Notes from the Field: Enhanced Surveillance for Raccoon Rabies Virus Variant and Vaccination of Wildlife for Management - Omaha, Nebraska, October 2023-July 2024.

On September 28, 2023, a kitten aged approximately 6 weeks found in Omaha, Nebraska, had test results positive for rabies at the Nebraska Veterinary Diagnostic Center (NVDC) after dying with neurologic signs and having bitten and scratched its caretakers. Preliminary investigation identified 10 exposed persons for whom postexposure prophylaxis (PEP)† was recommended. Subsequent variant-typing by NVDC yielded a presumptive positive result for the Eastern raccoon rabies virus variant (RRVV), which CDC confirmed on October 6.

Neighborhood income inequality associated with functional independence after ischemic stroke: a cohort study.

BACKGROUND: Individual measures of socioeconomic status have been associated with post-stroke disability in patients with ischemic stroke. However, it is not known whether the distribution of income in a community may have an impact on stroke recovery. We hypothesized that increased neighborhood income inequality (as measured by the Gini index) may be associated with a slower recovery after stroke. METHODS: This was a retrospective cohort study of adult patients hospitalized at a comprehensive stroke center with acute ischemic stroke between 1/1/2018-12/31/2019. Individual patient data was abstracted from the EHR, and zip code Gini index was obtained from the US Census Bureau. Binary logistic regression was used to assess the relationship between Gini index and functional independence (modified Rankin scale ≤2) at discharge and first outpatient follow-up. These models controlled for patient demographics, stroke risk factors, stroke severity, and stroke treatment. A second binary regression was also performed using a subset of patients to assess possible predictors of being discharged as recommended (i.e. having a discharge destination that was consistent with the recommendation of the inpatient medical team). RESULTS: Three hundred and thirty-seven patients were included in this analysis. The median time to first outpatient follow-up was 35 days. Zip code Gini index was not associated with functional independence at discharge but was associated with independence at follow-up (modified Rankin scale ≤2) such that patients from higher inequality neighborhoods had decreased odds of being independent. More specifically, each 1% increase in neighborhood Gini index was associated with 8% decreased odds of independence at follow-up (OR=0.923, 95% CI: 0.863-0.987). Being discharged as recommended was associated with increased odds of independence at follow-up (OR=3.359, 95% CI: 1.055-10.695). Greater income inequality (OR=0.909, 95% CI: 0.841-0.983) and Asian race (OR=0.093, 95% CI: 0.011-0.766) were associated with decreased odds of being discharged as recommended. CONCLUSION: Among a cohort of patients with ischemic stroke, increased neighborhood income inequality was associated with decreased odds of achieving functional independence up (modified Rankin scale ≤2) by the time of first outpatient follow-up (at a median of 35 days following discharge). This disparity may be driven by discharge destination and race.

Effect of benralizumab on inflammation in skin after intradermal allergen challenge in patients with moderate-to-severe atopic dermatitis.

Background: Atopic dermatitis (AD) is a skin barrier dysfunction characterized by tissue eosinophilia. Objective: In patients with AD, we evaluated the effect of eosinophil depletion with benralizumab on markers of inflammation in skin after intradermal allergen challenge. Methods: A total of 20 patients with moderate-to-severe AD completed a randomized, double-blind, placebo-controlled parallel-group study comparing 3 doses of benralizumab (30 mg each) administered subcutaneously every 4 weeks (n = 9) with placebo (n = 11). Allergen and saline control intradermal challenges were conducted before and after treatment, with skin biopsy samples collected 24 hours after challenge. Early and late cutaneous responses were measured by skin wheal size. Levels of eosinophils and IL-5 receptor-α-bearing cells, including eosinophil progenitor (EoP) cells, basophils, and mast cells, in papillary dermis were measured by immunofluorescence microscopy, and levels of EoP cells, hematopoietic progenitor cells, and type 2 innate lymphoid cells in the blood were measured by flow cytometry. Outcomes were compared between the placebo and benralizumab treatment groups by using the Mann-Whitney U test. Results: Benralizumab reduced eosinophil counts in the blood (P < .0001) and allergen-challenged skin, as measured by hematoxylin and eosin staining and eosinophil cationic protein antibody concentration (P < .05). Benralizumab lowered the levels of EoP cells, mast cells, and basophils in the skin, as well as the levels of EoP cells, hematopoietic progenitor cells, and type 2 innate lymphoid cells in the blood (all P < .05). There was a trend toward improvement in the early cutaneous response (P = .095) but no effect on the late cutaneous response. Conclusion: In patients with moderate-to-severe AD, benralizumab treatment significantly inhibited accumulation of eosinophils and other IL-5 receptor-α-expressing cells in the papillary dermis after intradermal allergen challenge. Targeting IL-5 receptor-α-positive cells did not modulate the size of the allergen-induced skin wheal (ClincialTrials.gov identifier NCT03563066).

