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Employment status is considered a determinant of health, yet returning to work is frequently a challenge after lower limb amputation. No studies have documented if working after lower limb amputation is associated with functional recovery. The study's purpose was to examine the influence of full-time employment on functioning after lower limb amputation.Multisite, cross-sectional study of 49 people with dysvascular lower limb amputation. Outcomes of interest included performance-based measures, the Component Timed-Up-and-Go test, the 2-min walk test, and self-reported measures of prosthetic mobility and activity participation.Average participant age was 62.1 ± 9.7 years, 39% were female and 45% were persons of color. Results indicated that 80% of participants were not employed full-time. Accounting for age, people lacking full-time employment exhibited significantly poorer outcomes of mobility and activity participation. Per regression analyses, primary contributors to better prosthetic mobility were working full-time (This study offers novel evidence of associations between employment and performance-based mobility outcomes after dysvascular lower limb amputation. Further research is required to determine cause-effect directionalities. These results provide the foundation for future patient-centered research into how work affects outcomes after lower limb amputation. IMPLICATIONS FOR REHABILITATIONLower limb amputation can pose barriers to employment and activity participation, potentially affecting the quality of life.This study found that the majority of people living with lower limb amputation due to dysvascular causes were not employed full-time and were exhibiting poorer prosthetic outcomes.Healthcare practitioners should consider the modifiable variable of employment when evaluating factors that may affect prosthetic mobility.The modifiable variable of self-efficacy should be assessed by healthcare professionals when evaluating factors that may affect prosthetic mobility.

Background Irritable Bowel Syndrome (IBS) is a prevalent, chronic gastrointestinal disorder that imposes a substantial socioeconomic burden. Peppermint oil is a frequently used treatment for IBS, but evidence about cost-effectiveness is lacking. Objective We aimed to assess cost-effectiveness of small-intestinal release peppermint oil versus placebo in IBS patients. Methods In a multicenter randomized placebo-controlled trial, cost-effectiveness was evaluated from a societal perspective. The incremental cost-effectiveness ratios (ICERs) were expressed as (1) incremental costs per Quality Adjusted Life Years (QALY), and (2) incremental costs per successfully treated patient, that is per abdominal pain responder (according to FDA definitions), both after an eight-week treatment period with placebo versus peppermint oil. Cost-utility and uncertainty were estimated using non-parametric bootstrapping. Sensitivity analyses were performed. Results The analysis comprised 126 patients (N = 64 placebo, N = 62 small-intestinal release peppermint oil). Peppermint oil was a dominant treatment compared to placebo in 46% of bootstrap replications. Peppermint oil was also more effective but at higher cost in 31% of replications. The net-benefit acceptability curve showed that peppermint oil has a 56% probability of being cost-effective at a conservative willingness-to-pay threshold of €10.000/QALY. Peppermint oil was also a dominant treatment per additional successfully treated patient according to FDA definitions, that is in 51% of replications. In this case, the acceptability curve showed an 89% probability of being cost-effective. Conclusions In patients with IBS, small-intestinal release peppermint oil appears to be a cost-effective treatment although there is uncertainty surrounding the ICER. When using abdominal pain responder as outcome measure for the ICER, peppermint oil has a high probability of being cost-effective. The use of peppermint oil, which is a low-cost treatment, can be justified by the modest QALY gains and slightly higher proportion of abdominal pain responders. More research and long-term data are necessary to confirm the cost-effectiveness of peppermint oil. NCT02716285.

Introduction Almost 30% of patients are non-responders to cardiac resynchronization therapy (CRT) with no improvement of heart failure (HF) symptoms and left ventricular ejection fraction (LVEF). Angiotensin Receptor Neprilysin Inhibitor (ARNI), a novel class of medication resulted in a significant improvement in HF with reduced ejection fraction (HFrEF) in recent trials. No data has been reported on the clinical effectiveness of ARNI in the specific HF patient cohort of CRT non-responders (CRT-NR). Objective Herein, we compared the efficacy of ARNI medication in a general HF patient population and in CRT-NR patients. Method CRT-NR patients on ARNI therapy initiated at least 6 months after CRT implantation in years 2019–2021 were enrolled. Criterium for CRT-NR was a no, or less than 10% improvement in LVEF measured with echocardiography 6 months post-implantation. HF patients on ARNI therapy from our HF Clinic were used as controls. Changes in LVEF, in NYHA functional class and in the level of NT-proBNP were compared before ARNI therapy initiation and 6 months thereafter in both groups. Results 70 patients (age: 66,03±9.06 years, 9 women) were enrolled in the CRT-NR and 135 patients (age 62,36±11.26 years; 31 women) in the control group. LVEF increased from 25,25±5.70% to 29,47±6.73% (p Conclusion ARNI therapy resulted in significant improvement in functional class, LVEF and HF biomarker level in CRT-NR patients, similarly to what was observed in a general HF patient cohort with no CRT. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Project no. TKP2021-EGA-18 has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the TKP2021-EGA funding scheme.

