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White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating brain health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. Lesion network mapping (LNM) enables us to infer if brain networks are connected to lesions and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed LNM to test the following hypotheses: (i) LNM-informed markers surpass WMH volumes in predicting cognitive performance; and (ii) WMH contributing to cognitive impairment map to specific brain networks. We analysed cross-sectional data of 3485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in four cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity to 480 atlas-based grey and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. We compared the capacity of total and regional WMH volumes and LNM scores in predicting cognitive function using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention/executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater connectivity to WMH, in grey and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network integrity, particularly in attention-related brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders.

White matter hyperintensities (WMH) and infarcts found on magnetic resonance imaging (MR infarcts) are common biomarkers of cerebrovascular disease. In this review, we summarize the methods, publications, and conclusions stemming from the Alzheimer's Disease Neuroimaging Initiative (ADNI) related to these measures. We combine analysis of WMH and MR infarct data from across the three main ADNI cohorts with a review of existing literature discussing new methodologies and scientific findings derived from these data. Although ADNI inclusion criteria were designed to minimize vascular risk factors and disease, data across all the ADNI cohorts found consistent trends of increasing WMH volumes associated with advancing age, female sex, and cognitive impairment. ADNI, initially proposed as a study to investigate biomarkers of AD pathology, has also helped elucidate the impact of asymptomatic cerebrovascular brain injury on cognition within a cohort relatively free of vascular disease. Future ADNI work will emphasize additional vascular biomarkers. HIGHLIGHTS: White matter hyperintensities (WMHs) are common to advancing age and likely reflect brain vascular injury among older individuals. WMH and to a lesser extent, magnetic resonance (MR) infarcts, affect risk for transition to cognitive impairment. WMHs and MR infarcts are present, even among Alzheimer's Disease Neuroimaging Initiative (ADNI) participants highly selected to have Alzheimer's disease (AD) as the primary pathology. WMH burden in ADNI is greater among individuals with cognitive impairment and has been associated with AD neurodegenerative markers and cerebral amyloidosis. The negative additive effects of cerebrovascular disease appear present, even in select populations, and future biomarker work needs to further explore this relationship.

INTRODUCTION: Recent technological advances have increased the risk that de-identified brain images could be re-identified from face imagery. The Alzheimers Disease Neuroimaging Initiative (ADNI) is a leading source of publicly available de-identified brain imaging, who quickly acted to protect participants privacy. METHODS: An independent expert committee evaluated 11 face-deidentification (de-facing) methods and selected four for formal testing. RESULTS: Effects of de-facing on brain measurements were comparable across methods and sufficiently small to recommend de-facing in ADNI. The committee ultimately recommended mri_reface for advantages in reliability, and for some practical considerations. ADNI leadership approved the committees recommendation, beginning in ADNI4. DISCUSSION: ADNI4 de-faces all applicable brain images before subsequent pre-processing, analyses, and public release. Trained analysts inspect de-faced images to confirm complete face removal and complete non-modification of brain. This paper details the history of the algorithm selection process and extensive validation, then describes the production workflows for de-facing in ADNI. HIGHLIGHTS: ADNI is implementing de-facing of MRI and PET beginning in ADNI4. De-facing alters face imagery in brain images to help protect privacy. Four algorithms were extensively compared for ADNI and mri_reface was chosen. Validation confirms mri_reface is robust and effective for ADNI sequences. Validation confirms mri_reface negligibly affects ADNI brain measurements.

The magnetic resonance imaging (MRI) Core has been operating since Alzheimer's Disease Neuroimaging Initiative's (ADNI) inception, providing 20 years of data including reliable, multi-platform standardized protocols, carefully curated image data, and quantitative measures provided by expert investigators. The overarching purposes of the MRI Core include: (1) optimizing and standardizing MRI acquisition methods, which have been adopted by many multicenter studies and trials worldwide and (2) providing curated images and numeric summary values from relevant MRI sequences/contrasts to the scientific community. Over time, ADNI MRI has become increasingly complex. To remain technically current, the ADNI MRI protocol has changed substantially over the past two decades. The ADNI 4 protocol contains nine different imaging types (e.g., three dimensional [3D] T1-weighted and fluid-attenuated inversion recovery [FLAIR]). Our view is that the ADNI MRI data are a greatly underutilized resource. The purpose of this paper is to educate the scientific community on ADNI MRI methods and content to promote greater awareness, accessibility, and use. HIGHLIGHTS: The MRI Core provides multi-platform standardized protocols, carefully curated image data, and quantitative analysis by expert groups. The ADNI MRI protocol has undergone major changes over the past two decades to remain technically current. As of April 25, 2024, the following numbers of image series are available: 17,141 3D T1w; 6877 FLAIR; 3140 T2/PD; 6623 GRE; 3237 dMRI; 2846 ASL; 2968 TF-fMRI; and 2861 HighResHippo (see Table 1 for abbreviations). As of April 25, 2024, the following numbers of quantitative analyses are available: FreeSurfer 10,997; BSI 6120; tensor based morphometry (TBM) and TBM-SYN 12,019; WMH 9944; dMRI 1913; ASL 925; TF-fMRI NFQ 2992; and medial temporal subregion volumes 2726 (see Table 4 for abbreviations). ADNI MRI is an underutilized resource that could be more useful to the research community.

Background and Objectives: Extreme heat events are increasing with climate change impacting human health. This study investigates the impact of extreme heat events on Emergency Department (ED) utilization by older adult patients. Materials and Methods: We conducted a study of all 324 non-federal hospital EDs in California during an 8-year period from data extracted from the California Department of Health Care Access and Information (HCAI). The study utilized a time-stratified case-crossover design to investigate ED visited in patients aged 65 years and older during 1-day and 2-day heat wave events. Extreme heat temperatures were measured and weighted using historical data at the zip code level at the 95th, 97.5th, and 99th percentiles 2012 through 2019. Conditional logistical regression was used to estimate the odds of ED visits during extreme heat events compared to non-extreme heat days. Stratified analyses by age and comorbidity status were conducted. Results: During the study period, 8,744,001 of ED visits among older patients were included in the study analysis. Odds ratios (OR) increased for during 1-day heat events (95th percentile (OR = 1.023, 95%CI: 1.020, 1.027), 97.5th percentile (OR = 1.030, 95%CI: 1.025, 1.035), 99th percentile (OR = 1.039, 95%CI: 1.032, 1.058)) and more so with 2-day heat wave events (95th percentile (OR = 1.031, 95%CI: 1.026, 1.036), 97.5th percentile (OR = 1.039, 95%CI: 1.031, 1.046), 99th percentile (OR = 1.044, 95%CI: 1.032, 1.058)). Older patients with three or more comorbidities had the highest odds of ED visits (OR = 1.085, 95%CI: 1.068, 1.112) at the 99th percentile. Conclusions: Our findings indicate that ED visits increase for older patients during extreme heat events, particularly with event intensity and duration. Older patients with at least one comorbidity were at greater risk.

