Machine learning approaches identify immunologic signatures of total and intact HIV DNA during long-term antiretroviral therapy.

Understanding the interplay between the HIV reservoir and the host immune system may yield insights into HIV persistence during antiretroviral therapy (ART) and inform strategies for a cure. Here, we applied machine learning (ML) approaches to cross-sectional high-parameter HIV reservoir and immunology data in order to characterize host-reservoir associations and generate new hypotheses about HIV reservoir biology. High-dimensional immunophenotyping, quantification of HIV-specific T cell responses, and measurement of genetically intact and total HIV proviral DNA frequencies were performed on peripheral blood samples from 115 people with HIV (PWH) on long-term ART. Analysis demonstrated that both intact and total proviral DNA frequencies were positively correlated with T cell activation and exhaustion. Years of ART and select bifunctional HIV-specific CD4 T cell responses were negatively correlated with the percentage of intact proviruses. A leave-one-covariate-out inference approach identified specific HIV reservoir and clinical-demographic parameters, such as age and biological sex, that were particularly important in predicting immunophenotypes. Overall, immune parameters were more strongly associated with total HIV proviral frequencies than intact proviral frequencies. Uniquely, however, expression of the IL-7 receptor alpha chain (CD127) on CD4 T cells was more strongly correlated with the intact reservoir. Unsupervised dimension reduction analysis identified two main clusters of PWH with distinct immune and reservoir characteristics. Using reservoir correlates identified in these initial analyses, decision tree methods were employed to visualize relationships among multiple immune and clinical-demographic parameters and the HIV reservoir. Finally, using random splits of our data as training-test sets, ML algorithms predicted with approximately 70% accuracy whether a given participant had qualitatively high or low levels of total or intact HIV DNA . The techniques described here may be useful for assessing global patterns within the increasingly high-dimensional data used in HIV reservoir and other studies of complex biology.

Post-acute COVID-19 outcomes including participant-reported long COVID: amubarvimab/romlusevimab versus placebo in the ACTIV-2 trial.

Background: It is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID. Methods: Non-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo. Findings: Participants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53-0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID. Interpretation: Amubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID. Funding: National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

Maternal history of angioma is associated with infantile hemangioma and port-wine stain in children: a population-based, cohort study of mother-child pairs from the United Kingdom.

The two most prevalent childhood vascular abnormalities are infantile hemangioma (IH) and port-wine stain (PWS). They become apparent shortly after birth but have distinct pathophysiology and clinical manifestations. The goal of this study was to determine if mother's history of angioma or PWS is associated with these vascular abnormalities. We evaluated an UK anonymized electronic medical records database with medical records that were linked between children and their mothers. Cox proportional hazards models were used to evaluate the association between maternal factors and the time of onset of either IH or PWS in children. Between 2004 and 2021, 639,085 children were linked to their mom's medical data with a total of 4,270,773 person-years of follow up. Children born to mothers with an angioma as compared to a mother without an angioma were more than 60% more likely to have an IH (HR: 1.64 [1.07, 2.52]). Children born to mothers with a PWS as compared to children born to mothers without a PWS were nearly 20 times more likely to have a PWS (18.95 [4.71,76.26]). Mothers with angiomas were not more likely to have children with PWS and mothers with PWS were not more likely to have children with IH. The effect estimates were minimally changed after adjustment. We demonstrated that children born to mothers with angiomas or PWS were at increased risk of IH or PWS, respectively.

A targeted CRISPR screen identifies ETS1 as a regulator of HIV latency.

