Health Research Partnership Research Articles

Who is telling the story? A systematic review of authorship for infectious disease research conducted in Africa, 1980–2016

IntroductionAfrica contributes little to the biomedical literature despite its high burden of infectious diseases. Global health research partnerships aimed at addressing Africa-endemic disease may be polarised. Therefore, we assessed the...

Levothyroxine to increase live births in euthyroid women with thyroid antibodies trying to conceive: the TABLET RCT

Background Thyroid autoantibodies, specifically thyroid peroxidase antibodies, have been associated with miscarriage and pre-term birth in women with a normal thyroid function. Small randomised controlled trials have found that treatment with levothyroxine may reduce such adverse outcomes in pregnancy. Objectives The Thyroid AntiBodies and LEvoThyroxine (TABLET) trial was conducted to explore the effects of levothyroxine in euthyroid women with thyroid peroxidase antibodies. A concurrent mechanistic study was conducted to examine the effect of levothyroxine on immune responses. Design This was a randomised, double-blind, placebo-controlled, multicentre study. Setting The TABLET trial was conducted in 49 hospitals across the UK between 2011 and 2016. Participants Euthyroid women who tested positive for thyroid peroxidase antibodies, were aged between 16 and 41 years and were trying to conceive either naturally or through assisted conception were eligible. Intervention Participants were randomised to levothyroxine at a dose of 50 µg daily or placebo. The intervention was commenced preconception and continued until the end of a pregnancy. Women were given a 12-month period to conceive from randomisation. Main outcome measures The primary outcome was live birth at ≥ 34 completed weeks of gestation. The secondary outcomes included miscarriage at < 24 weeks; clinical pregnancy at 7 weeks; ongoing pregnancy at 12 weeks; gestation at delivery; birthweight; appearance, pulse, grimace, activity and respiration (Apgar) scores; congenital abnormalities; and neonatal survival at 28 days of life. Methods Participants were randomised in a 1 : 1 ratio. Minimisation was implemented for age (< 35 or ≥ 35 years), number of previous miscarriages (0, 1 or 2, ≥ 3), infertility treatment (yes/no) and baseline thyroid-stimulating hormone concentration (≤ 2.5 or > 2.5 mlU/l) to achieve balanced trial arms. Women were followed up every 3 months while trying to conceive to check thyroid function and general well-being, and, once pregnant, were seen each trimester: 6–8 weeks, 16–18 weeks and 28 weeks. Any abnormal thyroid results were managed in line with clinical guidance at the time. Results Of the 19,556 women screened, 1420 women were eligible and 952 were randomised to receive levothyroxine (n = 476) or placebo (n = 476). Six women from each arm either were lost to follow-up or withdrew from the trial. A total 540 women became pregnant: 266 in the levothyroxine arm and 274 in the placebo arm. The live birth rate was 37% (176/470) in the levothyroxine group and 38% (178/470) in the placebo group, translating to a relative risk of 0.97 (95% confidence interval 0.83 to 1.14; p = 0.74) and an absolute risk difference of –0.4% (95% confidence interval –6.6% to 5.8%). A subset of 49 trial participants (26 in the levothyroxine arm and 23 in the placebo arm) were recruited to assess changes in their serum chemocytokine concentrations. Treatment with levothyroxine resulted in some changes in chemocytokine concentrations in the non-pregnant state and in early pregnancy, but these had no association with clinical outcome. Conclusions Levothyroxine therapy in a dose of 50 µg per day does not improve live birth rate in euthyroid women with thyroid peroxidase antibodies. Limitations Titration of the levothyroxine dose based on thyroid-stimulating hormone/thyroid peroxidase concentrations was not explored. Future work Future research could explore the efficacy of levothyroxine administered for the treatment of subclinical hypothyroidism. Trial registration Current Controlled Trials ISRCTN15948785 and EudraCT 2011-000719-19. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

To Succeed, One Health Must Win Animal Agriculture's Stronger Collaboration.

The One Health approach has received widespread international endorsements from professional, academic, and governmental organizations as the way forward in tackling complex interdisciplinary problems, such as emerging zoonotic diseases, antimicrobial resistance, and food safety. Yet conspicuously absent from US One Health training or research activities are the animal agricultural industries. Their absence is likely due to multiple factors, including the lack of appreciation for their potential problem-solving roles, as well as the industries' business-oriented fears that such engagement could cause them to suffer economic damage. As demands on the swine, poultry, egg, beef, and dairy production industries are closely linked to the above-mentioned complex problems, we must find new, nonthreatening ways to better engage and win animal agriculture's collaboration into One Health training and research partnerships for successful health problem solving. Without animal agricultural industries' improved cooperation, One Health's efforts to control these complex problems are not likely to succeed.

Robotic-assisted surgery compared with laparoscopic resection surgery for rectal cancer: the ROLARR RCT

