Disentangling oncogenic amplicons in esophageal adenocarcinoma.

Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that involve breakage-fusion-bridge cycles and extrachromosomal DNA are poorly understood. Here, we use 710 esophageal adenocarcinoma cases with matched samples and patient-derived organoids to disentangle complex amplicons and their associated mechanisms. Short-read sequencing identifies ERBB2, MYC, MDM2, and HMGA2 as the most frequent oncogenes amplified in extrachromosomal DNAs. We resolve complex extrachromosomal DNA and breakage-fusion-bridge cycles amplicons by integrating of de-novo assemblies and DNA methylation in nine long-read sequenced cases. Complex amplicons shared between precancerous biopsy and late-stage tumor, an enrichment of putative enhancer elements and mobile element insertions are potential drivers of complex amplicons' origin. We find that patient-derived organoids recapitulate extrachromosomal DNA observed in the primary tumors and single-cell DNA sequencing capture extrachromosomal DNA-driven clonal dynamics across passages. Prospectively, long-read and single-cell DNA sequencing technologies can lead to better prediction of clonal evolution in esophageal adenocarcinoma.

Neurological outcome following out of hospital cardiac arrest: Evaluation of performance of existing risk prediction models in a UK cohort.

Introduction: Out of hospital cardiac arrest (OHCA) is a common problem. Rates of survival are low and a proportion of survivors are left with an unfavourable neurological outcome. Four models have been developed to predict risk of unfavourable outcome at the time of critical care admission - the Cardiac Arrest Hospital Prognosis (CAHP), MIRACLE2, Out of Hospital Cardiac Arrest (OHCA), and Targeted Temperature Management (TTM) models. This evaluation evaluates the performance of these four models in a United Kingdom population and provides comparison to performance of the Acute Physiology and Chronic Health Evaluation II (APACHE-II) score. Methods: A retrospective evaluation of the performance of the models was conducted over a 43-month period in 414 adult, non-pregnant patients presenting consecutively following non-traumatic OHCA to the five units in our regional critical care network. Scores were generated for each model for where patients had complete data (CAHP = 347, MIRACLE2 = 375, OHCA = 356, TTM = 385). Cerebral Performance Category (CPC) outcome was calculated for each patient at last documented follow up and an unfavourable outcome defined as CPC ⩾ 3. Performance for discrimination of unfavourable outcome was tested by generating receiver operating characteristic (ROC) curves for each model and comparing the area under the curve (AUC). Results: Best performance for discrimination of unfavourable outcome was demonstrated by the high risk group of the CAHP score with an AUC of 0.87 [95% CI 0.83-0.91], specificity of 97.1% [95% CI 93.8-100] and positive predictive value (PPV) of 96.3% [95% CI 92.2-100]. The high risk group of the MIRACLE2 model, which is significantly easier to calculate, had an AUC of 0.81 [95% CI 0.76-0.86], specificity of 92.3% [95% CI 87.2-97.4] and PPV of 95.2% [95% CI 91.9-98.4]. Conclusion: The CAHP, MIRACLE2, OHCA and TTM scores all perform comparably in a UK population to the original development and validation cohorts. All four scores outperform APACHE-II in a population of patients resuscitated from OHCA. CAHP and TTM perform best but are more complex to calculate than MIRACLE2, which displays inferior performance.

A qualitative study evaluating barriers and enablers to improving antimicrobial use for the management of bacteriuria in hospitalized adults.

