A temperature-sensitive and less immunogenic Sendai virus for efficient gene editing.

Unlabelled: The therapeutic potential of gene editing technologies hinges on the development of safe and effective delivery methods. In this study, we developed a temperature-sensitive and less immunogenic Sendai virus (ts SeV) as a novel delivery vector for CRISPR-Cas9 and for efficient gene editing in sensitive human cell types with limited induction of an innate immune response. ts SeV demonstrates high transduction efficiency in human CD34 hematopoietic stem and progenitor cells (HSPCs) including transduction of the CD34/CD38/CD45RA/CD90(Thy1)/CD49f stem cell enriched subpopulation.

Non-viral DNA delivery and TALEN editing correct the sickle cell mutation in hematopoietic stem cells.

Sickle cell disease is a devastating blood disorder that originates from a single point mutation in the HBB gene coding for hemoglobin. Here, we develop a GMP-compatible TALEN-mediated gene editing process enabling efficient HBB correction via a DNA repair template while minimizing risks associated with HBB inactivation. Comparing viral versus non-viral DNA repair template delivery in hematopoietic stem and progenitor cells in vitro, both strategies achieve comparable HBB correction and result in over 50% expression of normal adult hemoglobin in red blood cells without inducing β-thalassemic phenotype.

A temperature-sensitive and interferon-silent Sendai virus vector for CRISPR-Cas9 delivery and gene editing in primary human cells.

The transformative potential of gene editing technologies hinges on the development of safe and effective delivery methods. In this study, we developed a temperature-sensitive and interferon-silent Sendai virus (ts SeV) as a novel delivery vector for CRISPR-Cas9 and for efficient gene editing in sensitive human cell types without inducing IFN responses. ts SeV demonstrates unprecedented transduction efficiency in human CD34+ hematopoietic stem and progenitor cells (HSPCs) including transduction of the CD34+/CD38-/CD45RA-/CD90+(Thy1+)/CD49f stem cell enriched subpopulation.

Predictors of fatal and nonfatal overdose after prescription of opioids for chronic pain: a systematic review and meta-analysis of observational studies.

Background: Higher doses of opioids, mental health comorbidities, co-prescription of sedatives, lower socioeconomic status and a history of opioid overdose have been reported as risk factors for opioid overdose; however, the magnitude of these associations and their credibility are unclear. We sought to identify predictors of fatal and nonfatal overdose from prescription opioids.

Methods: We systematically searched MEDLINE, Embase, CINAHL, PsycINFO and Web of Science up to Oct.

Long-term and serious harms of medical cannabis and cannabinoids for chronic pain: a systematic review of non-randomised studies.

Objective: To establish the prevalence of long-term and serious harms of medical cannabis for chronic pain.

Design: Systematic review and meta-analysis.

Data Sources: MEDLINE, EMBASE, PsycINFO and CENTRAL from inception to 1 April 2020.

Comparative benefits and harms of individual opioids for chronic non-cancer pain: a systematic review and network meta-analysis of randomised trials.

Background: Most systematic reviews of opioids for chronic pain have pooled treatment effects across individual opioids under the assumption they provide similar benefits and harms. We examined the comparative effects of individual opioids for chronic non-cancer pain through a network meta-analysis of randomised controlled trials.

Methods: We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials to March 2021 for studies that enrolled patients with chronic non-cancer pain, randomised them to receive different opioids, or opioids vs placebo, and followed them for at least 4 weeks.

Reporting quality of clinical trial protocols: a repeated cross-sectional study about the Adherence to SPIrit Recommendations in Switzerland, CAnada and GErmany (ASPIRE-SCAGE).

Objectives: Comprehensive protocols are key for the planning and conduct of randomised clinical trials (RCTs). Evidence of low reporting quality of RCT protocols led to the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist in 2013. We aimed to examine the quality of reporting of RCT protocols from three countries before and after the publication of the SPIRIT checklist.

Nonregistration, discontinuation, and nonpublication of randomized trials: A repeated metaresearch analysis.

