BackgroundConventional measures to evaluate COPD may fail to capture systemic problems, particularly musculoskeletal weakness and cardiovascular disease. Identifying these manifestations and assessing their association with clinical outcomes (ie, mortality, exacerbation and COPD hospital admission) is of increasing clinical importance.ObjectiveTo assess associations between 6 min walk distance (6MWD), heart rate, fibrinogen, C reactive protein (CRP), white cell count (WCC), interleukins 6 and 8 (IL-6 and IL-8), tumour necrosis factor-alpha, quadriceps maximum voluntary contraction, sniff nasal inspiratory pressure, short physical performance battery, pulse wave velocity, carotid intima-media thickness and augmentation index and clinical outcomes in patients with stable COPD.MethodsWe systematically searched electronic databases (August 2018) and identified 61 studies, which were synthesised, including meta-analyses to estimate pooled HRs, following Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.ResultsShorter 6MWD and elevated heart rate, fibrinogen, CRP and WCC were associated with higher risk of mortality. Pooled HRs were 0.80 (95% CI 0.73 to 0.89) per 50 m longer 6MWD, 1.10 (95% CI 1.02 to 1.18) per 10 bpm higher heart rate, 3.13 (95% CI 2.14 to 4.57) per twofold increase in fibrinogen, 1.17 (95% CI 1.06 to 1.28) per twofold increase in CRP and 2.07 (95% CI 1.29 to 3.31) per twofold increase in WCC. Shorter 6MWD and elevated fibrinogen and CRP were associated with exacerbation, and shorter 6MWD, higher heart rate, CRP and IL-6 were associated with hospitalisation. Few studies examined associations with musculoskeletal measures.ConclusionFindings suggest 6MWD, heart rate, CRP, fibrinogen and WCC are associated with clinical outcomes in patients with stable COPD. Use of musculoskeletal measures to assess outcomes in patients with COPD requires further investigation.Trial registration numberCRD42016052075.

BackgroundAlthough obesity is a well-known risk factor for adverse pregnancy outcomes, evidence is sparse about the effects of interpregnancy weight change on the risk of adverse perinatal complications in a subsequent pregnancy. The current study aims to assess the effect of interpregnancy weight change on the risk of developing gestational diabetes, pre-eclampsia, pregnancy induced hypertension, preterm birth, or delivering a large- or small-for-gestational age neonate.MethodsPubmed, Ovid Embase, ClinicalTrial.gov and the Cochrane library were systematically searched up until July 24th, 2019. Interpregnancy weight change was defined as the difference between pre-pregnancy weight of an index pregnancy and a consecutive pregnancy. Inclusion criteria included full text original articles reporting quantitative data about interpregnancy weight change in multiparous women with any time interval between consecutive births and the risk of any perinatal complication of interest. Studies reporting adjusted odds ratios and a reference group of − 1 to + 1 BMI unit change between pregnancies were harmonised by meta-analysis.ResultsTwenty-three cohort studies identified a total of 671,906 women with two or more consecutive pregnancies. Seven of these studies were included in the meta-analysis (280,672 women). Interpregnancy weight gain was consistently associated with a higher risk of gestational diabetes, pre-eclampsia, pregnancy induced hypertension and large-for-gestational age births. In contrast, interpregnancy weight loss was associated with a lower risk of delivering a large-for-gestational age neonate. The effect magnitude (relative risk) of interpregnancy weight gain on pregnancy induced hypertension or delivering a large-for-gestational age neonate was greater among women with a normal BMI in the index pregnancy compared to women with a starting BMI ≥25 kg/m2.ConclusionThese findings confirm that interpregnancy weight change impacts the risk of developing perinatal complications in a subsequent pregnancy. This provides evidence in support of guidelines encouraging women to achieve post-partum weight loss, as their risk of perinatal complications might be minimised if they return to their pre-pregnancy weight before conceiving again.Prospectively registered with PROSPERO (CRD42017067326).

