The optimal second-line therapy for older adults with type 2 diabetes mellitus: protocol for a systematic review and network meta-analysis using individual participant data (IPD).

BACKGROUND: Due to increasing life expectancy, almost half of people with type 2 diabetes are aged 65 years or over worldwide. When metformin alone does not control blood sugar, the choice of which second-line therapy to prescribe next is not clear from currently available evidence. The existence of frailty and comorbidities in older adults further increases the complexity of medical decision-making. As only a relatively small proportion of trials report results separately for older adults, the relative efficacy and safety of second-line therapies in older adults with type 2 diabetes mellitus are unknown and require further investigation. This individual participant data (IPD) network meta-analysis evaluates the relative efficacy and safety of second-line therapies on their own or in combination in older adults with type 2 diabetes mellitus. METHODS: All relevant published and unpublished trials will be identified. Studies published prior to 2015 will be identified from two previous comprehensive aggregate data network meta-analyses. Searches will be conducted in CENTRAL, MEDLINE, and EMBASE from 1st January 2015 onwards, and in clinicaltrials.gov from inception. Randomised controlled trials with at least 100 estimated older adults (≥ 65 years) receiving at least 24 weeks of intervention that assess the effects of glucose-lowering drugs on mortality, glycemia, vascular and other comorbidities outcomes, and quality of life will be eligible. The screening and data extraction process will be conducted independently by two researchers. The quality of studies will be assessed using the Cochrane risk of bias tool 2. Anonymised IPD of all eligible trials will be requested via clinical trial portals or by contacting the principal investigators or sponsors. Received data will be reanalysed where necessary to standardise outcome metrics. Network meta-analyses will be performed to determine the relative effectiveness of therapies. DISCUSSION: With the increasing number of older adults with type 2 diabetes worldwide, an IPD network meta-analysis using data from all eligible trials will provide new insights into the optimal choices of second-line antidiabetic drugs to improve patient management and reduce unnecessary adverse events and the subsequent risk of comorbidities in older adults. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021272686.

HIV Treatment Optimism Moderates the Relationship between Sexual Risk Behavior and HIV Risk Perception among Urban HIV-negative Gay, Bisexual, and Other Men who have Sex With Men.

Using baseline data of the Engage Cohort Study, a Canadian study of sexually active gay, bisexual and other men who have sex with men (GBM), we evaluated the association between sexual behavior and risk perception among HIV-negative participants and whether HIV treatment optimism moderated this relationship. Participants were recruited by respondent-driven-sampling (RDS). We defined high-risk sexual behavior in the past six months as any condomless anal sex with a casual partner (i.e. not the participant's main partner) with either unknown HIV-status where neither used pre-exposure prophylaxis or with a partner living with HIV having detectable/unknown viral load. We assessed HIV treatment optimism-skepticism using a 12-item scale. RDS-II-weighted adjusted logistic regression models examined associations with risk perception measured by the question "How would you assess your current risk of getting HIV?" (response options were on a 6-point Likert-scale ranging from "very unlikely" to "very likely", dichotomized into "No Perceived Risk" (very unlikely/unlikely) and "Perceived Risk" (somewhat likely/likely/very likely/I think I already have HIV). Of 1961 participants, engagement in high-risk sexual behavior was reported by 155 (17.0%), 62 (12.4%), 128 (17.2%) of participants in Montréal, Toronto, and Vancouver, respectively. High-risk sexual behavior increased the odds of perceived HIV risk (pooled adjusted odds ratio = 2.9, 95%CI = 2.2-3.8). HIV treatment optimism-skepticism scores moderated the relationship: for GBM engaging in high-risk sexual behavior, higher HIV treatment optimism-skepticism scores increased perceived HIV risk. Promoting awareness around advances related to HIV prevention and treatment is important for appropriate risk assessment and for increased engagement in prevention interventions.

