rui Su

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RS, ZW, XY and JL conceived of and coordinated the study. LH, OC, NW, SW and XW provides phenotype data. XY analyzed the data. XY and ZW wrote the manuscript. All authors read and approved the final manuscript.

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Yan, X., Li, J., He, L. et al. Accuracy of Genomic prediction for fleece traits in Inner Mongolia Cashmere goats. BMC Genomics 25 , 349 (2024). https://doi.org/10.1186/s12864-024-10249-7

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MINI REVIEW article

Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis.

• 1 College of Basic Medicine, Naval Medical University, Shanghai, China
• 2 Department of Traditional Chinese Medicine, Naval Medical University, Shanghai, China

Chronic fatigue syndrome (CFS) causes great harm to individuals and society. Elucidating the pathogenesis of CFS and developing safe and effective treatments are urgently needed. This paper reviews the functional changes in the hypothalamus-pituitary-adrenal (HPA) axis in patients with CFS and the associated neuroendocrine mechanisms. Despite some controversy, the current mainstream research evidence indicates that CFS patients have mild hypocortisolism, weakened daily variation in cortisol, a weakened response to the HPA axis, and an increase in negative feedback of the HPA axis. The relationship between dysfunction of the HPA axis and the typical symptoms of CFS are discussed, and the current treatment methods are reviewed.

Introduction

The term chronic fatigue syndrome (CFS) was first proposed by the U.S. Centers for Disease Control and Prevention in 1988 ( 1 ). To improve the definition and diagnostic criteria, the International CFS Study Group released two revisions in 1994 and 2003 ( 2 , 3 ) and gradually established the widely used “gold standard”; that is, CFS is a syndrome characterized by chronic fatigue that is clinically assessed, unexplained, persistent or recurrent, new or with a definite onset, non-congenital, not due to ongoing labor, and not relieved. Additionally, the occupational ability, educational ability, social ability and personal life of affected individuals are substantially worse than those before the illness. For the diagnosis of CFS, four or more of the following symptoms persist or recur for at least 6 months, the appearance of which does not occur prior to fatigue symptoms: ① severe impairment of short-term memory and concentration, causing a substantial decrease in occupational ability, educational ability, social ability and personal life compared with those before disease onset; ② sore throat and tenderness of the neck or axillary lymph nodes; ③ muscle pain and multiple joint pain not accompanied by swelling; ④ type, manner, and severity of headache attacks different from those before; ⑤ inability to recuperate after sleep; ⑥ and persistent fatigue for more than 24 hours after activity. It is estimated that 836,000 to 2.5 million people are affected with CFS in the U.S., with as many as a quarter being homebound or bedridden ( 4 ). However, considering the number of people affected and the harm caused, CFS has not received due research attention ( 5 ). Notably, in 2018, an article in “Nature” called for the reinitiation of CFS studies ( 6 ).

Due to the enormous complexity of CFS, its pathogenesis is still unclear. Some of the researchers suggest immunological, neuroendocrine and metabolic pathways that causes CFS, which indicates significant immune dysregulation ( 7 , 8 ). Neuroendocrine mechanisms have been the focus of some research. In 1991, several researchers focused on the hypothalamus-pituitary-adrenal (HPA) axis ( 9 ), and since then, the HPA axis has been a research hotspot in the field of neuroendocrine mechanisms. The HPA axis has three levels: the hypothalamus is the first level, and corticotropin releasing hormone (CRH) secreted by the hypothalamus activates the HPA axis; the pituitary gland is the second level, and CRH can promote the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland; and the adrenal gland acts as the third level and is regulated by ACTH, cortisol (CORT) secreted by the adrenal gland is the main functional product of the HPA axis. Additionally, CORT acts on the hypothalamus and the pituitary gland through a negative feedback mechanism, which inhibits the secretion of CRH and ACTH to stabilize CORT levels ( 10 ). The aim of this paper was to investigate the functional changes and impact of the HPA axis in patients with CFS and to review the current treatment methods.

HPA axis dysfunction in CFS patients

The plasma CORT levels in CFS patients were first reported by a researcher in 1981 ( 11 ). Since then, clinical factors have been gradually expanded to include urine CORT ( 12 ) and saliva CORT ( 13 ); additionally, because CORT secretion has diurnal variation and is pulsatile, observation times have also gradually changed from a single time point ( 14 ) to overall circadian rhythm ( 15 ).

Current mainstream research evidence supports that CFS patients have mild hypocortisolism, weakened daily variation in CORT, unresponsiveness of the HPA axis, and enhanced negative feedback from the HPA axis ( 16 ). Several studies have shown that, compared with those in healthy controls, the plasma ( 14 , 17 , 18 ), urine ( 12 ), and saliva ( 19 ) concentrations of CORT in CFS patients are significantly lower. In addition to observations at a single time point, changes in the circadian rhythm of the HPA axis have also been analyzed. Through the collection and comparison of saliva CORT concentrations at multiple time points in 24 hours, it was found that the CORT levels in CFS patients were lower in the morning and higher in the evening; that is, daily CORT variability was attenuated compared with that in normal controls ( 20 ). More intensive plasma collection revealed that the secretion rhythm of ACTH in CFS patients was significantly different from that in normal controls, with release decreasing during the physiological morning peak ( 21 ). These findings demonstrated an alteration in the secretion rhythm of the HPA axis. Using the Trier Social Stress Test (TSST), researchers found that, compared with healthy controls, CFS patients had a significantly reduced area under the ACTH response curve, with no significant difference in the area under the CORT response curve ( 22 ). Cortisol awakening response (CAR) was tested, and it was found that, compared with healthy controls, CFS patients with childhood trauma experienced a significantly reduced area under the CORT response curve and that their CORT response curves were flatter ( 23 ). In addition, women with CFS had significantly lower CAR levels than healthy women did, and the increase in the area under the response curve was also lower ( 24 ). An insulin tolerance test (ITT) showed that, in CFS patients, the area under the ACTH response curve was significantly reduced, while that of CORT was not significantly different from that for controls ( 25 , 26 ). This finding confirmed that there was a blunted response of the HPA axis. The enhancement of negative HPA axis feedback has been tested using the dexamethasone suppression test (DST). After the administration of 0.5 mg dexamethasone, the saliva CORT output was significantly lower in CFS patients than in healthy controls ( 27 ),the saliva CORT response significantly decreased ( 28 ). After the administration of 5 mg of prednisolone, the saliva CORT levels and urine CORT metabolite levels were significantly lower in CFS patients than in individuals in the control group, and the percentage of inhibition was significantly higher in CFS patients than in individuals in the control group ( 29 ), demonstrating the enhancement of negative feedback on the HPA axis ( Figure 1 ).

