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Objectives The primary aim of the present study is to examine the efficacy of an online intervention for poor sleep in the context of an ongoing stressful major life event, by assessing if this intervention can reduce insomnia severity at short-term (one week post-intervention) and long-term (one and three months post-intervention) follow-up time points. It is hypothesised that the intervention will: 1) reduce insomnia severity in poor sleepers, compared to wait-list control poor sleepers, and good sleepers; 2) reduce subjective symptoms of anxiety and depression in all groups, and 3) prevent the transition to acute insomnia in good sleepers. Trial design This study is a cluster randomised controlled trial. Participants Both healthy good sleepers, who do not report having any current sleep problems, and individuals who report having sleep problems, will be recruited for the present study. This is a single-site study (Northumbria University). This study will be delivered using the internet and there are no geographic restrictions. Individuals who self-report as poor sleepers will meet DSM-5 criteria for acute insomnia, which is where individuals: 1) have difficulties in falling asleep, staying asleep, or awakening too early for at least three nights per week, for a time period of between two weeks and three months; and 2) report experiencing distress or impairment caused by sleep loss. Both 1) and 2) must have occurred despite the individual having had an adequate opportunity for sleep during this time period. Good sleepers will be individuals who do not have current sleep problems. All participants must have a sufficient level of English comprehension to understand and complete study measures. Individuals cannot participate if they report having chronic sleep problems (where they have existed for more than three months immediately prior to providing consent), nor will individuals who are actively seeking treatment for their sleep problems irrespective of how long they have had the sleep problem. Individuals also cannot participate if they have a self-reported history of head injuries, or if they have a self-reported diagnosis of schizophrenia, epilepsy or personality disorder, as the distraction techniques involved in the insomnia intervention may increase rumination in individuals with these conditions, and influence the effectiveness of the intervention. Intervention and comparator Participants who receive the intervention will be provided with an online version of a self-help leaflet. A printed version of this leaflet has been successfully used in previous treatment studies, which have been conducted by our research group. Participants will be encouraged to download, save or print out this leaflet, which will be provided in PDF format. There will be no restrictions on use and participants will be encouraged to refer to this leaflet as often as they wish to. Briefly, this self-help leaflet aims to improve sleep by identifying and addressing sleep-related dysfunctional thinking by providing education about sleep, providing techniques to distract from intrusive worrisome thoughts at night, and providing guidelines for sleep-related stimulus control. The comparator is a wait-list control (i.e. where they will receive the intervention after a one month delay) group. Main outcomes The primary outcome measure will be insomnia severity, as measured using the Insomnia Severity Index (Bastien, Vallières, & Morin, 2001), assessed immediately prior to the intervention and at one week, one month and three months post-intervention, compared to baseline. Secondary outcome measures will include subjective mood, measured using the 7-item Generalised Anxiety Disorder Questionnaire (GAD-7; Spitzer, Kroenke, Williams, & Lowe, 2006)) and 9-item Patient Health Questionnaire (PHQ-9; Kroenke, Spitzer, & Williams, 2001), assessed immediately prior to the intervention, and one week, one month and three months post-intervention, compared to baseline. Additionally, subjective sleep continuity, derived from sleep diaries (Carney et al ., 2012), will be compared pre and post-intervention. Randomisation This study will operate as a cluster randomised controlled trial. Good sleepers will be randomised into an intervention or a no-intervention group, with a 1:1 allocation. Poor sleepers will be randomised into an intervention or wait-list control group, with a 1:1 allocation. Randomisation will be conducted automatically using Qualtrics study software, where block sizes will be equal and randomisation will be computer-generated. Blinding (masking) Participants will not be blinded to group assignment. The outcomes will be assessed by a blinded investigator. Numbers to be randomised (sample size) The minimum sample size is 60. A total of 30 poor sleepers will be randomised to the intervention or wait-list control group. A total of 30 good sleepers will be randomised to the intervention or no intervention group. Trial Status Recruitment for this study has yet to start. It is anticipated that recruitment will begin in August 2020 and end in April 2022. The current study protocol is version 1.0 (20 July 2020) Trial registration This study was prospectively registered in the ISRCTN registry (registration number ISRCTN43900695 , date of registration: 8 April 2020). Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2 ).

