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Background: Beta-blockers (BBs) are commonly prescribed to manage arrhythmias in children and adolescents without any standardised approach to establish BB adequacy. We invited all Canadian pediatric cardiologists to participate in an anonymous survey to understand practice variation in the assessment of BB adequacy in school-aged children and adolescents with arrhythmia or the potential for arrhythmia. Methods: An electronic survey approved by the Institutional Ethics Board was distributed by e-mail to 96 Canadian pediatric cardiologists who had been active in practice for at least 1 year. Incomplete surveys were excluded. Results: Forty-one cardiologists (43%) responded to all questions in the survey. Thirteen cardiologists (32%) reported always assessing BB adequacy, 17 (41%) did so only for specific arrhythmias, and 11 (27%) reported never performing such an assessment. A total of 19 cardiologists (46%) and 18 cardiologists (44%) reported using Holter monitoring and exercise testing, respectively, to assess beta receptor blockade adequacy. Thirteen cardiologists (32%) considered BB therapy adequate if Holter demonstrated a 20% decrease in heart rate (HR) from baseline, and 10 respondents (24%) defined adequate BB therapy using exercise testing as a 20% decrease in maximal HR or blood pressure from baseline. Conclusion: Despite wide variation in practice, Holter monitoring and exercise testing are commonly used methods to measure the adequacy of BB therapy. There are no standard criteria, but the majority (56%) reported using a 20% decrease in HR or blood pressure from the pretreatment state as a criterion for adequate BB therapy in children and adolescents with arrhythmia or the potential for arrhythmia. Résumé: Contexte: Les bêtabloquants (BB) sont couramment prescrits pour traiter les arythmies chez l’enfant et l’adolescent, en l’absence de méthode standardisée permettant d’établir le caractère adéquat du traitement par ces agents. Nous avons invité tous les cardiologues pédiatriques canadiens à participer anonymement à une enquête visant à rendre compte de la variabilité observée en pratique dans l’évaluation du caractère adéquat du traitement par BB chez l’enfant d’âge scolaire ou l’adolescent atteints d’arythmie ou susceptibles de l’être. Méthodologie: Un questionnaire électronique approuvé par le comité d’éthique en établissement a été distribué par courriel à 96 cardiologues pédiatriques canadiens en exercice depuis au moins un an. Les questionnaires partiellement remplis ont été exclus. Résultats: Parmi les participants, 41 cardiologues (43 %) ont répondu à toutes les questions de l’enquête. D’après les réponses obtenues, 13 cardiologues (32 %) évaluent toujours le caractère adéquat du traitement par BB, 17 (41 %) l’évaluent uniquement en présence de certains types d’arythmies et 11 (27 %) ne l’évaluent jamais. Au total, parmi les cardiologues interrogés, 19 (46 %) et 18 (44 %) affirment avoir recours respectivement à l’électrocardiographie (ECG) ambulatoire et à l’épreuve d’effort pour évaluer le caractère adéquat du blocage des récepteurs bêta. Ainsi, 13 cardiologues (32 %) jugent que le traitement par BB est adéquat si l’enregistrement ECG ambulatoire démontre une diminution de 20 % de la fréquence cardiaque (FC) maximale par rapport à la valeur de référence, et 10 cardiologues (24 %) estiment qu’il en est de même si le résultat obtenu à l’épreuve d’effort démontre une diminution de 20 % de la FC maximale ou de la pression artérielle par rapport aux valeurs de référence. Conclusion: Malgré de grandes variations observées en pratique, l’ECG ambulatoire et l’épreuve d’effort sont des méthodes couramment utilisées pour mesurer le caractère adéquat du traitement par BB. Il n’existe pas de critères standard, mais la majorité (56 %) des répondants ont indiqué qu’une diminution de 20 % de la FC ou de la pression artérielle par rapport aux valeurs de référence obtenues avant le traitement constitue un critère du caractère adéquat du traitement par BB chez l’enfant ou l’adolescent atteints d’arythmie ou susceptibles de l’être.

