Effects of treadmill running in a rat model of chronic kidney disease.

Chronic kidney disease (CKD) progression results in musculoskeletal dysfunction that is associated with a higher likelihood of hospitalization and is predictive of hospitalizations and mortality. Despite this, there is a lack of effective interventions to treat the musculoskeletal dysfunction. We studied treadmill running as an intervention to improve musculoskeletal health in a translational rat model that has slowly progressive CKD. CKD rats were subjected to treadmill exercise or no treadmill exercise for 10 weeks (n = 8 each group). Animals ran for 60 min, 5 times per week starting at a speed of 8 m/min and ending at 18 m/min (1 m/min increase/week). Treadmill training had no effect on muscle strength (assessed as maximally stimulated torque), half-relaxation time (time from peak torque to 50%) or muscle cross-sectional area. Overall, there were no biochemical improvements related to CKD progression. Skeletal muscle catabolism was higher than non-exercised animals without a concomitant change in muscle synthesis markers or regeneration transcription factors. These results suggest that aerobic exercise, achieved via treadmill running was not protective in CKD animals and actually produced potentially harmful effects (increased catabolism). Given the high prevalence and dramatic musculoskeletal mobility impairment in patients with CKD, there is a clear need to understand how to effectively prescribe exercise in order to benefit the musculoskeletal system.

Health service utilization and related costs attributable to diabetes.

AIMS: To estimate the health service use and direct healthcare costs attributable to diabetes using best available data and methods. METHODS: A nationally representative sample of adults aged ≥50 years was analysed (n=8107). Health service use in the previous 12 months included the number of general practitioner visits, outpatient department visits, hospital admissions, and accident and emergency department attendances. Multivariable negative binomial regression was used to estimate the associations between diabetes and frequency of visits. Average marginal effects were applied to unit costs for each health service and extrapolated to the total population, calculating the incremental costs associated with diabetes. RESULTS: The prevalence of diabetes was 8.0% (95% CI: 7.4, 8.6). In fully adjusted models, diabetes was associated with additional health service use. Compared to those without diabetes, people with diabetes have, on average, 1.49 (95% CI: 1.10, 1.88) additional general practitioner visits annually. Diabetes was associated with an 87% increase in outpatient visits, a 52% increase in hospital admissions and a 33% increase in accident and emergency department attendances (P<0.001). The incremental cost of this additional service use, nationally, is an estimated €88,894,421 annually, with hospital admissions accounting for 67% of these costs. CONCLUSION: Using robust methods, we identified substantially increased service use attributable to diabetes across the health system. Our findings highlight the urgent need to invest in the prevention and management of diabetes.

Correction to: Mother and Home Visitor Emotional Well-Being and Alignment on Goals for Home Visiting as Factors for Program Engagement.

The article "Mother and Home Visitor Emotional Well-Being and Alignment on Goals for Home Visiting as Factors for Program Engagement", written by L. Burrell, S. Crowne, K. Ojo, R. Snead, K. O'Neill, F. Cluxton­Keller and A. Duggan, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 31 May 2018 without open access.

Mother and Home Visitor Emotional Well-Being and Alignment on Goals for Home Visiting as Factors for Program Engagement.

Objectives Family engagement in home visiting (HV), as indicated by length of enrollment, is a major challenge as most families do not stay enrolled for the intended duration prescribed by HV models. This study examined maternal and visitor emotional well-being as factors for maternal satisfaction with the program in addressing reasons for enrolling in HV and program engagement and the role of their working alliance with the visitor as a mediator of this. Methods Longitudinal data were collected from 148 mothers and 54 visitors in 21 HV programs. Mothers completed surveys shortly after enrolling and 6 months later to assess attributes of the working alliance with their visitor. Visitors completed a survey to assess work-related well-being. HV program data were used to measure engagement. Results Mothers enrolled for multiple, diverse reasons, most often to promote child development and parenting (96%). Mothers' satisfaction with program efforts to address reasons for enrollment was highest for parenting (79%) and lowest for jobs and education (30%). Results of the mediational path model indicated that ratings of the visitor on goal alignment were positively associated with engagement. Maternal emotional availability and visitor work-related emotional exhaustion were negatively associated with engagement. Exploratory analyses suggested that ratings of the visitor on goal alignment were a stronger predictor of engagement for mothers with low emotional availability compared to other mothers. Conclusions for Practice Visitor alignment with mothers on goals and responsiveness to reasons for enrolling appear to be effective in promoting engagement. Individualizing services to reflect maternal goals and emotional capacity may be important strategies to address engagement challenges.

