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BackgroundDespite national testing guidelines, rates of testing for HIV, sexually transmitted infections, and hepatitis C remain lower than recommended for men who have sex with men (MSM) in the US. To help address this, the TakeMeHome (TMH) program was started in March 2020 by a consortium of public health organizations and dating apps - Building Healthy Online Communities - to work with health departments to increase access to HIV testing for MSM on dating apps.MethodsUsers of participating dating apps were sent messages about opportunities for testing with self-collected specimens through TMH. Program users were eligible to receive test kits if they lived in a participating zip code and were aged at least 18. Users who were interested in testing could order kits to be mailed to them for lab-based testing of HIV, hepatitis C, chlamydia, gonorrhea, and/or syphilis, depending on risk and availability in their zip code. Orders were sent via application programming interface (API) to Molecular Testing Labs (MTL) for fulfillment; kits were provided at no cost to the program user. Within approximately 24 hours of order receipt, MTL mailed program users a kit with required collection supplies, directions, and a link to a video instruction for self-collection. Program users received an automated email after testing was complete with a link to access results through their online account. Individuals with positive results on any of the relevant tests were directed to additional information and supported with linkage to additional testing or treatment, depending on local protocols.ResultsThe positivity rate of specimens processed through TMH was 1.4% for HIV, 0.6% for hepatitis C, and 2.9% for all STIs combined. The per-person positivity rate was 15.3% across all STIs.Conclusions: The TakeMeHome program demonstrates that self-collected lab-processed testing is feasible and effective at identifying new HIV and STI cases.

BackgroundThere is potential for adverse events from corticosteroid injections, including increase in blood glucose, decrease in bone mineral density and suppression of the hypothalamic-pituitary axis. Published studies note that doses lower than those commonly injected provide similar benefit.MethodsDevelopment of the practice guideline was approved by the Board of Directors of American Society of Regional Anesthesia and Pain Medicine with several other societies agreeing to participate. The scope of guidelines was agreed on to include safety of the injection technique (landmark-guided, ultrasound or radiology-aided injections); effect of the addition of the corticosteroid on the efficacy of the injectate (local anesthetic or saline); and adverse events related to the injection. Based on preliminary discussions, it was decided to structure the topics into three separate guidelines as follows: (1) sympathetic, peripheral nerve blocks and trigger point injections; (2) joints; and (3) neuraxial, facet, sacroiliac joints and related topics (vaccine and anticoagulants). Experts were assigned topics to perform a comprehensive review of the literature and to draft statements and recommendations, which were refined and voted for consensus (≥75% agreement) using a modified Delphi process. The United States Preventive Services Task Force grading of evidence and strength of recommendation was followed.ResultsThis guideline deals with the use and safety of corticosteroid injections for sympathetic, peripheral nerve blocks and trigger point injections for adult chronic pain conditions. All the statements and recommendations were approved by all participants after four rounds of discussion. The Practice Guidelines Committees and Board of Directors of the participating societies also approved all the statements and recommendations. The safety of some procedures, including stellate blocks, lower extremity peripheral nerve blocks and some sites of trigger point injections, is improved by imaging guidance. The addition of non-particulate corticosteroid to the local anesthetic is beneficial in cluster headaches but not in other types of headaches. Corticosteroid may provide additional benefit in transverse abdominal plane blocks and ilioinguinal/iliohypogastric nerve blocks in postherniorrhaphy pain but there is no evidence for pudendal nerve blocks. There is minimal benefit for the use of corticosteroids in trigger point injections.ConclusionsIn this practice guideline, we provided recommendations on the use of corticosteroids in sympathetic blocks, peripheral nerve blocks, and trigger point injections to assist clinicians in making informed decisions.

IntroductionPalbociclib is a widely used treatment for advanced breast cancer in older adults. However, the existing evidence regarding its safety and tolerability in this age group is inconsistent and limited to retrospective subgroup or pooled analyses.Materials and methodsWe conducted a prospective single-arm multicenter phase 2 study to evaluate the safety and tolerability of palbociclib in participants aged 70 years or older with advanced hormone receptor-positive breast cancer. Participants were given palbociclib in combination with their physician's choice of endocrine therapy (letrozole or fulvestrant). The primary endpoint was the incidence of grade 3+ adverse events (AEs) by six months. Secondary endpoints included AE-related dose delays, dose reductions, early discontinuations, and hospitalizations. Additionally, we compared these endpoints by age groups (70-74 and ≥ 75 years).ResultsOf the 90 participants (median age 74 years [70-87]) enrolled, 75.6% (95% confidence interval [CI], 65.4-84.0) had grade 3+ AEs by six months. The most frequent grade 3+ AEs were neutropenia (61%), fatigue (4%), and nausea (3%). Febrile neutropenia was uncommon (1.1%). Due to AEs, 36% had dose delays, 34% had dose reductions, 10% had early discontinuations, and 10% had hospitalizations. Compared to those aged 70-74 years, participants aged ≥75 years had higher rates of early discontinuations (5.9% vs 15.9%, a difference of 9.5% [95% CI 3.5%-22.5%]).DiscussionPalbociclib has an overall favorable safety profile in adults aged ≥70 with advanced breast cancer. However, adults ≥75 years had a trend toward higher rates of AE-related early discontinuations compared to those 70-74 years. Further research is needed to evaluate tolerability and improve the delivery of palbociclib in older adults.Clinicaltrialsgov:NCT03633331.

ObjectivesIndividuals increasingly experience delays or interruptions in schooling; we evaluate the association between these non-traditional education trajectories and mental health.MethodsUsing year-by-year education data for 7,501 National Longitudinal Survey of Youth 1979 participants, ages 14-48 (262,535 person-years of education data), we applied sequence analysis and a clustering algorithm to identify educational trajectory groups, incorporating both type and timing to credential. Linear regression models, adjusted for early-life confounders, evaluated relationships between educational trajectories and mental health component scores (MCS) from the 12-item short form instrument at age 50. We evaluated effect modification by race, gender, and race by gender.ResultsWe identified 24 distinct educational trajectories based on highest credential and educational timing. Compared to high school (HS) diplomas, < HS (beta=-3.41, 95%CI:-4.74,-2.07) and general educational development credentials (GEDs) predicted poorer MCS (beta=-2.07,95%CI:-3.16,-0.98). The following educational trajectories predicted better MCS: some college immediately after High School (beta=1.52, 95%CI:0.68,2.37), Associate degrees after long interruptions (beta=1.73, 95%CI:0.27,3.19), and graduate school soon after Bachelor's completion (beta=1.13, 95%CI:0.21,2.06). Compared to White men, Black women especially benefited from educational credentials higher than HS in predicting MCS.ConclusionsBoth type and timing of educational credential predicted mental health. Black women's mental higher especially benefited from higher educational credentials.

Vital to the treatment of influenza is the use of antivirals such as Oseltamivir (Tamiflu) and Zanamivir (Relenza); however, antiviral resistance is becoming an increasing problem for these therapeutics. The RNA-dependent RNA polymerase acidic N-terminal (PAN) endonuclease, a critical component of influenza viral replication machinery, is an antiviral target that was recently validated with the approval of Baloxavir Marboxil (BXM). Despite its clinical success, BXM has demonstrated susceptibility to resistance mutations, specifically the I38T, E23K, and A36 V mutants of PAN. To better understand the effects of these mutations on BXM resistance and improve the design of more robust therapeutics, this study examines key differences in protein-inhibitor interactions with two inhibitors and the I38T, E23K, and A36 V mutants. Differences in inhibitor binding were evaluated by measuring changes in binding to PAN using two biophysical methods. The binding mode of two distinct inhibitors was determined crystallographically with both wild-type and mutant forms of PAN. Collectively, these studies give some insight into the mechanism of antiviral resistance of these mutants.

Treatment of hematologic malignancies with patient-derived anti-CD19 chimeric antigen receptor (CAR) T-cells has demonstrated long-term remissions for patients with otherwise treatment-refractory advanced leukemia and lymphoma. Conversely, CAR T-cell treatment of solid tumors, including advanced gastric cancer (GC), has proven more challenging due to on-target off-tumor toxicities, poor tumor T-cell infiltration, inefficient CAR T-cell expansion, immunosuppressive tumor microenvironments, and demanding preconditioning regimens. We report the exceptional results of autologous Claudin18.2-targeted CAR T cells (CT041) in a patient with metastatic GC, who had progressed on four lines of combined systemic chemotherapy and immunotherapy. After two CT041 infusions, the patient had target lesion complete response and sustained an 8-month overall partial response with only minimal ascites. Moreover, tumor-informed circulating tumor DNA (ctDNA) reductions coincided with rapid CAR T-cell expansion and radiologic response. No severe toxicities occurred, and the patient's quality of life significantly improved. This experience supports targeting Claudin18.2-positive GC with CAR T-cell therapy and helps to validate ctDNA as a biomarker in CAR T-cell therapy. Clinical Insight: Claudin18.2-targeted CAR T cells can safely provide complete objective and ctDNA response in salvage metastatic GC.

