Engineered jumpers overcome biological limits via work multiplication.

For centuries, scientists have explored the limits of biological jump height1,2, and for decades, engineers have designed jumping machines3-18 that often mimicked or took inspiration from biological jumpers. Despite these efforts, general analyses are missing that compare the energetics of biological and engineered jumpers across scale. Here we show how biological and engineered jumpers have key differences in their jump energetics. The jump height of a biological jumper is limited by the work its linear motor (muscle) can produce in a single stroke. By contrast, the jump height of an engineered device can be far greater because its ratcheted or rotary motor can 'multiply work' during repeated strokes or rotations. As a consequence of these differences in energy production, biological and engineered jumpers should have divergent designs for maximizing jump height. Following these insights, we created a device that can jump over 30 metres high, to our knowledge far higher than previous engineered jumpers and over an order of magnitude higher than the best biological jumpers. Our work advances the understanding of jumping, shows a new level of performance, and underscores the importance of considering the differences between engineered and biological systems.

Intrinsic STAT4 Expression Controls Effector CD4 T Cell Migration and Th17 Pathogenicity.

Effector CD4 T cells are central to the development of autoimmune chronic inflammatory diseases, yet factors that mediate pathogenicity remain ill-defined. Single-nucleotide polymorphisms in the human STAT4 locus are associated with susceptibility to multiple autoimmune disorders, and Stat4 is linked to the pathogenic Th17 gene signature; however, Th17 cells differentiate independently of STAT4. Hence the interplay between STAT4 and CD4 T cell function, especially Th17 cells, during autoimmune disease is unclear. In this article, we demonstrate that CD4 T cell-intrinsic STAT4 expression is essential for the induction of autoimmune CNS inflammation in mice, in part by regulating the migration of CD4 T cells to the inflamed CNS. Moreover, unbiased transcriptional profiling revealed that STAT4 controls the expression of >200 genes in Th17 cells and is important for the upregulation of genes associated with IL-23-stimulated, pathogenic Th17 cells. Importantly, we show that Th17 cells specifically require STAT4 to evoke autoimmune inflammation, highlighting, to our knowledge, a novel function for STAT4 in Th17 pathogenicity.

Linking corticospinal tract activation and upper-limb motor control in adults with cerebral palsy.

AIM: To quantify the cervicomedullary motor evoked potentials (CMEPs) at the cervical spinal level in adults with cerebral palsy (CP) and determine if altered CMEPs are linked with upper-extremity motor function in this population. METHOD: This cross-sectional study consisted of a cohort of adults with CP (n = 15; mean age = 33 years 5 months [SD = 11 years 8 months]); Manual Ability Classification System levels I-IV) and neurotypical controls (n = 18; mean age = 30 years 10 months [SD = 10 years 4 months]), who were recruited to participate at an academic medical center. Adults with CP and typical adults (controls) were stimulated at the cervicomedullary junction to assess CMEPs at the cervical spinal cord level. Upper-extremity motor function was quantified using the Box and Blocks and Purdue Pegboard tests, self-reported upper-extremity function (UEF), and assessments of selective motor control. RESULTS: At higher stimulation levels, the contralateral CMEP responses of adults with CP were different from typical adults (p = 0.032). Reduced CMEP was correlated with reduced upper-limb function, including worse performance on the Box and Blocks (rho = 0.625, p = 0.025) and Purdue Pegboard tests (rho = 0.701, p = 0.010), lower self-reported UEF (rho = 0.761, p = 0.009), and overall selective motor control (rho = 0.731, p = 0.007). INTERPRETATION: Changes in the activation of spinal motoneurons through corticospinal pathways may have an important role in the altered upper-extremity motor function of individuals with CP.

Digital location tracking in the parent/caregiver-college student dyad.

