Weight change with antiretroviral switch from integrase inhibitor or tenofovir alafenamide-based to Doravirine-Based regimens in people with HIV.

BACKGROUND: Weight gain has been well-described with integrase strand transfer inhibitors (INSTIs) and tenofovir alafenamide (TAF). Doravirine (DOR) has been identified as a relatively "weight-neutral" drug; however, there is little data describing its effect on weight change in routine clinical practice. METHODS: We conducted a retrospective chart review of weight change among people with HIV changing from an INSTI- to a non-INSTI regimen with DOR. RESULTS: At the time of ART switch, among 49 people with HIV, the mean age was 47 years, 24% were female, and 75% had HIV-1 viral load <200 copies/mL. Most (55%) people with HIV were taking bictegravir/TAF/emtricitabine prior to the switch. Although 84% switched due to concerns about weight gain, only 16% had a weight gain of ≥10% in the year preceding, and 49% had no substantial change in weight. 86% switched to DOR/lamivudine/tenofovir disoproxil fumarate. A weight decrease (-2.6% [95% CI: -5.1, -0.1%, p = .041] was seen over the year following the ART switch. Weight change prior to switch was greatest in the year 2021 compared to 2019, 2020, and 2022. CONCLUSIONS: Overall, modest changes in weight were seen following ART switch from INSTI-based regimen to a DOR-based, non-INSTI regimen. Further investigations with larger people with HIV cohorts will be helpful to guide clinical practice, while the impact of the COVID-19 pandemic on weight change should also be considered.

Clinical and Microbial Determinants of Upper Respiratory Colonization with Streptococcus pneumoniae and Native Microbiota in People with HIV-1 and Control Adults.

BACKGROUND: The substantial risk for respiratory and invasive infections with Streptococcus pneumoniae (Spn) among people with HIV-1 (PWH) begins with asymptomatic colonization. The frequency of Spn colonization among U.S. adults with and without HIV-1 infection is not well-characterized in the conjugate vaccine era. METHODS: We determined Spn colonization frequency by culture and specific lytA gene QPCR and microbiota profile by 16S rRNA gene sequencing in nasopharyngeal (NP) and oropharyngeal (OP) DNA from 138 PWH and 93 control adults and associated clinical characteristics. RESULTS: The frequencies of Spn colonization among PWH and controls did not differ (11.6% vs 8.6%, respectively; p=0.46) using combined results of culture and PCR, independent of vaccination or behavioral risks. PWH showed altered microbiota composition (i.e., beta-diversity. NP: p=0.0028, OP: p=0.0098), decreased alpha-diversity (NP: p=0.024, OP: p=0.0045), and differences in the relative abundance of multiple bacterial taxa. Spn colonization was associated with altered beta-diversity in the NP (p=0.011), but not OP (p=0.21). CONCLUSIONS: Despite widespread conjugate vaccine and antiretroviral use, frequencies of Spn colonization among PWH and controls are currently consistent with those reported in the pre-conjugate era. The persistently increased risk of pneumococcal disease despite ART may relate to behavioral and immunologic variables other than colonization.

Cost-Effectiveness of HIV Screening in Emergency Departments: Results From the Pragmatic Randomized HIV Testing Using Enhanced Screening Techniques in Emergency Departments Trial.