Immune tolerance is maintained in lymphoid organs (LOs). Despite the presence of complex immune cell networks in non-LOs, it is unknown whether self-tolerance is maintained in these tissues. We developed a technique to restrict genetic recombination to regulatory T cells (Tregs) only in skin. Selective depletion of skin Tregs resulted in T cell-mediated inflammation of hair follicles (HFs). Suppression did not rely on CTLA-4, but instead on high-affinity interleukin-2 (IL-2) receptor expression by skin Tregs, functioning exclusively in a cell-extrinsic manner. In a novel model of HF stem cell (HFSC)-driven autoimmunity, we reveal that skin Tregs immunologically protect the HFSC niche. Finally, we used spatial transcriptomics to identify aberrant IL-2 signaling at stromal-HF interfaces in a rare form of human alopecia characterized by HFSC destruction and alopecia areata. Collectively, these results reveal the fundamental biology of Tregs in skin uncoupled from the systemic pool and elucidate a mechanism of self-tolerance.

IntroductionThe pace of innovation has accelerated in virtually every area of tau research in just the past few years.MethodsIn February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation.ResultsRepresenting academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research.DiscussionThe virtual meeting provided an opportunity to foster cross-sector collaboration and partnerships as well as a forum for updating colleagues on research-advancing tools and programs that are steadily moving the field forward.

Understanding risk perception and risk-taking among youth can inform targeted prevention efforts. Using a health beliefs model-informed framework, we analysed 8 semi-structured, gender-specific focus group discussions with 93 youth 15-24 years old (48% male, 52% female), drawn from the SEARCH trial in rural Kenya and Uganda in 2017-2018, coinciding with the widespread introduction of PrEP. Highly connected social networks and widespread uptake of antiretrovirals shaped youth HIV risk perception. Amid conflicting information about HIV prevention methods, youth felt exposed to multiple HIV risk factors like the high prevalence of HIV, belief that people with HIV(PWH) purposefully infect others, dislike of condoms, and doubts about PrEP efficacy. Young women also reported minimal sexual autonomy in the context of economic disadvantages, the ubiquity of intergenerational and transactional sex, and peer pressure from other women to have many boyfriends. Young men likewise reported vulnerability to intergenerational sex, but also adopted a sexual conquest mentality. Comprehensive sexuality education and economic empowerment, through credible and trusted sources, may moderate risk-taking. Messaging should leverage youth's social networks to spread fact-based, gender- and age-appropriate information. PrEP should be offered alongside other reproductive health services to address both pregnancy concerns and reduce HIV risk.

BackgroundInjectable cabotegravir was superior to daily oral tenofovir disoproxil fumarate plus emtricitabine for HIV prevention in two clinical trials. Both trials had the primary aim of establishing the HIV prevention efficacy of long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) compared with tenofovir disoproxil fumarate plus emtricitabine daily oral PrEP. Long-acting PrEP was associated with diagnostic delays and integrase strand-transfer inhibitor (INSTI) resistance. This report presents findings from the first unblinded year of the HIV Prevention Trials Network (HPTN) 083 study.MethodsThe HPTN 083 randomised controlled trial enrolled HIV-uninfected cisgender men and transgender women at elevated HIV risk who have sex with men, from 43 clinical research sites in Africa, Asia, Latin America, and the USA. Inclusion criteria included: a negative HIV serological test at the screening and study entry, undetectable HIV RNA levels within 14 days of study entry, age 18 years or older, overall good health as determined by clinical and laboratory evaluations, and a creatinine clearance of 60 mL/min or higher. Participants were randomly allocated to receive long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP. After study unblinding, participants remained on their original regimen awaiting an extension study. HIV infections were characterised retrospectively at a central laboratory. Here we report the secondary analysis of efficacy and safety for the first unblinded year. The primary outcome was incident HIV infection. Efficacy analyses were done on the modified intention-to-treat population using a Cox regression model. Adverse events were compared across treatment groups and time periods (blinded vs unblinded). This trial is registered with ClinicalTrials.gov, NCT02720094.FindingsOf the 4488 participants who contributed person-time to the blinded analysis, 3290 contributed person-time to the first unblinded year analysis between May 15, 2020, and May 14, 2021. Updated HIV incidence in the blinded phase was 0·41 per 100 person-years for long-acting injectable cabotegravir PrEP and 1·29 per 100 person-years for daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP (hazard ratio [HR] 0·31 [95% CI 0·17-0·58], p=0·0003). HIV incidence in the first unblinded year was 0·82 per 100 person-years for long-acting PrEP and 2·27 per 100 person-years for daily oral PrEP (HR 0·35 [0·18-0·69], p=0·002). Adherence to both study products decreased after study unblinding. Additional infections in the long-acting PrEP group included two with on-time injections; three with one or more delayed injections; two detected with long-acting PrEP reinitiation; and 11 more than 6 months after their last injection. Infection within 6 months of cabotegravir exposure was associated with diagnostic delays and INSTI resistance. Adverse events were generally consistent with previous reports; incident hypertension in the long-acting PrEP group requires further investigation.InterpretationLong-acting injectable cabotegravir PrEP retained high efficacy for HIV prevention in men and transgender women who have sex with men during the first year of open-label follow-up, with a near-identical HR for HIV risk reduction between long-acting injectable cabotegravir and daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP during the first year after unblinding compared with the blinded period. Extended follow-up further defined the risk period for diagnostic delays and emergence of INSTI resistance.FundingDivision of AIDS at the National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and Gilead Sciences.

Background: MLL-rearranged leukemias are a clinically challenging and biologically unique subtype of leukemias associated with poor prognosis. While novel therapeutic strategies have been primarily directed at epigenetic dysregulation, post-transcriptional gene regulatory mechanisms have emerged as important mediators in leukemogenesis and have the unexplored potential to be potent combinatorial therapeutic targets. Previously, we found that the RNA-binding protein IGF2BP3 is a critical regulator of MLL-AF4 leukemogenesis and represents a promising therapeutic target. Methods: We studied the combined effects of targeting IGF2BP3 and the Menin-MLL interaction in MLL-AF4 driven leukemia in vitro and in vivo, using genetic inhibition through CRISPR-Cas9 mediated deletion of Igf2bp3 and pharmacologic inhibition of the Menin-MLL interaction with commercially available inhibitors MI-503, MI-463, and MI-538. In vitro, we tested the human B-cell acute lymphoblastic leukemia cell lines, SEM, RS4;11 and NALM6, and MLL-Af4-transformed murine hematopoietic stem and progenitor cells (herein referred to as MLL-Af4 Lin-), derived from bone marrow of Cas9 mice. Results: Depletion of Igf2bp3 sensitized MLL-AF4 leukemia to the negative effects of Menin-MLL inhibition on leukemic cell growth, colony formation and leukemic initiating cells in vitro. Mechanistically, we found that both Igf2bp3 depletion and Menin-MLL inhibition led to increased differentiation in vitro and in vivo in functional readouts and by gene expression analyses. Both MI-503 treatment and IGF2BP3 knockdown in MLL-Af4 Lin- cells showed a shift towards more differentiated colony morphologies in colony formation assays, decreased expression of c-Kit and increased expression of maturation markers by flow cytometry, and morphologic changes consistent with increased differentiation. To gain insight into these phenotypic findings, we examined gene expression from MLL-Af4 Lin- cells with IGF2BP3 knockdown and treated with MI-503. Metascape analysis revealed significant enrichment in pathways involved in cell differentiation and activation, particularly in leukocytes. This was observed in both I3KO and MI-503 treated cells, with significant overlap in shared differentially expressed genes in both conditions. Next, we looked at the overlap between differentially expressed genes with MI-503 treatment and IGF2BP3 knockdown with targets identified from MLL-AF4 ChIP and IGF2BP3 CLIP in CD11b+ and MLL-Af4 Lin- cells. We found significant overlap between differentially expressed genes with MI-503 treatment and IGF2BP3 CLIP targets, suggesting that IGF2BP3 directly regulates genes that are affected by Menin-MLL inhibition. Furthermore, we saw overlap between differentially expressed genes with IGF2BP3 knockdown and MLL-AF4 ChIP targets identified in SEM and RS4;11 cells. These patterns highlight the interaction between the MLL-AF4 and IGF2BP3 transcriptomes and suggest a mechanism for the synergistic inhibition of leukemia by targeting both MLL-AF4 and IGF2BP3. To examine the combined effects of IGF2BP3 knockdown and Menin-MLL inhibition on leukemic engraftment and survival in vivo, we transplanted MLL-Af4 Lin- cells, depleted (or non-depleted) for IGF2BP3 and treated with MI-503 at 0.5 μM for 5 days, to initiate leukemia. We observed a significant decrease in peripheral blood leukemic engraftment with MI-503 treatment and IGF2BP3 knockdown. IGF2BP3 knockdown had a greater effect on survival and attenuating disease than MI-503 alone and showed enhanced anti-leukemic effects in combination. Conclusions: Our work shows that IGF2BP3 is an oncogenic amplifier of MLL-AF4 mediated leukemogenesis and is a potent therapeutic target and suggests a novel combinatorial approach to targeting leukemia at both the transcriptional and post-transcriptional level.

