Effectiveness of Helminth Therapy in the Prevention of Allograft Rejection: A Systematic Review of Allogeneic Transplantation.

Background: The unique immunomodulatory capacity of helminth parasites has been investigated as a novel strategy in the prevention of allograft rejection after transplantation. This review was conducted to fully evaluate the specific effects of helminth therapy on allograft survival reported in published studies of animal models of allogeneic transplantation. Method: Following PRISMA protocol guidelines, a literature search was conducted using PubMed, MEDLINE via OvidSP, along with additional manual searches of selected reference lists. Publications describing helminth intervention within allograft transplantation models were screened for relevance to eligibility criteria. Primary and secondary outcomes were extracted using standardized data collection tables. The SYRCLE risk of bias assessment tool was used for quality assessment. Due to heterogeneity of study designs, meta-analysis could not be performed; rather outcomes are presented as a narrative synthesis with concept mapping. This review was registered in PROSPERO with ID: CRD42018097175. Results: The literature search generated 1,443 publications, which after screening for relevance to the eligibility criteria yielded 15 publications for qualitative analysis. All 15 publications reported improvement to allograft survival as a result of helminth therapy. This prolonged allograft survival was not significantly different when helminth-derived products were used compared to live infection. However, the extent of positive impact on allograft survival was noted to be dependent on study design factors, such as the chronicity of the live helminth infection, allograft type and the species/genus of helminth selected. Conclusion: Both live and product-based helminth therapy have potential applications as novel immune regulators or adjuncts for the prevention of allograft rejection. However, there were differences in efficacy between different worms and preparations of worm-derived products. Therefore, further studies are required to determine the most appropriate worm for a specific allograft, to elucidate the optimal dose and route of administration, and to better understand the modulation of immune responses that can mediate tolerance

A bi-directional relationship between obesity and health-related quality of life : evidence from the longitudinal AusDiab study

Objective: To assess the prospective relationship between obesity and health-related quality of life, including a novel assessment of the impact of health-related quality of life on weight gain.Design and setting: Longitudinal, national, population-based Australian Diabetes, Obesity and Lifestyle (AusDiab) study, with surveys conducted in 1999/2000 and 2004/2005.Participants: A total of 5985 men and women aged 25 years at study entry.Main outcome measure(s): At both time points, height, weight and waist circumference were measured and self-report data on health-related quality of life from the SF-36 questionnaire were obtained. Cross-sectional and bi-directional, prospective associations between obesity categories and health-related quality of life were assessed.Results: Higher body mass index (BMI) at baseline was associated with deterioration in health-related quality of life over 5 years for seven of the eight health-related quality of life domains in women (all P0.01, with the exception of mental health, P&gt;0.05), and six out of eight in men (all P&lt;0.05, with the exception of role-emotional, P=0.055, and mental health, P&gt;0.05). Each of the quality-of-life domains related to mental health as well as the mental component summary were inversely associated with BMI change (all P&lt;0.0001 for women and P0.01 for men), with the exception of vitality, which was significant in women only (P=0.008). For the physical domains, change in BMI was inversely associated with baseline general health in women only (P=0.023).Conclusions: Obesity was associated with a deterioration in health-related quality of life (including both physical and mental health domains) in this cohort of Australian adults followed over 5 years. Health-related quality of life was also a predictor of weight gain over 5 years, indicating a bi-directional association between obesity and health-related quality of life. The identification of those with poor health-related quality of life may be important in assessing the risk of future weight gain, and a focus on health-related quality of life may be beneficial in weight management strategies.<br /

Randomised controlled comparison of the Health Survey Short Form (SF-12) and the Graded Chronic Pain Scale (GCPS) in telephone interviews versus self-administered questionnaires. Are the results equivalent?