STUDY OBJECTIVE: Identification of HIV remains a critical health priority for which emergency departments (EDs) are a central focus. The comparative cost-effectiveness of various HIV screening strategies in EDs remains largely unknown. The goal of this study was to compare programmatic costs and cost-effectiveness of nontargeted and 2 forms of targeted opt-out HIV screening in EDs using results from a multicenter, pragmatic randomized clinical trial. METHODS: This economic evaluation was nested in the HIV Testing Using Enhanced Screening Techniques in Emergency Departments (TESTED) trial, a multicenter pragmatic clinical trial of different ED-based HIV screening strategies conducted from April 2014 through January 2016. Patients aged 16 years or older, with normal mental status and not critically ill, or not known to be living with HIV were randomized to 1 of 3 HIV opt-out screening approaches, including nontargeted, enhanced targeted, or traditional targeted, across 4 urban EDs in the United States. Each screening method was fully integrated into routine emergency care. Direct programmatic costs were determined using actual trial results, and time-motion assessment was used to estimate personnel activity costs. The primary outcome was newly diagnosed HIV. Total annualized ED programmatic costs by screening approach were calculated using dollars adjusted to 2023 as were costs per patient newly diagnosed with HIV. One-way and multiway sensitivity analyses were performed. RESULTS: The trial randomized 76,561 patient visits, resulting in 14,405 completed HIV tests, and 24 (0.2%) new diagnoses. Total annualized new diagnoses were 12.9, and total annualized costs for nontargeted, enhanced targeted, and traditional targeted screening were $111,861, $88,629, and $70,599, respectively. Within screening methods, costs per new HIV diagnoses were $20,809, $23,554, and $18,762, respectively. Enhanced targeted screening incurred higher costs but with similar annualized new cases detected compared with traditional targeted screening. Nontargeted screening yielded an incremental cost-effectiveness ratio of $25,586 when compared with traditional targeted screening. Results were most sensitive to HIV prevalence and costs of HIV tests. CONCLUSION: Nontargeted HIV screening was more costly than targeted screening largely due to an increased number of HIV tests performed. Each HIV screening strategy had similar within-strategy costs per new HIV diagnosis with traditional targeted screening yielding the lowest cost per new diagnosis. For settings with budget constraints or very low HIV prevalences, the traditional targeted approach may be preferred; however, given only a slightly higher cost per new HIV diagnosis, ED settings looking to detect the most new cases may prefer nontargeted screening.

Construct validity and responsiveness of a health-related symptom index for persons either treated or monitored for anal high-grade squamous intraepithelial lesions (HSIL): AMC-A01/-A03.

PURPOSE: To determine whether treatment of anal high-grade squamous intraepithelial lesions (HSIL), vs active monitoring, is effective in reducing incidence of anal cancer in persons living with HIV, the US National Cancer Institute funded the Phase III ANal Cancer/HSIL Outcomes Research (ANCHOR) clinical trial. As no established patient-reported outcomes (PRO) tool exists for persons with anal HSIL, we sought to estimate the construct validity and responsiveness of the ANCHOR Health-Related Symptom Index (A-HRSI). METHODS: The construct validity phase enrolled ANCHOR participants who were within two weeks of randomization to complete A-HRSI and legacy PRO questionnaires at a single time point. The responsiveness phase enrolled a separate cohort of ANCHOR participants who were not yet randomized to complete A-HRSI at three time points: prior to randomization (T1), 14-70 (T2), and 71-112 (T3) days following randomization. RESULTS: Confirmatory factor analysis techniques established a three-factor model (i.e., physical symptoms, impact on physical functioning, impact on psychological functioning), with moderate evidence of convergent validity and strong evidence of discriminant validity in the construct validity phase (n = 303). We observed a significant moderate effect for changes in A-HRSI impact on physical functioning (standardized response mean = 0.52) and psychological symptoms (standardized response mean = 0.60) from T2 (n = 86) to T3 (n = 92), providing evidence of responsiveness. CONCLUSION: A-HRSI is a brief PRO index that captures health-related symptoms and impacts related to anal HSIL. This instrument may have broad applicability in other contexts assessing individuals with anal HSIL, which may ultimately help improve clinical care and assist providers and patients with medical decision-making.

Human cortical interneurons optimized for grafting specifically integrate, abort seizures, and display prolonged efficacy without over-inhibition.

Previously, we demonstrated the efficacy of human pluripotent stem cell (hPSC)-derived GABAergic cortical interneuron (cIN) grafts in ameliorating seizures. However, a safe and reliable clinical translation requires a mechanistic understanding of graft function, as well as the assurance of long-term efficacy and safety. By employing hPSC-derived chemically matured migratory cINs in two models of epilepsy, we demonstrate lasting efficacy in treating seizures and comorbid deficits, as well as safety without uncontrolled growth. Host inhibition does not increase with increasing grafted cIN densities, assuring their safety without the risk of over-inhibition. Furthermore, their closed-loop optogenetic activation aborted seizure activity, revealing mechanisms of graft-mediated seizure control and allowing graft modulation for optimal translation. Monosynaptic tracing shows their extensive and specific synaptic connections with host neurons, resembling developmental connection specificity. These results offer confidence in stem cell-based therapy for epilepsy as a safe and reliable treatment for patients suffering from intractable epilepsy.

