Reduced Muscle Sympathetic Nerve Activity Response to a Cold Pressor Test in Multiple Sclerosis

Multiple sclerosis (MS) is a neurodegenerative autoimmune disease characterized by demyelination in the central nervous system leading to potential impairments in the autonomic control of cardiovascular function. We have previously demonstrated individuals with MS exhibit a diminished ability to increase blood pressure in response to a hypotensive stimulus compared with healthy controls likely due to impaired sympathetic modulation of the vasculature. PURPOSE: The aim of the current investigation was to test the hypothesis that muscle sympathetic nerve activity (MSNA) responses to a cold pressor test (CPT) are reduced in individuals with MS compared to healthy controls. METHODS: Four patients with relapsing-remitting MS (2 females/2 males, EDSS \u3c 4) and 4 sex-, age- and mass-matched controls were instrumented for MSNA (peroneal nerve), mean arterial blood pressure (MAP; Finometer), and heart rate (HR). Subjects were exposed to a CPT by immersing a hand in ice water for 2 min. Mean cardiovascular and MSNA responses (burst frequency) at baseline and at 30 sec intervals during the CPT were compared between groups. RESULTS: Heart rate (P\u3c0.001) and MAP (P\u3c0.001) responses increased from baseline throughout the CPT but no group differences were observed (P=0.10 and P=0.78, respectively). At baseline, MSNA was similar between groups (MS: 2 ± 2 vs. CON: 14 ± 9 bursts/min; P=0.239). However, individuals with MS had blunted MSNA responses to CPT compared to healthy controls at 60 seconds (MS: 18 ± 14 vs. CON: 42 ± 10 bursts/min; P=0.033), at 90 seconds (MS: 16 ± 12 vs. CON: 44 ± 10 bursts/min; P=.017) and at 120 seconds (MS: 13 ± 12 vs. CON: 43 ± 13 bursts/min; P=.012). CONCLUSION: Individuals with MS appear to have an attenuated muscle sympathetic response to CPT. However, MAP appears to respond similarly to healthy controls potentially through other compensatory mechanisms

A Sub-arcsecond Survey Toward Class 0 Protostars in Perseus: Searching for Signatures of Protostellar Disks

We present a CARMA 1.3 mm continuum survey toward 9 Class 0 protostars in the Perseus molecular cloud at $\sim$0.3$^{\prime\prime}$ (70 AU) resolution. This study approximately doubles the number of Class 0 protostars observed with spatial resolutions $<$ 100 AU at millimeter wavelengths, enabling the presence of protostellar disks and proto-binary systems to be probed. We detect flattened structures with radii $>$ 100 AU around 2 sources (L1448 IRS2 and Per-emb-14) and these sources may be strong disk candidates. Marginally-resolved structures with position angles within 30$^{\circ}$ of perpendicular to the outflow are found toward 3 protostars (L1448 IRS3C, IRAS 03282+3035, and L1448C) and are considered disk candidates. Two others (L1448 IRS3B and IRAS 03292+3039) have resolved structure, possibly indicative of massive inner envelopes or disks; L1448 IRS3B also has a companion separated by 0.9$^{\prime\prime}$ ($\sim$210 AU). IC348-MMS does not have well-resolved structure and the candidate first hydrostatic core L1451-MMS is marginally resolved on 1$^{\prime\prime}$ scales. The strong disk candidate sources were followed-up with C$^{18}$O ($J=2\rightarrow1$) observations, detecting velocity gradients consistent with rotation, but it is unclear if the rotation is Keplerian. We compare the observed visibility amplitudes to radiative transfer models, finding that visibility amplitude ratios suggest a compact component (possibly a disk) is necessary for 5 of 9 Class 0 sources; envelopes alone may explain the other 4 systems. We conclude that there is evidence for the formation of large disks in the Class 0 phase with a range of radii and masses dependent upon their initial formation conditions.Comment: Accepted to ApJ, 58 pages, 19 Figures, 5 Table

Does an Evidence-Based Healthy Relationships Program for 9th Graders Show Similar Effects for 7th and 8th Graders? Results from 57 Schools Randomized to Intervention

Integrating social and emotional learning (SEL) programming throughout curricula to support the development of healthy behaviors and prevent violence is critical for a comprehensive approach to school health. This study used a post-test comparison design to evaluate a healthy relationships program for eighth grade students that applies a SEL approach. The program was adapted from the Fourth R, an evidence-based program for ninth graders, but matches the curriculum and developmental context for eighth graders. Surveys were collected post-intervention from 1012 students within 57 schools randomized to intervention or control conditions. Multivariate multilevel analysis accounted for the nested nature of students within schools. There were significant group differences on three of four outcomes following intervention, including improved knowledge about violence, critical thinking around the impact of violence, and identification of more successful coping strategies. There was no group difference on general acceptance of violence. Overall, students learned relevant information and strategies and were able to apply that knowledge to demonstrate critical thinking, suggesting that adapting an evidence-based approach for use with younger students provided similar benefits. These findings build a case for 2 years of consecutive evidence-based healthy relationships programming in grades 8 and 9, consistent with best practice guidelines