A resistive Q-switch for low-field NMR systems.

An NMR Q-switch was designed and constructed specifically for use with low-field NMR apparatus. This featured a comparatively simple resistive damping design. It served to reduce the r.f. probe ring-down time, and hence reduced the signal acquisition delay from 25 ms to 9 ms, on an Earth's magnetic field NMR system. The advantage of this earlier acquisition was demonstrated for both an aqueous suspension of iron oxide particles and using an NMR flow meter.

Retrospective review of Surgical Availability and Readiness in 8 African countries.

OBJECTIVES: The purpose of this study was to assess surgical availability and readiness in 8 African countries using the WHO's Service Availability and Readiness Assessment (SARA) tool. SETTING: We analysed data for surgical services, including basic and comprehensive surgery, comprehensive obstetric care, blood transfusion, and infection prevention, obtained from the WHO's SARA surveys in Sierra Leone, Uganda, Mauritania, Benin, Zambia, Burkina Faso, Democratic Republic of Congo and Togo. PRIMARY AND SECONDARY OUTCOME MEASURES: Among the facilities that were expected to offer surgical services (N=3492), there were wide disparities between the countries in the number of facilities per 100 000 population that reported offering basic surgery (1.0-12.1), comprehensive surgery (0.1-0.8), comprehensive obstetric care (0.1-0.8) and blood transfusion (0.1-0.8). Only 0.1-0.3 facilities per 100 000 population had all three bellwether procedures available, namely laparotomy, open fracture management and caesarean section. In all the countries, the facilities that reported offering surgical services generally had a shortage of the necessary items for offering the services and this varied greatly between the countries, with the facilities having on average 27-53% of the items necessary for offering basic surgery, 56-83% for comprehensive surgery, 49-72% for comprehensive obstetric care and 54-80% for blood transfusion. Furthermore, few facilities had all the necessary items present. However, facilities that reported offering surgical services had on average most of the necessary items for the prevention of infection. CONCLUSIONS: There are important gaps in the surgical services in the 8 African countries surveyed. Efforts are therefore urgently needed to address deficiencies in the availability and readiness to deliver surgical services in these nations, and this will require commitment from multiple stakeholders. SARA may be used to monitor availability and readiness at regular intervals, which will enable stakeholders to evaluate progress and identify gaps and areas for improvement.

Evaluating the implementation of a national clinical programme for diabetes to standardise and improve services: a realist evaluation protocol.

BACKGROUND: Over the last three decades in response to the growing burden of diabetes, countries worldwide have developed national and regional multifaceted programmes to improve the monitoring and management of diabetes and to enhance the coordination of care within and across settings. In Ireland in 2010, against a backdrop of limited dedicated strategic planning and engrained variation in the type and level of diabetes care, a national programme was established to standardise and improve care for people with diabetes in Ireland, known as the National Diabetes Programme (NDP). The NDP comprises a range of organisational and service delivery changes to support evidence-based practices and policies. This realist evaluation protocol sets out the approach that will be used to identify and explain which aspects of the programme are working, for whom and in what circumstances to produce the outcomes intended. METHODS/DESIGN: This mixed method realist evaluation will develop theories about the relationship between the context, mechanisms and outcomes of the diabetes programme. In stage 1, to identify the official programme theories, documentary analysis and qualitative interviews were conducted with national stakeholders involved in the design, development and management of the programme. In stage 2, as part of a multiple case study design with one case per administrative region in the health system, qualitative interviews are being conducted with frontline staff and service users to explore their responses to, and reasoning about, the programme's resources (mechanisms). Finally, administrative data will be used to examine intermediate implementation outcomes such as service uptake, acceptability, and fidelity to models of care. DISCUSSION: This evaluation is using the principles of realist evaluation to examine the implementation of a national programme to standardise and improve services for people with diabetes in Ireland. The concurrence of implementation and evaluation has enabled us to produce formative feedback for the NDP while also supporting the refinement and revision of initial theories about how the programme is being implemented in the dynamic and unstable context of the Irish healthcare system.

