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Patients with recent stroke or transient ischaemic attack are at high risk for a further vascular event, possibly leading to permanent disability or death. Although evidence-based treatments for secondary prevention are available, many patients do not achieve recommended behavioural modifications and pharmaceutical prevention targets in the long-term. We aimed to investigate whether a support programme for enhanced secondary prevention can reduce the frequency of recurrent vascular events. INSPiRE-TMS was an open-label, multicentre, international randomised controlled trial done at seven German hospitals with acute stroke units and a Danish stroke centre. Patients with non-disabling stroke or transient ischaemic attack within 2 weeks from study enrolment and at least one modifiable risk factor (ie, arterial hypertension, diabetes, atrial fibrillation, or smoking) were included. Computerised randomisation was used to allocate patients (1:1) either to the support programme in addition to conventional care or to conventional care alone. The support programme used feedback and motivational interviewing strategies with eight outpatient visits over 2 years aiming to improve adherence to secondary prevention targets. The primary outcome was the composite of major vascular events consisting of stroke, acute coronary syndrome, and vascular death, assessed in the intention-to-treat population (all patients who underwent randomisation, did not withdraw study participation, and had at least one follow-up). Outcomes were assessed at annual follow-ups using time-to-first-event analysis. All-cause death was monitored as a safety outcome. This trial is registered with ClinicalTrials.gov, NCT01586702. From Aug 22, 2011, to Oct 30, 2017, we enrolled 2098 patients. Of those, 1048 (50·0%) were randomly assigned to the support programme group and 1050 (50·0%) patients were assigned to the conventional care group. 1030 (98·3%) patients in the support group and 1042 (99·2%) patients in the conventional care group were included in the intention-to-treat analysis. The mean age of analysed participants was 67·4 years and 700 (34%) were women. After a mean follow-up of 3·6 years, the primary outcome of major vascular events had occurred in 163 (15·8%) of 1030 patients of the support programme group and in 175 (16·8%) of 1042 patients of the conventional care group (hazard ratio [HR] 0·92, 95% CI 0·75–1·14). Total major vascular event numbers were 209 for the support programme group and 225 for the conventional care group (incidence rate ratio 0·93, 95% CI 0·77–1·12; p=0·46) and all-cause death occurred in 73 (7·1%) patients in the support programme group and 85 (8·2%) patients in the conventional care group (HR 0·85, 0·62–1·17). More patients in the support programme group achieved secondary prevention targets (eg, in 1-year-follow-up 52% vs 42% [p<0·0001] for blood pressure, 62% vs 54% [p=0·0010] for LDL, 33% vs 19% [p<0·0001] for physical activity, and 51% vs 34% [p=0·0010] for smoking cessation). Provision of an intensified secondary prevention programme in patients with non-disabling stroke or transient ischaemic attack was associated with improved achievement of secondary prevention targets but did not lead to a significantly lower rate of major vascular events. Further research is needed to investigate the effects of support programmes in selected patients who do not achieve secondary prevention targets soon after discharge. German Federal Ministry of Education and Research, Pfizer, and German Stroke Foundation.

High and low protein diets fed to pregnant adolescent sows led to intrauterine growth retardation (IUGR). To explore underlying mechanisms, sow plasma metabolite and hormone concentrations were analyzed during different pregnancy stages and correlated with litter weight (LW) at birth, sow body weight and back fat thickness. Sows were fed diets with low (6.5%, LP), adequate (12.1%, AP), and high (30%, HP) protein levels, made isoenergetic by adjusted carbohydrate content. At -5, 24, 66, and 108 days post coitum (dpc) fasted blood was collected. At 92 dpc, diurnal metabolic profiles were determined. Fasted serum urea and plasma glucagon were higher due to the HP diet. High density lipoprotein cholesterol (HDLC), %HDLC and cortisol were reduced in HP compared with AP sows. Lowest concentrations were observed for serum urea and protein, plasma insulin-like growth factor-I, low density lipoprotein cholesterol, and progesterone in LP compared with AP and HP sows. Fasted plasma glucose, insulin and leptin concentrations were unchanged. Diurnal metabolic profiles showed lower glucose in HP sows whereas non-esterified fatty acids (NEFA) concentrations were higher in HP compared with AP and LP sows. In HP and LP sows, urea concentrations were 300% and 60% of AP sows, respectively. Plasma total cholesterol was higher in LP than in AP and HP sows. In AP sows, LW correlated positively with insulin and insulin/glucose and negatively with glucagon/insulin at 66 dpc, whereas in HP sows LW associated positively with NEFA. In conclusion, IUGR in sows fed high protein:low carbohydrate diet was probably due to glucose and energy deficit whereas in sows with low protein:high carbohydrate diet it was possibly a response to a deficit of indispensable amino acids which impaired lipoprotein metabolism and favored maternal lipid disposal.

