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Animal and epidemiologic studies indicate that air pollution may adversely affect fertility. Epidemiologic studies have been restricted largely to couples undergoing fertility treatment or have retrospectively ascertained time-to-pregnancy among pregnant women. | US |
Black adults who smoke are less likely to seek treatment and to succeed in quitting compared with other racial groups. The lack of efficacious and engaging trials for smoking cessation further contributes to this disparity. This study explored whether an acceptance and commitment therapy (ACT)-based smartphone application (iCanQuit) was more efficacious for smoking cessation than a United States Clinical Practice Guidelines (USCPG)-based smartphone application (QuitGuide) among Black adults. | US |
Organizing and annotating biological sample data is critical in data-intensive bioinformatics. Unfortunately, metadata formats from a data provider are often incompatible with requirements of a processing tool. There is no broadly accepted standard to organize metadata across biological projects and bioinformatics tools, restricting the portability and reusability of both annotated datasets and analysis software. | US |
Males have worse outcomes after hip fracture than female counterparts. Cognitive impairment (CI) also increases the risk of poor recovery from hip fracture; however, CI is under-recognized. Patient sex may contribute to this under-recognition through differential misclassification. The objective of this study was to measure under-recognition and differential misclassification of CI by patient sex. | US |
Patient engagement in research agenda setting is increasingly being seen as a strategy to improve the responsiveness of healthcare to patient priorities. Implementation of low-dose computed tomography (LDCT) screening for lung cancer is suboptimal, suggesting that research is needed. | US |
The collagen-induced arthritis mouse model is a widely studied autoimmune model of rheumatoid arthritis. In this model, autoimmune arthritis is induced by immunization of genetically susceptible strains of mice with type II collagen emulsified in complete Freund's adjuvant. This article describes the steps necessary for the acquisition, handling, and preparation of CII, in addition to the selection of mouse strains, proper immunization technique, and methods for evaluation of the incidence and severity of the autoimmune arthritis. In this model, the first signs of arthritis appear approximately 21 to 28 days after immunization. The protocols in this article should provide the investigator with all the necessary information required to reproducibly induce a high incidence of CIA in genetically susceptible strains of mice, and to critically evaluate the pathology of the disease. Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Basic Protocol: Induction of collagen-induced arthritis Support Protocol 1: Purification of type II collagen Support Protocol 2: Purification of type II collagen α1(II) chains Support Protocol 3: Assessment of arthritis incidence and severity Support Protocol 4: Measurement of CII specific antibody by indirect ELISA Support Protocol 5: Coupling CII to magnetic beads Support Protocol 6: Measuring CII-specific antibody by magnetic-bead based ELISA Support Protocol 7: Measurement of T cell responses to CII in CIA. | US |
In this article, we review two challenging computational questions in protein science: neoantigen prediction and protein structure prediction. Both topics have seen significant leaps forward by deep learning within the past five years, which immediately unlocked new developments of drugs and immunotherapies. We show that deep learning models offer unique advantages, such as representation learning and multi-layer architecture, which make them an ideal choice to leverage a huge amount of protein sequence and structure data to address those two problems. We also discuss the impact and future possibilities enabled by those two applications, especially how the data-driven approach by deep learning shall accelerate the progress towards personalized biomedicine. | US |
There is a growing interest in early phase dose-finding clinical trials studying combinations of several treatments. While the majority of dose finding designs for such setting were proposed for oncology trials, the corresponding designs are also essential in other therapeutic areas. Furthermore, there is increased recognition of recommending the patient-specific doses/combinations, rather than a single target one that would be recommended to all patients in later phases regardless of their characteristics. In this paper, we propose a dose-finding design for a dual-agent combination trial motivated by an opiate detoxification trial. The distinguishing feature of the trial is that the (continuous) dose of one compound is defined externally by the clinicians and is individual for every patient. The objective of the trial is to define the dosing function that for each patient would recommend the optimal dosage of the second compound. Via a simulation study, we have found that the proposed design results in high accuracy of individual dose recommendation and is robust to the model misspecification and assumptions on the distribution of externally defined doses. | United Kingdom |
