Erratum: Sociome Data Commons: A scalable and sustainable platform for investigating the full social context and determinants of health - ERRATUM.

[This corrects the article DOI: 10.1017/cts.2023.670.].

Utilization, quality, and spending for pediatric Medicaid enrollees with primary care in health centers vs non-health centers.

BACKGROUND: Limited research has explored the performance of health centers (HCs) compared to other primary care settings among children in the United States. We evaluated utilization, quality, and expenditures for pediatric Medicaid enrollees receiving care in HCs versus non-HCs. METHODS: This national cross-sectional study utilized 2012 Medicaid Analytic eXtract (MAX) claims to examine children 0-17 years with a primary care visit, stratified by whether majority (> 50%) of primary care visits were at HCs or non-HCs. Outcome measures include utilization (primary care visits, non-primary care outpatient visits, prescription claims, Emergency Department (ED) visits, hospitalizations) and quality (well-child visits, avoidable ED visits, avoidable hospitalizations). For children enrolled in fee-for-service Medicaid, we also measured expenditures. Propensity score-based overlap weighting was used to balance covariates. RESULTS: A total of 2,383,270 Medicaid-enrolled children received the majority of their primary care at HCs, while 18,540,743 did at non-HCs. In adjusted analyses, HC patients had 20% more primary care visits, 15% less non-primary care outpatient visits, and 21% less prescription claims than non-HC patients. ED visits were similar across the two groups, while HC patients had 7% lower chance of hospitalization than non-HC. Quality of care outcomes favored HC patients in main analyses, but results were less robust when excluding managed care beneficiaries. Total expenditures among the fee-for-service subpopulation were lower by $239 (8%) for HC patients. CONCLUSIONS: In this study of nationwide claims data to evaluate healthcare utilization, quality, and spending among Medicaid-enrolled children who receive primary care at HCs versus non-HCs, findings suggest primary care delivery in HCs may be associated with a more cost-effective model of healthcare for children.

A human obesity-associated MC4R mutation with defective Gq/11α signaling leads to hyperphagia in mice.

Melanocortin 4 receptor (MC4R) mutations are the most common cause of human monogenic obesity and are associated with hyperphagia and increased linear growth. While MC4R is known to activate Gsα/cAMP signaling, a substantial proportion of obesity-associated MC4R mutations do not affect MC4R/Gsα signaling. To further explore the role of specific MC4R signaling pathways in the regulation of energy balance, we examined the signaling properties of one such mutant, MC4R (F51L), as well as the metabolic consequences of MC4RF51L mutation in mice. The MC4RF51L mutation produced a specific defect in MC4R/Gq/11α signaling and led to obesity, hyperphagia, and increased linear growth in mice. The ability of a melanocortin agonist to acutely inhibit food intake when delivered to the paraventricular nucleus (PVN) was lost in MC4RF51L mice, as well as in WT mice in which a specific Gq/11α inhibitor was delivered to the PVN; this provided evidence that a Gsα-independent signaling pathway, namely Gq/11α, significantly contributes to the actions of MC4R on food intake and linear growth. These results suggest that a biased MC4R agonist that primarily activates Gq/11α may be a potential agent to treat obesity with limited untoward cardiovascular and other side effects.

High-energy Femoral Neck Fractures in Young Patients.

Femoral neck fractures in physiologically young patients typically occur from high-energy axial loading forces through the thigh with the hip in an abducted position. These fractures have a high rate of associated head, chest, abdominal, and musculoskeletal injuries. High-energy hip fractures differ from traditional geriatric hip fractures regarding incidence, mechanism, management algorithms, and complications. After adequate resuscitation, goals of treatment include anatomic reduction and stable fixation while maintaining vascularity of the femoral head, which can be achieved through a variety of different techniques. Prompt recognition and treatment of these fractures is crucial to achieve a successful outcome because these injuries are often associated with complications such as osteonecrosis, fixation failure, and nonunion.

Maternally transmitted anti-measles antibodies, and susceptibility to disease among infants in Chandigarh, India: A prospective birth cohort study.

