Cutaneous melanoma accounts for more than 70% of all skin cancer deaths. Follow-up surveillance is an integral part of melanoma patient care, to facilitate early detection of recurrences and subsequent primary melanomas. The purpose of this scoping review is to provide an overview of recently published melanoma surveillance guidelines from regional and national melanoma working groups.A systematic search for relevant studies in MEDLINE and Embase was conducted in September 2022 and was limited to publications from 2010 or later.A total of 1047 articles were retrieved, and after abstract and full text review, 26 articles from 19 different organizations met inclusion criteria. Life-long annual skin surveillance with a physician was recommended by 53% (9/17) of guidelines. Routine laboratory investigations were recommended by 7/19 guidelines. Regional lymph node ultrasound was recommended by 9/16 guidelines, most often in stage IB or higher, and was optional in 7/16 for patients who met specific criteria. Surveillance with PET-CT or CT and MRI was recommended by 15 and 11 guidelines, respectively, most commonly in stage IIC or higher, with a variable frequency and total duration. Five out of 9 guidelines indicated a preference for skin surveillance to be completed with a dermatologist.Guidelines were highly variable for many aspects of melanoma surveillance, which may be partly attributed to regional differences in healthcare workforce distribution and availability of imaging technologies. Further high-level studies are recommended to provide more evidence on the most effective clinical and imaging follow-up surveillance protocols. More than 70% of all deaths from skin cancer can be attributed to melanoma, due to its high metastatic potential. In recent decades, there has been an increase in the incidence and prevalence rates of malignant melanoma in developed countries. As a result of both genetic and environmental risk factors, individuals with a previous history of melanoma are at risk for developing subsequent primary melanomas.Cutaneous melanoma accounts for 5.2% of all new cancer diagnoses. With the development of new therapies to treat metastatic melanoma, it is possible that survival rates for metastatic melanoma may improve, especially if metastases are detected at an early stage. Complete surgical resection of oligometastases has also demonstrated a survival benefit but is typically limited to patients with isolated disease.Additionally, individuals with melanoma are at risk for developing recurrences after definitive management of the primary cutaneous tumor, which includes metastases to distant organs. Distant metastases have a significant adverse impact on melanoma survival rates.To help facilitate early detection of recurrences and subsequent primary melanomas, individuals with cutaneous melanoma are recommended to undergo clinical follow-up and, in some cases, routine surveillance imaging, in the years following the initial melanoma diagnosis. However, limited high-quality studies have been conducted to investigate the use of follow-up surveillance in melanoma patients. Additionally, the delivery of follow-up care may be impacted by regional availability of healthcare resources, including specialist physician care and surveillance imaging modalities. The purpose of this review is to provide an overview of recent international guidelines on follow-up care of melanoma patients and an analysis of the supporting evidence for surveillance recommendations.A database search for relevant studies in MEDLINE and Embase was conducted on September 10, 2022 using the following MeSH keywords: (‘melanoma’) AND (‘follow-up’ OR ‘surveillance’) AND (‘guidelines’ OR ‘recommendations’). A manual search of reference lists of included studies was performed to ensure all relevant studies were captured. To accurately reflect recent research advancements and current clinical practice, the literature search was limited to articles that were published from January 1, 2010 to September 10, 2022. Title, abstract, and full-text screening was completed in duplicate by two reviewers (L.J. and S.S.).National and international guidelines that contained recommendations on melanoma follow-up surveillance were eligible for inclusion. Guidelines were required to contain recommendations on at least one of either (i) clinical follow-up or (ii) surveillance investigations. If multiple versions of a guideline publication were published by a particular melanoma expert group, only the most recent publication was included in the review.Articles were excluded if the primary focus was not cutaneous melanoma. Additionally, publications which focused on staging or re-staging of symptomatic recurrent disease or monitoring of response to treatment were also excluded, as the focus of this review is on routine follow-up surveillance.Data extraction was completed by two reviewers (L.J. and S.S.). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist was used as a guide for development of this article.Supplemental Figure 1). Following title and abstract screening, a total of 87 publications underwent full text review and 18 met criteria for inclusion. An additional 8 citations from 3 different organizations  were identified after manual review of the citations in included articles.The MEDLINE and Embase database searches yielded 1047 articles . Countries that were represented by the published guidelines included Australia, Brazil, Canada, Croatia, France, Germany, Italy, New Zealand, Poland, Spain, Switzerland, the United Kingdom, and the United States. Multinational European guidelines were also included.Nineteen different national clinical practice guidelines were referenced from the 26 articles that met the inclusion criteria . Specific sun safety recommendations included variations of the following: (i) minimizing sun exposure during peak daylight hours, (ii) wearing sun-protective clothing, sunglasses, and a wide-brimmed hat, and (iii) applying broad-spectrum ultraviolet (UV) sunscreen regularly to sun-exposed skin when outdoors.Patient education on sun safety was discussed and recommended by 14 clinical practice guidelines . All 17 guidelines recommended that patients routinely complete self-exams. Individual recommendations varied amongst guidelines, but the following were frequently occurring instructions for patients: examination of the entire skin surface, examination of the surgical scar, and/or palpation of the regional lymph node basins. In the five guidelines that recommended a specific frequency of self-skin exams, the recommended frequency varied from once monthly to annually.Self-skin examination was discussed by 17 guidelines .The American Joint Committee on Cancer (AJCC) staging system for melanoma was used in all 19 clinical practice guideline publications. The seventh edition of the AJCC melanoma staging guidelines was published in 2009 and was used in 10 guidelines.Supplemental Table 2). The Brazilian Society of Dermatology guidelines only proposed recommendations for stage 0-II and did not provide surveillance guidelines for more advanced stages.Most guidelines (18/19) provided a definition for the high-risk category of melanoma patients based on AJCC stage. The most frequent definition of a high-risk surveillance group began at stage IIB (8/19 guidelines), while 7 guidelines selected stage IIC and 3 guidelines chose stage III as the earliest stages included in high-risk surveillance schedules . The recommendations for clinical surveillance can be stratified into two main categories: (i) life-long surveillance and (ii) fixed-duration surveillance. The most common recommendation was life-long surveillance at an annual frequency, which was recommended by 53% (9/17) of the guidelines. Fixed duration of clinical surveillance following a patient’s initial diagnosis or most recent change in AJCC staging was recommended by 47% (8/17) of the guidelines. Of these 8 guidelines, 4 recommended that routine clinical surveillance occur for a maximum time period of 10 years. The Canadian Melanoma Conference guidelines focused exclusively on surveillance in high-risk (stage IIB-IV) patients and recommended clinical surveillance for 5 years. Three guidelines recommended a stage-dependent, variable fixed-duration schedule. The Network of Catalan and Balearic Melanoma Centers recommended that follow-up occur for a duration of 3-5 years in melanoma in situ, while stage IB-IV melanoma patients should undergo follow-up for 10 years. Two guidelines from organizations in the United Kingdom, the National Institute for Health and Care Excellence and the British Association of Dermatology, recommended that patients with melanoma in situ may be discharged after post-surgical follow-up and do not require ongoing surveillance, while patients with advanced AJCC stages should be followed for up to 5 and 10 years, respectively.Seventeen guidelines provided recommendations for the total duration of skin surveillance with a healthcare provider . New Zealand’s National Melanoma Working Group and the European Society of Medical Oncology guidelines were not included in the tables. The National Melanoma Working Group guidelines focus exclusively on surveillance imaging and did not discuss healthcare provider-led clinical examination and the European Society of Medical Oncology guidelines did not present a specific timeline for clinical follow-up.Recommendations for clinical follow-up schedules are provided in 17 of the 19 guidelines . Each guideline stratified follow-up groups into low risk, intermediate risk and/or high-risk categories based on AJCC stage, with more frequent follow-up recommended in more advanced stages. Additionally, 16/17 guidelines recommended more frequent follow-up during the initial years of the total follow-up period. The period of more intensive surveillance occurred during the first 1-5 years after initial diagnosis, definitive management, or re-staging after disease progression. This was followed by a period of less frequent surveillance, then either stopping routine clinical surveillance completely or reducing the frequency to an annual, life-long schedule. The CMC guidelines were the only guidelines that recommended a fixed frequency of follow-up for the full duration of the surveillance period, with 6-monthly visits scheduled for the entire 5-year period of clinical surveillance.In the 17 guidelines that contained clinical follow-up recommendations, all guidelines recommended a stage-specific approach to determining the frequency of follow-up . Out of these 9 guidelines, 6 indicated a preference for one or two types of specialists, while 3 guidelines suggested multiple different disciplines that could oversee follow-up care. Five guidelines indicated that having clinical skin examinations with a dermatologist is preferrable and one guideline stated that clinical skin surveillance should be completed with either a dermatologist or a primary care physician. In the three guidelines that did not prefer a particular discipline to oversee follow-up, dermatologists, general practitioners, medical oncologists, and surgeons were listed as potential candidates.Nine guidelines included recommendations for the medical disciplines and experience of providers who should be involved in the clinical follow-up care of melanoma patients . The Cancer Council Australia guidelines recommended that follow-up skin surveillance with a provider who has experience in skin examination would be preferrable. The European Dermatology Forum, European Association of Dermato-Oncology and European Organization for Research and Treatment of Cancer guidelines preferred follow-up with a dermatologist due to their focused clinical training on skin examination and dermoscopy. However, as some European countries may have a limited number of practicing dermatologists, follow-up with a general practitioner that has completed additional training in dermoscopy is a suitable alternative.Six guidelines discussed expertise in dermoscopy as an important skill for skin surveillance providers to offer to their melanoma patients , chest x-ray (CXR), positron emission tomography with computed tomography (PET-CT), conventional CT with contrast, and brain magnetic resonance imaging (MRI).Specific recommendations on follow-up imaging are outlined in Supplemental Table 4). Of the guidelines which indicated that lymph node US is optional, 6 guidelines stated that lymph node US should be performed in patients who either did not undergo a sentinel lymph node biopsy (SLNB) as recommended or in individuals with a known positive SLNB who did not undergo a complete lymph node dissection. Fifteen guidelines recommended a specific stage to start regional lymph node US. Eight guidelines