Bax/Bak activation in the absence of Bid, Bim, Puma, and p53.

How BH3-only proteins activate Bax/Bak, the two gateway proteins of the mitochondria-dependent apoptotic pathway, remains incompletely understood. Although all pro-apoptotic BH3-only proteins are known to bind/neutralize the anti-apoptotic Bcl-2 proteins, the three most potent ones, Bid (tBid), Bim, and Puma, possess an additional activity of directly activating Bax/Bak in vitro. This latter activity has been proposed to be responsible for triggering Bax/Bak activation following apoptotic stimulation. To test this hypothesis, we generated Bid(-/)(-)Bim(-/)(-)Puma(-/)(-) (TKO), TKO/Bax(-/)(-)/Bak(-/)(-) (PentaKO), and PentaKO/Mcl-1(-/-) (HexaKO) HCT116 cells through gene editing. Surprisingly, although the TKO cells were resistant to several apoptotic stimuli, robust apoptosis was induced upon the simultaneous inactivation of Bcl-xL and Mcl-1, two anti-apoptotic Bcl-2 proteins known to suppress Bax/Bak activation and activity. Importantly, such apoptotic activity was completely abolished in the PentaKO cells. In addition, ABT-737, a BH3 mimetic that inhibits Bcl-xL/Bcl-w/Bcl-2, induced Bax activation in HexaKO cells reconstituted with endogenous level of GFP-Bax. Further, by generating TKO/p53(-/-) (QKO) cells, we demonstrated that p53, a tumor suppressor postulated to directly activate Bax, is not required for Bid/Bim/Puma-independent Bax/Bak activation. Together, these results strongly suggest that the direct activation activities of Bid (tBid), Bim, Puma, and p53 are not essential for activating Bax/Bak once the anti-apoptotic Bcl-2 proteins are neutralized.

Treating Problem Gambling Samples with Cognitive Behavioural Therapy and Mindfulness-Based Interventions: A Clinical Trial.

The problem gambling (PG) intervention literature is characterised by a variety of psychological treatments and approaches, with varying levels of evidence (PGRTC in Guideline for screening, assessment and treatment in problem and pathological gambling. Monash University, Melbourne, 2011). A recent PG systematic review (Maynard et al. in Res Soc Work Pract, 2015. doi: 10.1177/1049731515606977 ) and the success of mindfulness-based interventions to effectively treat disorders commonly comorbid with PG suggested mindfulness-based interventions may be effective for treating PG. The current study tested the effectiveness of three interventions to treat PGs: 1. case formulation driven Cognitive Behaviour Therapy (CBT); 2. manualised CBT; and 3. mindfulness-based treatment. All three interventions tested returned large effect size improvements in PG behaviour after seven sessions (Cohen's d range 1.46-2.01), at post-treatment and at 3 and 6-month follow-up. All of the interventions were rated as acceptable by participants at post-treatment. This study suggests that the mindfulness-based and TAU interventions used in the current study appear to be effective at reducing PG behavior and associated distress and they also appear to generalise to improvements in other measures such as quality of life-mental functioning and certain mindfulness facets more effectively than the manualised form of CBT utilised used here. Secondly, a brief mindfulness intervention delivered after psycho-education and a brief CBT intervention may be a useful supplement to traditional CBT treatments by addressing transdiagnostic processes such as rumination and thought suppression. Thirdly, CBT interventions continue to report effectiveness in reducing PG behaviour and associated distress consistent with the prevailing literature and clinical direction.

Restoring motor control and sensory feedback in people with upper extremity amputations using arrays of 96 microelectrodes implanted in the median and ulnar nerves.

