Search

Changing ocean temperatures are predicted to challenge marine organisms, especially when combined with other factors, such as ocean acidification. Acclimation, as a form of phenotypic plasticity, can however, moderate the consequences of changing environments for biota. Our understanding of how altered temperature and acidification together influence species acclimation responses is, however, limited compared to responses to single stressors. This study investigated how temperature and acidification affected the thermal tolerance and righting speed of the Girdled Dogwhelk, Trochia cingulata (Linnaeus, 1771). Whelks were acclimated for two weeks to combinations of three temperatures (11°C: cold, 13°C: moderate and 15°C: warm) and two pH regimes (8.0: moderate and 7.5: acidic). We measured the temperature sensitivity of righting response by generating thermal performance curves from individual data collected at seven test temperatures and determined critical thermal minima (CTmin) and maxima (CTmax). We found that T. cingulata has a broad basal thermal tolerance range (∼38°C) and after acclimation to the warm temperature regime, both the optimal temperature for maximum righting speed and CTmax increased. Contrary to predictions, acidification did not narrow this population's thermal tolerance but increased CTmax. These plastic responses are likely driven by the predictable exposure to temperature extremes measured in the field which originate from the local tidal cycle and the periodic acidification associated with ocean upwelling in the region. This acclimation ability suggests that T. cingulata has at least some capacity to buffer the thermal changes and increased acidification predicted to occur with climate change.

Contains fulltext : 291896.pdf (Publisher’s version ) (Closed access) AMOTL1 encodes angiomotin-like protein 1, an actin-binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricular anomalies, and gastrointestinal manifestations in individuals with variants in AMOTL1 affecting amino acids 157-161, a functionally undefined but highly conserved region. Three individuals with AMOTL1 variants outside this region are also described who had variable presentations with orofacial clefting and multi-organ disease. Our case cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157-161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.

Despite the existing body of research that considers altered ocean temperature and acidification as co-occurring stressors, our understanding of the consequences of such shifts remains limited. This is particularly problematic in relation to predators such as whelks, as they can exert strong top-down control of communities yet, as calcifying ectotherms, they are likely to be vulnerable to climate change. This study assessed the effects of simultaneous changes in water temperature and pH on the South African girdled dogwhelk Trochia cingulata. For 12 weeks, whelks were exposed to three temperatures, 9 °C (cooling), 13 °C (current) and 17 °C (warming), each at three target pH levels, 8.0 (current), 7.7 (intermediate) and 7.5 (extreme). For each treatment shell thickness, strength and shape were measured after 6 and 12 weeks, while mortality was recorded daily. Survival was not affected by pH and was highest at 9 °C. Almost all whelks exposed to warming died within 2 weeks. After 6 weeks, shell strength declined significantly as acidity increased, regardless of temperature, and shells of whelks held at 9 °C were thinner. By 12 weeks, whelks exposed to cooling and extreme pH had the weakest shells. Notably, temperature no longer influenced shell thickness, but whelks held at 9 °C became globular in shape. These changes in shell morphology likely resulted from the increased cost of shell maintenance in cool, acidic conditions. The differences observed at 6 and 12 weeks demonstrate how responses can change over time, a point that should be kept in mind when assessing species sensitivities to changing environments. The dominant effect of temperature highlights that T. cingulata is particularly vulnerable to warming, while regional cooling may pose a challenge with respect to shell morphology.

Neural tube defects (NTD) are among the most common congenital anomalies, affecting about 1:1000 births. In most cases, the etiology of NTD is multifactorial and the genetic variants associated with them remain largely unknown. There is extensive evidence from animal models over the past two decades implicating SHROOM3 in neural tube formation; however, its exact role in human disease has remained elusive. In this report, we present the first case of a human fetus with a homozygous loss of function variant in SHROOM3. The fetus presents with anencephaly and cleft lip and palate, similar to previously described Shroom3 mouse mutants and is suggestive of a novel monogenic cause of NTD. Our case provides clarification on the contribution of SHROOM3 to human development after decades of model organism research.

