Cost-effectiveness of cognitive behavioural and personalized exercise interventions for reducing fatigue in inflammatory rheumatic diseases.

OBJECTIVES: To estimate the cost-effectiveness of a cognitive behavioural approach (CBA) or a personalized exercise programme (PEP), alongside usual care (UC), in patients with inflammatory rheumatic diseases who report chronic, moderate to severe fatigue. METHODS: A within-trial cost-utility analysis was conducted using individual patient data collected within a multicentre, three-arm randomized controlled trial over a 56-week period. The primary economic analysis was conducted from the UK National Health Service (NHS) perspective. Uncertainty was explored using cost-effectiveness acceptability curves and sensitivity analysis. RESULTS: Complete-case analysis showed that, compared with UC, both PEP and CBA were more expensive [adjusted mean cost difference: PEP £569 (95% CI: £464, £665); CBA £845 (95% CI: £717, £993)] and, in the case of PEP, significantly more effective [adjusted mean quality-adjusted life year (QALY) difference: PEP 0.043 (95% CI: 0.019, 0.068); CBA 0.001 (95% CI: -0.022, 0.022)]. These led to an incremental cost-effectiveness ratio (ICER) of £13 159 for PEP vs UC, and £793 777 for CBA vs UC. Non-parametric bootstrapping showed that, at a threshold value of £20 000 per QALY gained, PEP had a probability of 88% of being cost-effective. In multiple imputation analysis, PEP was associated with significant incremental costs of £428 (95% CI: £324, £511) and a non-significant QALY gain of 0.016 (95% CI: -0.003, 0.035), leading to an ICER of £26 822 vs UC. The estimates from sensitivity analyses were consistent with these results. CONCLUSION: The addition of a PEP alongside UC is likely to provide a cost-effective use of health care resources.

Cost-utility analysis of shockwave lithotripsy vs ureteroscopic stone treatment in adults.

OBJECTIVES: To assess the cost-effectiveness, resource use implications, quality-adjusted life-years (QALYs) and cost per QALY of care pathways starting with either extracorporeal shockwave lithotripsy (SWL) or with ureteroscopic retrieval (ureteroscopy [URS]) for the management of ureteric stones. PATIENTS AND METHODS: Data on quality of life and resource use for 613 patients, collected prospectively in the Therapeutic Interventions for Stones of the Ureter (TISU) randomized controlled trial (ISRCTN 92289221), were used to assess the cost-effectiveness of two care pathways, SWL and URS. A health provider (UK National Health Service) perspective was adopted to estimate the costs of the interventions and subsequent resource use. Quality-of-life data were calculated using a generic instrument, the EuroQol EQ-5D-3L. Results are expressed as incremental cost-effectiveness ratios and cost-effectiveness acceptability curves. RESULTS: The mean QALY difference (SWL vs URS) was -0.021 (95% confidence interval [CI] -0.033 to -0.010) and the mean cost difference was -£809 (95% CI -£1061 to -£551). The QALY difference translated into approximately 10 more healthy days over the 6-month period for the patients on the URS care pathway. The probabaility that SWL is cost-effective is 79% at a society's willingness to pay (WTP) threshold for 1 QALY of £30,000 and 98% at a WTP threshold of £20,000. CONCLUSION: The SWL pathway results in lower QALYs than URS but costs less. The incremental cost per QALY is £39 118 cost saving per QALY lost, with a 79% probability that SWL would be considered cost-effective at a WTP threshold for 1 QALY of £30 000 and 98% at a WTP threshold of £20 000. Decision-makers need to determine if costs saved justify the loss in QALYs.

PROSPECT: 4- and 6-year follow-up of a randomised trial of surgery for vaginal prolapse.

INTRODUCTION AND HYPOTHESIS: Our aim was to compare the mid-term results of native tissue, biological xenograft and polypropylene mesh surgery for women with vaginal wall prolapse. METHODS: A total of 1348 women undergoing primary transvaginal repair of an anterior and/or posterior prolapse were recruited between January 2010 and August 2013 from 35 UK centres. They were randomised by remote allocation to native tissue surgery, biological xenograft or polypropylene mesh. We performed both 4- and 6-year follow-up using validated patient-reported outcome measures. RESULTS: At 4 and 6 years post-operation, there was no clinically important difference in Pelvic Organ Prolapse Symptom Score for any of the treatments. Using a strict composite outcome to assess functional cure at 6 years, we found no difference in cure among the three types of surgery. Half the women were cured at 6 years but only 10.3 to 12% of women had undergone further surgery for prolapse. However, 8.4% of women in the mesh group had undergone further surgery for mesh complications. There was no difference in the incidence of chronic pain or dyspareunia between groups. CONCLUSIONS: At the mid-term outcome of 6 years, there is no benefit from augmenting primary prolapse repairs with polypropylene mesh inlays or biological xenografts. There was no evidence that polypropylene mesh inlays caused greater pain or dyspareunia than native tissue repairs.

Marine-derived n-3 fatty acids therapy for stroke.