Objective: The objective of this study was to explore barriers and enablers to improving the management of bacteriuria in hospitalized adults. Design: Qualitative study. Setting: Nova Scotia, Canada. Participants: Nurses, physicians, and pharmacists involved in the assessment, diagnosis, and treatment of bacteriuria in hospitalized patients. Methods: Focus groups (FGs) were completed between May and July 2019. FG discussions were facilitated using an interview guide that consisted of open-ended questions coded to the theoretical domains framework (TDF) v2. Discussions were transcribed verbatim then independently coded to the TDFv2 by two members of the research team and compared. Thematic analysis was used to identify themes. Results: Thirty-three healthcare providers from five hospitals participated (15 pharmacists, 11 nurses, and 7 physicians). The use of antibiotics for the treatment of asymptomatic bacteriuria (ASB) was the main issue identified. Subthemes that related to management of ASB included: "diagnostic uncertainty," difficulty "ignoring positive urine cultures," "organizational challenges," and "how people learn." Barriers and/or enablers to improving the management of bacteriuria were mapped to 12 theoretical domains within these subthemes. Barriers and enablers identified by participants that were most extensively discussed related to the domains of environmental context and resources, belief about capabilities, social/professional role and identity, and social influences. Conclusions: Healthcare providers highlighted barriers and recognized enablers that may improve delivery of care to patients with bacteriuria. A wide range of barriers at the individual and organization level to address diagnostic challenges and improve workload should be considered to improve management of bacteriuria.

Improving equity of services for sexually transmitted infections through community pharmacies: A scoping review.

BACKGROUND: Pharmacists have the potential to improve care for marginalized populations. Stigmatized and racialized groups may not find traditional health services accessible in other settings. Research focused on health care access for these populations is fundamental in understanding how to improve health equity. OBJECTIVES: This scoping review aimed to determine how health equity is addressed within services offered through community pharmacies for sexually transmitted infections (STIs). METHODS: This scoping review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews Checklist. A comprehensive search strategy was developed with an academic librarian to capture studies containing search terms related to each of the following 3 topics: STIs, pharmacy, and underserved groups. PubMed and Embase were both searched up to July 2023 and search results were uploaded to the screening software Covidence. Two researchers independently screened titles, abstracts, and full texts. Articles were included if they reported evaluation of a pharmacy-based sexual health service and addressed health equity in service design or implementation. RESULTS: A total of 8 articles were identified that described services implemented for underserved groups. Four populations were identified: injection drug users, men who have sex with men, racial minorities, and those with low socioeconomic status. Equity was addressed through 2 mechanisms: location-based implementation of services in areas of high target population density or through specific targeting of marginalized populations in recruitment and promotion. All studies involved interventions for the prevention or testing services rather than assessment and treatment. CONCLUSIONS: Equity is not being readily addressed in pharmacy-based services for STIs yet evidence exists that considering equity in the design and implementation of services may improve reach to underserved populations.

Understanding the malignant potential of gastric metaplasia of the oesophagus and its relevance to Barrett's oesophagus surveillance: individual-level data analysis.

OBJECTIVE: Whether gastric metaplasia (GM) of the oesophagus should be considered as Barrett's oesophagus (BO) is controversial. Given concern intestinal metaplasia (IM) may be missed due to sampling, the UK guidelines include GM as a type of BO. Here, we investigated whether the risk of misdiagnosis and the malignant potential of GM warrant its place in the UK surveillance. DESIGN: We performed a thorough pathology and endoscopy review to follow clinical outcomes in a novel UK cohort of 244 patients, covering 1854 person years of follow-up. We complemented this with a comparative genomic analysis of 160 GM and IM specimens, focused on early molecular hallmarks of BO and oesophageal adenocarcinoma (OAC). RESULTS: We found that 58 of 77 short-segment (<3 cm) GM (SS-GM) cases (75%) continued to be observed as GM-only across a median of 4.4 years of follow-up. We observed that disease progression in GM-only cases and GM+IM cases (cases with reported GM on some occasions, IM on others) was significantly lower than in the IM-only cases (Kaplan-Meier, p=0.03). Genomic analysis revealed that the mutation burden in GM is significantly lower than in IM (p<0.01). Moreover, GM does not bear the mutational hallmarks of OAC, with an absence of associated signatures and driver gene mutations. Finally, we established that GM found adjacent to OAC is evolutionarily distant from cancer. CONCLUSION: SS-GM is a distinct entity from SS-IM and the malignant potential of GM is lower than IM. It is questionable whether SS-GM warrants inclusion in BO surveillance.