Background Robotic rectal cancer surgery is gaining popularity, but there are limited data about its safety and efficacy. Objective To undertake an evaluation of robotic compared with laparoscopic rectal cancer surgery to determine its safety, efficacy and cost-effectiveness. Design This was a multicentre, randomised trial comparing robotic with laparoscopic rectal resection in patients with rectal adenocarcinoma. Setting The study was conducted at 26 sites across 10 countries and involved 40 surgeons. Participants The study involved 471 patients with rectal adenocarcinoma. Recruitment took place from 7 January 2011 to 30 September 2014 with final follow-up on 16 June 2015. Interventions Robotic and laparoscopic rectal cancer resections were performed by high anterior resection, low anterior resection or abdominoperineal resection. There were 237 patients randomised to robotic and 234 to laparoscopic surgery. Follow-up was at 30 days, at 6 months and annually until 3 years after surgery. Main outcome measures The primary outcome was conversion to laparotomy. Secondary end points included intra- and postoperative complications, pathological outcomes, quality of life (QoL) [measured using the Short Form questionnaire-36 items version 2 (SF-36v2) and the Multidimensional Fatigue Inventory-20 (MFI-20)], bladder and sexual dysfunction [measured using the International Prostatic Symptom Score (I-PSS), the International Index of Erectile Function (IIEF) and the Female Sexual Function Index (FSFI)], and oncological outcomes. An economic evaluation considered the costs of robotic and laparoscopic surgery, including primary and secondary care costs up to 6 months post operation. Results Among 471 randomised patients [mean age 64.9 years, standard deviation (SD) 11.0 years; 320 (67.9%) men], 466 (98.9%) patients completed the study. Data were analysed on an intention-to-treat basis. The overall rate of conversion to laparotomy was 10.1% and occurred in 19 (8.1%) patients in the robotic-assisted group and in 28 (12.2%) patients in the conventional laparoscopic group {unadjusted risk difference 4.12% [95% confidence interval (CI) –1.35% to 9.59%], adjusted odds ratio 0.61 [95% CI 0.31 to –1.21]; p = 0.16}. Of the nine prespecified secondary end points, including circumferential resection margin positivity, intraoperative complications, postoperative complications, plane of surgery, 30-day mortality and bladder and sexual dysfunction, none showed a statistically significant difference between the groups. No difference between the treatment groups was observed for longer-term outcomes, disease-free and overall survival (OS). Males were at a greater risk of local recurrence than females and had worse OS rates. The costs of robotic and laparoscopic surgery, excluding capital costs, were £11,853 (SD £2940) and £10,874 (SD £2676) respectively. Conclusions There is insufficient evidence to conclude that robotic rectal surgery compared with laparoscopic rectal surgery reduces the risk of conversion to laparotomy. There were no statistically significant differences in resection margin positivity, complication rates or QoL at 6 months between the treatment groups. Robotic rectal cancer surgery was on average £980 more expensive than laparoscopic surgery, even when the acquisition and maintenance costs for the robot were excluded. Future work The lower rate of conversion to laparotomy in males undergoing robotic rectal cancer surgery deserves further investigation. The introduction of new robotic systems into the market may alter the cost-effectiveness of robotic rectal cancer surgery. Trial registration Current Controlled Trials ISRCTN80500123. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, with contributions from the Chief Scientist Office, Scottish Government Health and Social Care Directorate, the Health and Care Research Wales and the Health and Social Care Research and Development Division, Public Health Agency in Northern Ireland. The funders of the study had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript or the decision to submit for publication. The project will be published in full in Efficacy and Mechanism Evaluation; Vol. 6, No. 10. See the NIHR Journals Library website for further project information. Philip Quirke and Nicholas West were supported by Yorkshire Cancer Research Campaign and the MRC Bioinformatics initiative. David Jayne was supported by a NIHR Research Professorship.

Introduction to the Issue on Equity, Collaboration, and Empowerment in Mental Health Research Partnerships

Introduction to the Issue on Equity, Collaboration, and Empowerment in Mental Health Research Partnerships

Improving Research and Practice: Priorities for Young Adults with Intellectual/Developmental Disabilities and Mental Health Needs

ABSTRACT Introduction: The Intellectual and Developmental Disability Mental Health (IDD-MH) Research Partnership was created to learn about the experiences and needs of young adults with IDD-MH while accessing and using mental health services. Our national partnership consists of six young adults, five professionals, researchers at Boston University, and representatives from Self Advocates Becoming Empowered and The Arc of the United States. Our partnership worked together virtually for one year. Methods: We designed and conducted a web survey with young adults with IDD-MH ages 18–30 living in the United States (n = 76). We also completed four national storytelling sessions (1 in person, 3 virtual) that included young adults with IDD-MH (n = 10) and parents of young adults with IDD-MH (n = 6). Results: We identified eight priority topic areas for young adults with IDD-MH: Transition to Adulthood, Insurance & Financial Resources, Professionals’ Competence, Understanding the Experiences of People who Communicate Differently, Hospitalization, Medication, Alternatives to Medication, and Social Supports. Conclusions: Using what we learned, we generated recommendations to advance research and practice in areas important to young adults with IDD-MH. These recommendations highlight the importance of community-based options, choice, autonomy, and control for young adults with IDD-MH.

Very low-dose dexamethasone to facilitate extubation of preterm babies at risk of bronchopulmonary dysplasia: the MINIDEX feasibility RCT