RESUMEN: Evaluamos la asociación entre el comportamiento sexual y la percepción de riesgo entre los participantes VIH negativos y si el optimismo sobre el tratamiento del VIH moderó esta asociación. Definimos comportamiento sexual de alto riesgo en los últimos seis meses como cualquier sexo anal sin condón con una pareja casual con un estado de VIH desconocido donde ninguno utilizó profilaxis previa a la exposición o con una pareja que vive con el VIH y que tiene una carga viral detectable/desconocida. Se evaluó el optimismo sobre el tratamiento del VIH mediante una escala de 12 ítems. Los modelos de regresión logística ajustados examinaron las asociaciones con la percepción del riesgo ("Riesgo no percibido" vs. "Riesgo percibido"). De 1961 participantes, 155 (17,0%), 62 (12,4%), 128 (17,2%) de los participantes en Montreal, Toronto y Vancouver, informaron comportamiento sexual de alto riesgo. El comportamiento sexual de alto riesgo se mostró asociado con riesgo percibido. El optimismo sobre el tratamiento modero la asociación. Promover la conciencia sobre los avances relacionados con la prevención y el tratamiento del VIH es importante para una evaluación adecuada de los riesgos y una mayor participación en las intervenciones de prevención.

Mapping the landscape of histomorphological cancer phenotypes using self-supervised learning on unannotated pathology slides.

Cancer diagnosis and management depend upon the extraction of complex information from microscopy images by pathologists, which requires time-consuming expert interpretation prone to human bias. Supervised deep learning approaches have proven powerful, but are inherently limited by the cost and quality of annotations used for training. Therefore, we present Histomorphological Phenotype Learning, a self-supervised methodology requiring no labels and operating via the automatic discovery of discriminatory features in image tiles. Tiles are grouped into morphologically similar clusters which constitute an atlas of histomorphological phenotypes (HP-Atlas), revealing trajectories from benign to malignant tissue via inflammatory and reactive phenotypes. These clusters have distinct features which can be identified using orthogonal methods, linking histologic, molecular and clinical phenotypes. Applied to lung cancer, we show that they align closely with patient survival, with histopathologically recognised tumor types and growth patterns, and with transcriptomic measures of immunophenotype. These properties are maintained in a multi-cancer study.

Correction: Cingulate transcranial direct current stimulation in adults with HIV.

[This corrects the article DOI: 10.1371/journal.pone.0269491.].

Alzheimer-Type Cerebral Amyloidosis in the Context of HIV Infection: Implications for a Proposed New Treatment Approach.

Reverse transcriptase inhibitors (RTIs) are currently broadly prescribed for the treatment of HIV infection but are also thought to prevent Alzheimer's disease (AD) progression by protecting against amyloidosis. Our study evaluates the hypothesis that reverse transcriptase inhibitors protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection. We compiled a case series of participants from a prospective study of the neurological consequences of HIV infection at the HIV Neurobehavioral Research Program (HNRP) who had serial neuropsychological and neurological assessments and were on RTIs. Two participants had gross and microscopic examination and immunohistochemistry of the brain at autopsy; one was assessed clinically for Alzheimer's disease by cerebrospinal fluid (CSF) analysis of phosphorylated-Tau, Total-Tau and Aß42. Additionally, a larger cohort of 250 autopsied individuals was evaluated for presence of amyloid plaques, Tau, and related pathologies. Three older, virally suppressed individuals with HIV who had long-term treatment with RTIs were included in analyses. Two cases demonstrated substantial cerebral amyloid deposition at autopsy. The third case met clinical criteria for AD based on a typical clinical course and CSF biomarker profile. In the larger cohort of autopsied individuals, the prevalence of cerebral amyloidosis among people with HIV (PWH) was greater for those on RTIs. Our study showed that long-term RTI therapy did not protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection in these patients. Given the known toxicities of RTIs, it is premature to recommend them to individuals at risk or with Alzheimer's disease who do not have HIV infection.

Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.

The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.

Deep cell phenotyping and spatial analysis of multiplexed imaging with TRACERx-PHLEX.

The growing scale and dimensionality of multiplexed imaging require reproducible and comprehensive yet user-friendly computational pipelines. TRACERx-PHLEX performs deep learning-based cell segmentation (deep-imcyto), automated cell-type annotation (TYPEx) and interpretable spatial analysis (Spatial-PHLEX) as three independent but interoperable modules. PHLEX generates single-cell identities, cell densities within tissue compartments, marker positivity calls and spatial metrics such as cellular barrier scores, along with summary graphs and spatial visualisations. PHLEX was developed using imaging mass cytometry (IMC) in the TRACERx study, validated using published Co-detection by indexing (CODEX), IMC and orthogonal data and benchmarked against state-of-the-art approaches. We evaluated its use on different tissue types, tissue fixation conditions, image sizes and antibody panels. As PHLEX is an automated and containerised Nextflow pipeline, manual assessment, programming skills or pathology expertise are not essential. PHLEX offers an end-to-end solution in a growing field of highly multiplexed data and provides clinically relevant insights.

