Clustering Individuals Based on Similarity in Idiographic Factor Loading Patterns.

Idiographic measurement models such as p-technique and dynamic factor analysis (DFA) assess latent constructs at the individual level. These person-specific methods may provide more accurate models than models obtained from aggregated data when individuals are heterogeneous in their processes. Developing clustering methods for the grouping of individuals with similar measurement models would enable researchers to identify if measurement model subtypes exist across individuals as well as assess if the different models correspond to the same latent concept or not. In this paper, methods for clustering individuals based on similarity in measurement model loadings obtained from time series data are proposed. We review literature on idiographic factor modeling and measurement invariance, as well as clustering for time series analysis. Through two studies, we explore the utility and effectiveness of these measures. In Study 1, a simulation study is conducted, demonstrating the recovery of groups generated to have differing factor loadings using the proposed clustering method. In Study 2, an extension of Study 1 to DFA is presented with a simulation study. Overall, we found good recovery of simulated clusters and provide an example demonstrating the method with empirical data.

Adult Inception of Ketogenic Diet Therapy Increases Sleep during the Dark Cycle in C57BL/6J Wild Type and Fragile X Mice.

Sleep problems are a significant phenotype in children with fragile X syndrome. Our prior work assessed sleep-wake cycles in Fmr1KO male mice and wild type (WT) littermate controls in response to ketogenic diet therapy where mice were treated from weaning (postnatal day 18) through study completion (5-6 months of age). A potentially confounding issue with commencing treatment during an active period of growth is the significant reduction in weight gain in response to the ketogenic diet. The aim here was to employ sleep electroencephalography (EEG) to assess sleep-wake cycles in mice in response to the Fmr1 genotype and a ketogenic diet, with treatment starting at postnatal day 95. EEG results were compared with prior sleep outcomes to determine if the later intervention was efficacious, as well as with published rest-activity patterns to determine if actigraphy is a viable surrogate for sleep EEG. The data replicated findings that Fmr1KO mice exhibit sleep-wake patterns similar to wild type littermates during the dark cycle when maintained on a control purified-ingredient diet but revealed a genotype-specific difference during hours 4-6 of the light cycle of the increased wake (decreased sleep and NREM) state in Fmr1KO mice. Treatment with a high-fat, low-carbohydrate ketogenic diet increased the percentage of NREM sleep in both wild type and Fmr1KO mice during the dark cycle. Differences in sleep microstructure (length of wake bouts) supported the altered sleep states in response to ketogenic diet. Commencing ketogenic diet treatment in adulthood resulted in a 15% (WT) and 8.6% (Fmr1KO) decrease in body weight after 28 days of treatment, but not the severe reduction in body weight associated with starting treatment at weaning. We conclude that the lack of evidence for improved sleep during the light cycle (mouse sleep time) in Fmr1KO mice in response to ketogenic diet therapy in two studies suggests that ketogenic diet may not be beneficial in treating sleep problems associated with fragile X and that actigraphy is not a reliable surrogate for sleep EEG in mice.

Idiopathic pulmonary haemosiderosis.

In this paper, we report the case of a boy in early childhood who presented with iron-deficiency anaemia, initially thought to be nutritional, who had a subsequent diagnosis of idiopathic pulmonary haemosiderosis (IPH). This is a slowly progressive and life-threatening disorder and is of paramount importance that this is identified early and treated appropriately. His first chest CT was not typical for IPH, and this appearance should be highlighted (small cystic changes alone initially). He also had focal disease, which allowed us to make the diagnosis using CT-guided biopsy. During his treatment, he experienced an uncommon side effect to a commonly prescribed medication (bradycardia with methylprednisolone). Since starting azathioprine as a steroid-sparing agent, he has been doing well.

Preventing tuberculosis with community-based care in an HIV-endemic setting: a modelling analysis.