BackgroundPostnatal corticosteroids are used to improve lung function and reduce the incidence of bronchopulmonary dysplasia (BPD) in preterm babies. However, corticosteroids may be associated with adverse neurodevelopment. Despite a lack of evidence, some clinicians in the UK use very low-dose regimens of dexamethasone hoping for positive pulmonary effects and optimal neurodevelopment.ObjectivesTo assess the efficacy and safety of very low-dose dexamethasone at facilitating the extubation of ventilator-dependent preterm babies born at < 30 weeks’ gestation and who are at high risk of developing BPD.DesignA multicentre, randomised, masked, parallel-group, placebo-controlled Phase 2b trial. The trial was designed as a feasibility study for a subsequent trial of clinical effectiveness.SettingThe study was set in 11 tertiary neonatal units in the UK.ParticipantsVentilator-dependent preterm babies born at < 30 weeks’ gestation aged 10–21 days, receiving at least 30% inspired oxygen and at high risk of developing BPD. Exclusions were babies who had received previous courses of postnatal steroids for respiratory disease; had a severe congenital anomaly affecting the lungs, heart or central nervous system, or had a surgical abdominal procedure or patent ductus arteriosus ligation; and had an illness or medication for which postnatal corticosteroid would be contraindicated (e.g. confirmed or suspected acute sepsis, acute necrotising enterocolitis/focal intestinal perforation or cyclo-oxygenase therapy).InterventionsBabies were randomised to very low-dose dexamethasone (50 µg/kg/day for 13 doses) or a matched placebo. Samples of blood and bronchoalveolar lavage fluid from a subset of babies randomised at three participating sites were sent for cytokine analysis at randomisation and at days 5, 7, 10 and 14 of treatment.Primary outcomeTime to extubation.Secondary outcomesSecondary outcomes included rates of extubation by day 7 of the intervention; survival to 36 weeks’ postmenstrual age (PMA) or discharge home; respiratory morbidity to 36 weeks’ PMA or discharge home; cytokine profile; safety outcomes; and parent/family experience.ResultsThe main metric of feasibility, namely recruitment, proved difficult. There was a tendency for open-label medication and a higher than predicted rate of suspected/confirmed sepsis among babies. Recruitment was halted after 22 babies had been enrolled. It was found that, compared with the placebo group, a higher proportion of babies were extubated at day 7 of life [5/8 (62.5%) in the very low-dose dexamethasone group vs. 2/6 (33.3%) in the placebo group] and duration of invasive ventilation was lower (a median of 23 days for the very low-dose dexamethasone group vs. a median of 31 days for the placebo group) in the very low-dose dexamethasone group. This is supported by a trend for an increased requirement for open-label rescue steroids in control group babies (41.7% in the very low-dose dexamethasone group vs. 80% in the placebo group). Given the limited sample size, only descriptive statistics can be given; firm conclusions cannot be drawn.LimitationsSmall sample size and high rates of open-label treatment use.ConclusionsIt is not feasible to conduct the required pragmatic trial of clinical effectiveness.Future workAssessment of very low-dose dexamethasone in this patient group requires careful consideration.Study registrationClinical Controlled Trials ISRCTN81191607.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. The report will be published in full inEfficacy and Mechanism; Vol. 6, No. 8. See the NIHR Journals Library website for further project information. The funding for the cytokine analysis is provided by the Children’s Charity Cerebra and is being carried out beyond the lifespan of the NIHR funding.

Minocycline for negative symptoms of schizophrenia and possible mechanistic actions: the BeneMin RCT

Background In a previous trial we reported that the neuroprotective, anti-inflammatory antibiotic minocycline lessened the negative symptoms of schizophrenia compared with placebo over 1 year. The BeneMin study aimed to replicate this benefit and to determine whether or not there was associated preservation of grey matter, reduction in circulating inflammatory cytokines and enhancement of cognition. Objectives To determine the efficacy of minocycline on the negative symptoms of schizophrenia and the mechanistic role of neuroprotective, anti-inflammatory and cognitive enhancing actions. Methods Two hundred and seven patients with a current research diagnosis of schizophrenia within 5 years of onset were randomised by a permuted blocks algorithm to minocycline (300 mg/day) or matching placebo as an adjunct to their continuing treatment. The primary efficacy outcome variable was the negative symptom subscale score from the Positive and Negative Syndrome Scales at 2, 6, 9 and 12 months. The primary mechanistic (biomarker) variables were (1) medial prefrontal grey matter volume (GMV), (2) circulating cytokine interleukin (IL) 6 concentration and (3) dorsolateral prefrontal cortex functional magnetic resonance imaging (fMRI) activations during performance of the N-back task. Movement disorder, side effects and treatment adherence were monitored throughout the study. Results Compared with placebo, the addition of minocycline had no effect on the severity of negative symptoms [treatment effect difference –0.186, 95% confidence interval (CI) –1.225 to 0.854] across the 2-, 6-, 9- and 12-month follow-up visits. None of the mechanistic biomarkers was influenced by minocycline: left GMV –91.2 (95% CI –303.8 to 121.4), IL-6 0.072 (95% CI –0.118 to 0.262) and N-back fMRI 0.66 (95% CI –1.53 to 0.20). There were no statistically significant treatment effects on any of the secondary outcomes and no group differences at baseline. Most measures were stable over the 12 months. Twenty-five out of the 29 serious adverse events were hospital admission for worsening psychiatric state, which affected 10 minocycline-treated participants and six placebo-treated participants. Main outcome measures The addition of minocycline to standard treatment had no benefit on the symptoms of schizophrenia in this early phase sample. There was no evidence of a progressive neuropathic or inflammatory process affecting GMV. Limitations Although recruitment to target was achieved on time, only 43% (n = 89) of the 207 randomised patients completed 12 months of the study. However, 83% of those who started treatment remained on it and were assessed over 6 months. By contrast, no follow-up data were available for the cognitive and imaging markers in those who dropped out before the final 12-month assessments, and this reduced the power to detect treatment effects on these mechanistic variables. Patients were not selected for the presence of negative symptoms, and their initial overall psychopathology was, at most, moderate and, therefore, less likely to show treatment effects. Conclusions The results of the study do not support the use of adjunctive minocycline for the treatment of negative or other symptoms of schizophrenia within 2–5 years of onset. More secure evidence of central inflammation is needed before further trials are conducted at other stages of psychosis. Trial registration Current Controlled Trials ISRCTN49141214. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research partnership. The study was sponsored by Greater Manchester Mental Health NHS Foundation Trust and supported by the UK Clinical Research Network.

