Liver fibrosis assessed via non-invasive tests is associated with incident heart failure in a general population cohort.

AimsTo determine whether liver fibrosis is associated with heart failure in a general population cohort, and if genetic polymorphisms (PNPLA3 rs738409; TM6SF2 rs58542926), linked to increased risk of liver fibrosis and decreased risk of coronary artery disease, modify this association.MethodsUsing UK Biobank data, we prospectively examined the relationship between non-invasive fibrosis markers [NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4) and AST to platelet ratio index (APRI)] and incident hospitalization/death from heart failure (n=413,860). Cox-regression estimated hazard ratios (HR) for incident heart failure. Effects of PNPLA3 and TM6SF2 on the association between liver fibrosis and heart failure were estimated by stratifying for genotype, and testing for an interaction between genotype and liver fibrosis using a likelihood ratio test.Results12,527 incident cases of heart failure occurred over a median of 10.7 years. Liver fibrosis was associated with an increased risk of hospitalization or death from heart failure (multivariable adjusted high risk NFS score HR 1.59 [1.47-1.76], pConclusionIn the general population, serum markers of liver fibrosis are associated with increased hospitalization/death from heart failure. Genetic polymorphisms associated with liver fibrosis were not positively associated with elevated heart failure risk

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Pregnancy and neonatal outcomes of COVID-19: The PAN-COVID study

Objective To assess perinatal outcomes for pregnancies affected by suspected or confirmed SARS-CoV-2 infection. Methods Prospective, web-based registry. Pregnant women were invited to participate if they had suspected or confirmed SARS-CoV-2 infection between 1st January 2020 and 31st March 2021 to assess the impact of infection on maternal and perinatal outcomes including miscarriage, stillbirth, fetal growth restriction, pre-term birth and transmission to the infant. Results Between April 2020 and March 2021, the study recruited 8239 participants who had suspected or confirmed SARs-CoV-2 infection episodes in pregnancy between January 2020 and March 2021. Maternal death affected 14/8197 (0.2%) participants, 176/8187 (2.2%) of participants required ventilatory support. Pre-eclampsia affected 389/8189 (4.8%) participants, eclampsia was reported in 40/ 8024 (0.5%) of all participants. Stillbirth affected 35/8187 (0.4 %) participants. In participants delivering within 2 weeks of delivery 21/2686 (0.8 %) were affected by stillbirth compared with 8/4596 (0.2 %) delivering ≥ 2 weeks after infection (95 % CI 0.3–1.0). SGA affected 744/7696 (9.3 %) of livebirths, FGR affected 360/8175 (4.4 %) of all pregnancies. Pre-term birth occurred in 922/8066 (11.5%), the majority of these were indicated pre-term births, 220/7987 (2.8%) participants experienced spontaneous pre-term births. Early neonatal deaths affected 11/8050 livebirths. Of all neonates, 80/7993 (1.0%) tested positive for SARS-CoV-2. Conclusions Infection was associated with indicated pre-term birth, most commonly for fetal compromise. The overall proportions of women affected by SGA and FGR were not higher than expected, however there was the proportion affected by stillbirth in participants delivering within 2 weeks of infection was significantly higher than those delivering ≥ 2 weeks after infection. We suggest that clinicians’ threshold for delivery should be low if there are concerns with fetal movements or fetal heart rate monitoring in the time around infection

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation

Prevention and detection of liver disease in the general population

Liver disease is the third biggest cause of premature death in the UK, yet two of its main causes - alcohol consumption and obesity – are modifiable risk factors, potentially amenable to public health prevention interventions. Chronic liver disease is generally progressive, usually starting with mild fibrosis and continuing through to cirrhosis. Signs and symptoms often do not appear until disease is at an advanced stage. As a result, many patients present late to healthcare services and outcomes are poor. Consequently, this work focused on the general population of the UK, where prevention strategies would best be targeted. The aim is to better understand the epidemiology of those at risk of liver disease due to obesity and alcohol consumption, and how disease may be identified early in its course, in order to improve patient outcomes.To address this, large datasets from general population settings were analysed. This included conducting a meta-analysis of cohort studies, and analyses of national survey datasets. This thesis describes the distribution and overlap of alcohol and obesity risk factors for liver disease; risk of liver disease associated with individual risk factors and their combinations; distribution of non-invasive markers of liver disease; associations between non-invasive markers of liver disease and risk factors; and associations between overweight /obesity and calories from alcohol.Key findings were that the majority of the UK general population have at least one risk factor for liver disease and nearly 30% have multiple risk factors. Awareness of the risk factors for liver disease in the general population was very low (4%). There was a significantly increased risk of liver disease associated with the combination of drinking above recommended alcohol consumption guidelines and being overweight or obese (OR 3.60 (95%CI 3.22 to 4.02) for overweight, OR 5·84 (95%CI 5·09 to 6·70) for obese). Some 12% of the general population had acombination of increased alcohol consumption and increased BMI. We suggest the term ‘BAFLD to describe these people at risk of Both Alcohol and Fatty Liver Disease. Non-invasive markers of liver disease showed significant variation in positivity in the general population setting, they were not concordant and their performance differed significantly between risk factor categories. Abnormal liver blood tests were found in 11% of the population. Calorie consumption was higher in those who consumed alcohol, and alcohol calories were consumed in addition to usual calorie intake. Weekly calorific intake from alcoholic beverages increased significantly with increasing BMI. Mean extra calories on days when participants consumed alcohol were 428 kcal (95%CI 396 to 460).The data presented here further our knowledge of who is at risk of liver disease; the interplay of risk factors; the use of non-invasive markers in a general population setting; and the contribution of calories from alcohol in those with existing risk from increased BMI. It is hoped this evidence will inform risk stratification protocols, clinical pathways, prevention strategies and public health policy, in order to improve prevention and detection of chronic liver disease in the UK population