Figure 1 Diagram of functional changes in the HPA axis. The blue arrow represents a decreased level; the yellow lightning bolt represents a rhythm disorder. Abbreviations: CRH (corticotropin releasing hormone), ACTH (adrenocorticotropic hormone), CORT (cortisol), TSST (Trier Social Stress Test), CAR (cortisol awakening response), ITT (insulin tolerance test), DST (dexamethasone suppression test).

However, not all the study results are consistent with the mainstream conclusions. Several studies have shown that there is no significant difference between the CORT levels in CFS patients and those in healthy controls ( 30 ). Using the TSST, researchers found that childhood traumatic experience was not significantly associated with CORT output ( 31 ). There were no significant differences between a CFS group and a healthy control group in terms of CAR, daily CORT secretion curve, or CAR after DST ( 32 ). The differences between these studies may be explained by the study design and insufficient sample size. However, the mainstream conclusions still need verification through comprehensive studies with larger sample sizes ( 33 ).

The effects of HPA axis dysfunction in CFS patients

Because most studies tend to analyze patients who have been ill for many years, it is not clear whether HPA axis dysfunction is the cause or result of CFS ( 16 ). Therefore, some researchers have proposed that the changes in the HPA axis in CFS patients may be an incidental phenomenon that occurs later in the disease course rather than having special etiological significance ( 34 ). However, considering that HPA axis dysfunction may play an etiological and pathological role in CFS, it is still necessary to investigate the association of the HPA axis with typical symptoms of CFS ( 35 ).

Dysfunction of the HPA axis, especially hypocortisolemia, is often closely related to fatigue, pain, and increased pressure sensitivity. Various mechanism can explain such dysfunction. The release of different hormones may be reduced, thereby reducing the stimulation of receptors for each hormone. This may also be the result of the excessive secretion of a certain hormone, followed by the downregulated expression of the corresponding target receptor, increased sensitivity to the negative feedback of glucocorticoids, or increased relative resistance to CORT ( 36 ). Dysfunction of the HPA axis may also be mediated through immune mechanisms, especially HPA axis dysfunction characterized by hypocortisolism, which can weaken the ability of HPA axis hormones to suppress the immune system; therefore, relatively few physiological or psychological stress signals can be transmitted into inflammatory response through activating inflammasomes and the subsequent proinflammatory cytokines ( 37 , 38 ). Cytokine-mediated inflammation may also explain the widespread pain and pain hypersensitivity in CFS patients ( 39 ). In addition, the circadian rhythm of melatonin (MT) secretion, the most important sleep regulation factor, is opposite to that of the HPA axis, and there is an interaction between the two ( 40 ). In CFS patients, changes in the circadian rhythm of the HPA axis have been observed; the amplitude of the circadian secretion of CORT is reduced, the peak phase of CORT secretion is advanced, and the peak phase of MT secretion is delayed. Abnormalities in the peak phases of the two disorders can lead to sleep disorders, providing a neuroendocrine explanation for CFS patients’ difficulty falling asleep at night and easy awakening early in the morning ( 41 ).

Treatment of CFS patients with modern medicine

The 2023 updated guidelines of the CDC noted that there is currently no cure or approved treatment for CFS, with the management of symptoms being the only treatment approach. The guidelines recommend treatment for post-exertional malaise, sleep, pain, anxiety, stress, depression, orthostatic intolerance, and memory and attention problems, with an emphasis on activity management ( 42 ). Activity management involves patients finding their mental and physical activity limits and then planning their activities and rest to remain within these limits to avoid post-exertional malaise. Limits vary among individuals; therefore, recording activities and symptoms can help patients discover their personal limits, especially in the early stage of the disease. In addition, patients should be reminded not to try to increase activities beyond their limit even though the activity management plan is working well because post-exertional malaise can recur ( 43 ).

The largest study on this topic provided favorable evidence for the efficacy and safety of cognitive behavioral therapy and graded exercise therapy ( 44 , 45 ). However, when the data were re-analyzed, the results changed significantly ( 46 ). Subsequent studies have questioned their efficacy and safety ( 47 ). After comprehensive consideration, the CDC no longer recommends both for the treatment of CFS. Recently, new randomized controlled trials (RCTs) have been conducted to find more evidence, thus indicating that modern medicine is still making efforts to find a better treatment plan for CFS ( 48 , 49 ).

Regarding HPA axis dysfunction, randomized controlled trials have shown beneficial effects of hydrocortisone for some patients, but the overall evidence of its efficacy is insufficient ( 50 – 54 ). Long-term treatment is associated with adverse effects, including Cushing’s syndrome, osteoporosis, extreme mood changes and seizures ( 55 ); therefore, hydrocortisone was not included in the CDC guidelines.