IntroductionYoung adults with HIV (YWH) experience worse clinical outcomes than adults and have high rates of substance use (SU) and mental illness that impact their engagement in care and adherence to antiretroviral therapy (ART). The intervention for Virologic Suppression in Youth (iVY) aims to address treatment engagement/adherence, mental health (MH) and SU in a tailored manner using a differentiated care approach that is youth friendly. Findings will provide information about the impact of iVY on HIV virological suppression, MH and SU among YWH who are disproportionately impacted by HIV and at elevated risk for poor health outcomes.Methods and analysisThe iVY study will test the effect of a technology-based intervention with differing levels of resource requirements (ie, financial and personnel time) in a randomised clinical trial with an adaptive treatment strategy among 200 YWH (18-29 years old). The primary outcome is HIV virological suppression measured via dried blood spot. This piloted and protocolised intervention combines: (1) brief weekly sessions with a counsellor via a video-chat platform (video-counselling) to discuss MH, SU, HIV care engagement/adherence and other barriers to care; and (2) a mobile health app to address barriers such as ART forgetfulness, and social isolation. iVY has the potential to address important, distinct and changing barriers to HIV care engagement (eg, MH, SU) to increase virological suppression among YWH at elevated risk for poor health outcomes.Ethics and disseminationThis study and its protocols have been approved by the University of California, San Francisco Institutional Review Board. Study staff will work with a Youth Advisory Panel to disseminate results to YWH, participants and the academic community.Trial registration numberNCT05877729.

BACKGROUND: Prior case series suggest that a 5-day course of oral Paxlovid (nirmatrelvir/ritonavir) benefits some people with Long COVID, within and/or outside of the context of an acute reinfection. To the best of our knowledge, there have been no prior case series of people with Long COVID who have attempted longer courses of nirmatrelvir/ritonavir. METHODS: We documented a case series of 13 individuals with Long COVID who initiated extended courses (>5 days; range: 7.5-30 days) of oral nirmatrelvir/ritonavir outside (n=11) of and within (n=2) the context of an acute SARS-CoV-2 infection. Participants reported on symptoms and health experiences before, during, and after their use of nirmatrelvir/ritonavir. RESULTS: Among those who took a long course of nirmatrelvir/ritonavir outside of the context of an acute infection, some experienced a meaningful reduction in symptoms, although not all benefits persisted; others experienced no effect on symptoms. One participant reported intense stomach pain that precluded her from continuing her course. Among the two participants who took a long course of nirmatrelvir/ritonavir within the context of an acute reinfection, both eventually returned to their pre-re-infection baseline. DISCUSSION: Long courses of nirmatrelvir/ritonavir may have meaningful benefits for some people with Long COVID but not others. We encourage researchers to study who, how, and why nirmatrelvir/ritonavir benefits some and what course length is most effective, with the goal of informing clinical recommendations for using nirmatrelvir/ritonavir and/or other antivirals as a potential treatment for Long COVID.

Infection prevention program leaders report frequent use of criteria to distinguish recently recovered coronavirus disease 2019 (COVID-19) cases from actively infectious cases when incidentally positive asymptomatic patients were identified on routine severe acute respiratory coronavirus virus 2 (SARS-CoV-2) polymerase chain reaction (PCR) testing. Guidance on appropriate interpretation of high-sensitivity molecular tests can prevent harm from unnecessary precautions that delay admission and impede medical care.

ObjectivesDetermine whether patient-centered, streamlined HIV care achieves higher antiretroviral therapy (ART) uptake and viral suppression than the standard treatment model for people with HIV (PWH) reporting hazardous alcohol use.DesignCommunity cluster-randomized trial.MethodsThe Sustainable East Africa Research in Community Health trial (NCT01864603) compared an intervention of annual population HIV testing, universal ART, and patient-centered care with a control of baseline population testing with ART by country standard in 32 Kenyan and Ugandan communities. Adults (15 years or older) completed a baseline Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) and were classified as no/nonhazardous (AUDIT-C 0-2 women/0-3 men) or hazardous alcohol use (≥3 women/≥4 men). We compared year 3 ART uptake and viral suppression of PWH reporting hazardous use between intervention and control arms. We compared alcohol use as a predictor of year 3 ART uptake and viral suppression among PWH, by arm.ResultsOf 11,070 PWH with AUDIT-C measured, 1723 (16%) reported any alcohol use and 893 (8%) reported hazardous use. Among PWH reporting hazardous use, the intervention arm had higher ART uptake (96%) and suppression (87%) compared with control (74%, adjusted risk ratio [aRR] = 1.28, 95% CI: 1.19 to 1.38; and 72%, aRR = 1.20, 95% CI: 1.10 to 1.31, respectively). Within arm, hazardous alcohol use predicted lower ART uptake in control (aRR = 0.86, 95% CI: 0.78 to 0.96), but not intervention (aRR = 1.02, 95% CI: 1.00 to 1.04); use was not predictive of suppression in either arm.ConclusionsThe Sustainable East Africa Research in Community Health intervention improved ART uptake and viral suppression among PWH reporting hazardous alcohol use and eliminated gaps in ART uptake between PWH with hazardous and no/nonhazardous use. Patient-centered HIV care may decrease barriers to HIV care for PWH with hazardous alcohol use.

IntroductionWe previously reported that a 6-day continuous peripheral nerve block reduces established postamputation phantom pain. To provide patients and providers with the information to best inform treatment decisions, here we reanalyze the data and present the results in a more patient-centered format. We also provide information on patient-defined clinically relevant benefits to facilitate evaluation of available studies and guide future trial design.MethodsThe original trial enrolled participants with a limb amputation and phantom pain who were randomized to receive a 6-day continuous peripheral nerve block(s) of either ropivacaine (n=71) or saline (n=73) in a double-masked fashion. Here we calculate the percentage of each treatment group that experienced a clinically relevant improvement as defined by previous studies as well as present what the participants of our study defined as small, medium, and large analgesic improvements using the 7-point ordinal Patient Global Impression of Change scale.ResultsAmong patients who were given a 6-day ropivacaine infusion, 57% experienced at least a 2-point improvement on the 11-point numeric rating scale in their average and worst phantom pain 4 weeks postbaseline as compared with 26% (p

BackgroundTubular secretion is an important kidney function responsible for the clearance of numerous medications, including antibiotics and antivirals. It is unknown whether persons living with HIV have lower secretion compared with HIV-uninfected persons, which might predispose them to the risk of progressive kidney disease or adverse drug events.Setting and methodsWe evaluated a panel of 6 endogenous secretory solutes in 199 women living with HIV (WLWH) and 100 women without HIV enrolled in the Women's Interagency HIV Study. Secretory clearance was estimated as the urine-to-plasma ratio of each solute, with adjustment for urine tonicity. Using multivariable linear regression analysis, we compared differences in levels of secretory solute clearance between women with and without HIV and evaluated characteristics associated with secretion.ResultsWLWH were older (median 40 vs. 38 years) but had similar estimated glomerular filtration rate (eGFR, 96 vs. 100 mL/minute/1.73 m 2 ) compared with those without HIV. African American and Latino race, diabetes, diastolic blood pressure, smoking, hepatitis C, peak HIV viral load, and current and nadir CD4 count were associated with differences in clearance of at least 1 marker after multivariable adjustment. The secretory clearance of 3 solutes (cinnamoylglycine, kynurenic acid, and pyridoxic acid) were on average 10%-15% lower among WLWH compared with those without HIV independent of eGFR, albuminuria and chronic kidney disease risk factors, including HCV, and injection drug use.ConclusionsHIV is associated with reduced secretion among women with preserved eGFR. The implications of these findings for drug dosing and adverse events need to be evaluated.

