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In medical research, the Brier score (BS) and the area under the receiver operating characteristic (ROC) curves (AUC) are two common metrics used to evaluate prediction models of a binary outcome, such as using biomarkers to predict the risk of developing a disease in the future. The assessment of an existing prediction models using data with missing covariate values is challenging. In this article, we propose inverse probability weighted (IPW) and augmented inverse probability weighted (AIPW) estimates of AUC and BS to handle the missing data. An alternative approach uses multiple imputation (MI), which requires a model for the distribution of the missing variable. We evaluated the performance of IPW and AIPW in comparison with MI in simulation studies under missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR) scenarios. When there are missing observations in the data, MI and IPW can be used to obtain unbiased estimates of BS and AUC if the imputation model for the missing variable or the model for the missingness is correctly specified. MI is more efficient than IPW. Our simulation results suggest that AIPW can be more efficient than IPW, and also achieves double robustness from miss-specification of either the missingness model or the imputation model. The outcome variable should be included in the model for the missing variable under all scenarios, while it only needs to be included in missingness model if the missingness depends on the outcome. We illustrate these methods using an example from prostate cancer.

The impact of the oral microbiome on head and neck cancer pathogenesis and outcomes requires further study. 16s rRNA was isolated and amplified from pre-treatment oral wash samples for 52 cases and 102 controls. The sequences were binned into operational taxonomic units (OTUs) at the genus level. Diversity metrics and significant associations between OTUs and case status were assessed. The samples were binned into community types using Dirichlet multinomial models, and survival outcomes were assessed by community type. Twelve OTUs from the phyla Firmicutes, Proteobacteria, and Acinetobacter were found to differ significantly between the cases and the controls. Beta-diversity was significantly higher between the cases than between the controls (p < 0.01). Two community types were identified based on the predominant sets of OTUs within our study population. The community type with a higher abundance of periodontitis-associated bacteria was more likely to be present in the cases (p < 0.01), in older patients (p < 0.01), and in smokers (p < 0.01). Significant differences between the cases and the controls in community type, beta-diversity, and OTUs indicate that the oral microbiome may play a role in HNSCC.

We consider the patient-to-bed assignment problem that arises in hospitals. Both emergency patients who require hospital admission and elective patients who have had surgery need to be found a bed in the most appropriate ward. The patient-to-bed assignment problem arises when a bed request is made, but a bed in the most appropriate ward is unavailable. In this case, the next-best decision out of a many alternatives has to be made, according to some suitable decision making algorithm. We construct a Markov chain to model this problem in which we consider the effect on the length of stay of a patient whose treatment and recovery consists of several stages, and can be affected by stays in or transfers to less suitable wards. We formulate a dynamic program recursion to optimise an objective function and calculate the optimal decision variables, and discuss simulation techniques that are useful when the size of the problem is too large. We illustrate the theory with some numerical examples.

This study is the first attempt to systematically examine the impact of prior military service and childhood adversity on physical and psychological health outcomes during subsequent law enforcement employment. Given that at least one in five US law enforcement officers (LEOs) is a military veteran, and many law enforcement agencies provide preferential status for veterans in the hiring process, understanding the effects of prior military service on LEO physical and psychological well-being is important for supporting officer safety and wellness. Using nationally representative data, we examine the interrelationships between prior military service, combat deployments, childhood adversity, and three health outcomes during subsequent LE employment—PTSD, sleep problems, and suicidality. Contrary to prior research and our hypotheses, we found that prior military service and combat experience were not associated with an increased risk of PTSD, sleep problems, or suicidality. Furthermore, while greater exposure to adverse childhood experiences (ACEs) among non-veteran LEOs was linked with increased odds of PTSD, among veteran LEOs, greater ACE exposure was significantly linked with reduced odds of PTSD. We offer several possible explanations to account for these findings.

