A pre-specified statistical analysis plan for the VERIFY study : Vildagliptin efficacy in combination with metformin for early treatment of T2DM

Aims To ensure the integrity of the planned analyses and maximize the clinical utility of the VERIFY study results by describing the detailed concepts behind its statistical analysis plan (SAP) before completion of data collection and study database lock. The SAP will be adhered to for the final primary data analysis of the VERIFY trial. Materials and Methods Vildagliptin efficacy in combination with metformin for early treatment of T2DM (VERIFY) is an ongoing, multicentre, randomized controlled trial aiming to demonstrate the clinical benefits of glycaemic durability and glucose control achieved with an early combination therapy in newly-diagnosed type 2 diabetes (T2DM) patients. Results The SAP was initially designed at the study protocol conception phase and later modified, as reported here, in collaboration between the steering committee members, statisticians, and the VERIFY study leadership team. All authors were blinded to treatment allocation. An independent statistician has additionally retrieved and presented unblinded data to the independent data safety monitoring committee. An overview of the trial design with a focus on describing the fine-tuning of the analysis plan for the primary efficacy endpoint, risk of initial treatment failure, and secondary, exploratory and pre-specified subgroup analyses is provided here. Conclusion According to optimal trial practice, the details of the statistical analysis and data-handling plan prior to locking the database are reported here. The SAP accords with high-quality standards of internal validity to minimize analysis bias and will enhance the utility of the reported results for improved outcomes in the management of T2DM.Peer reviewe

Pediatric home mechanical ventilation: A Canadian Thoracic Society clinical practice guideline executive summary

Over the last 30 to 40 years, improvements in technology, as well as changing clinical practice regarding the appropriateness of long-term ventilation in patients with “non-curable” disorders, have resulted in increasing numbers of children surviving what were previously considered fatal conditions. This has come but at the expense of requiring ongoing, long-term prolonged mechanical ventilation (both invasive and noninvasive). Although there are many publications pertaining to specific aspects of home mechanical ventilation (HMV) in children, there are few comprehensive guidelines that bring together all of the current literature. In 2011 the Canadian Thoracic Society HMV Guideline Committee published a review of the available English literature on topics related to HMV in adults, and completed a detailed guideline that will help standardize and improve the assessment and management of individuals requiring noninvasive or invasive HMV. This current document is intended to be a companion to the 2011 guidelines, concentrating on the issues that are either unique to children on HMV (individuals under 18 years of age), or where common pediatric practice diverges significantly from that employed in adults on long-term home ventilation. As with the adult guidelines,1 this document provides a disease-specific review of illnesses associated with the necessity for long-term ventilation in children, including children with chronic lung disease, spinal muscle atrophy, muscular dystrophies, kyphoscoliosis, obesity hypoventilation syndrome, and central hypoventilation syndromes. It also covers important common themes such as airway clearance, the ethics of initiation of long-term ventilation in individuals unable to give consent, the process of transition to home and to adult centers, and the impact, both financial, as well as social, that this may have on the child\u27s families and caregivers. The guidelines have been extensively reviewed by international experts, allied health professionals and target audiences. They will be updated on a regular basis to incorporate any new information

Complex exon-intron marking by histone modifications is not determined solely by nucleosome distribution

It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons (“exon-intron marking”), linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing

Clinical utility of and correlation between Sniffin' Sticks and TIB smell identification test (TIBSIT) among Hong Kong Chinese with or without chronic rhinosinusitis

IntroductionOlfactory dysfunction (OD) is common among patients with chronic rhinosinusitis (CRS). Validated and culturally specific tests, such as the “Sniffin’ Sticks” test (SST) and the TIB Smell Identification Test (TIBSIT), are crucial for the diagnosis and monitoring of OD. However, they have not been utilised in Hong Kong Chinese and their correlations are unknown.MethodsTwelve CRS patients and twenty healthy volunteers were prospectively recruited from a joint allergy-otorhinolaryngology clinic in Hong Kong and performed both SST and TIBSIT. Demographics, baseline characteristics and all test results were compared and analysed.ResultsPatients with CRS demonstrated significantly lower test scores than healthy controls (all p < 0.001). Significant and strong correlations were observed between all composite and subtest scores, particularly between the composite SST and TIBSIT scores (ρ = 0.789, p < 0.001). Multivariate analysis demonstrated that the presence of CRS and increasing age were significantly associated with OD.ConclusionBoth SST and TIBSIT are useful olfactory tests and are strongly correlated among Hong Kong Chinese. We advocate that either test can be used for measuring OD among CRS patients