IntroductionTau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis.MethodsUsing head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale.ResultsA strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach.DiscussionPreliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification.HighlightsTested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

BackgroundTubal sterilization is the most commonly used method of contraception in the United States. Because contraceptive effectiveness influences contraceptive selection, we examined typical use failure rates after tubal sterilization in the United States.MethodsWe estimated rates of pregnancy after tubal sterilization using data from four waves of the National Survey of Family Growth (NSFG), representative samples of U.S. women aged 15 to 44 years, collected in 2002, 2006 to 2010, 2011 to 2013, and 2013 to 2015. Survey weighting was used in survival analysis to examine time to first pregnancy after tubal sterilization. Data from these participants were censored after a tubal reversal procedure, infertility treatment, hysterectomy, or bilateral oophorectomy. Reported pregnancy rates after tubal sterilization procedures were examined by using Kaplan-Meier curves and then multivariable Cox proportional-hazards models to examine the effects of age at tubal sterilization, race/ethnicity, education, Medicaid funding, and postpartum versus interval procedures.ResultsPregnancy after tubal sterilization was reported by 2.9 to 5.2% of participants across NSFG waves. In the most recent survey wave (2013 to 2015), the estimated percentage of participants with pregnancies within the first 12 months after a tubal sterilization procedure was 2.9%; at 120 months after tubal sterilization, the estimated percentage with a pregnancy was 8.4%. At all the time points examined, pregnancy after tubal sterilization was less common after postpartum procedures than after interval procedures; however, this difference was not evident in multivariable models. In multivariable models, chance of pregnancy decreased with age at time of tubal sterilization. Race/ethnicity, education, and Medicaid funding were not consistently associated with pregnancy after tubal sterilization.ConclusionsThese data suggest that there may be nontrivial rates of pregnancy after tubal sterilization.

BACKGROUND: This qualitative study aims to assess perspectives of clinicians and clinic staff on mail-order pharmacy dispensing for medication abortion. METHODS: Participants included clinicians and staff involved in implementing a mail-order dispensing model for medication abortion at eleven clinics in seven states as part of a prospective cohort study, which began in January 2020 (before the FDA removed the in-person dispensing requirement for mifepristone). From June 2021 to July 2022, we invited participants at the participating clinics, including six primary care and five abortion clinics, to complete a semi-structured video interview about their experiences. We then conducted qualitative thematic analysis of interview data, summarizing themes related to perceived benefits and concerns about the mail-order model, perceived patient interest, and potential barriers to larger-scale implementation. RESULTS: We conducted 24 interviews in total with clinicians (13 physicians and one nurse practitioner) and clinic staff (n = 10). Participants highlighted perceived benefits of the mail-order model, including its potential to expand abortion services into primary care, increase patient autonomy and privacy, and to normalize abortion services. They also highlighted key logistical, clinical, and feasibility concerns about the mail-order model, and specific challenges related to integrating abortion into primary care. CONCLUSION: Clinicians and clinic staff working in primary care and abortion clinics were optimistic that mail-order dispensing of medication abortion can improve the ability of some providers to provide abortion and enable more patients to access services. The feasibility of mail-order pharmacy dispensing of medication abortion following the Supreme Court Dobbs decision is to be determined. TRIAL REGISTRATION: Registry: Clinicaltrials.gov. TRIAL REGISTRATION NUMBER: NCT03913104. Date of registration: first submitted on April 3, 2019 and first posted on April 12, 2019.

Human inborn errors of immunity include rare disorders entailing functional and quantitative antibody deficiencies due to impaired B cells called the common variable immunodeficiency (CVID) phenotype. Patients with CVID face delayed diagnoses and treatments for 5 to 15 years after symptom onset because the disorders are rare (prevalence of ~1/25,000), and there is extensive heterogeneity in CVID phenotypes, ranging from infections to autoimmunity to inflammatory conditions, overlapping with other more common disorders. The prolonged diagnostic odyssey drives excessive system-wide costs before diagnosis. Because there is no single causal mechanism, there are no genetic tests to definitively diagnose CVID. Here, we present PheNet, a machine learning algorithm that identifies patients with CVID from their electronic health records (EHRs). PheNet learns phenotypic patterns from verified CVID cases and uses this knowledge to rank patients by likelihood of having CVID. PheNet could have diagnosed more than half of our patients with CVID 1 or more years earlier than they had been diagnosed. When applied to a large EHR dataset, followed by blinded chart review of the top 100 patients ranked by PheNet, we found that 74% were highly probable to have CVID. We externally validated PheNet using >6 million records from disparate medical systems in California and Tennessee. As artificial intelligence and machine learning make their way into health care, we show that algorithms such as PheNet can offer clinical benefits by expediting the diagnosis of rare diseases.

IntroductionAlthough dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete.MethodsWe applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43.ResultsFinal included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aβ/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility.DiscussionA novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies.HighlightsLatent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.

Extreme heat and wildfire smoke events are increasingly co-occurring in the context of climate change, especially in California. Extreme heat and wildfire smoke may have synergistic effects on population health that vary over space. We leveraged high-resolution satellite and monitoring data to quantify spatially varying compound exposures to extreme heat and wildfire smoke in California (2006-2019) at ZIP Code Tabulation Area (ZCTA) level. We found synergistic effects between extreme heat and wildfire smoke on daily cardiorespiratory hospitalizations at the state level. We also found spatial heterogeneity in such synergistic effects across ZCTAs. Communities with lower education attainment, lower health insurance coverage, lower income, lower proportion of automobile ownership, lower tree canopy coverage, higher population density, and higher proportions of racial/ethnic minorities experienced higher synergistic effects. This study highlights the need to incorporate compound hazards and environmental justice considerations into evidence-based policy development to protect populations from increasingly prevalent compound hazards.

