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1.
Frontline Gastroenterol ; 13(2): 133-139, 2022.
Article in English | MEDLINE | ID: mdl-35295751

ABSTRACT

There is an increasing demand and availability of bariatric surgery, with a range of procedures performed, some leading to altered upper gastrointestinal anatomy. The patient population undergoing bariatric surgery is also at increased risk of gallstones and biliary stone disease. Endoscopy (ie, endoscopic retrograde cholangiopancreatography) is the cornerstone of management of biliary stone disease, but may be challenging after bariatric surgery. In this review the endoscopic, surgery assisted, or percutaneous options that may be considered are discussed, based on the details of surgical anatomy and available expertise.

2.
BMC Med Inform Decis Mak ; 21(1): 281, 2021 10 12.
Article in English | MEDLINE | ID: mdl-34641870

ABSTRACT

BACKGROUND: An Informatics Consult has been proposed in which clinicians request novel evidence from large scale health data resources, tailored to the treatment of a specific patient. However, the availability of such consultations is lacking. We seek to provide an Informatics Consult for a situation where a treatment indication and contraindication coexist in the same patient, i.e., anti-coagulation use for stroke prevention in a patient with both atrial fibrillation (AF) and liver cirrhosis. METHODS: We examined four sources of evidence for the effect of warfarin on stroke risk or all-cause mortality from: (1) randomised controlled trials (RCTs), (2) meta-analysis of prior observational studies, (3) trial emulation (using population electronic health records (N = 3,854,710) and (4) genetic evidence (Mendelian randomisation). We developed prototype forms to request an Informatics Consult and return of results in electronic health record systems. RESULTS: We found 0 RCT reports and 0 trials recruiting for patients with AF and cirrhosis. We found broad concordance across the three new sources of evidence we generated. Meta-analysis of prior observational studies showed that warfarin use was associated with lower stroke risk (hazard ratio [HR] = 0.71, CI 0.39-1.29). In a target trial emulation, warfarin was associated with lower all-cause mortality (HR = 0.61, CI 0.49-0.76) and ischaemic stroke (HR = 0.27, CI 0.08-0.91). Mendelian randomisation served as a drug target validation where we found that lower levels of vitamin K1 (warfarin is a vitamin K1 antagonist) are associated with lower stroke risk. A pilot survey with an independent sample of 34 clinicians revealed that 85% of clinicians found information on prognosis useful and that 79% thought that they should have access to the Informatics Consult as a service within their healthcare systems. We identified candidate steps for automation to scale evidence generation and to accelerate the return of results. CONCLUSION: We performed a proof-of-concept Informatics Consult for evidence generation, which may inform treatment decisions in situations where there is dearth of randomised trials. Patients are surprised to know that their clinicians are currently not able to learn in clinic from data on 'patients like me'. We identify the key challenges in offering such an Informatics Consult as a service.


Subject(s)
Atrial Fibrillation , Stroke , Anticoagulants/therapeutic use , Atrial Fibrillation/drug therapy , Humans , Informatics , Referral and Consultation , Stroke/drug therapy , Treatment Outcome , Warfarin/therapeutic use
3.
Epidemiology ; 32(5): 744-755, 2021 09 01.
Article in English | MEDLINE | ID: mdl-34348396

