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Cardiovascular risk factors are associated with an increased risk of dementia. We assessed whether a multidomain intervention targeting these factors can prevent dementia in a population of community-dwelling older people. In this open-label, cluster-randomised controlled trial, we recruited individuals aged 70–78 years through participating general practices in the Netherlands. General practices within each health-care centre were randomly assigned (1:1), via a computer-generated randomisation sequence, to either a 6-year nurse-led, multidomain cardiovascular intervention or control (usual care). The primary outcomes were cumulative incidence of dementia and disability score (Academic Medical Center Linear Disability Score [ALDS]) at 6 years of follow-up. The main secondary outcomes were incident cardiovascular disease and mortality. Outcome assessors were masked to group assignment. Analyses included all participants with available outcome data. This trial is registered with ISRCTN, number ISRCTN29711771. Between June 7, 2006, and March 12, 2009, 116 general practices (3526 participants) within 26 health-care centres were recruited and randomly assigned: 63 (1890 participants) were assigned to the intervention group and 53 (1636 participants) to the control group. Primary outcome data were obtained for 3454 (98%) participants; median follow-up was 6·7 years (21 341 person-years). Dementia developed in 121 (7%) of 1853 participants in the intervention group and in 112 (7%) of 1601 participants in the control group (hazard ratio [HR] 0·92, 95% CI 0·71–1·19; p=0·54). Mean ALDS scores measured during follow-up did not differ between groups (85·7 [SD 6·8] in the intervention group and 85·7 [7·1] in the control group; adjusted mean difference −0·02, 95% CI −0·38 to 0·42; p=0·93). 309 (16%) of 1885 participants died in the intervention group, compared with 269 (16%) of 1634 participants in the control group (HR 0·98, 95% CI 0·80–1·18; p=0·81). Incident cardiovascular disease did not differ between groups (273 [19%] of 1469 participants in the intervention group and 228 [17%] of 1307 participants in the control group; HR 1·06, 95% CI 0·86–1·31; p=0·57). A nurse-led, multidomain intervention did not result in a reduced incidence of all-cause dementia in an unselected population of older people. This absence of effect might have been caused by modest baseline cardiovascular risks and high standards of usual care. Future studies should assess the efficacy of such interventions in selected populations. Dutch Ministry of Health, Welfare and Sport; Dutch Innovation Fund of Collaborative Health Insurances; and Netherlands Organisation for Health Research and Development.

There are two common misconceptions about case-control studies: that matching in itself eliminates (controls) confounding by the matching factors, and that if matching has been performed, then a “matched analysis” is required. However, matching in a case-control study does not control for confounding by the matching factors; in fact it can introduce confounding by the matching factors even when it did not exist in the source population. Thus, a matched design may require controlling for the matching factors in the analysis. However, it is not the case that a matched design requires a matched analysis. Provided that there are no problems of sparse data, control for the matching factors can be obtained, with no loss of validity and a possible increase in precision, using a “standard” (unconditional) analysis, and a “matched” (conditional) analysis may not be required or appropriate.

In November, 2015, an epidemic of microcephaly was reported in Brazil, which was later attributed to congenital Zika virus infection. 7830 suspected cases had been reported to the Brazilian Ministry of Health by June 4, 2016, but little is known about their characteristics. We aimed to describe these newborn babies in terms of clinical findings, anthropometry, and survival. We reviewed all 1501 liveborn infants for whom investigation by medical teams at State level had been completed as of Feb 27, 2016, and classified suspected cases into five categories based on neuroimaging and laboratory results for Zika virus and other relevant infections. Definite cases had laboratory evidence of Zika virus infection; highly probable cases presented specific neuroimaging findings, and negative laboratory results for other congenital infections; moderately probable cases had specific imaging findings but other infections could not be ruled out; somewhat probable cases had imaging findings, but these were not reported in detail by the local teams; all other newborn babies were classified as discarded cases. Head circumference by gestational age was assessed with InterGrowth standards. First week mortality and history of rash were provided by the State medical teams. Between Nov 19, 2015, and Feb 27, 2015, investigations were completed for 1501 suspected cases reported to the Brazilian Ministry of Health, of whom 899 were discarded. Of the remainder 602 cases, 76 were definite, 54 highly probable, 181 moderately probable, and 291 somewhat probable of congenital Zika virus syndrome. Clinical, anthropometric, and survival differences were small among the four groups. Compared with these four groups, the 899 discarded cases had larger head circumferences (mean Z scores −1·54 vs −3·13, difference 1·58 [95% CI 1·45–1·72]); lower first-week mortality (14 per 1000 vs 51 per 1000; rate ratio 0·28 [95% CI 0·14–0·56]); and were less likely to have a history of rash during pregnancy (20·7% vs 61·4%, ratio 0·34 [95% CI 0·27–0·42]). Rashes in the third trimester of pregnancy were associated with brain abnormalities despite normal sized heads. One in five definite or probable cases presented head circumferences in the normal range (above −2 SD below the median of the InterGrowth standard) and for one third of definite and probable cases there was no history of a rash during pregnancy. The peak of the epidemic occurred in late November, 2015. Zika virus congenital syndrome is a new teratogenic disease. Because many definite or probable cases present normal head circumference values and their mothers do not report having a rash, screening criteria must be revised in order to detect all affected newborn babies. Brazilian Ministry of Health, Pan American Health Organization, and Wellcome Trust.

