The Reliability of Auto-Injectors in Clinical Use: A Systematic Review.

Auto-injectors are medical devices designed for the self-administration of injections by patients and for easy administration by healthcare professionals in emergency situations. Although they vary in design and application, auto-injectors are typically built around a spring-loaded syringe. Despite their widespread use in a variety of clinical settings, there have been limited attempts to assess their reliability. This systematic review investigates the reliability of auto-injectors, identifies common causes of failure, and summarizes the overall rate of malfunction. A systematic review of research published on the PubMed and Cochrane Library databases was performed in July 2022. The relevant studies were assessed for their methodological quality and risk of bias prior to extracting key study outcomes on auto-injector reliability. Finally, a summary rate covering all eligible studies was calculated.  The search identified a total of 110 articles, of which ten were found to be suitable for inclusion. The risk of bias was low, and the methodological quality was high across the ten studies. Out of a total of 2,964 injections administered from an auto-injector, there were 12 device malfunctions, giving a summary rate of 0.40% (±0.23) auto-injector failures. The causes of malfunction varied in nature, with the majority of cases (58.3%) not being specified or not identified. This review has demonstrated that auto-injectors are reliable devices. Although further research on the nature of malfunctions is needed, the low rate of malfunctions supports training programs for healthcare professionals and patients on the optimum use and maintenance of auto-injectors. It provides a rationale for their continued development

Polymer reptation and nucleosome repositioning

We consider how beads can diffuse along a chain that wraps them, without becoming displaced from the chain; our proposed mechanism is analogous to the reptation of "stored length" in more familiar situations of polymer dynamics. The problem arises in the case of globular aggregates of proteins (histones) that are wound by DNA in the chromosomes of plants and animals; these beads (nucleosomes) are multiply wrapped and yet are able to reposition themselves over long distances, while remaining bound by the DNA chain.Comment: 9 pages, including 2 figures, to be published in Phys. Rev. Let

Double Dissociation of Format-Dependent and Number-Specific Neurons in Human Parietal Cortex

Based on neuroimaging methods, it is a commonly held view that numerical representation in the human parietal lobes is format independent. We used a transcranial magnetic stimulation adaptation paradigm to examine the existence of functionally segregated overlapping populations of neurons for different numerical formats and to reveal how numerical information is encoded and represented. Based on 2 experiments, we found that right parietal lobe stimulation showed a dissociation between digits and verbal numbers, whereas the left parietal lobe showed a double dissociation between the different numerical formats. Further analysis and modeling also excluded pre- or postrepresentational components as the source of the current effects. These results demonstrate that both parietal lobes are equipped with format-dependent neurons that encode quantity

Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval--A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity.

BACKGROUND: E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects. METHODS: Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day). RESULTS: In this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis. CONCLUSION: The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal. TRIAL REGISTRATION: EU Clinical Trials Register EudraCT 2010 020343 13

Emerging fungal pathogen Ophidiomyces ophiodiicola in wild European snakes

Snake fungal disease (SFD) is an emerging disease of conservation concern in eastern North America. $\textit{Ophidiomyces ophiodiicola}$, the causative agent of SFD, has been isolated from over 30 species of wild snakes from six families in North America. Whilst $\textit{O. ophiodiicola}$ has been isolated from captive snakes outside North America, the pathogen has not been reported from wild snakes elsewhere. We screened 33 carcasses and 303 moulted skins from wild snakes collected from 2010–2016 in Great Britain and the Czech Republic for the presence of macroscopic skin lesions and $\textit{O. ophiodiicola}$. The fungus was detected using real-time PCR in 26 (8.6%) specimens across the period of collection. Follow up culture and histopathologic analyses confirmed that both $\textit{O. ophiodiicola}$ and SFD occur in wild European snakes. Although skin lesions were mild in most cases, in some snakes they were severe and were considered likely to have contributed to mortality. Culture characterisations demonstrated that European isolates grew more slowly than those from the United States, and phylogenetic analyses indicated that isolates from European wild snakes reside in a clade distinct from the North American isolates examined. These genetic and phenotypic differences indicate that the European isolates represent novel strains of $\textit{O. ophiodiicola}$. Further work is required to understand the individual and population level impact of this pathogen in Europe.This work was undertaken as part of the Garden Wildlife Health project www.gardenwildlifehealth.org. Funding was provided by the UK Department for the Environment Food & Rural Affairs and Welsh Government through the Animal Plant & Health Agency’s Diseases of Wildlife Scheme Scanning Surveillance Programme (Project ED1600), the Esmée Fairbairn Foundation, the Universities Federation for Animal Welfare, and the U.S. Geological Survey

