The nutrition-related adverse events associated with immune checkpoint inhibitor treatment for patients with non-small cell lung cancer: A systematic review.

AIMS: Immune checkpoint inhibitor therapy used for lung cancer has significantly changed response and survival rates, however, the impact on patients' nutritional status remains largely unexplored. This review aims to identify common adverse events that increase nutrition risk induced in non-small cell lung cancer patients treated with immune checkpoint inhibitor therapy and assess impact on nutritional status. METHODS: PubMed, Medline and CINAHL were systematically searched in September 2023 for randomised controlled trials comparing immune checkpoint inhibitor treatment of non-small cell lung cancer to a control group. Treatment-related adverse events that increased nutrition impact symptoms identified in the patient-generated subjective global assessment and clinical guidelines were extracted and qualitatively analysed. Risk of bias was assessed using Cochrane Risk of Bias tool 2. RESULTS: Eleven eligible randomised controlled trial studies were identified and analysed. The data demonstrated immune checkpoint inhibitor treatment was associated with a lower percentage of reported nutrition impact symptoms, for example, decreased appetite, nausea, vomiting, compared to chemotherapy treatment. Conversely, immune checkpoint inhibitor treated patients recorded a greater percentage of immune-related adverse events that alter metabolism or nutrient absorption. CONCLUSION: Non-small cell lung cancer patients treated with immune checkpoint inhibitors still experience nutrition impact symptoms but less frequently than patients treated with chemotherapy. This combined with unique nutrition-related consequences from colitis and thyroid disorders induced by immune checkpoint inhibitor therapy indicates patients should be screened, assessed and interventions implemented to improve nutrition.

Efficacy and safety of n-3 fatty acids supplementation on depression: a systematic review and dose-response meta-analysis of randomised controlled trials.

We aimed to investigate the effectiveness of n-3 fatty acids supplementation on the risk of developing depression, depressive symptoms and remission of depression. We searched PubMed, Scopus and Web of Science from inception to December 2022 to find randomised trials of n-3 fatty acids supplementation in adults. We conducted random-effects meta-analyses to estimate standardised mean differences (SMD) and 95 % CI for continuous outcomes and risk difference and 95 % CI for binary outcomes. A total of sixty-seven trials were included. Each 1 g/d n-3 fatty acids supplementation significantly improved depressive symptoms in adults with and without depression (moderate-certainty evidence), with a larger improvement in patients with existing depression. Dose-response analyses indicated a U-shaped effect in patients with existing depression, with the greatest improvement at 1·5 g/d. The analysis showed that n-3 fatty acid supplementation significantly increased depression remission by 19 more per 100 in patients with depression (low-certainty evidence). Supplementation with n-3 fatty acids did not reduce the risk of developing depression among the general population, but it did improve the severity of depression among patients with existing depression.

Health education impact on knowledge and management of arboviral diseases in Kenya: Evidence from randomised control trials.

Communities' knowledge and management strategies are crucial for mitigating and controlling the threat of existing and emerging diseases. In this study, we conducted randomised control trials (RCT) to examine the impact of health education on households' knowledge and management of three Arboviral Diseases (ADs); Rift Valley fever, Chikungunya fever, and Dengue fever in Kenya. The study was based on a sample of 629 households drawn from the three of Kenya's AD hotspot counties; Baringo, Kwale, and Kilifi. Employing a difference-in-difference method, our findings indicate that health education intervention significantly improved households' understanding of ADs transmission modes, causes, and prevention strategies. However, this intervention did not sufficiently influence households' disease management behaviour. We recommend the implementation of community engagement and outreach initiatives which have the potential to drive behavioural changes at the household level, thus enhancing the management and control of ADs in Kenya.

A systematic review and meta-analysis of the long-term effects of physical activity interventions on objectively measured outcomes.