BackgroundDespite programs to address housing for Veterans, they continue to be at high risk of unstable housing. Interpersonal violence is also highly prevalent among Veterans and may contribute to unstable housing. Our study aimed to determine whether interpersonal violence was associated with unstable housing among Veterans, and how this association was influenced by common co-occurring conditions such as substance use and mental illness.MethodsVeterans in the Mind Your Heart Study (N = 741) completed survey data on history of interpersonal violence and access to housing in the prior year. Interpersonal violence was defined as experiencing sexual violence, physical violence, or mugging/physical attack using the Brief Trauma Questionnaire. Multivariable models examined associations between interpersonal violence and unstable housing. Primary models were adjusted for age and sex. Potential explanatory factors were added in subsequent models, including marital status, education, income, substance use disorder, PTSD, and other mental illness.ResultsVeterans who had experienced interpersonal violence had almost twice the odds of unstable housing after adjustment for age and sex (AOR 1.9, 95% CI 1.2-3.0). This association was attenuated in the fully adjusted model including substance use, PTSD, and other mental illness, illustrating the interdependence of these factors (AOR 1.5, 95% CI 0.91-2.5). Subtypes of interpersonal violence were individually associated with increased odds of unstable housing after adjustment for age and sex (physical abuse AOR 1.7, 95% CI 1.2-2.5; mugging/physical attack AOR 1.8, 95% CI 1.2-2.7; sexual violence AOR 1.4, 95% CI 0.89-2.2), but were no longer significant in the fully adjusted model.ConclusionsPrevious experiences of interpersonal violence were associated with unstable housing among Veterans. Substance use, PTSD, and other mental illness played an important role in this relationship-highlighting the potential to improve health outcomes through trauma informed approaches that address mental health, substance use, and housing concurrently.

BackgroundThe phase 2b proof-of-concept Antibody Mediated Prevention (AMP) trials showed that VRC01, an anti-HIV-1 broadly neutralising antibody (bnAb), prevented acquisition of HIV-1 sensitive to VRC01. To inform future study design and dosing regimen selection of candidate bnAbs, we investigated the association of VRC01 serum concentration with HIV-1 acquisition using AMP trial data.MethodsThe case-control sample included 107 VRC01 recipients who acquired HIV-1 and 82 VRC01 recipients who remained without HIV-1 during the study. We measured VRC01 serum concentrations with a qualified pharmacokinetic (PK) Binding Antibody Multiplex Assay. We employed nonlinear mixed effects PK modelling to estimate daily-grid VRC01 concentrations. Cox regression models were used to assess the association of VRC01 concentration at exposure and baseline body weight, with the hazard of HIV-1 acquisition and prevention efficacy as a function of VRC01 concentration. We also compared fixed dosing vs. body weight-based dosing via simulations.FindingsEstimated VRC01 concentrations in VRC01 recipients without HIV-1 were higher than those in VRC01 recipients who acquired HIV-1. Body weight was inversely associated with HIV-1 acquisition among both placebo and VRC01 recipients but did not modify the prevention efficacy of VRC01. VRC01 concentration was inversely correlated with HIV-1 acquisition, and positively correlated with prevention efficacy of VRC01. Simulation studies suggest that fixed dosing may be comparable to weight-based dosing in overall predicted prevention efficacy.InterpretationThese findings suggest that bnAb serum concentration may be a useful marker for dosing regimen selection, and operationally efficient fixed dosing regimens could be considered for future trials of HIV-1 bnAbs.FundingWas provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) (UM1 AI068614, to the HIV Vaccine Trials Network [HVTN]; UM1 AI068635, to the HVTN Statistical Data and Management Center [SDMC], Fred Hutchinson Cancer Center [FHCC]; 2R37 054165 to the FHCC; UM1 AI068618, to HVTN Laboratory Center, FHCC; UM1 AI068619, to the HPTN Leadership and Operations Center; UM1 AI068613, to the HIV Prevention Trials Network [HPTN] Laboratory Center; UM1 AI068617, to the HPTN SDMC; and P30 AI027757, to the Center for AIDS Research, Duke University (AI P30 AI064518) and University of Washington (P30 AI027757) Centers for AIDS Research; R37AI054165 from NIAID to the FHCC; and OPP1032144 CA-VIMC Bill & Melinda Gates Foundation.

Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in meningiomas, its relationship to other CDKN2A alterations on a transcriptomic, epigenomic, and copy number level has not yet been determined. We therefore utilized multidimensional molecular data of 1577 meningioma samples from 6 independent cohorts enriched for clinically aggressive meningiomas to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach. Homozygous CDKN2A/B deletions were identified in only 7.1% of cases but were associated with significantly poorer outcomes compared to tumors without these deletions. Heterozygous CDKN2A/B deletions were identified in 2.6% of cases and had similarly poor outcomes as those with homozygous deletions. Among tumors with intact CDKN2A/B (without a homozygous or heterozygous deletion), we found a distinct difference in outcome based on mRNA expression of CDKN2A, with meningiomas that had elevated mRNA expression (CDKN2Ahigh) having a significantly shorter time to recurrence. The expression of CDKN2A was independently prognostic after accounting for copy number loss and consistently increased with WHO grade and more aggressive molecular and methylation groups irrespective of cohort. Despite the discordant and mutually exclusive status of the CDKN2A gene in these groups, both CDKN2Ahigh meningiomas and meningiomas with CDKN2A deletions were enriched for similar cell cycle pathways but at different checkpoints. High mRNA expression of CDKN2A was also associated with gene hypermethylation, Rb-deficiency, and lack of response to CDK inhibition. p16 immunohistochemistry could not reliably differentiate between meningiomas with and without CDKN2A deletions but appeared to correlate better with mRNA expression. These findings support the role of CDKN2A mRNA expression as a biomarker of clinically aggressive meningiomas with potential therapeutic implications.

PurposeEganelisib (IPI-549) is a first-in-class, orally administered, highly selective PI3Kγ inhibitor with antitumor activity alone and in combination with programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitors in preclinical studies. This phase 1/1b first-in-human, MAcrophage Reprogramming in Immuno-Oncology-1 (NCT02637531) study evaluated the safety and tolerability of once-daily eganelisib as monotherapy and in combination with nivolumab in patients with solid tumors.Patients and methodsDose-escalation cohorts received eganelisib 10-60 mg as monotherapy (n = 39) and 20-40 mg when combined with nivolumab (n = 180). Primary endpoints included incidence of dose-limiting toxicities (DLT) and adverse events (AE).ResultsThe most common treatment-related grade ≥3 toxicities with monotherapy were increased alanine aminotransferase (ALT; 18%), aspartate aminotransferase (AST; 18%), and alkaline phosphatase (5%). No DLTs occurred in the first 28 days; however, toxicities meeting DLT criteria (mostly grade 3 reversible hepatic enzyme elevations) occurred with eganelisib 60 mg in later treatment cycles. In combination, the most common treatment-related grade ≥3 toxicities were increased AST (13%) and increased ALT and rash (10%). Treatment-related serious AEs occurred in 5% of monotherapy patients (grade 4 bilirubin and hepatic enzyme increases in one patient each) and 13% in combination (pyrexia, rash, cytokine release syndrome, and infusion-related reaction in ≥2 patients each). Antitumor activity was observed in combination, including patients who had progressed on PD-1/PD-L1 inhibitors.ConclusionsOn the basis of the observed safety profile, eganelisib doses of 30 and 40 mg once daily in combination with PD-1/PD-L1 inhibitors were chosen for phase 2 study.

