This study aimed to investigate a standardized apparent diffusion coefficient (ADC) ratio cut-off for identifying lymph node (LN) metastasis in malignant melanoma (MM), addressing the challenges of current non-invasive LN status diagnostics and dependences of absolute ADC values. This prospective, single-center study evaluated consecutive patients using diffusion-weighted MRI (DWI-MRI). We included 52 patients with early-stage MM who underwent sentinel lymph node (SLN) extraction, and 12 patients with advanced-stage MM and newly confirmed or progressive metastatic lymph nodes (MLNs). ADC values for positive and negative SLNs as well as MLNs were measured. Ratios of the ADC of SLNs or MLNs were calculated relative to benign contralateral LNs (cADC) and adjacent muscle tissue (mADC). ROC analysis identified cut-offs for absolute ADC values and relative ADC ratios. Diagnostic performance gained by regression was validated via machine learning (ML) classifiers, to evaluate robustness. A total of 64 patients (median age 68.5; IQR 61–77; 46.9

In nature, many animals respond to cold by entering hibernation, while in clinical settings, controlled cooling is used in transplantation and emergency medicine. However, the molecular mechanisms that enable cells to survive severe cold are still not fully understood. One key aspect of cold adaptation is the global downregulation of protein synthesis. Studying it in the nematode Caenorhabditis elegans, we find that the translation of most mRNAs continues in the cold, albeit at a slower rate, and propose that cold-specific gene expression is regulated primarily at the transcription level. Supporting this idea, we found that the transcription of certain cold-induced genes is linked to the activation of unfolded protein response (UPR) through the conserved IRE-1/XBP-1 signaling pathway. Our findings suggest that this pathway is triggered by cold-induced perturbations in proteins and lipids within the endoplasmic reticulum, and that its activation is beneficial for cold survival.

Highly Superior Autobiographical Memory (HSAM) is an extremely rare condition characterized by an individual's unparallelled ability to recall personal past events with exceptional detail and accuracy, including exact dates and days of the week, spanning many decades. The molecular underpinnings of HSAM are unknown. Here, we investigated an individual with HSAM through neuropsychological testing, structural brain imaging, and genetic analyses. HSAM was confirmed as an isolated exceptional cognitive ability, with brain imaging revealing exceptionally large volumes of regions within the hippocampal formation, which have been previously linked to autobiographical memory. Using whole exome sequencing of the HSAM individual and their unaffected parents, we identified a unique de novo missense variant in MYCBP2, which encodes an E3 ubiquitin-protein ligase. To explore the potential behavioral consequences of this variant, we introduced the homologous variant into C. elegans, which resulted in reduced forgetting and increased membrane-bound glutamate receptor in relevant neuronal cells. These findings show that the studied HSAM individual carries a unique, de novo missense variant in MYCBP2, which reduces forgetting in a model organism. The identification of functionally relevant genetic variants in individuals with superior memory traits has the potential to inform future research into memory-modulating therapies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study was funded through intramural funds of the University of Basel and by the Novartis Research Foundation (Novartis Forschungsstiftung) FreeNovation Award FN19-0000000028. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was approved by the Ethics Committee of Northwest and Central Switzerland. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

Background: Vertical transmission of maternal cancer cells to the child is extremely rare, but melanoma represents the most common culprit. The aim of this study is to determine individual risks for materno-fetal transmission of melanoma cells and to establish standardized procedures for pregnant melanoma patients and their offspring.Patients and methods: In this retrospective multicenter study, data on women with stage III or IV melanoma that had been diagnosed before, during or up to 12 months after pregnancy, were analyzed for the occurrence of metastases in the placenta or the infant.In addition, a literature search for previously described materno-fetal transmission in case of maternal melanoma was conducted. A historical patient group was established from these cases and a statistical analysis was performed (SAS, p<0.05 significant).Results: In total, 67 children born to women with stage III or IV melanoma were included. No placental or infant metastases were detected in any of the cases.The additional literature search revealed 37 cases with placental metastases and 14 cases with infant metastases (6 of them overlapping). Of the affected children, 10 (71.43%) died from their disease. Maternal death shortly after birth seems to be an unfavorable factor for transmission to the infant.Conclusion: The risk of materno-fetal transmission of maternal melanoma metastases seems to be much lower than anticipated based on former studies. However, thorough placental screening and systematic follow-up of the children resulting from pregnancies of high-risk melanoma patients should be performed.

Introduction: The aim of the study was to systematically analyze the influence of extracorporeal photopheresis (ECP) on the quality of life (LQ) and the course of the disease in patients with Mycosis Fungoides ( MF), as well as with Graft-versus-Host Disease (GvHD). Methods: LQ was monitored retrospectively by using the dermatology life quality index (DLQI) and Skindex29 test before ECP onset and after the last ECP. Disease parameters were assessed by objective criteria i.e. number of associated medical drugs taken, intervals between therapeutic cycles, gradual change of the disease, and eventual side-effects and complications of ECP therapy. Results: Fifty-one patients were treated with ECP during 2008-19; 19 out of 51 died, and follow-up was not completed in 13 patients. Finally, treatment protocols of 671 ECP procedures were evaluated in 19 patients (10 MF; 9 GvHD). MF and GvHD subpopulations did not differ in the individual scores of LQ questions, either before the outset or after the last ECP. DLQI and Skindex-29 scores were ameliorated by the ECP therapy (p= 0.001 and p< 0.001, respectively) due to improvement of individual scores of feelings, daily/social activities (p< 0.05), and functionality (p= 0.05). The median interval between ECP cycles was extended from two to eight weeks (p= 0.001). Needs of GvHD patients for drugs being received for the underlying disease were reduced (p= 0.035). Two of the 10 MF patients worsened from stage IIA to IIIA. Severe or minor side effects leading to a therapy interruption were not recorded. Conclusion: Patients with GvHD experienced a notable decrease in the administration of drugs for their underlying condition, and there were no instances of severe side effects that resulted in the discontinuation of treatment. ECP is safe and effective for the treatment of MF and GvHD.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Abstract Background A diversity of risk factors for ca-MRSA manifestations has been described so far. Up to date toxic contact dermatitis induced by plants has not been identified as one. Patients and Methods After intense skin contact with poison ivy in the US a 24-year-old Afro-American showed pronounced bullous contact dermatitis on the back of the neck and subsequently massive ca-MRSA furunculitis with proof of Panton-Valentine-leucocidin (PVL). After travelling to Germany, his German girlfriend developed a subacute ca-MRSA, PVL-positive superinfection of a mosquito bite at her lower leg. Both infections required surgical intervention. Results While the male patient displayed contact dermatitis by poison ivy, the female patient demonstrated two risk factors for ca-MRSA: contact with a ca-MRSA positive person and a predisposing skin lesion. Both cases underpin the role of ca-MRSA transmission and the potential severeness of wound infections in young and immunocompetent persons, just to be resolved by invasive intervention. Conclusions Marked and recalcitrant skin or soft tissue infections in otherwise healthy young patients require instant microbiological analysis and surgical intervention flanked by adequate antibiotic therapy. Contact dermatitis induced by plant toxins should be taken into consideration as possible risk factor for the acquisition of ca-MRSA.