BACKGROUND: Currently, with stroke burden increasing, there is a need to explore therapeutic options that ameliorate the acute insult. There is substantial evidence of a neuroprotective effect of marine-derived n-3 polyunsaturated fatty acids (PUFAs) in animal models of stroke, leading to a better functional outcome. OBJECTIVES: To assess the effects of administration of marine-derived n-3 PUFAs on functional outcomes and dependence in people with stroke. SEARCH METHODS: We searched the Cochrane Stroke Trials Register (last searched 31 May 2021), the Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 5), MEDLINE Ovid (from 1948 to 31 May 2021), Embase Ovid (from 1980 to 31 May 2021), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; from 1982 to 31 May 2021), Science Citation Index Expanded ‒ Web of Science (SCI-EXPANDED), Conference Proceedings Citation Index-Science - Web of Science (CPCI-S), and BIOSIS Citation Index. We also searched ongoing trial registers, reference lists, relevant systematic reviews, and used the Science Citation Index Reference Search. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing marine-derived n-3 PUFAs to placebo or open control (no placebo) in people with a history of stroke or transient ischaemic attack (TIA), or both. DATA COLLECTION AND ANALYSIS: At least two review authors independently selected trials for inclusion, extracted data, assessed risk of bias, and used the GRADE approach to assess the certainty of the body of evidence. We contacted study authors for clarification and additional information on stroke/TIA participants. We conducted random-effects meta-analysis or narrative synthesis, as appropriate. The primary outcome was efficacy (functional outcome) assessed using a validated scale, for example, the Glasgow Outcome Scale Extended (GOSE) dichotomised into poor or good clinical outcome, the Barthel Index (higher score is better; scale from 0 to 100), or the Rivermead Mobility Index (higher score is better; scale from 0 to 15). Our secondary outcomes were vascular-related death, recurrent events, incidence of other type of stroke, adverse events, quality of life, and mood. MAIN RESULTS: We included 30 RCTs; nine of them provided outcome data (3339 participants). Only one study included participants in the acute phase of stroke (haemorrhagic). Doses of marine-derived n-3 PUFAs ranged from 400 mg/day to 3300 mg/day. Risk of bias was generally low or unclear in most trials, with a higher risk of bias in smaller studies. We assessed results separately for short (up to three months) and longer (more than three months) follow-up studies. Short follow-up (up to three months) Functional outcome was reported in only one pilot study as poor clinical outcome assessed with the GOSE (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.36 to 1.68, P = 0.52; 40 participants; very low-certainty evidence). Mood (assessed with the GHQ-30, lower score better) was reported by only one study and favoured control (mean difference (MD) 1.41, 95% CI 0.07 to 2.75, P = 0.04; 102 participants; low-certainty evidence). We found no evidence of an effect of the intervention for the remainder of the secondary outcomes: vascular-related death (two studies, not pooled due to differences in population, RR 0.33, 95% CI 0.01 to 8.00, P = 0.50, and RR 0.33, 95% CI 0.01 to 7.72, P = 0.49; 142 participants; low-certainty evidence); recurrent events (RR 0.41, 95% CI 0.02 to 8.84, P = 0.57; 18 participants; very low-certainty evidence); incidence of other type of stroke (two studies, not pooled due to different type of index stroke, RR 6.11, 95% CI 0.33 to 111.71, P = 0.22, and RR 0.63, 95% CI 0.25 to 1.58, P = 0.32; 58 participants; very low-certainty evidence); and quality of life (physical component, MD -2.31, 95% CI -4.81 to 0.19, P = 0.07, and mental component, MD -2.16, 95% CI -5.91 to 1.59, P = 0.26; 1 study; 102 participants; low-certainty evidence). Adverse events were reported by two studies (57 participants; very low-certainty evidence), one trial reporting extracranial haemorrhage (RR 0.25, 95% CI 0.04 to 1.73, P = 0.16) and the other one reporting bleeding complications (RR 0.32, 95% CI 0.01 to 7.35, P = 0.47). Longer follow-up (more than three months) One small trial assessed functional outcome with both the Barthel Index for activities of daily living (MD 7.09, 95% CI -5.16 to 19.34, P = 0.26), and the Rivermead Mobility Index for mobility (MD 1.30, 95% CI -1.31 to 3.91, P = 0.33) (52 participants; very low-certainty evidence). We carried out meta-analysis for vascular-related death (RR 1.02, 95% CI 0.78 to 1.35, P = 0.86; 5 studies; 2237 participants; low-certainty evidence) and fatal recurrent events (RR 0.69, 95% CI 0.31 to 1.55, P = 0.37; 3 studies; 1819 participants; low-certainty evidence). We found no evidence of an effect of the intervention for mood (MD 1.00, 95% CI -2.07 to 4.07, P = 0.61; 1 study; 14 participants; low-certainty evidence). Incidence of other type of stroke and quality of life were not reported. Adverse events (all combined) were reported by only one study (RR 0.94, 95% CI 0.56 to 1.58, P = 0.82; 1455 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: We are very uncertain of the effect of marine-derived n-3 PUFAs therapy on functional outcomes and dependence after stroke as there is insufficient high-certainty evidence. More well-designed RCTs are needed, specifically in acute stroke, to determine the efficacy and safety of the intervention. Studies assessing functional outcome might consider starting the intervention as early as possible after the event, as well as using standardised, clinically relevant measures for functional outcomes, such as the modified Rankin Scale. Optimal doses remain to be determined; delivery forms (type of lipid carriers) and mode of administration (ingestion or injection) also need further consideration.