Background Differences in health effects of dietary α-linolenic acid (ALA) and DHA are mediated at least in part by differences in their effects on oxylipins. Objectives Time course and sex differences of plasma oxylipins in response to ALA- compared with DHA-rich supplements were examined. Methods Healthy men and women, aged 19-34 y and BMI 18-28 kg/m2, were provided with capsules containing ∼4 g/d of ALA or DHA in a randomized double-blind crossover study with >6-wk wash-in and wash-out phases. Plasma PUFA and oxylipin (primary outcome) concentrations at days 0, 1, 3, 7, 14, and 28 of supplementation were analyzed by GC and HPLC-MS/MS, respectively. Sex differences, supplementation and time effects, and days to plateau were analyzed. Results ALA supplementation doubled ALA concentrations, but had no effects on ALA oxylipins after 28 d, whereas DHA supplementation tripled both DHA and its oxylipins. Increases in DHA oxylipins were detected as early as day 1, and a plateau was reached by days 5-7 for 11 of 12 individual DHA oxylipins and for total DHA oxylipins. Nine individual DHA oxylipins reached a plateau in females with DHA supplementation, compared with only 4 in males. A similar time course and sex difference pattern occurred with EPA and its oxylipins with DHA supplementation. DHA compared with ALA supplementation also resulted in higher concentrations of 4 individual arachidonic acids, 1 linoleic acid, and 1 dihomo-γ-linolenic acid oxylipin, despite not increasing the concentrations of these fatty acids, further demonstrating that oxylipins do not always reflect their precursor PUFA. Conclusions DHA compared with a similar dose of ALA has greater effects on both n-3 and n-6 oxylipins in young, healthy adults, with differences in response to DHA supplementation occurring earlier and being greater in females. These findings can help explain differences in dietary effects of ALA and DHA.This study was registered at clinicaltrials.gov as NCT02317588.

Law enforcement officers’ health and wellness is important at the individual and community levels in terms of maintaining a fit workforce to uphold the mission of public safety. The current study was designed to assess officer wellness across the U.S. From a nationally representative random sample of 1,135 local and state agencies, a random, probability-based sample of officers was selected, oversampling for female officers. Latent class analyses were conducted to assess wellness profiles based on a set of eleven physical, psychological, and behavioral health indicators for 2,232 officers. Personal and professional characteristics were included as auxiliary variables in models of the resulting classes. Results from this sample indicated that over two-thirds of officers fit a healthy profile, whereas one in four officers presents with moderate health concerns and nearly 6% are classified in a profile of broad health concerns. In this sample, sexual assault in childhood, greater exposure to critical incidents, working a current rotation schedule, and being female were characteristics associated with broad health concerns. Emotional and/or physical assault in childhood, greater exposure to critical incidents, and being female were characteristics associated with moderate health concerns, whereas older age and being Hispanic were protective factors. In sum, full-time sworn law enforcement officers across the U.S. are reasonably healthy but their exposures to stressful situations put them at increased risk particularly in terms of post-traumatic stress, risky drinking, and suicidality. These results are important for agency administrators and policymakers to consider in terms of wellness programs, prevention efforts and budget allocations.

The purpose of this study was to estimate the effect of past and current rotating shift assignments on U.S. law enforcement officers' health outcomes. In a nationally representative sample of 2,867 officers, with an oversample of female officers, we estimated models of sleep quality and fatigue, physical health outcomes, and psychological health outcomes. Further, we examined individual and agency-level factors associated with officers who reported currently working a rotating shift, to investigate what patterns there may be in shift assignments. A history of rotating shift assignments was positively associated with lower sleep quality, and with hypertension, diabetes, and high cholesterol, but not with gastrointestinal disorders, perceived stress, emotional well-being, or suicidality. The associations of shiftwork with health outcomes did not vary by gender. Demographic characteristics did not predict current rotating shift assignments, but a longer history of shiftwork and more working hours did predict a current shift assignment. Attention to mitigating shift system designs as well as the effect of cumulative years of working a rotating shift for the benefit of officer health outcomes is warranted.

OBJECTIVE To assess comorbidity across five common health conditions. METHODS Surveys were collected from a probability-based sample of US law enforcement officers, and latent class models estimated for hypertension (HTN), high blood cholesterol (LDL), diabetes (DM), a gastrointestinal disorder (GI), and sleep apnea (SA). RESULTS The majority of officers (69.4%) were classified in a Healthy profile. One in four officers (23.7%) were classified in a LDL-HTN-DM profile. About 7% of officers were classified in a GI-SA-HTN profile. Age, sex, body mass index (BMI), exercise, and working a rotating shift assignment distinguished class membership. CONCLUSION Most officers reported good health. Law enforcement administrative or clinical assessments using readily accessible measures might be informative in identifying risk categories of need for more targeted prevention and treatment support.