Integrated management of cryptococcal meningitis and concurrent opportunistic infections to improve outcomes in advanced HIV disease: a randomised strategy trial.

Background: Mortality associated with HIV-associated cryptococcal meningitis remains high even in the context of clinical trials (24-45% at 10 weeks); mortality at 12-months is up to 78% in resource limited settings. Co-prevalent tuberculosis (TB) is common and preventable, and likely contributes to poor patient outcomes. Innovative strategies to increase TB preventative therapy (TPT) provision and uptake within this high-risk group are needed. Protocol: The IMPROVE trial (Integrated management of cryptococcal meningitis and concurrent opportunistic infections to improve outcomes in advanced HIV disease) is a nested open label, two arm, randomised controlled strategy trial to evaluate the safety (adverse events) and feasibility (adherence and tolerability) of two ultra-short course TPT strategies, in the context of recent diagnosis and treatment for cryptococcal meningitis. We will enrol 205 adults with HIV-associated cryptococcal meningitis from three hospitals in Uganda. Participants will be randomised to either inpatient initiation (early) or outpatient initiation (standard, week 6) of 1HP (one month of isoniazid and rifapentine). Participant follow-up is to include TB screening, 1HP pill counts and tolerability reviews on alternate weeks until week-18. The trial primary endpoint is TB-disease free 1HP treatment completion at 18-weeks, secondary endpoints: 1HP treatment completion, 1HP discontinuation, grade ≥3 adverse events and serious adverse events, drug-induced liver injury, incident active TB, 18-week survival; rifapentine, fluconazole and dolutegravir concentrations will be measured with intensive sampling in a pharmacokinetic sub-study of 15 eligible participants. Discussion: The IMPROVE trial will provide preliminary safety and feasibility data to inform 1HP TPT strategies for adults with advanced HIV disease and cryptococcal meningitis. The potential impact of demonstrating that inpatient initiation of 1HP TPT is safe and feasible amongst this high-risk subpopulation with advanced HIV disease, would be to expand the range of clinical encounters in which clinicians can feasibly provide 1HP, and therefore increase the reach of TPT as a preventative intervention. ISRCTN registration: ISRCTN18437550 (05/11/2021).

Prevalence, Determinants, and Trends in the Experience and Perpetration of Intimate Partner Violence Among a Cohort of Gay, Bisexual, and Other Men Who Have Sex with Men in Montréal, Toronto, and Vancouver, Canada (2017-2022).

Purpose: Longitudinal data on the experience and perpetration of intimate partner violence (IPV) among gay, bisexual, and other men who have sex with men (GBM) are limited. We estimated the prevalence of past 6-month (P6M) physical and/or sexual IPV (hereafter IPV) experience and perpetration, identified their determinants, and assessed temporal trends, including the impact of the coronavirus disease (COVID)-19 pandemic. Methods: We used data from the Engage Cohort Study (2017-2022) of GBM recruited using respondent-driven sampling in Montréal, Toronto, and Vancouver. Adjusted prevalence ratios (aPRs) for determinants and self-reported P6M IPV were estimated using generalized estimating equations, accounting for attrition (inverse probability of censoring weights) and relevant covariates. Longitudinal trends of IPV were also assessed. Results: Between 2017 and 2022, 1455 partnered GBM (median age 32 years, 82% gay, and 71% White) had at least one follow-up visit. At baseline, 31% of participants experienced IPV in their lifetime and 17% reported ever perpetrating IPV. During follow-up, IPV experience was more common (6%, 95% confidence interval [CI]: 5%-7%) than perpetration (4%, 95% CI: 3%-5%). Factors associated with P6M IPV experience included prior IPV experience (aPR: 2.68, 95% CI: 1.76-4.08), lower education (aPR: 2.31, 95% CI: 1.32-4.04), and substance use (injection aPR: 5.05, 95% CI: 2.54-10.05, non-injection aPR: 1.68, 95% CI: 1.00-2.82). Similar factors were associated with IPV perpetration. IPV was stable over time; periods of COVID-19 restrictions were not associated with IPV changes in this cohort. Conclusion: Prevalence of IPV was high among GBM. Determinants related to marginalization were associated with an increased risk of IPV. Interventions should address these determinants to reduce IPV and improve health.