Summary: Biliary tract cancers (BTCs) currently have no approved targeted therapies. Although genomic profiling of primary BTCs has identified multiple potential drug targets, accurate models are needed for their evaluation. Genomic profiling of 22 BTC cell lines revealed they harbor similar mutational signatures, recurrently mutated genes, and genomic alterations to primary tumors. Transcriptomic profiling identified two major subtypes, enriched for epithelial and mesenchymal genes, which were also evident in patient-derived organoids and primary tumors. Interrogating these models revealed multiple mechanisms of MAPK signaling activation in BTC, including co-occurrence of low-activity BRAF and MEK mutations with receptor tyrosine kinase overexpression. Finally, BTC cell lines with altered ERBB2 or FGFRs were exquisitely sensitive to specific targeted agents, whereas surprisingly, IDH1-mutant lines did not respond to IDH1 inhibitors in vitro. These findings establish BTC cell lines as robust models of primary disease, reveal specific molecular disease subsets, and highlight specific molecular vulnerabilities in these cancers. : Biological Sciences; Genetics; Genomics; Cancer Subject Areas: Biological Sciences, Genetics, Genomics, Cancer

Background: Medical therapy is often prescribed to reduce the rate of aortic dilatation and prevent aortic dissection in patients with bicuspid aortic valve (BAV) despite a lack of evidence. We conducted an anonymous survey to gain insight into Canadian clinical practice regarding medical therapy used to slow the progression of aortic dilatation in patients with BAV. Methods: A questionnaire was sent to 115 paediatric cardiologists and 18 adult congenital heart disease specialists in Canada. Results: Ninety of 113 paediatric cardiologists (80%) completing the questionnaire reported prescribing medication to reduce the rate of aortic dilatation. Some 75% (61/81) of them reported prescribing medications on the basis of aortic size z scores, and 78% (48/61) considered medication at a z score between ≥ 2 and < 5. The remaining 25% of responders (20/81) reported prescribing medications on the basis of absolute aortic diameter, and 80% (16/20) of them considered initiating medical therapy at an aortic diameter > 40 mm to < 50 mm. For practical purposes, however, 40% of respondents (45/113) would not or rarely consider medical therapy for this indication because of variation in the threshold for initiating treatment. Ten of 14 adult congenital heart disease specialists’ responses (71%), reported prescribing medications who were excluded because of missing data. Conclusion: The majority of Canadian paediatric cardiologists reported prescribing medications to slow the rate of aortic dilatation in patients with BAV. However, there is heterogeneity in the criteria to prescribe medical therapy. A multicenter randomized controlled trial is needed to establish the role of medical therapy in this patient population. Résumé: Introduction: En dépit du manque de données probantes, un traitement médical est souvent prescrit pour réduire le taux de dilatation aortique et prévenir la dissection aortique chez les patients ayant une bicuspidie aortique (BA). Nous avons mené une enquête anonyme pour avoir un aperçu de la pratique clinique au Canada en ce qui concerne le traitement médical utilisé pour ralentir la progression de la dilatation aortique chez les patients ayant une BA. Méthodes: Nous avons envoyé un questionnaire à 115 cardiologues en pédiatrie et à 18 spécialistes en cardiopathie congénitale de l’adulte du Canada. Résultats: Quatre-vingt-dix des 113 cardiologues en pédiatrie (80 %) ayant rempli le questionnaire ont signalé prescrire des médicaments pour réduire le taux de dilatation aortique. Certains d’entre eux, soit 75 % (61/81) ont signalé prescrire des médicaments en fonction du Z-score de la taille aortique, et 78 % (48/61) ont envisagé de prescrire les médicaments lorsque le Z-score était entre ≥ 2 et < 5. Les 25 % de répondants restants (20/81) ont signalé prescrire des médicaments en fonction du diamètre aortique absolu, et 80 % (16/20) d’entre eux ont envisagé de faire commencer le traitement médical lorsque le diamètre aortique était entre > 40 mm et < 50 mm. Concrètement, toutefois, 40 % des répondants (45/113) n’ont pas envisagé ou ont rarement envisagé de prescrire un traitement médical pour cette indication en raison de la variation dans le seuil de mise en place du traitement. Dix des 14 réponses (71 %) des spécialistes de la cardiopathie congénitale de l’adulte ont signalé prescrire des médicaments qui étaient exclus en raison de données manquantes. Conclusion: La majorité des cardiologues en pédiatrie du Canada ont signalé prescrire des médicaments pour ralentir le taux de dilatation aortique chez les patients ayant une BA. Toutefois, les critères utilisés pour prescrire un traitement médical sont hétérogènes. Un essai clinique multicentrique et à répartition aléatoire est nécessaire pour déterminer le rôle du traitement médical dans cette population de patients.