Purpose To analyze sleep characteristics as measured with polysomnography (PSG) in adults from the general population with and without physician-diagnosed atopic dermatitis (AD). Methods We analyzed data from participants from the German population-based Study of Health in Pomerania (SHIP) TREND-0. AD was diagnosed in a standardized skin examination. The following polysomnographic parameters were measured: total sleep duration (min), sleep latency (min), wake after sleep onset (WASO; min), rapid eye movement (REM) latency (min), sleep efficiency (%), total number of wakefulness and movement episodes, stages of sleep (%), and apnea-hypopnea index (AHI). Additionally, the subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). We compared sleep characteristics of participants with and without AD. Results Among 1187 participants, 47 (4.0%) had AD. We found no differences between participants with and without AD in any of the analyzed PSG parameters except for the total number of wakefulness and movement episodes and the percentage of REM sleep. Participants with AD had a higher number of wakefulness and movement episodes, and a lower proportion of REM sleep compared to those without AD. Regarding subjective sleep parameters, no significant differences were found between participants with and without AD. Conclusion Our data do not provide evidence for poor sleep quality in individuals with AD. Major limitations of the study include the unavailability of data on AD severity and the small number of participants with AD. Larger-scaled longitudinal studies considering disease severity and specific AD symptoms with an effect on sleep are required.

BACKGROUND: In this paper, the method of steam vein occlusion for the treatment of the great/small saphenous vein (GSV/SSV) was analyzed in terms of a therapeutic influence on the dynamic parameters of global vein function, its effects on subjective symptoms based on chronic venous insufficiency (CVI) and the side effects of the steam vein sclerosis (SVS). It has been questioned whether the effects of this method lead to a recommendation for routine clinical practice. METHODS: The venous drainage and the venous refilling time (T-0) of the leg treated were determined by photoplethysmography (Elcat, Wolfratshausen, Germany) before, six weeks and one year after the intervention to examine the effects on global venous function. Further changes of clinical symptoms and findings were assessed by the Venous Clinical Severity Score (VCSS), preoperatively and after one year, and the complication rate at 6-week follow-up was monitored. RESULTS: The SVS was performed on 167 veins (GSV: 124; SSV: 43) in a total of 156 patients. Eight patients (5.1%) did not attend the 6-week follow-up, while 29 patients (18.6%) were lost in the 1-year follow-up. Patients were suffering from symptoms such as leg pain and leg edema, which resulted in a VCSS of 9.4 (cumulated mean score of all patients) preoperatively. The T-0 was reduced to mean values of 20.6 s (GSV cohort) and 21 s (SSV cohort). The VCSS improved to 6.0 after one year. This correlated with the hemodynamic parameters. The T-0 increased in the GSV cohort after six weeks to 31.8 s, p < 0.001, and showed a nonsignificant improvement to 32.2 s, p = 0.509, in the 1-year check. The T-0 also increased in the SSV cohort significantly after 6 weeks to 30.1 s, p < 0.001, and showed a nonsignificant reduction after one year, p = 0.289. A total of 71% of the GSV and 69.8% of the SSV of the patients involved no complications following the treatment. Light complications (grade 1) occurred (reddening, hematoma, hyperpigmentation) in the majority: 24.2% of the GSV and 18.6% of the SSV. We noticed one grade 3 complication with thrombosis in the SSV cohort, which led to a pulmonary embolism. Forty-seven complete questionnaires were analyzed (responder rate: 28.1%); 40.4% of the patients had light complaints after the treatment, such as pain, warmth or local pressure sensations (Fig. 7); 63% of those patients noticed only slight pain at a maximum of 3 out of 10. The majority (91%) would recommend this procedure. CONCLUSION: The SVS revealed endoluminal catheter-based intervention to abolish venous reflux of the G/SSV as safe. As one therapeutic target is to eliminate venous reflux, effectiveness of a method cannot be based on sonographic data alone; one must further assess patients' symptoms and dynamic venous function. This data shows an improvement of patients' symptoms which correlated well with the improvement of the venous function in digital photoplethysmography. The SVS can be recommended as a catheter-based treatment in the future.

BACKGROUND:Edema and subjective leg complaints (e.g. pain, heaviness) after long standing or sitting, are defined as orthostatic leg complaints or occupational edema. Compression hosiery should help to prevent or decrease those symptoms.OBJECTIVE:Assess the effects on leg discomforts and leg volume and wearing comfort in two medical below-knee compression stocking types (A vs. B) with an interface pressure of 18 -20 mmHg and a below-knee-low-pressure support stocking (LPSS) with an interface pressure of 8-10mmHg (C).METHODS:Two different types of below-knee medical compression stockings and a LPSS were examined in this randomized, blinded, crossover trial in volunteers having leg discomforts and edema after being in an upright position during the day. Participants were divided into two cohorts, and each type of stocking was worn for three consecutive days in one week with a subsequent washout phase. The assessment of effects and wearing comfort was ascertained by questionnaires. Volume changes in the lower leg were measured with the Bodytronic 600® (Bauerfeind AG, Zeulenroda, Germany).RESULTS:A significant reduction of lower leg volume (mean stocking A: 204.7 ml; mean stocking B: 153.5 ml; mean stocking C: 48.2 ml) and a significant reduction of the life-quality dimension leg-complaints (p < 0.0001) was achieved by all three types of stockings. Compared to the LPSS both compression stockings decreased the lower leg volume significantly more (p < 0.001) and had a significant better fit (p < 0.001).CONCLUSION:Below-knee medical compression stockings with an interface pressure 18-21mmHg and LPSS with an interface pressure of 8-10 mmHg reduce significantly occupational orthostatic edema and leg discomforts which are due to long standing and sitting activities.

