Case Western Reserve University School of Medicine

Professional conduct embodies the treatment of patients, family members, and coworkers with dignity and kindness. These values underscore physicians’ unique position in society as healers and the vital importance of acknowledging diversity with sensitivity and compassion. The practice of medicine requires the highest standards of professionalism during clinical practice, education, and research. Modern medical bioethics is a framework composed of four pillars: patient autonomy, beneficence, nonmaleficence, and social justice. Physician impairment is the inability to safely fulfill these obligations of patient care secondary to substance use disorder, fatigue, or aging.

Importance Understanding environmental risk factors for gestational diabetes (GD) is crucial for developing preventive strategies and improving pregnancy outcomes. Objective To examine the association of county-level radon exposure with GD risk in pregnant individuals. Design, Setting, and Participants This multicenter, population-based cohort study used data from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) cohort, which recruited nulliparous pregnant participants from 8 US clinical centers between October 2010 and September 2013. Participants who had pregestational diabetes or were missing data on GD or county-level radon measurements were excluded from the current study. Data were analyzed from September 2023 to January 2024. Exposures County-level radon data were created by the Lawrence Berkeley National Laboratory based on the Environmental Protection Agency’s short- and long-term indoor home radon assessments. Radon exposure was categorized into 3 groups: less than 1, 1 to less than 2, and 2 or more picocuries (pCi)/L (to convert to becquerels per cubic meter, multiply by 37). Because radon, smoking, and fine particulate matter air pollutants (PM 2.5 ) may share similar biological pathways, participants were categorized by joint classifications of radon level (<2 and ≥2 pCi/L) with smoking status (never smokers and ever smokers) and radon level with PM 2.5 level (above or below the median). Main Outcomes and Measures The main outcome was GD, identified based on glucose tolerance testing and information from medical record abstraction. Multiple logistic regression models were used to assess the association between radon exposure and GD. Results Among the 9107 participants, mean (SD) age was 27.0 (5.6) years; 3782 of 9101 (41.6%) had ever used tobacco. The mean (SD) county-level radon concentration was 1.6 (0.9) pCi/L, and 382 participants (4.2%) had GD recorded. After adjusting for potential confounders, individuals living in counties with the highest radon level (≥2 pCi/L) had higher odds of developing GD compared with those living in counties with the lowest radon level (<1 pCi/L) (odds ratio [OR], 1.37; 95% CI, 1.02-1.84); after additional adjustment for PM 2.5 , the OR was 1.36 (95% CI, 1.00-1.86). Elevated odds of GD were also observed in ever smokers living in counties with a higher (≥2 pCi/L) radon level (OR, 2.09; 95% CI, 1.41-3.11) and participants living in counties with higher radon and PM 2.5 levels (OR, 1.93; 95% CI, 1.31-2.83), though no statistically significant interactions were observed. Conclusions and Relevance This cohort study suggests that higher radon exposure is associated with greater odds of GD in nulliparous pregnant individuals. Further studies are needed to confirm the results and elucidate the underlying mechanisms, especially with individual-level residential radon exposure assessment.

Purpose of Review This article discusses a tailored approach to managing cardiogenic shock and temporary mechanical circulatory support (tMCS). We also outline specific mobilization strategies for patients with different tMCS devices and configurations, which can be enabled by this tailored approach to cardiogenic shock management. Recent Findings Safe and effective mobilization of patients with cardiogenic shock receiving tMCS can be accomplished. Appropriate patient selection, tailored device management, and dynamic multidisciplinary approaches to mobilization are critical to success. Summary Cardiogenic shock is a heterogeneous condition characterized by end-organ dysfunction due to hypoperfusion and low cardiac output. Temporary mechanical circulatory support (tMCS) is an increasingly valuable tool in managing these patients, with various devices and configurations available. Critically ill patients receiving tMCS are at risk for complications and deconditioning associated with prolonged bed rest, making it essential to implement strategies that promote mobility when feasible. We advocate for a tailored approach to the selection and management of tMCS in patients with cardiogenic shock. This approach focuses on the early identification of patients who may benefit from tMCS before further deterioration, alongside the selection of devices that provide ventricular-specific support and facilitate upper-body cannulation to enhance mobilization while also considering patients’ potential exit strategies from tMCS. Understanding this approach is vital to appropriately facilitating safe and effective mobilization.

