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While primarily observed in adults, this case contributes valuable insights into the manifestation and management of this benign salivary gland tumor within the pediatric population. This paper reports the first documented case of sinonasal pleomorphic adenoma in pediatric otolaryngology, presenting a unique perspective on this rare nasal tumor in a 9-year-old boy. The patient presented with progressive nasal obstruction and epistaxis and underwent a smooth endoscopic resection of a 2-cm pleomorphic adenoma on the right anterior nasal septum. The subsequent discussion covered background, histology, imaging, and management strategies. Surgical removal with clear margins, particularly through the endoscopic approach, emerged as the primary and successful treatment method, minimizing morbidity and reducing recurrence risk. Long-term clinical surveillance is recommended due to an estimated 8.8% recurrence rate. In conclusion, this paper explains the challenges and solutions in diagnosing and treating sinonasal pleomorphic adenomas in children. It emphasizes the critical importance of early diagnosis, precise surgical intervention, and continuous monitoring, which are essential for achieving optimal patient outcomes.

Background: The efficacy and safety of bisphosphonate therapy for the treatment of osteoporosis and osteopenia in the setting of chronic kidney disease (CKD) is unclear. Objective: To determine the effect of bisphosphonate therapy on fractures, bone mineral density (BMD), and adverse events in adults across the spectrum of CKD and dialysis. Design: Systematic review and individual patient-level meta-analysis. Setting: Searches of Ageline, CINAHL, the Cochrane Library, EMBASE, and Medline from inception to August 25, 2016, supplemented with manual screening and clinicalstudydatarequest.com . Authors were contacted for individual patient-level data. Patients: Randomized, placebo-controlled trials with 100 or more participants that evaluated the treatment of primary osteoporosis/osteopenia in adult men and women with bisphosphonate therapy. Measurements: Study characteristics, quality, and data were assessed independently by 2 reviewers. Outcome measures were fractures, BMD, and adverse events including decline in estimated glomerular filtration rate (eGFR) and hypocalcemia (calcium 0.05). Limitations: Clinically significant heterogeneity among studies, lack of long-term follow-up and bone biopsy results, limited representation of stage G4 and G5 CKD patients. Conclusions: Chronic kidney disease potentially modifies the efficacy but not the safety of bisphosphonate therapy in osteopenia and osteoporosis. Registration: PROSPERO CRD42020145613

Abstract Since late 2021, highly pathogenic avian influenza (HPAI) viruses of A/goose/Guangdong/1/1996 (H5N1) lineage have caused widespread mortality in wild birds and poultry in the United States. Concomitant with the spread of HPAI viruses in birds are increasing numbers of mammalian infections, including wild and captive mesocarnivores and carnivores with central nervous system involvement. Here we report HPAI, A(H5N1) of clade 2.3.4.4b, in a common bottlenose dolphin (Tursiops truncatus) from Florida, United States. Pathological findings include neuronal necrosis and inflammation of the brain and meninges, and quantitative real time RT-PCR reveal the brain carried the highest viral load. Virus isolated from the brain contains a S246N neuraminidase substitution which leads to reduced inhibition by neuraminidase inhibitor oseltamivir. The increased prevalence of A(H5N1) viruses in atypical avian hosts and its cross-species transmission into mammalian species highlights the public health importance of continued disease surveillance and biosecurity protocols.