Oral morphine analgesia for preventing pain during invasive procedures in non-ventilated premature infants in hospital: the Poppi RCT

Background Identifying better pain management strategies for painful procedures performed in neonatal care is a clinical priority. Retinopathy of prematurity screening and heel-lance blood tests are essential clinical procedures, but adequate pain relief is not currently provided because of a lack of evidence-based analgesia. Morphine provides effective analgesia in older children and adults, but efficacy in infants is controversial. Morphine is, however, commonly used intravenously for sedation in ventilated infants. Objective The primary objective was to investigate whether or not a single 100 µg/kg morphine sulphate dose administered orally prior to painful clinical procedures provides effective analgesia. Design Single-centre, prospective, randomised controlled trial. Setting John Radcliffe Hospital, Oxford, UK. Participants Thirty-one infants of 34–42 weeks’ gestational age, requiring a heel lance and retinopathy of prematurity screening on the same test occasion. Interventions The study interventions were 100 µg/kg of oral morphine sulphate (intervention arm) or placebo (control arm) 1 hour before the clinically required procedures. Main outcome measures There were two co-primary outcomes: Premature Infant Pain Profile-Revised score (a higher score implies more nociceptive processing) during the 30-second period after retinopathy of prematurity screening, and the magnitude of noxious-evoked brain activity (a higher activity implies more nociceptive processing) following the heel lance. Physiological stability and safety were secondary outcomes. Results After 31 participants were randomised (30 studied and one withdrew), the predefined safety stopping boundary was passed as 3 of the 15 infants who received morphine had apnoeas requiring resuscitation with non-invasive positive-pressure ventilation in the 24 hours after drug administration, compared with 0 of the 15 infants who received placebo [difference in proportion 0.2, 80% confidence interval (adjusted to allow for planned multiple analyses) 0.05 to 1.00; p = 0.085]. The trial was therefore stopped because of profound respiratory adverse effects of morphine without suggestion of analgesic efficacy. There was no significant difference between the trial arms for either primary outcome (Premature Infant Profile-Revised score following retinopathy of prematurity screening mean score ± standard deviation – morphine: 11.1 ± 3.2; Premature Infant Pain Profile-Revised score following retinopathy of prematurity screening mean score ± standard deviation – placebo: 10.5 ± 3.4; mean difference in Premature Infant Pain Profile-Revised score following retinopathy of prematurity screening score 0.5, 95% confidence interval –2.0 to 3.0, p = 0.66; noxious-evoked brain activity following heel lancing median activity – morphine: 0.99, interquartile range 0.40–1.56; noxious-evoked brain activity following heel lancing median activity – placebo: 0.75, interquartile range 0.33–1.22; and median difference in noxious-evoked brain activity following heel lancing 0.25, 95% confidence interval –0.16 to 0.80, p = 0.25). Limitations The trial lacked power for the primary outcome measures because of early cessation. However, there was a trend across modalities favouring placebo, suggesting that it was unlikely that a clinically significant analgesic benefit would have been detected in the original proposed sample of 156 infants. Conclusions The administration of 100 µg/kg of oral morphine to non-ventilated premature infants has the potential for harm without analgesic benefit. Oral morphine is not recommended for retinopathy of prematurity screening, and caution is strongly advised if this is being considering for other acute painful procedures in non-ventilated premature infants. Future work Further clinical trials are essential to ascertain effective pain management for retinopathy of prematurity screening. Using multimodal measures with detailed physiological recordings provides a rigorous approach to assess analgesic efficacy and adverse effects, leading to greater mechanistic understanding of the drug effects. This is essential in future clinical trials of analgesics in infants. Patient and public involvement The research team worked closely with an on-site charity during the trial design, conduct, oversight and dissemination. Trial registration Clinical Controlled Trials ISRCTN82342359; EudraCT 2014-003237-25. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership. Funding was also received for the trial from the Wellcome Trust (reference numbers 095802 and 102076). The report will be published in full in Efficacy and Mechanism; Vol. 6, No. 9. See the National Institute for Health Research’s Journals Library website for further project information.

SUN-341 RESPECTFUL ENGAGEMENT OF INDIGENOUS PEOPLES IN A PAN-CANADIAN KIDNEY RESEARCH NETWORK

Kidney disease has a strong and disproportionate impact on the health of Indigenous communities in Canada. Therefore, a national strategy to improve kidney health must include meaningful, culturally appropriate engagement with Indigenous peoples. The Can-SOLVE CKD Network is a pan-Canadian patient-oriented kidney research initiative that is working to improve the health of all Canadians and bring Indigenous ways of knowing into health research. As part of the Can-SOLVE CKD Network, Indigenous patients, caregivers, researchers, and community leaders created an Indigenous Peoples’ Engagement and Research Council (IPERC). This council sits at the centre of the network and supports collaboration grounded in traditional values and partnerships with Indigenous peoples and communities. Using an ethical framework that encompasses the principles of ownership, control, access and possession and the elements of participatory research, IPERC is mandated to guide Can-SOLVE CKD research projects in respectful engagement of Indigenous communities. A key component of this work is the creation of a new training pathway, Wabishki Bizhiko Skaanj (“White Horse” in Anishinaabe), that will help researchers and patient partners build respectful partnerships with Indigenous peoples in health research. Wabishki Bizhiko Skaanj aims to enhance researchers’ knowledge of racial biases, Indigenous voices and stories, the impact of colonization, and culturally safe health research practices. Its objectives are closely aligned with those of the Can-SOLVE CKD Network. Participants are encouraged to look, listen, learn, and lead their way along the pathway by examining racial identities, privileges, and biases, as well as participating in interactive learning exercises, facilitated online modules and webinars. The Wabishki Bizhiko Skaanj learning pathway includes a focus on Indigenous Elders in research, including the role of Elders and how to foster meaningful and reciprocal relationships between researchers and Indigenous Elders/Knowledge Keepers. This training aims to create a culturally safe space for researchers, patients, and Elders to come together to gain understanding of a holistic context for scientific observations. Can-SOLVE CKD has created a culturally safe space for Indigenous individuals to participate in all aspects of patient-oriented kidney research. Through IPERC, the network has instituted guidelines on ceremony and Elder participation that ensure recognition of traditional knowledge and territories. Wabishki Bizhiko Skaanj represents a novel learning platform for Indigenous cultural safety in Canadian health research. By enhancing knowledge, self-awareness and strengthening cultural competency, this learning pathway is enabling all partners in health research to ultimately close the gaps in kidney health outcomes between Indigenous and non-Indigenous communities. Feedback from a pilot of the components has been very positive. The Can-SOLVE CKD Network offers a model for respectful engagement of Indigenous communities in health research. By adopting Indigenous ways of knowing and fostering cultural competency, the network is working to enhance kidney health outcomes and overall wellness for and with Indigenous peoples and communities across Canada.

