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ABSTRACT The Enterobacterial Rcs stress response system reacts to envelope stresses through a complex two-component phosphorelay system to regulate a variety of environmental response genes, such as capsular polysaccharide and flagella biosynthesis genes. However, beyond Escherichia coli, the stresses that activate Rcs are not well-understood. In this study, we used a Rcs system-dependent luminescent transcriptional reporter to screen a library of over 240 antimicrobial compounds for those that activated the Rcs system in Serratia marcescens, a Yersiniaceae family bacterium. Using an isogenic rcsB mutant to establish specificity, both new and expected activators were identified, including the short-chain fatty acid propionic acid, which is found at millimolar levels in the human gut. Propionic acid did not reduce the bacterial intracellular pH, as was hypothesized for its antibacterial mechanism. Instead, data suggest that the Rcs-activation by propionic acid is due, in part, to an inactivation of alanine racemase. This enzyme is responsible for the biosynthesis of d-alanine, which is an amino-acid that is required for the generation of bacterial cell walls. Consistent with what was observed in S. marcescens, in E. coli, alanine racemase mutants demonstrated elevated expression of the Rcs-reporter in a d-alanine-dependent and RcsB-dependent manner. These results suggest that host gut short-chain fatty acids can influence bacterial behavior via the activation of the Rcs stress response system. IMPORTANCE The Rcs bacterial stress response system responds to envelope stresses by globally altering gene expression to profoundly impact host-pathogen interactions, virulence, and antibiotic tolerance. In this study, a luminescent Rcs-reporter plasmid was used to screen a library of compounds for activators of Rcs. Among the strongest inducers was the short-chain fatty acid propionic acid, which is found at high concentrations in the human gut. This study suggests that gut short-chain fatty acids can affect both bacterial virulence and antibiotic tolerance via the induction of the Rcs system.

ABSTRACT Nontuberculous mycobacteria (NTM), including Mycobacterium avium, are clinically important pathogens in cystic fibrosis (CF). The innate immune response to M. avium remains incompletely understood. We evaluated the role of complement opsonization in neutrophil-mediated killing of M. avium. Killing assays were performed using neutrophils from healthy donors (HDs) and persons with CF (pwCF). Clinical isolates of M. avium were opsonized with plasma from HDs or pwCF, which was intact or heat-treated to inactivate complement. HD neutrophils had killing activity against M. avium opsonized with intact HD plasma and killing was significantly reduced when M. avium was opsonized with heat-inactivated HD plasma. When opsonized with HD plasma, CF neutrophils had killing activity against M. avium that was not different than HD neutrophils. When opsonized with intact plasma from pwCF, HD neutrophil killing of M. avium was significantly reduced. Opsonization of M. avium with C3-depleted serum or IgM-depleted plasma resulted in significantly reduced killing. Plasma C3 levels were elevated in pwCF with NTM infection compared to pwCF without NTM infection. These studies demonstrate that human neutrophils efficiently kill M. avium when opsonized in the presence of plasma factors from HD that include C3 and IgM. Killing efficiency is significantly lower when the bacteria are opsonized with plasma from pwCF. This indicates a novel role for opsonization in neutrophil killing of M. avium and a deficiency in complement opsonization as a mechanism of impaired M. avium killing in CF. IMPORTANCE Mycobacterium avium is a member of a group of bacterial species termed nontuberculous mycobacteria (NTM) that cause lung disease in certain populations, including persons with cystic fibrosis (CF). NTM infections are challenging to diagnose and can be even more difficult to treat. This study investigated how the immune system responds to M. avium infection in CF. We found that neutrophils, the most abundant immune cell in the lungs in CF, can effectively kill M. avium in individuals both with and without CF. Another component of the immune response called the complement system is also required for this process. Levels of complement proteins are altered in persons with CF who have a history of NTM compared to those without a history of NTM infection. These results add to our understanding of how the immune system responds to M. avium, which can help pave the way toward better diagnostic and treatment strategies.

Stomach cancer is a leading cause of cancer death. Helicobacter pylori is a bacterial gastric pathogen that is the primary risk factor for carcinogenesis, associated with its induction of inflammation and DNA damage. Dicarbonyl electrophiles are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. 2-hydroxybenzylamine (2-HOBA) is a natural compound derived from buckwheat seeds and acts as a potent scavenger of reactive aldehydes. Our goal was to investigate the effect of 2-HOBA on the pathogenesis of H. pylori infection. We used transgenic FVB/N insulin-gastrin (INS-GAS) mice as a model of gastric cancer. First, we found that 2-HOBA is bioavailable in the gastric tissues of these mice after supplementation in the drinking water. Moreover, 2-HOBA reduced the development of gastritis in H. pylori-infected INS-GAS mice without affecting the bacterial colonization level in the stomach. Further, we show that the development of gastric dysplasia and carcinoma was significantly reduced by 2-HOBA. Concomitantly, DNA damage were also inhibited by 2-HOBA treatment in H. pylori-infected mice. In parallel, DNA damage was inhibited by 2-HOBA in H. pylori-infected gastric epithelial cells in vitro. In conclusion, 2-HOBA, which has been shown to be safe in human clinical trials, represents a promising nutritional compound for the chemoprevention of the more severe effects of H. pylori infection.

Though physical activity (PA) is recommended during pregnancy, it remains unclear how occupational physical activity (OPA) and sedentary behavior (SB) contribute to activity patterns and health during pregnancy. The purpose of this secondary analysis was to determine if OPA pattern is a determinant of all-day PA and evaluate associations with pregnancy/infant health outcomes. Data was from two prospective cohorts with study visits each trimester: MoM Health (Pittsburgh, PA; n = 120) and PRAMS (Iowa City, Iowa; n = 20). Using employment status/job hours (self-reported in demographic questionnaires) and OPA from the Pregnancy Physical Activity Questionnaire, latent class analysis identified three groups: sitting (n = 61), part-time mixed (n = 9), and active (n = 29). A fourth group included non-working participants (n = 32). Device-based PA (ActiGraph GT3X), SB (activPAL3 micro), and blood pressure were measured each trimester. Glucose screening test, gestational age, gestational weight gain, adverse pregnancy outcomes (APOs: gestational hypertension, preeclampsia, eclampsia, gestational diabetes, intrauterine growth restriction, and preterm birth), and infant outcomes (length, weight, and sex) were abstracted from medical records. Associations between groups with APOs and pregnancy/infant health were calculated using linear/logistic regression with adjustment for age, pre-pregnancy BMI, education, and race. Self-reported participant characteristics were similar across groups, except education which was higher in the sitting versus other groups. All-day device-based PA differed across groups; for example, the sitting group had the highest SB across trimester (all p0.09). Compared to the non-working group, the risk of any APO was non-significantly higher in the sitting (OR = 2.27, 95%CI = 0.63-8.18) and active groups (OR = 2.40, 95%CI = 0.66-9.75), though not the part-time mixed (OR = 0.86, 95%CI = 0.08-9.1). OPA pattern is a determinant of all-day PA during pregnancy. Future studies with larger samples should examine associations between pregnancy OPA patterns and pregnancy/infant health.