Background: We previously found that 25% of 1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up. We aimed to assess a decade later (1) whether rates of completion and publication have increased; (2) the extent to which nonpublished RCTs can be identified in trial registries; and (3) the association between reporting quality of protocols and premature discontinuation or nonpublication of RCTs.

Methods And Findings: We included 326 RCT protocols approved in 2012 by research ethics committees in Switzerland, the United Kingdom, Germany, and Canada in this metaresearch study.

Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials.

Objective: To determine the benefits and harms of medical cannabis and cannabinoids for chronic pain.

Design: Systematic review and meta-analysis.

Data Sources: MEDLINE, EMBASE, AMED, PsycInfo, CENTRAL, CINAHL, PubMed, Web of Science, Cannabis-Med, Epistemonikos, and trial registries up to January 2021.

Reporting quality of trial protocols improved for non-regulated interventions but not regulated interventions: A repeated cross-sectional study.

Objectives: To investigate the adherence of randomised controlled trial (RCT) protocols evaluating non-regulated interventions (including dietary interventions, surgical procedures, behavioural and lifestyle interventions, and exercise programmes) in comparison with regulated interventions to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement.

Methods: We conducted a repeated cross-sectional investigation in a random sample of RCT protocols approved in 2012 (n = 257) or 2016 (n = 292) by research ethics committees in Switzerland, Germany, or Canada. We investigated the proportion of accurately reported SPIRIT checklist items in protocols of trials with non-regulated as compared to regulated interventions.

Rationale and design of repeated cross-sectional studies to evaluate the reporting quality of trial protocols: the Adherence to SPIrit REcommendations (ASPIRE) study and associated projects.

Background: Clearly structured and comprehensive protocols are an essential component to ensure safety of participants, data validity, successful conduct, and credibility of results of randomized clinical trials (RCTs). Funding agencies, research ethics committees (RECs), regulatory agencies, medical journals, systematic reviewers, and other stakeholders rely on protocols to appraise the conduct and reporting of RCTs. In response to evidence of poor protocol quality, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline was published in 2013 to improve the accuracy and completeness of clinical trial protocols.

Genome-wide transposon mutagenesis of paramyxoviruses reveals constraints on genomic plasticity.

The antigenic and genomic stability of paramyxoviruses remains a mystery. Here, we evaluate the genetic plasticity of Sendai virus (SeV) and mumps virus (MuV), sialic acid-using paramyxoviruses that infect mammals from two Paramyxoviridae subfamilies (Orthoparamyxovirinae and Rubulavirinae). We performed saturating whole-genome transposon insertional mutagenesis, and identified important commonalities: disordered regions in the N and P genes near the 3' genomic end were more tolerant to insertional disruptions; but the envelope glycoproteins were not, highlighting structural constraints that contribute to the restricted antigenic drift in paramyxoviruses.

Management of Acute Pain From Non-Low Back, Musculoskeletal Injuries : A Systematic Review and Network Meta-analysis of Randomized Trials.

Background: Patients and clinicians can choose from several treatment options to address acute pain from non-low back, musculoskeletal injuries.

Purpose: To assess the comparative effectiveness of outpatient treatments for acute pain from non-low back, musculoskeletal injuries by performing a network meta-analysis of randomized clinical trials (RCTs).

Data Sources: MEDLINE, EMBASE, CINAHL, PEDro (Physiotherapy Evidence Database), and Cochrane Central Register of Controlled Trials to 2 January 2020.

Systematic review of patient-oriented interventions to reduce unnecessary use of antibiotics for upper respiratory tract infections.

Background: Antibiotics are prescribed frequently for upper respiratory tract infections (URTIs) even though most URTIs do not require antibiotics. This over-prescription contributes to antibiotic resistance which is a major health problem globally. As physicians' prescribing behaviour is influenced by patients' expectations, there may be some opportunities to reduce antibiotic prescribing using patient-oriented interventions.

Long-term outcomes in syncope patients presenting to the emergency department: A systematic review.