suggested stage IB as the earliest stage to perform regional lymph node US. The remaining 7 guidelines recommended starting lymph node US at stage IA (n=1), IIA (n=1), IIB (n=1), IIC (n=2), and III (n=2).Regional lymph node US was discussed by 16 guidelines, recommended by 9 and listed as optional by 7 guidelines . The National Institute for Health and Care Excellence guidelines did not recommend specific imaging modalities but stated that imaging may occur at stage IIC or higher. Of the 17 guidelines that recommended imaging at a particular stage, 7 recommended IIC as the earliest AJCC stage to incorporate imaging into follow-up surveillance. Six guidelines recommended starting surveillance at stage IIB, one recommended stage II and two recommended stage III. The Cancer Council Australia guidelines suggested that follow-up imaging may be useful in patients with stage IIC or higher disease, but the potential for change in management based on findings should be taken into consideration when determining whether to incorporate PET-CT or CT imaging into a surveillance plan.PET-CT or CT for follow-up surveillance was recommended by 15 of the 19 clinical practice guidelines , due a higher sensitivity and specificity of PET-CT for detection of distant metastases. CT was preferred by 6 publications and one publication suggested that either PET-CT or CT may be performed, without a statement indicating a preference for either test. Limited regional accessibility of PET-CT and higher cost compared to conventional CT were listed as reasons for recommending CT over PET.Supplemental Table 4). The frequency of imaging was variable, ranging from every 3 months to every 12 months. Eight guidelines recommended a fixed frequency of imaging throughout the full surveillance period, while 6 guidelines recommended more frequent imaging in the first few years of surveillance, followed by a period of reduced frequency of surveillance until the end of the imaging surveillance period. Four guidelines recommended stage-adjusted frequencies, with less frequent imaging in earlier stages and more frequent imaging in the most advanced stages.The total duration of routine PET-CT or CT imaging ranged from 3 to 5 years in 14 guidelines . Two guidelines listed brain MRI as an optional investigation and six guidelines did not discuss brain MRI. Six guidelines suggested that brain MRI should be performed in patients with stage IIC or higher disease, while 5 guidelines suggested starting MRI surveillance at stage IIB. The recommended total duration of MRI surveillance ranged from 3 to 5 years. The frequency of MRI ranged from 3-monthly to 12-monthly intervals. Most guidelines recommended a fixed frequency of imaging throughout the surveillance period. Two guidelines recommended a higher initial frequency of imaging, followed by a period of reduced frequency surveillance prior to the end of the imaging surveillance period.Eleven guidelines recommended the use of brain MRI for surveillance of cerebral metastases . Three publications indicated that laboratory investigations were optional and 3 guidelines did not discuss the use of laboratory investigations in follow-up care. In the guidelines that recommended specific laboratory investigations or listed them as optional, S100B and lactate dehydrogenase (LDH) were listed as potential surveillance tests.Laboratory investigations were recommended for follow-up surveillance by 7/19 publications and were recommended against by 6 guidelines  have not been conducted to investigate the optimal frequency of self-examinations in patients with melanoma.Educating patients on both the importance of self-skin examination and how to perform self-examinations was emphasized by most clinical practice guidelines. Previous studies on self-skin examinations have found that regular self-skin examinations may lead to earlier detection of melanoma and reduced mortality. Overall, less than 5% of melanoma recurrences occur beyond 5 years after definitive management. However, several studies have suggested that there is an elevated risk of subsequent primary melanomas that persists beyond 10 years after the initial melanoma diagnosis. Therefore, combining time-limited clinical follow up with life-long self-skin examination could be a reasonable approach.Recommendations for clinical follow-up were highly variable. Recent studies have found that the peak incidence rates of melanoma recurrences and subsequent primary melanomas occur during the first 2-3 years after a melanoma diagnosis. In stage II melanoma, the reduced-frequency MELFO follow-up schedule recommends a higher intensity surveillance period consisting of 2-3 visits per year for the first 2 years, followed by 1-2 visits per year in year 3 and then annual visits in years 4-5.The frequency of clinical surveillance varied amongst guidelines. All guidelines recommended a stage-specific approach to follow-up schedules, with follow-up frequencies ranging from every 3 months to annually. The 2016 melanoma follow-up (MELFO) trial in Australia investigated follow-up frequencies in stage IB-IIC melanoma patients and found that there were no differences in detection of recurrences with a reduced frequency, stage-specific follow-up schedule compared to higher frequency surveillance schedules. In the context of the small number of dermatologists in Canada, GP-led follow-up, especially in low-risk melanomas, could be a sustainable approach.The guidelines did not indicate a strong preference for the specialties of healthcare providers who should oversee follow-up care. However, routine surveillance with a provider who has dermoscopy training and experience with conducting skin examinations was consistently recommended. A previous study that compared general practitioner (GP)-based follow-up in Scotland to specialist follow-up at a tertiary care center found that with brief additional training in skin surveillance, GP-led follow-up had similar health outcomes and high patient satisfaction ratings. In this review, 9/16 guidelines recommended routine lymph node US and 7/16 studies listed US as an optional imaging modality or suggested routine use only in individuals who did not undergo SLNB or complete lymph node dissection after a positive SLNB. Evidence regarding the utility of regional lymph node ultrasonography in routine surveillance of early-stage disease is inconclusive. A cohort study of 1149 stage IB and IIA melanoma patients found that there was no survival benefit of routine ultrasonography. However, the risk of lymph node metastases is higher in patients with more advanced disease and routine ultrasonography may be beneficial in patients with stage IIB or higher disease. A 2011 study by Krüger et al. found that in a cohort of 433 patients who were predominantly in stages II-IV, 67% (22/33) of lymph node recurrences were detected by ultrasonography in the absence of clinical suspicion. Bartlett et al. found that regional lymph node ultrasonography every 3-4 months in SLNB-positive patients was useful in identifying recurrences at a surgically resectable stage in the 13.0% of patients who experienced recurrence.Lymph node ultrasonography is the preferred surveillance test for regional lymph nodes. Previous studies have found that lymph node US is superior to clinical examination for detection of lymph node metastases and it has a sensitivity of 96% and a specificity of 99%. Most guidelines indicated that surveillance imaging should start at either stage IIB or IIC. Patients with stage 0-IIA melanoma are more likely to develop locoregional metastases than distant metastases, which are more frequently detected by self-exam or physician-led physical examination. Conversely, multiple studies have found that stage IIB and IIC patients have much higher rates of distant recurrences and detection of these recurrences by imaging. Approximately half of all patients with stage IIB, IIC and III melanoma had recurrences detected by surveillance PET-CT or CT in previous studies. A 2011 systematic review found that the sensitivity and specificity of PET-CT (86% and 91%) was significantly higher than conventional contrast-enhanced CT (63% and 78%) of the chest, abdomen and pelvis and PET alone (82% and 83%). However, CT-CAP may still be an acceptable choice in geographic regions with limited access to PET-CT and this was cited as a reason for recommending CT-CAP over PET-CT by some guidelines. CXR was shown to be inferior for detection of pulmonary metastases compared to CT in a previous prospective cohort study and was not recommended by most clinical practice guidelines. For screening to rule out potential brain metastases, MRI is the preferred imaging modality, as it has a higher resolution and can detect smaller metastases than CT and PET-CT.The use of PET-CT, conventional CT-CAP and/or MRI was discussed and recommended by most guidelines. Imaging surveillance was not recommended in patients with stage 0-IIA melanoma, as detection rates of distant recurrences by imaging tend to be lower than the false positive rates. One study estimated that 46% of patients had at least one false-positive result over a 5-year period with PET-CT or CT imaging every 6-12 months. A significant portion of patients with false positive imaging results subsequently undergo unnecessary diagnostic imaging and invasive surgical procedures. The potential benefits of early detection of recurrences must be balanced with the potential harms of unnecessary interventions and additional stress that may result from imaging surveillance. Additionally, high-quality evidence that supports a survival benefit from routine surveillance imaging is lacking in the current literature. However, with new emerging systemic therapies for metastatic melanoma, the survival benefits of surveillance imaging may become more evident.One potential concern with the use of routine surveillance imaging is the high rate of false positive test results. The false positive rate for PET-CT has been estimated to be between 7-14% and for conventional CT, the rate is up to 20%. However, S100B is also expressed by many different cell lineages and elevations have been associated with numerous other pathological states, including myocardial infarction, liver cirrhosis and chronic kidney disease. In one study that followed 1113 stage IB-IV melanoma patients over 2 years, 16% had false-negative and 12% had false-positive S100B results. The sensitivity and specificity of S100B were 55% and 88%, respectively. LDH is also used as a biomarker in melanoma staging to predict prognosis, but a previous study found that LDH had a low sensitivity for detecting new metastases during follow-up surveillance. Both S100B and LDH are unable to detect locoregional metastases and may not be useful in patients with early-stage disease.Guidelines on the use of routine laboratory testing differed substantially, with 63% (10/16) of guidelines recommending against routine use of laboratory tests for surveillance. Of the guidelines that recommended specific laboratory tests or listed optional tests, S100B and LDH were most frequently included. Serum S100B is secreted by human melanoma cells and elevated levels may indicate disease progression, presence of metastases and reduced survival odds. In a 2016 prospective cohort study that followed stage IIB, IIC and III melanoma patients for a median of 2.5 years, only 2.5% of patients had increased serum S100B or melanoma inhibitory activity protein as the first sign of metastasis.The role of serum laboratory testing in melanoma follow-up surveillance must be considered in the context of other surveillance modalities. Laboratory tests are often not the first sign of metastasis and more definitive radiologic imaging is needed to definitively determine if distant metastases are present.Overall, the quality of supporting evidence for many follow-up surveillance recommendations was limited, especially for surveillance imaging, due to a lack of RCTs that have been conducted on follow-up surveillance schedules. This was a major limitation that likely led to the significant differences in recommendations that were observed amongst the included studies in this review. Further study in RCTs is needed to investigate the utility of surveillance imaging in the follow-up care of melanoma patients. Another limitation in this review was the diversity of approaches within the 19 included guidelines with respect to evaluating the supporting evidence and strength of their recommendations. Six guidelines did not discuss the use of a particular evidence appraisal scheme and did not provide levels of evidence or evidence grading. Of the 13 guidelines that provided an assessment of evidence, different evidence appraisal guidelines were used, making it challenging to provide a quantitative comparison between guidelines. Additionally, most guidelines took both the available supporting evidence and the clinical experience of expert panelists into consideration to develop guidelines with real-world applicability to a particular geographic region. National healthcare systems may differ in terms of access to specialist care and imaging studies and some recommendations from national guidelines may not be applicable to the healthcare systems of other countries.In conclusion, this scoping review of global melanoma follow-up surveillance guidelines has demonstrated that there are significant differences in recommendations from different working groups and geographic regions. Further high-level studies are needed to provide more evidence on the most effective clinical and imaging follow-up surveillance protocols. In addition, careful consideration of disease prevalence, healthcare structure, workforce composition, and resources should be applied when developing guidelines for a specific jurisdiction or geographic location.Click here for additional data file.Supplemental material, Supplementary Material 1, for Surveillance After a Previous Cutaneous Melanoma Diagnosis: A Scoping Review of Melanoma Follow-Up Guidelines by Leah Johnston, Samantha Starkey, Ilya Mukovozov, Lynne Robertson, Teresa Petrella and Raed Alhusayen in Journal of Cutaneous Medicine and SurgeryClick here for additional data file.Supplemental material, Figure S1, for Surveillance After a Previous Cutaneous Melanoma Diagnosis: A Scoping Review of Melanoma Follow-Up Guidelines by Leah Johnston, Samantha Starkey, Ilya Mukovozov, Lynne Robertson, Teresa Petrella and Raed Alhusayen in Journal of Cutaneous Medicine and Surgery