A Multi-Sample Comparison and Rasch Analysis of the Evaluation of Children's Listening and Processing Skills Questionnaire.

OBJECTIVES: Assessing listening difficulties and associated complaints can be challenging. Often, measures of peripheral auditory functions are within normal ranges, making clinicians feel unsure about proper management strategies. The range and nature of observed or experienced difficulties might be better captured using a qualitative measure. The Evaluation of Children's Listening and Processing Skills (ECLiPS) questionnaire was designed to broadly profile the auditory and cognitive problems often present in children with listening difficulties. This 38-item questionnaire was initially standardized in British children aged 6 to 11 years, was subsequently modified for use with North-American children, and was recently translated into Flemish-Dutch. This study aimed to compare typical scores of the Flemish version with the UK and US versions, and to evaluate and compare its psychometric quality based on Rasch analysis. DESIGN: We selected 112 Flemish children aged 6 to 11 years with verified normal hearing and typical development, and asked two caregivers of every child to fill out the ECLiPS. Data from two comparator samples were analyzed, including responses for 71 North-American children and 650 British children. Typical values for ECLiPS factors and aggregates were determined as a function of age and gender, and meaningful differences across samples were analyzed. Rasch analyses were performed to evaluate whether ECLiPS response categories work as intended, and whether item scores fit a linear equal interval measurement scale that works the same way for everyone. Item and person metrics were derived, including separation and reliability indices. We investigated whether items function similarly across linguistically and culturally different samples. RESULTS: ECLiPS scores were relatively invariant to age. Girls obtained higher scores compared with boys, mainly for items related to memory and attention, and pragmatic and social skills. Across ECLiPS versions, the most pronounced differences were found for items probing social skills. With respect to its psychometric quality, ECLiPS response categories work as intended, and ECLiPS items were found to fit the Rasch measurement scale. Cultural differences in responses were noted for some items, belonging to different factors. Item separation and reliability indices generally pointed toward sufficient variation in item difficulty. In general, person separation (and reliability) metrics, quantifying the instrument's ability to distinguish between poor and strong performers (in a reproducible manner), were low. This is expected from samples of typically developing children with homogeneous and high levels of listening ability. CONCLUSIONS: Across the languages assessed here, the ECLiPS caregiver questionnaire was verified to be a psychometrically valid qualitative measure to assess listening and processing skills, which can be used to support the assessment and management of elementary school children referred with LiD.

Whole Genome Sequencing of Mycobacterium tuberculosis under routine conditions in a high-burden area of multidrug-resistant tuberculosis in Peru.

Whole Genome Sequencing (WGS) is a promising tool in the global fight against tuberculosis (TB). The aim of this study was to evaluate the use of WGS in routine conditions for detection of drug resistance markers and transmission clusters in a multidrug-resistant TB hot-spot area in Peru. For this, 140 drug-resistant Mycobacterium tuberculosis strains from Lima and Callao were prospectively selected and processed through routine (GenoType MTBDRsl and BACTEC MGIT) and WGS workflows, simultaneously. Resistance was determined in accordance with the World Health Organization mutation catalogue. Agreements between WGS and BACTEC results were calculated for rifampicin, isoniazid, pyrazinamide, moxifloxacin, levofloxacin, amikacin and capreomycin. Transmission clusters were determined using different cut-off values of Single Nucleotide Polymorphism differences. 100% (140/140) of strains had valid WGS results for 13 anti-TB drugs. However, the availability of final, definitive phenotypic BACTEC MGIT results varied by drug with 10-17% of invalid results for the seven compared drugs. The median time to obtain results of WGS for the complete set of drugs was 11.5 days, compared to 28.6-52.6 days for the routine workflow. Overall categorical agreement by WGS and BACTEC MGIT for the compared drugs was 96.5%. Kappa index was good (0.65≤k≤1.00), except for moxifloxacin, but the sensitivity and specificity values were high for all cases. 97.9% (137/140) of strains were characterized with only one sublineage (134 belonging to "lineage 4" and 3 to "lineage 2"), and 2.1% (3/140) were mixed strains presenting two different sublineages. Clustering rates of 3.6% (5/140), 17.9% (25/140) and 22.1% (31/140) were obtained for 5, 10 and 12 SNP cut-off values, respectively. In conclusion, routine WGS has a high diagnostic accuracy to detect resistance against key current anti-TB drugs, allowing results to be obtained through a single analysis and helping to cut quickly the chain of transmission of drug-resistant TB in Peru.