It has recently been reported how to quantify inter-individual differences in the response to an exercise intervention using the standard deviation of the change scores, as well as how to appraise these differences for clinical relevance. In a parallel-group randomised controlled trial, the key trigger for further investigation into inter-individual responses is when the standard deviation of change in the intervention sample is substantially larger than the same standard deviation derived from a suitable comparator sample. ‘True’ and clinically relevant inter-individual differences in response can then be plausibly expected, and potential moderators and mediators of the inter-individual differences can be explored. We now aim to critically review the research on the inter-individual differences in response to exercise training, focusing on maximal oxygen uptake ( V O 2 max). A literature search through the relevant bibliographic databases resulted in the identification of six relevant studies that were published prior to the influential HEalth, RIsk factors, exercise Training And GEnetics (HERITAGE) Family Study. Only one of these studies was found to include a comparator arm. Re-analysis of the data from this study, accounting for random within-subjects variation, revealed an absence of clinically important inter-individual differences in the response of V O 2 max to exercise training. The standard deviation of change was, in fact, larger (±5.6 mL/kg/min) for the comparator than the intervention group (±3.7 mL/kg/min). We located over 180 publications that resulted from the HERITAGE Family Study, but we could not find a comparator arm in any of these studies. Some authors did not explain this absence, while others reasoned that only inter-individual differences in exercise response were of interest, thus the intervention sample was investigated solely. We also found this absence of a comparator sample in on-going studies. A perceived high test–retest reliability is offered as a justification for the absence of a comparator arm, but the test–retest reliability analysis for the HERITAGE Family Study was over a much shorter term than the length of the actual training period between baseline and follow-up measurements of V O 2 max. We also scrutinised the studies in which twins have been investigated, resulting in concerns about how genetic influences on the magnitude of general within-subjects variability has been partitioned out (again in the absence of a comparator no-training group), as well as with the intra-class correlation coefficient approach to data analysis. Twin pairs were found to be sometimes heterogeneous for the obviously influential factors of sex, age and fitness, thereby inflating an unadjusted coefficient. We conclude that most studies on inter-individual differences in V O 2 max response to exercise training have no comparator sample. Therefore, true inter-individual differences in response cannot be quantified, let alone appraised for clinical relevance. For those studies with a comparator sample, we found that the inter-individual differences in training response were not larger than random within-subjects variation in V O 2 max over the same time period as the training intervention.

Purpose Dietary nitrate supplementation increases nitric oxide (NO) bioavailability and reduces blood pressure (BP). Inter-individual differences in these responses are suspected but have not been investigated using robust designs, e.g., replicate crossover, and appropriate statistical models. We examined the within-individual consistency of the effects of dietary nitrate supplementation on NO biomarkers and BP, and quantified inter-individual response differences. Methods Fifteen healthy males visited the laboratory four times. On two visits, participants consumed 140 ml nitrate-rich beetroot juice (~ 14.0mmol nitrate) and, on the other two visits, they consumed 140 ml nitrate-depleted beetroot juice (~ 0.03mmol nitrate). Plasma nitrate and nitrite concentrations were measured 2.5 h post-supplementation. BP was measured pre- and 2.5 h post-supplementation. Between-replicate correlations were quantified for the placebo-adjusted post-supplementation plasma nitrate and nitrite concentrations and pre-to-post changes in BP. Within-participant linear mixed models and a meta-analytic approach estimated participant-by-condition treatment response variability. Results Nitrate-rich beetroot juice supplementation elevated plasma nitrate and nitrite concentrations and reduced systolic (mean:-7mmHg, 95%CI: -3 to -11mmHg) and diastolic (mean:-6mmHg, 95%CI: -2 to -9mmHg) BP versus placebo. The participant-by-condition interaction response variability from the mixed model was ± 7mmHg (95%CI: 3 to 9mmHg) for systolic BP and consistent with the treatment effect heterogeneity t = ± 7mmHg (95%CI: 5 to 12mmHg) derived from the meta-analytic approach. The between-replicate correlations were moderate-to-large for plasma nitrate, nitrite and systolic BP ( r  = 0.55 to 0.91). Conclusions The effects of dietary nitrate supplementation on NO biomarkers and systolic BP varied significantly from participant to participant. The causes of this inter-individual variation deserve further investigation. Trial registration: https://clinicaltrials.gov/study/NCT05514821 .