Endothelial cells synthesize biochemical signals to coordinate a response to insults, resolve inflammation and restore barrier integrity. Vascular cells release a variety of vasoactive bioactive lipid metabolites during the inflammatory response and produce pro-resolving mediators (e.g., Lipoxin A4, LXA4) in cooperation with leukocytes and platelets to bring a halt to inflammation. Aspirin, used in a variety of cardiovascular and pro-thrombotic disorders (e.g., atherosclerosis, angina, preeclampsia), potently inhibits proinflammatory eicosanoid formation. Moreover, aspirin stimulates the synthesis of pro-resolving lipid mediators (SPM), so-called Aspirin-Triggered Lipoxins (ATL). We demonstrate that cytokines stimulated a time- and dose-dependent increase in PGI2 (6-ketoPGF1α) and PGE2 formation that is blocked by aspirin. Eicosanoid production was caused by cytokine-induced expression of cyclooxygenase-2 (COX-2). We also detected increased production of pro-resolving LXA4 in cytokine-stimulated endothelial cells. The R-enantiomer of LXA4, 15-epi-LXA4, was enhanced by aspirin, but only in the presence of cytokine challenge, indicating dependence on COX-2 expression. In contrast to previous reports, we detected arachidonate 5-lipoxygenase (ALOX5) mRNA expression and its cognate protein (5-lipoxygenase, 5-LOX), suggesting that endothelial cells possess the enzymatic machinery necessary to synthesize both pro-inflammatory and pro-resolving lipid mediators independent of added leukocytes or platelets. Finally, we observed that, endothelial cells produced LTB4 in the absence of leukocytes. These results indicate that endothelial cells produce both pro-inflammatory and pro-resolving lipid mediators in the absence of other cell types and aspirin exerts pleiotropic actions influencing both COX and LOX pathways.

The COVID-19 pandemic has impacted the daily lives of individuals across the world as multiple variants continue introducing new complexities. In December 2021, which is when we conducted our study, pressure to resume the normalcy of daily life was mounting as a new variant, Omicron, was rapidly spreading. A variety of at-home tests detecting SARS-CoV-2, known to the general public as "COVID tests," were available for consumers to purchase. In this study, we conducted conjoint analysis utilizing an internet-based survey by presenting consumers (n = 583) with 12 different hypothetical at-home COVID test concepts that varied on five attributes (price, accuracy, time, where-to-buy, and method). Price was identified as the most important attribute, because participants were very price sensitive. Quick turnaround time and high accuracy were also identified as important. Additionally, although 64% of respondents were willing to take an at-home COVID test, only 22% reported they had previously taken the test. On December 21, 2021, President Biden announced the U.S. government would purchase 500 million at-home rapid tests and distribute them for free to Americans. Given the importance of price to participants, this policy of providing free at-home COVID tests was directionally appropriate.

Objectives Evaluate construct validity of Patient-Reported Outcomes Measurement Information System (PROMIS) Paediatric measures of symptoms and functioning against measures of disease activity among youth with juvenile idiopathic arthritis (JIA) or systemic lupus erythematosus (SLE).Design Cross-sectional associations among PROMIS measures and clinical metrics of disease activity were estimated.Setting Seven clinical sites of the Childhood Arthritis and Rheumatology Alliance (CARRA) in the USA.Participants Youth aged 8–17 years enrolled in the CARRA Registry.Intervention PROMIS measures were collected and associations with clinical measures of disease activity estimated, by condition, in bivariate and multivariable analyses with adjustment for sociodemographics, insurance status, medications and disease duration.Main outcome measures PROMIS Paediatric measures of mobility, physical activity, fatigue, pain interference, family relationships, peer relationships, depressive symptoms, psychological stress, anxiety, and meaning and purpose, and clinical metrics of disease.Results Among 451 youth (average age 13.8 years, 71% female), most (n=393, 87%) had a JIA diagnosis and the remainder (n=58, 13%) had SLE. Among participants with JIA, those with moderate/high compared with low/inactive disease had, on average, worse mobility (multivariable regression coefficient and 95% CIs) (−7.40; −9.30 to –5.50), fatigue (3.22; 1.02 to 5.42), pain interference (4.76; 3.04 to 6.48), peer relationships (−2.58; −4.52 to –1.64), depressive symptoms (3.00; 0.96 to 5.04), anxiety (2.48; 0.40 to 4.56) and psychological stress (2.52; 0.68 to 4.36). For SLE, youth with active versus inactive disease had on average worse mobility (−5.07; −10.15 to 0.01) but PROMIS Paediatric measures did not discriminate participants with active and inactive disease in adjusted analyses.Conclusions Seven PROMIS Paediatric measures discriminated between active and inactive disease in youth with JIA. Results advance the usefulness of PROMIS for understanding well-being and improving interventions for youth with JIA, but larger studies are needed to determine utility in SLE cohorts.Trial registration number National Institute of Arthritis and Musculoskeletal and Skin Diseases (U19AR069522).

Background Studies in several fields of medicine have found that women published less during the COVID-19 pandemic, potentially due to an increase in domestic responsibilities. This study examines whether a similar pattern exists for female authorship in ophthalmology. Purpose To compare the proportions of female authorship published in high-impact ophthalmology journals before and during the COVID-19 pandemic. Methods A cross-sectional study analyzing authorship gender of articles published during the COVID-19 pandemic (between July and September 2020) compared with matched articles published in the same journals before the COVID-19 pandemic (between July and September 2019). Gender of the first and last authors was analyzed using an online gender determination tool. Results A total of 577 articles and 1,113 authors were analyzed. There was no significant difference in the average number of publications by male and female authors before and during the COVID-19 pandemic. There was a significant increase in the percentage of female first authorship from the prepandemic period (32%) to during the COVID-19 pandemic (40%; p = 0.01), but no significant increase in the last authorship (p > 0.05). When analyzing only research articles, a similar increase in female first authorship was noted when comparing the publications before (31%) and during the COVID-19 pandemic (43%; p = 0.02). No significant differences were noted when analyzing the editorials (p > 0.05). Conclusion While disparities continue to exist between male and female authorship, an increase in female first authorship was noted during the COVID-19 pandemic for overall articles as well as research articles. Precis During the COVID-19 pandemic, female authorship as first and last authors of peer-reviewed articles in high-impact ophthalmology journals was below 50%. However, while the overall rates of female authorship were unchanged, female first authorship significantly increased during the pandemic. These results differ from studies published in other medical fields that demonstrated a decrease in female authorship during the COVID-19 pandemic.

IntroductionVisuomotor impairments have been demonstrated in preclinical AD in individuals with a positive family history of dementia and APOE e4 carriers. Previous behavioral findings have also reported sex-differences in performance of visuomotor tasks involving a visual feedback reversal. The current study investigated the relationship between grey and white matter changes and non-standard visuomotor performance, as well as the effects of APOE status, family history of dementia, and sex on these brain-behavior relationships.MethodsOlder adults (n = 49) with no cognitive impairments completed non-standard visuomotor tasks involving a visual feedback reversal, plane-change, or combination of the two. Participants with a family history of dementia or who were APOE e4 carriers were considered at an increased risk for AD. T1-weighted anatomical scans were used to quantify grey matter volume and thickness, and diffusion tensor imaging measures were used to quantify white matter integrity.ResultsIn APOE e4 carriers, grey and white matter structural measures were associated with visuomotor performance. Regression analyses showed that visuomotor deficits were predicted by lower grey matter thickness and volume in areas of the medial temporal lobe previously implicated in visuomotor control (entorhinal and parahippocampal cortices). This finding was replicated in the diffusion data, where regression analyses revealed that lower white matter integrity (lower FA, higher MD, higher RD, higher AxD) was a significant predictor of worse visuomotor performance in the forceps minor, forceps major, cingulum, inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), and uncinate fasciculus (UF). Some of these tracts overlap with those important for visuomotor integration, namely the forceps minor, forceps major, SLF, IFOF, and ILF.ConclusionThese findings suggest that measuring the dysfunction of brain networks underlying visuomotor control in early-stage AD may provide a novel behavioral target for dementia risk detection that is easily accessible, non-invasive, and cost-effective. The results also provide insight into the structural differences in inferior parietal lobule that may underlie previously reported sex-differences in performance of the visual feedback reversal task.