Prior to the age of measles vaccination, infants are believed to be protected against measles by passively transferred maternal antibodies. However, the quantity and quality of such protection have not been well established in the Indian setting. We undertook this study to characterize the transfer and decline in maternal anti-measles antibodies among infants, and determine their susceptibility to measles. In this population-based, birth-cohort study, we enrolled pregnant women and their newborn infants, from a catchment area of 30 Anganwadis in Chandigarh, India. We collected maternal blood at delivery, and infant blood samples at birth, and 3, 6, and 9 months of age. Anti-measles IgG antibodies were measured using quantitative ELISA. We assessed antibody decline using log-linear models. In total, 428 mother-infant dyads were enrolled, and data from 413 dyads were analyzed. At birth, 91.5% (95% CI: 88.8, 94.2) of infants had protective antibody levels, which declined to 26.3% (95% CI: 21.0%, 31.9) at 3 months, 3.4% (95% CI: 0.9, 5.9) at 6 months, and 2.1% (95% CI: 0.1, 4.1) at 9 months. Younger mothers transferred lower levels of antibodies to their infants. We concluded that the majority of infants are susceptible to measles as early as three months of age, much earlier than their eligibility to receive measles vaccination.

Using Spinal Anesthesia and a Fracture Table for Closed Reduction of an Obturator Foramen Hip Dislocation: A Case Report.

CASE: A 37-year-old man with a right obturator foramen hip dislocation underwent closed reduction under spinal anesthesia with the use of a fracture traction table. CONCLUSION: This novel technique provides surgeons and anesthesiologists an alternative method of treating obturator foramen hip dislocations that provides a more controlled reduction and less need for assistants.

Citizen science reporting indicates geographic and phenotypic drivers of road use and mortality in a threatened rattlesnake.

Roads may influence the selection of phenotypic traits of wildlife. In particular, the likelihood of vehicle collisions with wildlife may vary depending on body coloration in contrast to the road, which may be exaggerated by cultural attitudes toward the species. The timber rattlesnake Crotalus horridus is a threatened species that varies widely in coloration, and their color pattern could influence thermoregulatory use of roads and visibility to motorists. Moreover, better-camouflaged snakes may have higher road mortality in areas where environmental interest is lower and, perhaps, negative attitudes toward wildlife are more prevalent. We used citizen scientist observations of timber rattlesnakes from iNaturalist and categorized for each rattlesnake the surface they were on, its color pattern, and whether they were alive. We combined iNaturalist data with Google Trends data to characterize regional variation in environmental interest. We discovered that lighter-colored snakes were more likely to be found on roads, as were snakes further south, west, and on warmer days. Once on a road, coloration did not influence survival regardless of road type or environmental interest. However, snakes on asphalt roads or on southern roads were more likely to be found dead. The higher likelihood of lighter-colored snakes being found on roads suggests that they are at a greater overall risk of road death, potentially selecting for darker coloration. Citizen scientist behavior may at least partly underlie the influence of latitude on the results, however, and further work in the application of citizen science data to such research questions is warranted.

Sociome Data Commons: A scalable and sustainable platform for investigating the full social context and determinants of health.

Background/Objective: Non-clinical aspects of life, such as social, environmental, behavioral, psychological, and economic factors, what we call the sociome, play significant roles in shaping patient health and health outcomes. This paper introduces the Sociome Data Commons (SDC), a new research platform that enables large-scale data analysis for investigating such factors. Methods: This platform focuses on "hyper-local" data, i.e., at the neighborhood or point level, a geospatial scale of data not adequately considered in existing tools and projects. We enumerate key insights gained regarding data quality standards, data governance, and organizational structure for long-term project sustainability. A pilot use case investigating sociome factors associated with asthma exacerbations in children residing on the South Side of Chicago used machine learning and six SDC datasets. Results: The pilot use case reveals one dominant spatial cluster for asthma exacerbations and important roles of housing conditions and cost, proximity to Superfund pollution sites, urban flooding, violent crime, lack of insurance, and a poverty index. Conclusion: The SDC has been purposefully designed to support and encourage extension of the platform into new data sets as well as the continued development, refinement, and adoption of standards for dataset quality, dataset inclusion, metadata annotation, and data access/governance. The asthma pilot has served as the first driver use case and demonstrates promise for future investigation into the sociome and clinical outcomes. Additional projects will be selected, in part for their ability to exercise and grow the capacity of the SDC to meet its ambitious goals.