<p>Abstract</p> <p>Background</p> <p>The most commonly used survey methods are self-administered questionnaires, telephone interviews, and a mixture of both. But until now evidence out of randomised controlled trials as to whether patient responses differ depending on the survey mode is lacking. Therefore this study assessed whether patient responses to surveys depend on the mode of survey administration. The comparison was between mailed, self-administered questionnaires and telephone interviews.</p> <p>Methods</p> <p>A four-armed, randomised controlled two-period change-over design. Each patient responded to the same survey twice, once in written form and once by telephone interview, separated by at least a fortnight. The study was conducted in 2003/2004 in Germany. 1087 patients taking part in the German Acupuncture Trials (GERAC cohort study), who agreed to participate in a survey after completing acupuncture treatment from an acupuncture-certified family physician for headache, were randomised. Of these, 823 (664 women) from the ages of 18 to 83 (mean 51.7) completed both parts of the study. The main outcome measure was the comparison of the scores on the 12-Item Short-Form Health Survey (SF-12) and the Graded Chronic Pain Scale (GCPS) questionnaire for the two survey modes.</p> <p>Results</p> <p>Computer-aided telephone interviews (CATI) resulted in significantly fewer missing data (0.5%) than did mailed questionnaires (2.8%; p < 0.001). The analysis of equivalence revealed a difference between the survey modes only for the SF-12 mental scales. On average, reported mental status score was 3.5 score points (2.9 to 4.0) lower on the self-administered questionnaire compared to the telephone interview. The order of administration affected results. Patients who responded to the telephone interview first reported better mental health in the subsequent paper questionnaire (mean difference 2.8 score points) compared to those who responded to the paper questionnaire first (mean difference 4.1 score points).</p> <p>Conclusion</p> <p>Despite the comparatively high cost of telephone interviews, they offer clear advantages over mailed self-administered questionnaires as regards completeness of data. Only items concerning mental status were dependent on the survey mode and sequence of administration. Items on physical status were not affected. Normative data for standardized telephone questionnaires could contribute to a better comparability with the results of the corresponding standardized paper questionnaires.</p

A population-based lifestyle intervention to promote healthy weight and physical activity in people with cardiac disease: The PANACHE (Physical Activity, Nutrition And Cardiac HEalth) study protocol

<p>Abstract</p> <p>Background</p> <p>Maintaining a healthy weight and undertaking regular physical activity are important for the secondary prevention of cardiovascular disease (CVD). However, many people with CVD are overweight and insufficiently active. In addition, in Australia only 20-30% of people requiring cardiac rehabilitation (CR) for CVD actually attend. To improve outcomes of and access to CR the efficacy, effectiveness and cost-effectiveness of alternative approaches to CR need to be established.</p> <p>This research will determine the efficacy of a telephone-delivered lifestyle intervention, promoting healthy weight and physical activity, in people with CVD in urban and rural settings. The control group will also act as a replication study of a previously proven physical activity intervention, to establish whether those findings can be repeated in different urban and rural locations. The cost-effectiveness and acceptability of the intervention to CR staff and participants will also be determined.</p> <p>Methods/Design</p> <p>This study is a randomised controlled trial. People referred for CR at two urban and two rural Australian hospitals will be invited to participate. The intervention (healthy weight) group will participate in four telephone delivered behavioural coaching and goal setting sessions over eight weeks. The coaching sessions will be on weight, nutrition and physical activity and will be supported by written materials, a pedometer and two follow-up booster telephone calls. The control (physical activity) group will participate in a six week intervention previously shown to increase physical activity, consisting of two telephone delivered behavioural coaching and goal setting sessions on physical activity, supported by written materials, a pedometer and two booster phone calls. Data will be collected at baseline, eight weeks and eight months for the intervention group (baseline, six weeks and six months for the control group). The primary outcome is weight change. Secondary outcomes include physical activity, sedentary time and nutrition habits. Costs will be compared with outcomes to determine the relative cost-effectiveness of the healthy weight and physical activity interventions.</p> <p>Discussion</p> <p>This study addresses a significant gap in public health practice by providing evidence for the efficacy and cost-effectiveness of a low cost, low contact, high reach intervention promoting healthy weight and physical activity among people with CVD in rural and urban areas in Australia. The replication arm of the study, undertaken by the control group, will demonstrate whether the findings of the previously proven physical activity intervention can be generalised to new settings. This population-based approach could potentially improve access to and outcomes of secondary prevention programs, particularly for rural or disadvantaged communities.</p> <p>Trial Registration</p> <p>ACTRN12610000102077</p

Efficacy of a multimodal physiotherapy treatment program for hip osteoarthritis: a randomised placebo-controlled trial protocol

<p>Abstract</p> <p>Background</p> <p>Hip osteoarthritis (OA) is a common condition leading to pain, disability and reduced quality of life. There is currently limited evidence to support the use of conservative, non-pharmacological treatments for hip OA. Exercise and manual therapy have both shown promise and are typically used together by physiotherapists to manage painful hip OA. The aim of this randomised controlled trial is to compare the efficacy of a physiotherapy treatment program with placebo treatment in reducing pain and improving physical function.</p> <p>Methods</p> <p>The trial will be conducted at the University of Melbourne Centre for Health, Exercise and Sports Medicine. 128 participants with hip pain greater or equal to 40/100 on visual analogue scale (VAS) and evidence of OA on x-ray will be recruited. Treatment will be provided by eight community physiotherapists in the Melbourne metropolitan region. The active physiotherapy treatment will comprise a semi-structured program of manual therapy and exercise plus education and advice. The placebo treatment will consist of sham ultrasound and the application of non-therapeutic gel. The participants and the study assessor will be blinded to the treatment allocation. Primary outcomes will be pain measured by VAS and physical function recorded on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) immediately after the 12 week intervention. Participants will also be followed up at 36 weeks post baseline.</p> <p>Conclusions</p> <p>The trial design has important strengths of reproducibility and reflecting contemporary physiotherapy practice. The findings from this randomised trial will provide evidence for the efficacy of a physiotherapy program for painful hip OA.</p> <p>Trial Registration</p> <p>Australian New Zealand Clinical Trials Registry reference: ACTRN12610000439044</p