Human Immunodeficiency virus (HIV) infection is regulated by a wide array of host cell factors that combine to influence viral transcription and latency. To understand the complex relationship between the host cell and HIV latency, we performed a lentiviral CRISPR screen that targeted a set of host cell genes whose expression or activity correlates with HIV expression. We further investigated one of the identified factors - the transcription factor ETS1 and found that it is required for maintenance of HIV latency in a primary CD4 T cell model. Interestingly, ETS1 played divergent roles in actively infected and latently infected CD4 T cells, with knockout of ETS1 leading to reduced HIV expression in actively infected cells, but increased HIV expression in latently infected cells, indicating that ETS1 can play both a positive and negative role in HIV expression. CRISPR/Cas9 knockout of ETS1 in CD4 T cells from ART-suppressed people with HIV (PWH) confirmed that ETS1 maintains transcriptional repression of the clinical HIV reservoir. Transcriptomic profiling of ETS1-depleted cells from PWH identified a set of host cell pathways involved in viral transcription that are controlled by ETS1 in resting CD4 T cells. In particular, we observed that ETS1 knockout increased expression of the long non-coding RNA MALAT1 that has been previously identified as a positive regulator of HIV expression. Furthermore, the impact of ETS1 depletion on HIV expression in latently infected cells was partially dependent on MALAT1. Overall, these data demonstrate that ETS1 is an important regulator of HIV latency and influences expression of several cellular genes, including MALAT1, that could have a direct or indirect impact on HIV expression. Author Summary: HIV latency is a major obstacle for the eradication of HIV. However, molecular mechanisms that restrict proviral expression during therapy are not well understood. Identification of host cell factors that silence HIV would create opportunities for targeting these factors to reverse latency and eliminate infected cells. Our study aimed to explore mechanisms of latency in infected cells by employing a lentiviral CRISPR screen and CRISPR/Cas9 knockout in primary CD4 T cells. These experiments revealed that ETS1 is essential for maintaining HIV latency in primary CD4 T cells and we further confirmed ETS1's role in maintaining HIV latency through CRISPR/Cas9 knockout in CD4 T cells from antiretroviral therapy (ART)-suppressed individuals with HIV. Transcriptomic profiling of ETS1-depleted cells from these individuals identified several host cell pathways involved in viral transcription regulated by ETS1, including the long non-coding RNA MALAT1. Overall, our study demonstrates that ETS1 is a critical regulator of HIV latency, affecting the expression of several cellular genes that directly or indirectly influence HIV expression.

Analysis of the effect of HDAC inhibitors on the formation of the HIV reservoir.

The HIV reservoir is more dynamic than previously thought with around 70% of the latent reservoir originating from viruses circulating within 1 year of the initiation of antiretroviral therapy (ART). In an ex vivo model system of HIV latency, it was reported that early exposure to class I histone deacetylase (HDAC) inhibitors might prevent these more recently infected cells from entering a state of stable viral latency. This finding raises the possibility that co-administration of HDAC inhibitors at the time of ART initiation may prevent the establishment of much of the HIV reservoir. Here, we tested the effects of the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) and panobinostat co-administered at the time of ART initiation on the formation of the viral reservoir in HIV-infected humanized mice. As previously shown, SAHA and panobinostat were well tolerated in humanized mice. Unexpectedly, co-administration of SAHA resulted in an increase in the frequency of CD4+ cells carrying HIV DNA but did not alter the frequency of cell-associated HIV RNA in HIV-infected, ART-treated humanized mice. Co-administration of panobinostat did not alter levels of cell-associated HIV DNA or RNA. Our in vivo findings indicate that co-administration of HDAC inhibitors initiated at the same time of ART treatment does not prevent recently infected cells from entering latency.IMPORTANCECurrent antiretroviral therapy (ART) does not eradicate cells harboring replication-competent HIV reservoir. Withdrawal of ART inevitably results in a rapid viremia rebound. The HIV reservoir is more dynamic than previously thought. Early exposure to class I histone deacetylase (HDAC) inhibitors inhibit these more recently infected cells from entering a state of stable viral latency in an ex vivo model of latency, raising the possibility that co-administration of HDAC inhibitors at the time of ART initiation may reduce much of the HIV reservoir. Here, we tested the effects of the HDAC inhibitors suberoylanilide hydroxamic acid or panobinostat during ART initiation on the formation of the viral reservoir in HIV-infected humanized mice. Our in vivo study indicates that in contrast to in vitro observations, the co-administration of HDAC inhibitors at the same time of ART initiation does not prevent recently infected cells from entering latency.

Challenges in designing a randomized, double-blind noninferiority trial for treatment of acne: The SD-ACNE trial.

