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Background: Intersection of gender and race and/or ethnicity in academic medicine is understudied; we aim to understand these factors in relation to scholarly achievements for neurology faculty. Methods: Faculty from 19 US neurology departments completed a survey (2021-2022) to report rank, leadership positions, publications, funded projects, awards, and speaker invitations. Regression analyses examined effects of gender, race, and their intersectionality on these achievements. Women, Black/Indigenous/People of Color (BIPOC), and BIPOC women were comparator groups. Results: Four hundred sixty-two faculty responded: 55% women, 43% men; 31% BIPOC, 63% White; 21% BIPOC women, 12% BIPOC men, 36% White women, 31% White men. Men and White faculty are more likely to be full professors than women and BIPOC faculty. The number of leadership positions, funded projects, awards, and speaker invitations are significantly greater in White compared to BIPOC faculty. Relative to BIPOC women, the number of leadership positions is significantly higher among BIPOC men, White women, and White men. Publication numbers for BIPOC men are lower, number of funded projects and speaker invitations for White women are higher, and number of awards among White men and White women is higher compared to BIPOC women. Discussion: Our study highlights that inequities in academic rank, award number, funded projects, speakership invitations, and leadership roles disproportionately impacted BIPOC women. More studies are needed to evaluate gender and race and/or ethnicity intersectionality effects on faculty achievements, reasons for inequities, recognition, and potential solutions.

Objective: To investigate the perceptions of lactation experiences of neurology faculty and the impact of lactation time on academic achievement. Materials and Methods: This was a cross-sectional study utilizing a survey administered across 19 academic neurology centers in the United States. Respondents self-identified as having children and answered questions about lactation at work. Demographic information; academic achievement including publications, guest speakerships, awards, leadership roles, and funding; and perception of lactation experience were analyzed. Results: Among 162 respondents, 83% took lactation time at work. Thirty-seven percent reported lack of employer support for lactation, 46% were dissatisfied with their lactation experience, 59% did not receive compensation for lactation time, 62% did not have blocked clinical time, 73% reported relative value units were not adjusted to accommodate lactation, and 43% reported lack of access to private lactation space. Women spent on average 9.5 months lactating per child and desired 2.4 further months of lactation. There was no difference in all measures of self-reported academic achievement between women who did and did not take lactation time when measured across all career stages. Conclusions: Although a majority of respondents took lactation time at work, perceptions of employer support for lactation were low, and expectations for work productivity were not adjusted to accommodate lactation time. Taking lactation time at work did not decrease self-reported academic achievement. System-level best practices designed to support lactating faculty should be developed to guide academic institutions.

This study investigates the excess mortality, both all-cause and due to suicide, among individuals with schizotypal disorder (SD) compared to the general population. Using individual-level data from the Swedish National Patient Register and the Cause of Death Register, we analyzed mortality in 998 patients diagnosed with SD from 2006 to 2017. Our primary outcomes were all-cause mortality and suicide mortality, with baseline variables including sex, age, and psychiatric comorbidities. Results indicated significantly elevated mortality rates for both all-cause mortality (Standardized Mortality Ratio (SMR) 5.2) and suicide (SMR 23.4). Substance use disorders, personality disorders, and ADHD were identified as significant predictors of increased all-cause mortality. Notably, having a personality disorder in conjunction with schizotypal disorder resulted in a markedly increased risk of suicide. The study underscores the urgent need for targeted interventions and improved diagnostic precision to reduce premature mortality in this vulnerable population. Additionally, the relatively low prevalence of SD diagnoses in Sweden highlights a potential underdiagnosis or misclassification issue. These findings have critical implications for clinical practice and public health efforts, emphasizing the necessity for comprehensive care strategies and suicide prevention