Fish oil, the most abundant natural source of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), is a limited resource; however, terrestrial oils are used as an alternative in fish nutrition. The liver of Atlantic salmon is able to synthesize these two long-chain n-3 polyunsaturated fatty acids (n-3LC-PUFAs) from α-linolenic acid (ALA), but the dietary levels of EPA + DHA and the ratios of linoleic acid (LNA) to ALA may affect its abilities. Feeding Atlantic salmon four experimental diets containing EPA + DHA at 0.3 and 1.0% of dietary levels accompanied with high and low LNA/ALA ratios showed that low LNA/ALA ratios increased the proportions of EPA + DHA in phospholipids (PLs) and neutral lipids (NLs). The pattern of PL-to-NL ratios of n-3 LC-PUFA proportions matched the saw tooth pattern of LNA/ALA ratios in diets. Overall, when fish oil is removed from salmon diets, the dietary LNA/ALA ratio must be reduced to stimulate biosynthesis of n-3 LC-PUFAs in the liver.

Chagas disease is caused by infection with the parasite protozoan Trypanosoma cruzi and affects about 8 million people in 21 countries in Latin America. Treatment of this disease are still based on the use of benznidazole or nifurtimox, which both present low cure rates in the chronic phase and often have many undesirable side effects. Herein, we describe the synthesis of flavones and evaluation of their trypanocidal activity. The flavones were tested to in vitro against Trypanosoma cruzi and amongst the 13 compounds tested, 6 of these demonstrated some modest trypanocidal activity in vitro. Enhancements in anti T. cruzi activity were noted for flavones bearing either nitro or methoxy substituents. Moreover, very low cytotoxicities were maintained with methoxy groups which suggests that this functional group favors more selective trypanocidal compounds.

Endothelial cells regulate vascular homeostasis through the secretion of various paracrine molecules, including bioactive lipids, but little is known regarding the enzymes responsible for generating these lipids under either physiological or pathophysiological conditions. Arachidonate lipoxygenase (ALOX) expression was therefore investigated in confluent and nonconfluent EA.h926 endothelial cells, which represent the normal quiescent and proliferative states, respectively. mRNAs for ALOX15, ALOX15B, and ALOXE3 were detected in EA.hy926 cells, with the highest levels present in confluent cells compared to nonconfluent cells. In contrast, ALOX5, ALOX12, and ALOX12B mRNAs were not detected. At the protein level, only ALOX15B and ALOXE3 were detected but only in confluent cells. ALOXE3 was also observed in confluent human umbilical artery endothelial cells (HUAEC), indicating that its expression, although previously unreported, may be a general feature of endothelial cells. Exposure to laminar flow further increased ALOXE3 levels in EA.hy926 cells and HUAECs. The evidence obtained in this study indicates that proliferative status and shear stress are both important factors that mediate endothelial ALOX gene expression. The presence of ALOX15B and ALOXE3 exclusively in quiescent human endothelial cells suggests their activity likely contributes to the maintenance of a healthy endothelium.

In mathematical biology, there is a great deal of interest in producing continuum models by scaling discrete agent-based models governed by local stochastic rules. We discuss a particular example of this approach: a model for the proliferation of neural crest cells that can help us understand the development of Hirschprung’s disease, a potentially-fatal condition in which the enteric nervous system of a new-born child does not extend all the way through the intestine and colon. Our starting point is a discrete-state, continuous-time Markov chain model proposed by Hywood et al. (2013a) for the location of the neural crest cells that make up the enteric nervous system. Hywood et al. (2013a) scaled their model to derive an approximate second order partial differential equation describing how the limiting expected number of neural crest cells evolve in space and time. In contrast, we exploit the relationship between the above-mentioned Markov chain model and the well-known Yule-Furry process to derive the exact form of the scaled version of the process. Furthermore, we provide expressions for other features of the domain agent occupancy process, such as the variance of the marginal occupancy at a particular site, the distribution of the number of agents that are yet to reach a given site and a stochastic description of the process itself.

