BACKGROUND & AIMS:Currently, the main treatment for celiac disease (CD) is the gluten-free diet (GFD). This observational cohort study investigated the impact of CD and 1 year of GFD on gut function and microbiome. METHODS:A total of 36 newly diagnosed patients and 36 healthy volunteers (HVs) were studied at baseline and at 12-month follow-up. Small bowel water content (SBWC), whole gut transit time (WGTT), and colon volumes were measured by magnetic resonance imaging. Stool sample DNA was subjected to shotgun metagenomic sequencing. Species-level abundances and gene functions, including CAZymes (carbohydrate active enzymes) were determined. RESULTS:SBWC was significantly higher in people with CD (157 ± 15 mL) vs (HVs 100 ± 12 mL) (P = .003). WGTT was delayed in people with CD (68 ± 8 hours) vs HVs (41 ± 5 hours) (P = .002). The differences reduced after 12 months of GFD but not significantly. Well-being in the CD group significantly improved after GFD but did not recover to control values. CD fecal microbiota showed a high abundance of proteolytic gene functions, associated with Escherichia coli, Enterobacter, and Peptostreptococcus. GFD significantly reduced Bifidobacteria and increased Blautia wexlerae. Microbiome composition correlated positively with WGTT, colonic volume, and Akkermansia municphilia but negatively with B wexerelae. Following GFD, the reduction in WGTT and colonic volume was significantly associated with increased abundance of B wexlerae. There were also significant alterations in CAZyme profiles, specifically starch- and arabinoxylan-degrading families. CONCLUSIONS:CD impacted gut function and microbiota. GFD ameliorated but did not reverse these effects, significantly reducing Bifidobacteria associated with reduced intake of resistant starch and arabinoxylan from wheat. CLINICALTRIALS:gov, number: NCT02551289.

Background People with cystic fibrosis (CF) can experience recurrent chest infections, pancreatic exocrine insufficiency and gastrointestinal symptoms. New cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs improve lung function but gastrointestinal effects are unclear. We aimed to see if a CFTR modulator (tezacaftor-ivacaftor,TEZ/IVA) improves gastrointestinal outcomes in CF. Methods We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (2019-2020) at Nottingham University Hospitals. The effects of TEZ/IVA on gut physiology were measured using MRI. Participants were randomly assigned to treatment sequences AB or BA (A:TEZ/IVA, B:placebo, each 28 days), with a 28-day washout period. Participants had serial MRI scans at baseline and after 19-23 days of each treatment. Due to the COVID-19 pandemic, a protocol amendment allowed for observer-blind comparisons prior to and during TEZ/IVA. In such cases, participants were not blind to the treatment but researchers remained blind. The primary outcome was oro-caecal transit time (OCTT). Secondary outcomes included MRI metrics, symptoms and stool biomarkers. Results We randomised 13 participants. Before the COVID-19 pandemic 8 participants completed the full protocol and 1 dropped out. The remaining 4 participants followed the amended protocol. There were no significant differences between placebo and TEZ/IVA for OCTT (TEZ/IVA >360minutes [225,>360] vs. placebo 330minutes [285,>360], p=0.8) or secondary outcomes. There were no adverse events. Conclusions Our data contribute to a research gap in the extra-pulmonary effects of CFTR modulators. We found no effect after TEZ/IVA on MRI metrics of gut function, GI symptoms or stool calprotectin. Effects might be detectable with larger studies, longer treatment or more effective CFTR modulators. ClinicalTrials.gov registration NCT04006873 (02/07/2019)

BackgroundInjuries in children aged under 5 years most commonly occur in the home and disproportionately affect those living in the most disadvantaged communities. The 'Safe at Home' (SAH) national home safety equipment scheme, which ran in England between 2009 and 2011, has been shown to reduce injury-related hospital admissions, but there is little evidence of cost-effectiveness. Materials and methodsCost-effectiveness analysis from a health and local government perspective. Measures were the incremental cost-effectiveness ratio per hospital admission averted (ICER) and cost-offset ratio (COR), comparing SAH expenditure to savings in admission expenditure. The study period was split into three periods: T1 (years 0-2, implementation); T2 (years 3-4) and T3 (years 5-6). Analyses were conducted for T2 versus T1 and T3 versus T1. ResultsTotal cost of SAH was 9 pound 518 066. 202 223 hospital admissions in the children occurred during T1-3, costing 3 pound 320 000. Comparing T3 to T1 SAH reduced admission expenditure by 924 pound per month per local authority and monthly admission rates by 0.5 per local authority per month compared with control areas. ICER per admission averted was 4209 pound for T3 versus T1, with a COR of 0.29 pound, suggesting that 29p was returned in savings on admission expenditure for every pound spent on SAH. ConclusionSAH was effective at reducing hospital admissions due to injury and did result in some cost recovery when taking into admissions only. Further analysis of its cost-effectiveness, including emergency healthcare, primary care attendances and wider societal costs, is likely to improve the return on investment further.

