76 Developing a protocol for a systematic review and meta-analysis of observational studies comparing direct oral anticoagulants with vitamin K antagonists for stroke prevention in people aged over 75 with atrial fibrillation

Introduction: Randomised controlled trials (RCTs) have demonstrated that anticoagulation by direct oral anticoagulants (DOACs) or vitamin-K-antagonists (VKAs) reduces the risk of stroke in people with atrial fibrillation. RCTs of DOACs demonstrated that they were non-inferior to VKAs and had a lower incidence of major bleeding. However, it is uncertain whether these results extrapolate to older people who were under-represented in these trials. This abstract describes the development of a protocol for a systematic review of observational studies to investigate whether the rates of ischaemic stroke and major bleeding differ between older patients treated with DOACs and vitamin-K-antagonists.Methods: The research question, search, inclusion and exclusion criteria were developed iteratively using the PICOS acronym as the base:Population– People aged over 75 with atrial fibrillationIntervention– DOACsComparator– Vitamin K antagonistsOutcomes– Stroke and major bleedingStudy design– Observational studiesResults: A systematic review protocol of observational studies was derived and registered with PROSPERO (CRD42018081696). The primary outcomes to be assessed were effectiveness (ischaemic stroke prevention) and safety (bleeding). In outline, Medline, EMBASE, Scopus and Web of Science will be searched from 2009 to present. Reference list searches will be used to identify further relevant studies. Manufacturers of DOACs will be contacted to request unpublished data. Data will be extracted independently by two reviewers using a pre-piloted form. Study data will be quantitatively synthesised and standard meta-analyses will be undertaken for each pair of treatment comparisons. Preliminary database searches have identified 13,623 citations. From abstract and title review it is expected that 400 will be eligible for full text review.Conclusions: This systematic review of observational data will complement the evidence from RCTs to provide an insight into the effectiveness and safety of these medications in older patients who have historically been be underrepresented in clinical trials. The findings of this review will provide important information for patients and practitioners alike

Skin Pharmacokinetics of Transdermal Scopolamine:Measurements and Modeling

Prediction of skin absorption and local bioavailability from topical formulations remains a difficult task. An important challenge in forecasting topical bioavailability is the limited information available about local and systemic drug concentrations post application of topical drug products. Commercially available transdermal patches, such as Scopoderm (Novartis Consumer Health UK), offer an opportunity to test these experimental approaches as systemic pharmacokinetic data are available with which to validate a predictive model. The long-term research aim, therefore, is to develop a physiologically based pharmacokinetic model (PBPK) to predict the dermal absorption and disposition of actives included in complex dermatological products. This work explored whetherin vitrorelease and skin permeation tests (IVRT and IVPT, respectively), andin vitroandin vivostratum corneum (SC) and viable tissue (VT) sampling data, can provide a satisfactory description of drug “input rate” into the skin and subsequently into the systemic circulation.In vitrorelease and skin permeation results for scopolamine were consistent with the previously reported performance of the commercial patch investigated. New skin sampling data on the dermatopharmacokinetics (DPK) of scopolamine also accurately reflected the rapid delivery of a “priming” dose from the patch adhesive, superimposed on a slower, rate-controlled input from the drug reservoir. The scopolamine concentration versus time profiles in SC and VT skin compartments,in vitroandin vivo, taken together with IVRT release and IVPT penetration kinetics, reflect the input rate and drug delivery specifications of the Scopoderm transdermal patch and reveal the importance of skin binding with respect to local drug disposition. Further data analysis and skin PK modeling are indicated to further refine and develop the approach outlined.</p

Nadolol in Pregnancy: A medical student’s reflection on her pregnancy

Hypertension is a common concern during pregnancy. Beta-blockers are one potential treatment, but third trimester exposure has correlated with an increased risk of perinatal events. Nadolol, a nonselective beta blocker, has properties that differ from those of its selective counterparts, including longer half-life, decreased protein binding, and renal excretion in the unchanged form. There is very limited data on the use of nadolol during pregnancy, and its safety has not been completely evaluated. This case study documents the perinatal outcomes of nadolol use throughout a medical student’s pregnancy and explores the experience in obtaining and undergoing medical care

The incidence of primary glomerulonephritis worldwide:a systematic review of the literature

Background. Little is known about the worldwide variation in incidence of primary glomerulonephritis (GN). The objective of this review was to critically appraise studies of incidence published in 1980-2010 so that an overall view of trends of these diseases can be found. This would provide important information for determining changes in rates and understanding variations between countries. Methods. All relevant papers found through searches of Medline, Embase and ScienceDirect were critically appraised and an assessment was made of the reliability of the reported incidence data. Results. This review includes 40 studies of incidence of primary GN from Europe, North and South America, Canada, Australasia and the Middle East. Rates for the individual types of disease were found to be in adults, 0.2/100 000/year for membrano-proliferative GN, 0.2/100 000/year for mesangio-proliferative GN, 0.6/100 000/year for minimal change disease, 0.8/100 000/year for focal segmental glomerulosclerosis, 1.2/100 000/year for membranous nephropathy and 2.5/100 000/year for IgA nephropathy. Rates were lower in children at around 0.1/100 000/year with the exception of minimal change disease where incidence was reported to be 2.0/100 000/year in Caucasian children with higher rates in Arabian children (9.2/100 000/year) and Asian children (6.2-15.6/100 000/year). Conclusions. This study found that incidence rates of primary GN vary between 0.2/100 000/year and 2.5/100 000/ year. The incidence of IgA nephropathy is at least 2.5/100 000/year in adults; this disease can exist subclinically and is therefore only detected by chance in some patients. In addition, referral policies for diagnostic biopsy vary between countries. This will affect the incidence rates found