The Burden of Plastic Surgery Related Disease in Canada: A Perspective Based on the 2019 Global Burden of Disease Study.

Purpose: Identifying the burden of disease related to plastic and reconstructive surgery in Canada will provide timely population-based data, inform policy, and generate support for research funding. Methods and Patients: Data on the burden of disease (ie, prevalence, incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years [DALYs]), were extracted from the Global Burden of Disease 2019 results tool for all available and relevant plastic surgery diseases. The economic burden of disease in Canadian dollars was calculated based on prior studies. Data are presented as either rates (per 100 000) or counts with the associated uncertainty interval. Results: In 2019, plastic surgery related conditions in Canada had an overall age-standardized DALY rate of 556 per 100 000 [463-664]. Of these conditions, breast cancer was responsible for approximately 50% of the overall burden of disease, with an age-standardized DALY rate of 268 per 100 000 [244-294] followed by squamous cell carcinoma (66 per 100 000 [45-94]) and thermal burns (61 per 100 000 [46-82]). Age-standardized incidence rates were highest for cellulitis (2654 per 100 000 [2502-2812]). Breast cancer had the highest age-standardized cost of care of all plastic surgery related diseases, at $5.1 billion, approximately half of the total age-standardized cost of $10.6 billion for included plastic surgery diseases. Conclusion: Plastic and reconstructive surgery related diseases, particularly breast cancer, thermal burns, and malignant melanoma, are responsible for a high burden of disease and significant cost to the Canadian healthcare system. These results will help guide national healthcare policy and should provide support to directing funding and research efforts toward impactful diseases facing the Canadian healthcare system.

Objectif: L'identification de la morbidité des maladies liées à la chirurgie plastique et reconstructrice au Canada fournira des données en temps opportun reposant sur la population, permettra de renseigner les politiques et générer un soutien pour le financement de la recherche. Méthodes et patients: Des données sur la morbidité des maladies (c.-à-d. prévalence, incidence, mortalité, années de vie perdues [YLL], années vécues avec une invalidité [YLD], et années de vie corrigées pour l'invalidité [AVCI ou DALY]) ont été extraites de l'outil de résultats sur la morbidité mondiale des maladies 2019 pour toutes les affections disponibles et pertinentes pour la chirurgie plastique. Le poids économique de la maladie en dollars canadiens (CAD) a été calculé sur la base d'études antérieures. Les données sont présentées sous forme de taux (pour 100 000) ou de nombres avec les intervalles d'incertitude (IdI) associés. Résultats: En 2019, les troubles liés à la chirurgie plastique au Canada avaient un taux d'AVCI global standardisé pour l'âge de 556 pour 100 000 (463-664). Parmi ces affections, le cancer du sein était responsable d'environ 50% du fardeau global de la maladie avec un taux d'AVCI standardisé pour l'âge de 268 pour 100 000 (244-294) suivi du cancer épidermoïde (carcinome à cellules squameuses) (66 pour 100 000 [45-94]) et des brûlures thermiques (61 pour 100 000 [46-82]). Les incidences standardisées pour l'âge étaient les plus élevées pour la cellulite (2 654 pour 100 000 [2 502-2 812]). Le cancer du sein avait le coût des traitements standardisé pour l'âge le plus élevé de toutes les maladies liées à la chirurgie plastique, avec 5,1 milliards de dollars, soit environ la moitié des dépenses totales standardisées pour l'âge de 10,6 milliards de dollars pour les maladies incluses liées à la chirurgie plastique. Conclusion: Les maladies liées à la chirurgie plastique et reconstructrive, et plus particulièrement le cancer du sein, les brûlures thermiques et le mélanome malin, sont responsables d'une importante morbidité et de coûts significatifs pour le système de santé canadien. Ces résultats aideront à guider la politique nationale de soins de santé et devraient fournir un soutien pour orienter le financement et les efforts de recherche vers des maladies ayant les plus grandes répercussions sur le système de soins de santé canadien. Mots-clés: chirurgie plastique, morbidité, années de vie corrigées pour l'invalidité, fardeau global de la maladie, coût des soins, morbidité de la maladie.