interventions to improve outcomes for individuals with schizotypal disorder., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose of Review: To summarize the literature on neurologic care for transgender and gender-diverse (TGD) people and provide implications for clinical practice., Recent Findings: There are limited data on the frequency and management of neurologic conditions among TGD people. TGD people have a higher prevalence of various neurologic conditions compared with cisgender or general population cohorts, including migraine, subjective cognitive decline, sleep disturbances, functional disorders, and cerebrovascular disease. Gender-affirming hormone therapy interacts with commonly prescribed neurologic medications and increases stroke risk among transfeminine people. Sex hormones and sex chromosomes may play a role in neurodegeneration and disability progression in neuroimmunologic diseases. Clitoral reduction surgeries on intersex children can cause neurologic disability and sexual dysfunction in adulthood. Socioeconomic disparities among TGD people contribute to health care barriers., Summary: Neurologists should consider the unique experiences and health care needs of TGD people in their clinical practice and research protocols., Competing Interests: G. Zeigler has been reimbursed for travel-related expenses for speaking at the American College of Osteopathic Neurologists and Psychiatrists Mid-Year Meeting. She had honoraria donated for speaking at the American Academy of Neurology Annual Meeting. C.A. Harrington: No financial disclosures. N. Rosendale receives research funding from the American Academy of Neurology and NIH StrokeNet Fellowship. She receives royalties from McGraw Hill for authorship of a chapter in Current Medical Diagnosis and Treatment 2022 and 2023. She is associate editor of DEI for Continuum. C. Ganos receives research support from the VolkswagenStiftung (Freigeist AZ 94268). He also receives honoraria for educational activities from the Movement Disorder Society. V. Roldan: No financial disclosures. A. Pace received compensation from Abbvie for a one-time speaking engagement on including sexual and gender minority individuals in clinical research. S. Alick-Lindstrom: No financial disclosures. C. Orozco-Poore: No financial disclosures. W. Deeb: Fellowship educational grant for movement disorders from Medtronic. He receives royalties from Rose publishing for co-authorship of Living with Parkinson's Disease. M.L. Hansen: No financial disclosures. Z P. L'Erario has served as expert witness for plaintiff for Weiss Law, PC and receives consultancy payments regarding transgender neurologic health care from medical colleges and universities within the United States. They are on the editorial board of Neurology: Clinical Practice. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

Purpose: Stereotactic EEG (SEEG) is gaining increasing popularity in the United States. Patients undergoing SEEG have unique challenges, and their needs are different compared with noninvasive cases. We aim to describe the medical, nursing, and other institutional practices of SEEG evaluations among tertiary referral (level IV) epilepsy centers accredited by the National Association of Epilepsy Centers., Methods: We analyzed data obtained from a Research Electronic Data Capture (REDCap) survey we formulated and distributed to directors of all level IV epilepsy centers listed by the National Association of Epilepsy Center. Most questions were addressed to the adult and pediatric SEEG programs separately., Results: Among 199 epilepsy center directors invited to complete the survey, 90 (45%) responded. Eighty-three centers (92%) reported they perform SEEG evaluations. Of the 83 respondents, 56 perform SEEG in adult and 47 in pediatric patients. Twenty-two centers evaluate both pediatric and adult subjects. The highest concordance of SEEG workflow was in (1) epilepsy monitoring unit stay duration (1-2 weeks, 79% adult and 85% pediatric programs), (2) use of sleep deprivation (94% both adult and pediatric) and photic stimulation (79% adult and 70% pediatric) for seizure activation, (3) performing electrical cortical stimulation at the end of SEEG evaluation after spontaneous seizures are captured (84% adult and 88% pediatric), and (4) daily head-wrap inspection (76% adult and 80% pediatric). Significant intercenter variabilities were noted in the other aspects of SEEG workflow., Conclusions: Results showed significant variability in SEEG workflow across polled centers. Prospective, multicenter protocols will help the future development and harmonization of optimal practice patterns., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 by the American Clinical Neurophysiology Society.)