The Determining Effective Testing in Emergency Departments and Care Coordination on Treatment Outcomes (DETECT) for Hepatitis C (Hep C) Linkage-to-Care Trial: rationale and design of an emergency department-based randomized clinical trial of linkage-to-care strategies for hepatitis C.

BACKGROUND: Hepatitis C (HCV) poses a major public health problem in the USA. While early identification is a critical priority, subsequent linkage to a treatment specialist is a crucial step that bridges diagnosed patients to treatment, cure, and prevention of ongoing transmission. Emergency departments (EDs) serve as an important clinical setting for HCV screening, although optimal methods of linkage-to-care for HCV-diagnosed individuals remain unknown. In this article, we describe the rationale and design of The Determining Effective Testing in Emergency Departments and Care Coordination on Treatment Outcomes (DETECT) for Hepatitis C (Hep C) Linkage-to-Care Trial. METHODS: The DETECT Hep C Linkage-to-Care Trial will be a single-center prospective comparative effectiveness randomized two-arm parallel-group superiority trial to test the effectiveness of linkage navigation and clinician referral among ED patients identified with untreated HCV with a primary hypothesis that linkage navigation plus clinician referral is superior to clinician referral alone when using treatment initiation as the primary outcome. Participants will be enrolled in the ED at Denver Health Medical Center (Denver, CO), an urban, safety-net hospital with approximately 75,000 annual adult ED visits. This trial was designed to enroll a maximum of 280 HCV RNA-positive participants with one planned interim analysis based on methods by O'Brien and Fleming. This trial will further inform the evaluation of cost effectiveness, disparities, and social determinants of health in linkage-to-care, treatment, and disease progression. DISCUSSION: When complete, the DETECT Hep C Linkage-to-Care Trial will significantly inform how best to perform linkage-to-care among ED patients identified with HCV. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04026867 Original date: July 1, 2019 URL: https://clinicaltrials.gov/ct2/show/NCT04026867.

The Determining Effective Testing in Emergency Departments and Care Coordination on Treatment Outcomes (DETECT) for Hepatitis C (Hep C) Screening Trial: rationale and design of a multi-center pragmatic randomized clinical trial of hepatitis C screening in emergency departments.

BACKGROUND: Early identification of HCV is a critical health priority, especially now that treatment options are available to limit further transmission and provide cure before long-term sequelae develop. Emergency departments (EDs) are important clinical settings for HCV screening given that EDs serve many at-risk patients who do not access other forms of healthcare. In this article, we describe the rationale and design of The Determining Effective Testing in Emergency Departments and Care Coordination on Treatment Outcomes (DETECT) for Hepatitis C (Hep C) Screening Trial. METHODS: The DETECT Hep C Screening Trial is a multi-center prospective pragmatic randomized two-arm parallel-group superiority trial to test the comparative effectiveness of nontargeted and targeted HCV screening in the ED with a primary hypothesis that nontargeted screening is superior to targeted screening when identifying newly diagnosed HCV. This trial will be performed in the EDs at Denver Health Medical Center (Denver, CO), Johns Hopkins Hospital (Baltimore, MD), and the University of Mississippi Medical Center (Jackson, MS), sites representing approximately 225,000 annual adult visits, and designed using the PRECIS-2 framework for pragmatic trials. When complete, we will have enrolled a minimum of 125,000 randomized patient visits and have performed 13,965 HCV tests. In Denver, the Screening Trial will serve as a conduit for a distinct randomized comparative effectiveness trial to evaluate linkage-to-HCV care strategies. All sites will further contribute to embedded observational studies to assess cost effectiveness, disparities, and social determinants of health in screening, linkage-to-care, and treatment for HCV. DISCUSSION: When complete, The DETECT Hep C Screening Trial will represent the largest ED-based pragmatic clinical trial to date and all studies, in aggregate, will significantly inform how to best perform ED-based HCV screening. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04003454 . Registered on 1 July 2019.

Responses to a Neutralizing Monoclonal Antibody for Hospitalized Patients With COVID-19 According to Baseline Antibody and Antigen Levels : A Randomized Controlled Trial.