OBJECTIVES: To perform individual record linkage of women undergoing screening with cell-free DNA (cfDNA), combined first-trimester screening (CFTS), second-trimester serum screening (STSS), and/or prenatal and postnatal cytogenetic testing with the aim to (1) obtain population-based estimates of utilization of prenatal screening and invasive diagnosis, (2) analyze the performance of different prenatal screening strategies, and (3) report the residual risk of any major chromosomal abnormality following a low-risk aneuploidy screening result. METHODS: This was a retrospective study of women residing in the state of Victoria, Australia, who underwent prenatal screening or invasive prenatal diagnosis in 2015. Patient-funded cfDNA referrals from multiple providers were merged with state-wide results for government-subsidized CFTS, STSS and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were obtained to ascertain cases of false-negative screening results and atypical chromosomal abnormalities. Individual record linkage was performed using LinkageWizTM . RESULTS: During the study period, there were 79 140 births and 66 166 (83.6%) women underwent at least one form of aneuploidy screening. Linkage data were complete for 93.5% (n = 61 877) of women who underwent screening, and of these, 73.2% (n = 45 275) had CFTS alone, 20.2% (n = 12 486) had cfDNA alone; 5.3% (n = 3268) had STSS alone, 1.3% (n = 813) had both CFTS and cfDNA, and

It was widely reported that the 2015 UK general election represented a breakthrough election for the Conservative party among ethnic minority voters – specifically that their vote share among minorities increased, and overtook that of Labour for the first time among some groups. I show that analysis using more representative data yields markedly different results. Looking at (i) party preference from 2010 to 2015, and (ii) reported vote shares from a nationally representative probability survey, I show that the Conservatives increased their support among Hindus - but the Labour party gained in support elsewhere. This is due to movement away from the Liberal Democrats, 2010 minority supporters of the Liberal Democrats moved to supporting Labour rather than the Conservatives in 2015 at a ratio of 2:1. There is also considerable individual-level volatility in party support among ethnic minorities, which is masked by a high level of stability at the aggregate level.

Author(s): Ferdinandusse, Sacha; McWalter, Kirsty; Te Brinke, Heleen; IJlst, Lodewijk; Mooijer, Petra M; Ruiter, Jos PN; van Lint, Alida EM; Pras-Raves, Mia; Wever, Eric; Millan, Francisca; Guillen Sacoto, Maria J; Begtrup, Amber; Tarnopolsky, Mark; Brady, Lauren; Ladda, Roger L; Sell, Susan L; Nowak, Catherine B; Douglas, Jessica; Tian, Cuixia; Ulm, Elizabeth; Perlman, Seth; Drack, Arlene V; Chong, Karen; Martin, Nicole; Brault, Jennifer; Brokamp, Elly; Toro, Camilo; Gahl, William A; Macnamara, Ellen F; Wolfe, Lynne; Undiagnosed Diseases Network; Waisfisz, Quinten; Zwijnenburg, Petra JG; Ziegler, Alban; Barth, Magalie; Smith, Rosemarie; Ellingwood, Sara; Gaebler-Spira, Deborah; Bakhtiari, Somayeh; Kruer, Michael C; van Kampen, Antoine HC; Wanders, Ronald JA; Waterham, Hans R; Cassiman, David; Vaz, Frederic M | Abstract: PurposeIn this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).MethodsFollowing next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.ResultsAll patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.ConclusionHeterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.

Pathogenic heterozygous variants in the NOTCH1 gene are known to be associated with both left and right-sided congenital cardiac anomalies with strikingly incomplete penetrance and variable phenotypic expressivity. De novo NOTCH1 whole gene deletion has been reported rarely in the literature and its association with cardiac defects is less well established. Here, we report four cases of NOTCH1 gene deletion from two families associated with a spectrum of congenital heart defects from bicuspid aortic valve to complex cardiac anomalies. This is the first description of a familial NOTCH1 deletion, showing apparently high penetrance, which may be unique to this mechanism of disease. Immunohistochemical staining of cardiac tissue demonstrated reduced levels of NOTCH1 expression in both the left and right ventricular outflow tracts. These cases suggest that haploinsufficiency caused by NOTCH1 gene deletion is associated with both mild and severe cardiac defects, similar to those caused by pathogenic variants in the gene, but with apparently higher, if not complete, penetrance.