Crop yields are vulnerable to climate change. We assess the global impacts of climate change on agricultural systems under two climate projections (RCP8.5 and RCP4.5) to quantify the difference in impacts if climate change were reduced. We also employ two different socioeconomic pathways (SSP3 and SSP5) to assess the sensitivity of results to the underlying socioeconomic conditions. The integrated-Population-Economy-Technology-Science (iPETS) model, a global integrated assessment model for projecting future energy use, land use and emissions, is used in conjunction with the Community Earth System Model (CESM), and particularly its land surface component, the Community Land Model (CLM), to evaluate climate change impacts on agriculture. iPETS results are produced at the level of nine world regions for the period 2005–2100. We employ climate impacts on crop yield derived from CLM, driven by CESM simulations of the two RCPs. These yield effects are applied within iPETS, imposed on baseline and mitigation scenarios for SSP3 and SSP5 that are consistent with the RCPs. We find that the reduced level of warming in RCP4.5 (relative to RCP8.5) can have either positive or negative effects on the economy since crop yield either increases or decreases with climate change depending on assumptions about CO2 fertilization. Yields are up to 12 % lower, and crop prices are up to 15 % higher, in RCP4.5 relative to RCP8.5 if CO2 fertilization is included, whereas yields are up to 22 % higher, and crop prices up to 22 % lower, if it is not. We also find that in the mitigation scenarios (RCP4.5), crop prices are substantially affected by mitigation actions as well as by climate impacts. For the scenarios we evaluated, the development pathway (SSP3 vs SSP5) has a larger impact on outcomes than climate (RCP4.5 vs RCP8.5), by a factor of 3 for crop prices, 11 for total cropland use, and 35 for GDP on global average.

Dansgaard–Oeschger (D–O) events, millennial-scale climate oscillations between stadial and interstadial conditions (of up to 10–15 ∘C in amplitude at high northern latitudes), occurred throughout the Marine Isotope Stage 3 (MIS3; 27.8–59.4 ka) period. The climate modelling community up to now has not been able to answer the question of whether our climate models are too stable to simulate D–O events. To address this, this paper lays the ground-work for a MIS3 D–O protocol for general circulation models which are used in the International Panel for Climate Change (IPCC) assessments. We review the following: D–O terminology, community progress on simulating D–O events in these IPCC-class models (processes and published examples), and evidence about the boundary conditions under which D–O events occur. We find that no model exhibits D–O-like behaviour under pre-industrial conditions. Some, but not all, models exhibit D–O-like oscillations under MIS3 and/or full glacial conditions. Greenhouse gases and ice sheet configurations are crucial. However most models have not run simulations of long enough duration to be sure which models show D–O-like behaviour, under either MIS3 or full glacial states. We propose a MIS3 baseline protocol at 34 ka, which features low obliquity values, medium to low MIS3 greenhouse gas values, and the intermediate ice sheet configuration, which our review suggests are most conducive to D–O-like behaviour in models. We also provide a protocol for a second freshwater (Heinrich-event-preconditioned) experiment, since previous work suggests that this variant may be helpful in preconditioning a state in models which is conducive to D–O events. This review provides modelling groups investigating MIS3 D–O oscillations with a common framework, which is aimed at (1) maximising the chance of the occurrence of D–O-like events in the simulations, (2) allowing more precise model–data evaluation, and (3) providing an adequate central point for modellers to explore model stability.