BORIS/CTCFL epigenetically reprograms clustered CTCF binding sites into alternative transcriptional start sites.

BACKGROUND: Pervasive usage of alternative promoters leads to the deregulation of gene expression in carcinogenesis and may drive the emergence of new genes in spermatogenesis. However, little is known regarding the mechanisms underpinning the activation of alternative promoters. RESULTS: Here we describe how alternative cancer-testis-specific transcription is activated. We show that intergenic and intronic CTCF binding sites, which are transcriptionally inert in normal somatic cells, could be epigenetically reprogrammed into active de novo promoters in germ and cancer cells. BORIS/CTCFL, the testis-specific paralog of the ubiquitously expressed CTCF, triggers the epigenetic reprogramming of CTCF sites into units of active transcription. BORIS binding initiates the recruitment of the chromatin remodeling factor, SRCAP, followed by the replacement of H2A histone with H2A.Z, resulting in a more relaxed chromatin state in the nucleosomes flanking the CTCF binding sites. The relaxation of chromatin around CTCF binding sites facilitates the recruitment of multiple additional transcription factors, thereby activating transcription from a given binding site. We demonstrate that the epigenetically reprogrammed CTCF binding sites can drive the expression of cancer-testis genes, long noncoding RNAs, retro-pseudogenes, and dormant transposable elements. CONCLUSIONS: Thus, BORIS functions as a transcription factor that epigenetically reprograms clustered CTCF binding sites into transcriptional start sites, promoting transcription from alternative promoters in both germ cells and cancer cells.

Incidence, Mortality, and Survival of Merkel Cell Carcinoma: A Systematic Review of Population Based-Studies.

BACKGROUND: Merkel Cell Carcinoma (MCC) is a rare, aggressive skin cancer that most commonly occurs in UV-exposed body sites. Its epidemiology in different geographies and populations is not well characterised. OBJECTIVE: The objective of this systematic review is to summarize evidence on the incidence, mortality, and survival rates of MCC from population-based studies. METHODS: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from database inception to June 6th, 2023. No geographic, age or date exclusions were applied. We included population-based studies of MCC that reported the incidence, survival, or mortality rate, and considered systematic reviews. A data-charting form was created and validated to identify variables to extract. Two reviewers then independently charted the data for each included study with patient characteristics, and estimates of incidence rate, mortality rate, and survival rate and assessed the quality of included studies using the Joanna Briggs Institute Checklist for Prevalence studies, Newcastle-Ottawa Scale and Assessment of Multiple Systematic Reviews. We abstracted age-, sex-, stage- and race-stratified outcomes, and synthesized comparisons between strata narratively and using vote counting. We assessed the certainty of evidence for those comparisons using the Grading of Recommendations, Assessments, Developments and Evaluations framework. RESULTS: We identified 11,472 citations, of which 52 studies from 24 countries met our inclusion criteria. Stage 1 and the head and neck were the most frequently reported stage and location at diagnosis. The incidence of MCC is increasing over time (high certainty), with the highest reported incidences reported in Southern hemisphere countries (Australia [2.5 per 100,000], New Zealand [0.96 per 100,000]) (high certainty). Male patients generally had higher incidence rates compared to female patients (high certainty), although there were some variations over time periods. Survival rates varied, with lower survival and/or higher mortality associated with male sex (moderate certainty), higher stage at diagnosis (moderate-to-high certainty), older age (moderate certainty), and immunosuppression (low-to-moderate certainty). CONCLUSIONS: MCC is increasing in incidence and may increase further given the ageing population of many countries. The prognosis of MCC is poor, particularly for males, those who are immunosuppressed, and patients diagnosed at higher stages or at an older age.

An updated catalog of CTCF variants associated with neurodevelopmental disorder phenotypes.