ZusammenfassungHintergrundDie Basis für adäquate psychoonkologische Betreuung ist die Identifikation von Patienten mit psychosozialem Unterstützungsbedarf. Die Deutsche Arbeitsgemeinschaft für Psychoonkologie empfiehlt hierfür das Hornheider Screening‐Instrument (HSI). Die Frage: „Ist jemand in Ihrer Familie durch den Krankenhausaufenthalt besonders belastet?“ soll die krankheitsbedingte familiäre Belastung erfassen. Doch ist dieses Item für ambulante und stationäre Patienten gleichermaßen geeignet? Studienziel war zu überprüfen, wie sich das Ersetzen des Originalitems auf die Testgüte dieser modifizierten Version des HSI und die Häufigkeit psychosozialer Belastungen auswirkt.Patienten und Methodik92 ambulante und 98 stationäre Hauttumorpatienten schätzten ihre psychosoziale Situation mittels verschiedener Fragebögen ein.ErgebnisseIm Vergleich zu stationären Patienten bejahten weniger als halb so viele ambulante Patienten das Item. Wurde die Frage ersetzt durch: „Ist jemand in Ihrer Familie durch Ihre Erkrankung beziehungsweise den Krankheitsverlauf besonders belastet?“ zeigte sich dieser Setting‐bedingte Unterschied nicht. Das „Alternativ‐Item“ und die „Modifizierte Version des HSI“ (HSI‐MV) erwiesen sich dem Originalitem und dem Original‐HSI hinsichtlich aller untersuchten Kriterien überlegen.SchlussfolgerungenDie HSI‐MV kann als reliables und valides Instrument für die systematische Erhebung des psychosozialen Betreuungsbedarfes im ambulanten und stationären Setting eingesetzt werden. Je nach Versorgungskapazität ist ein Schwellenwert von ≥ 5 oder ≥ 4 geeignet. Zusätzlich zum Screening sollte der Unterstützungswunsch erfragt werden.

Data regarding the epidemiology of atopic dermatitis (AD) and associated atopic and psychological comorbidity in adults are limited. Previous population-based studies among European adults revealed AD prevalences ranging from 4.4% to 7.1%.1 Evidence suggests that AD is associated with a higher risk of other atopic disorders,2 and indicates that AD is related to depression and suicidal ideation in adult age.3 Moreover, somatization has been related to skin disorders,4 but data regarding the association of AD with somatization are rare. The present study aimed (i) to investigate the prevalence of physician-diagnosed AD by sex and age and (ii) to examine the association of physician-diagnosed AD with (indicators of) atopic and psychological comorbidities in a general population sample of adults. We analyzed data from 3035 participants (aged 20–83 years) from the Study of Health in Pomerania (SHIP)-TREND-0, a population-based project conducted in northeast Germany. The methods are detailed in the Appendix S1. In brief, AD was diagnosed by dermatologists in a standardized clinical examination. Using self-reports, we collected data on the lifetime history of allergy, hay fever, hyposensitization and asthma, and data on psychological comorbidities including depressive symptoms, suicidal tendencies and somatic symptoms. The overall prevalence of AD was 4.7% (95% CI 3.9–5.5%). Men and women did not differ in AD prevalence (4.2% vs. 5.3%; p = .696). The prevalence of AD significantly decreased across age (OR = 0.97; 95% CI 0.96–0.98) (Figure S1). Individuals with AD reported more often a higher level of school education, but a lower household income (Table S1). Multivariable regression analyses revealed positive associations of AD with allergy, hay fever, hyposensitization and asthma (Table 1). The relationship of AD with depressive symptoms and suicidal tendencies was non-significant, but we found evidence for an association of AD with somatic symptoms (Table 2). Back and lower back pain, neck and shoulder pain and joint pain were the most frequently reported somatic symptoms (Figure S2). The AD prevalence found in the present study was somewhat lower than the rates reported from other European countries,1 which might be explained by different measurements of AD and reference periods in previous research. Importantly, the majority of studies is based on self-reports of AD,1 which have limited validity. Our data contribute to the literature demonstrating that AD is related to multiple atopic comorbidities, but are in contrast to previous findings suggesting an association of AD with depression and suicidality.3 When interpreting these conflicting results, it must be noted that existing studies in this regard have limited comparability due to differences in study design and measurement of AD, depression and suicidality. Our finding that somatization is an important comorbidity is novel and may be significant for patient care. Somatization is important to consider because somatic symptoms may be one way to communicate psychological distress or mask depression.5 The following limitations should be noted. First, one-time skin examination as applied in the present study is likely to exclude mild or transient AD cases,6 potentially leading to underestimation of the AD prevalence. Second, disease severity might be a moderator of the association between AD and comorbidities, but data regarding AD severity were not available. Third, due to the study design, no causal inference can be drawn. In summary, the present study is the first to provide data about the prevalence of physician-diagnosed AD in a German adult general population sample. Our data confirm previous findings indicating that AD may be a systemic disease involving numerous allergic, respiratory and psychological comorbidities,2 and suggest that somatization is an important condition which needs awareness among dermatologists. Future research in longitudinal population-based cohorts with standardized assessments of AD and comorbidities is required. SHIP is part of the Community Medicine Research Network of the University of Greifswald, Germany. Examinations were funded by the Federal Ministry of Education and Research (Grant No. 03ZIK012), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Dr. Piontek, Dr. Ittermann, Dr. Arnold, Prof. Völzke and Prof. Baumeister have nothing to disclose. Prof. Apfelbacher reported consulting fees from Dr Wolff Group, Sanofi Genzyme, LEO Pharma; payment or honoraria for lectures, etc. from AstraZeneca; support for attending meetings and/or travel from Dr Wolff Group; and participation on a Data Safety Monitoring Board or Advisory Board in Dr Wolff Group. Prof. Apfelbacher is co-chair of the Harmonising Outcome Measures for Eczema (HOME) initiative. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Atopic dermatitis (AD) is a chronic, pruritic skin disease with increasing incidence (Mathiesen and Thomsen, 2019Mathiesen S.M. Thomsen S.F. The prevalence of atopic dermatitis in adults: systematic review on population studies.Dermatol Online J. 2019; 25: 13030Crossref PubMed Google Scholar). Although AD is classically thought of as a pediatric disease, recent studies have shown high rates of disease in adults as well, with a prevalence in Europe between 2.2% and 17.6% (Kowalska-Olędzka et al., 2019Kowalska-Olędzka E. Czarnecka M. Baran A. Epidemiology of atopic dermatitis in Europe.J Drug Assess. 2019; 8: 126-128Crossref PubMed Google Scholar). There is a growing body of evidence that sex hormones play a role in the complex interplay of ADs pathophysiology, influencing immunological pathways and the skin (Kanda et al., 2019Kanda N. Hoashi T. Saeki H. The roles of sex hormones in the course of atopic dermatitis.Int J Mol Sci. 2019; 20: 4660Crossref PubMed Scopus (59) Google Scholar). Previous epidemiological studies showed that serum levels of testosterone, dehydroepiandrosterone (Mihály et al., 2015Mihály J. Sonntag D. Krebiehl G. Szegedi A. Töröcsik D. Rühl R. Steroid concentrations in patients with atopic dermatitis: reduced plasma dehydroepiandrosterone sulfate and increased cortisone levels [published correction appears in Br J Dermatol 2015;172:1688].Br J Dermatol. 2015; 172: 285-288Crossref PubMed Scopus (5) Google Scholar), and estradiol were significantly lower in adult patients with AD than in healthy controls. In addition, sex hormones might influence ADs symptoms in women exposed to high fluctuating hormone concentrations (Cho et al., 2010Cho S. Kim H.J. Oh S.H. Park C.O. Jung J.Y. Lee K.H. The influence of pregnancy and menstruation on the deterioration of atopic dermatitis symptoms.Ann Dermatol. 2010; 22: 180-185Crossref PubMed Scopus (38) Google Scholar; Kanda et al., 2019Kanda N. Hoashi T. Saeki H. The roles of sex hormones in the course of atopic dermatitis.Int J Mol Sci. 2019; 20: 4660Crossref PubMed Scopus (59) Google Scholar). Yet, some studies reported no association between sex hormones and AD (Ebata et al., 1996Ebata T. Itamura R. Aizawa H. Niimura M. Serum sex hormone levels in adult patients with atopic dermatitis.J Dermatol. 1996; 23: 603-605Crossref PubMed Scopus (26) Google Scholar; Kasperska-Zajac et al., 2007Kasperska-Zajac A. Brzoza Z. Rogala B. Serum concentration of dehydroepiandrosterone sulfate and testosterone in women with severe atopic eczema/dermatitis syndrome.J Investig Allergol Clin Immunol. 2007; 17: 160-163PubMed Google Scholar). This study aims to examine the link between a large panel of sex hormones and AD in two independent studies to cover the time span of adolescence to young adulthood (Behavior and Mind Health Study [BeMIND]) as well as adulthood until old age (Study of Health in Pomerania [SHIP-TREND]). First, we used the BeMIND study as a longitudinal cohort study of a general population sample of adolescents and young adults from Dresden (Beesdo-Baum et al., 2020Beesdo-Baum K. Voss C. Venz J. Hoyer J. Berwanger J. Kische H. et al.The Behavior and Mind Health (BeMIND) study: methods, design and baseline sample characteristics of a cohort study among adolescents and young adults.Int J Methods Psychiatr Res. 2020; 29: e1804Crossref PubMed Scopus (17) Google Scholar). After exclusions, valid baseline data were available for n = 979 participants. Second, we used the SHIP-TREND study, a longitudinal cohort study of a general population sample of adults in West Pomerania (Völzke et al., 2011Völzke H. Alte D. Schmidt C.O. Radke D. Lorbeer R. Friedrich N. et al.Cohort profile: the study of health in Pomerania.Int J Epidemiol. 2011; 40: 294-307Crossref PubMed Scopus (826) Google Scholar). Valid baseline data were available for n = 992 participants. Both study protocols and their amendments were accepted by the ethics committee of the Technische Universität Dresden (Dresden, Germany)/Institutional Ethics and Scientific Review Committee of the University of Greifswald (Greifswald, Germany), and written informed consent was obtained from each participant and from all legal guardians (for minors). In BeMIND, AD was assessed by three items in an online questionnaire. (i) Did you ever suffer from neurodermatitis? (ii) Do you currently suffer from neurodermatitis? (iii) Has it been treated by a doctor? In SHIP-TREND, AD was assessed by the following questions: (i) Did you previously suffer from neurodermatitis but not at the moment? (ii) Do you currently suffer from neurodermatitis? (iii) Has it been diagnosed by a doctor? For participant`s better understanding, the term AD was replaced by the term neurodermatitis in the questionnaires. In addition, AD was diagnosed by a dermatologist, categorizing AD as acute, subacute, and chronic (overlap with self-reported diagnosis: 85.1%). In general, the diagnosis by a dermatologist is methodically preferable to a self-reported diagnosis or presence of a disease, but for the sake of comparability with the BeMIND study, we used the self-reports as the primary outcome and the diagnosis by a dermatologist further in sensitivity analyses. The outcome variable lifetime AD refers to the first question in BeMIND and to questions 1 and 2 in SHIP-TREND. The outcome current AD refers in both studies to the second question. Sex hormones were assessed as hair testosterone and hair dehydroepiandrosterone concentrations in BeMIND (Stalder and Kirschbaum, 2012Stalder T. Kirschbaum C. Analysis of cortisol in hair--state of the art and future directions.Brain Behav Immun. 2012; 26: 1019-1029Crossref PubMed Scopus (457) Google Scholar) by chemiluminescence immunoassays. In SHIP-TREND, serum testosterone, androstenedione, estradiol, and estrone concentrations were measured using liquid chromatography‒tandem mass spectrometry (methods for covariables and details of hair hormone measurement are provided in Supplementary Materials and Methods). All statistical analyses were conducted sex specific. In cross-sectional regression analyses, associations were analyzed using age- and multivariable-adjusted logistic regression models with effects presented as OR and their 95% confidence interval. Subsequently, we performed several sensitivity analyses ([i] AD diagnosed by a dermatologist; [ii] exclusion of oral contraceptives use; [iii] confounder: Tanner stage [Dirven-Meijer et al., 2008Dirven-Meijer P.C. Glazenburg E.J. Mulder P.G. Oranje A.P. Prevalence of atopic dermatitis in children younger than 4 years in a demarcated area in central Netherlands: the West Veluwe Study Group.Br J Dermatol. 