Development and validation of a risk prediction model of preterm birth for women with preterm labour symptoms (the QUIDS study): A prospective cohort study and individual participant data meta-analysis.

BACKGROUND: Timely interventions in women presenting with preterm labour can substantially improve health outcomes for preterm babies. However, establishing such a diagnosis is very challenging, as signs and symptoms of preterm labour are common and can be nonspecific. We aimed to develop and externally validate a risk prediction model using concentration of vaginal fluid fetal fibronectin (quantitative fFN), in combination with clinical risk factors, for the prediction of spontaneous preterm birth and assessed its cost-effectiveness. METHODS AND FINDINGS: Pregnant women included in the analyses were 22+0 to 34+6 weeks gestation with signs and symptoms of preterm labour. The primary outcome was spontaneous preterm birth within 7 days of quantitative fFN test. The risk prediction model was developed and internally validated in an individual participant data (IPD) meta-analysis of 5 European prospective cohort studies (2009 to 2016; 1,783 women; mean age 29.7 years; median BMI 24.8 kg/m2; 67.6% White; 11.7% smokers; 51.8% nulliparous; 10.4% with multiple pregnancy; 139 [7.8%] with spontaneous preterm birth within 7 days). The model was then externally validated in a prospective cohort study in 26 United Kingdom centres (2016 to 2018; 2,924 women; mean age 28.2 years; median BMI 25.4 kg/m2; 88.2% White; 21% smokers; 35.2% nulliparous; 3.5% with multiple pregnancy; 85 [2.9%] with spontaneous preterm birth within 7 days). The developed risk prediction model for spontaneous preterm birth within 7 days included quantitative fFN, current smoking, not White ethnicity, nulliparity, and multiple pregnancy. After internal validation, the optimism adjusted area under the curve was 0.89 (95% CI 0.86 to 0.92), and the optimism adjusted Nagelkerke R2 was 35% (95% CI 33% to 37%). On external validation in the prospective UK cohort population, the area under the curve was 0.89 (95% CI 0.84 to 0.94), and Nagelkerke R2 of 36% (95% CI: 34% to 38%). Recalibration of the model's intercept was required to ensure overall calibration-in-the-large. A calibration curve suggested close agreement between predicted and observed risks in the range of predictions 0% to 10%, but some miscalibration (underprediction) at higher risks (slope 1.24 (95% CI 1.23 to 1.26)). Despite any miscalibration, the net benefit of the model was higher than "treat all" or "treat none" strategies for thresholds up to about 15% risk. The economic analysis found the prognostic model was cost effective, compared to using qualitative fFN, at a threshold for hospital admission and treatment of ≥2% risk of preterm birth within 7 days. Study limitations include the limited number of participants who are not White and levels of missing data for certain variables in the development dataset. CONCLUSIONS: In this study, we found that a risk prediction model including vaginal fFN concentration and clinical risk factors showed promising performance in the prediction of spontaneous preterm birth within 7 days of test and has potential to inform management decisions for women with threatened preterm labour. Further evaluation of the risk prediction model in clinical practice is required to determine whether the risk prediction model improves clinical outcomes if used in practice. TRIAL REGISTRATION: The study was approved by the West of Scotland Research Ethics Committee (16/WS/0068). The study was registered with ISRCTN Registry (ISRCTN 41598423) and NIHR Portfolio (CPMS: 31277).

Cost-effectiveness and value of information analysis of NephroCheck and NGAL tests compared to standard care for the diagnosis of acute kidney injury.

BACKGROUND: Early and accurate acute kidney injury (AKI) detection may improve patient outcomes and reduce health service costs. This study evaluates the diagnostic accuracy and cost-effectiveness of NephroCheck and NGAL (urine and plasma) biomarker tests used alongside standard care, compared with standard care to detect AKI in hospitalised UK adults. METHODS: A 90-day decision tree and lifetime Markov cohort model predicted costs, quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) from a UK NHS perspective. Test accuracy was informed by a meta-analysis of diagnostic accuracy studies. Clinical trial and observational data informed the link between AKI and health outcomes, health state probabilities, costs and utilities. Value of information (VOI) analysis informed future research priorities. RESULTS: Under base case assumptions, the biomarker tests were not cost-effective with ICERs of £105,965 (NephroCheck), £539,041 (NGAL urine BioPorto), £633,846 (NGAL plasma BioPorto) and £725,061 (NGAL urine ARCHITECT) per QALY gained compared to standard care. Results were uncertain, due to limited trial data, with probabilities of cost-effectiveness at £20,000 per QALY ranging from 0 to 99% and 0 to 56% for NephroCheck and NGAL tests respectively. The expected value of perfect information (EVPI) was £66 M, which demonstrated that additional research to resolve decision uncertainty is worthwhile. CONCLUSIONS: Current evidence is inadequate to support the cost-effectiveness of general use of biomarker tests. Future research evaluating the clinical and cost-effectiveness of test guided implementation of protective care bundles is necessary. Improving the evidence base around the impact of tests on AKI staging, and of AKI staging on clinical outcomes would have the greatest impact on reducing decision uncertainty.