ABSTRACT

BACKGROUND: Cross-sectional measures of body mass index (BMI) are associated with cardiovascular disease (CVD) incidence, but less is known about whether weight change affects the risk of CVD. METHODS: We estimated the effect of 2-y weight change interventions on 7-y risk of CVD (CVD death, myocardial infarction, stroke, hospitalization from coronary heart disease, and heart failure) by emulating hypothetical interventions using electronic health records. We identified 138,567 individuals with 45-69 years of age without chronic disease in England from 1998 to 2016. We performed pooled logistic regression, using inverse-probability weighting to adjust for baseline and time-varying confounders. We categorized each individual into a weight loss, maintenance, or gain group. RESULTS: Among those of normal weight, both weight loss [risk difference (RD) vs. weight maintenance = 1.5% (0.3% to 3.0%)] and gain [RD = 1.3% (0.5% to 2.2%)] were associated with increased risk for CVD compared with weight maintenance. Among overweight individuals, we observed moderately higher risk of CVD in both the weight loss [RD = 0.7% (-0.2% to 1.7%)] and the weight gain group [RD = 0.7% (-0.1% to 1.7%)], compared with maintenance. In the obese, those losing weight showed lower risk of coronary heart disease [RD = -1.4% (-2.4% to -0.6%)] but not of stroke. When we assumed that chronic disease occurred 1-3 years before the recorded date, estimates for weight loss and gain were attenuated among overweight individuals; estimates for loss were lower among obese individuals. CONCLUSION: Among individuals with obesity, the weight-loss group had a lower risk of coronary heart disease but not of stroke. Weight gain was associated with increased risk of CVD across BMI groups. See video abstract at, http://links.lww.com/EDE/B838.


Subject(s)
Cardiovascular Diseases , Body Mass Index , Cardiovascular Diseases/epidemiology , Cross-Sectional Studies , Electronic Health Records , Humans , Overweight/epidemiology , Risk Factors
4.
Sci Rep ; 11(1): 2938, 2021 02 03.
Article in English | MEDLINE | ID: mdl-33536532

ABSTRACT

Reducing the burden of late-life morbidity requires an understanding of the mechanisms of ageing-related diseases (ARDs), defined as diseases that accumulate with increasing age. This has been hampered by the lack of formal criteria to identify ARDs. Here, we present a framework to identify ARDs using two complementary methods consisting of unsupervised machine learning and actuarial techniques, which we applied to electronic health records (EHRs) from 3,009,048 individuals in England using primary care data from the Clinical Practice Research Datalink (CPRD) linked to the Hospital Episode Statistics admitted patient care dataset between 1 April 2010 and 31 March 2015 (mean age 49.7 years (s.d. 18.6), 51% female, 70% white ethnicity). We grouped 278 high-burden diseases into nine main clusters according to their patterns of disease onset, using a hierarchical agglomerative clustering algorithm. Four of these clusters, encompassing 207 diseases spanning diverse organ systems and clinical specialties, had rates of disease onset that clearly increased with chronological age. However, the ages of onset for these four clusters were strikingly different, with median age of onset 82 years (IQR 82-83) for Cluster 1, 77 years (IQR 75-77) for Cluster 2, 69 years (IQR 66-71) for Cluster 3 and 57 years (IQR 54-59) for Cluster 4. Fitting to ageing-related actuarial models confirmed that the vast majority of these 207 diseases had a high probability of being ageing-related. Cardiovascular diseases and cancers were highly represented, while benign neoplastic, skin and psychiatric conditions were largely absent from the four ageing-related clusters. Our framework identifies and clusters ARDs and can form the basis for fundamental and translational research into ageing pathways.


Subject(s)
Aging , Cardiovascular Diseases/epidemiology , Data Science , Mental Disorders/epidemiology , Neoplasms/epidemiology , Age of Onset , Aged , Aged, 80 and over , Cluster Analysis , Cost of Illness , Electronic Health Records/statistics & numerical data , Female , Humans , Male , Middle Aged , Primary Health Care/statistics & numerical data , Risk Factors , Unsupervised Machine Learning
5.
J Hepatol ; 74(1): 20-30, 2021 01.
Article in English | MEDLINE | ID: mdl-32882372

ABSTRACT

BACKGROUND & AIMS: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. METHODS: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. RESULTS: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], pz = 4.8×10-5) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5×10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSIONS: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. LAY SUMMARY: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.