2008; 158: 846-847Crossref PubMed Scopus (18) Google Scholar]; [iv] confounder age of onset; comorbid atopic conditions [allergic rhinitis, allergic asthma]; [v] stratifying by acute, subacute or chronic AD, respectively; vs. participants without AD in SHIP-TREND). Statistical power was calculated using the Stata command power (BeMIND = 0.84; SHIP-TREND = 0.81). In BeMIND, the weighted mean age of the analyzed study population was 17.9 years (SEM = 0.08). In SHIP-TREND, the weighted mean age of the analyzed study population was 48.6 years (SEM = 0.53) (Table 1). We found that cross-sectional analyses with sex hormones and AD yielded no consistent significant results in both sexes. The age-adjusted significant association of androstenedione and AD in SHIP-TREND was rendered nonsignificant after multivariable adjustment (Table 2). In all sensitivity analyses, the overall estimates including the levels of significance remained unchanged (Supplementary Table S1, Supplementary Table S2, Supplementary Table S3).Table 1Baseline Characteristics of the Study Populations in BeMIND and SHIP-TRENDBaselineCharacteristicsBeMINDTotal Analysis Sample (n = 979)BeMINDLifetime AD (n = 77)BeMINDNo Lifetime AD (n = 902)SHIP-TRENDTotal Analysis Sample (n = 992)SHIP-TRENDLifetime AD (n = 47)SHIP-TRENDNo Lifetime AD (n = 945)Age, y, mean (SEM)17.9 (0.08)17.6 (0.32)17.9 (0.08)48.6 (0.53)45.8 (2.83)48.7 (0.54)Sex, female, %47.652.247.852.661.452.5Education, %Low2.102.11.201.2Middle16.519.215.59.912.79.7High78.476.079.888.987.389.1Other2.94.72.5000Lifetime AD, %7.910004.731000Current AD, %3.943.802.047.60Waist circumference, cm78.2 (0.41)77.4 (1.17)78.2 (0.44)87.7 (0.43)83.7 (1.58)88.3 (0.42)Current smoker, %16.315.919.223.225.123.1Physically inactive, %35.537.332.125.636.425.1Sobriety, %23.124.420.211.121.710.6Use of oral contraceptives, %6.17.85.98.812.98.6Hair Testosterone, pg/mgMale0.96 (0.04)0.77 (0.11)0.97 (0.45)———Female0.54 (0.19)0.52 (0.05)0.54 (0.02)———Hair DHEA, pg/mgMale38.8 (2.7)40.7 (11.3)38.6 (2.7)———Female29.6 (1.3)31.6 (4.6)29.4 (1.4)———Serum Testosterone, nmol/l———Male———17.9 (0.27)19.5 (1.3)17.8 (0.27)Female———0.87 (0.02)0.86 (0.09)0.87 (0.01)Serum Androstendione, nmol/L———Male———3.21 (0.07)3.17 (0.35)3.22 (0.07)Female———2.62 (0.06)2.42 (0.22)2.63 (0.65)Serum Estrone, nmol/l———Male———124.5 (2.3)126.1 (9.57)124.6 (2.37)Female———189.2 (9.6)151.5 (25.1)191.7 (10.1)Serum Estradiol, nmol/l———Male———78.8 (1.44)89.1 (9.33)78.5 (1.46)Female———306.5 (20.2)344.1 (70.1.9)305.4 (20.4)Abbreviations: AD, atopic dermatitis; BeMIND, Behavior and Mind Health Study; DHEA, dehydroepiandrosterone; SHIP-TREND, Study of Health in Pomerania.Data are weighted percentages or mean (SEM). Open table in a new tab Table 2Cross-Sectional Associations of Sex Hormones with AD in BeMIND and SHIP-TRENDBeMINDHair TestosteroneHair DHEASHIP-TRENDSerum TestosteroneSerum AndrostenedioneSerum EstradiolSerum EstroneMalesFemalesMalesFemalesMalesFemalesMalesFemalesMalesFemalesMalesFemalesOR (95% CI)AD, lifetimeAge adjusted0.62 (0.30–1.29)0.95 (0.47–1.91)1.05 (0.97–1.13)0.74 (0.21–2.71)1.05 (0.97–1.13)0.74 (0.21–2.71)0.96 (0.71–1.32)0.66 (0.45–0.98)0.99 (0.98–1.00)0.99 (0.99–1.01)1.01 (0.99–1.02)0.99 (0.99–1.01)Multivariable adjusted0.61 (0.29–1.27)0.94 (0.46–1.88)1.02 (0.93–1.11)0.69 (0.17–2.69)1.02 (0.93–1.11)0.69 (0.17–2.69)1.01 (0.61–1.32)0.59 (0.41–1.02)1.01 (0.99–1.01)0.99 (0.99–1.01)1.01 (0.99–1.00)0.99 (0.99–1.01)AD, currentAge adjusted0.51 (0.17–1.54)0.88 (0.33–2.31)1.01 (0.97–1.14)0.51 (0.11–2.46)1.01 (0.97–1.14)0.51 (0.11–2.46)0.69 (0.45–1.08)0.63 (0.41–0.98)0.99 (0.97–1.01)0.99 (0.97–1.01)1.01 (0.97–1.02)0.99 (0.99–1.01)Multivariable adjusted0.54 (0.18–1.66)0.88 (0.32–2.39)0.97 (0.84–1.12)0.57 (0.15–2.19)0.97 (0.84–1.12)0.57 (0.15–2.19)0.62 (0.34–1.14)0.67 (0.43–1.06)0.99 (0.97–1.01)0.99 (0.98–1.01)1.01 (0.97–1.02)0.99 (0.96–1.02)Abbreviations: AD, atopic dermatitis; BeMIND, Behavior and Mind Health Study; CI, confidence interval; DHEA, dehydroepiandrosterone; SHIP-TREND, Study of Health in Pomerania.Data are weighted ORs and their 95% CIs. The multivariable model was adjusted for age; waist circumference; smoking status; physical inactivity; alcohol consumption; and hair color, frequency of hair cleaning, and hair treatment with heat in BeMIND. Open table in a new tab Abbreviations: AD, atopic dermatitis; BeMIND, Behavior and Mind Health Study; DHEA, dehydroepiandrosterone; SHIP-TREND, Study of Health in Pomerania. Data are weighted percentages or mean (SEM). Abbreviations: AD, atopic dermatitis; BeMIND, Behavior and Mind Health Study; CI, confidence interval; DHEA, dehydroepiandrosterone; SHIP-TREND, Study of Health in Pomerania. Data are weighted ORs and their 95% CIs. The multivariable model was adjusted for age; waist circumference; smoking status; physical inactivity; alcohol consumption; and hair color, frequency of hair cleaning, and hair treatment with heat in BeMIND. Contrarily to our hypotheses, neither baseline endogenous androgens nor estrogens were associated consistently with AD. Our findings link well with those of previous epidemiological research, reporting no association between sex hormones and AD in females (Ebata et al., 1996Ebata T. Itamura R. Aizawa H. Niimura M. Serum sex hormone levels in adult patients with atopic dermatitis.J Dermatol. 1996; 23: 603-605Crossref PubMed Scopus (26) Google Scholar; Kasperska-Zajac et al., 2007Kasperska-Zajac A. Brzoza Z. Rogala B. Serum concentration of dehydroepiandrosterone sulfate and testosterone in women with severe atopic eczema/dermatitis syndrome.J Investig Allergol Clin Immunol. 2007; 17: 160-163PubMed Google Scholar) and males (Nikolakis et al., 2016Nikolakis G. Stratakis C.A. Kanaki T. Slominski A. Zouboulis C.C. Skin steroidogenesis in health and disease.Rev Endocr Metab Disord. 2016; 17: 247-258Crossref PubMed Scopus (46) Google Scholar). Other studies, however, provided evidence for a link between sex hormones and AD in special settings (pregnancy, course of menstrual cycle [Cho et al., 2010Cho S. Kim H.J. Oh S.H. Park C.O. Jung J.Y. Lee K.H. The influence of pregnancy and menstruation on the deterioration of atopic dermatitis symptoms.Ann Dermatol. 2010; 22: 180-185Crossref PubMed Scopus (38) Google Scholar; Raghunath et al., 2015Raghunath R.S. Venables Z.C. Millington G.W. The menstrual cycle and the skin.Clin Exp Dermatol. 