The United States COVID-19 Forecast Hub dataset

Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Respiratory Care Considerations for Children with Medical Complexity

Children with medical complexity (CMC) are a growing population of diagnostically heterogeneous children characterized by chronic conditions affecting multiple organ systems, the use of medical technology at home as well as intensive healthcare service utilization. Many of these children will experience either a respiratory-related complication and/or they will become established on respiratory technology at home during their care trajectory. Therefore, healthcare providers need to be familiar with the respiratory related complications commonly experienced by CMC as well as the indications, technical and safety considerations and potential complications that may arise when caring for CMC using respiratory technology at home. This review will outline the most common respiratory disease manifestations experienced by CMC, and discuss various respiratory-related treatment options that can be considered, including tracheostomy, invasive and non-invasive ventilation, as well as airway clearance techniques. The caregiver requirements associated with caring for CMC using respiratory technology at home will also be reviewed

Respiratory Care Considerations for Children with Medical Complexity

Children with medical complexity (CMC) are a growing population of diagnostically heterogeneous children characterized by chronic conditions affecting multiple organ systems, the use of medical technology at home as well as intensive healthcare service utilization. Many of these children will experience either a respiratory-related complication and/or they will become established on respiratory technology at home during their care trajectory. Therefore, healthcare providers need to be familiar with the respiratory related complications commonly experienced by CMC as well as the indications, technical and safety considerations and potential complications that may arise when caring for CMC using respiratory technology at home. This review will outline the most common respiratory disease manifestations experienced by CMC, and discuss various respiratory-related treatment options that can be considered, including tracheostomy, invasive and non-invasive ventilation, as well as airway clearance techniques. The caregiver requirements associated with caring for CMC using respiratory technology at home will also be reviewed

Respiratory Diagnostic Tools in Neuromuscular Disease

Children with neuromuscular disease (NMD) are at risk of acquiring respiratory complications. Both clinical assessments and respiratory diagnostic tests are important to optimize the respiratory health and care of such children. The following respiratory diagnostic tools and their utility for evaluating children with NMD are discussed in this article: lung function testing (spirometry and lung volumes), peak cough flow (PCF), respiratory muscle strength testing, oximetry, capnography, and polysomnography

Understanding patients' views and willingness toward the use of telehealth in a cancer genetics service in Asia

Telehealth is a growing field, its pertinence magnified by COVID-19 causing the accelerated digitalization of the world. Given the significant global demand to provide telehealth services, it is important to explore patient receptiveness toward this alternative service model, particularly from regions where it has yet to be implemented. We conducted a cross-sectional study to understand the views and willingness of patients toward the use of telehealth for cancer genetic counseling. A survey was completed by 160 patients of the National Cancer Centre Singapore, and descriptive statistics were used to analyze the data. The study found that 95.6% (n = 153/160) of participants did not have prior telehealth experience. Most participants were willing or neutral toward having genetic counseling by phone (n = 114/160, 71.3%) and video (n = 106/160, 66.3%). However, majority prefer in-person appointments for first (n = 127/160, 79.4%) and follow-up (n = 97/160, 60.6%) visits over telehealth. Majority agreed that a phone/video consultation would meet most of their needs but voiced concerns regarding privacy and sharing of information (n = 79/160, 49.4% for phone; n = 74/160, 46.3% for video) and whether their emotional needs could be met (n = 61/160, 38.1%). Participants' age, employment status, income, mode of transportation to the appointment, and whether special arrangements were made to attend the in-person appointment were associated with receptivity to telehealth genetic counseling (p ≤ .05 for all). This study adds diversity to existing literature and demonstrates that patients from Asia are generally willing and accepting of the use of telehealth in a cancer genetics service. This will help meet increasing global demand of telehealth consultations in the post-pandemic new norm. Furthermore, it will also provide services for underserved populations and patients requiring urgent testing in a timely manner. Further studies are needed to explore the cost-effectiveness and fair billing methods, as well as willingness and acceptability of telehealth genetic counseling in post-COVID times.National Medical Research Council (NMRC)This work was supported by National Medical Research Council (NMRC)