The mechanisms underlying alcohol-induced breast carcinogenesis are not fully understood but may involve hormonal changes.ADH1B (Alcohol Dehydrogenase 1B) variant (rs1229984).We investigated cross-sectional associations between self-reported alcohol intake and serum or plasma concentrations of oestradiol, oestrone, progesterone , testosterone, androstenedione, DHEAS (dehydroepiandrosterone sulphate) and SHBG (sex hormone binding globulin) in 45 431 pre-menopausal and 173 476 post-menopausal women. We performed multivariable linear regression separately for UK Biobank, EPIC (European Prospective Investigation into Cancer and Nutrition) and EHBCCG (Endogenous Hormones and Breast Cancer Collaborative Group), and meta-analysed the results. For testosterone and SHBG, we also conducted two-sample Mendelian Randomization (MR) and colocalisation using the ADH1B between alcohol intake and higher free testosterone and lower SHBG (PP4: 0.81 and 0.97 respectively).Alcohol intake was positively, though weakly, associated with all hormones , with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal oestradiol to 6.6% for post-menopausal DHEAS. There was an inverse association of alcohol with SHBG in post-menopausal women but a small positive association in pre-menopausal women. MR identified positive associations of alcohol intake with total testosterone  and free testosterone , and an inverse association with SHBG . Colocalisation suggested a shared causal locus at Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk. Alcoholic beverages are commonly consumed in many populations and are known to be causally associated with increased risk of several diseases including breast cancer , 2. The Earlier intervention studies have reported an acute increase in serum/plasma concentrations of oestrogens and/or androgens within hours after intake of alcohol –8 in preIn the study reported here, we combined data from 14 cohort studies and conducted cross-sectional analyses to provide the most comprehensive evidence to date on the associations of usual alcohol intake with serum or plasma concentrations of oestradiol, oestrone, testosterone, androstenedione, dehydroepiandrosterone sulphate (DHEAS) and SHBG in pre- and post-menopausal women, and with progesterone in premenopausal women only. To examine the potential causal associations with testosterone and SHBG, we also conducted two-sample Mendelian Randomization (MR) and colocalisation analyses.Data from the UK Biobank, EPIC (European Prospective Investigation into Cancer and Nutrition) and 12 other studies included in the EHBCCG (Endogenous Hormones and Breast Cancer Collaborative Group) consortium were used.This is a prospective cohort study involving about 500 000 adults, including over 270 000 women, aged 40–69 years when recruited between 2006 and 2010. At the initial assessment visit, usual alcohol intake was assessed using a touchscreen questionnaire, and blood samples were collected from which serum was prepared and concentrations of hormones and SHBG were measured using chemiluminescent immunoassays. The current analysis included pre-menopausal women, who reported they had not had their menopause , and were younger than 50 years of age, and post-menopausal women, who reported they had gone through menopause, or were 55 years or older, or reported a bilateral oophorectomy; those who had a prior history of cancer ((except for non-melanoma skin cancer) or reported currently using hormone therapy (hormone replacement therapy (HRT) and/or oral contraceptives (OCs)) were excluded. Detailed information on the study design and methodology , calculaThis is a prospective cohort study involving about 520 000 adults, including over 360 000 women, aged 25–70 years when recruited from 23 centres across 10 European countries between 1992 and 2000. Diet, including usual alcohol intake, was measured by country-specific questionnaires that were validated against reference measurements based on twelve 24-hour diet recall interviews . Blood sThe EPIC study data for breast cancer were included in the EHBCCG but the EPIC data were analysed separately here because, since the publication of the collaborative analyses, more nested case-control studies of other cancer sites have been conducted and hormone assay data are now available for a larger sample of women.Of the seven prospective studies of pre-menopausal women included in the collaborative analysis, three wiDetails of the individual studies included in this analysis are presented in the Supplementary Materials. These include: references for component studies within EPIC and EHBCCG (Supplementary Table S1), number of women who contributed to each hormone analysis (Supplementary Table S2), measurement of usual alcohol intake (Supplementary Table S3), and blood sample (serum vs. plasma), type of assay and coeffcients of variation for the measured hormones and SHBG (Supplementary Table S4). In all studies, concentrations of free oestradiol and testosterone were calculated from those of total oestradiol and testosterone respectively and of SHBG, assuming that the binding of these hormones to serum SHBG and albumin follows the law of mass action . As albuAnalyses were undertaken separately for pre- and post-menopausal women in UK Biobank, EPIC and EHBCCG. STATA 17  was used for all analyses.Hormone concentrations were logarithmically transformed. In pre-menopausal women, concentrations were standardised for phase of the menstrual cycle  with residuals from the mean for each cycle phase. The cycle phase was determined using forward dating (UK Biobank ), or bot2, 22.5–24.9 kg/m2, 25–27.4 kg/m2, 27.5–29.9 kg/m2, 30–34.9 kg/m2, ≥ 35 kg/m2), number of full-term pregnancies , past use of hormone therapy , age at menopause  and menopausal type . The study-specific results were then pooled using fixed-effect meta-analysis. Potential differences in the estimates by menopausal status were assessed using the Chi-square test for heterogeneity.For each study, hormone concentrations and 95% confidence intervals (CIs) per 10 g/day (approximately one standard drink/day) increment in alcohol intake were estimated using multivariable linear regression models, adjusting for individual component studies (EPIC and EHBCCG), case-control status (EPIC and EHBCCG), age at blood collection , previous alcohol use among non-current drinkers (UK Biobank and EPIC), smoking , body mass index (BMI) . In both pre- and post-menopausal women, subgroup analyses were undertaken for total oestradiol, oestrone and total testosterone by type of the assay used ; the individual studies that contributed to each assay type are presented in Supplementary Table S5. Sensitivity analyses were undertaken by restricting the sample to those who reported alcohol intake of < 15 g/day, to those who reported intake of < 30 g/day (i.e. excluding heavy drinkers), and also to those whose blood samples were collected during an ovulatory cycle  .ADH1B (Alcohol Dehydrogenase 1B) gene (rs1229984) for self-reported alcohol intake (number of drinks per week) was extracted from a GWAS (genome-wide association study) meta-analysis undertaken by the GWAS and Sequencing Consortium of Alcohol and Nicotine Use (GSCAN) [ADH1B that oxidises ethanol to acetaldehyde, resulting in unpleasant reactions and limiting further drinking [n = 226 223) to avoid sample overlap between the GWAS for alcohol intake and that for hormone concentrations. The ADH1B variant explains 0.19% of the variance in alcohol intake.A genetic instrument in the  (GSCAN) . This vagene rs12984 for sdrinking . While tdrinking . EstimatSummary statistics for the association of rs1229984 with SD increments in the concentrations of hormones and SHBG were obtained from a publicly available GWAS of all women, irrespective of menopausal status, from the UK Biobank, extracted from the OpenGWAS platform  dataset; data onMR assesses the associations between exposure(s) and outcome(s) using genetic variants associated with the exposure of interest as instrumental variables. A Wald ratio was calculated using the “TwoSampleMR”  package ADH1B variant, colocalisation analyses were conducted to identify the presence of a shared causal locus between alcohol intake and concentrations of testosterone and SHBG where a conventionally significant association was observed in MR analyses. The “coloc” package [−3, p2 = 10−4, and p12 = 10−5, or approximately a 75% prior belief that a signal will only be observed in the GSCAN GWAS and < 0.01% prior belief in favour of colocalisation between the two traits at a given locus [Colocalisation assesses the probability that two traits are affected by the same genetic variants at a given locus. Using the  package  in R was package . Priors en locus .In total, 45 431 pre-menopausal  and 173 476 post-menopausal  women were included in this analysis. heterogeneity by menopausal status = 0.04 for total oestradiol and 0.0002 for calculated free oestradiol). The concentrations were 2.2%  and 3.8%  higher, respectively, per 10 g/day increment in alcohol intake (approximately one drink/day) in post-menopausal women .Alcohol intake was positively associated with testosterone concentrations in both pre- and post-menopausal women . Per 10 Similarly, alcohol intake was positively associated with concentrations of androstenedione and DHEAS in both pre- and post-menopausal women . Per 10 heterogeneity<0.0001; Alcohol intake was positively associated with SHBG concentration in pre-menopausal women but inversely associated in post-menopausal women  in the follicular phase but positively associated  in the luteal phase , to those who reported intake of < 30 g/day (data not shown), or to samples collected during ovulatory cycles (data not shown).Effect estimates for the association of rs1229984 with alcohol intake and with concentrations of testosterone and SHBG are presented in Supplementary Table S6.ADH1B  and free testosterone , and lower concentration of SHBG  . ColocalIn this meta-analysis involving over 45 000 pre-menopausal and 173 000 post-menopausal women, we found positive associations of alcohol intake with concentrations of sex hormones. We also found an inverse association with SHBG in post-menopausal women and some evidence of a small positive association in pre-menopausal women. The genetic analyses supported potential causal associations of alcohol intake with higher free testosterone and lower SHBG.Alcohol may influence oestrogen concentrations by altering its metabolism and clearance , or by aOur observational analyses showed positive associations of alcohol with oestrone in both pre- and post-menopausal women and with oestradiol in post-menopausal women. Although the overall association with oestradiol in pre-menopausal women was not significant, we found a weak inverse association in the follicular phase and a weak positive association in the luteal phase. In contrast, in an earlier cross-over trial, daily alcohol intake for three consecutive menstrual cycles significantly increased plasma