INTRODUCTION: As college students navigate new developmental milestones, many families rely on digital technology to stay connected and aid in the transition to adulthood. Digital location tracking apps allow for parental monitoring in new ways that may have implications for youth development. Although recent research has begun to examine prevalence and motivations for digital location tracking in adolescence, we know little about how and why families continue to track into the transition to college, and how this may relate to perceptions of helicopter and autonomy supportive parenting. METHODS: In a cross-sectional study of 706 community college and 4-year university students in the Southeastern United States, we describe prevalence and sociodemographic differences in parent/caregiver digital location tracking of their college student children, and how this may be associated with perceptions of helicopter parenting and parent/caregiver autonomy support. RESULTS: Findings suggest that digital location tracking is a fairly common practice among college students, with nearly half of the sample endorsing currently or previously being digitally location tracked by their parent/caregiver. Younger, White, and higher socioeconomic status students were more likely to be tracked. Those students who were currently being digitally location tracked tended to perceive their primary parent/caregiver as engaging in more helicopter parenting and as less supportive of their autonomy. CONCLUSIONS: This brief report provides preliminary insight into parent/caregiver digital location tracking of their college student children. It is our hope that future research will further examine how digital location tracking may be helping or hindering attainment of developmental milestones in the digital age.

Using Data Science for Mechanistic Insights and Selectivity Predictions in a Non-Natural Biocatalytic Reaction.

The study of non-natural biocatalytic transformations relies heavily on empirical methods, such as directed evolution, for identifying improved variants. Although exceptionally effective, this approach provides limited insight into the molecular mechanisms behind the transformations and necessitates multiple protein engineering campaigns for new reactants. To address this limitation, we disclose a strategy to explore the biocatalytic reaction space and garner insight into the molecular mechanisms driving enzymatic transformations. Specifically, we explored the selectivity of an "ene"-reductase, GluER-T36A, to create a data-driven toolset that explores reaction space and rationalizes the observed and predicted selectivities of substrate/mutant combinations. The resultant statistical models related structural features of the enzyme and substrate to selectivity and were used to effectively predict selectivity in reactions with out-of-sample substrates and mutants. Our approach provided a deeper understanding of enantioinduction by GluER-T36A and holds the potential to enhance the virtual screening of enzyme mutants.

Prognostic value of plasma circulating tumor DNA fraction across four common cancer types: a real-world outcomes study.

BACKGROUND: Genomic analysis of circulating tumor DNA (ctDNA) is increasingly incorporated into the clinical management of patients with advanced cancer. Beyond tumor profiling, ctDNA analysis also can enable calculation of circulating tumor fraction (TF), which has previously been found to be prognostic. While most prognostic models in metastatic cancer are tumor type specific and require significant patient-level data, quantification of TF in ctDNA has the potential to serve as a pragmatic, tumor-agnostic prognostic tool. PATIENTS AND METHODS: This study utilized a cohort of patients in a nationwide de-identified clinico-genomic database with metastatic castration-resistant prostate cancer (mCRPC), metastatic breast cancer (mBC), advanced non-small-cell lung cancer (aNSCLC), or metastatic colorectal cancer (mCRC) undergoing liquid biopsy testing as part of routine care. TF was calculated based on single-nucleotide polymorphism aneuploidy across the genome. Clinical, disease, laboratory, and treatment data were captured from the electronic health record. Overall survival (OS) was evaluated by TF level while controlling for relevant covariables. RESULTS: A total of 1725 patients were included: 198 mCRPC, 402 mBC, 902 aNSCLC, and 223 mCRC. TF ≥10% was highly correlated with OS in univariable analyses for all cancer types: mCRPC [hazard ratio (HR) 3.3, 95% confidence interval (CI) 2.04-5.34, P < 0.001], mBC (HR 2.4, 95% CI 1.71-3.37, P < 0.001), aNSCLC (HR 1.68, 95% CI 1.34-2.1, P < 0.001), and mCRC (HR 2.11, 95% CI 1.39-3.2, P < 0.001). Multivariable assessments of TF had similar point estimates and CIs, suggesting a consistent and independent association with survival. Exploratory analysis showed that TF remained consistently prognostic across a wide range of cutpoints. CONCLUSIONS: Plasma ctDNA TF is a pragmatic, independent prognostic biomarker across four advanced cancers with potential to guide clinical conversations around expected treatment outcomes. With further prospective validation, ctDNA TF could be incorporated into care paradigms to enable precision escalation and de-escalation of cancer therapy based on patient-level tumor biology.

Acidic Methanol Treatment Facilitates Matrix-Assisted Laser Desorption Ionization-Mass Spectrometry Imaging of Energy Metabolism.