BACKGROUND Non-alcoholic fatty liver disease (NAFLD) represents a growing public health concern, with patients having higher risk of morbidity and mortality. It has a considerably high prevalence in the general population, estimated 20%-40% in Europe, and is asymptomatic until late in the disease course. It is therefore important to identify and validate tools that predict hard outcomes such as mortality for use in clinical practice in risk-stratifying NAFLD patients. AIM To evaluate available evidence on the use of non-invasive test(s) as prognostic factors for mortality in NAFLD. METHODSWe performed electronic searches of Medline and EMBASE (Ovid) until 7th January 2021 of studies in NAFLD populations. Prognostic markers included serum biomarkers, non-invasive scoring systems, and non-invasive imaging. The population included all spectrums of disease severity, including NAFLD and non-alcoholic steatohepatitis (NASH). Outcomes included all-cause, and cardiovascular mortality. All non-invasive tests were synthesised in a narrative systematic review. Finally, we conducted a meta-analysis of non-invasive scoring systems for predicting all-cause and cardiovascular mortality, calculating pooled hazard ratios and 95% confidence (STATA 16.1). RESULTS Database searches identified 2850 studies - 24 were included. 16 studies reported non-invasive scoring systems, 10 studies reported individual biomarkers, and 1 study reported imaging modalities. 4 studies on non-invasive scoring systems (6324 participants) had data available for inclusion in the meta-analysis. The non-invasive scoring system that performed best at predicting all-cause mortality was NAFLD fibrosis score (NFS) [pHR 3.07 (1.62-5.83)], followed by fibrosis-4 index [pHR 3.06 (1.54-6.07)], BARD [pHR 2.87 (1.27-6.46)], and AST to platelet ratio index [pHR 1.90 (1.32-2.73)]. NFS was also prognostic of cardiovascular-related mortality[pHR 3.09 (1.78-5.34)]. CONCLUSION This study reaffirms that non-invasive scoring systems, especially NFS, are reliable prognostic markers of all-cause mortality and cardiovascular mortality in NAFLD patients. These findings can inform clinical practice in risk stratifying NAFLD patients.

ObjectiveIf non-invasive markers of liver fibrosis were recorded frequently enough in clinical practice, it might be feasible to use them for opportunistic community screening for liver disease. We aimed to determine their current pattern of usage in the national primary care population in Wales.DesignUsing the Secure Anonymised Information Linkage (SAIL) Databank at Swansea University (2000–2017), we quantified the frequency of common liver blood tests (aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count and albumin) used in fibrosis marker algorithms. We examined measurement variation by age and sex.ResultsDuring the 18-year study period, there were 2 145 178 adult patients with at least one blood test available for analysis. Over the study period, the percentage of SAIL patients receiving an ALT test in each year increased from 2% to 33%, with platelet count and albumin measurement increasing by a similar factor. AST testing, although initially rising, had decreased to 1% by the end of the study. AST and ALT values varied by age and sex, particularly in males with the upper normal range of ALT values decreasing rapidly from 90 U/L at age 30 to 45 U/L by age 80.ConclusionThe reduction in AST testing to only 1% of the adult population limits the use of many non-invasive liver marker algorithms. To enable widespread screening, alternative algorithms for liver fibrosis that do not depend on AST should be developed. Liver fibrosis markers should be modified to include age-specific and sex-specific normal ranges.