Treatment of CFS patients with traditional Chinese medicine

Due to limited treatment options, many CFS patients receive traditional medicine and alternative therapies, including traditional Chinese medicine (TCM) ( 56 ). The modern medical term “chronic fatigue syndrome” does not accurately correspond to the TCM literature. According to its clinical symptoms, “CFS” is often categorized as “asthenia” ( 57 ). The main characteristics of “fatigue” were first described during the Han Dynasty in one of the most important works of TCM: “Synopsis of the Golden Chamber” by Zhongjing Zhang ( 58 ). In summary, the etiology includes the following four aspects: ① damage to five internal organs (including qi, blood, yin, and yang) caused by exogenous invasion; ② fatigue (including physical, mental, and sexual fatigue); ③ emotional imbalance (happiness, anger, worry, obsessive thoughts, sadness, fear, and shock); ④ and improper diet ( 59 ). There are many methods used by TCM to treat CFS, including acupuncture, massage, cupping, and Chinese medicine, which can relieve pain and improve quality of life ( 58 ).

Although it is still not clear whether HPA axis dysfunction is the cause or an incidental phenomenon of CFS, the HPA axis is clearly a potentially important target for studying treatment strategies ( 35 ). Table 1 lists the 7 RCTs of TCM treatment methods that reported changes in HPA axis indicators ( 60 – 66 ). Six studies reported changes in CORT levels. The treatments included pestle needle therapy combined with electric acupuncture, Fuyang cupping, five-element gongdiao (positive mode) music combined with Lixujieyu decoction, acupoint sticking, Lixujieyu decoction, and electric acupuncture ( 60 – 62 , 64 – 66 ). In a study of CFS patients treated with pestle needle therapy combined with electric acupuncture, the CORT level in patients was lower after treatment than before treatment ( 60 ). The remaining 5 studies reported that treatment effectively increased CORT levels ( 61 , 62 , 64 – 66 ) and increased the circadian secretion amplitude of saliva CORT and restored CORT peak phase that had tended to shift forward ( 66 ). Three studies reported changes in ACTH levels. The treatments included pestle needle therapy combined with electric acupuncture, scalp acupuncture, and acupoint sticking; all the reported treatment methods effectively increased ACTH levels ( 60 , 63 , 64 ). One study reported changes in MT, and treatment with electric acupuncture increased salivary MT levels and increased the variation in diurnal salivary MT secretion, restoring MT peak phases that had tended to shift backward ( 66 ). The occurrence of a CORT regulation exception in these clinical studies has sparked our thinking ( 60 ). A number of animal experiments have shown that CFS model rats exhibit hyperfunction of the HPA axis and that after TCM treatment, CORT levels significantly decrease ( 67 – 73 ). A study showed that when the body is subjected to a variety of noxious stimuli, HPA axis function increases, and the release of ACTH and CORT increases, thereby improving tolerance to stimulation and survival. When the regulatory ability is disrupted, HPA axis function is inhibited, adrenal function decreases, and the CORT concentration decreases ( 74 , 75 ). Therefore, we speculate that the HPA axis has two disordered states, i.e., a hyperactive state and an inhibitory state, and that these states are related to the duration of stress. In most established animal models, the animals are in a state of HPA axis hyperactivity due to short modeling time. The patients in clinical studies are mostly chronically ill and more likely to be in an inhibitory state. In the absence of HPA axis inhibition, TCM treatment methods may not be limited to simply increasing or decreasing the level of a certain hormone but can resolve HPA axis dysfunction. That is, TCM therapeutic approaches have a bi-directional regulatory effect on HPA axis dysfunction in CFS. Although TCM treatment methods provide new possibilities for the treatment of CFS, as suggested by evidence-based research, the relevant RCT studies have deficiencies in terms of experimental design, random allocation concealment, blinding, and safety reporting, thus limiting the interpretation of evidence. Considering these limitations, it is necessary to conduct RCT studies with larger samples and more standardized treatments to provide evidence for the efficacy and safety of TCM treatment methods ( 76 – 78 ).

Table 1 RCTs of TCM treatment methods that reported changes in HPA axis indicators.

Summary and outlook

Given the negative impacts of CFS on individuals and society, there is an urgent need to elucidate the pathogenesis of CFS and develop safe and effective treatments. In this paper, we reviewed the changes in HPA axis function in CFS patients. Although controversial, the current mainstream research evidence still indicates that CFS patients have mild hypocortisolism, weakened diurnal variations in CORT, unresponsiveness of the HPA axis, and enhanced negative feedback from the HPA axis. We also discussed the association between HPA axis dysfunction and typical symptoms of CFS. Finally, the current treatment methods were reviewed. Due to the lack of modern medical treatments approved for CFS at this time, TCM treatment methods have the potential to become a new treatment strategy; in particular, TCM may have a two-way regulatory effect and resolve HPA axis dysfunction. However, due to limited evidence, it is necessary to conduct RCTs with larger sample sizes and more standardized protocols to provide additional data.