Hypocretin / Orexin Receptor 1 Knockdown in GABA or Dopamine Neurons in the Ventral Tegmental Area Differentially Impact Mesolimbic Dopamine and Motivation for Cocaine.

The hypocretins/orexins (HCRT) have been demonstrated to influence motivation for cocaine through actions on dopamine (DA) transmission. Pharmacological or genetic disruption of the hypocretin receptor 1 (Hcrtr1) reduces cocaine self-administration, blocks reinstatement of cocaine seeking, and decreases conditioned place preference for cocaine. These effects are likely mediated through actions in the ventral tegmental area (VTA) and resulting alterations in DA transmission. For example, HCRT drives VTA DA neuron activity and enhances the effects of cocaine on DA transmission, while disrupting Hcrtr1 attenuates DA responses to cocaine. These findings have led to the perspective that HCRT exerts its effects through Hcrtr1 actions in VTA DA neurons. However, this assumption is complicated by the observation that Hcrtr1 are present on both DA and GABA neurons in the VTA and HCRT drives the activity of both neuronal populations. To address this issue, we selectively knocked down Hcrtr1 on either DA or GABA neurons in the VTA and examined alterations in DA transmission and cocaine self-administration in female and male rats. We found that Hcrtr1 knockdown in DA neurons decreased DA responses to cocaine, increased days to acquire cocaine self-administration, and reduced motivation for cocaine. Although, Hcrtr1 knockdown in GABA neurons enhanced DA responses to cocaine, this manipulation did not affect cocaine self-administration. These observations indicate that while Hcrtr1 on DA versus GABA neurons exert opposing effects on DA transmission, only Hcrtr1 on DA neurons affected acquisition or motivation for cocaine - suggesting a complex interplay between DA transmission and behavior.

Crowd-sourced observations of a polyphagous moth reveal evidence of allochronic speciation varying along a latitudinal gradient.

Allochronic speciation, where reproductive isolation between populations of a species is facilitated by a difference in reproductive timing, depends on abiotic factors such as seasonality and biotic factors such as diapause intensity. These factors are strongly influenced by latitudinal trends in climate, so we hypothesized that there is a relationship between latitude and divergence among populations separated by life history timing. Hyphantria cunea (the fall webworm), a lepidopteran defoliator with red and black colour morphs, is hypothesized to be experiencing an incipient allochronic speciation. However, given their broad geographic range, the strength of allochronic speciation may vary across latitude. We annotated >11,000 crowd-sourced observations of fall webworm to model geographic distribution, phenology, and differences in colour phenotype between morphs across North America. We found that red and black morph life history timing differs across North America, and the phenology of morphs diverges more in warmer climates at lower latitudes. We also found some evidence that the colour phenotype of morphs also diverges at lower latitudes, suggesting reduced gene flow between colour morphs. Our results demonstrate that seasonality in lower latitudes may increase the strength of allochronic speciation in insects, and that the strength of sympatric speciation can vary along a latitudinal gradient. This has implications for our understanding of broad-scale speciation events and trends in global biodiversity.

Developing Research-Informed Guidance on Preparing Pharmacy Students to Care for Diverse Populations.

OBJECTIVE: The purpose of this study was to develop research-informed guidance on how to better prepare students for working with diverse populations through exposure to diversity representation within case-based learning materials. METHODS: This was a qualitative interpretive phenomenological study using audio-recorded semi-structured interviews for data collection. Interviews were conducted virtually with 15 recent program alumni from Dalhousie University and 15 members from underrepresented communities in Nova Scotia, Canada. Audio-recordings were transcribed verbatim and framework analysis was used to code and categorize data. Themes were interpreted from categorized data and a conceptual model was developed based on the results. RESULTS: The conceptual model highlighted that awareness of diversity and health equity paired with practice and application of learning were perceived to be important for preparing graduates for practice. It was found that awareness could be best achieved through exposure to diversity within cases. To effectively expose students, programs must deliberately identify diverse populations to include, seek perspectives and engagement from those populations when writing cases, ensure conscientious representation of diversity without reinforcing stereotypes, and provide resources for discussion and further learning. CONCLUSION: Through the development of a conceptual model, this study provided research-informed guidance representing diversity within case-based learning materials. Findings support the notion that representation of diversity must be deliberate, conscientious, and collaborative with those offering diverse perspectives and lived experiences.

Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia.

Intestinal metaplasia in the esophagus (Barrett's esophagus IM, or BE-IM) and stomach (GIM) are considered precursors for esophageal and gastric adenocarcinoma, respectively. We hypothesize that BE-IM and GIM follow parallel developmental trajectories in response to differing inflammatory insults. Here, we construct a single-cell RNA-sequencing atlas, supported by protein expression studies, of the entire gastrointestinal tract spanning physiologically normal and pathologic states including gastric metaplasia in the esophagus (E-GM), BE-IM, atrophic gastritis, and GIM. We demonstrate that BE-IM and GIM share molecular features, and individual cells simultaneously possess transcriptional properties of gastric and intestinal epithelia, suggesting phenotypic mosaicism. Transcriptionally E-GM resembles atrophic gastritis; genetically, it is clonal and has a lower mutational burden than BE-IM. Finally, we show that GIM and BE-IM acquire a protumorigenic, activated fibroblast microenvironment. These findings suggest that BE-IM and GIM can be considered molecularly similar entities in adjacent organs, opening the path for shared detection and treatment strategies. SIGNIFICANCE: Our data capture the gradual molecular and phenotypic transition from a gastric to intestinal phenotype (IM) in the esophagus and stomach. Because BE-IM and GIM can predispose to cancer, this new understanding of a common developmental trajectory could pave the way for a more unified approach to detection and treatment. See related commentary by Stachler, p. 1291. This article is highlighted in the In This Issue feature, p. 1275.

Development of Quality Indicators to Evaluate the Appropriateness of Empiric Antimicrobial Use in Pediatric Patients.

Background: Use of quality indicators is one strategy recommended to assess antimicrobial prescribing for pediatric inpatients. Objective: To achieve consensus from infectious diseases clinicians on quality indicators that characterize appropriate empiric antimicrobial use for the management of infectious syndromes in pediatric inpatients. Methods: This study was completed using the Delphi technique. The research team developed an initial list of quality indicators, informed by a literature search. A multidisciplinary group of health care providers with expertise in infectious diseases was invited to participate. The list was disseminated to this panel of experts using Opinio survey software. The experts were asked to rate the indicators on a 9-point Likert scale in relation to the following criterion: "The importance of each item in determining appropriateness considering benefit or harm at the individual or population level". Consensus was defined as at least 75% agreement and a median score of 7 or higher. Results: Twelve of 31 invited experts completed at least 1 round of the survey, and 10 completed all rounds. Consensus was achieved on 28 of 31 proposed indicators after 3 rounds. Indicators with consensus were categorized under "empiric choice" (n = 12 indicators), "dose" (n = 5), "duration" (n = 2), "administration" (n = 4), "diagnosis" (n = 2), and "documentation" (n = 3). Six of the indicators for which consensus was achieved were rephrased by the experts. Conclusions: Consensus was achieved on quality indicators to assess the appropriateness of empiric antimicrobial use in pediatric patients. Clinicians and researchers can use these consensus-based indicators to assess adherence to best practice.