Aneurysms and pseudoaneurysms in dialysis access

Aneurysms are a common and often difficult complication seen with arteriovenous vascular access for haemodialysis. The purpose of this narrative review is to define and describe the scale of the problem and suggested therapeutic strategies. A narrative review of the published literature illustrated by individual cases is presented with the aim of summarising the relevant literature. The definitions of aneurysm are inconsistent throughout the literature and therefore systematic review is impossible. They vary from qualitative descriptions to quantitative definitions using absolute size, relative size and also size plus characteristics. The incidence and aetiology are also ill defined but separation into true aneurysms and false, or pseudoaneurysms may be helpful in planning treatment, which may be conservative, surgical or radiological. The lack of useful definitions and classification along with the multitude of management strategies proposed make firm evidence based conclusions difficult to draw. Further robust well designed studies are required to define best practice for this common problem

The microaerophilic microbiota of de-novo paediatric inflammatory bowel disease: the BISCUIT study

&lt;p&gt;Introduction: Children presenting for the first time with inflammatory bowel disease (IBD) offer a unique opportunity to study aetiological agents before the confounders of treatment. Microaerophilic bacteria can exploit the ecological niche of the intestinal epithelium; Helicobacter and Campylobacter are previously implicated in IBD pathogenesis. We set out to study these and other microaerophilic bacteria in de-novo paediatric IBD.&lt;/p&gt; &lt;p&gt;Patients and Methods: 100 children undergoing colonoscopy were recruited including 44 treatment naïve de-novo IBD patients and 42 with normal colons. Colonic biopsies were subjected to microaerophilic culture with Gram-negative isolates then identified by sequencing. Biopsies were also PCR screened for the specific microaerophilic bacterial groups: Helicobacteraceae, Campylobacteraceae and Sutterella wadsworthensis.&lt;/p&gt; &lt;p&gt;Results: 129 Gram-negative microaerophilic bacterial isolates were identified from 10 genera. The most frequently cultured was S. wadsworthensis (32 distinct isolates). Unusual Campylobacter were isolated from 8 subjects (including 3 C. concisus, 1 C. curvus, 1 C. lari, 1 C. rectus, 3 C. showae). No Helicobacter were cultured. When comparing IBD vs. normal colon control by PCR the prevalence figures were not significantly different (Helicobacter 11% vs. 12%, p = 1.00; Campylobacter 75% vs. 76%, p = 1.00; S. wadsworthensis 82% vs. 71%, p = 0.312).&lt;/p&gt; &lt;p&gt;Conclusions: This study offers a comprehensive overview of the microaerophilic microbiota of the paediatric colon including at IBD onset. Campylobacter appear to be surprisingly common, are not more strongly associated with IBD and can be isolated from around 8% of paediatric colonic biopsies. S. wadsworthensis appears to be a common commensal. Helicobacter species are relatively rare in the paediatric colon.&lt;/p&gt

Sensitivity of the UK clinical practice research datalink to detect neurodevelopmental effects of medicine exposure in utero:comparative analysis of an antiepileptic drug-exposed cohort

Introduction: Electronic healthcare data have several advantages over prospective observational studies, but the sensitivity of data on neurodevelopmental outcomes and its comparability with data generated through other methodologies is unknown. Objectives: The objectives of this study were to determine whether data from the UK Clinical Practice Research Datalink (CPRD) produces similar risk estimates to a prospective cohort study in relation to the risk of neurodevelopmental disorders (NDDs) following prenatal antiepileptic drug (AED) exposure. Methods: A cohort of mother–child pairs of women with epilepsy (WWE) was identified in the CPRD and matched to a cohort without epilepsy. The study period ran from 1 January 2000 to 31 March 2007 and children were required to be in the CPRD at age 6 years. AED exposure during pregnancy was determined from prescription data and children with an NDD diagnosis by 6 years were identified from Read clinical codes. The prevalence and risk of NDDs was calculated for mother–child pairs in WWE stratified by AED regimen and for those without epilepsy. Comparisons were made with the results of the prospective Liverpool and Manchester Neurodevelopment Group study which completed assessment on 201 WWE and 214 without epilepsy at age 6 years. Results: In the CPRD, 1018 mother–child pairs to WWE and 6048 to women without epilepsy were identified. The CPRD identified a lower prevalence of NDDs than the prospective study. In both studies, NDDs were more frequently reported in children of WWE than women without epilepsy, although the CPRD risk estimate was lower (2.16 vs. 0.96%, p < 0.001 and 7.46 vs. 1.87%, p = 0.0128). NDD prevalence differed across AED regimens but the CPRD data did not replicate the significantly higher risk of NDDs following in utero monotherapy valproate exposure (adjusted odds ratio [ORadj] 2.02, 95% confidence interval [CI] 0.52–7.86) observed in the prospective study (ORadj 6.05, 95% CI 1.65–24.53). Conclusion: It was possible to identify NDDs in the CPRD; however, the CPRD appears to under-record these outcomes. Larger studies are required to investigate further

Microbiota of De-Novo Pediatric IBD : Increased Faecalibacterium Prausnitzii and Reduced Bacterial Diversity in Crohn's But Not in Ulcerative Colitis

ACKNOWLEDGMENTS We are grateful for the expertise of our sequencing provider NewGene and in particular for the support and help of Dr Jonathan Coxhead.Mrs Karen McIntyre and Dr Dagmar Kastner were invaluable in identifying patients for recruitment in Dundee. Mrs Ann Morrice provided administrative support in Aberdeen. Dr Paul Henderson gave helpful comments on the manuscript. We appreciate the generosity of the families who freely gave their time and samples to make this study possible and the theatre staff of all centers who allowed time for sample collection during busy endoscopy lists.Peer reviewedPublisher PD