Actin cytoskeleton remodeling primes RIG-I-like receptor activation.

The current dogma of RNA-mediated innate immunity is that sensing of immunostimulatory RNA ligands is sufficient for the activation of intracellular sensors and induction of interferon (IFN) responses. Here, we report that actin cytoskeleton disturbance primes RIG-I-like receptor (RLR) activation. Actin cytoskeleton rearrangement induced by virus infection or commonly used reagents to intracellularly deliver RNA triggers the relocalization of PPP1R12C, a regulatory subunit of the protein phosphatase-1 (PP1), from filamentous actin to cytoplasmic RLRs. This allows dephosphorylation-mediated RLR priming and, together with the RNA agonist, induces effective RLR downstream signaling. Genetic ablation of PPP1R12C impairs antiviral responses and enhances susceptibility to infection with several RNA viruses including SARS-CoV-2, influenza virus, picornavirus, and vesicular stomatitis virus. Our work identifies actin cytoskeleton disturbance as a priming signal for RLR-mediated innate immunity, which may open avenues for antiviral or adjuvant design.

Effect of case and control definitions on genome-wide association study (GWAS) findings.

Genome-wide association studies (GWAS) have significantly advanced our understanding of the genetic underpinnings of diseases, but case and control cohort definitions for a given disease can vary between different published studies. For example, two GWAS for the same disease using the UK Biobank data set might use different data sources (i.e., self-reported questionnaires, hospital records, etc.) or different levels of granularity (i.e., specificity of inclusion criteria) to define cases and controls. The extent to which this variability in cohort definitions impacts the end-results of a GWAS study is unclear. In this study, we systematically evaluated the effect of the data sources used for case and control definitions on GWAS findings. Using the UK Biobank, we selected three diseases-glaucoma, migraine, and iron-deficiency anemia. For each disease, we designed 13 GWAS, each using different combinations of data sources to define cases and controls, and then calculated the pairwise genetic correlations between all GWAS for each disease. We found that the data sources used to define cases for a given disease can have a significant impact on GWAS end-results, but the extent of this depends heavily on the disease in question. This suggests the need for greater scrutiny on how case cohorts are defined for GWAS.

The role of breastfeeding support in racial/ethnic disparities in breastfeeding practices.

BACKGROUND: Persistent racial/ethnic disparities in breastfeeding practices in the United States are well documented but the underlying causes remain unclear. While racial/ethnic disparities are often intertwined with socioeconomic disparities in breastfeeding, studies suggest that lack of breastfeeding support from family, health care organizations and workplaces may contribute to racial/ethnic disparities in breastfeeding rates. No studies have investigated the extent to which racial/ethnic disparities in breastfeeding practices can be explained by breastfeeding support. METHODS: We used survey data from participants of a federal nutrition assistance program in Los Angeles County, the most populous county in the United States, to examine causal mechanisms underlying racial/ethnic disparities in breastfeeding in five groups: Spanish-speaking Latina, English-speaking Latina, Non-Hispanic White (NHW), Non-Hispanic Black (NHB) and Non-Hispanic Asian (NHA). Applying causal mediation analysis, this study estimated the proportion of racial/ethnic differences in breastfeeding ('any' breastfeeding, i.e., partial or exclusive) rates at 6 months that could be explained by differential access to breastfeeding support from family, birth hospitals and workplaces. RESULTS: NHB and English-speaking Latina mothers were less likely, and Spanish-speaking Latina mothers more likely to breastfeed through 6 months than NHW mothers. Lack of breastfeeding support from family, hospitals and workplaces accounted for approximately 68% of the difference in any breastfeeding rates at 6 months between NHW and NHB mothers and 36% of the difference between NHW and English-speaking Latina mothers. CONCLUSION: These findings highlight the importance of improving support from family, hospitals and workplaces for breastfeeding mothers to reduce racial/ethnic disparities in breastfeeding.

Changing the default meal option at university events to reduce harmful environmental impacts: Six randomized controlled trials.

