Margit Burmeister

Cannabis exposure has increased with greater legalization, yet little is known about cannabis and its possibly relevant impacts on hair biology. The literature suggests that inhalative byproducts and endocannabinoid signaling can affect processes that may affect anagen stability, and, as hair follicles are metabolically active organs susceptible to oxidative and inflammatory damage, they could be affected as well. Therefore, this study intends to understand whether population-based cannabis exposure behaviors statistically correlate with symptoms characteristic of diffuse shedding when applied to a virtual population. A synthetic dataset of 140 individuals was generated using a Monte Carlo framework parameterized by published trichoscopy-based follicular density values, national cannabis use statistics, and psychometric properties reported for hair loss and dermatologic quality of life measures. Cannabis exposure, density, and SAHL scores were sampled from probability distributions specified by published means, standard deviations, and plausible covariance structures rather than from individual-level patient data. The simulated dataset was then subjected to Pearson correlations, linear regression, and ANCOVA with demographic covariates. Higher cannabis exposure was associated with increased SAHL severity (r = 0.31, p < 0.01) and reduced follicular density (r = -0.38, p < 0.05). Both associations remained statistically significant after covariate adjustment, and female-assigned profiles showed larger effect magnitudes. These associations reflect patterns in the modeled population structure rather than clinical observations, but they parallel mechanistic pathways described in oxidative stress and hair cycle research. As a simulation study, these results cannot establish causality and are limited by underlying assumptions in the source distributions. However, they demonstrate that publicly available data and computational modeling can be combined to generate preliminary hypotheses about how cannabis exposure patterns may align with characteristics observed in telogen effluvium. Future work should integrate empirical biomarkers, longitudinal imaging, and clinical datasets to determine whether these modeled patterns correspond to measurable biological effects.

Polygenic risk scores (PRSs) can reduce lifetime disease risk by guiding embryo selection during in vitro fertilization (IVF). We performed genome-wide association meta-analyses totaling ∼1.5 million individuals to construct state-of-the-art PRSs for nine diseases: Alzheimer’s disease, breast cancer, coronary artery disease, endometriosis, hypertension, prostate cancer, rheumatoid arthritis, type 1 diabetes, and type 2 diabetes. The resulting predictors achieved liability-scale R ² values of up to 22.9% for type 2 diabetes, matching or exceeding previously published benchmarks across all scores. Three PRS - Alzheimer’s disease, prostate cancer, and type 2 diabetes - explained over 75% of the common-SNP heritability. Within-family validation in 40,872 siblings across 18,840 families showed that, for eight of nine diseases, predictive performance was comparable to population-level results, confirming substantial direct genetic effects. Modeling of embryo selection suggests that couples with five euploid embryos could achieve 27-67% relative risk reduction across diseases. While the limitations of genetic data availability meant that these estimates were performed in European ancestry samples, we performed validation in the multi-ancestry US-based All of Us Biobank, demonstrating significant statistical power across ancestries. These findings support the clinical applicability of PRS-guided embryo selection to reduce the burden of common diseases.

Objectives: Spinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene has recently been recognized as a common cause of late‐onset hereditary cerebellar ataxia. Here we present the first report of this disease in the US population, characterizing its clinical manifestations, disease progression, pathological abnormalities, and response to 4‐aminopyridine in a cohort of 102 patients bearing GAA repeat expansions.Methods: We compiled a series of patients with SCA27B, recruited from 5 academic centers across the United States. Clinical manifestations and patient demographics were collected retrospectively from clinical records in an unblinded approach using a standardized form. Post‐mortem analysis was done on 4 brains of patients with genetically confirmed SCA27B.Results: In our cohort of 102 patients with SCA27B, we found that SCA27B was a late‐onset (57 ± 12.5 years) slowly progressive ataxia with an episodic component in 51% of patients. Balance and gait impairment were almost always present at disease onset. The principal finding on post‐mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis. Similar to European populations, a high percent of patients 21/28 (75%) reported a positive treatment response with 4‐aminopyridine.Interpretation: Our study further estimates prevalence and further expands the clinical, imaging and pathological features of SCA27B, while looking at treatment response, disease progression, and survival in patients with this disease. Testing for SCA27B should be considered in all undiagnosed ataxia patients, especially those with episodic onset. ANN NEUROL 2024;96:1092–1103

Accumulation of sphingolipids, especially sphingosines, in the lysosomes is a key driver of several lysosomal storage diseases. The transport mechanism for sphingolipids from the lysosome remains unclear. Here, we identified SPNS1, which shares the highest homology to SPNS2, a sphingosine-1-phosphate (S1P) transporter, functions as a transporter for lysolipids from the lysosome. We generated Spns1 -KO cells and mice and employed lipidomic and metabolomic approaches to reveal SPNS1 ligand identity. Global KO of Spns1 caused embryonic lethality between E12.5 and E13.5 and an accumulation of sphingosine, lysophosphatidylcholines (LPC), and lysophosphatidylethanolamines (LPE) in the fetal livers. Similarly, metabolomic analysis of livers from postnatal Spns1 -KO mice presented an accumulation of sphingosines and lysoglycerophospholipids including LPC and LPE. Subsequently, biochemical assays showed that SPNS1 is required for LPC and sphingosine release from lysosomes. The accumulation of these lysolipids in the lysosomes of Spns1 -KO mice affected liver functions and altered the PI3K/AKT signaling pathway. Furthermore, we identified 3 human siblings with a homozygous variant in the SPNS1 gene. These patients suffer from developmental delay, neurological impairment, intellectual disability, and cerebellar hypoplasia. These results reveal a critical role of SPNS1 as a promiscuous lysolipid transporter in the lysosomes and link its physiological functions with lysosomal storage diseases.