Author contributions

YZ: Writing – original draft, Writing – review & editing. LW: Writing – original draft, Writing – review & editing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by Military TCM service capability enhancement project (2023ZY003).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

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1. Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, et al. Chronic fatigue syndrome: a working case definition. Ann Internal Med . (1988) 108:387–9. doi: 10.7326/0003-4819-108-3-387

CrossRef Full Text | Google Scholar

2. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Internal Med . (1994) 121:953–9. doi: 10.7326/0003-4819-121-12-199412150-00009

3. Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, et al. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res . (2003) 3:25. doi: 10.1186/1472-6963-3-25

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Clayton EW. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: an IOM report on redefining an illness. Jama . (2015) 313:1101–2. doi: 10.1001/jama.2015.1346

5. Wadman M. For chronic fatigue syndrome, a ‘shifting tide’ at NIH. Sci (New York NY) . (2016) 354:691–2. doi: 10.1126/science.354.6313.691

6. Maxmen A. A reboot for chronic fatigue syndrome research. Nature . (2018) 553:14–7. doi: 10.1038/d41586-017-08965-0

7. Gil A, Hoag GE, Salerno JP, Hornig M, Klimas N, Selin LK. Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/anti-pathogen agent in a retrospective case series. Brain behavior Immun - Health . (2024) 36:100720. doi: 10.1016/j.bbih.2023.100720

8. Liu X, Liu S, Ren R, Wang X, Han C, Liu Z. A cross-sectional study exploring the relationship between symptoms of anxiety/depression and P50 sensory gating in adult patients diagnosed with chronic fatigue syndrome/myalgic encephalomyelitis. Front Neurosci . (2023) 17:1286340. doi: 10.3389/fnins.2023.1286340

9. Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJ, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab . (1991) 73:1224–34. doi: 10.1210/jcem-73-6-1224

10. Holloway AL, Lerner TN. Hidden variables in stress neurobiology research. Trends Neurosci . (2024) 47:9–17. doi: 10.1016/j.tins.2023.10.006

11. Poteliakhoff A. Adrenocortical activity and some clinical findings in acute and chronic fatigue. J psychosomatic Res . (1981) 25:91–5. doi: 10.1016/0022-3999(81)90095-7

12. Scott LV, Dinan TG. Urinary free cortisol excretion in chronic fatigue syndrome, major depression and in healthy volunteers. J Affect Disord . (1998) 47:49–54. doi: 10.1016/s0165-0327(97)00101-8

13. Young AH, Sharpe M, Clements A, Dowling B, Hawton KE, Cowen PJ. Basal activity of the hypothalamic-pituitary-adrenal axis in patients with the chronic fatigue syndrome (neurasthenia). Biol Psychiatry . (1998) 43:236–7. doi: 10.1016/s0006-3223(97)00404-6

14. Cevik R, Gur A, Acar S, Nas K, Sarac AJ. Hypothalamic-pituitary-gonadal axis hormones and cortisol in both menstrual phases of women with chronic fatigue syndrome and effect of depressive mood on these hormones. BMC musculoskeletal Disord . (2004) 5:47. doi: 10.1186/1471-2474-5-47

15. MacHale SM, Cavanagh JT, Bennie J, Carroll S, Goodwin GM, Lawrie SM. Diurnal variation of adrenocortical activity in chronic fatigue syndrome. Neuropsychobiology . (1998) 38:213–7. doi: 10.1159/000026543

16. Papadopoulos AS, Cleare AJ. Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome. Nat Rev Endocrinol . (2011) 8:22–32. doi: 10.1038/nrendo.2011.153

17. Turan T, Izgi HB, Ozsoy S, Tanrıverdi F, Basturk M, Asdemir A, et al. The effects of galantamine hydrobromide treatment on dehydroepiandrosterone sulfate and cortisol levels in patients with chronic fatigue syndrome. Psychiatry Invest . (2009) 6:204–10. doi: 10.4306/pi.2009.6.3.204

18. Gur A, Cevik R, Nas K, Colpan L, Sarac S. Cortisol and hypothalamic-pituitary-gonadal axis hormones in follicular-phase women with fibromyalgia and chronic fatigue syndrome and effect of depressive symptoms on these hormones. Arthritis Res Ther . (2004) 6:R232–8. doi: 10.1186/ar1163

19. Jerjes WK, Cleare AJ, Wessely S, Wood PJ, Taylor NF. Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome. J Affect Disord . (2005) 87:299–304. doi: 10.1016/j.jad.2005.03.013

20. Nater UM, Youngblood LS, Jones JF, Unger ER, Miller AH, Reeves WC, et al. Alterations in diurnal salivary cortisol rhythm in a population-based sample of cases with chronic fatigue syndrome. Psychosomatic Med . (2008) 70:298–305. doi: 10.1097/PSY.0b013e3181651025

21. Di Giorgio A, Hudson M, Jerjes W, Cleare AJ. 24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome. Psychosomatic Med . (2005) 67:433–40. doi: 10.1097/01.psy.0000161206.55324.8a

22. Gaab J, Rohleder N, Heitz V, Engert V, SChad T, Schürmeyer TH, et al. Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome. Psychoneuroendocrinology . (2005) 30:188–98. doi: 10.1016/j.psyneuen.2004.06.008

23. Heim C, Nater UM, Maloney E, Boneva R, Jones JF, Reeves WC. Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine dysfunction. Arch Gen Psychiatry . (2009) 66:72–80. doi: 10.1001/archgenpsychiatry.2008.508

24. Nater UM, Maloney E, Boneva RS, Gurbaxani BM, Lin JM, Jones JF, et al. Attenuated morning salivary cortisol concentrations in a population-based study of persons with chronic fatigue syndrome and well controls. J Clin Endocrinol Metab . (2008) 93:703–9. doi: 10.1210/jc.2007-1747

25. Gaab J, Engert V, Heitz V, SChad T, Schürmeyer TH, Ehlert U. Associations between neuroendocrine responses to the Insulin Tolerance Test and patient characteristics in chronic fatigue syndrome. J psychosomatic Res . (2004) 56:419–24. doi: 10.1016/s0022-3999(03)00625-1