Background Unintentional home injuries are a leading cause of preventable death in young children. Safety education and equipment provision improve home safety practices, but their impact on injuries is less clear. Between 2009 and 2011, a national home safety equipment scheme was implemented in England (Safe At Home), targeting high-injury-rate areas and socioeconomically disadvantaged families with children under 5. This provided a ‘natural experiment’ for evaluating the scheme’s impact on hospital admissions for unintentional injuries. Methods Controlled interrupted time series analysis of unintentional injury hospital admission rates in small areas (Lower Layer Super Output Areas (LSOAs)) in England where the scheme was implemented (intervention areas, n=9466) and matched with LSOAs in England and Wales where it was not implemented (control areas, n=9466), with subgroup analyses by density of equipment provision. Results 57 656 homes receiving safety equipment were included in the analysis. In the 2 years after the scheme ended, monthly admission rates declined in intervention areas (−0.33% (−0.47% to −0.18%)) but did not decline in control areas (0.04% (−0.11%–0.19%), p value for difference in trend=0.001). Greater reductions in admission rates were seen as equipment provision density increased. Effects were not maintained beyond 2 years after the scheme ended. Conclusions A national home safety equipment scheme was associated with a reduction in injury-related hospital admissions in children under 5 in the 2 years after the scheme ended. Providing a higher number of items of safety equipment appears to be more effective in reducing injury rates than providing fewer items.

Key Points Question Is the risk of dementia among persons 55 years or older associated with the use of different types of anticholinergic medication? Findings In this nested case-control study of 58 769 patients with a diagnosis of dementia and 225 574 matched controls, there were statistically significant associations of dementia risk with exposure to anticholinergic antidepressants, antiparkinson drugs, antipsychotic drugs, bladder antimuscarinics, and antiepileptic drugs after adjusting for confounding variables. Meaning The associations observed for specific types of anticholinergic medication suggest that these drugs should be prescribed with caution in middle-aged and older adults.

Antidepressants are one of the most commonly prescribed medications in young and middle-aged adults, but there is relatively little information on their safety across a range of adverse outcomes in this age group. This study aimed to assess associations between antidepressant treatment and several adverse outcomes in people aged 20–64 years diagnosed with depression.

OBJECTIVE To investigate the associations between direct oral anticoagulants DOACs) and risks of bleeding, ischaemic stroke, venous thromboembolism, and all cause mortality compared with warfarin. DESIGN Prospective open cohort study. SETTING UK general practices contributing to QResearch or Clinical Practice Research Datalink. PARTICIPANTS 132 231 warfarin, 7744 dabigatran, 37 863 rivaroxaban, and 18 223 apixaban users without anticoagulant prescriptions for 12 months before study entry, subgrouped into 103 270 patients with atrial fibrillation and 92 791 without atrial fibrillation between 2011 and 2016. MAIN OUTCOME MEASURES Major bleeding leading to hospital admission or death. Specific sites of bleeding and all cause mortality were also studied. RESULTS In patients with atrial fibrillation, compared with warfarin, apixaban was associated with a decreased risk of major bleeding adjusted hazard ratio 0.66, 95% confidence interval 0.54 to 0.79) and intracranial bleeding 0.40, 0.25 to 0.64); dabigatran was associated with a decreased risk of intracranial bleeding 0.45, 0.26 to 0.77). An increased risk of all cause mortality was observed in patients taking rivaroxaban 1.19, 1.09 to 1.29) or on lower doses of apixaban 1.27, 1.12 to 1.45). In patients without atrial fibrillation, compared with warfarin, apixaban was associated with a decreased risk of major bleeding 0.60, 0.46 to 0.79), any gastrointestinal bleeding 0.55, 0.37 to 0.83), and upper gastrointestinal bleeding 0.55, 0.36 to 0.83); rivaroxaban was associated with a decreased risk of intracranial bleeding 0.54, 0.35 to 0.82). Increased risk of all cause mortality was observed in patients taking rivaroxaban 1.51, 1.38 to 1.66) and those on lower doses of apixaban 1.34, 1.13 to 1.58). CONCLUSIONS Overall, apixaban was found to be the safest drug, with reduced risks of major, intracranial, and gastrointestinal bleeding compared with warfarin. Rivaroxaban and low dose apixaban were, however, associated with increased risks of all cause mortality compared with warfarin.