We know little about mammalian anemotaxis, wind-sensing. Recently, however, Hartmann and colleagues showed whisker-based anemotaxis in rats. To investigate how whiskers sense airflow, we tracked whisker tips in anesthetized or cadaver rats under no airflow, low airflow and high (fan-blowing) airflow. Whisker tips showed little movement under no airflow conditions and all whisker tips moved during high airflow. Low airflow conditions – most similar to naturally occurring wind stimuli – engaged whisker tips differentially. Most whiskers moved little, the long supraorbital whisker showed maximal displacement and α, A1, β, and γ whiskers also showed movements. The long supraorbital whisker differs from other whiskers in its exposed dorsal position, upward bending, length and thin diameter.Ex vivoextracted long supraorbital whiskers also showed exceptional airflow displacement, suggesting whisker-intrinsic biomechanics mediate the unique airflow-sensitivity. Micro computed tomography revealed that the ring-wulst – the follicle structure receiving the most sensitive afferents – was more complete/ closed in supraorbital and other wind-sensitive whiskers than in non-wind-sensitive whiskers, suggesting specialization of the supraorbital for omni-directional sensing. We localized and targeted the cortical supraorbital whisker representation in simultaneous Neuropixels recordings with D/E-row whisker barrels. Responses to wind-stimuli were stronger in the supraorbital whisker representation than in D/E-row barrel cortex. We assessed the behavioral significance of whiskers in an airflow-sensing paradigm. We observed that rats spontaneously turn towards airflow stimuli in complete darkness. Selective trimming of wind-responsive whiskers diminished airflow turning responses more than trimming of non-wind-responsive whiskers. Lidocaine injections targeted to supraorbital whisker follicles also diminished airflow turning responses compared to control injections. We conclude that supraorbital whiskers act as wind antennae.New and NoteworthyAnimals rely on sensory processing of airflow (anemotaxis) to guide navigation and survival. We examined mechanisms of rat anemotaxis by combining whisker tracking, biomechanical analysis, micro computed tomography of follicle structure, Neuropixels recordings in the barrel field, behavior of airflow turning and whisker interference by trimming and lidocaine injections. This diversity of methods led to a coherent pattern of results. Whiskers greatly differ in their airflow sensitivity and strongly wind-responsive whiskers – in particular long supraorbital whiskers – determine behavioral responses to airflow stimuli in rats.

1AbstractBackgroundPreterm birth is associated with atypical cognitive and socioemotional outcomes in childhood. Secure infant attachment protects against adverse outcomes, but could be modified by alterations in the early caregiving environment inherent to essential neonatal intensive care or co-morbidities of preterm birth. We aimed to test the hypothesis that preterm birth is associated with differences in infant attachment, and to investigate clinical, neurodevelopmental and socioeconomic variables that are associated with infant attachment.Methods82 preterm and 75 term infants with mean (range) gestational age at birth 29.5 (22.1 – 32.9) and 39.6 (36.4 – 42.1) weeks, respectively, completed the Still-Face Paradigm (SFP) at nine months of corrected age. Attachment dimensions and categories were obtained from infant responses to the SFP during the reunion episode using a published coding scheme, and an alternative principal component (PC) and clustering strategy. Neurodevelopment was assessed using the Vineland Adaptive Behavior Scales, and socioeconomic status was operationalized as neighborhood deprivation.ResultsPreterm and term infants significantly differed in fretfulness, attentional PC scores and in their distribution between attachment clusters (p-values ≤ 0.3); with preterm infants exhibiting less fretful and more neutral responses to the SFP. Preterm and term infants did not significantly differ in distress, attentiveness to caregivers, emotional PC scores, or in their distribution between attachment styles (p-values ≥ .13). In the whole sample, fretfulness correlated with socioeconomic deprivation (rs= −0.18, p-value = .02).ConclusionsData reveal subtle attachment differences between preterm and term infants at nine months of age, which may not always be captured by traditional approaches for categorizing attachment. Findings suggests that caregiver-infant attachment relationships may not be fully resilient to the effects of prematurity on the developing infant, but this depends on how attachment is measured. Our results highlight putative links between socioeconomic deprivation and infant attachment that warrant further study.

The onset of COVID-19 left people feeling unsettled, confused, and afraid of what tomorrow may hold. As university professors specializing in health communication, we too were left with these same feelings. As health communication scholars, we focus on issues surrounding illness, risk, crisis, care, health inequities, and wellness. COVID-19 is a health crisis, yes, but it has also changed the way we operate not only in higher education but in daily life. We begin this essay with an overview of COVID-19 and its impact on students, educators, and administrators. Then, we suggest four best practices to foster a community of care in the classroom during and beyond the COVID-19 pandemic.

Animals evolved in complex environments, producing a wide range of behaviors, including navigation, foraging, prey capture, and conspecific interactions, which vary over timescales ranging from milliseconds to days. Historically, these behaviors have been the focus of study for ecology and ethology, while systems neuroscience has largely focused on short timescale behaviors that can be repeated thousands of times and occur in highly artificial environments. Thanks to recent advances in machine learning, miniaturization, and computation, it is newly possible to study freely moving animals in more natural conditions while applying systems techniques: performing temporally specific perturbations, modeling behavioral strategies, and recording from large numbers of neurons while animals are freely moving. The authors of this review are a group of scientists with deep appreciation for the common aims of systems neuroscience, ecology, and ethology. We believe it is an extremely exciting time to be a neuroscientist, as we have an opportunity to grow as a field, to embrace interdisciplinary, open, collaborative research to provide new insights and allow researchers to link knowledge across disciplines, species, and scales. Here we discuss the origins of ethology, ecology, and systems neuroscience in the context of our own work and highlight how combining approaches across these fields has provided fresh insights into our research. We hope this review facilitates some of these interactions and alliances and helps us all do even better science, together.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Hungarian Government Research Fund, Szív- és érkutatási kiválóságközpont (IRONHEART) Background In approximately 30-40% of cases, the left ventricular systolic function does not improve following cardiac resynchronization therapy (CRT; non-responders). Currently, the role of right ventricular (RV) systolic function is yet not well established. Our aim was to assess the RV systolic function with 3D echocardiography in CRT patients. Methods We involved 24 patients (12–12 CRT responder and non-responder) who received CRT in our department, and whose 1-year follow-up data were available. We considered the patients "responder" when the left ventricular ejection fraction (LV EF) improved with at least 10% after CRT implantation. We characterized several 3D and 2D parameters of RV using a dedicated RV analysis software, such as RV ejection fraction (EF), body surface area-indexed end-diastolic (EDVi) and end-systolic (ESVi) volumes, free-wall longitudinal (RV GLS) and radial strains. Results After the follow-up, LV EF was 43 ± 8% in responders and 26 ± 7% in non-respoders (p Conclusions The lower RV EF based on mainly the longitudinal function of RV indicates non-respondence to CRT, however, it is not associated with RV dilation, i.e. adverse remodelling. These results suggest mechanical abnormality of RV function in the background of impaired EF.

