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BackgroundA single assessment of psychological distress, which includes depression and anxiety, has been associated with increased mortality in patients with coronary heart disease, but the prognostic importance of persistence of distress symptoms is less certain.AimTo determine whether intermittent and/or persistent psychological distress is associated with long-term cardiovascular (CV) and total mortality in patients with stable coronary artery disease.Methods950 participants in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial completed at least four General Health Questionnaires (GHQ-30) at baseline and after ½, 1, 2 and 4 years. In a landmark analysis from 4 years, Cox proportional hazards models evaluated the risk of CV and total mortality by increasing levels of psychological distress: never distressed, sometimes any severity (GHQ score >5), persistent mild (GHQ score >5 on three or more occasions) and persistent moderate distress (GHQ score >10) on three or more occasions, over a median of 12.1 (IQR 8.6–12.5) years. The models were both unadjusted and adjusted for known baseline risk factors.ResultsPersistent moderate or greater psychological stress was reported on three or more assessments by 35 (3.7%) subjects. These patients had a higher risk of both CV death (adjusted HR 3.94, 95% CI 2.05 to 7.56, p<0.001) and all-cause mortality (adjusted HR 2.85, 95% CI 1.74 to 4.66, p<0.001) compared with patients with no distress. In contrast, patients who reported persistent mild distress (n=73, 7.7%) on three or more visits, and those who met criteria for distress on only one or two assessments (n=255, 26.8%), did not have an increased risk of CV or all-cause mortality during follow-up.ConclusionIn patients with stable coronary artery disease, persistent psychological distress of at least moderate severity is associated with a substantial increase in CV and all-cause mortality.

Cerebrovascular disease is the second leading cause of death worldwide 1 , 2 and the leading cause of long-term disability in developed countries. 3 , 4 There has been controversy about whether there is an association between cholesterol levels and the risk of stroke; a meta-analysis found no clear evidence of such an association. 5 Most of the studies made no distinction between ischemic and hemorrhagic strokes, which have different pathophysiologic mechanisms. A positive association between increasing cholesterol levels and ischemic stroke due to atherothrombosis in a large artery may be offset by a possible association between low cholesterol levels and hemorrhagic stroke. Studies of . . .

Fresh strawberries (Fragaria x ananassa) are valued for their characteristic red color, juicy texture, distinct aroma, and sweet fruity flavor. In this study, genetic and environmentally induced variation is exploited to capture biochemically diverse strawberry fruit for metabolite profiling and consumer rating. Analyses identify fruit attributes influencing hedonics and sensory perception of strawberry fruit using a psychophysics approach. Sweetness intensity, flavor intensity, and texture liking are dependent on sugar concentrations, specific volatile compounds, and fruit firmness, respectively. Overall liking is most greatly influenced by sweetness and strawberry flavor intensity, which are undermined by environmental pressures that reduce sucrose and total volatile content. The volatile profiles among commercial strawberry varieties are complex and distinct, but a list of perceptually impactful compounds from the larger mixture is better defined. Particular esters, terpenes, and furans have the most significant fits to strawberry flavor intensity. In total, thirty-one volatile compounds are found to be significantly correlated to strawberry flavor intensity, only one of them negatively. Further analysis identifies individual volatile compounds that have an enhancing effect on perceived sweetness intensity of fruit independent of sugar content. These findings allow for consumer influence in the breeding of more desirable fruits and vegetables. Also, this approach garners insights into fruit metabolomics, flavor chemistry, and a paradigm for enhancing liking of natural or processed products.

Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated brexanolone (USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of γ-aminobutyric acid (GABAA) receptors, for the treatment of post-partum depression. For this double-blind, randomised, placebo-controlled trial, we enrolled self-referred or physician-referred female inpatients (≤6 months post partum) with severe post-partum depression (Hamilton Rating Scale for Depression [HAM-D] total score ≥26) in four hospitals in the USA. Eligible women were randomly assigned (1:1), via a computer-generated randomisation program, to receive either a single, continuous intravenous dose of brexanolone or placebo for 60 h. Patients and investigators were masked to treatment assignments. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all randomised patients who started infusion of study drug or placebo and who had a completed baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Patients were followed up until day 30. This trial is registered with ClinicalTrials.gov, number NCT02614547. This trial was done between Dec 15, 2015 (first enrolment), and May 19, 2016 (final visit of the last enrolled patient). 21 women were randomly assigned to the brexanolone (n=10) and placebo (n=11) groups. At 60 h, mean reduction in HAM-D total score from baseline was 21·0 points (SE 2·9) in the brexanolone group compared with 8·8 points (SE 2·8) in the placebo group (difference −12·2, 95% CI −20·77 to −3·67; p=0·0075; effect size 1·2). No deaths, serious adverse events, or discontinuations because of adverse events were reported in either group. Four of ten patients in the brexanolone group had adverse events compared with eight of 11 in the placebo group. The most frequently reported adverse events in the brexanolone group were dizziness (two patients in the brexanolone group vs three patients in the placebo group) and somnolence (two vs none). Moderate treatment-emergent adverse events were reported in two patients in the brexanolone group (sinus tachycardia, n=1; somnolence, n=1) and in two patients in the placebo group (infusion site pain, n=1; tension headache, n=1); one patient in the placebo group had a severe treatment-emergent adverse event (insomnia). In women with severe post-partum depression, infusion of brexanolone resulted in a significant and clinically meaningful reduction in HAM-D total score, compared with placebo. Our results support the rationale for targeting synaptic and extrasynaptic GABAA receptors in the development of therapies for patients with post-partum depression. A pivotal clinical programme for the investigation of brexanolone in patients with post-partum depression is in progress. Sage Therapeutics, Inc.

Breeding for a subjective goal such as flavor is challenging, as many blueberry cultivars are grown worldwide, and identifying breeding targets relating to blueberry flavor biochemistry that have a high degree of genetic control and low environmental variability are priorities. A variety of biochemical compounds and physical characters induce the sensory responses of taste, olfaction, and somatosensation, all of which interact to create what is perceived flavor. The goal of this study was to identify the flavor compounds with a larger genetic versus environmental component regulating their expression over an array of cultivars, locations, and years. Over the course of three years, consumer panelists rated overall liking, texture, sweetness, sourness, and flavor intensity of 19 southern highbush blueberry (Vaccinium corymbosum hybrids) genotypes in 30 sensory panels. Significant positive correlations to overall liking of blueberry fruit (P<0.001) were found with sweetness (R2 = 0.70), texture (R2 = 0.68), and flavor (R2 = 0.63). Sourness had a significantly negative relationship with overall liking (R2 = 0.55). The relationship between flavor and texture liking was also linear (R2 = 0.73, P<0.0001) demonstrating interaction between olfaction and somatosensation. Partial least squares analysis was used to identify sugars, acids, and volatile compounds contributing to liking and sensory intensities, and revealed strong effects of fructose, pH, and several volatile compounds upon all sensory parameters measured. To assess the feasibility of breeding for flavor components, a three year study was conducted to compare genetic and environmental influences on flavor biochemistry. Panelists could discern genotypic variation in blueberry sensory components, and many of the compounds affecting consumer favor of blueberries, such as fructose, pH, β-caryophyllene oxide and 2-heptanone, were sufficiently genetically controlled that allocating resources for their breeding is worthwhile.

Data from the Global Burden of Disease study indicate that there were 319,400 deaths due to rheumatic heart disease and 33.4 million cases of rheumatic heart disease in 2015. The highest death and prevalence rates were found in Oceania, South Asia, and central sub-Saharan Africa.