BACKGROUND: Although physical activity interventions are frequently reported to be effective, long-term changes are needed to generate meaningful health benefits. There are criticisms that evaluations of physical activity interventions mostly report short-term outcomes and that these are often self-reported rather than measured objectively. This study therefore aimed to assess the long-term (at least 24 month) effectiveness of behavioural interventions on objectively measured physical activity. METHODS: We conducted a systematic review with a meta-analysis of effects on objectively measured physical activity. We searched: Cochrane CENTRAL, EMBASE, PsychInfo, CINAHL and Pubmed up to 10th January 2022. Studies were included if they were in English and included a physical intervention that assessed physical activity in the long-term (defined as at least 24 months). RESULTS: Eight studies with 8480 participants were identified with data suitable for meta-analysis. There was a significant effect of interventions on daily steps 24 months post baseline (four studies, SMD: 0.15, 95% CI: 0.02 to 0.28) with similar results at 36 to 48 months of follow up (four studies, SMD: 0.17, 95% CI: 0.07 to 0.27). There was a significant effect of interventions on moderate-to-vigorous physical activity 24 months post baseline (four studies, SMD: 0.18 95% CI: 0.07 to 0.29) and at 36 to 48 months (three studies, SMD: 0.16 95% CI: 0.09 to 0.23). The mean effect size was small. However, the changes in moderate-to-vigorous physical activity and steps per day were clinically meaningful in the best-performing studies. CONCLUSION: This review suggests that behavioural interventions can be effective in promoting small, but clinically meaningful increases in objectively measured physical activity for up to 48 months. There is therefore a need to develop interventions that can achieve greater increases in long-term physical activity with greater efficiency.

Comparative efficacy of pulmonary surfactant in respiratory distress syndrome in preterm infants: a Bayesian network meta-analysis.

Introduction: The comparative efficacy of pulmonary surfactant in the treatment of respiratory distress syndrome in preterm infants remains unclear. We aimed to evaluate the effectiveness of different pulmonary surfactant in the treatment of respiratory distress syndrome in preterm infants and to provide an evidence-based reference for clinical use. Material and methods: MEDLINE, Embase, The Cochrane Library, and Clinical Trials databases were electronically searched from inception to January 2019. Two reviewers independently screened literature and extracted data, and then R and RevMan 5.3 software packages were used to perform network meta-analysis. Results: The relative risk of respiratory distress syndrome in preterm infants associated with six different pulmonary surfactant was analysed, including beractant (Survanta), surfactant A (Alveofact), calfactant (Infasurf), poractant (Curosurf), lucinactant (Surfaxin), and colfosceril (Exosurf). Patients with the following drugs appeared to have significantly reduced mortality of respiratory distress syndrome compare with beractant: surfactant A (OR = 0.53, 95% CI: 0.31-0.90), calfactant (OR = 0.91, 95% CI: 0.85-0.97), poractant (OR = 0.72, 95% CI: 0.67-0.77), lucinactant (OR = 0.80, 95% CI: 0.71-0.90), and colfosceril (OR = 0.93, 95% CI: 0.87-0.99). The SUCRA (surface under the cumulative ranking) values for each of the drugs were: beractant (8.9%), surfactant A (93.8%), calfactant (40.3%), poractant (65.4%), lucinactant (59.8%), and colfosceril (31.6%). Conclusions: Compared with beractant, other pulmonary surfactants are more effective to reduce the mortality of respiratory distress syndrome in preterm infants. Surfactant A drugs appeared to have the best efficacy in reducing mortality of respiratory distress syndrome in preterm infants.

Herpes zoster vaccine effectiveness against herpes zoster and postherpetic neuralgia in New Zealand: a retrospective cohort study.

