The Ottawa Statement implementation guidance document for cluster randomized trials in the hemodialysis setting.

Research teams are increasingly interested in using cluster randomized trial (CRT) designs to generate practice-guiding evidence for in-center maintenance hemodialysis. However, CRTs raise complex ethical issues. The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials, published in 2012, provides 15 recommendations to address ethical issues arising within 7 domains: justifying the CRT design, research ethics committee review, identifying research participants, obtaining informed consent, gatekeepers, assessing benefits and harms, and protecting vulnerable participants. But applying the Ottawa Statement recommendations to CRTs in the hemodialysis setting is complicated by the unique features of the setting and population. Here, with the help of content experts and patient partners, we co-developed this implementation guidance document to provide research teams, research ethics committees, and other stakeholders with detailed guidance on how to apply the Ottawa Statement recommendations to CRTs in the hemodialysis setting, the result of a 4-year research project. Thus, our work demonstrates how the voices of patients, caregivers, and all stakeholders may be included in the development of research ethics guidance.

Phospholipase D1 Attenuation Therapeutics Promotes Resilience against Synaptotoxicity in 12-Month-Old 3xTg-AD Mouse Model of Progressive Neurodegeneration.

Abrogating synaptotoxicity in age-related neurodegenerative disorders is an extremely promising area of research with significant neurotherapeutic implications in tauopathies including Alzheimer's disease (AD). Our studies using human clinical samples and mouse models demonstrated that aberrantly elevated phospholipase D1 (PLD1) is associated with amyloid beta (Aß) and tau-driven synaptic dysfunction and underlying memory deficits. While knocking out the lipolytic PLD1 gene is not detrimental to survival across species, elevated expression is implicated in cancer, cardiovascular conditions and neuropathologies, leading to the successful development of well-tolerated mammalian PLD isoform-specific small molecule inhibitors. Here, we address the importance of PLD1 attenuation, achieved using repeated 1 mg/kg of VU0155069 (VU01) intraperitoneally every alternate day for a month in 3xTg-AD mice beginning only from ~11 months of age (with greater influence of tau-driven insults) compared to age-matched vehicle (0.9% saline)-injected siblings. A multimodal approach involving behavior, electrophysiology and biochemistry corroborate the impact of this pre-clinical therapeutic intervention. VU01 proved efficacious in preventing in later stage AD-like cognitive decline affecting perirhinal cortex-, hippocampal- and amygdala-dependent behaviors. Glutamate-dependent HFS-LTP and LFS-LTD improved. Dendritic spine morphology showed the preservation of mushroom and filamentous spine characteristics. Differential PLD1 immunofluorescence and co-localization with Aß were noted.

Germline specification and axis determination in viviparous and oviparous pea aphids: conserved and divergent features.

Aphids are hemimetabolous insects that undergo incomplete metamorphosis without pupation. The annual life cycle of most aphids includes both an asexual (viviparous) and a sexual (oviparous) phase. Sexual reproduction only occurs once per year and is followed by many generations of asexual reproduction, during which aphids propagate exponentially with telescopic development. Here, we discuss the potential links between viviparous embryogenesis and derived developmental features in the pea aphid Acyrthosiphon pisum, particularly focusing on germline specification and axis determination, both of which are key events of early development in insects. We also discuss potential evolutionary paths through which both viviparous and oviparous females might have come to utilize maternal germ plasm to drive germline specification. This developmental strategy, as defined by germline markers, has not been reported in other hemimetabolous insects. In viviparous females, furthermore, we discuss whether molecules that in other insects characterize germ plasm, like Vasa, also participate in posterior determination and how the anterior localization of the hunchback orthologue Ap-hb establishes the anterior-posterior axis. We propose that the linked chain of developing oocytes and embryos within each ovariole and the special morphology of early embryos might have driven the formation of evolutionary novelties in germline specification and axis determination in the viviparous aphids. Moreover, based upon the finding that the endosymbiont Buchnera aphidicola is closely associated with germ cells throughout embryogenesis, we propose presumptive roles for B. aphidicola in aphid development, discussing how it might regulate germline migration in both reproductive modes of pea aphids. In summary, we expect that this review will shed light on viviparous as well as oviparous development in aphids.

