Final Report of the Commission on Presidential Disability and the Twenty-Fifth Amendment

This Report examines the Twenty-Fifth Amendment to identify potential difficulties in presidential succession and makes recommendations

Safety of topical corticosteroids in atopic eczema:an umbrella review

Objective: An umbrella review summarising all safety data from systematic reviews of topical corticosteroids (TCS) in adults and children with atopic eczema .Methods: Embase, MEDLINE, PubMed, Cochrane Database of Systematic Reviews and the Centre of Evidence Based Dermatology map of eczema systematic reviews searched until 7th November 2018 and Epistemonikos until 2nd March 2021. Reviews were included if they assessed safety of TCS in atopic eczema and searched >1 database using a reproducible search strategy. Review quality assessed using AMSTAR-2. PROSPERO registration: CRD42018079409. Results: 38 systematic reviews included, 34 low/critically low quality. Treatment and follow-up usually short (2-4 weeks). Key findings: TCS versus emollient/vehicle: No meta-analyses identified for skin-thinning. Two 2-week randomised controlled trials (RCTs) found no significant increased risk with very potent TCS (0/196 TCS vs 0/33 vehicle in children and 6/109 TCS vs 2/50 vehicle, age unknown). Biochemical adrenal suppression (cortisol) was 3.8% (95% CI 2.4%-5.8%) in a meta-analysis of 11 uncontrolled observational studies (any potency TCS, 522 children). Effects reversed when treatment ceased. TCS versus topical calcineurin inhibitors (TCIs): Meta-analysis showed higher relative risk of skin-thinning with TCS (RR 4.86, 95% CI 1.06-22.28, n=4128, four RCTs, including one 5-year RCT). Eight cases in 2068 participants, 7 using potent TCS. No evidence of growth suppression.Once daily versus more frequent TCS: No meta-analyses identified. No skin-thinning in one RCT (3 weeks potent TCS, n=94) or biochemical adrenal suppression in two RCTs (up to 2 weeks very potent/moderate TCS, n=129).TCS twice/week to prevent flares (‘weekend therapy’) versus vehicle: No meta-analyses identified. No evidence of skin-thinning in five RCTs. One RCT found biochemical adrenal suppression (2/44 children, potent TCS).Conclusions: We found no evidence of harm when TCS used intermittently “as required” to treat flares or “weekend therapy” to prevent flares. However, long-term safety data was limited

Schistosoma mansoni Larval Extracellular Vesicle protein 1 (SmLEV1) is an immunogenic antigen found in EVs released from pre-acetabular glands of invading cercariae.

Funder: IBERS, Aberystwyth University PhD studentshipFunder: Higher Education Funding Council for Wales (HEFCW) - Global Challenges Research FundExtracellular Vesicles (EVs) are an integral component of cellular/organismal communication and have been found in the excreted/secreted (ES) products of both protozoan and metazoan parasites. Within the blood fluke schistosomes, EVs have been isolated from egg, schistosomula, and adult lifecycle stages. However, the role(s) that EVs have in shaping aspects of parasite biology and/or manipulating host interactions is poorly defined. Herein, we characterise the most abundant EV-enriched protein in Schistosoma mansoni tissue-migrating schistosomula (Schistosoma mansoni Larval Extracellular Vesicle protein 1 (SmLEV1)). Comparative sequence analysis demonstrates that lev1 orthologs are found in all published Schistosoma genomes, yet homologs are not found outside of the Schistosomatidae. Lifecycle expression analyses collectively reveal that smlev1 transcription peaks in cercariae, is male biased in adults, and is processed by alternative splicing in intra-mammalian lifecycle stages. Immunohistochemistry of cercariae using a polyclonal anti-recombinant SmLEV1 antiserum localises this protein to the pre-acetabular gland, with some disperse localisation to the surface of the parasite. S. mansoni-infected Ugandan fishermen exhibit a strong IgG1 response against SmLEV1 (dropping significantly after praziquantel treatment), with 11% of the cohort exhibiting an IgE response and minimal levels of detectable antigen-specific IgG4. Furthermore, mice vaccinated with rSmLEV1 show a slightly reduced parasite burden upon challenge infection and significantly reduced granuloma volumes, compared with control animals. Collectively, these results describe SmLEV1 as a Schistosomatidae-specific, EV-enriched immunogen. Further investigations are now necessary to uncover the full extent of SmLEV1's role in shaping schistosome EV function and definitive host relationships

