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Machine learning is a class of algorithms able to handle a large number of predictors with potentially nonlinear relationships. By applying machine learning to obesity, researchers can examine how risk factors across multiple settings (e.g.,school and home) interact to best predict childhood obesity risk. In this narrative review, we provide an overview of studies that have applied machine learning to predict childhood obesity using a combination of sociodemographic and behavioral risk factors. The objective is to summarize the key determinants of obesity identified in existing machine learning studies and highlight opportunities for future machine learning applications in the field. Of 15 peer-reviewed studies, approximately half examined early childhood (0–24 months of age) determinants. These studies identified child's weight history (e.g.,history of overweight/obesity or large increases in weight-related measures between birth and 24 months of age) and parental overweight/obesity (current or prior) as key risk factors, whereas the remaining studies indicated that social factors and physical inactivity were important in middle childhood and late childhood/adolescence. Across age groups, findings suggested that race/ethnic-specific models may be needed to accurately predict obesity from middle childhood onward. Future studies should consider using existing large data sets to take advantage of the benefits of machine learning and should collect a wider range of novel risk factors (e.g.,psychosocial and sociocultural determinants of health) to better predict childhood obesity. Ultimately, such research can aid in the development of effective obesity prevention interventions, particularly ones that address the disproportionate burden of obesity experienced by racial/ethnic minorities.

Animal models of kidney disease suggest a protective role for female sex hormones but in humans, some authorities assert that female sex is a risk factor for acute kidney injury (AKI). To better understand the risk of AKI, we studied the strength of association between sex and AKI incidence in hormonally distinct age groups across the life span.

Pain plays a significant role in emergency department (ED) visits, however safe and effective nonpharmacologic options are needed. Prior studies of acupuncture in the ED reported pain reduction with minimal side effects, but most were small and single site.

Oral squamous cell carcinoma (OSCC) patients generally have a poor prognosis, because of the invasive nature of these tumors. In comparing transcription profiles between OSCC tumors with a more invasive (worst pattern of tumor invasion 5) versus a less invasive (worst pattern of tumor invasion 3) pattern of invasion, we identified a total of 97 genes that were overexpressed at least 1.5-fold in the more invasive tumor subtype. The most functionally relevant genes were assessed using in vitroinvasion assays with an OSCC cell line (UM-SCC-1). Individual siRNA knockdown of 15 of these 45 genes resulted in significant reductions in tumor cell invasion compared to a nontargeting siRNA control. One gene whose knockdown had a strong effect on invasion corresponded to apolipoprotein E (APOE). Both matrix degradation and the number of mature invadopodia were significantly decreased with APOEknockdown. APOEknockdown also resulted in increased cellular cholesterol, consistent with APOE's role in regulating cholesterol efflux. APOEknockdown resulted in decreased levels of phospho–extracellular signal–regulated kinase 1/2, phospho–c-Jun N-terminal kinase, and phospho-cJun, as well as decreased activator protein 1 (AP-1) activity. Expression of matrix metalloproteinase 7 (MMP7), an AP-1 target, was also significantly decreased. Our findings suggest that APOE protein plays a significant role in OSCC tumor invasion because of its effects on cellular cholesterol and subsequent effects on cell signaling and AP-1 activity, leading to changes in the expression of invasion-related proteins, including MMP7.

Efforts to identify and target glioblastoma (GBM) drivers have primarily focused on receptor tyrosine kinases (RTKs). Clinical benefits, however, have been elusive. Here, we identify an SRY-related box 2 (SOX2) transcriptional regulatory network that is independent of upstream RTKs and capable of driving glioma-initiating cells. We identified oligodendrocyte lineage transcription factor 2 (OLIG2) and zinc-finger E-box binding homeobox 1 (ZEB1), which are frequently co-expressed irrespective of driver mutations, as potential SOX2 targets. In murine glioma models, we show that different combinations of tumor suppressor and oncogene mutations can activate Sox2, Olig2, and Zeb1 expression. We demonstrate that ectopic co-expression of the three transcription factors can transform tumor-suppressor-deficient astrocytes into glioma-initiating cells in the absence of an upstream RTK oncogene. Finally, we demonstrate that the transcriptional inhibitor mithramycin downregulates SOX2 and its target genes, resulting in markedly reduced proliferation of GBM cells in vivo.

