Anal cancer screening among women with HIV: provider experiences and system-level challenges.

Women living with HIV (WLWH) are at increased risk of anal cancer compared to women without HIV, often due to persistent human papillomavirus (HPV) infections. This paper describes current practices and challenges conducting anal cancer screening for WLWH at an urban integrated safety-net system and a non-profit community-based HIV clinic. We conducted 25 semi-structured interviews with clinical and administrative stakeholders to assess knowledge, clinic practices and procedures, and experiences with anal cancer screening. Interview transcripts and fieldnotes were thematically analyzed using an iterative deductive and inductive coding scheme. Findings were organized by the Consolidated Framework for Implementation Research (CFIR) domains and constructs. Provider-level barriers to conducting anal cancer screening included limited knowledge of guidelines. System-level barriers included: structural characteristics such as lack of coordination between clinics to discern provider roles and responsibilities; and limitations in available resources such as configuration of electronic health records and infrastructure to manage referrals of abnormal anal Pap results. We conclude that anal cancer screening and follow-up for WLWH requires organization and coordination between multiple care teams, updated clinical information systems to facilitate communication and support anal Pap ordering and result documentation, and infrastructure that includes policies and protocols for management of abnormal results.Trial registration: ClinicalTrials.gov identifier: NCT02135419.

Perception and adaptation of receptive prosody in autistic adolescents.

A fundamental aspect of language processing is inferring others' minds from subtle variations in speech. The same word or sentence can often convey different meanings depending on its tempo, timing, and intonation-features often referred to as prosody. Although autistic children and adults are known to experience difficulty in making such inferences, the science remains unclear as to why. We hypothesize that detail-oriented perception in autism may interfere with the inference process if it lacks the adaptivity required to cope with the variability ubiquitous in human speech. Using a novel prosodic continuum that shifts the sentence meaning gradiently from a statement (e.g., "It's raining") to a question (e.g., "It's raining?"), we have investigated the perception and adaptation of receptive prosody in autistic adolescents and two groups of non-autistic controls. Autistic adolescents showed attenuated adaptivity in categorizing prosody, whereas they were equivalent to controls in terms of discrimination accuracy. Combined with recent findings in segmental (e.g., phoneme) recognition, the current results provide the basis for an emerging research framework for attenuated flexibility and reduced influence of contextual feedback as a possible source of deficits that hinder linguistic and social communication in autism.

Improving Cardiovascular Disease Primary Prevention Treatment Thresholds in a New England Health Care System.

Background: Atherosclerotic cardiovascular disease (ASCVD) risk estimation based on the pooled cohort equation (PCE) overestimates in population-based cohorts. Whether it performs equally across disaggregated demographics in health care populations is less known. Objectives: The purpose of the study was to recalibrate PCE and rederive prevention thresholds in a contemporary health care system and evaluate its performance across sociodemographics. Methods: We retrospectively inspected electronic health records between 2010 to 2012 and 2020 to 2022 within Mass General Brigham health care in New England region. We compared performance of the original vs recalibrated PCE measured by calibration, discrimination, reclassification rate, and net benefit among 160,926 patients aged 40 to 79 years and without prior ASCVD or lipid-lowering medication. Results: Of the 160,926 patients (mean age: 54.6 ± 8.6 years; 61.4% female), 20,373 (12.7%) developed ASCVD over 10 years. The original PCE globally underestimated ASCVD risk (observed vs predicted incidence rate: 0.13 vs 0.05). Recalibration upclassified risk primarily among individuals with low-to-borderline risk by the original PCE and additionally identified 40% of patients who had undergone ASCVD events yet deemed statin-ineligible based on the original PCE. Treatment thresholds yielding the greatest net benefit were ≥24.0% for women (+23.3%) vs ≥26.0% for men (+18.7%), whereas ≥26.0% for White or other race (+24.7%) vs ≥14.0% Black or African American (+12.5%), respectively. Specifically, Hispanic or Latino and non-Hispanic Black patients conferred the greatest sensitivity improvement at ≥12.3% threshold compared to higher ≥23.6% among non-Hispanic Asian or Pacific Islanders. Generally, lower thresholds earlier in life were optimal. Conclusions: Recalibration and personalized treatment thresholds derived within a health system may improve prevention treatment allocation efficiency.

Applications of identity-based theories to understand the impact of stigma and camouflaging on mental health outcomes for autistic people.