Background: Herpes zoster (HZ) and associated complications cause significant burden to older people. A HZ vaccination programme was introduced in Aotearoa New Zealand in April 2018 with a single dose vaccine for those aged 65 years and a four-year catch up for 66-80 year-olds. This study aimed to assess the 'real-world' effectiveness of the zoster vaccine live (ZVL) against HZ and postherpetic neuralgia (PHN). Methods: We conducted a nationwide retrospective matched cohort study from 1 April 2018 to 1 April 2021 using a linked de-identified patient level Ministry of Health data platform. A Cox proportional hazards model was used to estimate ZVL vaccine effectiveness (VE) against HZ and PHN adjusting for covariates. Multiple outcomes were assessed in the primary (hospitalised HZ and PHN - primary diagnosis) and secondary (hospitalised HZ and PHN: primary and secondary diagnosis, community HZ) analyses. A sub-group analysis was carried out in, adults ≥ 65 years old, immunocompromised adults, Maori, and Pacific populations. Findings: A total of 824,142 (274,272 vaccinated with ZVL matched with 549,870 unvaccinated) New Zealand residents were included in the study. The matched population was 93.4% immunocompetent, 52.2% female, 80.2% European (level 1 ethnic codes), and 64.5% were 65-74 years old (mean age = 71.1±5.0). Vaccinated versus unvaccinated incidence of hospitalised HZ was 0.16 vs. 0.31/1,000 person-years and 0.03 vs. 0.08/1000 person-years for PHN. In the primary analysis, the adjusted overall VE against hospitalised HZ and hospitalised PHN was 57.8% (95% CI: 41.1-69.8) and 73.7% (95% CI:14.0-92.0) respectively. In adults ≥ 65 years old, the VE against hospitalised HZ was 54.4% (95% CI: 36.0-67.5) and VE against hospitalised PHN was 75·5% (95% CI: 19.9-92.5). In the secondary analysis, the VE against community HZ was 30.0% (95% CI: 25.6-34.5). The ZVL VE against hospitalised HZ for immunocompromised adults was 51.1% (95% CI: 23.1-69.5), and PHN hospitalisation was 67.6% (95% CI: 9.3-88.4). The VE against HZ hospitalisation for Maori was 45.2% (95% CI: -23.2-75.6) and for Pacific Peoples was 52.2% (95% CI: -40.6 -83·7). Interpretation: ZVL was associated with a reduction in risk of hospitalisation from HZ and PHN in the New Zealand population. Funding: Wellington Doctoral Scholarship awarded to JFM.

The use of platelet-rich plasma therapy in treating tennis elbow: A critical review of randomised control trials.

Tennis elbow (TE) is a painful and debilitating condition of the elbow. Recently, the use of orthobiologics, such as platelet-rich-plasma (PRP), has been proposed to promote tendon regeneration. Despite their popularity, there is a paucity of updated reviews on the use of PRP compared with other treatment modalities for treating TE. The aim of this review is to summarise high quality studies that compare the use of PRP therapy with other therapies for TE and to identify areas where further research is warranted. This systematic review was performed in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. A comprehensive literature search of PubMed, Scopus and Cochrane Library databases was undertaken in May 2021. Articles were screened for the following criteria: randomised control trials (RCTs) involving PRP in at least one of the treatment arms for tennis elbow. The quality of the RCTs included were analysed for their risk of bias using the modified Cochrane Collaboration Risk of Bias Assessment Tool for randomised trials. A total of 20 RCTs of which 1520 TE patients were analysed. The RCTs included in this review compared PRP with various treatment modalities routinely used in clinical practice such as physiotherapy, steroid injections, Autologous Whole Blood (AWB) and surgical interventions. With regards to the quality of RCTs, collectively, selection bias was found to be low risk however, performance bias in terms of blinding of participants and personnel performed poorly. Of the 20 RCTs, only 5 studies were classified as low risk of bias. In these 5 studies, 2 RCTs compared PRP with steroids and reported contrasting results, 1 RCT compared PRP with AWB injections which reported both to be similarly efficacious, 3 RCTs included a placebo group and only 1 reported superior effects with PRP. There are 2 main types of PRP classified according to the number of pro-inflammatory leukocyte i.e. leukocyte-rich and leukocyte-poor PRP. However, only 8 studies documented the formulation of PRP used. While the heterogeneity of PRP formulations could in-part explain the reported differences in outcomes, overall there is limited robust evidence to recommend PRP therapy for TE. Further research is required to establish the optimal formulation and administration of PRP injections. Proper documentation of TE patients need to be standardised before concrete recommendations on the use of PRP therapy may be offered.

The effect of low-level laser therapy on diabetic foot ulcers: A meta-analysis of randomised controlled trials.