Social Determinants and Consequences of Pain: Towards Multilevel, Intersectional, and Life Course Perspectives.

Despite wide endorsement of a biopsychosocial framework for pain, social aspects of pain remain rarely addressed in the context of pain prevention and management. In this review, we aim to: 1) examine the broad scope of social determinants and consequences of pain and their interactions across multiple levels of organization, and 2) provide a framework synthesizing existing concepts and potential areas for future work on social aspects of pain, drawing upon socioecological, intersectional, and life course approaches. Integrating interdisciplinary theory and evidence, we outline pathways through which multilevel social factors and pain may affect each other over time. We also provide a brief summary of intrapersonal aspects of pain which are thought to operate at the interface between individuals and the social context. Progressing from micro- to macro-level factors, we illustrate how social determinants of pain can directly or indirectly contribute to pain experiences, expression, risk, prognosis, and impact across populations. We consider: a) at the interpersonal level, the roles of social comparison, social relatedness, social support, social exclusion, empathy and interpersonal conflict; b) at the group or community level, the roles of intimacy groups, task groups, social categories, and loose associations; and c) at the societal level, the roles of political, economic, and cultural systems, as well as their policies and practices. We present examples of multilevel consequences of pain across these levels and discuss opportunities to reduce the burden and inequities of pain by expanding multilevel social approaches in pain research and practice. PERSPECTIVE: Despite wide endorsement of a biopsychosocial framework for pain, social aspects of pain are often unclearly defined, hindering their use in pain prevention, management, and research. We summarize the scope of social aspects of pain and provide a framework synthesizing existing concepts and potential areas for future work.

The impact of intimate partner violence on PrEP adherence among U.S. Cisgender women at risk for HIV.

BACKGROUND: Cisgender women account for 1 in 5 new HIV infections in the United States, yet remain under-engaged in HIV prevention. Women experiencing violence face risk for HIV due to biological and behavioral mechanisms, and barriers to prevention, such as challenges to Pre-Exposure Prophylaxis for HIV Prevention (PrEP) adherence. In this analysis, we aim to characterize intimate partner violence (IPV) among cisgender heterosexual women enrolled in a PrEP demonstration project and assess the associations with PrEP adherence. METHODS: Adherence Enhancement Guided by Individualized Texting and Drug Levels (AEGiS) was a 48-week single-arm open-label study of PrEP adherence in HIV-negative cisgender women in Southern California (N = 130) offered daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). From 6/2016 to 10/2018, women completed a survey reporting HIV risk behavior and experiences of any IPV (past 90-days) and IPV sub-types (past-year, lifetime) and biological testing for HIV/STIs at baseline, and concentrations of tenofovir-diphosphate (TFV-DP) in dried blood spots at weeks 4, 12, 24, 36, and 48. Outcomes were TFV-DP concentrations consistent with ≥ 4 or ≥ 6 doses/week at one or multiple visits. Multivariable logistic regression models were conducted to examine associations. RESULTS: Past-90-day IPV was reported by 34.4% of participants, and past-year and lifetime subtypes reported by 11.5-41.5%, and 21.5-52.3%, respectively. Women who engaged in sex work and Black women were significantly more likely to report IPV than others. Lifetime physical IPV was negatively associated with adherence at ≥ 4 doses/week at ≥ 3 of 5 visits, while other relationships with any IPV and IPV sub-types were variable. CONCLUSION: IPV is an indication for PrEP and important indicator of HIV risk; our findings suggest that physical IPV may also negatively impact long-term PrEP adherence. CLINICAL TRIALS REGISTRATION: NCT02584140 (ClinicalTrials.gov), registered 15/10/2015.

Hippo-YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass.

Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP/TAZ signalling in adipocytes by deletion of the upstream regulators Lats1 and Lats2 results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP/TAZ-TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo-YAP/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription.

Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models.

Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.