Comparing Clinician Consensus Recommendations to Patient-reported Opioid Use Across Multiple Hospital Systems.

OBJECTIVE: We compare consensus recommendations for 5 surgical procedures to prospectively collected patient consumption data. To address local variation, we combined data from multiple hospitals across the country. SUMMARY OF BACKGROUND DATA: One approach to address the opioid epidemic has been to create prescribing consensus reports for common surgical procedures. However, it is unclear how these guidelines compare to patient-reported data from multiple hospital systems. METHODS: Prospective observational studies of surgery patients were completed between 3/2017 and 12/2018. Data were collected utilizing post-discharge surveys and chart reviews from 5 hospitals (representing 3 hospital systems) in 5 states across the USA. Prescribing recommendations for 5 common surgical procedures identified in 2 recent consensus reports were compared to the prospectively collected aggregated data. Surgeries included: laparoscopic cholecystectomy, open inguinal hernia repair, laparoscopic inguinal hernia repair, partial mastectomy without sentinel lymph node biopsy, and partial mastectomy with sentinel lymph node biopsy. RESULTS: Eight hundred forty-seven opioid-naïve patients who underwent 1 of the 5 studied procedures reported counts of unused opioid pills after discharge. Forty-one percent did not take any opioid medications, and across all surgeries, the median consumption was 3 5 mg oxycodone pills or less. Generally, consensus reports recommended opioid quantities that were greater than the 75th percentile of consumption, and for 2 procedures, recommendations exceeded the 90th percentile of consumption. CONCLUSIONS: Although consensus recommendations were an important first step to address opioid prescribing, our data suggests that following these recommendations would result in 47%-56% of pills prescribed remaining unused. Future multi-institutional efforts should be directed toward refining and personalizing prescribing recommendations.

Addressing feasibility challenges to delivering intradialytic exercise interventions: a theory-informed qualitative study.

BACKGROUND: Intradialytic exercise (IDE) may improve physical function and health-related quality of life. However, incorporating IDE into standard hemodialysis care has been slow due to feasibility challenges. We conducted a multicenter qualitative feasibility study to identify potential barriers and enablers to IDE and generate potential solutions to these factors. METHODS: We conducted 43 semistructured interviews with healthcare providers and patients across 12 hospitals in Ontario, Canada. We used the Theoretical Domains Framework and directed content analysis to analyze the data. RESULTS: We identified eight relevant domains (knowledge, skills, beliefs about consequences, beliefs about capabilities, environmental context and resources, goals, social/professional role and identity, and social influences) represented by three overarching categories: knowledge, skills and expectations: lack of staff expertise to oversee exercise, uncertainty regarding exercise risks, benefits and patient interest, lack of knowledge regarding exercise eligibility; human, material and logistical resources: staff concerns regarding workload, perception that exercise professionals should supervise IDE, space, equipment and scheduling conflict concerns; and social dynamics of the unit: local champions and patient stories contribute to IDE sustainability. We developed a list of actionable solutions by mapping barriers and enablers to behavior change techniques. We also developed a feasibility checklist of 47 questions identifying key factors to address prior to IDE launch. CONCLUSIONS: Evidence-based solutions to identified barriers to and enablers of IDE and a feasibility checklist may help recruit and support units, staff and patients and address key challenges to the delivery of IDE in diverse clinical and research settings.

The European Bioinformatics Institute in 2020: building a global infrastructure of interconnected data resources for the life sciences.