Animal agriculture is a leading contributor to greenhouse gas emissions and other harmful environmental impacts, which underscores the need to shift away from the consumption of animal-based products. One promising nudge intervention is making plant-based meals the default option, so we tested this approach at six different university events across four academic institutions for effecting sustainable dietary change. Event attendees pre-selected their meal on one of two randomly assigned RSVP forms: one with a plant-based default and one with a meal with meat default. The results from our randomized controlled trial showed that participants had a 43-percentage point greater probability of selecting the plant-based meal when it was indicated as the default option. This effect was similar across events and academic institutions, which indicates that this default intervention is generalizable and can be successfully implemented at university events. The combined effect of using plant-based defaults at these six events was an estimated reduction of 104,387 kg of CO2 emissions, 299.9 m2 of land use, 959.0 g of nitrogen use, and 259.5 g of phosphorus use, which represent roughly 45-46.2% reductions in harmful environmental impacts relative to the meals chosen when using a meat default. Given the significance and magnitude of these environmental benefits, our results support the widespread implementation of plant-based defaults for helping universities improve their sustainability.

Glucagon blockade restores functional ß-cell mass in type 1 diabetic mice and enhances function of human islets.

We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted ß-cell survival and enhanced the recovery of insulin+ islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of ß-cell apoptosis which allows for robust assessment of ß-cell regeneration following caspase-8-induced diabetes, Ab-4 drove a 6.7-fold increase in ß-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially driven by α-cell-to-ß-cell conversion. Following hyperglycemic onset in nonobese diabetic (NOD) mice, Ab-4 treatment promoted improvements in C-peptide levels and insulin+ islet mass was dramatically increased. Lastly, diabetic mice receiving human islet xenografts showed stable improvements in glycemic control and increased human insulin secretion.

Developing a novel causal inference algorithm for personalized biomedical causal graph learning using meta machine learning.

BACKGROUND: Modeling causality through graphs, referred to as causal graph learning, offers an appropriate description of the dynamics of causality. The majority of current machine learning models in clinical decision support systems only predict associations between variables, whereas causal graph learning models causality dynamics through graphs. However, building personalized causal graphs for each individual is challenging due to the limited amount of data available for each patient. METHOD: In this study, we present a new algorithmic framework using meta-learning for learning personalized causal graphs in biomedicine. Our framework extracts common patterns from multiple patient graphs and applies this information to develop individualized graphs. In multi-task causal graph learning, the proposed optimized initial guess of shared commonality enables the rapid adoption of knowledge to new tasks for efficient causal graph learning. RESULTS: Experiments on one real-world biomedical causal graph learning benchmark data and four synthetic benchmarks show that our algorithm outperformed the baseline methods. Our algorithm can better understand the underlying patterns in the data, leading to more accurate predictions of the causal graph. Specifically, we reduce the structural hamming distance by 50-75%, indicating an improvement in graph prediction accuracy. Additionally, the false discovery rate is decreased by 20-30%, demonstrating that our algorithm made fewer incorrect predictions compared to the baseline algorithms. CONCLUSION: To the best of our knowledge, this is the first study to demonstrate the effectiveness of meta-learning in personalized causal graph learning and cause inference modeling for biomedicine. In addition, the proposed algorithm can also be generalized to transnational research areas where integrated analysis is necessary for various distributions of datasets, including different clinical institutions.

Explainable synthetic image generation to improve risk assessment of rare pediatric heart transplant rejection.

Expert microscopic analysis of cells obtained from frequent heart biopsies is vital for early detection of pediatric heart transplant rejection to prevent heart failure. Detection of this rare condition is prone to low levels of expert agreement due to the difficulty of identifying subtle rejection signs within biopsy samples. The rarity of pediatric heart transplant rejection also means that very few gold-standard images are available for developing machine learning models. To solve this urgent clinical challenge, we developed a deep learning model to automatically quantify rejection risk within digital images of biopsied tissue using an explainable synthetic data augmentation approach. We developed this explainable AI framework to illustrate how our progressive and inspirational generative adversarial network models distinguish between normal tissue images and those containing cellular rejection signs. To quantify biopsy-level rejection risk, we first detect local rejection features using a binary image classifier trained with expert-annotated and synthetic examples. We converted these local predictions into a biopsy-wide rejection score via an interpretable histogram-based approach. Our model significantly improves upon prior works with the same dataset with an area under the receiver operating curve (AUROC) of 98.84% for the local rejection detection task and 95.56% for the biopsy-rejection prediction task. A biopsy-level sensitivity of 83.33% makes our approach suitable for early screening of biopsies to prioritize expert analysis. Our framework provides a solution to rare medical imaging challenges currently limited by small datasets.