In 2018, nearly 800,000 HIV positive individuals in South Africa were unaware of their status. Traditional healers see patients who avoid health clinics, including those who refuse HIV testing. This manuscript details the results of a qualitative study to understand traditional healer perspectives on performing healer-initiated HIV counseling and testing HIV in rural South Africa. We conducted 30 structured in-depth, in-person interviews between April and June 2019 to elicit traditional healer attitudes towards partnering with local health services to perform HIV counseling and testing with their patients. Healers reported that while some patients are open about their HIV status, others lie about it due to stigma around the disease. This creates challenges with concurrent treatment, which healers believe leads to allopathic and/or traditional medication treatment failure. Most healers expressed both an interest and a willingness to perform HIV counseling and testing. Healers felt that by performing testing in the community, it would overcome issues related to HIV stigma, as well as a lack of confidentiality and trust with health care workers at the clinic. Trained traditional healers may be able to bridge the testing gap between “non-testers” and the allopathic health system, essentially “opening” thousands of new testing locations with little financial investment.

Silver-based bimetallic catalysts for the oxygen reduction reaction (ORR) are promising for a wide variety of renewable energy technologies, including alkaline fuel cells and metal-air batteries. T...

BACKGROUND & AIMS: Peppermint oil is frequently used to treat irritable bowel syndrome (IBS), despite a lack of evidence for efficacy from high-quality controlled trials. We studied the efficacy and safety of small-intestinal-release peppermint oil in patients with IBS and explored the effects of targeted ileocolonic-release peppermint oil. METHODS: We performed a double-blind trial of 190 patients with IBS (according to Rome IV criteria) at 4 hospitals in The Netherlands from August 2016 through March 2018; 189 patients were included in the intent-to-treat analysis (mean age, 34.0 years; 77.8% female; 57.7% in primary care), and 178 completed the study. Patients were randomly assigned to groups given 182 mg small-intestinal-release peppermint oil, 182 mg ileocolonic-release peppermint oil, or placebo for 8 weeks. The primary endpoint was abdominal pain response, as defined by the US Food and Drug Administration: at least a 30% decrease in the weekly average of worst daily abdominal pain compared with baseline in at least 4 weeks. The co-primary endpoint was overall relief of IBS symptoms, as defined by the European Medicines Agency. Secondary endpoints included abdominal pain, discomfort, symptom severity, and adverse events. RESULTS: Abdominal pain response did not differ significantly between the peppermint oil and placebo groups: 29 of 62 patients in the small-intestinal-release peppermint oil group had a response (46.8%, P = .170 vs placebo), 26 of 63 patients in the ileocolonic-release peppermint oil group had a response (41.3%, P = .385 vs placebo), and 22 of 64 patients in the placebo group had a response (34.4%). We did not find differences among the groups in overall relief (9.7%, P = .317 and 1.6%, P = .351 vs 4.7% for placebo). The small intestinal peppermint oil did, however, produce greater improvements than placebo in secondary outcomes of abdominal pain (P = .016), discomfort (P = .020), and IBS severity (P = .020). Adverse events, although mild, were more common in both peppermint oil groups (P < .005). CONCLUSIONS: In a randomized trial of patients with IBS, we found that neither small-intestinal-release nor ileocolonic-release peppermint oil (8 weeks) produced statistically significant reductions in abdominal pain response or overall symptom relief, when using US Food and Drug Administration/European Medicines Agency recommended endpoints. The small-intestinal-release peppermint oil did, however, significantly reduce abdominal pain, discomfort, and IBS severity. These findings do not support further development of ileocolonic-release peppermint oil for treatment of IBS. Clinicaltrials.gov, Number: NCT02716285. ispartof: GASTROENTEROLOGY vol:158 issue:1 pages:123-136 ispartof: location:United States status: published

PURPOSE: Functional dependency is a known determinant of surgical risk. To enhance our understanding of the relationship between dependency and adverse surgical outcomes, we studied how postoperative mortality following a surgical complication was impacted by preoperative functional dependency. METHODS: We explored a historical cohort of 6,483,387 surgical patients within the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). All patients ≥ 18 years old within the ACS-NSQIP from 2007 to 2017 were included. RESULTS: There were 6,222,611 (96.5%) functionally independent, 176,308 (2.7%) partially dependent, and 47,428 (0.7%) totally dependent patients. Within 30 days postoperatively, 57,652 (0.9%) independent, 15,075 (8.6%) partially dependent, and 10,168 (21.4%) totally dependent patients died. After adjusting for confounders, increasing functional dependency was associated with increased odds of mortality (Partially Dependent OR: 1.72, 99% CI: 1.66 to 1.77; Totally Dependent OR: 2.26, 99% CI: 2.15 to 2.37). Dependency also significantly impacted mortality following a complication; however, independent patients usually experienced much stronger increases in the odds of mortality. There were six complications not associated with increased odds of mortality. Model diagnostics show our model was able to distinguish between patients who did and did not suffer 30-day postoperative mortality nearly 96.7% of the time. CONCLUSIONS: Within our cohort, dependent surgical patients had higher rates of comorbidities, complications, and odds of 30-day mortality. Preoperative functional status significantly impacted the level of postoperative mortality following a complication, but independent patients were most affected.

Academic success and how to achieve it takes diverse forms, depending on who's asked. We suggest that happiness, impact, and longevity can be achieved with professional effort and support that balances the toil and joys of one's chosen path.