INTRODUCTION: Antiretroviral therapy (ART) and tuberculosis preventive treatment (TPT) both prevent tuberculosis (TB) disease and deaths among people living with HIV. Differentiated care models, including community-based care, can increase the uptake of ART and TPT to prevent TB in settings with a high burden of HIV-associated TB, particularly among men. METHODS: We developed a gender-stratified dynamic model of TB and HIV transmission and disease progression among 100,000 adults ages 15-59 in KwaZulu-Natal, South Africa. We drew model parameters from a community-based ART initiation and resupply trial in sub-Saharan Africa (Delivery Optimization for Antiretroviral Therapy, DO ART) and other scientific literature. We simulated the impacts of community-based ART and TPT care programmes during 2018-2027, assuming that community-based ART and TPT care were scaled up to similar levels as in the DO ART trial (i.e. ART coverage increasing from 49% to 82% among men and from 69% to 83% among women) and sustained for 10 years. We projected the number of TB cases, deaths and disability-adjusted life years (DALYs) averted relative to standard, clinic-based care. We calculated programme costs and incremental cost-effectiveness ratios from the provider perspective. RESULTS: If community-based ART care could be implemented with similar effectiveness to the DO ART trial, increased ART coverage could reduce TB incidence by 27.0% (range 21.3%-34.1%) and TB mortality by 34.6% (range 24.8%-42.2%) after 10 years. Increasing both ART and TPT uptake through community-based ART with TPT care could reduce TB incidence by 29.7% (range 23.9%-36.0%) and TB mortality by 36.0% (range 26.9%-43.8%). Community-based ART with TPT care reduced gender disparities in TB mortality rates, with a projected 54 more deaths annually among men than women (range 11-103) after 10 years of community-based care versus 109 (range 41-182) in standard care. Over 10 years, the mean cost per DALY averted by community-based ART with TPT care was $846 USD (range $709-$1012). CONCLUSIONS: By substantially increasing coverage of ART and TPT, community-based care for people living with HIV could reduce TB incidence and mortality in settings with high burdens of HIV-associated TB and reduce TB gender disparities.

Synthesis, Structure, and Properties of CuBiSeCl2: A Chalcohalide Material with Low Thermal Conductivity.

Mixed anion halide-chalcogenide materials have recently attracted attention for a variety of applications, owing to their desirable optoelectronic properties. We report the synthesis of a previously unreported mixed-metal chalcohalide material, CuBiSeCl2 (Pnma), accessed through a simple, low-temperature solid-state route. The physical structure is characterized through single-crystal X-ray diffraction and reveals significant Cu displacement within the CuSe2Cl4 octahedra. The electronic structure of CuBiSeCl2 is investigated computationally, which indicates highly anisotropic charge carrier effective masses, and by experimental verification using X-ray photoelectron spectroscopy, which reveals a valence band dominated by Cu orbitals. The band gap is measured to be 1.33(2) eV, a suitable value for solar absorption applications. The electronic and thermal properties, including resistivity, Seebeck coefficient, thermal conductivity, and heat capacity, are also measured, and it is found that CuBiSeCl2 exhibits a low room temperature thermal conductivity of 0.27(4) W K-1 m-1, realized through modifications to the phonon landscape through increased bonding anisotropy.

Enhanced cervical cancer and HIV interventions reduce the disproportionate burden of cervical cancer cases among women living with HIV: A modeling analysis.

INTRODUCTION: Women living with HIV experience heightened risk of cervical cancer, and over 50% of cases in Southern Africa are attributed to HIV co-infection. Cervical cancer interventions tailored by HIV status delivered with HIV antiretroviral therapy (ART) for treatment can decrease cancer incidence, but impact on HIV-related disparities remains understudied. METHODS: Using a dynamic model calibrated to KwaZulu-Natal, South Africa, we projected HIV prevalence, cervical cancer incidence, and proportion of cancer cases among women living with HIV between 2021-2071. Relative to the status quo of moderate intervention coverage, we modeled three additive scenarios: 1) ART scale-up only; 2) expanded human papillomavirus (HPV) vaccination, screening, and treatment; and 3) catch-up HPV vaccination and enhanced screening for women living with HIV. RESULTS: Under the status quo, HIV prevalence among women aged 15+ decreased from a median of 35% [Uncertainty Range (UR): 26-42%] in 2021 to 25% [19-34%] in 2071. The proportion of cervical cancer cases that were women living with HIV declined from 73% [63-86%] to 58% [47-74%], but incidence remained 4.3-fold [3.3-5.7] that of women without HIV. ART scale-up reduced HIV prevalence in 2071, but increased the incidence rate ratio to 5.2 [3.7-7.3]. Disparities remained after expanding cancer interventions for all women (incidence rate ratio: 4.8 [3.6-7.6]), while additional catch-up HPV vaccination and screening for women living with HIV decreased the incidence rate ratio to 2.7 [1.9-3.4] in 2071. CONCLUSIONS: Tailored cervical cancer interventions for women living with HIV can counteract rising cancer incidence incurred by extended life expectancy on ART and reduce disparate cancer burden.