26. Gaab J, Hüster D, Peisen R, Engert V, Heitz V, SChad T, et al. Hypothalamic-pituitary-adrenal axis reactivity in chronic fatigue syndrome and health under psychological, physiological, and pharmacological stimulation. Psychosomatic Med . (2002) 64:951–62. doi: 10.1097/01.psy.0000038937.67401.61

27. Gaab J, Hüster D, Peisen R, Engert V, SChad T, Schürmeyer TH, et al. Low-dose dexamethasone suppression test in chronic fatigue syndrome and health. Psychosomatic Med . (2002) 64:311–8. doi: 10.1097/00006842-200203000-00015

28. Van Den Eede F, Moorkens G, Hulstijn W, Van Houdenhove B, Cosyns P, Sabbe BG, et al. Combined dexamethasone/corticotropin-releasing factor test in chronic fatigue syndrome. psychol Med . (2008) 38:963–73. doi: 10.1017/s0033291707001444

29. Jerjes WK, Taylor NF, Wood PJ, Cleare AJ. Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome. Psychoneuroendocrinology . (2007) 32:192–8. doi: 10.1016/j.psyneuen.2006.12.005

30. Inder WJ, Prickett TC, Mulder RT. Normal opioid tone and hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome despite marked functional impairment. Clin Endocrinol . (2005) 62:343–8. doi: 10.1111/j.1365-2265.2005.02220.x

31. Kempke S, Luyten P, De Coninck S, Van Houdenhove B, Mayes LC, Claes S. Effects of early childhood trauma on hypothalamic-pituitary-adrenal (HPA) axis function in patients with Chronic Fatigue Syndrome. Psychoneuroendocrinology . (2015) 52:14–21. doi: 10.1016/j.psyneuen.2014.10.027

32. Mommersteeg PM, Heijnen CJ, Verbraak MJ, van Doornen LJ. Clinical burnout is not reflected in the cortisol awakening response, the day-curve or the response to a low-dose dexamethasone suppression test. Psychoneuroendocrinology . (2006) 31:216–25. doi: 10.1016/j.psyneuen.2005.07.003

33. Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P, Claes SJ. Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. Neuropsychobiology . (2007) 55:112–20. doi: 10.1159/000104468

34. Roberts AD, Papadopoulos AS, Wessely S, Chalder T, Cleare AJ. Salivary cortisol output before and after cognitive behavioural therapy for chronic fatigue syndrome. J Affect Disord . (2009) 115:280–6. doi: 10.1016/j.jad.2008.09.013

35. Tomas C, Newton J, Watson S. A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. ISRN Neurosci . (2013) 2013:784520. doi: 10.1155/2013/784520

36. Fries E, Hesse J, Hellhammer J, Hellhammer DH. A new view on hypocortisolism. Psychoneuroendocrinology . (2005) 30:1010–6. doi: 10.1016/j.psyneuen.2005.04.006

37. Raison CL, Miller AH. Malaise, melancholia and madness: the evolutionary legacy of an inflammatory bias. Brain behavior Immun . (2013) 31:1–8. doi: 10.1016/j.bbi.2013.04.009

38. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol . (2009) 27:229–65. doi: 10.1146/annurev.immunol.021908.132715

39. Van Houdenhove B, Luyten P. Customizing treatment of chronic fatigue syndrome and fibromyalgia: the role of perpetuating factors. Psychosomatics . (2008) 49:470–7. doi: 10.1176/appi.psy.49.6.470

40. Ling X, Zhimin L. Pineal melatonin and the hypothalamic-pituitary-adrenal axis. Shanghai Med J . (2009) 32:163–5.

Google Scholar

41. Yihui Z, Fanrong L, Cisong C, Xi W. The study on pathological rhythm characteristics of chronic fatigue syndrome. Chin J Pract Internal Med . (2008) 28:444–6. doi: 10.3969/j.issn.1005-2194.2008.06.010

42. Treatment of ME/CFS. Centers for disease control and prevention(2021). Available online at: https://www.cdc.gov/me-cfs/treatment/ .

43. Bateman L, Bested AC, Bonilla HF, Chheda BV, Chu L, Curtin JM, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: essentials of diagnosis and management. Mayo Clinic Proc . (2021) 96:2861–78. doi: 10.1016/j.mayocp.2021.07.004

44. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet (London England) . (2011) 377:823–36. doi: 10.1016/s0140-6736(11)60096-2

45. White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. psychol Med . (2013) 43:2227–35. doi: 10.1017/s0033291713000020

46. Wilshire CE, Kindlon T, Courtney R, Matthees A, Tuller D, Geraghty K, et al. Rethinking the treatment of chronic fatigue syndrome-a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychol . (2018) 6:6. doi: 10.1186/s40359-018-0218-3

47. Geraghty K, Hann M, Kurtev S. Myalgic encephalomyelitis/chronic fatigue syndrome patients’ reports of symptom changes following cognitive behavioural therapy, graded exercise therapy and pacing treatments: Analysis of a primary survey compared with secondary surveys. J Health Psychol . (2019) 24:1318–33. doi: 10.1177/1359105317726152

48. Gaunt DM, Brigden A, Harris SRS, Hollingworth W, Jago R, Solomon-Moore E, et al. Graded exercise therapy compared to activity management for paediatric chronic fatigue syndrome/myalgic encephalomyelitis: pragmatic randomized controlled trial. Eur J Pediatr . (2024). doi: 10.1007/s00431-024-05458-x

49. van der Schaaf ME, Geerligs L, Toni I, Knoop H, Oosterman JM. Disentangling pain and fatigue in chronic fatigue syndrome: a resting state connectivity study before and after cognitive behavioral therapy. psychol Med . (2024), 1–14. doi: 10.1017/s0033291723003690