Our purpose was to perform a meta-analysis to evaluate the effect of Low-level laser therapy (LLLT) on diabetic foot ulcers (DFUs). The PubMed, Cochrane, Embase, Web of Science, Chinese BioMedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), VIP and Wanfang databases were searched systematically up to August 27, 2020. Studies that met the inclusion criteria were included in the analysis. A total of 13 randomised controlled trials (RCTs) and 413 patients were analysed. Compared with the control group, LLLT significantly increased the complete healing rate (risk ratio [RR] = 2.10, 95% confidence interval [CI] 1.56-2.83, P < .00001), reduced the ulcer area (standardised mean difference [SMD] = 3.52, 95% CI 1.65-5.38, P = .0002), and shortened the mean healing time (SMD = -1.40, 95% CI -1.90 to -0.91, P < .00001) of patients with DFUs. The quality of the evidence was very low according to the GRADE system. LLLT is a promising and effective adjuvant treatment to accelerate the healing of DFUs. Further evidence from larger samples and higher quality RCTs is needed to prove the effect of LLLT and to determine the most appropriate parameters for the healing of DFUs.

The Anti-osteoporosis Effects of Natto on Bone Mineral Density in Perimenopausal Women.

Objective and Aims: This study aims to conduct a systematic review and meta-analysis for prospective studies to investigate the improvement effects of natto on bone mineral density (BMD) in perimenopausal women. METHODS: PubMed, EMBASE and Cochrane database searched upto February 2019. This study was carried out according to the PRISMA guidelines10 for systematic reviews. The protocol of the review was registered in the PROSPERO registry (CRD42019133183). RESULTS: The review identified 3 unique prospective studies comprising 1658 non-overlapping participants. Meta-analysis showed that natto could significantly improve lumbar bone mineral density (BMD) (P=0.002, WMD=0.26; 95% CI:0.09-0.43) in cohort studies. However, the randomized controlled study showed no statistical difference between the two (P=0.31, WMD=0.05; 95% CI:- 0.05-0.15). In addition, natto significantly improved the BMD of the femoral neck in a cohort study and randomized control study (P=0.03, WMD=0.42). 95% CI:0.05-0.79, I2= 72%); (P < 0.0001, WMD=0.16; 95% CI:0.08-0.24), respectively. However, all studies demonstrated that natto has no improvement effects on a hip joint (BMD). In that, the cohort study showed no statistical significance between the natto intake group and the control group (P=0.21, WMD=0.10). 95% CI:-0.06-0.25, I2= 18%) and the randomized controlled study also showed no statistical significance between the natto intake group and the control group (P=0.09, WMD=-0.06). 95% CI:-0.13- 0.01). CONCLUSION: Through our current systematic review and meta-analyize of these prosepctive studies of natto's anti-osteoporostic effecs on BMD, we found that the dietary intake of natto demonstrated a improving effects on the BMD of the femoral neck, but has no effects on the hip joint. Such interesting results may be related to the differences between anatomical structure between various tissues. Besides that, the results of the RCT study and cohort study on the lumbar spine were not the same, which may be related to the fact that participants in the RCT study were Caucasian and participants in the cohort study were Asian. Therefore, more large-sample and high-quality RCT studies are needed to further clarify the improvement effect of natto on osteoporosis.

Changes in technology acceptance among older people with dementia: the role of social robot engagement.