Using A Standardized Nomenclature to Semantically Map Oncology-Related Concepts from Common Data Models to a Pediatric Cancer Data Model.

The Pediatric Cancer Data Commons (PCDC) comprises an international community whose ironclad commitment to data sharing is combatting pediatric cancer in an unprecedented way. The byproduct of their data sharing efforts is a gold-standard consensus data model covering many types of pediatric cancer. This article describes an effort to utilize SSSOM, an emerging specification for semantically-rich data mappings, to provide a "hub and spoke" model of mappings from several common data models (CDMs) to the PCDC data model. This provides important contributions to the research community, including: 1) a clear view of the current coverage of these CDMs in the domain of pediatric oncology, and 2) a demonstration of creating standardized mappings. These mappings can allow downstream crosswalk for data transformation and enhance data sharing. This can guide those who currently create and maintain brittle ad hoc data mappings in order to utilize the growing volume of viable research data.

The role of selenoproteins in neutrophils during inflammation.

Polymorphonuclear neutrophils (PMNs)-derived ROS are involved in the regulation of multiple functions of PMNs critical in both inflammation and its timely resolution. Selenium is an essential trace element that functions as a gatekeeper of cellular redox homeostasis in the form of selenoproteins. Despite their well-studied involvement in regulating functions of various immune cells, limited studies have focused on the regulation of selenoproteins in PMN and their associated functions. Ex-vivo treatment of murine primary bone marrow derived PMNs with bacterial endotoxin lipopolysaccharide (LPS) indicated temporal regulation of several selenoprotein genes at the mRNA level. However, only glutathione peroxidase 4 (Gpx4) was significantly upregulated, while Selenof, Selenow, and Gpx1 were significantly downregulated in a temporal manner at the protein level. Exposure of PMNs isolated from tRNASec (Trsp)fl/fl S100A8Cre (TrspN) PMN-specific selenoprotein knockout mice, to the Gram-negative bacterium, Citrobacter rodentium, showed decreased bacterial growth, reduced phagocytosis, as well as impaired neutrophil extracellular trap (NET) formation ability, when compared to the wild-type PMNs. Increased extracellular ROS production upon LPS stimulation was also observed in TrspN PMNs that was associated with upregulation of Alox12, Cox2, and iNOS, as well as proinflammatory cytokines such as TNFα and IL-1ß. Our data indicate that the inhibition of selenoproteome expression results in alteration of PMN proinflammatory functions, suggesting a potential role of selenoproteins in the continuum of inflammation and resolution.

Measles Vaccination Immunogenicity and Association with Caste in Chandigarh, India.

Measles affects those of lower socioeconomic status disproportionately. This study evaluated the impact of measles vaccination on antibody titers 3 months after vaccination across different socioeconomic groups, with a focus on caste. In total, 169 infants in Chandigarh, India, had serum samples collected immediately prior to vaccination at 9 months of age and 3 months later. Overall, 126 infants (76%) were seropositive (antibody titers > 12 mIU/mL), 26 (16%) were borderline (8-12 mIU/mL), and 14 (8%) were seronegative (< 8 mIU/mL). Seropositivity (versus borderline/seronegative infants) was 0.78 times as high among individuals from the historically marginalized scheduled castes/scheduled tribes compared with the others caste grouping (95% CI, 0.62-0.98). Antibody response was not tied to anthropometric measures but was attenuated among scheduled castes/scheduled tribes with higher incomes. This study provides observational evidence that social structures can be associated with individual immune responses.

Measles seroprevalence in persons over one year of age in Chandigarh, India.