Telmisartan to reduce insulin resistance in HIV-positive individuals on combination antiretroviral therapy: the TAILoR dose-ranging Phase II RCT

BackgroundCombination antiretroviral therapy (cART) is the standard for human immunodeficiency virus (HIV) infection treatment but can result in metabolic abnormalities, such as insulin resistance, dyslipidaemia and lipodystrophy, which can increase the risk of cardiovascular disease.ObjectiveThe objective of the trial was to evaluate whether or not telmisartan, an angiotensin II receptor antagonist and a peroxisome proliferator-activated receptor-γ partial agonist, could reduce insulin resistance in HIV-positive individuals on cART, and affect blood and imaging biomarkers of cardiometabolic disease.DesignA Phase II, multicentre, randomised, open-labelled, dose-ranging trial of telmisartan over a period of 48 weeks with an adaptive design comprising two stages was used to identify the optimal dose of telmisartan. Participants were randomised to receive one of the three doses of telmisartan (20, 40 and 80 mg) or no intervention (control).SettingRecruitment was from 19 HIV specialist centres in the UK.ParticipantsA total of 377 patients infected with HIV who met the prespecified inclusion/exclusion criteria.Interventions20-, 40- and 80-mg tablets of telmisartan.Main outcome measuresThe primary outcome measure was reduction in the homeostatic model assessment of insulin resistance (HOMA-IR), a marker of insulin resistance, at 24 weeks. Secondary outcome measures were changes in plasma lipid profile; Quantitative Insulin Sensitivity Check Index (QUICKI) and revised QUICKI, alternative markers of insulin resistance, plasma adipokines (adiponectin, leptin, interleukin 8, tumour necrosis factor alpha, resistin); high-sensitivity C-reactive protein (hs-CRP); body fat redistribution, as measured by magnetic resonance imaging/proton magnetic resonance spectroscopy; changes in renal markers (albumin-to-creatinine ratio, neutrophil gelatinase-associated lipocalin); and tolerability to telmisartan.ResultsAt the interim analysis, 80 mg of telmisartan was taken forward into the second stage of the study. Baseline characteristics were balanced across treatment arms. There were no differences in HOMA-IR [0.007, standard error (SE) 0.106], QUICKI (0.001, SE 0.001) and revised QUICKI (0.002, SE 0.002) at 24 weeks between the telmisartan (80 mg;n = 106) and non-intervention (n = 105) arms. Longitudinal analysis over 48 weeks showed that there was no change in HOMA-IR, lipid or adipokine levels; however, but there were significant, but marginal, improvements in revised QUICKI [0.004, 95% confidence interval (CI) 0.000 to 0.008] and plasma hs-CRP (–0.222, 95% CI –0.433 to –0.011) over 48 weeks. Substudies also showed a significant reduction in the liver fat content at 24 weeks (1.714, 95% CI –2.787 to –0.642;p = 0.005) and urinary albumin excretion at 48 weeks (–0.665, 95% CI –1.31 to –0.019;p = 0.04). There were no differences in serious adverse events between the telmisartan and control arms.LimitationsThe patients had modest elevations of HOMA-IR at baseline, and our trial could have been under-powered to detect smaller improvements in insulin resistance over time.ConclusionsUsing a novel adaptive design, we demonstrated that there was no significant effect of telmisartan (80 mg) on the primary outcome measure of HOMA-IR and some secondary outcomes (plasma lipids and adipokines). Telmisartan did lead to favourable, and biologically plausible, changes of the secondary longitudinal outcome measures: revised QUICKI, hs-CRP, hepatic fat accumulation and urinary albumin excretion. Taken collectively, our findings showed that telmisartan did not reduce insulin resistance in patients infected with HIV on antiretrovirals.Future workThe mechanistic basis of adipocyte regulation will be studied to allow for development of biomarkers and interventions.Trial registrationCurrent Controlled Trials ISRCTN51069819.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership.

Dopamine Augmented Rehabilitation in Stroke (DARS): a multicentre double-blind, randomised controlled trial of co-careldopa compared with placebo, in addition to routine NHS occupational and physical therapy, delivered early after stroke on functional recovery