BACKGROUND: In a randomized, placebo-controlled, clinical trial, bamlanivimab, a SARS-CoV-2-neutralizing monoclonal antibody, given in combination with remdesivir, did not improve outcomes among hospitalized patients with COVID-19 based on an early futility assessment. OBJECTIVE: To evaluate the a priori hypothesis that bamlanivimab has greater benefit in patients without detectable levels of endogenous neutralizing antibody (nAb) at study entry than in those with antibodies, especially if viral levels are high. DESIGN: Randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04501978). SETTING: Multicenter trial. PATIENTS: Hospitalized patients with COVID-19 without end-organ failure. INTERVENTION: Bamlanivimab (7000 mg) or placebo. MEASUREMENTS: Antibody, antigen, and viral RNA levels were centrally measured on stored specimens collected at baseline. Patients were followed for 90 days for sustained recovery (defined as discharge to home and remaining home for 14 consecutive days) and a composite safety outcome (death, serious adverse events, organ failure, or serious infections). RESULTS: Among 314 participants (163 receiving bamlanivimab and 151 placebo), the median time to sustained recovery was 19 days and did not differ between the bamlanivimab and placebo groups (subhazard ratio [sHR], 0.99 [95% CI, 0.79 to 1.22]; sHR > 1 favors bamlanivimab). At entry, 50% evidenced production of anti-spike nAbs; 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1000 ng/L. Among those without and with nAbs at study entry, the sHRs were 1.24 (CI, 0.90 to 1.70) and 0.74 (CI, 0.54 to 1.00), respectively (nominal P for interaction = 0.018). The sHR (bamlanivimab vs. placebo) was also more than 1 for those with plasma antigen or nasal viral RNA levels above median level at entry and was greatest for those without antibodies and with elevated levels of antigen (sHR, 1.48 [CI, 0.99 to 2.23]) or viral RNA (sHR, 1.89 [CI, 1.23 to 2.91]). Hazard ratios for the composite safety outcome (<1 favors bamlanivimab) also differed by serostatus at entry: 0.67 (CI, 0.37 to 1.20) for those without and 1.79 (CI, 0.92 to 3.48) for those with nAbs. LIMITATION: Subgroup analysis of a trial prematurely stopped because of futility; small sample size; multiple subgroups analyzed. CONCLUSION: Efficacy and safety of bamlanivimab may differ depending on whether an endogenous nAb response has been mounted. The limited sample size of the study does not allow firm conclusions based on these findings, and further independent trials are required that assess other types of passive immune therapies in the same patient setting. PRIMARY FUNDING SOURCE: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

Comparison of HIV Screening Strategies in the Emergency Department: A Randomized Clinical Trial.

Importance: The National HIV Strategic Plan for the US recommends HIV screening in emergency departments (EDs). The most effective approach to ED-based HIV screening remains unknown. Objective: To compare strategies for HIV screening when integrated into usual ED practice. Design, Setting, and Participants: This randomized clinical trial included patients visiting EDs at 4 US urban hospitals between April 2014 and January 2016. Patients included were ages 16 years or older, not critically ill or mentally altered, not known to have an HIV positive status, and with an anticipated length of stay 30 minutes or longer. Data were analyzed through March 2021. Interventions: Consecutive patients underwent concealed randomization to either nontargeted screening, enhanced targeted screening using a quantitative HIV risk prediction tool, or traditional targeted screening as adapted from the Centers for Disease Control and Prevention. Screening was integrated into clinical practice using opt-out consent and fourth-generation antigen-antibody assays. Main Outcomes and Measures: New HIV diagnoses using intention-to-treat analysis, absolute differences, and risk ratios (RRs). Results: A total of 76 561 patient visits were randomized; median (interquartile range) age was 40 (28-54) years, 34 807 patients (51.2%) were women, and 26 776 (39.4%) were Black, 22 131 (32.6%) non-Hispanic White, and 14 542 (21.4%) Hispanic. A total of 25 469 were randomized to nontargeted screening; 25 453, enhanced targeted screening; and 25 639, traditional targeted screening. Of the nontargeted group, 6744 participants (26.5%) completed testing and 10 (0.15%) were newly diagnosed; of the enhanced targeted group, 13 883 participants (54.5%) met risk criteria, 4488 (32.3%) completed testing, and 7 (0.16%) were newly diagnosed; and of the traditional targeted group, 7099 participants (27.7%) met risk criteria, 3173 (44.7%) completed testing, and 7 (0.22%) were newly diagnosed. When compared with nontargeted screening, targeted strategies were not associated with a higher rate of new diagnoses (enhanced targeted and traditional targeted combined: difference, -0.01%; 95% CI, -0.04% to 0.02%; RR, 0.7; 95% CI, 0.30 to 1.56; P = .38; and enhanced targeted only: difference, -0.01%; 95% CI, -0.04% to 0.02%; RR, 0.70; 95% CI, 0.27 to 1.84; P = .47). Conclusions and Relevance: Targeted HIV screening was not superior to nontargeted HIV screening in the ED. Nontargeted screening resulted in significantly more tests performed, although all strategies identified relatively low numbers of new HIV diagnoses. Trial Registration: ClinicalTrials.gov Identifier: NCT01781949.

