Citations

Abstract Toxicology testing for drugs associated with scenarios such as recreational use or substance use disorder can be performed in support of the emergency department (ED) for specific patient populations such as pediatrics and trauma. These compounds were historically referred to as drugs of abuse (DOA); although the word “abuse” is recognized as potentially stigmatizing, no replacement terminology for DOA has emerged in current guidelines. This document refers to these compounds as drugs or substances of misuse, and acknowledges the need for less-stigmatizing language that more fully encompasses the range of uses for these drugs. This literature-driven, consensus guidance document provides recommendations primarily targeted to US hospital-based laboratories performing urine drug testing (UDT) in support of the ED. Indications for ordering UDT and related testing in both pediatric and adult populations are summarized. Further, recommendations are made for testing that should be available at all facilities with rapid turnaround, and how to perform and report testing. The advantages and disadvantages of immunoassays and mass spectrometry, as well as common challenges, are reviewed. Indications for mass-spectrometry assays and more extensive testing (e.g., novel psychoactive substances) are also provided. Future directions for improvements in laboratory technology to improve the utility of this testing are outlined. All laboratories should collaborate with ED leadership, medical toxicologists and poison control centers to optimize and update test menus to reflect local drug use patterns, ensure test methodologies and results meet clinical needs, and educate clinical staff regarding assay limitations and accurate test interpretation.

Background: In younger patients (<60 years) with cryptogenic stroke (CS) presumed to be patent foramen ovale (PFO)-related, the standard approach involves transcatheter PFO closure combined with antithrombotic therapy. However, due to their exclusion from randomized clinical trials (RCTs), no formal recommendations exist for patients ⩾60 years. This study had two objectives (1) to compare the efficacy and safety of PFO closure versus antithrombotic therapy alone (ATA) exclusively in older patients (⩾60 years) and (2) to assess the outcomes of PFO closure in patients ⩾ 60 years versus < 60 years. Methods: We searched PubMed, Embase, Web of Science, and ScienceDirect databases to obtain articles in all languages from January 2004 until July 2025. The primary outcome was risk of recurrent stroke during follow-up. Secondary outcomes were risk of new-onset atrial fibrillation (AF), all-cause mortality, and in-hospital complications. PROSPERO registration ID: CRD420250652870. Results: Only one RCT (post hoc evaluation of the DEFENSE-PFO trial) and 11 observational studies were included. In patients aged ⩾ 60 years, risk of recurrent stroke was lower when PFO was closed compared with ATA (5.48% vs 10.05%, respectively, hazard ratio (HR) = 0.56, 95% confidence interval (CI) = 0.45–0.80, p < 0.001, I 2 = 45.6%). All-cause mortality was also lower for PFO closure versus ATA (1.73% vs 7.59%, respectively, HR = 0.41; 95% CI = 0.19–0.90, p = 0.02; I 2 = 43.8%). There was no difference between PFO closure and ATA in risk of new-onset AF (HR = 1.13, 95% CI = 0.53–2.44, p = 0.74). Compared with patients < 60 years, individuals ⩾ 60 years who underwent PFO closure had a higher risk of recurrent stroke (2.94% vs 1.04%, respectively, HR = 3.47; 95% CI = 1.61–7.48; p = 0.001), new-onset AF (4.86% vs 1.01%, respectively, HR = 4.12; 95% CI = 1.90–8.95; p < 0.001), and all-cause mortality during follow-up (8.32% vs 0.39%, respectively, HR = 8.24; 95% CI = 3.49–19.46; p < 0.0001). In-hospital complications after PFO closure were comparable between two age groups. Due to insufficient data, we were not able to perform a subgroup analysis based on anatomic features of PFO, antithrombotic regimen, or occluder devices. Conclusion: Based on available data, which is predominantly derived from observational studies, PFO closure is associated with a reduced risk of recurrent stroke compared to ATA in patients over 60 years. However, these findings are subjected to limitations, including the potential for selection bias, unmeasured confounding, and insufficient long-term follow-up. Furthermore, long-term randomized trials are essential to definitively confirm efficacy and establish clinical guidelines for PFO closure in this older population.

