Publications by authors named "Amy Taylor"

196 Publications

Sarcopenia is highly prevalent in children with autoimmune liver diseases and is linked to visceral fat and parent-perceived general health.

Liver Int 2021 Nov 24. Epub 2021 Nov 24.

Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Background: Patients with autoimmune hepatitis (AIH) and primary or autoimmune sclerosing cholangitis are at nutritional risk; their body composition and has not been extensively studied. We aimed to describe their body composition and identify clinical links.

Methods: Using magnetic resonance imaging (MRI), two reviewers segmented total psoas muscle area (tPMSA), visceral fat area (VFA) and subcutaneous fat area (mm ) and measured visceral and subcutaneous thickness (mm). Clinical, laboratory and quality of life (QoL; using PedsQL) data were collected. Sarcopenia was defined as tPMSA ≤5th percentile. Analysis of variance, Wilcoxon rank test and multivariable modelling were performed. A paediatric cohort with non-alcoholic fatty liver disease (NAFLD) was used as a comparator following propensity score matching.

Results: Fifty-eight patients with autoimmune liver disease (AILD) (33 [57%] with AIH) were included: median age 16 years (interquartile range [IQR]: 13-18), 33 (57%) male. Median time from diagnosis to MRI was 15 months (IQR: 2-39 months). Two patients (3%) had a BMIz indicative of mild malnutrition. tPMSA was measurable in 52 subjects (90%). Of those, 25 (48%) had sarcopenia. Sarcopenic patients had a lower blood urea nitrogen compared to non-sarcopenic (median [IQR]: 9.5 [8.0, 12.0] vs 11 [10, 14] mg/dL; P = .023). There was no difference in corticosteroid use between groups. The VFA of sarcopenic patients was higher (3156 [2064, 7492]) vs 2084 [688, 3092]) mm ; P = .005). Patient-reported QoL negatively associated with VFA and general health negatively associated with VFA. Compared with NAFLD, the odds ratio for sarcopenia with AILD was 14.5 (95% confidence interval: 2.3-90.7).

Conclusion: In autoimmune liver diseases, sarcopenia is highly prevalent, associated with increased visceral fat and QoL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/liv.15108DOI Listing
November 2021

Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia.

Nat Cancer 2021 Oct 27;2(10):1002-1017. Epub 2021 Sep 27.

Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, UK.

DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such as the cytidine analogs decitabine or azacytidine, has demonstrated clinical benefit in hematologic malignancies. These nucleoside analogs are incorporated into replicating DNA where they inhibit DNA cytosine methyltransferases DNMT1, DNMT3A and DNMT3B through irreversible covalent interactions. These agents induce notable toxicity to normal blood cells thus limiting their clinical doses. Herein we report the discovery of GSK3685032, a potent first-in-class DNMT1-selective inhibitor that was shown via crystallographic studies to compete with the active-site loop of DNMT1 for penetration into hemi-methylated DNA between two CpG base pairs. GSK3685032 induces robust loss of DNA methylation, transcriptional activation and cancer cell growth inhibition in vitro. Due to improved in vivo tolerability compared with decitabine, GSK3685032 yields superior tumor regression and survival mouse models of acute myeloid leukemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594913PMC
October 2021

Spousal associations of serum metabolomic profiles by nuclear magnetic resonance spectroscopy.

Sci Rep 2021 Nov 3;11(1):21587. Epub 2021 Nov 3.

School of Medicine, University of Glasgow, New Lister Building, Glasgow Royal Infirmary, Glasgow, G31 2ER, UK.

Phenotype-based assortative mating is well established in humans, with the potential for further convergence through a shared environment. To assess the correlation within infertile couples of physical, social, and behavioural characteristics and 155 circulating metabolic measures. Cross sectional study at a tertiary medical center of 326 couples undertaking IVF. Serum lipids, lipoprotein subclasses, and low-molecular weight metabolites as quantified by NMR spectroscopy (155 metabolic measures). Multivariable and quantile regression correlations within couples of metabolite profiles. Couples exhibited statistical correlations of varying strength for most physical, social, and behavioural characteristics including age, height, alcohol consumption, education, smoking status, physical activity, family history and ethnicity, with correlation coefficients ranging from 0.22 to 0.73. There was no evidence of within couple associations for BMI and weight, where the correlation coefficients were - 0.03 (95% CI - 0.14, 0.08) and 0.01 (95% CI - 0.10, 0.12), respectively. Within spousal associations of the metabolite measurements were all positive but with weak to modest magnitudes, with the median correlation coefficient across all 155 measures being 0.12 (range 0.01-0.37 and interquartile range 0.10-0.18). With just four having associations stronger than 0.3: docosahexaenoic acid (0.37, 95% CI 0.22, 0.52), omega-3 fatty acids (0.32, 95% CI 0.20, 0.43) histidine (0.32, 95% CI 0.23, 0.41) and pyruvate (0.32, 95% CI 0.22, 0.43). Infertile couples exhibit spousal similarities for a range of demographic and serum metabolite measures, supporting initial assortative mating, with diet-derived metabolites suggesting possible subsequent convergence of their individual metabolic profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-00531-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566506PMC
November 2021

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

Lancet Oncol 2021 11 19;22(11):1618-1631. Epub 2021 Oct 19.

University Hospital Southampton, Southampton, UK; Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.

Background: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants.

Methods: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual.

Findings: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0).

Interpretation: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings.

Funding: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(21)00522-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576477PMC
November 2021

How to Respond to a Ransomware Attack? One Radiation Oncology Department's Response to a Cyber-Attack on Their Record and Verify System.

Pract Radiat Oncol 2021 Oct 10. Epub 2021 Oct 10.

Department of Radiation Oncology, Sidney Kimmel Cancer Center at Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.