Measles continues to result in focal outbreaks in India, despite over three decades of universal infant vaccination. The aims of this study were to examine measles immunity in the population of Chandigarh, India, and to compare immunity by vaccination vs. natural infection. In a cross-sectional study of individuals 1-60 years selected from 30 communities within Chandigarh during 2017-2018, measles immunity was assessed using serological surveys. Seropositivity was compared across demographic groups, and by prior history of vaccination and natural history of infection. Among those 1-20 years old, measles seropositivity, and histories of measles vaccination or prior measles diagnosis were separately assessed as outcomes in logistic regression models, with demographic factors as independent variables. Among 1690 participants, 94% were seropositive, and 6% had borderline or negative antibody levels. Of those positive, 30% had prior vaccination, 16% had a history of natural infection, and 54% had an unknown history. Over 50% of individuals among those >20 years old, had unknown history of immunity. In the multivariable regression models, vaccination was more common in younger ages (P < .0001), and in males compared to females (P = .0220), and in those with more education (P < .0001). The majority of the population was seropositive, and seropositivity increased with age. Older age groups were more likely to be protected because of previous natural infection, whereas younger age groups were protected by vaccination. There was inequity in vaccination coverage by gender, and maternal education status.

The role of imaging in diagnosis and management of malignant peritoneal mesothelioma: a systematic review.

PURPOSE: Imaging of the peritoneum and related pathology is a challenge. Among peritoneal diseases, malignant peritoneal mesothelioma (MPeM) is an uncommon tumor with poor prognosis. To date, there are no specific guidelines or imaging protocols dedicated for the peritoneum and MPeM. The objective of this study was to analyze the literature describing imaging modalities used for MPeM to determine their relative clinical efficacy and review commonly reported imaging features of MPeM to promote standardized reporting. METHODS: We performed a systematic review of original research articles discussing imaging modalities in MPeM from 1999 to 2020. Effectiveness measures and common findings were compared across imaging modalities. RESULTS: Among 582 studies analyzed, the most-used imaging modality was CT (54.3%). In the differentiation of MPeM from peritoneal carcinomatosis, one study found CT had a diagnostic sensitivity of 53%, specificity of 100%, and accuracy of 68%. Two studies found fluorodeoxyglucose positron emission tomography (FDG-PET) had sensitivity of 86-92%, specificity of 83-89%, and accuracy of 87-89%. Another study found magnetic resonance imaging (MRI) was the best predictor of the peritoneal carcinomatosis index. Characteristics shown to best differentiate MPeM from other diseases included ascites, peritoneal thickening, mesenteric thickening, pleural plaques, maximum tumor dimension, and number of masses. CONCLUSION: Most published MPeM imaging studies utilized CT. PET/CT or MRI appear promising, and future studies should compare effectiveness of these modalities. MPeM imaging reports should highlight ascites, number of and maximum tumor dimension, peritoneal/mesenteric thickening, and associated pleural plaques, allowing for better aggregation of MPeM imaging data across studies.

Selenophosphate synthetase 1 deficiency exacerbates osteoarthritis by dysregulating redox homeostasis.

Aging and mechanical overload are prominent risk factors for osteoarthritis (OA), which lead to an imbalance in redox homeostasis. The resulting state of oxidative stress drives the pathological transition of chondrocytes during OA development. However, the specific molecular pathways involved in disrupting chondrocyte redox homeostasis remain unclear. Here, we show that selenophosphate synthetase 1 (SEPHS1) expression is downregulated in human and mouse OA cartilage. SEPHS1 downregulation impairs the cellular capacity to synthesize a class of selenoproteins with oxidoreductase functions in chondrocytes, thereby elevating the level of reactive oxygen species (ROS) and facilitating chondrocyte senescence. Cartilage-specific Sephs1 knockout in adult mice causes aging-associated OA, and augments post-traumatic OA, which is rescued by supplementation of N-acetylcysteine (NAC). Selenium-deficient feeding and Sephs1 knockout have synergistic effects in exacerbating OA pathogenesis in mice. Therefore, we propose that SEPHS1 is an essential regulator of selenium metabolism and redox homeostasis, and its dysregulation governs the progression of OA.

Clinical Spectrum of Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Protection From Symptomatic Reinfection.