concentrations of ovulatory oestradiol but not follicular or luteal oestradiol .The less conclusive findings observed for oestradiol in pre-menopausal women may be related to the challenges in measuring this hormone reliably; measurement based on a single serum sample may not reflect its long-term average as the hormone level varies substantially across the menstrual cycle. We standardised oestradiol concentrations for phase of the menstrual cycle in the observational analyses, but this may not be sufficient to account for all the variation . MoreoveAlcohol might influence progesterone concentration by altering its metabolism in the liver , 10, butAlcohol may influence androgen concentrations by altering their secretion from the ovaries and/or adrenal glands, or their metabolism in the liver . PreviouIn this meta-analysis, we found positive associations of alcohol with testosterone, androstenedione and DHEAS in both pre- and post-menopausal women. The association with testosterone seemed to be of greater magnitude in pre-menopausal women even after restricting to those with intake of < 15 g/day, which might be due to biological differences or possibly due to differences in the accuracy of self-reported alcohol intake by menopausal status. The associations with androstenedione and DHEAS did not differ by menopausal status.ADH1B locus with free but not total testosterone. This raises the question as to whether or not alcohol has a direct causal effect on testosterone concentration, because the strong association with free testosterone could be related to the inverse association of alcohol intake with SHBG concentrations as discussed below.In the MR analyses, genetically predicted alcohol intake was positively associated with testosterone concentrations, with a larger effect on free testosterone compared to total testosterone. We observed strong colocalisation for alcohol intake at the Alcohol may influence SHBG concentrations by affecting hormonal balance , cytokinADH1B locus identified an inverse association, which is consistent with our observational findings because the GWAS for SHBG was conducted in the UK Biobank where the majority of women were post-menopausal. As SHBG binds testosterone to a greater degree than oestradiol, any reduction in SHBG caused by alcohol would be expected to have a bigger effect in increasing the bioavailable fraction of testosterone than oestradiol as observed in our analyses.Similarly in this meta-analysis, we found an inverse association of alcohol intake with SHBG in post-menopausal women and some evidence of a small positive association in pre-menopausal women; the latter was driven by the results from UK Biobank with no association in the other datasets, therefore this observation should be interpreted cautiously. The MR and colocalisation analyses at the Alcohol has been associated with an increased risk of several cancers, including female breast cancer , 44. In To our knowledge, this is the largest study on this topic. Our meta-analysis involved over 45 000 pre-menopausal and 173 000 post-menopausal women, enabling us to undertake important subgroup analyses by menopausal status, cycle phase in pre-menopausal women and assay type. We additionally conducted MR and colocalisation analyses to support the observational results where possible.Our main exposure, alcohol intake, was self-reported. While self-reported measures of alcohol intake may have reasonable levels of reliability and validity , underreOur meta-analysis confirmed positive associations of alcohol intake with sex hormones, including the more bioavailable fractions. There was also an inverse association with SHBG in post-menopausal women and some evidence of a small positive association in pre-menopausal women. Genetic analyses supported potential causal overall associations with higher free testosterone and lower SHBG. These associations are likely to contribute to the effect of alcohol on breast cancer risk.


Eating disorders, such as binge eating disorder, are commonly associated with difficulties with emotion regulation and mental-health complications. However, the relationship between eating-disorder symptoms, difficulties with emotion regulation, and mental health in people with binge eating disorder is unclear. Thus, we investigated associations between eating-disorder symptoms, difficulties with emotion regulation, and mental health in 119 adults with binge eating disorder. Participants were assessed with the Eating Disorder Examination Questionnaire, Loss of Control over Eating Scale, Difficulties in Emotion Regulation Scale, Depression Anxiety and Stress Scale, and the 12-Item Short Form Survey at the pre-treatment phase of a randomized controlled trial. Structural-equation-modelling path analysis was used to investigate relationships between variables. We found that (1) eating-disorder behaviors had a direct association with depression, anxiety, and stress; (2) depression, psychological stress, difficulties with emotion regulation, and eating-disorder psychopathology had a direct association with mental-health-related quality of life; and (3) eating-disorder psychopathology/behaviors and stress had a direct association with difficulties with emotion regulation. Our findings show that depression, stress, difficulties with emotion regulation, and eating-disorder psychopathology were related in important ways to mental-health complications in people with binge eating disorder. Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) by recurrent binge-eating episodes that have occurred at least once a week for the past three months [DSM-5 criteria for BED also require that people experience at least three of the following five features: (1) eating much more quickly than normal; (2) eating until feeling excessively full; (3) overeating when not feeling physically hungry; (4) eating alone because of embarrassment related to the amount of food consumed; and (5) feeling disgusted, depressed or very guilty after binging, and reported marked distress with the binge eating [Binge eating disorder (BED) is an eating disorder characterized in the e months . Binge-ee months . The DSMeatures:  eating mPeople with BED commonly experience comorbid mental-health problems. For instance, a systematic review found that BED is significantly associated with depression , and anoIn addition to poor mental health, people with eating disorders can experience difficulties with emotion regulation. Effective emotion regulation is the awareness, understanding, and acceptance of emotions, modulation of emotional arousal, and the ability to act in desired ways regardless of emotional state . EmotionThe existing literature indicates that there is an elevated occurrence of difficulties with emotion-regulation and mental-health problems in people with eating disorders such as BED. However, more research in this field is necessary, as difficulties with emotion regulation can be a risk factor for severe mental-health complications  in people with eating disorders . Thus, i> 18 years; (2) BED, according to the DSM 5 criteria [> 27 and <45 kg/m2; (4) being literate; (5) access to a computer with internet; (6) access to a private room to participate in the online therapy sessions; (7) time available to participate in the whole program; and (8) access to a scale and stadiometer to measure their body weight and height. Exclusion criteria were (1) having bariatric surgery in the previous 24 months; (2) simultaneous participation in another treatment for weight loss or binge eating; (3) clinical conditions that interfere with weight control ; (4) being pregnant; and (5) severe psychiatric disorder  or a high suicide risk.We assessed data from pre-treatment measures of participants of a randomized controlled trial that investigated the efficacy of two different online treatment programs for people with BED and comorbid overweight or obesity . ParticiRecruitment of participants from the general community occurred via advertisements on the University of São Paulo’s social media from August 2020 to June 2022. The advertisement indicated that the research project offered online group therapy for people with BED and comorbid overweight or obesity, and included a link to a survey that could be completed by people that were interested in participating in the randomized controlled trial. This link led to an online screening survey with questions that assessed the inclusion/exclusion criteria, demographic characteristics, and contact information. Potentially eligible participants were invited for a semi-structured clinical interview via videoconference with a member of the research team. The interviewers assessed whether participants met the DSM-5 criteria for BED described in The study was approved by the Research Ethics Committee of the University of São Paulo’s Faculty of Medicine Hospital (CAAE: 19551419.1.0000.0068) in Brazil.A self-report questionnaire was used to collect information on age, sex, race, body weight, height, occupation, marital status, and income.The EDE-Q is a widely used 28-item self-report questionnaire derived from the “gold standard” interview for the assessments of eating disorders, namely the Eating Disorder Examination . The EDEThe experience of loss of control over eating constitutes a clinically significant feature of eating disorders. However, this feature is assessed only in a dichotomous “yes or no” manner in the EDE-Q, and this may lead to imprecise assessments. Therefore, the LOCES was used in the current study to complement assessments from the EDE-Q. The LOCES is a 24-item self-report scale that is used to assess the severity of a core feature of eating disorders, namely the loss of control over eating . Each itThe DERS is a 36-item self-report scale that is widely used to assess clinically relevant difficulties in emotion regulation . The DERThe DASS-21 is a self-report scale with 21 items that is used to assess the magnitude of symptoms of depression (7 items), anxiety (7 items), and psychological stress (7 items) in both clinical and non-clinical samples . Each itThe SF-12 is a reliable measure used to assess mental and physical HRQoL in different population groups . The SF-p < 0.05) bivariate relationship with any of the clinical features were entered into the path model within a structural-equation-modelling (SEM) framework [Firstly, we documented the descriptive data for demographic characteristics  and clinical features ; and categorical variables were presented as percentages. Next, we examined the associations of demographic characteristics with mean scores for all clinical features. We calculated a correlation matrix to explore potential correlations among clinical features. Theoretically relevant indices that showed a significant  for objective binge-eating episodes; 10.5  for subjective binge-eating episodes; 3.75  for eating-disorder psychopathology, 81.9  for loss of control over eating; 100.3  for difficulties with emotion regulation; 15.6  for depression; 10.3  for anxiety; 20.8  for psychological stress; and 32.7  for mental HRQoL see .Association of participant’s demographic characteristics and mean scores for all clinical features are shown in 2(15) = 18.06, p = 0.92; CFI = 1.00, TLI = 1.00, RMSEA < 0.001, and SRMR = 0.04.p < 0.01), eating-disorder psychopathology , psychological stress , and difficulties with emotion regulation  showed significant direct associations with mental HRQoL (p < 0.01) via psychological stress or depression; loss of control over eating  via difficulties with emotion regulation or depression; objective binge-eating episodes  via eating-disorder psychopathology; and subjective binge-eating episodes  via eating-disorder psychopathology or psychological stress.Depression , eating-disorder psychopathology , and loss of control over eating  showed significant direct associations with difficulties with emotion regulation (p < 0.01).Psychological stress , anxiety , psychological stress , and difficulties with emotion regulation  showed significant direct associations with depression (p < 0.01).Loss of control over eating  and loss of control over eating  showed significant direct associations with anxiety.Objective binge-eating episodes  and anxiety  showed significant direct associations with psychological stress.Subjective binge-eating episodes  and subjective binge-eating episodes  showed significant direct associations with eating-disorder psychopathology.Objective binge-eating episodes  and eating-disorder psychopathology  showed significant direct associations with loss of control over eating.Objective binge-eating episodes  objective binge eating had a direct association with anxiety; (2) subjective binge eating had a direct association with psychological