BACKGROUND: People with narcolepsy are at increased risk for hypertension and cardiovascular disease; excessive sodium intake is linked to both. METHODS: We studied patients with narcolepsy and office systolic blood pressures (BPs) of 130 to 155 mm Hg taking twice-nightly high-sodium oxybate for ≥6 weeks who switched to low-sodium oxybate at the same dosage. The primary end point was the change from baseline in mean 24-hour ambulatory systolic BP at the end of treatment (≈6 weeks after switching). Secondary and exploratory end points included changes in diastolic BP, office BP, and 24-hour sodium excretion. RESULTS: Patients (n=43) had a mean age of 45 years, were 65% female, 33% on antihypertensives, with baseline mean (SD) office BP of 138.0/85.2 (5.7/6.6). Mean (SD) total high- and low-sodium oxybate dosages of 8.0 (1.1) and 8.1 (1.1) g/night, respectively, represented 1456.5 (206.2) and 117.8 (16.3) mg of sodium. The median 24-hour urinary sodium was 4278 mg/d at baseline and 2703 mg/d at the end of treatment (median change, 1288 mg/d). Mean (SE) 24-hour ambulatory systolic BPs at baseline and study end were 132.3 (1.8) and 128.2 (1.8) mm Hg (least-squares mean change, −4.1 [95% CI, −6.9 to −1.4] mm Hg; 1-sided P =0.0019). BP changes by narcolepsy subtype, sex, body mass index, baseline office BP, and baseline antihypertensive use were consistent with the overall effect size. CONCLUSIONS: People with narcolepsy switching from high- to low-sodium oxybate showed substantially reduced daily medication-related sodium intake and significant 24-hour BP reductions. These results demonstrate the importance of reducing pharmaceutical sodium content in this elevated cardiovascular risk patient population. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05869773.

Abstract Background Dystonia and Parkinson's disease (PD) exhibit clinical and genetic overlap, but the relevance of dystonia gene variants in PD remains unclear. Objective The aim was to assess the frequency of dystonia‐linked pathogenic variants in PD. Methods We screened sequencing data from 15,684 individuals (8272 PD, 3200 atypical parkinsonism, and 4212 unaffected) from the Global Parkinson's Genetics Program (GP2) and Accelerating Medicines Partnership‐Parkinson's Disease (AMP‐PD) for variants in genes linked to isolated dystonia, dystonia‐parkinsonism, and myoclonus‐dystonia. Results Pathogenic variants were identified only in PD patients. Forty‐five PD individuals (0.54%) carried 26 distinct (likely) pathogenic variants in nine dystonia‐linked genes, most frequently in GCH1 , followed by VPS16 . Conclusion Though rare, pathogenic variants in dystonia‐linked genes are present in clinically and pathologically diagnosed PD. Our results reinforce GCH1 as a PD‐relevant gene with clinical implications, whereas variants identified in other genes are rare and of uncertain relation to the PD phenotype. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Importance Inherited pathogenic variants (PVs) in known predisposition genes can greatly increase breast cancer risk, but the combined impact of PV status, family history, and other factors on breast cancer risk in the general US population has not been well described. Objective To evaluate population-based breast cancer risk estimates for those with established PVs overall and stratified by first-degree family history of breast cancer and other factors. Design, Setting, and Participants This study used pooled data from 13 US-based breast cancer case-control studies participating in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Enrollment for individual studies occurred between 1976 and 2013, and results are based on data released March 2023, with analyses conducted from June 2022 to July 2025. Exposures PVs, breast cancer family history, self-reported race and ethnicity, and established risk factors. Main Outcomes and Measures Breast cancer rate ratios for PVs in 7 genes were estimated from the CARRIERS consortium. PV status and incidence and mortality statistics were combined using the Individualized Coherent Absolute Risk Estimation (iCARE) model to estimate conditional cumulative breast cancer risks and 95% CIs, stratified by family history and standardized to the US population. Models that incorporated population-based data and published estimates for established epidemiologic risk factors were also evaluated. Results A total of 67 692 women were studied, including 33 841 who were diagnosed with breast cancer. PVs in ATM , BRCA1 , BRCA2 , CHEK2 , and PALB2 were strongly associated with breast cancer risk, with BRCA1 and PALB2 PVs showing evidence of heterogeneity by family history. In models considering PVs, family history, and established risk factors, the estimated cumulative risks of breast cancer by age 50 years ranged from 2.4% (95% CI, 2.4-2.4) in women with no PVs and no family history to 35.5% (95% CI, 21.6-55.1) in PALB2 PV carriers with a family history. Among women who have not been diagnosed with breast cancer by age 50 years, the cumulative risk of breast cancer by age 80 years ranged from 11.1% (95% CI, 11.0-11.2) in noncarriers with no family history to 70.5% (95% CI, 52.8-83.5) for PALB2 carriers with a family history. PV-specific cumulative risk estimates varied across subgroups defined by race and ethnicity and potentially modifiable epidemiologic risk factors. Conclusions and Relevance In this study, population-based estimates of cumulative breast cancer risk for established PVs, as informed by the CARRIERS case-control sample, varied by family history and potentially modifiable risk factors. These estimates provide guidance for identifying individuals who will most benefit from enhanced screening and prevention strategies.