Pressor and Sympathetic Responses to Graded Skeletal Muscle Metaboreflex Activation in Females with Relapsing-Remitting Multiple Sclerosis

Multiple sclerosis (MS) is a progressive disease characterized by demyelination in the central nervous system which disproportionately impacts females. Previous studies suggest MS-related exercise intolerance may be due to abnormal control of arterial blood pressure (BP) via the skeletal muscle metaboreflex. However, few studies have been performed and equivocal results reported. Discontinuity in prior data may be due to limited perturbation of metaboreflex activation using only low and moderate intensity exercise. PURPOSE: The purpose of this investigation was to test the hypothesis that females with MS have blunted BP and sympathetic responses to graded static handgrip (HG) exercise and isolated metaboreflex activation during postexercise ischemia (PEI) compared to healthy controls. METHODS: In 7 females with relapsing-remitting MS and 9 healthy female controls beat-to-beat BP (finometer) and muscle sympathetic nerve activity (MSNA; peroneal microneurography) were recorded at rest and during two minutes of handgrip performed at 30% and 40% maximum voluntary contraction followed by two minutes of PEI to isolate the muscle metaboreflex. RESULTS: There were no differences in resting mean arterial pressure (MAP; P= 0.16) or MSNA burst frequency (P= 0.15) between MS and controls. MAP and MSNA increased during 30% HG (MS: Δ19.8 ± 9.1 mmHg vs. Con: Δ17.8 ± 5.4 mmHg; P= 0.30 and MS: Δ17 ± 12 bursts/min vs. Con: Δ18 ± 17 bursts/min; P= 0.46) and 40% HG (MS: Δ29.3 ± 8.0 mmHg vs. Con: Δ30.0 ± 6.9 mmHg; P= 0.43 and MS: Δ36 ± 16 bursts/min vs. Con: Δ40 ± 9 bursts/min; P= 0.30) with no differences between groups. Likewise, MAP and MSNA responses were also not different during PEI post 30% HG (MS: Δ15.8 ± 7.6 mmHg vs. Con: Δ15.8 ± 6.4 mmHg; P= 0.50 and MS: Δ15 ± 9 bursts/min vs. Con: Δ11 ± 7 bursts/min; P= 0.19) or PEI post 40% HG (MS: Δ25.8 ± 6.3 mmHg vs. Con: Δ22.6 ± 8.2 mmHg; P= 0.43 and MS: Δ23 ± 13 bursts/min vs. Con: Δ24 ± 7 bursts/min; P= 0.46) between MS and controls. CONCLUSION: These preliminary data suggest intact skeletal muscle metaboreflex control of arterial BP in females with MS

Navigating the challenges of digital health innovation: considerations and solutions in developing online and smartphone application based interventions for mental health disorders

This article presents an analysis of challenges and considerations when developing digital mental health innovations. Recommendations include collaborative working between clinicians, researchers, industry and service users in order to successfully navigate challenges and to ensure e-therapies are engaging, acceptable, evidence based, scalable and sustainable

Identifying nonalcoholic fatty liver disease patients with active fibrosis by measuring extracellular matrix remodeling rates in tissue and blood.

Excess collagen synthesis (fibrogenesis) in the liver plays a causal role in the progression of nonalcoholic fatty liver disease (NAFLD). Methods are needed to identify patients with more rapidly progressing disease and to demonstrate early response to treatment. We describe here a novel method to quantify hepatic fibrogenesis flux rates both directly in liver tissue and noninvasively in blood. Twenty-one patients with suspected NAFLD ingested heavy water (2 H2 O, 50-mL aliquots) two to three times daily for 3-5 weeks prior to a clinically indicated liver biopsy. Liver collagen fractional synthesis rate (FSR) and plasma lumican FSR were measured based on 2 H labeling using tandem mass spectrometry. Patients were classified by histology for fibrosis stage (F0-F4) and as having nonalcoholic fatty liver or nonalcoholic steatohepatitis (NASH). Magnetic resonance elastography measurements of liver stiffness were also performed. Hepatic collagen FSR in NAFLD increased with advancing disease stage (e.g., higher in NASH than nonalcoholic fatty liver, positive correlation with fibrosis score and liver stiffness) and correlated with hemoglobin A1C. In addition, plasma lumican FSR demonstrated a significant correlation with hepatic collagen FSR.ConclusionUsing a well-characterized cohort of patients with biopsy-proven NAFLD, this study demonstrates that hepatic scar in NASH is actively remodeled even in advanced fibrosis, a disease that is generally regarded as static and slowly progressive. Moreover, hepatic collagen FSR correlates with established risks for fibrotic disease progression in NASH, and plasma lumican FSR correlates with hepatic collagen FSR, suggesting applications as direct or surrogate markers, respectively, of hepatic fibrogenesis in humans. (Hepatology 2017;65:78-88)