Behavioral trade-offs and multitasking by elk in relation to predation risk from Mexican gray wolves.

Predator non-consumptive effects (NCE) can alter prey foraging time and habitat use, potentially reducing fitness. Prey can mitigate NCEs by increasing vigilance, chewing-vigilance synchronization, and spatiotemporal avoidance of predators. We quantified the relationship between Mexican wolf (Canis lupus baileyi) predation risk and elk (Cervus canadensis) behavior. We conducted behavioral observations on adult female elk and developed predation risk indices using GPS collar data from Mexican wolves, locations of elk killed by wolves, and landscape covariates. We compared a priori models to determine the best predictors of adult female behavior and multitasking. Metrics that quantified both spatial and temporal predation risk were the most predictive. Vigilance was positively associated with increased predation risk. The effect of predation risk on foraging and resting differed across diurnal periods. During midday when wolf activity was lower, the probability of foraging increased while resting decreased in high-risk areas. During crepuscular periods when elk and wolves were most active, increased predation risk was associated with increased vigilance and slight decreases in foraging. Our results suggest elk are temporally avoiding predation risk from Mexican wolves by trading resting for foraging, a trade-off often not evaluated in behavioral studies. Probability of multitasking depended on canopy openness and an interaction between maternal period and predation risk; multitasking decreased prior to parturition and increased post parturition in high-risk areas. Openness was inversely related to multitasking. These results suggest adult female elk are altering the type of vigilance used depending on resource availability/quality, current energetic needs, and predation risk. Our results highlight potentially important, but often-excluded behaviors and trade-offs prey species may use to reduce the indirect effects of predation and contribute additional context to our understanding of predator-prey dynamics.

Emotional Freedom Techniques (EFT) Tapping for Pediatric Emergency Department Staff During the COVID-19 Pandemic: Evaluation of a Pilot Intervention.

Objective: Emergency-department (ED) staff may experience psychologic distress due to the stressful nature of their work. The COVID-19 pandemic exacerbated this distress. Emotional Freedom Techniques (EFT) tapping, a somatic psychophysiologic intervention combining vibratory acupressure with elements of cognitive-behavioral and exposure therapies, can reduce psychologic distress. This study tested the short-term effect of 10-minute EFT tapping on the psychologic distress of pediatric ED staff responding to COVID-19. Materials and Methods: During the COVID-19 pandemic, diverse staff in the pediatric ED of a New York City teaching hospital participated in this single-group study. A licensed creative arts therapist led participants in 10-minute EFT tapping sessions. A self-report questionnaire with 7 items based on the Trauma Exposure Response framework was administered immediately pre- and postintervention. Standardized mean differences between both timepoints were calculated. Results: There were statistically significant reductions for 6 of the 7 items studied, including stress (3.32-2.14), obsessive and intrusive thoughts (2.50-1.85), feelings of pressure (3.20-2.17), loneliness (1.84-1.44), and emotional and physical pain (2.28-1.70); all P < 0.001. No significant changes in professional satisfaction were reported following the intervention. Conclusions: Despite the limitations of a single-arm study design, a 10-minute brief EFT tapping session was a promising way to reduce short-term psychologic distress in pediatric ED health care workers. Future studies, including rigorous randomized controlled trials, are needed to evaluate the effectiveness of brief EFT tapping interventions in other settings.

Exposure to Sublethal Concentrations of Lead (Pb) Affects Ecologically Relevant Behaviors in House Sparrows (Passer domesticus).