Rationale & Objective: Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on reducing treatment toxicities, notably through reduction of exposure to glucocorticoids. Glucocorticoid-sparing therapies such as avacopan are not widely available in many countries, and patients are exposed to high glucocorticoid doses. There is little data concerning what clinicians should accept as the lowest glucocorticoid dosing that can be used in induction therapy for AAV. Study Design: International, online survey. Setting & Participants: Clinicians in various countries with experience in managing vasculitis. Exposure and Outcomes: Survey questions to gauge interest and preferences in studying an induction of remission regimen for severe AAV using only 2 or 4 weeks of glucocorticoids without avacopan. Data collected included general opinions about standard of care for induction agents, glucocorticoids, and avacopan. Respondents were presented with 3 candidate trial designs, 2 of which proposed a combination of cyclophosphamide and rituximab induction. Analytical Approach: Using a 10-point Likert scale, respondents ranked each candidate trial on its usefulness in demonstrating whether a minimal glucocorticoid regimen would be safe and effective and their willingness to randomize into the trial. Results: There were 210 respondents to the survey. The candidate trials were rated moderate-to-high for usefulness to demonstrate safety and efficacy (scores 6-7/10), and moderate (scores 5-6/10) for willingness to randomize. Four-week glucocorticoid duration was preferred to 2 weeks, and combination cyclophosphamide-rituximab with 4-week glucocorticoids was the most preferred design. Forty-two percent of respondents felt avacopan had to be incorporated into a minimal GC trial design to want to recruit patients. Limitations: Representativeness of survey sample and generalizability of findings. Conclusions: Combination cyclophosphamide-rituximab may be the ideal way of studying minimal glucocorticoid use in severe AAV. Given its increasing uptake, incorporating avacopan into a potential trial design is important. Plain Language Summary: Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on using less glucocorticoids to limit side effects. New drugs that drastically limit glucocorticoid use are not available in many countries. Studies are needed to find other ways of reducing glucocorticoid exposure to treat AAV, but it is unclear how best to achieve this. We administered a survey to doctors with experience in treating AAV and had them grade different combinations of widely available treatments with 2 or 4 weeks of glucocorticoids. We found that a combination of 2 doses cyclophosphamide with 2 doses rituximab and 4 weeks of glucocorticoids was the preferred treatment. The results will guide the development of a trial studying minimal use of glucocorticoids for the treatment of AAV.

Abstract Background Using digital technologies to provide services and supports remotely may improve efficiency and accessibility of healthcare, and support people with disabilities to live independently. This study aimed to explore the experience of using digital technologies to access and provide disability services and supports during the Covid-19 pandemic, from the perspective of people with disabilities, families and service providers. Methods Using a multiple case study design, we purposively sampled three cases based on service user characteristics and geographical reach of the service. We conducted semi-structured interviews with 40 service users and service providers. Topic guides and analysis were informed by the Consolidated Framework for Implementation Research (CFIR). Analysis followed a largely deductive approach, using the CFIR constructs as a coding framework. A summary memo was developed for each case. Influence and strength of each construct was rated to identify constructs that influenced implementation of digital technologies. Ratings were compared across services to identify facilitators and barriers to implementation. Results Service users and providers were positive about using digital technologies to access and provide disability services and supports remotely. Advantages over in-person delivery included reduced travel time, increased opportunity for peer support and peer learning, more choice and opportunity to participate in activities, and an enhanced sense of self while accessing services from the secure environment of their home. The urgency to identify new modes of service delivery to meet the needs of service users during Covid-19 was a strong facilitator but did not necessarily result in successful implementation. Other factors that were strong facilitators were the use of adaptations to enable service users to access the online service, service users’ willingness to try the online service, service users’ persistence when they encountered challenges, and the significant time and effort that service providers made to support service users to participate in the online service. Barriers to implementation included the complexity of accessing online platforms, poor design quality of online platforms, and organisations prioritising in-person delivery over online services. Conclusions These findings may allow service providers to leverage facilitators that support implementation of online disability services and supports.

Background: Individuals receiving hemodialysis often experience concurrent symptoms during treatment and frequently report feeling unwell after dialysis. The degree to which intradialytic symptoms are related, and which specific symptoms may impair health-related quality of life (HRQoL) is uncertain. Objectives: To explore intradialytic symptoms clusters, and the relationship between intradialytic symptom clusters with dialysis treatment recovery time and HRQoL. Design/setting: We conducted a post hoc analysis of a prospective cohort study of 118 prevalent patients receiving hemodialysis in two centers in Calgary, Alberta and Hamilton, Ontario, Canada. Participants: Adults receiving hemodialysis treatment for at least 3 months, not scheduled for a modality change within 6 weeks of study commencement, who could provide informed consent and were able to complete English questionnaires independently or with assistance. Methods: Participants self-reported the presence (1 = none to 5 = very much ) of 10 symptoms during each dialysis treatment, the time it took to recover from each treatment, and weekly Kidney Disease Quality of Life 36-Item–Short Form (KDQoL-36) assessments. Principal component analysis identified clusters of intradialytic symptoms. Mixed-effects, ordinal and linear regression examined the association between symptom clusters and recovery time (categorized as 0, >0 to 2, >2 to 6, or >6 hours), and the physical component and mental component scores (PCS and MCS) of the KDQoL-36. Results: One hundred sixteen participants completed 901 intradialytic symptom questionnaires. The most common symptom was lack of energy (56% of treatments). Two intradialytic symptom clusters explained 39% of the total variance of available symptom data. The first cluster included bone or joint pain, muscle cramps, muscle soreness, feeling nervous, and lack of energy. The second cluster included nausea/vomiting, diarrhea and chest pain, and headache. The first cluster (median score: −0.56, 25th to 75th percentile: −1.18 to 0.55) was independently associated with longer recovery time (odds ratio [OR] 1.62 per unit difference in score, 95% confidence interval [CI]: 1.23-2.12) and decreased PCS (−0.72 per unit difference in score, 95% CI: −1.29 to −0.15) and MCS scores (−0.82 per unit difference in score, 95% CI: −1.48 to −0.16), whereas the second cluster was not (OR 1.24, 95% CI: 0.97-1.58; PCS 0.19, 95% CI −0.46 to 0.83; MCS −0.72, 95% CI: −1.50 to 0.06). Limitations: This was an exploratory analysis of a small data set from 2 centers. Further work is needed to externally validate these findings to confirm intradialytic symptom clusters and the generalizability of our findings. Conclusions: Intradialytic symptoms are correlated. The presence of select intradialytic symptoms may prolong the time it takes for a patient to recover from a dialysis treatment and impair HRQoL.