Impact of HIV-1 Infection and Antigen Class on T Follicular Helper Cell Responses to Pneumococcal Polysaccharide-Protein Conjugate Vaccine-13.

Pneumococcal infections are common and serious complications of HIV-1 disease. Prevention has been compromised by the limited magnitude and quality of Ab responses to T cell-independent type 2 pneumococcal capsular polysaccharides (PPS). The pneumococcal polysaccharide-protein conjugate vaccine-13 (PCV-13) contains PPS conjugated to the T cell-dependent protein (diphtheria toxoid [DT] [CRM197]). We investigated the differential response to PPS and DT by human Ab-secreting B cells (ASC) after immunization with PCV-13 in newly diagnosed healthy HIV+ and control adults. The numbers of PPS-specific IgG ASC increased significantly and similarly in HIV+ and controls. However, DT-specific IgG ASC increased in controls but not HIV+ subjects. To determine the cellular basis of these disparate responses to DT and PPS, we characterized the frequency and activation of T follicular helper (Tfh) cells, the predominant T cell subset providing B cell help. Expression of inducible T cell costimulator (ICOS), which sustains Tfh function and phenotype, increased significantly among controls, when compared with the HIV+ group. Increases in ICOS+ Tfh correlated with changes in T-dependent, DT-specific IgG ASC in controls but not in HIV+ In contrast, ICOS expression did not correlate with T cell-independent type 2 PPS-specific ASC in either group. Of note, upon optimized ex vivo stimulation, CD4 T cells from HIV+ subjects differentiated into Tfh cells and formed synapses with Raji B cells at frequencies similar to that of controls. In summary, PCV-13-induced increase in ICOS expression on Tfh was associated with responses to DT, which was compromised in recently diagnosed healthy HIV+ adults and can be restored ex vivo by providing effective Tfh-differentiating signals.

Epigenetic regulation of satellite cell fate during skeletal muscle regeneration.

In response to muscle injury, muscle stem cells integrate environmental cues in the damaged tissue to mediate regeneration. These environmental cues are tightly regulated to ensure expansion of muscle stem cell population to repair the damaged myofibers while allowing repopulation of the stem cell niche. These changes in muscle stem cell fate result from changes in gene expression that occur in response to cell signaling from the muscle environment.Integration of signals from the muscle environment leads to changes in gene expression through epigenetic mechanisms. Such mechanisms, including post-translational modification of chromatin and nucleosome repositioning, act to make specific gene loci more, or less, accessible to the transcriptional machinery. In youth, the muscle environment is ideally structured to allow for coordinated signaling that mediates efficient regeneration. Both age and disease alter the muscle environment such that the signaling pathways that shape the healthy muscle stem cell epigenome are altered. Altered epigenome reduces the efficiency of cell fate transitions required for muscle repair and contributes to muscle pathology. However, the reversible nature of epigenetic changes holds out potential for restoring cell fate potential to improve muscle repair in myopathies.In this review, we will describe the current knowledge of the mechanisms allowing muscle stem cell fate transitions during regeneration and how it is altered in muscle disease. In addition, we provide some examples of how epigenetics could be harnessed therapeutically to improve regeneration in various muscle pathologies.

