Report of the Integrated Stroke Care Workshop

The Stroke Project has been underway since October 2000. This workshop represented the first mechanism where by issues surrounding the project have been addressed by the multi- disciplinary stroke team and the Darent Valley Hospital Staff. Approximately 35 members of staff attended the workshop, demonstrating the high level of interest and ownership. Currently, the hospital receives an average eight or nine new stroke admissions a week. The turnover is such that patients suffering from stroke account for around 22-23 occupied beds in the acute hospital at any point in time. In the past the Acute Trust had had a lead Stroke Physician responsible for 20 designated stroke beds within a stroke unit. In that system many (but not all) cases of acute stroke admitted under the General Physicians would have been referred to the stroke unit and had their acute care and acute rehabilitation provided on site in that unit. At that time the overall number of beds occupied by cases of stroke was around 28- 29

Genome mining and characterisation of a novel transaminase with remote stereoselectivity

Microbial enzymes from pristine niches can potentially deliver disruptive opportunities in synthetic routes to Active Pharmaceutical Ingredients and intermediates in the Pharmaceutical Industry. Advances in green chemistry technologies and the importance of stereochemical control, further underscores the application of enzyme-based solutions in chemical synthesis. The rich tapestry of microbial diversity in the oceanic ecosystem encodes a capacity for novel biotransformations arising from the chemical complexity of this largely unexplored bioactive reservoir. Here we report a novel omega-transaminase discovered in a marine sponge Pseudovibrio sp. isolate. Remote stereoselection using a transaminase has been demonstrated for the first time using this novel protein. Application to the resolution of an intermediate in the synthesis of sertraline highlights the synthetic potential of this novel biocatalyst discovered through genomic mining. Integrated chemico-genomics revealed a unique substrate profile, while molecular modelling provided structural insights into this 'first in class' selectivity at a remote chiral centre

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Census of older people in acute medical beds in Medway Hospital

The objective of the study was to provide information on the current service utilisation, the casemix and the division of clinical work load between general medicine and elderly care, as they relate to acute inpatient medical care for persons aged sixty-five and over

The planning population for childhood illnesses potentially requiring admission. Report 3 Service Innovations Background Research Rapid Reviews (SIBR3)

The provision of services for infants, children and adolescents takes place in a dynamic environment in which a range of factors stimulate change. There is now a groundswell of informed opinion which sees the NHS acute sector of the future as one in which changes to hospital configuration are expected. The debate has been taken up with a number of stakeholders and has produced a range of reviews and reports on potential pathways for change. The government has set down a ten year strategy for modernisation, and substantial contribution from various clinical working parties has been made particularly in the area of paediatric, surgical, anaesthetic, trauma and intensive care services. (NHS July 2000, Royal College of Surgeons in England (RCSE) Nov 2000, RCSE Dec 2000, RCSE BOA July 2000, JWP BMA, RCP Lon. RCSE, July 1998, Royal Surgical Colleges of Great Britain and Ireland, July 1998, RCSE June1997, Royal College of Anaesthetists and RCSE 1996, Royal College of Nursing 2000, Department of Health 1996). This has been against a background, nationally, of increasing concerns regarding the quality of services for children. There are common issues which effect service configuration nationally, however, any specific catchment is going to have issues which are unique to itself. Much of the recent literature on re-configuration of services has emphasised the importance of locally derived solutions. (Smith 1999). One of the more considered propositions for future hospital configurations has been the networking model put forward in the Royal College of Surgeons of England’s report on the provision of elective surgical services, (RCSE 2000). While acknowledging that the optimal population catchments, recommended for paediatric surgery and trauma centres are c.1.5 million, it is considered that the feasibility of configuring the nation’s acute hospitals solely around single centres with such catchments is considered totally impractical. The need for both demographic and service responsiveness, led the report’s contributors to favour a more practical alternative, which would be to develop hospital networks serving populations of 500,000. (Even this is a challenging proposition in a system where 60% of hospitals are currently serving populations of 300,000 or less and only 10% serve a population of 500,000 or more.) This would see services with different emphases distributed across networks of hospitals, where separation was more related to intensity of care and severity of risk than in the traditional clinical divisions based on speciality alone. Elective and lower risk care does need not necessarily require a full complement of acute support services and may be better served by appropriate levels of back up (eg. high dependency support services and rapid retrieval systems with appropriate referral policies and guidance)