The prevention of human immunodeficiency virus (HIV) infection has recently emphasized the use of pre- and post-exposure prophylaxis (PrEP and PEP), both of which were highly effective in prevention of HIV infection. Since the last published guidance regarding the cotreatment of people with anti-seizure medications (ASM) and antiretroviral treatments (ARTs) in 2012, both fields have numerous new medication options. Historically, cotreatment of HIV and seizures could be challenging with increased risk of virologic failure and barriers in access to health care due to global availability, social determinants of health, and stigma of both HIV and seizures. In this narrative review, we describe the data-driven and expected bidirectional pharmacokinetic (PK) interactions between guideline-based PrEP and PEP treatment and ASM, as well as overlapping side effects. There are many ASMs with no known interaction with PrEP or PEP regimens. The interactions focus on enzyme inducing ASMs, valproate, and lamotrigine. Most prominently, enzyme inducing ASMs lower serum levels of tenofovir-containing PrEP regimens and elements of PEP (dolutegravir, raltegravir, and ritonavir), which increased risk of virologic treatment failure in people with HIV but have unclear clinical significance on the effectiveness of PrEP and PEP. In addition, ritonavir treatment in PEP may significantly lower lamotrigine serum levels even during the 4 weeks of treatment, which may increase risk for breakthrough seizures during PEP and skin reactions after discontinuation of ritonavir. In addition to PK interactions, overlapping side effects are common including osteopenia, hepatic toxicity, and other gastrointestinal effects. This narrative review aims to be a resource for all clinicians prescribing ASMs so that they can create a welcoming environment to enable successful treatment of seizures and reduce the risk of HIV infection in people at risk. In addition, we highlight knowledge gaps and areas of unmet need that can be addressed with future studies., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: No pharmaceutical company contributed to or reviewed this manuscript in any stage of development. Dr Kerr received honoraria for his work as Associate Editor for Epilepsia and review articles for Medlink Neurology, is a paid consultant for SK Life Sciences (cenobamate), UCB (levetiracetam and brivaracetam), EpiTel, Jazz Pharmaceuticals (cannabidiol), Cerebral Therapeutics (intra-ventricular valproate), and Biohaven Pharmaceuticals, has collaborative or data use agreements with Eisai (perampanel), Janssen (topiramate), Radius Health, and GSK (levetiracetam, lamotrigine, cabotegravir, lamivudine, zidovudine, dolutegravir, rilpivirine). Prof. Wilmshurst has received honoraria for her work as Associate Editor for Epilepsia and Chief Editor for the Pediatric Neurology subsection of Frontiers in Neurology, and as a member of the national South African advisory boards for Novartis (carbamazepine, oxcarbazepine) and Sanofi (valproate). Dr. Eyal was a consultant for TrueMed, Israel (eslicarbazepine), BioPass, and the Israeli Ministry of Health. The remaining authors have no conflicts of interest to disclose., (© The Author(s) 2024.)

Introduction: This study examines the usability and comfort of a behind-the-ear seizure detection device called brain seizure detection (BrainSD) that captures ictal electroencephalogram (EEG) data using four scalp electrodes., Methods: This is a feasibility study. Thirty-two patients admitted to a level 4 Epilepsy Monitoring Unit were enrolled. The subjects wore BrainSD and the standard 21-channel video-EEG simultaneously. Epileptologists analyzed the EEG signals collected by BrainSD and validated it using video-EEG data to confirm its accuracy. A poststudy survey was completed by each participant to evaluate the comfort and usability of the device. In addition, a focus group of UT Southwestern epileptologists was held to discuss the features they would like to see in a home EEG-based seizure detection device such as BrainSD., Results: In total, BrainSD captured 11 of the 14 seizures that occurred while the device was being worn. All 11 seizures captured on BrainSD had focal onset, with three becoming bilateral tonic-clonic and one seizure being of subclinical status. The device was worn for an average of 41 hours. The poststudy survey showed that most users found the device comfortable, easy-to-use, and stated they would be interested in using BrainSD. Epileptologists in the focus group expressed a similar interest in BrainSD., Conclusions: Brain seizure detection is able to detect EEG signals using four behind-the-ear electrodes. Its comfort, ease-of-use, and ability to detect numerous types of seizures make BrainSD an acceptable at-home EEG detection device from both the patient and provider perspective., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 by the American Clinical Neurophysiology Society.)

Drug-resistant epilepsy (DRE) is often treated with surgery or neuromodulation. Specifically, responsive neurostimulation (RNS) is a widely used therapy that is programmed to detect abnormal brain activity and intervene with tailored stimulation. Despite the success of RNS, some patients require further interventions. However, having an RNS device in situ is a hindrance to the performance of neuroimaging techniques. Magnetoencephalography (MEG), a non-invasive neurophysiologic and functional imaging technique, aids epilepsy assessment and surgery planning. MEG performed post-RNS is complicated by signal distortions. This study proposes an independent component analysis (ICA)-based approach to enhance MEG signal quality, facilitating improved assessment for epilepsy patients with implanted RNS devices. Three epilepsy patients, two with RNS implants and one without, underwent MEG scans. Preprocessing included temporal signal space separation (tSSS) and an automated ICA-based approach with MNE-Python. Power spectral density (PSD) and signal-to-noise ratio (SNR) were analyzed, and MEG dipole analysis was conducted using single equivalent current dipole (SECD) modeling. The ICA-based noise removal preprocessing method substantially improved the signal-to-noise ratio (SNR) for MEG data from epilepsy patients with implanted RNS devices. Qualitative assessment confirmed enhanced signal readability and improved MEG dipole analysis. ICA-based processing markedly enhanced MEG data quality in RNS patients, emphasizing its clinical relevance.