Introduction: CTCF-related disorder (CRD) is a neurodevelopmental disorder (NDD) caused by monoallelic pathogenic variants in CTCF. The first CTCF variants in CRD cases were documented in 2013. To date, 76 CTCF variants have been further described in the literature. In recent years, due to the increased application of next-generation sequencing (NGS), growing numbers of CTCF variants are being identified, and multiple genotype-phenotype databases cataloging such variants are emerging. Methods: In this study, we aimed to expand the genotypic spectrum of CRD, by cataloging NDD phenotypes associated with reported CTCF variants. Here, we systematically reviewed all known CTCF variants reported in case studies and large-scale exome sequencing cohorts. We also conducted a meta-analysis using public variant data from genotype-phenotype databases to identify additional CTCF variants, which we then curated and annotated. Results: From this combined approach, we report an additional 86 CTCF variants associated with NDD phenotypes that have not yet been described in the literature. Furthermore, we describe and explain inconsistencies in the quality of reported variants, which impairs the reuse of data for research of NDDs and other pathologies. Discussion: From this integrated analysis, we provide a comprehensive and annotated catalog of all currently known CTCF mutations associated with NDD phenotypes, to aid diagnostic applications, as well as translational and basic research.

Upper Extremity Infection Related to Intravenous Drug Use: Considering the True Cost of the COVID-19 Pandemic and Lockdown.

BACKGROUND: The COVID-19 pandemic caused significant morbidity and mortality in people who inject drugs (PWID). Upper extremity soft tissue infections are frequently associated with intravenous drug use (IVDU) due to poor compliance with aseptic technique. In Canada, multiple safe injection sites providing clean injection supplies closed, leaving many PWID with no alternatives to inject safely. It was hypothesized that these closures will correspond with increased morbidity and mortality among PWID. The main objective of this study was to determine the effect of the COVID-19 pandemic on the incidence of upper extremity infections in PWID. METHODS: This was a retrospective chart review study. The primary outcome of interest was the frequency of upper extremity infections in PWID. Data were filtered to include only those patients presenting to the emergency department between March to June of 2019 and 2020. Chi-squared analysis was used to compare the number of IVDU patients among patients with upper extremity skin infections between these time periods. RESULTS: The number of IVDU patients treated for upper extremity infections in Hamilton significantly increased during the pandemic, relative risk = 2.0 (95% confidence interval [CI]: 1.3-2.9, P = .0012,) while total upper extremity infections numbers have decreased overall. During the pandemic, PWID made up a larger proportion of upper extremity infections (χ2 = 10.444, P = .00123). Demographic data such as age and sex of IVDU patients presenting with upper extremity infection was not significantly affected by the pandemic. CONCLUSIONS: The effect of the pandemic on accessing harm reduction services has led to evident increases in morbidity as described by this study. Further research on the impact of closures in PWID is needed to quantify these harms and work toward mitigation strategies.

Clinical predictive models in equine medicine: A systematic review.

Clinical predictive models use a patient's baseline demographic and clinical data to make predictions about patient outcomes and have the potential to aid clinical decision making. The extent of equine clinical predictive models is unknown in the literature. Using PubMed and Google Scholar, we systematically reviewed the predictive models currently described for use in equine patients. Models were eligible for inclusion if they were published in a peer-reviewed article as a multivariable model used to predict a clinical/laboratory/imaging outcome in an individual horse or herd. The agreement of at least two authors was required for model inclusion. We summarised the patient populations, model development methods, performance metric reporting, validation efforts, and, using the Predictive model Risk of Bias Assessment Tool (PROBAST), assessed the risk of bias and applicability concerns for these models. In addition, we summarised the index conditions for which models were developed and provided detailed information on included models. A total of 90 predictive models and 9 external validation studies were included in the final systematic review. A plurality of models (41%) was developed to predict outcomes associated with colic, for example, need for surgery or survival to discharge. All included models were at high risk of bias, defined as failing one or more PROBAST signalling questions, primarily for analysis-related reasons. Importantly, a high risk of bias does not necessarily mean that models are unusable, but that they require more careful consideration prior to clinical use. Concerns about applicability were low for the majority of models. Systematic reviews such as this can serve to increase veterinarians' awareness of predictive models, including evaluation of their performance and their use in different patient populations.

Study of n-Alkanethiol Self-Assembly Behavior on Iron Particles: Effect of Alkyl Chain Length and Adsorption Solvent on Resulting Iron-Based Magnetorheological Fluids.