OBJECTIVE: Emerging technologies such as social robots have shown to be effective in reducing loneliness and agitation for older people with dementia. However, the acceptance of technology (specifically social robots) was found to be low for older people with dementia. The current understanding of changes in technology acceptance following direct exposure is limited and lacks rigorous study design. This study examined the change in technology acceptance after a direct interaction with a humanoid social robot (Kabochan) that was deployed for long-term care facilities' residents with dementia. METHODS: The technology acceptance was assessed using randomised control trials for a time frame of 32 weeks. A total of 103 residents clinically diagnosed with dementia, with a mean age of 87.2 years (SD = 7.4), were recruited from seven long-term care facilities in Hong Kong and were randomly allocated to either Kabochan-engagement group or control group. Participants in the engagement group interacted with Kabochan in an individual, non-facilitated approach. The behavioural engagement with Kabochan was observed by care workers and recorded into constructive engagement and non-engagement. Questionnaire surveys were taken placed at pre- and post-exposure with Kabochan to measure attitudes and beliefs towards technology. The questionnaire was based on previous studies on technology acceptance and included attitudes towards technology, perceived usefulness, perceived ease of use, technology self-efficacy, technology anxiety, and facilitating conditions. RESULTS: Perceived ease of use was improved at week 32 for participants who interacted with Kabochan (F = 4.239, p = 0.042) with a small effect (ηp2 = 0.043) in comparison to usual care group. Results further demonstrated that the magnitude of belief changes was related to the intensity of constructive behavioural engagement. Specifically, resident-robot behavioural engagement moderately improved attitudes towards technology (F = 11.62, p < 0.001, ηp2 = 0.11) and perceived usefulness (F = 5.75, p = 0.02, ηp2 = 0.06). CONCLUSIONS: The study tentatively supports that exposure to Kabochan has potential for changing perceived ease of use but not for other beliefs and attitudes towards technology among long-term care residents with dementia. Direct engagement with a humanoid social robot might be promising in improving the perceived ease of use towards technology.

Changes to aspects of ongoing randomised controlled trials with fixed designs.

BACKGROUND: Despite careful planning, changes to some aspects of an ongoing randomised clinical trial (RCT), with a fixed design, may be warranted. We sought to elucidate the distinction between legitimate versus illegitimate changes to serve as a guide for less experienced clinical trialists and other stakeholders. METHODS: Using data from a large trial of statin therapy for secondary prevention, we generated a set of simulated trial datasets under the null hypothesis (H0) and a set under an alternative hypothesis (H1). Through analysis of these simulated trials, we assessed the performance of the strategy of changing aspects of the design/analysis with knowledge of treatment allocation (illegitimate) versus the strategy of making changes without knowledge of treatment allocation (legitimate). Performance was assessed using the type 1 error, as well as measures of absolute and relative bias in the treatment effect. RESULTS: Illegitimate changes led to a relative bias of 61% under H1, and a type 1 error rate under H0 of 23%-well in excess of the 5% significance level targeted. Legitimate changes produced unbiased estimates under H1 and did not inflate the type 1 error rate under H0. CONCLUSIONS: Changes to pre-specified aspects of the design and analysis of an ongoing RCT may be a necessary response to unforeseen circumstances. Such changes risk introducing a bias if undertaken with knowledge of treatment allocation. Legitimate changes need to be adequately documented to provide assurance to all stakeholders of their validity.

Moving beyond the descriptive in psychotherapy research.

There are challenges to conducting randomised controlled trials in psychotherapy. This article therefore discusses methodological advances in applying this design to the field. The application of evidence-based practice to psychotherapy means that people with psychological problems, clinicians, health services and any third-party payers can confidently choose from a range of effective treatments that are best suited to an individual's needs.

Efficacy of mycophenolate mofetil as a remission induction therapy in antineutrophil cytoplasmic antibody: associated vasculitis-a meta-analysis.

OBJECTIVES: A few studies on antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treatments have shown the therapeutic efficacy of mycophenolate mofetil (MMF). However, the therapeutic efficacy of MMF compared with that of cyclophosphamide (CYC) in patients with AAV has not been established. We conducted a systematic review and meta-analysis to assess the efficacy of MMF as a remission induction therapy in patients with AAV comparing it with the efficacy of CYC. METHODS: We searched randomised controlled trials (RCTs) comparing the efficacy of MMF with that of CYC in patients with AAV on three different websites: PubMed, Cochrane Library and Google Scholar. We compared the difference in the relative risk (RR) of each outcome based on a Mantel-Haenszel random-effects model. RESULTS: We analysed data from four RCTs with 300 patients for the study. The 6-month remission rate (RR 1.09, 95% CI 0.86 to 1.38, p=0.48), the 6-month ANCA negativity (RR 1.31, 95% CI 0.91 to 1.90, p=0.15) and the long-term relapse rate (RR 1.36, 95% CI 0.80 to 2.31, p=0.26) were all similar between the two treatments. The rates of death, infection and leucopenia were also similar between the two groups (RR 1.05, 95% CI 0.40 to 2.74, p=0.93; RR 1.26, 95% CI 0.79 to 2.01, p=0.33; RR 0.45, 95% CI 0.16 to 1.32, p=0.15, respectively). CONCLUSIONS: We found no difference between the therapeutic efficacy of MMF and that of CYC in patients with AAV. MMF may be an alternative remission induction therapy in patients with non-life-threatening AAV.