Germline variants in the 3′ untranslated region (3′UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3′UTR of the KRAS oncogene, referred to as the KRAS variant, is associated with both cancer risk and altered tumor biology. Here, we test the hypothesis that the KRAS variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS variant-positive EOC patients. As this variant seems to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival. EOC patients with complete clinical data were genotyped for the KRAS variant and analyzed for outcome ( n =536), response to neoadjuvant chemotherapy ( n =125) and platinum resistance (n= 306). Outcome was separately analyzed for women with known BRCA mutations ( n= 79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were used to confirm altered sensitivity to chemotherapy associated with the KRAS variant. Finally, the KRAS variant was directly targeted through small-interfering RNA/miRNA oligonucleotides in cell lines and survival was measured. Postmenopausal EOC patients with the KRAS variant were significantly more likely to die of ovarian cancer by multivariate analysis (hazard ratio=1.67, 95% confidence interval: 1.09–2.57, P =0.019, n =279). Perhaps explaining this finding, EOC patients with the KRAS variant were significantly more likely to be platinum resistant (odds ratio=3.18, confidence interval: 1.31–7.72, P =0.0106, n= 291). In addition, direct targeting of the KRAS variant led to a significant reduction in EOC cell growth and survival in vitro . These findings confirm the importance of the KRAS variant in EOC, and indicate that the KRAS variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this study supports the hypothesis that these tumors have continued dependence on such 3′UTR lesions, and that direct targeting may be a viable future treatment approach.

Understanding how impacts may differ across alternative levels of future climate change is necessary to inform mitigation and adaptation measures. The Benefits of Reduced Anthropogenic Climate changE (BRACE) project assesses the differences in impacts between two specific climate futures: a higher emissions future with global average temperature increasing about 3.7 °C above pre-industrial levels toward the end of the century and a moderate emissions future with global average warming of about 2.5 °C. BRACE studies in this special issue quantify avoided impacts on physical, managed, and societal systems in terms of extreme events, health, agriculture, and tropical cyclones. Here we describe the conceptual framework and design of BRACE and synthesize its results. Methodologically, the project combines climate modeling, statistical analysis, and impact assessment and draws heavily on large ensembles using the Community Earth System Model. It addresses uncertainty in future societal change by employing two pathways for future socioeconomic development. Results show that the benefits of reduced climate change within this framework vary substantially across types of impacts. In many cases, especially related to extreme heat events, there are substantial benefits to mitigation. The benefits for some heat extremes are statistically significant in some regions as early as the 2020s and are widespread by mid-century. Benefits are more modest for agriculture and exposure to some health risks. Benefits are negative for agriculture when CO2 fertilization is incorporated. For several societal impacts, the effect on outcomes of alternative future societal development pathways is substantially larger than the effect of the two climate scenarios.

Background Women with a breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2) mutation are at increased risk for developing breast and ovarian cancer. Various reproductive and hormonal factors have been shown to modify the risk of breast cancer. These studies suggest that estrogen exposure and deprivation are important in the etiology of hereditary cancer. Many patients are interested in the possibility of an adverse effect of fertility treatment on breast cancer risk. It is important to evaluate whether or not infertility per se or exposure to fertility medications increase the risk of breast cancer in genetically predisposed women. Methods We conducted a matched case-control study of 1,380 pairs of women with a BRCA1 or BRCA2 mutation to determine if a history of infertility, the use of fertility medications, or undergoing in vitro fertilization (IVF) were associated with and increased the risk of breast cancer. Results Sixteen percent of the study subjects reported having experienced a fertility problem and 4% had used a fertility medication. Women who had used a fertility medication were not at significantly increased risk of breast cancer (odds ratio [OR] = 1.21; 95% confidence interval [CI] = 0.81-1.82) compared to non-users. Furthermore, there was no risk associated with a history of use of a fertility medication when the subjects were stratified by parity: (OR = 1.29; 95% CI = 0.83-2.01 for nulliparous women and OR = 0.81; 95% CI = 0.30-2.22 for parous women). Conclusions The results of this study suggest that the use of fertility medications does not adversely affect the risk of breast cancer among BRCA mutation carriers. Given the small sizes of the exposed subgroups, these findings should be interpreted with caution and confirmatory studies are required.