Subject(s)
Acyltransferases/genetics , Liver Cirrhosis , Liver/pathology , Membrane Proteins/genetics , Non-alcoholic Fatty Liver Disease , Alanine Transaminase/blood , Drug Discovery , Genetic Predisposition to Disease , Humans , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/genetics , Polymorphism, Single Nucleotide
8.
J Hepatol ; 73(2): 241-251, 2020 08.
Article in English | MEDLINE | ID: mdl-32247823

ABSTRACT

BACKGROUND & AIMS: MRI-based corrected T1 (cT1) is a non-invasive method to grade the severity of steatohepatitis and liver fibrosis. We aimed to identify genetic variants influencing liver cT1 and use genetics to understand mechanisms underlying liver fibroinflammatory disease and its link with other metabolic traits and diseases. METHODS: First, we performed a genome-wide association study (GWAS) in 14,440 Europeans, with liver cT1 measures, from the UK Biobank. Second, we explored the effects of the cT1 variants on liver blood tests, and a range of metabolic traits and diseases. Third, we used Mendelian randomisation to test the causal effects of 24 predominantly metabolic traits on liver cT1 measures. RESULTS: We identified 6 independent genetic variants associated with liver cT1 that reached the GWAS significance threshold (p <5×10-8). Four of the variants (rs759359281 in SLC30A10, rs13107325 in SLC39A8, rs58542926 in TM6SF2, rs738409 in PNPLA3) were also associated with elevated aminotransferases and had variable effects on liver fat and other metabolic traits. Insulin resistance, type 2 diabetes, non-alcoholic fatty liver and body mass index were causally associated with elevated cT1, whilst favourable adiposity (instrumented by variants associated with higher adiposity but lower risk of cardiometabolic disease and lower liver fat) was found to be protective. CONCLUSION: The association between 2 metal ion transporters and cT1 indicates an important new mechanism in steatohepatitis. Future studies are needed to determine whether interventions targeting the identified transporters might prevent liver disease in at-risk individuals. LAY SUMMARY: We estimated levels of liver inflammation and scarring based on magnetic resonance imaging of 14,440 UK Biobank participants. We performed a genetic study and identified variations in 6 genes associated with levels of liver inflammation and scarring. Participants with variations in 4 of these genes also had higher levels of markers of liver cell injury in blood samples, further validating their role in liver health. Two identified genes are involved in the transport of metal ions in our body. Further investigation of these variations may lead to better detection, assessment, and/or treatment of liver inflammation and scarring.


Subject(s)
Cation Transport Proteins/genetics , Fatty Liver/genetics , Liver Cirrhosis/genetics , Liver , Metabolic Syndrome/genetics , Europe/epidemiology , Fatty Liver/epidemiology , Female , Genetic Predisposition to Disease , Genetic Variation , Genome-Wide Association Study , Humans , Liver/diagnostic imaging , Liver/pathology , Liver Cirrhosis/epidemiology , Magnetic Resonance Imaging/methods , Male , Mendelian Randomization Analysis , Metabolic Syndrome/epidemiology , Middle Aged , Polymorphism, Single Nucleotide , Protective Factors , Risk Assessment/methods
9.
Lancet Digit Health ; 1(2): e63-e77, 2019 06.
Article in English | MEDLINE | ID: mdl-31650125