The digitization of healthcare for patient safety and efficiency introduced third party networks into closed hospital systems increasing the probability of cyberattacks and their consequences(1). In April 2021, a major vendor of a Radiation Oncology (RO) record and verify system (RVS) suffered a ransomware attack, affecting our department and many others across the United States. This article summarizes our response to the ransomware event including workflows, team member roles, responsibilities, communications and departmental recovery. The RVS created or housed accurate patient dose records for 6 locations. The immediate response to the ransomware attack was to shut down the system including the ability to treat patients. With the utilization of the hospital EMR and pre-existing interfaces with RVS, the department was able to safely continue patient radiotherapy treatments innovatively utilizing a direct Digital Imaging and Communications in Medicine (DICOM) transfer of patient data to the linear accelerators and implementing paper charting. No patients were treated in the first 24 hours of the attack. Within 48 hours of the ransomware event, 50% of patients were treated, and within 1 week, 95% of all patients were treated using direct DICOM transfer and paper charts. The RVS was completely unavailable for 2.5 weeks and full functionality was not restored for 4.5 weeks. A phased approach was adopted for re-introduction of patient treatments back into the RVS. Human capital costs included communication, outreach, workflow creation, quality assurance and extended clinical hours. Key lessons learned were to have a back-up of essential information, employ 'dry run' emergency training, having consistent parameter requirements across different vendor hardware and software, and having a plan for the recovery effort of restoring normal operations once software is operational. The provided report presents valuable information for the development of cyber-attack preparedness for RO departments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prro.2021.09.011DOI Listing
October 2021

Aquaculture Reuse Water, Genetic Line, and Vaccination Affect Rainbow Trout () Disease Susceptibility and Infection Dynamics.

Front Immunol 2021 22;12:721048. Epub 2021 Sep 22.

National Center for Cool and Cold Water Aquaculture, Agricultural Research Service, United States Department of Agriculture (USDA), Kearneysville, WV, United States.

Infectious hematopoietic necrosis virus (IHNV) and are major pathogens of farmed rainbow trout. Improved control strategies are desired but the influence of on-farm environmental factors that lead to disease outbreaks remain poorly understood. Water reuse is an important environmental factor affecting disease. Prior studies have established a replicated outdoor-tank system capable of varying the exposure to reuse water by controlling water flow from commercial trout production raceways. The goal of this research was to evaluate the effect of constant or pulsed reuse water exposure on survival, pathogen prevalence, and pathogen load. Herein, we compared two commercial lines of rainbow trout, Clear Springs Food (CSF) and Troutex (Tx) that were either vaccinated against IHNV with a DNA vaccine or sham vaccinated. Over a 27-day experimental period in constant reuse water, all fish from both lines and treatments, died while mortality in control fish in spring water was <1%. Water reuse exposure, genetic line, vaccination, and the interaction between genetic line and water exposure affected survival (<0.05). Compared to all other water sources, fish exposed to constant reuse water had 46- to 710-fold greater risk of death (<0.0001). Tx fish had a 2.7-fold greater risk of death compared to CSF fish in constant reuse water ( 0.001), while risk of death did not differ in spring water (=0.98). Sham-vaccinated fish had 2.1-fold greater risk of death compared to vaccinated fish (=0.02). Both IHNV prevalence and load were lower in vaccinated fish compared to sham-vaccinated fish, and unexpectedly, load associated with fin/gill tissues from live-sampled fish was lower in vaccinated fish compared to sham-vaccinated fish. As a result, up to forty-five percent of unvaccinated fish were naturally co-infected with and IHNV and the coinfected fish exhibited the highest IHNV loads. Under laboratory challenge conditions, co-infection with and IHNV overwhelmed IHNV vaccine-induced protection. In summary, we demonstrate that exposure to reuse water or multi-pathogen challenge can initiate complex disease dynamics that can overwhelm both vaccination and host genetic resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.721048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493035PMC
September 2021

Secondary Interventions After TEVAR for Aortic Dissection.

Tech Vasc Interv Radiol 2021 Jun 26;24(2):100753. Epub 2021 Jul 26.

Division of Vascular and Interventional Radiology, Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, VA. Electronic address:

The goal of thoracic endograft placement in type B aortic dissection is to prevent aneurysmal degeneration and other complications. Although TEVAR is a highly effective tool for managing type B aortic dissection, many patients will require additional interventions. In this article, we present a case-based review of techniques for the management of persistent false lumen perfusion and stent-graft induced new entry tears after TEVAR for aortic dissection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tvir.2021.100753DOI Listing
June 2021

Clinical Impact of an Antibiotic Time Out Initiative at an Academic Medical Center.

Hosp Pharm 2021 Aug 27;56(4):343-346. Epub 2020 Jan 27.

The Ohio State University Wexner Medical Center, Columbus, USA.

Various strategies aimed at limiting inappropriate antimicrobial use including antibiotic time out (ATO) have been proposed to combat the development of antimicrobial resistance, yet there are limited studies that have assessed the impact of ATO on clinical outcomes. This single-center retrospective study reviewed the effect of a passive ATO strategy by comparing 100 adult patients with an ATO matched by infection type to 100 antibiotic-treated adult patients lacking an ATO note. No difference in clinical outcomes was observed, however, ATO did result in improved optimization of antibiotic selection and duration, and reduction of piperacillin/tazobactam and vancomycin use. Further studies are warranted to evaluate the impact of ATO on clinical outcomes of a larger homogenous population with specified infectious diagnoses and clinical characteristics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0018578719901274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326851PMC
August 2021

Cross-sectional analysis of educational inequalities in primary prevention statin use in UK Biobank.

Heart 2021 Jul 27. Epub 2021 Jul 27.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Objective: Identify whether participants with lower education are less likely to report taking statins for primary cardiovascular prevention than those with higher education, but an equivalent increase in underlying cardiovascular risk.

Methods: Using data from a large prospective cohort study, UK Biobank, we calculated a QRISK3 cardiovascular risk score for 472 097 eligible participants with complete data on self-reported educational attainment and statin use (55% female participants; mean age 56 years). We used logistic regression to explore the association between (i) QRISK3 score and (ii) educational attainment on self-reported statin use. We then stratified the association between QRISK3 score and statin use, by educational attainment to test for interactions.

Results: There was evidence of an interaction between QRISK3 score and educational attainment. Per unit increase in QRISK3 score, more educated individuals were more likely to report taking statins. In women with ≤7 years of schooling, a one unit increase in QRISK3 score was associated with a 7% higher odds of statin use (OR 1.07, 95% CI 1.07 to 1.07). In women with ≥20 years of schooling, a one unit increase in QRISK3 score was associated with an 14% higher odds of statin use (OR 1.14, 95% CI 1.14 to 1.15). Comparable ORs in men were 1.04 (95% CI 1.04 to 1.05) for ≤7 years of schooling and 1.08 (95% CI 1.08, 1.08) for ≥20 years of schooling.

