Recognition of nonself is necessary to activate Drosophila's immune response against an insect parasite.

BACKGROUND: Innate immune responses can be activated by pathogen-associated molecular patterns (PAMPs), danger signals released by damaged tissues, or the absence of self-molecules that inhibit immunity. As PAMPs are typically conserved across broad groups of pathogens but absent from the host, it is unclear whether they allow hosts to recognize parasites that are phylogenetically similar to themselves, such as parasitoid wasps infecting insects. RESULTS: Parasitoids must penetrate the cuticle of Drosophila larvae to inject their eggs. In line with previous results, we found that the danger signal of wounding triggers the differentiation of specialized immune cells called lamellocytes. However, using oil droplets to mimic infection by a parasitoid wasp egg, we found that this does not activate the melanization response. This aspect of the immune response also requires exposure to parasite molecules. The unidentified factor enhances the transcriptional response in hemocytes and induces a specific response in the fat body. CONCLUSIONS: We conclude that a combination of danger signals and the recognition of nonself molecules is required to activate Drosophila's immune response against parasitic insects.

The neurodevelopmental spectrum of synaptic vesicle cycling disorders.

In this review, we describe and discuss neurodevelopmental phenotypes arising from rare, high penetrance genomic variants which directly influence synaptic vesicle cycling (SVC disorders). Pathogenic variants in each SVC disorder gene lead to disturbance of at least one SVC subprocess, namely vesicle trafficking (e.g. KIF1A and GDI1), clustering (e.g. TRIO, NRXN1 and SYN1), docking and priming (e.g. STXBP1), fusion (e.g. SYT1 and PRRT2) or re-uptake (e.g. DNM1, AP1S2 and TBC1D24). We observe that SVC disorders share a common set of neurological symptoms (movement disorders, epilepsies), cognitive impairments (developmental delay, intellectual disabilities, cerebral visual impairment) and mental health difficulties (autism, ADHD, psychiatric symptoms). On the other hand, there is notable phenotypic variation between and within disorders, which may reflect selective disruption to SVC subprocesses, spatiotemporal and cell-specific gene expression profiles, mutation-specific effects, or modifying factors. Understanding the common cellular and systems mechanisms underlying neurodevelopmental phenotypes in SVC disorders, and the factors responsible for variation in clinical presentations and outcomes, may translate to personalized clinical management and improved quality of life for patients and families.

Virtual Interactive Surgical Skills Classroom: A Parallel-group, Non-inferiority, Adjudicator-blinded, Randomised Controlled Trial (VIRTUAL).

OBJECTIVE: This study evaluated the efficacy of virtual classroom training (VCT) in comparison to face-to-face training (FFT) and non-interactive computer-based learning (CBL) for basic surgical skills training. DESIGN: This was a parallel-group, non-inferiority, prospective randomised controlled trial with three intervention groups conducted in 2021. There were three intervention groups with allocation ratio 1:1:1. Outcome adjudicators were blinded to intervention assignment. Interventions consisted of 90-minute training sessions. VCT was delivered via the BARCO weConnect platform, FFT was provided in-person by expert instructors and CBL was carried out by participants independently. The primary outcome was post-intervention Objective Structured Assessment of Technical Skills score, adjudicated by two experts and adjusted for baseline proficiency. The assessed task was to place three interrupted sutures with hand-tied knots. SETTING: This multicentre study recruited from five medical schools in London. PARTICIPANTS: Inclusion criteria were medical student status and access to a personal computer and smartphone. One hundred fifty-nine eligible individuals applied online. Seventy-two participants were randomly selected and stratified by subjective and objective suturing experience prior to permuted block randomization. RESULTS: Twenty-four participants were allocated to each intervention, all were analysed per-protocol. The sample was 65.3% female with mean age 21.3 (SD 2.1). VCT was non-inferior to FFT (adjusted difference 0.44, 95% CI: -0.54 to 1.75, delta 0.675), VCT was superior to CBL (adjusted difference 1.69, 95% CI: 0.41-2.96) and FFT was superior to CBL (adjusted difference 1.25, 95% CI: 0.20-2.29). The costs per-attendee associated with VCT, FFT and CBL were £22.15, £39.69 and £16.33 respectively. Instructor hours used per student for VCT and FFT were 0.25 and 0.75, respectively. CONCLUSIONS: VCT provides greater accessibility and resource efficiency compared to FFT, with similar educational benefit. VCT has the potential to improve global availability and accessibility of surgical skills training.

Virtual Interactive Surgical Skills Classroom: Protocol for a Parallel-Group, Noninferiority, Adjudicator-Blinded, Randomized Controlled Trial (VIRTUAL).