Abstract Background Critically ill patients require complex care and experience unique needs during and after their stay in the intensive care unit (ICU). Discharging or transferring a patient from the ICU to a hospital ward or back to community care (under the care of a general practitioner) includes several elements that may shape patient outcomes and overall experiences. The aim of this study was to answer the question: what elements facilitate a successful, high-quality discharge from the ICU? Methods This scoping review is an update to a review published in 2015. We searched MEDLINE, EMBASE, CINAHL, and Cochrane databases from 2013-December 3, 2020 including adult, pediatric, and neonatal populations without language restrictions. Data were abstracted using different phases of care framework models, themes, facilitators, and barriers to the ICU discharge process. Results We included 314 articles from 11,461 unique citations. Two-hundred and fifty-eight (82.2%) articles were primary research articles, mostly cohort (118/314, 37.6%) or qualitative (51/314, 16.2%) studies. Common discharge themes across all articles included adverse events, readmission, and mortality after discharge (116/314, 36.9%) and patient and family needs and experiences during discharge (112/314, 35.7%). Common discharge facilitators were discharge education for patients and families (82, 26.1%), successful provider-provider communication (77/314, 24.5%), and organizational tools to facilitate discharge (50/314, 15.9%). Barriers to a successful discharge included patient demographic and clinical characteristics (89/314, 22.3%), healthcare provider workload (21/314, 6.7%), and the impact of current discharge practices on flow and performance (49/314, 15.6%). We identified 47 discharge tools that could be used or adapted to facilitate an ICU discharge. Conclusions Several factors contribute to a successful ICU discharge, with facilitators and barriers present at the patient and family, health care provider, and organizational level. Successful provider-patient and provider-provider communication, and educating and engaging patients and families about the discharge process were important factors in a successful ICU discharge.

OBJECTIVES We examined whether pericardial adipose tissue (PAT) is predictive of prediabetes and type 2 diabetes over time. METHODS In total, 2,570 adults without prediabetes/diabetes from the Coronary Artery Risk Development in Young Adults Study were followed up over 15 years. PAT volume was measured by computed tomography scans, and the new onset of prediabetes/diabetes was examined 5 years, 10 years, and 15 years after the PAT measurements. Multivariable Cox regression models were used to examine the association between the tertile of PAT and incident prediabetes/diabetes up to 15 years later. The predictive ability of PAT (vs. waist circumference [WC], body mass index [BMI], waist-to-height ratio [WHtR]) for prediabetes/diabetes was examined by comparing the area under the receiver operating characteristic curve (AUC). RESULTS The highest tertile of PAT was associated with a 1.56 times (95% confidence interval [CI], 1.03 to 2.34) higher rate of diabetes than the lowest tertile; however, no association was found between the highest tertile of PAT and prediabetes in the fully adjusted models, including additional adjustment for BMI or WC. In the fully adjusted models, the AUCs of WC, BMI, WHtR, and PAT for predicting diabetes were not significantly different, whereas the AUC of WC for predicting prediabetes was higher than that of PAT. CONCLUSIONS PAT may be a significant predictor of hyperglycemia, but this association might depend on the effect of BMI or WC. Additional work is warranted to examine whether novel adiposity indicators can suggest advanced and optimal information to supplement the established diagnosis for prediabetes/diabetes.

Background: People living with HIV (PLWH) are at risk for falls due to polypharmacy, unhealthy substance (risky alcohol and/or illicit drug) use, low physical activity, and frailty combined with typical age-related physical changes. Fall prevention is needed to reduce the morbidity related to falls and fractures, however, there is a paucity of data on the design of a fall prevention intervention and whether it can be delivered virtually. We describe the protocol of a pilot randomized trial of a virtual occupational therapy fall prevention intervention for people with HIV at high risk for falls and recent alcohol and/or drug use. Method: PLWH will be recruited from the Boston ARCH 4F Cohort study, an observational study of PLWH to examine the impact of alcohol on falls. Trial participants will be randomized to either an occupational therapy-led fall prevention intervention or provided with written education about fall prevention and alcohol use (control). The 10-week fall prevention intervention was based upon results from qualitative interviews with PLWH about falls and will consist of weekly virtual group sessions, home exercises and phone-check-ins, delivered by occupational therapists. The primary outcome measures will be number of groups attended and a participant-completed satisfaction survey. Change in number of falls, alcohol and other drug use, and physical functioning will be examined. Discussion: A virtual occupational therapy fall prevention intervention addresses the emerging concern of fall risk in PLWH and alcohol use. This pilot study will provide preliminary estimates of fall-related outcomes as well as feasibility of study procedures for a larger trial. ClinicalTrials.gov Identifier: NCT04804579. Boston University Protocol Record H-41041

IntroductionNon-standard visuomotor integration requires the interaction of large networks in the brain. Previous findings have shown that non-standard visuomotor performance is impaired in individuals with specific dementia risk factors (family history of dementia and presence of the APOE ε4 allele) in advance of any cognitive impairments. These findings suggest that visuomotor impairments are associated with early dementia-related brain changes. The current study examined the underlying resting state functional connectivity (RSFC) associated with impaired non-standard visuomotor performance, as well as the impacts of dementia family history, sex, and APOE status.MethodsCognitively healthy older adults (n = 48) were tested on four visuomotor tasks where reach and gaze were increasingly spatially dissociated. Participants who had a family history of dementia or the APOE ε4 allele were considered to be at an increased risk for AD. To quantify RSFC within networks of interest, an EPI sequence sensitive to BOLD contrast was collected. The networks of interest were the default mode network (DMN), somatomotor network (SMN), dorsal attention network (DAN), ventral attention network (VAN), and frontoparietal control network (FPN).ResultsIndividuals with the ε4 allele showed abnormalities in RSFC between posterior DMN nodes that predicted poorer non-standard visuomotor performance. Specifically, multiple linear regression analyses revealed lower RSFC between the precuneus/posterior cingulate cortex and the left inferior parietal lobule as well as the left parahippocampal cortex. Presence of the APOE ε4 allele also modified the relationship between mean DAN RSFC and visuomotor control, where lower mean RSFC in the DAN predicted worse non-standard visuomotor performance only in APOE ε4 carriers. There were otherwise no effects of family history, APOE ε4 status, or sex on the relationship between RSFC and visuomotor performance for any of the other resting networks.ConclusionThe preliminary findings provide insight into the impact of APOE ε4-related genetic risk on neural networks underlying complex visuomotor transformations, and demonstrate that the non-standard visuomotor task paradigm discussed in this study may be used as a non-invasive, easily accessible assessment tool for dementia risk.