stress; (3) loss of control over eating had a direct association with anxiety and depression; and (4) eating-disorder psychopathology had a direct association with mental HRQoL. Moreover, we found that eating-disorder psychopathology and loss of control over eating had a direct association with less effective emotion regulation. Lastly, we found that depression and psychological stress had a direct association with mental HRQoL, and psychological stress had a direct association with less effective emotion regulation.Our study showed that several factors can be associated with poor mental HRQoL in people with BED. Our findings suggest that it is important to address a range of mental-health problems, i.e., depression, psychological stress, difficulties with emotion regulation, and eating-disorder psychopathology, to enhance mental HRQoL in this population. Thus, people with BED may require comprehensive assessment and treatment approaches—rather than treatments focused only on the cessation of binge-eating episodes—to improve their mental health. For instance, it is important that clinicians working with clients with BED assess their clients’ levels of depression, psychological stress, and difficulties with emotion regulation, and provide the required specialized therapies to address these complications when necessary. Clinicians can ask their clients with BED to complete self-report scales such as the DASS-21 and DERS to assess their mental-health status and difficulties with emotion regulation ,24. It mOur findings also enable a better understanding of the occurrence of difficulties with emotion regulation in people with BED. We found that eating-disorder psychopathology, loss of control over eating, and psychological stress had a direct association with less effective emotion regulation in our sample of adults with BED. This finding suggests that a reduction in eating-disorder symptoms through CBT , and redIn addition to direct relationships between eating-disorder symptoms, difficulties with emotion regulation, and mental health in people with BED, we also found significant indirect relationships. These indirect relationships were described in detail in the Results section; nonetheless, here we provide a summary: (1) objective and subjective binge eating, loss of control over eating, and anxiety showed an indirect association with mental-health-related quality of life; (2) eating-disorder psychopathology showed an indirect association with depression; and (3) anxiety showed an indirect association with difficulties with emotion regulation. We found multiple direct and indirect relationships between eating-disorder symptoms, difficulties with emotion regulation, and poor mental health in people with BED. Overall, the relationships that were found in our study provide a better understanding of the complexity of psychopathology associated with BED. However, our findings do not substitute individualized clinical assessments of symptoms of BED and associated mental-health complications. Clinicians working with clients with BED will need to conduct individual assessments of eating-disorder symptoms, difficulties with emotion regulation, and mental-health status, to understand how these factors influence each other in order to plan individualized treatments.Our findings also have implications for research on treatment outcomes for people with BED. A significant number of treatment trials for BED focus on the reduction or abstinence of binge eating as an outcome, and neglect broader aspects of mental health and mental HRQoL . This liThis study has several strengths and limitations. Notable strengths include the use of an advanced statistical analytical approach —to examine complex causal models. Additionally, we included several measures of eating-disorder symptoms  and aspects of mental health  in a sample of adults with BED. The combined use of these different statistical analyses and measures allowed us to examine relationships between eating-disorder symptoms, difficulties with emotion regulation, and mental health, in a comprehensive and reliable manner. The main limitation of our study is that we used a cross-sectional design, and causal inferences cannot be made. Another potential limitation is that 90.8% of the study sample was female. There were no significant differences between males and females in difficulties-with-emotion-regulation scores in our sample; however, our findings may not be generalizable to males with BED or people with BED in regions with significant cultural differences. Additionally, a potential limitation is that all data used for statistical analyses in this study were obtained via self-report measures. It is possible that we could have obtained more accurate clinical data if instead of self-report measures we used semi-structured interviews, such as the Eating Disorder Examination . A finalIn summary, our study found multiple direct and indirect relationships between eating-disorder symptoms, difficulties with emotion regulation, and mental-health status in adults with BED. We found that depression, psychological stress, difficulties with emotion regulation, and eating-disorder psychopathology had a direct association with mental HRQoL. Additionally, eating-disorder psychopathology, loss of control over eating, and psychological stress had a direct association with difficulties with emotion regulation. Thus, research involving the evaluation of clinical-trial outcomes as well as real-world treatment plans for people with BED should address comprehensively the symptoms of depression, psychological stress, difficulties with emotion regulation, eating-disorder psychopathology  and loss of control over eating.


This study assessed the experiences of elite aquatic athletes with coronavirus disease 2019 (COVID-19) during the first World Championship conducted without social distancing and an isolation “bubble”. An online questionnaire was completed by 812 athletes  to provide data on demographics, sports activity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates, symptoms, reinfection, vaccination status, and psychological aspects. The answers revealed that 49.4% of athletes had experienced SARS-CoV-2 infection. The infection rates varied significantly across different aquatic sports, with open water swimmers having the lowest (28%) and water polo players (67%) and artistic swimmers (61%) having the highest infection rates (p < 0.0001). The majority reported mild (51%) or moderate (27%) symptoms, while 16% remained asymptomatic. Reinfection occurred in 13%, and 10% of initial infections led to long COVID, with fatigue (65%) and shortness of breath (48%) being the most common long-term symptoms. Significantly, 92% of athletes received at least two vaccine doses and reported a positive vaccination experience (median score of 8 out of 10 for each shot). Mood changes and subjective performance drops significantly correlated with the overall experience scores . In conclusion, most athletes experienced a benign disease course despite a relatively high infection rate. This study provides valuable insights into the COVID-19 experiences of elite aquatic athletes. The findings emphasize the importance of vaccination initiatives, monitoring psychological well-being and the need to fortify athletes’ resilience in the face of future health challenges. Evaluating the global impact of the COVID-19 pandemic on athletes is challenging, given the international variability in incidence and disease intensity4.The first wave of the COVID-19 pandemic carried the risk of unforeseen health issues, which raised the question of the optimal return to play and potential cardiac and respiratory complications6.However, the most significant questions regarding possible cardiac involvement have been answered8. In contrast with the initial extensive post-COVID screening practice10, current recommendations do not require comprehensive return-to-play examinations for all athletes12, as nowadays, the course of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is predominantly mild, without complications16.In addition, athletic performance may be influenced by the long COVID syndrome, which may lead to a delayed return to play17. However, the experience gained from the postponed Tokyo Olympics informed the organization of other significant sports events, including the 2022 FIFA World Cup18.Athletes participating in water sports have been particularly affected by the consequences of SARS-CoV-2 infection and long COVID syndrome. This has involved the postponement or cancellation of numerous international events, including the 2020 Tokyo Olympics17. These factors altered periodised training programmes, affecting athletes’ physical performance and mental health20.In addition, training opportunities were significantly limited due to the temporary closure of training sites, including swimming pools22. Some concerns have arisen regarding vaccination-related myocarditis, and vigilant monitoring seemed rational, considering myocarditis’ implication in athletes23. Nevertheless, one must also consider optimal timing for vaccination to mitigate potential side effects and the impact on athletic performance24.Fortunately, the development of vaccines has significantly reduced the number of severe casesCurrently, there is a dearth of data regarding aquatic athlete experiences during the pandemic. Athlete infection and reinfection rates and disease course relative to the general population are unknown, as are their vaccination status and ability to cope with added psychological hardship. In addition, most surveys and studies focus on local trends, with little application to global experiences and disease patterns.This study aimed to assess the COVID-19 experience of a unique multinational cohort of elite aquatic athletes competing in the first global sports event without the imposition of an isolation “bubble”. We used a digital questionnaire to collect data on the infection rate, disease course, symptoms of SARS-CoV-2 infection, vaccination experiences and psychological well-being.As a part of a collaboration between the World Aquatics ) Sports Medicine Committee, the AQUA COVID-19 Task Force and the Semmelweis University, we created an anonymised questionnaire focusing on the basic demographics, sports activity, previous SARS-CoV-2 infection(s), vaccination status and psychological aspects of the pandemic. This study presents cross-sectional, retrospective data. Hereafter, we use the term “COVID-19” to refer to the disease with clinical symptoms. Correspondingly, we employed the term “SARS-CoV-2 infection” to encompass both symptomatic and asymptomatic presentation.Accredited athletes voluntarily completed the questionnaire during the 19th FINA 2022 World Championship in Budapest, Hungary, between June 13 and July 13, 2022, adding 10 extra days after the end of the event. The link and QR code pertaining to the form were distributed by volunteers during the event and were forwarded to the teams. The athletes filled in the English-language forms on their own electronic devices, usually taking 5–10 min to complete.The questionnaire comprised 60 single-choice, multiple-choice, scale-type (1–10 points) and open questions. Firstly, we assessed the sociodemographic factors such as age, sex, nationality, aquatic discipline , training hours and years spent in training. We asked about previous SARS-CoV-2 infection(s), including their course and severity. Athletes were asked to identify the time of their infection(s) within six-month periods, starting with the end of 2019, the first half of 2020, and so on. Furthermore, we explored athlete vaccination status and collected psychological data concerning individual perceptions of the pandemic. The questionnaire used for data collection is found in Supplement 25.Athletes were categorised according to symptoms. Mild symptoms involved smell or taste disturbance, cough, fever, headache, fatigue (or significant weakness), palpitations (sensation of fast heart rate), eye pain, muscle or joint pain, and rhinorrhoea. Shortness of breath, chest pain and loss of consciousness without hospitalisation were regarded as moderate symptoms. Those who needed hospital care were identified as participants with a severe disease course, regardless of symptoms and symptom count. Symptom severity categories were created as follows: asymptomatic (1), mild (2), moderate (3), and severe (4). Based on the answers, we created an ordinal variable with seven categories regarding symptom length  intervals were shorter during the second infection than during the first infection (p = 0.0001).Ninety-four per cent of the athletes (n = 769) received at least one dose of a COVID-19 vaccine, 92% received a second dose, and 