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Background: Obesity disproportionately affects marginalized and low-income populations. Birth parent obesity from the prenatal period and childhood has been associated with child obesity. It is unknown whether prenatal or postnatal birth parent obesity has differential effects on subsequent changes in adiposity and metabolic health in children. Objectives: We evaluated how birth parent obesity 7 y after delivery was associated with child body composition changes and cardiometabolic health in midchildhood and further assessed the influence of the perinatal and postpartum period on associations. Methods: Black and Dominican pregnant individuals were enrolled, and dyads (n = 319) were followed up at child age 7 and 9 y. Measures included, height, weight, waist circumference (WC), and percent body fat (BF%). Multiple linear regression was used to relate postpartum weight status with child outcomes accounting for attrition, and a series of secondary analyses were conducted with additional adjustment for perinatal weight status, gestational weight gain (GWG), and/or long-term weight retention to evaluate how these factors influenced associations. Results: Almost one-quarter (23%) of birth parents and 24.1% children were classified with obesity at child age 7 y, while at 9 y, 30% of children had obesity. Birth parent obesity at child age 7 y was associated with greater changes, from ages 7 to 9 y, in child BMI z-score (ß: 0.13; 95% CI: 0.02, 0.24) and BF% (ß: 1.15; 95% CI: 0.22, 2.09) but not obesity at age 9 y. All observed associations crossed the null after additional adjustment for prenatal factors. Conclusions: Birth parent obesity at 7-y postpartum is associated with greater gains in child BMI z-score and BF% in midchildhood. These associations diminish after accounting for prenatal size, suggesting a lasting impact of the perinatal environment and that interventions supporting families from the prenatal period through childhood are needed.

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Due to their natural history and ecological attributes, turtles are excellent organisms for studies of heavy metal contamination. Turtles have a large geographical distribution, occupy different aquatic habitats, and occupy various trophic levels. The present study investigated mercury bioaccumulation in the carnivorous chelonian Chelus fimbriata (Matamata turtle) and Hg biomagnification in relation to its aquatic food chain in the middle Rio Negro, AM-Brazil. Tissue samples of muscle, carapace and claws were collected from 26 C. fimbriata individuals, as well as collections of autotrophic energy sources found in the turtle's aquatic habitat area. The samples were collected in February-March/2014 and analyzed for THg concentrations and carbon (δ13C) and nitrogen (δ15N) stable isotopes. The highest THg levels were found in claws (3780 ng.g-1), carapace (3622 ng.g-1) and muscle (403 ng.g-1), which were found to be significantly different [F(2.73) = 49.02 p < 0.01]. However, THg concentrations in muscle tissue were below the consumption threshold indicated by the WHO and Brazilian Health Ministry. The average δ13C and δ15N values in Matamata samples were -31.7‰ and 11.9‰, respectively. The principal energy source sustaining the food chain of C. fimbriata was found to be terrestrial shrubs, with smaller contributions from emergent aquatic herbaceous plants and algae, while δ15N values showed its trophic position to be two levels above the autotrophic energy sources. There was a positive correlation between THg and turtle size, while a significant relationship was found between THg and δ15N, showing strong biomagnification in the food chain of C. fimbriata: y = 0.21x + 0.46; r2 = 0.45; p < 0.001, for which the slope presented a value of 0.21.

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OBJECTIVE: The objective of this study was to examine associations between umbilical cord mitochondrial DNA copy number (mtDNAcn) and adiposity across childhood. METHODS: In a prospective birth cohort of Dominican and African American children from New York City, New York (1998-2006), mtDNAcn was measured in cord blood. Children (N = 336) were evaluated for their height, weight, and bioimpedance at age 5, 7, 9, and 11 years. We used linear mixed-effects models to assess associations of mtDNAcn tertiles in cord blood with child BMI, BMI z scores, fat mass index, and body fat percentage. Latent class growth models and interactions between mtDNAcn and child age or child age2 were used to assess associations between age and adiposity trajectories. RESULTS: BMI was, on average, 1.5 kg/m2 higher (95% CI: 0.58, 2.5) in individuals with mtDNAcn in the low- compared with the middle-mtDNAcn tertile. Results were similar for BMI z score, fat mass index, and body fat percentage. Moreover, children in the low-mtDNAcn group had increased odds of being in an "increasing" or "high-stable" adiposity class. CONCLUSIONS: Lower mtDNAcn at birth may predict greater childhood adiposity, highlighting the potential key role of perinatal mitochondrial function in adiposity during development.