50. McKenzie R, O’Fallon A, Dale J, Demitrack M, Sharma G, Deloria M, et al. Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial. Jama . (1998) 280:1061–6. doi: 10.1001/jama.280.12.1061

51. Cleare AJ, Heap E, Malhi GS, Wessely S, O’Keane V, Miell J. Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet (London England) . (1999) 353:455–8. doi: 10.1016/s0140-6736(98)04074-4

52. Blockmans D, Persoons P, Van Houdenhove B, Lejeune M, Bobbaers H. Combination therapy with hydrocortisone and fludrocortisone does not improve symptoms in chronic fatigue syndrome: a randomized, placebo-controlled, double-blind, crossover study. Am J Med . (2003) 114:736–41. doi: 10.1016/s0002-9343(03)00182-7

53. Smith ME, Haney E, McDonagh M, Pappas M, Daeges M, Wasson N, et al. Treatment of myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review for a national institutes of health pathways to prevention workshop. Ann Internal Med . (2015) 162:841–50. doi: 10.7326/m15-0114

54. Whiting P, Bagnall AM, Sowden AJ, Cornell JE, Mulrow CD, Ramírez G. Interventions for the treatment and management of chronic fatigue syndrome: a systematic review. Jama . (2001) 286:1360–8. doi: 10.1001/jama.286.11.1360

55. Buchman AL. Side effects of corticosteroid therapy. J Clin Gastroenterol . (2001) 33:289–94. doi: 10.1097/00004836-200110000-00006

56. Li Y, Yang J, Chau CI, Shi J, Chen X, Hu H, et al. Is there a role for traditional and complementary medicines in managing chronic fatigue? a systematic review of randomized controlled trials. Front Pharmacol . (2023) 14:1266803. doi: 10.3389/fphar.2023.1266803

57. Zhaohui Z, Lihua L. New progress of traditional Chinese medicine in the treatment of chronic fatigue syndrome. World Chin Med . (2021) 16:991–5. doi: 10.3969/j.issn.1673-7202.2021.06.026

58. Yan Y, Yidan W, Dongdong Z, Lin F. Research progress of chronic fatigue syndrome treated by Chinese and western medicine. Inf Traditional Chin Med . (2019) 36:122–5. doi: 10.19656/j.cnki.1002-2406.190128

59. Chen R, Moriya J, Yamakawa J, Takahashi T, Kanda T. Traditional chinese medicine for chronic fatigue syndrome. Evidence-Based complementary Altern medicine: eCAM . (2010) 7:3–10. doi: 10.1093/ecam/nen017

60. Luoji L, Quan L, Anmin H, Honglian P, Fengmei L. Discussion of the effect of Chuzhen combined with electroacupuncture on patients with chronic fatigue syndrome of Yang deficiency based on Fuyang theory. China’s Naturopathy . (2023) 31:35–9. doi: 10.19621/j.cnki.11-3555/r.2023.2111

61. Tian L, Xiaochen Z, Chenchen Z, Congcong W, Qing L, Tielang L. Effect of fuyang cupping on beishu functional belt on clinical efficacy and cortisol in patients with chronic fatigue syndrome. Guiding J Traditional Chin Med Pharmacol . (2023) 29:94–8. doi: 10.13862/j.cn43-1446/r.2023.05.020

62. Zhixing C, Zhenxian Z, Lili W, Yuanshu Y. Clinical observation of five-element gongdiao (positive mode) music combined with Lixujieyu decoction in the treatment of chronic fatigue syndrome. Acta Universitatis Traditionis Medicalis Sinensis Pharmacologiaeque Shanghai . (2015) 29:18–22. doi: 10.16306/j.1008-861x.2015.03.006

63. Chunfeng G, Zhongren S. Clinical observation of scalp acupuncture in the treatment of chronic fatigue syndrome. Acta Chin Med Pharmacol . (2014) 42:65–6. doi: 10.19664/j.cnki.1002-2392.2014.02.023

64. Xinghua C, Haiqiong C, Limei Z, Yang W. Effect of acupoint sticking on chronic fatigue syndrome and endocrine function. Shanghai J Acupuncture Moxibustion . (2014) 33:618–20. doi: 10.13460/j.issn.1005-0957.2014.07.0618

65. Ye Z, Zhenxian Z, Min C, Lili W, Yang W. Effect of deficiency-regulating and depression-relieving formula on 5-HT and cortisol in chronic fatigue syndrome. Liaoning J Traditional Chin Med . (2012) 39:1295–6. doi: 10.13192/j.ljtcm.2012.07.102.zhangy.050

66. Yihui Z, Fangrong L, Xi W, Cisong C. Mechanism of electric acupuncture on saliva CS and MT circadian rhythm in chronic fatigue syndrome. Shandong Med J . (2007) 47:18–20. doi: 10.3969/j.issn.1002-266X.2007.28.007

67. Mingzhu P, Jian L, Bing R, Jun J, Huanan L. Effect of abdominal manipulation on remodeling of hippocampal neurons in chronic stress-induced chronic fatigue syndrome and its mechanism of negative feedback regulation of hippocampus-HPA axis. J Jilin Univ (Medicine Edition) . (2021) 47:842–8. doi: 10.13481/j.1671-587X.20210404

68. Peng Z, Jianping Y, Xiaoqian J, Shiyun C, Jingjing L, Liansha H, et al. Effect of “Beishu points” Electroacupuncture stimulation on CRHmRNA, ACTH and CORT in rats with chronic fatigue sydome. Guiding J Traditional Chin Med Pharmacol . (2018) 24:32–5 + 41. doi: 10.13862/j.cnki.cn43-1446/r.2018.12.009