Post-partum depression is associated with substantial morbidity, and improved pharmacological treatment options are urgently needed. We assessed brexanolone injection (formerly SAGE-547 injection), a positive allosteric modulator of γ-aminobutyric-acid type A (GABAA) receptors, for the treatment of moderate to severe post-partum depression. We did two double-blind, randomised, placebo-controlled, phase 3 trials, at 30 clinical research centres and specialised psychiatric units in the USA. Eligible women were aged 18–45 years, 6 months post partum or less at screening, with post-partum depression and a qualifying 17-item Hamilton Rating Scale for Depression (HAM-D) score (≥26 for study 1; 20–25 for study 2). Women with renal failure requiring dialysis, anaemia, known allergy to allopregnanolone or to progesterone, or medical history of schizophrenia, bipolar disorder, or schizoaffective disorder were excluded. Patients were randomly assigned (1:1:1) to receive a single intravenous injection of either brexanolone 90 μg/kg per h (BRX90), brexanolone 60 μg/kg per h (BRX60), or matching placebo for 60 h in study 1, or (1:1) BRX90 or matching placebo for 60 h in study 2. Patients, the study team, site staff, and the principal investigator were masked to treatment allocation. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all patients who started infusion of study drug or placebo, had a valid HAM-D baseline assessment, and had at least one post-baseline HAM-D assessment. The safety population included all randomised patients who started infusion of study drug or placebo. Patients were followed up until day 30. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT02942004 (study 1) and NCT02942017 (study 2). Participants were enrolled between Aug 1, 2016, and Oct 19, 2017, in study 1, and between July 25, 2016, and Oct 11, 2017, in study 2. We screened 375 women simultaneously across both studies, of whom 138 were randomly assigned to receive either BRX90 (n=45), BRX60 (n=47), or placebo (n=46) in study 1, and 108 were randomly assigned to receive BRX90 (n=54) or placebo (n=54) in study 2. In study 1, at 60 h, the least-squares (LS) mean reduction in HAM-D total score from baseline was 19·5 points (SE 1·2) in the BRX60 group and 17·7 points (1·2) in the BRX90 group compared with 14·0 points (1·1) in the placebo group (difference −5·5 [95% CI −8·8 to −2·2], p=0·0013 for the BRX60 group; −3·7 [95% CI −6·9 to −0·5], p=0·0252 for the BRX90 group). In study 2, at 60 h, the LS mean reduction in HAM-D total score from baseline was 14·6 points (SE 0·8) in the BRX90 group compared with 12·1 points (SE 0·8) for the placebo group (difference −2·5 [95% CI −4·5 to −0·5], p=0·0160). In study 1, 19 patients in the BRX60 group and 22 patients in the BRX90 group had adverse events compared with 22 patients in the placebo group. In study 2, 25 patients in the BRX90 group had adverse events compared with 24 patients in the placebo group. The most common treatment-emergent adverse events in the brexanolone groups were headache (n=7 BRX60 group and n=6 BRX90 group vs n=7 placebo group for study 1; n=9 BRX90 group vs n=6 placebo group for study 2), dizziness (n=6 BRX60 group and n=6 BRX90 group vs n=1 placebo group for study 1; n=5 BRX90 group vs n=4 placebo group for study 2), and somnolence (n=7 BRX60 group and n=2 BRX90 group vs n=3 placebo group for study 1; n=4 BRX90 group vs n=2 placebo group for study 2). In study 1, one patient in the BRX60 group had two serious adverse events (suicidal ideation and intentional overdose attempt during follow-up). In study 2, one patient in the BRX90 group had two serious adverse events (altered state of consciousness and syncope), which were considered to be treatment related. Administration of brexanolone injection for post-partum depression resulted in significant and clinically meaningful reductions in HAM-D total score at 60 h compared with placebo, with rapid onset of action and durable treatment response during the study period. Our results suggest that brexanolone injection is a novel therapeutic drug for post-partum depression that has the potential to improve treatment options for women with this disorder. Sage Therapeutics, Inc.

In response to the ongoing SARS-CoV-2 pandemic in the UK, the COVID-19 Genomics UK (COG-UK) consortium was formed to rapidly sequence SARS-CoV-2 genomes as part of a national-scale genomic surveillance strategy. The network consists of universities, academic institutes, regional sequencing centres and the four UK Public Health Agencies. We describe the development and deployment of CLIMB-COVID, an encompassing digital infrastructure to address the challenge of collecting and integrating both genomic sequencing data and sample-associated metadata produced across the COG-UK network.