ABSTRACT

Background: To effectively prevent, detect, and treat health conditions that affect people during their lifecourse, health-care professionals and researchers need to know which sections of the population are susceptible to which health conditions and at which ages. Hence, we aimed to map the course of human health by identifying the 50 most common health conditions in each decade of life and estimating the median age at first diagnosis. Methods: We developed phenotyping algorithms and codelists for physical and mental health conditions that involve intensive use of health-care resources. Individuals older than 1 year were included in the study if their primary-care and hospital-admission records met research standards set by the Clinical Practice Research Datalink and they had been registered in a general practice in England contributing up-to-standard data for at least 1 year during the study period. We used linked records of individuals from the CALIBER platform to calculate the sex-standardised cumulative incidence for these conditions by 10-year age groups between April 1, 2010, and March 31, 2015. We also derived the median age at diagnosis and prevalence estimates stratified by age, sex, and ethnicity (black, white, south Asian) over the study period from the primary-care and secondary-care records of patients. Findings: We developed case definitions for 308 disease phenotypes. We used records of 2 784 138 patients for the calculation of cumulative incidence and of 3 872 451 patients for the calculation of period prevalence and median age at diagnosis of these conditions. Conditions that first gained prominence at key stages of life were: atopic conditions and infections that led to hospital admission in children (<10 years); acne and menstrual disorders in the teenage years (10-19 years); mental health conditions, obesity, and migraine in individuals aged 20-29 years; soft-tissue disorders and gastro-oesophageal reflux disease in individuals aged 30-39 years; dyslipidaemia, hypertension, and erectile dysfunction in individuals aged 40-59 years; cancer, osteoarthritis, benign prostatic hyperplasia, cataract, diverticular disease, type 2 diabetes, and deafness in individuals aged 60-79 years; and atrial fibrillation, dementia, acute and chronic kidney disease, heart failure, ischaemic heart disease, anaemia, and osteoporosis in individuals aged 80 years or older. Black or south-Asian individuals were diagnosed earlier than white individuals for 258 (84%) of the 308 conditions. Bone fractures and atopic conditions were recorded earlier in male individuals, whereas female individuals were diagnosed at younger ages with nutritional anaemias, tubulointerstitial nephritis, and urinary disorders. Interpretation: We have produced the first chronological map of human health with cumulative-incidence and period-prevalence estimates for multiple morbidities in parallel from birth to advanced age. This can guide clinicians, policy makers, and researchers on how to formulate differential diagnoses, allocate resources, and target research priorities on the basis of the knowledge of who gets which diseases when. We have published our phenotyping algorithms on the CALIBER open-access Portal which will facilitate future research by providing a curated list of reusable case definitions. Funding: Wellcome Trust, National Institute for Health Research, Medical Research Council, Arthritis Research UK, British Heart Foundation, Cancer Research UK, Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Department of Health and Social Care (England), Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), Economic and Social Research Council, Engineering and Physical Sciences Research Council, National Institute for Social Care and Health Research, and The Alan Turing Institute.


Subject(s)
Age of Onset , Forecasting , Health Status , Mental Disorders , Adolescent , Adult , Aged , Aged, 80 and over , Algorithms , Child , Databases, Factual , Electronic Health Records , England/epidemiology , Female , Humans , Male , Mental Disorders/diagnosis , Middle Aged , Population Surveillance/methods , State Medicine , Young Adult
10.
BMJ Open ; 9(9): e031070, 2019 09 06.
Article in English | MEDLINE | ID: mdl-31494620

ABSTRACT

OBJECTIVES: Patients with liver disease frequently require hospitalisation with infection often the trigger. Influenza vaccination is an effective infection prevention strategy in healthy and elderly but is often perceived less beneficial in patients with liver disease. We investigated whether influenza vaccination triggered serological response and prevented hospitalisation and death in liver disease. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, EMBASE, PubMed and CENTRAL up to January 2019. ELIGIBILITY CRITERIA: Randomised or observational studies of the effects of influenza vaccine in adults with liver disease. DATA EXTRACTION AND SYNTHESIS: Two reviewers screened studies, extracted data and assessed risk of bias and quality of evidence. Primary outcomes were all-cause hospitalisation and mortality. Secondary outcomes were cause-specific hospitalisation and mortality, and serological vaccine response. Random-effects meta-analysis was used to estimate pooled effects of vaccination. RESULTS: We found 10 041 unique records, 286 were eligible for full-text review and 12 were included. Most patients had viral liver disease. All studies were of very low quality. Liver patients both with and without cirrhosis mounted an antibody response to influenza vaccination, and vaccination was associated with a reduction in risk of hospital admission from 205/1000 to 149/1000 (risk difference -0.06, 95% CI -0.07 to 0.04) in patients with viral liver disease. Vaccinated patients were 27% less likely to be admitted to hospital compared with unvaccinated patients (risk ratio 0.73, 95% CI 0.66 to 0.80). No effect against all-cause or cause-specific mortality or cause-specific hospitalisation was found. CONCLUSIONS: The low quantity and quality of the evidence means that the protective vaccine effect may be uncertain. Considering the high risk of serious health outcomes from influenza infection in patients with liver disease and the safety and low cost of vaccination, overall, the potential benefits of seasonal vaccination both to patients and the healthcare systems are likely to outweigh the costs and risks associated with vaccination. PROSPERO REGISTRATION NUMBER: CRD42017067277.