69. Xiaohong L, Bin Y, Xiaojun W, Mingyan X, Fanchao Z, Liuting W, et al. Effects of Xiaoyao powder on HPA axis, IL-13 and IL-17 in rats with chronic restraint stress of liver stagnation and spleen deficiency syndrome. Lishizhen Med Materia Med Res . (2017) 28:1815–6. doi: 10.3969/j.issn.1008-0805.2017.08.008

70. Yi T, Qi L, Li J, Le JJ, Shao L, Du X, et al. Moxibustion upregulates hippocampal progranulin expression. Neural regeneration Res . (2016) 11:610–6. doi: 10.4103/1673-5374.180746

71. Li Z, Ganghui J. Effects of moxibustion on behavior and hormone levels of hypothalamus-pituitary-adrenergic axis of the model rat with chronic fatigue syndrome. Shandong J Traditional Chin Med . (2014) 33:301–3. doi: 10.16295/j.cnki.0257-358x.2014.04.023

72. Hangzhou L, Mingzhuang L. The effect of acupoint catgut embedding on behavior and hormone levels of hypothalamic-pituitary-adrenocortical axis in rats with chronic fatigue. J Guiyang Coll Traditional Chin Med . (2009) 31:62–5. doi: 10.16588/j.cnki.issn1002-1108.2009.06.016

73. Yunfei C, Wenjia Y, Shengguang F, Xiaodan Z. Experimental study on hormones of HPA-axis with electro-acupuncture by CFS model rats. Chin Arch Traditional Chin Med . (2007) 25:1146–9. doi: 10.13193/j.archtcm.2007.06.59.chenyf.023

74. Xinghua C, Juan Y, Wei S, Chunzhi T. Effects of acupuncture on blood adrenocorticotrophic hormone and cortisol in chronic fatigue syndrome. Chin J Integr Med Cardio-/Cerebrovascuiar Dis . (2011) 9:1320–2. doi: 10.3969/j.issn.1672-1349.2011.11.024

75. Yanhui L, Qiaolin M, Bin H, Zhonglei W. Current state about researches on selection of experimental indexs mechanisms of acupuncture underlying improvement of chronic fatigue syndrome. Acupuncture Res . (2021) 46:980–4. doi: 10.13702/j.1000-0607.200998

76. Fang Y, Yue BW, Ma HB, Yuan YP. Acupuncture and moxibustion for chronic fatigue syndrome: A systematic review and network meta-analysis. Medicine . (2022) 101:e29310. doi: 10.1097/md.0000000000029310

77. Zhang Q, Gong J, Dong H, Xu S, Wang W, Huang G. Acupuncture for chronic fatigue syndrome: a systematic review and meta-analysis. Acupuncture medicine: J Br Med Acupuncture Soc . (2019) 37:211–22. doi: 10.1136/acupmed-2017-011582

78. Wang T, Xu C, Pan K, Xiong H. Acupuncture and moxibustion for chronic fatigue syndrome in traditional Chinese medicine: a systematic review and meta-analysis. BMC complementary Altern Med . (2017) 17:163. doi: 10.1186/s12906-017-1647-x

Keywords: chronic fatigue syndrome, hypothalamus-pituitary-adrenal axis, dysfunction, modern medicine, traditional Chinese medicine

Citation: Zhang Y-D and Wang L-N (2024) Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis. Front. Endocrinol. 15:1373748. doi: 10.3389/fendo.2024.1373748

Received: 20 January 2024; Accepted: 28 March 2024; Published: 10 April 2024.

Reviewed by:

Copyright © 2024 Zhang and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Li-Na Wang, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Research in progress blog

Bmc ‘research in progress’ photo competition 2018: winning images.

Today we announce the winning entries from our BMC ‘Research in progress’ photography competition. In this blog we reveal the winning image, the runner up and a handful of other stunning entries.

Davy Falkner 14 Dec 2018

Earlier in the year we launched the second annual BMC ‘Research in progress’ competition, following the success of the inaugural competition in 2017, in which we received a host of amazing images.

Once again, we asked you to send us photographs reflecting innovation, curiosity, integrity and most of all, your enthusiasm for science and progress.

Here we present the winning image, the runner up and a selection of entries that caught the eyes of our judging panel.

Winning image

The winning image of a mouse kidney has been obtained by diffusion tensor imaging, an MRI-based imaging technique. The bright neon colors represent the orientation of different tubules, which collect filtrate from blood passing through the kidney and process it into urine.

Speaking to us about his winning entry, Nian said: “It’s my great honor to receive this award. The image shows the complex 3D tubular structures of a mouse kidney. It was taken at the Center for In Vivo Microscopy (Directed by Prof. G. Allan Johnson), where our research focuses on developing novel MRI methods to detect tissue microstructures. The non-destructive nature of MRI and its ability to assess the renal microstructure in 3D make it a promising tool to understand the complex structures of the renal system.”

The runner up – submitted by An-Lun Chin, at the Brain Research Center, National Tsing Hua University, Taiwan – is a high-resolution 3D reconstruction of a Drosophila head, showing the nervous system, muscles, cuticles, and visual sensory system. Drosophila melanogaster is a species of fly, known generally as the common fruit fly. It is widely used for biological research.

We want to say a huge congratulations to our winner and runner up, Nian and An-Lun, and a massive thank you to all those who entered. Our judges were astounded by both the volume and quality of the submissions.

All images have been released under a Creative Commons Attribution 4.0 License , so everyone is welcome and encouraged to share them freely, while attributing the image author.

Below you can see some of the highly commended images and those deserving special mention.

Highly commended

School children from a remote village of Suderbans Island gaze at a microchip during their visit to a national research institute in the city of Kolkata, India.