Understanding usual care in randomised controlled trials of complex interventions: A multi-method approach.

BACKGROUND: Evaluations of complex interventions compared to usual care provided in palliative care are increasing. Not describing usual care may affect the interpretation of an intervention's effectiveness, yet how it can be described remains unclear. AIM: To demonstrate the feasibility of using multi-methods to describe usual care provided in randomised controlled trials (RCTs) of complex interventions, shown within a feasibility cluster RCT. DESIGN: Multi-method approach comprising usual care questionnaires, baseline case note review and focus groups with ward staff completed at study end. Thematic analysis of qualitative data, descriptive statistics of quantitative data, followed by methodological triangulation to appraise approach in relation to study aim. SETTING/PARTICIPANTS: Four general medical wards chosen from UK hospitals. Purposive sampling of healthcare professionals for usual care questionnaires, and focus groups. Review of 20 patients' notes from each ward who died during admission or within 100 days of discharge. RESULTS: Twenty-three usual care questionnaires at baseline, two focus groups comprising 20 healthcare professionals and 80 case note reviews. Triangulation of findings resulted in understanding the usual care provided to the targeted population in terms of context, structures, processes and outcomes for patients, families and healthcare professionals. Usual care was described, highlighting (1) similarities and embedded practices, (2) heterogeneity and (3) subtle changes in care during the trial within and across sites. CONCLUSIONS: We provide a feasible approach to defining usual care that can be practically adopted in different settings. Understanding usual care enhances the reliability of tested complex interventions, and informs research and policy priorities.

Dyadic interventions to promote physical activity and reduce sedentary behaviour: systematic review and meta-analysis.

Several interventions have targeted dyads to promote physical activity (PA) or reduce sedentary behaviour (SB), but the evidence has not been synthesised. Sixty-nine studies were identified from MEDLINE, PsycINFO, and Web of Science, and 59 were included in the main meta-analyses (providing 72 independent tests). Intervention details, type of dyadic goal, participant characteristics, and methodological quality were extracted and their impact on the overall effect size was examined. Sensitivity analyses tested effect robustness to (a) the effects of other statistically significant moderators; (b) outliers; (c) data included for participants who were not the main target of the intervention. Dyadic interventions had a small positive, highly heterogeneous, effect on PA g = .203, 95% CI [0.123-0.282], compared to comparison conditions including equivalent interventions targeting individuals. Shared target-oriented goals (where both dyad members hold the same PA goal for the main target of the intervention) and peer/friend dyads were associated with larger effect sizes across most analyses. Dyadic interventions produced a small homogeneous reduction in SB. Given dyadic interventions promote PA over-and-above equivalent interventions targeting individuals, these interventions should be more widespread. However, moderating factors such as the types of PA goal and dyad need to be considered to maximise effects.

Surveying knowledge, practice and attitudes towards intervention fidelity within trials of complex healthcare interventions.