Contexte: L'utilisation d'indicateurs de qualité est l'une des stratégies recommandées pour évaluer la prescription d'antimicrobiens aux patients pédiatriques hospitalisés. Objectif: Parvenir à un consensus, entre les cliniciens des maladies infectieuses, portant sur les indicateurs de qualité qui caractérisent l'utilisation empirique appropriée des antimicrobiens pour la prise en charge des syndromes infectieux chez les patients pédiatriques hospitalisés. Méthodes: Cette étude a été réalisée à l'aide de la technique Delphi. L'équipe de recherche a dressé une liste initiale d'indicateurs de qualité éclairée par une recherche documentaire. Un groupe multidisciplinaire de prestataires de soins de santé ayant une expertise dans le domaine des maladies infectieuses a été invité à participer. La liste a été diffusée à ce panel d'experts à l'aide du logiciel d'enquête Opinio. Les experts ont été invités à noter les indicateurs sur une échelle de Likert de 9 points par rapport au critère suivant : « L'importance de chaque élément pour déterminer la pertinence compte tenu du bienfait ou du dommage à l'échelle individuelle ou de la population ¼. Le consensus était défini comme « Un accord d'au moins 75 % et un score médian d'au moins 7 ¼. Résultats: Douze des 31 experts invités ont terminé au moins 1 cycle de l'enquête et 10 les ont tous terminés. Un consensus a été atteint pour 28 des 31 indicateurs proposés après 3 cycles. Les indicateurs qui ont atteint le consensus ont été classés en « choix empirique ¼ (n = 12 indicateurs), « dose ¼ (n = 5), « durée ¼ (n = 2), « administration ¼ (n = 4), « diagnostic ¼ (n = 2) et « documentation ¼ (n = 3). Six indicateurs faisant consensus ont été reformulés par les experts. Conclusions: Un consensus a été atteint pour les indicateurs de qualité visant à évaluer l'utilisation empirique appropriée des antimicrobiens chez les patients pédiatriques. Les cliniciens et les chercheurs peuvent utiliser ces indicateurs basés sur le consensus pour évaluer le respect des meilleures pratiques.

Evaluating the impact of incorporating clinical practice guidelines for the management of infectious diseases into an electronic application (e-app).

OBJECTIVES: To improve dissemination and accessibility of guidelines to healthcare providers at our institution, guidance for infectious syndromes was incorporated into an electronic application (e-app). The objective of this study was to compare empiric antimicrobial prescribing before and after implementation of the e-app. DESIGN: This study was a before-and-after trial. SETTING: A tertiary-care, public hospital in Halifax, Canada. PARTICIPANTS: This study included pediatric patients admitted to hospital who were empirically prescribed an antibiotic for an infectious syndrome listed in the e-app. METHODS: Data were collected from medical records. Prescribing was independently assessed considering patient-specific characteristics using a standardized checklist by 2 members of the research team. Assessments of antimicrobial prescribing were compared, and discrepancies were resolved through discussion. Empiric antimicrobial prescribing before and after implementation of the e-app was compared using interrupted time-series analysis. RESULTS: In total, 237 patients were included in the preimplementation arm and 243 patients were included in the postimplementation arm. Pneumonia (23.8%), appendicitis (19.2%), and sepsis (15.2%) were the most common indications for antimicrobial use. Empiric antimicrobial use was considered optimal in 195 (81.9%) of 238 patients before implementation compared to 226 (93.0%) 243 patients after implementation. An immediate 15.5% improvement (P = .019) in optimal antimicrobial prescribing was observed following the implementation of the e-app. CONCLUSIONS: Empiric antimicrobial prescribing for pediatric patients with infectious syndromes improved after implementation of an e-app for dissemination of clinical practice guidelines. The use of e-apps may also be an effective strategy to improve antimicrobial use in other patient populations.

A Systematic Review of Antimicrobial Stewardship Interventions to Improve Management of Bacteriuria in Hospitalized Adults.