OBJECTIVE:To assess associations between different antidepressant treatments and rates of three cardiovascular outcomes (myocardial infarction, stroke or transient ischaemic attack, and arrhythmia) in people with depression.DESIGN:Cohort study.SETTING:UK general practices contributing to the QResearch primary care database.PARTICIPANTS:238,963 patients aged 20 to 64 years with a first diagnosis of depression between 1 January 2000 and 31 July 2011.EXPOSURES:Antidepressant class (tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants), dose, duration of use, and commonly prescribed individual antidepressant drugs.MAIN OUTCOME MEASURES:First diagnoses of myocardial infarction, stroke or transient ischaemic attack, and arrhythmia during five years' follow-up. Cox proportional hazards models were used to estimate hazard ratios, adjusting for potential confounding variables.RESULTS:During five years of follow-up, 772 patients had a myocardial infarction, 1106 had a stroke or transient ischaemic attack, and 1452 were diagnosed as having arrhythmia. No significant associations were found between antidepressant class and myocardial infarction over five years' follow-up. In the first year of follow-up, patients treated with selective serotonin reuptake inhibitors had a significantly reduced risk of myocardial infarction (adjusted hazard ratio 0.58, 95% confidence interval 0.42 to 0.79) compared with no use of antidepressants; among individual drugs, fluoxetine was associated with a significantly reduced risk (0.44, 0.27 to 0.72) and lofepramine with a significantly increased risk (3.07, 1.50 to 6.26). No significant associations were found between antidepressant class or individual drugs and risk of stroke or transient ischaemic attack. Antidepressant class was not significantly associated with arrhythmia over five years' follow-up, although the risk was significantly increased during the first 28 days of treatment with tricyclic and related antidepressants (adjusted hazard ratio 1.99, 1.27 to 3.13). Fluoxetine was associated with a significantly reduced risk of arrhythmia (0.74, 0.59 to 0.92) over five years, but citalopram was not significantly associated with risk of arrhythmia even at high doses (1.11, 0.72 to 1.71 for doses ≥ 40 mg/day).CONCLUSIONS:This study found no evidence that selective serotonin reuptake inhibitors are associated with an increased risk of arrhythmia or stroke/transient ischaemic attack in people diagnosed as having depression between the ages of 20 to 64 or that citalopram is associated with a significantly increased risk of arrhythmia. It found some indication of a reduced risk of myocardial infarction with selective serotonin reuptake inhibitors, particularly fluoxetine, and of an increased risk with lofepramine.

Background: Epilepsy is a serious condition which can profoundly affect an individual's life. While there is some evidence to suggest an association between antidepressant use and epilepsy and seizures it is conflicting and not conclusive. Antidepressant prescribing is rising in the UK so it is important to quantify absolute risks with individual antidepressants to enable shared decision making with patients. In this study we assess and quantify the association between antidepressant treatment and the risk of epilepsy and seizures in a large cohort of patients diagnosed with depression aged between 20 and 64 years.Methods: Data on 238,963 patients with a diagnosis of depression aged 20 to 64 from 687 UK practices were extracted from the QResearch primary care database. We used Cox's proportional hazards to analyse the time to the first recorded diagnosis of epilepsy/seizures, excluding patients with a prior history and estimated hazard ratios for antidepressant exposure adjusting for potential confounding variables.Results: In the first 5 years of follow-up, 878 (0.37 %) patients had a first diagnosis of epilepsy/seizures with the hazard ratio (HR) significantly increased (P < 0.01) for all antidepressant drug classes and for 8 of the 11 most commonly prescribed drugs. The highest risks (in the first 5 years) compared with no treatment were for trazodone (HR 5.41, 95 % confidence interval (CI) 3.05 to 9.61, number needed to harm (NNH) 65), lofepramine (HR 3.09, 95 % CI 1.73 to 5.50, NNH 138), venlafaxine (HR 2.84, 95 % CI 1.97 to 4.08, NNH 156) and combined antidepressant treatment (HR 2.73, 95 % CI 1.52 to 4.91, NNH 166).Conclusions: Risk of epilepsy/seizures is significantly increased for all classes of antidepressant. There is a need for individual risk-benefit assessments in patients being considered for antidepressant treatment, especially those with ongoing mild depression or with additional risk factors. Residual confounding and indication bias may influence our results, so confirmation may be required from additional studies.