Marine-derived n-3 fatty acids therapy for stroke.

BACKGROUND: Currently, with stroke burden increasing, there is a need to explore therapeutic options that ameliorate the acute insult. There is substantial evidence of a neuroprotective effect of marine-derived n-3 polyunsaturated fatty acids (PUFAs) in experimental stroke, leading to a better functional outcome. OBJECTIVES: To assess the effects of administration of marine-derived n-3 PUFAs on functional outcomes and dependence in people with stroke.Our secondary outcomes were vascular-related death, recurrent events, incidence of other type of stroke, adverse events, quality of life, and mood. SEARCH METHODS: We searched the Cochrane Stroke Group trials register (6 August 2018), the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, January 2019), MEDLINE Ovid (from 1948 to 6 August 2018), Embase Ovid (from 1980 to 6 August 2018), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; from 1982 to 6 August 2018), Science Citation Index Expanded ‒ Web of Science (SCI-EXPANDED), Conference Proceedings Citation Index-Science - Web of Science (CPCI-S), and BIOSIS Citation Index. We also searched ongoing trial registers, reference lists, relevant systematic reviews, and used the Science Citation Index Reference Search. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing marine-derived n-3 PUFAs to placebo or open control (no placebo) in people with a history of stroke or transient ischaemic attack (TIA), or both. DATA COLLECTION AND ANALYSIS: At least two review authors independently selected trials for inclusion, extracted data, assessed risk of bias, and used the GRADE approach to assess the quality of the body of evidence. We contacted study authors for clarification and additional information on stroke/TIA participants. We conducted random-effects meta-analysis or narrative synthesis, as appropriate. The primary outcome was efficacy (functional outcome) assessed using a validated scale e.g. Glasgow Outcome Scale Extended (GOSE) dichotomised into poor or good clinical outcome, Barthel Index (higher score is better; scale from 0 to 100) or Rivermead Mobility Index (higher score is better; scale from 0 to 15). MAIN RESULTS: We included 29 RCTs; nine of them provided outcome data (3339 participants). Only one study included participants in the acute phase of stroke (haemorrhagic). Doses of marine-derived n-3 PUFAs ranged from 400 mg/day to 3300 mg/day. Risk of bias was generally low or unclear in most trials, with a higher risk of bias in smaller studies. We assessed results separately for short (up to three months) and longer (more than three months) follow-up studies.Short follow-up (up to three months)Functional outcome was reported in only one pilot study as poor clinical outcome assessed with GOSE (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.36 to 1.68; 40 participants; very low quality evidence). Mood (assessed with GHQ-30, lower score better), was reported by only one study and favoured control (mean difference (MD) 1.41, 95% CI 0.07 to 2.75; 102 participants; low-quality evidence).We found no evidence of an effect of the intervention for the remainder of the secondary outcomes: vascular-related death (two studies, not pooled due to differences in population, RR 0.33, 95% CI 0.01 to 8.00, and RR 0.33, 95% CI 0.01 to 7.72; 142 participants; low-quality evidence); recurrent events (RR 0.41, 95% CI 0.02 to 8.84; 18 participants; very low quality evidence); incidence of other type of stroke (two studies, not pooled due to different type of index stroke, RR 6.11, 95% CI 0.33 to 111.71, and RR 0.63, 95% CI 0.25 to 1.58; 58 participants; very low quality evidence); and quality of life (physical component mean difference (MD) -2.31, 95% CI -4.81 to 0.19, and mental component MD -2.16, 95% CI -5.91 to 1.59; one study; 102 participants; low-quality evidence).Adverse events were reported by two studies (57 participants; very low quality evidence), one trial reporting extracranial haemorrhage (RR 0.25, 95% CI 0.04 to 1.73) and the other one reporting bleeding complications (RR 0.32, 95% CI 0.01 to 7.35).Longer follow-up (more than three months)One small trial assessed functional outcome with both Barthel Index (MD 7.09, 95% CI -5.16 to 19.34) for activities of daily living, and Rivermead Mobility Index (MD 1.30, 95% CI -1.31 to 3.91) for mobility (52 participants; very low quality evidence). We carried out meta-analysis for vascular-related death (RR 1.02, 95% CI 0.78 to 1.35; five studies; 2237 participants; low-quality evidence) and fatal recurrent events (RR 0.69, 95% CI 0.31 to 1.55; three studies; 1819 participants; low-quality evidence).We found no evidence of an effect of the intervention for mood (MD 1.00, 95% CI -2.07 to 4.07; one study; 14 participants; low-quality evidence). Incidence of other type of stroke and quality of life were not reported.Adverse events (all combined) were reported by only one study (RR 0.94, 95% CI 0.56 to 1.58; 1455 participants; low-quality evidence). AUTHORS' CONCLUSIONS: We are very uncertain of the effect of marine-derived n-3 PUFAs therapy on functional outcomes and dependence after stroke as there is insufficient high-quality evidence. More well-designed RCTs are needed, specifically in acute stroke, to determine the efficacy and safety of the intervention.Studies assessing functionality might consider starting the intervention as early as possible after the event, as well as using standardised clinically-relevant measures for functional outcomes, such as the modified Rankin Scale. Optimal doses remain to be determined; delivery forms (type of lipid carriers) and mode of administration (ingestion or injection) also need further consideration.