Conclusion: Per unit increase in QRISK3 score, individuals with lower educational attainment were less likely to report using statins, likely contributing to health inequalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/heartjnl-2021-319238DOI Listing
July 2021

The prognostic role of cardiac positron emission tomography imaging in patients with sarcoidosis: A systematic review.

J Nucl Cardiol 2021 Aug 6;28(4):1545-1552. Epub 2021 Jul 6.

Houston Methodist Debakey Heart & Vascular Center, 6550 Fannin Street, Smith Tower - Suite 1801, Houston, TX, 77030, USA.

Purpose: Sarcoidosis is a multi-systemic inflammatory disease of unknown etiology. Cardiac sarcoidosis (CS) has been reported in as much as 25% of patients with systemic involvement. Fluorodeoxyglucose (FDG) positron emission tomography (PET) has a high diagnostic sensitivity/specificity in the diagnosis of CS. The aim of this review is to summarize evidence on the prognostic role of FDG PET.

Methods: Studies were identified by searching MEDLINE from inception to October 2020. Medical subject headings (MeSH) terms for sarcoidosis; cardiac and FDG PET imaging were used. Studies of any design assessing the prognostic role of FDG PET in patients with either suspected or confirmed cardiac sarcoidosis imaging done at baseline were included. Abnormal PET was defined as abnormal metabolism (presence of focal or focal-on-diffuse uptake of FDG) OR abnormal metabolism and a perfusion defect. Studies reporting any outcome measure were included. Pooled risk ratio for the composite outcome of MACE was done.

Results: A total of 6 studies were selected for final inclusion (515 patients, 53.4% women, 19.8% racial minorities.) Studies were institution based, retrospective in design and enrolled consecutive patients. All were observational in nature and published in English. All studies used a qualitative assessment of PET scans (abnormal FDG uptake with or without abnormal perfusion). Two studies assessed quantitative metrics (summed stress score in segments with abnormal FDG uptake, standardized uptake value and cardiac metabolic activity.) All studies reported major adverse cardiovascular events (MACE) as a composite outcome. After a mean follow up ranging from 1.4 to 4.1 years, there were a total of 105 MACE. All studies included death (either all-cause death or sudden cardiac death) and ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation) as a component of MACE. Four of the six studies adjusted for several characteristics in their analysis. All four studies used left ventricular ejection fraction (LVEF). However, other adjustment variables were not consistent across studies. Five studies found a positive prognostic association with the primary outcome, two of which assessing right ventricular uptake.

Conclusion: Although available evidence indicates FDG PET can be used in the risk stratification of patients with CS, our findings show further studies are needed to quantify the effect in this patient group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12350-021-02681-zDOI Listing
August 2021

Findings of Russian literature on the clinical application of Eleutherococcus senticosus (Rupr. & Maxim.): A narrative review.

J Ethnopharmacol 2021 Oct 2;278:114274. Epub 2021 Jun 2.

Saint-Petersburg State Chemical Pharmaceutical University, Prof. Popov, 14, Saint-Petersburg, 197376, Russia.

Ethnopharmacological Relevance: Eleutherococcus senticosus (Rupr. et Maxim.) Maxim (ES) (syn. Acanthopanax senticosus (Rupr. & Maxim.) Harms) is a medicinal plant used in traditional medicine of Russian Far East and East Asia and known as an adaptogen - a category of herbal medicinal products which have non-specific inter-system anti-stress effects throughout the human body. ES was first established as a medicinal plant officially in the pharmacopeia of the Union of Soviet Socialist Republics (USSR) in 1962, and is currently recommended by the European Medicines Agency (EMA) to be prescribed to treat symptoms of asthenia such as fatigue and weakness.

Aim Of The Review: During the time of the USSR, a distinct research directive was undertaken on ES to examine substances which improve stamina and endurance, with over 1000 studies published. Due to security measures within the former USSR these papers were not accessible to the public and were never translated into English. This is the first study to make findings of the USSR studies on ES available to the international research and scientific community.

Methods: This study was an archival retrieval. References for studies were sought from printed journal and conference preceding's publications, then located within library catalogues of three libraries in St Petersburg Russia. Eligibility criteria included human clinical trials examining the efficacy of ES in any condition, published in the Russian language in the Soviet Union.

Results: A total of 46 studies published between 1962 and 1986 in the USSR were sourced. Of the retrieved articles, 29 were reported as placebo-controlled trials, 11 were reported as controlled trials and six studies did not report the study design. Trends in studies were those reporting on healthy volunteers (n=21) at a dose of 2 ml extract/day (n=14) examining outcomes such as physical and mental stamina under varying conditions, normal work conditions, high temperatures and high altitudes, incidence or prophylaxis of colds and influenza (n=5), effects on color perception and vision (n=2), work capacity (n=1), cognitive effects (n=1), prophylaxis of hearing loss (n=3), effects on blood cell counts (n=2) and sensitivity to UV radiation (n=1).

Conclusions: ES appears to exhibit benefits for cognitive function and physical and mental endurance and its effect as a respiratory system infection prophylaxis treatment are promising. This study is the first to publish the findings of clinical trials on ES from the USSR, which supports the traditional use and offers a valuable contribution to the body of evidence on medicinal uses of ES when the data is applied within the context of its limitations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jep.2021.114274DOI Listing
October 2021

Mendelian randomisation for mediation analysis: current methods and challenges for implementation.

Eur J Epidemiol 2021 May 7;36(5):465-478. Epub 2021 May 7.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Mediation analysis seeks to explain the pathway(s) through which an exposure affects an outcome. Traditional, non-instrumental variable methods for mediation analysis experience a number of methodological difficulties, including bias due to confounding between an exposure, mediator and outcome and measurement error. Mendelian randomisation (MR) can be used to improve causal inference for mediation analysis. We describe two approaches that can be used for estimating mediation analysis with MR: multivariable MR (MVMR) and two-step MR. We outline the approaches and provide code to demonstrate how they can be used in mediation analysis. We review issues that can affect analyses, including confounding, measurement error, weak instrument bias, interactions between exposures and mediators and analysis of multiple mediators. Description of the methods is supplemented by simulated and real data examples. Although MR relies on large sample sizes and strong assumptions, such as having strong instruments and no horizontally pleiotropic pathways, our simulations demonstrate that these methods are unaffected by confounders of the exposure or mediator and the outcome and non-differential measurement error of the exposure or mediator. Both MVMR and two-step MR can be implemented in both individual-level MR and summary data MR. MR mediation methods require different assumptions to be made, compared with non-instrumental variable mediation methods. Where these assumptions are more plausible, MR can be used to improve causal inference in mediation analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10654-021-00757-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159796PMC
May 2021

Cognitive Behavioral Therapy for Mood and Insomnia in Persons With Dementia: A Systematic Review.

