PERI-operative biologic DMARD management: stoppage or COntinuation during orthoPaEdic operations (the PERISCOPE trial) – a study protocol for a pragmatic, UK multicentre, superiority randomised controlled trial with an internal pilot, economic evaluation and nested qualitative study

Introduction Biological disease-modifying antirheumatic drugs (bDMARDs) have revolutionised the treatment of inflammatory arthritis (IA). However, many people with IA still require planned orthopaedic surgery to reduce pain and improve function. Currently, bDMARDs are withheld during the perioperative period due to potential infection risk. However, this predisposes patients to IA flares and loss of disease control. The question of whether to stop or continue bDMARDs in the perioperative period has not been adequately addressed in a randomised controlled trial (RCT). Methods and analysis PERISCOPE is a multicentre, superiority, pragmatic RCT investigating the stoppage or continuation of bDMARDs. Participants will be assigned 1:1 to either stop or continue their bDMARDs during the perioperative period. We aim to recruit 394 adult participants with IA. Potential participants will be identified in secondary care hospitals in the UK, screened by a delegated clinician. If eligible and consenting, baseline data will be collected and randomisation completed. The primary outcome will be the self-reported PROMIS-29 (Patient Reported Outcome Measurement Information System) over the first 12 weeks postsurgery. Secondary outcome measures are as follows: PROMIS - Health Assessment Questionnaire (PROMIS-HAQ), EQ-5D-5L, Disease activity: generic global Numeric Rating Scale (patient and clinician), Self-Administered Patient Satisfaction scale, Health care resource use and costs, Medication use, Surgical site infection, delayed wound healing, Adverse events (including systemic infections) and disease-specific outcomes (according to IA diagnosis). The costs associated with stopping and continuing bDMARDs will be assessed. A qualitative study will explore the patients’ and clinicians’ acceptability and experience of continuation/stoppage of bDMARDs in the perioperative period and the impact postoperatively

Redundancy and cooperativity in the mechanics of compositely crosslinked filamentous networks

The actin cytoskeleton in living cells has many types of crosslinkers. The mechanical interplay between these different crosslinker types is an open issue in cytoskeletal mechanics. We develop a framework to study the cooperativity and redundancy in the mechanics of filamentous networks with two types of crosslinkers: crosslinkers that allow free rotations of filaments and crosslinkers that do not. The framework consists of numerical simulations and an effective medium theory on a percolating triangular lattice. We find that the introduction of angle-constraining crosslinkers significantly lowers the filament concentrations required for these networks to attain mechanical integrity. This cooperative effect also enhances the stiffness of the network and suppresses non-affine deformations at a fixed filament concentration. We further find that semiflexible networks with only freely-rotating crosslinks are mechanically very similar to compositely crosslinked flexible networks with both networks exhibiting the same scaling behavior. We show that the network mechanics can either be redundant or cooperative depending on the relative energy scale of filament bending to the energy stored in the angle-constraining crosslinkers, and the relative concentration of crosslinkers. Our results may have implications for understanding the role of multiple crosslinkers even in a system without bundle formation or other structural motifs.Comment: 21 pages, 5 figure

A Scoping Review of Home Produced Heroin and Amphetamine Type Stimulant Substitutes: Implications for Prevention, Treatment and Policy

Several home-produced substances such as krokodil and boltushka are prevalent in many Eastern European countries. Anecdotal reports of its use have been circulating in Germany and Norway; however, this has not been confirmed. Its use has also been reported by the media in the USA, although only one confirmed report of its use exists. Home-produced drugs are associated with high levels of morbidity and a number of complex health issues such as the spread of blood borne viruses, gangrene, and internal organ damage. The high incidence of HIV rates amongst people who inject home-produced substances is a public health concern. The resulting physical health consequences of injecting these crude substances are very severe in comparison to heroin or amphetamine acquired in black markets. Due to this fact and the increased mortality associated with these substances, professionals in the area of prevention, treatment, and policy development need to be cognisant of the presentation, harms, and the dangers associated with home-produced substances globally. This scoping review aimed to examine existing literature on the subject of home-produced heroin and amphetamine-type stimulant substitutes. The review discussed the many implications such research may have in the areas of policy and practice. Data were gathered through the use of qualitative secondary resources such as journal articles, reports, reviews, case studies, and media reports. The home production of these substances relies on the utilisation of precursor drugs such as less potent stimulants, tranquillizers, analgesics, and sedatives or natural plant ingredients. The Internet underpins the facilitation of this practice as recipes, and diverted pharmaceutical sales are available widely online, and currently, ease of access to the Internet is evident worldwide. This review highlights the necessity of prevention, education, and also harm reduction related to home-produced drugs and also recommends consistent monitoring of online drug fora, online drug marketplaces, and unregulated pharmacies

An integrated expression atlas of miRNAs and their promoters in human and mouse

MicroRNAs (miRNAs) are short non-coding RNAs with key roles in cellular regulation. As part of the fifth edition of the Functional Annotation of Mammalian Genome (FANTOM5) project, we created an integrated expression atlas of miRNAs and their promoters by deep-sequencing 492 short RNA (sRNA) libraries, with matching Cap Analysis Gene Expression (CAGE) data, from 396 human and 47 mouse RNA samples. Promoters were identified for 1,357 human and 804 mouse miRNAs and showed strong sequence conservation between species. We also found that primary and mature miRNA expression levels were correlated, allowing us to use the primary miRNA measurements as a proxy for mature miRNA levels in a total of 1,829 human and 1,029 mouse CAGE libraries. We thus provide a broad atlas of miRNA expression and promoters in primary mammalian cells, establishing a foundation for detailed analysis of miRNA expression patterns and transcriptional control regions