Objective To assess the associations between different antidepressant treatments and the rates of suicide and attempted suicide or self harm in people with depression. Design Cohort study. Setting Patients registered with UK general practices contributing data to the QResearch database. Participants 238 963 patients aged 20 to 64 years with a first diagnosis of depression between 1 January 2000 and 31 July 2011, followed up until 1 August 2012. Exposures Antidepressant class (tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants), dose, and duration of use, and commonly prescribed individual antidepressant drugs. Cox proportional hazards models were used to calculate hazard ratios adjusting for potential confounding variables. Main outcome measures Suicide and attempted suicide or self harm during follow-up. Results During follow-up, 87.7% (n=209 476) of the cohort received one or more prescriptions for antidepressants. The median duration of treatment was 221 days (interquartile range 79-590 days). During the first five years of follow-up 198 cases of suicide and 5243 cases of attempted suicide or self harm occurred. The difference in suicide rates during periods of treatment with tricyclic and related antidepressants compared with selective serotonin reuptake inhibitors was not significant (adjusted hazard ratio 0.84, 95% confidence interval 0.47 to 1.50), but the suicide rate was significantly increased during periods of treatment with other antidepressants (2.64, 1.74 to 3.99). The hazard ratio for suicide was significantly increased for mirtazapine compared with citalopram (3.70, 2.00 to 6.84). Absolute risks of suicide over one year ranged from 0.02% for amitriptyline to 0.19% for mirtazapine. There was no significant difference in the rate of attempted suicide or self harm with tricyclic antidepressants (0.96, 0.87 to 1.08) compared with selective serotonin reuptake inhibitors, but the rate of attempted suicide or self harm was significantly higher for other antidepressants (1.80, 1.61 to 2.00). The adjusted hazard ratios for attempted suicide or self harm were significantly increased for three of the most commonly prescribed drugs compared with citalopram: venlafaxine (1.85, 1.61 to 2.13), trazodone (1.73, 1.26 to 2.37), and mirtazapine (1.70, 1.44 to 2.02), and significantly reduced for amitriptyline (0.71, 0.59 to 0.85). The absolute risks of attempted suicide or self harm over one year ranged from 1.02% for amitriptyline to 2.96% for venlafaxine. Rates were highest in the first 28 days after starting treatment and remained increased in the first 28 days after stopping treatment. Conclusion Rates of suicide and attempted suicide or self harm were similar during periods of treatment with selective serotonin reuptake inhibitors and tricyclic and related antidepressants. Mirtazapine, venlafaxine, and trazodone were associated with the highest rates of suicide and attempted suicide or self harm, but the number of suicide events was small leading to imprecise estimates. As this is an observational study the findings may reflect indication biases and residual confounding from severity of depression and differing characteristics of patients prescribed these drugs. The increased rates in the first 28 days of starting and stopping antidepressants emphasise the need for careful monitoring of patients during these periods.

Background Antidepressants are among the most commonly prescribed drugs in primary care in England and their use is increasing. This is largely due to longer durations of treatment of depression. Observational studies have shown some differences in adverse outcomes associated with different antidepressant drugs but relatively little is known about their relative safety particularly with long term use. The primary aim of this study is to determine the relative and absolute risks of pre-defined adverse events comparing different classes of antidepressant drugs in adults aged under 65 years and diagnosed with depression. Methods/design The study will identify a cohort of patients with a first recorded diagnosis of depression between 1/1/2000 and 31/07/2011, and made between the ages of 20 to 64 years using a large primary care database (QResearch). Patients will be followed up until 1/08/2012. Details of all prescriptions for antidepressants in patients in the cohort will be extracted, including the date of each prescription, the type of antidepressant drug, the dose and total quantity prescribed. Prospectively recorded data will be used to ascertain information on adverse outcomes that occurred during follow-up and after entry into the cohort. These are: all-cause mortality, suicide, attempted suicide/self-harm, sudden death, antidepressant overdose/poisoning, myocardial infarction, stroke/transient ischaemic attack, cardiac arrhythmia, epilepsy/seizures, upper gastrointestinal bleeding, falls, fractures, adverse drug reactions and motor vehicle crashes. Cox proportional hazard models will be used to estimate the association of the outcomes with class of antidepressant drug adjusting for potential confounding variables. The analyses will also examine associations by duration and dose and with the most frequently prescribed individual antidepressant drugs. Self-controlled case series analyses will be used to estimate the relative incidence of the outcomes of interest for defined time periods of antidepressant use. Discussion The results of this study will help to establish the relative safety and balance of risks for different antidepressant drugs in people aged under 65.