Alzheimer Dis Assoc Disord 2021 Oct-Dec 01;35(4):366-373

Houston Veterans Affairs Health Services Research and Development Service Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center.

Background: Cognitive behavioral therapy (CBT) is a goal-oriented intervention that aims to improve detrimental emotional or behavioral distress by modifying individuals' thought processes. This review evaluates the efficacy and specific adaptations of CBT in persons with mild cognitive impairment and dementia.

Methods: A literature search of PubMed, Embase, and PsycINFO was conducted up to March 2020. Study quality was assessed using the Cochrane risk of bias criteria.

Results: Twelve publications were identified. Seven of the studies demonstrated CBT efficacy to improve depression, anxiety, and/or quality of life. One study's positive postintervention outcome became insignificant with longer term follow up. Two of the studies improved sleep outcomes. Four studies integrated caregivers into intervention delivery. Three studies utilized content, memory, and adherence adaptations aimed to improve intervention efficacy. Two studies included adaptations to address caregiver burden and depression.

Conclusion: There is strong evidence to suggest that CBT is associated with improvements in anxiety, depression, and quality of life in persons with mild cognitive impairment and dementia. CBT showed a reduction in insomnia and improvements in sleep quality. However, there is insufficient evidence to draw conclusions on the effects of CBT on insomnia. These results suggest that further investigation into insomnia outcomes is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/WAD.0000000000000454DOI Listing
October 2020

Job stress and its relationship with nurses' autonomy and nurse-physician collaboration in intensive care unit.

J Nurs Manag 2021 Oct 17;29(7):2084-2091. Epub 2021 May 17.

Department of Intensive Care Nursing, Nursing and Midwifery school, Urmia University of Medical Sciences, Urmia, Iran.

Aims: To determine nurses' job stress and its relationship with professional autonomy and nurse-physician collaboration in intensive care unit (ICU).

Background: Low professional autonomy, high job stress and lack of nurse-physician collaboration can affect nursing care in ICU and the main reasons ICU nurses leave the occupation or transfer to other clinical units.

Methods: A cross-sectional, correlational study was conducted on 398 nurses in teaching hospitals in Urmia, Iran, in 2020. Data were collected using the Dempster Practice Behaviors Scale, the Health and Safety Executive tool and the Jefferson Scale of Attitudes toward Physician-Nurse Collaboration.

Results: The mean job stress (115.53 ± 12.42) and professional autonomy (102.19 ± 11.88) of ICU nurses were 'moderate', and nurse-physician collaboration (74.25 ± 5.10) was 'good'. There was a positive relationship between professional autonomy and job stress (r = .506) and nurse-physician collaboration (r = .242). Professional autonomy was a predictor of job stress in nurses (p < .000), and work experience in ICU can cause job stress in nurses (p = .024).

Conclusion: Increasing nurses' professional autonomy causes an increase in job stress and improves nurse-physician collaboration in ICU.

Implications For Nursing Management: Nursing managers should implement practical strategies to improve nurses' autonomy, enhance nurse-physician collaboration and decrease their job stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jonm.13343DOI Listing
October 2021

Adapting the modified barium swallow: modifications to improve safety in the setting of airborne respiratory illnesses like COVID-19.

Abdom Radiol (NY) 2021 07 27;46(7):3058-3065. Epub 2021 Mar 27.

Russell H. Morgan Department of Radiology and Radiologic Sciences, Johns Hopkins University School of Medicine, 1800 Orleans St, Zayed 4030B, Baltimore, MD, 21287, USA.

No guidance exists on how to safely perform modified barium swallows (MBS) in the midst of the COVID-19 pandemic or other communicable airborne respiratory infections (C-ARI). MBS has the potential to become an aerosol generating procedure (AGP) as it may trigger a cough or necessitate suctioning which may result in transmission of C-ARI putting patients and health care workers at risk. Regulations and best practices from international and US governmental and commercial agencies were reviewed. This review led to the multidisciplinary development of best practices of the safety measures and structural requirements to avoid transmission of SARS-CoV-2 or other C-ARIs when performing MBS. Implementation of these best practices resulted in structural changes to the fluoroscopy suite and protocol workflows. This enabled patients with COVID-19 to undergo MBS while maintaining patient and staff safety including mitigation of potential risk of onward transmission of SARS-CoV-2 to other patients. With proper modifications, MBS can be safely performed on patients with C-ARI such as COVID-19 while maintaining patient and health care worker (HCW) safety.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00261-021-03025-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998084PMC
July 2021

Association of genetic liability to smoking initiation with e-cigarette use in young adults: A cohort study.

PLoS Med 2021 03 18;18(3):e1003555. Epub 2021 Mar 18.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.

Background: Tobacco smoking and e-cigarette use are strongly associated, but it is currently unclear whether this association is causal, or due to shared factors that influence both behaviours such as a shared genetic liability. The aim of this study was to investigate whether polygenic risk scores (PRS) for smoking initiation are associated with ever use of e-cigarettes.

Methods And Findings: Smoking initiation PRS were calculated for young adults (N = 7,859, mean age = 24 years, 51% male) of European ancestry in the Avon Longitudinal Study of Parents and Children, a prospective birth cohort study initiated in 1991. PRS were calculated using the GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN) summary statistics. Five thresholds ranging from 5 × 10-8 to 0.5 were used to calculate 5 PRS for each individual. Using logistic regression, we investigated the association between smoking initiation PRS and the main outcome, self-reported e-cigarette use (n = 2,894, measured between 2016 and 2017), as well as self-reported smoking initiation and 8 negative control outcomes (socioeconomic position at birth, externalising disorders in childhood, and risk-taking in young adulthood). A total of 878 young adults (30%) had ever used e-cigarettes at 24 years, and 150 (5%) were regular e-cigarette users at 24 years. We observed positive associations of similar magnitude between smoking initiation PRS (created using the p < 5 × 10-8 threshold) and both smoking initiation (odds ratio (OR) = 1.29, 95% CI 1.19 to 1.39, p < 0.001) and ever e-cigarette use (OR = 1.24, 95% CI 1.14 to 1.34, p < 0.001) by the age of 24 years, indicating that a genetic predisposition to smoking initiation is associated with an increased risk of using e-cigarettes. At lower p-value thresholds, we observed an association between smoking initiation PRS and ever e-cigarette use among never smokers. We also found evidence of associations between smoking initiation PRS and some negative control outcomes, particularly when less stringent p-value thresholds were used to create the PRS, but also at the strictest threshold (e.g., gambling, number of sexual partners, conduct disorder at 7 years, and parental socioeconomic position at birth). However, this study is limited by the relatively small sample size and potential for collider bias.