Background Dopamine is a key modulator of striatal function and learning, and may improve motor recovery after stroke. Seven small trials of dopamine agonists after stroke have provided equivocal evidence of the clinical effectiveness of dopamine agonists in improving motor recovery. Design Dopamine Augmented Rehabilitation in Stroke was a multicentre, randomised, double-blind, placebo-controlled trial with stroke patients randomised to receive 6 weeks of co-careldopa (Sinemet®, Merck Sharp & Dohme Ltd) or placebo in combination with occupational and physical rehabilitation. Methods The primary outcome measure was the proportion of patients walking independently at 8 weeks [Rivermead Mobility Index (RMI) score of ≥ 7 points and ‘yes’ to item 7 on the RMI]. Secondary outcome measures assessed physical functioning, pain, cognition, mood, fatigue and carer burden at 8 weeks, 6 months and 12 months. Results Between May 2011 and March 2014, 593 patients (mean age 68.5 years) and 165 carers (mean age 59.7 years) were recruited from stroke rehabilitation units; 308 patients were randomised to co-careldopa and 285 to placebo at a median of 15 days following stroke onset. The study drug was to be taken 45–60 minutes before therapy, which included motor activities (mean 23.2 and 24.8 sessions in the co-careldopa and placebo groups, respectively). The mean number of investigational medicinal product doses taken was 20.6 in the co-careldopa group and 22.4 in the placebo group. Ability to walk independently was not improved at 8 weeks [40.6% (co-careldopa) vs. 44.6% (placebo); odds ratio 0.78, 95% confidence interval (CI) 0.53 to 1.15], 6 months [51.6% (co-careldopa) vs. 53.3% (placebo)] or 12 months [51.6% (co-careldopa) vs. 56.8% (placebo)]. There were no significant differences for Barthel Index, Nottingham Extended Activities of Daily Living, ABILHAND Manual Ability Measure or Modified Rankin Scale, pain or fatigue at any time point. Montreal Cognitive Assessment scores did not significantly differ; the majority of participants had cognitive impairment at baseline, which improved during 12 months’ follow-up. No difference was observed in General Health Questionnaire 12-item version scores between groups at 8 weeks and 12 months but, at 6 months, those in the co-careldopa group reported significantly better general health [mean difference (MD) –1.33, 95% CI –2.57 to –0.10]. Mortality at 12 months was not significantly different. Carers in the placebo group reported significantly greater burden at 6 months (MD 5.05, 95% CI 0.10 to 10.01) and 12 months (MD 7.52, 95% CI 1.87 to 13.18). Conclusion Co-careldopa in addition to routine NHS occupational and physical therapy is not clinically effective or cost-effective in improving walking, physical functioning, mood or cognition following stroke. We recommend further research to develop imaging and clinical markers that would allow identification of promising drug therapies that would enhance motor therapy in improving walking ability and arm function. Further research is needed to compare strategies of giving drug therapy intermittently immediately prior to therapy sessions or as continuous background daily administration. Limitations In total, 10.3% of patients were lost to follow-up at 8 weeks and < 10% of patients met the strict per-protocol definition. Despite this, the findings are robust and generalisable to patients with limited mobility in the first few weeks after stroke. Trial registration Current Controlled Trials ISRCTN99643613. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

Enabling Greater Private Sector Participation in Health Research in the Philippines

Objective. This study reviewed the current health research and development environment in the Philippines with respect to the engagement between the public and private sectors. The overall objective was to identify the role of the private sector in health research and identify barriers and opportunities for successful public-private health research partnerships.
 Methods. Key informant interviews were conducted using a semi-structured interview tool. Secondary data such as annual reports and project funding documents from the Philippine Council for Health Research and Development were also analyzed.
 Results. The roles of the private sector when engaging with the public sector for research and development were identified as generators, funders, and adopters of research. Information gathered showed that there were several institutional and practice barriers to the successful collaboration of the public and private sectors, however there were also lessons learned from the successes of cases such as the Axis-Knee System, Sambong, and Lagundi technologies.
 Conclusion. The collaboration and partnership of the public and private sectors can be mutually beneficial. Government initiative to increase the ease of collaboration with the private sector in health research was found to be a necessary step to stimulate a productive health research environment.

Developing and applying a framework to understand mechanisms of action in group-based, behaviour change interventions: the MAGI mixed-methods study

Background Theories and meta-analyses have elucidated individual-level mechanisms of action in behaviour change interventions. Although group-based interventions are commonly used to support health-related behaviour change, such interventions rarely consider theory and research (e.g. from social psychology) on how group-level mechanisms can also influence personal change. Objectives The aim was to enhance understanding of mechanisms of action in group-based behaviour change interventions. The objectives were to (1) develop a potentially generalisable framework of change processes in groups, (2) test the framework by analysing group session recordings to identify examples illustrating group processes and facilitation techniques and (3) explore links between group-level mechanisms and outcomes. Data sources In this mixed-methods study, the research team reviewed literature, conducted consultations and analysed secondary data (i.e. delivery materials and 46 audio-recordings of group sessions) from three group-based weight loss interventions targeting diet and physical activity: ‘Living Well Taking Control’ (LWTC), ‘Skills for weight loss Maintenance’ and ‘Waste the Waist’. Quantitative LWTC programme data on participant characteristics, attendance and outcomes (primarily weight loss) were also used. Methods Objectives were addressed in three stages. In stage 1, a framework of change processes in groups was developed by reviewing literature on groups (including theories, taxonomies of types of change techniques, qualitative studies and measures of group processes), analysing transcripts of 10 diverse group sessions and consulting with four group participants, four facilitators and 31 researchers. In stage 2, the framework was applied in analysing 28 further group sessions. In stage 3, group-level descriptive analyses of available quantitative data from 67 groups and in-depth qualitative analyses of two groups for which comprehensive quantitative and qualitative data were available were conducted to illustrate mixed-methods approaches for exploring links between group processes and outcomes. Results Stage 1 resulted in development of the ‘Mechanisms of Action in Group-based Interventions’ (MAGI) framework and definitions, encompassing group intervention design features, facilitation techniques, group dynamic and development processes, interpersonal change processes, selective intrapersonal change processes operating in groups, and contextual factors. In stage 2, a coding schema was developed, refined and applied to identify examples of framework components in group sessions, confirming the content validity of the framework for weight loss interventions. Stage 3 demonstrated considerable variability in group characteristics and outcomes and illustrated how the framework could be applied in integrating group-level qualitative and quantitative data to generate and test hypotheses about links between group mechanisms and outcomes (e.g. to identify features of more or less successful groups). Limitations The framework and examples were primarily derived from research on weight loss interventions, and may require adaptations/additions to ensure applicability to other types of groups. The mixed-methods analyses were limited by the availability and quality of the secondary data. Conclusions This study identified, defined, categorised into a framework and provided examples of group-level mechanisms that may influence behaviour change. Future work The framework and mixed-methods approaches developed provide a resource for designers, facilitators and evaluators to underpin future research on, and delivery of, group-based interventions. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

Advances, Challenges and Opportunities for Integrative Health Research Partnerships in Latin America and the Caribbean

Advances, Challenges and Opportunities for Integrative Health Research Partnerships in Latin America and the Caribbean