This paper reports findings from a crowdsourced replication. Eighty-five independent teams attempted a computational replication of results reported in an original study of policy preferences and immigration by fitting the same statistical models to the same data. The replication involved an experimental condition. Random assignment put participating teams into either the transparent group that received the original study and code, or the opaque group receiving only a methods section, rough results description and no code. The transparent group mostly verified the numerical results of the original study with the same sign and p-value threshold (95.7%), while the opaque group had less success (89.3%). Exact numerical reproductions to the second decimal place were far less common (76.9% and 48.1%), and the number of teams who verified at least 95% of all effects in all models they ran was 79.5% and 65.2% respectively. Therefore, the reliability we quantify depends on how reliability is defined, but most definitions suggest it would take a minimum of three independent replications to achieve reliability. Qualitative investigation of the teams’ workflows reveals many causes of error including mistakes and procedural variations. Although minor error across researchers is not surprising, we show this occurs where it is least expected in the case of computational reproduction. Even when we curate the results to boost ecological validity, the error remains large enough to undermine reliability between researchers to some extent. The presence of inter-researcher variability may explain some of the current “reliability crisis” in the social sciences because it may be undetected in all forms of research involving data analysis. The obvious implication of our study is more transparency. Broader implications are that researcher variability adds an additional meta-source of error that may not derive from conscious measurement or modeling decisions, and that replications cannot alone resolve this type of uncertainty.

The implications of climate change for biological invasions are multifaceted and vary along the invasion process. Changes in vectors and pathways are likely to manifest in changes in transport routes and destinations, together with altered transit times and traffic volume. Ultimately, changes in the nature of why, how, and where biota are transported and introduced will pose biosecurity challenges. These challenges will require increased human and institutional capacity, as well as proactive responses such as improved early detection, adaptation of present protocols and innovative legal instruments. Invasion success and spread are expected to be moderated by the physiological response of alien and native biota to environmental changes and the ensuing changes in biotic interactions. These in turn will likely affect management actions aimed at eradicating, containing, and mitigating invasions, necessitating an adaptive approach to management that is sensitive to potentially unanticipated outcomes.

Background Reducing saturated fat reduces serum cholesterol, but effects on other intermediate outcomes may be less clear. Additionally, it is unclear whether the energy from saturated fats eliminated from the diet are more helpfully replaced by polyunsaturated fats, monounsaturated fats, carbohydrate or protein. Objectives To assess the effect of reducing saturated fat intake and replacing it with carbohydrate (CHO), polyunsaturated (PUFA), monounsaturated fat (MUFA) and/or protein on mortality and cardiovascular morbidity, using all available randomised clinical trials. Search methods We updated our searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid) and Embase (Ovid) on 15 October 2019, and searched Clinicaltrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) on 17 October 2019. Selection criteria Included trials fulfilled the following criteria: 1) randomised; 2) intention to reduce saturated fat intake OR intention to alter dietary fats and achieving a reduction in saturated fat; 3) compared with higher saturated fat intake or usual diet; 4) not multifactorial; 5) in adult humans with or without cardiovascular disease (but not acutely ill, pregnant or breastfeeding); 6) intervention duration at least 24 months; 7) mortality or cardiovascular morbidity data available. Data collection and analysis Two review authors independently assessed inclusion, extracted study data and assessed risk of bias. We performed random-effects meta-analyses, meta-regression, subgrouping, sensitivity analyses, funnel plots and GRADE assessment. Main results We included 15 randomised controlled trials (RCTs) (16 comparisons, ~59,000 participants), that used a variety of interventions from providing all food to advice on reducing saturated fat. The included long-term trials suggested that reducing dietary saturated fat reduced the risk of combined cardiovascular events by 21% (risk ratio (RR) 0.79; 95% confidence interval (CI) 0.66 to 0.93, 11 trials, 53,300 participants of whom 8% had a cardiovascular event, I² = 65%, GRADE moderate-quality evidence). Meta-regression suggested that greater reductions in saturated fat (reflected in greater reductions in serum cholesterol) resulted in greater reductions in risk of CVD events, explaining most heterogeneity between trials. The number needed to treat for an additional beneficial outcome (NNTB) was 56 in primary prevention trials, so 56 people need to reduce their saturated fat intake for ~four years for one person to avoid experiencing a CVD event. In secondary prevention trials, the NNTB was 32. Subgrouping did not suggest significant differences between replacement of saturated fat calories with polyunsaturated fat or carbohydrate, and data on replacement with monounsaturated fat and protein was very limited. We found little or no effect of reducing saturated fat on all-cause mortality (RR 0.96; 95% CI 0.90 to 1.03; 11 trials, 55,858 participants) or cardiovascular mortality (RR 0.95; 95% CI 0.80 to 1.12, 10 trials, 53,421 participants), both with GRADE moderate-quality evidence. There was little or no effect of reducing saturated fats on non-fatal myocardial infarction (RR 0.97, 95% CI 0.87 to 1.07) or CHD mortality (RR 0.97, 95% CI 0.82 to 1.16, both low-quality evidence), but effects on total (fatal or non-fatal) myocardial infarction, stroke and CHD events (fatal or non-fatal) were all unclear as the evidence was of very low quality. There was little or no effect on cancer mortality, cancer diagnoses, diabetes diagnosis, HDL cholesterol, serum triglycerides or blood pressure, and small reductions in weight, serum total cholesterol, LDL cholesterol and BMI. There was no evidence of harmful effects of reducing saturated fat intakes. Authors' conclusions The findings of this updated review suggest that reducing saturated fat intake for at least two years causes a potentially important reduction in combined cardiovascular events. Replacing the energy from saturated fat with polyunsaturated fat or carbohydrate appear to be useful strategies, while effects of replacement with monounsaturated fat are unclear. The reduction in combined cardiovascular events resulting from reducing saturated fat did not alter by study duration, sex or baseline level of cardiovascular risk, but greater reduction in saturated fat caused greater reductions in cardiovascular events.