Detection of small molecule metabolites (SMM), particularly those involved in energy metabolism using MALDI-mass spectrometry imaging (MSI), is challenging due to factors including ion suppression from other analytes present (e.g., proteins and lipids). One potential solution to enhance SMM detection is to remove analytes that cause ion suppression from tissue sections before matrix deposition through solvent washes. Here, we systematically investigated solvent treatment conditions to improve SMM signal and preserve metabolite localization. Washing with acidic methanol significantly enhances the detection of phosphate-containing metabolites involved in energy metabolism. The improved detection is due to removing lipids and highly polar metabolites that cause ion suppression and denaturing proteins that release bound phosphate-containing metabolites. Stable isotope infusions of [13C6]nicotinamide coupled to MALDI-MSI ("Iso-imaging") in the kidney reveal patterns that indicate blood vessels, medulla, outer stripe, and cortex. We also observed different ATP:ADP raw signals across mouse kidney regions, consistent with regional differences in glucose metabolism favoring either gluconeogenesis or glycolysis. In mouse muscle, Iso-imaging using [13C6]glucose shows high glycolytic flux from infused circulating glucose in type 1 and 2a fibers (soleus) and relatively lower glycolytic flux in type 2b fiber type (gastrocnemius). Thus, improved detection of phosphate-containing metabolites due to acidic methanol treatment combined with isotope tracing provides an improved way to probe energy metabolism with spatial resolution in vivo.

Large-area periodically-poled lithium niobate wafer stacks optimized for high-energy narrowband terahertz generation.

Periodically-poled lithium niobate (PPLN) sources consisting of custom-built stacks of large-area wafers provide a unique opportunity to systematically study the multi-cycle terahertz (THz) generation mechanism as they are assembled layer-by-layer. Here we investigate and optimize the THz emission from PPLN wafer stacks as a function of wafer number, pump fluence, pulse duration and chirp, wafer separation, and pump focusing. Using 135 µm-thick, 2"-diameter wafers we generate high-energy, narrowband THz pulses with central frequencies up to 0.39 THz, directly suitable for THz-driven particle acceleration applications. We explore the multi-cycle pulse build-up with increasing wafer numbers using electro-optic sampling measurements, achieving THz conversion efficiencies up to 0.17%, while demonstrating unique control over the pulse length and bandwidth these sources offer. Guided by simulations, observed frequency-dependence on both stack-mounting and pump focusing conditions have been attributed to inter-wafer etalon and Gouy phase-shifts respectively, revealing subtle features that are critical to the understanding and performance of PPLN wafer-stack sources for optimal narrowband THz generation.

Thermogenic carbon release from the Central Atlantic magmatic province caused major end-Triassic carbon cycle perturbations.

The Central Atlantic magmatic province (CAMP), the end-Triassic mass extinction (ETE), and associated major carbon cycle perturbations occurred synchronously around the Triassic-Jurassic (T-J) boundary (201 Ma). Negative carbon isotope excursions (CIEs) recorded in marine and terrestrial sediments attest to the input of isotopically light carbon, although the carbon sources remain debated. Here, we explore the effects of mantle-derived and thermogenic carbon released from the emplacement of CAMP using the long-term ocean-atmosphere-sediment carbon cycle reservoir (LOSCAR) model. We have tested a detailed emission scenario grounded by numerous complementary boundary conditions, aiming to model the full extent of the carbon cycle perturbations around the T-J boundary. These include three negative CIEs (i.e., Marshi/Precursor, Spelae/Initial, Tilmanni/Main) with sharp positive CIEs in between. We show that a total of ∼24,000 Gt C (including ∼12,000 Gt thermogenic C) replicates the proxy data. These results indicate that thermogenic carbon generated from the contact aureoles around CAMP sills represents a credible source for the negative CIEs. An extremely isotopically depleted carbon source, such as marine methane clathrates, is therefore not required. Furthermore, we also find that significant organic carbon burial, in addition to silicate weathering, is necessary to account for the positive δ13C intervals following the negative CIEs.

MEASURING PATIENT EXPERIENCE OF ORAL HEALTH CARE: A CALL TO ACTION.