Genome-wide association studies (GWASs) have uncovered susceptibility loci associated with psychiatric disorders such as bipolar disorder (BP) and schizophrenia (SCZ). However, most of these loci are in non-coding regions of the genome, and the causal mechanisms of the link between genetic variation and disease risk is unknown. Expression quantitative trait locus (eQTL) analysis of bulk tissue is a common approach used for deciphering underlying mechanisms, although this can obscure cell-type-specific signals and thus mask trait-relevant mechanisms. Although single-cell sequencing can be prohibitively expensive in large cohorts, computationally inferred cell-type proportions and cell-type gene expression estimates have the potential to overcome these problems and advance mechanistic studies. Using bulk RNA-seq from 1,730 samples derived from whole blood in a cohort ascertained from individuals with BP and SCZ, this study estimated cell-type proportions and their relation with disease status and medication. For each cell type, we found between 2,875 and 4,629 eGenes (genes with an associated eQTL), including 1,211 that are not found on the basis of bulk expression alone. We performed a colocalization test between cell-type eQTLs and various traits and identified hundreds of associations that occur between cell-type eQTLs and GWASs but that are not detected in bulk eQTLs. Finally, we investigated the effects of lithium use on the regulation of cell-type expression loci and found examples of genes that are differentially regulated according to lithium use. Our study suggests that applying computational methods to large bulk RNA-seq datasets of non-brain tissue can identify disease-relevant, cell-type-specific biology of psychiatric disorders and psychiatric medication.

Objective: To assess the effects of prenatal counseling about the maternal health benefits of lactation on postpartum knowledge, breastfeeding intentions, and infant feeding behaviors. Materials and Methods: We conducted a randomized trial with 411 nulliparous U.S.-born women carrying a singleton gestation. Participants were recruited online; after completing a baseline survey that assessed breastfeeding knowledge and intentions, participants were randomized to receive a 10-minute virtual counseling session about the benefits of breastfeeding or attention-control counseling about smoke-free homes. We collected data on breastfeeding knowledge, intentions, and infant feeding behaviors through 12 months postpartum and conducted an intention-to-treat analysis. Results: On enrollment, awareness of the maternal health benefits of lactation was similarly low in both study groups. Postpartum, participants who received this prenatal counseling intervention had significantly greater awareness that breastfeeding decreases maternal risk of breast cancer, ovarian cancer, diabetes, heart disease, and rheumatoid arthritis (p

(1) Background: Clinical results on the effects of excess sugar consumption on insulin sensitivity are conflicting, possibly due to differences in sugar type and the insulin sensitivity index (ISI) assessed. Therefore, we compared the effects of consuming four different sugars on insulin sensitivity indices derived from oral glucose tolerance tests (OGTT). (2) Methods: Young adults consumed fructose-, glucose-, high-fructose corn syrup (HFCS)-, sucrose-, or aspartame-sweetened beverages (SB) for 2 weeks. Participants underwent OGTT before and at the end of the intervention. Fasting glucose and insulin, Homeostatic Model Assessment-Insulin Resistance (HOMA-IR), glucose and insulin area under the curve, Surrogate Hepatic Insulin Resistance Index, Matsuda ISI, Predicted M ISI, and Stumvoll Index were assessed. Outcomes were analyzed to determine: (1) effects of the five SB; (2) effects of the proportions of fructose and glucose in all SB. (3) Results: Fructose-SB and the fructose component in mixed sugars negatively affected outcomes that assess hepatic insulin sensitivity, while glucose did not. The effects of glucose-SB and the glucose component in mixed sugar on muscle insulin sensitivity were more negative than those of fructose. (4) Conclusion: the effects of consuming sugar-SB on insulin sensitivity varied depending on type of sugar and ISI index because outcomes assessing hepatic insulin sensitivity were negatively affected by fructose, and outcomes assessing muscle insulin sensitivity were more negatively affected by glucose.

IntroductionAdverse childhood experiences (ACEs) are common and have been associated with poor developmental outcomes. We aimed to investigate the relationship between early ACE exposure, subsequent diagnosis of developmental delay, and receipt of developmental delay services by young children. In addition, we aimed to assess the impact of health-promoting behaviors such as breastfeeding and daily reading on these relationships.MethodsIn this cross-sectional analysis of nationally-representative data from the 2017-2018 National Survey of Children's Health, we examined the relationship between ACEs, prior breastfeeding, daily reading, and developmental delay diagnosis among 7837 children aged 3-5 years, using multivariate logistic regression to adjust for family, personal, and sociodemographic characteristics.ResultsWe found a dose-dependent relationship between ACEs and developmental delay diagnosis; compared to those without ACEs, developmental delay was more common among those with either one ACE (aOR = 2.03, 95% CI 1.17-3.52) or two or more ACEs (aOR = 2.34, 95% CI 1.25-4.37). Neither breastfeeding (exclusively breastfed for 6 months vs. never breastfed aOR = 0.70, 95% CI 0.33-1.46) nor daily reading (no reading versus daily reading aOR = 1.15, CI 0.57-2.33) were associated with incidence of developmental delay among study participants. There was no significant difference in receipt of services intended to meet developmental needs between children with and without ACEs.DiscussionChildren with very early ACE exposure are at increased risk for diagnosis of developmental delay. Early screening for ACEs and developmental delay may mitigate the early developmental manifestations of ACE exposure in vulnerable children.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partners Scientific Board (PPSB) encompasses members from industry, biotechnology, diagnostic, and non-profit organizations that have until recently been managed by the Foundation for the National Institutes of Health (FNIH) and provided financial and scientific support to ADNI programs. In this article, we review some of the major activities undertaken by the PPSB, focusing on those supporting the most recently completed National Institute on Aging grant, ADNI3, and the impact it has had on streamlining biomarker discovery and validation in Alzheimer's disease. We also provide a perspective on the gaps that may be filled with future PPSB activities as part of ADNI4 and beyond. HIGHLIGHTS: The Private Partners Scientific board (PPSB) continues to play a key role in enabling several Alzheimer's Disease Neuroimaging Initiative (ADNI) activities. PPSB working groups have led landscape assessments to provide valuable feedback on new technologies, platforms, and methods that may be taken up by ADNI in current or future iterations.