OC 8360 GLOBAL HEALTH RESEARCH AND ITS ROLE IN IMPROVING HEALTH AND HEALTH EQUITY IN AFRICA

BackgroundHealth research has the potential to generate knowledge that may be used to improve health and health equity. This has led to calls for African governments to dedicate at least 2% of their national budgets to heath research, but such resource allocations have never been achieved. Rather, most of health research in Africa continues to be funded by high-income countries (HICs) and involves collaborative partnerships between researchers in high-income countries and those in Africa. These research partnerships have many benefits, but they also raise ethical issues related to justice and fairness in global health research.MethodsThe ‘Research for Health Justice Framework’ makes recommendations on how global health research partnerships may foster the ideals of justice through their selection of research populations and questions, research capacity strengthening, delivery of ancillary care and the provision of post-trial benefits. We applied these criteria to collaborative genomics research consortia in Africa (an example of global health research in Africa).ResultsThe results show that the lack of national health research priorities in most African countries hinders the intention of global health actors to use global health research as a means of promoting global health equity. Furthermore, capacity building efforts need to be more coordinated and monitored. The responsibility for this lies with several actors.ConclusionThe potential for global health research to improve the health capability of countries in Africa will require that attention is paid to research that improves the health of people in Africa and that global health research partnerships identify, first and foremost, what kind of capacity strengthening is required and who is responsible for this activity. African governments and research institutions can play a role to help global health research improve health and health equity in Africa, in ways that are sustainable.

Championing Equity, Empowerment, and Transformational Leadership in (Mental Health) Research Partnerships: Aligning Collaborative Work With the Global Development Agenda.

Through a narrative synthesis of existing literature on research partnerships, the paper underscores four core values championed in public policy and practice: equity, empowerment, transformational leadership, and treating mental health research as a cooperative inquiry. Building on these values, the author maps the challenges before mental health researchers in forging resilient, egalitarian, and committed Global North-South partnerships within the context of current global development agenda. Reports appraising the UN Millennium Development Goals lament how the goal of developing global partnerships to combat health, gender, and economic inequities has remained under-realized. Emphasis has been placed on the great need to augment Sustainable Development Goals (SDG) in ways where partnership processes would drive development and human rights agenda for the most afflicted, under-resourced, and marginalized in the world. Global North-South partnerships result in fewer lasting benefits to Global South-a regressive trend that is critically analyzed. The need for Global North to adopt ethical and responsible stances while creating/curating new knowledge is discussed. Being responsible is not only imperative for Global North researchers; it is imperative for both North and South researchers to adopt a dialogical approach in clarifying and sharing roles, responsibilities, access, and leadership in developing scholarship and praxis in mental health. The importance of de-centering hierarchies, valuing reciprocity in one another, improving communication, demonstrating empathy, and sharing resources and benefits are found to be key components in the narrative synthesis towards achieving greater empowerment and equity. The paper reflects on the potential problems in engagement and development of de-centered and transformational leadership in partnerships and implications for research ethics in the context of lower-and-middle-income countries. Lastly, the author in a bid to encourage global partnerships suggests that engaging in transparent and bi-directional conversations regarding these issues and realigning research priorities along the four core values will contribute to greater success in research collaborations (across cultural contexts) and more so in the global mental health field.

A multicenter randomized controlled study to evaluate whether neuromuscular electrical stimulation improves the absolute walking distance in patients with intermittent claudication compared with best available treatment

ObjectiveTo assess the clinical efficacy of a neuromuscular electrical stimulation (NMES) device to improve the absolute walking distance in patients with intermittent claudication as an adjunct to the local standard care available at the study sites compared with local standard care alone. MethodsThis open, multicenter, randomized controlled trial included eight participating centers in England. Sites are equally distributed between those that provide supervised exercise therapy programs and those that do not. Patients with intermittent claudication meeting the eligibility criteria and providing consent will be randomized, depending on the center type, to either NMES and locally available standard care or standard care alone. The primary end point is change in absolute walking distance at 3 months (the end of the intervention period) by treadmill testing. Secondary outcomes include quality of life, compliance with the interventions, economic evaluation of the NMES device, and lower limb hemodynamic measures to further the understanding of underlying mechanisms. Recruitment commenced in March 2018 and will continue for a total of 15 months. The Neuromuscular Electrical Stimulation Improves the Absolute Walking Distance in Patients with Intermittent Claudication trial is funded by the UK Efficacy and Mechanism Evaluation Programme, Medical Research Council, and National Institute for Health Research partnership.

Sperm selection for assisted reproduction by prior hyaluronan binding: the HABSelect RCT