Background: Fatigue is prevalent among hospital nurses and has been linked to medical errors and decreased patient safety. However, little is known regarding the relationship between occupational physical activity, sedentary behavior, and fatigue.Objective: To assess the impact of 12-hour shifts on nurses’ fatigue and its relationship to occupational physical activity and sedentary behavior.Design: Prospective-cohort study designSetting(s): Midwestern trauma one academic medical centerParticipants: A total of 80 registered nurses working 12-hour day and night shifts participated in this study and completed momentary measures of fatigue (texting, aim one). Only 52 participants were included in aim two analyses (included activity monitoring, aim two).Methods: Occupational patterns of momentary fatigue was measured via ecological momentary assessments. Occupational physical activity and sedentary behaviors (e.g., step count, time spent sitting, standing, and walking) were measured for 14 continuous days using the ActivPAL3 micro activity monitor. Mixed models were used to examine the effects of shift type and time within a shift on occupational fatigue. General estimation equations were used to examine the relationship between time spent sitting, standing, and walking on fatigue.Results: Regardless of shift type, nurses exhibited a significant rise in fatigue; however, the rise was greater during night shifts compared to day shifts. Walking was positively associated with fatigue during day shifts, and negatively associated with fatigue during night shifts.Conclusions: The rise in fatigue was greater among nurses working night shifts compared to day shifts, which could place them at greater risk for fatigue-related consequences. The relationship between walking and fatigue was moderated by shift-type.Tweetable abstract: Nursing fatigue rises during 12-hour shifts, but the rise is greater for those working night shifts @DrRobertoBenzo

A survey evaluation was conducted in the division of cardiology at a tertiary care academic centre to assess barriers, facilitators, acceptability, and feasibility of virtual care during the COVID-19 pandemic. Survey responses from 26 health care providers, 45 patients, and 2 caregivers showed that virtual visits (primarily by telephone) were feasible and generally acceptable to most respondents. Key opportunities for improvement included availability of easy-to-use video platforms, space and equipment in clinics, provision of information to patients before visits, and appropriate selection of patients for virtual visits. Results will inform optimization of virtual care during this pandemic and beyond. Résumé: Une enquête a été menée dans la division de cardiologie d'un centre universitaire de soins tertiaires pour évaluer les facteurs qui entravent ou facilitent les soins virtuels pendant la pandémie de COVID-19, ainsi que l'acceptabilité et la faisabilité de ces soins. Selon les réponses fournies par 26 dispensateurs de soins de santé, 45 patients et deux aidants sondés, les visites virtuelles (principalement par téléphone) sont réalisables et généralement acceptables pour la plupart des répondants. Les principales possibilités d'amélioration concernent l'offre de plateformes vidéo conviviales, l'espace et l’équipement dans les cliniques, la fourniture de renseignements aux patients avant les visites et la sélection appropriée des patients pour les visites virtuelles. Les résultats permettront d'optimiser les soins virtuels au cours de cette pandémie et par la suite.

Abstract The objective of this study was to determine the effects of dietary fibre level and source on faecal ceftiofur metabolites concentrations after intramuscular administration of therapeutic ceftiofur hydrochloride in finisher pigs. Pens of finisher pigs (n = 36), with an equal number of barrows and gilts, were randomly assigned to 1 of 3 dietary treatment groups: basal diet composed of corn grain and soy bean meal with no supplement and formulated to contain 8.7% neutral detergent fibre (NDF), supplemented with 20% distillers dried grains with solubles (a byproduct of the ethanol production from corn grain) formulated to contain 13.6% NDF, primarily insoluble fibre or supplemented with 14.5% sugar beet pulp formulated to contain 13.6% NDF. Faecal samples were collected 6–8 hr after ceftiofur injection from treated and untreated pen‐mate pigs on days 1 and 3 of the 3‐day treatment regimen. Faecal concentrations of ceftiofur metabolites, including the major metabolite, desfuroylceftiofur, were analysed by reverse‐phase high pressure liquid chromatography with ultraviolet detection. Overall, the faecal concentrations of ceftiofur metabolites did not differ significantly between the dietary treatments. The mean concentrations of metabolites tended to be lower (p = .1) on day 3 compared to day 1 of the 3‐day treatment regimen. Faecal concentrations of metabolites were not affected by the gender of the finisher pigs. The concentrations of ceftiofur metabolites in the faeces are likely reflective of the microbial activity in the hindgut. Our data suggest that the fibre level and source used in the study did not affect the faecal concentrations of ceftiofur metabolites.

Foodborne disease is a significant global health problem, with low- and middle-income countries disproportionately affected. Given that most fresh animal and vegetable foods in LMICs are bought in informal food systems, much the burden of foodborne disease in LMIC is also linked to informal markets. Developing estimates of the national burden of foodborne disease and attribution to specific food products will inform decision-makers about the size of the problem and motivate action to mitigate risks and prevent illness. This study provides estimates for the burden of foodborne disease caused by selected hazards in two African countries (Burkina Faso and Ethiopia) and attribution to specific foods. Country-specific estimates of the burden of disease in 2010 for Campylobacter spp., enterotoxigenic Escherichia coli (ETEC), Shiga-toxin producing E. coli and non-typhoidal Salmonella enterica were obtained from WHO and updated to 2017 using data from the Global Burden of Disease study. Attribution data obtained from WHO were complemented with a dedicated Structured Expert Judgement study to estimate the burden attributable to specific foods. Monte Carlo simulation methods were used to propagate uncertainty. The burden of foodborne disease in the two countries in 2010 was largely similar to the burden in the region except for higher mortality and disability-adjusted life years (DALYs) due to Salmonella in Burkina Faso. In both countries, Campylobacter caused the largest number of cases, while Salmonella caused the largest number of deaths and DALYs. In Burkina Faso, the burden of Campylobacter and ETEC increased from 2010 to 2017, while the burden of Salmonella decreased. In Ethiopia, the burden of all hazards decreased. Mortality decreased relative to incidence in both countries. In both countries, the burden of poultry meat (in DALYs) was larger than the burden of vegetables. In Ethiopia, the burdens of beef and dairy were similar, and somewhat lower than the burden of vegetables. The burden of foodborne disease by the selected pathogens and foods in both countries was substantial. Uncertainty distributions around the estimates spanned several orders of magnitude. This reflects data limitations, as well as variability in the transmission and burden of foodborne disease associated with the pathogens considered.

This paper outlines the collaborative efforts between the Korea Aerospace Research Institute (KARI) and the National Aeronautics and Space Administration (NASA) Johnson Space Center (JSC) for the Flight Dynamics (FD) operation of the Korea Pathfinder Lunar Orbiter (KPLO). From the outset of the KPLO program, the joint KARI KPLO FD team and NASA JSC Flight Operations Directorate (FOD) have devoted significant time and effort towards ensuring the mission’s success. This paper begins by introducing the aims and scope of the collaborative work, followed by a detailed description of the efforts made between the KPLO FD team and JSC FOD. This includes the top-level concept, interface architecture, test results, established operation procedures/timeline, and the summary of the joint rehearsal conducted. Finally, the paper discusses the challenges and lessons learned from this journey, particularly from the practical FD operational perspectives. Thanks to the joint team’s collaborative efforts, KPLO has successfully entered lunar orbit and is performing its mission exceptionally well. The joint experience has fostered mutual trust between KARI and NASA JSC, serving as a foundation for further cooperation and collaboration. The efforts and outcomes described in this work will provide valuable insights to experts worldwide who are willing to foster similar international collaborations in the future.