OBJECTIVE: To determine whether implementation of antimicrobial stewardship (AMS) interventions improve management of bacteriuria in hospitalized adults. DATA SOURCES: EMBASE, MEDLINE, CINAHL, and Clinical Trials Registries via Cochrane CENTRAL were searched from inception through May 2021. Reference lists of included studies were searched, and Scopus was used to retrieve articles that cited included references. STUDY SELECTION AND DATA EXTRACTION: Randomized and nonrandomized trials, controlled before-after studies, interrupted time-series studies, and repeated measures studies evaluating AMS interventions for hospitalized adult inpatients with bacteriuria were included. Risk of bias was assessed independently by 3 team members and compared. Results were summarized descriptively. DATA SYNTHESIS: The search yielded 5509 articles, of which 13 met inclusion criteria. Most common interventions included education (N = 8) and audit and feedback (N = 5) alone or in combination with other interventions. Where assessed, resource and antimicrobial use primarily decreased and appropriateness of antimicrobial use improved; however, impact on guideline adherence was variable. All studies were rated as having unclear or serious risk of bias. This review summarizes and assesses the quality of evidence for AMS interventions to improve the management of bacteriuria. Results provide guidance to both AMS teams and researchers aiming to develop and/or evaluate AMS interventions for management of bacteriuria. CONCLUSIONS: This review demonstrated benefit of AMS interventions on management of bacteriuria. However, most studies had some risk of bias, and an overall effect across studies is unclear due to heterogeneity in outcome measures.

Barriers and Facilitators Related to Delivery of Hospital Pharmacy Services to Women, Children, and Their Families during a Pandemic: A Qualitative Study.

Background: When the COVID-19 pandemic was declared in March 2020, health care professionals were challenged to adapt quickly and efficiently to change their work practices. However, an evidence-informed approach has not yet been used to systematically gather data on barriers and facilitators related to delivery of hospital pharmacy services in Canada. Objectives: The primary objective was to identify and describe barriers and facilitators related to the delivery of hospital pharmacy services to women, children, and their families during the COVID-19 pandemic. The secondary objective was to provide recommendations for improvement in delivery of pharmacy services to enhance patient care during pandemics. Methods: This qualitative study involved semistructured virtual interviews with pharmacists who worked in direct or nondirect patient care throughout the pandemic (since March 2020) at women's and/or children's hospitals in Canada. Individual interviews were completed virtually using conferencing software. An interview guide mapped to the Theoretical Domains Framework version 2 (TDFV2) was used to facilitate the interviews. Interviews were audio-recorded and transcribed verbatim by the principal investigator. Transcribed interviews were coded, mapped to the TDFV2, and analyzed using thematic analysis. Results: Interviews were completed with 21 pharmacists in 7 provinces across Canada. Barriers and facilitators coded to the TDFV2 were grouped into 4 main themes: communication and collaboration, adaptability, health and well-being, and preparedness. Conclusions: Participants highlighted a significant number of barriers that they experienced during the COVID-19 pandemic; overall, however, participants reported that they felt prepared for subsequent waves of the COVID-19 pandemic and future pandemics.