The challenges faced in the design, conduct and analysis of surgical randomised controlled trials

Randomised evaluations of surgical interventions are rare; some interventions have been widely adopted without rigorous evaluation. Unlike other medical areas, the randomised controlled trial (RCT) design has not become the default study design for the evaluation of surgical interventions. Surgical trials are difficult to successfully undertake and pose particular practical and methodological challenges. However, RCTs have played a role in the assessment of surgical innovations and there is scope and need for greater use. This article will consider the design, conduct and analysis of an RCT of a surgical intervention. The issues will be reviewed under three headings: the timing of the evaluation, defining the research question and trial design issues. Recommendations on the conduct of future surgical RCTs are made. Collaboration between research and surgical communities is needed to address the distinct issues raised by the assessmentof surgical interventions and enable the conduct of appropriate and well-designed trials.The Health Services Research Unit is funded by the Scottish Government Health DirectoratesPeer reviewedPublisher PD

The HAC Trial (Harmonic for Acute Cholecystitis) Study. Randomized, double-blind, controlled trial of Harmonic(H) versus Monopolar Diathermy (M) for laparoscopic cholecystectomy (LC) for acute cholecystitis (AC) in adults

<p>Abstract</p> <p>Background</p> <p>In the developmental stage of laparoscopic cholecystectomy (LC) it was considered 'unsafe' or 'technically difficult' to perform laparoscopic cholecystectomy for acute cholecystitis (AC). With increasing experience in laparoscopic surgery, a number of centers have reported on the use of laparoscopic cholecystectomy for acute cholecystitis, suggesting that it is technically feasible but at the expense of a high conversion rate, which can be up to 35 per cent and common bile duct lesions.</p> <p>The HARMONIC SCALPEL(R) (H) is the leading ultrasonic cutting and coagulating surgical device, offering surgeons important benefits including: minimal lateral thermal tissue damage, minimal charring and desiccation.</p> <p>Harmonic Scalpel technology reduces the need for ligatures with simultaneous cutting and coagulation: moreover there is not electricity to or through the patient Harmonic Scalpel has a greater precision near vital structures and it produces minimal smoke with improved visibility in the surgical field.</p> <p>In retrospective series LC performed with H was demonstrated feasible and effective with minimal operating time and blood loss: it was reported also a low conversion rate (3.9%).</p> <p>However there are not prospective randomized controlled trials showing the advantages of H compared to MD (the commonly used electrical scalpel) in LC.</p> <p>Methods/Design</p> <p>Aim of this RCT is to demonstrate that H can decrease the conversion rate compared to MD in LC for AC, without a significant increase of morbidity.</p> <p>The patients will be allocated in two groups: in the first group the patient will be submitted to early LC within 72 hours after the diagnosis with H while in the second group will be submitted to early LC within 72 hours with MD.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier: NCT00746850</p

Big data and data repurposing – using existing data to answer new questions in vascular dementia research

Introduction: Traditional approaches to clinical research have, as yet, failed to provide effective treatments for vascular dementia (VaD). Novel approaches to collation and synthesis of data may allow for time and cost efficient hypothesis generating and testing. These approaches may have particular utility in helping us understand and treat a complex condition such as VaD. Methods: We present an overview of new uses for existing data to progress VaD research. The overview is the result of consultation with various stakeholders, focused literature review and learning from the group’s experience of successful approaches to data repurposing. In particular, we benefitted from the expert discussion and input of delegates at the 9th International Congress on Vascular Dementia (Ljubljana, 16-18th October 2015). Results: We agreed on key areas that could be of relevance to VaD research: systematic review of existing studies; individual patient level analyses of existing trials and cohorts and linking electronic health record data to other datasets. We illustrated each theme with a case-study of an existing project that has utilised this approach. Conclusions: There are many opportunities for the VaD research community to make better use of existing data. The volume of potentially available data is increasing and the opportunities for using these resources to progress the VaD research agenda are exciting. Of course, these approaches come with inherent limitations and biases, as bigger datasets are not necessarily better datasets and maintaining rigour and critical analysis will be key to optimising data use