Abstract Background Moderate-to-vigorous intensity physical activity (MVPA) is associated with favorable self-rated mental and physical health. Conversely, poor self-rated health in these domains could precede unfavorable shifts in activity. We evaluated bidirectional associations of accelerometer-estimated time spent in stationary behavior (SB), light intensity physical activity (LPA), and MVPA with self-rated health over 10 years in in the CARDIA longitudinal cohort study. Methods Participants (n = 894, age: 45.1 ± 3.5; 63% female; 38% black) with valid accelerometry wear and self-rated health at baseline (2005–6) and 10-year follow-up (2015–6) were included. Accelerometry data were harmonized between exams and measured mean total activity and duration (min/day) in SB, LPA, and MVPA; duration (min/day) in long-bout and short-bout SB (≥30 min vs.

Abstract. Introduction:. Central sensitization (CS) involves dysfunctional central nervous system pain modulation resulting in heightened pain perception. Central sensitization is not commonly assessed among patients with opioid use disorder (OUD), despite the fact that pain has been implicated in the development, maintenance, and relapse of OUD and chronic opioid use may produce opioid-induced hyperalgesia. Central sensitization is a plausibly important mechanism underlying the complex relationship between OUD and chronic pain. However, this premise is largely untested. Methods:. Participants with OUD (n = 141) were recruited from an academic addiction treatment center in Columbus, Ohio. An established surrogate measure of CS, the American College of Rheumatology 2011 Fibromyalgia Survey Criteria, was administered using electronic survey. Participants also responded to questions about pain interference (Brief Pain Inventory), quality of life (RAND-36), and items regarding pain beliefs and expectations of pain and addiction treatment. Descriptive analyses, Spearman rho correlations, and Mann–Whitney U tests were performed. Results:. Hypothesized relationships were confirmed between degree of CS, pain interference, and health-related quality of life. Degree of CS was also positively correlated with greater endorsement of pain as a reason for the onset, maintenance, and escalation of OUD; treatment delay; and OUD relapse. Participants with the American College of Rheumatology 2011 Fibromyalgia Survey Criteria ≥13 had significantly greater endorsement of pain as a reason for delaying OUD treatment, continuing and increasing opioid use, and precipitating OUD relapse. Conclusions:. This study provides early evidence CS may underlie previously observed connections between clinically salient features of chronic pain and OUD, potentially informing future mechanistic research and precision treatment.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin with 2 etiologies. Merkel cell polyomavirus (MCPyV) integration is present in about 80% of all MCC. Virus-positive MCC (MCCP) tumors have few somatic mutations and usually express WT p53 (TP53). By contrast, virus-negative MCC (MCCN) tumors present with a high tumor mutational burden and predominantly UV mutational signature. MCCN tumors typically contain mutated TP53. MCCP tumors express 2 viral proteins: MCPyV small T antigen and a truncated form of large T antigen. MCPyV ST specifically activates expression of MDM2, an E3 ubiquitin ligase of p53, to inhibit p53-mediated tumor suppression. In this study, we assessed the efficacy of milademetan, a potent, selective, and orally available MDM2 inhibitor in several MCC models. Milademetan reduced cell viability of WT p53 MCC cell lines and triggered a rapid and sustained p53 response. Milademetan showed a dose-dependent inhibition of tumor growth in MKL-1 xenograft and patient-derived xenograft models. Here, along with preclinical data for the efficacy of milademetan in WT p53 MCC tumors, we report several in vitro and in vivo models useful for future MCC studies.

Macrophages play a crucial role in the inflammatory response to the human stomach pathogen Helicobacter pylori, which infects half of the world’s population and causes gastric cancer. Recent studies have highlighted the importance of macrophage immunometabolism in their activation state and function. We have demonstrated that the cysteine-producing enzyme cystathionine γ-lyase (CTH) is upregulated in humans and mice with H. pylori infection. Here, we show that induction of CTH in macrophages by H. pylori promoted persistent inflammation. Cth–/– mice had reduced macrophage and T cell activation in H. pylori–infected tissues, an altered metabolome, and decreased enrichment of immune-associated gene networks, culminating in decreased H. pylori–induced gastritis. CTH is downstream of the proposed antiinflammatory molecule, S-adenosylmethionine (SAM). Whereas Cth–/– mice exhibited gastric SAM accumulation, WT mice treated with SAM did not display protection against H. pylori–induced inflammation. Instead, we demonstrated that Cth-deficient macrophages exhibited alterations in the proteome, decreased NF-κB activation, diminished expression of macrophage activation markers, and impaired oxidative phosphorylation and glycolysis. Thus, through altering cellular respiration, CTH is a key enhancer of macrophage activation, contributing to a pathogenic inflammatory response that is the universal precursor for the development of H. pylori–induced gastric disease.

Abstract Background Prior to the COVID-19 pandemic, physicians experienced unprecedented levels of burnout. The uncertainty of the ongoing COVID-19 pandemic along with increased workload and difficult medical triage decisions may lead to a further decline in physician psychological health. Methods We searched Medline, EMBASE, and PsycINFO for primary research from database inception (Medline [1946], EMBASE [1974], PsycINFO [1806]) to November 17, 2020. Titles and abstracts were screened by one of three reviewers and full-text article screening and data abstraction were conducted independently, and in duplicate, by three reviewers. Results From 6223 unique citations, 480 articles were reviewed in full-text, with 193 studies (of 90,499 physicians) included in the final review. Studies reported on physician psychological symptoms and management during seven infectious disease outbreaks (severe acute respiratory syndrome [SARS], three strains of Influenza A virus [H1N1, H5N1, H7N9], Ebola, Middle East respiratory syndrome [MERS], and COVID-19) in 57 countries. Psychological symptoms of anxiety (14.3–92.3%), stress (11.9–93.7%), depression (17–80.5%), post-traumatic stress disorder (13.2–75.2%) and burnout (14.7–76%) were commonly reported among physicians, regardless of infectious disease outbreak or country. Younger, female (vs. male), single (vs. married), early career physicians, and those providing direct care to infected patients were associated with worse psychological symptoms. Interpretation Physicians should be aware that psychological symptoms of anxiety, depression, fear and distress are common, manifest differently and self-management strategies to improve psychological well-being exist. Health systems should implement short and long-term psychological supports for physicians caring for patients with COVID-19.

Abstract Background Early infant diagnosis of HIV infection is challenging in sub-Saharan Africa, particularly in rural areas, leading to delays in diagnosis and treatment. Use of a point-of-care test would overcome many challenges. This study evaluated the validity of a novel point-of-care p24 antigen detection test (LYNX) in rural and urban settings in southern Zambia. Methods Two studies were conducted: a cross-sectional study from 2014 to 2015 at Macha Hospital (LYNX Hospital study) and a longitudinal study from 2016 to 2018 at 12 health facilities in Southern Province, Zambia (NSEBA study). In both studies, children attending the facilities for early infant diagnosis were enrolled and a blood sample was collected for routine testing at the central lab and immediate on-site testing with the LYNX test. The performance of the LYNX test was measured in comparison to nucleic acid-based testing at the central lab. Results In the LYNX Hospital study, 210 tests were performed at a median age of 23.5 weeks (IQR: 8.9, 29.0). The sensitivity and specificity of the test were 70.0 and 100.0%, respectively. In the NSEBA study, 2608 tests were performed, including 1305 at birth and 1222 on children ≥4 weeks of age. For samples tested at birth, sensitivity was 13.6% (95% CI: 2.9, 34.9) and specificity was 99.6% (95% CI: 99.1, 99.9). While specificity was high for all ages, sensitivity increased with age and was higher for participants tested at ≥4 weeks of age (80.6%; 95% CI: 67.4, 93.7). Children with positive nucleic acid tests were more likely to be negative by the LYNX test if their mother received antiretroviral therapy during pregnancy (60.7% vs. 24.2%; p = 004). Conclusions Considering the high specificity and moderate sensitivity that increased with age, the LYNX test could be of value for early infant diagnosis for infants ≥4 weeks of age, particularly in rural areas where centralized testing leads to long delays. Point-of-care tests with moderate sensitivity and high specificity that are affordable, easy-to-use, and easily implemented and maintained should be developed to expand access to testing and deliver same-day results to infants in areas where it is not feasible to implement nucleic acid-based point-of-care assays.