HIV incidence continues to be unacceptably high in Eastern and Southern Africa, with women disproportionately affected. An increased per-contact risk of HIV acquisition among African, Caribbean, and other Black (ACB) women has been associated with the higher prevalence of bacterial vaginosis (BV) in these communities, wherein the vaginal microbiota is predominated by diverse pro-inflammatory anaerobic bacteria. However, while the vaginal microbiota in BV-free women is typically predominated by one of several different Lactobacillus spp., the degree of HIV protection afforded by a Lactobacillus-predominant vaginal microbiota also varies considerably. Specifically, L. crispatus is associated with an immunoregulatory genital immune environment, exclusion of BV-associated bacteria, and reduced HIV risk. In contrast, less HIV protection or exclusion of BV-associated bacteria and fewer immune benefits have been associated with L. iners-which is unfortunately the most common Lactobacillus species among ACB women. These species-specific clinical differences are underpinned by substantial genomic differences between Lactobacillus species: for instance, the much smaller genome of L. iners lacks the coding sequence for D-lactic acid dehydrogenase and cannot produce the D-lactate isomer that enhances HIV trapping in mucus but encodes for epithelial cell toxins and stress resistance proteins that may enhance bacterial survival in the context of microbiota and environmental fluctuations. While more studies are needed to elucidate whether differences in HIV protection between Lactobacillus species are due to direct genital immune effects or the exclusion of proinflammatory BV-associated bacteria, the current body of work suggests that for BV treatment to succeed as an HIV prevention strategy, it may be necessary to induce a vaginal microbiota that is predominated by specific (non-iners) Lactobacillus species. Video abstract. | Canada |
Lead (Pb) exposure is a global health hazard causing a wide range of adverse health outcomes. Yet, the mechanisms of Pb toxicology remain incompletely understood, especially during pregnancy. To uncover biological pathways impacted by Pb exposure, this study investigated serum metabolomic profiles during the third trimester of pregnancy that are associated with blood Pb and bone Pb. | US |
Obesity and related comorbidities are major health concerns among many US immigrant populations. Emerging evidence suggests a potential involvement of the gut microbiome. Here, we evaluated gut microbiome features and their associations with immigration, dietary intake, and obesity in 2640 individuals from a population-based study of US Hispanics/Latinos. | US |
There is a dearth of instruments that have been developed and validated for use with children living with HIV under the age of 17 years in the Kenyan context. We examined the psychometric properties and measurement invariance of a short version of the Berger HIV stigma scale administered to perinatally HIV-infected adolescents in a rural setting on the Kenyan coast. | United Kingdom |
RNA molecules undergo a vast array of chemical post-transcriptional modifications (PTMs) that can affect their structure and interaction properties. In recent years, a growing number of PTMs have been successfully mapped to the transcriptome using experimental approaches relying on high-throughput sequencing. Oxford Nanopore direct-RNA sequencing has been shown to be sensitive to RNA modifications. We developed and validated Nanocompore, a robust analytical framework that identifies modifications from these data. Our strategy compares an RNA sample of interest against a non-modified control sample, not requiring a training set and allowing the use of replicates. We show that Nanocompore can detect different RNA modifications with position accuracy in vitro, and we apply it to profile m<sup>6</sup>A in vivo in yeast and human RNAs, as well as in targeted non-coding RNAs. We confirm our results with orthogonal methods and provide novel insights on the co-occurrence of multiple modified residues on individual RNA molecules. | United Kingdom |
Nonsense-mediated mRNA decay (NMD) is an mRNA degradation pathway that eliminates transcripts containing premature termination codons (PTCs). Half-lives of the mRNAs containing PTCs demonstrate that a small percent escape surveillance and do not degrade. It is not known whether this escape represents variable mRNA degradation within cells or, alternatively cells within the population are resistant. Here we demonstrate a single-cell approach with a bi-directional reporter, which expresses two β-globin genes with or without a PTC in the same cell, to characterize the efficiency of NMD in individual cells. We found a broad range of NMD efficiency in the population; some cells degraded essentially all of the mRNAs, while others escaped NMD almost completely. Characterization of NMD efficiency together with NMD regulators in single cells showed cell-to-cell variability of NMD reflects the differential level of surveillance factors, SMG1 and phosphorylated UPF1. A single-cell fluorescent reporter system that enabled detection of NMD using flow cytometry revealed that this escape occurred either by translational readthrough at the PTC or by a failure of mRNA degradation after successful translation termination at the PTC. | US |