Age-associated motor and cognitive deficits increase the risk of falls, a major cause of morbidity and mortality. Because of the significant ramifications of falls, many interventions have been proposed, but few have aimed to prevent falls via an integrated approach targeting both motor and cognitive function. We aimed to test the hypothesis that an intervention combining treadmill training with non-immersive virtual reality (VR) to target both cognitive aspects of safe ambulation and mobility would lead to fewer falls than would treadmill training alone. We carried out this randomised controlled trial at five clinical centres across five countries (Belgium, Israel, Italy, the Netherlands, and the UK). Adults aged 60–90 years with a high risk of falls based on a history of two or more falls in the 6 months before the study and with varied motor and cognitive deficits were randomly assigned by use of computer-based allocation to receive 6 weeks of either treadmill training plus VR or treadmill training alone. Randomisation was stratified by subgroups of patients (those with a history of idiopathic falls, those with mild cognitive impairment, and those with Parkinson's disease) and sex, with stratification per clinical site. Group allocation was done by a third party not involved in onsite study procedures. Both groups aimed to train three times per week for 6 weeks, with each session lasting about 45 min and structured training progression individualised to the participant's level of performance. The VR system consisted of a motion-capture camera and a computer-generated simulation projected on to a large screen, which was specifically designed to reduce fall risk in older adults by including real-life challenges such as obstacles, multiple pathways, and distracters that required continual adjustment of steps. The primary outcome was the incident rate of falls during the 6 months after the end of training, which was assessed in a modified intention-to-treat population. Safety was assessed in all patients who were assigned a treatment. This study is registered with ClinicalTrials.gov, NCT01732653. Between Jan 6, 2013, and April 3, 2015, 302 adults were randomly assigned to either the treadmill training plus VR group (n=154) or treadmill training alone group (n=148). Data from 282 (93%) participants were included in the prespecified, modified intention-to-treat analysis. Before training, the incident rate of falls was similar in both groups (10·7 [SD 35·6] falls per 6 months for treadmill training alone vs 11·9 [39·5] falls per 6 months for treadmill training plus VR). In the 6 months after training, the incident rate was significantly lower in the treadmill training plus VR group than it had been before training (6·00 [95% CI 4·36–8·25] falls per 6 months; p<0·0001 vs before training), whereas the incident rate did not decrease significantly in the treadmill training alone group (8·27 [5·55–12·31] falls per 6 months; p=0·49). 6 months after the end of training, the incident rate of falls was also significantly lower in the treadmill training plus VR group than in the treadmill training group (incident rate ratio 0·58, 95% CI 0·36–0·96; p=0·033). No serious training-related adverse events occurred. In a diverse group of older adults at high risk for falls, treadmill training plus VR led to reduced fall rates compared with treadmill training alone. European Commission.

