<h3>Importance</h3><p>Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear.</p><h3>Objective</h3><p>To investigate the germline genetic architecture of 1244 patients with osteosarcoma.</p><h3>Design, Setting, and Participants</h3><p>Whole-exome sequencing (n = 1104) or targeted sequencing (n = 140) of the DNA of 1244 patients with osteosarcoma from 10 participating international centers or studies was conducted from April 21, 2014, to September 1, 2017. The results were compared with the DNA of 1062 individuals without cancer assembled internally from 4 participating studies who underwent comparable whole-exome sequencing and 27 173 individuals of non-Finnish European ancestry who were identified through the Exome Aggregation Consortium (ExAC) database. In the analysis, 238 high-interest cancer-susceptibility genes were assessed followed by testing of the mutational burden across 736 additional candidate genes. Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons. Patients were subsequently compared with individuals in the ExAC group. All data were analyzed from June 1, 2017, to July 1, 2019.</p><h3>Main Outcomes and Measures</h3><p>The frequency of rare pathogenic or likely pathogenic genetic variants.</p><h3>Results</h3><p>Among 1244 patients with osteosarcoma (mean [SD] age at diagnosis, 16 [8.9] years [range, 2-80 years]; 684 patients [55.0%] were male), an analysis restricted to individuals with European ancestry indicated a significantly higher pathogenic or likely pathogenic variant burden in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma compared with the control group (732 vs 994, respectively;<i>P</i> = 1.3 × 10⁻¹⁸). A pathogenic or likely pathogenic cancer-susceptibility gene variant was identified in 281 of 1004 patients with osteosarcoma (28.0%), of which nearly three-quarters had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene. The frequency of a pathogenic or likely pathogenic cancer-susceptibility gene variant was 128 of 1062 individuals (12.1%) in the control group and 2527 of 27 173 individuals (9.3%) in the ExAC group. A higher than expected frequency of pathogenic or likely pathogenic variants was observed in genes not previously linked to osteosarcoma (eg,<i>CDKN2A</i>,<i>MEN1, VHL, POT1, APC</i>,<i>MSH2</i>, and<i>ATRX</i>) and in the Li-Fraumeni syndrome-associated gene,<i>TP53</i>.</p><h3>Conclusions and Relevance</h3><p>In this study, approximately one-fourth of patients with osteosarcoma unselected for family history had a highly penetrant germline mutation requiring additional follow-up analysis and possible genetic counseling with cascade testing.</p>

Human papillomavirus (HPV) infection is common in women and also the main cause of cervical cancer. Based on a dynamic compartmental model, we aimed to evaluate the population impact and cost-effectiveness of strategies that combined cervical cancer screening and HPV schoolgirl vaccination for Chinese women. The effectiveness of interventions was assessed by comparing modeled scenarios to the status quo, where a 3-y cervical cancer screening program remained at a 20% coverage and without a universal HPV vaccination program. Our study demonstrated that increasing screening coverage from 20% to 50% would reduce the high-risk HPV (HR-HPV) prevalence to 5.4%, whereas a universal schoolgirl vaccination program using the quadrivalent vaccine (qHPV) with a coverage of 50% would reduce the prevalence to 2.9% by 2069. Scaling-up the cervical screening coverage to 50% will prevent 16,012 (95% CI: 8,791 to 25,913) Disability-Adjusted Life-Years (DALYs) per year, with an incremental cost-effectiveness ratio (ICER) of US$ 10,958 (95% CI: $169 to $26,973)/DALY prevented. At the current qHPV price, vaccinating 50% of school girls will prevent 13,854 (95% CI: 8,355 to 20,776) DALYs/year, but the corresponding incremental cost-effectiveness ratio (ICER, US$ 83,043, 95% CI: $52,234 to $138,025) exceeds cost-effectiveness threshold (i.e., 3 times GDP per-capita of China: $30,792). The qHPV vaccine requires at least a 50% price reduction to be cost-effective. Vaccinating schoolgirls will result in a large population health benefit in the long term, but such a universal HPV vaccination program can only be cost-effective with a substantial price reduction.