Feeding Ration Impacts Larval Pimephales Promelas 7-Day Subchronic Growth Endpoint: Case Study with Perfluorooctanesulfonic Acid.

The larval fathead minnow, Pimephales promelas, 7-day subchronic survival and growth standard toxicity test method is commonly used for research and regulatory testing of effluents and compounds, including emerging contaminants such as Perfluorooctanesulfonic Acid (PFOS). Existing feeding guidelines for testing are described in multiple methods but are open to interpretation. The current study sought to determine the impact of feeding ration on P. promelas survival and biomass during a subchronic exposure to PFOS. The study was conducted in two phases: (1) a control experiment to determine the most significant feeding ration factors that maximize biomass, with consideration to laboratory logistics, and (2) application of down-selected feeding rations in a PFOS exposure to determine toxicity reference values. The control optimization study supported that feeding ration and feeding frequency were significant factors in fish biomass. In the subsequent PFOS study, fish were fed a high or low ration of Artemia twice daily, while exposed to 0.3 to 3.4 mg/L PFOS. Fish fed a high ration of Artemia had significantly (p < 0.05) greater biomass than fish fed a low ration in all exposure concentrations except 3.4 mg/L, where survival was low in both treatments. The feeding ration was not a significant factor on the survival endpoint for either treatment, but the PFOS concentration was (p < 0.0001) (high ration LC50 = 2.44 mg/L; low ration LC50 = 2.25 mg/L). These findings contribute to a better understanding of the impact feeding ration has in toxicity assessments and downstream regulatory decisions.

Childhood Listening and Associated Cognitive Difficulties Persist Into Adolescence.

OBJECTIVE: Listening difficulty (LiD) refers to the challenges individuals face when trying to hear and comprehend speech and other sounds. LiD can arise from various sources, such as hearing sensitivity, language comprehension, cognitive function, or auditory processing. Although some children with LiD have hearing loss, many have clinically normal audiometric thresholds. To determine the impact of hearing and cognitive factors on LiD in children with a clinically normal audiogram, we conducted a longitudinal study. The Evaluation of Children's Listening & Processing Skills (ECLiPS), a validated and standardized caregiver evaluation tool, was used to group participants as either LiD or typically developing (TD). Our previous study aimed to characterize LiD in 6- to 13-year-old children during the project's baseline, cross-sectional phase. We found that children with LiD needed a higher signal-to-noise ratio during speech-in-speech tests and scored lower on all assessed components of the NIH Cognition Toolbox than TD children. The primary goal of this study was to examine if the differences between LiD and TD groups are temporary or enduring throughout childhood. DESIGN: This longitudinal study had three data collection waves for children with LiD and TD aged 6 to 13 years at Wave 1, followed by assessments at 2-year (Wave 2) and 4-year (Wave 3) intervals. Primary analysis focused on data from Waves 1 and 2. Secondary analysis encompassed all three waves despite high attrition at Wave 3. Caregivers completed the ECLiPS, while participants completed the Listening in Spatialized Noise-Sentences (LiSN-S) test and the NIH-Toolbox Cognition Battery during each wave. The analysis consisted of (1) examining longitudinal differences between TD and LiD groups in demographics, listening, auditory, and cognitive function; (2) identifying functional domains contributing to LiD; and (3) test-retest reliability of measures across waves. Mixed-effect models were employed to analyze longitudinal data. RESULTS: The study enrolled 169 participants, with 147, 100, and 31 children completing the required testing during Waves 1, 2, and 3, respectively. The mean ages at these waves were 9.5, 12.0, and 14.0 years. On average, children with LiD consistently underperformed TD children in auditory and cognitive tasks across all waves. Maternal education, auditory, and cognitive abilities independently predicted caregiver-reported listening skills. Significant correlations between Waves 1 and 2 confirmed high, long-term reliability. Secondary analysis of Wave 3 was consistent with the primary analyses of Waves 1 and 2, reinforcing the enduring nature of listening difficulties. CONCLUSION: Children with LiD and clinically normal audiograms experience persistent auditory, listening, and cognitive challenges through at least adolescence. The degree of LiD can be independently predicted by maternal education, cognitive processing, and spatial listening skills. This study underscores the importance of early detection and intervention for childhood LiD and highlights the role of socioeconomic factors as contributors to these challenges.