Coronavirus Disease 2019 Temperature Trajectories Correlate With Hyperinflammatory and Hypercoagulable Subphenotypes.

OBJECTIVES: Body temperature trajectories of infected patients are associated with specific immune profiles and survival. We determined the association between temperature trajectories and distinct manifestations of coronavirus disease 2019. DESIGN: Retrospective observational study. SETTING: Four hospitals within an academic healthcare system from March 2020 to February 2021. PATIENTS: All adult patients hospitalized with coronavirus disease 2019. INTERVENTIONS: Using a validated group-based trajectory model, we classified patients into four previously defined temperature trajectory subphenotypes using oral temperature measurements from the first 72 hours of hospitalization. Clinical characteristics, biomarkers, and outcomes were compared between subphenotypes. MEASUREMENTS AND MAIN RESULTS: The 5,903 hospitalized coronavirus disease 2019 patients were classified into four subphenotypes: hyperthermic slow resolvers (n = 1,452, 25%), hyperthermic fast resolvers (1,469, 25%), normothermics (2,126, 36%), and hypothermics (856, 15%). Hypothermics had abnormal coagulation markers, with the highest d-dimer and fibrin monomers (p < 0.001) and the highest prevalence of cerebrovascular accidents (10%, p = 0.001). The prevalence of venous thromboembolism was significantly different between subphenotypes (p = 0.005), with the highest rate in hypothermics (8.5%) and lowest in hyperthermic slow resolvers (5.1%). Hyperthermic slow resolvers had abnormal inflammatory markers, with the highest C-reactive protein, ferritin, and interleukin-6 (p < 0.001). Hyperthermic slow resolvers had increased odds of mechanical ventilation, vasopressors, and 30-day inpatient mortality (odds ratio, 1.58; 95% CI, 1.13-2.19) compared with hyperthermic fast resolvers. Over the course of the pandemic, we observed a drastic decrease in the prevalence of hyperthermic slow resolvers, from representing 53% of admissions in March 2020 to less than 15% by 2021. We found that dexamethasone use was associated with significant reduction in probability of hyperthermic slow resolvers membership (27% reduction; 95% CI, 23-31%; p < 0.001). CONCLUSIONS: Hypothermics had abnormal coagulation markers, suggesting a hypercoagulable subphenotype. Hyperthermic slow resolvers had elevated inflammatory markers and the highest odds of mortality, suggesting a hyperinflammatory subphenotype. Future work should investigate whether temperature subphenotypes benefit from targeted antithrombotic and anti-inflammatory strategies.

Dephosphorylation of the RNA sensors RIG-I and MDA5 by the phosphatase PP1 is essential for innate immune signaling.

RIG-I and MDA5 have emerged as key cytosolic sensors for the detection of RNA viruses and lead to antiviral interferon (IFN) production. Recent studies have highlighted the importance of posttranslational modifications for controlling RIG-I antiviral activity. However, the regulation of MDA5 signal-transducing ability remains unclear. Here, we show that MDA5 signaling activity is regulated by a dynamic balance between phosphorylation and dephosphorylation of its caspase recruitment domains (CARDs). Employing a phosphatome RNAi screen, we identified PP1α and PP1γ as the primary phosphatases that are responsible for MDA5 and RIG-I dephosphorylation and that lead to their activation. Silencing of PP1α and PP1γ enhanced RIG-I and MDA5 CARD phosphorylation and reduced antiviral IFN-ß production. PP1α- and PP1γ-depleted cells were impaired in their ability to induce IFN-stimulated gene expression, which resulted in enhanced RNA virus replication. This work identifies PP1α and PP1γ as regulators of antiviral innate immune responses to various RNA viruses, including influenza virus, paramyxovirus, dengue virus, and picornavirus.

Integrating multi-omics data by learning modality invariant representations for improved prediction of overall survival of cancer.