BACKGROUND: Surveys to measure patients' experiences of health care are common practice in general medical care to improve patient centered care. However, such questionnaires are not consistently used to capture the patient's experience of oral health care. Because patient experience is an important component of oral health care, there is an urgent need to measure it in the oral health care setting. PURPOSE: The purpose of this article is to illustrate the need for patient experience measurement in oral health care, highlight the challenges such measurement in this setting faces, and provide a set of next steps to advance care experience measurement for dental patients. BASIC PROCEDURES: We conducted a comprehensive review of the literature examining patient experience measurement in medical and oral health care. This focused on studies aimed at understanding the current measurement landscape and existing measurement tools. We also gathered additional information and perspectives through discussions with key informants and stakeholders. MAIN FINDINGS: There is a critical need for patient experience measurement in oral health care. To develop a program to measure patient experiences of oral care, the following should be done: (1) convene stakeholders and get their buy-in; (2) develop a patient experiences of oral health conceptual framework; (3) develop a survey tool that captures key aspects of patient experiences of oral health; (4) pilot the survey tool; (5) assess the survey tool...s psychometric properties; and (6) refine and finalize the survey tool. PRINCIPLE CONCLUSIONS: To advance the measurement of the quality of oral health care, we outline a stepwise methodology that captures dental patient experiences of oral health care.

Clinical Factors and Outcomes When Real-World Heart Teams Overruled STS Risk Scores in TAVR Cases.

Objectives: This study was conducted to determine why heart teams recommended transcatheter aortic valve replacement (TAVR) versus surgical AVR (SAVR) for patients at low predicted risk of mortality (PROM) and describe outcomes of these cases. Background: Historically, referral to TAVR was based predominately on the Society of Thoracic Surgeons (STS) risk model's PROM >3%. In selected cases, heart teams had latitude to overrule these scores. The clinical reasons and outcomes for these cases are unclear. Methods: Retrospective data were gathered for all TAVR and SAVR cases conducted by 9 hospitals between 2013 and 2017. Results: Cases included TAVR patients with STS PROM >3% (n = 2,711) and ≤3% (n = 415) and SAVR with STS PROM ≤3% (n = 1,438). Leading reasons for recommending TAVR in the PROM ≤3% group were frailty (57%), hostile chest (22%), severe lung disease (16%), and morbid obesity (13%), and 44% of cases had multiple reasons. Most postoperative and 30-day outcomes were similar between TAVR groups, but the STS PROM ≤3% group had a one-day shorter length of stay (2.5 ± 3.4 vs. 3.5 ± 4.7 days; p ≤ 0.001) and higher one-year survival (91.6% vs. 86.0%, p=0.002). In patients with STS PROM ≤3%, 30-day mortality was higher for TAVR versus SAVR (2.0% vs. 0.6%; p < 0.001). Conclusions: Heart teams recommended TAVR in patients with STS PROM ≤3% primarily due to frailty, hostile chest, severe lung disease, and/or morbid obesity. Similar postoperative outcomes between these patients and those with STS PROM >3% suggest that decisions to overrule STS PROM ≤3% were merited and may have reduced SAVR 30-day mortality rate.

A pilot study assessing the feasibility and acceptability of Project UPLIFT adapted for patients with psychogenic nonepileptic seizures.

BACKGROUND: People with psychogenic nonepileptic seizures (PNES) are at elevated risk of multiple psychiatric comorbidities. Current treatment gaps highlight the need for time-limited, distance-delivered interventions that can be cost-effectively delivered to patients with PNES. Project UPLIFT is a self-management program addressing mood problems in epilepsy that has not previously been adapted for PNES. The purpose of this study was to assess the feasibility and acceptability of UPLIFT for patients with PNES. METHODS: Project UPLIFT was minimally adapted by a multidisciplinary research group at Dartmouth-Hitchcock Medical Center. Participants were recruited into a nonrandomized pilot study and were assessed at baseline, after completing the intervention, and at 1-month follow-up. RESULTS: The intervention was adapted and delivered without additional modification. A total of eight participants enrolled in the trial, and six participated in the first session. All six participants who started UPLIFT completed the intervention, with a 98% attendance record across the eight sessions. At follow-up, 100% reported that UPLIFT provided useful tools for daily life. All participants continued using UPLIFT after completing the program, and 83% felt it helped with seizure management. Preliminary results provide proof-of-concept for future efficacy trials. CONCLUSION: This study provides initial support for the feasibility and acceptability of Project UPLIFT, minimally adapted for patients with PNES. As a time-limited program that can be distance-delivered to groups of patients, UPLIFT may be well-suited for the healthcare environment brought on by the COVID-19 pandemic.