BACKGROUND/AIMS: Excessive use of antibiotics has led to development of antibiotic resistance and other antibiotic-associated complications. Dermatologists prescribe more antibiotics per clinician than any other major specialty, with much of this use for acne. Alternative acne treatments are available but are used much less often than antibiotics, at least partially because dermatologists feel that they are less effective. Spironolactone, a hormonal therapy with antiandrogen effects that can address the hormonal pathogenesis of acne, may represent a therapeutic alternative to oral antibiotics for women with acne. However, the comparative effects of spironolactone and oral antibiotics in the treatment of acne have not been definitively studied. The Spironolactone versus Doxycycline for Acne: A Comparative Effectiveness, Noninferiority Evaluation (SD-ACNE) trial aims to answer whether spironolactone, in addition to standard topical therapy, is noninferior to doxycycline (an oral antibiotic) for women with acne. Several interesting challenges arose in the development of this study, including determining acceptability of the comparative regimens to participating dermatologists, identifying data to support a noninferiority margin, and establishing a process for unblinding participants after they completed the study while maintaining the blind for study investigators. METHODS: We present the scientific and clinical rationale for the decisions made in the design of the trial, including input from key stakeholders through a Delphi consensus process. RESULTS: The Spironolactone versus Doxycycline for Acne: A Comparative Effectiveness, Noninferiority Evaluation trial (NCT04582383) is being conducted at a range of community and academic sites in the United States. To maximize external validity and inform clinical practice, the study is designed with broad eligibility criteria and no prohibition of use of topical medications. Participants in the trial will be randomized to receive either spironolactone 100 mg/day or doxycycline hyclate 100 mg/day for 16 weeks. The primary outcome is the absolute decrease in inflammatory lesion count, and we have established a noninferiority margin of four inflammatory lesions. Secondary outcomes include the percentage of participants achieving Investigator Global Assessment success, change in quality of life, and microbiome changes and diversity. CONCLUSIONS: The Spironolactone versus Doxycycline for Acne: A Comparative Effectiveness, Noninferiority Evaluation trial will have substantial implications for the treatment of acne and antibiotic stewardship. In addition, this study will provide important information on the effect of these systemic agents on the development of changes to the microbiome and antibiotic resistance in a healthy population of patients.

Advancing Toward a Human Immunodeficiency Virus Cure: Initial Progress on a Difficult Path.

Therapies to eradicate human immunodeficiency virus (HIV) infection, sparing lifelong antiviral therapy, are a still-distant goal. But significant advances have been made to reverse HIV latency while antiretroviral therapy (ART) is maintained to allow targeting of the persistent viral reservoir, to test interventions that could clear cells emerging from latent infection, and to improve HIV cure research assays and infrastructure. Steady progress gives hope that future therapies to clear HIV infection may relieve individuals and society of the burden of HIV.

Nanoparticle delivery of Tat synergizes with classical latency reversal agents to express HIV antigen targets.

Limited cellular levels of the HIV transcriptional activator Tat are one contributor to proviral latency that might be targeted in HIV cure strategies. We recently demonstrated that lipid nanoparticles containing HIV tat mRNA induce HIV expression in primary CD4 T cells. Here, we sought to further characterize tat mRNA in the context of several benchmark latency reversal agents (LRAs), including inhibitor of apoptosis protein antagonists (IAPi), bromodomain and extra-Terminal motif inhibitors (BETi), and histone deacetylase inhibitors (HDACi). tat mRNA reversed latency across several different cell line models of HIV latency, an effect dependent on the TAR hairpin loop. Synergistic enhancement of tat mRNA activity was observed with IAPi, HDACi, and BETi, albeit to variable degrees. In primary CD4 T cells from durably suppressed people with HIV, tat mRNA profoundly increased the frequencies of elongated, multiply-spliced, and polyadenylated HIV transcripts, while having a lesser impact on TAR transcript frequencies. tat mRNAs alone resulted in variable HIV p24 protein induction across donors. However, tat mRNA in combination with IAPi, BETi, or HDACi markedly enhanced HIV RNA and protein expression without overt cytotoxicity or cellular activation. Notably, combination regimens approached or in some cases exceeded the latency reversal activity of maximal mitogenic T cell stimulation. Higher levels of tat mRNA-driven HIV p24 induction were observed in donors with larger mitogen-inducible HIV reservoirs, and expression increased with prolonged exposure time. Combination LRA strategies employing both small molecule inhibitors and Tat delivered to CD4 T cells are a promising approach to effectively target the HIV reservoir.