AI has changed the landscape of health professions education. With the hype now behind us, we find ourselves in the phase of reckoning, considering what's next; where do we start and how can educators use these powerful tools for daily teaching and learning. We recognize the great need for training to use AI meaningfully for education. Boyer's model of scholarship provides a pedagogical approach for teaching with AI and how to maximize these efforts towards scholarship. By offering practical solutions and demonstrating their usefulness, this Twelve tips article demonstrates how to apply AI towards scholarship by leveraging the capabilities of the tools. Despite their potential, our recommendation is to exercise caution against AI dependency and to role model responsible use of AI by evaluating AI outputs critically with a commitment to accuracy and scrutinize for hallucinations and false citations.

Background Despite recognition of the need to increase underrepresented groups (URG) engagement in Alzheimer’s disease and related dementias (ADRD) studies, enrollment remains low. As a first step in examining these disparities, these analyses aimed to compare referral sources for Alzheimer’s Disease Research Centers (ADRC) enrollment of URG participants. Method These analyses included data from 48,330 participants across 46 ADRCs, obtained through the National Alzheimer’s Coordinating Center Uniform Data Set. Generalized logistic regression models with generalized estimating equations were used to examine the association of racial/ethnic group and professional vs non‐professional referral source. The ‘professional’ category included referrals made by healthcare professionals or ADRC staff, while the ‘non‐professional’ category included referrals made by self, family or friends. This association was examined across the entire sample, and then individuals who had completed magnetic resonance imaging (MRI). The analyses were adjusted for age, gender, education, visit year, and categorical CDR with random site effect to adjust for study site. Result Descriptive statistics are shown in Table 1. Non‐Hispanic Black and Asian participants were less likely to have completed an MRI. Across the entire sample, Non‐Hispanic Black and Non‐Hispanic Asian participants were less likely to be referred by a professional contact than Non‐Hispanic White participants (Table 2). In those who had completed an MRI, there were no significant differences across the racial groups, although we note that the sample sizes for those with MRI were much smaller (Table 3). Results for both analyses were similar when only participants who had a diagnosis of MCI or dementia and a global CDR of 0.5 or 1 at baseline were included. Conclusion One major factor leading to lower rates of URG participation in ADRD research is disproportionately fewer healthcare professional referrals. To develop and optimize ADRC recruitment strategies, future studies are needed to explore reasons for differences in URG referrals by healthcare professionals and non‐professionals.

Background For clinical trials or patient care, reports from a person familiar with the trajectory of a participant’s cognitive and functional performance (i.e., proxies) may improve adjudication of events, such as mild cognitive impairment and dementia. Proxies offer a unique perspective on cognitive status that is different from what is captured through standard cognitive examinations. Clinical trials in which cognitive status is adjudicated, such as the Systolic Blood Pressure Intervention (SPRINT) trial, provide information about the contributions and consistency of proxies throughout extended follow‐up. Method SPRINT participants named proxies and relationship to them at study onset. Proxies provided information for the Functional Activities Questionnaire and Dementia Questionnaire. We collapsed proxy relationships into seven categories and evaluated the proportion of proxies in each category at baseline and how frequently the same proxy was retained to the last visit. We explored associations between proxy relationship and various baseline demographics and examined the association between not having a proxy, as well as proxy relationship, and adjudicated outcome. Result Of the 9,361 randomized SPRINT participants (35.6% female, mean age 67.9 years), 7,586 (81%) participants listed a proxy relationship from which we identified 7 categories: spouse/partner (51.7%), child (23.6%), sibling (8.7%), other family member (6.2%), and unrelated (8.8%). Male participants were more likely to name a spouse as their proxy (64%) while female participants more likely to name a child (42%). The overall consistency of proxy continuation between the baseline and final SPRINT visit (mean 6.9 years) was 90.7%. Proxy consistency from first visit to last visit for a child was 94.8%, spouse/partner (91.9%) brother/sister (87.5%), other family member (82.4%), non‐related (81.2%), and parent (78.2%). Adjudications that resulted in ‘Cannot Classify’ were greatest for proxies who were parents (15%) followed by none (12%), sibling and grandchild (9%), child and unrelated (7%), spouse and other family (6%). Conclusion The majority of proxies in SPRINT were immediate family members (spouse, child, or sibling). Over 90% of identified proxies at baseline continued to be available over a mean of almost 7 years of follow‐up. Not having a proxy available led to a higher rate of ‘cannot classify’ adjudications.