Background The frequent prescribing of psychotropics and high prevalence of polypharmacy among older adults with intellectual disabilities require close monitoring. Aims To describe change in prevalence, predictors and health outcomes of psychotropic use during the four waves (2009/2010, 2013/2014, 2016/2017, 2019/2020) of the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing (IDS-TILDA). Method Eligible participants were adults (≥40 years) with intellectual disabilities who participated in all four waves of IDS-TILDA and who reported medication use for the entire period. Differences between groups were tested using Cochran's Q test for binary variables and the McNemar–Bowker test for variables with more than two categories. Generalised estimating equation models were used to assess associations between psychotropic use, participants’ characteristics and health outcomes. Results Across waves (433 participants) there were no significant differences in prevalence of psychotropic use (61.2–64.2%) and psychotropic polypharmacy (42.7–38.3%). Antipsychotics were the most used subgroup, without significant change in prevalence between waves (47.6–44.6%). A significant decrease was observed for anxiolytics (26.8–17.6%; P < 0.001) and hypnotics/sedatives (14.1–9.0%; P < 0.05). A significant increase was recorded for antidepressants (28.6–35.8%; P < 0.001) and mood-stabilising agents (11.5–14.6%; P < 0.05). Psychotropic polypharmacy (≥2 psychotropics) was significantly associated with moderate to total dependence in performing activities of daily living over the 10-year period (OR = 1.80, 95% CI 1.21–2.69; P < 0.05). Conclusions The study indicates an increase in usage of some classes of psychotropic, a reduction in others and no change in the relatively high rate of antipsychotic use over 10 years in a cohort of older adults with intellectual disabilities and consequent risk of psychotropic polypharmacy and medication-related harm.

Plain English summary People with kidney failure receiving hemodialysis are faced with complex symptoms that impact their day-to-day functioning and quality of life. Patient-reported outcome measures (PROMs) are tools used by patients to directly communicate symptoms to their care team and guide symptom-focused care. Little is known about how PROMs could be integrated into the team-based care models of outpatient hemodialysis centres. In this study, we conducted interviews with people receiving hemodialysis and their clinicians about their perspectives on how PROMs could support interdisciplinary symptom management (i.e., integration of expertise to achieve common management goals). Participants described how the interrelatedness of symptoms was well suited to an integrated care approach and how PROMs enhanced communication and access to information across team members. In cases where symptoms persisted despite appropriate treatment, patients and clinicians explained how PROMs served as a tool to set realistic goals and reshape illness perception. Findings from this study suggest that access to resources, role flexibility, and established relationships within hemodialysis centres are important for sustaining PROM use in this setting.

Abstract Traditional genetic testing for patients with gastrointestinal stromal tumors (GISTs) focus on those with syndromic features. To assess whether expanded genetic testing of GIST patients could identify hereditary cancer predisposition, we analyzed matched tumor-germline sequencing results from 103 patients with GISTs over a 6-year period. Germline pathogenic/likely pathogenic (P/LP) variants in GIST-associated genes (SDHA, SDHB, SDHC, NF1, KIT) were identified in 69% of patients with KIT/PDGFRA-wildtype GISTs, 63% of whom did not have any personal or family history of syndromic features. To evaluate the frequency of somatic versus germline variants identified in tumor-only sequencing of GISTs, we analyzed 499 de-identified tumor-normal pairs. P/LP variants in certain genes (e.g., BRCA1/2, SDHB) identified in tumor-only sequencing of GISTs were almost exclusively germline in origin. Our results provide guidance for genetic testing of GIST patients and indicate that germline testing should be offered to all patients with KIT/PDGFRA-wildtype GISTs regardless of their history of syndromic features.