Summary: Background: The Lancet Commission on Global Surgery established the Three Delays framework, categorising delays in accessing timely surgical care into delays in seeking care (First Delay), reaching care (Second Delay), and receiving care (Third Delay). Globally, knowledge gaps regarding delays for fracture care, and the lack of large prospective studies informed the rationale for our international observational study. We investigated delays in hospital admission as a surrogate for accessing timely fracture care and explored factors associated with delayed hospital admission. Methods: In this prospective observational substudy of the ongoing International Orthopaedic Multicenter Study in Fracture Care (INORMUS), we enrolled patients with fracture across 49 hospitals in 18 low-income and middle-income countries, categorised into the regions of China, Africa, India, south and east Asia, and Latin America. Eligible patients were aged 18 years or older and had been admitted to a hospital within 3 months of sustaining an orthopaedic trauma. We collected demographic injury data and time to hospital admission. Our primary outcome was the number of patients with open and closed fractures who were delayed in their admission to a treating hospital. Delays for patients with open fractures were defined as being more than 2 h from the time of injury (in accordance with the Lancet Commission on Global Surgery) and for those with closed fractures as being a delay of more than 24 h. Secondary outcomes were reasons for delay for all patients with either open or closed fractures who were delayed for more than 24 h. We did logistic regression analyses to identify risk factors of delays of more than 2 h in patients with open fractures and delays of more than 24 h in patients with closed fractures. Logistic regressions were adjusted for region, age, employment, urban living, health insurance, interfacility referral, method of transportation, number of fractures, mechanism of injury, and fracture location. We further calculated adjusted relative risk (RR) from adjusted odds ratios, adjusted for the same variables. This study was registered with ClinicalTrials.gov, NCT02150980, and is ongoing. Findings: Between April 3, 2014, and May 10, 2019, we enrolled 31 255 patients with fractures, with a median age of 45 years (IQR 31–62), of whom 19 937 (63·8%) were men, and 14 524 (46·5%) had lower limb fractures, making them the most common fractures. Of 5256 patients with open fractures, 3778 (71·9%) were not admitted to hospital within 2 h. Of 25 999 patients with closed fractures, 7141 (27·5%) were delayed by more than 24 h. Of all regions, Latin America had the greatest proportions of patients with delays (173 [88·7%] of 195 patients with open fractures; 426 [44·7%] of 952 with closed fractures). Among patients delayed by more than 24 h, the most common reason for delays were interfacility referrals (3755 [47·7%] of 7875) and Third Delays (cumulatively interfacility referral and delay in emergency department: 3974 [50·5%]), while Second Delays (delays in reaching care) were the least common (423 [5·4%]). Compared with other methods of transportation (eg, walking, rickshaw), ambulances led to delay in transporting patients with open fractures to a treating hospital (adjusted RR 0·66, 99% CI 0·46–0·93). Compared with patients with closed lower limb fractures, patients with closed spine (adjusted RR 2·47, 99% CI 2·17–2·81) and pelvic (1·35, 1·10–1·66) fractures were most likely to have delays of more than 24 h before admission to hospital. Interpretation: In low-income and middle-income countries, timely hospital admission remains largely inaccessible, especially among patients with open fractures. Reducing hospital-based delays in receiving care, and, in particular, improving interfacility referral systems are the most substantial tools for reducing delays in admissions to hospital. Funding: National Health and Medical Research Council of Australia, Canadian Institutes of Health Research, McMaster Surgical Associates, and Hamilton Health Sciences.