Supervised machine learning to predict reduced depression severity in people with epilepsy through epilepsy self-management intervention.

OBJECTIVE: To develop a classifier that predicts reductions in depression severity in people with epilepsy after participation in an epilepsy self-management intervention. METHODS: Ninety-three people with epilepsy from three epilepsy self-management randomized controlled trials from the Managing Epilepsy Well (MWE) Network integrated research database met the inclusion criteria. Supervised machine learning algorithms were utilized to develop prediction models for changes in self-reported depression symptom severity. Features considered by the machine learning classifiers include age, gender, race, ethnicity, education, study type, baseline quality of life, and baseline depression symptom severity. The models were trained and evaluated on their ability to predict clinically meaningful improvement (i.e., a reduction of greater than three points on the nine-item Patient Health Questionnaire (PHQ-9)) between baseline and follow-up (<=12 weeks) depression scores. Models tested were a Multilayer Perceptron (ML), Random Forest (RF), Support Vector Machine (SVM), Logistic Regression with Stochastic Gradient Descent (SGD), K-nearest Neighbors (KNN), and Gradient Boosting (GB). A separate, outside dataset of 41 people with epilepsy was used in a validation exercise to examine the top-performing model's generalizability and performance with external data. RESULTS: All six classifiers performed better than our baseline mode classifier. Support Vector Machine had the best overall performance (average area under the curve [AUC] = 0.754, highest subpopulation AUC = 0.963). Our analysis of the SVM features revealed that higher baseline depression symptom severity, study type (i.e., intervention program goals), higher baseline quality of life, and race had the strongest influence on increasing the likelihood that a subject would experience a clinically meaningful improvement in depression scores. From the validation exercise, our top-performing SVM model performed similarly or better than the average SVM model with the outside dataset (average AUC = 0.887). SIGNIFICANCE: We trained an SVM classifier that offers novel insight into subject-specific features that are important for predicting a clinically meaningful improvement in subjective depression scores after enrollment in a self-management program. We provide evidence for machine learning to select subjects that may benefit most from a self-management program and indicate important factors that self-management programs should collect to develop improved digital tools.

Dissemination and implementation strategies for physical activity guidelines among adults with disability, chronic conditions, and pregnancy: a systematic scoping review.

BACKGROUND: Physical activity guidelines for adults with disability, chronic conditions, and pregnancy (i.e., specific populations) have been developed to provide guidance for engaging in physical activity. However, specific populations remain considerably less physically active compared to the general population, presenting a knowledge-practice gap. PURPOSE: The purpose of this systematic scoping review was to identify and evaluate strategies for disseminating and implementing physical activity guidelines among specific populations and/or stakeholders (e.g., healthcare professionals) in Canada. METHODS: Five search approaches (peer-reviewed literature databases, grey literature database, custom Google search engines, targeted web-based searches, and content expert consultation) identified records documenting and/or evaluating strategies that had been used to disseminate or implement guidelines from a predetermined list. Systematic and scoping review protocols were followed. Risk of bias assessments were conducted for all studies that evaluated strategies. RESULTS: Eighty-one records reported dissemination strategies (n = 42), implementation strategies (n = 28), or both (n = 11). Twenty-two studies reporting on 29 evaluated strategies were deemed "serious" or "high" risk of bias. Common guideline dissemination and implementation strategies are deliberated and recommendations for future practice are made. CONCLUSIONS: Findings may inform future dissemination and implementation efforts for physical activity guidelines in Canada or similar countries.

Aortic root management in acute type A aortic dissection: A nationwide analysis.