Conclusions: Our results indicate that there may be a shared genetic aetiology between smoking and e-cigarette use, and also with socioeconomic position, externalising disorders in childhood, and risky behaviour more generally. This indicates that there may be a common genetic vulnerability to both smoking and e-cigarette use, which may reflect a broad risk-taking phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pmed.1003555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971530PMC
March 2021

The Behavioural Display of Compassion in Radiation Therapy: Purpose, Meaning and Interpretation.

J Med Imaging Radiat Sci 2020 12 13;51(4S):S59-S71. Epub 2020 Nov 13.

Weston Park Cancer Centre, Whitham Road, Sheffield S10 2SJ, UK.

Introduction: Providing high quality patient care is a worldwide standard of proficiency across the radiographic workforce. As compassion and compassionate behaviours are considered synonymous with patient-centred care, the focus of professional practice throughout healthcare should be on a system that places compassion at its heart. Inadequate care and dispassionate practice have been blamed for failings within the National Health Service. United Kingdom healthcare legislation has been criticised for its failure to provide meaning or clarity to practical compassionate care. Consequently, it has hindered the ability of National Health Service Trusts, service delivery managers and Medical Radiation Technologists to interpret and implement policy recommendations regarding compassionate practice at a local level.

Aims: To support the implementation of compassionate legislation, the study sought to understand the perspectives of those in receipt and those delivering compassionate practice. The research aimed to develop a context specific definition of compassion and identify commonly recognised compassionate behaviours. This article reports on the display of compassion through the behaviours of Medical Radiation Technologists.

Methods/materials: Co-production underpinned the qualitative methodological inquiry and design of the research. Eleven focus groups were conducted, five with Medical Radiation Technologists three with cancer patients and care-givers and three with student Medical Radiation Technologists. On completion of thematic analysis from those groups, three co-production workshops were conducted, integrating the data to ensure the co-produced findings were equally representative of the perspectives of the three participant groups.

Results: An understanding of compassionate display is illustrated through the construction of a conceptual framework. The findings established observable behaviours which a Medical Radiation Technologist must engage in to undertake compassionate display. Three compassionate behavioural classifications were established through the analysis; 'embodied connection', 'characteristic expression' and 'indicative communication'. A Medical Radiation Technologist must engage in all the three core behaviours to gain comprehension of the patient and person. Comprehension enables the Medical Radiation Technologist to establish practices that aim to address the compassionate needs of the patient.

Discussion/conclusion: Adoption of the behaviours by Medical Radiation Technologists should enhance compassionate care received by patients within clinical practice. The conceptual framework provides both a theoretical and practical understanding of compassionate display, making it a valuable tool for training and assessment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmir.2020.08.003DOI Listing
December 2020

Risk of neuropsychiatric and cardiovascular adverse events following treatment with varenicline and nicotine replacement therapy in the UK Clinical Practice Research Datalink: a case-cross-over study.

Addiction 2021 06 14;116(6):1532-1545. Epub 2020 Dec 14.

Department of Non-communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, LSHTM, London, UK.

Background And Aims: Varenicline and nicotine replacement therapy (NRT) are the most commonly used medications to quit smoking. Given their widespread use, monitoring adverse risks remains important. This study aimed to estimate the neuropsychiatric and cardiovascular risks associated with varenicline and NRT as used in routine UK care.

Design: Case-cross-over study.

Setting: UK-based electronic primary care records in the Clinical Practice Research Datalink from 2006 to 2015 linked to hospital and mortality data sets.

Participants: Adult smokers (n =282,429) observed during periods when exposed and not exposed to either varenicline or NRT.

Measurements: Main outcomes included suicide, self-harm, myocardial infarction (MI), all-cause death and cause-specific death [MI, chronic obstructive pulmonary disease (COPD)]. In primary analyses, conditional logistic regression was used to compare the chance of varenicline or NRT exposure during the risk period (90 days prior to the event) with the chance of exposure during an earlier single reference period (91-180 days prior to the event) or multiple 90-day reference periods to increase statistical power.

Findings: In the primary analyses, findings were inconclusive for the associations between varenicline and the main outcomes using a single reference period, while NRT was associated with MI [odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.18-1.67]. Using multiple reference periods, varenicline was associated with an increased risk of self-harm (OR = 1.32, 95% CI = 1.12-1.56) and suicide (OR = 3.56, 95% CI = 1.32-9.60) but a reduction in all-cause death (OR = 0.75, 95% CI = 0.61-0.93). NRT was associated with MI (OR = 1.54, 95% CI = 1.36-1.74), self-harm (OR = 1.30, 95% CI = 1.18-1.44) and deaths from MI (OR = 1.53, 95% CI = 1.11-2.10), COPD (OR = 1.33, 95% CI = 1.14-1.56) and all causes (OR = 1.28, 95% CI = 1.18-1.40) when using multiple reference periods.

Conclusions: There appear to be positive associations between (1) nicotine replacement therapy (NRT) and myocardial infarction, death and risk of self-harm and (2) varenicline and increased risk of self-harm and suicide, as well as a negative association between varenicline and all-cause death. The associations may not be causal. They may reflect health changes at the time of smoking cessation (nicotine replacement therapy is prescribed for people with cardiac problems) or be associated with quit attempts (exposure to both medicines was associated with self-harm).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/add.15338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246946PMC
June 2021

ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation.

Cell Death Differ 2021 04 12;28(4):1379-1397. Epub 2020 Nov 12.