Inner ear drug delivery is a major area of research and development, but relatively little is known about basic drug metabolism in the cochlea. Additionally, the use of potentially ototoxic drugs such as NSAIDs, chemotherapeutics and aminoglycosides is common, but little is known about the role of metabolism in ototoxicity of those drugs. To address those issues, we compared expression of major Cytochromes P450 (Cyps), UDP-glucuronosyl-transferases (Ugts), sulfotransferases (Sults), and drug transporters between cochleae and liver, an organ with high expression, in mice using qPCR and enzyme kinetics. Together, the tested drug-metabolizing enzymes (DMEs) and transporters account for metabolism of approximately 70–80% of all medically important drugs in the body. Expression of most Cyps was low in the cochlea compared to liver, but three displayed similar expression levels to the liver, and one (Cyp2c65) had significantly higher levels of expression in the cochlea (1.9 ± 0.06 fold vs. liver). Enzyme kinetics revealed undetectable levels of p450 activity in the cochlea, especially as compared to the liver. Similar results were obtained for expression of Ugts and Sults. Interestingly, expression of most transporters was also low, with one major exception: Mdr1/P-glycoprotein (P-gp), which is generally thought to be highly expressed in liver and poorly expressed in most of the nervous system, was 3-fold greater in cochlea. Importantly, P-gp is known to protect other tissues from toxicity of cancer drugs by acting as an efflux pump. Our data demonstrate overall low levels of expression of DMEs and transporters in the cochlea, and identify a few that may be important to consider when designing and testing drugs for local delivery to the inner ear.

Despite the centrality of dating relationships for teens, it is unclear whether the influence of romantic partners’ alcohol use on adolescents’ under-age drinking is distinct from the influence of peers and parents. To address this gap, this study used longitudinal data from a population-based sample of 825 adolescents (49% male, 51% female), ages 12 to 19. Adolescents completed a survey using laptops for privacy, and a parent completed a survey separately. Ordinary least squares and logistic regression models assessed alcohol use frequency and alcohol problems and included dating partners’ drinking, adolescents’ prior drinking, peers’ drinking, parents’ substance use, parental monitoring, and sociodemographic background characteristics. Alcohol use frequency and alcohol problems were influenced by dating partners’ alcohol use and dating partners’ influence was stronger on older adolescents and male adolescents. The study results are useful for public health messaging and prevention efforts by demonstrating the influence of parents, peers, and dating partners on teens’ alcohol use.

We previously demonstrated that endogenous phosphatidic acid (PA) promotes liver regeneration after acetaminophen (APAP) hepatotoxicity. Here, we hypothesized that exogenous PA is also beneficial. To test that, we treated mice with a toxic APAP dose at 0 h, followed by PA or vehicle (Veh) post-treatment. We then collected blood and liver at 6, 24, and 52 h. Post-treatment with PA 2 h after APAP protected against liver injury at 6 h, and the combination of PA and N-acetyl-l-cysteine (NAC) reduced injury more than NAC alone. Interestingly, PA did not affect canonical mechanisms of APAP toxicity. Instead, transcriptomics revealed that PA activated interleukin-6 (IL-6) signaling in the liver. Consistent with that, serum IL-6 and hepatic signal transducer and activator of transcription 3 (Stat3) phosphorylation increased in PA-treated mice. Furthermore, PA failed to protect against APAP in IL-6-deficient animals. Interestingly, IL-6 expression increased 18-fold in adipose tissue after PA, indicating that adipose is a source of PA-induced circulating IL-6. Surprisingly, however, exogenous PA did not alter regeneration, despite the importance of endogenous PA in liver repair, possibly due to its short half-life. These data demonstrate that exogenous PA is also beneficial in APAP toxicity and reinforce the protective effects of IL-6 in this model., Graphical abstract Exogenous phosphatidic acid (PA) increases interleukin-6 (IL-6) production in peripheral adipose tissue. The IL-6 then enters circulation and signals to the liver to reduce early acetaminophen (APAP)-induced liver injury.Image 1

While the fundamental relevance of kinship behavior for evolutionary and behavioral biology has long been recognized, the examination of kinship behavior from a neuroscience perspective is still in its infancy. Kinship is highly conserved from single-celled organisms to humans, where kin preferences are prevalent in behavior and vocal communication. Kin recognition mechanisms are varied, with evidence for both genetic and both prenatal as well as postnatal learning-based kin recognition. Learned kinship mechanisms are predominant in vertebrates and allow for flexibility regarding the concept of kin. We review new evidence for the lateral septum and its role in kinship behavior. We further discuss the discovery of nepotopy, a topographical representation of kin- and nonkin-responsive neurons in the lateral septum. Neural representations of self/other, familiar/unfamiliar, and nepotopy (kin/nonkin) may support a circuit-level framework for a social template through which the mammalian brain learns, categorizes, and selects behavior based on perceived identity.

Background and aim Acetaminophen (APAP) overdose is a major cause of acute liver injury, but the role of macrophages in the propagation of the hepatotoxicity is controversial. Early research revealed that macrophage inhibitors protect against APAP injury. However, later work demonstrated that macrophage ablation by acute pre-treatment with liposomal clodronate (LC) exacerbates the toxicity. To our surprise, during other studies, we observed that pre-treatment twice with LC seemed to protect against APAP hepatotoxicity, in contrast to acute pre-treatment. The aim of this study was to confirm that observation and to explore the mechanisms. Methods We treated mice with empty liposomes (LE) or LC twice per week for 1 week before APAP overdose and collected blood and liver tissue at 0, 2, and 6 h post-APAP. We then measured liver injury (serum alanine aminotransferase activity, histology), APAP bioactivation (total glutathione, APAP-protein adducts), oxidative stress (oxidized glutathione (GSSG)), glutamate-cysteine ligase subunit c (Gclc) mRNA, and nuclear factor erythroid 2-related factor (Nrf2) immunofluorescence. We also confirmed the ablation of macrophages by F4/80 immunohistochemistry. Results Pre-treatment twice with LC dramatically reduced F4/80 staining, protected against liver injury, and reduced oxidative stress at 6 h post-APAP, without affecting APAP bioactivation. Importantly, Gclc mRNA was higher in the LC group at 0 h and total glutathione was higher at 2 h, indicating accelerated glutathione re-synthesis after APAP overdose due to greater basal glutamate-cysteine ligase. Oxidative stress was lower in the LC groups at both time points. Finally, total Nrf2 immunofluorescence was higher in the LC group. Conclusions We conclude that multiple pre-treatments with LC protect against APAP by accelerating glutathione re-synthesis through glutamate-cysteine ligase. Investigators using twice or possibly more LC pre-treatments to deplete macrophages, including peritoneal macrophages, should be aware of this possible confounder.