Redefining risk of liver disease in the general population: analysis of the Health Survey for England 2016

Background and aims: the health, financial and societal arguments for public health action to prevent lifestyle related liver disease are clear. Primary care has frequently been suggested as a key location for prevention strategies. Evidence on the most appropriate cut-offs for liver biochemistry and indirect fibrosis markers, which may be used for screening before more definitive assessment, has predominantly been gathered in patients with existing liver disease. These thresholds may not be suitable in community settings. For the first time liver function tests, from a sample representative of the general population in England, are available. We explored the distribution of risk factors for liver disease, liver function test results and liver fibrosis scores in the Health Survey for England (HSE) 2016.Method: cross-sectional survey with interview, examination and blood tests. Multi-stage, stratified, random probability sample designed to be representative of the population living in private households in England. Participants: 7,826 adults aged 18 years and over, of whom 3,791 had a blood test. Exposures and markers: Risk factors were alcohol consumption >14 units/wk, body mass index ≥25 and diabetes. Liver function tests were Alanine aminotransferase (ALT) and Aspartate Aminotransferase (AST). Liver fibrosis scores calculated were FIB-4 score (high>2.67), APRI score (high≥1.0), AST:ALT ratio (high>0.8), BARD score (high≥2).Results: 85.5% (84.4 to 86.7%,n=5670) of the population representative sample have at least one risk factor for liver disease. 25.9% (24.4 to 27.5%,n=4685) have two or more risk factors. 2.5% (2.0 to 3.1%,n=3388) had a high FIB-4; 11.5% (10.3 to 12.8%,n=3607) had a raised ALT; 86.0% (84.5 to 87.3%,n=3424) had a high AST:ALT ratio. Only 5.1% (4.3 to 6.0%,n=4031) of those with at least one risk factor and 7.9% (6.1 to 10.1%,n=3749) of those with two or more risk factors had been told by a health professional that they were at risk of liver disease. 12.9% (11.8 to 14.1%, n=4722) of the sample and 17.7% (10.9 to 27.3%, n=85) of those with a high FIB-4 score report ever being tested for liver disease.Conclusion: this is the first analysis of liver biochemistry and indirect fibrosis markers in a sample representative of the general population of England. Modifiable lifestyle risk factors for liver disease are present in more than 85% of participants. Multiple risk factors are common and may be synergistic. Commonly used liver function tests and fibrosis scores showed large variation in positivity. Awareness of risk and testing for liver disease was low, even in those with multiple risk factors. The best approach to achieve detection of liver disease in primary care remains unclear

The combined effect of alcohol and obesity on risk of liver disease: a systematic review and meta-analysis

Background: liver disease caused by alcohol and obesity is preventable by risk factor modification. Evidence from individual studies on risk in patients who have both risk factors is inconsistent. We performed a systematic review and meta-analysis to quantify the risk of liver disease associated with combinations of BMI and alcohol consumption. Methods: the full study protocol is registered with PROSPERO (CRD42016046508). Inclusion criteria were: English language publications in peer-reviewed journals; adults from general population cohorts without pre-existing liver disease; BMI and alcohol quantifiably measured; follow-up at least 10 years duration. Outcomes were incident morbidity/mortality from cirrhosis and/or hepatocellular carcinoma. A one-stage meta-analysis was performed on original count data, using a Poisson regression log-linear model. The log-linear model has the property that joint effects are multiplicative. Reference categories were normal weight (BMI<25) and alcohol consumption above zero but within UK limits (<112 g/wk). Results: the search identified 2589 studies. 50 underwent full text review. Eight cohorts (Two from the USA, six from Europe) were included in the meta-analysis, totalling 1,029,962 participants. There was no interaction between alcohol and obesity in the model. Risks of liver disease in those with both increased BMI and alcohol consumption were significantly increased and were multiplicative, as per the properties of the log-linear model (figure 1). Compared to normal weight participants drinking <112 g/wk (UK recommended limit), the relative risk of liver disease in those who were overweight and drinking above limits was 3.60 (95%CI 3.22-4.02) and the relative risk in those who were obese and drinking above limits was 5.84 (95%CI 5.09–6.70). Conclusion: overweight and obese patients drinking >112 g/wk are at significantly increased risk of liver disease. This risk should inform lifestyle advice given to patients and risk stratification by healthcare professionals. Alcohol thresholds imposed in NAFLD criteria and pathways may mean that patients with both increased BMI and alcohol risk factors, at risk of Both Alcohol and Fatty Liver Disease (BAFLD), are not receiving appropriate risk assessment or clinical care. The current guidelines for alcohol consumption may not be appropriate for obese patient