e18765 Background: An estimated 94,000 women have newly diagnosed gynecologic cancer (ovarian, uterine, cervical, and vulvovaginal) annually–with rates increasing over the last 20 years. Surgical site infections (SSIs) complicate up to 4% of all hysterectomies in the United States. Other surgical sequelae, such as operative length, estimated blood loss, wound dehiscence, and 30-day readmission, further complicate the post-surgical course of this vulnerable population. Methods: A quality improvement initiative was conducted in a large academic health system between January to June 2022 to investigate whether implementing an SSI bundle, defined as a set of 11 evidence-based practices performed collaboratively, can reduce intraoperative and postoperative complications. The study population included women who received gynecologic oncologic surgery. To evaluate trends following the implementation of an SSI prevention bundle, we studied two time periods: 1/1/22-3/31/22 and 4/1/22-6/30/22. Trends were analyzed using chi-squared and a two-sample t-test. Results: Over our six-month study period, 233 patients underwent primary gynecologic oncologic surgery. Robotic-assisted hysterectomies were the most common (27.89%, n = 65), followed by total abdominal hysterectomies (21%, n = 49), laparoscopic hysterectomies (7.72%, n = 18), and supracervical hysterectomies (3%, n = 7). An invasive, abdominal approach was needed for less than half of the surgeries for whom intraoperative and postoperative outcomes were measured (46.35%, n = 108). Following the implementation of our SSI bundle, there was a rise in estimated blood loss (134.49 to 252.67 mL), operative length (199.24 to 227.23 min), and length of stay (1.58 to 2.20 days). Yet, there was a decline in the SSI rate from 4.62% to 3.7% (p = 0.97) and 30-day all-cause readmission from 12.96% to 7.4% (p < 0.05). The overall incidence of 30-day wound dehiscence also declined over six months from 3.7% to 1.85% (p = 0.74). Upon intersectional analysis, patients with SSI were older (55.93 vs. 62, p = 0.39) and were more likely to be obese (BMI 27.04 vs. 31.06, p < 0.05). Individuals with functional status limitations, ECOG score > 2, had longer lengths of stays (4.7 vs. 1.76 days, p < 0.05), estimated blood loss (230 vs. 185.9 mL, p = 0.12), and operative length (374 vs. 205.2 min, p < 0.001). Those with a supracervical hysterectomy also had a longer length of stays (4 days, p < 0.05), blood loss (921.43 mL, p < 0.001), and operative lengths (315.14 min, p < 0.001). Conclusions: Following the implementation of an evidence-based SSI quality improvement project, cancer patients had fewer SSI, hospital readmissions, and wound dehiscence. High ECOG scores, supracervical hysterectomies, and obesity were all associated with worse postoperative outcomes. Prospective studies on postoperative surgical quality are needed to improve care for our most vulnerable patients.

We performed a secondary analysis of the National Institutes of Health-sponsored Adaptive COVID-19 Treatment Trial (ACTT-2) randomized controlled trial and found that baricitinib was associated with a 50% reduction in secondary infections after controlling for baseline and postrandomization patient characteristics. This finding provides a novel mechanism of benefit for baricitinib and supports the safety profile of this immunomodulator for the treatment of coronavirus disease 2019.

BackgroundSubstance use (SU) contributes to poor health outcomes, yet limited data exist to inform strategies to optimize SU treatment among persons with human immunodeficiency virus (HIV). We describe SU and SU treatment utilization among women with and without HIV in the Women's Interagency HIV Study (WIHS).MethodsWe included data from women enrolled in WIHS from 2013 to 2020. Current SU was self-reported, nonmedical use of drugs in the past year, excluding use of only marijuana. SU treatment utilization was self-reported use of a drug treatment program in the past year. Multivariable regression models were used to investigate associations between participant characteristics and SU treatment.ResultsAmong 2559 women (1802 women living with HIV [WWH], 757 women without HIV), 14% reported current SU. Among those with current SU (n = 367), 71% reported crack/cocaine followed by 40% reporting opioids, and 42% reported any treatment in the past year. The most common treatments were methadone (64%), Narcotics Anonymous (29%), inpatient programs (28%), and outpatient programs (16%). Among women using opioids (n = 147), 67% reported methadone use in the past year compared to 5% using buprenorphine/naloxone. Multivariable analysis showed lower odds of treatment utilization among WWH with concurrent alcohol or marijuana use. Visiting a psychiatrist/counselor was associated with higher odds of treatment. Among WWH, SU treatment was not associated with HIV-related clinical outcomes.ConclusionsTreatment utilization was high, especially for methadone use. Our results highlight opportunities for accessing SU treatment for WWH, such as the need to prioritize buprenorphine and comprehensive, wraparound services in HIV care settings.

PurposeAdvanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features.Experimental designDiscovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55).ResultsInfiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%).ConclusionsAn infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

HPTN 083 demonstrated that injectable cabotegravir (CAB) was superior to oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for HIV prevention in cisgender men and transgender women who have sex with men. We previously analyzed 58 infections in the blinded phase of HPTN 083 (16 in the CAB arm and 42 in the TDF-FTC arm). This report describes 52 additional infections that occurred up to 1 year after study unblinding (18 in the CAB arm and 34 in the TDF-FTC arm). Retrospective testing included HIV testing, viral load testing, quantification of study drug concentrations, and drug resistance testing. The new CAB arm infections included 7 with CAB administration within 6 months of the first HIV-positive visit (2 with on-time injections, 3 with ≥1 delayed injection, and 2 who restarted CAB) and 11 with no recent CAB administration. Three cases had integrase strand transfer inhibitor (INSTI) resistance (2 with on-time injections and 1 who restarted CAB). Among 34 CAB infections analyzed to date, diagnosis delays and INSTI resistance were significantly more common in infections with CAB administration within 6 months of the first HIV-positive visit. This report further characterizes HIV infections in persons receiving CAB preexposure prophylaxis and helps define the impact of CAB on the detection of infection and the emergence of INSTI resistance.

ObjectivesTo determine whether hydroxychloroquine (HCQ) is safe and effective at preventing COVID-19 infections among health care workers (HCWs).MethodsIn a 1: 1 randomized, placebo-controlled, double-blind, parallel-group, superiority trial at 34 US clinical centers, 1360 HCWs at risk for COVID-19 infection were enrolled between April and November 2020. Participants were randomized to HCQ or matched placebo. The HCQ dosing included a loading dose of HCQ 600 mg twice on day 1, followed by 400 mg daily for 29 days. The primary outcome was a composite of confirmed or suspected COVID-19 clinical infection by day 30, defined as new-onset fever, cough, or dyspnea and either a positive SARS-CoV-2 polymerase chain reaction test (confirmed) or a lack of confirmatory testing due to local restrictions (suspected).ResultsStudy enrollment closed before full accrual due to recruitment challenges. The primary end point occurred in 41 (6.0%) participants receiving HCQ and 53 (7.8%) participants receiving placebo. No difference in the proportion of participants experiencing clinical infection (estimated difference of -1.8%, 95% confidence interval -4.6-0.9%, P = 0.20) was identified nor any significant safety issues.ConclusionOral HCQ taken as prescribed appeared safe among HCWs. No significant clinical benefits were observed. The study was not powered to detect a small but potentially important reduction in infection.Trial registrationNCT04334148.

BackgroundPatient understanding of their care, supported by physician involvement and consistent communication, is key to positive health outcomes. However, patient and care team characteristics can hinder this understanding.ObjectiveWe aimed to assess inpatients' understanding of their care and their perceived receipt of mixed messages, as well as the associated patient, care team, and hospitalization characteristics.DesignWe administered a 30-item survey to inpatients between February 2020 and November 2021 and incorporated other hospitalization data from patients' health records.ParticipantsRandomly selected inpatients at two urban academic hospitals in the USA who were (1) admitted to general medicine services and (2) on or past the third day of their hospitalization.Main measuresOutcome measures include (1) knowledge of main doctor and (2) frequency of mixed messages. Potential predictors included mean notes per day, number of consultants involved in the patient's care, number of unit transfers, number of attending physicians, length of stay, age, sex, insurance type, and primary race.Key resultsA total of 172 patients participated in our survey. Most patients were unaware of their main doctor, an issue related to more daily interactions with care team members. Twenty-three percent of patients reported receiving mixed messages at least sometimes, most often between doctors on the primary team and consulting doctors. However, the likelihood of receiving mixed messages decreased with more daily interactions with care team members.ConclusionsPatients were often unaware of their main doctor, and almost a quarter perceived receiving mixed messages about their care. Future research should examine patients' understanding of different aspects of their care, and the nature of interactions that might improve clarity around who's in charge while simultaneously reducing the receipt of mixed messages.