Background Following consumption of a meal, circulating glucose concentrations can rise and then fall briefly below the basal/fasting concentrations. This phenomenon is known as reactive hypoglycaemia but to date no researcher has explored potential inter-individual differences in response to meal consumption. Objective We conducted a secondary analysis of existing data to examine inter-individual variability of reactive hypoglycaemia in response to breakfast consumption. Methods Using a replicate crossover design, 12 healthy, physically active men (age: 18–30 y, body mass index: 22.1 to 28.0 kg⋅m − 2 ) completed two identical control (continued overnight fasting) and two breakfast (444 kcal; 60% carbohydrate, 17% protein, 23% fat) conditions in randomised sequences. Blood glucose and lactate concentrations, serum insulin and non-esterified fatty acid concentrations, whole-body energy expenditure, carbohydrate and fat oxidation rates, and appetite ratings were determined before and 2 h after the interventions. Inter-individual differences were explored using Pearson’s product-moment correlations between the first and second replicates of the fasting-adjusted breakfast response. Within-participant covariate-adjusted linear mixed models and a random-effects meta-analytical approach were used to quantify participant-by-condition interactions. Results Breakfast consumption lowered 2-h blood glucose by 0.44 mmol/L (95%CI: 0.76 to 0.12 mmol/L) and serum NEFA concentrations, whilst increasing blood lactate and serum insulin concentrations (all p  < 0.01). Large, positive correlations were observed between the first and second replicates of the fasting-adjusted insulin, lactate, hunger, and satisfaction responses to breakfast consumption (all r  > 0.5, 90%CI ranged from 0.03 to 0.91). The participant-by-condition interaction response variability (SD) for serum insulin concentration was 11 pmol/L (95%CI: 5 to 16 pmol/L), which was consistent with the τ-statistic from the random-effects meta-analysis (11.7 pmol/L, 95%CI 7.0 to 22.2 pmol/L) whereas effects were unclear for other outcome variables (e.g., τ-statistic value for glucose: 0 mmol/L, 95%CI 0.0 to 0.5 mmol/L). Conclusions Despite observing reactive hypoglycaemia at the group level, we were unable to detect any meaningful inter-individual variability of the reactive hypoglycaemia response to breakfast. There was, however, evidence that 2-h insulin responses to breakfast display meaningful inter-individual variability, which may be explained by relative carbohydrate dose ingested and variation in insulin sensitivity of participants.

