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This article examines heterogeneity in adverse events and conditions and how low-income African American young adults respond. Although nearly all individuals in the sample report at least one instance of adversity, the nature and frequency of adversity varies, as do the responses. Some individuals see their lives and plans derailed; others engage in more protective strategies. For still others, adversity presents a difficult trade-off between surviving and thriving. We formalize this trade-off as an extension of a basic model of costly human capital investments. The model shows that a rational, fully informed individual facing this brutal trade-off, in an effort to survive the fallout of adversity, may optimally choose not to make high-return investments that promote thriving in the future. Improved policy design would recognize this type of trade-off.

Ataxia with anti-regulator of G-protein signaling 8 autoantibodies (RGS8-Abs) is an autoimmune disease recently described in four patients. The present study aimed to identify other patients with RGS8-Abs, describe their clinical features, including the link between RGS8-related autoimmune cerebellar ataxia (ACA) and cancer. Patients with RGS8-Abs were identified retrospectively in the biological collections of the French Reference Center for Paraneoplastic Neurological Syndrome and the University of California San Francisco Center for Encephalitis and Meningitis. Clinical data were collected, and cerebrospinal fluid, serum, and tumor pathological samples were retrieved to characterize the autoantibodies and the associated malignancies. Only three patients with RGS8-Abs were identified. All of them presented with a pure cerebellar ataxia of mild to severe course, unresponsive to current immunotherapy regimens for ACA. Two patients presented with a Hodgkin lymphoma of the rare specific subtype called nodular lymphocyte-predominant Hodgkin lymphoma, with very mild extension. Autoantibodies detected in all patients enriched the same epitope on the RGS8 protein, which is an intracellular protein physiologically expressed in Purkinje cells but also ectopically expressed specifically in lymphoma cells of patients with RGS8-related ACA. The present results and those of the four cases previously described suggest that RGS8-Abs define a new paraneoplastic neurological syndrome of extreme rarity found mostly in middle-aged males that associates pure cerebellar ataxia and a particular lymphoma specifically expressing the RGS8 antigen. As in other paraneoplastic ACA with intracellular antigen, the disease course is severe, and patients tend to exhibit a poor response to immune therapy.

BackgroundPrenatal folate supplementation has been consistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity and led to inconclusive results.MethodsWe evaluated whether ∼2,900 single-nucleotide polymorphisms (SNP) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control studies in the Childhood Cancer and Leukemia International Consortium (n = 9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software.ResultsNone of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni P-value of 5 × 10-6 and less-stringent P-value of 3.5 × 10-5 accounting for the number of "independent" SNPs). None of the 10 top (nonsignificant) SNPs and corresponding genes overlapped across ancestry groups.ConclusionsThis large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups.ImpactGenetic variants in the folate pathway alone do not appear to substantially influence childhood acute lymphoblastic leukemia risk. Other mechanisms such as gene-folate interaction, DNA methylation, or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

Sound speed is a critical parameter in ocean acoustic studies, as it determines the propagation and interpretation of recorded sounds. The potential for exploiting oceanic vessel noise as a sound source of opportunity to estimate ocean sound speed profile is investigated. A deep learning-based inversion scheme, relying upon the underwater radiated noise of moving vessels measured by a single hydrophone, is proposed. The dataset used for this study consists of Automatic Identification System data and acoustic recordings of maritime vessels transiting through the Santa Barbara Channel between January 2015 and December 2017. The acoustic recordings and vessel descriptors are used as predictors for regressing sound speed for each meter in the top 200 m of the water column, where sound speeds are most variable. Multiple (typically ranging between 4 and 10) transits were recorded each day; therefore, this dataset provides an opportunity to investigate whether multiple acoustic observations can be leveraged together to improve inversion estimates. The proposed single-transit and multi-transit models resulted in depth-averaged root-mean-square errors of 1.79 and 1.55 m/s, respectively, compared to the seasonal average predictions of 2.80 m/s.