Evolutionary theory and behavioral biology suggest that kinship is an organizing principle of social behavior. The neural mechanisms that mediate kinship behavior are, however, not known. Experiments confirm a sibling-approach preference in young rat pups and a sibling-avoidance-preference in older pups. Lesions of the lateral septum eliminate such kin preferences. In vivo juxta-cellular and whole-cell patch-clamp recordings in the lateral septum show multisensory neuronal responses to kin and non-kin stimuli. Non-kin odor-responsive neurons are located dorsally and kin-odor responsive neurons are located ventrally in the lateral septum. With development, the fraction of kin-responsive lateral septal neurons decrease and ongoing firing rates increase. Lesion effects, developmental changes and the ordered representation of response preferences according to kinship—an organization we refer to as nepotopy—point to a key role of the lateral septum in organizing mammalian kinship behavior., Kinship behavior in rodents has been documented in the laboratory setting but the neural mechanisms that mediate kinship behavior are not known. Here, the authors show that the lateral septum has a key role in organizing mammalian kinship behavior.

Introduction High incidence of bleeding events remains a key risk for patients taking anticoagulants, especially those in need of long-term combination therapy with antiplatelet agents. As a consequence, patients may not receive clinically indicated combination antithrombotic therapy. Here, we report on VE-1902, a member of a novel class of precision oral anticoagulants (PROACs) that combines effective anticoagulation with reduced bleeding in preclinical testing. Methods and results Acting through covalent, reversible active-site modification of thrombin similar to a previously described molecule [ 1 ], VE-1902 shows potency and selectivity for thrombin inhibition in human plasma comparable to clinically relevant direct thrombin inhibitors (DTI) such as argatroban and dabigatran (thrombin generation assay ETP EC50 = 1.3 μM compared to 0.36 μM and 0.31 μM for argatroban and dabigatran; >100-fold selectivity against related serine proteases). Unlike the current anticoagulants, VE-1902 does not significantly inhibit thrombin-mediated platelet activation in in vivo models of thrombosis. In the thrombin generation assay, the compound inhibits thrombin formation without significantly delaying the initiation phase of the clotting cascade. These features are possibly responsible for the observed reduced bleeding in tail bleeding and saphenous vein bleeding models. Consistent with this novel pharmacological profile, VE-1902 shows efficacious anticoagulation in several fibrin-driven animal models of thrombosis (arteriovenous shunt, venous stasis thrombosis, and thrombin-induced thromboembolism models), whereas it does not significantly prevent arterial occlusion in the platelet dependent FeCl3 model. Conclusions By leaving platelet activation following vascular injury mostly unaffected, VE-1902, and the PROACs more generally, represent a new generation of precision anticoagulants with reduced bleeding risk.

Background Traditional healers are frequently exposed to hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) through the widespread practice of traditional “injections”, in which the healer performs dozens of subcutaneous incisions using a razor blade to rub herbs directly into bloodied tissue. An average healer in Agincourt, a rural northeastern sub-district in Mpumalanga province, South Africa, experiences approximately 1500 occupational blood exposures over the course of their lifetime. Healers in Agincourt have an HIV prevalence of 30% compared to 19% in the general population, and healers who report exposure to patient blood have an adjusted 2.4-fold higher odds of being HIV-positive than those with no exposure. Although research on appropriate PPE use has been well documented for allopathic care providers, little is known about the practices of traditional healers. Methods This qualitative study was conducted with 30 traditional healers who practice in the rural Bushbuckridge sub-district of Mpumalanga province, northeastern South Africa. We elicited traditional healer attitudes towards glove use during traditional treatments – including patient baths, injections, or other treatments that exposed healers to patient blood or open sores. Results While 90% of healers reported using latex gloves during some treatments, the majority do not use them regularly. Most employ a combination of gloves, plastic shopping bags, bread bags, paper, and sticks to prevent blood exposure. Healers reported plastic bags slipping or breaking during procedures, exposing them to patient blood. Only three healers consistently used gloves, regardless of the cost. Conclusions Inadequate PPE use and high HIV prevalence make traditional healers particularly susceptible to contracting HIV in rural South Africa. Despite positive attitudes, consistent glove use remains low due to financial constraints and glove availability. Addressing issues of accessibility and cost of gloves for traditional healers could have a significant impact on the adherence to PPE and, in turn, reduce new HIV infections among this high-risk group.

The purpose of this work is to identify and analyze the meanings that students in undergraduate courses in Physical Education and related courses have regarding professional practice in the field of health and their understanding about leisure. Traditionally, the area of Physical Education and related courses has received strong influence from the natural sciences, and this tradition has influenced the performance of the professional in the health field. The problem with this often and exclusively biomedical orientation, is that professionals are faced with increased pressure to prescribe exercise and do not understand how to deal with people’s health covering aspects such as subjectivity, cultural issue, the health care. The methodological procedures used were bibliographic search and field research, from semi-structured interviews with undergraduate students of Physical Education and related courses, Brazilians and Americans, characterizing this study as qualitative. The results from this study indicate that undergraduate Physical Education students and related courses have some understanding of the purpose of their work related to quality of life, wellbeing, health and absence of disease. In addition, the majority of respondents understand leisure only from the rest, disregarding the possibilities of fun and personal and social development. We conclude, therefore, that the vision of respondents with respect to health and leisure was even initial, is fundamental to have an effective future professional activities access to reference both the biological sciences as the humanities.