Abstract Study Objectives Using the necessary replicate-crossover design, we investigated whether there is interindividual variability in home-assessed sleep in response to acute exercise. Methods Eighteen healthy men (mean [SD]: 26[6] years) completed two identical control (8 hour laboratory rest, 08:45–16:45) and two identical exercise (7 hour laboratory rest; 1 hour laboratory treadmill run [62(7)% peak oxygen uptake], 15:15–16:15) trials in randomized sequences. Wrist-worn actigraphy (MotionWatch 8) measured home-based sleep (total sleep time, actual wake time, sleep latency, and sleep efficiency) two nights before (nights 1 and 2) and three nights after (nights 3–5) the exercise/control day. Pearson’s correlation coefficients quantified the consistency of individual differences between the replicates of control-adjusted exercise responses to explore: (1) immediate (night 3 minus night 2); (2) delayed (night 5 minus night 2); and (3) overall (average post-intervention minus average pre-intervention) exercise-related effects. Within-participant linear mixed models and a random-effects between-participant meta-analysis estimated participant-by-trial response heterogeneity. Results For all comparisons and sleep outcomes, the between-replicate correlations were nonsignificant, ranging from trivial to moderate (r range = −0.44 to 0.41, p ≥ .065). Participant-by-trial interactions were trivial. Individual differences SDs were small, prone to uncertainty around the estimates indicated by wide 95% confidence intervals, and did not provide support for true individual response heterogeneity. Meta-analyses of the between-participant, replicate-averaged condition effect revealed that, again, heterogeneity (τ) was negligible for most sleep outcomes. Conclusions Control-adjusted sleep in response to acute exercise was inconsistent when measured on repeated occasions. Interindividual differences in sleep in response to exercise were small compared with the natural (trial-to-trial) within-subject variability in sleep outcomes. Clinical trials information https://clinicaltrials.gov/study/NCT05022498. Registration number: NCT05022498. Graphical Abstract Graphical Abstract

Helen Handoll and Greg Atkinson describe how a published letter took on a surprising new life

To quantify the influence of baseline pain levels on weight change at one-year follow-up in patients attending a National Health Service specialist weight management programme. We compared one-year follow-up weight (body mass) change between patient sub-groups of none-to-mild, moderate, and severe pain at baseline. A mean sub-group difference in weight change of ≥5kg was considered clinically relevant. Of the 141 complete cases, n = 43 (30.5%) reported none-to-mild pain, n = 44 (31.2%) reported moderate pain, and n = 54 (38.3%) reported severe pain. Covariate-adjusted mean weight loss (95%CI) was similar for those with none-to-mild (8.1kg (4.2 to 12.0kg)) and moderate pain (8.3kg (4.9 to 11.7kg). The mean weight loss of 3.0kg (-0.4 to 6.4kg) for the severe pain group was 5.1kg (-0.6 to 10.7, p = 0.08) lower than the none-to-mild pain group and 5.3kg (0.4 to 10.2kg, p = 0.03) lower than the moderate pain group. Patients with severe pain upon entry to a specialist weight management service in England achieve a smaller mean weight loss at one-year follow-up than those with none-to-moderate pain. The magnitude of the difference in mean weight loss was clinically relevant, highlighting the importance of addressing severe persistent pain in obese patients undertaking weight management programmes.

IntroductionPreterm and small for gestational age (SGA) infants are at increased risk of poor growth, disability and delayed development. While growing up they are also at increased risk of obesity, diabetes and later heart disease. The risk of such adverse outcomes may be altered by how preterm and SGA infants are fed after birth. Faltering postnatal growth is common due to failure to achieve recommended high energy and protein intakes, and thus preterm and SGA infants are often provided with supplemental nutrition soon after birth. Enhanced nutrition has been associated with improved early growth and better cognitive development. However, limited evidence suggests that faster growth may increase the risk for later adiposity, metabolic and cardiovascular disease, and that such risks may differ between girls and boys.Methods and analysisWe will search Ovid MEDLINE, Embase, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, controlled-trials.com, ClinicalTrials.gov and anzctr.org.au for randomised trials that studied the effects of macronutrient supplements for preterm and SGA infants on (i) developmental and metabolic and (ii) growth outcomes after hospital discharge. The outcomes will be (i) cognitive impairment and metabolic risk (co-primary) and (ii) body mass index. Individual participant data (IPD) from all available trials will be included using an intention-to-treat approach. A one-stage procedure for IPD meta-analysis (MA) will be used, accounting for clustering of participants within studies. Exploratory subgroup analyses will further investigate sources of heterogeneity, including sex and size of infants, different timing, duration and type of supplements.Ethics and disseminationThis IPD-MA is approved by the University of Auckland Human Participants Ethics Committee (reference number: 019874). Individual studies have approval from relevant local ethics committees. Results will be disseminated in a peer-reviewed journal and presented at international conferences.PROSPERO registration numberCRD42017072683