Global contamination of environments with lead (Pb) poses threats to many ecosystems and populations. While exposure to Pb is toxic at high concentrations, recent literature has shown that lower concentrations can also cause sublethal, deleterious effects. However, there remains relatively little causal investigation of how exposure to lower concentrations of environmental Pb affects ecologically important behaviors. Behaviors often represent first-line responses of an organism and its internal physiological, molecular, and genetic responses to a changing environment. Hence, better understanding how behaviors are influenced by pollutants such as Pb generates crucial information on how species are coping with the effects of pollution more broadly. To better understand the effects of sublethal Pb on behavior, we chronically exposed adult wild-caught, captive house sparrows (Passer domesticus) to Pb-exposed drinking water and quantified a suite of behavioral outcomes: takeoff flight performance, activity in a novel environment, and in-hand struggling and breathing rate while being handled by an experimenter. Compared to controls (un-exposed drinking water), sparrows exposed to environmentally relevant concentrations of Pb exhibited decreases in takeoff flight performance and reduced movements in a novel environment following 9-10 weeks of exposure. We interpret this suite of results to be consistent with Pb influencing fundamental neuro-muscular abilities, making it more difficult for exposed birds to mount faster movements and activities. It is likely that suppression of takeoff flight and reduced movements would increase the predation risk of similar birds in the wild; hence, we also conclude that the effects we observed could influence fitness outcomes for individuals and populations altering ecological interactions within more naturalistic settings.

Alcohol Withdrawal Severity Measures for Identifying Patients Requiring High-Intensity Care.

OBJECTIVES: Alcohol withdrawal syndrome (AWS) may progress to require high-intensity care. Approaches to identify hospitalized patients with AWS who received higher level of care have not been previously examined. This study aimed to examine the utility of Clinical Institute Withdrawal Assessment Alcohol Revised (CIWA-Ar) for alcohol scale scores and medication doses for alcohol withdrawal management in identifying patients who received high-intensity care. DESIGN: A multicenter observational cohort study of hospitalized adults with alcohol withdrawal. SETTING: University of Chicago Medical Center and University of Wisconsin Hospital. PATIENTS: Inpatient encounters between November 2008 and February 2022 with a CIWA-Ar score greater than 0 and benzodiazepine or barbiturate administered within the first 24 hours. The primary composite outcome was patients who progressed to high-intensity care (intermediate care or ICU). INTERVENTIONS: None. MAIN RESULTS: Among the 8742 patients included in the study, 37.5% (n = 3280) progressed to high-intensity care. The odds ratio for the composite outcome increased above 1.0 when the CIWA-Ar score was 24. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) at this threshold were 0.12 (95% CI, 0.11-0.13), 0.95 (95% CI, 0.94-0.95), 0.58 (95% CI, 0.54-0.61), and 0.64 (95% CI, 0.63-0.65), respectively. The OR increased above 1.0 at a 24-hour lorazepam milligram equivalent dose cutoff of 15 mg. The sensitivity, specificity, PPV, and NPV at this threshold were 0.16 (95% CI, 0.14-0.17), 0.96 (95% CI, 0.95-0.96), 0.68 (95% CI, 0.65-0.72), and 0.65 (95% CI, 0.64-0.66), respectively. CONCLUSIONS: Neither CIWA-Ar scores nor medication dose cutoff points were effective measures for identifying patients with alcohol withdrawal who received high-intensity care. Research studies for examining outcomes in patients who deteriorate with AWS will require better methods for cohort identification.

α-catenin middle- and actin-binding domain unfolding mutants differentially impact epithelial strength and sheet migration.