Institute of Molecular and Cell Biology, A*STAR Research Entities, Singapore, 138673, Singapore.

Motor neurons (MNs) are highly energetic cells and recent studies suggest that altered energy metabolism precede MN loss in amyotrophic lateral sclerosis (ALS), an age-onset neurodegenerative disease. However, clear mechanistic insights linking altered metabolism and MN death are still missing. In this study, induced pluripotent stem cells from healthy controls, familial ALS, and sporadic ALS patients were differentiated toward spinal MNs, cortical neurons, and cardiomyocytes. Metabolic flux analyses reveal an MN-specific deficiency in mitochondrial respiration in ALS. Intriguingly, all forms of familial and sporadic ALS MNs tested in our study exhibited similar defective metabolic profiles, which were attributed to hyper-acetylation of mitochondrial proteins. In the mitochondria, Sirtuin-3 (SIRT3) functions as a mitochondrial deacetylase to maintain mitochondrial function and integrity. We found that activating SIRT3 using nicotinamide or a small molecule activator reversed the defective metabolic profiles in all our ALS MNs, as well as correct a constellation of ALS-associated phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41418-020-00664-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027637PMC
April 2021

Management of intussusception in children: A systematic review.

J Pediatr Surg 2021 Mar 6;56(3):587-596. Epub 2020 Oct 6.

Department of Pediatric Surgery, University of Texas McGovern Medical School and Children's Memorial Hermann Hospital, Houston, TX.

Objective: The goal of this systematic review by the American Pediatric Surgical Association Outcomes and Evidence-Based Practice Committee was to develop recommendations for the management of ileocolic intussusception in children.

Methods: The ClinicalTrials.gov, Embase, PubMed, and Scopus databases were queried for literature from January 1988 through December 2018. Search terms were designed to address the following topics in intussusception: prophylactic antibiotic use, repeated enema reductions, outpatient management, and use of minimally invasive techniques for children with intussusception. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were followed. Consensus recommendations were derived based on the best available evidence.

Results: A total of 83 articles were analyzed and included for review. Prophylactic antibiotic use does not decrease complications after radiologic reduction. Repeated enema reductions may be attempted when clinically appropriate. Patients can be safely observed in the emergency department following enema reduction of ileocolic intussusception, avoiding hospital admission. Laparoscopic reduction is often successful.

Conclusions: Regarding intussusception in hemodynamically stable children without critical illness, pre-reduction antibiotics are unnecessary, non-operative outpatient management should be maximized, and minimally invasive techniques may be used to avoid laparotomy.

Level Of Evidence: Level 3-5 (mainly level 3-4) TYPE OF STUDY: Systematic Review of level 1-4 studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpedsurg.2020.09.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920908PMC
March 2021

Associations between reasons for vaping and current vaping and smoking status: Evidence from a UK based cohort.

Drug Alcohol Depend 2020 12 19;217:108362. Epub 2020 Oct 19.

MRC Integrative Epidemiology Unit at the University of Bristol, United Kingdom; School of Psychological Science, University of Bristol, United Kingdom; NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol, United Kingdom.

Background: This study aimed to discover which young adults vape, the reasons given for vaping, and which reasons for vaping are associated with continued vaping/smoking.

Methods: In a UK cohort of 3,994 young adults, we explored the association of retrospectively-recalled reasons for vaping by 23 years (collected between 2015 and 2016) with vaping/smoking status at 24 years (collected between 2016 and 2017). Using logistic regression, we assessed the association with vaping behaviour among ever vapers who had ever smoked (n = 668), and with smoking behaviour among individuals who regularly smoked prior to vaping (n = 412).

Results: Vaping to quit smoking was associated with higher likelihood of vaping (odds ratio [OR] = 3.51, 95 % confidence interval [95 % CI] = 2.29-5.38), but lower likelihood of smoking at 24 years (OR = 0.50, 95 %CI = 0.32 to 0.78). Vaping to cut down smoking was associated with higher likelihood of vaping (OR = 2.90, 95 % CI = 1.87-4.50) and smoking at 24 years (OR = 1.62, 95 % CI = 1.02-2.58). Vaping out of curiosity was associated with lower likelihood of vaping at 24 years (OR = 0.41, 95 %CI = 0.26 to 0.63) but higher likelihood of smoking at 24 years (OR = 1.66, 95 % CI = 1.04-2.65).

Conclusions: Intention to quit appears important for young adults to stop smoking using e-cigarettes. Public health strategies that encourage vaping specifically for smoking cessation may encourage quitting among young adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.drugalcdep.2020.108362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768186PMC
December 2020

Role of the Metabolic Profile in Mediating the Relationship Between Body Mass Index and Left Ventricular Mass in Adolescents: Analysis of a Prospective Cohort Study.

J Am Heart Assoc 2020 10 8;9(20):e016564. Epub 2020 Oct 8.

MRC Integrative Epidemiology Unit Population Health Sciences University of Bristol United Kingdom.

Background We aimed to quantify the role of the plasma metabolic profile in explaining the effect of adiposity on cardiac structure. Methods and Results Body mass index (BMI) was measured at age 11 in the Avon Longitudinal Study of Parents and Children. Left ventricular mass indexed to height (LVMI) was assessed by echocardiography at age 17. The metabolic profile was quantified via H-nuclear magnetic resonance spectroscopy at age 15. Multivariable confounder (maternal age, parity, highest qualification, maternal smoking, prepregnancy BMI, prepregnancy height, household social class, adolescent birthweight, adolescent smoking, fruit and vegetable consumption, and physical activity)-adjusted linear regression estimated the association of BMI with LVMI and mediation by metabolic traits. We considered 156 metabolomic traits individually and jointly as principal components explaining 95% of the variance in the nuclear magnetic resonance platform and assessed whether the principal components for the metabolic traits added to the proportion of the association explained by putative cardiovascular risk factors (systolic and diastolic blood pressures, insulin, triglycerides, low-density lipoprotein cholesterol, and glucose). A 1 kg/m higher BMI was associated with a 0.70 g/m (95% CI, 0.53-0.88 g/m) and 0.66 g/m (95% CI, 0.53-0.79 g/m) higher LVMI in males (n=437) and females (n=536), respectively. Putative risk factors explained 3% (95% CI, 2%-5%) of this association in males, increasing to 10% (95% CI, 8%-13%) when including metabolic principal components. In females, the standard risk factors explained 3% (95% CI, 2%-5%) of the association and did not increase when including the metabolic principal components. Conclusions The addition of the nuclear magnetic resonance-measured metabolic traits appears to mediate more of the association of BMI on LVMI than the putative risk factors alone in adolescent males, but not females.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.016564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763376PMC
October 2020

Association of the functional ovarian reserve with serum metabolomic profiling by nuclear magnetic resonance spectroscopy: a cross-sectional study of ~ 400 women.