α-Thalassemia X-linked intellectual disability (ATR-X) syndrome is a neurodevelopmental disorder caused by mutations in the ATRX gene that encodes a SNF2-type chromatin-remodeling protein. The ATRX protein regulates chromatin structure and gene expression in the developing mouse brain and early inactivation leads to DNA replication stress, extensive cell death, and microcephaly. However, the outcome of Atrx loss of function postnatally in neurons is less well understood. We recently reported that conditional inactivation of Atrx in postnatal forebrain excitatory neurons (ATRX-cKO) causes deficits in long-term hippocampus-dependent spatial memory. Thus, we hypothesized that ATRX-cKO mice will display impaired hippocampal synaptic transmission and plasticity. In the present study, evoked field potentials and current source density analysis were recorded from a multichannel electrode in male, urethane-anesthetized mice. Three major excitatory synapses, the Schaffer collaterals to basal dendrites and proximal apical dendrites, and the temporoammonic path to distal apical dendrites on hippocampal CA1 pyramidal cells were assessed by their baseline synaptic transmission, including paired-pulse facilitation (PPF) at 50-ms interpulse interval, and by their long-term potentiation (LTP) induced by theta-frequency burst stimulation. Baseline single-pulse excitatory response at each synapse did not differ between ATRX-cKO and control mice, but baseline PPF was reduced at the CA1 basal dendritic synapse in ATRX-cKO mice. While basal dendritic LTP of the first-pulse excitatory response was not affected in ATRX-cKO mice, proximal and distal apical dendritic LTP were marginally and significantly reduced, respectively. These results suggest that ATRX is required in excitatory neurons of the forebrain to achieve normal hippocampal LTP and PPF at the CA1 apical and basal dendritic synapses, respectively. Such alterations in hippocampal synaptic transmission and plasticity could explain the long-term spatial memory deficits in ATRX-cKO mice and provide insight into the physiological mechanisms underlying intellectual disability in ATR-X syndrome patients.

Research shows that ethnic minority candidates often face an electoral penalty at the ballot box. In this study, we argue that this penalty depends on both candidate and voter characteristics, and that pro-minority policy positions incur a greater penalty than a candidate’s ethnic background itself. Using a conjoint experiment embedded in a panel study of British voters, we investigate the relative contributions of candidate ethnicity, policy positions, affirmative action, and voter attitudes to this electoral penalty. We find that although Pakistani (Muslim) candidates are penalized directly for their ethnicity, black Caribbean candidates receive on average the same levels of support as white British ones. However, black Caribbean candidates suffer conditional discrimination where they are penalized if they express support for pro-minority policies, and all candidates are penalized for having been selected through an affirmative action initiative. We also find that some white British voters are more inclined to support a black Caribbean candidate than a white British one, all else being equal. These voters (one quarter of our sample) have cosmopolitan views on immigration, and a strong commitment to anti-prejudice norms. However, despite efforts across parties to increase the ethnic diversity of candidates for office, many voters’ preferences continue to pose barriers toward descriptive and substantive representation of ethnic minority groups.