Objectives: Identifying social needs is a growing priority in primary care, but there is significant variation in how patients access services to meet such needs. This study identifies predictors of successful linkage with a community health worker (CHW) among patients with social needs seen in an outpatient setting.Methods: This study uses a cross-sectional analysis of social needs assessments administered in an urban health system between April 2018 and December 2019. Social needs included: food insecurity, housing quality, housing instability, healthcare cost, healthcare related transportation, utilities, care for dependents, legal assistance, safety, and getting along with household members. Patients with at least 1 social need and accepting help were included in the analysis. On contact with a CHW, patients were entered into a separate database. The primary outcome was successful “linkage,” defined by having a positive social needs assessment in the medical record and a corresponding record in the CHW database. Multivariate logistic regression was used to assess predictors of linkage.Results: Among patients with at least 1 social need accepting help, 25% (758/3064) were linked to a CHW. Positive predictors included female gender (OR 1.28 [95% CI 1.01-1.63]), Spanish language preference compared to English (1.51 [1.14-1.03]), and having a food related need (1.35 [1.03-1.79]). Negative predictors included age 18 to 65 (0.34 [0.17-0.71] for age 18-24) and 0 to 5 (0.45 [0.24-0.78]) compared to over 65, non-Hispanic White race compared to Hispanic race (0.39 [0.18-0.84]), and having needs of getting along with household members (0.52 [0.38-0.71]) and safety (0.64 [0.42-0.98]).Conclusions: Twenty-five percent of patients who had at least 1 social need and were accepting help had a successful CHW linkage. Predictors of linkage suggest areas of further system-level improvements to screening and referral interventions to target at risk patients and communities.

Introduction:Among 2-19-year-olds in the United States (US), 26.2% of Hispanic/Latino youth vs. 16.6% of non-Hispanic White youth experience obesity (body mass index [BMI] percentile ≥age- and sex-specific 95thBMI percentile). While health behaviors are important, psychological and sociocultural measures vary across racial/ethnic groups and may underpin obesity disparities. Machine learning is one statistical approach that can be used to identify determinants of obesity. However, few studies have applied these methods to childhood obesity research, with most studies only examining traditional risk factors and creating a single model across all racial/ethnic groups. Our objective was to identify key predictors of BMI percentile in Hispanic/Latino youth to help design childhood obesity interventions that reduce health disparities.Hypothesis:We hypothesized that a BMI percentile prediction model developed for Hispanic/Latino youth would identify both traditional and novel risk factors as important determinants.Methods:Hispanic/Latino 8-16-year-olds from the 4 US sites of the Hispanic Community Children’s Health Study/Study of Latino Youth (SOL Youth) were examined (n=1,466). BMI percentiles were determined via measured height and weight and CDC growth charts. A supervised machine learning approach, Least Absolute Shrinkage and Selection Operator (LASSO) regression, was used with BMI percentile as the outcome. There were 98 predictor variables examined spanning demographics; health behaviors; and environmental, psychological, and sociocultural measures. LASSO-selected variables were entered into a multivariable linear regression model to obtain effect estimates. P-values were adjusted for both multiple testing and the variable selection process and assessed with α<0.025. Models incorporated survey weights, and missing data were imputed.Results:A LASSO model with 30 variables yielded the optimum mean squared error (MSE; R2=0.37), but a 12-variable solution was selected based on MSE and parsimony. Four associations were statistically significant. Perception of being larger than the “ideal” body weight (β=8.75 [95% CI: 8.21, 12.13]), reporting disordered eating (β=12.61 [95% CI: 10.64, 14.91]), and having a parent with obesity (β=4.90 [95% CI: 3.49, 17.75]) were associated with a higher BMI percentile. Spending >$5 weekly on snacks/beverages/fast food (β=-4.62 [95% CI: -19.18, -2.09]) was associated with a lower BMI percentile.Conclusions:Psychological and parental factors predicted higher BMI percentile and greater money spent on snacks/beverages/fast food predicted lower BMI percentile among Hispanic/Latino youth in the US. Addressing Hispanic/Latino youth’s relationships with food, body weight, and parents may be important in obesity interventions. Longitudinal research is needed to clarify directionality and replicate novel findings.

•Increased cannabis use over 6 months was associated with reduced odds of quitting cigarettes at 6 months among people with HIV.•Preliminary evidence suggests that increasing cannabis use may impact cigarette cessation among people with HIV who are motivated to quit cigarettes.•Interventions that address cigarette and cannabis use concurrently warrant further investigation.