2015; 40: 111-115Crossref PubMed Scopus (47) Google Scholar]) and lower sex hormone levels in male patients with AD than in controls (Ebata et al., 1996Ebata T. Itamura R. Aizawa H. Niimura M. Serum sex hormone levels in adult patients with atopic dermatitis.J Dermatol. 1996; 23: 603-605Crossref PubMed Scopus (26) Google Scholar; Kimata, 2007Kimata H. Elevation of testosterone and reduction of transepidermal water loss by viewing a humorous film in elderly patients with atopic dermatitis.Acta Medica (Hradec Kralove). 2007; 50: 135-137Crossref PubMed Scopus (5) Google Scholar). Previous findings of lower testosterone concentrations in patients with AD were mostly obtained in older men (Kimata, 2007Kimata H. Elevation of testosterone and reduction of transepidermal water loss by viewing a humorous film in elderly patients with atopic dermatitis.Acta Medica (Hradec Kralove). 2007; 50: 135-137Crossref PubMed Scopus (5) Google Scholar), which might rather reflect the considerable phenomenological overlap between aging, hormonal changes, and clinical comorbidity instead of an AD-specific effect. The impact of sex hormones on AD might further be modulated by receptors and its sensitivity and intraindividual changes of sex hormone concentrations (Watanabe et al., 2018Watanabe Y. Makino E. Tajiki-Nishino R. Koyama A. Tajima H. Ishimota M. et al.Involvement of estrogen receptor α in pro-pruritic and pro-inflammatory responses in a mouse model of allergic dermatitis.Toxicol Appl Pharmacol. 2018; 355: 226-237Crossref PubMed Scopus (14) Google Scholar). The lack of association in this study might be due to the population-based approach with a relevant but low prevalence of AD and the overall low severity of AD. It might be supposed that neuroendocrinological changes may only be observed in clinical studies investigating patients with severe symptoms or relevant comorbidities, for example, the complement of the atopic triad. In addition, the type of AD might be important (not assessed in this study) because the intrinsic type of AD (10–20% of all patients with AD) with normal IgE might show different pathophysiological pathways from those of the extrinsic type. We consider the main strength of this study in the use of two independent, large, population-based cohorts with standardized data collection. Owing to the different age ranges and hormone panels in the two studies, they were not applied comparatively but complementarily. Limitations might have arisen from regional samples and the lack of information on polycystic ovarian syndrome and exact menstrual cycle timing (Supplementary Table S4). In summary, the findings of this study did not confirm the associations of endogenous sex hormones with AD in two population-based samples. Given the impact of stages of life with high fluctuation of sex hormones on AD severity in previous literature, future research with specific subgroups (participant in puberty, pregnancy, menopausal transition) in longitudinal analyses would be valuable. For Behavior and Mind Health Study, data that support the findings of this study are available from the corresponding author on reasonable request. For the Study of Health in Pomerania, data are publicly available for scientific and quality control purposes. The informed consent obtained from the participants of the Study of Health in Pomerania studies does not cover data storage in public databases owing to confidentially reasons. Data usage can be applied for through www.fvcm.med.uni-greifswald.de/dd_service/data_use_intro.php?lang=ger, an interface provided by the host institute of the Study of Health in Pomerania study to ensure compliance with all legislation. The staff of the Transferstelle ([email protected]) will on request detail the restrictions and any conditions under which access to the data may be provided and support with the application for the data. Hanna Kische: http://orcid.org/0000-0001-9235-7346 Anke Hannemann: http://orcid.org/0000-0003-4420-5449 Catharina Voss: http://orcid.org/0000-0002-5039-1949 Matthias Nauck: http://orcid.org/0000-0002-6678-7964 Henry Völzke: http://orcid.org/0000-0001-7003-399X Lars Pieper: http://orcid.org/0000-0003-0181-0112 Katja Beesdo-Baum: http://orcid.org/0000-0002-9687-5527 Andreas Arnold: http://orcid.org/0000-0002-8975-0320 The authors state no conflict of interest. The authors wish to thank Clemens Kirschbaum for his helpful contributions to this manuscript and his expertise in analyzing hair sex hormones. Behavior and Mind Health Study is part of the research program The epidemiology of functional and dysfunctional behavioral and psychological factors in health and disease funded by the German Federal Ministry of Education and Research (project numbers 01ER1303 and 01ER1703). The Study of Health in Pomerania is part of the Community Medicine Research Network of the University Medicine Greifswald (Germany), which is supported by the German Federal State of Mecklenburg-West Pomerania. The first author (HK) has been funded by the Maria-Reiche Habilitation fund of the Technische Universität Dresden during the conduct of the study. Conceptualization: HK, AH, KBB, AA; Formal Analysis: HK; Funding Acquisition: HV, KBB; Investigation: HK, CV, AA; Methodology: LP; Project Administration: CV, MN, HV, LP, KBB; Resources: MN; Supervision: KBB, AA; Validation: AH; Visualization: HK, AA; Writing - Original Draft Preparation: HK, AH; Writing - Review and Editing: CV, MN, HV, LP, KBB, AA To obtain the markers of long-term testosterone, dehydroepiandrosterone, and cortisol secretion, hair samples were taken by trained study personnel. Two hair strands of 3 mm in diameter each were cut as close as possible to the scalp from a posterior vertex position at baseline and at 1-year follow-up. The proximal 3 cm hair segment was used for analyses. On the basis of an average hair growth rate of 1 cm per month, these measurements reflect steroid hormone secretion within 3 months before assessment. Analyses were carried out at the laboratory of the Biopsychology Unit at Technische Universität Dresden (Dresden, Germany). The preanalytic procedures are described in detail elsewhere (Stalder and Kirschbaum, 2012Stalder T. Kirschbaum C. Analysis of cortisol in hair--state of the art and future directions.Brain Behav Immun. 