OBJECTIVE: An important goal of neuroprosthetic research is to establish bidirectional communication between the user and new prosthetic limbs that are capable of controlling >20 different movements. One strategy for achieving this goal is to interface the prosthetic limb directly with efferent and afferent fibres in the peripheral nervous system using an array of intrafascicular microelectrodes. This approach would provide access to a large number of independent neural pathways for controlling high degree-of-freedom prosthetic limbs, as well as evoking multiple-complex sensory percepts. APPROACH: Utah Slanted Electrode Arrays (USEAs, 96 recording/stimulating electrodes) were implanted for 30 days into the median (Subject 1-M, 31 years post-amputation) or ulnar (Subject 2-U, 1.5 years post-amputation) nerves of two amputees. Neural activity was recorded during intended movements of the subject's phantom fingers and a linear Kalman filter was used to decode the neural data. Microelectrode stimulation of varying amplitudes and frequencies was delivered via single or multiple electrodes to investigate the number, size and quality of sensory percepts that could be evoked. Device performance over time was assessed by measuring: electrode impedances, signal-to-noise ratios (SNRs), stimulation thresholds, number and stability of evoked percepts. MAIN RESULTS: The subjects were able to proportionally, control individual fingers of a virtual robotic hand, with 13 different movements decoded offline (r = 0.48) and two movements decoded online. Electrical stimulation across one USEA evoked >80 sensory percepts. Varying the stimulation parameters modulated percept quality. Devices remained intrafascicularly implanted for the duration of the study with no significant changes in the SNRs or percept thresholds. SIGNIFICANCE: This study demonstrated that an array of 96 microelectrodes can be implanted into the human peripheral nervous system for up to 1 month durations. Such an array could provide intuitive control of a virtual prosthetic hand with broad sensory feedback.

Density of GFAP-immunoreactive astrocytes is decreased in left hippocampi in major depressive disorder.

Neuroimaging and postmortem studies of subjects with major depressive disorder (MDD) reveal smaller hippocampal volume with lengthening duration of illness. Pathology in astrocytes may contribute significantly to this reduced volume and to the involvement of the hippocampus in MDD. Postmortem hippocampal tissues were collected from 17 subjects with MDD and 17 psychiatrically-normal control subjects. Sections from the body of the hippocampus were immunostained for glial fibrillary acidic protein (GFAP), a marker of intermediate filament protein expressed in astrocytes. The density of GFAP-immunoreactive astrocytes was measured in the hippocampus using 3-dimensional cell counting. Hippocampal subfields were also assessed for GFAP-immunoreactive area fraction. In CA1, there was a significant positive correlation between age and either density or area fraction in MDD. The density of astrocytes in the hilus, but not CA1 or CA2/3, was significantly decreased only in depressed subjects not taking an antidepressant drug, but not for depressed subjects taking an antidepressant drug. The area fraction of GFAP-immunoreactivity was significantly decreased in the dentate gyrus in women but not men with depression. In CA2/3, the area fraction of GFAP-immunoreactivity was inversely correlated with the duration of depression in suicide victims. Astrocyte contributions to neuronal function in the hilus may be compromised in depressed subjects not taking antidepressant medication. Due to the cross-sectional nature of the present study of postmortem brain tissue, it remains to be determined whether antidepressant drug treatment prevented a decrease in GFAP-immunoreactive astrocyte density or restored cell density to normal levels.

The pharmacokinetics of intravenous fenoldopam in healthy, awake cats.

Fenoldopam is a selective dopamine-1 receptor agonist that improves diuresis by increasing renal blood flow and perfusion and causing peripheral vasodilation. Fenoldopam has been shown to induce diuresis and be well-tolerated in healthy cats. It is used clinically in cats with oliguric kidney injury at doses extrapolated from human medicine and canine studies. The pharmacokinetics in healthy beagle dogs has been reported; however, pharmacokinetic data in cats are lacking. The goal of this study was to determine pharmacokinetic data for healthy, awake cats receiving an infusion of fenoldopam. Six healthy, awake, client-owned cats aged 2-6 years old received a 120-min constant rate infusion of fenoldopam at 0.8 µg/kg/min followed by a 20-min washout period. Ascorbate stabilized plasma samples were collected during and after the infusion for the measurement of fenoldopam concentration by HPLC with mass spectrometry detection. This study showed that the geometric mean of the volume of distribution, clearance, and half-life (198 mL/kg, 46 mL/kg/min, and 3.0 mins) is similar to pharmacokinetic parameters for humans. No adverse events were noted. Fenoldopam at a constant rate infusion of 0.8 µg/kg per min was well tolerated in healthy cats. Based on the results, further evaluation of fenoldopam in cats with kidney disease is recommended.