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ABSTRACT: CD20 is an established therapeutic target in B-cell malignancies. The CD20 × CD3 bispecific antibody mosunetuzumab has significant efficacy in B-cell non-Hodgkin lymphomas (NHLs). Because target antigen loss is a recognized mechanism of resistance, we evaluated CD20 expression relative to clinical response in patients with relapsed and/or refractory NHL in the phase 1/2 GO29781 trial investigating mosunetuzumab monotherapy. CD20 was studied using immunohistochemistry (IHC), RNA sequencing, and whole-exome sequencing performed centrally in biopsy specimens collected before treatment at predose, during treatment, or upon progression. Before treatment, most patients exhibited a high proportion of tumor cells expressing CD20; however, in 16 of 293 patients (5.5%) the proportion was <10%. Analyses of paired biopsy specimens from patients on treatment revealed that CD20 levels were maintained in 29 of 30 patients (97%) vs at progression, where CD20 loss was observed in 11 of 32 patients (34%). Reduced transcription or acquisition of truncating mutations explained most but not all cases of CD20 loss. In vitro modeling confirmed the effects of CD20 variants identified in clinical samples on reduction of CD20 expression and missense mutations in the extracellular domain that could block mosunetuzumab binding. This study expands the knowledge about the occurrence of target antigen loss after anti-CD20 therapeutics to include CD20-targeting bispecific antibodies and elucidates mechanisms of reduced CD20 expression at disease progression that may be generalizable to other anti-CD20 targeting agents. These results also confirm the utility of readily available IHC staining for CD20 as a tool to inform clinical decisions. This trial was registered at www.ClinicalTrials.gov as #NCT02500407.

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Abstract Background To illustrate how (standardised) effect sizes (ES) vary based on calculation method and to provide considerations for improved reporting. Methods Data from three trials of tanezumab in subjects with osteoarthritis were analyzed. ES of tanezumab versus comparator for WOMAC Pain (outcome) was defined as least squares difference between means (mixed model for repeated measures analysis) divided by a pooled standard deviation (SD) of outcome scores. Three approaches to computing the SD were evaluated: Baseline (the pooled SD of WOMAC Pain values at baseline [pooled across treatments]); Endpoint (the pooled SD of these values at the time primary endpoints were assessed); and Median (the median pooled SD of these values based on the pooled SDs across available timepoints). Bootstrap analyses were used to compute 95% confidence intervals (CI). Results ES (95% CI) of tanezumab 2.5 mg based on Baseline, Endpoint, and Median SDs in one study were - 0.416 (- 0.796, - 0.060), - 0.195 (- 0.371, - 0.028), and - 0.196 (- 0.373, - 0.028), respectively; negative values indicate pain improvement. This pattern of ES differences (largest with Baseline SD, smallest with Endpoint SD, Median SD similar to Endpoint SD) was consistent across all studies and doses of tanezumab. Conclusion Differences in ES affect interpretation of treatment effect. Therefore, we advocate clearly reporting individual elements of ES in addition to its overall calculation. This is particularly important when ES estimates are used to determine sample sizes for clinical trials, as larger ES will lead to smaller sample sizes and potentially underpowered studies. Trial Registration Clinicaltrials.gov NCT02697773, NCT02709486, and NCT02528188.