A mixed-methods evaluation of a community pharmacy signposting service to a commercial weight-loss provider.

OBJECTIVE: Community pharmacies could provide access for clients to commercial weight management organizations. We evaluated recruitment, referral and outcomes of adults provided with free vouchers by community pharmacies to attend Scottish Slimmers classes. DESIGN: Prospective cohort design with qualitative interviews with clients and pharmacy personnel. Scottish Slimmers collected weight and attendance data. SETTING: Pharmacies in Aberdeen City, Scotland. SUBJECTS: Clients aged ≥18 years with BMI≥30 kg/m2. RESULTS: Ten of twenty-three pharmacies were recruited; eight successfully recruited clients. Of 129 clients recruited, ninety-seven (75 %) attended at least one class and fifty-one (40 %) attended all twelve classes. At baseline, clients' mean weight was 99·4 (sd 17·5) kg, mean BMI was 37·8 (sd 6·0) kg/m2. After 12 weeks, mean weight change was -3·7 % (last observation carried forward) or -2·8 % (baseline observation carried forward) for all ninety-seven clients. Client interviews indicated that many individuals would have not addressed their weight problems if this referral service had not been available. They had positive attitudes towards the pharmacy signposting service, attributed to the use of consultation rooms for privacy, receiving professional service from personnel and ongoing support and encouragement. The free provision of 12-week access facilitated participation. Service providers had positive attitudes and indicated their willingness to provide this service in future. CONCLUSIONS: Community pharmacies could be used to increase access to weight management services, with pharmacy personnel providing additional support to clients. Future provision of pharmacy referral schemes should be evaluated on a larger scale with an economic evaluation.

Changes in the relationship between asthma and associated risk factors over fifty years.

BACKGROUND: Childhood asthma is a common condition whose prevalence is changing. We hypothesized that the relationship between asthma and associated risk factors has changed over a 50-year period. METHODS: An ecological study design was used. Children aged 8-13 attending schools in Aberdeen city were surveyed on seven occasions between 1964 and 2014. The following were determined: history of asthma, history of eczema, parental smoking, parental asthma, sex and socio-economic status. Analysis was by a structural change model with two knots. The outcome reported was the change in odds ratio between asthma and a given risk factor during a given period. RESULTS: There were 23,241 questionnaires distributed and 17,439 returned (75%). The odds ratio (OR) for a child with asthma to have eczema increased between 1989 and 1999 by 1.031 [95% CI 1.028, 1.035] and by 1.042 between 2004 and 2014 [1.038, 1.047]. The OR for a child with asthma to have a parent who smoked rose by 1.032 [1.028, 1.036] between 1989 and 1999 and by 1.043 [1.038, 1.047] between 2004 and 2014), and to have a parent with asthma (1.027 [1.022, 1.031] for 1994-99 and 1.042 [1.037, 1.048] for 2004-2014). The OR for a child with asthma being male, but not and being from the most deprived communities, rose between 1989-1999 and 2004-2014. CONCLUSIONS: The relationship between asthma prevalence and particular risk factors changed over the 50-year period of study, and this might reflect changes in children's environment and/or susceptibility.

Differences in Body Mass Index between Siblings Who Are Discordant for Exposure to Antenatal Maternal Smoking.

BACKGROUND: Maternal smoking during pregnancy is associated with increased childhood body mass index (BMI), but the relationship may be due to confounding by maternal factors. This study tested the hypothesis that siblings born to mothers who begin to smoke between pregnancies will have higher BMI than older unexposed siblings. METHODS: Maternal details from the Aberdeen Maternity and Neonatal Databank were linked to the Study of Trends in Obesity in North East Scotland which holds offspring BMI at 5 years of age. Change in maternal smoking status between pregnancies was linked to offspring BMI and also to the difference in BMI between siblings. RESULTS: Maternal smoking status in successive pregnancies was linked to child BMI at age 5 years in 6581 mother-child pairs of whom 718 included sibling pars. Children whose mothers had quit, started smoking or smoked in consecutive pregnancies had higher BMI compared with those not exposed to maternal smoking. Siblings born after onset of maternal smoking had higher mean BMI z score (0.19, 95% confidence interval (CI) 0.01, 0.36) compared with unexposed older siblings. Mean BMI z score was also higher by mean of 0.10 (95% CI 0.01, 0.20) in younger sibling compared with older siblings born to mothers who smoked in both pregnancies. BMI z score was not significantly different between siblings whose mothers quit between pregnancies. CONCLUSIONS: In utero exposure to maternal smoking during pregnancy may increase the likelihood of increased BMI in childhood.