Subject(s)
Hospitalization/trends , Immunogenicity, Vaccine , Influenza Vaccines/administration & dosage , Influenza, Human/prevention & control , Liver Diseases/immunology , Adult , Cause of Death , Chronic Disease , Humans , Influenza Vaccines/immunology , Influenza, Human/epidemiology , Liver Diseases/mortality , Randomized Controlled Trials as Topic
11.
J Hepatol ; 71(3): 594-602, 2019 09.
Article in English | MEDLINE | ID: mdl-31226389

ABSTRACT

BACKGROUND & AIMS: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. METHODS: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. RESULTS: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10-8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. CONCLUSION: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. LAY SUMMARY: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.


Subject(s)
Genome-Wide Association Study/methods , Hemochromatosis Protein/genetics , Hemochromatosis/genetics , Hepcidins/genetics , Iron/blood , Liver/metabolism , Adult , Aged , Biomarkers/blood , Cohort Studies , Female , Humans , Magnetic Resonance Imaging/methods , Male , Mendelian Randomization Analysis , Middle Aged , Phenotype , Polymorphism, Single Nucleotide , United Kingdom
12.
Diagn Progn Res ; 3: 10, 2019.
Article in English | MEDLINE | ID: mdl-31143841

ABSTRACT

BACKGROUND: Driven by alcohol consumption and obesity, the prevalence of non-viral liver disease in the UK is increasing. Due to its silent and slow nature, the progression of liver disease is currently unpredictable and challenging to monitor. The latest National Institute for Health Care Excellence cirrhosis guidelines call for a validated risk tool that would allow general practitioners to identify patients that are at high risk of developing cirrhosis. METHODS: Using linked electronic health records from the Clinical Practice Research Datalink (a database of > 10 million patients in England), we aim to develop and validate a prediction model to estimate 2-, 5- and 10-year risk of cirrhosis. The model will provide individualised cirrhosis risk predictions for adult primary care patients, free from underlying liver disease or viral hepatitis infection, whose liver blood test results come back abnormal. We will externally validate the model in patients from 30 further Clinical Practice Research Datalink general practices in England. DISCUSSION: The prediction model will provide estimates of cirrhosis risk in primary care patients with abnormal liver blood test results to guide referral to secondary care, to identify patients who are in serious need of preventative health interventions and to help reassure patients at low risk of cirrhosis in the long term.

13.
BMJ Open ; 9(1): e025664, 2019 01 29.
Article in English | MEDLINE | ID: mdl-30700489

ABSTRACT

INTRODUCTION: Use of albumin therapy is recommended for management of disease complications in cirrhosis. The effectiveness of albumin to prevent specific disease complications and death, however, is less clear. METHODS AND ANALYSIS: We will search Medline (Ovid), Embase (Ovid), Cochrane Hepato-Biliary Controlled Trials Register and Cochrane Central Register of Controlled Trials for published reports on randomised controlled trials and observational studies on the effectiveness of intravenous albumin therapy to prevent spontaneous bacterial peritonitis, renal dysfunction and death in cirrhotic patients. Two independent reviewers will screen the studies for eligibility, extract data and assess risk of bias and quality of evidence using Grading of Recommendations Assessment, Development and Evaluation system. Random effects meta-analyses will be performed when appropriate. ETHICS AND DISSEMINATION: As no primary data will be collected, a formal ethical approval is not required. We plan to publish the results of this study in a relevant peer-reviewed journal or journals. The study results may also be presented at relevant conferences and meetings. PROSPERO REGISTRATION NUMBER: CRD42018100798.