IntroductionAntiphospholipid syndrome (APS) is an autoimmune disease characterised by thrombosis (arterial, venous or small vessel) or obstetrical events and persistent antiphospholipid antibodies (aPL), according to the Sydney classification criteria. Many studies have performed cluster analyses among patients with primary APS and associated autoimmune disease, but none has focused solely on primary APS. We aimed to perform a cluster analysis among patients with primary APS and asymptomatic aPL carriers without any autoimmune disease, to assess prognostic value.MethodsIn this multicentre French cohort study, we included all patients with persistent APS antibodies (Sydney criteria) measured between January 2012 and January 2019. We excluded all patients with systemic lupus erythematosus or other systemic autoimmune diseases. We performed hierarchical cluster analysis on the factor analysis of mixed data coordinates results with baseline patient characteristics to generate clusters.ResultsWe identified four clusters: cluster 1, comprising 'asymptomatic aPL carriers', with low risk of events during follow-up; cluster 2, the 'male thrombotic phenotype', with older patients and more venous thromboembolic events; cluster 3, the 'female obstetrical phenotype', with obstetrical and thrombotic events; and cluster 4, 'high-risk APS', which included younger patients with more frequent triple positivity, antinuclear antibodies, non-criteria manifestations and arterial events. Regarding survival analyses, asymptomatic aPL carriers relapsed less frequently than the others, but no other differences in terms of relapse rates or deaths were found between clusters.ConclusionsWe identified four clusters among patients with primary APS, one of which was 'high-risk APS'. Clustering-based treatment strategies should be explored in future prospective studies.

PurposeIntraoperative detection and removal of microscopic residual disease (MRD) remain critical to the outcome of cancer surgeries. Today's minimally invasive surgical procedures require miniaturization and surgical integration of highly sensitive imagers to seamlessly integrate into the modern clinical workflow. However, current intraoperative imagers remain cumbersome and still heavily dependent on large lenses and rigid filters, precluding further miniaturization and integration into surgical tools.ProceduresWe have successfully engineered a chip-scale intraoperative micro-imager array-without optical filters or lenses-integrated with lanthanide-based alloyed upconverting nanoparticles (aUCNPs) to achieve tissue imaging using a single micro-chip. This imaging platform is able to leverage the unique optical properties of aUCNPs (long luminescent lifetime, high-efficiency upconversion, no photobleaching) by utilizing a time-resolved imaging method to acquire images using a 36-by-80-pixel, 2.3 mm [Formula: see text] 4.8 mm silicon-based electronic imager micro-chip, that is, less than 100-µm thin. Each pixel incorporates a novel architecture enabling automated background measurement and cancellation. We have validated the performance, spatial resolution, and the background cancellation scheme of the imaging platform, using resolution test targets and mouse prostate tumor sample intratumorally injected with aUCNPs. To demonstrate the ability to image MRD, or tumor margins, we evaluated the imaging platform in visualizing a single-cell thin section of the injected prostate tumor sample.ResultsTested on USAF resolution targets, the imager is able to achieve a resolution of 71 µm. We have also demonstrated successful background cancellation, achieving a signal-to-background ratio of 8 when performing ex vivo imaging on aUCNP-injected prostate tumor sample, improved from originally 0.4. The performance of the imaging platform on single-cell layer sections was also evaluated and the sensor achieved a signal-to-background ratio of 4.3 in resolving cell clusters with sizes as low as 200 cells.ConclusionThe imaging system proposed here is a scalable chip-scale ultra-thin alternative for bulky conventional intraoperative imagers. Its novel pixel architecture and background correction scheme enable visualization of microscopic-scale residual disease while remaining completely free of lenses and filters, achieving an ultra-miniaturized form factor-critical for intraoperative settings.

PurposeCombination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4-blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600-mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy.Patients and methodsIn a phase III trial, patients with treatment-naive BRAFV600-mutant metastatic melanoma were randomly assigned to receive either combination nivolumab/ipilimumab (arm A) or dabrafenib/trametinib (arm B) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D). The primary end point was 2-year overall survival (OS). Secondary end points were 3-year OS, objective response rate, response duration, progression-free survival, crossover feasibility, and safety.ResultsA total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rank P = .010). Step 1 progression-free survival favored arm A (P = .054). Objective response rates were arm A: 46.0%; arm B: 43.0%; arm C: 47.8%; and arm D: 29.6%. Median duration of response was not reached for arm A and 12.7 months for arm B (P < .001). Crossover occurred in 52% of patients with documented disease progression. Grade ≥ 3 toxicities occurred with similar frequency between arms, and regimen toxicity profiles were as anticipated.ConclusionCombination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

BackgroundImportant insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people.MethodsIn this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated.Findings192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p

ObjectivesMobility (international/internal migration, and localized mobility) is a key driver of the HIV epidemic. While mobility is associated with higher-risk sexual behavior in women, a possible association with condom, modern contraceptive, and dual method use among women living with HIV (WLHIV), is unknown. In addition, HIV status and sexual behaviors such as relationship concurrency may also affect condom, modern contraceptive, and dual method use.Study designWe surveyed sexually active women (N = 1067) aged 15 to 49 in 12 communities in Kenya and Uganda participating in a test-and-treat trial in 2015 to 2016. Generalized (unordered) multinomial logistic regression models accounting for community clustering examined associations between mobility (overnight travel away from home in past 6 months and any migration within past 2 years) and condom, modern contraceptive (i.e., oral contraceptive pills, injectables, intrauterine devices, implants, vasectomy, tubal ligation; excluding male/female condoms), and dual method use within past 6 months, adjusting for key covariates such as HIV status and relationship concurrency.ResultsWLHIV relative to HIV-negative women (ratios of relative risk [RRR] = 3.76, 95% confidence interval [CI]: 2.40-5.89), and women in concurrent relative to monogamous relationships (RRR = 4.03, 95% CI 1.9-8.50) had higher odds of condom use alone. In contraceptive use models, WLHIV relative to HIV-negative women were less likely to use modern contraceptive methods alone (RRR = 0.51, 95% CI 0.36-0.73). Relationship concurrency (RRR = 4.51, 95% CI 2.10-9.67) and HIV status (RRR = 3.97, 95% CI 2.43-6.50) were associated with higher odds of dual method use while mobility was marginally associated with higher odds of dual method use (RRR = 1.65, 95% CI 0.99-2.77, p = 0.057).ConclusionsMobility had a potential impact on dual method use in Kenya and Uganda. In addition, our findings highlight that WLHIV were using condoms and dual methods more, but modern contraceptives less, than HIV-negative women. Those in concurrent relationships were also more likely to use condoms or dual methods. These findings suggest that in a context of high mobility, women may be appropriately assessing risks and taking measures to protect themselves and their partners from unintended pregnancies and acquisition and transmission of HIV.ImplicationsOur findings point to a need to strengthen accessibility of sexual and reproductive health services for both mobile and residentially stable women in settings of high mobility and high HIV prevalence.

IntroductionApproximately half of individuals with posttraumatic stress disorder (PTSD) may meet criteria for other psychiatric disorders, and PTSD symptoms are associated with diminished health and psychosocial functioning. However, few studies examine the longitudinal progression of PTSD symptoms concurrent with related symptom domains and functional outcomes, such that may neglect important longitudinal patterns of symptom progression beyond PTSD specifically.MethodsTherefore, we used longitudinal causal discovery analysis to examine the longitudinal interrelations among PTSD symptoms, depressive symptoms, substance abuse, and various other domains of functioning in five longitudinal cohorts representing veterans (n = 241), civilians seeking treatment for anxiety disorders (n = 79), civilian women seeking treatment for post-traumatic stress and substance abuse (n = 116), active duty military members assessed 0-90 days following TBI (n = 243), and civilians with a history of TBI (n = 43).ResultsThe analyses revealed consistent, directed associations from PTSD symptoms to depressive symptoms, independent longitudinal trajectories of substance use problems, and cascading indirect relations from PTSD symptoms to social functioning through depression as well as direct relations from PTSD symptoms to TBI outcomes.DiscussionOur findings suggest PTSD symptoms primarily drive depressive symptoms over time, tend to show independence from substance use symptoms, and may cascade into impairment in other domains. The results have implications for refining conceptualization of PTSD co-morbidity and can inform prognostic and treatment hypotheses about individuals experiencing PTSD symptoms along with co-occurring distress or impairment.