Drops of Death and Life: Venom extraction from the spider Lasiodora sp. This spider venom shown dozens of toxins with different targets. New studies demonstrate interesting activities against various human pathogens.

Special mention

A Madlebrot Fractal fed to a deep dream algortithm that was trained on autoportraits of the author resulting in this hallucination of fractal eyes. The photo is generated by Artificial Intelligence, research and patience.

A farther Dyeing Poison Frog ( Dendrobates tinctorius ) carrying a tadpole while wearing a tracking device. Poison frogs are small inhabitants of the South American rainforests. They are well known for their flashy anti-predator warning colors and their parental behavior. In many species, males shuttle tadpoles from land to small pools of water piggy-back style on their backs. Even such colorful animals can be extremely hard to observe and follow in their natural rainforest habitat.

We deployed miniature radio-transmitters to study the behavior and movement patterns of these small frogs (only 4 centimeters long). In this photograph, a male Dyeing Poison Frog is carrying his single tadpole (the black mass on his back) while wearing a color-matched radio-transmitter allowing to track his movements. Photographed during a study in the Nouragues Nature Reserve, French Guiana.

During plant in vitro propagation, it is quite common to have contaminations by molds, yeasts or bacteria from the environment: sometimes their growth causes the formation of fluffly and colored structures. In this case the contamination surrounding a small grapevine plant looks like some kind of cake.

A group of crane flies in the Southern Philippines create a stunning natural display that is a male aggregation called ‘Lekking’. This behavior can be seen in many species and though it is believed to help improve reproduction, studies are still ongoing as to how these insects do this and how it evolved into what it is now. This particular species of crane flies are in danger of losing their natural habitat in the forest due to climate change and their absence is affecting the balance of our ecosystem. Researchers and conservationists are currently figuring out how to save them from disappearing.

This is a picture of a cochlea I dissected and labelled by immunohistochemistry. After that the cochlea was clarified and the picture was taken with a Light-sheet microscope. The inner ear shelters the cochlea, a spiral of cells whose role is to capture the air vibration through the hair cells (labelled in red). These unique cells convert sounds into electrical signals that are relayed to the brain via the neuronal fibers (labelled in green). All the other cell nuclei are labelled in blue. I consider myself lucky to be able to work on such a beautiful and complex structure, which has yet to be fully understood.

I live on a farm and I work with plants. Part of the farm has a small Andean forest that borders a hydrangea crop. On the edge of the forest I found a “gallina ciega” possibly of the species Caprimulgus sp. This bird is nocturnal. When we found it, we were surprised by its ability to blend into the vegetation, especially on the trunk of a tree. Every day we saw the bird on the same trunk, but only after a while we saw that the bird was with its chick. During the day the mother and the chick remain quiet; it seems that they enter into a state of meditation, which makes it very difficult to see them.

Climbing is in the spirit of athletes, to conquer difficulties and limitations. Climbing is in the spirit of scientists, to fulfill  impossible missions. Climbing is also in the spirit of a little ant, to see the views from the top of the plant. An ant was climbing on a flower towards its top end when I took this photo. I had been waiting for 27 minutes before this fleeting moment, when the ant stood still for a second. I think this is the attitude of research; be patient and be determined.

Microorganisms (bacteria, archaea, microeukaryotes) in marine environments secrete a diverse array of exopolymeric substances (EPS) which may be involved in microbial adhesion to solid surfaces and biofilm formation. EPS has also been shown to be involved in emulsification of hydrocarbon oils to enhance biodegradation, mediating the fate and mobility of heavy metals and trace metal nutrients, or interacting with dissolved and/or particulate organic matter. An important role of EPS is in forming marine snow—floating or suspended particles that harbor a community of microorganisms and drive the biological pump.

EPS also plays a key role in marine oil snow (MOS) that forms as a consequence of oil spillage. This image shows the formation of MOS by bacteria that were enriched on the sea surface of the Gulf of Mexico during the Deepwater Horizon oil spill. It shows the MOS particles (blue and white) viewed under the light microscope amongst a sea of oil droplets (brown spheres), of which many were observed embedded within the amorphous matrix of the MOS.

Starfish or Sea Stars are echinoderms that have the ability to regenerate any part of their body. These creatures are excellent model systems to study regeneration, and scientists have found sea star regeneration genes closely related to genes found in homo sapiens. They believe that these unique species contain clues to uncovering potential pathways of regeneration. Additionally, these creatures have developed a powerful foot glue that allows their 15,000 tiny tube feet as seen in the picture to bond indefinitely to any object that they come across. Researchers are currently trying to unravel the proteins that form these adhesives with unique underwater properties.

The image is a collage of photographs of colonic-forming endothelial cells (ECFCs) isolated from peripheral blood of patients undergoing cardiovascular surgery. The photographs were taken on a mobile phone, using a phase contrast optical microscope, 20x objective. The image aims to show how the cells, although they are of the same cell type, vary in morphology; some are more round, others more elongated, some more confluent than others. As these are cells from different people, the image is a microscopic demonstration of how diverse organisms of the same species can be. The objective of this collage is therefore to recognize diversity, as an essential aspect of our existence.

Frontal face of a jumping spider (Salticidae). Jumping spiders have well developed eyes and can actually form images.

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One Comment

Most extraordinary images. Very inspirational.

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• Latest Posts

Davy Falkner

Latest posts by davy falkner ( see all ).

• BMC ‘Research in progress’ photo competition 2018: winning images - 14th December 2018
• BMC ‘Research in progress’ photo competition – one week to go! - 9th November 2018
• I Heart Research: We speak to the winner of last year’s ‘Research in progress’ photo competition - 7th November 2018

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