55% a third dose. Detailed vaccination data are presented in Fig. The athletes provided a median of 6 (IQR 4–7) points for the overall well-being score during the pandemic. The median point for mood changes was 6 (IQR 4–8), and reduced physical performance was 5 (IQR 3–7). The severity of (the first) infection weakly correlated with the overall experience scores . Mood changes showed a strong, and subjective performance drop showed a moderate correlation with the overall experience scores . Female athletes reported slightly worse mood change scores than male athletes . Regarding psychological support, 19% reported a need and subsequently received psychotherapy, while 17% required assistance but could not access psychological support. However, 14% of the athletes were provided support despite not requiring it. The remaining half of the study cohort did not need or receive any help.In this paper, we present the results of a comprehensive COVID-19 survey of aquatic athletes who participated in the FINA 19th World Championship, which was the first world aquatic championship after major COVID-19 waves subsided. The principal findings of this paper include a high SARS-CoV-2 infection rate in athletes, with a higher incidence in team sports. The symptoms were mostly mild; however, long COVID syndrome was detected in 10% of the athletes. High symptom counts predicted a higher burden of long COVID syndrome. The second SARS-CoV-2 infection was mostly reported to be milder, with fewer symptoms and fewer missed training days than the first. The vaccination rate among this athlete population was high (92%), predominantly reporting mild post-vaccination symptoms. Mood changes and subjective drop in performance were important in the athletes’ overall pandemic experience.30. The infection affected 8–10% of the overall population, which proved more frequent in athletes31. One of the largest longitudinal studies from 2020, which summarised the results of almost 10,000 athletes from 13 universities, and found a SARS-CoV-2 infection rate of 30.4%, with a 2.3% prevalence of myocarditis32. In this study, the overall COVID-19 infection rate was 49.4%, with 3% of severe cases requiring hospitalisation.The COVID-19 disease and its sequelae have affected all levels of society, including the field of professional sports. The course of infection, combined with quarantine and confinement requirements, took a toll on the quality of life of athletes during the period of the pandemic. Reduced physical activity, impaired sleep quality, altered daily activity, increased anxiety, diminished cardiorespiratory fitness, and less desirable nutritional habits were among the reported consequences34. This has distinct application to a cohort of elite aquatic athletes preparing for world championships.The higher perceived infection rate may have been due to an extended observational period and more rigorous screening of athletes. Vigorous training may also impair immune function rendering athletes more susceptible to infections with post-exercise immunosuppression through an altered helper T-cell response and elevated stress hormone levels36.We concluded that close physical contact is one key factor driving the increased SARS-CoV-2 infection rates, particularly among athletes in team sports. Indeed, in this study, the occurrence of infection was the highest among water polo players and artistic swimmers while the lowest among open water swimmers. This aligns with reports of higher transmission of SARS-CoV-2 infection in team sports35. Interestingly, in our cohort, female athletes had higher rates of SARS-CoV-2 transmission, but symptom severity did not differ between the sexes. Other authors suggest that young female athletes have a lower risk of severe symptoms and remain dominantly asymptomatic38.In a Swiss COVID-19 survey assessing the prevalence and symptoms of the infection in elite athletes, the disease prevalence was less than 20%, with a male predominance41. In our findings, the main symptoms were headache, fever and cough. Different SARS-CoV-2 variants have been linked to distinct symptom profiles and diseases. In a prospective registry of collegiate athletes, the most common symptoms detected between September and December 2020 were loss of taste or smell, headache, muscle pain, cough, fatigue and fever, similar to our data gained about the second half of the year 202039.Similarly, most studies have reported mild to moderate COVID-19 symptoms in athletes42. Schwellnus et al. associated symptom clustering with different return-to-play times and compared COVID-19 with other acute respiratory illnesses. They found that return-to-play after COVID-19 was significantly longer than in the other group (IQRs 16–40 vs 7–22 days) and, generally, symptom cluster is associated with prolonged missed training times with excess fatigue in particular43.However, the exact missed training time interval is scarcely reported in athletes and may be dependent on several factors. In our findings, most athletes missed 1–2 weeks of training which might involve the role of quarantine, symptom severity, and closure of training sites, among others. According to Krzywanski et al.’s findings, COVID-19’s impact has been higher than other respiratory tract infections regarding missed training. The surveyed elite Polish athletes (n = 1073) reported that 12–13% lost training days due to COVID-19, which is expressly lower than what the multinational aquatic athletes showed7. A study including 4186 post-COVID patients assessed the prevalence of long COVID syndrome in the average population and found a slightly higher incidence (13.3%) of persistent (> 4 weeks) symptoms8. Our previous findings in a prospective cohort of 322 athletes showed a long COVID occurrence of 8%, highlighting differences between age groups, where adult and master athletes were more likely to develop long-standing symptoms5. We previously showed that increasing age and a worse symptom severity score predicted long COVID occurrence. Nevertheless, in this dataset, including predominantly young adults, we found that only acute symptom count was an independent predictor of developing long COVID.Our study detected long COVID syndrome in 10% of the athletes. A systematic review and meta-analysis of 43 studies covering 11,518 athletes reported a long COVID syndrome rate of 8.3%45. Good et al. reported that the reinfection rate was as low as 0.8% in a pre-omicron (Delta wave) student-athlete cohort. In our study, the reinfection rate was 13%, with fewer and milder symptoms and fewer missed training days than the first infection. This phenomenon may be related to the different SARS-CoV-2 variants47. Another explanation might be that athletes encountered the second infection with an already primed immune system either through prior infection or vaccination. Another insight might be that vaccine roll-out helped mitigate the disease severity. In addition, our relatively high reinfection rate may be explained by the fact that most SARS-CoV-2 infections occurred in the first half of 2022 during the Omicron variant outbreak. Furthermore, elite athletes usually have strict medical control due to the pre-competition screenings and regular health check-ups; thus, it is more likely that mild or asymptomatic (re)infections are recognized. In contrast, the reinfection rate in the non-athletic population was relatively low until the Omicron era48.The SARS-CoV-2 reinfection of athletes has not been extensively described in the literature, with case reports and low case number studies available21. The duration of side effects was generally short, lasting no more than three days. An infographic paper by Rankin et al. found that the vaccination in athletes was generally well tolerated, the majority of the side effects were mild, and the missed training period was as low as 4 days49. Oudjedi et al. found that 55% of the surveyed Algerian athletes (n = 273) reported side effects after COVID-19 vaccination, of which fever and local pain were the most prevalent. These findings generally align with our data. Nonetheless, for athletes with the dominant use of the upper extremities, the timing of the vaccine administration may be decisive due to the possible local side effects24.Almost all (94%) of our participants had been administered at least one dose of a COVID-19 vaccine, and 92% received the second shot as well. With a high vaccination rate, the athletes reported a relatively low burden of adverse side effects and only a few major ones, similar to the general population51.In spite of the increasing SARS-CoV-2 vaccination rate, the number of infected cases also surged, which may reflect the lower efficacy of the vaccines against the newer Omicron variants as described in the literature52. A study examining 310 athletes from different continents and diverse sports disciplines found that maladaptive perfectionism was related to numerous mental health indicators. They also concluded that competitive athletes showed signs of a negative emotional state during the pandemic. Even so, the anxiety, stress, and depressive symptoms were less prevalent in athletes with proper coping strategies53. Based on our results, mood changes and subjective performance drop correlated closely with the overall experience during the pandemic; 36% of the athletes reported needing psychological support. Female athletes reported slightly worse mood change scores compared to male athletes. Several studies found similar data regarding the post-COVID mental health of female athletes55. Notably, half of the athletes questioned did not need psychological support. However, it is not apparent whether this is reflective of adequate coping skills—such as cognitive restructuring and emotional calm—or not. Also, 17% of the surveyed athletes were unable to obtain psychological support despite their need, reflecting the importance of providing appropriate psychological help in the context of sport.The COVID-19 pandemic has brought uncertainty to the lives of athletes and non-athletes, leading to stress, anxiety, depression and other mental disordersThis self-reported, retrospective study is based on a monolingual (English) survey, and the language barrier may have impacted the answers of non-native English speakers. In addition, we do not have any information about the type and methods of SARS-CoV-2 testing, nor could we confirm the validity of other reported health-related variables. Consequently, the potential lack of accuracy and incompleteness of the answer sheets may have slightly influenced the data quality. In addition, the exact date of any positive tests could not be verified through institutional medical sources.In this multinational cohort study of elite aquatic athletes, despite a high SARS-CoV-2 infection rate, the majority experienced only mild to moderate symptoms, while athletes with more severe disease courses had a higher incidence of long COVID syndrome. Team sports participants presented with a higher infection transmission rate compared to individual athletes, likely due to close bodily contact. The 13% reinfection rate aligns with previously published research findings. Promisingly, nearly all athletes had received at least two doses of the COVID-19 vaccine, indicating a broad vaccination acceptance in aquatic athletes worldwide, with short-term and mild side effects. Notably, psychological aspects significantly influenced athletes’ perceptions of the pandemic. Overall, this study suggests that aquatic athletes have coped well with the physical and moderately well with the psychological consequences of the COVID-19 pandemic. Nevertheless, post-pandemic follow-up will be crucial to assess the complex effects on athletes’ long-term physical and mental health. The findings of the study can offer guidance to sports organizations and health authorities in designing targeted strategies for pandemic preparedness tailored to elite aquatic athletes. The higher infection transmission rates in team sports underscore the importance of implementing specific safety measures during training and competing to minimize viral spread. In addition, the high vaccination acceptance rate among athletes highlights the importance of promoting vaccination in sports communities to ensure a safer and more resilient sports milieu during potential future health crises. Furthermore, the acknowledgement of the impact of psychological aspects on athletes’ pandemic experience emphasizes the need for continued support and psychological interventions to safeguard athletes’ mental well-being during challenging times. These pragmatic implications can enhance the overall health of elite aquatic athletes in the face of future pandemics or health challenges.Supplementary Information.