Approximately half of all patients with heart failure have preserved left ventricular ejection fraction (LVEF), yet in contrast to heart failure with reduced ejection fraction (HFrEF), no treatments have yet been shown to be effective at improving outcomes.1 Neurohumoral activation is observed in heart failure across the full spectrum of left ventricular function2; however, pharmacological inhibition of the renin–angiotensin aldosterone system (RAAS) has only been shown to improve survival and reduce hospitalisation in HFrEF.1 We therefore performed a Cochrane systematic review and meta-analysis to synthesize all available evidence to investigate the effects of RAAS inhibition in heart failure patients with a LVEF >40%. This patient population comprises both heart failure with mid-range ejection fraction (40%–49%) and heart failure with preserved ejection fraction (HFpEF, >50%), as defined in current guidelines1. We searched for randomised controlled trials (RCTs) investigating pharmacological neurohumoral inhibition with beta-blockers (BB), ACE inhibitors (ACEI), angiotensin receptor blockers (ARB), mineralocorticoid receptor antagonists (MRA) and angiotensin receptor–neprilysin inhibitors, in adult patients (≥ 18 years old) with heart failure and LVEF >40%. We searched MEDLINE, Embase and the Cochrane Central Register of Controlled Trials on 25 July 2017. The primary outcomes were cardiovascular (CV) mortality, heart failure hospitalisation and hyperkalaemia; and the secondary outcomes were all-cause mortality, quality of life (measured using either the Minnesota Living with Heart Failure (MLHF) Questionnaire or Kansas City Cardiomyopathy Questionnaire ). We undertook meta-analysis for each drug class and outcome. when data were available from more than one clinical trial. We used a fixed-effect model unless heterogeneity was high (I²≥50%) when a random-effect model was used. We assessed the quality of evidence for each comparison using the GRADE ( Grading of Recommendations, Assessment, Development and Evaluations ) methodology. The review was conducted in accordance with the guidelines provided in the Cochrane Handbook,3 and reported findings …

In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.

New approaches to evidence synthesis, which use human effort and machine automation in mutually reinforcing ways, can enhance the feasibility and sustainability of living systematic reviews. Human effort is a scarce and valuable resource, required when automation is impossible or undesirable, and includes contributions from online communities (“crowds”) as well as more conventional contributions from review authors and information specialists. Automation can assist with some systematic review tasks, including searching, eligibility assessment, identification and retrieval of full-text reports, extraction of data, and risk of bias assessment. Workflows can be developed in which human effort and machine automation can each enable the other to operate in more effective and efficient ways, offering substantial enhancement to the productivity of systematic reviews. This paper describes and discusses the potential—and limitations—of new ways of undertaking specific tasks in living systematic reviews, identifying areas where these human/machine “technologies” are already in use, and where further research and development is needed. While the context is living systematic reviews, many of these enabling technologies apply equally to standard approaches to systematic reviewing.

Background Observational studies have confirmed the benefits of adherence to a Mediterranean dietary pattern on cardiovascular disease (CVD) but the randomised controlled trial (RCT) evidence is limited. Objective To determine the effectiveness of a Mediterranean-style diet for the primary and secondary prevention of CVD. Methods We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Web of Science, DARE, HTA, NHS EED and trial registers (September 2018). We selected RCTs in healthy adults and adults at high risk of CVD (primary prevention) and those with established CVD (secondary prevention). Both of the following key components were required for our definition of a Mediterranean-style diet: high monounsaturated/saturated fat ratio and a high intake of plant based foods, including fruits, vegetables, and legumes. The intervention could be dietary advice, provision of relevant foods or both. The comparison group received either no intervention, minimal intervention, usual care or another dietary intervention. Outcomes included clinical events and CVD risk factors. We included only studies with follow-up periods of 3 months or more. Results Overall, 30 RCTs (12,461 participants randomised) and 7 ongoing trials met our inclusion criteria, whereas 22 primary prevention trials and 6 secondary prevention trials were analysed. Low quality evidence shows little or no effect of the PREDIMED (7747 randomised) intervention (advice to follow a Mediterranean diet plus supplemental extra virgin olive oil or tree nuts) compared to a low fat diet on CVD mortality (HR 0.81 (95% CI 0.5, 1.32)) or total mortality (HR 1.0 (95% CI 0.81, 1.24)) over 4.8 years. There was however a reduction in the number of strokes with the PREDIMED intervention (HR 0.6 (95% CI 0.45, 0.8), moderate quality evidence). For secondary prevention, in the Lyon Diet Heart Study (605 CVD patients), there was moderate quality evidence of a reduction in CVD mortality (HR 0.35 (95% CI 0.15, 0.82)) and total mortality (HR 0.44 (95% CI 0.21, 0.92)) with the intervention, over 46 months. For CVD risk factors, in primary prevention trials, there was low quality evidence for a possible small reduction in total cholesterol (−0.16 mmol/L (95% CI −0.32, 0.00), and moderate quality evidence for a reduction in SBP (−2.99 mmHg (95% CI −3.45, −2.53)) and DBP (−2.0 mmHg (95% CI −2.29, −1.71)). In secondary prevention trials, there was moderate quality evidence of no effect of a Mediterranean-style diet on lipid levels and low or very low quality evidence for blood pressure. Conclusions Despite the relatively large number of studies included in this review, there is still some uncertainty regarding the effects of a Mediterranean-style diet on clinical endpoints and CVD risk factors for both primary and secondary prevention. The ongoing studies may provide more certainty in the future.