BACKGROUND: Intervention fidelity is the degree to which interventions have been implemented as intended by their developers. Assessing fidelity is crucial for accurate interpretation of intervention effectiveness, but fidelity is often poorly addressed within trials of complex healthcare interventions. The reasons for this are unclear, and information on the use of methods to enhance and assess fidelity in trials of complex interventions remains insufficient. This study aimed to explore the knowledge, practice and attitudes towards intervention fidelity amongst researchers, triallists and healthcare professionals involved with the design and conduct of trials of complex healthcare interventions. METHODS: An online survey consisting of closed and open-ended questions exploring four sections (Demographics, Fidelity knowledge, Practice and Attitudes) was conducted. This was an opportunistic sample of individuals with experience of direct involvement in trials of complex healthcare interventions (e.g. design/development, conduct, evaluation). RESULTS: Data from 264 participants representing 15 countries were analysed. The majority (65.9%, n = 174) of participants identified themselves as 'Researchers'. The majority of participants were familiar with the term "intervention fidelity" (69.7%, n = 184) and indicated that fidelity is important (89.7%, n = 236). Mean self-reported understanding of fidelity was moderate. Although 68% (n = 182) had previously used strategies to assess (e.g. audio/video-recording sessions) and enhance (e.g. training manual) fidelity in trials of complex interventions, only a limited proportion of participants indicated always reporting these strategies in subsequent publications (30.9%, n = 56). Poor knowledge or understanding was the most commonly cited barrier to addressing intervention fidelity in trials (77.4%, n = 202). Over half of respondents (52.1%, n = 137) had never completed specific fidelity training or research, and the vast majority (89.7%, n = 236) would welcome specific training in this area. CONCLUSION: Despite good awareness of intervention fidelity and its importance, poor knowledge and understanding appears to be a key factor limiting how intervention fidelity is addressed in trials of complex interventions. Participants identified a need for further training and education in this area. Additionally, clarification of the terminology, definition and components of intervention fidelity would facilitate better understanding of the concept. A discrepancy between participants' use of fidelity strategies and subsequent reporting raises concerns around inadequate fidelity reporting in the trials literature.

Impact of levothyroxine therapy on obstetric, neonatal and childhood outcomes in women with subclinical hypothyroidism diagnosed in pregnancy: a systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To determine in women with subclinical hypothyroidism diagnosed in pregnancy whether levothyroxine treatment compared with control, impacts important obstetrical or childhood outcomes (specifically IQ) in randomised controlled trials. DESIGN: Systematic review and meta-analysis. STUDY ELIGIBILITY CRITERIA: Randomised trials which met all the following were included: (1) reported original data of women with subclinical hypothyroidism diagnosed in pregnancy (by any prespecified study definition); (2) randomised to either levothyroxine or control (placebo or no treatment); (3) reported obstetrical outcomes and/or childhood neurodevelopmental outcomes and (4) published from 1980 to January 2018 in either English or French language. DATA SOURCES: Medline, EMBASE, CINAHL, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov. OUTCOME MEASURES: Obstetrical, neonatal and childhood outcomes including: miscarriage, gestational hypertension, pre-eclampsia, preterm delivery, mode of delivery, neonatal intensive care unit admission, birth weight, gestational age at delivery, childhood IQ and neurodevelopmental scores. Risk of bias assessment Cochrane Risk of Bias Tool (Modified) for Quality Assessment of Randomised Controlled Trials RESULTS: Three trials of low to unclear risk of bias with 1837 participants were included. Two studies were meta-analysed for maternal and neonatal outcomes and two studies for childhood IQ. No statistically significant differences were found for any clinical outcomes with levothyroxine therapy compared with control. LIMITATIONS: Only three trials were identified for inclusion. CONCLUSIONS: This review, based on three randomised trials in women with subclinical hypothyroidism diagnosed in pregnancy, found no evidence of benefit of levothyroxine therapy on obstetrical, neonatal, childhood IQ or neurodevelopmental outcomes. Current trial evidence does not support the treatment of subclinical hypothyroidism diagnosed in pregnancy. PROSPERO REGISTRATION NUMBER: CRD4201707980.

Effective sample size estimation for a mechanical ventilation trial through Monte-Carlo simulation: Length of mechanical ventilation and Ventilator Free Days.