Background: People with HIV (PWH) are at increased risk for venous thromboembolism (VTE). We conducted this study to characterize VTE including provoking factors among PWH in the current treatment era., Methods: We included PWH with VTE between 2010 and 2020 at 6 sites in the CFAR Network of Integrated Clinical Systems cohort. We ascertained for possible VTE using diagnosis, VTE-related imaging, and VTE-related procedure codes, followed by centralized adjudication of primary data by expert physician reviewers. We evaluated sensitivity and positive predictive value of VTE ascertainment approaches. VTEs were classified by type and anatomic location. Reviewers identified provoking factors such as hospitalizations, infections, and other potential predisposing factors such as smoking., Results: We identified 557 PWH with adjudicated VTE: 239 (43%) had pulmonary embolism with or without deep venous thrombosis, and 318 (57%) had deep venous thrombosis alone. Ascertainment with clinical diagnoses alone missed 6% of VTEs identified with multiple ascertainment approaches. DVTs not associated with intravenous lines were most often in the proximal lower extremities. Among PWH with VTE, common provoking factors included recent hospitalization (n = 134, 42%), infection (n = 133, 42%), and immobilization/bed rest (n = 78, 25%). Only 57 (10%) PWH had no provoking factor identified. Smoking (46%), HIV viremia (27%), and injection drug use (22%) were also common., Conclusions: We conducted a robust adjudication process that demonstrated the benefits of multiple ascertainment approaches followed by adjudication. Provoked VTEs were more common than unprovoked events. Nontraditional and modifiable potential predisposing factors such as viremia and smoking were common., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Mammographic density (MD), after accounting for age and body mass index (BMI), is a strong heritable risk factor for breast cancer. Genome-wide association studies (GWAS) have identified 64 SNPs in 55 independent loci associated with MD in women of European ancestry. Their associations with MD in Asian women, however, are largely unknown., Method: Using linear regression adjusting for age, BMI, and ancestry-informative principal components, we evaluated the associations of previously reported MD-associated SNPs with MD in a multi-ethnic cohort of Asian ancestry. Area and volumetric mammographic densities were determined using STRATUS (N = 2450) and Volpara™ (N = 2257). We also assessed the associations of these SNPs with breast cancer risk in an Asian population of 14,570 cases and 80,870 controls., Results: Of the 61 SNPs available in our data, 21 were associated with MD at a nominal threshold of P value < 0.05, all in consistent directions with those reported in European ancestry populations. Of the remaining 40 variants with a P-value of association > 0.05, 29 variants showed consistent directions of association as those previously reported. We found that nine of the 21 MD-associated SNPs in this study were also associated with breast cancer risk in Asian women (P < 0.05), seven of which showed a direction of associations that was consistent with that reported for MD., Conclusion: Our study confirms the associations of 21 SNPs (19/55 or 34.5% out of all known MD loci identified in women of European ancestry) with area and/or volumetric densities in Asian women, and further supports the evidence of a shared genetic basis through common genetic variants for MD and breast cancer risk., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT)., Experimental Design: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case-control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls., Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)-like (N = 226). We then examined their association with breast cancer risk in the case-control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35-3.41), 1.57 (95% CI, 1.41-1.75), and 1.19 (95% CI, 1.08-1.31), respectively. The meta-analysis of population-specific datasets showed similar results., Conclusions: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers., (©2023 The Authors; Published by the American Association for Cancer Research.)

People living with neurologic conditions have historically been among the most marginalized groups in society. Advances in science and medicine have helped prevent, manage, or even cure many of these disorders. The byproduct of these successes is an aging population and members of the population at large with neurologic diseases and their sequelae. These sequelae may be imperceptible to others but often include a loss of skills or independence, which negatively impact a person's psychosocial and socioeconomic status, particularly when either activities of daily living are compromised or the affected individuals possess limited social and financial supports systems., (Published by Elsevier Inc.)

Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C-/- cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C-depleted cancer cells. Case-control association studies of deleterious variants in women with breast and ovarian cancer and noncancer controls showed associations with moderate breast cancer risk [OR, 3.92; 95% confidence interval (95% CI), 2.18-7.59] and high ovarian cancer risk (OR, 14.8; 95% CI, 7.71-30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers., Significance: Functional analysis of the impact of a large number of missense variants on RAD51C function provides insight into RAD51C activity and information for classification of the cancer relevance of RAD51C variants., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: People with human immunodeficiency virus (HIV) infection (PWH) are at higher risk of myocardial infarction (MI) than those without HIV. About half of MIs in PWH are type 2 (T2MI), resulting from mismatch between myocardial oxygen supply and demand, in contrast to type 1 MI (T1MI), which is due to primary plaque rupture or coronary thrombosis. Despite worse survival and rising incidence in the general population, evidence-based treatment recommendations for T2MI are lacking. We used polygenic risk scores (PRS) to explore genetic mechanisms of T2MI compared to T1MI in PWH., Methods: We derived 115 PRS for MI-related traits in 9541 PWH enrolled in the Centers for AIDS Research Network of Integrated Clinical Systems cohort with adjudicated T1MI and T2MI. We applied multivariate logistic regression analyses to determine the association with T1MI and T2MI. Based on initial findings, we performed gene set enrichment analysis of the top variants composing PRS associated with T2MI., Results: We found that T1MI was strongly associated with PRS for cardiovascular disease, lipid profiles, and metabolic traits. In contrast, PRS for alcohol dependence and cholecystitis, significantly enriched in energy metabolism pathways, were predictive of T2MI risk. The association remained after the adjustment for actual alcohol consumption., Conclusions: We demonstrate distinct genetic traits associated with T1MI and T2MI among PWH further highlighting their etiological differences and supporting the role of energy regulation in T2MI pathogenesis., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: We present post-vaccination nasal shedding findings from the phase IV, community-based, triple-blinded RCT conducted to assess efficacy of trivalent LAIV and inactivated influenza vaccines in rural north India., Methods: Children aged 2-10 years received LAIV or intranasal placebo across 2015 and 2016, as per initial allocation. On days 2 and 4 post-vaccination, trained study nurses collected nasal swabs from randomly selected subset of trial participants based on operational feasibility, accounting for 10.0% and 11.4% of enrolled participants in 2015 and 2016, respectively. Swabs were collected in viral transport medium and transported under cold chain to laboratory for testing by reverse transcriptase real-time polymerase chain reaction., Results: In year 1, on day 2 post-vaccination, 71.2% (74/104) of LAIV recipients shed at least one of vaccine virus strains compared to 42.3% (44/104) on day 4. During year 1, on day 2 post-vaccination, LAIV-A(H1N1)pdm09 was detected in nasal swabs of 12% LAIV recipients, LAIV-A(H3N2) in 41%, and LAIV-B in 59%. In year 2, virus shedding was substantially lower; 29.6% (32/108) of LAIV recipients shed one of the vaccine virus strains on day 2 compared to 21.3% on day 4 (23/108)., Conclusion: At day 2 post-vaccination in year 1, two-thirds of LAIV recipients were shedding vaccine viruses. Shedding of vaccine viruses varied between strains and was lower in year 2. More research is needed to determine the reason for lower virus shedding and vaccine efficacy for LAIV-A(H1N1)pdm09., (© 2023 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: External quality assessments (EQAs) for the molecular detection of human respiratory syncytial virus (RSV) are necessary to ensure the standardisation of reliable results. The Phase II, 2019-2020 World Health Organization (WHO) RSV EQA included 28 laboratories in 26 countries. The EQA panel evaluated performance in the molecular detection and subtyping of RSV-A and RSV-B. This manuscript describes the preparation, distribution, and analysis of the 2019-2020 WHO RSV EQA., Methods: Panel isolates underwent whole genome sequencing and in silico primer matching. The final panel included nine contemporary, one historical virus and two negative controls. The EQA panel was manufactured and distributed by the UK National External Quality Assessment Service (UK NEQAS). National laboratories used WHO reference assays developed by the United States Centers for Disease Control and Prevention, an RSV subtyping assay developed by the Victorian Infectious Diseases Reference Laboratory (Australia), or other in-house or commercial assays already in use at their laboratories., Results: An in silico analysis of isolates showed a good match to assay