Allogeneic stem cell transplant-derived T cells have the potential to seek and eliminate sites of residual cancer that escaped primary therapy. Oncolytic myxoma virus (MYXV) exhibits potent anti-cancer efficacy against human cancers like multiple myeloma (MM) and can arm transplant-derived T cells to become more effective cancer killers in vitro and in an immunodeficient xenotransplant murine model. Here, we tested ex vivo MYXV virotherapy against residual murine MM in immunocompetent mice using an allogeneic mouse-mouse model. In contrast to all human MM cell lines previously tested, the murine MM cell line tested here was highly resistant to direct MYXV infection and oncolysis in vitro. Despite this in vitro resistance, we found that ex vivo MYXV-armed allogeneic bone marrow (BM) transplantation dramatically ablated pre-seeded residual MM in vivo. Unexpectedly, we show that both neutrophils and activated T cells from the donor function as virus-armed carrier cells, and MYXV-preloaded cells enhanced MM killing. Our results demonstrate a novel therapeutic paradigm for residual cancer, in which multiple classes of allotransplant leukocytes can be armed by MYXV ex vivo to enhance the graft-versus-tumor effects.

Summary: Background: Globally, fall-related injuries are a substantial problem, and 80% of fatal falls occur in low-income and middle-income countries. We aimed to measure time from injury to hip-fracture surgery in people aged 50 years or older living in low-income and middle-income regions, as well as to measure the proportion of patients with surgical stabilisation of their hip fracture within 72 h of admission to hospital and to identify risk factors associated with surgical delay. Methods: For this secondary analysis, we analysed data collected from Africa, Latin America, China, India, and Asia (excluding China and India) for the International Orthopaedic Multicentre Study in Fracture Care (INORMUS) between March 29, 2014, and June 15, 2022. Patients from INORMUS were included in this analysis if they were aged 50 years or older and had an isolated, primary hip fracture sustained from a ground-level fall. Staff at participating hospitals identified patients with musculoskeletal injury and referred them for assessment of eligibility. We report time from injury to surgery as three distinct time periods: time from injury to hospital admission, time from admission to surgery, and a total time from injury to surgery. Date and time of injury were self-reported by patients at the time of study recruitment. If time to hospital admission after injury exceeded 24 h, patients reported the primary reason for delayed admission. Reasons for surgery, no surgery, and surgical delay were reported by the treating team. For patients undergoing surgery, multivariable regression analyses were used to identify risk factors for surgical delay. Findings: 4486 adults aged 50 years or older with an isolated, primary hip fracture were enrolled in INORMUS from 55 hospitals in 24 countries. Countries were grouped into five regions: Africa (418 [9·3%] of 4486), Latin America (558 [12·4%]), China (1680 [37·4%]), India (1059 [23·6%]) and Asia (excluding China and India; 771 [17·2%]). Of 4486 patients, 3805 (84·8%) received surgery. The rate of surgery was similar in all regions except in Africa, where only 193 (46·3%) of 418 patients had surgery. Overall, 2791 (62·2%) of 4486 patients were admitted to hospital within 24 h of injury. However, 1019 (22·7%) of 4486 patients had delayed hospital admission of 72 h or more from injury. The two most common reasons for delayed admission of more than 24 h were transfer from another hospital (522 [36·2%] of 1441) and delayed care-seeking because patients thought the injury would heal on its own (480 [33·3%]). Once admitted to hospital, 1451 (38·1%) of 3805 patients who received surgery did so within 72 h (median 4·0 days [IQR 1·7–6·0]). Regional variation was seen in the proportion of patients receiving surgery within 72 h of hospital admission (92 [17·9%] of 514 in Latin America, 53 [27·5%] of 193 in Africa, 454 [30·9%] of 1471 in China, 318 [44·4%] of 716 in Asia [excluding China and India], and 534 [58·6%] of 911 in India). Of all 3805 patients who received operative treatment, 2353 (61·8%) waited 72 h or more from hospital admission. From time of injury, the proportion of patients who were surgically stabilised within 72 h was 889 (23·4%) of 3805 (50 [9·7%] of 517 in Latin America, 31 [16·1%] of 193 in Africa, 277 [18·8%] of 1471 in China, 189 [26·4%] of 716 in Asia [excluding China and India], and 342 [37·5%] of 911 in India). Interpretation: Access to surgery within 72 h of hospital admission was poor, with factors that affected time to surgery varying by region. Data are necessary to understand existing pathways of hip-fracture care to inform the local development of quality-improvement initiatives. Funding: The National Health and Medical Research Council of Australia, the Canadian Institutes of Health Research, McMaster Surgical Associates, Hamilton Health Sciences, and the US National Institutes of Health.