Breast and ovarian cancers are the second and the fifth leading causes of cancer death among women. Predicting the overall survival of breast and ovarian cancer patients can facilitate the therapeutics evaluation and treatment decision making. Multi-scale multi-omics data such as gene expression, DNA methylation, miRNA expression, and copy number variations can provide insights on personalized survival. However, how to effectively integrate multi-omics data remains a challenging task. In this paper, we develop multi-omics integration methods to improve the prediction of overall survival for breast cancer and ovarian cancer patients. Because multi-omics data for the same patient jointly impact the survival of cancer patients, features from different -omics modality are related and can be modeled by either association or causal relationship (e.g., pathways). By extracting these relationships among modalities, we can get rid of the irrelevant information from high-throughput multi-omics data. However, it is infeasible to use the Brute Force method to capture all possible multi-omics interactions. Thus, we use deep neural networks with novel divergence-based consensus regularization to capture multi-omics interactions implicitly by extracting modality-invariant representations. In comparing the concatenation-based integration networks with our new divergence-based consensus networks, the breast cancer overall survival C-index is improved from 0.655±0.062 to 0.671±0.046 when combing DNA methylation and miRNA expression, and from 0.627±0.062 to 0.667±0.073 when combing miRNA expression and copy number variations. In summary, our novel deep consensus neural network has successfully improved the prediction of overall survival for breast cancer and ovarian cancer patients by implicitly learning the multi-omics interactions.

Understanding children's perspectives of the influences on their dietary behaviours.

OBJECTIVE: This study aimed to examine the intrapersonal, interpersonal, environmental and macrosystem influences on dietary behaviours among primary school children in Singapore. DESIGN: A qualitative interpretive approach was used in this study. Focus group discussions guided by the socio-ecological model (sem), of which transcripts were analysed deductively using the sem and inductively using thematic analysis to identify themes at each sem level. SETTING: Two co-educational public primary schools in Singapore. PARTICIPANTS: A total of 48 children (n 26 girls) took part in the semi-structured focus group discussions. Their mean age was 10·8 years (sd = 0·9, range 9-12 years), and the majority of the children were Chinese (n 36), along with some Indians (n 8) and Malays (n 4). RESULTS: Children's knowledge of healthy eating did not necessarily translate into healthy dietary practices and concern for health was a low priority. Instead, food and taste preferences were pivotal influences in their food choices. Parents had a large influence on children with regards to their accessibility to food, their attitudes and values towards food. Parental food restriction led to some children eating in secrecy. Peer influence was not frequently reported by children. Competitions in school incentivised children to consume fruits and vegetables, but reinforcements from teachers were inconsistent. The proximity of fast-food chains in the neighbourhood provided children easy access to less healthy foods. Health advertisements on social media rather than posters worked better in drawing children's attention. CONCLUSIONS: Findings highlighted important factors that should be considered in future nutrition interventions targeting children.

Effects of prenatal exposure to pyrethroid pesticides on neurodevelopment of 1-year- old children: A birth cohort study in China.

Pregnant women have been ubiquitously exposed to pyrethroid pesticides. Previous studies, mainly based on third trimester measurements of maternal urinary pyrethroid metabolites, have reported inconsistent findings in the effects of prenatal pyrethroid exposure on children's neurodevelopmental outcomes. The purpose of this study was to clarify if pyrethroid exposure during the entire three trimesters of pregnancy may be associated with deleterious effects on infant neurodevelopmental status, particularly at a high dosage of exposure. We measured maternal urinary concentrations of pyrethroid metabolites in all trimesters of pregnancy and assessed children's neurodevelopment at one year of age using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). Multiple linear regression models were used to estimate the effects of metabolites (3-PBA, 4 F-3-PBA, cis-DBCA) in each trimester on BSID-III composite scores. Logistic regression analyses were applied to predict developmental delay vs non-delayed status (cut-off composite score of below 80 for developmental delay) based on the maternal levels of pyrethroid metabolites. In the first, second and third trimesters of pregnancy, the detection rates of pyrethroid metabolites were 94.7%, 90.7%, and 89.0%; the 50th percentiles of exposure level were 0.24 µg/g, 0.24 µg/g and 0.21 µg/g for 3-PBA, 0.14 µg/g, 0.17 µg/g and 0.15 µg/g for 4 F-3PBA, 0.21 µg/g, 0.25 µg/g and 0.19 µg/g for cis-DBCA respectively. In the second trimester, 3-PBA was inversely associated with Cognition and Language scores [ß = -3.34 (95% CI = -6.11, -0.57) and ß = -2.90 (95% CI = -5.20, -0.61), respectively], and significantly increased the risk of Cognition and Language developmental delay [OR= 1.64 (95% CI = 1.03, 2.62) and OR = 1.52 (95% CI = 1.06, 2.19), respectively]; cis-DBCA was inversely associated with Adaptive Behavior scores [ß = -0.73 (95% CI = -1.27, -0.19)], and significantly increased the risk of Adaptive Behavior developmental delay [OR= 1.11 (95% CI = 1.02, 1.21)]. When the maternal levels of pyrethroid metabolites were stratified into the regression models according to the 90th percentile of exposure, in the first trimester, Cognition and Motor scores were inversely associated with higher cis-DBCA [ß = -7.19 (95% CI = -12.97, -1.41) and ß = -8.20 (95% CI = -13.35, -3.05), respectively], Language scores were inversely associated with higher 3-PBA [ß = -6.01 (95% CI = -10.96, -1.06)]; in the second trimester, Cognition scores were inversely associated with higher cis-DBCA [ß = -6.64 (95% CI = -12.51, -0.76)], Language scores were inversely associated with higher 3-PBA [ß = -5.17 (95% CI = -10.07, -0.27)] and cis-DBCA [ß = -5.40 (95% CI = -10.28, -0.52)]. We concluded that pyrethroid exposure in the first and second trimesters was associated with poorer infants neurodevelopmental outcomes at one year of age, and these effects were particularly pronounced at high levels of pyrethroid exposure.