α-catenin (α-cat) displays force-dependent unfolding and binding to actin filaments through direct and indirect means, but features of adherens junction structure and function most vulnerable to loss of these allosteric mechanisms have not been directly compared. By reconstituting an α-cat F-actin-binding domain unfolding mutant known to exhibit enhanced binding to actin (α-cat-H0-FABD+) into α-cat knockout Madin Darby Canine Kidney (MDCK) cells, we show that partial loss of the α-cat catch bond mechanism (via an altered H0 α-helix) leads to stronger epithelial sheet integrity with greater colocalization between the α-cat-H0-FABD+ mutant and actin. α-cat-H0-FABD+ -expressing cells are less efficient at closing scratch-wounds, suggesting reduced capacity for more dynamic cell-cell coordination. Evidence that α-cat-H0-FABD+ is equally accessible to the conformationally sensitive α18 antibody epitope as WT α-cat and shows similar vinculin recruitment suggests this mutant engages lower tension cortical actin networks, as its M-domain is not persistently open. Conversely, α-cat-M-domain salt-bridge mutants with persistent recruitment of vinculin and phosphorylated myosin light chain show only intermediate monolayer adhesive strengths, but display less directionally coordinated and thereby slower migration speeds during wound-repair. These data show α-cat M- and FABD-unfolding mutants differentially impact cell-cell cohesion and migration properties, and suggest signals favoring α-cat-cortical actin interaction without persistent M-domain opening may improve epithelial monolayer strength through enhanced coupling to lower tension actin networks.

Accessing Mg-Ion Storage in V2PS10 via Combined Cationic-Anionic Redox with Selective Bond Cleavage.

Magnesium batteries attract interest as alternative energy-storage devices because of elemental abundance and potential for high energy density. Development is limited by the absence of suitable cathodes, associated with poor diffusion kinetics resulting from strong interactions between Mg2+ and the host structure. V2PS10 is reported as a positive electrode material for rechargeable magnesium batteries. Cyclable capacity of 100 mAh g-1 is achieved with fast Mg2+ diffusion of 7.2 × ${\times }$ 10-11-4 × ${\times }$ 10-14 cm2 s-1. The fast insertion mechanism results from combined cationic redox on the V site and anionic redox on the (S2)2- site; enabled by reversible cleavage of S-S bonds, identified by X-ray photoelectron and X-ray absorption spectroscopy. Detailed structural characterisation with maximum entropy method analysis, supported by density functional theory and projected density of states analysis, reveals that the sulphur species involved in anion redox are not connected to the transition metal centres, spatially separating the two redox processes. This facilitates fast and reversible Mg insertion in which the nature of the redox process depends on the cation insertion site, creating a synergy between the occupancy of specific Mg sites and the location of the electrons transferred.

Effects of Soy Protein Isolate on Fragile X Phenotypes in Mice.

Obesity is a pediatric epidemic that is more prevalent in children with developmental disabilities. We hypothesize that soy protein-based diets increase weight gain and alter neurobehavioral outcomes. Our objective herein was to test matched casein- and soy protein-based purified ingredient diets in a mouse model of fragile X syndrome, Fmr1KO mice. The experimental methods included assessment of growth; 24-7 activity levels; motor coordination; learning and memory; blood-based amino acid, phytoestrogen and glucose levels; and organ weights. The primary outcome measure was body weight. We find increased body weight in male Fmr1KO from postnatal day 6 (P6) to P224, male wild type (WT) from P32-P39, female Fmr1KO from P6-P18 and P168-P224, and female Fmr1HET from P9-P18 as a function of soy. Activity at the beginning of the light and dark cycles increased in female Fmr1HET and Fmr1KO mice fed soy. We did not find significant differences in rotarod or passive avoidance behavior as a function of genotype or diet. Several blood-based amino acids and phytoestrogens were significantly altered in response to soy. Liver weight was increased in WT and adipose tissue in Fmr1KO mice fed soy. Activity levels at the beginning of the light cycle and testes weight were greater in Fmr1KO versus WT males irrespective of diet. DEXA analysis at 8-months-old indicated increased fat mass and total body area in Fmr1KO females and lean mass and bone mineral density in Fmr1KO males fed soy. Overall, dietary consumption of soy protein isolate by C57BL/6J mice caused increased growth, which could be attributed to increased lean mass in males and fat mass in females. There were sex-specific differences with more pronounced effects in Fmr1KO versus WT and in males versus females.

On-Tissue Spatial Proteomics Integrating MALDI-MS Imaging with Shotgun Proteomics Reveals Soy Consumption-Induced Protein Changes in a Fragile X Syndrome Mouse Model.