Maternal obesity in Africa: a systematic review and meta-analysis.

BACKGROUND: Maternal obesity is emerging as a public health problem, recently highlighted together with maternal under-nutrition as a 'double burden', especially in African countries undergoing social and economic transition. This systematic review was conducted to investigate the current evidence on maternal obesity in Africa. METHODS: MEDLINE, EMBASE, Scopus, CINAHL and PsycINFO were searched (up to August 2014) and identified 29 studies. Prevalence, associations with socio-demographic factors, labour, child and maternal consequences of maternal obesity were assessed. Pooled risk ratios comparing obese and non-obese groups were calculated. RESULTS: Prevalence of maternal obesity across Africa ranged from 6.5 to 50.7%, with older and multiparous mothers more likely to be obese. Obese mothers had increased risks of adverse labour, child and maternal outcomes. However, non-obese mothers were more likely to have low-birthweight babies. The differences in measurement and timing of assessment of maternal obesity were found across studies. No studies were identified either on the knowledge or attitudes of pregnant women towards maternal obesity; or on interventions for obese pregnant women. CONCLUSIONS: These results show that Africa's levels of maternal obesity are already having significant adverse effects. Culturally adaptable/sensitive interventions should be developed while monitoring to avoid undesired side effects.

Patterns of dietary intake and serum carotenoid and tocopherol status are associated with biomarkers of chronic low-grade systemic inflammation and cardiovascular risk.

Dietary modification may affect inflammatory processes and protect against chronic disease. In the present study, we examined the relationship between dietary patterns, circulating carotenoid and tocopherol concentrations, and biomarkers of chronic low-grade systemic inflammation in a 10-year longitudinal study of Scottish postmenopausal women. Diet was assessed by FFQ during 1997-2000 (n 3237, mean age 54·8 (SD 2·2) years). Participants (n 2130, mean age 66·0 (SD 2·2) years) returned during 2007-11 for follow-up. Diet was assessed by FFQ (n 1682) and blood was collected for the analysis of serum high-sensitivity C-reactive protein (hs-CRP), IL-6, serum amyloid A, E-selectin, lipid profile and dietary biomarkers (carotenoids, tocopherols and retinol). Dietary pattern and dietary biomarker (serum carotenoid) components were generated by principal components analysis. A past 'prudent' dietary pattern predicted serum concentrations of hs-CRP and IL-6 (which decreased across the quintiles of the dietary pattern; P= 0·002 and P= 0·001, respectively; ANCOVA). Contemporary dietary patterns were also associated with inflammatory biomarkers. The concentrations of hs-CRP and IL-6 decreased across the quintiles of the 'prudent' dietary pattern (P= 0·030 and P= 0·006, respectively). hs-CRP concentration increased across the quintiles of a 'meat-dominated' dietary pattern (P= 0·001). Inflammatory biomarker concentrations decreased markedly across the quintiles of carotenoid component score (P< 0·001 for hs-CRP and IL-6, and P= 0·016 for E-selectin; ANCOVA). Prudent dietary pattern and carotenoid component scores were negatively associated with serum hs-CRP concentration (unstandardised ß for prudent component: -0·053, 95% CI -0·102, -0·003; carotenoid component: -0·183, 95% CI -0·233, -0·134) independent of study covariates. A prudent dietary pattern (which reflects a diet high in the intakes of fish, yogurt, pulses, rice, pasta and wine, in addition to fruit and vegetable consumption) and a serum carotenoid profile characteristic of a fruit and vegetable-rich diet are associated with lower concentrations of intermediary markers that are indicative of CVD risk reduction.

Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis.

Sepsis is a massive inflammatory response mediated by infection, characterized by oxidative stress, release of cytokines, and mitochondrial dysfunction. Melatonin accumulates in mitochondria, and both it and its metabolites have potent antioxidant and anti-inflammatory activities and may be useful in sepsis. We undertook a phase I dose escalation study in healthy volunteers to assess the tolerability and pharmacokinetics of 20, 30, 50, and 100 mg oral doses of melatonin. In addition, we developed an ex vivo whole blood model under conditions mimicking sepsis to determine the bioactivity of melatonin and the major metabolite 6-hydroxymelatonin at relevant concentrations. For the phase I trial, oral melatonin was given to five subjects in each dose cohort (n = 20). Blood and urine were collected for measurement of melatonin and 6-hydroxymelatonin, and symptoms and physiological measures were assessed. Validated sleep scales were completed. No adverse effects after oral melatonin, other than mild transient drowsiness with no effects on sleeping patterns, were seen, and no symptoms were reported. Melatonin was rapidly cleared at all doses with a median [range] elimination half-life of 51.7 [29.5-63.2] min across all doses. There was considerable variability in maximum melatonin levels within each dose cohort, but 6-hydoxymelatonin sulfate levels were less variable and remained stable for several hours. For the ex vivo study, blood from 20 volunteers was treated with lipopolysaccharide and peptidoglycan plus a range of concentrations of melatonin/6-hydroxymelatonin. Both melatonin and 6-hydroxymelatonin had beneficial effects on sepsis-induced mitochondrial dysfunction, oxidative stress, and cytokine responses at concentrations similar to those achieved in vivo.

