Comprehensive interrogation of gene lists from genome-scale cancer screens with oncoEnrichR

Genome-scale screening experiments in cancer produce long lists of candidate genes that require extensive interpretation for biological insight and prioritization for follow-up studies. Interrogation of gene lists frequently represents a significant and time-consuming undertaking, in which experimental biologists typically combine results from a variety of bioinformatics resources in an attempt to portray and understand cancer relevance. As a means to simplify and strengthen the support for this endeavor, we have developed oncoEnrichR, a flexible bioinformatics tool that allows cancer researchers to comprehensively interrogate a given gene list along multiple facets of cancer relevance. oncoEnrichR differs from general gene set analysis frameworks through the integration of an extensive set of prior knowledge specifically relevant for cancer, including ranked gene-tumor type associations, literature-supported proto-oncogene and tumor suppressor gene annotations, target druggability data, regulatory interactions, synthetic lethality predictions, as well as prognostic associations, gene aberrations and co-expression patterns across tumor types. The software produces a structured and user-friendly analysis report as its main output, where versions of all underlying data resources are explicitly logged, the latter being a critical component for reproducible science. We demonstrate the usefulness of oncoEnrichR through interrogation of two candidate lists from proteomic and CRISPR screens. oncoEnrichR is freely available as a web-based service hosted by the Galaxy platform ( https://oncotools.elixir.no ), and can also be accessed as a stand-alone R package ( https://github.com/sigven/oncoEnrichR ).     

Development of a core outcome set for venous leg ulceration (CoreVen) research evaluations (protocol)

BackgroundA venous leg ulcer is a chronic leg wound caused by poor venous blood circulation in the lower limbs. It is a recurring condition causing pain, malodour, reduced mobility, and depression. Randomised controlled trials evaluating treatments for venous leg ulcers provide important evidence to inform clinical decision-making. However, for findings to be useful, outcomes need to be clinically meaningful, consistently reported across trials, and fully reported. Research has identified the large number of outcomes reported in venous leg ulcer trials, impacting both synthesis of results, and clinical decision-making. To address this, a core outcome set will be developed. A core outcome set is an agreed standardised set of outcomes which should be, as a minimum, measured and reported in all trials which evaluate treatment effectiveness for a given indication. A core outcome set has the potential to reduce research waste, improve the utility of RCTs, reduce reporting bias, facilitate treatment comparisons across different sources of evidence and expedite the production of systematic reviews, meta-analyses and evidence-based clinical guidelines.AimThe aim of this project is to develop a core outcome set for research evaluating the effectiveness of interventions for treating venous leg ulceration.MethodsThrough a scoping review of the literature on venous leg ulceration, we will firstly identify a list of candidate outcome domains (broad categories in relation to what is being measured) from randomised controlled trials and qualitative research, and outcomes (specific methods in relation to what is being measured). In two further stages, we will use the resulting lists of outcome domains and outcomes to design two online surveys. A range of stakeholders will be invited to participate in the surveys and they will be asked to indicate which outcome domains and outcomes are most important and should be considered as core in future research reports.     

Comparison of microscopic features of bone false starts produced by reciprocating saw blades and handsaws of the same class

In cases of criminal dismemberment, the analysis of saw marks helps to determine the class of the saw used. The present study compared the microscopic features of experimental false starts performed on three freshly defleshed human femurs. 150 lesions were produced using three reciprocating blades and two hand saws of similar class. Two groups of tools were created according to the class of the blades: group 1 (teeth per inch = 6, alternating set) and group 2 (teeth per inch = 24, wavy set).The minimum width of the kerf was always thicker with reciprocating blades than that of the handsaw of the same class. This fact is linked to the thickness of the blades and not necessarily to the fast forth and back motion of the blades. Shape kerf profiles and shape of the walls were very confusing, with a lot of variation of the false starts caused by the reciprocating blades and the risk of misclassification (rip teeth versus crosscut teeth, alternating set versus wavy set). Striae on the kerf floor and bone islands were more consistent.The main conclusions are, first, that usual features of false starts achieved by reciprocating saw blades used in this work vary a great deal and may lead to misclassification of the saw class, and second, that no criterion has been found to differentiate reciprocating blades and handsaws. These results demonstrate that we have to be very prudent while estimating the possible saw from a false start in a real forensic case.     