ObjectivesTo assess access to abortion pills offered by clinics providing state-funded family planning services in California.MethodsWe attempted to make two scripted calls to a 20% random sample of family planning clinics in California, stratified by county, as "secret shoppers" in 2020 and 2021.ResultsClinic staff responded to 407 calls. Only 50 respondents (12%) reported their clinic offered abortion pills and 23 respondents (6%) accurately indicated to callers that abortion pills were available free to low-income individuals in California. Most (68%) clinics that did not offer abortion pills could not direct callers to a clinic that did offer abortion pills.ConclusionsEfforts are needed to increase the number of clinics providing medication abortion services in California. Clinic staff need training to provide accurate information about medication abortion.

BACKGROUND & AIMS: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated. METHODS: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44. RESULTS: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures. CONCLUSIONS: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell-mediated destruction of the intestinal epithelium in UC.

Mechanisms of resilience against tau pathology in individuals across the Alzheimer's disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer's disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = -0.062, P = 0.032), higher education level (Stβinteraction = -0.072, P = 0.011) and higher intracranial volume (Stβinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer's disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.

BackgroundPolicies to restrict population mobility are a commonly used strategy to limit the transmission of contagious diseases. Among measures implemented during the COVID-19 pandemic were dynamic stay-at-home orders informed by real-time, regional-level data. California was the first state in the U.S. to implement this novel approach; however, the effectiveness of California's four-tier system on population mobility has not been quantified.MethodsUtilizing data from mobile devices and county-level demographic data, we evaluated the impact of policy changes on population mobility and explored whether demographic characteristics explained variability in responsiveness to policy changes. For each California county, we calculated the proportion of people staying home and the average number of daily trips taken per 100 persons, across different trip distances and compared this to pre-COVID-19 levels.ResultsWe found that overall mobility decreased when counties moved to a more restrictive tier and increased when moving to a less restrictive tier, as the policy intended. When placed in a more restrictive tier, the greatest decrease in mobility was observed for shorter and medium-range trips, while there was an unexpected increase in the longer trips. The mobility response varied by geographic region, as well as county-level median income, gross domestic product, economic, social, and educational contexts, the prevalence of farms, and recent election results.ConclusionsThis analysis provides evidence of the effectiveness of the tier-based system in decreasing overall population mobility to ultimately reduce COVID-19 transmission. Results demonstrate that socio-political demographic indicators drive important variability in such patterns across counties.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. β-Catenin (CTNNB1)-mutated HCC represents 30% of cases of the disease with no precision therapeutics available. Using chemical libraries derived from clinical multi-kinase inhibitor (KI) scaffolds, we screened HCC organoids to identify WNTinib, a KI with exquisite selectivity in CTNNB1-mutated human and murine models, including patient samples. Multiomic and target engagement analyses, combined with rescue experiments and in vitro and in vivo efficacy studies, revealed that WNTinib is superior to clinical KIs and inhibits KIT/mitogen-activated protein kinase (MAPK) signaling at multiple nodes. Moreover, we demonstrate that reduced engagement on BRAF and p38α kinases by WNTinib relative to several multi-KIs is necessary to avoid compensatory feedback signaling-providing a durable and selective transcriptional repression of mutant β-catenin/Wnt targets through nuclear translocation of the EZH2 transcriptional repressor. Our studies uncover a previously unknown mechanism to harness the KIT/MAPK/EZH2 pathway to potently and selectively antagonize CTNNB1-mutant HCC with an unprecedented wide therapeutic index.

Introduction: The lactational amenorrhea method (LAM) of postpartum contraception is more effective than typical use of condoms or birth control pills. However, LAM may be underutilized due to incomplete perinatal counseling. Methods: We compared perceptions of the effectiveness of postpartum contraceptives including LAM among U.S.-born nulliparous pregnant women recruited using social media for a trial (NCT04601987). We used descriptive statistics to summarize data. Results: Of 760 individuals screened, 627 were invited to participate, and 451 (72%) were enrolled. Most (81%) had a college degree; 79% intended to breastfeed for at least 1 month. Only 8% believed exclusive breastfeeding reduces the chance of pregnancy "a lot" within 6 months of delivery and 2% indicated that exclusive breastfeeding is typically more effective than birth control pills or condoms. Compared with those planning to use other postpartum contraceptives, the 17% of respondents who planned to use LAM were more likely to know that breastfeeding delays return of menses (84% versus 44%, p ≤ 0.0001) and provides protection from pregnancy until menses return (54% versus 22%, p ≤ 0.0001). Although 25% of those planning to use LAM believed exclusive breastfeeding reduces pregnancy risk by "a lot," only 5% thought LAM is more effective than birth control pills and only 9% thought that it is more effective than condoms. Conclusions/Implications: First-time U.S. mothers are often unaware of breastfeeding's effects on menses and fertility. Clinicians providing counseling about postpartum contraceptive options should include more information on LAM.

Women's health care has evolved significantly since it was first acknowledged as an integral part of internal medicine training more than two decades ago. To update and clarify core competencies in sex- and gender-based women's health for general internists, the Society of General Internal Medicine (SGIM) Women and Medicine Commission prepared the following Position Paper, approved by the SGIM council in 2023. Competencies were developed using several sources, including the 2021 Accreditation Council for Graduate Medical Education Program Requirements for Internal Medicine and the 2023 American Board of Internal Medicine Certification Examination Blueprint. These competencies are relevant to the care of patients who identify as women, as well as gender-diverse individuals to whom these principles apply. They align with pivotal advances in women's health and acknowledge the changing context of patients' lives, reaffirming the role of general internal medicine physicians in providing comprehensive care to women.

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient (OL-Kir4.1-deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.