Data resources at the European Bioinformatics Institute (EMBL-EBI, https://www.ebi.ac.uk/) archive, organize and provide added-value analysis of research data produced around the world. This year's update for EMBL-EBI focuses on data exchanges among resources, both within the institute and with a wider global infrastructure. Within EMBL-EBI, data resources exchange data through a rich network of data flows mediated by automated systems. This network ensures that users are served with as much information as possible from any search and any starting point within EMBL-EBI's websites. EMBL-EBI data resources also exchange data with hundreds of other data resources worldwide and collectively are a key component of a global infrastructure of interconnected life sciences data resources. We also describe the BioImage Archive, a deposition database for raw images derived from primary research that will supply data for future knowledgebases that will add value through curation of primary image data. We also report a new release of the PRIDE database with an improved technical infrastructure, a new API, a new webpage, and improved data exchange with UniProt and Expression Atlas. Training is a core mission of EMBL-EBI and in 2018 our training team served more users, both in-person and through web-based programmes, than ever before.

The ELIXIR Core Data Resources: fundamental infrastructure for the life sciences.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The European Bioinformatics Institute in 2018: tools, infrastructure and training.

The European Bioinformatics Institute (https://www.ebi.ac.uk/) archives, curates and analyses life sciences data produced by researchers throughout the world, and makes these data available for re-use globally (https://www.ebi.ac.uk/). Data volumes continue to grow exponentially: total raw storage capacity now exceeds 160 petabytes, and we manage these increasing data flows while maintaining the quality of our services. This year we have improved the efficiency of our computational infrastructure and doubled the bandwidth of our connection to the worldwide web. We report two new data resources, the Single Cell Expression Atlas (https://www.ebi.ac.uk/gxa/sc/), which is a component of the Expression Atlas; and the PDBe-Knowledgebase (https://www.ebi.ac.uk/pdbe/pdbe-kb), which collates functional annotations and predictions for structure data in the Protein Data Bank. Additionally, Europe PMC (http://europepmc.org/) has added preprint abstracts to its search results, supplementing results from peer-reviewed publications. EMBL-EBI maintains over 150 analytical bioinformatics tools that complement our data resources. We make these tools available for users through a web interface as well as programmatically using application programming interfaces, whilst ensuring the latest versions are available for our users. Our training team, with support from all of our staff, continued to provide on-site, off-site and web-based training opportunities for thousands of researchers worldwide this year.

Perioperative Considerations for Tracheostomies in the Era of COVID-19.

The morbidity, mortality, and blistering pace of transmission of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented worldwide health crisis. Coronavirus disease 2019 (COVID-19), the disease produced by SARS-CoV-2 infection, is remarkable for persistent, severe respiratory failure requiring mechanical ventilation that places considerable strain on critical care resources. Because recovery from COVID-19-associated respiratory failure can be prolonged, tracheostomy may facilitate patient management and optimize the use of mechanical ventilators. Several important considerations apply to plan tracheostomies for COVID-19-infected patients. After performing a literature review of tracheostomies during the severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks, we synthesized important learning points from these experiences and suggested an approach for perioperative teams involved in these procedures during the COVID-19 pandemic. Multidisciplinary teams should be involved in decisions regarding timing and appropriateness of the procedure. As the theoretical risk of disease transmission is increased during aerosol-generating procedures (AGPs), stringent infectious precautions are warranted. Personal protective equipment (PPE) should be available and worn by all personnel present during tracheostomy. The number of people in the room should be limited to those absolutely necessary. Using the most experienced available operators will minimize the total time that staff is exposed to an infectious aerosolized environment. An approach that secures the airway in the safest and quickest manner will minimize the time any part of the airway is open to the environment. Deep neuromuscular blockade (train-of-four ratio = 0) will facilitate surgical exposure and prevent aerosolization due to patient movement or coughing. For percutaneous tracheostomies, the bronchoscopist should be able to reintubate if needed. Closed-loop communication must occur at all times among members of the team. If possible, after tracheostomy is performed, waiting until the patient is virus-free before changing the cannula or downsizing may reduce the chances of health care worker infection. Tracheostomies in COVID-19 patients present themselves as extremely high risk for all members of the procedural team. To mitigate risk, systematic meticulous planning of each procedural step is warranted along with strict adherence to local/institutional protocols.