primer/probes. The panel was distributed to 28 laboratories. Isolates were correctly identified in 98% of samples for detection and 99.6% for subtyping., Conclusions: The WHO RSV EQA 2019-2020 showed that laboratories performed at high standards. Updating the composition of RSV molecular EQAs with contemporary strains to ensure representation of circulating strains, and ensuring primer matching with EQA panel viruses, is advantageous in assessing diagnostic competencies of laboratories. Ongoing EQAs are recommended because of continued evolution of mismatches between current circulating strains and existing primer sets., Competing Interests: No conflict of interest is declared by authors., (© 2023 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Breast parenchymal texture features, including grayscale variation (V), capture the patterns of texture variation on a mammogram and are associated with breast cancer risk, independent of mammographic density (MD). However, our knowledge on the genetic basis of these texture features is limited., Methods: We conducted a genome-wide association study of V in 7040 European-ancestry women. V assessments were generated from digitized film mammograms. We used linear regression to test the single-nucleotide polymorphism (SNP)-phenotype associations adjusting for age, body mass index (BMI), MD phenotypes, and the top four genetic principal components. We further calculated genetic correlations and performed SNP-set tests of V with MD, breast cancer risk, and other breast cancer risk factors., Results: We identified three genome-wide significant loci associated with V: rs138141444 (6q24.1) in ECT2L, rs79670367 (8q24.22) in LINC01591, and rs113174754 (12q22) near PGAM1P5. 6q24.1 and 8q24.22 have not previously been associated with MD phenotypes or breast cancer risk, while 12q22 is a known locus for both MD and breast cancer risk. Among known MD and breast cancer risk SNPs, we identified four variants that were associated with V at the Bonferroni-corrected thresholds accounting for the number of SNPs tested: rs335189 (5q23.2) in PRDM6, rs13256025 (8p21.2) in EBF2, rs11836164 (12p12.1) near SSPN, and rs17817449 (16q12.2) in FTO. We observed significant genetic correlations between V and mammographic dense area (r g  = 0.79, P = 5.91 × 10 -5 ), percent density (r g  = 0.73, P = 1.00 × 10 -4 ), and adult BMI (r g  =  - 0.36, P = 3.88 × 10 -7 ). Additional significant relationships were observed for non-dense area (z =  - 4.14, P = 3.42 × 10 -5 ), estrogen receptor-positive breast cancer (z = 3.41, P = 6.41 × 10 -4 ), and childhood body fatness (z =  - 4.91, P = 9.05 × 10 -7 ) from the SNP-set tests., Conclusions: These findings provide new insights into the genetic basis of mammographic texture variation and their associations with MD, breast cancer risk, and other breast cancer risk factors., (© 2022. The Author(s).)

Background: Acute viral respiratory infections are a major health burden in children worldwide. In recent years, rapid and sensitive multiplex nucleic acid amplification tests (NAATs) have replaced conventional methods for routine virus detection in the clinical laboratory., Objective/study Design: We compared BioFire® FilmArray® Respiratory Panel (FilmArray V1.7), Luminex NxTag® Respiratory Pathogen Panel (NxTag RPP) and Applied Biosystems TaqMan Array Card (TAC) for the detection of eight viruses in pediatric respiratory specimens. Results from the three platforms were analyzed with a single-plex real-time RT-PCR (rRT-PCR) assay for each virus., Results: Of the 170/210 single-plex virus-positive samples, FilmArray detected a virus in 166 (97.6%), TAC in 163 (95.8%) and NxTag RPP in 160 (94.1%) samples. The Positive Percent Agreement (PPA) of FilmArray, NxTag RPP and TAC was highest for influenza B (100%, 100% and 95.2% respectively) and lowest for seasonal coronaviruses on both FilmArray (90.2%) and NxTag RPP (81.8%), and for parainfluenza viruses 1- 4 on TAC (84%). The Negative Percent Agreement (NPA) was lowest for rhinovirus/enterovirus (92.9%, 96.7% and 97.3%) on FilmArray, NxTag RPP and TAC respectively. NPA for all three platforms was highest (100%) for both parainfluenza viruses 1- 4 and influenza A and B, and 100% for human metapneumovirus with TAC as well., Conclusion: All three multiplex platforms displayed high overall agreement (&gt;90%) and high NPA (&gt;90%), while PPA was pathogen dependent and varied among platforms; high PPA (&gt;90%) was observed for FilmArray for all eight viruses, TAC for six viruses and NxTag RPP for 4 viruses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The clinical presentation of varicella in unvaccinated persons, with skin vesicles and scabs, has facilitated the use of rapid diagnostic methods for confirming disease. Polymerase chain reaction (PCR) assays are the diagnostic method of choice. The sharp decline in unmodified cases of varicella due to the US varicella vaccination program has led to fewer healthcare providers being familiar with varicella presentation and an increased reliance on laboratory diagnosis to confirm suspected