Background Pre-term pre-eclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide. A multi-centre randomized–controlled trial has shown that first-trimester screening followed by treatment of high-risk women with aspirin reduces the risk of pre-term pre-eclampsia. However, the biomarkers currently employed in risk prediction are only weakly associated with the outcome. Methods We conducted a case–cohort study within the Pregnancy Outcome Prediction study to analyse untargeted maternal serum metabolomics in samples from 12, 20, 28 and 36 weeks of gestational age (wkGA) in women with pre-eclampsia delivering at term (n = 165) and pre-term (n = 29), plus a random sample of the cohort (n = 325). We used longitudinal linear mixed models to identify candidate metabolites at 20/28 wkGA that differed by term pre-eclampsia status. Candidates were validated using measurements at 36 wkGA in the same women. We then tested the association between the 12-, 20- and 28-wkGA measurements and pre-term pre-eclampsia. We externally validated the association using 24- to 28-wkGA samples from the Born in Bradford study (25 cases and 953 controls). Results We identified 100 metabolites that differed most at 20/28 wkGA in term pre-eclampsia. Thirty-three of these were validated (P < 0.0005) at 36 wkGA. 4-Hydroxyglutamate and C-glycosyltryptophan were independently predictive at 36 wkGA of term pre-eclampsia. 4-Hydroxyglutamate was also predictive (area under the receiver operating characteristic curve, 95% confidence interval) of pre-term pre-eclampsia at 12 (0.673, 0.558–0.787), 20 (0.731, 0.657–0.806) and 28 wkGA (0.733, 0.627–0.839). The predictive ability of 4-hydroxyglutamate at 12 wkGA was stronger than two existing protein biomarkers, namely PAPP-A (0.567, 0.439–0.695) and placenta growth factor (0.589, 0.463–0.714). Finally, 4-hydroxyglutamate at 24–28 wkGA was positively associated with pre-eclampsia (term or pre-term) among women from the Born in Bradford study. Conclusions 4-hydroxyglutamate is a novel biochemical predictor of pre-eclampsia that provides better first-trimester prediction of pre-term disease than currently employed protein biomarkers.

SummaryBackgroundA third of deaths in the UK from ruptured abdominal aortic aneurysm (AAA) are in women. In men, national screening programmes reduce deaths from AAA and are cost-effective. The benefits, harms, and cost-effectiveness in offering a similar programme to women have not been formally assessed, and this was the aim of this study.MethodsWe developed a decision model to assess predefined outcomes of death caused by AAA, life years, quality-adjusted life years, costs, and the incremental cost-effectiveness ratio for a population of women invited to AAA screening versus a population who were not invited to screening. A discrete event simulation model was set up for AAA screening, surveillance, and intervention. Relevant women-specific parameters were obtained from sources including systematic literature reviews, national registry or administrative databases, major AAA surgery trials, and UK National Health Service reference costs.FindingsAAA screening for women, as currently offered to UK men (at age 65 years, with an AAA diagnosis at an aortic diameter of ≥3·0 cm, and elective repair considered at ≥5·5cm) gave, over 30 years, an estimated incremental cost-effectiveness ratio of £30 000 (95% CI 12 000–87 000) per quality-adjusted life year gained, with 3900 invitations to screening required to prevent one AAA-related death and an overdiagnosis rate of 33%. A modified option for women (screening at age 70 years, diagnosis at 2·5 cm and repair at 5·0 cm) was estimated to have an incremental cost-effectiveness ratio of £23 000 (9500–71 000) per quality-adjusted life year and 1800 invitations to screening required to prevent one AAA-death, but an overdiagnosis rate of 55%. There was considerable uncertainty in the cost-effectiveness ratio, largely driven by uncertainty about AAA prevalence, the distribution of aortic sizes for women at different ages, and the effect of screening on quality of life.InterpretationBy UK standards, an AAA screening programme for women, designed to be similar to that used to screen men, is unlikely to be cost-effective. Further research on the aortic diameter distribution in women and potential quality of life decrements associated with screening are needed to assess the full benefits and harms of modified options.FundingUK National Institute for Health Research Health Technology Assessment programme.

AimsWe aimed to (1) assess the association between lipoprotein(a) [Lp(a)] concentration and incident type-2 diabetes in the Bruneck study, a prospective population-based study, and (2) combine findings with evidence from published studies in a literature-based meta-analysis.MethodsWe used Cox proportional hazards models to calculate hazard ratios (HR) for incident type-2 diabetes over 20 years of follow-up in 815 participants of the Bruneck study according to their long-term average Lp(a) concentration. For the meta-analysis, we searched Medline, Embase and Web of Science for relevant prospective cohort studies published up to October 2016.ResultsIn the Bruneck study, there was a 12% higher risk of type-2 diabetes for a one standard deviation lower concentration of log Lp(a) (HR = 1.12 [95% CI 0.95–1.32]; P = 0.171), after adjustment for age, sex, alcohol consumption, body mass index, smoking status, socioeconomic status, physical activity, systolic blood pressure, HDL cholesterol, log high-sensitivity C-reactive protein and waist–hip ratio. In a meta-analysis involving four prospective cohorts with a total of 74,575 participants and 4514 incident events, the risk of type-2 diabetes was higher in the lowest two quintiles of Lp(a) concentrations (weighted mean Lp(a) = 3.3 and 7.0 mg/dL, respectively) compared to the highest quintile (62.9 mg/dL), with the highest risk of type-2 diabetes seen in quintile 1 (HR = 1.28 [1.14–1.43]; P < 0.001).ConclusionsThe current available evidence from prospective studies suggests that there is an inverse association between Lp(a) concentration and risk of type-2 diabetes, with a higher risk of type-2 diabetes at low Lp(a) concentrations (approximately <7 mg/dL).Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-017-0520-z) contains supplementary material, which is available to authorized users.