Hispanic/Latino children have the highest risk of acute lymphoblastic leukemia (ALL) in the US compared to other racial/ethnic groups, yet the basis of this remains incompletely understood. Through genetic fine-mapping analyses, we identified a new independent childhood ALL risk signal near IKZF1 in self-reported Hispanic/Latino individuals, but not in non-Hispanic White individuals, with an effect size of ∼1.44 (95% confidence interval = 1.33-1.55) and a risk allele frequency of ∼18% in Hispanic/Latino populations and

Online learning is one form of distance education mediated through information and communications technology. We used a descriptive research design to develop and validate a multidimensional instrument to assess readiness and motivations for online learning. We provided a theoretical framework to better understand the concept of readiness for online learning and motivations to learn online. We assessed the need for a professional online Master's degree in Agricultural Education from Clemson University and participants' experience with online learning. Participants in this study included 531 Cooperative Extension agents, Natural Resource Conservation Agency, Farm Service Agency employees, and School-based agricultural educators from South Carolina, North Carolina, and Georgia. Of those, 96 participants completed the open-ended question. The study findings revealed that the survey instrument is a valid and reliable tool. Most participants reported a tendency for self-directed learning as they indicated having higher learning expectations performances. Individuals who perceive themselves as capable of performing a specific task or behavior have high levels of self-efficacy. Participants expressed that distance from campus--no need to relocate, and flexibility were their primary motivators to enroll in online learning. Many prefer using asynchronous technologies since they provide a more convenient environment where they can work at their own pace and better balance their work and school responsibilities. Results may also suggest that participants who are motivated to pursue an online degree place a high value on being self-directed learners since they can plan, monitor, and evaluate their own learning process.

Granulomatous amebic encephalitis, caused by the free-living amebae Balamuthia mandrillaris or Acanthamoeba species, is a rare and deadly infectious syndrome with a current mortality rate of >90%. Much work remains to define the optimal treatment for these infections. Here, we provide a comprehensive overview of the supporting evidence behind antimicrobials currently recommended by the Centers for Disease Control and Prevention (CDC) with updated statistics on survival rates and medication usage from the CDC Free-Living Ameba Database. We also discuss promising treatments, especially the emerging therapeutic agent nitroxoline, and provide recommendations for the next steps in this area.

Antimicrobial resistant lower respiratory tract infections are an increasing public health threat and an important cause of global mortality. The lung microbiome can influence susceptibility of respiratory tract infections and represents an important reservoir for exchange of antimicrobial resistance genes. Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene burden, however, corollary studies in the lung microbiome remain absent. We performed an observational study of children and adults with acute respiratory failure admitted to the intensive care unit. From tracheal aspirate RNA sequencing data, we evaluated age-related differences in detectable antimicrobial resistance gene expression in the lung microbiome. Using a multivariable logistic regression model, we find that detection of antimicrobial resistance gene expression was significantly higher in adults compared with children after adjusting for demographic and clinical characteristics. This association remained significant after additionally adjusting for lung bacterial microbiome characteristics, and when modeling age as a continuous variable. The proportion of adults expressing beta-lactam, aminoglycoside, and tetracycline antimicrobial resistance genes was higher compared to children. Together, these findings shape our understanding of the lung resistome in critically ill patients across the lifespan, which may have implications for clinical management and global public health.

Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P

Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide library for phage display immunoprecipitation and sequencing (PhIP-seq) in profiling mouse autoantibodies. This library was validated using 7 genetically distinct mouse lines across a spectrum of autoreactivity. Mice deficient in antibody production (Rag2-/- and μMT) were used to model nonspecific peptide enrichments, while cross-reactivity was evaluated using anti-ovalbumin B cell receptor-restricted OB1 mice as a proof of principle. The PhIP-seq approach was then utilized to interrogate 3 distinct autoimmune disease models. First, serum from Lyn-/- IgD+/- mice with lupus-like disease was used to identify nuclear and apoptotic bleb reactivities. Second, serum from nonobese diabetic (NOD) mice, a polygenic model of pancreas-specific autoimmunity, was enriched in peptides derived from both insulin and predicted pancreatic proteins. Lastly, Aire-/- mouse sera were used to identify numerous autoantigens, many of which were also observed in previous studies of humans with autoimmune polyendocrinopathy syndrome type 1 carrying recessive mutations in AIRE. These experiments support the use of murine proteome-wide PhIP-seq for antigenic profiling and autoantibody discovery, which may be employed to study a range of immune perturbations in mouse models of autoimmunity profiling.

Two independent temporal-spatial clusters of hospital-onset Rhizopus infections were evaluated using whole-genome sequencing (WGS). Phylogenetic analysis confirmed that isolates within each cluster were unrelated despite epidemiological suspicion of outbreaks. The ITS1 region alone was insufficient for accurate analysis. WGS has utility for rapid rule-out of suspected nosocomial Rhizopus outbreaks.