Self-assembled monolayers (SAMs) of organic molecules on metal surfaces are a type of inexpensive surface coating often used to improve metal substrate properties for sensors, electrochemistry, and nanofabrication applications. Iron, specifically, is one of the most commonly used metals, both as a pure metal and as an alloy due to its high conductivity, strong ferromagnetism, and low cost. However, magnetorheological fluids, which have shown impressive energy dampening in fields from civil infrastructure to biomedical devices utilizing iron dispersions, have suffered from low reliability and efficiency due to iron particle oxidation, corrosion, and settling. To understand the effect of self-assembled monolayers on iron and both the adsorbed particle's resistance against aggregation and performance impact, this work performs an in-depth study on alkanethiol-based self-assembled monolayers on iron particles. Adsorption of alkanethiols and the generation of SAMs on micron-sized iron particles were evaluated as a function of adsorption solvent polarity and alkanethiol chain length. Maximum alkanethiol loading, determined from appropriate isotherms, was found to strongly be a function of both parameters. Alkanethiol adsorption increased with increasing alkyl chain length and increasing solvent log P values in polar solvents. With respect to magnetorheologically relevant parameters, alkanethiol adsorption did not show any significant effect on both the magnetic properties of iron (as particles) and fluid on-state yield stress. The colloidal stability of n-alkanethiol adsorbed iron-based magnetorheological fluids (MRFs) was a function of both n-alkanethiol chain length and the iron particle adsorption solvent. MRFs composed of hexadecanethiol adsorbed iron prepared in polar solvents like methanol and ethanol showed excellent sedimentation stability compared to all other MRFs prepared in this study.

Junior medical doctors' decision making when using advance care directives to guide treatment for people with dementia: a cross-sectional vignette study.

BACKGROUND: Junior medical doctors have a key role in discussions and decisions about treatment and end-of-life care for people with dementia in hospital. Little is known about junior doctors' decision-making processes when treating people with dementia who have advance care directives (ACDs), or the factors that influence their decisions. To describe among junior doctors in relation to two hypothetical vignettes involving patients with dementia: (1) their legal compliance and decision-making process related to treatment decisions; (2) the factors influencing their clinical decision-making; and (3) the factors associated with accurate responses to one hypothetical vignette. METHOD: A cross-sectional survey of junior doctors, including trainees, interns, registrars and residents, on clinical rotation in five public hospitals located in one Australian state. The anonymous, investigator-developed survey was conducted between August 2018 and June 2019. Two hypothetical vignettes describing patients with dementia presenting to hospital with an ACD and either: (1) bacterial pneumonia; or (2) suspected stroke were presented in the survey. Participants were asked to indicate whether they would commence treatment, given the ACD instructions described in each vignette. RESULTS: Overall, 116 junior doctors responded (35% consent rate). In Vignette 1, 58% of respondents (n = 67/116) selected the legally compliant option (i.e. not commence treatment). Participants who chose the legally compliant option perceived 'following patient wishes' (n = 32/67; 48%) and 'legal requirements to follow ACDs' (n = 32/67; 48%) as equally important reasons for complying with the ACD. The most common reason for not selecting the legally compliant option in Vignette 1 was the 'ACD is relevant in my decision-making process, but other factors are more relevant' (n = 14/37; 38%). In Vignette 2, 72% of respondents (n = 83/116) indicated they would commence treatment (i.e. not follow the ACD) and 18% (n = 21/116) selected they would not commence treatment. (i.e. follow the ACD). Similar reasons influenced participant decision-making in Vignette 2, a less legally certain scenario. CONCLUSIONS: There are critical gaps in junior doctors' compliance with the law as it relates to the implementation of ACDs. Despite there being differences in relation to the legal answer and its certainty, clinical and ethical factors guided decision-making over and above the law in both vignettes. More education and training to guide junior doctors' clinical decision-making and ensure compliance with the law is required.

Junior Medical Officers' knowledge of advance care directives and substitute decision making for people without decision making capacity: a cross sectional survey.