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OBJECTIVE: In the presurgical evaluation of patients with drug-resistant epilepsy (DRE), occasionally, patients do not experience spontaneous typical seizures (STS) during a stereo-electroencephalography (SEEG) study, which limits its effectiveness. We sought to identify risk factors for patients who did not have STS during SEEG and to analyze the clinical outcomes for this particular set of patients. METHODS: We conducted a retrospective analysis of all patients with DRE who underwent depth electrode implantation and SEEG recordings between January 2013 and December 2018. RESULTS: SEEG was performed in 155 cases during this period. 11 (7.2%) did not experience any clinical seizures (non-STS group), while 143 experienced at least one patient-typical seizure during admission (STS group). No significant differences were found between STS and non-STS groups in terms of patient demographics, lesional/non-lesional epilepsy ratio, pre-SEEG seizure frequency, number of ASMs used, electrographic seizures or postoperative seizure outcome in those who underwent resective surgery. Statistically significant differences were found in the average number of electrodes implanted (7.0 in the non-STS group vs. 10.2 in STS), days in Epilepsy Monitoring Unit (21.8 vs. 12.8 days) and the number of cases that underwent resective surgery following SEEG (27.3% vs. 60.8%), respectively. The three non-STS patients (30%) who underwent surgery, all had their typical seizures triggered during ECS studies. Three cases were found to have psychogenic non-epileptic seizures. None of the patients in the non-STS group were offered neurostimulation devices. Five of the non-STS patients experienced transient seizure improvement following SEEG. SIGNIFICANCE: We were unable to identify any factors that predicted lack of seizures during SEEG recordings. Resective surgery was only offered in cases where ECS studies replicated patient-typical seizures. Larger datasets are required to be able to identify factors that predict which patients will fail to develop seizures during SEEG.

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BACKGROUND: The impact of cirrhosis and portal hypertension on perioperative outcomes of minimally invasive left lateral sectionectomies remains unclear. We aimed to compare the perioperative outcomes between patients with preserved and compromised liver function (noncirrhotics versus Child-Pugh A) when undergoing minimally invasive left lateral sectionectomies. In addition, we aimed to determine if the extent of cirrhosis (Child-Pugh A versus B) and the presence of portal hypertension had a significant impact on perioperative outcomes. METHODS: This was an international multicenter retrospective analysis of 1,526 patients who underwent minimally invasive left lateral sectionectomies for primary liver malignancies at 60 centers worldwide between 2004 and 2021. In the study, 1,370 patients met the inclusion criteria and formed the final study group. Baseline clinicopathological characteristics and perioperative outcomes of these patients were compared. To minimize confounding factors, 1:1 propensity score matching and coarsened exact matching were performed. RESULTS: The study group comprised 559, 753, and 58 patients who did not have cirrhosis, Child-Pugh A, and Child-Pugh B cirrhosis, respectively. Six-hundred and thirty patients with cirrhosis had portal hypertension, and 170 did not. After propensity score matching and coarsened exact matching, Child-Pugh A patients with cirrhosis undergoing minimally invasive left lateral sectionectomies had longer operative time, higher intraoperative blood loss, higher transfusion rate, and longer hospital stay than patients without cirrhosis. The extent of cirrhosis did not significantly impact perioperative outcomes except for a longer duration of hospital stay. CONCLUSION: Liver cirrhosis adversely affected the intraoperative technical difficulty and perioperative outcomes of minimally invasive left lateral sectionectomies.

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Antiretroviral therapy has been effective in suppressing HIV viral load and enabling people living with HIV to experience longer, more conventional lives. However, as people living with HIV are living longer, they are developing aging-related diseases prematurely and are more susceptible to comorbidities that have been linked to chronic inflammation. Coincident with HIV infection and aging, drug abuse has also been independently associated with gut dysbiosis, microbial translocation, and inflammation. Here, we hypothesized that injection drug use would exacerbate HIV-induced immune activation and inflammation, thereby intensifying immune dysfunction. We recruited 50 individuals not using injection drugs (36/50 HIV+) and 47 people who inject drugs (PWID, 12/47 HIV+). All but 3 of the HIV+ subjects were on antiretroviral therapy. Plasma immune profiles were characterized by immunoproteomics, and cellular immunophenotypes were assessed using mass cytometry. The immune profiles of HIV+/PWID-, HIV-/PWID+, and HIV+/PWID+ were each significantly different from controls; however, few differences between these groups were detected, and only 3 inflammatory mediators and 2 immune cell populations demonstrated a combinatorial effect of injection drug use and HIV infection. In conclusion, a comprehensive analysis of inflammatory mediators and cell immunophenotypes revealed remarkably similar patterns of immune dysfunction in HIV-infected individuals and in people who inject drugs with and without HIV-1 infection.