Background Plasma amyloid‐beta (Aβ) 42/40 ratio and phosphorylated tau 181 (pTau181) are promising blood biomarkers for AD. Compared to heterogenous clinical phenotypes, they are more objective and proximal to the pathological hallmarks of Aβ plaques and tau tangles. Biomarker‐guided clustering using Aβ42/40 and pTau181 can potentially establish subpopulations that share similar mechanisms of AD and treatment responses. Method Plasma biomarkers were measured using Simoa™ Neuro‐3Plex, 4Plex, and pTau181 Advantage V2 assays. To eliminate potential confounding effects, age, sex, and study center were regressed out of Aβ42/40 and pTau181 using a quadratic regression model. Adjusted biomarkers were then normalized for unsupervised K‐means clustering, with the optimal number of clusters determined by the elbow method and Silhouette score. To interpret the cluster profiles, we explored the differences in demographics and clinical features between clusters. We also examined the association between clusters and neuropsychological tests adjusting for age, sex, study center, APOE e4 alleles, and diagnosis. Result We analyzed plasma biomarkers from 593 Amish individuals (age ³ 60 years old) living in Ohio and Indiana. 62% were females, and the average age was 81.7 ± 5.7 years. Utilizing plasma Aβ42/40 and pTau181, the clustering approach yielded six distinct clusters (N = 92, 95, 94, 152, 75, and 85) whose composition was driven by varying burdens of amyloid and tau pathology. There was no significant difference in proportion of cognitive impairment or of family structure across clusters. As expected, the low Aβ42/40 and high ptau cluster (Cluster 6) featured a significantly higher proportion of APOE e4 carriers than other clusters combined (51% vs 22%, p = 0.002). No significant associations were found between clusters and neuropsychological tests. Conclusion The integrated analysis of plasma Aβ42/40 and pTau181 in the Amish established six clusters with varying levels of amyloid and tau burden, suggesting possible differences that need to be further explored. Examination of potential genetic or pathophysiological differences across the clusters are underway.