Abstract Purpose For pediatric lymphoma, quantitative FDG PET/CT imaging features such as metabolic tumor volume (MTV) are important for prognosis and risk stratification strategies. However, feature extraction is difficult and time-consuming in cases of high disease burden. The purpose of this study was to fully automate the measurement of PET imaging features in PET/CT images of pediatric lymphoma. Methods 18F-FDG PET/CT baseline images of 100 pediatric Hodgkin lymphoma patients were retrospectively analyzed. Two nuclear medicine physicians identified and segmented FDG avid disease using PET thresholding methods. Both PET and CT images were used as inputs to a three-dimensional patch-based, multi-resolution pathway convolutional neural network architecture, DeepMedic. The model was trained to replicate physician segmentations using an ensemble of three networks trained with 5-fold cross-validation. The maximum SUV (SUVmax), MTV, total lesion glycolysis (TLG), surface-area-to-volume ratio (SA/MTV), and a measure of disease spread (Dmaxpatient) were extracted from the model output. Pearson’s correlation coefficient and relative percent differences were calculated between automated and physician-extracted features. Results Median Dice similarity coefficient of patient contours between automated and physician contours was 0.86 (IQR 0.78–0.91). Automated SUVmax values matched exactly the physician determined values in 81/100 cases, with Pearson’s correlation coefficient (R) of 0.95. Automated MTV was strongly correlated with physician MTV (R = 0.88), though it was slightly underestimated with a median (IQR) relative difference of − 4.3% (− 10.0–5.7%). Agreement of TLG was excellent (R = 0.94), with median (IQR) relative difference of − 0.4% (− 5.2–7.0%). Median relative percent differences were 6.8% (R = 0.91; IQR 1.6–4.3%) for SA/MTV, and 4.5% (R = 0.51; IQR − 7.5–40.9%) for Dmaxpatient, which was the most difficult feature to quantify automatically. Conclusions An automated method using an ensemble of multi-resolution pathway 3D CNNs was able to quantify PET imaging features of lymphoma on baseline FDG PET/CT images with excellent agreement to reference physician PET segmentation. Automated methods with faster throughput for PET quantitation, such as MTV and TLG, show promise in more accessible clinical and research applications.

Abstract Background The COVID-19 pandemic has placed sustained demand on health systems globally, and the capacity to provide critical care has been overwhelmed in some jurisdictions. It is unknown which triage criteria for allocation of resources perform best to inform health system decision-making. We sought to summarize and describe existing triage tools and ethical frameworks to aid healthcare decision-making during infectious disease outbreaks. Methods We conducted a rapid review of triage criteria and ethical frameworks for the allocation of critical care resources during epidemics and pandemics. We searched Medline, EMBASE, and SCOPUS from inception to November 3, 2020. Full-text screening and data abstraction were conducted independently and in duplicate by three reviewers. Articles were included if they were primary research, an adult critical care setting, and the framework described was related to an infectious disease outbreak. We summarized each triage tool and ethical guidelines or framework including their elements and operating characteristics using descriptive statistics. We assessed the quality of each article with applicable checklists tailored to each study design. Results From 11,539 unique citations, 697 full-text articles were reviewed and 83 articles were included. Fifty-nine described critical care triage protocols and 25 described ethical frameworks. Of these, four articles described both a protocol and ethical framework. Sixty articles described 52 unique triage criteria (29 algorithm-based, 23 point-based). Few algorithmic- or point-based triage protocols were good predictors of mortality with AUCs ranging from 0.51 (PMEWS) to 0.85 (admitting SOFA > 11). Most published triage protocols included the substantive values of duty to provide care, equity, stewardship and trust, and the procedural value of reason. Conclusions This review summarizes available triage protocols and ethical guidelines to provide decision-makers with data to help select and tailor triage tools. Given the uncertainty about how the COVID-19 pandemic will progress and any future pandemics, jurisdictions should prepare by selecting and adapting a triage tool that works best for their circumstances.

Introduction: Digital biomarkers may act as a tool for early detection of changes in cognition. It is important to understand public perception of technologies focused on monitoring cognition to better guide the design of these tools and inform patients appropriately about the associated risks and benefits. Health care systems may also play a role in the clinical, legal, and financial implications of such technologies. Objective: To evaluate public opinion on the use of passive technology for monitoring cognition. Methods: This was a one-time, Internet-based survey conducted in English and Spanish. Results: Within the English survey distributed in the USA (n = 173), 58.1% of respondents would be highly likely to agree to passive monitoring of cognition via a smartphone application. Thirty-eight percent of those with a higher degree of experience with technology were likely to agree to monitoring versus 20% of those with less experience with technology (p = 0.003). Sixty-two percent of non-health-care professionals were likely to agree to monitoring versus 45% of health-care workers (p = 0.012). There were significant concerns regarding privacy (p < 0.01). We compared the surveys answered in Spanish in Costa Rica via logistic regression (n = 43, total n = 216), adjusting for age, education level, health-care profession, owning a smartphone, experience with technology, and perception of cognitive decline. Costa Rican/Spanish-speaking respondents were 7 times more likely to select a high probability of agreeing to such a technology (p < 0.01). English-speaking respondents from the USA were 5 times more likely to be concerned about the impact on health insurance (p = 0.001) and life insurance (p = 0.01). Conclusions: Understanding public perception and ethical implications should guide the design of digital biomarkers for cognition. Privacy and the health-care system in which the participants take part are 2 major factors to be considered. It is the responsibility of researchers to convey the ethical and legal implications of cognition monitoring.

Background: Black patients seeking addiction care experience poorer treatment access, retention, and outcomes when compared to White counterparts. Black patients may have elevated group-based medical mistrust, which has been associated with poorer health outcomes and increased experiences of racism across multiple healthcare contexts. The relationship between group-based medical mistrust and expectations for addiction treatment among Black individuals remains untested. Methods: A total of 143 Black participants were recruited from two addiction treatment centers in Columbus, Ohio. Participants completed the Group Based Medical Mistrust Scale (GBMMS) and answered questions related to expectations of addiction treatment. Descriptive analysis and Spearman's rho correlations were performed to assess for relationships between group-based medical mistrust and expectations of care. Results: Group-based medical mistrust in Black patients was associated with self-reported delay in accessing addiction treatment, anticipation of racism during addiction treatment, non-adherence and discrimination-precipitated relapse. However, non-adherence to treatment was least strongly correlated with group-based medical mistrust demonstrating an opportunity for engagement. Conclusion: Group-based medical mistrust is associated with Black patients’ care expectations when seeking addiction treatment. Use of the GBMMS within addiction medicine to address themes of mistrust in patients, and potential biases in providers, may improve treatment access and outcomes.