A review of the role of sulfur (S) in crop production is presented, with a particular emphasis on major crops including corn (Zea mays L.), rice (Oryza sativa L.), and wheat (Triticum aestivum L.). Specifically, S demand and availability, nutritive effects in improving yield, its effect on quality in major crops, different diagnostic methods, and future perspectives of S research are discussed. Sulfur plays a crucial role in synthesizing proteins, chlorophyll, enzymes, and vitamins, as well as influencing general metabolic and photosynthetic mechanisms. In the early 1950s, S deficiency was only noted in specific soils, but now it is becoming universally deficient. The amount of plant-available S in the soil has decreased by 34–86 % between 2000 and 2020, leaving crop production at risk. The reasons for widespread S deficiency include lower industrial atmospheric deposition, stricter environmental laws, prevailing management practices such as selection of high-yielding varieties, increased use of low S fertilizers, decreased use of S containing fungicides and insecticides, and in some cases reduced tillage intensity. Nonetheless, researchers have attempted to trans-genetically produce more S-use-efficient crops, explored possibilities where S metabolites could contribute to synergism in interactions of plant and rhizosphere microorganisms in enhancing S mineralization. Moreover, proven strategies tailored to S are necessary to increase site-specific management. Owing to the significant role of S in crop production, it is important to explore improvement in S uptake, S use efficiency, systematic S fertilizing strategies, and precise and timely S diagnostic tools.

Children frequently present with symptoms of palpitations. These symptoms can occur in isolation or in association with other presentations such as chest pain, presyncope, or syncope. Usually, their symptoms are episodic in occurrence; therefore, establishment of symptom-rhythm correlation is challenging but critical for accurate diagnosis and management. We reviewed the use of smartphone-based wireless electrocardiogram monitoring with AliveCor Kardia, to establish symptom-rhythm correlation in a paediatric case series at a single Canadian tertiary care centre. Résumé: Les enfants présentent fréquemment des symptômes de palpitations. Ces symptômes peuvent se produire isolément ou en association avec d’autres manifestations comme la douleur thoracique, la présyncope ou la syncope. Habituellement, les symptômes sont épisodiques, d’où la difficulté d’établir une corrélation entre les symptômes et le rythme cardiaque, un exercice pourtant essentiel pour poser un diagnostic précis et assurer la prise en charge du patient. Nous avons passé en revue les données relatives à la surveillance électrocardiographique sans fil effectuée au moyen d’un téléphone intelligent via la technologie Kardia d’AliveCor afin d’établir une telle corrélation dans une série de cas pédiatriques issue d’un même centre de soins tertiaires canadien.