Background Late‐Onset Alzheimer’s Disease (LOAD) is characterized by genetic heterogeneity and there is no single model explaining the genetic mode of inheritance. To date, more than 70 genetic loci associated with AD have been identified but they explain only a small proportion of AD heritability. Structural variants (SVs) may explain some of the missing AD heritability, and specifically, their segregation in AD families has yet to be investigated. Method We analyzed WGS data from 197 NHW families (926 subjects, 58.5% affected) and 214 CH families (1,340 subjects, 59.17% affected). Manta, Absinthe, and MELT were used for large insertions/deletions calling from short‐read WGS, combined with Sniffles2 calls from 4 ONT‐sequenced genomes and an external SV call set from HGSVC on 32 PacBio‐sequenced genomes from the 1000 Genomes Project. Genotyping produced a unified project‐level VCF. We identified 45,251 insertions and 76,566 deletions genome‐wide. Variants were tested for segregation and pathogenicity using Annot‐SV, cadd‐SV, and Variant Effect Predictor. Segregation required SV presence in all affected family members and only in unaffected members five years younger than average disease onset. Result We identified 453 insertions and 598 deletions segregating in 78.68% and 87.31% of NHW families, respectively. In CH families, 432 insertions and 460 deletions were segregating in 75.23% and 72.90% of the families, respectively. Genes overlapping with the SVs exhibited high expression levels in brain tissues. Notably, around 93% of insertions and 76% of deletions segregating in NHW and CH families were less than 1 kilobase pair (1kbp) in length. A total of 79 insertions and 96 deletions were found to be segregating in both NHW and CH families. Interestingly, a segregating insertion was observed in CH families overlapping within the CACNA2D3 gene, which was previously reported in a CH GWAS for clinical AD. A deletion segregating in NHW overlapped with the PSEN1, and another in a CH family overlapped with the PTK2B gene. Conclusion Our findings suggested that there are several SVs associated with familial AD across CH and NHW families. Prioritizing the SVs based on their effects on gene function and expression will be helpful in understanding their contributions in AD.

Background Malawians, in Sub‐Saharan Africa (SSA), face the double burden of HIV and Alzheimer’s disease and related dementia (ADRD). The life expectancy among HIV‐positive people on antiretroviral therapy has increased consistently over the past 25 years. The purpose of the study was to determine the prevalence of dementia among people living with HIV (PLWHIV) and the general population without HIV as a comparison group in Malawi. Methods We conducted a retrospective medical records review of four hundred consecutive patients from a single tertiary health center (200 PLWHIV from the HIV clinic and 200 without HIV from an outpatient clinic) in Lilongwe, Malawi. Since there was no electronic medical records system in Malawi, trained data collectors manually reviewed the medical records based on the instrument devices and the definitions between August 2023 and October 2023. We examined dementia prevalence and clinical characteristics including age, gender, and other clinical history between PLWHIV and the comparison group. Results The PLWHIV group was significantly younger than the comparison group (mean age = 44.23±8.07 vs. 57.67±16.28; p<2e‐16), while there was no significant difference in sex (male 55% vs. 50%; p = 0.37). The overall prevalence of dementia was higher in PLWHIV than that in the comparison group (22% vs. 10%; p = 1.4e‐03 before adjusting for age and p = 1.9e‐07 after adjusting for age). Prevalence difference was higher in the older individuals (age>50; 39% vs. 13%; p = 3.2e‐4 before adjusting for age and p = 4.9e‐07 after adjusting for age). Dementia increased with age in both groups: 13% (age<45), 17% (45‐64), and 22% (65 and over), but more rapidly in PLWHIV than in the comparison group (17%, 28% and 50% vs. 5%, 4% and 20% respectively). Conclusion This is the first study to demonstrate prevalence of dementia in PLWHIV was significantly higher than that of the general population in Malawi. We confirmed the increased risk of dementia in PLWHIV and provided valuable groundwork for future ADRD research in SSA, specifically in Malawi.

Hematopoietic stem cells must mitigate myriad stressors throughout their lifetime to ensure normal blood cell generation. Here, we uncover unfolded protein response stress sensor inositol-requiring enzyme-1α (IRE1α) signaling in hematopoietic stem and progenitor cells (HSPCs) as a safeguard against myeloid leukemogenesis. Activated in part by an NADPH oxidase-2 mechanism, IRE1α-induced X-box binding protein-1 (XBP1) mediated repression of pro-leukemogenic programs exemplified by the Wnt–β-catenin pathway. Transcriptome analysis and genome-wide mapping of XBP1 targets in HSPCs identified an ‘18-gene signature’ of XBP1-repressed β-catenin targets that were highly expressed in acute myeloid leukemia (AML) cases with worse prognosis. Accordingly, IRE1α deficiency cooperated with a myeloproliferative oncogene in HSPCs to cause a lethal AML in mice, while genetic induction of XBP1 suppressed the leukemia stem cell program and activity of patient-derived AML cells. Thus, IRE1α–XBP1 signaling safeguards the integrity of the blood system by restricting pro-leukemogenic programs in HSPCs.