Differences in school factors associated with adolescent HPV vaccination initiation and completion coverage in three Australian states.

BackgroundSchools are the primary setting for the delivery of adolescent HPV vaccination in Australia. Although this strategy has achieved generally high vaccination coverage, gaps persist for reasons that are mostly unknown. This study sought to identify school-level correlates of low vaccination course initiation and completion in New South Wales, Tasmania, and Western Australia to inform initiatives to increase uptake.MethodsInitiation was defined as the number of first doses given in a school in 2016 divided by vaccine-eligible student enrolments. Completion was the number of third doses given in a school in 2015-2016 divided by the number of first doses. Low initiation and completion were defined as coverage ≤ 25thpercentile of all reporting schools. We investigated correlations between covariates using Spearman's rank correlation coefficients. Due to multicollinearity, we used univariable logistic regression to investigate associations between school characteristics and low coverage.ResultsMedian initiation was 84.7% (IQR: 75.0%-90.4%) across 1,286 schools and median completion was 93.8% (IQR: 86.0%-97.3%) across 1,295 schools. There were strong correlations between a number of school characteristics, particularly higher Indigenous student enrolments and lower attendance, increasing remoteness, higher postcode socioeconomic disadvantage, and smaller school size. Characteristics most strongly associated with low initiation in univariate analyses were small school size, location in Tasmania, and schools catering for special educational needs. Low completion was most strongly associated with schools in Tasmania and Western Australia, remote location, small size, high proportion of Indigenous student enrolments, and low attendance rates.ConclusionThis study provides indicative evidence that characteristics of schools and school populations are associated with the likelihood of low initiation and completion of the HPV vaccination course. The findings will guide further research and help target initiatives to improve vaccination uptake in schools with profiles associated with lower coverage

Frequent Arousal from Hibernation Linked to Severity of Infection and Mortality in Bats with White-Nose Syndrome

White-nose syndrome (WNS), an emerging infectious disease that has killed over 5.5 million hibernating bats, is named for the causative agent, a white fungus (Geomyces destructans (Gd)) that invades the skin of torpid bats. During hibernation, arousals to warm (euthermic) body temperatures are normal but deplete fat stores. Temperature-sensitive dataloggers were attached to the backs of 504 free-ranging little brown bats (Myotis lucifugus) in hibernacula located throughout the northeastern USA. Dataloggers were retrieved at the end of the hibernation season and complete profiles of skin temperature data were available from 83 bats, which were categorized as: (1) unaffected, (2) WNS-affected but alive at time of datalogger removal, or (3) WNS-affected but found dead at time of datalogger removal. Histological confirmation of WNS severity (as indexed by degree of fungal infection) as well as confirmation of presence/absence of DNA from Gd by PCR was determined for 26 animals. We demonstrated that WNS-affected bats aroused to euthermic body temperatures more frequently than unaffected bats, likely contributing to subsequent mortality. Within the subset of WNS-affected bats that were found dead at the time of datalogger removal, the number of arousal bouts since datalogger attachment significantly predicted date of death. Additionally, the severity of cutaneous Gd infection correlated with the number of arousal episodes from torpor during hibernation. Thus, increased frequency of arousal from torpor likely contributes to WNS-associated mortality, but the question of how Gd infection induces increased arousals remains unanswered