The European Bioinformatics Institute in 2017: data coordination and integration.

The European Bioinformatics Institute (EMBL-EBI) supports life-science research throughout the world by providing open data, open-source software and analytical tools, and technical infrastructure (https://www.ebi.ac.uk). We accommodate an increasingly diverse range of data types and integrate them, so that biologists in all disciplines can explore life in ever-increasing detail. We maintain over 40 data resources, many of which are run collaboratively with partners in 16 countries (https://www.ebi.ac.uk/services). Submissions continue to increase exponentially: our data storage has doubled in less than two years to 120 petabytes. Recent advances in cellular imaging and single-cell sequencing techniques are generating a vast amount of high-dimensional data, bringing to light new cell types and new perspectives on anatomy. Accordingly, one of our main focus areas is integrating high-quality information from bioimaging, biobanking and other types of molecular data. This is reflected in our deep involvement in Open Targets, stewarding of plant phenotyping standards (MIAPPE) and partnership in the Human Cell Atlas data coordination platform, as well as the 2017 launch of the Omics Discovery Index. This update gives a birds-eye view of EMBL-EBI's approach to data integration and service development as genomics begins to enter the clinic.

Ethical Issues in Pragmatic Cluster-Randomized Trials in Dialysis Facilities.

A pragmatic cluster-randomized trial (CRT) is a research design that may be used to efficiently test promising interventions that directly inform dialysis care. While the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials provides general ethical guidance for CRTs, the dialysis setting raises additional considerations. In this article, we outline ethical issues raised by pragmatic CRTs in dialysis facilities. These issues may be divided into 7 key domains: justifying the use of cluster randomization, adopting randomly allocated individual-level interventions as a facility standard of care, conducting benefit-harm analyses, gatekeepers and their responsibilities, obtaining informed consent from research participants, patient notification, and including vulnerable participants. We describe existing guidelines relevant to each domain, illustrate how they were considered in the Time to Reduce Mortality in End-Stage Renal Disease (TiME) trial (a prototypical pragmatic hemodialysis CRT), and highlight remaining areas of uncertainty. The following is the first step in an interdisciplinary mixed-methods research project to guide the design and conduct of pragmatic CRTs in dialysis facilities. Subsequent work will expand on these concepts and when possible, argue for a preferred solution.

Cytomegalovirus immunoglobulin G titers do not predict reactivation risk in immunocompetent hosts.

Cytomegalovirus (CMV) reactivation occurs in roughly one-third of immunocompetent patients during critical illness, and is associated with worse outcomes. These outcomes have prompted consideration of early antiviral prophylaxis, but two-third of patients would receive unnecessary treatment. Tissue viral load has been associated with risk of reactivation in murine models, and recent work has suggested a relationship between immune responses to CMV and underlying viral load. We, therefore, sought to confirm the hypothesis that serum CMV-specific immunoglobulin G (IgG) correlates with tissue viral load, and might be used to predict the risk of reactivation during critical illness. We confirm that there is a good correlation between tissue viral load and serum CMV-specific IgG after laboratory infection of inbred mice. Further, we show that naturally infected outbred hosts have variable tissue viral DNA loads that do not correlate well with serum IgG. Perhaps as a consequence, CMV-specific IgG was not predictive of reactivation events in immunocompetent humans. When reactivation did occur, those with the lowest IgG levels had longer durations of reactivation, but IgG quartiles were not associated with differing peak DNAemia. Together our data suggest that CMV-specific IgG titers diverge from tissue viral loads in outbred immunocompetent hosts, and their importance for the control of reactivation events remains unclear.