Autistic people have long been conceptualized from a deficit-based model of disability, but recent self-advocates and scholars have asserted the importance of recognizing autism as both a disability and an important part of a person's social identity. The autistic identity is subject to specific stigma and stressors beyond everyday discrimination and prejudice, which can have many downstream implications on mental health and well-being. Prior research on camouflaging has explained both quantitatively and qualitatively how autistic people conform to norms and mask their autistic traits to better fit in with non-autistic societal standards. Given this paradigm shift in understanding autistic peoples' lived experiences, researchers must also begin to reshape the theories guiding their work in order to improve diagnosis, intervention, and supports. This review examines the extant research on identity-related stigma and camouflaging and their subsequent impacts on mental health outcomes in autism. A model is proposed integrating identity-based theories-specifically the social model of disability, social identity theory, and minority stress model-to explain relationships across research areas and better explain the experiences of autistic people. We discuss how identity-based theories can be applied in autism research to better understand the impacts of stigma and camouflaging on autistic peoples' lived experiences and reduce disparities in their mental health outcomes.

Assessing the geographic specificity of pH prediction by classification and regression trees.

Soil pH effects a wide range of critical biogeochemical processes that dictate plant growth and diversity. Previous literature has established the capacity of classification and regression trees (CARTs) to predict soil pH, but limitations of CARTs in this context have not been fully explored. The current study collected soil pH, climatic, and topographic data from 100 locations across New York's Temperate Deciduous Forests (in the United States of America) to investigate the extrapolative capacity of a previously developed CART model as compared to novel CART and random forest (RF) models. Results showed that the previously developed CART underperformed in terms of predictive accuracy (RRMSE = 14.52%) when compared to a novel tree (RRMSE = 9.33%), and that a novel random forest outperformed both models (RRMSE = 8.88%), though its predictions did not differ significantly from the novel tree (p = 0.26). The most important predictors for model construction were climatic factors. These findings confirm existing reports that CART models are constrained by the spatial autocorrelation of geographic data and encourage the restricted application of relevant machine learning models to regions from which training data was collected. They also contradict previous literature implying that random forests should meaningfully boost the predictive accuracy of CARTs in the context of soil pH.

Resolving self-association of a therapeutic antibody by formulation optimization and molecular approaches.

A common challenge encountered during development of high concentration monoclonal antibody formulations is preventing self-association. Depending on the antibody and its formulation, self-association can be seen as aggregation, precipitation, opalescence or phase separation. Here we report on an unusual manifestation of self-association, formation of a semi-solid gel or "gelation." Therapeutic monoclonal antibody C4 was isolated from human B cells based on its strong potency in neutralizing bacterial toxin in animal models. The purified antibody possessed the unusual property of forming a firm, opaque white gel when it was formulated at concentrations >30 mg/mL and the temperature was <6°C. Gel formation was reversible with temperature. Gelation was affected by salt concentration or pH, suggesting an electrostatic interaction between IgG monomers. A comparison of the C4 amino acid sequences to consensus germline sequences revealed differences in framework regions. A C4 variant in which the framework sequence was restored to the consensus germline sequence did not gel at 100 mg/mL at temperatures as low as 1°C. Additional genetic analysis was used to predict the key residue(s) involved in the gelation. Strikingly, a single substitution in the native antibody, replacing heavy chain glutamate 23 with lysine (E23K), was sufficient to prevent gelation. These results indicate that the framework region is involved in intermolecular interactions. The temperature dependence of gelation may be related to conformational changes near glutamate 23 or the regions it interacts with. Molecular engineering of the framework can be an effective approach to resolve the solubility issues of therapeutic antibodies.

Murine alveolar macrophages limit replication of vaccinia virus.

Because of concerns about zoonotic transmission of monkeypox to humans and the bioterrorism threat posed by orthopoxviruses, there is renewed interest in probing cellular and molecular mechanisms of host defense to these pathogens. In particular, it is essential to understand viral-host interactions in the respiratory tract, which is the route of infection for smallpox and a likely route of transmission for monkeypox. In this study, we analyze functions of alveolar macrophages in poxvirus infection, using a recombinant vaccinia virus expressing firefly luciferase to quantify infection in mice and cell culture. Depletion of alveolar macrophages with liposomal clodronate worsens the overall severity of infection in mice, including greater replication and systemic dissemination of vaccinia as determined by bioluminescence imaging. Absence of alveolar macrophages increases total numbers of granulocytes and granulocytes/monocyte progenitor cells in the lungs during vaccinia infection, indicating that protective effects of alveolar macrophages may be mediated in part by reducing the host inflammation. Alveolar macrophages also limit vaccinia infection in respiratory epithelium, as shown by a co-culture model of cell lines derived from alveolar macrophages and lung epithelium. Collectively, these data demonstrate that alveolar macrophages are key determinants of host defense against local and systemic infection with poxviruses.