OBJECTIVE: Acute type A aortic dissection (ATAAD) is a life-threatening condition and surgical repair often includes aortic valve replacement (AVR). Aortic valve repair (AVr) is increasingly being reported with favorable outcomes from single-center experiences. This study examined national trends and outcomes of AVr in patients with ATAAD. METHODS: Adults with a primary diagnosis of acute thoracic aortic dissection who underwent proximal aortic surgery from January 2016 to December 2017 were obtained from the National Inpatient Sample. Patients were stratified into an isolated aortic surgery group (no aortic valve procedure), concomitant AVR, or concomitant AVr groups. The primary outcome was in-hospital mortality and secondary outcomes included stroke, acute kidney injury, heart block, and bleeding. Propensity score matching was used to address patient and hospital-level confounders between AVR and AVr groups. RESULTS: In total, 5115 patients underwent surgery for ATAAD and were included. Overall, 3220 (63%) underwent isolated ATAAD repair, while 1120 (22%) had concomitant AVR, and 775 (15%) had concomitant AVr. In 455 propensity-matched pairs, there was no difference in mortality or stroke between AVr and AVR groups, however, heart block (1.1% vs. 7.5%, p < .001) and bleeding (65.9% vs. 81.3%, p < .001) were significantly less common among those who underwent AVr. Patients who underwent AVr had shortest LOS (11.9 vs. 13.5 days, p < .001). There were no differences in outcomes of AVr in ATAAD based on hospital size or teaching status. CONCLUSION: In selected patients, AVr is being performed safely in the setting of ATAAD with mortality and composite outcomes comparable to AVR.

Evaluating psychotherapist competence: Testing the generalizability of clinical competence assessments of graduate trainees.

Health service psychology (HSP) graduate programs are shifting from knowledge- to competency-based assessments of trainees' psychotherapy skills. This study used Generalizability Theory to test the dependability of psychotherapy competence assessments based on video observation of trainees. A 10-item rating form was developed from a collection of forms used by graduate programs (n = 102) in counseling and clinical psychology, and a review of the common factors research literature. This form was then used by 11 licensed psychologists to rate eight graduate trainees while viewing 129, approximately 5-min video clips from their psychotherapy sessions with clients (n = 22) at a graduate program's training clinic. Generalizability analyses were used to forecast how the number of raters and clients, and length of observation time impact the dependability of ratings in various rating designs. Raters were the primary source of error variance in ratings, with rater main effects (leniency bias) and dyadic effects (rater-target interactions) contributing 24% and 7% of variance, respectively. Variance due to segments (video clips) was also substantial, suggesting that therapist performance varies within the same counseling session. Generalizability coefficients (G) were highest for crossed rating designs and reached maximum levels (G > .50) after four raters watched each therapist working with three clients and observed 15 min per dyad. These findings suggest that expert raters show consensus in ratings even without rater training and only limited direct observation. Future research should investigate the validity of competence ratings as predictors of outcome. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Chronic jetlag-induced alterations in pancreatic diurnal gene expression.

Cell-autonomous circadian clocks exist in nearly every organ and function to maintain homeostasis through a complex series of transcriptional-translational feedback loops. The response of these peripheral clocks to external perturbations, such as chronic jetlag and shift work, has been extensively investigated. However, an evaluation of the effects of chronic jetlag on the mouse pancreatic transcriptome is still lacking. Herein, we report an evaluation of the diurnal variations encountered in the pancreatic transcriptome following exposure to an established chronic jetlag protocol. We found approximately 5.4% of the pancreatic transcriptome was rhythmic. Following chronic jetlag, we found the number of rhythmic transcripts decreased to approximately 3.6% of the transcriptome. Analysis of the core clock genes, which orchestrate circadian physiology, revealed that nearly all exhibited a shift in the timing of peak gene expression-known as a phase shift. Similarly, over 95% of the rhythmically expressed genes in the pancreatic transcriptome exhibited a phase shift, many of which were found to be important for metabolism. Evaluation of the genes involved in pancreatic exocrine secretion and insulin signaling revealed many pancreas-specific genes were also rhythmically expressed and several displayed a concomitant phase shift with chronic jetlag. Phase differences were found 9 days after normalization, indicating a persistent failure to reentrain to the new light-dark cycle. This study is the first to evaluate the endogenous pancreatic clock and rhythmic gene expression in whole pancreas over 48 h, and how the external perturbation of chronic jetlag affects the rhythmic expression of genes in the pancreatic transcriptome.

Examining sex differences in sitting-induced microvascular dysfunction: Insight from acute vitamin C supplementation.