Immobilisation predicts adverse outcomes in patients in the surgical intensive care unit (SICU). Attempts to mobilise critically ill patients early after surgery are frequently restricted, but we tested whether early mobilisation leads to improved mobility, decreased SICU length of stay, and increased functional independence of patients at hospital discharge. We did a multicentre, international, parallel-group, assessor-blinded, randomised controlled trial in SICUs of five university hospitals in Austria (n=1), Germany (n=1), and the USA (n=3). Eligible patients (aged 18 years or older, who had been mechanically ventilated for <48 h, and were expected to require mechanical ventilation for ≥24 h) were randomly assigned (1:1) by use of a stratified block randomisation via restricted web platform to standard of care (control) or early, goal-directed mobilisation using an inter-professional approach of closed-loop communication and the SICU optimal mobilisation score (SOMS) algorithm (intervention), which describes patients’ mobilisation capacity on a numerical rating scale ranging from 0 (no mobilisation) to 4 (ambulation). We had three main outcomes hierarchically tested in a prespecified order: the mean SOMS level patients achieved during their SICU stay (primary outcome), and patient's length of stay on SICU and the mini-modified functional independence measure score (mmFIM) at hospital discharge (both secondary outcomes). This trial is registered with ClinicalTrials.gov (NCT01363102). Between July 1, 2011, and Nov 4, 2015, we randomly assigned 200 patients to receive standard treatment (control; n=96) or intervention (n=104). Intention-to-treat analysis showed that the intervention improved the mobilisation level (mean achieved SOMS 2·2 [SD 1·0] in intervention group vs 1·5 [0·8] in control group, p<0·0001), decreased SICU length of stay (mean 7 days [SD 5–12] in intervention group vs 10 days [6–15] in control group, p=0·0054), and improved functional mobility at hospital discharge (mmFIM score 8 [4–8] in intervention group vs 5 [2–8] in control group, p=0·0002). More adverse events were reported in the intervention group (25 cases [2·8%]) than in the control group (ten cases [0·8%]); no serious adverse events were observed. Before hospital discharge 25 patients died (17 [16%] in the intervention group, eight [8%] in the control group). 3 months after hospital discharge 36 patients died (21 [22%] in the intervention group, 15 [17%] in the control group). Early, goal-directed mobilisation improved patient mobilisation throughout SICU admission, shortened patient length of stay in the SICU, and improved patients’ functional mobility at hospital discharge. Jeffrey and Judy Buzen.

Estimates of familial risk of inflammatory bowel diseases (IBDs), Crohn's disease (CD), and ulcerative colitis (UC) are needed for counseling of patients and could be used to target future prevention. We aimed to provide comprehensive population-based estimates of familial risk of IBD. The study encompassed the entire Danish population during 1977-2011 (N=8,295,773; 200 million person-years). From national registries, we obtained information on diagnosis date of IBD (N=45,780) and family ties. Using Poisson regression, we estimated incidence rate ratios (IRRs) of IBD in relatives of IBD cases compared with individuals with relatives of the same type without IBD. The risk of CD was significantly increased in first-degree (IRR, 7.77; 95% confidence interval (CI), 7.05-8.56), second-degree (IRR, 2.44; 95% CI, 2.01-2.96), and third-degree relatives (IRR, 1.88; 95% CI, 1.30-2.71) to patients with CD, and was less pronounced in relatives to UC cases. Likewise, the risk of UC was increased in first-degree (IRR, 4.08; 95% CI, 3.81-4.38), second-degree (IRR, 1.85; 95% CI, 1.60-2.13), and third-degree relatives (IRR, 1.51; 95% CI, 1.07-2.12) of UC cases, and less pronounced in relatives of CD cases. IRRs increased with two or more IBD-affected relatives and were modified by age, with the highest family-related IRR observed in early life. The risk of IBD is significantly increased in first -, second-, and third-degree relatives of IBD-affected cases, with up to 12% of all IBD cases being family cases. The risk is particularly pronounced in young individuals.

The Paris climate agreement aims at holding global warming to well below 2 degrees Celsius and to “pursue efforts” to limit it to 1.5 degrees Celsius. To accomplish this, countries have submitted Intended Nationally Determined Contributions (INDCs) outlining their post-2020 climate action. Here we assess the effect of current INDCs on reducing aggregate greenhouse gas emissions, its implications for achieving the temperature objective of the Paris climate agreement, and potential options for overachievement. The INDCs collectively lower greenhouse gas emissions compared to where current policies stand, but still imply a median warming of 2.6–3.1 degrees Celsius by 2100. More can be achieved, because the agreement stipulates that targets for reducing greenhouse gas emissions are strengthened over time, both in ambition and scope. Substantial enhancement or over-delivery on current INDCs by additional national, sub-national and non-state actions is required to maintain a reasonable chance of meeting the target of keeping warming well below 2 degrees Celsius. The objective of the Paris climate agreement is to limit global-average temperature increase to well below 2 degrees Celsius above pre-industrial levels and to further pursue limiting it to 1.5 degrees Celsius; here, the adequacy of the national plans submitted in preparation for this agreement is assessed, and it is concluded that substantial enhancement or over-delivery on these plans is required to have a reasonable chance of achieving the Paris climate objective. Paris climate action plans assessed The principal climate goal of the Paris Agreement of December 2015 is to hold the increase in the global average temperature to well below 2 degrees Celsius above pre-industrial levels and to pursue efforts to limit the temperature increase to 1.5 degrees above pre-industrial levels. This Perspective assesses the national plans submitted to the Paris meeting for post-2020 action to reduce global greenhouse gas emission by 2030. It also provides projections for global mean temperature increase over the twenty-first century that would be consistent with the present national plans and discusses options that may help to reduce greenhouse gas emissions to levels that are more consistent with maintaining a reasonable chance of meeting the well below 2 degrees Celsius climate target.