Non-disclosure of human immunodeficiency virus (HIV) status can hinder optimal health outcomes for people living with HIV (PLHIV). We sought to explore experiences with and correlates of disclosure among PLHIV participating in a study of population mobility. Survey data were collected from 1081 PLHIV from 2015-16 in 12 communities in Kenya and Uganda participating in a test-and-treat trial (SEARCH, NCT#01864603). Pooled and sex-stratified multiple logistic regression models examined associations of disclosure with risk behaviors controlling for covariates and community clustering. At baseline, 91.0% (n = 984) of PLHIV had disclosed their serostatus. Amongst those who had never disclosed, 31% feared abandonment (47.4% men vs. 15.0% women; p = 0.005). Non-disclosure was associated with no condom use in the past 6 months (aOR = 2.44; 95%CI, 1.40-4.25) and with lower odds of receiving care (aOR = 0.8; 95%CI, 0.04-0.17). Unmarried versus married men had higher odds of non- disclosure (aOR = 4.65, 95%CI, 1.32-16.35) and no condom use in the past 6 months (aOR = 4.80, 95%CI, 1.74-13.20), as well as lower odds of receiving HIV care (aOR = 0.15; 95%CI, 0.04-50 0.49). Unmarried versus married women had higher odds of non-disclosure (aOR = 3.14, 95%CI, 1.47-6.73) and lower odds of receiving HIV care if they had never disclosed (aOR = 0.05, 95%CI, 0.02-0.14). Findings highlight gender differences in barriers to HIV disclosure, use of condoms, and engagement in HIV care. Interventions focused on differing disclosure support needs for women and men are needed and may help facilitate better care engagement for men and women and improve condom use in men.

BackgroundConcerns have been raised about the utility of self-report assessments in predicting future suicide attempts. Clinicians in pediatric emergency departments (EDs) often are required to assess suicidal risk. The Death Implicit Association Test (IAT) is an alternative to self-report assessment of suicidal risk that may have utility in ED settings.MethodsA total of 1679 adolescents recruited from 13 pediatric emergency rooms in the Pediatric Emergency Care Applied Research Network were assessed using a self-report survey of risk and protective factors for a suicide attempt, and the IAT, and then followed up 3 months later to determine if an attempt had occurred. The accuracy of prediction was compared between self-reports and the IAT using the area under the curve (AUC) with respect to receiver operator characteristics.ResultsA few self-report variables, namely, current and past suicide ideation, past suicidal behavior, total negative life events, and school or social connectedness, predicted an attempt at 3 months with an AUC of 0.87 [95% confidence interval (CI), 0.84-0.90] in the entire sample, and AUC = 0.91, (95% CI 0.85-0.95) for those who presented without reported suicidal ideation. The IAT did not add significantly to the predictive power of selected self-report variables. The IAT alone was modestly predictive of 3-month attempts in the overall sample ((AUC = 0.59, 95% CI 0.52-0.65) and was a better predictor in patients who were non-suicidal at baseline (AUC = 0.67, 95% CI 0.55-0.79).ConclusionsIn pediatric EDs, a small set of self-reported items predicted suicide attempts within 3 months more accurately than did the IAT.

BackgroundPostamputation phantom pain is notoriously persistent with few validated treatments. Cryoneurolysis involves the application of low temperatures to reversibly ablate peripheral nerves. The authors tested the hypothesis that a single cryoneurolysis treatment would decrease phantom pain 4 months later.MethodsThe authors enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. The primary outcome was the change in average phantom pain intensity between baseline and 4 months as measured with a numeric rating scale (0 to 10), after which an optional crossover treatment was offered. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction.ResultsPretreatment phantom pain scores were similar in both groups, with a median [quartiles] of 5.0 [4.0, 6.0] for active treatment and 5.0 [4.0, 7.0] for sham. After 4 months, pain intensity decreased by 0.5 [-0.5, 3.0] in patients given cryoneurolysis (n = 71) versus 0 [0, 3] in patients given sham (n = 73), with an estimated difference (95% CI) of -0.1 (-1.0 to 0.7), P = 0.759. Following their statistical gatekeeping protocol, the authors did not make inferences or draw conclusions on secondary endpoints. One serious adverse event occurred after a protocol deviation in which a femoral nerve cryolesion was induced just below the inguinal ligament-instead of the sensory-only saphenous nerve-which resulted in quadriceps weakness, and possibly a fall and clavicle fracture.ConclusionsPercutaneous cryoneurolysis did not decrease chronic lower extremity phantom limb pain 4 months after treatment. However, these results were based upon the authors' specific study protocol, and since the optimal cryoneurolysis treatment parameters such as freeze duration and anatomic treatment location remain unknown, further research is warranted.Editor’s perspective

Background: Technology-based directly observed therapy (DOT) is more cost-effective and efficient compared with in-person monitoring visits for medication adherence. While some evidence shows these technologies are feasible and acceptable, there is limited evidence collating information across medical conditions or in the context of HIV prevention, care, and treatment.Objectives: We conducted a scoping review to understand the current evidence on the acceptability, feasibility, and efficacy of digital DOT to improve medication adherence and, specifically, to determine if digital DOT had been used to improve adherence for HIV prevention, care, and treatmentMethods: We searched the electronic databases PubMed, Embase, and the Web of Science in January 2021 for any published studies with terms related to digital technologies and DOT. We included peer-reviewed studies in any population, from any country, for any outcome, and excluded conference abstracts. We included three types of digital DOT interventions: synchronous DOT, asynchronous DOT, and automated DOT. We provide an assessment of the current evidence, gaps in literature, and opportunities for intervention development regarding the use digital DOT to improve antiretroviral therapy (ART) adherence, specifically in the field of HIV.Results: We identified 28 studies that examined digital DOT. All studies found digital DOT to be acceptable and feasible. Patients using digital DOT had higher rates of treatment completion, observed doses, and adherence compared with in-person DOT, although data were limited on adherence. Only one study examined HIV prevention, and none examined ART adherence for HIV treatment.Conclusions: Digital DOT is acceptable and feasible but has not been used to remotely monitor and support ART adherence for people living with HIV.

BackgroundThe HPTN 083 trial demonstrated that long-acting cabotegravir (CAB-LA) was superior to tenofovir-disoproxil fumarate/emtricitabine for human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP). Integrase strand transfer inhibitor (INSTI) resistance-associated mutations (RAMs) were detected in some participants with HIV infection. We used a low viral load INSTI genotyping assay to evaluate the timing of emergence of INSTI RAMs and assessed whether HIV screening with a sensitive RNA assay would have detected HIV infection before INSTI resistance emerged.MethodsSingle-genome sequencing to detect INSTI RAMs was performed for samples with viral loads

Resilience and optimism may not only have main effects on health outcomes, but may also moderate and buffer negative effects of stressors. We examined whether dispositional resilience and optimism moderate the associations between HIV-related stigma in health care settings and health-related outcomes (trust in HIV health care providers and depression symptoms) among women living with HIV (WLHIV). One thousand four hundred five WLHIV in nine US cities completed validated questionnaires for cross-sectional analyses. Higher self-reported experienced and anticipated stigma and lower resilience and optimism were associated with higher depression symptoms and with lower trust in HIV providers. Importantly, resilience moderated the effects of experienced stigma (but not of anticipated stigma): When resilience was high, the association of experienced stigma with higher depression symptoms and lower trust in HIV providers was weaker compared with when resilience was low. Further, significant moderation effects suggested that when optimism was high, experienced and anticipated stigma was both less strongly associated with depression symptoms and with lower trust in one's HIV care providers compared with when optimism was low. Thus, the effects of experienced stigma on depression symptoms and provider trust were moderated by both resilience and optimism, but the effects of anticipated stigma were moderated only by optimism. Our findings suggest that in addition to their main effects, resilience and optimism may function as buffers against the harmful effects of stigma in health care settings. Therefore, optimism and resilience may be valuable intervention targets to reduce depression symptoms or improve trust in providers among populations that experience or anticipate stigma, such as WLHIV.

Rationale: Human immunodeficiency virus (HIV) infection is associated with chronic lung disease and impaired pulmonary function; however, longitudinal pulmonary function phenotypes in HIV are undefined. Objectives: To identify pulmonary function trajectories, their determinants, and outcomes. Methods: We used data from participants with HIV in the Pittsburgh HIV Lung Cohort with three or more pulmonary function tests between 2007 and 2020. We analyzed post-bronchodilator forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC, and diffusing capacity of the lung for carbon monoxide (DlCO) using group-based trajectory modeling to identify subgroups of individuals whose measurements followed a similar pattern over time. We examined the association between participant characteristics and trajectories using multivariable logistic regression. In exploratory adjusted analyses restricted to individuals with available plasma cytokine data, we investigated the association between 18 individual standardized cytokine concentrations and trajectories. We compared mortality, dyspnea prevalence, respiratory health status, and 6-minute-walk distance between phenotypes. Results: A total of 265 participants contributed 1,606 pulmonary function measurements over a median follow-up of 8.1 years. We identified two trajectories each for FEV1 and FVC: "low baseline, slow decline" and "high baseline, rapid decline." There were three trajectory groups for FEV1/FVC: "rapid decline," "moderate decline," and "slow decline." Finally, we identified two trajectories for DlCO: "baseline low" and "baseline high." The low baseline, slow decline FEV1 and FVC, rapid decline, and moderate decline FEV1/FVC, and baseline low DlCO phenotypes were associated with increased dyspnea prevalence, worse respiratory health status, and decreased 6-minute-walk distance. The baseline low DlCO phenotype was also associated with worse mortality. Current smoking and pack-years of smoking were associated with the adverse FEV1, FEV1/FVC, and DlCO phenotypes. Detectable viremia was the only HIV marker associated with the adverse DlCO phenotype. C-reactive protein and endothelin-1 were associated with the adverse FEV1 and FVC phenotypes, and endothelin-1 trended toward an association with the adverse DlCO phenotype. Conclusions: We identified novel, distinct longitudinal pulmonary function phenotypes with significant differences in characteristics and outcomes. These findings highlight the importance of lung dysfunction over time in people with HIV and should be validated in additional cohorts.