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OBJECTIVES: Mechanical power (MP) transferred from the ventilator to the lungs has been proposed as a summary variable that may impact mortality in children with acute respiratory distress syndrome (ARDS). To date, no study has shown an association between higher MP and mortality in children with ARDS. DESIGN: Secondary analysis of a prospective observational study. SETTING: Single-center, tertiary, academic PICU. PATIENTS: Five hundred forty-six intubated children with ARDS enrolled between January 2013 and December 2019 receiving pressure-controlled ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Higher MP was associated with increased mortality (adjusted hazard ratio [HR] 1.34 per 1 sd increase, 95% CI 1.08-1.65; p = 0.007). When assessing the contribution of individual components of MP, only positive end-expiratory pressure (PEEP) was associated with mortality (HR 1.32; p = 0.007), whereas tidal volume, respiratory rate, and driving pressure (ΔP = [peak inspiratory pressure (PIP)-PEEP]) were not. Finally, we tested whether there remained an association when specific terms were removed from the MP equation by calculating MP from static strain (remove ΔP), MP from dynamic strain (remove PEEP), and mechanical energy (remove respiratory rate). MP from static strain (HR 1.44; p < 0.001), MP from dynamic strain (HR 1.25; p = 0.042), and mechanical energy (HR 1.29; p = 0.009) were all associated with mortality. MP was associated with ventilator-free days only when using MP normalized to predicted body weight, but not when using measured weight. CONCLUSIONS: Higher MP was associated with mortality in pediatric ARDS, and PEEP appears to be the component most consistently driving this association. As higher PEEP is used in sicker patients, the association between MP and mortality may reflect a marker of illness severity rather than MP itself being causal for mortality. However, our results support future trials testing different levels of PEEP in children with ARDS as a potential means to improve outcome.

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Mitochondrial DNA copy number (mtDNAcn) dynamics throughout childhood are poorly understood. We profiled mtDNAcn from birth through adolescence and evaluated how the prenatal environment influences mtDNAcn across childhood. Data were collected from children from New York City followed through 18 years. Using duplexed qRT-PCR, we quantified mtDNAcn relative to nuclear DNA in blood collected from the umbilical cord (n = 450), children aged 5-7 (n = 510), and adolescents aged 15-18 (n = 278). We examined mtDNAcn across childhood with linear mixed-effects models (LMM). Relative mtDNAcn was lowest at birth (mean ± SD: 0.67 ± 0.35) and increased in childhood (1.24 ± 0.50) then slightly declined in adolescence (1.13 ± 0.44). We observed no differences in mtDNAcn by sex or race/ethnicity. mtDNAcn was positively associated with prenatal environmental tobacco smoke exposure (0.077 [ 0.01, 0.14] change in relative mtDNAcn) but negatively associated with maternal completion of high school (-0.066 [-0.13, 0.00]), with the receipt of public assistance at birth (-0.074 [-0.14, -0.01]), and when mother born outside the U.S (-0.061 [-0.13, 0.003]). Infant birth outcomes were not associated with mtDNAcn. MtDNAcn levels were dynamic through childhood and associated with some prenatal factors, underscoring the need for the investigation of longitudinal mtDNAcn for human health research.