Integrated Single-cell Multiomic Analysis of HIV Latency Reversal Reveals Novel Regulators of Viral Reactivation.

Despite the success of antiretroviral therapy, human immunodeficiency virus (HIV) cannot be cured because of a reservoir of latently infected cells that evades therapy. To understand the mechanisms of HIV latency, we employed an integrated single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq) approach to simultaneously profile the transcriptomic and epigenomic characteristics of ∼ 125,000 latently infected primary CD4+ T cells after reactivation using three different latency reversing agents. Differentially expressed genes and differentially accessible motifs were used to examine transcriptional pathways and transcription factor (TF) activities across the cell population. We identified cellular transcripts and TFs whose expression/activity was correlated with viral reactivation and demonstrated that a machine learning model trained on these data was 75%-79% accurate at predicting viral reactivation. Finally, we validated the role of two candidate HIV-regulating factors, FOXP1 and GATA3, in viral transcription. These data demonstrate the power of integrated multimodal single-cell analysis to uncover novel relationships between host cell factors and HIV latency.

Adult and infantile seborrheic dermatitis: update on current state of evidence and potential research frontiers.

Seborrheic dermatitis (SD) is a highly prevalent dermatological condition globally. The condition demonstrates bimodal presentation with what is commonly thought to be two subtypes: adult/adolescent seborrheic dermatitis (ASD) and infantile seborrheic dermatitis (ISD). Despite the common prevalence of ASD and ISD, there remains uncertainty around the underlying pathogenetic mechanisms, risk factors, and appropriate classification of the disease(s). This narrative review summarizes the current understanding of the epidemiology, presentation, and pathogenetic factors like epidermal barrier dysfunction, lipid abnormalities, and cutaneous microbiome for ASD and ISD. Elements such as immune responsiveness, neuroendocrine factors, and genetics in these disease states are also investigated. Throughout our review, we highlight shared features and discrepancies between ASD and ISD that are present in the literature and discuss potential avenues for future research that explore these disease states. We aim to contribute to the medical discourse on ASD and ISD and increase awareness of the need for additional research around these conditions, ultimately informing better targeting of therapeutics moving forward.

The histone methyltransferase SETD2 regulates HIV expression and latency.

Understanding the mechanisms that drive HIV expression and latency is a key goal for achieving an HIV cure. Here we investigate the role of the SETD2 histone methyltransferase, which deposits H3K36 trimethylation (H3K36me3), in HIV infection. We show that prevention of H3K36me3 by a potent and selective inhibitor of SETD2 (EPZ-719) leads to reduced post-integration viral gene expression and accelerated emergence of latently infected cells. CRISPR/Cas9-mediated knockout of SETD2 in primary CD4 T cells confirmed the role of SETD2 in HIV expression. Transcriptomic profiling of EPZ-719-exposed HIV-infected cells identified numerous pathways impacted by EPZ-719. Notably, depletion of H3K36me3 prior to infection did not prevent HIV integration but resulted in a shift of integration sites from highly transcribed genes to quiescent chromatin regions and to polycomb repressed regions. We also observed that SETD2 inhibition did not apparently affect HIV RNA levels, indicating a post-transcriptional mechanism affecting HIV expression. Viral RNA splicing was modestly reduced in the presence of EPZ-719. Intriguingly, EPZ-719 exposure enhanced responsiveness of latent HIV to the HDAC inhibitor vorinostat, suggesting that H3K36me3 can contribute to a repressive chromatin state at the HIV locus. These results identify SETD2 and H3K36me3 as novel regulators of HIV integration, expression and latency.

Antihypertensive Medications and Risk of Melanoma and Keratinocyte Carcinomas: A Systematic Review and Meta-Analysis.