PURPOSE: Lower limb microvascular dysfunction resulting from prolonged sitting (PS) bouts has been revealed to occur independent of sex. Although acute antioxidant supplementation has been reported to blunt conduit artery dysfunction following PS in young males, it is unknown if this protective effect extends to the microvasculature or is relevant in young females, who possess intrinsic vascular protective mechanisms specific to antioxidant defense. Therefore, this study employed an acute antioxidant supplementation to further examine sex differences during PS with a specific focus on microvascular function. METHODS: On two separate visits, 14 females (23 ± 3 years) and 12 males (25 ± 4 years) had leg microvascular function (LMVF) assessed (via the passive leg movement technique) before and after 1.5 h of sitting. Prior to each visit, one gram of vitamin C (VC) or placebo (PL) was consumed. RESULTS: PS significantly reduced LMVF [PL: (M: -34 ± 20; F: -23 ± 18%; p < 0.01) independent of sex (p = 0.7)], but the VC condition only blunted this reduction in males (VC: -3 ± 20%; p < 0.01), but not females (VC: -18 ± 25%; p = 0.5). CONCLUSION: Young males and females reported similar reductions LMVF following PS, but only the young males reported a preservation of LMVF following the VC supplementation. This finding in young females was highlighted by substantial variability in LMVF measures in response to the VC condition that was unrelated to changes in the potential contributors to sitting-induced reductions in LMVF (e.g. lower limb venous pooling, reduced arterial shear rate). NEW AND NOTEWORTHY: In this study, we employed an acute Vitamin C (VC) supplementation to examine sex differences in leg microvascular function (LMVF) following a bout of prolonged sitting. This study revealed that prolonged sitting reduced LMVF independent of sex, but only young males reported an attenuation to this lowered LMVF following VC supplementation. The young females revealed substantial variability in sitting-induced changes to LMVF that could not be explained by the potential contributors to sitting-induced reductions in LMVF (e.g. lower limb venous pooling, reduced arterial shear rate).

Design, synthesis and analysis of novel sphingosine kinase-1 inhibitors to improve oral bioavailability.

The sphingomyelin pathway is important in cell regulation and determining cellular fate. Inhibition of sphingosine kinase isoform 1 (SK1) within this pathway, leads to a buildup of sphingosine and ceramide, two molecules directly linked to cell apoptosis, while decreasing the intracellular concentration of sphingosine-1-phosphate (S1P), a molecule linked to cellular proliferation. Recently, an inhibitor capable of inhibiting SK1 in vitro was identified, but also shown to be ineffective in vivo. A set of compounds designed to assess the impact of synthetic modifications to the hydroxynaphthalene ring region of the template inhibitor with SK1 to obtain a compound with increased efficacy in vivo. Of these fifteen compounds, 4A was shown to have an IC50 = 6.55 µM with improved solubility and in vivo potential.

A systematic literature review of recommendations for referral to specialty care for patients with epilepsy.

OBJECTIVE: In epilepsy, patients who receive appropriate care receive treatment that differs substantially from those that do not. Given the need for a more detailed assessment of the role of specialty referral in the care of patients with epilepsy, this systematic literature review identified epilepsy care guidelines and recommendations that specifically address when and why people with epilepsy should be referred to specialty care. METHODS: This study identified recent (in the last 10 years) publications that made best-practice recommendations for referring people with epilepsy to a neurologist or epileptologist. We searched six databases in December 2018: MEDLINE (PubMed), Cochrane Library, ProQuest, Web of Science, CINAHL (Ebsco), Scopus (Elsevier). Search terms included "Epilepsy" OR "Seizures," "Guideline" OR "Practice Parameter," and "Referral." RESULTS: The 15 full-text articles identified included formal guidelines, summaries of these guidelines, or professional commentary that builds upon existing guidelines. Most of these publications came from the U.K and its National Institute for Health and Care Excellence. Overall, the included recommendations for referral varied considerably both for new-onset and refractory epilepsy. Although these recommendations were not consistent, it is reasonable to refer patients following the failure of 2 anti-seizure medication (ASM) trials. SIGNIFICANCE: Guidelines and informal recommendations are not consistent regarding best practices for specialty care referral for patients with epilepsy. These guidelines and recommendations should consider the context of care in real-world settings and suggest pragmatic approaches that optimize seizure control and functioning.