BACKGROUND: Traditional face-to-face training (FFT) for basic surgical skills is inaccessible and resource-intensive. Noninteractive computer-based learning is more economical but less educationally beneficial. Virtual classroom training (VCT) is a novel method that permits distanced interactive expert instruction. VCT may optimize resources and increase accessibility. OBJECTIVE: We aim to investigate whether VCT is superior to computer-based learning and noninferior to FFT in improving proficiency in basic surgical skills. METHODS: This is a protocol for a parallel-group, noninferiority, randomized controlled trial. A sample of 72 undergraduates will be recruited from 5 medical schools in London. Participants will be stratified by subjective and objective suturing experience level and allocated to 3 intervention groups at a 1:1:1 ratio. VCT will be delivered using the BARCO weConnect software, and FFT will be provided by expert instructors. Optimal student-to-teacher ratios of 12:1 for VCT and 4:1 for FFT will be maintained. The assessed task will be interrupted suturing with hand-tied knots. RESULTS: The primary outcome will be the postintervention Objective Structured Assessment of Technical Skills score, adjudicated by 2 experts blinded to the study and adjusted for baseline proficiency. The noninferiority margin (δ) will be defined using historical data. CONCLUSIONS: This study will serve as a comprehensive appraisal of the suitability of virtual basic surgical skills classroom training as an alternative to FFT. Our findings will assist the development and implementation of further resource-efficient, accessible, virtual basic surgical skills training programs during the COVID-19 pandemic and in the future. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number ISRCTN12448098; https://www.isrctn.com/ISRCTN12448098. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/28671.

The impact of public hospital closure on medical and residency education: implications and recommendations.

BACKGROUND: Challenges around safety-net hospital closure have impacted medical student and resident exposure to urban public healthcare sites that may influence their future practice choices. OBJECTIVE: To assess the impact of the closure of a public safety-net teaching hospital for the clinical medical education of Charles Drew University medical students and residents. METHOD: Retrospective cohort study of medical students' and residents' and clinical placement into safety-net experiences after the closure of the primary teaching hospital. RESULTS: The hospital closure impacted both medical student and residency training experiences. Only 71% (17/24) of medical student rotations and 13% (23/180) of residents were maintained at public safety-net clinical sittings. The closure of the public safety-net hospital resulted in the loss of 36% of residency training spots sponsored by historically black medical schools in the United States and an even larger negative impact on the number of physicians training in underserved urban areas of Los Angeles County. CONCLUSION: While the medical educational program changes undertaken in the wake of hospital closure have negatively affected the immediate clinical educational experiences of medical students and residents, it remains to be seen whether the training site location changes will alter their long-term preferences in specialty choice and practice location.

The impact of an adrenal incidentaloma algorithm on the evaluation of adrenal nodules.

OBJECTIVE: To determine the impact of the use of an electronic medical record tool on the evaluation of adrenal incidentalomas. METHODS: Retrospective chart review was used to compare rates of hormone testing and follow up imaging for adrenal incidentalomas. Patients whose radiology reports contained an algorithm with recommendations, based on our 2013 clinical guideline for the workup of these nodules, were compared to those whose imaging reports did not contain the algorithm. RESULTS: For patients whose Radiology reports contained the algorithm, 69% had hormonal testing versus 43% of controls (p < 0.0001). By contrast, 57% of study group patients had a follow up imaging study, compared to 51% of controls (p = 0.1000). However, when the 18% of controls that were given guidance by the radiologist to perform follow-up imaging were excluded from those who received no guidance, there was a statistically significant difference in the rate of follow up imaging (57% vs 48%, p < 0.0001). CONCLUSION: Implementation of a clinical algorithm for the evaluation of adrenal incidentalomas in radiology reports and on the intranet site of a major clinical center led to improved rates of hormone testing. There was also a significant increase in the rate of follow up imaging, compared to when no guidance was given. Additional efforts to further improve performance are needed to increase the detection of clinically significant lesions, particularly hormone secreting tumors that should be removed.

Postmortem vitreous bevacizumab levels of an infant treated for retinopathy of prematurity.

We report the vitreous concentration of bevacizumab after injection for the treatment of retinopathy of prematurity (ROP). A premature neonate diagnosed with type 1 ROP was treated in both eyes with 0.625 mg intravitreal bevacizumab injection at 32 weeks' postconceptual age. Eleven weeks later there was complete regression clinically, but the patient died. Vitreous samples taken at autopsy revealed a bevacizumab vitreous concentration of 41.57 ng/ml. Histopathology of the retina showed residual preretinal neovascularization. Bevacizumab elimination from the infant vitreous is similar to that of adults, and, although complete regression was clinically apparent, it was not confirmed histopathologically.

Diet and mental health in the Arctic: is diet an important risk factor for mental health in circumpolar peoples?--a review.