Contexte: Lors de la déclaration de la pandémie de COVID-19 en mars 2020, les professionnels de la santé ont été mis au défi de s'adapter rapidement et efficacement à la situation en changeant leurs pratiques professionnelles. Cependant, une approche fondée sur des données probantes pour recueillir systématiquement des données sur les obstacles à la prestation des services de pharmacie hospitalière au Canada et les éléments facilitant celle-ci n'a pas encore été utilisée de manière systématique. Objectifs: L'objectif principal consistait à identifier et à décrire les obstacles à la prestation de services de pharmacie hospitalière aux femmes, aux enfants et à leur famille et les éléments facilitant celle-ci pendant la pandémie de COVID-19. L'objectif secondaire consistait, quant à lui, à fournir des recommandations pour améliorer la prestation de services de pharmacie afin d'améliorer les soins aux patients pendant une pandémie. Méthodes: Cette étude qualitative comprenait des entrevues virtuelles semi-structurées avec des pharmaciens ayant travaillé dans le domaine des soins directs ou non directs aux patients tout au long de la pandémie (depuis mars 2020) dans des hôpitaux pour femmes et/ou enfants au Canada. Les entretiens individuels ont été réalisés virtuellement à l'aide d'un logiciel de conférence. Un guide d'entretien adapté de la 2e version du cadre des domaines théoriques (TDFV2) [Theoretical Domains Framework] a été utilisé pour faciliter les entretiens. Ceux-ci ont été enregistrés sur bande audio et retranscrits textuellement par le chercheur principal. Les entretiens ainsi retranscrits ont été codés, reportés sur le TDFV2 et analysés par thème. Résultats: Des entrevues ont été réalisées auprès de 21 pharmaciens dans 7 provinces du Canada. Les obstacles et les éléments facilitateurs codés selon le TDFV2 ont été regroupés en 4 grands thèmes: communication et collaboration; adaptabilité; santé et bien-être; et état de préparation. Conclusions: Les participants ont mentionné un nombre important d'obstacles qu'ils ont rencontrés pendant la pandémie de COVID-19; dans l'ensemble, cependant, les participants ont déclaré qu'ils se sentaient préparés aux vagues ultérieures de la pandémie de COVID-19 et aux futures pandémies.

Anesthetic Management of a Patient With S-Adenosylhomocysteine Hydrolase Deficiency: A Case Report.

S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare congenital disorder in methionine metabolism with minimal guidelines regarding anesthetic management. This case report describes a 19-year-old man presenting for a liver biopsy in interventional radiology due to a history of elevated aminotransferases and creatine kinase. He received dextrose-containing fluids and a total intravenous anesthetic to avoid rhabdomyolysis and hyperkalemia. Anesthetic goals for patients with AHCY deficiency should focus on avoiding rhabdomyolysis, minimizing postoperative ventilatory compromise, monitoring for potential coagulopathy, and providing anxiolysis.

Disease and medication burden of medically complex adolescents seen in an interdisciplinary transitional care clinic.

PURPOSE: Transitional care for adolescents with complex diseases, who are entering adulthood, is challenging. The purpose of this study is to quantify the disease and medication burden of this population, who are transitioning though an interdisciplinary specialty clinic. METHODS: This study is a retrospective observational study of all patients seen in a transitional care clinic between July 2012 and March 2015. The main outcomes assessed included disease state and medication burden. Descriptive statistics, along with the paired t-test and McNemar's test, were used. RESULTS: The study cohort included 216 patients. The median patient age was 20.7 years, and the median number of clinic encounters was 6. Patients had at least 1 of 8 primary diagnoses. On average, patients took medications from 5 classes and used 3 dose forms. Among 163 patients who had medication reconciliation performed, the average number of medication classes increased by 0.44±1.53 (p = 0.0003). There was an average increase of 3.70%(SD±36.31%; p = 0.27) in the number of required medication lab assessments ordered for patients who had medication reconciliation performed. CONCLUSION: There is a high disease and medication burden among adolescent patients with complex disease states who are to transition to adult care.

Craniofacial features of 3q29 deletion syndrome: Application of next-generation phenotyping technology.

3q29 deletion syndrome (3q29del) is a recurrent deletion syndrome associated with neuropsychiatric disorders and congenital anomalies. Dysmorphic facial features have been described but not systematically characterized. This study aims to detail the 3q29del craniofacial phenotype and use a machine learning approach to categorize individuals with 3q29del through analysis of 2D photos. Detailed dysmorphology exam and 2D facial photos were ascertained from 31 individuals with 3q29del. Photos were used to train the next-generation phenotyping algorithm DeepGestalt (Face2Gene by FDNA, Inc, Boston, MA) to distinguish 3q29del cases from controls and all other recognized syndromes. Area under the curve of receiver operating characteristic curves (AUC-ROC) was used to determine the capacity of Face2Gene to identify 3q29del cases against controls. In this cohort, the most common observed craniofacial features were prominent forehead (48.4%), prominent nose tip (35.5%), and thin upper lip vermillion (25.8%). The FDNA technology showed an ability to distinguish cases from controls with an AUC-ROC value of 0.873 (p = 0.006) and led to the inclusion of 3q29del as one of the supported syndromes. This study found a recognizable facial pattern in 3q29del, as observed by trained clinical geneticists and next-generation phenotyping technology. These results expand the potential application of automated technology such as FDNA in identifying rare genetic syndromes, even when facial dysmorphology is subtle.

Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes.

BACKGROUND: ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans. METHODS: To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants. RESULTS: We report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. The variants included four missense variants inherited in trans to loss-of-function alleles (p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val)), a homozygous missense variant p.(Arg327Pro), and a heterozygous non-frameshift indel p.(Lys568del). Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy. Drosophila studies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles leading to early developmental lethality. Further, we showed that Phe50Leu, Gly236Val, and Arg327Pro cause neurogenesis defects. On the contrary, Leu77Val and Arg170Trp are partial loss-of-function alleles that cause progressive locomotion defects and whose expression leads to an increase in autophagy and mitophagy in adult muscles. CONCLUSION: Our findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation.

Heterogeneous Pulmonary Phenotypes in Filamin A Mutation-Related Lung Disease.

Background: Interstitial lung disease (ILD) has been recently reported in a few patients with pathogenic variants in the Filamin A (FLNA) gene with variable presentation and prognosis. This study evaluated the respiratory manifestations and clinical features in children with FLNA disease. Methods: We conducted a retrospective review of pediatric patients with variants in FLNA in a tertiary children's hospital. The clinical features, genotype, management, and outcomes were analyzed. Results: We identified 9 patients with variants in FLNA aged 15 months to 24 years, 4 females and 5 males. Six patients had abnormal chest imaging ranging from mild interstitial prominence to atelectasis, interstitial densities, and hyperinflation. Three patients with ILD presented during the neonatal period or early infancy with respiratory distress or respiratory failure requiring supplemental oxygen or assisted ventilation via tracheostomy. We report male twins with the same FLNA variant and lung disease, but different ages and clinical features at presentation eventually culminating in respiratory failure requiring assisted ventilation. All patients had FLNA variants identified by FLNA sequencing, had abnormal echocardiograms, and none of the patients underwent lung biopsy or lung transplantation. The outcomes were variable and could be as severe as chronic respiratory failure. Conclusion: The wide spectrum of respiratory manifestations and abnormal chest imaging in our study highlights the importance of evaluation for lung disease in patients with variants in FLNA. FLNA sequencing in suspected cases with ILD may obviate the need for a lung biopsy, prompt surveillance for progressive lung disease, and evaluation for associated clinical features.

Self-care education across Canadian pharmacy schools: Curriculum survey findings.

BACKGROUND: Self-care instruction in pharmacy curricula is essential given the impact pharmacists have in caring for patients in the community and their evolving role in this area. The primary objective of this study was to strengthen our current understanding of self-care education across undergraduate Canadian pharmacy programs. METHODS: A national curriculum survey and follow-up phone interview was conducted in 2019 to assess the quantity and quality of self-care instruction across Canadian pharmacy schools. Representatives were selected based on theirparticipation in the Association of Faculties of Pharmacy of Canada Self-Care Therapeutics and Minor Ailments special interest group. RESULTS: Responses were received from all 10 pharmacy schools in Canada. Self-care education varies across Canadian pharmacy curricula, reflecting differences in scopes of practice across provinces, topics of interest and availability of space within curricula by the various faculties. Specifically, there was considerable variability in the number of hours devoted to self-care education, course content and methods for integration and teaching. CONCLUSIONS: Results of this study may help inform and evolve self-care curricula across the country. We argue that strategies for enhancing current programs may include establishing a minimum number of core hours and topics, expanding natural health product content and curricular content oversight by a lead faculty member. Can Pharm J (Ott) 2021;154:xx-xx.