Some antihypertensive medications are photosensitizing. The implications for skin cancer risk remain unclear because results from prior studies are inconsistent and as new evidence is published. We performed a systematic review and meta-analysis to evaluate the association between antihypertensives and common skin cancers (cutaneous squamous cell carcinoma, basal cell carcinoma, and melanoma) and to evaluate dose-response relationships. Forty-four articles met inclusion criteria, and 42 could be meta analyzed. Increased risks were seen for basal cell carcinoma with calcium channel blockers (relative risk [RR] = 1.17, 95% confidence interval [CI] = 1.11-1.22), diuretics (RR = 1.06, 95% CI = 1.03-1.10), and thiazides (RR = 1.10, 95% CI = 1.04-1.16); for squamous cell carcinoma with calcium channel blockers (RR = 1.08, 95% CI = 1.01-1.14), diuretics (RR = 1.29, 95% CI = 1.17-1.43), and thiazides (RR = 1.36, 95% CI = 1.15-1.61); and for melanoma in angiotensin-converting enzyme inhibitors (RR = 1.09, 95% CI = 1.03-1.14), calcium channel blockers (RR = 1.08, 95% CI = 1.03-1.12), and thiazides (RR = 1.09, 95% CI = 1.02-1.17). The quality of evidence was low or very low. We observed evidence for dose-response for thiazides with basal cell carcinoma; angiotensin-converting enzyme inhibitors, diuretics, and thiazides with squamous cell carcinoma; and angiotensin-converting enzyme inhibitors, diuretics, and thiazides with melanoma. Our meta-analysis supports a potential causal association between some antihypertensives, particularly diuretics, and skin cancer risk.

Antihypertensive Medications and Eczematous Dermatitis in Older Adults.

Importance: Rates of physician-diagnosed eczema have been increasing among older adults, but little is known regarding the pathophysiologic processes and best treatments in this subgroup. Preliminary data suggest that medications-antihypertensive medications in particular-may contribute to eczematous dermatitis; however, there are limited population-based data on the proportion of eczematous dermatitis diagnoses among older adults that may be attributed to antihypertensive drugs. Objectives: To determine whether antihypertensive drug use is associated with eczematous dermatitis in older adults. Design, Settings, and Participants: This was a longitudinal cohort study of a population-based sample of individuals 60 years and older without a diagnosis of eczematous dermatitis at baseline. It was conducted at primary care practices participating in The Health Improvement Network in the United Kingdom from January 1, 1994, to January 1, 2015. Data analyses were performed from January 6, 2020, to February 6, 2024. Exposure: Exposure date by first prescription for an antihypertensive drug within each drug class. Main outcome measures: Newly active eczematous dermatitis was based on the first date for 1 of the 5 most common eczema codes used in a previously validated algorithm. Results: Among the total study sample of 1 561 358 older adults (mean [SD] age, 67 [9] years; 54% female), the overall prevalence of eczematous dermatitis was 6.7% during a median (IQR) follow-up duration of 6 (3-11) years. Eczematous dermatitis incidence was higher among participants receiving antihypertensive drugs than those who did not (12 vs 9 of 1000 person-years of follow-up). Adjusted Cox proportional hazard models found that participants who received any antihypertensive drugs had a 29% increased hazard rate of any eczematous dermatitis (hazard ratio [HR], 1.29; 95% CI, 1.26-1.31). When assessing each antihypertensive drug class individually, the largest effect size was observed for diuretic drugs (HR, 1.21; 95% CI, 1.19-1.24) and calcium channel blockers (HR, 1.16; 95% CI, 1.14-1.18), and the smallest effect sizes were for angiotensin-converting enzyme inhibitors (HR, 1.02; 95% CI, 1.00-1.04) and ß-blockers (HR, 1.04; 95% CI, 1.02-1.06). Conclusions and Relevance: This cohort study found that antihypertensive drugs were associated with a small increased rate of eczematous dermatitis, with effect sizes largest for calcium channel blockers and diuretic drugs, and smallest for angiotensin-converting enzyme inhibitors and ß-blockers. Although additional research is needed to understand the mechanisms underlying the association, these data could be helpful to clinicians to guide management when a patient presents with eczematous dermatitis in older age.

Imaging the large-scale and cellular response to focal traumatic brain injury in mouse neocortex.