Background: The understanding of gender differences in inflammatory bowel disease (IBD) patients is an important step towards tailored treatment for the individual patient. The aim of this study was to compare disease phenotype, clinical manifestations, disease activity, and healthcare utilization between men and women with Crohn's disease (CD) and ulcerative colitis (UC).Methods: Two multicenter observational cohort studies with a prospective design were used to explore the differences between men and women regarding demographic and phenotypic characteristics and healthcare utilization. Detailed data on IBD-phenotype was mainly available from the Dutch IBD Biobank, while the COIN cohort provided healthcare utilization data.Results: In the Dutch IBD Biobank study, 2118 CD patients and 1269 UC patients were analyzed. Female CD patients were more often current smokers, and male UC patients were more often previous smokers. Early onset CD (Conclusions: Sex differences in patients with IBD include age of onset, disease location, and EIM prevalence. No large differences in therapeutic management of IBD were observed between men and women with IBD.

Increasing the activity of Ag-based catalysts for the oxygen reduction reaction (ORR) is important for improving the performance and economic outlook of alkaline-based fuel cell and metal–air battery technologies. In this work, we prepare CuAg thin films with controllable compositions using electron beam physical vapor deposition. X-ray diffraction analysis indicates that this fabrication route yields metastable miscibility between these two thermodynamically immiscible metals, with the thin films consisting of a Ag-rich and a Cu-rich phase. Electrochemical testing in 0.1 M potassium hydroxide showed significant ORR activity improvements for the CuAg films. On a geometric basis, the most active thin film (Cu70Ag30) demonstrated a 4-fold activity improvement vs pure Ag at 0.8 V vs the reversible hydrogen electrode. Furthermore, enhanced ORR kinetics for Cu-rich (>50 at. % Cu) thin films was demonstrated by a decrease in Tafel slope from 90 mV/dec, a commonly observed value for Ag catalysts, to 45 mV/dec. S...

We have developed a novel class of specifically engineered, dimerized cyclodextrin nanostructures for the encapsulation of toxic biomolecules such as 7-ketocholesterol (7KC). 7KC accumulates over time and causes dysfunction in many cell types, linking it to several age-related diseases including atherosclerosis and age-related macular degeneration (AMD). Presently, treatments for these diseases are invasive, expensive, and show limited benefits. Cyclodextrins (CDs) are cyclic glucose oligomers utilized to capture small, hydrophobic molecules. Here, a combination of in silico, in vitro, and ex vivo methods is used to implement a synergistic rational drug design strategy for developing CDs to remove atherogenic 7KC from cells and tissues. Mechanisms by which CDs encapsulate sterols are discussed, and we conclude that covalently linked head-to-head dimers of βCDs have substantially improved affinity for 7KC compared to monomers. We find that inclusion complexes can be stabilized or destabilized in ways that allow the design of CD dimers with increased 7KC selectivity while maintaining an excellent safety profile. These CD dimers are being developed as therapeutics to treat atherosclerosis and other debilitating diseases of aging.

Photoelectrochemical (PEC) hydrogen production makes possible the direct conversion of solar energy into chemical fuel. In this work, PEC photoanodes consisting of GaAs nanowire (NW) arrays were fabricated, characterized, and then demonstrated for the oxygen evolution reaction (OER). Uniform and periodic GaAs nanowire arrays were grown on a heavily n-doped GaAs substrates by metal–organic chemical vapor deposition selective area growth. The nanowire arrays were characterized using cyclic voltammetry and impedance spectroscopy in a non-aqueous electrochemical system using ferrocene/ferrocenium (Fc/Fc+) as a redox couple, and a maximum oxidation photocurrent of 11.1 mA/cm2 was measured. GaAs NW arrays with a 36 nm layer of nickel oxide (NiO x ) synthesized by atomic layer deposition were then used as photoanodes to drive the OER. In addition to acting as an electrocatalyst, the NiO x layer served to protect the GaAs NWs from oxidative corrosion. Using this strategy, GaAs NW photoanodes were successfully used for the oxygen evolution reaction. This is the first demonstration of GaAs NW arrays for effective OER, and the fabrication and protection strategy developed in this work can be extended to study any other nanostructured semiconductor materials systems for electrochemical solar energy conversion.

Background Diarrhea is an important cause of morbidity and mortality worldwide. In Africa and Ghana in particular, it is estimated to contribute directly to 19 and 25% of pediatric mortality among children under 5 years, respectively. Methods Surveillance for hospitalized acute diarrheal illness was initiated in November 2010 through October 2012 in a referral hospital in southern Ghana, and a teaching hospital in northern Ghana. Consenting hospitalized patients who met a standardized case definition for acute diarrheal illness provided demographic and epidemiologic data. Stool samples were collected and tested by culture for bacteria and by enzyme immunoassays for a panel of viruses and parasites. Results A total of 429 patients were enrolled; 216 (50.3%) were under 5 years, and 221 (51.5%) were females. Stool samples were received from 153 patients. Culture isolates included Shigella sp., Salmonella spp., Plesiomonas sp. and Vibrio cholerae. Of 147 samples tested for viruses, 41 (27.9%) were positive for rotaviruses, 11 (7.5%) for astroviruses, 10 (6.8%) for noroviruses, and 8 (5.4%) for adenoviruses. Of 116 samples tested for parasitic infections; 4 (3.4%) were positive for Cryptosporidium sp. and 3 (2.6%) for Giardia lamblia. Of the enrolled patients, 78.8% had taken antibiotics prior to sample collection. Conclusions Diarrheal pathogens were identified across all ages, however, predominantly (81%) in the children under 5 years of age. This study also detected high antibiotic use which has the potential of increasing antibiotic resistance. The most common enteric pathogen detected (49.4%) was rotavirus. Electronic supplementary material The online version of this article (doi:10.1186/s13104-017-2621-x) contains supplementary material, which is available to authorized users.

An experimental investigation into the growth of polyurea films by molecular layer deposition was performed by examining trends in the growth rate, crystallinity, and orientation of chains as a function of backbone flexibility. Growth curves obtained for films containing backbones of aliphatic and phenyl groups indicate that an increase in backbone flexibility leads to a reduction in growth rate from 4 to 1 A/cycle. Crystallinity measurements collected using grazing incidence X-ray diffraction and Fourier transform infrared spectroscopy suggest that some chains form paracrystalline, out-of-plane stacks of polymer segments with packing distances ranging from 4.4 to 3.7 A depending on the monomer size. Diffraction intensity is largely a function of the homogeneity of the backbone. Near-edge X-ray absorption fine structure measurements for thin and thick samples show an average chain orientation of ∼25° relative to the substrate across all samples, suggesting that changes in growth rate are not caused by dif...