Missing values are common in health research and omitting participants with missing data often leads to loss of statistical power, biased estimates and, consequently, inaccurate inferences. We critically reviewed the challenges posed by missing data in medical research and approaches to address them. To achieve this more efficiently, these issues were analyzed and illustrated through a systematic review on the reporting of missing data and imputation methods (prediction of missing values through relationships within and between variables) undertaken in risk prediction studies of undiagnosed diabetes. Prevalent diabetes risk models were selected based on a recent comprehensive systematic review, supplemented by an updated search of English-language studies published between 1997 and 2014. Reporting of missing data has been limited in studies of prevalent diabetes prediction. Of the 48 articles identified, 62.5% (n = 30) did not report any information on missing data or handling techniques. In 21 (43.8%) studies, researchers opted out of imputation, completing case-wise deletion of participants missing any predictor values. Although imputation methods are encouraged to handle missing data and ensure the accuracy of inferences, this has seldom been the case in studies of diabetes risk prediction. Hence, we elaborated on the various types and patterns of missing data, the limitations of case-wise deletion and state-of the-art methods of imputations and their challenges. This review highlights the inexperience or disregard of investigators of the effect of missing data in risk prediction research. Formal guidelines may enhance the reporting and appropriate handling of missing data in scientific journals.

Background/Objectives: Blood donors attending a donation session may be deferred from donating blood due to a failure to meet low hemoglobin (Hb) thresholds. This costs the blood donor service, and donors, valuable time and resources. In addition, donors who are deferred may have more symptoms and as a direct and/or indirect effect of their experience return rates of donors deferred for low Hb are reduced, even in repeat donors. It is therefore vital that low Hb deferral (LHD) is minimized. The aim of this updated systematic review is to expand the evidence base for factors which affect a donor's risk of deferral due to low Hb. Materials/Methods: Studies were identified by searching MEDLINE, Embase, The Cochrane Library and the WHO International Clinical Trials Registry to March 2019. Demographic data, donor history, hematological/biological factors and the primary outcome of deferral due to low Hb were extracted. Our primary outcome was deferral due to low Hb. Analyses were descriptive and quantitative; pooled odds ratios (ORs) and 95% confidence intervals (CIs) were obtained by meta-analysis using random effects models. Results: A total of 116 studies met the inclusion criteria. Meta-analysis showed a significantly greater risk of LHD in females compared with males in studies applying universal Hb thresholds for males and females (OR 14.62 95%CI 12.43-17.19) and in those which used sex-specific thresholds (OR 5.73, 95%CI 4.36-7.53). Higher rates of LHD were also associated with increasing age in men, low body weight, shorter inter-donation interval, donors of Hispanic or African descent, higher ambient temperature, donors with low ferritin levels and donation in a fixed donor center. There was conflicting evidence on the effect of new and repeat donor status, and blood group. Conclusion: This work has strengthened the evidence of the previous review in identifying factors that should be considered in studies of donor deferral and highlighting areas in need of further study, including ABO and Rh blood groups, previous platelet donation, diet, smoking, time of day, and genetic data. These factors may lead to individually tailored donation criteria for safe and efficient donation in the future.

BackgroundThe frequencies of apolipoprotein L1 (APOL1) variants and their associations with chronic kidney disease (CKD) vary substantially in populations from Africa. Moreover, available studies have used very small sample sizes to provide reliable estimates of the frequencies of these variants in the general population. We determined the frequency of the two APOL1 risk alleles (G1 and G2) and investigated their association with renal traits in a relatively large sample of mixed-ancestry South Africans. APOL1 risk variants (G1: rs60910145 and rs73885319; G2: rs71785313) were genotyped in 859 African mixed ancestry individuals using allele-specific TaqMan technology. Glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations.ResultsThe frequencies of rs73885319, rs60910145 and rs71785313 risk alleles were respectively, 3.6 %, 3.4 %, and 5.8 %, resulting in a 1.01 % frequency of the APOL1 two-risk allele (G1:G1 or G1:G2 or G2:G2). The presence of the two-risk allele increased serum creatinine with a corresponding reduction in eGFR (either MDRD or CKD-EPI based). In dominant and log-additive genetic models, significant associations were found between rs71785313 and systolic blood pressure (both p ≤ 0.025), with a significant statistical interaction by diabetes status, p = 0.022, reflecting a negative non-significant effect in nondiabetics and a positive effect in diabetics.ConclusionsAlthough the APOL1 variants are not common in the mixed ancestry population of South Africa, the study does provide an indication that APOL1 variants may play a role in conferring an increased risk for renal and cardiovascular risk in this population.