Road construction and paving bring socio-economic benefits to receiving regions but can also be drivers of deforestation and land cover change. Road infrastructure often increases migration and illegal economic activities, which in turn affect local hydrology, wildlife, vegetation structure and dynamics, and biodiversity. To evaluate the full breadth of impacts from a coupled natural-human systems perspective, information is needed over a sufficient timespan to include pre- and post-road paving conditions. In addition, the spatial scale should be appropriate to link local human activities and biophysical system components, while also allowing for upscaling to the regional scale. A database was developed for the tri-national frontier in the Southwestern Amazon, where the Inter-Oceanic Highway was constructed through an area of high biological value and cultural diversity. Extensive socio-economic surveys and botanical field work are combined with remote sensing and reanalysis data to provide a rich and unique database, suitable for coupled natural-human systems research.

Data are lacking regarding the impact of visible pigment on rectal swab diagnostic accuracy. We describe the test characteristics of rectal swabs with and without pigment in children with gastroenteritis. Between December 2014 and September 2017, children (age, 18 years) with 3 episodes of vomiting and/or diarrhea in a 24-h period and symptoms for 7 days were enrolled through two pediatric emergency departments and from a province-wide nursing telephone advice line in Alberta, Canada. Specimens were analyzed by employing nucleic acid amplification panels. The primary outcomes were the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the rectal swabs, with stool specimen results being used as the reference standard. An enteropathogen was detected in 76.0% (1,399/1,841) of the paired specimens. A total of 54.4% (1,001/1841) of the swabs had visible pigment. The respective enteropathogen detection characteristics of swabs with and without visible pigment were as follows: 92.2% (95% confidence interval [CI], 90.0%, 94.0%) versus 83.7% (95% CI, 80.5%, 86.4%) for sensitivity, 94.3% (95% CI, 90.5%, 96.6%) versus 91.2% (95% CI, 86.3%, 94.5%) for specificity, 97.9% (95% CI, 96.4%, 98.8%) versus 96.5% (95% CI, 94.5%, 97.8%) for PPV, and 80.9% (95% CI, 76.0%, 85.1%) versus 65.8% (95% CI, 60.0%, 71.1%) for NPV. Processing of swabs without visible pigment would increase the rate of identification of positive swabs from 50.0% (682/1,365) to 88.3% (1,205/1,365). There is a modest decrease in the reliability of a negative test on swabs without evidence of pigment, but the overall yield is significantly greater when they are not excluded from testing. Hence, rectal swabs without visible feces should not be routinely rejected from testing.

Background: We conducted an epigenome-wide association study (EWAS) on obesity in healthy youth and young adults and further examined to what extent identified signals influenced gene expression and were independent of cell type composition and obesity-related cardio-metabolic risk factors. Genome-wide DNA methylation data from leukocytes were obtained from 700 African Americans aged 14-36. We also measured genome-wide DNA methylation data from neutrophils as well as genome-wide gene expression data from leukocytes in a subset of samples (n = 188). Results: The EWAS identified 76 obesity-related CpG sites in leukocytes with p < 1 × 10-7. In silico replication in the ARIC study of 2097 African Americans aged 47-70 validated 54 CpG sites. Out of the 54 CpG sites, 29 associations with obesity were novel and 37 were replicated in neutrophils. Fifty one CpG sites were associated with at least one cardio-metabolic risk factor; however, the number reduced to 9 after adjustment for obesity. Sixteen CpG sites were associated with expression of 17 genes in cis, of which 5 genes displayed differential expression between obese cases and lean controls. We also replicated 71.5% of obesity-related CpG sites previously reported. Conclusion: In this study of youth and young adults, we identified 29 novel CpG sites associated with obesity and replicated the majority of the CpG sites previously identified. We further demonstrated that the majority of the obesity-related CpG sites in leukocytes were not driven by cell composition or obesity-related cardio-metabolic risk factors. We also provided the direct link between DNA methylation-gene expression-obesity for 5 genes.