Patients with differences in sex development or intersex traits (DSD/I) struggle to find clinically competent care in adulthood. We sought to describe the surgical exposure of Urogynecology and Reconstructive Pelvic Surgery (URPS) fellows who had previously trained in ObGyn (URPS-Gyn) to patients with DSD/I and their interest in performing 18 relevant procedures. We hypothesized that most graduating fellows would not have had exposure to many of the surgeries. We administered a cross-sectional online questionnaire of graduating URPS-Gyn fellows from April to June 2021. Questions assessed procedural knowledge, training, and clinical interest. Of 56 eligible URPS-Gyn fellows graduating in 2021, a total of 14 completed the survey. Twelve (86%) had heard about most procedures (14 out of 18 surgeries listed); however, there was heterogeneity in exposure to specific surgeries and self-reported preparedness to perform them. Respondents were more interested in performing procedures that they were prepared to perform. Only 6 out of 11 who responded to questions about beliefs in training felt that it was important for residents to receive training regarding surgeries for patients with intersex traits, and only 8 felt it important for fellows to receive this surgical training. Three anticipated seeing patients with intersex traits. Graduating URPS-Gyn fellows expressed interest in performing surgeries to meet the needs of patients with DSD/I. However, respondents had heterogeneous exposure and self-assessments of their proficiency. URPS-Gyn providers may be key collaborators in providing care for the growing number of adults with DSD/I seeking care.

Purpose Describe aims, methods, characteristics of donors, donor corneas and recipients, and potential impact of the Diabetes Endothelial Keratoplasty Study (DEKS). Methods The DEKS is a randomized, clinical trial to assess graft success and endothelial cell density (ECD) 1 year after Descemet membrane endothelial keratoplasty (DMEK) using corneas from donors with versus without diabetes in a 1:2 minimization assignment. Diabetes severity in the donor is assessed by medical history, postmortem HbA1c, and donor skin advanced glycation end-products and oxidation markers. A central image analysis reading center assesses baseline donor, 1-month and 1-year postoperative ECD. Results The DEKS used corneas from 1154 donors for 1421 DMEK procedures on 1097 participants (324 bilateral) at 28 clinical sites. Forty-eight tissue preparations failed (3%). Mean donor age was 65 years; mean eye bank–determined screening ECD was 2709 cells/mm ² . Ultimately, 106 (9%) of 1154 donors without diabetes history were classified as diabetic based on postmortem HbA1c ≥6.5%, and 509 (36%) of 1421 donor lenticules were classified as coming from diabetic donors. Recipients were 58% female, 96% White, and 53% phakic. Study eyes were treated for Fuchs endothelial corneal dystrophy (96%), pseudophakic corneal edema (2%), and failed endothelial keratoplasty (2%). Mean recipient age was 70 years; 21% had diabetes history and 26 (2%) had central laboratory determined HbA1c ≥6.5% without diabetes history. Conclusions The DEKS will increase understanding of factors related to DMEK success while determining whether diabetes and/or diabetes severity in the donor and/or recipient adversely affects graft success and endothelial cell loss.