BMC Med 2020 08 31;18(1):247. Epub 2020 Aug 31.

School of Medicine, Glasgow Royal Infirmary, New Lister Building, University of Glasgow, Glasgow, G31 2ER, UK.

Background: Women with diminished ovarian reserve are known to have increased cardiovascular risk, whether there is a continuous association between the ovarian reserve biomarkers; anti-Müllerian hormone (AMH), antral follicle count (AFC) and cardio-metabolic risk factors are unknown.

Methods: A cross-sectional study of 398 women intending to undergo IVF with pre-treatment early follicular AMH and AFC measurements. Serum lipids, lipoprotein subclasses and low-molecular-weight metabolites were quantified by NMR spectroscopy (155 metabolic measures). Associations were analysed using multivariable regression.

Results: Participants were mean 35.5 (SD 4.43) years old and had a median AMH of 16 pmol/l (IQR 8.8, 28.0 pmol/l) and a median AFC of 12 (IQR 7.16). AMH showed positive associations with HDL, omega-6 and polyunsaturated fatty acids and the amino acids isoleucine, leucine and tyrosine, with effects ranging from 0.11 (95%CI 0.004 to 0.21) for total lipids in small HDL to 0.16 (0.06 to 0.26) for isoleucine, for a mean difference of one SD of metabolite per one SD increment in AMH, and negatively with acetate: - 0.31(- 0.22, - 0.004) SD per 1 SD AMH. AFC was positively associated with alanine, glutamine and glycine. Results were consistent, though less precisely estimated, when restricted to those women who were preparing for treatment because of their partner's infertility.

Conclusions: In women intending to have IVF, AMH and AFC were not associated with traditional lipid measured but were associated with a number of novel cardiovascular risk factors. Prospective studies will be required for replication, determination of causality and confirmation that ovarian reserve is impacting on metabolism rather than variation in metabolism is influencing ovarian reserve.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12916-020-01700-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457540PMC
August 2020

Vedolizumab Therapy in Children With Primary Sclerosing Cholangitis: Data From the Pediatric Primary Sclerosing Cholangitis Consortium.

J Pediatr Gastroenterol Nutr 2020 10;71(4):459-464

University of Utah and Intermountain Primary Children's Hospital, Salt Lake City, UT.

Objectives: Most patients with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD). The liver and colon express MAdCAM-1, a target of lymphocyte homing integrins. Vedolizumab (VDZ) is an α4β7 integrin antibody used to treat IBD. We investigated liver outcomes in children with PSC-IBD treated with VDZ.

Methods: Patients were identified within the Pediatric PSC Consortium, a multicenter research registry. Retrospective demographic, phenotypic, biochemical, radiological, histopathologic and IBD data for up to 1 year of VDZ therapy were collected. Liver biochemical and IBD responses were defined as: a 75% or greater reduction in initial γ-glutamyltransferase (GGT), or a GGT that fell to <50 IU/L and improved Mayo endoscopy grade or IBD activity scores after 9 to 12 months.

Results: Thirty-seven patients were identified from 19 centers. VDZ was initiated at median age of 16 years [IQR 15-18], 69% were male, 65% had large duct involvement, 19% had (Metavir F3/F4) fibrosis and 59% had ulcerative colitis. Of 32 patients with abnormal GGT at baseline, 22% had a liver biochemical response after 9 to 12 months. For IBD, 32% achieved remission, 30% had a clinical response, and 38% had no response. Final GGT after 9 to 12 months was 51 [IQR 28-71] in IBD patients in remission versus 127 [IQR 63-226] in those with active IBD, (P = 0.066).

Conclusions: Liver biochemistry worsened over time in IBD unresponsive to VDZ but remained unchanged in IBD patients in remission. VDZ did not improve liver biochemistry in pediatric PSC-IBD. Progressive liver disease may be more common in patients with medically refractory IBD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0000000000002855DOI Listing
October 2020

Investigating the added value of biomarkers compared with self-reported smoking in predicting future e-cigarette use: Evidence from a longitudinal UK cohort study.

PLoS One 2020 14;15(7):e0235629. Epub 2020 Jul 14.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.

Biomarkers can be used to assess smoking behaviour more accurately and objectively than self-report. This study assessed the association between cotinine (a biomarker of smoke exposure) and later e-cigarette use among a population who were unexposed to e-cigarettes in youth. Young people in the Avon Longitudinal Study of Parents and Children took part in the study. We observed associations between cotinine at 15 years (measured between 2006 and 2008 before the wide availability of e-cigarettes) and self-reported ever use of e-cigarettes at 22 (measured between 2014 and 2015 when e-cigarettes were widely available) using logistic regression. A range of potential confounders were adjusted for (age, sex, body mass index, alcohol use and passive smoke exposure). Additionally, we adjusted for the young people's self-reported smoking status/history to explore potential misreporting and measurement error. In a sample of N = 1,194 young people, cotinine levels consistent with active smoking at 15 years were associated with increased odds of e-cigarette ever use at 22 years (Odds Ratio [OR] = 7.24, 95% CI 3.29 to 15.93) even when self-reported active smoking status at age 16 (OR = 3.14, 95% CI 1.32 to 7.48) and latent classes of smoking behaviour from 14 to 16 (OR = 2.70, 95% CI 0.98 to 7.44) were included in the model. Cotinine levels consistent with smoking in adolescence were strongly associated with increased odds of later e-cigarette use, even after adjusting for reported smoking behaviour at age 16 and smoking transitions from 14 to 16.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235629PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360042PMC
September 2020

Sporadic vestibular schwannoma: a molecular testing summary.

J Med Genet 2021 04 23;58(4):227-233. Epub 2020 Jun 23.

Clinical Genetics, Manchester University NHS Foundation Trust, Manchester, UK

Objectives: Cases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis.