Chromosome replication is performed by a complex and intricate ensemble of proteins termed the replisome, where the DNA polymerases Polδ and Polε, DNA polymerase α-primase (Polα) and accessory proteins including AND-1, CLASPIN and TIMELESS–TIPIN (respectively known as Ctf4, Mrc1 and Tof1–Csm3 in Saccharomyces cerevisiae) are organized around the CDC45–MCM–GINS (CMG) replicative helicase(1–7). Because a functional human replisome has not been reconstituted from purified proteins, how these factors contribute to human DNA replication and whether additional proteins are required for optimal DNA synthesis are poorly understood. Here we report the biochemical reconstitution of human replisomes that perform fast and efficient DNA replication using 11 purified human replication factors made from 43 polypeptides. Polε, but not Polδ, is crucial for optimal leading-strand synthesis. Unexpectedly, Polε-mediated leading-strand replication is highly dependent on the sliding-clamp processivity factor PCNA and the alternative clamp loader complex CTF18–RFC. We show how CLASPIN and TIMELESS–TIPIN contribute to replisome progression and demonstrate that, in contrast to the budding yeast replisome(8), AND-1 directly augments leading-strand replication. Moreover, although AND-1 binds to Polα(9,10), the interaction is dispensable for lagging-strand replication, indicating that Polα is functionally recruited via an AND-1-independent mechanism for priming in the human replisome. Collectively, our work reveals how the human replisome achieves fast and efficient leading-strand and lagging-strand DNA replication, and provides a powerful system for future studies of the human replisome and its interactions with other DNA metabolic processes.

Antibiotics are the most commonly prescribed medications in the pediatric outpatient setting, yet 30% to 50% of these prescriptions are deemed to be unnecessary. Outpatient antimicrobial stewardship is the concerted effort to monitor and improve antibiotic use in the community setting. The best methods of conducting antimicrobial stewardship in the outpatient setting are currently unknown, and an individualized approach is likely needed. In this review, we discuss the importance of, resources for, and research supporting outpatient antimicrobial stewardship and review ways an individual pediatric provider can further steward efforts. [ Pediatr Ann . 2022;51(5):e196–e201.]

Funder: Doris Duke Charitable Foundation; Id: http://dx.doi.org/10.13039/100000862, Funder: UConn Office of the Vice President for Research, Biodiversity is in crisis, and insects are no exception. To understand insect population and community trends globally, it is necessary to identify and synthesize diverse datasets representing different taxa, regions, and habitats. The relevant literature is, however, vast and challenging to aggregate. The Entomological Global Evidence Map (EntoGEM) project is a systematic effort to search for and catalogue studies with long‐term data that can be used to understand changes in insect abundance and diversity. Here, we present the overall EntoGEM framework and results of the first completed subproject of the systematic map, which compiled sources of information about changes in dragonfly and damselfly (Odonata) occurrence, abundance, biomass, distribution, and diversity. We identified 45 multi‐year odonate datasets, including 10 studies with data that span more than 10 years. If data from each study could be gathered or extracted, these studies could contribute to analyses of long‐term population trends of this important group of indicator insects. The methods developed to support the EntoGEM project, and its framework for synthesizing a vast literature, have the potential to be applied not only to other broad topics in ecology and conservation, but also to other areas of research where data are widely distributed.

Teacher stress and burnout contribute to attrition and stress-related health concerns. Despite some positive effects, previous mindfulness-based interventions (MBI) have failed to incorporate key elements of methodological rigor and have included large dosages despite research suggesting that such dosages are iatrogenic. The current study demonstrates the efficacy of a brief MBI (bMBI; four sessions, six total hours) to reduce self-reported stress, burnout, and depression, and suggests the bMBI can protect against deleterious impacts to physiological functioning. The study informs the design and implementation of future MBIs, including strategies for reducing intervention dosages, in order to improve effectiveness and maximize cost-effectiveness.