The vast majority of disease-associated single nucleotide polymorphisms (SNP) identified from genome-wide association studies (GWAS) are localized in non-coding regions. A significant fraction of these variants impact transcription factors binding to enhancer elements and alter gene expression. To functionally interrogate the activity of such variants we developed snpSTARRseq, a high-throughput experimental method that can interrogate the functional impact of hundreds to thousands of non-coding variants on enhancer activity. snpSTARRseq dramatically improves signal-to-noise by utilizing a novel sequencing and bioinformatic approach that increases both insert size and the number of variants tested per loci. Using this strategy, we interrogated known prostate cancer (PCa) risk-associated loci and demonstrated that 35% of them harbor SNPs that significantly altered enhancer activity. Combining these results with chromosomal looping data we could identify interacting genes and provide a mechanism of action for 20 PCa GWAS risk regions. When benchmarked to orthogonal methods, snpSTARRseq showed a strong correlation with in vivo experimental allelic-imbalance studies whereas there was no correlation with predictive in silico approaches. Overall, snpSTARRseq provides an integrated experimental and computational framework to functionally test non-coding genetic variants.

BACKGROUND: Influenza virus is responsible for a large global burden of disease, especially in children. Multiple Organ Dysfunction Syndrome (MODS) is a life-threatening and fatal complication of severe influenza infection. METHODS: We measured RNA expression of 469 biologically plausible candidate genes in children admitted to North American pediatric intensive care units with severe influenza virus infection with and without MODS. Whole blood samples from 191 influenza-infected children (median age 6.4 years, IQR: 2.2, 11) were collected a median of 27 hours following admission; for 45 children a second blood sample was collected approximately seven days later. Extracted RNA was hybridized to NanoString mRNA probes, counts normalized, and analyzed using linear models controlling for age and bacterial co-infections (FDR q

ObjectivesAs the social and legal acceptance of cannabis use grows, health professionals must understand and mitigate the impact of cannabis use in the perinatal period. Here we compare the prevalence of tobacco and cannabis use during and after pregnancy in California, a state that recently legalized cannabis use.MethodsMeasures of tobacco and cannabis use during and after pregnancy were obtained from California's Maternal and Infant Health Assessment, an annual population-based survey of California resident women with a live birth. To allow analysis of county-level variation, we pooled data from the 35 counties with the largest numbers of births from 2017 to 2019.ResultsCannabis use was more than twice as common as cigarette smoking among pregnant women (4.9% vs. 2.1%) in California. This difference was even more pronounced in some counties; for example, in Los Angeles, cannabis use was four times more prevalent than cigarette use. Either during or soon after birth, 7.3% of women in California reported cannabis use. Of those who smoked tobacco cigarettes prior to pregnancy, 73% quit before their third trimester of pregnancy, though 33.0% of these women reported a post-partum relapse in cigarette use.ConclusionsStates that have legalized cannabis must attend to the increasing prevalence of perinatal cannabis use, as well as concurrent use with tobacco and other substances. Efforts to support cannabis cessation should draw from successful public health approaches in tobacco control.

Although both medication abortion (MAB) and aspiration procedures are safe and effective, the Supreme Court decision in Dobbs v. Jackson Women's Health Organization removed federal protection of access to abortion services. Abortion access is now illegal or severely limited in many states, leading to delays in abortion care for patients in all states. In this rapidly evolving landscape, primary care physicians (PCPs) must be familiar with laws surrounding abortion care in their own and neighboring states. PCPs must also be prepared to expedite abortion care by sharing resources, obtaining testing when needed, and counseling patients about expected outcomes following abortion.

BackgroundTubal ligation remains common in the USA, especially among low-income patients.ObjectiveTo compare the effectiveness and safety of intrauterine contraceptives (IUC) to laparoscopic tubal ligation for Medicaid clients.DesignWe partnered with patient and clinician stakeholders to conduct a retrospective cohort study using California Medicaid claims for patients who had an IUC placed or laparoscopic tubal ligation performed in 2008-2014, excluding procedures performed within 42 days of a birth. We applied log-linear (Poisson) event-history regression models for clustered person-period data to adjust for sociodemographic variables and pre-procedure health status when examining associations between these contraceptive procedures and claims related to contraceptive failure, complications, and pain in the first year post-procedure.Key resultsWe identified 35,705 patients who had a levonorgestrel IUC placed, 23,628 patients who had a copper IUC placed, and 23,965 patients who underwent laparoscopic tubal ligation. In unadjusted analyses, rates of pregnancy within 1 year were similar following levonorgestrel IUC (2.40%) or copper IUC placement (2.99%) or tubal ligation (2.64%). In adjusted analyses, compared to tubal ligation, pregnancy was less common following placement of a levonorgestrel IUC (adj IRR 0.72, 95% CI 0.64-0.82) and similar with placement of a copper IUC (adj IRR 0.92, 95% CI 0.82-1.05). Procedural complications such as infection (0.35% vs. 2.91%) were significantly less common with IUC placement than tubal ligation. Claims for pelvic and abdominal pain decreased in frequency with time since all procedures; 6 to 12 months post-procedure, pelvic pain claims were less common after levonorgestrel IUC (adj IRR 0.69, 95% CI 0.65-0.73) or copper IUC placement (adj IRR 0.70, 95% CI 0.66-0.75) than tubal ligation.ConclusionsIUC appears at least as effective as laparoscopic tubal ligation at 1-year post-procedure with lower rates of infection and pelvic pain 6 to 12 months post-procedure.Clinical trial registrationNCT03438682.

ObjectiveTo evaluate the effects of increased access to immediate postpartum contraceptive implants (IPI) on repeat pregnancy and contraceptive use rates among patients with opioid use disorder (OUD).Materials and methodsBetween 2016 and 2018, 194 postpartum patients with OUD were offered the option of IPI placement at an institution with limited immediate postpartum long-acting reversible contraception availability and followed for one-year postpartum. Differences in pregnancy rates between participants who did and did not choose IPI were examined using logistic regression with inverse probability of treatment weighting from propensity scores accounting for differences between the two groups.ResultsAmong 194 participants, 96 (49.5%) chose an IPI and 98 (50.5%) chose an alternative method or no contraception (non-IPI). Among IPI participants, 76 (80.9%) continued to use their implant at one-year postpartum. Overall, 19 participants had a repeat pregnancy and 11 (57.9%) were unintended. In multivariable analyses, repeat pregnancy was more likely among those who did not choose IPI (OR 9.90; 95% CI 3.58-27.03) than those who did. Participants with OUD and who used alcohol (11.66; 1.38, 98.20) or cocaine (2.72; 1.23, 5.99) during pregnancy were more likely to choose IPI. Participants who were married (0.28; 0.09, 0.89), engaged in OUD treatment prior to pregnancy (0.48; 0.25, 0.93), and happier when they found out about their pregnancy (0.87; 0.77, 0.98) were less likely to choose IPI.ConclusionOffering patients with OUD the option of IPI is associated with high utilisation and continuation rates, and low rates of repeat pregnancy within one-year postpartum.