Intervention Strategies and Lessons Learned From a Student-Led Initiative to Support Lactating Women in the University Setting.

The benefits of breastfeeding for mother and baby are strongly supported by research. However, lactating parents who return to school or work soon after delivery face many barriers to continued breastfeeding. This article presents a student-led initiative to support lactation at a large public university that emerged from advocacy efforts of student mothers of color. The socioecological model was used as a framework to understand and address the multifaceted influences on breastfeeding practices. Project activities included providing breastfeeding education to lactating parents and their partners, measuring availability and accessibility of lactation spaces, improving lactation spaces, connecting university stakeholders, and strengthening university lactation policies. The project achieved the following outcomes: formation of a stakeholder group with members across campus departments, improvement in accessibility and appropriateness of lactation spaces, provision of breastfeeding services through workshops and one-on-one appointments with lactation educators, and creation and dissemination of an online toolkit outlining parents' lactation rights and support available on campus. Comprehensive lactation support at universities is essential to enhance educational and professional equity for women and to promote postpartum and infant health. Throughout the project implementation, the team learned many lessons that can help guide similar university initiatives.

Dermal adipocytes contribute to the metabolic regulation of dermal fibroblasts.

Dermal fibroblasts are an essential population of skin cells. They are not only responsible for synthesis and remodelling of the extracellular matrix of the dermis, but also communicate with other skin cells via autocrine and paracrine interactions. Skin-associated dermal adipocytes reside below the reticular dermis. Strong lipolysis is observed during the regression of dermal adipocytes. However, the nature of the local intercellular crosstalk in which lipids released by dermal adipocytes affecting the metabolism of adjacent skin fibroblasts has not yet been examined. With the use of a series of novel mouse models that allow us to manipulate adipocytes, we demonstrate that dermal adipocytes can modulate the structure of the dermis through regulating extracellular matrix production in dermal fibroblasts. Fatty acids released by dermal adipocytes are involved in this process. Our observations offer new in vivo insights into the role of dermal adipocyte-derived lipids in influencing metabolism of adjacent local cells in the skin through a paracrine effect in the microenvironment of the dermal adipocyte.

Longitudinal trajectories of adiposity-related measures from age 2-5 years in a population of low-income Hispanic children.

