Case Report Treated Follicular Lymphoma, Recurrent Invasive Pneumococcal Disease, Nonresponsiveness to Vaccination, and a Unique Pneumococcus

A nonneutropenic patient with treated low-grade non-Hodgkin's (Follicular) lymphoma and secondary hypogammaglobulinemia recovered from pneumococcal pneumonia and septicemia (serotype 7F; ST191) subsequent to influenza A H1N1 (2009). Both infections were potentially vaccine preventable. The patient then developed pneumococcal meningitis due to a serotype 35F pneumococcus with a unique Multilocus Sequence Type (ST7004) which was not vaccine preventable. Patient management was influenced by host predisposition to pneumococcal infection, antibiotic intolerance, and poor response to polysaccharide pneumococcal vaccine. Indirect immunofluorescence with anti-human immunoglobulin confirmed a poor or intermediate response to Pneumovax II. Prophylactic erythromycin was initiated, and immunoglobulin transfusions were also commenced as a preventive strategy. ST7004 is a single locus variant of ST1635 which has been associated with the serotype 35F capsule in England. The spi gene in ST7004, which differentiates it from ST1635, is the same as the spi gene present in ST191 which could have arisen from the first disease episode suggesting that horizontal gene transfer may have occurred between different populations of pneumococci present within the patient in an attempt to evade vaccination selection pressure

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

Adaptive Virtual Reality Games for Rehabilitation of Motor Disorders

This paper describes the development of a Virtual Reality (VR) based therapeutic training system aimed at encourage stroke patients with upper limb motor disorders to practice physical exercises. The system contains a series of physically-based VR games. Physically-based simulation provides realistic motion of virtual objects by modelling the behaviour of virtual objects and their responses to external force and torque based on physics laws. We present opportunities for applying physics simulation techniques in VR therapy and discuss their potential therapeutic benefits to motor rehabilitation. A framework for physically-based VR rehabilitation systems is described which consists of functional tasks and game scenarios designed to encourage patients’ physical activity in highly motivating, physics-enriched virtual environments where factors such as gravity can be scaled to adapt to individual patient’s abilities and in-game performance

Improving participation and engagement with a COVID-19 surveillance programme in an outpatient setting

BACKGROUND: On 3 August 2020, Public Health Scotland commenced a prospective surveillance study to monitor the prevalence of COVID-19 among asymptomatic outpatients attending dental clinics across 14 health boards in Scotland. OBJECTIVES: The primary aim of this quality improvement project was to increase the number of COVID-19 tests carried out in one of the participating sites, Glasgow Dental Hospital and School. The secondary aim was to identify barriers to patient participation and staff engagement when implementing a public health initiative in an outpatient setting. METHOD: A quality improvement working group met weekly to discuss hospital findings, identify drivers and change ideas. Details on reasons for patient non-participation were recorded and questionnaires on project barriers were distributed to staff. In response to findings, rapid interventions were implemented to fast-track increases in the numbers of tests being carried out. RESULTS: Over 16 weeks, 972 tests were carried out by Glasgow Dental Hospital and School Secondary Care Services. The number of tests per week increased from 19 (week 1) to 129 (week 16). This compares to a similar ‘control’ site, where the number of tests carried out remained unchanged; 38 (week 1) to 36 (week 16). The most frequent reason given for non-participation was fear that the swab would hurt. For staff, lack of time and forgetting to ask patients were identified as the most significant barriers. CONCLUSION: Public health surveillance programmes can be integrated rapidly into outpatient settings. This project has shown that a quality improvement approach can be successful in integrating such programmes. The key interventions used were staff engagement initiatives and front-line data collection. Implementation barriers were also identified using staff questionnaires

Structural variants at the BRCA1/2 loci are a common source of homologous repair deficiency in high grade serous ovarian carcinoma

PURPOSE: The abundance and effects of structural variation at BRCA1/2 in tumours are not well understood. In particular, the impact of these events on homologous recombination repair deficiency (HRD) has yet to be demonstrated. EXPERIMENTAL DESIGN: Exploiting a large collection of whole genome sequencing data from high grade serous ovarian carcinoma (N=205) together with matched RNA-seq for the majority of tumours (N=150), we have comprehensively characterised mutation and expression at BRCA1/2. RESULTS: In addition to the known spectrum of short somatic mutations (SSMs), we discover that multi-megabase structural variants (SVs) are a frequent, unappreciated source of BRCA1/2 disruption in these tumours, and we find a genome wide enrichment for large deletions at the BRCA1/2 loci across the cohort. These SVs independently affect a substantial proportion of patients (16%) in addition to those affected by SSMs (24%), conferring homologous recombination repair deficiency (HRD) and impacting patient survival. We also detail compound deficiencies involving SSMs and SVs at both loci, demonstrating that the strongest risk of HRD emerges from combined SVs at both BRCA1 and BRCA2 in the absence of SSMs. Further, these SVs are abundant and disruptive in other cancer types. CONCLUSIONS: These results extend our understanding of the mutational landscape underlying HRD, increase the number of patients predicted to benefit from therapies exploiting HRD, and suggest there is currently untapped potential in SV detection for patient stratification