Fragile X syndrome (FXS), the leading cause of inherited intellectual disability and autism, is caused by the transcriptional silencing of the FMR1 gene, which encodes the fragile X messenger ribonucleoprotein (FMRP). FMRP interacts with numerous brain mRNAs that are involved in synaptic plasticity and implicated in autism spectrum disorders. Our published studies indicate that single-source, soy-based diets are associated with increased seizures and autism. Thus, there is an acute need for an unbiased protein marker identification in FXS in response to soy consumption. Herein, we present a spatial proteomics approach integrating mass spectrometry imaging with label-free proteomics in the FXS mouse model to map the spatial distribution and quantify levels of proteins in the hippocampus and hypothalamus brain regions. In total, 1250 unique peptides were spatially resolved, demonstrating the diverse array of peptidomes present in the tissue slices and the broad coverage of the strategy. A group of proteins that are known to be involved in glycolysis, synaptic transmission, and coexpression network analysis suggest a significant association between soy proteins and metabolic and synaptic processes in the Fmr1KO brain. Ultimately, this spatial proteomics work represents a crucial step toward identifying potential candidate protein markers and novel therapeutic targets for FXS.

Toward an understanding of the role of the exposome on fragile X phenotypes.

Fragile X syndrome (FXS) is the leading known monogenetic cause of autism with an estimated 21-50% of FXS individuals meeting autism diagnostic criteria. A critical gap in medical care for persons with autism is an understanding of how environmental exposures and gene-environment interactions affect disease outcomes. Our research indicates more severe neurological and metabolic outcomes (seizures, autism, increased body weight) in mouse and human models of autism spectrum disorders (ASD) as a function of diet. Thus, early-life exposure to chemicals in the diet could cause or exacerbate disease outcomes. Herein, we review the effects of potential dietary toxins, i.e., soy phytoestrogens, glyphosate, and polychlorinated biphenyls (PCB) in FXS and other autism models. The rationale is that potentially toxic chemicals in the diet, particularly infant formula, could contribute to the development and/or severity of ASD and that further study in this area has potential to improve ASD outcomes through dietary modification.

Alveolar epithelial regeneration in the aging lung.

Advancing age is the most important risk factor for the development of and mortality from acute and chronic lung diseases, including pneumonia, chronic obstructive pulmonary disease, and pulmonary fibrosis. This risk was manifest during the COVID-19 pandemic, when elderly people were disproportionately affected and died from SARS-CoV-2 pneumonia. However, the recent pandemic also provided lessons on lung resilience. An overwhelming majority of patients with SARS-CoV-2 pneumonia, even those with severe disease, recovered with near-complete restoration of lung architecture and function. These observations are inconsistent with historic views of the lung as a terminally differentiated organ incapable of regeneration. Here, we review emerging hypotheses that explain how the lung repairs itself after injury and why these mechanisms of lung repair fail in some individuals, particularly the elderly.

Ketogenic Diet Affects Sleep Architecture in C57BL/6J Wild Type and Fragile X Mice.

Nearly half of children with fragile X syndrome experience sleep problems including trouble falling asleep and frequent nighttime awakenings. The goals here were to assess sleep-wake cycles in mice in response to Fmr1 genotype and a dietary intervention that reduces hyperactivity. Electroencephalography (EEG) results were compared with published rest-activity patterns to determine if actigraphy is a viable surrogate for sleep EEG. Specifically, sleep-wake patterns in adult wild type and Fmr1KO littermate mice were recorded after EEG electrode implantation and the recordings manually scored for vigilance states. The data indicated that Fmr1KO mice exhibited sleep-wake patterns similar to wild type littermates when maintained on a control purified ingredient diet. Treatment with a high-fat, low-carbohydrate ketogenic diet increased the percentage of non-rapid eye movement (NREM) sleep in both wild type and Fmr1KO mice during the dark cycle, which corresponded to decreased activity levels. Treatment with a ketogenic diet flattened diurnal sleep periodicity in both wild type and Fmr1KO mice. Differences in several sleep microstructure outcomes (number and length of sleep and wake bouts) supported the altered sleep states in response to a ketogenic diet and were correlated with altered rest-activity cycles. While actigraphy may be a less expensive, reduced labor surrogate for sleep EEG during the dark cycle, daytime resting in mice did not correlate with EEG sleep states.

Population health impact, cost-effectiveness, and affordability of community-based HIV treatment and monitoring in South Africa: A health economics modelling study.