BACKGROUND: We estimated longitudinal trajectories of body mass index (BMI) z-score and percentile, weight for height (WFH) z-score and percentile, and percentage of the 95th BMI percentile (BMIp95) among low-income Hispanic children ages 2-5 years to provide normative data for this population and compare the behavior of different measures. METHODS: Longitudinal height and weight measurements obtained from 18,072 Hispanic children aged 2-5 years enrolled in the Special Supplemental Nutrition Program for Women, Infants and Children in Los Angeles County were analyzed. Trajectories of adiposity-related measures were estimated using mixed models, stratified by sex and BMI percentile at age 2 years. RESULTS: For children in the 5th-85th BMI percentile at age 2 years, all adiposity-related measures rose during ages 2-3.5 years; during ages 3.5-5 years, BMI-based measures increased, BMIp95 decreased, and WFH-based measures were stable. For children exceeding the 85th BMI percentile at age 2 years, measures generally trended downward during ages 2-5 years, except for BMIp95, which had variable trends. CONCLUSIONS: Adiposity measures changed at different rates as children grew during ages 2-3.5 years compared to ages 3.5-5 years, and different measures displayed different trends. Studies should consider examining multiple measures and focusing on change relative to a comparison group. IMPACT: To address the childhood obesity epidemic, information on normative trajectories of adiposity-related measures in at-risk populations of young children is needed. Longitudinal analysis of data collected from low-income Hispanic children during ages 2-5 years revealed different patterns for different adiposity measures and for ages 2-3.5 years versus 3.5-5 years. Child obesity studies should consider examining multiple adiposity measures and focus on change relative to a comparison group to avoid misinterpreting longitudinal patterns.

Regional differences in the impact of the COVID-19 pandemic on food sufficiency in California, April-July 2020: implications for food programmes and policies.

OBJECTIVE: To evaluate regional differences in factors associated with food insufficiency during the initial months of the COVID-19 pandemic among three major metropolitan regions in California, a state with historically low participation rates in the Supplementation Nutrition Assistance Program, the nation's largest food assistance programme. DESIGN: Analysis of cross-sectional data from phase 1 (23 April-21 July 2020) of the US Census Household Pulse Survey, a weekly national online survey. SETTING: California, and three Californian metropolitan statistical areas (MSA), including San Francisco-Oakland-Berkeley, Los Angeles-Long Beach-Anaheim and Riverside-San Bernardino-Ontario MSA. PARTICIPANTS: Adults aged 18 years and older living in households. RESULTS: Among the three metropolitan areas, food insufficiency rates were lowest in the San Francisco-Oakland-Berkeley MSA. Measures of disadvantage (e.g., having low-income, being unemployed, recent loss of employment income and pre-pandemic food insufficiency) were widely associated with household food insufficiency. However, disadvantaged households in the San Francisco Bay Area, the area with the lowest poverty and unemployment rates, were more likely to be food insufficient compared with those in the Los Angeles-Long Beach-Anaheim and Riverside-San Bernardino-Ontario MSA. CONCLUSIONS: Food insufficiency risk among disadvantaged households differed by region. To be effective, governmental response to food insufficiency must address the varied local circumstances that contribute to these disparities.

The role of income and neighbourhood poverty in the association between the 2009 Special Supplemental Nutrition Program for Women, Infants and Children (WIC) food package change and child obesity among WIC-participating children in Los Angeles County, 2003-2016.

OBJECTIVE: To determine whether a previously reported association between the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) food package change and reduced child obesity risk among WIC-participating children in Los Angeles County holds across levels of family income and neighbourhood poverty. DESIGN: Analysis of prospectively collected WIC administrative data. The outcome was obesity at age 4 years (BMI-for-age ≥ 95th percentile). Poisson regression was applied to a matched sample (n 79 502) to determine if the association between the WIC food package change and child obesity was modified by family income (<50 % federal poverty level (FPL), 50-100 % FPL, >100 % but <185 % FPL) and neighbourhood poverty. SETTING: Los Angeles County, California. PARTICIPANTS: Children who participated in WIC in Los Angeles County between 2003 and 2016; children were grouped as receiving the old WIC food package (2003-2009) or the new WIC food package (2010-2016). RESULTS: Receiving the new WIC food package (i.e., post-2009) was associated with 7-18 % lower obesity risk across all family income categories. Neither family income nor neighbourhood poverty significantly modified the association between the WIC food package and child obesity. However, certain sub-groups seemed to benefit more from the food package change than others. In particular, boys from families with income above poverty but residing in the poorest neighbourhoods experienced the greatest reductions in obesity risk (relative risk = 0·77; 95 % CI 0·66, 0·88). CONCLUSIONS: The WIC food package revisions were associated with reduced childhood obesity risk among all WIC-participating families in Los Angeles County, across levels of income eligibility and neighbourhood poverty.

Did COVID-19 Affect Time to Presentation in the Setting of Pediatric Testicular Torsion?