The monitoring of longer term prescriptions of antidepressants: observational study in a primary care setting.

BACKGROUND: There is little evidence to guide the frequency of review for patients taking antidepressants in the longer term. OBJECTIVES: To measure the frequency with which patients on longer term courses of antidepressants have their treatment monitored in primary care and to identify patient characteristics associated with the frequency of monitoring. METHODS: A cohort of patients who were receiving antidepressants continuously for at least two years was identified from four general practices. Data were collected from patients' general medical records. The dates of all GP consultations and whether they included a documented review of antidepressant therapy were recorded, along with patient characteristics hypothesized to influence the frequency of monitoring. RESULTS: The frequency of antidepressant review consultations and proportion of participants being reviewed during a specific year of antidepressant therapy decreased with increasing year of antidepressant therapy. Individuals who receive antidepressants for an overt mental health reason; undergo more dose and drug changes; and who are referred to the community mental health team have their antidepressant therapy reviewed more often during the first five years of antidepressant therapy. CONCLUSION: As many patients on longer term courses of antidepressants are not being appropriately reviewed, a 'chronic disease management approach' to depression in primary care is advocated.

Reducing drug related deaths: a pre-implementation assessment of knowledge, barriers and enablers for naloxone distribution through general practice.

BACKGROUND: The Scottish Naloxone Programme aims to reduce Scotland's high number of drug-related deaths (DRDs) caused by opiate overdose. It is currently implemented through specialist drug services but General Practitioners (GPs) are likely to have contact with drug using patients and their families and are therefore in an ideal position to direct them to naloxone schemes, or provide it themselves. This research gathered baseline data on GP's knowledge of and willingness to be involved in DRD prevention, including naloxone administration, prior to the implementation of primary care based delivery. METHODS: Mixed methods were used comprising a quantitative, postal survey and qualitative telephone interviews. A questionnaire was sent to 500 GPs across Scotland. An initial mailing was followed by a reminder. A shortened questionnaire containing seven key questions was posted as a final reminder. Telephone interviews were conducted with 17 GPs covering a range of demographic characteristics and drug user experience. RESULTS: A response rate of 55% (240/439) was achieved. There was some awareness of the naloxone programme but little involvement (3.3%), 9% currently provided routine overdose prevention, there was little involvement in displaying overdose prevention information (<20%). Knowledge of DRD risk was mixed. There was tentative willingness to be involved in naloxone prescribing with half of respondents willing to provide this to drug users or friends/family. However half were uncertain GP based naloxone provision was essential to reduce DRDs.Factors enabling naloxone distribution were: evidence of effectiveness, appropriate training, and adding to the local formulary. Interviewees had limited awareness of what naloxone distribution in primary care may involve and considered naloxone supply as a specialist service rather than a core GP role. Wider attitudinal barriers to involvement with this group were expressed. CONCLUSIONS: There was poor awareness of the Scottish National Naloxone Programme in participants. Results indicated GPs did not currently feel sufficiently skilled or knowledgeable to be involved in naloxone provision. Appropriate training was identified as a key requirement.

Short-stay urgent hospital admissions of children with convulsions: A mixed methods exploratory study to inform out of hospital care pathways.

OBJECTIVE: To inform interventions focused on safely reducing urgent paediatric short stay admissions (SSAs) for convulsions. METHODS: Routinely acquired administrative data from hospital admissions in Scotland between 2015-2017 investigated characteristics of unscheduled SSAs (an urgent admission where admission and discharge occur on the same day) for a diagnosis of febrile and/or afebrile convulsions. Semi-structured interviews to explore perspectives of health professionals (n = 19) making referral or admission decisions about convulsions were undertaken. Interpretation of mixed methods findings was complemented by interviews with four parents with experience of unscheduled SSAs of children with convulsion. RESULTS: Most SSAs for convulsions present initially at hospital emergency departments (ED). In a subset of 10,588 (11%) of all cause SSAs with linked general practice data available, 72 (37%) children with a convulsion contacted both the GP and ED pre-admission. Within 30 days of discharge, 10% (n = 141) of children admitted with afebrile convulsions had been readmitted to hospital with a further convulsion. Interview data suggest that panic and anxiety, through fear that the situation is life threatening, was a primary factor driving hospital attendance and admission. Lengthy waits to speak to appropriate professionals exacerbate parental anxiety and can trigger direct attendance at ED, whereas some children with complex needs had direct access to convulsion professionals. CONCLUSIONS: SSAs for convulsions are different to SSAs for other conditions and our findings could inform new efficient convulsion-specific pre and post hospital pathways designed to improve family experiences and reduce admissions and readmissions.