A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.

BACKGROUND: LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19. METHODS: In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5. RESULTS: On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47). CONCLUSIONS: Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).

Advantages and challenges for noninvasive atrial fibrillation ablation.

PURPOSE: Although catheter ablation is an effective therapy for atrial fibrillation (AF), risks remain and improved efficacy is desired. Stereotactic radiotherapy is a well-established therapy used to noninvasively treat malignancies with precision. We sought to evaluate stereotactic arrhythmia radioablation (STAR) as a therapeutic option for treating AF. METHODS AND RESULTS: Three cancer patients with drug refractory AF were enrolled. Planning software using 3-D CT of the left atrium was used to design a desired ablation volume encompassing antral circumferential pulmonary vein isolation, roof and floor lines to create a "box" lesion set. After planning, patients were treated in the radioablation suite. STAR was able to deliver the intended radiation dose to the target in all 3 patients. No complications were observed over a follow-up period of 24 months. One patient with paroxysmal AF died from deterioration of cancer. The autopsy revealed evidence of fibroblasts and fibrogenesis in the region of atrial tissues targeted with radioablation. In one of these patients, left atrial posterior wall electrograms recorded from the esophagus before and 3 months after STAR indicated successful electrical isolation. CONCLUSIONS: This is the first report of non-invasive radioablation of the left atrium with demonstration of successful electrical isolation. Although STAR may be safe and effective in delivering ablative energy to the left atrium, further evaluation is warranted regarding effectiveness.

Characteristics of REPRIEVE Trial Participants Identifying Across the Transgender Spectrum.

Because persons who identify across the transgender spectrum (PATS) are a key population in human immunodeficiency virus (HIV) yet are underreported in HIV and cardiovascular research, we aimed to characterize this population within the REPRIEVE global clinical trial (n = 7770). Acceptance of gathering gender identity was high (96%). Participation by PATS was 1.7% overall, 2.4% among natal males, 0.3% among natal females, and varied across geographic regions (from 0% in sub-Saharan Africa to 2.3% in High Income Region). Thirty percent of natal male PATS identified other than transgender. Some characteristics differed by gender. Most notably, 38% of natal male PATS receiving gender-affirming treatment had waist circumference >102 cm (compared with ≤25% in other groups). Given that PATS is a key population, HIV research should routinely report trial participation and outcomes by gender in addition to natal sex, to provide the results needed to optimize medical care to PATS.

Stereotactic arrhythmia radioablation for refractory scar-related ventricular tachycardia.

BACKGROUND: Recently, stereotactic radiosurgery has been applied to arrhythmias (stereotactic arrhythmia radioablation [STAR]), with promising results reported in patients with refractory scar-related ventricular tachycardia (VT), a cohort with known high morbidity and mortality. OBJECTIVE: Herein, we describe our experience with STAR, detailing its early and mid- to long-term results. METHODS: This is a pilot prospective study of patients undergoing STAR for refractory scar-related VT. The anatomical target for radioablation was defined on the basis of the clinical VT morphology, electroanatomic mapping, and study-specific preprocedural imaging with cardiac computed tomography. The target volume was treated with a prescription radiation dose of 25 Gy delivered in a single fraction by CyberKnife in an outpatient setting. Ventricular arrhythmias and radiation-related adverse events were monitored at follow-up to determine STAR efficacy and safety. RESULTS: Five patients (100% men; mean age 63 ± 12 years; 80% with ischemic cardiomyopathy; left ventricular ejection fraction 34% ± 15%) underwent STAR. Radioablation was delivered in 82 ± 11 minutes without acute complications. During a mean follow-up of 12 ± 2 months, all patients experienced clinically significant mid- to late-term ventricular arrhythmia recurrence; 2 patients died of complications associated with their advanced heart failure. There were no clinical or imaging evidence of radiation-induced complications in the organs at risk surrounding the scar targeted by radioablation. CONCLUSION: Despite good initial results, STAR did not result in effective arrhythmia control in the long term in a selected high-risk population of patients with scar-related VT. The safety profile was confirmed to be favorable, with no radiation-related complications observed during follow-up. Further studies are needed to explain these disappointing results.

Factors associated with tenofovir diphosphate concentrations in dried blood spots in persons living with HIV.