FDA“治疗等效性评价供企业用指导原则”（草案）介绍

美国食品药品管理局（FDA）于2022年7月发布了"治疗等效性评价供企业用指导原则"（草案）。该指导原则阐明了FDA治疗等效性的标准以及治疗等效性编码系统，目的是准确评价仿制药与参比制剂的治疗等效性并通过治疗等效性代码，在"橙皮书"中迅速检索到治疗等效的仿制药。而中国目前尚无类似的指导原则，详细介绍FDA该指导原则主要内容，期望对中国加强仿制药的治疗等效性评价和加速完善和实施符合国情的治疗等效性编码系统有所帮助。     

Safety and immunogenicity of NVX-CoV2373 (TAK-019) vaccine in healthy Japanese adults: Interim report of a phase I/II randomized controlled trial

BackgroundWe evaluated the safety and immunogenicity of NVX-CoV2373, a recombinant SARS-CoV-2 nanoparticle vaccine, in healthy Japanese participants.MethodsThis phase 1/2, randomized, observer-blind, placebo-controlled trial conducted in Japan (two sites), enrolled healthy Japanese adults aged ≥ 20 years with no history/risk of SARS-CoV-2 infection and no prior exposure to other approved/investigational SARS-CoV-2 vaccines or treatments. Participants were stratified by age (< 65 or ≥ 65 years) and randomized to receive two doses of either NVX-CoV2373 (5 μg SARS-CoV-2 rS; 50 μg Matrix-M1) or placebo, 21 days apart. Primary outcomes were safety and immunogenicity assessed by serum IgG antibody levels against SARS-CoV-2 rS protein on day 36. Herein, we report the primary data analysis at 4 weeks after the second dose, ahead of 12-month follow-up completion (data cut-off: 8 May 2021).ResultsBetween 12 February 2021 and 17 March 2021, 326 subjects were screened, and 200 participants enrolled and randomized: NVX-CoV2373, n = 150; placebo, n = 50. Solicited adverse events (AEs) through 7 days after each injection occurred in 121/150 (80.7%) and 11/50 (22.0%) participants in the NVX-CoV2373 and placebo arms, respectively. In the NVX-CoV2373 arm, tenderness and injection site pain were the most frequently reported solicited AEs after each vaccination, irrespective of age. Robust immune responses occurred with NVX-CoV2373 (n = 150) by day 36: IgG geometric mean fold rise (95% confidence interval) 259 (219, 306); seroconversion rate 100% (97.6, 100). No such response occurred with placebo (n = 49).ConclusionTwo doses of NVX-CoV2373 given with a 21-day interval demonstrated acceptable safety and induced robust anti-SARS-CoV-2 immune responses in healthy Japanese adults. Funding: Takeda Pharmaceutical Company Limited and Japan Agency for Medical Research and Development (AMED). ClinicalTrials.gov identifier: NCT04712110.     

Effectiveness of virtual reality in the treatment of hand function in children with cerebral palsy: A systematic review

Study DesignSystematic review.IntroductionChildren with cerebral palsy (CP) may have limited use of their hands for functional activities and for fine motor skills. Virtual reality (VR) is a relatively new and innovative approach to facilitate hand function in children with CP.Purpose of the StudyThe primary purpose of this study was to determine the effectiveness of VR as an intervention to improve hand function in children with CP compared to either conventional physiotherapy or other therapeutic interventions. The secondary purpose was to classify the outcomes evaluated according to the International Classification of Functioning, Disability and Health (ICF) dimensions.MethodsA International prospective register of systematic reviews (PROSPERO)-registered literature search was carried out in August 2015 in MEDLINE, CINAHL, ERIC, HealthSTAR, AMED, BNI, Embase, PsycINFO, PEDro, Cochrane Central Register, DARE, OTSeeker, REHABDATA, HaPI, CIRRIE, and Scopus. PRISMA guidelines were followed. Only randomized controlled trials (RCTs) were included, and their methodological qualities were examined using the Cochrane collaboration's risk of bias (RoB) tool. A narrative synthesis was performed.ResultsThe 6 RCTs published on this topic provide conflicting results. Four studies reported improved hand function (2 low RoB, 1 high RoB, and 1 unclear RoB), whereas 2 studies reported no improvement. All of the RCTs reported the activity element of ICF, but no study explicitly described the effect of VR intervention based on the ICF model.ConclusionThe role of VR ti imrpove hand fucntion in children with CP is unclear due to limited evidence; use as an adjunct has some support.     