BACKGROUND: There are few data on the full spectrum of disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across the lifespan from community-based or nonclinical settings. METHODS: We followed 2338 people in Managua, Nicaragua, aged <94 years from March 2020 through March 2021. SARS-CoV-2 infection was identified through real-time reverse transcription polymerase chain reaction (RT-PCR) or through enzyme-linked immunosorbent assay. Disease presentation was assessed at the time of infection or retrospectively by survey at the time of blood collection. RESULTS: There was a large epidemic that peaked between March and August 2020. In total, 129 RT-PCR-positive infections were detected, for an overall incidence rate of 5.3 infections per 100 person-years (95% confidence interval [CI], 4.4-6.3). Seroprevalence was 56.7% (95% CI, 53.5%-60.1%) and was consistent from age 11 through adulthood but was lower in children aged ≤10 years. Overall, 31.0% of the infections were symptomatic, with 54.7% mild, 41.6% moderate, and 3.7% severe. There were 2 deaths that were likely due to SARS-CoV-2 infection, yielding an infection fatality rate of 0.2%. Antibody titers exhibited a J-shaped curve with respect to age, with the lowest titers observed among older children and young adults and the highest among older adults. When compared to SARS-CoV-2-seronegative individuals, SARS-CoV-2 seropositivity at the midyear sample was associated with 93.6% protection from symptomatic reinfection (95% CI, 51.1%-99.2%). CONCLUSIONS: This population exhibited a very high SARS-CoV-2 seropositivity with lower-than-expected severity, and immunity from natural infection was protective against symptomatic reinfection.

Epidemics of chikungunya, Zika, and COVID-19 reveal bias in case-based mapping.

Accurate tracing of epidemic spread over space enables effective control measures. We examined three metrics of infection and disease in a pediatric cohort (N≈3,000) over two chikungunya and one Zika epidemic, and in a household cohort (N=1,793) over one COVID-19 epidemic in Managua, Nicaragua. We compared spatial incidence rates (cases/total population), infection risks (infections/total population), and disease risks (cases/infected population). We used generalized additive and mixed-effects models, Kulldorf's spatial scan statistic, and intracluster correlation coefficients. Across different analyses and all epidemics, incidence rates considerably underestimated infection and disease risks, producing large and spatially non-uniform biases distinct from biases due to incomplete case ascertainment. Infection and disease risks exhibited distinct spatial patterns, and incidence clusters inconsistently identified areas of either risk. While incidence rates are commonly used to infer infection and disease risk in a population, we find that this can induce substantial biases and adversely impact policies to control epidemics.

Analysis of reasons for loss to follow up in a prospective study in Chandigarh, India and impact from telecom changes.

OBJECTIVE: Mobile phones are used in research studies, to enroll and follow-up participants, collect data, and implement mHealth initiatives. We conducted a longitudinal study in a birth cohort, where infants were required to make four scheduled visits by 12 months of age. Families of those failing to attend scheduled follow-up visits, were contacted telephonically to ascertain the reasons, which were categorized as: not interested to continue participating, migrated, phone disconnected due to telecom change, or other reason. RESULTS: A total of 413 mother-infant dyads were enrolled. The overall attrition was 56%, with majority occurring at the first follow-up visit. This temporally coincided with a telecom service provider announcing strong incentives to switch providers. Attrition monotonically decreased at subsequent visits. The reasons were: moved away (13%), no longer interested (8%), phone disconnected (7%), and multiple other reasons (28%), the majority of whom had unreachable phones. Those who remained in the study and those lost to follow-up were similar on most demographic variables. Among common reasons for attrition in cohort studies, we experienced a new dimension introduced by telecom changes. These findings underscore the need to consider unexpected reasons for attrition in longitudinal studies, and design more robust methods to follow-up participants.

Macrophage Selenoproteins Restrict Intracellular Replication of Francisella tularensis and Are Essential for Host Immunity.