Multiple sclerosis (MS) is a multifocal and progressive inflammatory disease of the central nervous system (CNS). However, the compartmentalized pathology of the disease affecting various anatomical regions including gray and white matter and lack of appropriate disease models impede understanding of the disease. Utilizing single-nucleus RNA-sequencing and multiplex spatial RNA mapping, we generated an integrated transcriptomic map comprising leukocortical, cerebellar and spinal cord areas in normal and MS tissues that captures regional subtype diversity of various cell types with an emphasis on astrocytes and oligodendrocytes. While we found strong cross-regional diversity among glial subtypes in control tissue, regional signatures become more obscure in MS. This suggests that patterns of transcriptomic changes in MS are shared across regions and converge on specific pathways, especially those regulating cellular stress and immune activation. In addition, we found evidence that a subtype of white matter oligodendrocytes appearing across all three CNS regions adopt pro-remyelinating gene signatures in MS. In summary, our data suggest that cross-regional transcriptomic glial signatures overlap in MS, with different reactive glial cell types capable of either exacerbating or ameliorating pathology.

BackgroundUnhealthy alcohol use is a significant health issue for the US population. The US Preventive Services Task Force (USPSTF) recommends screening adults 18 years or older for unhealthy alcohol use during primary care visits.ObjectivesTo evaluate alcohol screening among ambulatory visits made by US adult primary care patients and identify characteristics predictive of alcohol screening.DesignA series of cross-sectional analysis of the National Ambulatory Medical Care Survey (NAMCS) data collected from 2014 to 2016 was used to examine US primary care providers' use of alcohol screening questionnaires and delivery of counseling on alcohol use.ParticipantsA total of 19,213 visits made by patients aged 18 years or older to a US primary care physician trained in family medicine or internal medicine.Main measuresAdministration of a validated alcohol screening questionnaire and counseling/education on alcohol use. Variation in alcohol screening by patient demographic characteristics, reason for office visit, length of office visit, chronic medical conditions, evaluation by assigned primary care physician, new patient to practice, and region.Key resultsAlcohol screening with a validated questionnaire occurred during 2.6% (95% Cl: 0.9%, 4.3%) of visits. Alcohol counseling, provided either by the physician or by referral, was documented in 0.8% (95% Cl: 0.3%, 1.3%) of visits. Screening was significantly more likely if patients were seen by their assigned primary care physician (adjOR 4.38 (95% Cl: 1.41, 13.61)), a new patient to the practice (adjOR 4.18 (95% Cl: 2.30, 7.79)), or had several chronic medical conditions (adjOR 3.40 (95% Cl: 1.48, 7.78)). Patients' sex, race/ethnicity, age group, or length of appointment time was not associated with screening for unhealthy alcohol use.ConclusionsScreening for unhealthy alcohol use using a validated questionnaire is uncommonly performed during US primary care visits. Interventions or incentives may be needed to increase uptake of USPSTF alcohol screening recommendations.

BACKGROUND: High-quality contraceptive counseling is critical to support Veterans reproductive autonomy and promote healthy outcomes. OBJECTIVE: To describe perceived quality of contraceptive counseling in Veterans Health Administration (VA) primary care and assess factors associated with perceived high- and low-quality contraceptive counseling. DESIGN: Cross-sectional study using data from the Examining Contraceptive Use and Unmet Need in women Veterans (ECUUN) national telephone survey. PARTICIPANTS: Veterans aged 18-44 who received contraceptive services from a VA primary care clinic in the past year (N=506). MAIN MEASURES: Perceived quality of contraceptive counseling was captured by assessing Veterans agreement with 6 statements regarding provider counseling adapted from the Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey. High-quality counseling was defined as a top score of strongly agreeing on all 6 items; low-quality counseling was defined as not agreeing (neutral, disagreeing, or strongly disagreeing) with >3 items. We constructed two multivariable models to assess associations between patient-, provider-, and system-level factors and perceived high-quality (Model 1) and perceived low-quality counseling (Model 2). KEY RESULTS: Most participants strongly agreed that their providers listened carefully (74%), explained things clearly (77%), and spent enough time discussing things (71%). Lower proportions strongly agreed that their provider discussed more than one option (54%), discussed pros/cons of various methods (44%), or asked which choice they thought was best for them (62%). In Model 1, Veterans who received care in a Womens Health Clinic (WHC) had twice the odds of perceiving high-quality counseling (aOR=1.99; 95%CI=1.24-3.22). In Model 2, Veterans who received care in a WHC (aOR=0.49; 95%CI=0.25-0.97) or from clinicians who provide cervical cancer screening (aOR=0.49; 95%CI=0.26-0.95) had half the odds of perceiving low-quality counseling. CONCLUSIONS: Opportunities exist to improve the quality of contraceptive counseling within VA primary care settings, including more consistent efforts to seek patients perspectives with respect to contraceptive decisions.

ObjectivesTo assess emergency contraception (EC) service provision by California's family planning clinics.Study designWe made 2 scripted calls to a random sample of 309 family planning clinics.ResultsWe reached one hundred ninety-four clinics on 2 occasions, although only 183 (59%) could be reached with the information provided online by California's office of family planning. Of these 194 clinics, 27% responded that the clinic did not provide EC and 43% offered only levonorgestrel EC. Only 1 clinic asked about recent sexual assault and one other about their weight.ConclusionsPrompt access to effective EC remains challenging in California. Clinic staff responding to requests for EC should provide trauma-informed care.

Many genetic variants affect disease risk by altering context-dependent gene regulation. Such variants are difficult to study mechanistically using current methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs). To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for identifying genotypic and allele-specific effects on chromatin that are also associated with disease. In prostate cancer, CWAS identified regulatory elements and androgen receptor-binding sites that explained the association at 52 of 98 known prostate cancer risk loci and discovered 17 additional risk loci. CWAS implicated key developmental transcription factors in prostate cancer risk that are overlooked by eQTL-based approaches due to context-dependent gene regulation. We experimentally validated associations and demonstrated the extensibility of CWAS to additional epigenomic datasets and phenotypes, including response to prostate cancer treatment. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting transcriptional regulation.