BACKGROUND: For the benefits of advance care planning to be realised during a hospital admission, the treating team must have accurate knowledge of the law pertaining to implementation of advance care directives (ACDs) and substitute decision making. AIMS: To determine in a sample of Junior Medical Officers (JMOs): (1) knowledge of the correct order to approach people as substitute decision makers if a patient does not have capacity to consent to treatment; (2) knowledge of the legal validity of ACDs when making healthcare decisions for persons without capacity to consent to treatment, including the characteristics associated with higher knowledge; and (3) barriers to enacting ACDs. METHODS: A cross-sectional survey was conducted at five public hospitals in New South Wales, Australia. Interns, residents, registrars, and trainees on clinical rotation during the recruitment period were eligible to participate. Consenting participants completed an anonymous pen-and-paper survey. RESULTS: A total of 118 JMOs completed a survey (36% return rate). Fifty-five percent of participants were female and 56.8% were aged 20-29 years. Seventy-five percent of JMOs correctly identified a Guardian as the first person to approach if a patient did not have decision-making capacity, and 74% correctly identified a person's spouse or partner as the next person to approach. Only 16.5% identified all four persons in the correct order, and 13.5% did not identify any in the correct order. The mean number of correct responses to the questions assessing knowledge of the legal validity of ACDs was 2.6 (SD = 1.1) out of a possible score of 6. Only 28 participants (23.7%) correctly answered four or more knowledge statements correctly. None of the explored variables were significantly associated with higher knowledge of the legal validity of ACDs. Uncertainty about the currency of ACDs and uncertainty about the legal implications of relying on an ACD when a patient's family or substitute decision maker disagree with it were the main barriers to enacting ACDs. CONCLUSION: JMOs knowledge of the legal validity of ACDs for persons without decision making capacity and the substitute decision making hierarchy is limited. There is a clear need for targeted education and training to improve knowledge in this area for this cohort.

Acute onset of blisters in an infant with acrodermatitis enteropathica: A case report.

We represent a pediatric case of the congenital disorder caused by zinc malabsorption, acrodermatitis enteropathica, presenting with acute onsetof blisters. Although blisters can be seen in this condition, it is not always a key feature and can therefore be overlooked when considering a differential diagnosis of acute blistering in infancy. We therefore review the common and less common features of this cutaneous eruption as well as provide an extensive differential diagnosis for acute blistering in infancy. We also emphasize the importance of lifelong treatment with zinc supplementation in these children.

CRISPR Deletion of a SVA Retrotransposon Demonstrates Function as a cis-Regulatory Element at the TRPV1/TRPV3 Intergenic Region.

SINE-VNTR-Alu (SVA) retrotransposons are a subclass of transposable elements (TEs) that exist only in primate genomes. TE insertions can be co-opted as cis-regulatory elements (CREs); however, the regulatory potential of SVAs has predominantly been demonstrated using bioinformatic approaches and reporter gene assays. The objective of this study was to demonstrate SVA cis-regulatory activity by CRISPR (clustered regularly interspaced short palindromic repeats) deletion and subsequent measurement of direct effects on local gene expression. We identified a region on chromosome 17 that was enriched with human-specific SVAs. Comparative gene expression analysis at this region revealed co-expression of TRPV1 and TRPV3 in multiple human tissues, which was not observed in mouse, highlighting key regulatory differences between the two species. Furthermore, the intergenic region between TRPV1 and TRPV3 coding sequences contained a human specific SVA insertion located upstream of the TRPV3 promoter and downstream of the 3' end of TRPV1, highlighting this SVA as a candidate to study its potential cis-regulatory activity on both genes. Firstly, we generated SVA reporter gene constructs and demonstrated their transcriptional regulatory activity in HEK293 cells. We then devised a dual-targeting CRISPR strategy to facilitate the deletion of this entire SVA sequence and generated edited HEK293 clonal cell lines containing homozygous and heterozygous SVA deletions. In edited homozygous ∆SVA clones, we observed a significant decrease in both TRPV1 and TRPV3 mRNA expression, compared to unedited HEK293. In addition, we also observed an increase in the variability of mRNA expression levels in heterozygous ∆SVA clones. Overall, in edited HEK293 with SVA deletions, we observed a disruption to the co-expression of TRPV1 and TRPV3. Here we provide an example of a human specific SVA with cis-regulatory activity in situ, supporting the role of SVA retrotransposons as contributors to species-specific gene expression.

The use of noninvasive imaging techniques in the diagnosis of melanoma: a prospective diagnostic accuracy study.