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Infection with Plasmodium falciparum can lead to a range of severe to minimal symptoms, occasionally resulting in death in young children or nonimmune adults. In areas of high transmission, older children and adults generally suffer only mild or asymptomatic malaria infections and rarely develop severe disease. The immune features underlying this apparent immunity to severe disease remain elusive. To gain insight into host responses associated with severe and mild malaria, we conducted a longitudinal study of five children who first presented with severe malaria and, 1 month later, with mild malaria. Employing peripheral blood whole-genome profiling, we identified 68 genes that were associated with mild malaria compared to their expression in the severe malaria episode (paired Students t test, P < 0.05). These genes reflect the interferon (IFN) pathway and T cell biology and include IFN-induced protein transcripts 1 to 3, oligoadenylate synthetases 1 and 3, and the T cell markers cathepsin W and perforin. Gene set enrichment analysis identified Gene Ontology (GO) pathways associated with mild malaria to include the type I interferon-mediated signaling pathway (GO 0060337), T cell activation (GO 0042110), and other GO pathways representing many aspects of immune activation. In contrast, only six genes were associated with severe malaria, including thymidine kinase 1, which was recently found to be a biomarker of cerebral malaria susceptibility in the murine model, and carbonic anhydrase, reflecting the blood's abnormal acid base environment during severe disease. These data may provide potential insights to inform pathogenesis models and the development of therapeutics to reduce severe disease outcomes due to P. falciparum infection.

Infection with Plasmodium falciparumcan lead to a range of severe to minimal symptoms, occasionally resulting in death in young children or nonimmune adults. In areas of high transmission, older children and adults generally suffer only mild or asymptomatic malaria infections and rarely develop severe disease. The immune features underlying this apparent immunity to severe disease remain elusive. To gain insight into host responses associated with severe and mild malaria, we conducted a longitudinal study of five children who first presented with severe malaria and, 1 month later, with mild malaria. Employing peripheral blood whole-genome profiling, we identified 68 genes that were associated with mild malaria compared to their expression in the severe malaria episode (paired Students ttest, P< 0.05). These genes reflect the interferon (IFN) pathway and T cell biology and include IFN-induced protein transcripts 1 to 3, oligoadenylate synthetases 1 and 3, and the T cell markers cathepsin W and perforin. Gene set enrichment analysis identified Gene Ontology (GO) pathways associated with mild malaria to include the type I interferon-mediated signaling pathway (GO 0060337), T cell activation (GO 0042110), and other GO pathways representing many aspects of immune activation. In contrast, only six genes were associated with severe malaria, including thymidine kinase 1, which was recently found to be a biomarker of cerebral malaria susceptibility in the murine model, and carbonic anhydrase, reflecting the blood's abnormal acid base environment during severe disease. These data may provide potential insights to inform pathogenesis models and the development of therapeutics to reduce severe disease outcomes due to P. falciparuminfection.

Genetic heterogeneity between individuals confounds the comparison of gene profiling of multiple myeloma (MM) cells versus normal plasma cells (PCs). To overcome this barrier, we compared the gene expression profile of CD138+ MM cells from a patient bone marrow (BM) sample with CD138+ PCs from a genetically identical twin BM sample using microarray profiling. Two hundred and ninety-six genes were up-regulated and 103 genes were down-regulated at least 2-fold in MM cells versus normal twin PCs. Highly expressed genes in MM cells included cell survival pathway genes such as mcl-1, dad-1, caspase 8, and FADD-like apoptosis regulator (FLIP); oncogenes/transcriptional factors such as Jun-D, Xbp-1, calmodulin, Calnexin, and FGFR-3; stress response and ubiquitin/proteasome pathway–related genes and various ribosomal genes reflecting increased metabolic and translational activity. Genes that were down-regulated in MM cells versus healthy twin PCs included RAD51, killer cell immunoglobulin-like receptor protein, and apoptotic protease activating factor. Microarray results were further confirmed by Western blot analyses, immunohistochemistry, fluorescent in situ hybridization (FISH), and functional assays of telomerase activity and bone marrow angiogenesis. This molecular profiling provides potential insights into mechanisms of malignant transformation in MM. For example, FGFR3, xbp-1, and both mcl-1 and dad-1 may mediate transformation, differentiation, and survival, respectively, and may have clinical implications. By identifying genes uniquely altered in MM cells compared with normal PCs in an identical genotypic background, the current study provides the framework to identify novel therapeutic targets.