BackgroundAssociations between maternal tobacco exposure during pregnancy and childhood acute lymphoblastic leukemia (ALL) have yielded mixed results. This may be due to biases in self-reported smoking or other differences in individual-level risk factors. We utilized a biological marker of maternal tobacco exposure to evaluate the association between maternal tobacco exposure during pregnancy, genetics, and subsequent childhood ALL risk in two large population-based studies of childhood ALL in California.MethodsMaternal exposure to tobacco smoke was assessed with a validated methylation marker (cg05575921) of the aryl hydrocarbon receptor repressor (AHRR) gene in newborn dried blood spots. We adjusted for sex, birthweight, gestational age, mode of delivery, year of birth, AHRR quantitative trait locus (mQTL) rs77111113, and a polygenetic risk score for childhood ALL. We additionally adjusted for principal components in a gene-environment interaction testing method that incorporates gene-only and environment-only effects along with interactions.ResultsAHRR hypomethylation overall was not associated with childhood ALL. In gene-environment interaction testing, several genetic variants displayed significant interaction with AHRR hypomethylation and childhood ALL.ConclusionsOur results suggest that novel candidates in PTPRK and DPP6 may play a role in tobacco-related leukemogenesis. Further research is necessary to better understand the effects of tobacco and these variants on childhood ALL risk.ImpactDespite the lack of an overall "main effect," tobacco exposure during pregnancy affects childhood ALL risk depending on specific genetic variants.

Abstract Background In 2021, an estimated 750,000 people died from malaria. Despite this significant burden, globally, malaria incidence and mortality rates have substantially dropped over the last 30 years. However, growth in spending on malaria and improved outcomes have recently stagnated. This development has made it more important than ever to understand what constitutes efficient spending on malaria. Methods Data from various sources, including disaggregated data on malaria spending from the WHO Global Malaria Programme, National Health Accounts, and the Global Burden of Disease 2021 study was used in this study. The National Health Account report is produced at the end of a national accounting exercise that aims to map the flow of financial resources from all perspectives—incl. sources, agencies—in the health sector. Malaria spending estimates for all malaria-endemic countries from 2000 to 2020, with government and donor spending disaggregated into 11 key programme areas were generated in this study. Then, these spending estimates were combined with outcome data and estimated country efficiency using robust non-parametric stochastic frontier analysis and linear regression to examine the types of malaria spending associated with better malaria outcomes. Results Across malaria-endemic countries, there is wide variation in malaria spending, with spending associated with the malaria burden within the country. Argentina, Paraguay, and Turkmenistan stood out as examples of low spending relative to their respective malaria incident per person at risk rates, while the Philippines, Guatemala, and Sri Lanka stood out as countries with case fatality ratios that were low relative to their malaria spending. Having a greater proportion of malaria spending sourced from donors or on prevention was associated with increases in incidence efficiency, while having a greater proportion of spending on anti-malarial medicines was associated with increases in case fatality efficiency. Conclusions Prioritization of spending on prevention, anti-malarial medicines, and health systems strengthening can fight incident cases and fatalities simultaneously, especially in resource-scarce, malaria-endemic countries. Furthermore, improving the availability, frequency of collection, and quality of detailed disaggregated spending data is essential to support work that strengthens the evidence base on spending efficiency and work that improves understanding of how spending on malaria could be leveraged to bridge gaps in equity across population groups.

Abstract Secondary bacterial pneumonia (2°BP) is associated with significant morbidity following respiratory viral infection, yet remains incompletely understood. In a prospective cohort of 112 critically ill adults intubated for COVID-19, we comparatively assess longitudinal airway microbiome dynamics and the pulmonary transcriptome of patients who developed 2°BP versus controls who did not. We find that 2°BP is significantly associated with both mortality and corticosteroid treatment. The pulmonary microbiome in 2°BP is characterized by increased bacterial RNA mass and dominance of culture-confirmed pathogens, detectable days prior to 2°BP clinical diagnosis, and frequently also present in nasal swabs. Assessment of the pulmonary transcriptome reveals suppressed TNFα signaling in patients with 2°BP, and sensitivity analyses suggest this finding is mediated by corticosteroid treatment. Further, we find that increased bacterial RNA mass correlates with reduced expression of innate and adaptive immunity genes in both 2°BP patients and controls. Taken together, our findings provide fresh insights into the microbial dynamics and host immune features of COVID-19-associated 2°BP, and suggest that suppressed immune signaling, potentially mediated by corticosteroid treatment, permits expansion of opportunistic bacterial pathogens.