Community-based delivery and monitoring of antiretroviral therapy (ART) for HIV has the potential to increase viral suppression for individual- and population-level health benefits. However, the cost-effectiveness and budget impact are needed for public health policy. We used a mathematical model of HIV transmission in KwaZulu-Natal, South Africa, to estimate population prevalence, incidence, mortality, and disability-adjusted life-years (DALYs) from 2020 to 2060 for two scenarios: 1) standard clinic-based HIV care and 2) five-yearly home testing campaigns with community ART for people not reached by clinic-based care. We parameterised model scenarios using observed community-based ART efficacy. Using a health system perspective, we evaluated incremental cost-effectiveness and net health benefits using a threshold of $750/DALY averted. In a sensitivity analysis, we varied the discount rate; time horizon; costs for clinic and community ART, hospitalisation, and testing; and the proportion of the population receiving community ART. Uncertainty ranges (URs) were estimated across 25 best-fitting parameter sets. By 2060, community ART following home testing averted 27.9% (UR: 24.3-31.5) of incident HIV infections, 27.8% (26.8-28.8) of HIV-related deaths, and 18.7% (17.9-19.7) of DALYs compared to standard of care. Adolescent girls and young women aged 15-24 years experienced the greatest reduction in incident HIV (30.7%, 27.1-34.7). In the first five years (2020-2024), community ART required an additional $44.9 million (35.8-50.1) annually, representing 14.3% (11.4-16.0) of the annual HIV budget. The cost per DALY averted was $102 (85-117) for community ART compared with standard of care. Providing six-monthly refills instead of quarterly refills further increased cost-effectiveness to $78.5 per DALY averted (62.9-92.8). Cost-effectiveness was robust to sensitivity analyses. In a high-prevalence setting, scale-up of decentralised ART dispensing and monitoring can provide large population health benefits and is cost-effective in preventing death and disability due to HIV.

α-catenin mechanosensitivity as a route to cytokinesis failure through sequestration of LZTS2.

Epithelial cells can become polyploid upon tissue injury, but mechanosensitive cues that trigger this state are poorly understood. Using α-catenin (α-cat) knock-out Madin Darby Canine Kidney (MDCK) cells reconstituted with wild-type and mutant forms of α-cat as a model system, we find that an established α-cat actin-binding domain unfolding mutant designed to reduce force-sensitive binding to F-actin (α-cat-H0-FABD+) can promote cytokinesis failure, particularly along epithelial wound-fronts. Enhanced α-cat coupling to cortical actin is neither sufficient nor mitotic cell-autonomous for cytokinesis failure, but critically requires the mechanosensitive Middle-domain (M1-M2-M3) and neighboring cells. Disease relevant α-cat M-domain missense mutations known to cause a form of retinal pattern dystrophy (α-cat E307K or L436P) are associated with elevated binucleation rates via cytokinesis failure. Similar binucleation rates are seen in cells expressing an α-cat salt-bridge destabilizing mutant (R551A) designed to promote M2-M3 domain unfurling at lower force thresholds. Since binucleation is strongly enhanced by removal of the M1 as opposed to M2-M3 domains, cytokinetic fidelity is most sensitive to α-cat M2-M3 domain opening. To identify α-cat conformation-dependent proximity partners that contribute to cytokinesis, we used a biotin-ligase approach to distinguished proximity partners that show enhanced recruitment upon α-cat M-domain unfurling (R551A). We identified Leucine Zipper Tumor Suppressor 2 (LZTS2), an abscission factor previously implicated in cytokinesis. We confirm that LZTS2 enriches at the midbody, but discover it also localizes to tight and tricellular junctions. LZTS2 knock-down promotes binucleation in both MDCK and Retinal Pigmented Epithelial (RPE) cells. α-cat mutants with persistent M2-M3 domain opening showed elevated junctional enrichment of LZTS2 from the cytosol compared α-cat wild-type cells. These data implicate LZTS2 as a mechanosensitive effector of α-cat that is critical for cytokinetic fidelity. This model rationalizes how persistent mechano-activation of α-cat may drive tension-induced polyploidization of epithelia post-injury and suggests an underlying mechanism for how pathogenic α-cat mutations drive macular dystrophy.