Randomised control trials have sought to seek to improve mechanical ventilation treatment. However, few trials to date have shown clinical significance. It is hypothesised that aside from effective treatment, the outcome metrics and sample sizes of the trial also affect the significance, and thus impact trial design. In this study, a Monte-Carlo simulation method was developed and used to investigate several outcome metrics of ventilation treatment, including 1) length of mechanical ventilation (LoMV); 2) Ventilator Free Days (VFD); and 3) LoMV-28, a combination of the other metrics. As these metrics have highly skewed distributions, it also investigated the impact of imposing clinically relevant exclusion criteria on study power to enable better design for significance. Data from invasively ventilated patients from a single intensive care unit were used in this analysis to demonstrate the method. Use of LoMV as an outcome metric required 160 patients/arm to reach 80% power with a clinically expected intervention difference of 25% LoMV if clinically relevant exclusion criteria were applied to the cohort, but 400 patients/arm if they were not. However, only 130 patients/arm would be required for the same statistical significance at the same intervention difference if VFD was used. A Monte-Carlo simulation approach using local cohort data combined with objective patient selection criteria can yield better design of ventilation studies to desired power and significance, with fewer patients per arm than traditional trial design methods, which in turn reduces patient risk. Outcome metrics, such as VFD, should be used when a difference in mortality is also expected between the two cohorts. Finally, the non-parametric approach taken is readily generalisable to a range of trial types where outcome data is similarly skewed.

Effects of early mobilisation in patients after cardiac surgery: a systematic review.

BACKGROUND: Early mobilisation is prescribed after cardiac surgery to prevent postoperative complications, decrease length of hospital stay, and augment return to daily activities. OBJECTIVE: To evaluate the evidence for the effects of early mobilisation in patients after cardiac surgery on length of hospital stay, functional capacity and postoperative complications. DATA SOURCES: The data sources used were Medline, Embase, CINAHL, PEDro, Web of Science and Cochrane Central Register of Controlled Trials. STUDY SELECTION: Randomised controlled trials of early mobilisation after cardiac surgery. Study selection was not restricted by language or publication time. STUDY APPRAISAL AND SYNTHESIS METHODS: The methodological quality of each article was appraised with the PEDro scale. All review phases (selection, data extraction and appraisal) were conducted by two investigators, and a third investigator provided consensus. RESULTS: Nine trials were selected. The PEDro scale showed that the studies had a low risk of bias (range 5 to 9 points). The trials revealed diversity in techniques used for mobilisation, as well as periods considered early for the start of the intervention. Early mobilisation groups had improved outcomes compared with control groups without treatment. Generally, these advantages did not differ when groups of interventions were compared. LIMITATIONS: It was not possible to perform a meta-analysis due to the variability of the interventions proposed as early mobilisation. CONCLUSIONS: Regardless of the techniques used as mobilisation, the essential point is to avoid bed rest. Early mobilisation seems to be important to prevent postoperative complications, improve functional capacity and reduce length of hospital stay in patients after cardiac surgery.

Scandcleft randomised trials of primary surgery for unilateral cleft lip and palate: 6. Dental arch relationships in 5 year-olds.

BACKGROUND AND AIM: Good dentofacial growth is a major goal in the treatment of unilateral cleft lip and palate (UCLP). The aim was to evaluate dental arch relationships at age 5 years after four different protocols of primary surgery for UCLP. DESIGN: Three parallel randomised clinical trials were undertaken as an international multi-centre study by 10 cleft teams in five countries: Denmark, Finland, Sweden, Norway, and the UK. METHODS: Three different surgical procedures for primary palatal repair (Arms B, C, D) were tested against a common procedure (Arm A) in the total cohort of 448 children born with non-syndromic UCLP. Study models of 418 patients (273 boys) at the mean age of 5.1 years (range = 4.8-7.0) were available. Dental arch relationships were assessed using the 5-year index by a blinded panel of 16 orthodontists. Kappa statistics were calculated to assess reliability. The trials were tested statistically with t- and Chi-square tests. RESULTS: Good-to-very good levels of intra- and interrater reliability were obtained (0.71-0.94 and 0.70-0.87). Comparisons within each trial showed no statistically significant differences in the mean 5-year index scores or their distributions between the common method and the local team protocol. The mean index scores varied from 2.52 (Trial 2, Arm C) to 2.94 (Trial 3, Arm D). CONCLUSION: The results of the three trials do not provide statistical evidence that one technique is better than the others. Further analysis of the possible influence of individual surgical skill and learning curve are being pursued in this dataset. TRIAL REGISTRATION: ISRCTN29932826.