Methods: Cases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in on blood samples for all patients, and tumour DNA samples when available. and screening was also performed in patient subgroups.

Results: Age at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline variants were confirmed in 2% of patients. Pathogenic germline variants in were found in 3% of all tested patients, with a higher rate of 5% in patients <30 years. No pathogenic variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic variants, including those with germline pathogenic variants.

Conclusions: Undiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of function is a common event in VS tumours and may represent a targetable common pathway in VS tumourigenesis. These data also support the multi-hit mechanism of -associated VS tumourigenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2020-107022DOI Listing
April 2021

The effects of age at menarche and first sexual intercourse on reproductive and behavioural outcomes: A Mendelian randomization study.

PLoS One 2020 15;15(6):e0234488. Epub 2020 Jun 15.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.

There is substantial variation in the timing of significant reproductive life events such as menarche and first sexual intercourse. Life history theory explains this variation as an adaptive response to an individual's environment and it is important to examine how traits within life history strategies affect each other. Here we applied Mendelian randomization (MR) methods to investigate whether there is a causal effect of variation in age at menarche and age at first sexual intercourse (markers or results of exposure to early life adversity) on outcomes related to reproduction, education and risky behaviour in UK Biobank (N = 114 883-181 255). Our results suggest that earlier age at menarche affects some traits that characterize life history strategies including earlier age at first and last birth, decreased educational attainment, and decreased age at leaving education (for example, we found evidence for a 0.26 year decrease in age at first birth per year decrease in age at menarche, 95% confidence interval: -0.34 to -0.17; p < 0.001). We find no clear evidence of effects of age at menarche on other outcomes, such as risk taking behaviour. Age at first sexual intercourse was also related to many life history outcomes, although there was evidence of horizontal pleiotropy which violates an assumption of MR and we therefore cannot infer causality from this analysis. Taken together, these results highlight how MR can be applied to test predictions of life history theory and to better understand determinants of health and social behaviour.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234488PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295202PMC
August 2020

Metabolic characterisation of disturbances in the APOC3/triglyceride-rich lipoprotein pathway through sample-based recall by genotype.

Metabolomics 2020 06 3;16(6):69. Epub 2020 Jun 3.

MRC Integrative Epidemiology Unit at University of Bristol, Bristol, BS8 2BN, UK.

Introduction: High plasma triacylglyceride levels are known to be associated with increased risk of atherosclerotic cardiovascular disease. Apolipoprotein C-III (apoC-III) is a key regulator of plasma triacylglyceride levels and is associated with hypertriglyceridemia via a number of pathways. There is consistent evidence for an association of cardiovascular events with blood apoC-III level, with support from human genetic studies of APOC3 variants. As such, apoC-III has been recognised as a potential therapeutic target for patients with severe hypertriglyceridaemia with one of the most promising apoC-III-targeting drugs, volanesorsen, having recently progressed through Phase III trials.

Objectives: To exploit a rare loss of function variant in APOC3 (rs138326449) to characterise the potential long-term treatment effects of apoC-III targeting interventions on the metabolome.

Methods: In a recall-by-genotype study, 115 plasma samples were analysed by UHPLC-MS to acquire non-targeted metabolomics data. The study included samples from 57 adolescents and 33 adults. Overall, 12 985 metabolic features were tested for an association with APOC3 genotype.

Results: 161 uniquely annotated metabolites were found to be associated with rs138326449(APOC3). The highest proportion of associated metabolites belonged to the acyl-acyl glycerophospholipid and triacylglyceride metabolite classes. In addition to the anticipated (on-target) reduction of metabolites in the triacylglyceride and related classes, carriers of the rare variant exhibited previously unreported increases in levels of a number of metabolites from the acyl-alkyl glycerophospholipid class.

Conclusion: Overall, our results suggest that therapies targeting apoC-III may potentially achieve a broad shift in lipid profile that favours better metabolic health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11306-020-01689-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270992PMC
June 2020

Family History of Cluster Headache: A Systematic Review.

JAMA Neurol 2020 07;77(7):887-896

McGovern Medical School, Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston.

Importance: Genetic and environmental factors are thought to contribute to cluster headache, and cluster headache can affect multiple members of a family. A thorough understanding of its inheritance is critical to understanding the pathogenesis of this debilitating disease.

Objective: To systematically review family history rates and inheritance patterns of cluster headache.

Evidence Review: A systematic review was performed in PubMed, Embase, and Cochrane Library. Search criteria were created by a librarian. Articles published between 1985 and 2016, after the publication date of a large review in 1985, were analyzed independently by 2 neurologists to identify family history rates and pedigrees. Pedigrees were analyzed by a genetic counselor.

Findings: A total of 1995 studies were found (1988 through the search criteria and 7 through other means). Forty articles met inclusion criteria: 22 large cohort studies, 1 twin-based study, and 17 case reports or small case series. Across the 22 large cohort studies, the positive family history rate of cluster headache varied between 0% and 22%, with a median of 8.2%. The largest 5 studies, of 1134, 785, 693, 609, and 500 probands each, had a positive family history in 18.0% (numerator not provided), 5.1% (40 of 785 cases), 10.0% (numerator not provided), 2.0% (12 of 609 cases), and 11.2% (56 of 500 cases), respectively. No meta-analysis was performed, given differences in methodologies. Separately, 1 twin-based study examined 37 twin pairs and reported a concordance rate of 5.4% (2 pairs). Finally, 67 pedigrees were identified. Most pedigrees (46 of 67 [69%]) were consistent with an autosomal dominant pattern, but 19 of 67 (28%) were consistent with an autosomal recessive inheritance pattern; 10 pedigrees of probable or atypical cluster headache were identified, and all were consistent with an autosomal dominant inheritance pattern. The sex ratio for cluster headache in identified pedigrees was 1.39 (103:74) in affected men and boys compared with affected women and girls, which is lower than that of the general cluster headache population.

Conclusions And Relevance: Cluster headache is an inherited disorder in a subset of families and is associated with multiple hereditary patterns. There is an unexpectedly high preponderance of women and girls with familial cluster headache; genetic subanalyses limited to female participants are necessary to further explore this observation, because these data are otherwise masked by the higher numbers of male participants with cluster headache. Overall, this systematic review supports the notion that familial cluster headache is likely the result of multiple susceptibility genes as well as environmental factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2020.0682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644512PMC
July 2020
-->