BACKGROUND: Early detection of melanoma is crucial to improving the detection of thin curable melanomas. Noninvasive, computer-assisted methods have been developed to use at the bedside to aid in diagnoses but have not been compared directly in a clinical setting. OBJECTIVE: We conducted a prospective diagnostic accuracy study comparing a dermatologist's clinical examination at the bedside, teledermatology, and noninvasive imaging techniques (FotoFinder, MelaFind, and Verisante Aura). METHODS: A total of 184 patients were recruited prospectively from an outpatient dermatology clinic, with lesions imaged, assessed, and excised. Skin specimens were assessed by 2 blinded pathologists, providing the gold standard comparison. RESULTS: Fifty-nine lesions from 56 patients had a histopathologic diagnosis of melanoma, whereas 150 lesions from 128 patients were diagnosed as benign. Sensitivities and specificities were, respectively, MelaFind (82.5%, 52.4%), Verisante Aura (21.4%, 86.2%), and FotoFinder Moleanalyzer Pro (88.1%, 78.8%). The sensitivity and specificity of the teledermoscopist (84.5% and 82.6%, respectively) and local dermatologist (96.6% and 32.2%, respectively) were also compared. LIMITATIONS: There are inherent limitations in using pathology as the gold standard to compare sensitivities and specificities. CONCLUSION: This study demonstrates that the highest sensitivity and specificity of the instruments were established with the FotoFinder Moleanalyzer Pro, which could be a valuable tool to assist with, but not replace, clinical decision making.

Knowledge and confidence of junior medical doctors in discussing and documenting resuscitation plans: a cross-sectional survey.

BACKGROUND: A resuscitation plan is a medically authorised order to use or withhold resuscitation interventions. Absence of appropriate resuscitation orders exposes patients to the risk of invasive medical interventions that may be of questionable benefit depending on individual circumstances. AIMS: To describe among junior doctors: (i) self-reported confidence discussing and completing resuscitation plans; (ii) knowledge of resuscitation policy including whether resuscitation plans are legally enforceable and key triggers for completion; and (iii) the factors associated with higher knowledge of triggers for completing resuscitation plans. METHODS: A cross-sectional survey was conducted at five hospitals. Junior doctors on clinical rotation were approached at scheduled training sessions, before or after ward rounds or at change of rotation orientation days and provided with a pen-and-paper survey. RESULTS: A total of 118 junior doctors participated. Most felt confident discussing (79%; n = 92) and documenting (87%; n = 102) resuscitation plans with patients. However, only 45% (n = 52) of doctors correctly identified that resuscitation plans are legally enforceable medical orders. On average, doctors correctly identified 6.8 (standard deviation = 1.8) out of 10 triggers for completing a resuscitation plan. Doctors aged >30 years were four times more likely to have high knowledge of triggers for completing resuscitation plans (odds ratio 4.28 (95% confidence interval 1.54-11.89); P = 0.0053). CONCLUSION: Most junior doctors feel confident discussing and documenting resuscitation plans. There is a need to improve knowledge about legal obligations to follow completed resuscitation plans, and about when resuscitation plans should be completed to ensure they are completed with patients who are most at risk.

Sleep Apnea in Maintenance Hemodialysis: A Mixed-Methods Study.

RATIONALE & OBJECTIVE: More than 50% of hemodialysis patients experience sleep disturbance and most have coexisting sleep apnea. However, how sleep apnea affects sleep and the overall experience of patients with chronic kidney disease treated by hemodialysis has not been evaluated. STUDY DESIGN: A mixed-methods design, incorporating cross-sectional observational and descriptive qualitative methodologies. SETTING & PARTICIPANTS: Patients receiving maintenance hemodialysis in Newcastle, New South Wales, Australia, with newly diagnosed sleep apnea (apnea-hypopnea index ≥ 5 per hour). ASSESSMENTS: In-laboratory polysomnography to assess sleep apnea and objective sleep parameters. Epworth Sleepiness Scale to assess daytime symptoms. A semi-structured qualitative interview to explore patient experience. ANALYTICAL APPROACH: Descriptive and iterative thematic analysis. RESULTS: We analyzed 36 patients with newly diagnosed sleep apnea and interviewed 26 (mean age, 62 years, median apnea-hypopnea index, 32 per hour). Severity of sleep apnea did not affect patients' sleep duration, sleep efficiency, or self-reported Epworth Sleepiness Scale score. From the qualitative interviews, 4 themes emerged: "broken sleep" related to short sleep duration, with waking and dozing off a common sleep cycle, caused by uncontrolled pain and dialysis. Many participants reported regularly "feeling unrefreshed" on waking. "Impact of sleep disturbance" included reduced physical, mental, and self-management capacity. Finally, interviewees described the need to use strategies to "soldier on" with symptoms. LIMITATIONS: Participants' views are only transferrable to hemodialysis patients with sleep apnea. CONCLUSIONS: Our findings suggest that severity of sleep apnea does not affect sleep time or patient-reported daytime sleepiness; however, hemodialysis patients with sleep apnea report disturbed and unrefreshed sleep and the debilitating effects of sleep disturbance is profound. Broken and unrefreshed sleep were the dominant symptoms of sleep apnea and should be assessed routinely to identify patients with sleep apnea and improve quality of life in patients with chronic kidney disease treated with hemodialysis.