The essential micronutrient Selenium (Se) is co-translationally incorporated as selenocysteine into proteins. Selenoproteins contain one or more selenocysteines and are vital for optimum immunity. Interestingly, many pathogenic bacteria utilize Se for various biological processes suggesting that Se may play a role in bacterial pathogenesis. A previous study had speculated that Francisella tularensis, a facultative intracellular bacterium and the causative agent of tularemia, sequesters Se by upregulating Se-metabolism genes in type II alveolar epithelial cells. Therefore, we investigated the contribution of host vs. pathogen-associated selenoproteins in bacterial disease using F. tularensis as a model organism. We found that F. tularensis was devoid of any Se utilization traits, neither incorporated elemental Se, nor exhibited Se-dependent growth. However, 100% of Se-deficient mice (0.01 ppm Se), which express low levels of selenoproteins, succumbed to F. tularensis-live vaccine strain pulmonary challenge, whereas 50% of mice on Se-supplemented (0.4 ppm Se) and 25% of mice on Se-adequate (0.1 ppm Se) diet succumbed to infection. Median survival time for Se-deficient mice was 8 days post-infection while Se-supplemented and -adequate mice was 11.5 and >14 days post-infection, respectively. Se-deficient macrophages permitted significantly higher intracellular bacterial replication than Se-supplemented macrophages ex vivo, corroborating in vivo observations. Since Francisella replicates in alveolar macrophages during the acute phase of pneumonic infection, we hypothesized that macrophage-specific host selenoproteins may restrict replication and systemic spread of bacteria. F. tularensis infection led to an increased expression of several macrophage selenoproteins, suggesting their key role in limiting bacterial replication. Upon challenge with F. tularensis, mice lacking selenoproteins in macrophages (TrspM) displayed lower survival and increased bacterial burden in the lung and systemic tissues in comparison to WT littermate controls. Furthermore, macrophages from TrspM mice were unable to restrict bacterial replication ex vivo in comparison to macrophages from littermate controls. We herein describe a novel function of host macrophage-specific selenoproteins in restriction of intracellular bacterial replication. These data suggest that host selenoproteins may be considered as novel targets for modulating immune response to control a bacterial infection.

Constitutive Oxidative Stress by SEPHS1 Deficiency Induces Endothelial Cell Dysfunction.

The primary function of selenophosphate synthetase (SEPHS) is to catalyze the synthesis of selenophosphate that serves as a selenium donor during selenocysteine synthesis. In eukaryotes, there are two isoforms of SEPHS (SEPHS1 and SEPHS2). Between these two isoforms, only SEPHS2 is known to contain selenophosphate synthesis activity. To examine the function of SEPHS1 in endothelial cells, we introduced targeted null mutations to the gene for SEPHS1, Sephs1, in cultured mouse 2H11 endothelial cells. SEPHS1 deficiency in 2H11 cells resulted in the accumulation of superoxide and lipid peroxide, and reduction in nitric oxide. Superoxide accumulation in Sephs1-knockout 2H11 cells is due to the induction of xanthine oxidase and NADPH oxidase activity, and due to the decrease in superoxide dismutase 1 (SOD1) and 3 (SOD3). Superoxide accumulation in 2H11 cells also led to the inhibition of cell proliferation and angiogenic tube formation. Sephs1-knockout cells were arrested at G2/M phase and showed increased gamma H2AX foci. Angiogenic dysfunction in Sephs1-knockout cells is mediated by a reduction in nitric oxide and an increase in ROS. This study shows for the first time that superoxide was accumulated by SEPHS1 deficiency, leading to cell dysfunction through DNA damage and inhibition of cell proliferation.

Identification of Signaling Pathways for Early Embryonic Lethality and Developmental Retardation in Sephs1-/- Mice.

Selenophosphate synthetase 1 (SEPHS1) plays an essential role in cell growth and survival. However, the underlying molecular mechanisms remain unclear. In the present study, the pathways regulated by SEPHS1 during gastrulation were determined by bioinformatical analyses and experimental verification using systemic knockout mice targeting Sephs1. We found that the coagulation system and retinoic acid signaling were most highly affected by SEPHS1 deficiency throughout gastrulation. Gene expression patterns of altered embryo morphogenesis and inhibition of Wnt signaling were predicted with high probability at E6.5. These predictions were verified by structural abnormalities in the dermal layer of Sephs1-/- embryos. At E7.5, organogenesis and activation of prolactin signaling were predicted to be affected by Sephs1 knockout. Delay of head fold formation was observed in the Sephs1-/- embryos. At E8.5, gene expression associated with organ development and insulin-like growth hormone signaling that regulates organ growth during development was altered. Consistent with these observations, various morphological abnormalities of organs and axial rotation failure were observed. We also found that the gene sets related to redox homeostasis and apoptosis were gradually enriched in a time-dependent manner until E8.5. However, DNA damage and apoptosis markers were detected only when the Sephs1-/- embryos aged to E9.5. Our results suggest that SEPHS1 deficiency causes a gradual increase of oxidative stress which changes signaling pathways during gastrulation, and afterwards leads to apoptosis.