2012; 26: 1019-1029Crossref PubMed Scopus (577) Google Scholar). Briefly, samples were washed twice in 2.5 ml isopropanol for 3 minutes, and steroid hormones were extracted from 7.5 mg of whole, nonpulverized hair using 1.8 ml methanol for 18 hours at room temperature. A total of 1.6 ml of the clear supernatant was transferred into a new 2 ml tube. Androgens and cortisol were measured using commercially available chemiluminescence immunoassays with high sensitivity (IBL-International, Hamburg, Germany). Hair and hair cosmetic-related information (hair color, frequency of hair cleaning, and hair treatment with heat) was obtained in a separate short interview. In Behavior and Mind Health Study, sex, age, and further sociodemographic information were assessed during the computer-assisted personal interview at the first personal appointment. At the second personal appointment, physical inactivity, alcohol and smoking habits, and information about hair treatment and medications, including information about oral contraceptives and corticoid medication, were assessed by personal interview together with hair sampling and were subsequently categorized. In this assessment, alcohol consumption was categorized into five self-reported categories, including never, on special occasions, once or twice in a month, once or twice in a week, and daily/almost daily. Self-reported information about smoking habits were categorized as current and no current smoker/never smoker. Waist circumference was measured utilizing a tape midway between the lower rib margin and the iliac crest in the horizontal plane rounded to the nearest millimeter. Tanner stage as an index of pubertal maturation was assessed by sex-specific questions in an online questionnaire. Individuals were told to rate themselves on sex-appropriate schematic drawings (pubic hair and genitalia development for boys; pubic hair and breasts development for girls). These self-ratings were averaged to generate scores from 1 (prepubertal) to 5 (adult) (Tanner, 1962Tanner J.M. Growth at adolescence. Oxford Blackwell Scientific Publications, Hoboken, NJ1962Google Scholar). In females, detailed information about menstruation status was not available at baseline. Education refers to low (attendance at main school [secondary school in Germany with lower secondary education [level 2 according to the International Standard Classification of Education], secondary modern school qualification), middle (high-school diploma, attendance of middle school [type of secondary/junior high school for ages 10–16 years]), high (academic high school, grammar school in Germany [secondary school International Standard Classification of Education level 3], college, senior technical college, university degree), and other (all other types of school). In the Study of Health in Pomerania, trends and sociodemographic and behavioral characteristics and medical history were assessed through a computer-assisted personal interview. In this assessment, mean daily alcohol consumption was calculated using beverage-specific pure ethanol volume proportions. Self-reported information about smoking habits was categorized into current, former, and never smokers. Individuals participating in physical training <1 hour a week during winter or summer were classified as physically inactive. Women were stratified into premenopausal and postmenopause statuses, categorizing all women aged <40 years and between ages 40 and 60 years who reported still experiencing menstrual cycling as premenopausal and all women aged >60 years together with all women between ages 40 and 60 years who reported experiencing no menstrual cycle as postmenopausal (details of this classification were previously published [Schwarz et al., 2007Schwarz S. Völzke H. Alte D. Schwahn C. Grabe H.J. Hoffmann W. et al.Menopause and determinants of quality of life in women at midlife and beyond: the study of health in pomerania (SHIP).Menopause. 2007; 14: 123-134Crossref PubMed Scopus (56) Google Scholar]). Waist circumference was measured utilizing a tape midway between the lower rib margin and the iliac crest in the horizontal plane rounded to the nearest millimeter. Oral contraceptive use was defined according to Anatomical Therapeutic Chemical classification code G03A. Educational status was assessed through a computer-assisted personal interview. Education refers to low (no graduation or attendance at main school for 9 years), middle (attendance of middle school [type of secondary/junior high school for ages 10–16 years]), high (academic high school, grammar school in Germany [secondary school International Standard Classification of Education level 3], college, senior technical college, university degree), and other (all other types of school).Supplementary Table S1Cross-Sectional Associations of Sex Hormones with AD in BeMIND without Participants Using Oral ContraceptivesHair TestosteroneHair DHEAFemalesOR (95% CI)AD, lifetimeAge adjusted1.03 (0.50–2.11)1.01 (0.99–1.01)Multivariable adjusted0.99 (0.48–2.07)1.01 (0.99–1.01)AD, currentAge adjusted0.94 (0.34–2.57)1.00 (0.98–1.01)Multivariable adjusted0.95 (0.33–2.69)1.01 (0.98–1.01)Abbreviations: AD, atopic dermatitis; BeMIND, Behavior and Mind Health Study; CI, confidence interval; DHEA, dehydroepiandrosterone.Data are weighted ORs and their 95% CIs. The multivariable model was adjusted for age, waist circumference, smoking status, physical inactivity, alcohol consumption, hair color, frequency of hair cleaning, and hair treatment with heat. Open table in a new tab Supplementary Table S2Cross-Sectional Associations of Sex Hormones with Diagnosed AD in SHIP-TRENDSerum TestosteroneSerum AndrostendioneSerum EstroneSerum EstradiolMalesFemalesMalesFemalesMalesFemalesMalesFemalesOR (95% CI)AD, currentAge adjusted1.04 (0.98–1.12)0.92 (0.33–2.53)0.94 (0.66–1.33)0.97 (0.71–1.33)0.97 (0.96–0.99)0.99 (0.99–1.01)0.98 (0.96–1.01)0.99 (0.99–1.01)Multivariable adjusted1.03 (0.96–1.13)0.92 (0.35–2.39)0.94 (0.69–1.30)1.01 (0.73–1.39)0.97 (0.97–0.99)0.97 (0.96–1.01)0.98 (0.96–1.01)0.99 (0.99–1.01)Abbreviations: AD, atopic dermatitis; CI, confidence interval; SHIP-TREND, Study of Health in Pomerania.Data are weighted ORs and their 95% CIs. The multivariable model was adjusted for age, waist circumference, smoking status, physical inactivity, and alcohol consumption. The outcome AD was diagnosed by a dermatologist and categorized as acute, subacute, and chronic. Open table in a new tab Supplementary Table S3Cross-Sectional Associations of Sex Hormones with AD in SHIP-TREND, Stratified by Acute, Subacute, and Chronic ADCurrent