Antenatal size, early childhood growth, and asthma within a cohort created by data linkage.

INTRODUCTION: The gestation when small for gestational age (SGA) is first associated with asthma is not well understood. Here, we use routinely acquired data from 10 weeks gestation to up to 28 years of age to test the hypothesis that SGA before birth is associated with an increased risk for asthma in a large population born between 1987 and 2015. METHODS: Databases were linked to produce a single database that held antenatal fetal ultrasound measurements; maternal characteristics; birth measurements; childhood anthropometric measurements at age 5 years; hospital admission data (1987-2015); and family doctor prescribing (2009-2015). Asthma admission and receipt of any asthma medications were the outcomes. Analyses related single and then multiple anthropometric measurements to asthma outcomes. RESULTS: Outcome data were available for 63,930 individuals. Increased length in the first-trimester size was associated with a reduced odds ratio (OR) for asthma admission of 0.991 [0.983, 0.998] per mm increase and also a shorter time to first admission, with a hazard ratio risk of 0.987 [0.980, 0.994] per mm increase. Independent of all earlier measurements, increased height at 5 years (available in a subset of 15,760) was associated with reduced OR for an asthma admission, with OR of 0.874 [0.790, 0.967] per z score. Longitudinal measurements of weight were not related to asthma outcomes. CONCLUSIONS: Longer first-trimester length is associated with more favorable asthma outcomes, and subsequently, increased height in childhood is also independently associated with more favorable asthma outcomes. Interventions that reduce SGA and encourage healthy postnatal growth might improve asthma outcomes.

Insights from and limitations of data linkage studies: analysis of short-stay urgent admission referral source from routinely collected Scottish data.

INTRODUCTION: This study identified the referral source for urgent short-stay admissions (SSAs) and compared characteristics of children with SSA stratified by different referral sources. METHODS: Routinely acquired data from urgent admissions to Scottish hospitals during 2015-2017 were linked to data held by the three referral sources: emergency department (ED), out-of-hours (OOH) service and general practice (GP). RESULTS: There were 171 039 admissions including 92 229 (54%) SSAs. Only 171 (19%) of all of Scotland's GP practices contributed data. Among the subgroup of 10 588 SSAs where GP data were available (11% all SSA), there was contact with the following referral source on the day of admission: only ED, 1853 (18%); only GP, 3384 (32%); and only OOH, 823 (8%). Additionally, 2165 (20%) had contact with more than one referral source, and 1037 (10%) had contact with referral source(s) on the day before the admission. When all 92 229 SSAs were considered, those with an ED referrer were more likely to be for older children, of white ethnicity, living in more deprived communities and diagnosed with asthma, convulsions or croup. The odds ratio for an SSA for a given condition differed by referral source and ranged from 0.07 to 1.9 (with reference to ED referrals). CONCLUSION: This study yielded insights and potential limitations regarding data linkage in a healthcare setting. Data coverage, particularly from primary care, needs to improve further. Evidence from data linkage studies can inform future intervention designed to provide safe integrated care pathways.

Identifying and prioritising future interventions with stakeholders to improve paediatric urgent care pathways in Scotland, UK: a mixed-methods study.

OBJECTIVES: To identify and prioritise interventions, from the perspectives of parents and health professionals, which may be alternatives to current unscheduled paediatric urgent care pathways. DESIGN: FLAMINGO (FLow of AdMissions in chIldren and youNG peOple) is a sequential mixed-methods study, with public and patient involvement (PPI) throughout. Data linkage for urgent admissions and three referral sources: emergency department, out of hours service and general practice, was followed by qualitative interviews with parents and professionals. Findings were presented and discussed at a stakeholder intervention prioritisation event. SETTING: National Health Service in Scotland, UK. PARTICIPANTS: Quantitative data: children with urgent medical admission to hospital from 2015 to 2017. Qualitative interviews: parents and health professionals with experiences of urgent short stay hospital admissions of children. PPI engagement was conducted with nine parent-toddler groups and a university-based PPI advisory group. Stakeholder event: parents, health professionals and representatives from Scottish Government, academia, charities and PPI attended. RESULTS: Data for 171 039 admissions which included 92 229 short stay admissions were analysed and 48 health professionals and 21 parents were interviewed. The stakeholder event included 7 parents, 12 health professionals and 28 other stakeholders. Analysis and synthesis of all data identified seven interventions which were prioritised at the stakeholder event: (1) addressing gaps in acute paediatric skills of health professionals working in community settings; (2) assessment and observation of acutely unwell children in community settings; (3) creation of holistic children's 'hubs'; (4) adoption of 'hospital at home' models; and three specialised care pathways for subgroups of children; (5) convulsions; (6) being aged <2 years old; and (7) wheeze/bronchiolitis. Stakeholders prioritised interventions 1, 2 and 3; these could be combined into a whole population intervention. Barriers to progressing these include resources, staffing and rurality. CONCLUSIONS: Health professionals and families want future interventions that are patient-centred, community-based and aligned to outcomes that matter to them.