Spinocerebellar ataxia (SCA) type 7 (SCA7) is caused by a CAG trinucleotide repeat expansion in the ataxin 7 (ATXN7) gene, which results in polyglutamine expansion at the amino terminus of the ATXN7 protein. Although ATXN7 is expressed widely, the best characterized symptoms of SCA7 are remarkably tissue specific, including blindness and degeneration of the brain and spinal cord. While it is well established that ATXN7 functions as a subunit of the Spt Ada Gcn5 acetyltransferase (SAGA) chromatin modifying complex, the mechanisms underlying SCA7 remain elusive. Here, we review the symptoms of SCA7 and examine functions of ATXN7 that may provide further insights into its pathogenesis. We also examine phenotypes associated with polyglutamine expanded ATXN7 that are not considered symptoms of SCA7.

Abstract Background Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway is common in many malignancies, including head and neck squamous cell carcinoma (HNSCC). Despite pre-clinical and clinical studies, outcomes from targeting the PI3K pathway have been underwhelming and the development of drug resistance poses a significant barrier to patient treatment. In the present study, we examined mechanisms of acquired resistance to the PI3Kα inhibitor alpelisib (formerly BYL719) in HNSCC cell lines and patient-derived xenografts (PDXs). Methods Five unique PDX mouse models and three HNSCC cell lines were used. All cell lines and xenografts underwent genomic characterization prior to study. Serial drug treatment was conducted in vitro and in vivo to develop multiple, clinically-significant models of resistance to alpelisib. We then used reverse phase protein arrays (RPPAs) to profile the expression of proteins in parental and drug-resistant models. Top hits were validated by immunoblotting and immunohistochemistry. Flow cytometric analysis and RNA interference studies were then used to interrogate the molecular mechanisms underlying acquired drug resistance. Results Prolonged treatment with alpelisib led to upregulation of TAM family receptor tyrosine kinases TYRO3 and AXL. Importantly, a significant shift in expression of both TYRO3 and AXL to the cell surface was detected in drug-resistant cells. Targeted knockdown of TYRO3 and AXL effectively re-sensitized resistant cells to PI3Kα inhibition. In vivo, resistance to alpelisib emerged following 20–35 days of treatment in all five PDX models. Elevated TYRO3 expression was detected in drug-resistant PDX tissues. Downstream of TYRO3 and AXL, we identified activation of intracellular MAPK signalling. Inhibition of MAPK signalling also re-sensitized drug-resistant cells to alpelisib. Conclusions We have identified TYRO3 and AXL receptors to be key mediators of resistance to alpelisib, both in vitro and in vivo. Our findings suggest that pan-TAM inhibition is a promising avenue for combinatorial or second-line therapy alongside PI3Kα inhibition. These findings advance our understanding of the role TAM receptors play in modulating the response of HNSCC to PI3Kα inhibition and suggest a means to prevent, or at least delay, resistance to PI3Kα inhibition in order to improve outcomes for HNSCC patients.

Abstract Background Little is known about patient-provider communication on gestational weight gain among women pregnant with twins, a growing population at high risk for adverse maternal and neonatal outcomes. We examined if women’s report of provider advice on gestational weight gain was consistent with the Institute of Medicine (IOM) weight gain guidelines for twin pregnancies, and the association of provider advice on weight gain with women’s weight gain during their twin pregnancy. Methods We conducted a cross-sectional survey of 276 women who delivered twins and received prenatal care in the United States. The 2009 IOM provisional weight gain guidelines for twin pregnancies defined whether provider advice on weight gain and women’s weight gain were below, within, or above guidelines. Multinomial logistic regression examined associations between provider advice on weight gain with women’s weight gain, after adjustment for maternal age, gestational age at delivery, education, parity, twin type, use of assisted reproductive technologies and pre-pregnancy BMI category. Results Approximately 30% of women described provider advice on weight gain below the IOM guidelines, 60% within, and 10% above guidelines. Compared to women who reported weight gain advice within guidelines, women who reported advice below guidelines or who reported no advice were 7.1 (95% CI: 3.2, 16.0) and 2.7 (95% CI: 1.3, 5.6) times more likely to gain less than recommended, respectively. Women who reported provider advice above guidelines were 4.6 (95% CI: 1.5, 14.2) times more likely to exceed guidelines. Conclusions Provider advice on gestational weight gain may be an important predictor of women’s weight gain during twin pregnancies, highlighting the critical need for accurate provider counseling to optimize health outcomes.

Abstract Background Autoimmune diseases have been associated with changes in the gut microbiome. In this study, the gut microbiome was evaluated in individuals with dry eye and bacterial compositions were correlated to dry eye (DE) measures. We prospectively included 13 individuals with who met full criteria for Sjögren’s (SDE) and 8 individuals with features of Sjögren’s but who did not meet full criteria (NDE) for a total of 21 cases as compared to 21 healthy controls. Stool was analyzed by 16S pyrosequencing, and associations between bacterial classes and DE symptoms and signs were examined. Results Results showed that Firmicutes was the dominant phylum in the gut, comprising 40–60% of all phyla. On a phyla level, subjects with DE (SDE and NDE) had depletion of Firmicutes (1.1-fold) and an expansion of Proteobacteria (3.0-fold), Actinobacteria (1.7-fold), and Bacteroidetes (1.3-fold) compared to controls. Shannon’s diversity index showed no differences between groups with respect to the numbers of different operational taxonomic units (OTUs) encountered (diversity) and the instances these unique OTUs were sampled (evenness). On the other hand, Faith’s phylogenetic diversity showed increased diversity in cases vs controls, which reached significance when comparing SDE and controls (13.57 ± 0.89 and 10.96 ± 0.76, p = 0.02). Using Principle Co-ordinate Analysis, qualitative differences in microbial composition were noted with differential clustering of cases and controls. Dimensionality reduction and clustering of complex microbial data further showed differences between the three groups, with regard to microbial composition, association and clustering. Finally, differences in certain classes of bacteria were associated with DE symptoms and signs. Conclusions In conclusion, individuals with DE had gut microbiome alterations as compared to healthy controls. Certain classes of bacteria were associated with DE measures.

Abstract Background Sedentary behavior (SED) is a potential risk factor for poor pregnancy outcomes. We evaluated the validity of several common and one new method to assess SED across three trimesters of pregnancy. Methods This cohort study of pregnant women measured objective and self-reported SED each trimester via thigh-worn activPAL3 micro (criterion), waist-worn Actigraph GT3X, and self-report from the Pregnancy Physical Activity Questionnaire (PPAQ) and the de novo Sedentary Behavior Two Domain Questionnaire (SB2D). SED (hours per day) and percent time in SED (SED%) from activPAL were compared to GT3X, SB2D, and PPAQ using Pearson’s r, ICC, Bland-Altman analysis, and comparison of criterion SED and SED% across tertiles of alternative methods. Results Fifty-eight women (mean age 31.5 ± 4.8 years; pre-pregnancy BMI 25.1 ± 5.6 kg/m2; 76% white) provided three trimesters of valid activPAL data. Compared to activPAL, GT3X had agreement ranging from r = 0.54–0.66 and ICC = 0.52–0.65. Bland-Altman plots revealed small mean differences and unpatterned errors, but wide limits of agreement (greater than ±2 h and ± 15%). The SB2D and PPAQ had r