To improve understanding of Alzheimer's disease, large observational studies are needed to increase power for more nuanced analyses. Combining data across existing observational studies represents one solution. However, the disparity of such datasets makes this a non-trivial task. Here, a machine learning approach was applied to impute longitudinal neuropsychological test scores across two observational studies, namely the Australian Imaging, Biomarkers and Lifestyle Study (AIBL) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) providing an overall harmonised dataset. MissForest, a machine learning algorithm, capitalises on the underlying structure and relationships of data to impute test scores not measured in one study aligning it to the other study. Results demonstrated that simulated missing values from one dataset could be accurately imputed, and that imputation of actual missing data in one dataset showed comparable discrimination (p < 0.001) for clinical classification to measured data in the other dataset. Further, the increased power of the overall harmonised dataset was demonstrated by observing a significant association between CVLT-II test scores (imputed for ADNI) with PET Amyloid-β in MCI APOE-ε4 homozygotes in the imputed data (N = 65) but not for the original AIBL dataset (N = 11). These results suggest that MissForest can provide a practical solution for data harmonization using imputation across studies to improve power for more nuanced analyses. | US |
Angiogenesis is an important process in the formation and maintenance of tissues which is driven by a complex system of intracellular and intercellular signaling mechanisms. Endothelial cells taking part in early angiogenesis must select their phenotype as either a tip cells (leading, migratory) or a stalk cells (following). Recent experiments have demonstrated that rapid calcium oscillations within active cells characterize this phenotype selection process and that these oscillations play a necessary role in governing phenotype selection and eventual vessel architecture. In this work, we develop a mathematical model capable of describing these oscillations and their role in phenotype selection then use it to improve our understanding of the biological mechanisms at play. We developed a model based on two previously published and experimentally validated mathematical models of calcium and angiogenesis then use our resulting model to simulate various multi-cell scenarios. We are able to capture essential calcium oscillation dynamics and intercellular communication between neighboring cells. The results of our model show that although the late DLL4 (a transmembrane protein that activates Notch pathway) levels of a cell are connected with its initial IP3 (Inositol 1,4,5-trisphosphate) level, cell-to-cell communication determines its eventual phenotype. | Canada |
The isocyanate monomer 1,6-hexamethylene diisocyanate (HDI) and one of its trimers, HDI isocyanurate, are airway and skin sensitizers contained in polyurethane paint. The toxic response of cultured skin cells to these compounds was measured by evaluating the isocyanate concentrations at which 50% of the cells die (i.e., lethal concentration 50%, LC<sub>50</sub>) because the relative toxicity of each form of HDI should be considered when exposure limits of HDI-based paints are set. By using a luminescent ATP-viability assay, we compared the cytotoxic effects of HDI monomer and HDI isocyanurate on cultured human skin cells (keratinocytes, fibroblasts, and melanocytes) after 4-h isocyanate exposures using culture media with varying levels of nutrients in order to also determine the effects of media composition on isocyanate toxicity. Before analysis, experimental wells were normalized to controls containing cells that were cultured with the same vehicle and media. The measured mean LC<sub>50</sub> values ranged from 5 to 200 µM across the experimental conditions, in which HDI isocyanurate in protein-devoid media was the most toxic to cells, producing the lowest LC<sub>50</sub> values. For HDI monomer, keratinocytes were the most resistant to its toxicity and melanocytes were the most susceptible. However, when exposed to HDI isocyanurate, the opposite was observed, with melanocytes being the most resilient and the keratinocytes and fibroblasts were more susceptible. Depending on the type of skin cells, dose-response data indicated that HDI isocyanurate was 2-6 times more toxic than HDI monomer when using protein-devoid media whereas HDI isocyanurate was 4-13 times more toxic than HDI monomer when protein-rich media was used. Therefore, if the protein-devoid saline medium alone were used for these experiments, then a significant under-estimation of their relative toxicities in protein-rich environments would have resulted. This difference is because HDI monomer toxicity was more attenuated by the presence of protein in the culture media than HDI isocyanurate toxicity. Thus, conclusions based on comparative toxicity studies and consequent inference applied to potential human toxicity can be affected by in vitro culture media conditions. The physiochemical difference in reactivity of the two forms of HDI to biological molecules most likely explains the observed toxicity differences and may have implications for skin penetration, adverse effects like skin sensitization, and systemic responses like asthma. Future studies are warranted to investigate differences in the biological availability, cellular toxicity, and immunologic sensitization mechanisms for HDI monomer and HDI isocyanurate. | US |