Combined growth hormone and insulin-like growth factor 1 rescues growth retardation in glucocorticoid-treated mdx mice but does not prevent osteopenia

Short stature and osteoporosis are common in Duchenne muscular dystrophy (DMD) and its pathophysiology may include an abnormality of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, which is further exacerbated by long-term glucocorticoid (GC) treatment. Hence, an agent that has anabolic properties and may improve linear growth would be beneficial in this setting and therefore requires further exploration. A 5-week-old x-linked muscular dystrophy (mdx) mice were used as a model of DMD. They were treated with prednisolone ± GH + IGF-1 for 4 weeks and then compared to control mdx mice to allow the study of both growth and skeletal structure. GC reduced cortical bone area, bone fraction, tissue area and volume and cortical bone volume, as assessed by micro computed tomography (CT) In addition, GC caused somatic and skeletal growth retardation but improved grip strength. The addition of GH + IGF-1 therapy rescued the somatic growth retardation and induced additional improvements in grip strength (16.9% increase, P  < 0.05 compared to control). There was no improvement in bone microarchitecture (assessed by micro-CT and static histomorphometry) or biomechanical properties (assessed by three-point bending). Serum bone turnover markers (Serum procollagen 1 intact N-terminal propeptide (P1NP), alpha C-terminal telopeptide (αCTX)) also remained unaffected. Further work is needed to maximise these gains before proceeding to clinical trials in boys with DMD

Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury

Sandwich-cultured hepatocytes (SCH) are metabolically competent and have proper localization of basolateral and canalicular transporters with functional bile networks. Therefore, this cellular model is a unique tool that can be used to estimate biliary excretion of compounds. SCH have been used widely to assess hepatobiliary disposition of endogenous and exogenous compounds and metabolites. Mechanistic modeling based on SCH data enables estimation of metabolic and transporter-mediated clearances, which can be employed to construct physiologically-based pharmacokinetic models for prediction of drug disposition and drug-drug interactions in humans. In addition to pharmacokinetic studies, SCH also have been employed to study cytotoxicity and perturbation of biological processes by drugs and hepatically-generated metabolites. Human SCH can provide mechanistic insights underlying clinical drug-induced liver injury (DILI). In addition, data generated in SCH can be integrated into systems pharmacology models to predict potential DILI in humans. In this review, applications of SCH in studying hepatobiliary drug disposition and bile acid-mediated DILI are discussed. An example is presented to show how data generated in the SCH model was used to establish a quantitative relationship between intracellular bile acids and cytotoxicity, and how this information was incorporated into a systems pharmacology model for DILI prediction

Interventions to improve antibiotic prescribing practices for hospital inpatients