Neutrophils are peripheral blood‐circulating leukocytes that play a pivotal role in host defense against bacterial pathogens which upon activation, they release web‐like chromatin structures called neutrophil extracellular traps (NETs). Here, we analyzed and compared the importance of myeloid differentiation factor 88 (MYD88), peptidyl arginine deiminase 4 (PAD4), and gasdermin D (GSDMD) for NET formation in vivo following sepsis and neutrophilia challenge. Injection of lipopolysaccharide (LPS)/E. coli or the transgenic expression of granulocyte colony‐stimulating factor (G‐CSF), each induced NET‐mediated lethal vascular occlusions in mice with combined genetic deficiency in Dnase1 and Dnase1l3 (D1/D1l3−/−). In accordance with the signaling of toll‐like receptors, Myd88/D1/D1l3−/− animals were protected from the formation of lethal intravascular NETs during septic conditions. However, this protection was not observed during neutrophilia. It was unexpected to find that both Gsdmd/D1/D1l3−/− and Pad4/D1/D1l3−/− mice were fully capable of forming NETs upon LPS/E.coli challenge. Sepsis equally triggered a similar inflammatory response in these mice characterized by formation of DNA‐rich thrombi, vessel occlusions, and mortality from pulmonary embolism, compared to D1/D1l3−/− mice. Pharmacologic GSDMD inhibitors did not reduce PMA‐stimulated NET formation in ex vivo models either. Similarly, neither Pad4 nor GSDMD deficiency affected intravascular occlusive NET formation upon neutrophilia challenge. The magnitude of NET production, multi‐organ damage, and lethality were comparable to those observed in challenged control mice. In conclusion, our data indicate that NET formation during experimental sepsis and neutrophilia is regulated by distinct stimulus‐dependent pathways that may be independent of canonical PAD4 and GSDMD.

Background Meningiomas exhibit considerable clinical and biological heterogeneity. We previously identified four distinct molecular groups (immunogenic, NF2-wildtype, hypermetabolic, proliferative) that address much of this heterogeneity. Despite the utility of these groups, the stochasticity of clustering methods and the use of multi-omics data for discovery limits the potential for classifying prospective cases. We sought to address this with a dedicated classifier. Methods Using an international cohort of 1698 meningiomas, we constructed and rigorously validated a machine learning-based molecular classifier using only DNA methylation data as input. Original and newly-predicted molecular groups were compared using DNA methylation, RNA sequencing, copy number profiles, whole exome sequencing, and clinical outcomes. Results We show that group-specific outcomes in the validation cohort are nearly identical to those originally described, with median PFS of 7.4 (4.9-Inf) years in hypermetabolic tumors and 2.5 (2.3-5.3) years in proliferative tumors (not reached in the other groups). Tumors classified as NF2-wildtype had no NF2 mutations, and 51.4% had canonical mutations previously described in this group. RNA pathway analysis revealed upregulation of immune-related pathways in the immunogenic group, metabolic pathways in the hypermetabolic group and cell-cycle programs in the proliferative group. Bulk deconvolution similarly revealed enrichment of macrophages in immunogenic tumours and neoplastic cells in hypermetabolic and proliferative tumours with similar proportions to those originally described. Conclusions Our DNA methylation-based classifier, which is publicly available for immediate clinical use, recapitulates the biology and outcomes of the original molecular groups as assessed using multiple metrics/platforms that were not used in its training.

The oestrogen receptor (ER or ERα), a nuclear hormone receptor that drives most breast cancer¹, is commonly activated by phosphorylation at serine 118 within its intrinsically disordered N-terminal transactivation domain2,3. Although this modification enables oestrogen-independent ER function, its mechanism has remained unclear despite ongoing clinical trials of kinase inhibitors targeting this region4, 5–6. By integration of small-angle X-ray scattering and nuclear magnetic resonance spectroscopy with functional studies, we show that serine 118 phosphorylation triggers an unexpected expansion of the disordered domain and disrupts specific hydrophobic clustering between two aromatic-rich regions. Mutations mimicking this disruption rescue ER transcriptional activity, target-gene expression and cell growth impaired by a phosphorylation-deficient S118A mutation. These findings, driven by hydrophobic interactions, extend beyond electrostatic models and provide mechanistic insights into intrinsically disordered proteins⁷, with implications for other nuclear receptors⁸. This fundamental sequence–structure–function relationship advances our understanding of intrinsic ER disorder, crucial for developing targeted breast cancer therapeutics.