cases. The mild, atypical presentation of the disease in vaccinated persons (fewer skin lesions, mostly maculopapular) has made it more challenging for providers to recognize and also to collect samples to detect the virus. Nonetheless, PCR is highly sensitive and specific in confirming modified disease if adequate samples are provided. While a positive PCR result is confirmatory, interpreting a negative result can prove to be more challenging in determining whether suspected varicella is falsely negative or attributable to other causes. Enhanced education of healthcare providers is critical for adequate specimen collection from modified varicella cases. In addition, more sensitive commercial serologic assays are needed in the United States for varicella immunity testing in the vaccine era., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

A woman in her 30s with unclear history of cirrhosis presented to the emergency department with 8 months of worsening bilateral hand tremors, falls, depressed mood, altered mental status, difficulty swallowing and faecal/urinary incontinence. The patient was diagnosed with liver cirrhosis 6 years prior based on outside hospital ultrasound and liver biopsy. The hospital inpatient neurology team was promptly consulted for evaluation of worsening mental status. Kayser-Fleischer rings were visible without slit-lamp examination on clinical exam, as were prominent hand tremors and ataxia on finger-nose-finger task. Brain MRI showed increased T2/FLAIR (fluid-attenuated inversion recovery) signal within the thalami, midbrain and pons demonstrating a 'double panda sign'. Laboratory findings confirmed a diagnosis of Wilson's disease. Penicillamine and subsequent zinc therapy were initiated. Patient was eventually discharged home with plans for outpatient physical therapy and hepatology management. Two months from presentation, the patient reported significant improvement in ataxia, motor function, swallow function and incontinence., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Elevated blood levels of C-reactive protein (CRP) have been linked to colorectal cancer (CRC) survival. We evaluated genetic variants associated with CRP levels and their interactions with sex and lifestyle factors in association with CRC-specific mortality. Our study included 16 142 CRC cases from the International Survival Analysis in Colorectal Cancer Consortium. We identified 618 common single nucleotide polymorphisms (SNPs) associated with CRP levels from the NHGRI-EBI GWAS Catalog. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between SNPs and CRC-specific mortality adjusting for age, sex, genotyping platform/study and principal components. We investigated their interactions with sex and lifestyle factors using likelihood ratio tests. Of 5472 (33.9%) deaths accrued over up to 10 years of follow-up, 3547 (64.8%) were due to CRC. No variants were associated with CRC-specific mortality after multiple comparison correction. We observed strong evidence of interaction between variant rs1933736 at FRK gene and sex in relation to CRC-specific mortality (corrected P interaction  = .0004); women had higher CRC-specific mortality associated with the minor allele (HR = 1.11, 95% CI = 1.04-1.19) whereas an inverse association was observed for men (HR = 0.88, 95% CI = 0.82-0.94). There was no evidence of interactions between CRP-associated SNPs and alcohol, obesity or smoking. Our study observed a significant interaction between sex and a CRP-associated variant in relation to CRC-specific mortality. Future replication of this association and functional annotation of the variant are needed., (© 2021 UICC.)

Epilepsy surgery is superior to prolonged medical therapy in patients with drug-resistant focal epilepsy, but reports on epilepsy surgery outcomes for patients with a genetic etiology are limited, especially in adults. This is the first documented report of a stereoelectroencephalography (SEEG) evaluation and resective surgery outcome in an adult patient with epilepsy related to SCN8A mutation. We describe a patient with epilepsy related to SCN8A mutation which was reported as a variant of uncertain significance at time of his pre-surgical evaluation and reclassified as likely pathogenic about 3 years after resective epilepsy surgery. Most of his pre-surgical evaluation results suggested right temporal lobe epilepsy, but few reported semiological symptoms, ictal SPECT, and neuropsychology results were discordant, and brain MRI was non-lesional. Therefore, SEEG was recommended; ultimately, seizures were localized to the right hippocampus. He was seizure-free for 1.5 years after right anterior temporal lobectomy, then reported three focal to bilateral tonic-clonic (FBTC) seizures in the subsequent 12 months (preoperatively, 6 focal impaired awareness seizures and 4-6 FBTC per year). This case demonstrates that epilepsy surgery reduced seizure burden in a patient with SCN8A-related epilepsy granting him short-term seizure freedom after resection, and then decreased seizure frequency after relapse compared to the preoperative