The analytical sensitivity of high-sensitivity cardiac troponin T (hsTnT) assays has enabled rapid myocardial infarction rule-out algorithms for emergency department (ED) presentations. Few studies have analyzed the real-world impact of hsTnT algorithms on outcomes and operations. | US |
Nonignorable technical variation is commonly observed across data from multiple experimental runs, platforms, or studies. These so-called batch effects can lead to difficulty in merging data from multiple sources, as they can severely bias the outcome of the analysis. Many groups have developed approaches for removing batch effects from data, usually by accommodating batch variables into the analysis (one-step correction) or by preprocessing the data prior to the formal or final analysis (two-step correction). One-step correction is often desirable due it its simplicity, but its flexibility is limited and it can be difficult to include batch variables uniformly when an analysis has multiple stages. Two-step correction allows for richer models of batch mean and variance. However, prior investigation has indicated that two-step correction can lead to incorrect statistical inference in downstream analysis. Generally speaking, two-step approaches introduce a correlation structure in the corrected data, which, if ignored, may lead to either exaggerated or diminished significance in downstream applications such as differential expression analysis. Here, we provide more intuitive and more formal evaluations of the impacts of two-step batch correction compared to existing literature. We demonstrate that the undesired impacts of two-step correction (exaggerated or diminished significance) depend on both the nature of the study design and the batch effects. We also provide strategies for overcoming these negative impacts in downstream analyses using the estimated correlation matrix of the corrected data. We compare the results of our proposed workflow with the results from other published one-step and two-step methods and show that our methods lead to more consistent false discovery controls and power of detection across a variety of batch effect scenarios. Software for our method is available through GitHub (https://github.com/jtleek/sva-devel) and will be available in future versions of the $\texttt{sva}$ R package in the Bioconductor project (https://bioconductor.org/packages/release/bioc/html/sva.html). | US |
Office-based opioid treatment (OBOT) is an evidence-based treatment model for opioid use disorder (OUD) offered by both addiction and general primary care providers (PCPs). Calls exist for more PCPs to offer OBOT. Few studies have been conducted on the primary care characteristics of OBOT patients. | US |
Are menstrual cycle characteristics throughout the reproductive lifespan associated with cancer risk? | US |
Type III CRISPR-Cas systems have a unique mode of interference, involving crRNA-guided recognition of nascent RNA and leading to DNA and RNA degradation. How type III systems acquire new CRISPR spacers is currently not well understood. Here, we characterize CRISPR spacer uptake by a type III-A system within its native host, Streptococcus thermophilus. Adaptation by the type II-A system in the same host provided a basis for comparison. Cas1 and Cas2 proteins were critical for type III adaptation but deletion of genes responsible for crRNA biogenesis or interference did not detectably change spacer uptake patterns, except those related to host counter-selection. Unlike the type II-A system, type III spacers are acquired in a PAM- and orientation-independent manner. Interestingly, certain regions of plasmids and the host genome were particularly well-sampled during type III-A, but not type II-A, spacer uptake. These regions included the single-stranded origins of rolling-circle replicating plasmids, rRNA and tRNA encoding gene clusters, promoter regions of expressed genes and 5' UTR regions involved in transcription attenuation. These features share the potential to form DNA secondary structures, suggesting a preferred substrate for type III adaptation. Lastly, the type III-A system adapted to and protected host cells from lytic phage infection. | US |
Within animal populations there is variation among individuals in their tendency to be social, where more sociable individuals associate more with other individuals. Consistent inter-individual variation in 'sociability' is considered one of the major axes of personality variation in animals along with aggressiveness, activity, exploration and boldness. Not only is variation in sociability important in terms of animal personalities, but it holds particular significance for, and can be informed by, two other topics of major interest: social networks and collective behaviour. Further, knowledge of what generates inter-individual variation in social behaviour also holds applied implications, such as understanding disorders of social behaviour in humans. In turn, research using non-human animals in the genetics, neuroscience and physiology of these disorders can inform our understanding of sociability. For the first time, this review brings together insights across these areas of research, across animal taxa from primates to invertebrates, and across studies from both the laboratory and field. We