Positive emotions have long-lasting benefits for human development. Understanding the connections between daily travel behavior and emotional well-being will not only help transportation practitioners identify concrete strategies to improve user experiences of transportation services, but also help health practitioners to identify innovative solutions for improving public health. Prior research on the subject had focused on limited travel behavior dimensions such as travel mode and/or travel duration. Other dimensions such as travel purpose and travel companionship have received limited attention. Using data from the 2012–2013 American Time Use Survey, this paper applied the generalized ordered logistic regression approach and examined how the mode, duration, purpose, and companionship characteristics of a trip shape six different emotions during the trip, including happy, meaningful, tired, stressful, sad, and pain. After controlling for personal demographics, health conditions, and residential locations, we find that biking is the happiest mode; public transit is the least happy and least meaningful; and utilitarian walking for transportation is associated with all four negative emotions. Trip duration has a negative association with happiness and a positive association with stress. Travel for discretionary purposes such as leisure, exercise, and community activities is generally associated with higher levels of positive emotions and lower levels of negative emotions than travel for work or household maintenance. Trips with eating and drinking purposes appear to be the happiest and trips with the purpose of spiritual and/or volunteering activities appear to be the most meaningful. Travel with family especially children or travel with friends is happier and more meaningful than travel alone. Transportation planners in the U.S. are recommended to promote biking behavior, improve transit user experiences, and implement spatial planning strategies for creating a built environment conducive to shorter trips, more discretionary trips, and more joint trips with family and friends.

BACKGROUND: Antiretroviral therapy (ART) administered in clinical trial settings virtually eliminates the sexual transmission of human immunodeficiency virus (HIV) in serodiscordant couples, but effectiveness of treatment as prevention in the community is debated. Conflicting results from previous analyses in a Chinese cohort underscore the importance of determining effectiveness of ART delivered in resource limited settings.\n\nMETHODS: All available years of data (2006-2012) from local disease control records of HIV patients and their seronegative spouses in Henan Province, China, were analyzed using marginal structural Cox models to estimate the effect of ART in the initially infected partner his or her partner's HIV seroconversion risk.\n\nRESULTS: We observed 157 seroconversion events in 4916 serosdiscordant couples, for an incidence rate of 0.59 cases per 100 person-years (PY) (95% confidence interval [CI], .51-.70). Of these, 84 occurred after the index partner had initiated ART (0.43/100PY; 95% CI, .35-.53) and 73, whereas index partners were untreated (5.87/100 PY; 95% CI, 4.65-7.42). In a marginal structural Cox model weighted for confounding and censoring, the hazard ratio (HR) for HIV transmission was 0.52 (95% CI, .34-.82). ART efficacy varied significantly by time period; least effective in the early phase from 2006 to 2008 (HR, 0.68; 95% CI, .34-1.36) but far more protective from 2009 onward (HR, 0.33; 95% CI, .20-.55).\n\nCONCLUSIONS: ART can provide HIV-infected persons in resource-limited setting substantial protection against sexual transmission. Effectiveness in the Henan cohort appears to have increased over time, suggesting that quality of care and service infrastructure may be integral to successful use of treatment for prevention.

Numerous controlled experiments find that elevated ground-level ozone concentrations ([O3]) damage crops and reduce yield. There have been no estimates of the actual yield losses in the field in the United States from [O3], even though such estimates would be valuable for projections of future food production and for cost-benefit analyses of reducing ground-level [O3]. Regression analysis of historical yield, climate, and [O3] data for the United States were used to determine the loss of production due to O3 for maize (Zea mays) and soybean (Glycine max) from 1980 to 2011, showing that over that period production of rain-fed fields of soybean and maize were reduced by roughly 5% and 10%, respectively, costing approximately $9 billion annually. Maize, thought to be inherently resistant to O3, was at least as sensitive as soybean to O3 damage. Overcoming this yield loss with improved emission controls or more tolerant germplasm could substantially increase world food and feed supply at a time when a global yield jump is urgently needed.

In March 2020, public health officials in every US states were scrambling for data to help predict and prepare for "the surge" of hospitalizations due to COVID-19. While there were credible websites reporting on the daily number of cases and deaths in each state (e.g., Johns Hopkins), these data were insufficient for predicting the real-time stress on the hospital systems: cases were under-reported due to lack of testing capability and deaths are a lagging indicator. This information gap drove the team at the University of Minnesota's Carlson School of Management to launch the COVID-19 Hospitalization Tracking Project (https://carlsonschool.umn.edu/mili-misrc-covid19-tracking-project)-a daily state-by-state view on the number of hospitalizations.