Background: Several medication choices are available for acute and prophylactic treatment of refractory supraventricular tachycardia (SVT) in infants. There are almost no controlled trials, and medication choices are not necessarily evidence based. Our objective was to report the effectiveness of management strategies for infant SVT. Methods: A registry of infants admitted to hospital with re-entrant SVT and no haemodynamically significant heart disease were prospectively followed at 11 international tertiary care centres. In addition, a systematic review of studies on infant re-entrant SVT in MEDLINE and EMBASE was conducted. Data on demographics, symptoms, acute and maintenance treatments, and outcomes were collected. Results: A total of 2534 infants were included: n = 108 from the registry (median age, 9 days [0-324 days], 70.8% male) and n = 2426 from the literature review (median age, 14 days; 62.3% male). Propranolol was the most prevalent acute (61.4%) and maintenance treatment (53.8%) in the Registry, whereas digoxin was used sparingly (4.0% and 3.8%, respectively). Propranolol and digoxin were used frequently in the literature acutely (31% and 33.2%) and for maintenance (17.8% and 10.1%) (P < 0.001). No differences in acute or prophylactic effectiveness between medications were observed. Recurrence was higher in the Registry (25.0%) vs literature (13.4%) (P

Sea buckthorn is a natural source of vitamins and several other bioactive compounds such as carotenoids and flavonoids, which have been claimed to lower cholesterol, platelet aggregation, blood pressure and blood sugar. In addition, sea buckthorn is considered to be useful in treating tumours, stomach ulcers, skin diseases and arsenic poisoning. Accumulating evidence suggests that sea buckthorn is a promising plant that could serve as a natural remedy for the reduction of cardiovascular disease (CVD) risk and other health related problems such as diabetes, inflammatory diseases, thrombosis and cancer. However, double blind clinical trials need to be conducted to evaluate the efficacy and safety of sea buckthorn products in the prevention and therapy of CVD as well as other medical conditions. This mini review is focused on the beneficial effects of sea buckthorn with particular emphasis on the preventive and therapeutic aspects of CVD.

Background: Individuals with COPD have increased sensitivity to traffic-related air pollution (TRAP) such as diesel exhaust (DE), but little is known about the acute effects of TRAP on exercise responses in COPD., Research Question: Does exposure before exercise to TRAP (DE titrated to 300 μg/m 3 particulate matter < 2.5 μm in diameter [DE 300 ]) show greater adverse effects on exercise endurance, exertional dyspnea, and cardiorespiratory responses to exercise in participants with mild to moderate COPD compared with former smokers with normal spirometry and healthy control participants?, Study Design and Methods: In this double-blind, randomized, placebo-controlled, crossover study, 11 healthy control participants, nine former smokers without COPD, and nine former smokers with COPD were separately exposed to filtered air (FA) and DE 300 for 2 h separated by a minimum of 4 weeks. Participants performed symptom-limited constant load cycling tests within 2.5 h of exposure with detailed cardiorespiratory and exertional symptom measurements., Results: A significant negative effect of TRAP on exercise endurance time was found in healthy control participants (DE 300 vs FA, 10.2 ± 8.2 min vs 12.9 ± 9.5 min, respectively; P = .03), but not in former smokers without COPD (10.1 ± 6.9 min vs 12.2 ± 8.0 min, respectively; P = .57) or former smokers with COPD (9.8 ± 6.4 min vs 8.4 ± 6.6 min, respectively; P = .31). Furthermore, significant increases in inspiratory duty cycle and absolute end-expiratory and end-inspiratory lung volumes were observed, and dyspnea ratings were elevated at select submaximal measurement times only in healthy control participants., Interpretation: Contrary to our hypothesis, it was the healthy control participants, rather than the former smokers with and without COPD, who were negatively impacted by TRAP during exercise., Trial Registry: ClinicalTrials.gov; No.: NCT02236039; URL: www., Clinicaltrials: gov., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Fetal compressive intrapericardial teratoma is a rare and life-threatening condition, qualifying as a high-acuity low-occurrence (HALO) event. To prepare for delivery and immediate neonatal management, specialists from pediatric cardiology, cardiac surgery, maternal-fetal-medicine, neonatology, cardiac anesthesia, critical care, clinical perfusion, obstetrical nursing, and operating room nursing convened. An in situ operating room simulation was used to identify