Background Antibiotic resistance is a major public health problem. Infections caused by multidrug-resistant bacteria are associated with prolonged hospital stay and death compared with infections caused by susceptible bacteria. Appropriate antibiotic use in hospitals should ensure effective treatment of patients with infection and reduce unnecessary prescriptions. We updated this systematic review to evaluate the impact of interventions to improve antibiotic prescribing to hospital inpatients. Objectives To estimate the effectiveness and safety of interventions to improve antibiotic prescribing to hospital inpatients and to investigate the effect of two intervention functions: restriction and enablement. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library), MEDLINE, and Embase. We searched for additional studies using the bibliographies of included articles and personal files. The last search from which records were evaluated and any studies identified incorporated into the review was January 2015. Selection criteria We included randomised controlled trials (RCTs) and non-randomised studies (NRS). We included three non-randomised study designs to measure behavioural and clinical outcomes and analyse variation in the effects: non- randomised trials (NRT), controlled before-after (CBA) studies and interrupted time series (ITS) studies. For this update we also included three additional NRS designs (case control, cohort, and qualitative studies) to identify unintended consequences. Interventions included any professional or structural interventions as defined by the Cochrane Effective Practice and Organisation of Care Group. We defined restriction as 'using rules to reduce the opportunity to engage in the target behaviour (or increase the target behaviour by reducing the opportunity to engage in competing behaviours)'. We defined enablement as 'increasing means/reducing barriers to increase capability or opportunity'. The main comparison was between intervention and no intervention. Data collection and analysis Two review authors extracted data and assessed study risk of bias. We performed meta-analysis and meta-regression of RCTs and meta-regression of ITS studies. We classified behaviour change functions for all interventions in the review, including those studies in the previously published versions. We analysed dichotomous data with a risk difference (RD). We assessed certainty of evidence with GRADE criteria. Main results This review includes 221 studies (58 RCTs, and 163 NRS). Most studies were from North America (96) or Europe (87). The remaining studies were from Asia (19), South America (8), Australia (8), and the East Asia (3). Although 62% of RCTs were at a high risk of bias, the results for the main review outcomes were similar when we restricted the analysis to studies at low risk of bias. More hospital inpatients were treated according to antibiotic prescribing policy with the intervention compared with no intervention based on 29 RCTs of predominantly enablement interventions (RD 15%, 95% confidence interval (CI) 14% to 16%; 23,394 participants; high-certainty evidence). This represents an increase from 43% to 58% .There were high levels of heterogeneity of effect size but the direction consistently favoured intervention. The duration of antibiotic treatment decreased by 1.95 days (95% CI 2.22 to 1.67; 14 RCTs; 3318 participants; high-certainty evidence) from 11.0 days. Information from non-randomised studies showed interventions to be associated with improvement in prescribing according to antibiotic policy in routine clinical practice, with 70% of interventions being hospital-wide compared with 31% for RCTs. The risk of death was similar between intervention and control groups (11% in both arms), indicating that antibiotic use can likely be reduced without adversely affecting mortality (RD 0%, 95% CI -1% to 0%; 28 RCTs; 15,827 participants; moderate-certainty evidence). Antibiotic stewardship interventions probably reduce length of stay by 1.12 days (95% CI 0.7 to 1.54 days; 15 RCTs; 3834 participants; moderate-certainty evidence). One RCT and six NRS raised concerns that restrictive interventions may lead to delay in treatment and negative professional culture because of breakdown in communication and trust between infection specialists and clinical teams (low-certainty evidence). Both enablement and restriction were independently associated with increased compliance with antibiotic policies, and enablement enhanced the effect of restrictive interventions (high-certainty evidence). Enabling interventions that included feedback were probably more effective than those that did not (moderate-certainty evidence). There was very low-certainty evidence about the effect of the interventions on reducing Clostridium difficile infections (median -48.6%, interquartile range -80.7% to -19.2%; 7 studies). This was also the case for resistant gram-negative bacteria (median -12.9%, interquartile range -35.3% to 25.2%; 11 studies) and resistant gram-positive bacteria (median -19.3%, interquartile range -50.1% to +23.1%; 9 studies). There was too much variance in microbial outcomes to reliably assess the effect of change in antibiotic use. Heterogeneity of intervention effect on prescribing outcomes We analysed effect modifiers in 29 RCTs and 91 ITS studies. Enablement and restriction were independently associated with a larger effect size (high-certainty evidence). Feedback was included in 4 (17%) of 23 RCTs and 20 (47%) of 43 ITS studies of enabling interventions and was associated with greater intervention effect. Enablement was included in 13 (45%) of 29 ITS studies with restrictive interventions and enhanced intervention effect. Authors' conclusions We found high-certainty evidence that interventions are effective in increasing compliance with antibiotic policy and reducing duration of antibiotic treatment. Lower use of antibiotics probably does not increase mortality and likely reduces length of stay. Additional trials comparing antibiotic stewardship with no intervention are unlikely to change our conclusions. Enablement consistently increased the effect of interventions, including those with a restrictive component. Although feedback further increased intervention effect, it was used in only a minority of enabling interventions. Interventions were successful in safely reducing unnecessary antibiotic use in hospitals, despite the fact that the majority did not use the most effective behaviour change techniques. Consequently, effective dissemination of our findings could have considerable health service and policy impact. Future research should instead focus on targeting treatment and assessing other measures of patient safety, assess different stewardship interventions, and explore the barriers and facilitators to implementation. More research is required on unintended consequences of restrictive interventions

Hidden negative linear compressibility in lithium L-tartrate†

Development of artificial muscles, next-generation pressure sensors and precision optics relies on advances in materials with anomalous mechanical properties. Negative linear compressibility, NLC, is one such rare, counterintuitive phenomenon, in which a material expands along one axis under hydrostatic pressure. Both classical and recent NLC materials face a pay-off between the active pressure range and magnitude of NLC, and in the vast majority of cases the NLC effect decreases with pressure. By decoupling the mechanical behaviour of building units for the first time in a winerack framework containing two different strut types, we show that lithium L-tartrate exhibits NLC with a maximum value, Kmax = -21 TPa^-1, and an overall NLC capacity, χNLC = 5.1 %, that are comparable to the most exceptional materials to date. Furthermore, the contributions from molecular strut compression and angle opening interplay to give rise to so-called “hidden” negative linear compressibility, in which NLC is absent at ambient pressure, switched on at 2 GPa and sustained up to the limit of our experiment, 5.5 GPa. Analysis of the changes in crystal structure using variable-pressure synchrotron X-ray diffraction reveals new chemical and geometrical design rules to assist the discovery of other materials with exciting hidden anomalous mechanical properties