Globally, treatment outcomes for people with multi-drug/rifampin-resistant tuberculosis (MDR/RR-TB) are sub-optimal, with MDR/RR-TB programs further weakened due to the COVID-19 pandemic, and in Haiti, by severe civil unrest. We assessed the impact of these disruptions on treatment outcomes at GHESKIO, in Port-au-Prince, Haiti. We conducted a retrospective analysis including all adults (age ≥18 years) who initiated MDR/RR-TB treatment at GHESKIO from 2010 to 2020. We assessed predictors of poor treatment outcome using multivariable logistic regression, adjusting for baseline characteristics and year of treatment. 453 patients initiated treatment for MDR/RR-TB at GHESKIO. Median age was 31 , 233 (51.4%) were male, and 100 (22.1%) were living with HIV. Three hundred sixty-nine patients (81.5%) achieved cure, 42 (9.3%) died, 40 (8.8%) were lost to follow-up and 2 (<1%) failed treatment. HIV status was associated with poor treatment outcome ) but there was no difference by year of treatment initiation. Outcomes for patients with MDR/RR-TB remained outstanding, even during the COVID-19 pandemic and severe civil unrest in Haiti. We attribute this resilience in care to the adaptability of program staff and provision of economic and psychosocial support. The COVID-19 pandemic has reversed years of progress in the fight to eliminate tuberculosis worldwide with re-distribution of resources from fighting TB to fighting COVID-19 exacerbating already-poor rates of treatment success . In HaitThe Haitian Group for the Study of Kaposi’s Sarcoma and Opportunistic Infections (GHESKIO) is located in Port-au-Prince, Haiti, and has established a MDR/RR-TB treatment program with a focus on patient-centered care, in line with recommendations by the World Health Organization (WHO) and global health policy makers . We prevGHESKIO is a non-governmental organization that has provided free HIV and TB care since 1982, and MDR/RR-TB care since 2008. GHESKIO has an inpatient MDR-TB treatment hospital with an on-site biosafety level 3 (BSL-3) laboratory. All patients ≥18 years of age with microbiologic evidence of resistance to rifampin who initiated MDR/RR-TB treatment from March 2010 to December 2020 were included in the study. Treatment outcomes were available approximately 20–24 months following treatment initiation; all patients who initiated treatment in December 2020 had outcomes available by the end of 2022.plus  or Xpert MTB/RIF . Xpert MTB/RIF was preferentially used after May 2011. Samples with evidence of rifampin resistance by molecular testing were cultured using liquid media  and solid media (Lowenstein-Jensen slant), and first and second-line drug susceptibility (DST) testing was conducted in accordance with the manufacturer’s recommendations, as described previously .–13.11–13Sputum smear microscopy and cultures were obtained per national guidelines, which varied slightly over time; at a minimum, smears and cultures were conducted monthly during the intensive phase, then every other month, and then again monthly during the final 3 to 5 months of treatment. Culture conversion was defined as 2 consecutive negative cultures at least 30 days apart. Treatment outcomes were defined according to the 2014 WHO guidelines . Cure waThrough 2014, patients were hospitalized for intensive therapy, which included approximately the first 10 months, while they received an injectable medication (kanamycin or capreomycin). Initially they were hospitalized in an inpatient facility, but in January 2010 it was destroyed in a devastating earthquake, and patients were hospitalized in individual tents in a field hospital until the inpatient GHESKIO MDR-TB hospital was opened in 2015. The same year, the length of inpatient hospitalization was decreased; patients were discharged after they had converted to culture-negative . After discharge, patients were followed at home, with all doses observed through directly observed treatment (DOT) supervised by a community health worker (CHW) or a nurse (for doses that included an injectable agent). Nearly all patients were treated with long-course, standard therapy (at least 20 months in duration).During home visits, the DOT provider queried patients about symptoms, checked vital signs, and photographed the patient taking their medication. These activities were recorded at each visit using mobile phones equipped with global positioning system (GPS) devices. Patients with severe symptoms were immediately referred for medical attention. Team meetings  were held for patients who missed medication doses and/or visits to help identify and overcome specific barriers to adherence. Medical visits (physician and/or nurse) were scheduled as needed, and at least monthly.Patients were offered psychosocial support through individual counseling sessions and monthly group support meetings. At the time of diagnosis, patients were requested to specify a family member or friend to provide support for the treatment period, including attending all medical visits and monthly group meetings with medical team members and other patients. At each medical visit, patients were provided with transportation subsidies and telephone cards. At each monthly group meeting, the medical team provided social support, treatment literacy counseling, and dry food rations totaling about USD $25 per patient. Each time a patient successfully completed treatment, they were awarded with a treatment completion certificate and an end-of-treatment prize (USD $200 in cash).During times of severe civil unrest that had the potential to impact travel to clinic, CHWs and nurses switched to phone-based DOT for patients who could not receive in-person DOT. This provided a safe method of communication between clinic providers and the patient. This phone-based communication was also utilized when patients were unable to travel to clinic due to safety concerns. GHESKIO staff frequently reached out to patients to help them remain engaged in care, even if this engagement was virtual. Additionally, depots were set up in safer areas of Port-au-Prince, where patients were able to obtain their medications if they felt that travel to GHESKIO was too dangerous, and patients were provided with several weeks’ reserve supply of medications to facilitate adherence if they were unable to receive medications.GHESKIO’s inpatient MDR-TB facility was designed by the Model of Architecture Serving Society (MASS) Design Group, a non-profit architectural firm, with a focus on minimizing the risk of TB transmission . The hosDemographic and clinical data were extracted from the GHESKIO electronic medical record, the GHESKIO laboratory database and hard-copy paper charts. Year of treatment initiation was categorized as a binary variable, based on whether it occurred prior to 2018, or during or after 2018, as 2018 marked the period when civil unrest increasingly affected day-to-day activities in Port-au-Prince. Treatment outcomes were dichotomized into successful  and unsuccessful . Log-binomial regression was used to determine predictors of unsuccessful treatment as a composite outcome and death and LTFU as individual outcomes. Predictors were considered if there was a sample size of at least 10 patients. Variables with a p-value of <0.20 or a relative risk (RR) of <0.80 or >1.2 in the univariable model were considered for inclusion in the multivariable model. All analyses were conducted with R software (Version 4.0.5).It was not feasible to obtain informed consent due to the retrospective nature of the research. This study used routinely collected data stored in the medical record for patients receiving care at GHESKIO. The study was approved by the institutional review boards of GHESKIO, Weill Cornell Medicine and Brigham and Women’s Hospital.From 2010 to 2020, 453 adult patients were treated for MDR/RR-TB at GHESKIO; of these 331 (73.1%) initiated treatment prior to 2018. The median age was 31  and 233 (51.4%) patients were male . A totalIn total, 369 (81.5%) patients have achieved cure, 42 (9.3%) have died, 40 (8.8%) have been loss to follow-up (LTFU) and 2 (<1%) experienced treatment failure . Among tIn the univariate analysis examining poor treatment outcome as a composite , positive HIV status  was associated with unsuccessful treatment outcome; receiving high-dose INH  was associated with a successful treatment outcome. The multivariable analysis yielded similar results, with an adjusted RR (aRR) 1.65  for positive HIV status. For those receiving high-dose INH, the aRR 0.56  trended towards significance. Resistance to fluoroquinolone or second-line injectable was not included in the adjusted model given the small sample size . There wOur results demonstrate that it is possible to maintain superb MDR/RR-TB outcomes in a resource-poor setting with tremendous barriers to accessible care. We attribute the resilience of GHESKIO’s MDR/RR-TB program to three key factors: adaptable staff, economic support, and psychosocial support. GHESKIO’s approach to TB care is not new–Dr. Paul Farmer, co-founder of Partners in Health (PIH), advocated for a biosocial approach to TB care for decades. This approach is based on the “5 S’s”: staff, stuff, space, systems and social support which serve as the foundation of healthcare strengthening at PIH , 20. GHEGHESKIO’s staff routinely adapted their provision of care to current events. When necessary, DOT was performed by cell phone with patients photographing themselves taking medicine and sharing these pictures with staff. Medication depots were created in safe neighborhoods so that patients could obtain their medications without putting themselves at risk. Additionally, patients were provided with several weeks’ reserve supply of medications to facilitate adherence if they were unable to receive medications. Finally, GHESKIO deployed CHWs to surrounding communities to provide information regarding COVID-19, thus combatting the misinformation and stigmatization experienced in Haiti and globally , 22.The COVID-19 pandemic, in particular, highlights the importance of GHESKIO’s work and its ability to adapt. Globally, COVID-19 has negatively impacted HIV and TB care, maternal and child health and noncommunicable disease management , 23–26. Patients with MDR/RR-TB face economic barriers which, if not addressed, contribute to poor treatment outcomes –29. GHESLack of social