BACKGROUND:When exposure is infrequent, propensity-score matching results in reduced precision because it discards a large proportion of unexposed patients. To our knowledge, the relative performance of propensity-score stratification in these circumstances has not been examined. METHODS:Using an empirical example of the association of first trimester statin exposure (prevalence = 0.04%) with risk of congenital malformations and 1,000 simulated cohorts (n = 20,000) with eight combinations of exposure prevalence (0.5%, 1%, 5%, 10%) and outcome risk (3.5%, 10%), we compared four propensity-score-based approaches to confounding adjustment(1) matching (1:1, 1:5, full), (2) stratification in 10, 50, and 100 strata by entire cohort propensity-score distribution, (3) stratification in 10, 50, and 100 strata by exposed group propensity-score distribution, (4) standardized mortality ratio (SMR) weighting. Weighted generalized linear models were used to derive effect estimates after weighting unexposed according to the distribution of the exposed in their stratum for the stratification approaches. RESULTS:In the empirical example, propensity-score stratification (cohort) approaches resulted in greater imbalances in covariate distributions between statin-exposed and unexposed compared with propensity-score stratification (exposed) and matching. In simulations, propensity-score stratification (exposed) resulted in smaller relative bias than the cohort approach with 10 and 50 strata, and greater precision than matching and SMR weighting at 0.5% and 1% exposure prevalence, but similar performance at 5% and 10%. CONCLUSION:For exposures with prevalence under 5%, propensity-score stratification with fine strata, based on the exposed group propensity-score distribution, produced the best results. For more common exposures, all approaches were equivalent.

Misconceptions about the impact of case—control matching remain common. We discuss several subtle problems associated with matched case-control studies that do not arise or are minor in matched cohort studies: (1) matching, even for non-confounders, can create selection bias; (2) matching distorts dose-response relations between matching variables and the outcome; (3) unbiased estimation requires accounting for the actual matching protocol as well as for any residual confounding effects; (4) for efficiency, identically matched groups should be collapsed; (5) matching may harm precision and power; (6) matched analyses may suffer from sparse-data bias, even when using basic sparse-data methods. These problems support advice to limit case-control matching to a few strong wellmeasured confounders, which would devolve to no matching if no such confounders are measured. On the positive side, odds ratio modification by matched variables can be assessed in matched case-control studies without further data, and when one knows either the distribution of the matching factors or their relation to the outcome in the source population, one can estimate and study patterns in absolute rates. Throughout, we emphasize distinctions from the more intuitive impacts of cohort matching.

The faecal metagenome of a cohort of 145 European women with normal, impaired or diabetic glucose control was characterized and discriminant metagenomic markers for type 2 diabetes were identified; the discriminant markers differed from those of a recent Chinese cohort, suggesting that metagenomic predictive tools may need to be specific for age and geographic location. Gut markers for diabetes risk Recent evidence has suggested that altered gut microbiota are associated with various metabolic diseases including obesity, diabetes and cardiovascular disease. Fredrik Bäckhed and colleagues characterized the faecal metagenome of a cohort of European women with normal, impaired or diabetic glucose control and compared these findings to a recently described Chinese cohort. Their analysis reveals differences in the discriminant metagenomic markers for type 2 diabetes between the two cohorts, suggesting that metagenomic predictive tools may have to be specific for age and geographical populations under investigation. Type 2 diabetes (T2D) is a result of complex gene–environment interactions, and several risk factors have been identified, including age, family history, diet, sedentary lifestyle and obesity. Statistical models that combine known risk factors for T2D can partly identify individuals at high risk of developing the disease. However, these studies have so far indicated that human genetics contributes little to the models, whereas socio-demographic and environmental factors have greater influence 1 . Recent evidence suggests the importance of the gut microbiota as an environmental factor, and an altered gut microbiota has been linked to metabolic diseases including obesity 2 , 3 , diabetes 4 and cardiovascular disease 5 . Here we use shotgun sequencing to characterize the faecal metagenome of 145 European women with normal, impaired or diabetic glucose control. We observe compositional and functional alterations in the metagenomes of women with T2D, and develop a mathematical model based on metagenomic profiles that identified T2D with high accuracy. We applied this model to women with impaired glucose tolerance, and show that it can identify women who have a diabetes-like metabolism. Furthermore, glucose control and medication were unlikely to have major confounding effects. We also applied our model to a recently described Chinese cohort 4 and show that the discriminant metagenomic markers for T2D differ between the European and Chinese cohorts. Therefore, metagenomic predictive tools for T2D should be specific for the age and geographical location of the populations studied.