The Kuiper Belt is a distant region of the Solar System. On 1 January 2019, the New Horizons spacecraft flew close to (486958) 2014 MU69, a Cold Classical Kuiper Belt Object, a class of objects that have never been heated by the Sun and are therefore well preserved since their formation. Here we describe initial results from these encounter observations. MU69 is a bi-lobed contact binary with a flattened shape, discrete geological units, and noticeable albedo heterogeneity. However, there is little surface color and compositional heterogeneity. No evidence for satellites, ring or dust structures, gas coma, or solar wind interactions was detected. By origin MU69 appears consistent with pebble cloud collapse followed by a low velocity merger of its two lobes., 43 pages, 8 figure

OBJECTIVES: To explore the association between timing of diagnosis of common autosomal trisomies, maternal age, and socio-economic status (SES). DESIGN: Retrospective study of cytogenetic diagnoses of trisomy 21 (T21), trisomy 18 (T18), and trisomy 13 (T13) in Victoria, Australia, in 2015 to 2016, stratified by timing (prenatal less than 17 weeks gestation, prenatal including or greater than or 17 weeks gestation, and postnatal before 12 months of age), maternal age, and SES region. Utilisation of prenatal testing following a live-born T21 infant was ascertained via record linkage. RESULTS: Among 160 230 total births were 571 diagnoses of T21 and 246 of T18/T13. The overall and live birth prevalences of T21 were 3.56 and 0.47 per 1000 births, respectively. Compared with women from disadvantaged SES regions, women from high SES regions were more likely to have a prenatal diagnosis of a trisomy before 17 weeks than after (P