Recent studies using cell type–specific knockout mouse models have improved our understanding of the pathophysiological relevance of suppressor of lin-12-like–HMG-CoA reductase degradation 1 (SEL1L-HRD1) endoplasmic reticulum–associated (ER-associated) degradation (ERAD); however, its importance in humans remains unclear, as no disease variant has been identified. Here, we report the identification of 3 biallelic missense variants of SEL1L and HRD1 (or SYVN1) in 6 children from 3 independent families presenting with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, hypotonia, and/or ataxia. These SEL1L (p.Gly585Asp, p.Met528Arg) and HRD1 (p.Pro398Leu) variants were hypomorphic and impaired ERAD function at distinct steps of ERAD, including substrate recruitment (SEL1L p.Gly585Asp), SEL1L-HRD1 complex formation (SEL1L p.Met528Arg), and HRD1 activity (HRD1 p.Pro398Leu). Our study not only provides insights into the structure-function relationship of SEL1L-HRD1 ERAD, but also establishes the importance of SEL1L-HRD1 ERAD in humans.

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.

Gamification, the application of gaming elements to increase enjoyment and engagement, has the potential to improve the effectiveness of digital health interventions, while the effectiveness of competition gamification components remains poorly understood on residency. To address this gap, we evaluate the effect of smartphone-based gamified team competition intervention on daily step count and sleep duration via a micro-randomized trial on medical interns. Our aim is to assess potential improvements in the factors (namely step count and sleep) that may help interns cope with stress and improve well-being. In 1779 interns, team competition intervention significantly increases the mean daily step count by 105.8 steps (SE 35.8, p = 0.03) relative to the no competition arm, while does not significantly affect the mean daily sleep minutes (p = 0.76). Moderator analyses indicate that the causal effects of competition on daily step count and sleep minutes decreased by 14.5 steps (SE 10.2, p = 0.16) and 1.9 minutes (SE 0.6, p = 0.003) for each additional week-in-study, respectively. Intra-institutional competition negatively moderates the causal effect of competition upon daily step count by −90.3 steps (SE 86.5, p = 0.30). Our results show that gamified team competition delivered via mobile app significantly increases daily physical activity which suggests that team competition can function as a mobile health intervention tool to increase short-term physical activity levels for medical interns. Future improvements in strategies of forming competition opponents and introducing occasional competition breaks may improve the overall effectiveness.

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 studies with 88,316 MD cases and 902,757 controls to previously reported data from individuals of European ancestry. This includes samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latinx participants (32%). The multi-ancestry GWAS identified 190 significantly associated loci, 53 of them novel. For previously reported loci from GWAS in European ancestry the power-adjusted transferability ratio was 0.6 in the Hispanic/Latinx group and 0.3 in each of the other groups. Fine-mapping benefited from additional sample diversity: the number of credible sets with ≤5 variants increased from 3 to 12. A transcriptome-wide association study identified 354 significantly associated genes, 205 of them novel. Mendelian Randomisation showed a bidirectional relationship with BMI exclusively in samples of European ancestry. This first multi-ancestry GWAS of MD demonstrates the importance of large diverse samples for the identification of target genes and putative mechanisms.

During their first year of medical residency (internship), 35% of training physicians in the United States suffer at least one depression episode. We assessed whether there is a similar increase of depression among first year residents in China, and identified predictors of depression in the two systems. 1006 residents across three cohorts (2016–2017, 2017–2018 and 2018–2019) at Shanghai Jiao Tong University and Peking Union Medical College were assessed in parallel with three cohorts of 7028 residents at 100 + US institutions. The Patient Health Questionnaire-9 (PHQ-9) depressive symptoms were measured at baseline and quarterly. Demographic, personal and residency factors were assessed as potential predictors of PHQ-9 depression scores. Similar to training interns in the US, the proportion of participants in China who met depression criteria at least once during the first year of residency increased substantially, from 9.1 to 35.1%. History of depression and symptoms at baseline were common factors significantly associated with depression during residency. By contrast, neuroticism, early family environment, female gender and not being coupled were associated with depression risk only in the US, while young age was a predictor of depression only in China. Fear of workplace violence also was a predictor in China. Long duty hours and reduced sleep duration emerged as training predictors of depression in both countries. The magnitude of depression increase and work-related drivers of depression were similar between China and the US, suggesting a need for effective system reforms in both systems.