and introduce key team members, derive and practice the anticipated clinical management algorithm, position human and equipment resources strategically, and ensure that each specialist team was familiar with the environment and available equipment. As rehearsed in the simulation, the cesarean delivery of the patient and neonatal cardiac surgery was uncomplicated and yielded a favourable clinical outcome. A patient-specific HALO simulation preparation (PSHSP) can facilitate positive clinical outcomes and improve health care team confidence in HALO scenarios such as the birth of newborns anticipated to have cardiorespiratory instabilty., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Unexplained cardiac arrest (UCA) is rare in children. Despite investigations, the etiology in up to one-half of patients remains unknown., Objective: The purpose of this study was to assess the management and outcomes of pediatric UCA survivors through the Canadian Pediatric Heart Rhythm Network., Methods: A retrospective case series of children (age 1-19 years) who presented with UCA between January 1, 2004, and November 1, 2017, was conducted. Patients with known heart disease pre-UCA were excluded. UCA details, investigations, genetic test results, treatment, implantable cardioverter-defibrillator (ICD) data, subsequent diagnoses, and family screening data were collected., Results: Forty-six patients (61% male) were survivors of sudden unexpected death and met inclusion criteria at 8 participating sites. Median age at UCA was 13.8 years (interquartile range [IQR] 9-16 years). Baseline retrievable investigations included electrocardiogram (96%), echocardiogram (85%), exercise stress test (73%), and cardiac magnetic resonance imaging (57%). The presumed etiology for the UCA was identified in 24 (52%), mainly long QT syndrome or catecholaminergic polymorphic ventricular tachycardia. Genetic testing was performed in 33 of 46 (72%), with pathogenic/likely pathogenic variants identified in 13 of 33 (39%) and variants of uncertain significance in 8 of 33 (24%). ICDs were implanted in 35 of 46 (76%). Over median follow-up of 36 months (IQR 17-57 months), 8 of 35 had arrhythmia events captured on device interrogation. Families of 26 of 46 patients(57%) underwent screening, leading to a cardiac diagnosis in 6 of 26 families., Conclusion: A cause for UCA was not identified in nearly 50% of patients despite extensive investigations, including cascade screening. A large proportion (75%) of ICD shocks occurred in patients without a diagnosis., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

A next-generation sequencing method was developed that can distinguish single-stranded modifications from low-frequency somatic mutations present on both strands of DNA in formalin-fixed paraffin-embedded colorectal cancer samples. We applied this method for analytical validation of the Praxis Extended RAS Panel, a US Food and Drug Administration-approved companion diagnostic for panitumumab, on the Illumina MiSeqDx platform. With the use of the TruSeq amplicon workflow, both strands of DNA from the starting material were interrogated independently. Mutations were reported only if found on both strands; artifacts usually present on only one strand would not be reported. A total of 56 mutations were targeted within the KRAS and NRAS genes. A minimum read depth of 1800× per amplicon is required per sample but averaged >30,000× at maximum multiplexing levels. Analytical validation studies were performed to determine the simultaneous detection of mutations on both strands, reproducibility, assay detection level, precision of the assay across various factors, and the impact of interfering substances. In conclusion, this assay can clearly distinguish single-stranded artifacts from low-frequency mutations. Furthermore, the assay is accurate, precise, and reproducible, can achieve consistent detection of a mutation at 5% mutation frequency, exhibits minimal impact from tested interfering substances, and can simultaneously detect 56 mutations in a single run using 10 samples plus controls., (Copyright © 2020 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