Traumatic brain injury (TBI) affects neural function at the local injury site and also at distant, connected brain areas. However, the real-time neural dynamics in response to injury and subsequent effects on sensory processing and behavior are not fully resolved, especially across a range of spatial scales. We used in vivo calcium imaging in awake, head-restrained male and female mice to measure large-scale and cellular resolution neuronal activation, respectively, in response to a mild/moderate TBI induced by focal controlled cortical impact (CCI) injury of the motor cortex (M1). Widefield imaging revealed an immediate CCI-induced activation at the injury site, followed by a massive slow wave of calcium signal activation that traveled across the majority of the dorsal cortex within approximately 30 s. Correspondingly, two-photon calcium imaging in primary somatosensory cortex (S1) found strong activation of neuropil and neuronal populations during the CCI-induced traveling wave. A depression of calcium signals followed the wave, during which we observed atypical activity of a sparse population of S1 neurons. Longitudinal imaging in the hours and days after CCI revealed increases in the area of whisker-evoked sensory maps at early time points, in parallel to decreases in cortical functional connectivity and behavioral measures. Neural and behavioral changes mostly recovered over hours to days in our M1-TBI model, with a more lasting decrease in the number of active S1 neurons. Our results in unanesthetized mice describe novel spatial and temporal neural adaptations that occur at cortical sites remote to a focal brain injury.

Sequence Analysis of Inducible, Replication-Competent Virus Reveals No Evidence of HIV-1 Evolution During Suppressive Antiviral Therapy, Indicating a Lack of Ongoing Viral Replication.

Background: Persistence of HIV-1 in reservoirs necessitates life-long antiretroviral therapy (ART). There are conflicting data using genetic analysis on whether persistence includes an actively replicating reservoir with strong evidence arguing against replication. Methods: We investigated the possibility of ongoing viral evolution during suppressive therapy by comparing near full-length viral genomic sequences using phylogenetic analysis of viral RNA in plasma before therapy initiation early after infection and from virus induced to grow from the latent reservoir after a period of suppressive ART. We also focused our analysis on evidence of selective pressure by drugs in the treatment regimen and at sites of selective pressure by the adaptive immune response. Results: Viral genomes induced to grow from the latent reservoir from 10 participants with up to 9 years on suppressive ART were highly similar to the nearly homogeneous sequences in plasma taken early after infection at ART initiation. This finding was consistent across the entire genome and when the analysis focused on sites targeted by the drug regimen and by host selective pressure of antibody and cytotoxic T cells. The lack of viral evolution away from pretherapy sequences in spite of demonstrated selective pressure is most consistent with a lack of viral replication during reservoir persistence. Conclusions: These results do not support ongoing viral replication as a mechanism of HIV-1 persistence during suppressive ART.

Characterization of Treatment Resistance and Viral Kinetics in the Setting of Single-Active Versus Dual-Active Monoclonal Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: Monoclonal antibodies (mAbs) represent a crucial antiviral strategy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but it is unclear whether combination mAbs offer a benefit over single-active mAb treatment. Amubarvimab and romlusevimab significantly reduced the risk of hospitalizations or death in the ACTIV-2/A5401 trial. Certain SARS-CoV-2 variants are intrinsically resistant against romlusevimab, leading to only single-active mAb therapy with amubarvimab in these variants. We evaluated virologic outcomes in individuals treated with single- versus dual-active mAbs. METHODS: Participants were nonhospitalized adults at higher risk of clinical progression randomized to amubarvimab plus romlusevimab or placebo. Quantitative SARS-CoV-2 RNA levels and targeted S-gene next-generation sequencing was performed on anterior nasal samples. We compared viral load kinetics and resistance emergence between individuals treated with effective single- versus dual-active mAbs depending on the infecting variant. RESULTS: Study participants receiving single- or dual-active mAbs had similar demographics, baseline nasal viral load, symptom score, and symptom duration. Compared with single-active mAb treatment, treatment with dual-active mAbs led to faster viral load decline at study days 3 (P < .001) and 7 (P < .01). Treatment-emergent resistance mutations were more likely to be detected after amubarvimab plus romlusevimab treatment than with placebo (2.6% vs 0%; P < .001) and were more frequently detected in the setting of single-active compared with dual-active mAb treatment (7.3% vs 1.1%; P < .01). Single-active and dual-active mAb treatment resulted in similar decrease in rates of hospitalizations or death. CONCLUSIONS: Compared with single-active mAb therapy, dual-active mAbs led to similar clinical outcomes but significantly faster viral load decline and a lower risk of emergent resistance.