OBJECTIVES: To determine factors associated with interindividual variability in tenofovir diphosphate (TFV-DP) concentrations in dried blood spots (DBSs) among persons living with HIV (PLWH). METHODS: PLWH who were at least 18 years old and taking tenofovir disoproxil fumarate-containing ART were prospectively recruited and enrolled from a clinical cohort and followed longitudinally (up to three visits over 48 weeks). With log-transformed TFV-DP concentrations in DBSs as the outcome, mixed-model regression analyses were used to assess associations between self-reported 3 month ART adherence, race and other clinical covariates (gender, age, BMI, CD4+ T cell count, estimated glomerular filtration rate, haematocrit, duration on current ART and anchor drug class) on TFV-DP in DBSs. RESULTS: Five hundred and twenty-seven participants (1150 person-visits) were analysed. Adjusting for race and other clinical covariates, every 10% increase in self-reported 3 month ART adherence was associated with an average TFV-DP concentration increase in DBSs of 28% (95% CI: 24%-32%; P < 0.0001). In the same model, female participants had 20% (95% CI: 3%-40%; P = 0.02) higher TFV-DP concentrations in DBSs, compared with male participants, and every 1 kg/m2 increase in BMI was associated with a decrease in TFV-DP concentration in DBSs by 2% (95% CI: -3% to -1%; P < 0.0001). CONCLUSIONS: Individual patient characteristics were predictive of TFV-DP concentration in DBSs in PLWH receiving tenofovir disoproxil fumarate-based ART. Future research to incorporate these predictors into the interpretation of this ART adherence biomarker, and to establish whether these associations extend to PLWH taking tenofovir alafenamide-containing ART, is needed.

Noninvasive stereotactic radioablation for the treatment of atrial fibrillation: First-in-man experience.

PURPOSE: Catheter ablation is an effective therapy for atrial fibrillation (AF). However, risks remain, and improved efficacy is desired. Stereotactic body radiotherapy (SBRT) is a well-established therapy used to noninvasively treat malignancies and functional disorders with precision. We evaluated the feasibility of stereotactic radioablation for treating paroxysmal AF. METHODS: Two patients with drug-refractory paroxysmal AF underwent pulmonary vein isolation with SBRT. After placement of a percutaneous active fixation temporary pacing lead tracking fiducial, computed tomography (CT) angiography was performed to define left atrial anatomy. A tailored planning treatment volume was created to deliver contiguous linear ablations to isolate the pulmonary veins and posterior wall. Patients were treated on an outpatient basis in the radioablation suite. Clinical follow-up was performed through at least 24 months after therapy. RESULTS: Both patients successfully underwent SBRT planning and treatment without significant early or long-term side effects up to 48 months of follow-up. One patient had AF recurrence after 6 months free of arrhythmia, while the second patient remains free of AF after 24 months with fibrosis detected on MRI scan consistent with the ablation lesion set. An incidentally noted small pericardial effusion occurred in one patient. CONCLUSION: Stereotactic radioablation may be feasible for the treatment of drug-refractory AF. Further evaluation is warranted.

Short Communication: Cascade of Antiretroviral Therapy Adherence in Virologically Suppressed Persons Living with HIV.

Variable adherence to antiretroviral therapy (ART) can maintain HIV viral suppression, but our understanding of the ART adherence continuum remains limited. In a clinical cohort of adult persons living with HIV treated with a tenofovir (TFV) disoproxil fumarate/emtricitabine (TDF/FTC)-based regimen, data on 3-month self-reported adherence and dried blood spots (DBS) for TFV diphosphate (TFV-DP) and FTC triphosphate (FTC-TP) were collected. Among 521 participants in whom DBS were available upon enrollment, 333 were virologically suppressed (<20 copies/mL). Only 145 (44%) of them reported 100% 3-month adherence, and 69 (21%) had drug concentrations in the highest adherence categories (TFV-DP ≥1,850 fmol/punch and quantifiable FTC-TP). These findings demonstrate a wide range of ART adherence and drug exposure associated with viral suppression, indicating that modern regimens are pharmacologically forgiving. Additional research is needed to understand the biologic effects of variable adherence and drug exposure beyond plasma virologic suppression.