Systematic review of available evidence on 11 high-priced inpatient orphan drugs

__Background__: Attention for Evidence Based Medicine (EBM) is growing, but evidence for orphan drugs is argued to be limited and inferior. This study systematically reviews the available evidence on clinical effectiveness, costeffectiveness and budget impact for orphan drugs. __Methods__: A systematic review was performed in PubMed, Embase, NHS EED and HTA databases for 11 inpatient orphan drugs listed on the Dutch policy rule on orphan drugs. For included studies, we determined the type of study and various study characteristics. __Results__: A total of 338 studies met all inclusion criteria. Almost all studies (96%) focused on clinical effectiveness of the drug. Of these studies, most studies were case studies (41%) or observational studies (39%). However, for all orphan diseases at least one experimental or quasi-experimental study was found, and a randomized clinical trial was available for 60% of the orphan drugs. Eight studies described the cost-effectiveness of an orphan drug; an equal number described an orphan drug’s budget impact. __Conclusions__: Despite the often heard claim that RCTs are not feasible for orphan drugs, we found that an RCT was available in 60% of o

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

The International Sexual Health And Reproductive Health Survey (I-SHARE-1): A Multi-Country Analysis of Adults from 30 Countries Prior to and During the Initial COVID-19 Wave

Background: The COVID-19 pandemic forced billions of people to shelter in place, altering social and sexual relationships worldwide. In many settings, COVID-19 threatened already precarious health services. However, there is limited evidence to date about changes to sexual and reproductive health (SRH) during the initial wave of COVID-19 disease. To address this gap, our team organized a multi-country, cross-sectional online survey as part of a global consortium. Methods: Consortium research teams conducted online surveys in 30 countries. Sampling methods included convenience, online panels, and population-representative. Primary outcomes included sexual behaviors, partner violence, and SRH service utilization, and we compared three months prior to and three months after policy measures to mitigate COVID-19. We used established indicators and analyses pre-specified in our protocol. We conducted meta-analyses for primary outcomes and graded the certainty of the evidence using Cochrane methods. Descriptive analyses included 22,724 individuals in 25 countries. Five additional countries with sample sizes <200 were included in descriptive meta-analyses. Results: Respondents were mean age 34 years; most identified as women (15160; 66.7%), cis-gender (19432; 86.6%) and heterosexual (16592; 77.9%). Among 4546 respondents with casual partners, condom use stayed the same for 3374 (74.4%) people and 640 (14.1%) people reported a decline. Fewer respondents reported physical or sexual partner violence during COVID-19 measures (1063/15144, 7.0%) compared to the period before COVID-19 measures (1469/15887, 9.3%). COVID-19 measures impeded access to condoms (933/10790, 8.7%), contraceptives (610/8175, 7.5%), and HIV/STI testing (750/1965, 30.7%). Pooled estimates from meta-analysis indicate during COVID-19 measures, 32.3% (95% CI 23.9-42.1) of people needing HIV/STI testing had hindered access, 4.4% (95% CI 3.4-5.4) experienced partner violence, and 5.8% (95% CI 5.4-8.2) decreased casual partner condom use (moderate certainty of evidence for each outcome). Meta-analysis findings were robust in sensitivity analyses that examined country income level, sample size, and sampling strategy. Conclusion: Open science methods are feasible to organize research studies as part of emergency responses. The initial COVID-19 wave impacted SRH behaviors and access to services across diverse global settings

Obesity in adults: a 2022 adapted clinical practice guideline for Ireland

This Clinical Practice Guideline (CPG) for the management of obesity in adults in Ireland, adapted from the Canadian CPG, defines obesity as a complex chronic disease characterised by excess or dysfunctional adiposity that impairs health. The guideline reflects substantial advances in the understanding of the determinants, pathophysiology, assessment, and treatment of obesity. It shifts the focus of obesity management toward improving patient-centred health outcomes, functional outcomes, and social and economic participation, rather than weight loss alone. It gives recommendations for care that are underpinned by evidence-based principles of chronic disease management; validate patients' lived experiences; move beyond simplistic approaches of "eat less, move more" and address the root drivers of obesity. People living with obesity face substantial bias and stigma, which contribute to increased morbidity and mortality independent of body weight. Education is needed for all healthcare professionals in Ireland to address the gap in skills, increase knowledge of evidence-based practice, and eliminate bias and stigma in healthcare settings. We call for people living with obesity in Ireland to have access to evidence-informed care, including medical, medical nutrition therapy, physical activity and physical rehabilitation interventions, psychological interventions, pharmacotherapy, and bariatric surgery. This can be best achieved by resourcing and fully implementing the Model of Care for the Management of Adult Overweight and Obesity. To address health inequalities, we also call for the inclusion of obesity in the Structured Chronic Disease Management Programme and for pharmacotherapy reimbursement, to ensure equal access to treatment based on health-need rather than ability to pay

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

With W/Ringing Ears: an audiovisual response

This work emerges from The Panacousticon, a performative response in the form of a script by Caroline Wilkins (2016, 109-118) to an original essay by Freddie Rokem on eavesdropping in classical theatre (2015). As a sequel it has developed into a co-authored digital work in collaboration with multi-media artist Leona Jones. With W/Ringing Ears draws a link between the Panacousticon, a listening device invented in the 1600s by philosopher Athanasius Kircher, and both analogue and digital tools of surveillance emerging over the last two centuries, presented in the form of images of eavesdropping. It comprises a re-worked audio script based on the original and excerpts from sound recordings made from this new material. Emerging from the images is a contextual provocation on hearsay and virtual (mis-)information assailing our ears at this time of pandemic crisis, as well as the re-appearance of the original play script by Wilkins. The oral event of philosophising rebounds from the aural one. The acts of speaking and listening lead to the act of philosophising. Thus an initial experience of immediacy develops into a joint audio-phonic work, an acoustic act, a live encounter between performance and philosophy