Subject(s)
Albumins/administration & dosage , Bacterial Infections/prevention & control , Kidney/physiopathology , Liver Cirrhosis/drug therapy , Peritonitis/prevention & control , Administration, Intravenous , Humans , Kidney/drug effects , Liver Cirrhosis/complications , Liver Cirrhosis/mortality , Research Design , Systematic Reviews as Topic
14.
Gastroenterology ; 156(3): 824, 2019 02.
Article in English | MEDLINE | ID: mdl-30659832
15.
Gastroenterology ; 155(2): 303-306.e2, 2018 08.
Article in English | MEDLINE | ID: mdl-29775600

ABSTRACT

Interleukin 6 (IL6) is an inflammatory cytokine; signaling via its receptor (IL6R) is believed to contribute to development of inflammatory bowel diseases (IBD). The single nucleotide polymorphism rs2228145 in IL6R associates with increased levels of soluble IL6R (s-IL6R), as well as reduced IL6R signaling and risk of inflammatory disorders; its effects are similar to those of a therapeutic monoclonal antibody that blocks IL6R signaling. We used the effect of rs2228145 on s-IL6R level as an indirect marker to investigate whether reduced IL6R signaling associates with risk of ulcerative colitis (UC) or Crohn's disease (CD). In a genome-wide meta-analysis of 20,550 patients with CD, 17,647 patients with UC, and more than 40,000 individuals without IBD (controls), we found that rs2228145 (scaled to a 2-fold increase in s-IL6R) was associated with reduced risk of CD (odds ratio 0.876; 95% confidence interval 0.822-0.933; P = .00003) or UC (odds ratio 0.932; 95% confidence interval 0.875-0.996; P = .036). These findings indicate that therapeutics designed to block IL6R signaling might be effective in treatment of IBD.


Subject(s)
Colitis, Ulcerative/genetics , Crohn Disease/genetics , Genetic Predisposition to Disease , Receptors, Interleukin-6/genetics , Genotype , Humans , Polymorphism, Single Nucleotide
16.
BMJ Open ; 8(3): e018223, 2018 03 16.
Article in English | MEDLINE | ID: mdl-29549199

ABSTRACT

INTRODUCTION: In advanced chronic liver disease, diseases caused by common bacteria Streptococcus pneumoniae or influenza virus put people at an increased risk of serious health complications and death. The effectiveness of the available vaccines in reducing the risk of poor health outcomes, however, is less clear. METHODS AND ANALYSIS: We will search Medline (Ovid), Embase (Ovid), PubMed and Cochrane Central Register of Controlled Trials for published reports on randomised controlled trials and observational studies on the effectiveness of pneumococcal and influenza vaccines in people with chronic liver disease. Two independent reviewers will screen the studies for eligibility, extract data and assess study quality and risk of bias. Random effects meta-analyses will be performed as appropriate. ETHICS AND DISSEMINATION: Formal ethical approval is not required, as no primary data will be collected for this study. We will publish results of this study in relevant peer-reviewed medical journal or journals. Where possible, the study results will also be presented as posters or talks at relevant medical conferences and meetings. PROSPERO REGISTRATION NUMBER: CRD42017067277.


Subject(s)
Influenza Vaccines , Influenza, Human/prevention & control , Liver Diseases/complications , Pneumococcal Infections/prevention & control , Pneumococcal Vaccines , Chronic Disease , Humans , Streptococcus pneumoniae , Systematic Reviews as Topic
17.
J Clin Pediatr Dent ; 41(2): 154-160, 2017.
Article in English | MEDLINE | ID: mdl-28288298