Abstract There is growing evidence that prey perceive the risk of predation and alter their behavior in response, resulting in changes in spatial distribution and potential fitness consequences. Previous approaches to mapping predation risk across a landscape quantify predator space use to estimate potential predator‐prey encounters, yet this approach does not account for successful predator attack resulting in prey mortality. An exception is a prey kill site that reflects an encounter resulting in mortality, but obtaining information on kill sites is expensive and requires time to accumulate adequate sample sizes. We illustrate an alternative approach using predator scat locations and their contents to quantify spatial predation risk for elk (Cervus canadensis) from multiple predators in the Rocky Mountains of Alberta, Canada. We surveyed over 1300 km to detect scats of bears (Ursus arctos/U. americanus), cougars (Puma concolor), coyotes (Canis latrans), and wolves (C. lupus). To derive spatial predation risk, we combined predictions of scat‐based resource selection functions (RSFs) weighted by predator abundance with predictions that a predator‐specific scat in a location contained elk. We evaluated the scat‐based predictions of predation risk by correlating them to predictions based on elk kill sites. We also compared scat‐based predation risk on summer ranges of elk following three migratory tactics for consistency with telemetry‐based metrics of predation risk and cause‐specific mortality of elk. We found a strong correlation between the scat‐based approach presented here and predation risk predicted by kill sites and (r = .98, p

Abstract Major Histocompatibility Complex (MHC) genes are one of the most polymorphic gene groups known in vertebrates. MHC genes also exhibit allelic variants that are shared among taxa, referred to as trans‐specific polymorphism (TSP). The role that selection plays in maintaining such high diversity within species, as well as TSP, is an ongoing discussion in biology. In this study, we used deep‐sequencing techniques to characterize MHC class IIb gene diversity in three sympatric species of darters. We found at least 5 copies of the MHC gene in darters, with 126 genetic variants encoding 122 unique amino acid sequences. We identified four supertypes based on the binding properties of proteins encoded by the sequences. Although each species had a unique pool of variants, many variants were shared between species pairs and across all three species. Phylogenetic analysis showed that the variants did not group together monophyletically based on species identity or on supertype. An expanded phylogenetic analysis showed that some darter alleles grouped together with alleles from other percid fishes. Our findings show that TSP occurs in darters, which suggests that balancing selection is acting at the genotype level. Supertypes, however, are most likely evolving convergently, as evidenced by the fact that alleles do not form monophyletic groups based on supertype. Our research demonstrates that selection may be acting differently on MHC genes at the genotype and supertype levels, selecting for the maintenance of high genotypic diversity while driving the convergent evolution of similar MHC phenotypes across different species.

Fetal growth restriction (FGR) is associated with adverse perinatal outcomes. Pre-eclampsia (PreE) increases the associated perinatal morbidity and mortality. The structure of the umbilical cord in the setting of FGR and PreE is understudied. This study aimed to examine changes in the umbilical cord (UC) composition in pregnancies complicated by FGR and FGR with PreE. UC from gestational age-matched pregnancies with isolated FGR (n = 5), FGR+PreE (n = 5) and controls (n = 5) were collected, and a portion of the UC was processed for histologic and proteomic analysis. Manual segmentation analysis was performed to measure cross-section analysis of umbilical cord regions. Wharton's Jelly samples were analyzed on a tims-TOF Pro. Spectral count and ion abundance data were analyzed, creating an intersection dataset from multiple mass spectrometry search and inference engines. UCs from FGR and FGR with PreE had lower cross-sectional area and Wharton's Jelly area compared with control (p = 0.03). When comparing FGR to control, 28 proteins were significantly different in abundance analysis and 34 in spectral count analysis (p < 0.05). Differential expression analysis between PreE with FGR vs controls demonstrated that 48 proteins were significantly different in abundance and 5 in spectral count. The majority of changes occurred in proteins associated with extracellular matrix, cellular process, inflammatory, and angiogenesis pathways. The structure and composition of the UC is altered in pregnancies with FGR and FGR with PreE. Future work in validating these proteomic differences will enable identification of therapeutic targets for FGR and FGR with PreE.

The amygdaloid complex, including the basolateral nucleus (BLA), contributes crucially to emotional and cognitive brain functions, and is a major target of research in both humans and rodents. However, delineating structural amygdala plasticity in both normal and disease-related contexts using neuroimaging has been hampered by the difficulty of unequivocally identifying the boundaries of the BLA. This challenge is a result of the poor contrast between BLA and the surrounding gray matter, including other amygdala nuclei. Here, we describe a novel diffusion tensor imaging (DTI) approach to enhance contrast, enabling the optimal identification of BLA in the rodent brain from magnetic resonance (MR) images. We employed this methodology together with a slice-shifting approach to accurately measure BLA volumes. We then validated the results by direct comparison to both histological and cellular-identity (parvalbumin)-based conventional techniques for defining BLA in the same brains used for MRI. We also confirmed BLA connectivity targets using DTI-based tractography. The novel approach enables the accurate and reliable delineation of BLA. Because this nucleus is involved in and changed by developmental, degenerative and adaptive processes, the instruments provided here should be highly useful to a broad range of neuroimaging studies. Finally, the principles used here are readily applicable to numerous brain regions and across species.

In this time of global pandemic, there has been much adult discourse around what children need both academically and at home, emphasizing structure and continued learning across content areas. Missing from these discussions and recommendations are the perspectives of children themselves. Children, many of whom lack access to their own communication devices as well as social media and personal e-mail accounts, have felt the impact of separation from peers. This article examines ways in which a diverse group of 9- and 10-year-old children resisted the isolating circumstances early in the COVID-19 pandemic through creating and repurposing digital spaces to connect with friends, classmates, and family members. 1

Shared automated vehicles (SAVs) offering a fixed-route transit may compete well against privately operated vehicles. This paper analyzes the system costs of all travelers along a 6.4-kilometer (4-mile) corridor under different penetration rates for 10-seat SAVs. The work prices out walking, waiting, riding, and driving times for all travelers in the corridor, along with vehicle ownership, parking, and operating costs. Results show that such self-driving mini-buses or SAVs lower total costs per passenger-kilometer traveled when SAV mode split exceeds 20 percent, even though walking and waiting are valued at relatively high cost. Such vehicles dramatically free up pavement (and parking) space, and perform even better when parking costs at drivers’ destinations are high.

Early life adversity (ELA) comprises a wide variety of negative experiences during early life and has been linked to cognitive impairments, reduced experiences of pleasure (anhedonia), and other long-term consequences implying that ELA impacts the reward circuitry. In this study, we focused on the projections from the dorsal raphe (DR) to the ventral tegmental area (VTA) and on to the nucleus accumbens (NAcc), an important pathway within the reward circuit. We hypothesized that ELA alters connectivity within the DR-VTA-NAcc pathway, associated with deficient reward seeking behaviors in adulthood. We used the limited bedding and nesting model to induce ELA in mice and measured reward-related behaviors in adulthood using the three-chamber social interaction and sucrose preference tests. High resolution ex vivo diffusion tensor imaging (DTI) was acquired and processed for regional DTI metrics, including tractography to assess circuit organization. We found brain-wide changes in radial diffusivity (RD) and altered connectivity of the reward circuit in the ELA group. DR-VTA-NAcc circuit tractography and axial diffusivity (AD) along this tract exhibited dispersed organization where AD was increased in the VTA segment. Behaviorally, ELA elicited a social anhedonia-like phenotype in adulthood with decreased direct social approach and time spent with peers in the three-chamber task, and no overt differences in sucrose preference. Our findings suggest that reward circuits, assessed using DTI, are altered following ELA and that these changes may reflect enduring reward deficits.