support has been associated with LTFU among persons with MDR/RR-TB . GHESKIOIn our cohort, we found that mortality rates were higher in PWH. This has been reported in other studies as well , 37. It Our findings are limited in part due to changing regimens over time, which makes it challenging to determine to what extent specific regimens may have affected our outcomes. The study was conducted in a single treatment facility which may not be representative of the entire country. The cohort was limited to those patients who initiated treatment prior to or in 2020, and thus had treatment outcomes available at the time of publication of this manuscript. This may not capture the long-term impacts of COVID-19. Providing economic and social support does require significant commitment and resources which may impact the generalizability of our outcomes to other regions. Haiti is a low resource country, however, which highlights that the distribution of resources to individuals with TB is important and achievable.We report ongoing outstanding treatment outcomes for MDR/RR-TB in Port-au-Prince, Haiti, in spite of major civil unrest and disruptions from the COVID-19 pandemic. We attribute this success to the provision of adaptive services and economic and social support.S1 Data*This is the dataset upon which the data presented in this manuscript is based. Variables: Patient_ID: unique anonymous identifier for each patient; Tx initiation year: The time frame during which the patient received treatment; Age_cat: age at time of TB diagnosis, grouped into 10-year groups; Sex: self-reported sex of the patient; HIV: HIV serostatus at time of diagnosis; Education: highest educational level obtained by the patient (self-reported), grouped into a binary variable; Income: self-reported daily income of the patient, grouped into a binary variable; Outcome: TB treatment outcome based on World Health Organization definitions; preXDR: detailing whether a patient had resistance to a second-line injectable agent or fluoroquinolone, with 0 = no, 1 = yes; Tx Cohort: the describes the treatment cohort the patient was in for the study’s primary analysis; regimen with high dose INH, a regimen with BDQ, or a regimen containing neither.(XLSX)Click here for additional data file.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affects the respiratory system. During the global coronavirus disease (COVID-19) pandemic, COVID-19-associated neurological diseases have been increasingly reported, including peripheral nervous system diseases, such as Guillain–Barré syndrome (GBS). Acute motor-sensory axonal polyneuropathy (AMSAN), is a GBS variant associated with COVID-19. To date, there are no reports of GBS cases with thalamic injury and dynamic evolution with fluctuating GBS symptoms. In this report, we describe the first case of COVID-19-associated AMSAN accompanied by a thalamic lesion and discuss the magnetic resonance imaging (MRI) findings.A 76-year-old woman, with known co-morbid type 2 diabetes mellitus, presented to the emergency room with complaints of weakness and paraesthesia in both her legs and arms for 4 days, and fever and dry cough for the past 5 days. A nasopharyngeal swab for SARS-CoV-2 returned positive. The patient had not received specific treatment for COVID-19 infection. Neurological examination disclosed symmetric weakness  and areflexia in both the legs and feet. No cranial nerves were involved. Following a neuro-electro-physiology study to evaluate neurological symptoms, AMSAN was suggested. Cerebrospinal fluid (CSF) analysis showed elevated protein levels that confirmed the diagnosis of GBS. The patient was subsequently treated with intravenous immune globulin (IVIG), which improved her neurological symptoms . However, urinary retention, dysarthria, dysphagia, bilateral facial paralysis, facial diplegia, bucking, and motor alalia gradually appeared, followed by aggravated paralysis . After being hospitalized for 16 days, the patient underwent continuous plasma exchange (PE) treatment for a duration of 3 days. Following treatment, the patient’s neurological symptoms and paralysis gradually improved  over 2 weeks. Meanwhile, we observed that the patient’s cerebral magnetic resonance imaging (MRI) findings dynamically evolved along with the fluctuation of her GBS symptoms, mainly in terms of the changes in T2 hyperintensity in the right thalamus accompanied by microhaemorrhages. The inflammation index was normal. We considered a wide range of possible causes including hypoxia, drugs, toxins, and metabolic derangements but these were excluded.The AMSAN variant of GBS secondary to COVID-19 infection is severe and can cause extensive damage to the peripheral nerves system. The deterioration of symptoms in the patient after early immunotherapy may indicate treatment-related fluctuation (TRF) and could be attributed to immune rebound. Moreover, an excessive immune response post-COVID-19 infection may trigger concurrent damage to the central nervous system, indicating secondary harm to brain small blood vessels and nerve units. For suspected cases of GBS complicated by COVID-19, it is essential to conduct early brain MRI examinations in addition to routine peripheral nervous system evaluations to promptly detect any intracranial lesions. This facilitates appropriate immunotherapy and improves patient prognosis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19), primarily affects the respiratory system. During the global COVID-19 pandemic, neurological complications of COVID-19 have been increasingly reported, including Guillain–Barré syndrome (GBS) . The AMSOn January 6, 2023, during the COVID-19 epidemic in this region of China, a 76-year-old woman, with known co-morbid type 2 diabetes mellitus, presented to the emergency room of our hospital, the Third Grade First Class Hospital, with complaints of weakness and paraesthesia in both her legs and arms for four days, and fever and dry cough for the past 5 days. A nasopharyngeal swab for SARS-CoV-2 returned positive. The patient had received the inactivated COVID-19 virus vaccine one year ago, and had not been administered any other specific antiviral therapy for a COVID-19 infection.On admission, baseline laboratory investigations were performed . A nasopOn further investigation, the neuro-electrophysiology  examinatAfter some improvement of the limb weakness following treatment with IVIG, the patient experienced aggravated symptoms including choking on water, slurred speech, weakness during chewing, reduced muscle strength, and urinary retention. The neurological examination on day 11 reported the patient as conscious, with dysarthria, bilateral eyelid closure weakness, a left eye fissure of 6 mm and a right eye fissure of 4 mm, a flattened left nasolabial fissure, tongue deviation towards the right side on attempted protrusion, grade 3 upper limb muscle strength, grade 1 lower limb muscle strength, negative patellar reflex (−), and negative Babinski sign (−). The above symptoms continued to aggravate. On January 19, 2022, a re-examination with cerebral MRI revealed that the right thalamus had T1 hypointensity and a more pronounced T2 hyperintensity than before. Moreover, hypointensity was detected on the susceptibility-weighted imaging (SWI), while no hyperintensity was noted on the diffusion-weighted imaging (DWI) –L. AfterSeveral variants of GBS exist. It is an immune-mediated polyneuropathy that is most often preceded by an infection. In this report, we described a patient with AMSAN, a variant of GBS, that presented with a thalamic lesion, and was associated with COVID-19.AMSAN is more commonly associated with COVID-19 in Asia . In our Another hypothesis has suggested the direct invasion of peripheral nerves by SARS-COV-2. The olfactory nerve is the most common cranial nerve that is directly affected in this way . Our casAfter admission, we performed a series of cerebral MRI examinations on this patient. When we compared and analyzed the images obtained during hospitalization and those obtained before disease onset, we were surprised that cerebral MRI showed an emerging SWI signal from microhaemorrhage in the right thalamus with a slightly enhanced T2 signal at the early stage of the disease. As the disease aggravated, the T2 hyperintensity in the right thalamus was significantly more intense and the coverage was larger. However, the T2 hyperintensity and T1 hypointensity of the right thalamus resolved when clinical symptoms improved. The abnormal T2 signal in the right thalamus evolved synchronously and dynamically with the changes in clinical symptoms. At the same time, in Bickerstaff brainstem encephalitis, a variant of GBS, is known to cause damage to the brainstem. However, it mainly affects the cranial nerves and the reticular activating system. Moreover, the condition does not have any indications on medical imaging, such as cerebral MRI . In our AMSAN variants of GBS secondary to COVID-19 can cause severe peripheral nerve damage. The deterioration of symptoms in the patient after early immunotherapy may indicate treatment-related fluctuation (TRF) and could be attributed to immune rebound. Moreover, an excessive immune response post-COVID-19 infection may trigger concurrent damage to the central nervous system, indicating secondary harm to brain small blood vessels and nerve units. For suspected cases of GBS complicated by COVID-19, it is essential to conduct early brain MRI examinations in addition to routine peripheral nervous system evaluations to promptly detect any intracranial lesions. This facilitates appropriate immunotherapy and improves patient prognosis. Our study demonstrates that immunomodulatory therapy, such as the use of immunomodulatory drugs, can significantly alleviate both peripheral and central nervous system damage in patients with AMSAN variant GBS associated with COVID-19. This suggests that immunomodulatory drugs hold promising therapeutic value in addressing neurological symptoms related to COVID-19.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the patients/ participants was not required to participate in this study in accordance with the national legislation and the institutional requirements. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.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.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.