BackgroundFrom this retrospective study, we aimed to (1) describe the prevalence and characteristics of non-criteria features in primary antiphospholipid syndrome (p-APS) and (2) determine their prognostic value.MethodsThis retrospective French multicenter cohort study included all patients diagnosed with p-APS (Sydney criteria) between January 2012 and January 2019. We used Kaplan-Meier and adjusted Cox proportional hazards models to compare the incidence of relapse in p-APS with and without non-criteria manifestations.ResultsOne hundred and seventy-nine patients with p-APS were included during the study time, with a median age of 52.50 years [39.0; 65.25] and mainly women (n = 112; 62.6%). Among them, forty-three patients (24.0%) presented at least one non-criteria manifestation during the follow-up: autoimmune cytopenias (n = 17; 39.5%), Libman Sachs endocarditis (n = 5; 11.6%), APS nephropathy (n = 4; 9.3%), livedo reticularis (n = 8; 18.6%), and neurological manifestations (n = 12; 27.9%). In comparison to p-APS without any non-criteria manifestations (n = 136), p-APS with non-criteria features had more arterial thrombosis (n = 24; 55.8% vs n = 48; 35.3%; p = 0.027) and more frequent pre-eclampsia (n = 6; 14.3% vs n = 4; 3.1%; p = 0.02). The prevalence of triple positivity was significantly increased in patients with non-criteria features (n = 20; 47.6% vs n = 25; 19.8%; p = 0.001). Patients with p-APS and non-criteria manifestations (n = 43) received significantly more additional therapies combined with vitamin K antagonists and/or antiaggregants. Catastrophic APS (CAPS) tended to be more frequent in p-APS with non-criteria features (n = 2; 5.1% vs none; p = 0.074). The p-APS with non-criteria manifestations had significantly increased rates of relapse (n = 20; 58.8% vs 33; 33.7%; p = 0.018) in bivariate analysis, but in survival analyses, the hazard ratio (HR) of relapse was not significantly different between the two groups (HR at 1.34 [0.67; 2.68]; p = 0.40).ConclusionsThe presence of non-criteria features is important to consider, as they are associated with particular clinical and laboratory profiles, increased risk of relapse, and need for additional therapies. Prospective studies are necessary to better stratify the prognosis and the management of p-APS.

BackgroundMethamphetamine (MA) use increased during COVID-19, with men who have sex with men (MSM) exhibiting 3-fold greater use than heterosexual men. Understanding links between reported MA use and COVID-19 prevention behaviors among MSM can inform current transmission risks for HIV, Monkeypox, and other infectious diseases.MethodsThis study assesses relationships between self-reported pattern of MA use (past six months; past two weeks) and reported COVID-19 preventive behaviors, adjusting for participant characteristics (HIV serostatus, race/ethnicity, employment and housing stability), in a cohort of ethnically diverse MSM in Los Angeles, California, between April 1 and September 30, 2020.ResultsCompared to those who reported no MA use, MSM who reported weekly or more MA use in the past six months were significantly less likely to use COVID-19 protective behaviors of physical distancing (61.8% vs. 81.6%; AOR = 0.39, 95% CI [0.19, 0.81]), of avoiding public transportation (34.5% vs. 60.3%; AOR = 0.42, 95% CI [0.21, 0.83]) and of avoiding traveling overall (32.7% vs. 62.6%; AOR = 0.32, 95% CI [0.16, 0.63]). Parallel findings were observed in analyses of past two-week reported MA use and COVID-19 protective behaviors.ConclusionFindings highlight ways in which reported MA use frequency links with avoidance of reported preventive behaviors for COVID-19 in urban diverse MSM. Findings also provide evidence to guide public health interventions in future outbreaks of COVID-19 and other infectious diseases among MSM.

BackgroundThe COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear.ObjectiveTo evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial).DesignACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4]).Setting94 hospitals in 10 countries (86% U.S. participants).ParticipantsAdults hospitalized with COVID-19.InterventionSOC.Measurements28-day mortality and recovery.ResultsAlthough outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages.LimitationUnmeasured confounding.ConclusionChanges in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas.Primary funding sourceNational Institute of Allergy and Infectious Diseases.

PurposeInvestigate whether adjuvant everolimus, an mTOR inhibitor, improves progression-free survival (PFS) in advanced-stage head and neck squamous cell carcinoma (HNSCC) and provide outcomes related to correlative biological factors associated with disease control.Patients and methodsThis was a prospective, randomized, double-blind phase II trial of patients with advanced-stage HNSCC from 13 institutions who were confirmed disease-free post-definitive therapy and enrolled between December 2010 and March 2015. Patients received adjuvant everolimus or placebo daily (10 mg, oral) for a maximum of 1 year. p16 IHC as a surrogate marker for human papillomavirus infection and whole-exome sequencing were performed. Cox proportional hazard models estimated hazard rates. Log-rank tests evaluated differences in survival. The primary endpoint was PFS. Secondary endpoints and objectives included overall survival (OS) and toxicity assessment.Results52 patients [median (range) age, 58 (37-76) years; 43 men (83%), 9 women (17%)] were randomized to placebo (n = 24) or everolimus (n = 28). PFS favored everolimus, but was not significant [log-rank P = 0.093; HR = 0.44; 95% confidence interval (CI), 0.17-1.17]. There was no difference in OS (P = 0.29; HR = 0.57; 95% CI, 0.20-16.2). Everolimus resulted in significant improvement in PFS for p16-negative patients (n = 31; P = 0.031; HR = 0.26; 95% CI, 0.07-0.97), although subgroup analysis showed no difference for p16-positive patients (n = 21; P = 0.93). Further, PFS was significantly higher in TP53-mutated (TP53mut) patients treated with everolimus compared with placebo (log-rank P = 0.027; HR = 0.24; 95% CI, 0.06-0.95). No treatment difference was seen in patients with TP53 wild-type tumors (P = 0.79).Conclusionsp16-negative and TP53mut patients may benefit from adjuvant treatment with everolimus.

FMR1 premutation cytosine-guanine-guanine repeat expansion alleles are relatively common mutations in the general population that are associated with a neurodegenerative disease (fragile X-associated tremor/ataxia syndrome), reproductive health problems and potentially a wide range of additional mental and general health conditions that are not yet well-characterised. The International Fragile X Premutation Registry (IFXPR) was developed to facilitate and encourage research to better understand the FMR1 premutation and its impact on human health, to facilitate clinical trial readiness by identifying and characterising diverse cohorts of individuals interested in study participation, and to build community and collaboration among carriers, family members, researchers and clinicians around the world. Here, we describe the development and content of the IFXPR, characterise its first 747 registrants from 32 countries and invite investigators to apply for recruitment support for their project(s). With larger numbers, increased diversity and potentially the future clinical characterisation of registrants, the IFXPR will contribute to a more comprehensive and accurate understanding of the fragile X premutation in human health and support treatment studies.

Background and purposePrevious studies suggest that mechanisms and outcomes in patients with COVID-19-associated stroke differ from those in patients with non-COVID-19-associated strokes, but there is limited comparative evidence focusing on these populations. The aim of this study, therefore, was to determine if a significant association exists between COVID-19 status with revascularization and functional outcomes following thrombectomy for large vessel occlusion (LVO), after adjustment for potential confounding factors.MethodsA cross-sectional, international multicenter retrospective study was conducted in consecutively admitted COVID-19 patients with concomitant acute LVO, compared to a control group without COVID-19. Data collected included age, gender, comorbidities, clinical characteristics, details of the involved vessels, procedural technique, and various outcomes. A multivariable-adjusted analysis was conducted.ResultsIn this cohort of 697 patients with acute LVO, 302 had COVID-19 while 395 patients did not. There was a significant difference (p