Impact of cytomegalovirus load on host response to sepsis.

There is a decades old association between cytomegalovirus reactivation and sepsis in immune-competent hosts. Much has been learned about this relationship, which has been described as bidirectional, meaning that the virus incites and is incited by the host's inflammatory response. More recent work has suggested that chronic viral infection leaves the host with exaggerated immunity to bacterial infections. In this review, the relationship between CMV and host responses to sepsis are reviewed, with particular attention to the impact that tissue viral load contributes to this phenomenon.

Case Study: Fatal Exertional Rhabdomyolysis Possibly Related to Drastic Weight Cutting.

Rapid weight loss or "weight cutting" is a dangerous practice that is ubiquitous in modern combat sports yet underrepresented in the medical literature. We present a case of exertional rhabdomyolysis in a mixed martial artist with sickle cell trait to illustrate the hazards of weight cutting and ensuing critical illness. Sickle cell trait is known to predispose patients to exertional rhabdomyolysis, and multiple fatal cases have been reported in the setting of strenuous exercise. Dehydration and consequent electrolyte abnormalities make combat sport athletes with sickle cell trait particularly vulnerable to this entity. This case suggests a potential role for sickle cell trait screening in this population and underscores the need for safer weight-control practices and monitoring among all combat sport athletes.

Implementation of a Physician-Patient Attachment Initiative in Alberta.

Attachment to a primary care physician (PCP) is a foundational component of the Patient's Medical Home. Yet how can attachment exist in a system that does not limit where patients seek care? This article describes a top-down approach with the ideologies of a bottom-up collaborative to address attachment within an Alberta primary care network. The steps taken to reduce the number of patients listed on multiple PCP panels from 27% to 4% will be described. Learnings from this initiative suggest that direct involvement with providers, coupled with engaged physician leadership, can create a local system of information delivery that supports the attachment of patients to their most responsible PCP.

Trial of short-course antimicrobial therapy for intraabdominal infection.

BACKGROUND: The successful treatment of intraabdominal infection requires a combination of anatomical source control and antibiotics. The appropriate duration of antimicrobial therapy remains unclear. METHODS: We randomly assigned 518 patients with complicated intraabdominal infection and adequate source control to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy (control group), or to receive a fixed course of antibiotics (experimental group) for 4±1 calendar days. The primary outcome was a composite of surgical-site infection, recurrent intraabdominal infection, or death within 30 days after the index source-control procedure, according to treatment group. Secondary outcomes included the duration of therapy and rates of subsequent infections. RESULTS: Surgical-site infection, recurrent intraabdominal infection, or death occurred in 56 of 257 patients in the experimental group (21.8%), as compared with 58 of 260 patients in the control group (22.3%) (absolute difference, -0.5 percentage point; 95% confidence interval [CI], -7.0 to 8.0; P=0.92). The median duration of antibiotic therapy was 4.0 days (interquartile range, 4.0 to 5.0) in the experimental group, as compared with 8.0 days (interquartile range, 5.0 to 10.0) in the control group (absolute difference, -4.0 days; 95% CI, -4.7 to -3.3; P<0.001). No significant between-group differences were found in the individual rates of the components of the primary outcome or in other secondary outcomes. CONCLUSIONS: In patients with intraabdominal infections who had undergone an adequate source-control procedure, the outcomes after fixed-duration antibiotic therapy (approximately 4 days) were similar to those after a longer course of antibiotics (approximately 8 days) that extended until after the resolution of physiological abnormalities. (Funded by the National Institutes of Health; STOP-IT ClinicalTrials.gov number, NCT00657566.).

The European Bioinformatics Institute in 2016: Data growth and integration.