A valued voice: A qualitative analysis of parental decision‐making preferences in emergent paediatric surgery

Abstract Introduction Shared decision‐making, with an emphasis on patient autonomy, is often advised in healthcare decision‐making. However, this may be difficult to implement in emergent settings. We have previously demonstrated that when considering emergent operations for their children, parents prefer surgeon guidance as opposed to shared decision‐making. Here, we interviewed parents of paediatric patients who had undergone emergent operations to better understand parental decision‐making preferences. Methods Parents of paediatric patients who underwent surgery over the past 5 years at a University‐based, tertiary children's hospital for cancer, an emergent operation while in the neonatal intensive care unit (NICU) or extracorporeal membrane oxygenation (ECMO) were invited to complete a 60‐min semi‐structured interview. Interviews were digitally recorded and transcribed verbatim. Thematic content analysis was performed via deductive and inductive analysis. An iterative approach to thematic sampling/data analysis was used. Results Thematic saturation was achieved after 12 interviews (4 cancer, 5 NICU and 3 ECMO). Five common themes were identified: (1) recommendations from surgeons are valuable; (2) ‘lifesaving mode’: parents felt there were no decisions to be made; (3) effective ways of obtaining information about treatment; (4) shared decision‐making as a ‘dialogue’ or ‘discussion’ and (5) parents as a ‘valued voice’ to advocate for their children. Conclusions When engaging in decision‐making regarding emergent surgical procedures for their children, parents value a surgeon's recommendation. Parents felt that discussion or dialogue with surgeons defined shared decision‐making, and they believed that the opportunity to ask questions gave them a ‘valued voice’, even when they felt there were no decisions to be made. Patient or Public Contribution For this study, we interviewed parents of paediatric patients who had undergone emergent operations to better understand parental decision‐making preferences. Parents thus provided all the data for the study

Can progress in reducing alcohol-impaired driving fatalities be resumed? Results of a workshop sponsored by the Transportation Research Board, Alcohol, Other Drugs, and Transportation Committee (ANB50)

<p><b>Objective:</b> Despite successes in the 1980s and early 1990s, progress in reducing impaired driving fatalities in the United States has stagnated in recent years. Since 1997, the percentage of drivers involved in fatal crashes with illegal blood alcohol concentration (BAC) levels has remained at approximately 20 to 22%. Many experts believe that public complacency, competing social and public health issues, and the lack of political fortitude have all contributed to this stagnation. The number of alcohol-related crashes, injuries, and fatalities is still unacceptable, and most are preventable. The public needs to be aware that the problem presented by drinking drivers has not been solved. Political leaders need guidance on which measures will affect the problem, and stakeholders need to be motivated once again to implement effective strategies.</p> <p><b>Methods:</b> The National Academy of Sciences (NAS) Transportation Research Board (TRB), Alcohol, Other Drugs, and Transportation Committee (ANB50) sponsored a workshop held at the NAS facility in Woods Hole, Massachusetts, on August 24–25, 2015, to discuss the lack of progress in reducing impaired driving and to make recommendations for future progress. A total of 26 experts in research and policy related to alcohol-impaired driving participated in the workshop. The workshop began by examining the static situation in the rate of alcohol-impaired driving fatal crashes to determine what factors may be inhibiting further progress. The workshop then discussed 8 effective strategies that have not been fully implemented in the United States. Workshop participants (16 of the 26) rated their top 3 strategies.</p> <p><b>Results:</b> 3 strategies received the most support: 1. </p><p>Impose administrative sanctions for drivers with BACs = 0.05 to 0.08 g/dL.</p>2. <p>Require alcohol ignition interlocks for all alcohol-impaired driving offenders.</p>3. <p>Increase the frequency of sobriety checkpoints, including enacting legislation to allow them in the 11 states that currently prohibit them.</p><p></p> <p>Impose administrative sanctions for drivers with BACs = 0.05 to 0.08 g/dL.</p> <p>Require alcohol ignition interlocks for all alcohol-impaired driving offenders.</p> <p>Increase the frequency of sobriety checkpoints, including enacting legislation to allow them in the 11 states that currently prohibit them.</p> <p>5 other important strategies included the following: (1) increase alcohol taxes to raise the price and reduce alcohol consumption; (2) reengage the public and raise the priority of impaired driving; (3) lower the illegal per se BAC limit to 0.05 for a criminal offense; (4) develop and implement in-vehicle alcohol detection systems; and (5) expand the use of screening and brief interventions in medical facilities.</p> <p><b>Conclusions:</b> Each of these strategies is proven to be effective, yet all are substantially underutilized. Each is used in some jurisdictions in the United States or Canada, but none is used extensively. Any one of the 3 strategies implemented on a widespread basis would decrease impaired driving crashes, injuries, and fatalities. Based on the research, all 3 together would have a substantial impact on the problem.</p