Introduction: Long-term outcomes among syncope patients are not well studied to guide physicians regarding outpatient testing and follow-up. The objective of this study was to conduct a systematic review for outcomes at 1-year or later among ED syncope patients.

Methods: We searched Cochrane Central, Medline, Medline in Process, PubMed, Embase, and the Cumulative Index to Nursing databases from inception to December 2018.

Reporting preclinical anesthesia study (REPEAT): Evaluating the quality of reporting in the preclinical anesthesiology literature.

Poor reporting quality may contribute to irreproducibility of results and failed 'bench-to-bedside' translation. Consequently, guidelines have been developed to improve the complete and transparent reporting of in vivo preclinical studies. To examine the impact of such guidelines on core methodological and analytical reporting items in the preclinical anesthesiology literature, we sampled a cohort of studies.

Management of acute musculoskeletal pain (excluding low back pain): protocol for a systematic review and network meta-analysis of randomised trials.

Introduction: Acute, non-low back-related musculoskeletal pain is common and associated with significant socioeconomic costs. No review has evaluated all interventional studies for acute musculoskeletal pain, which limits attempts to make inferences regarding the relative effectiveness of treatments.

Methods And Analysis: We will conduct a systematic review of all randomised controlled trials evaluating therapies for acute musculoskeletal pain (excluding low back pain).

Opioids for Chronic Noncancer Pain: A Systematic Review and Meta-analysis.

Importance: Harms and benefits of opioids for chronic noncancer pain remain unclear.

Objective: To systematically review randomized clinical trials (RCTs) of opioids for chronic noncancer pain.

Data Sources And Study Selection: The databases of CENTRAL, CINAHL, EMBASE, MEDLINE, AMED, and PsycINFO were searched from inception to April 2018 for RCTs of opioids for chronic noncancer pain vs any nonopioid control.

Evaluating Progression-Free Survival as a Surrogate Outcome for Health-Related Quality of Life in Oncology: A Systematic Review and Quantitative Analysis.

Importance: Progression-free survival (PFS) has become a commonly used outcome to assess the efficacy of new cancer drugs. However, it is not clear if delay in progression leads to improved quality of life with or without overall survival benefit.

Objective: To evaluate the association between PFS and health-related quality of life (HRQoL) in oncology through a systematic review and quantitative analysis of published randomized clinical trials.

IL-15 regulates susceptibility of CD4 T cells to HIV infection.

HIV integrates into the host genome to create a persistent viral reservoir. Stimulation of CD4 memory T lymphocytes with common γc-chain cytokines renders these cells more susceptible to HIV infection, making them a key component of the reservoir itself. IL-15 is up-regulated during primary HIV infection, a time when the HIV reservoir established.

Idiosyncratic Mòjiāng virus attachment glycoprotein directs a host-cell entry pathway distinct from genetically related henipaviruses.

In 2012, cases of lethal pneumonia among Chinese miners prompted the isolation of a rat-borne henipavirus (HNV), Mòjiāng virus (MojV). Although MojV is genetically related to highly pathogenic bat-borne henipaviruses, the absence of a conserved ephrin receptor-binding motif in the MojV attachment glycoprotein (MojV-G) indicates a differing host-cell recognition mechanism. Here we find that MojV-G displays a six-bladed β-propeller fold bearing limited similarity to known paramyxoviral attachment glycoproteins, in particular at host receptor-binding surfaces.

Reporting of imaging diagnostic accuracy studies with focus on MRI subgroup: Adherence to STARD 2015.

Purpose: To evaluate adherence of diagnostic accuracy studies in imaging journals to the STAndards for Reporting of Diagnostic accuracy studies (STARD) 2015. The secondary objective was to identify differences in reporting for magnetic resonance imaging (MRI) studies.

Materials And Methods: MEDLINE was searched for diagnostic accuracy studies published in imaging journals in 2016.

Efficient and Robust Reverse Genetics Systems.

The notoriously low efficiency of reverse genetics systems has posed a limiting barrier to the study of viruses in this family. Previous approaches to reverse genetics have utilized a wide variety of techniques to overcome the technical hurdles. Although robustness (i.