BackgroundSperm selection for intracytoplasmic sperm injection (ICSI) has traditionally relied on standardised methods of sperm processing combined with subjective sperm selection (motility/morphology). In 2012, live birth rates (LBRs) stood at ≈24% per cycle started (32% per cycle reaching embryo transfer).Objective(s)The main clinical objective was to determine the benefits of a hyaluronan (HA)-based sperm selection process for physiological intracytoplasmic sperm injection (PICSI). A parallel, mechanistic objective evaluated sperm chromatin integrity and the potential of PICSI to compensate for poor sperm quality.DesignA Phase III, parallel-arm, blinded randomised controlled trial (RCT) of efficacy of PICSI versus ICSI alongside mechanistic evaluation.SettingThe RCT ran from February 2014 to August 2016, involving NHS (n = 14) and private (n = 2) UK hospital or satellite clinics. Mechanistic work was conducted in three university-based research laboratories and a partnering small–medium enterprise from June 2015 to December 2017.ParticipantsCouples undergoing an ICSI procedure using freshly ejaculated sperm with female partners aged between 18 and 43 years and male partners aged between 18 and 55 years.InterventionHealth and Care Professions Council-registered embryologists used the Medicines and Healthcare products Regulatory Agency-registered (HA-coated) PICSI™ dish (Origio, Måløv, Denmark) to select a single sperm for injection. Control couples received standard care.Main outcome measuresClinical – the primary outcome was full-term live birth (≥ 37 weeks’ gestation). Secondary outcome measures were confirmed clinical pregnancy (CP), miscarriage following confirmation and preterm live birth (< 37 weeks’ gestation). Mechanistic – measurement models were designed for deoxyribonucleic acid (DNA) fragmentation, compaction and HA binding [HA binding score (HBS)].ResultsA total of 2772 couples were randomised and 2752 couples were included in the primary analysis (PICSI,n = 1371; and ICSI,n = 1381). Clinical – primary outcome: 379 out of 1381 (27.4% PICSI) and 346 out of 1371 (25.2% ICSI) couples who were randomised (up to 24 hours before treatment) into the trial achieved a term live birth ≥ 37 weeks’ gestation [odds ratio (OR) 1.12, 95% confidence interval (CI) 0.94 to 1.34;p = 0.18]. Subgroup analyses did not reveal differences in treatment effects for HBS, maternal age, previous miscarriage, follicle-stimulating hormone or anti-Müllerian hormone levels and paternal sperm concentrations. Secondary outcomes: CP was achieved for 487 out of 1382 (35.2% PICSI) and 491 out of 1375 (35.7%, ICSI) couples (OR 0.98, 95% CI 0.84 to 1.15;p = 0.80). Miscarriage affected 60 out of 1381 (4.3% PICSI) and 96 out of 1371 (7.0% ICSI) of couples (OR 0.61, 95% CI 0.43 to 0.84;p = 0.003). Preterm LBRs were 46 out of 1381 (3.3% PICSI) and 45 out of 1371 (3.3% ICSI) (OR 1.02, 95% CI 0.67 to 1.55;p = 0.94). Mechanistic: in the subset of samples examined, HBS correlated with sperm motility, concentration, fertilisation rate and DNA fragmentation. Sperm DNA compaction was weakly associated with clinical pregnancy rates (CPRs), but neither HBS nor DNA fragmentation was predictive of any clinical outcome.LimitationsEmbryologists were not blinded and limited data were available from poorer samples and non-random sample selection in the mechanistic cohort. Prepared rather than raw semen was used for tests of DNA integrity.ConclusionsPICSI offered no clear advantage in relation to the primary outcome. PICSI led to a reduced miscarriage risk, but had no effect on CPR or preterm LBR.Future workRe-evaluate PICSI focusing on CP and miscarriage rates and consider aspects of sperm quality that PICSI favours.Trial registrationCurrent Controlled Trials ISRCTN99214271.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. The research is also supported by the NIHR Infrastructure at Leeds and the NIHR Clinical Research Network.

Lightmasks that prevent dark adaptation for non-central diabetic macular oedema: the CLEOPATRA RCT

Background Hypoxia may contribute to the development and progression of diabetic macular oedema (DMO) and diabetic retinopathy. The photoreceptors are the most metabolically active cells in the retina and the rod photoreceptors consume the maximal amount of oxygen for dark adaptation. Therefore, a lightmask emitting 500- to 505-nm light and worn at night during sleep may prevent rod-related dark adaptation and, thereby, reduce the retinal oxygen consumption and improve or prevent progression of DMO and diabetic retinopathy as evidenced in small short-term studies. Objectives The clinical effectiveness and safety of using a lightmask to prevent dark adaptation as a treatment and preventative option was evaluated for DMO over 24 months. Design A Phase III, multicentre, prospective, single-masked, randomised controlled clinical trial that evaluated the clinical effectiveness and safety of a lightmask that prevents dark adaptation to treat and prevent non-central DMO versus standard care (i.e. non-lightmask arm) at 24 months. A subset of participants also enrolled for a mechanistic substudy that evaluated the role of hypoxia in DMO. Setting Fifteen NHS clinical sites in the UK. Participants Adults with non-centre-involving DMO. Intervention The participants were randomly assigned (1 : 1) to being offered a lightmask (Noctura 400 Sleep Masks, Polyphotonix Medical Ltd, Durham, UK) to wear at night during sleep to prevent dark adaptation or to the non-lightmask arm (standard care) for 24 months. The participants were evaluated every 4 months. Main outcome measure The primary outcome was defined as a change in retinal thickness at the zone of maximum thickness measured by spectral domain optical coherence tomography at 24 months in the study eye, analysed using a linear mixed-effects model that estimated adjusted treatment effects at both 12 and 24 months. Results A total of 308 participants were recruited between April 2014 and May 2015. A total of 155 participants in the lightmask arm and 153 in the control arm contributed to the intention-to-treat strategy. The lightmask arm did not show any difference in effect compared with the non-lightmask arm [adjusted mean difference between arms –0.65 µm, 95% confidence interval –6.90 to 5.59 µm; p = 0.84). The compliance of wearing the lightmask was suboptimal, as recorded electronically, from the returned lightmasks. There were no lightmask-related severe adverse events. The mechanistic study aimed at studying the effect of improving hypoxia by inhaling 100% oxygen or by offering lightmasks to wear during sleep at night over 12 months did not demonstrate any clinically beneficial effect on DMO. Conclusion The lightmask, as offered in this trial to prevent dark adaptation, did not show any treatment or preventative effect in participants with non-central oedema or diabetic retinopathy at 24 months. No effect was seen as early as 4 months when compliance was higher. Future work Future research is needed to evaluate the role of rod-induced hypoxia in the pathogenesis of DMO and diabetic retinopathy. Trial registration Current Controlled Trials ISRCTN85596558. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership. The report will be published in full in Efficacy and Mechanism Evaluation; Vol. 6, No. 2. See the NIHR Journals Library website for further project information. The lightmasks were purchased at a discounted rate from Polyphotonix Medical Ltd.