Abstract Objective This study aimed to understand the factors limiting access to medications for the preventive treatment of migraine and to improve access to evidence‐based preventive care. Background For decades, the effective use of medication for the preventive treatment of migraine was limited by slow onset, slow and complex dose titration schedules, modest benefits, drug interactions, frequent side effects, and very low long‐term adherence. The calcitonin gene‐related peptide (CGRP) targeted preventive medications mitigate some of these limitations and demonstrated substantial therapeutic benefits in a significant proportion of adults with migraine. The American Headache Society considers these medications among the first‐line options for migraine prevention, although access to them remains limited. The American Migraine Foundation hosted a single‐day, multidisciplinary expert panel discussion to identify barriers to optimal preventive care and developed recommendations to address them. Methods Participants identified and prioritized barriers and used a modified nominal group technique to achieve consensus on them. A series of moderated discussions in plenary and breakout sessions was used to create possible solutions. Modified nominal group technique was also employed to achieve consensus on the priorities among these barriers and to achieve whole‐group consensus on the recommendations. Ethical issues that inform access were discussed. Results Participants included eight neurologists and board‐certified headache specialists, six representatives of reimbursement decision‐makers, six employees of life sciences companies, four patient advocates with lived experience with migraine, and a medical ethicist. Among those who have consulted healthcare professionals and received a diagnosis of migraine, we identified four main barriers to accessing preventive treatment: restrictive prior authorization requirements, the perceived lack of real‐world evidence and treatment guidelines, the need for clinician education, and the need for patient education. Consensus recommendations for eliminating barriers centered on using new evidence to evaluate policies that restrict the selection of first‐line therapies, initiating/improving collaboration among stakeholders, sharing of data and best practices, and increased training. Participants agreed to explore novel definitions of the value of preventive treatment and to establish the Migraine Prevention Network to facilitate ongoing cooperation and collective action. However, due to financial limitations, staffing changes, and time constraints, post‐meeting discussions led to a shift from establishing a broad Migraine Prevention Network to forming smaller task forces focused on the top‐priority barriers (real‐world evidence and The Patient Playbook ) identified through collaborative voting among American Headache Society, American Migraine Foundation, and industry stakeholders. Conclusions Adults with migraine face multiple barriers in accessing novel migraine‐specific, CGRP‐targeted preventive treatment. Stakeholders in the delivery of care, including clinicians, reimbursement decision‐makers, life sciences companies, and patient and clinician advocates, may be able to overcome many of these barriers and improve access by working with and on behalf of patients.