An LSTM-based adversarial variational autoencoder framework for self-supervised neural decoding of behavioral choices.

Objective.This paper presents data-driven solutions to address two challenges in the problem of linking neural data and behavior: (1) unsupervised analysis of behavioral data and automatic label generation from behavioral observations, and (2) extraction of subject-invariant features for the development of generalized neural decoding models.Approach. For behavioral analysis and label generation, an unsupervised method, which employs an autoencoder to transform behavioral data into a cluster-friendly feature space is presented. The model iteratively refines the assigned clusters with soft clustering assignment loss, and gradually improves the learned feature representations. To address subject variability in decoding neural activity, adversarial learning in combination with a long short-term memory-based adversarial variational autoencoder (LSTM-AVAE) model is employed. By using an adversary network to constrain the latent representations, the model captures shared information among subjects' neural activity, making it proper for cross-subject transfer learning.Main results. The proposed approach is evaluated using cortical recordings of Thy1-GCaMP6s transgenic mice obtained via widefield calcium imaging during a motivational licking behavioral experiment. The results show that the proposed model achieves an accuracy of 89.7% in cross-subject neural decoding, outperforming other well-known autoencoder-based feature learning models. These findings suggest that incorporating an adversary network eliminates subject dependency in representations, leading to improved cross-subject transfer learning performance, while also demonstrating the effectiveness of LSTM-based models in capturing the temporal dependencies within neural data.Significance. Results demonstrate the feasibility of the proposed framework in unsupervised clustering and label generation of behavioral data, as well as achieving high accuracy in cross-subject neural decoding, indicating its potentials for relating neural activity to behavior.

Role of Posterior Medial Thalamus in the Modulation of Striatal Circuitry and Choice Behavior.

The posterior medial (POm) thalamus is heavily interconnected with sensory and motor circuitry and is likely involved in behavioral modulation and sensorimotor integration. POm provides axonal projections to the dorsal striatum, a hotspot of sensorimotor processing, yet the role of POm-striatal projections has remained undetermined. Using optogenetics with slice electrophysiology, we found that POm provides robust synaptic input to direct and indirect pathway striatal spiny projection neurons (D1- and D2-SPNs, respectively) and parvalbumin-expressing fast spiking interneurons (PVs). During the performance of a whisker-based tactile discrimination task, POm-striatal projections displayed learning-related activation correlating with anticipatory, but not reward-related, pupil dilation. Inhibition of POm-striatal axons across learning caused slower reaction times and an increase in the number of training sessions for expert performance. Our data indicate that POm-striatal inputs provide a behaviorally relevant arousal-related signal, which may prime striatal circuitry for efficient integration of subsequent choice-related inputs.

Efficacy and safety of crisaborole ointment, 2%, in participants aged ≥45 years with stasis dermatitis: Results from a fully decentralized, randomized, proof-of-concept phase 2a study.

BACKGROUND: Crisaborole ointment, 2%, is a nonsteroidal topical phosphodiesterase 4 inhibitor approved for the treatment of mild-to-moderate atopic dermatitis. OBJECTIVE: To evaluate the efficacy and safety of crisaborole in stasis dermatitis (SD). METHODS: In this randomized, double-blind, vehicle-controlled, decentralized phase 2a study (NCT04091087), 65 participants aged ≥45 years with SD without active ulceration received crisaborole or vehicle (1:1) twice-daily for 6 weeks. The primary end point was percentage change from baseline in total sign score at week 6 based on in-person assessment. RESULTS: Crisaborole-treated participants had significantly reduced total sign score from baseline versus vehicle based on in-person (nondermatologist) assessment (-32.4% vs -18.1%, P = .0299) and central reader (dermatologists) assessment of photographs (-52.5% vs -10.3%, P = .0004). Efficacy according to success and improvement per Investigator's Global Assessment score and lesional percentage body surface area reached statistical significance based on central reader but not in-person assessments. Skin and subcutaneous tissue disorders were common all-causality treatment-emergent adverse events with crisaborole. LIMITATIONS: Small sample size and short treatment duration were key limitations. In-person assessment was not conducted by dermatologists. CONCLUSION: Crisaborole improved signs and symptoms of SD and was well tolerated. Central reader assessment represents a promising approach for siteless clinical research.