New technologies are revolutionising biological research and its applications by making it easier and cheaper to generate ever-greater volumes and types of data. In response, the services and infrastructure of the European Bioinformatics Institute (EMBL-EBI, www.ebi.ac.uk) are continually expanding: total disk capacity increases significantly every year to keep pace with demand (75 petabytes as of December 2015), and interoperability between resources remains a strategic priority. Since 2014 we have launched two new resources: the European Variation Archive for genetic variation data and EMPIAR for two-dimensional electron microscopy data, as well as a Resource Description Framework platform. We also launched the Embassy Cloud service, which allows users to run large analyses in a virtual environment next to EMBL-EBI's vast public data resources.

Novel Method Suggests Global Superiority of Short-Duration Antibiotics for Intra-abdominal Infections.

Desirability of outcome ranking and response adjusted for duration of antibiotic risk (DOOR/RADAR) are novel and innovative methods of evaluating data in antibiotic trials. We analyzed data from a noninferiority trial of short-course antimicrobial therapy for intra-abdominal infection (STOP-IT), and results suggest global superiority of short-duration therapy for intra-abdominal infections.

Species-level identification of the blowfly Chrysomya megacephala and other Diptera in China by DNA barcoding.

The blowfly Chrysomya megacephala, or oriental latrine fly, is the most common human-associated fly of the oriental and Australasian regions. Chrysomya megacephala is of particular interest for its use in forensic entomology and because it is a disease vector. The larvae are economically important as feed for livestock and in traditional Chinese medicine. Identification of adults is straightforward, but larvae and fragments of adults are difficult to identify. We collected C. megacephala, its allies Chrysomya pinguis and Protophormia terraenovae, as well as flies from 11 other species from 52 locations around China, then sequenced 658 base pairs of the COI barcode region from 645 flies of all 14 species, including 208 C. megacephala, as the basis of a COI barcode library for flies in China. While C. megacephala and its closest relative C. pinguis are closely related (mean K2P divergence of 0.022), these species are completely non-overlapping in their barcode divergences, thus demonstrating the utility of the COI barcode region for the identification of C. megacephala. We combined the 208 C. megacephala sequences from China with 98 others from public databases and show that worldwide COI barcode diversity is low, with 70% of all individuals belonging to one of three haplotypes that differ by one or two substitutions from each other, reflecting recent anthropogenic dispersal from its native range in Eurasia.

Impact of the NAP-1 strain on disease severity, mortality, and recurrence of healthcare-associated Clostridium difficile infection.

OBJECTIVES: Studies are conflicting regarding the association of the North American pulsed-field gel electrophoresis type 1 (NAP1) strain in Clostridium difficile infection (CDI) and outcomes. We evaluated the association of NAP1 with healthcare-associated CDI disease severity, mortality, and recurrence at our academic medical center. METHODS: Healthcare-associated CDI cases were identified from November 1, 2011 through January 31, 2013. Multivariable regression models were used to evaluate the associations of NAP1 with severe disease (based on the Hines VA severity score index), mortality, and recurrence. RESULTS: Among 5424 stool specimens submitted to the Clinical Microbiology Laboratory, 292 (5.4%) were positive for C. difficile by polymerase chain reaction (PCR) on or after hospital day 4; 70 (24%) of these specimens also tested positive for NAP1. During the study period, 247 (85%) patients had non-severe disease and 45 (15%) patients had severe disease. Among patients with non-severe disease, 65 (26%) had NAP1 and among patients with severe disease, 5 (11%) had NAP1. After controlling for potential confounders, NAP1 was not associated with an increased likelihood of severe disease (adjusted odds ratio [aOR] = 0.35; 95% confidence interval [CI], 0.13-0.93), in-hospital mortality (aOR = 1.02; 95% CI, 0.53-1.96), or recurrence (aOR = 1.16, 95% CI, 0.36-3.77). CONCLUSIONS: The NAP1 strain did not increase disease severity, mortality, or recurrence in this study, although the incidence of NAP1-positive healthcare associated-CDI was low. The role of strain typing in outcomes and treatment selection in patients with healthcare-associated CDI remains uncertain.