Learning to live with a hand nerve disorder: A constructed grounded theory

Study DesignGrounded theory.IntroductionThe broader perspective of health offered by the World Health Organization's International Classification of Functioning, Disability and Health has had a significant bearing on how we view the measurement of health outcomes after surgical or therapy interventions for peripheral nerve disorders affecting the hand. The value of the patient's perspective is now recognized and outcomes which reflect this are being advocated in the clinical management and support of this population.Purpose of the StudyThis qualitative study sought to explore the lived experience of a hand nerve disorder and in particular the impact on body structure/function, activities, and participation.MethodsIn depth, one-to-one interviews with 14 people with a range of hand nerve disorders were conducted. Constructivist grounded theory methods were used to collect and analyze the data. Patients were also given the option of taking photographs to visually represent what it is like to live with a nerve disorder, to bring with them for discussion during the interview.ResultsThe impact of hand nerve disorders forms part of a wider narrative on adaptation. A process of “struggling” and then “overcoming” was experienced. This was followed by an interior aspect of adaptation described as “accepting.” This gave rise to participants “transforming,” being changed as a result of the journey that they had been on.ConclusionsThis study provides an explanatory theory on the adaptive process following a hand nerve disorder which may inform future patient-therapist interactions.     

Solution‐driven approaches to generic substitution challenges – a survey among international experts

The main objective of this study was to explore the perception and understanding of economic, legal, and social barriers that may restrain generic uptake among recognized international experts in health care, and to identify and verify recommendations on how to streamline generic substitution (GS) at no expense of therapeutic safety. A questionnaire survey was devised, and experts with world‐renowned expertise in the field of generic medicinal products were selected. Almost 3/4 of respondents claimed that all drugs that satisfy bioequivalence criteria represent similar efficacy and adverse effects, and 1/4 of respondents believed that some differences could be reported. The majority of experts supported (i) the right of patients to refuse GS, (ii) the right of physicians to veto GS, and (iii) the introduction of a statutory obligation to provide patients with access to the cheapest generics available on the market. The main obstacles to more general uptake of generics were as follows: (i) perception of generics as lower quality products, (ii) absence of a transparent policy governing GS, and (iii) disincentives to pharmacists and physicians. Among the most popular recommendations were as follows: (i) introduction of various measures to aid physicians in generic prescribing, (ii) setting clear guidelines specifying when GS is not advisable, (iii) supporting competition on the generic market. The views of experts and the resulting recommendations were strongly affected by their opinion on the bioequivalence of generics. From this analysis, we have selected several principal recommendations which could help shape successful healthcare policies regarding GS.     

中医药核心指标集研究利益相关群体选择实施要点＊

核心指标集是通过一系列规范的研制过程，形成某种疾病所有相关临床研究必须报告的、统一的、标准化的最小指标集合。确定哪些指标为核心结局指标，需要经过不同利益相关群体层层筛选并最终达成共识决定。相关利益群体的代表性，决定了核心指标集的系统性和合理性。因此，在核心指标集研制过程中利益相关群体的选择至关重要。本文对中医药核心指标集研制中利益相关群体的种类选择、样本量、参与环节、权重分配以及患者代表群的特殊性等相关要点进行归纳总结，以期为中医药核心指标集研究的开展提供方法学借鉴。     

Immunogenicity and safety of a quadrivalent inactivated influenza vaccine in children 6–59 months of age: A phase 3, randomized,noninferiority study

Background

In the Southern Hemisphere 2010 influenza season, Seqirus’ split-virion, trivalent inactivated influenza vaccine was associated with increased reports of fevers and febrile reactions in young children. A staged clinical development program of a quadrivalent vaccine (Seqirus IIV4 [S-IIV4]; Afluria® Quadrivalent/Afluria Quad?/Afluria Tetra?), wherein each vaccine strain is split using a higher detergent concentration to reduce lipid content (considered the cause of the increased fevers and febrile reactions), is now complete.