Defective Influenza A Virus RNA Products Mediate MAVS-Dependent Upregulation of Human Leukocyte Antigen Class I Proteins.

Influenza A virus (IAV) increases the presentation of class I human leukocyte antigen (HLA) proteins that limit antiviral responses mediated by natural killer (NK) cells, but molecular mechanisms for these processes have not yet been fully elucidated. We observed that infection with A/Fort Monmouth/1/1947(H1N1) IAV significantly increased the presentation of HLA-B, -C, and -E on lung epithelial cells. Virus entry was not sufficient to induce HLA upregulation because UV-inactivated virus had no effect. Aberrant internally deleted viral RNAs (vRNAs) known as mini viral RNAs (mvRNAs) and defective interfering RNAs (DI RNAs) expressed from an IAV minireplicon were sufficient for inducing HLA upregulation. These defective RNAs bind to retinoic acid-inducible gene I (RIG-I) and initiate mitochondrial antiviral signaling (MAVS) protein-dependent antiviral interferon (IFN) responses. Indeed, MAVS was required for HLA upregulation in response to IAV infection or ectopic mvRNA/DI RNA expression. The effect was partially due to paracrine signaling, as we observed that IAV infection or mvRNA/DI RNA-expression stimulated production of IFN-ß and IFN-λ1 and conditioned media from these cells elicited a modest increase in HLA surface levels in naive epithelial cells. HLA upregulation in response to aberrant viral RNAs could be prevented by the Janus kinase (JAK) inhibitor ruxolitinib. While HLA upregulation would seem to be advantageous to the virus, it is kept in check by the viral nonstructural 1 (NS1) protein; we determined that NS1 limits cell-intrinsic and paracrine mechanisms of HLA upregulation. Taken together, our findings indicate that aberrant IAV RNAs stimulate HLA presentation, which may aid viral evasion of innate immunity.IMPORTANCE Human leukocyte antigens (HLAs) are cell surface proteins that regulate innate and adaptive immune responses to viral infection by engaging with receptors on immune cells. Many viruses have evolved ways to evade host immune responses by modulating HLA expression and/or processing. Here, we provide evidence that aberrant RNA products of influenza virus genome replication can trigger retinoic acid-inducible gene I (RIG-I)/mitochondrial antiviral signaling (MAVS)-dependent remodeling of the cell surface, increasing surface presentation of HLA proteins known to inhibit the activation of an immune cell known as a natural killer (NK) cell. While this HLA upregulation would seem to be advantageous to the virus, it is kept in check by the viral nonstructural 1 (NS1) protein, which limits RIG-I activation and interferon production by the infected cell.

AAGAB Mutations in 18 Canadian Families With Punctate Palmoplantar Keratoderma and a Possible Link to Cancer.

BACKGROUND: Punctate palmoplantar keratoderma type 1 (PPPK1) presents in late childhood to adulthood with multiple small discrete hyperkeratotic papules on palms and soles. PPPK1 is an autosomal dominant skin disease caused by AAGAB mutations. It has been suggested that PPPK1 may be associated with an increased predisposition to systemic malignancies. OBJECTIVES: To evaluate the presence of AAGAB mutations in Canadian families with PPPK1 and the possible increased predisposition to systemic malignancies. METHODS: Eighteen unrelated Canadian families with PPPK1 were recruited for this study. Genomic DNA was extracted from saliva and PCR amplification was performed for all AAGAB exons and exon/intron junctions. PCR products were sequenced and analyzed for mutations. A family history of malignancy was obtained from the index case and, when possible, from other family members. RESULTS: We have identified 5 heterozygous AAGAB loss of function mutations in 11 families. The mutation c.370 C>T, p.Arg124* was the most prevalent and was identified in 6 families. A splice site mutation, c.451+3delAAGT, was identified in 2 families. The other mutations c.473delG, p.Gly158Glufs*0; c.550-551insAAT, p.Gly183*; and c.505-506 dupAA, p.Asn169Lysfs*6 were each identified in 1 family. Different cancers were reported in 11 families (Table 1 and Supplemental Figure S1). CONCLUSIONS: AAGAB mutations were found in 11 of 18 families with PPPK1. In some families there appears to be an association with cancer.