BACKGROUND: The people living in Arctic and Subarctic environments have adapted to cold temperatures, short growing seasons, and low precipitation, but their traditional ways are now changing due to increased contact with Western society. The rapid alteration of circumpolar cultures has led to generational changes in diet from traditional foods to the processed groceries common in modern stores. OBJECTIVES: Develop a link between changing traditional diets and mental health that may have substantial consequences for circumpolar peoples. METHODS: Review of English language literature pertaining to the northern circumpolar environments of the world that consist of the Arctic and Subarctic areas. Electronic resources such as ISI Web of Science and PubMed were utilized, using keywords such as arctic, circumpolar, diet, omega-3 fatty acids, mental health, seasonal affective disorder, and suicide. In addition, we used the cited references of obtained articles and the extensive University of Alaska Fairbanks library collections to identify additional publications that were not available from the electronic resources. The years covered were not restricted to any particular period, although 83% of the sources were published in the last 16 years. CONCLUSION: The change in traditional diets has already led to increased health problems, such as obesity, cardiovascular disease, and diabetes, while the mental health of circumpolar peoples has also declined substantially during the same time period. The decline in mental health is characterized by increased rates of depression, seasonal affective disorder, anxiety, and suicide, that now often occur at higher rates than in lower-latitude populations. Studies in non-circumpolar peoples have shown that diet can have profound effects on neuronal and brain development, function, and health. Therefore, we hypothesize that diet is an important risk factor for mental health in circumpolar peoples.

Comparative analysis of empiric antimicrobial treatments for skin and soft tissue infections in newly hospitalized patients.

PURPOSE: Intravenous vancomycin is the standard empiric treatment for complicated skin and soft tissue infections (SSTIs) due to its coverage against methicillin-resistant Staphylococcus aureus (MRSA). The objective of this study was to compare the hospital length of stay (LOS) between vancomycin-treated patients and patients receiving newer anti-MRSA agents. The study also aimed to identify factors associated with therapy change in patients receiving vancomycin on admission. METHODS: Electronic medical records were used to conduct this retrospective cohort study. The LOS was compared among 5 groups of adult patients with admission diagnoses for SSTI who were initiated on linezolid, daptomycin, ceftaroline, tigecycline, or vancomycin. Survival analysis was used to identify factors associated with therapy change from vancomycin to another study medication. RESULTS: Vancomycin was prescribed in 1046 (92%) admissions. Although none of the between-group differences in LOS reached statistical significance, there was a trend toward shorter LOS in vancomycin-treated patients compared to linezolid-treated patients (P = .059). Coagulopathy was independently associated with increased likelihood of therapy change from vancomycin (hazard ratio = 4.71; P <.001). CONCLUSIONS: In the treatment of SSTI, newer agents result in LOS comparable to vancomycin. In patients initiated on vancomycin, therapy change was associated with longer LOS. Coagulopathy was independently associated with increased probability of therapy change.

Histopathologic changes in the extraocular muscle in centronuclear myopathy with a Dynamin 2 mutation.

BACKGROUND: Centronuclear myopathy (CNM) is a rare inherited neuromuscular disorder characterized by centrally placed nuclei in striated muscle. In this report, we describe the histological changes in the extraocular muscle (EOM) from a CNM patient with a mutation in Dynamic 2 (DNM2). MATERIALS AND METHODS: A 33-year-old Caucasian female presented with horizontal diplopia and left exotropia for 6 months prior to which she was asymptomatic. Her past medical history was significant for CNM, diagnosed based on a left quadriceps biopsy with onset of lower extremity weakness in her late 20s. She underwent a left medial rectus (LMR) resection and a left lateral rectus (LLR) recession. The resected muscle was analyzed using light and electron microscopy. Screening for mutations in the DNM2 gene was carried out and the detected mutation was confirmed by direct sequencing. Expression of the DNM2 protein was performed using immunohistochemistry (IHC). RESULTS: Pathology of the EOM revealed 17% centrally located muscle nuclei in contrast to 90% in the quadriceps, variable fiber size, normal ultrastructure of the EOM and normal distribution of DNM2 by IHC. Genetic analysis revealed a heterozygous R369W mutation in the DNM2 gene. CONCLUSION: The histological changes in the EOM in this CNM patient were mild, which reflected the mild alterations in function seen in this patient. The ophthalmologist seeing patients with new onset strabismus and a history of a myopathy should consider this entity in the differential diagnosis that could be confirmed by a muscle biopsy and mutational analysis.

Atypical Peters plus syndrome with new associations.

Peters plus syndrome is a rare condition, with ocular and systemic malformations. We describe a case of unilateral Peters anomaly with previously unreported systemic findings associated with this syndrome. In addition, autopsy findings suggested that severe developmental angle anomalies may be the cause of glaucoma in some of these patients.