Abstract Guideline concordant opioid therapy is a key part of the concerted effort to address the opioid crisis in the United States. The study aimed to compare the rates of guideline concordant care between veterans who solely used VA services (mono users) and veterans who used both VA services and community care (dual-system users). We used electronic health record data from the Washington DC and Baltimore VA Medical Centers from 2015 to 2019. We provided descriptive statistics as well as generalized estimating equations models to find associations between mono vs. dual-system users and each guideline outcome, controlling for demographic factors and comorbid conditions. The study found that overall rates of guideline concordant care were high in both mono and dual-system users with over 90% adherence rates for the majority of recommendations. However, there were variations in adherence to specific guidelines, with urine drug screening at initiation being the least commonly followed recommendation (8.9% of mono-user opioid initiators and 11.2% of dual-user initiators). This study also found that there was no consistent pattern of higher guideline adherence in mono vs. dual-system users but did show that through the course of this study (2015–2019) overall rates of guideline concordance increased. Future research will explore additional guideline recommendations and potential coordination issues among dual-system users.

Abstract Background With the advances in high-throughput sequencing and bioinformatic pipelines, mitochondrial genomes have become increasingly popular for phylogenetic analyses across different clades of invertebrates. Despite the vast rise in available mitogenomic datasets of molluscs, one class of aplacophoran molluscs – Solenogastres (or Neomeniomorpha) – is still neglected. Results Here, we present six new mitochondrial genomes from five families of Solenogastres (Amphimeniidae, Gymnomeniidae, Proneomeniidae, Pruvotinidae, Simrothiellidae), including the first complete mitogenomes, thereby now representing three of the four traditional orders. Solenogaster mitogenomes are variable in size (ranging from approximately 15,000 bp to over 17,000 bp). The gene order of the 13 protein coding genes and two rRNA genes is conserved in three blocks, but considerable variation occurs in the order of the 22 tRNA genes. Based on phylogenetic analyses and reconstruction of ancestral mitochondrial genomes of Aculifera, the position of (1) trnD gene between atp8 and atp6, (2) trnT and P genes between atp6 and nad5, and (3) trnL1 gene between G and E, resulting in a ‘MCYWQGL1E’-block of tRNA genes, are all three considered synapomorphies for Solenogastres. The tRNA gene block ‘KARNI’ present in Polyplacophora and several conchiferan taxa is dissolved in Solenogastres. Conclusion Our study shows that mitogenomes are suitable to resolve the phylogenetic relationships among Aculifera and within Solenogastres, thus presenting a cost and time efficient compromise to approach evolutionary history in these clades.

Abstract Schizophrenia and schizoaffective disorder present burdens to patients and health systems through elevated healthcare resource utilization (HCRU) and costs. However, there is a paucity of evidence describing these burdens across payor types. To identify unmet needs, this study characterized patients with schizophrenia or schizoaffective disorder by payor type. We identified patients aged 12–94 years with newly diagnosed schizophrenia or schizoaffective disorder (index date) between 01/01/2014 and 08/31/2020 with continuous enrollment for 12 months before and after index date from the Healthcare Integrated Research Database. After stratifying by post-index relapse frequency (0, 1, or ≥2) and payor type (commercial, Medicare Advantage/Supplemental (Medigap)/Part D, or managed Medicaid), we examined patient characteristics, treatment patterns, HCRU, costs, and relapse patterns and predictors. During follow-up, 25% of commercial patients, 29% of Medicare patients, and 37% of Medicaid patients experienced relapse. Atypical antipsychotic discontinuation was most common among Medicaid patients, with 65% of these patients discontinuing during follow-up. Compared to commercial patients, Medicare and Medicaid patients had approximately half as many psychotherapy visits during follow-up (12 vs. 5 vs. 7 visits, respectively). Relative to baseline, average unadjusted all-cause costs during follow-up increased by 105% for commercial patients, 66% for Medicare patients, and 77% for Medicaid patients. Patients with schizophrenia or schizoaffective disorder had high HCRU and costs but consistently low psychotherapy utilization, and they often discontinued pharmacologic therapy and experienced relapse. These findings illustrate the high burden and unmet need for managing these conditions and opportunities to improve care for underserved patients.