Abstract Introduction This study investigated differences in opinions about neurodegenerative disorders (NDD) in countries with large populations and expanded access to healthcare. Methods A 5-point Likert scale survey assessed opinions of 30–59-year-olds, pertaining to their parents and NDD conditions. 100 surveys, translated into native languages, were acquired in eight developed countries. Positive (somewhat- or strongly-agree) vs. other responses, sex, and country were submitted to logistic regression and Chi-squared analyses. Results “It is important for me to know if my parent has a risk for developing a NDD condition in the future, even if nothing can be currently done to prevent or cure those diseases” had higher positive responses in Australia (92%) compared to Germany (74%) and the USA (78%). “I believe that knowing about my parent’s risk for developing a NDD condition will help me assist in the planning of their future” had higher number of positive responses in Australia (91%) versus Japan (70%), Germany (76%), Italy (80%) and UK (80%). “If my parent(s) was found to be at risk for a NDD condition, I would want to learn more about medications and adaptive therapies that could delay onset” was responded to more positively in Australia (92%), Canada (78%), France (87%), Germany (78%), Italy (88%), UK (88%), and USA (81%) versus Japan (60%). Conclusions Australians responded more positively to questions related to care of a parent with a NDD disorder. These findings suggest cultural differences that could influence education and support systems requirements for sleep medicine providers and NDD patients.

Abstract Background Hemoglobin A1c is used to assess glycemic control to both diagnose and monitor diabetes mellitus. Several different methodologies are available including high performance liquid chromatography (HPLC), capillary electrophoresis (CE), and immunoassay (IA). These methods are standardized and traceable to the Diabetes Control and Complications Trial (DCCT). The aim of this study was to evaluate the difference in HbA1c results between methods and percent of reportable results in variant samples. Methods The HPLC (Bio-Rad Laboratories, Inc; D-100), the CE(Sebia Inc; Capillarys 3), and IA(Roche Diagnostics Inc; Tina-quant Generation 3) were compared using two sets of residual patient samples left after physician ordered testing was complete: 1) samples with an absence of abnormal hemoglobin peaks (i.e. non-variant) detected by HPLC; 2) samples with abnormal hemoglobin peaks (i.e. variant) characterized by hemoglobin electrophoresis performed clinically or lacking an A1c peak by HPLC/CE. The samples were tested within manufacturers stability claims. 317 non-variant samples were compared between the HPLC and CE methods. The absolute difference was calculated for each method using this equation (HbA1c%avg – HbA1c%X) where HbA1c%avg is the average of the methods that produced reportable results and X is the result from each method evaluated. Differences less than or equal to +/-0.3% were considered acceptable. 28 of the 317 non-variant and 47 variant samples were tested by all 3 methodologies. The 47 variant samples grouped into 3 cohorts: common heterozygous variants (HbC, HbD, HbE, HbS and HbF, n=10), uncommon heterozygous variants (n=29) and homozygous variants lacking HbA (n=8). The absolute differences in variant sample results were calculated for samples that did not surpass manufacturer’s claims for producing an accurate result. The frequency of producing a numeric result in variant samples was calculated for each method. Results The HPLC/CE non-variant sample comparison (N=317) had results spanning the measuring range (3.8% - 14.0%) with average(range) of absolute difference=0.1(-0.4to0.6%) with 293/317(92.4%) samples within +/-0.3%. The HPLC/CE/IA non-variant sample comparison (N=28) had a result range=4.0%-9.4%, the average(range) of difference=0.1(-0.2to0.5%) with 25/28 (89.2%) of samples within +/-0.3%. Common heterozygous variant samples gave numeric results with no disqualifying flags in 9 of 10(HPLC), 8 of 10(CE), and 9 of 10(IA) samples tested. The average(range) difference from average=0.0(-0.3,0.5%) for HPLC, 0.0(-0.2,0.3%) for CE, and -0.1(-0.6,0.2%) for IA. Uncommon variant samples gave results in 4 of 29 (HPLC), 20 of 29 (CE), and 26 of 29 (IA) of samples tested. The average(range) difference from average=-0.1(-0.3,0.1%) for HPLC, 0.0(-1.0,1.1%) for CE, and 0.0(-1.1,1.0%) for IA. The homozygous variant (no HbA) samples gave results in 0 of 8 (HPLC), 0 of 8 (CE), and 4 of 8 (IA) of those tested. Conclusion All three methods meet their claims for accurately measuring hemoglobin A1c from non-variant and common hemoglobin variants. The advantage of HPLC and CE is the ability to identify hemoglobin variants that may impact HbA1c quantitation. The IA method provides the most numeric results. IA gave results even when HbA was absent. The lab should understand the capabilities and limitations of their HbA1c method on the population served.