Our previous study demonstrated that 2-methoxyestradiol (2ME2), an estrogen derivative, induces apoptosis in multiple myeloma (MM) cells; however, the related transcriptional events are unclear. In the present study, we used oligonucleotide microarrays to identify genes altered during 2ME2-induced apoptosis in MM cells. 2ME2 triggers an early transient induction of genes known to trigger cell death and repression of growth/survival-related genes. Many genes regulating cell defense/repair machinery also were transiently induced. Since 2ME2 also induces apoptosis in MM cells resistant to conventional therapies such as dexamethasone (Dex), we compared the gene profiles of 2ME2-treated and Dex-resistant MM cells. Our results suggest that 2ME2 overcomes Dex resistance by modulating genes that confer chemoresistance in MM cells. Microarray results were confirmed by Northern and Western blot analyses. A comparative analysis of selected genes from freshly isolated MM patient cells and 2ME2-treated MM.1S MM cells further provides an in vivo relevance of our in vitro studies. Collectively, these findings suggest genetic events mediating anti-MM activity of 2ME2, as well as mechanisms whereby 2ME2 overcomes Dex resistance in MM cells. These studies may therefore allow improved therapeutic use of 2ME2, based upon targeting genes that regulate MM cell growth and survival.

Ceruloplasmin (Cp) was found to promote the oxidative damage to DNA, as evidenced by the formation of 8-hydroxy-2'-deoxyguanosine and strand breaks, when incubated with H2O2 in vitro. The capacity of Cp to enhance oxidative damage to DNA was inhibited by hydroxyl radical scavengers such as sodium azide and mannitol, a metal chelator, diethylenetriaminepenta-acetic acid, and catalase. Although the oxidized protein resulted in an increase in the content of carbonyl groups, the ferroxidase activity and the proteolytic susceptibility were not significantly altered. The release of a portion of Cu from Cp was observed, and conformational alterations were indicated by the changes in fluorescence spectra. Based on these results, we suggest that damage to DNA is mediated in the H2O2/Cp system via the generation of ·OH by released Cu2+ and/or loosely bound Cu exposed from oxidatively damaged Cp through the conformational change. The release of Cu from Cp during oxidative stress could enhance the formation of reactive oxygen species and could also potentiate cellular damage.

Background. Persons with HIV (PWH) smoke cigarettes at much higher rates than the general population in the US, and smoking is now the leading cause of death in US PWH. Efforts to control the tobacco use epidemic in PWH have met with limited success, and the factors associated with successful cessation are not well delineated. There is a particular dearth of knowledge regarding PWH ex-smokers who have successfully quit smoking cigarettes for the long term. Methods. We pooled data from three separate sources of PWH smokers and ex-smokers (reporting complete abstinence for ≥ one year with biochemical verification at the time of data collection) from New York City, collected sociodemographic and behavioral information from them in structured interviews, and obtained their DNA samples. Univariate and rigorous multivariate analytic strategies were employed to determine the sociobehavioral and genetic factors that distinguished PWH smokers from ex-smokers. Results. We compared 142 current/recent smokers to 52 biochemically confirmed ex-smokers. The mean age of the participants was 53.3±9.9 years, 49.5% were female, and 76.3% were Black/African American. Successful quitters had significantly lower anxiety scores and were less likely to report hazardous alcohol use or to use marijuana or cocaine. On multivariate analysis utilizing a conservative analytic approach, of 156 single nucleotide variants (SNV) within 12 a priori candidate genes, only the 37148248 T->C variant of gene SLC25A21 on chromosome 14 was associated with long-term cessation. Conclusions. In this study, we report behavioral variables associated with long-term abstinence in PWH ex-smokers, and we also report the first genetic correlation of successful cessation in a PWH population yet described.

DIGITALIS and related steroid glycosides exert two well established action: augmentation of the contractile force of cardiac muscle, the basis for the clinical use of these drugs; and inhibition of Na-K-ATPase, a ubiquitous membrane enzyme concerned with maintenance of transcellular ionic gradients. There is much evidence to support the disputed view that the inotropic effect of the cardiotonic steroids is a direct result of Na-K-ATPase inhibition1,2. In a previous study3a large number of steroids, drugs and other substances were screened for potential activity in a radioreceptor assay for cardiac glycosides. High affinity saturable binding of 3H-ouabain to a particulate fraction from dog heart was highly specific and antagonised only by cardioactive glycosides or their aglycones and certain steroids related to hydroxyprogesterone. The most potent progestins active in the binding assay shared certain structural features: a 17α-acetoxy moiety and unsaturation or substitution in the B ring. Of the 17α-acetate progestins available for testing in the radioreceptor assay, chlormadinone acetate (CMA), 3,5-diene-3-one-17α-ol-6-chloro-pregn-17-acetate, was the most active. In this report we describe results of studies with CMA designed to ascertain other potential digitalis-like actions. Digitalis-sensitive processes include ion and sugar flux in rat hemi-diaphragm4and guinea pig atrium5and Na-K-ATPase activity in several tissues2.