Development and impact of a tailored eHealth resource on fibromyalgia patient's self-management and self-efficacy: A mixed methods approach.

Aim: To develop an eHealth resource to support fibromyalgia patients and explore it for usability and impact on their self-management and self-efficacy. Background: Fibromyalgia is a complex, non-progressive chronic condition characterised by a bewildering array of symptoms for patients to self-manage. International guidelines recommend patients receive illness-specific information once diagnosed to promote self-management and improve health-related quality of life. Design: A 3-phase mixed methods exploratory sequential design. Methods: Qualitative interviews explored the information and self-management needs of fibromyalgia patients attending a large tertiary hospital in Dublin. Identified themes together with an extensive review of the literature of interventions proven to be impactful by patients with fibromyalgia were utilised in the design and development of the eHealth resource. The resource was tested for usability and impact using pre and post-intervention outcomes measures. Results: Patient interviews highlighted a lack of easy accessible evidenced information to support self-management implicating the urgent need for a practical solution through development of a tailored eHealth resource. Six themes emerged for inclusion; illness knowledge, primary symptoms, treatment options, self-management strategies, practical support and reliable resources. Forty-five patients who tested the site for usability and impact demonstrated a statistically significant improvement in self-efficacy after 4 weeks access with a medium positive effect size. Patients with the most severe fibromyalgia impact scores pre-intervention demonstrated the most improvement after 4 weeks. Patients gave the resource a System Usability Score A rating, highly recommending it for fellow patients diagnosed with fibromyalgia. Conclusions: The study demonstrated how the development of a novel eHealth resource positively impacted fibromyalgia patients' self-efficacy to cope with this debilitating condition. Impact: This study suggests that access to eHealth can positively impact patients self-efficacy, has the potential to be a template for eHealth development in other chronic conditions, supporting advanced nurse practitioners working in chronic disease management.

High-entropy alloy screening for halide perovskites.

As the concept of high-entropy alloying (HEA) extends beyond metals, new materials screening methods are needed. Halide perovskites (HP) are a prime case study because greater stability is needed for photovoltaics applications, and there are 322 experimentally observed HP end-members, which leads to more than 1057 potential alloys. We screen HEAHP by first calculating the configurational entropy of 106 equimolar alloys with experimentally observed end-members. To estimate enthalpy at low computational cost, we turn to the delta-lattice parameter approach, a well-known method for predicting III-V alloy miscibility. To generalize the approach for non-cubic crystals, we introduce the parameter of unit cell volume coefficient of variation (UCV), which does a good job of predicting the experimental HP miscibility data. We use plots of entropy stabilization versus UCV to screen promising alloys and identify 102 HEAHP of interest.

Access to care and impact on HIV treatment interruptions during the COVID-19 pandemic among people living with HIV in British Columbia.

INTRODUCTION: The COVID-19 pandemic has changed healthcare service delivery. We examined the overall impact of COVID-19 on people living with HIV in British Columbia (BC), Canada, with a special focus on the potential impact of COVID-19 on antiretroviral treatment interruptions (TIs). METHODS: Purposive sampling was used to enrol people living with HIV aged ≥19 years across BC into the STOP HIV/AIDS Program Evaluation study between January 2016 and September 2018. Participants completed surveys at baseline enrolment and 18 and 36 months later. Additional COVID-19 questions were added to the survey in October 2020. TIs were defined as >60 days late for antiretroviral therapy (ART) refill using data from the BC HIV Drug Treatment Program. Generalized linear mixed models were used to examine trends in TIs over time and associations with reported health service access. RESULTS: Of 581 participants, 6.1%-7.7% experienced a TI during each 6-month period between March 2019 and August 2021. The frequency of TIs did not statistically increase during the COVID-19 epidemic. Among the 188 participants who completed the COVID-19 questionnaire, 32.8% reported difficulty accessing healthcare during COVID-19, 9.7% reported avoiding continuing a healthcare service due to COVID-19-related concerns, and 74.6% reported using virtual healthcare services since March 2020. In multivariable analysis, the odds of a TI in any 6-month period were not significantly different from March to August 2019. None of the reported challenges to healthcare services were associated with TIs. CONCLUSIONS: Although some participants reported challenges to accessing services or avoidance of services due to COVID-19, TIs were not more likely during COVID-19 than before.