Supporting families managing childhood eczema:Developing and optimising Eczema Care Online using qualitative research

Background: childhood eczema is often poorly controlled due to under-use of emollients and topical corticosteroids. Parents/carers report practical and psychosocial barriers to managing their child’s eczema, including child resistance. Online interventions could potentially support parents/carers; however, rigorous research developing such interventions has been limited. Aim: to develop an online behavioural intervention to help parents/carers manage and co-manage their child’s eczema. Design and setting: Intervention development using a theory-, evidence- and Person-Based Approach with qualitative research. Methods: a systematic review and qualitative synthesis (32 studies) and interviews with parents/carers (N=30) were used to identify barriers and facilitators to effective eczema management, and a prototype intervention was developed. Think-aloud interviews with parents/carers (N=25) were then used to optimise the intervention to increase its acceptability and feasibility. Results: qualitative research identified that parents/carers had concerns about using emollients and topical corticosteroids; incomplete knowledge and skills around managing eczema; and reluctance to transitioning to co-managing eczema with their child. Think-aloud interviews highlighted that while experienced parents/carers felt they knew how to manage eczema, some information about how to use treatments was still new. Techniques for addressing barriers included: providing a rationale explaining how emollients and topical corticosteroids work; demonstrating how to use treatments; and highlighting that the intervention provided new, up-to-date information. Conclusions: parents/carers need support in effectively managing and co-managing their child’s eczema. The key output of this research is Eczema Care Online (ECO) for Families; an online intervention for parents/carers of children with eczema, which is being evaluated in a randomised trial

Population-based trends in pregnancy hypertension and pre-eclampsia: an international comparative study

Objective: The objective of this study was to compare international trends in pre-eclampsia rates and in overall pregnancy hypertension rates (including gestational hypertension, pre-eclampsia and eclampsia). Design: Population data (from birth and/or hospital records) on all women giving birth were available from Australia (two states), Canada (Alberta), Denmark, Norway, Scotland, Sweden and the USA (Massachusetts) for a minimum of 6 years from 1997 to 2007. All countries used the 10th revision of the International Classification of Diseases, except Massachusetts which used the 9th revision. There were no major changes to the diagnostic criteria or methods of data collection in any country during the study period. Population characteristics as well as rates of pregnancy hypertension and pre-eclampsia were compared. Results: Absolute rates varied across the populations as follows: pregnancy hypertension (3.6% to 9.1%), pre-eclampsia (1.4% to 4.0%) and early-onset preeclampsia (0.3% to 0.7%). Pregnancy hypertension and/or pre-eclampsia rates declined over time in most populations. This was unexpected given that factors associated with pregnancy hypertension such as prepregnancy obesity and maternal age are generally increasing. However, there was also a downward shift in gestational age with fewer pregnancies reaching 40 weeks. Conclusion: The rate of pregnancy hypertension and pre-eclampsia decreased in northern Europe and Australia from 1997 to 2007, but increased in Massachusetts. The use of a different International Classification of Diseases coding version in Massachusetts may contribute to the difference in trend. Elective delivery prior to the due date is the most likely explanation for the decrease observed in Europe and Australia. Also, the use of interventions that reduce the risk of pregnancy hypertension and/or progression to pre-eclampsia (low-dose aspirin, calcium supplementation and early delivery for mild hypertension) may have contributed to the decline

Colour relationalism and the real deliverances of introspection

Colour relationalism holds that the colours are constituted by relations to subjects. Anti-relationalists have claimed that this view stands in stark contrast to our phenomenally-informed, pre-theoretic intuitions. Is this claim right? Cohen and Nichols’ recent empirical study suggests not, as about half of their participants seemed to be relationalists about colour. Despite Cohen and Nichols’ study, we think that the anti-relationalist’s claim is correct. We explain why there are good reasons to suspect that Cohen and Nichols’ experimental design skewed their results in favour of relationalism. We then run an improved study and find that most of our participants seem to be anti-relationalists. We find some other interesting things too. Our results suggest that the majority of ordinary people find it no less intuitive that colours are objective than that shapes are objective. We also find some evidence that when those with little philosophical training are asked about the colours of objects, their intuitions about colour and shape cases are similar, but when asked about people’s colour ascriptions, their intuitions about colour and shape cases differ