Impacts of Contrasting Alfalfa Production Systems on the Drivers of Carabid Beetle (Coleoptera: Carabidae) Community Dynamics.

Growing concerns about the environmental consequences of chemically based pest control strategies have precipitated a call for the development of integrated, ecologically based pest management programs. Carabid or ground beetles (Coleoptera:Carabidae) are an important group of natural enemies of common agricultural pests such as aphids, slugs, and other beetles. Alfalfa (Medicago sativa L.) is one of the most common forage crop species in the semi-arid western United States. In 2011, Montana alone produced 4.0 × 10(6 )Mg of alfalfa on 8.1 × 10(5 )ha for gross revenue in excess of US$4.3 × 10(8), making it the third largest crop by revenue. We conducted our study over the 2012 and 2013 growing seasons. Each year, our study consisted of three sites each with adjacent systems of monoculture alfalfa, alfalfa nurse cropped with hay barley, and an uncultivated refuge consisting of a variety of forbs and grasses. Carabid community structure differed and strong temporal shifts were detected during both 2012 and 2013. Multivariate fuzzy set ordination suggests that variation in canopy height among the three vegetation systems was primarily responsible for the differences observed in carabid community structure. Land managers may be able to enhance carabid species richness and total abundance by creating a heterogeneous vegetation structure, and nurse cropping in particular may be effective strategy to achieve this goal.

Mixed treatment comparison meta-analysis of porcine circovirus type 2 (PCV2) vaccines used in piglets.

Porcine circovirus type 2 (PCV2) vaccination is globally one of the most commonly used intervention strategies in growing pigs since several products became commercially available in 2006. While multiple trials have described the efficacy of individual PCV2 vaccines relative to non-vaccination, few studies provide product-to-product comparisons of efficacy. Given the well-documented efficacy of PCV2 vaccines, information about the comparative efficacy of available vaccines is more relevant to producers and veterinarians than comparison to non-vaccination. The objective of this study was to provide comparative estimates of changes in average daily gain effect associated with the use of the commercially available PCV2 vaccines. PubMed, CAB Abstracts, AGRICOLA, the USA Department of Agriculture Center for Veterinary Biologics database of licenses and provisions, and the proceedings of the Annual Meeting of the American Association of Swine Veterinarians, the Allen D. Leman Swine Conference, the Iowa State University Swine Disease Conference for Swine Practitioners, and the International Pig Veterinary Society Congress were used as the sources of information. Trials of licensed PCV2 vaccines administered according to manufacturers' specifications to intensively raised piglets with a known herd porcine reproductive and respiratory syndrome virus (PRRSV) status were considered relevant to the meta-analysis. Relevant studies had to report average daily gain (ADG) from weaning to finish and PCV2 infection had to be naturally occurring.

Lung clearance index: evidence for use in clinical trials in cystic fibrosis.

The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group's work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF.

Investigating the role of macrophages in tumor formation using a MaFIA mouse model.

Tumor-associated macrophages (TAMs) interact with tumors in their development, growth and metastatic activities. Using a transgenic mouse model that allows for the selective depletion of macrophages we were able to access the macrophage's potential to facilitate metastasis. In the MaFIA (Macrophage Fas-Induced Apoptosis) mouse, transgene-expressing cells of the myeloid lineage undergo death by apoptosis in the presence of the drug AP20187. Enhanced green fluorescent protein (EGFP) was fused to the suicide gene to allow identification of transgene-expressing cells. Tumor induction was accomplished by subdermal and intravenous injections of B16-F10 melanoma cells. Metastasis in mice with depleted macrophages was compared to metastasis in normal control mice. The lungs and kidneys were examined for metastatic cells. The macrophage-depleted groups showed significantly less metastasis (P>0.001) compared to the control groups. We theorize that macrophages may aid the metastatic process by fusing with melanoma cells. Using appropriate cell markers and fluorescence-activated cell sorting, we were able to detect a small population of double-positive cells. We confirmed cell fusion by microscopic analysis, visualizing the cell's morphology by both immunohistochemistry and immunofluorescence. The presence of double-positive cells suggests macrophage/cancer cell fusion could be a possible mechanism for metastasis.