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Background: Bartonella species are fastidious gram-negative vector-borne bacteria with a wide range of mammalian reservoirs. While it is understood that some species of Bartonella are human pathogens, the extent of human exposure to Bartonella species (both pathogenic and nonpathogenic) is yet to be fully understood. Materials and Methods: To this end, residual sera from participants enrolled in undifferentiated fever studies in Cambodia, Ghana, Laos, and Peru were screened for the presence of IgG antibodies against Bartonella quintana and Bartonella henselae, using the FOCUS diagnostics Dual Spot- Bartonella IgG Immunofluorescence assay. Forty-eight patients with suspected or confirmed Bartonella bacilliformis exposure or infection in Peru were screened to assess cross-reactivity of the FOCUS assay for IgG against other Bartonella species. Results: Ten of 13 patients with confirmed B. bacilliformis infection were Bartonella-specific IgG positive, and overall, 36/48 of the samples were positive. In addition, 79/206, 44/200, 101/180, and 57/100 of the samples from Peru, Laos, Cambodia, and Ghana, respectively, were Bartonella-specific IgG positive. Furthermore, ectoparasite pools from Cambodia, Laos, and Peru were tested using quantitative real-time PCR (qPCR) for the presence of Bartonella DNA. Of the sand fly pools collected in Peru, 0/196 were qPCR positive; 15/140 flea pools collected in Cambodia were qPCR positive; while 0/105 ticks, 0/22 fleas, and 0/3 louse pools collected in Laos tested positive for Bartonella DNA. Conclusion: Evidence of Bartonella in fleas from Cambodia supports the possibility that humans are exposed to Bartonella through this traditional vector. However, Bartonella species were not found in fleas, ticks, or lice from Laos, or sand flies from Peru. This could account for the lower positive serology among the population in Laos and the strictly localized nature of B. bacilliformis infections in Peru. Human exposure to the Bartonella species and Bartonella as a human pathogen warrants further investigation.

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Quorum sensing is an intercellular signaling mechanism that enables bacterial cells to coordinate population-level behaviors. How quorum sensing functions in natural habitats remains poorly understood. Vibrio fischeri is a bacterial symbiont of the Hawaiian bobtail squid Euprymna scolopes and depends on LuxI/LuxR quorum sensing to produce the symbiotic trait of bioluminescence. A previous study demonstrated that animals emit light when co-colonized by a Δlux mutant, which lacks several genes within the lux operon that are necessary for bioluminescence production, and a LuxI- mutant, which cannot synthesize the quorum signaling molecule N-3-oxohexanoyl-homoserine lactone. Here, we build upon that observation and show that populations of LuxI- feature elevated promoter activity for the lux operon. We find that population structures comprising of Δlux and LuxI- are attenuated within the squid, but a wild-type strain enables the LuxI- strain type to be maintained in vivo. These experimental results support a model of interpopulation signaling, which provides basic insight into how quorum sensing functions within the natural habitats found within a host.

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BACKGROUND: Marine recruits training at Parris Island experienced an unexpectedly high rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, despite preventive measures including a supervised, 2-week, pre-entry quarantine. We characterize SARS-CoV-2 transmission in this cohort. METHODS: Between May and November 2020, we monitored 2,469 unvaccinated, mostly male, Marine recruits prospectively during basic training. If participants tested negative for SARS-CoV-2 by quantitative polymerase chain reaction (qPCR) at the end of quarantine, they were transferred to the training site in segregated companies and underwent biweekly testing for 6 weeks. We assessed the effects of coronavirus disease 2019 (COVID-19) prevention measures on other respiratory infections with passive surveillance data, performed phylogenetic analysis, and modeled transmission dynamics and testing regimens. RESULTS: Preventive measures were associated with drastically lower rates of other respiratory illnesses. However, among the trainees, 1,107 (44.8%) tested SARS-CoV-2-positive, with either mild or no symptoms. Phylogenetic analysis of viral genomes from 580 participants revealed that all cases but one were linked to five independent introductions, each characterized by accumulation of mutations across and within companies, and similar viral isolates in individuals from the same company. Variation in company transmission rates (mean reproduction number R 0 ; 5.5 [95% confidence interval [CI], 5.0, 6.1]) could be accounted for by multiple initial cases within a company and superspreader events. Simulations indicate that frequent rapid-report testing with case isolation may minimize outbreaks. CONCLUSIONS: Transmission of wild-type SARS-CoV-2 among Marine recruits was approximately twice that seen in the community. Insights from SARS-CoV-2 outbreak dynamics and mutations spread in a remote, congregate setting may inform effective mitigation strategies.