There is increasing evidence to support the use of anesthetics to affect operative fields during endoscopic sinus surgery and thus the speed, thoroughness, and safety of the surgery itself. Previous research has suggested preoperative beta-blockers improve surgical fields (SFs); our study is novel in showing the impact of a beta-blocker infusion on SFs during sinus surgery. A prospective, randomized, double-blind, placebo-controlled trial was conducted in 40 patients. Patients undergoing endoscopic sinus surgery for chronic rhinosinusitis received a constant infusion of i.v. esmolol or saline in addition to a standard inhaled anesthetic protocol. At regular 15-minutes intervals, the quality of SF, heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were assessed. Total blood loss was also recorded. Average vital sign parameters (HR/SBP/DBP) were significantly lower in the esmolol group (69.1/90.2/55.1 versus 77.2/99.5/63.5; p < 0.01). The esmolol infusion improved SFs relative to control (2.3 versus 2.6; p = 0.045). Esmolol infusion resulted in good SFs (grades 1 and 2) more often than poor fields (grades 3 and 4); on the contrary, the control group showed more poor than good SFs (chi-square; p = 0.04). A correlation between increasing HR and worsening SFs was identified (r = 0.259; p = 0.002). The control group had significantly higher average blood loss (1.3 versus 0.8 mL/min; p = 0.037). Esmolol-induced relative hypotension and bradycardia during endoscopic sinus surgery achieves significantly improved SFs relative to saline control.

One quarter to one third of patients eligible for systemic thrombolysis are on antiplatelet therapy at presentation. In this study, we aimed to assess the safety and efficacy of intravenous thrombolysis in stroke patients on prescribed antiplatelet therapy in the WAKE-UP trial. WAKE-UP was a multicenter, randomized, double-blind, placebo-controlled clinical trial to study the efficacy and safety of MRI-guided intravenous thrombolysis with alteplase in patients with an acute stroke of unknown onset time. The medication history of all patients randomized in the WAKE-UP trial was documented. The primary safety outcome was any sign of hemorrhagic transformation on follow-up MRI. The primary efficacy outcome was favorable functional outcome defined by a score of 0-1 on the modified Rankin scale at 90 days after stroke, adjusted for age and baseline stroke severity. Logistic regression models were fitted to study the association of prior antiplatelet treatment with outcome and treatment effect of intravenous alteplase. Of 503 randomized patients, 164 (32.6%) were on antiplatelet treatment. Patients on antiplatelet treatment were older (70.3 vs. 62.8 years,  <  0.001), and more frequently had a history of hypertension, atrial fibrillation, diabetes, hypercholesterolemia, and previous stroke or transient ischaemic attack. Rates of symptomatic intracranial hemorrhage and hemorrhagic transformation on follow-up imaging did not differ between patients with and without antiplatelet treatment. Patients on prior antiplatelet treatment were less likely to achieve a favorable outcome (37.3% vs. 52.6%,  = 0.014), but there was no interaction of prior antiplatelet treatment with intravenous alteplase concerning favorable outcome (  = 0.355). Intravenous alteplase was associated with higher rates of favorable outcome in patients on prior antiplatelet treatment with an adjusted odds ratio of 2.106 (95% CI 1.047-4.236). Treatment benefit of intravenous alteplase and rates of post-treatment hemorrhagic transformation were not modified by prior antiplatelet intake among MRI-selected patients with unknown onset stroke. Worse functional outcome in patients on antiplatelets may result from a higher load of cardiovascular co-morbidities in these patients.