The standard circulating biomarker of liver injury in both clinical settings and drug safety testing is alanine aminotransferase (ALT). However, ALT elevations sometimes lack specificity for tissue damage. To identify novel serum biomarkers with greater specificity for injury, we combined unique animal models with untargeted proteomics, followed by confirmation with immunoblotting. Using proteomics, we identified 109 proteins in serum from mice with acetaminophen (APAP)-induced liver injury that were not detectable in serum from mice with benign ALT elevations due to high-dose dexamethasone (Dex). We selected 4 (alcohol dehydrogenase 1A1 [Aldh1a1], aldehyde dehydrogenase 1 [Adh1], argininosuccinate synthetase 1 [Ass1], and adenosylhomocysteinase [Ahcy]) with high levels for further evaluation. Importantly, all 4 were specific for injury when using immunoblots to compare serum from Dex-treated mice and mice with similar lower ALT elevations due to milder models of APAP or bromobenzene-induced liver injury. Immunoblotting for ALDH1A1, ADH1, and ASS1 in serum from APAP overdose patients without liver injury and APAP overdose patients with mild liver injury revealed that these candidate biomarkers can be detected in humans with moderate liver injury as well. Interestingly, further experiments with serum from rats with bile duct ligation-induced liver disease indicated that Aldh1a1 and Adh1 are not detectable in serum in cholestasis and may therefore be specific for hepatocellular injury and possibly even drug-induced liver injury, in particular. Overall, our results strongly indicate that ALDH1A1, ADH1, and ASS1 are promising specific biomarkers for liver injury. Adoption of these biomarkers could improve preapproval drug safety assessment.

Introduction Public awareness of electronic nicotine delivery systems (ENDS) has increased over time, and the perception that ENDS offer a safer alternative to cigarettes may lead some pregnant women to use them to reduce cigarette smoking during pregnancy. No previous studies have used metabolite levels in hair to measure nicotine exposure for ENDS users during pregnancy. We aimed to measure and compare levels of nicotine, cotinine, and tobacco-specific nitrosamines (TSNAs) in hair samples from pregnant women who were current ENDS users, current smokers, and current non-smokers. We also aimed to estimate the association between ENDS use/smoking and smallness for gestational age (SGA). Methods We used hair specimens from pregnant women who were dual users (ENDS and cigarettes), smokers, and non-smokers from a prospective cohort study to estimate exposure to nicotine, cotinine, and TSNAs. The exposure biomarkers and self-reports of smoking and ENDS use were used in log-binomial regression models to estimate risk ratios (RRs) for SGA among offspring. Results Nicotine concentrations for pregnant dual users were not significantly different from those for smokers (11.0 and 10.6 ng/mg hair, respectively; p=0.58). Similarly, levels of cotinine, and TSNAs for pregnant dual users were not lower than those for smokers. The RR for SGA was similar for dual users and smokers relative to nonsmokers, (RR=3.5, 95% CI: 0.8-14.8) and (RR=3.3, 95% CI: 0.9-11.6), respectively. Using self-reports confirmed by hair nicotine, the RR values for dual ENDS users and smokers were 8.3 (95% CI: 1.0-69.1) and 7.3 (95% CI:1.0-59.0), respectively. Conclusions We did not observe lower levels of nicotine, cotinine, and TSNAs for current dual users compared to smokers during pregnancy. The risk of SGA for offspring of pregnant dual users was similar to that for offspring of pregnant smokers. Future studies are needed to further estimate the magnitude of the association between ENDS use and smallness for gestational age.

Introduction: Anticoagulants, while an effective prophylactic for ischemic stroke increase a patient’s risk of major bleeding. There is currently an unmet need for new anticoagulants with the ideal combination of efficacy and low bleeding risk. Here we describe the in vitro and in vivo pharmacology of two development candidates VE-01902 and VE-02851, expected to enter phase I clinical trials in 2018 and 2019 respectively. These compounds belong to a new class of anti-coagulants, the PRecision Oral AntiCoagulants (PROACs), which inhibit fibrinogen cleavage at potencies comparable to the known Direct Thrombin Inhibitors (DTIs) while only weakly inhibiting thrombin induced platelet activation in plasma and whole blood. Methods: Enzyme activity assays by optical methods. Platelet status by expression of CD62P by flow cytometry. In vitro coagulation by Thrombin Generation Assay (TGA). In vivo efficacy and bleeding risk evaluated by rodent models of thrombosis and bleeding time tests. Results and Conclusions: The PROACs are a class of compounds that share a unique mechanism of action: reversible covalent inhibitors of thrombin with slow enzyme kinetics. We examined Thrombin Generation in platelet Poor Plasma (PPP) and Platelet Rich Plasma (PRP) of VE-01902 and VE-02851 and compared it to the known DTIs argatroban and dabigatran. In both plasma samples the PROACs potently inhibit the propagation phase (Endogenous Thrombin Potential (ETP)) while, unlike the known DTIs, only weakly affect the initiation phase of thrombin generation (10 to 20-fold weaker). In the PRP samples the PROACs do not significantly affect platelet activation even while suppressing ETP. To better understand the unique in vitro properties of the PROACs we studied the activity of multiple key factors of the coagulation cascade. Like argatroban and dabigatran, the PROACs protect mice from the effects of thrombin-induced pulmonary embolism and inhibit clot formation in the arteriovenous shunt rat model. However unlike these DTIs, they do not significantly inhibit platelet activation in either of these rodent models. Despite its strong anticoagulant properties, the PROACs show significantly lower bleeding than comparators.