ADSHIP-TRENDFemalesSerum TestosteroneSerum AndrostenedioneSerum EstradiolSerum EstroneMalesFemalesMalesFemalesMalesFemalesMalesOR (95% CI)Acute1.01 (0.92–1.11)0.84 (0.21–3.36)0.78 (0.31–1.91)1.02 (0.35–2.92)0.98 (0.95–1.01)0.99 (0.97–1.01)0.96 (0.94–0.99)0.80 (0.64–1.01)Subacute1.01 (0.94–1.09)0.58 (0.14–2.44)0.93 (0.61–1.42)0.97 (0.63–1.49)0.99 (0.97–1.02)1.01 (0.99–1.02)0.97 (0.96–1.01)0.99 (0.99–1.01)Chronic1.07 (0.96–1.18)1.35 (0.43–4.22)1.07 (0.85–1.36)1.01 (0.60–1.69)0.97 (0.92–1.03)1.00 (0.97–1.03)0.97 (0.95–1.02)1.01 (0.99–1.03)Abbreviations: AD, atopic dermatitis; CI, confidence interval; SHIP-TREND, Study of Health in Pomerania.Data are weighted ORs and their 95% CIs. Presented is the multivariable model adjusted for age, waist circumference, smoking status, physical inactivity, and alcohol consumption. n = 7 for participants with acute AD, n = 25 for participants with subacute AD, and n = 8 for participants with chronic AD. Not every participant with AD has data regarding the used variable (acute, subacute, or chronic AD). Open table in a new tab Supplementary Table S4Additional Strengths and Limitations of this StudyBeMINDSHIP-TRENDOutcomeADLimitationStrengthAssessment of AD limited to self-report.In addition to self-reported AD, AD was assessed by dermatologist's diagnoses, categorizing AD as acute, subacute, and chronic.PredictorSex hormonesLimitationStrengthNo assessment of estrogens.Assessment of a large panel of sex hormones, including testosterone, androstenedione, estrone, estradiol.StrengthLimitationAssessment of sex hormones by hair samples, providing a long-term measurement. Using the simple and noninvasive collection of hair samples in BeMIND by trained and supervised study personnel ensures a standardized sampling method (in contrast to salivary samples with diurnal fluctuation and participant-responsible collection).Snapshot measurement of sex hormones in plasma.Measurement of sex hormonesLimitationStrengthFurther limitations were the hormone measurement through immunoassay, instead of liquid chromatography‒tandem mass spectrometry, especially regarding the low concentrations of androgens in females.The large panel of sex hormones was measured through liquid chromatography‒tandem mass spectrometry.Abbreviations: AD, Atopic dermatitis; BeMIND, Behavior and Mind Health Study; SHIP-TREND, Study of Health in Pomerania. Open table in a new tab Abbreviations: AD, atopic dermatitis; BeMIND, Behavior and Mind Health Study; CI, confidence interval; DHEA, dehydroepiandrosterone. Data are weighted ORs and their 95% CIs. The multivariable model was adjusted for age, waist circumference, smoking status, physical inactivity, alcohol consumption, hair color, frequency of hair cleaning, and hair treatment with heat. Abbreviations: AD, atopic dermatitis; CI, confidence interval; SHIP-TREND, Study of Health in Pomerania. Data are weighted ORs and their 95% CIs. The multivariable model was adjusted for age, waist circumference, smoking status, physical inactivity, and alcohol consumption. The outcome AD was diagnosed by a dermatologist and categorized as acute, subacute, and chronic. Abbreviations: AD, atopic dermatitis; CI, confidence interval; SHIP-TREND, Study of Health in Pomerania. Data are weighted ORs and their 95% CIs. Presented is the multivariable model adjusted for age, waist circumference, smoking status, physical inactivity, and alcohol consumption. n = 7 for participants with acute AD, n = 25 for participants with subacute AD, and n = 8 for participants with chronic AD. Not every participant with AD has data regarding the used variable (acute, subacute, or chronic AD). Abbreviations: AD, Atopic dermatitis; BeMIND, Behavior and Mind Health Study; SHIP-TREND, Study of Health in Pomerania.

The Musashi family of RNA-binding proteins controls several biological processes including stem cell maintenance, cell division and neural function. Previously, we demonstrated that the C. elegans Musashi ortholog, msi-1, regulates forgetting via translational repression of the Arp2/3 actin-branching complex. However, the mechanisms controlling MSI-1 activity during the regulation of forgetting are currently unknown. Here we investigated the effects of protein phosphorylation on MSI-1 activity. We showed that MSI-1 function is likely controlled by alterations of its activity rather than its expression levels. Furthermore, we found that MSI-1 is phosphorylated and using mass spectrometry we identified MSI-1 phosphorylation at three residues (T18, S19 and S34). CRISPR-based manipulations of MSI-1 phosphorylation sites revealed that phosphorylation is necessary for MSI-1 function in both short- and long-term aversive olfactory associative memory. Thus, our study provides insight into the mechanisms regulating memory-related MSI-1 activity and may facilitate the development of novel therapeutic approaches.

Musashi RNA-binding proteins (MSIs) retain a pivotal role in stem cell maintenance, tumorigenesis, and nervous system development. Recently, we showed in C. elegans that Musashi (MSI-1) actively promotes forgetting upon associative learning via a 3'UTR-dependent translational expression of the Arp2/3 actin branching complex. Here, we investigated the evolutionary conserved role of MSI proteins and the effect of their pharmacological inhibition on memory. Expression of human Musashi 1 (MSI1) and Musashi 2 (MSI2) under the endogenous Musashi promoter fully rescued the phenotype of msi-1(lf) worms. Furthermore, pharmacological inhibition of human MSI1 and MSI2 activity using (-)- gossypol resulted in improved memory retention, without causing locomotor, chemotactic, or learning deficits. No drug effect was observed in msi-1(lf) treated worms. Using Western blotting and confocal microscopy, we found no changes in MSI-1 protein abundance following (-)- gossypol treatment, suggesting that Musashi gene expression remains unaltered and that the compound exerts its inhibitory effect post-translationally. Additionally, (-)- gossypol suppressed the previously seen rescue of the msi-1(lf) phenotype in worms expressing human MSI1 specifically in the AVA neuron, indicating that (-)- gossypol can regulate the Musashi pathway in a memory-related neuronal circuit in worms. Finally, treating aged worms with (-)- gossypol reversed physiological age-dependent memory decline. Taken together, our findings indicate that pharmacological inhibition of Musashi might represent a promising approach for memory modulation.