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BACKGROUND: The California-Mexico border region is a high-volume trauma area with populations of widely disparate socioeconomic status. This work analyzed differences in demographics and mechanism of injury in children using the Area Deprivation Index (ADI), a composite measure of 17 markers of neighborhood socioeconomic disadvantage. METHODS: A retrospective review was performed of pediatric patients evaluated at the regional Level I Pediatric Trauma Center between 2008 and 2018. Collected data included patient demographics and injury characteristics. Patient addresses were correlated to neighborhood disadvantage level using ADI quintiles, with a higher quintile representing greater socioeconomic disadvantage. RESULTS: A total of 9,715 children were identified, of which 4,307 (44%) were Hispanic. Hispanic children were more likely to live in more disadvantaged neighborhoods than non-Hispanic children (p < 0.001). There were markedly different injury mechanisms in neighborhoods with greater socioeconomic disadvantage (higher ADI) compared with those with less socioeconomic disadvantage. Sports-related and nonmotorized vehicular trauma predominated in less disadvantaged neighborhoods, while higher ADI quintiles were strongly associated with pedestrian versus automobile, motorized vehicle accidents/collisions, and nonaccidental injuries (p < 0.001). CONCLUSION: This analysis represents the first study to characterize pediatric traumatic injury patterns based upon the neighborhood ADI metric. Area Deprivation Index can be a useful resource in identifying disparities in pediatric trauma and children at increased risk for vehicular and abusive injury who may benefit from increased resource allocation, social support, and prevention programs. LEVEL OF EVIDENCE: Prognostic and epidemiological, Level III.

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To perform a systematic review focusing on the prognosis of oral cavity squamous cell carcinoma (OSCC) in young patients (≤40 years old) compared to older (>40 years old). Four databases were used in our search strategy. First, all titles were systematically organized using the Covidence platform online. In the second phase, 118 full texts of potentially eligible studies were analyzed by reviewers independently and in pairs. Twelve studies were considered eligible for data extraction. The relapse was higher in the young than in controls (pooled relative risk (RR) = 1.31; 95% CI [1.10-1.56]). The 5-year disease-free survival (DFS) was worse in young group (pooled hazard ratio (HR) = 0.73; 95% CI [0.63-0.85]) but the 5-year overall survival (OS) estimate was similar between the groups (pooled HR = 0.84; 95% CI [0.70-1.00]). While the 5-year OS was similar between groups, the number of relapses and 5-year DFS were worse in patients with OSCC ≤40 years old.

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Research on glutamatergic neurotransmission has focused mainly on the function of presynaptic and postsynaptic neurons, leaving astrocytes with a secondary role only to ensure successful neurotransmission. However, recent evidence indicates that astrocytes contribute actively and even regulate neuronal transmission at different levels. This review establishes a framework by comparing glutamatergic components between neurons and astrocytes to examine how astrocytes modulate or otherwise influence neuronal transmission. We have included the most recent findings about the role of astrocytes in neurotransmission, allowing us to understand the complex network of neuron-astrocyte interactions. However, despite the knowledge of synaptic modulation by astrocytes, their contribution to specific physiological and pathological conditions remains to be elucidated. A full understanding of the astrocyte's role in neuronal processing could open fruitful new frontiers in the development of therapeutic applications.

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In this study, we genotyped samples from environmental reservoirs (surface water and soil), colonized rat specimens, and cases of human severe leptospirosis from an endemic urban slum in Brazil, to determine the molecular epidemiology of pathogenic Leptospira and identify pathways of leptospirosis infection. We identified a well-established population of Leptospira interrogans serovar Copenhageni common to human leptospirosis cases, and animal and environmental reservoirs. This finding provides genetic evidence for a potential environmental spillover pathway for rat-borne leptospirosis through the environment in this urban community and highlights the importance of environmental and social interventions to reduce spillover infections.

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