Repair mechanisms after acetaminophen (APAP) hepatotoxicity are poorly understood. We recently discovered that phosphatidic acid (PA) increases in mice and humans after APAP overdose, and is critical for liver regeneration. Here, we hypothesized that PA inhibits glycogen synthase kinase-3β (GSK3β), a component of canonical Wnt/β-catenin signaling, after APAP overdose. To test that, we treated mice with 300 mg/kg APAP at 0 h followed by vehicle or 20 mg/kg of the glycerol 3-phosphate acyltransferase inhibitor FSG67 at 3, 24 and 48 h. Some mice also received the GSK3 inhibitor L803-mts. Blood and liver were collected at multiple time points. Consistent with our earlier results, FSG67 did not affect toxicity (ALT, histology), APAP bioactivation (total glutathione), or oxidative stress (oxidized glutathione), but did reduce expression of proliferating cell nuclear antigen (PCNA) at 52 h. We then measured GSK3β phosphorylation and found it was dramatically decreased by FSG67 at 24 h, before PCNA dropped. Expression of cyclin D1, downstream of Wnt/β-catenin, was also reduced. To determine if the effect of FSG67 on GSK3β is important, we treated mice with FSG67 and L803-mts after APAP. Importantly, L803-mts rescued hepatocyte proliferation and survival. Our data indicate PA and lysoPA may support recovery after APAP overdose by inhibiting GSK3β.

Background: Although some studies have found that incarceration is associated with young adults’ poor health, confounding factors including adolescent health risks, and mediating influences such as stress have not been examined in the same study. We assessed whether variation in criminal justice system experience (none, arrest only, incarceration) influenced young adults’ self-reported depressive symptoms and poor physical health after accounting for prospective risks to health including adolescent health risks. We then assessed whether stress mediated associations between criminal justice involvement and the two health indicators. Methods: Data are from Toledo Adolescent Relationships Study (TARS) (n =990), which included young adults, age 22-29, who have matured during the era characterized by mass incarceration. The dependent variables included a depressive symptoms scale and self-reported poor health. The adolescent health risks included economic disadvantage, body mass index, delinquency, problems with drugs, and prior depressive symptoms. We considered stress as a mediating variable. Sociodemographic characteristics included race/ethnicity, age, and gender. We used ordinary least squares regression and logistic regression analyses. We tested gender, race/ethnicity, and age interactions. Results: In multivariable models, incarceration, and adolescent health risks (economic disadvantage, prior depression, problems with drugs) were associated with young adults’ depressive symptoms, and stress was a mediating influence. Adolescent delinquency and stress, but not incarceration, were significantly associated with young adults’ self-reported poor health. Conclusion: This study provided a more nuanced understanding of incarceration and health by accounting for several key confounding factors and testing stress as a mechanism underlying the association. Care for prisoner health during and after incarceration is important for successful reintegration.

So-called “flipped” classrooms are increasingly popular in postsecondary settings because they give students greater ownership of their learning and foster collaborative instruction. However, these approaches can present difficulties for instructors, who can feel that their expertise and authority is being displaced, and for students, who can find flipped classrooms confusing. Using the metaphor of the craftsman’s workshop as a guide, this essay presents a flipped classroom model that focuses on the “craft” of learning, in which instructors and students play specific roles and work together to understand educational content.

Liver, the major metabolic organ in the body, is known for its remarkable capacity to regenerate. Whereas partial hepatectomy (PHx) is a popular model for the study of liver regeneration, the liver also regenerates after acute injury, but less is known about the mechanisms that drive it. Recent studies have shown that liver regeneration is critical for survival in acute liver failure (ALF), which is usually due to drug-induced liver injury (DILI). It is sometimes assumed that the signaling pathways involved are similar to those that regulate regeneration after PHx, but there are likely to be critical differences. A better understanding of regeneration mechanisms after DILI and hepatotoxicity in general could lead to development of new therapies for ALF patients and new biomarkers to predict patient outcome. Here, we summarize what is known about the mechanisms of liver regeneration and repair after hepatotoxicity. We also review the literature in the emerging field of liver regeneration biomarkers.

To understand the function of cortical circuits, it is necessary to catalog their cellular diversity. Past attempts to do so using anatomical, physiological or molecular features of cortical cells have not resulted in a unified taxonomy of neuronal or glial cell types, partly due to limited data. Single-cell transcriptomics is enabling, for the first time, systematic high-throughput measurements of cortical cells and generation of datasets that hold the promise of being complete, accurate and permanent. Statistical analyses of these data reveal clusters that often correspond to cell types previously defined by morphological or physiological criteria and that appear conserved across cortical areas and species. To capitalize on these new methods, we propose the adoption of a transcriptome-based taxonomy of cell types for mammalian neocortex. This classification should be hierarchical and use a standardized nomenclature. It should be based on a probabilistic definition of a cell type and incorporate data from different approaches, developmental stages and species. A community-based classification and data aggregation model, such as a knowledge graph, could provide a common foundation for the study of cortical circuits. This community-based classification, nomenclature and data aggregation could serve as an example for cell type atlases in other parts of the body.

We utilized gas-phase condensation to deposit size-selected Pd nanoparticles (NPs) on Mg nanofilms and systematically studied the catalytic conversion to localized MgH2 nanodomains upon exposure to hydrogen. Atomic force microscopy (AFM), aberration corrected transmission electron microscopy (TEM), and electron energy-loss spectroscopy (EELS) experiments were applied to map localized embryonic hydride nanodomains protruding from the Mg surface as a function of hydrogenation time, NP surface coverage, applied hydrogen pressure, and NP size. The results show that Pd NPs dissociate hydrogen and create atomic hydrogen pathways for hydrogenating the Mg nanofilm. The Pd NPs also inhibit oxidation of the underlying Mg nanofilm. Interestingly, the Mg nanofilm could be fully hydrogenated with a small quantity of Pd NPs at room temperature and modest hydrogen pressures. The localized hydrogenation enables improved control over the spatial distribution of hydride nanodomains making this configuration promising for future on-board hydrogen storage applications.