Pig-to-Nonhuman Primates Pancreatic Islet Xenotransplantation: An Overview

The therapy of type 1 diabetes is an open challenging problem. The restoration of normoglycemia and insulin independence in immunosuppressed type 1 diabetic recipients of islet allotransplantation has shown the potential of a cell-based diabetes therapy. Even if successful, this approach poses a problem of scarce tissue supply. Xenotransplantation can be the answer to this limited donor availability and, among possible candidate tissues for xenotransplantation, porcine islets are the closest to a future clinical application. Xenotransplantation, with pigs as donors, offers the possibility of using healthy, living, and genetically modified islets from pathogen-free animals available in unlimited number of islets. Several studies in the pig-to-nonhuman primate model demonstrated the feasibility of successful preclinical islet xenotransplantation and have provided insights into the critical events and possible mechanisms of immune recognition and rejection of xenogeneic islet grafts. Particularly promising results in the achievement of prolonged insulin independence were obtained with newly developed, genetically modified pigs islets able to produce immunoregulatory products, using different implantation sites, and new immunotherapeutic strategies. Nonetheless, further efforts are needed to generate additional safety and efficacy data in nonhuman primate models to safely translate these findings into the clinic

The Effects of Herbivory by a Mega- and Mesoherbivore on Tree Recruitment in Sand Forest, South Africa

Herbivory by megaherbivores on woody vegetation in general is well documented; however studies focusing on the individual browsing effects of both mega- and mesoherbivore species on recruitment are scarce. We determined these effects for elephant Loxodonta africana and nyala Tragelaphus angasii in the critically endangered Sand Forest, which is restricted to east southern Africa, and is conserved mainly in small reserves with high herbivore densities. Replicated experimental treatments (400 m2) in a single forest patch were used to exclude elephant, or both elephant and nyala. In each treatment, all woody individuals were identified to species and number of stems, diameter and height were recorded. Results of changes after two years are presented. Individual tree and stem densities had increased in absence of nyala and elephant. Seedling recruitment (based on height and diameter) was inhibited by nyala, and by elephant and nyala in combination, thereby preventing recruitment into the sapling stage. Neither nyala or elephant significantly reduced sapling densities. Excluding both elephant and nyala in combination enhanced recruitment of woody species, as seedling densities increased, indicating that forest regeneration is impacted by both mega- and mesoherbivores. The Sand Forest tree community approached an inverse J-shaped curve, with the highest abundance in the smaller size classes. However, the larger characteristic tree species in particular, such as Newtonia hildebrandtii, were missing cohorts in the middle size classes. When setting management goals to conserve habitats of key importance, conservation management plans need to consider the total herbivore assemblage present and the resulting browsing effects on vegetation. Especially in Africa, where the broadest suite of megaherbivores still persists, and which is currently dealing with the ‘elephant problem’, the individual effects of different herbivore species on recruitment and dynamics of forests and woodlands are important issues which need conclusive answers

Links Between Hydrothermal Environments, Pyrophosphate, Na+, and Early Evolution

The discovery that photosynthetic bacterial membrane-bound inorganic pyrophosphatase (PPase) catalyzed light-induced phosphorylation of orthophosphate (Pi) to pyrophosphate (PPi) and the capability of PPi to drive energy requiring dark reactions supported PPi as a possible early alternative to ATP. Like the proton-pumping ATPase, the corresponding membrane-bound PPase also is a H+-pump, and like the Na+-pumping ATPase, it can be a Na+-pump, both in archaeal and bacterial membranes. We suggest that PPi and Na+ transport preceded ATP and H+ transport in association with geochemistry of the Earth at the time of the origin and early evolution of life. Life may have started in connection with early plate tectonic processes coupled to alkaline hydrothermal activity. A hydrothermal environment in which Na+ is abundant exists in sediment-starved subduction zones, like the Mariana forearc in the W Pacific Ocean. It is considered to mimic the Archean Earth. The forearc pore fluids have a pH up to 12.6, a Na+-concentration of 0.7 mol/kg seawater. PPi could have been formed during early subduction of oceanic lithosphere by dehydration of protonated orthophosphates. A key to PPi formation in these geological environments is a low local activity of water

Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P = 0.005 and P = 0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohn’s disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.