Abstract Introduction: The purpose of this study is to evaluate the effectiveness of opportunistic salpingectomy (OS), a procedure that aims to remove only the fallopian tubes of general population risk women, for the prevention of epithelial ovarian cancer. Currently, the method of prevention for individuals at high risk of ovarian cancer involves a bilateral salpingo-oophorectomy (BSO), a procedure that removes both the fallopian tubes and ovaries. However, this procedure is not recommended for individuals of the general population, who make up about 80% of ovarian cancers, due to negative health implications to the cardiovascular and skeletal systems because of surgically induced menopause. The effectiveness of the OS in preventing ovarian cancers and how the procedure impacts the histotype distribution of ovarian cancers remains unknown. Study Methods: This study uses a population-based approach and a case-based approach to determine the effectiveness of OS and its impact on histotype distribution, respectively. For the population-based analysis, we will search through clinical databases to acquire cases of individuals who have had an OS and a tumor. A control population who have their fallopian tubes in-tact will also be acquired. A cox-proportional hazard analysis will be performed to determine the effectiveness of the procedure. Using pathological records, the case-based ascertainment of tumors from individuals who have had an OS will be selected and reviewed for histotype confirmation. Fallopian tubes of these patients will also be reviewed for precursor lesions. This cohort will be compared to a historical histotype distribution of ovarian cancers. Results: For the population-based approach, we have to date, identified less than five serous ovarian cancers in individuals who have had an OS (n=40, 477). A comparator surgery was used as a control and showed 21 cancers. For the case-based approach, we have partnered with 23 collaborating institutions from around the world to identify tumors in individuals who have had an OS. We have identified 26 epithelial ovarian cancers, with the most lethal gynecological histotype, high grade serous carcinoma (HGSC), accounting for 23.1% of the total proportion of epithelial ovarian cancer cases (n=6/26). This is significantly less than the historical histotype distribution of HGSC, which is 69.3% (Fisher’s exact test, p&lt;0.0001). One HGSC case had a precursor lesion called a serous tubal intraepithelial carcinoma (STIC) while reviewing fallopian tubes of this individual. TP53 mutation analysis on one HGSC tumor sample showed a frameshift mutation in TP53 (c229fs) with the tumor and the corresponding STIC staining negative for p53 protein expression by immunohistochemistry. Conclusion: This evidence demonstrates the effectiveness of opportunistic salpingectomy for the prevention of ovarian cancer and shows a histotype distribution shift, with the most lethal gynecological malignancy having a significant reduction in cases following the procedure. Citation Format: Ramlogan Sowamber, Alice J. Mei, Paramdeep Kaur, Julianne McLeod, Emily McKay, Alex Lukey, Jamie Bakkum-Gamez, Natalia Buza, Paul Cohen, Kyle Devins, Rhonda Farrell, Christine Garcia, Blake Gilks, Ellen Goode, Anjelica Hodgson, Brooke Howitt, Pei Hui, Jutta Huvila, Anthony Karnezis, Kianoosh Keyhanian, Mary Kinloch, Martin Köbel, Felix KF. Kommoss, Lawrence Kushi, Janice S. Kwon, Kara Long-Roche, Anais Malpica, Jessica N. McAlpine, Dianne Miller, Esther Oliva, Andrea Palicelli, Aleksandra Paliga, Carlos Parra-Herran, Celeste Leigh Pearce, Sharnel Perera, Jurgen M. Piek, Haiyan Qiu, Joseph Rabban, Robert Rome, Miranda Steenbeek, Rebecca Stone, Aline Talhouk, Kristin M. Tischer, Britton Trabert, Penelope M. Webb, John R. Zalcberg, Gillian E. Hanley, David G. Huntsman. Evaluating the effectiveness of opportunistic salpingectomy (OS) for the prevention of epithelial ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B045.