show there are mixed results in whether and how sociability correlates with other major behavioural traits. Whether and in what direction these correlations are observed may differ with individual traits such as sex and body condition, as well as ecological conditions. A large body of evidence provides the proximate mechanisms for why individuals vary in their social tendency. Evidence exists for the importance of genes and their expression, chemical messengers, social interactions and the environment in determining an individual's social tendency, although the specifics vary with species and other variables such as age, and interactions amongst these proximate factors. Less well understood is how evolution can maintain consistent variation in social tendencies within populations. Shifts in the benefits and costs of social tendencies over time, as well as the social niche hypothesis, are currently the best supported theories for how variation in sociability can evolve and be maintained in populations. Increased exposure to infectious diseases is the best documented cost of a greater social tendency, and benefits include greater access to socially transmitted information. We also highlight that direct evidence for more sociable individuals being safer from predators is lacking. Variation in sociability is likely to have broad ecological consequences, but beyond its importance in the spread of infectious diseases, direct evidence is limited to a few examples related to dispersal and invasive species biology. Overall, our knowledge of inter-individual variation in sociability is highly skewed towards the proximate mechanisms. Our review also demonstrates, however, that considering research from social networks and collective behaviour greatly enriches our understanding of sociability, highlighting the need for greater integration of these approaches into future animal personality research to address the imbalance in our understanding of sociability as a personality trait. | United Kingdom |
Despite multiple trials demonstrating that procalcitonin (PCT) is an effective tool for antibiotic stewardship, inconsistent application in real-world settings continues to fuel controversy regarding its clinical utility. We sought to determine rates of concordance between PCT results and antibiotic prescribing in hospitalized patients. | US |
This study examined interparental conflict as a curvilinear predictor of children's reactivity to interparental conflict and, in turn, their school problems across three annual measurements. Participants included 243 preschool children (M<sub>age</sub>  = 4.60 years; 56% girls) and their parents from racially (e.g., 48% Black; 16% Latinx) diverse backgrounds. Interparental conflict was a significant quadratic predictor of children's emotional reactivity (β = .23) and behavioral dysregulation (β = .27) to conflict over a 1-year period. The robust association between interparental conflict and behavioral dysregulation weakened at high levels of interparental conflict. In contrast, interparental conflict more strongly predicted children's emotional reactivity as conflict exposure increased. Children's emotional reactivity, in turn, predicted their greater school problems 1 year later (β = .25). | US |
Orthodontic treatment is often accompanied with prescription of softer foods to patients. The question to ask is, is this prescribed load regimen congruent with Wolff's law, and does it provide an adequate mechanical stimulus to maintain the functional health of periodontal complex? This question was answered by studying the effects of mice chewing on soft food (SF) and hard food (HF) while undergoing experimental tooth movement (ETM). | US |
Colorectal cancer (CRC) is the third leading cause of cancer in the United States, and inflammatory bowel disease patients have an increased risk of developing CRC due to chronic intestinal inflammation with it being the cause of death in 10% to 15% of inflammatory bowel disease patients. TIPE2 (TNF-alpha-induced protein 8-like 2) is a phospholipid transporter that is highly expressed in immune cells and is an important regulator of immune cell function. | US |
In vitro selection experiments identified viruses resistant to integrase strand transfer inhibitors (INSTIs) carrying mutations in the G-tract (six guanosines) of the 3'-polypurine tract (3'-PPT). A clinical study also reported that mutations in the 3'-PPT were observed in a patient receiving dolutegravir monotherapy. However, recombinant viruses with the 3'-PPT mutations that were found in the clinical study were recently shown to be susceptible to INSTIs. | US |
Over the past several decades, there have been advances in diagnosis and treatment of neonatal herpes simplex virus (HSV) disease. There has been no recent comprehensive evaluation of the impact of these advances on the management and outcomes for neonates with HSV. | US |
To establish the utility of anatomic optical coherence tomography (aOCT) in evaluating internal nasal valve (INV). | US |
Survivorship care plans (SCP) should outline pertinent information about cancer treatment and follow-up. | US |
This study aimed at developing a 3D reduced field-of-view imaging (3D-rFOVI) technique using a 2D radiofrequency (RF) pulse, and demonstrating its ability to achieve isotropic high spatial resolution and reduced image distortion in echo planar imaging (EPI). | US |