The process of identifying suitable genome-wide association (GWA) studies and formatting the data to calculate multiple polygenic risk scores on a single genome can be laborious. Here, we present a centralized polygenic risk score calculator currently containing over 250,000 genetic variant associations from the NHGRI-EBI GWAS Catalog for users to easily calculate sample-specific polygenic risk scores with comparable results to other available tools. Polygenic risk scores are calculated either online through the Polygenic Risk Score Knowledge Base (PRSKB; https://prs.byu.edu ) or via a command-line interface. We report study-specific polygenic risk scores across the UK Biobank, 1000 Genomes, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), contextualize computed scores, and identify potentially confounding genetic risk factors in ADNI. We introduce a streamlined analysis tool and web interface to calculate and contextualize polygenic risk scores across various studies, which we anticipate will facilitate a wider adaptation of polygenic risk scores in future disease research.

BackgroundPostpartum contraception counseling and method use vary widely among patients who had a preterm birth. We performed this study to explore what issues and concerns individuals with preterm infants requiring intensive care describe as influencing their postpartum contraceptive choices.MethodsWe conducted a qualitative study using semi-structured interviews with participants who gave birth to a singleton preterm infant admitted to the neonatal intensive care unit (NICU). We explored pregnancy, childbirth, postpartum care, and NICU experiences, as well as future reproductive plans and postpartum contraceptive choices. Two coders used a constant-comparative approach to code transcripts and identify themes.ResultsWe interviewed 26 participants: 4 (15%) gave birth at less than 26, 6 (23%) at 26 to 27 6/7, 8 (31%) at 28 to 31 6/7, and 8 (31%) at 32 to 36 6/7 weeks of gestation. We identified three main themes related to future pregnancy plans and contraception choice. First, participants frequently described their preterm birth and their infants' NICU hospitalization as traumatic experiences that affected plans for future pregnancies. The loss of control in predicting or preventing a future preterm birth and uncertainty about their premature child's future medical needs resulted in participants wanting to avoid going through the same experience with another child. Second, participants chose contraception based on previous personal experiences, desired method features, and advice from others. Last, having a preterm birth did not result in any ambivalence among those who desired permanent contraception.ConclusionsPreterm birth influences future pregnancy plans. When discussing reproductive goals with patients, clinicians should be aware of potential trauma associated with a premature birth, assess for whether patients want to discuss contraception, and center the conversation around individual needs if patients do desire contraceptive counseling.

Background: Alcohol and binge drinking pose significant health risks, especially for underage women; nonetheless, binge drinking is common. Materials and Methods: To evaluate the effectiveness of the PartyWise intervention in increasing awareness of sex differences in the risks of binge drinking, we used social media to enroll 520 female adolescents aged 15-19 years in a randomized controlled trial. Intervention participants received telephone screening, a brief counseling intervention with web-based resources (http://www.partywise.org), and up to 8 weekly text messages. Results: At baseline, most (71%) participants reported alcohol consumption in the prior month and 44% reported binge drinking (four or more drinks on one occasion), without differences between study groups; 79% of participants were aware of sex-based differences in alcohol risks. At follow-up, intervention recipients were more knowledgeable about sex-based differences in alcohol risks (adjusted odds ratio [adj OR] 8.87, 95% confidence interval [CI] 3.35-23.49 at 3 months; adj OR 2.44, 95% CI 1.21-4.90 at 9 months) and more likely to accurately define binge drinking (adj OR 1.63, 95% CI 1.02-2.60 at 3 months; OR 1.37, 95% CI 0.89-2.06 at 9 months). Although rates of any binge drinking in the past month remained similar between groups, intervention recipients were less likely to report binge drinking more than once in the past 30 days (22% vs. 32%, adj OR 0.58, 95% CI 0.35-0.99 at 3 months; 27% vs. 30%, adj OR 0.97, 95% CI 0.60-1.55 at 9 months). Conclusions: The PartyWise intervention is a promising approach to increasing awareness of the risks of binge drinking for underage women in a remotely delivered platform. Clinical Trials Registration: The Share Health Study: Teen Social Connections and Health (Phase 2), NCT03842540, https://clinicaltrials.gov/ct2/show/NCT03842540?id=NCT03842540&draw=2&rank=1.

Anticoagulation poses unique challenges for women of reproductive age. Clinicians prescribing anticoagulants must counsel patients on issues ranging from menstruation and the possibility of developing a hemorrhagic ovarian cyst to teratogenic risks and safety with breastfeeding. Abnormal uterine bleeding affects up to 70% of young women who are treated with anticoagulation. As such, thoughtful clinical guidance is required to avoid having young women who are troubled by their menses, dose reduce, or prematurely discontinue their anticoagulation, leaving them at increased risk of recurrent thrombosis. Informed by a review of the medical literature, we present current recommendations for assisting patients requiring anticoagulation with menstrual management, prevention of hemorrhagic ovarian cysts, and avoiding unintended pregnancy. The subdermal implant may be considered a first-line option for those requiring anticoagulation, given its superior contraceptive effectiveness and ability to reliably reduce risk of hemorrhagic ovarian cysts. All progestin-only formulations-such as the subdermal implant, intrauterine device, injection, or pills-are generally preferred over combined hormonal pills, patch, or ring. Tranexamic acid, and in rare cases endometrial ablation, may also be useful in managing menorrhagia and dysmenorrhea. During pregnancy, enoxaparin remains the preferred anticoagulant and warfarin is contraindicated. Breastfeeding women may use warfarin, but direct oral anticoagulants are not recommended given their limited safety data. This practical guide for clinicians is designed to inform discussions of risks and benefits of anticoagulation therapy for women of reproductive age.