Objective Interstitial lung diseases (ILDs) are a heterogeneous group of disorders that can develop in patients with connective tissue diseases. Establishing autoimmunity in ILD impacts prognosis and treatment. Patients with ILD are screened for autoimmunity by measuring antinuclear autoantibodies, rheumatoid factors, and other nonspecific tests. However, this approach may miss autoimmunity that manifests as autoantibodies to tissue antigens not previously defined in ILD. Methods We use Phage Immunoprecipitation‐Sequencing (PhIP‐Seq) to conduct an autoantibody discovery screen of patients with ILD and controls. We screened for novel autoantigen candidates using PhIP‐Seq. We next developed a radio‐labeled binding assay and validated the leading candidate in 398 patients with ILD recruited from two academic medical centers and 138 blood bank individuals that formed our reference cohort. Results PhIP‐Seq identified 17 novel autoreactive targets, and machine learning classifiers derived from these targets discriminated ILD serum from controls. Among the 17 candidates, we validated CDHR5 and found CDHR5 autoantibodies in patients with rheumatologic disorders and importantly, patients not previously diagnosed with autoimmunity. Using survival and transplant free–survival data available from one of the two centers, patients with CDHR5 autoantibodies showed worse survival compared with other patients with connective tissue disease ILD. Conclusion We used PhIP‐Seq to define a novel CDHR5 autoantibody in a subset of select patients with ILD. Our data complement a recent study showing polymorphisms in the CDHR5‐IRF7 gene locus strongly associated with titer of anticentromere antibodies in systemic sclerosis, creating a growing body of evidence suggesting a link between CDHR5 and autoimmunity.

Abstract Trace levels of biologically precipitated magnetite (Fe3O4) nanocrystals are present in the tissues of many living organisms, including those of plants. Recent work has also shown that magnetite nanoparticles are powerful ice nucleation particles (INPs) that can initiate heterogeneous freezing in supercooled water just below the normal melting temperature. Hence there is a strong possibility that magnetite in plant tissues might be an agent responsible for triggering frost damage, even though the biological role of magnetite in plants is not understood. To test this hypothesis, we investigated supercooling and freezing mortality in cloves of garlic (Allium sativum), a species which is known to have moderate frost resistance. Using superconducting magnetometry, we detected large numbers of magnetite INPs within individual cloves. Oscillating magnetic fields designed to torque magnetite crystals in situ and disturb the ice nucleating process produced significant effects on the temperature distribution of supercooling, thereby confirming magnetite’s role as an INP in vivo. However, weak oscillating fields increased the probability of freezing, whereas stronger fields decreased it, a result that predicts the presence of magnetite binding agents that are loosely attached to the ice nucleating sites on the magnetite crystals.

The purpose of this manuscript is to examine the implications of the current ideological underpinnings of sport education programs (SEPs) in the United States (U.S.) and present a new equity-minded and anti-ism sport education (EASE) framework that reflects a paradigm shift towards equity-mindedness, anti-ism, cultural responsiveness, inclusive excellence, and transformational leadership. The sport industry has transformed from modest recreational activities for leisure entertainment at the local levels into a multi-billion-dollar global corporatized industry with far-reaching economic, political and sociocultural impacts. Despite the growth in popularity of SEPs, a major area of concern is the lack of critical reflection on their sociopolitical and cultural origins of the curriculum and corresponding metrics of success. Thus, we argue current SEPs (e.g. sport management, sport administration, sport leadership, sport business, parks and recreation, and sport entertainment, hospitality, and tourism) perpetuate colorblind racism, sexism, and classism based on their philosophical foundations. In an effort to reflect a responsiveness to an increasingly global and multicultural sport industry, we present a new EASE framework for preparing professionals to ignite transformational change in and through sport in the twenty-first century.

Campus maps and architectural images from institutional websites were used to compare 45 collegiate institutions cited in prior literature as manifesting traits of either conventional or nonconformist student cultures. Based on person--environment interaction theory, it was anticipated that the physical traits of campuses associated with conventional student cultures would be more uniform than those of campuses associated with nonconformist student cultures. Nonparametric tests revealed significant differences in the anticipated direction on three of six aspects of architectural design (i.e., color, roofline, and ornamentation). Differences in uniformity of campus layout were in the anticipated direction but fell slightly short of statistical significance.