baseline., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background: Although a human adenovirus (HAdV) vaccine is available for military use, officers-in-training are not routinely vaccinated. We describe an HAdV-associated respiratory outbreak among unvaccinated cadets at the US Coast Guard Academy and its impact on cadet training., Methods: We defined a case as a cadet with new onset cough or sore throat during August 1-October 4, 2019. We reviewed medical records and distributed a questionnaire to identify cases and to estimate impact on cadet training. We performed real-time polymerase chain reaction testing on patient and environmental samples and whole genome sequencing on a subset of positive patient samples., Results: Among the 1072 cadets, 378 (35%) cases were identified by medical records (n = 230) or additionally by the questionnaire (n = 148). Of the 230 cases identified from medical records, 138 (60%) were male and 226 (98%) had no underlying conditions. From questionnaire responses, 113 of 228 (50%) cases reported duty restrictions. Of cases with respiratory specimens, 36 of 50 (72%) were HAdV positive; all 14 sequenced specimens were HAdV-4a1. Sixteen (89%) of 18 environmental specimens from the cadet dormitory were HAdV-positive., Conclusions: The HAdV-4-associated outbreak infected a substantial number of cadets and significantly impacted cadet training. Routine vaccination could prevent HAdV respiratory outbreaks in this population., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Purpose: To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast., Materials and Methods: The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM , BARD1 , BRCA1 , BRCA2 , BRIP1 , CDH1 , CHEK2 , PALB2 , PTEN , RAD51C , RAD51D , and TP53 ) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC)., Results: The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2 , ATM , and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC., Conclusion: The study establishes that PVs in ATM , BRCA2 , CDH1 , CHEK2 , and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk., Competing Interests: Jeffrey N. WeitzelSpeakers' Bureau: AstraZeneca Celine M. VachonStock and Other Ownership Interests: Exact Sciences (I)Research Funding: GRAILPatents, Royalties, Other Intellectual Property: Breast Density softwareTravel, Accommodations, Expenses: GRAIL Allison W. KurianResearch Funding: Myriad GeneticsOther Relationship: Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, Genentech Rachid KaramEmployment: Ambry GeneticsResearch Funding: Ambry GeneticsTravel, Accommodations, Expenses: Ambry Genetics Elizabeth ChaoEmployment: Ambry Genetics Amal YussufEmployment: Ambry Genetics Tina PesaranEmployment: Ambry Genetics/Konica Minolta Jill S. DolinskyEmployment: Ambry Genetics Holly LaDucaEmployment: Ambry GeneticsStock and Other Ownership Interests: Ambry Genetics Eric C. PolleyResearch Funding: GRAIL Susan M. DomchekHonoraria: AstraZeneca, Clovis Oncology, Bristol Myers SquibbResearch Funding: AstraZeneca, Clovis Oncology Fergus J. CouchConsulting or Advisory Role: AstraZenecaSpeakers' Bureau: Ambry Genetics, QiagenResearch Funding: GRAILTravel, Accommodations, Expenses: GRAIL, QiagenOther Relationship: Ambry GeneticsNo other potential conflicts of interest were reported.

Purpose: The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years., Methods: A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs., Results: The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1 , BRCA2 , and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)-negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2 , PALB2 , BRCA2 , and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1 , BRCA2 , and PALB2 ., Conclusion: This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening., Competing Interests: Jeffrey N. WeitzelSpeakers' Bureau: AstraZeneca Amal YussufEmployment: Ambry Genetics Celine M. VachonStock and Other Ownership Interests: Exact SciencesResearch Funding: GRAILPatents, Royalties, Other Intellectual Property: Breast Density softwareTravel, Accommodations, Expenses: GRAIL Tina PesaranEmployment: Ambry Genetics/Konica MinoltaTravel, Accommodations, Expenses: Ambry Genetics/Konica Minolta Irene M. OngEmployment: Propeller HealthStock and Other Ownership Interests: AyrFlo Rachid KaramEmployment: Ambry GeneticsResearch Funding: Ambry GeneticsTravel, Accommodations, Expenses: Ambry Genetics Holly LaDucaEmployment: Ambry GeneticsStock and Other Ownership Interests: Ambry Genetics Jill S. DolinskyEmployment: Ambry Genetics Elizabeth ChaoEmployment: Ambry Genetics Eric C. PolleyResearch Funding: GRAIL Susan M. DomchekHonoraria: AstraZeneca, Clovis Oncology, Bristol Myers SquibbResearch Funding: AstraZeneca, Clovis OncologyOpen Payments Link: https://openpaymentsdata.cms.gov/physician/917904 Fergus J. CouchConsulting or Advisory Role: AstraZenecaSpeakers' Bureau: Ambry Genetics, QiagenResearch Funding: GRAILTravel, Accommodations, Expenses: GRAIL, QiagenOther Relationship: Ambry GeneticsNo other potential conflicts of interest were reported.