ObjectiveTo compare real-world effectiveness of hysteroscopic to laparoscopic sterilization.DesignRetrospective cohort of Medicaid claims for hysteroscopic or laparoscopic sterilization procedures performed in California, 2008-2014. After excluding postpartum procedures, we applied log-linear (Poisson) event-history regression models for clustered person-period data, weighted for propensity to receive either sterilization procedures, and adjusted for sociodemographic and clinical variables to examine the poststerilization pregnancy rates.SettingClinics, hospitals.Patient(s)Women aged 18-50 years with Medicaid claims between January 1, 2008, and August 31, 2014.Intervention(s)Hysteroscopic or laparoscopic sterilization procedure.Main outcome measure(s)Poststerilization pregnancy measured by pregnancy-related claims.Result(s)Among women with hysteroscopic (n = 5,906) or laparoscopic (n = 23,965) sterilization, poststerilization pregnancy claims were identified for 4.74% of women after hysteroscopic sterilization and 5.57% after laparoscopic sterilization. The pregnancy rates decreased over time after either procedure. Twelve months after the procedure, the crude incidence of pregnancy claims was higher for hysteroscopic sterilization than for laparoscopic sterilization (3.26 vs. 2.61 per 100 woman-years), but the propensity-weighted adjusted incidence rate ratio was 1.06 (95% confidence interval [CI], 0.85-1.26). Between 13 and 24 months after the procedure, there were fewer pregnancies for women after hysteroscopic sterilizations than for those after laparoscopic sterilizations (adjusted incidence rate ratio, 0.63 [95% CI, 0.45-0.88]), with no statistically significant differences in later years. The cumulative pregnancy rates 5 years after sterilization were lower with hysteroscopic sterilization than with laparoscopic sterilization (6.26 vs. 7.22 per 100 woman-years; propensity-weighted, adjusted risk ratio, 0.76 [95% CI, 0.62-0.90]). The poststerilization pregnancy rates varied by age and race/ethnicity.Conclusion(s)The pregnancy rates after female sterilization are higher than expected, whether performed hysteroscopically or laparoscopically. These findings are reassuring that the effectiveness of hysteroscopic sterilization was not inferior to laparoscopic sterilization.Clinical trial registration numberNCT03438682.

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks.

Adolescents and young adults (AYAs, 15-39 years) are the largest uninsured population in the Unites States, increasing the likelihood of late-stage cancer diagnosis and poor survival. We evaluated the associations between the Affordable Care Act (ACA), insurance coverage, stage at diagnosis and survival among AYAs with lymphoma. We used data from the California Cancer Registry linked to Medicaid enrollment files on AYAs diagnosed with a primary non-Hodgkin (NHL; n = 5959) or Hodgkin (n = 5378) lymphoma pre-ACA and in the early and full ACA eras. Health insurance was categorized as continuous Medicaid, discontinuous Medicaid, Medicaid enrollment at diagnosis/uninsurance, other public and private. We used multivariable regression models for statistical analyses. The proportion of AYAs uninsured/Medicaid enrolled at diagnosis decreased from 13.4% pre-ACA to 9.7% with full ACA implementation, while continuous Medicaid increased from 9.3% to 29.6% during this time (P

Objective(s)To estimate the effectiveness, acceptability, and feasibility of medication abortion with mifepristone dispensed by a mail-order pharmacy after in-person clinical assessment.Study designThis is an interim analysis of an ongoing prospective cohort study conducted at five sites. Clinicians assessed patients in clinic and, if they were eligible for medication abortion and ≤ 63 days' gestation, electronically sent prescriptions for mifepristone 200 mg orally and misoprostol 800 mcg buccally to a mail-order pharmacy, which shipped medications for next-day delivery. Participants completed surveys three and 14 days after enrollment, and we abstracted medical chart data.ResultsBetween January 2020 and April 2021 we enrolled 240 participants and obtained clinical outcome information for 227 (94.6%); 3 reported not taking either medication. Of those with abortion outcome information (N = 224), 216 (96.4%) completed day-3 and 212 (94.6%) day-14 surveys. Of the 224 that took medications, none reported taking past 70 days' gestation, and complete medication abortion occurred for 217 participants (96.9%, 95% CI 93.7%-98.7%). Most received medications within three days (82.1%, 95% CI 76.5%-86.9%). In the day-3 survey, 95.4% (95% CI 91.7%-97.8%) reported being very (88.4%) or somewhat (6.9%) satisfied with receiving medications by mail. In the day-14 survey, 89.6% (95% CI 84.7%-93.4%) said they would use the mail-order service again if needed. Eleven (4.9%, 95% CI 2.5%-8.6%) experienced adverse events; two were serious (one blood transfusion, one hospitalization), and none were related to mail-order pharmacy dispensing.ConclusionsMedication abortion with mail-order pharmacy dispensing of mifepristone appears effective, feasible, and acceptable to patients.ImplicationsThe in-person dispensing requirement for mifepristone, codified in the drug's Risk Evaluation and Mitigation Strategy, should be removed.

ObjectiveTo evaluate the real-world safety of hysteroscopic compared with laparoscopic surgical sterilization.MethodsWe conducted a retrospective cohort study of Medicaid claims for hysteroscopic or laparoscopic sterilization procedures performed in California, 2008-2014, among women aged 18-50 years. After excluding postpartum procedures, we applied log-linear (Poisson) event-history regression models for clustered person-period data, weighted for propensity to receive either sterilization procedures, and adjusted for sociodemographic and clinical characteristics that may affect outcomes of interest to patients and physicians. We assessed the following outcomes: procedural complications, additional surgical procedures (eg, hysterectomy), repeat sterilization procedures, pelvic pain, pelvic inflammatory disease (PID), abdominal pain, nonabdominal pain, and abnormal uterine bleeding.ResultsWe identified 5,906 women who had undergone hysteroscopic and 23,965 who had undergone laparoscopic sterilization. After adjusting for sociodemographic and health history, women who had hysteroscopic sterilization were less likely to have claims for procedural complications (eg, transfusion, P

BackgroundPrevious latent class analysis of adults with acute respiratory distress syndrome (ARDS) identified two phenotypes, distinguished by the degree of inflammation. We aimed to identify phenotypes in children with ARDS in whom developmental differences might be important, using a latent class analysis approach similar to that used in adults.MethodsThis study was a secondary analysis of data aggregated from the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial and the Genetic Variation and Biomarkers in Children with Acute Lung Injury (BALI) ancillary study. We used latent class analysis, which included demographic, clinical, and plasma biomarker variables, to identify paediatric ARDS (PARDS) phenotypes within a cohort of children included in the RESTORE and BALI studies. The association of phenotypes with clinically relevant outcomes and the performance of paediatric data in adult ARDS classification algorithms were also assessed.Findings304 children with PARDS were included in this secondary analysis. Using latent class analysis, a two-class model was a better fit for the cohort than a one-class model (p