OBJECTIVES: To determine if boys with acute testicular torsion, a surgical emergency requiring prompt diagnosis and treatment to optimize salvage of the testicle, delayed presentation to a medical facility and experienced an extended duration of symptoms (DoS), and secondarily, a higher rate of orchiectomy, during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Single-center, descriptive retrospective chart review of boys presenting with acute testicular torsion from March 15, to May 4, 2020 ("during COVID-19" or group 2), as well as for the same time window in the 5-year period from 2015 to 2019 ("pre-COVID-19" or group 1). RESULTS: A total of 78 boys met inclusion criteria, group 1 (n = 57) and group 2 (n = 21). The mean age was 12.86 ± 2.63 (group 1) and 12.86 ± 2.13 (group 2). Mean DoS before presentation at a medical facility was 23.2 ± 35.0 hours in group 1 compared with 21.3 ± 29.7 hours in group 2 (P < 0.37). When DoS was broken down into acute (<24 hours) versus delayed (≥24 hours), 41 (71.9%) of 57 boys in group 1 and 16 (76.2%) of 21 boys in group 2 presented within less than 24 hours of symptom onset (P < 0.78). There was no difference in rate of orchiectomy between group 1 and group 2 (44.7% vs 25%, P < 0.17), respectively. CONCLUSIONS: Boys with acute testicular torsion in our catchment area did not delay presentation to a medical facility from March 15, to May 4, 2020, and did not subsequently undergo a higher rate of orchiectomy.

Critical role for cholesterol in Lassa fever virus entry identified by a novel small molecule inhibitor targeting the viral receptor LAMP1.

Lassa fever virus (LASV) is endemic in West Africa and causes severe hemorrhagic fever and sensorineural hearing loss. We identified a small molecule inhibitor of LASV and used it to analyze the mechanism of entry. Using a photo-reactive analog that retains antiviral activity as a probe, we identified the inhibitor target as lysosome-associated membrane protein 1 (LAMP1), a host factor that binds to the LASV glycoprotein (GP) during infection. We found that LAMP1 binding to LASV GP is cholesterol-dependent, and that the inhibitor blocks infection by competing with cholesterol in LAMP1. Mutational analysis of a docking-based model identified a putative inhibitor binding site in the cholesterol-binding pocket within the LAMP1 domain that binds GP. These findings identify a critical role for cholesterol in LASV entry and a potential target for therapeutic intervention.

The new child food package is associated with reduced obesity risk among formula fed infants participating in the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) in Los Angeles County, California, 2003-2016.

BACKGROUND: The Special Supplemental Nutrition Program for Women, Infants and Children (WIC) changed the food packages provided to its participants in 2009, to better align them with the Dietary Guidelines for Americans. Previous research found that the 2009 WIC food package change was associated with reduced obesity risk, particularly among breastfed infants but also among those who were never breastfed. The objective of this study was to determine if the new child food package introduced in 2009, including more produce and whole grains for 1-4-year old children, was associated with healthier growth trajectories and reduced obesity risk at age 4 years among children who were exclusively formula fed during infancy. METHODS: Administrative data on WIC-participating children in Los Angeles County, 2003-2016, were used (N = 74,871), including repeated measures of weight and length (or height); child's age, gender, and race/ethnicity; maternal education and language; and family poverty. Gender-stratified spline mixed models were used to examine weight-for-height z-score (WHZ) growth trajectories from 0 to 4 years and Poisson regression models were used to assess obesity (BMI-for-age > 95th percentile) at age 4. The main independent variable was duration of receipt (dose) of the new child package, categorized as 0, > 0 to < 1, 1 to < 2, 2 to < 3, 3 to < 4, and 4 years. RESULTS: WHZ growth trajectories were similar for children across new child package dose groups. Boys and girls who were fully formula fed during infancy but received the new child food package for 4 years had a 7% (RR = 0.93; 95%CI = 0.89-0.98) and a 6% (RR = 0.94; 95%CI = 0.89-0.99) lower obesity risk, respectively, compared to children who received the new child food package for 0 years. There were no differences in obesity risk for children receiving < 4 years of the new child package vs. 0 years. CONCLUSIONS: Providing healthy foods during childhood to children who were exclusively formula fed as infants was associated with modest improvements in obesity outcomes. While breastfeeding promotion should still be prioritized among WIC participants, providing healthy foods during childhood may provide health benefits to formula fed children, who comprise a sizeable proportion of children served by WIC.