Although people with HIV have experienced a dramatic increase in survival following introduction of antiretroviral therapy, they suffer an increased burden of chronic diseases. Both HIV and HCV have been associated with increased atherosclerosis, with data suggesting that this is also the case for cardiac dysfunction and heart failure in the absence of coronary heart disease. Available studies are limited by use of HIV-negative controls lacking the increased frequency of cardiovascular risk factors typically seen with HIV or HCV, and have largely focused on men. We leveraged the well-matched participants with and without HIV of the WIHS to perform echocardiograms 12 years (median) apart to test the hypothesis that HIV and HCV are associated with development of cardiac dysfunction. WIHS participants from Bronx and Brooklyn completing Echo in 2004-05 were invited for repeat Echo in 2014-18. Of 376 women with Echo at both time points, 299 had interpretable scans and were free of baseline left ventricular systolic dysfunction (LVSD, EF<54%) or diastolic dysfunction (LVDD) (2016 ASE criteria). Baseline characteristics of the study cohort by HCV and HIV status are shown in Table 1. There were 59 new cases of LVDD (61 with LVDD or LVSD). As detailed in Table 2, whereas women with isolated HIV or HCV did not show increased incidence of LVDD, those with HIV-HCV coinfection had >2-fold higher risk after adjustment for risk factors. In conclusion, in this first study of long-term incidence of cardiac dysfunction in HIV and HCV, HIV-HCV coinfection in women more than doubled the risk, highlighting the need to optimize prevention and treatment of these conditions.

ABSTRACTMost patients with cerebral malaria (CM) sustain cerebral microvascular sequestration of Plasmodium falciparum-infected red blood cells (iRBCs). Although many young children are infected with P. falciparum, CM remains a rare outcome; thus, we hypothesized that specific host conditions facilitate iRBC cerebral sequestration. To identify these host factors, we compared the peripheral whole-blood transcriptomes of Malawian children with iRBC cerebral sequestration, identified as malarial-retinopathy-positive CM (Ret+CM), to the transcriptomes of children with CM and no cerebral iRBC sequestration, defined as malarial-retinopathy-negative CM (Ret-CM). Ret+CM was associated with upregulation of 103 gene set pathways, including cytokine, blood coagulation, and extracellular matrix (ECM) pathways (P< 0.01; false-discovery rate [FDR] of <0.05). Neutrophil transcripts were the most highly upregulated individual transcripts in Ret+CM patients. Activated neutrophils can modulate diverse host processes, including the ECM, inflammation, and platelet biology to potentially facilitate parasite sequestration. Therefore, we compared plasma neutrophil proteins and neutrophil chemotaxis between Ret+CM and Ret-CM patients. Plasma levels of human neutrophil elastase, myeloperoxidase, and proteinase 3, but not lactoferrin or lipocalin, were elevated in Ret+CM patients, and neutrophil chemotaxis was impaired, possibly related to increased plasma heme. Neutrophils were rarely seen in CM brain microvasculature autopsy samples, and no neutrophil extracellular traps were found, suggesting that a putative neutrophil effect on endothelial cell biology results from neutrophil soluble factors rather than direct neutrophil cellular tissue effects. Meanwhile, children with Ret-CM had lower levels of inflammation, higher levels of alpha interferon, and upregulation of Toll-like receptor pathways and other host transcriptional pathways, which may represent responses that do not favor cerebral iRBC sequestration.IMPORTANCEThere were approximately 198 million cases of malaria worldwide in 2013, with an estimated 584,000 deaths occurring mostly in sub-Saharan African children. CM is a severe and rare form of Plasmodium falciparuminfection and is associated with high rates of mortality and neurological morbidity, despite antimalarial treatment. A greater understanding of the pathophysiology of CM would allow the development of adjunctive therapies to improve clinical outcomes. A hallmark of CM is cerebral microvasculature sequestration of P. falciparum-infected red blood cells (iRBCs), which results in vasculopathy in some patients. Our data provide a global analysis of the host pathways associated with CM and newly identify an association of activated neutrophils with brain iRBC sequestration. Products of activated neutrophils could alter endothelial cell receptors and coagulation to facilitate iRBC adherence. Future studies can now examine the role of neutrophils in CM pathogenesis to improve health outcomes.