We report a case of recurrent strokes in a healthy teenager after complete closure of atrial septal defect with Gore Septal Occluder (W.L. Gore and Associates, Newark, DE) device. The disk of the device produced a friction injury to the left atrial endocardium promoting thrombus formation with subsequent embolization to the brain requiring surgical intervention., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Identifying spinal landmarks by palpation is a prerequisite to many manual therapy procedures. Understanding if landmark depth changes with a subject's body mass index (BMI) may help clinicians attribute importance to their palpation findings. In this study, 105 consecutive subjects were referred for lumbar magnetic resonance imaging (MRI) in a hospital setting. Four blinded examiners measured T1-weighted MRI images to quantify the depth of spinous and transverse processes in the lumbar spine. For each process, a linear mixed-effects model was carried out by gender with depth as the outcome and BMI as a covariate. The average BMI for males (n = 57) was 27.52 kg/m(2) and 27.02 kg/m(2) for females. The mean landmark depth was 22.77 mm, 23.00 mm, 27.40 mm, 33.40 mm, 36.65 mm for spinous processes L1-L5 respectively and 69.35 mm and 69.41 mm for the left and right L4 transverse processes. The inter-evaluator, intra-class correlation coefficient averaged 0.98 for all depth measurements. The linear relationship between depth and BMI was statistically significant for all landmarks in females and only for spinous processes in males. In conclusion, the strength of the correlations observed suggests that although landmark depth increases with subject BMI, other factors may influence this correlation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A tool that can differentiate ischemic stroke from other neurological conditions (eg, hemorrhagic stroke, high-altitude cerebral edema) in the field could enable more rapid thrombolysis when appropriate. The resources (eg, an MRI or CT scanner) to investigate stroke at high altitude may be limited, and hence a portable tool would be of benefit. Such a tool may also be of benefit in emergency departments when CT scanning is not available. We report a case of a 49-year-old man who, while climbing at 5900 m, suffered a left middle cerebral infarct. The clinical diagnosis was supported using 2D Power Doppler. The patient received aspirin and continuous transcranial Doppler was used for its potential therapeutic effects for 12 hours. The patient was then evacuated to a hospital in Kathmandu over the next 48 hours. This case report suggests that portable ultrasound could be used in the prehospital arena to enable early diagnosis of thrombotic stroke., (Copyright © 2011 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.)

Sleep-disordered breathing may make the eye vulnerable due to the direct effect of hypoxia or it can involve pathways that lead to impaired autoregulation of optic nerve perfusion. In this review, we discuss our present understanding of the interactions that occur between sleep-disordered breathing and the eye, with particular attention to discussing possible links with glaucoma, nonarteritic anterior ischemic optic neuropathy, visual field defects, papilledema, and floppy eyelid syndrome. The importance of understanding these relationships is the positive benefits to ocular health that can derive when sleep-disordered breathing is diagnosed and treated.

Objective: To examine medication-related problems from the perspective of patients with a chronic condition and to identify how they may be supported in managing their medication., Methods: Patients prescribed medication for cardiovascular disease were recruited through five general medical surgeries and four community pharmacies in south London. Data were collected in 98 face-to-face interviews in participants' own homes. Interviews were designed to enable a detailed and holistic exploration of medication-related problems from participants' perspectives. Data were audio-recorded and transcribed verbatim to allow qualitative analysis., Results: Five broad categories of medication-related problem emerged which were examined in the context of patients' perspectives on, and experiences of, the use of medicines and health services. These were concerns about and management of side effects; differing views regarding the use of medicines; cognitive, practical and sensory problems; lack of information or understanding; and problems with access to, and organisation of, services., Conclusion: All categories of problem had potential implications for the success of therapy in that they created barriers to adherence, access to medication or informed decision-making. The study demonstrated how patients actively engage in decision-making about their medicines in the home, if not in the consultation., Practice Implications: The five categories of problem provide a focus for interventions by health professionals to support patients in achieving optimal theory outcomes. They demonstrate the need for a comprehensive approach, spanning patient education to the systems of delivery of care. Within the NHS in Britain, policy and practice initiatives are being designed to achieve this end. Further research should focus on the evaluation of professional practices and service developments in supporting patients in the self-management of their medicines.