ABSTRACT

PURPOSE: Sedation is becoming more commonplace for pediatric patients undergoing minor procedures. Fortunately, electronic monitors have contributed to a reduction in the associated respiratory adverse events (RAEs). To test the hypothesis that adding the pretracheal stethoscope (PTS) to standard monitoring methods (SMMs) may improve RAE detection in sedated pediatric dental patients, the frequency of RAEs detected by SMMs (i.e. visual observation, capnography, and pulse oximetry) was compared to that detected by SMMs alongside continuous PTS auscultation. STUDY DESIGN: A prospective, randomised, controlled trial was performed with 100 pediatric patient participants of ASA≤2, who were scheduled to receive dental treatment under 0.75 mg/kg and oxygen. Patients were randomised into Groups A (n=50; SMMs) and B (n=50; SMMs+PTS). Inclusion criteria were behavioral management problems and intolerance to dental treatment despite behavioral management techniques or nitrous oxide administration. Exclusion criteria were high-risk conditions for RAEs, altered mental status, gastrointestinal disorders, parental refusal of conscious sedation and failure of previous conscious sedation. An anesthesist was present throughout the dental treatments. RESULTS: RAEs were detected in 10 (20%) and 22(44%) Group A and B patients respectively (p=0.01). The majority of RAEs within Group B were detected by PTS auscultation (n=19). Capnography produced 13 and 15 false-positive results in Groups A and B respectively, whereas the PTS produced 4(8%) false-positive results in Group B (p=0.009). CONCLUSIONS: PTS was found to be useful for detecting RAEs during pediatric dental sedation with 0.75mg/kg midazolam and oxygen, in the presence of an anesthesist.


Subject(s)
Auscultation , Hypnotics and Sedatives/administration & dosage , Midazolam/administration & dosage , Oxygen/administration & dosage , Airway Obstruction/diagnosis , Anesthesia, Dental , Apnea/diagnosis , Capnography , Child , Child, Preschool , Female , Humans , Hypoventilation/diagnosis , Laryngismus/diagnosis , Male , Oximetry , Prospective Studies
18.
Science ; 352(6284): 474-7, 2016 Apr 22.
Article in English | MEDLINE | ID: mdl-26940866

ABSTRACT

Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.


Subject(s)
Consanguinity , Health , Histone-Lysine N-Methyltransferase/genetics , Adult , DNA Mutational Analysis , Drug Prescriptions , Exome/genetics , Female , Fertility , Gene Knockout Techniques , Genes, Lethal , Genetic Loci , Genome, Human , Homologous Recombination , Homozygote , Humans , Male , Mothers , Pakistan/ethnology , Phenotype , United Kingdom
19.
20.
Clin Teach ; 10(2): 118-23, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23480115

ABSTRACT

BACKGROUND: There are increasing opportunities for junior doctors to deliver teaching as well as formally develop teaching skills. Near-peer teaching (NPT) programmes, like that established in South-East Scotland, not only provide additional learning opportunities for students but also have potential benefits for the teachers. CONTEXT: Achieving the multiple competencies required of both the medical school and the foundation programme poses significant challenges. Medical students have reduced exposure to bedside teaching, which may be contributing to the concerns raised regarding the clinical skills of recently graduated junior doctors. NPT increases the pool of tutors available to students, helps facilitate both practical and small group teaching and has other advantages, such as peer tutors being more approachable than senior staff. INNOVATION: The NPT programme in South-East Scotland was devised by a group of junior doctors keen to improve, expand and formalise NPT. It started in 2006 as one NPT programme, with 73 tutorials delivered by 18 tutors. Last year across four NPT programmes, 324 tutorials were delivered by 108 tutors, with all tutors receiving formal tutor training. In this article we describe the South-East Scotland model, and offer guidance for those interested in setting up similar programmes elsewhere. IMPLICATIONS: NPT, delivered by trained junior doctors, is now well established in every hospital in South-East Scotland. Our NPT model facilitates evidence-based teaching by junior doctors, is popular amongst both junior doctors and students, is sustainable and can be used as a practical example for how to generate NPT programmes elsewhere.


Subject(s)
Medical Staff, Hospital , Peer Group , Staff Development/methods , Teaching/methods , Clinical Competence , Humans , Learning , Program Development
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