Background\ud \ud The Seven Countries study in the 1960s showed that populations in the Mediterranean region experienced lower coronary heart disease (CHD) mortality probably as a result of different dietary patterns. Later observational studies have confirmed the benefits of adherence to a Mediterranean dietary pattern on cardiovascular disease (CVD) risk factors but clinical trial evidence is more limited.\ud \ud Objectives\ud \ud To determine the effectiveness of a Mediterranean-style dietfor the primary and secondary prevention of CVD. \ud \ud Search methods\ud \ud We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9);MEDLINE (Ovid, 1946 to 25 September 2018); Embase (Ovid, 1980 to2018 week 39); Web of Science Core Collection (ThomsonReuters, 1900 to 26 September 2018); DARE Issue 2 of 4, 2015 (Cochrane Library); HTA Issue 4 of 4, 2016 (Cochrane Library); NHSEED Issue 2 of 4, 2015 (Cochrane Library). We searched trial registers and applied no language restrictions.\ud \ud Selection criteria\ud \ud We selected randomised controlled trials (RCTs) in healthy adults and adults at high risk of CVD (primary prevention) and those with established CVD (secondary prevention). Both of the following key components were required to reach our definition of a Mediterranean-style diet: high monounsaturated/saturated fat ratio (use of olive oil as main cooking ingredient and/or consumption of other traditional foods high in monounsaturated fats such as tree nuts) and a high intake of plant-based foods, including fruits, vegetables and legumes. Additional components included: low to moderate red wine consumption; high consumption of whole grains and cereals; low consumption of meat and meat products and increased consumption of fish; moderate consumption of milk and dairy products. The intervention could be dietary advice, provision of relevant foods, or both. The comparison group received either no intervention, minimal intervention, usual care or another dietary intervention. Outcomes included clinical events and CVD risk factors. We included only studies with follow-up periods of three months or more defined as the intervention period plus post intervention follow-up.\ud \ud Data collection and analysis\ud \ud Two review authors independently assessed studies for inclusion, extracted data and assessed risk of bias. We conducted four maincomparisons:\ud \ud 1. Mediterranean dietary intervention versus no intervention or minimal intervention for primary prevention;\ud 2. Mediterranean dietary intervention versus another dietary intervention for primary prevention;\ud 3. Mediterranean dietary intervention versus usual care forsecondary prevention;\ud 4. Mediterranean dietary intervention versus another dietary intervention for secondary prevention. \ud \ud Main results\ud \ud In this substantive review update, 30 RCTs (49 papers) (12,461participants randomised) and seven ongoing trials met our inclusion criteria. The majority of trials contributed to primary prevention: comparisons 1 (nine trials) and 2 (13 trials). Secondary prevention trials were included for comparison 3 (two trials) and comparison 4 (four trials plus an additional two trials that were excluded from the main analyses due to published concerns regarding the reliability of the data).Two trials reported on adverse events where these were absent or minor (low- to moderate-quality evidence). No trials reported on costs or health-related quality of life. \ud \ud Primary prevention\ud \ud The included studies for comparison 1 did not report on clinical endpoints (CVD mortality, total mortality or non-fatal endpoints such as myocardial infarction or stroke). The PREDIMED trial (included in comparison 2) was retracted and re-analysed following concerns regarding randomisation at two of 11 sites. Low-quality evidence shows little or no effect of the PREDIMED (7747 randomised)intervention (advice to follow a Mediterranean diet plus supplemental extra-virgin olive oil or tree nuts) compared to a low-fat diet onCVD mortality (hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.50 to 1.32) or total mortality (HR 1.0, 95% CI 0.81 to 1.24)over 4.8 years. There was, however, a reduction in the number of strokes with the PREDIMED intervention (HR 0.60, 95% CI 0.45to 0.80), a decrease from 24/1000 to 14/1000 (95% CI 11 to 19), moderate-quality evidence). For CVD risk factors for comparison 1there was low-quality evidence for a possible small reduction in total cholesterol (-0.16 mmol/L, 95% CI -0.32 to 0.00) and moderate-quality evidence for a reduction in systolic (-2.99 mmHg (95% CI -3.45 to -2.53) and diastolic blood pressure (-2.0 mmHg, 95% CI -2.29 to -1.71), with low or very low-quality evidence of little orno effect on LDL or HDL cholesterol or triglycerides. For comparison2 there was moderate-quality evidence of a possible small reduction in LDL cholesterol (-0.15 mmol/L, 95% CI -0.27 to -0.02) andtriglycerides (-0.09 mmol/L, 95% CI -0.16 to -0.01) with moderateor low-quality evidence of little or no effect on total or HDLcholesterol or blood pressure.\ud \ud Secondary prevention\ud \ud For secondary prevention, the Lyon Diet Heart Study (comparison 3) examined the effect of advice to follow a Mediterranean diet and supplemental canola margarine compared to usual care in 605 CHD patients over 46 months and there was low-quality evidence of a reduction in adjusted estimates for CVD mortality (HR 0.35, 95% CI 0.15 to 0.82) and total mortality (HR 0.44, 95% CI 0.21 to0.92) with the intervention. Only one small trial (101 participants) provided unadjusted estimates for composite clinical endpoints for comparison 4 (very low-quality evidence of uncertain effect). For comparison 3 there was low-quality evidence of little or no effect of a Mediterranean-style diet on lipid levels and very low-quality evidence for blood pressure. Similarly, for comparison 4 where only two trials contributed to the analyses there was low or very low-quality evidence of little or no effect of the intervention on lipid levels or blood pressure. \ud \ud Authors’ conclusions\ud \ud Despite the relatively large number of studies included in this review, there is still some uncertainty regarding the effects of a Mediterranean-style diet on clinical endpoints and CVD risk factors for both primary and secondary prevention. The quality of evidence for the modest benefits on CVD risk factors in primary prevention is low or moderate, with a small number of studies reporting minimal harms. There is a paucity of evidence for secondary prevention. The ongoing studies may provide more certainty in the future.\ud