Background: Bleeding is the most common adverse event in those with cardiovascular (CV) disease receiving antithrombotic therapy, and it most commonly occurs in the gastrointestinal (GI) tract. Clinicians often dismiss bleeding as an adverse event that is reversible with effective antithrombotic therapy, but bleeding is associated with substantial morbidity and mortality, most likely mediated through an increased risk of CV events. Reducing the burden of bleeding requires knowledge of the potentially modifiable risk factors for bleeding and the potentially modifiable risk factors for adverse outcomes after bleeding. Methods: INTERBLEED is an international, multicentre, 2-component, observational study, with an incident case-control study examining the risk factors for GI bleeding, and a prospective cohort study of risk factors for CV events after GI bleeding. Cases either have CV disease and present to the hospital with GI bleeding or develop GI bleeding during hospitalization. Controls have CV disease, but no history of GI bleeding. We use a questionnaire to obtain detailed information on known and potential risk factors for GI bleeding and for CV events and outcomes after bleeding. We obtain CV and anthropometric measurements, perform functional and cognitive assessments, and follow participants at 3 months and 12 months. Results: As of April 1, 2022, the study is ongoing in 10 countries at 31 centres and has recruited 2407 cases and 1478 controls. Conclusions: Knowledge of risk factors for bleeding, and risk factors for CV events and functional decline after bleeding, will help develop strategies to prevent bleeding and subsequent complications. Résumé: Contexte: L’hémorragie est l’effet indésirable le plus fréquent chez les patients atteints de maladies cardiovasculaires (CV) qui reçoivent un traitement antithrombotique, et elle survient le plus souvent dans le tractus gastro-intestinal (GI). Les cliniciens considèrent souvent l’hémorragie comme une simple manifestation indésirable réversible par un traitement antithrombotique efficace, mais une morbidité et une mortalité considérables y sont associées, probablement en raison d’un risque accru d’événements CV. Une réduction du fardeau de l’hémorragie nécessite une connaissance des facteurs de risque potentiellement modifiables tant de l’hémorragie que des événements indésirables qui surviennent après l’hémorragie. Méthodologie: INTERBLEED est une étude internationale, observationnelle et multicentrique à deux volets; le premier volet est une étude cas-témoins incidents visant à examiner les facteurs de risque d’hémorragie GI, alors que le second volet est une étude de cohorte prospective visant à examiner les facteurs de risque d’événements CV après une hémorragie GI. Les cas sont des patients atteints de maladies CV qui consultent les services hospitaliers pour une hémorragie GI ou qui présentent une hémorragie GI en cours d’hospitalisation. Les témoins sont des patients atteints de maladies CV, mais sans antécédents d’hémorragie GI. Un questionnaire est utilisé pour obtenir des renseignements détaillés au sujet de facteurs de risque connus et potentiels d’hémorragie GI et d’événements CV et d’autres résultats de santé après une hémorragie. Des mesures cardiovasculaires et anthropométriques ainsi que des évaluations fonctionnelles et cognitives sont réalisées, et les participants sont revus après trois mois et 12 mois. Résultats: En date du 1er avril 2022, l’étude est en cours dans 10 pays et 31 établissements de santé; 2 407 cas et 1 478 témoins ont été recrutés. Conclusions: La connaissance des facteurs de risque d’hémorragie, ainsi que des facteurs de risque d’événements CV et de déclin fonctionnel à la suite d’une hémorragie, aidera à mettre en place des stratégies pour prévenir les hémorragies et les complications qui peuvent en découler.

BackgroundNatural language processing (NLP) has the potential to automate the reading of radiology reports, but there is a need to demonstrate that NLP methods are adaptable and reliable for use in real-world clinical applications.MethodsWe tested the F1 score, precision, and recall to compare NLP tools on a cohort from a study on delirium using images and radiology reports from NHS Fife and a population-based cohort (Generation Scotland) that spans multiple National Health Service health boards. We compared four off-the-shelf rule-based and neural NLP tools (namely, EdIE-R, ALARM+, ESPRESSO, and Sem-EHR) and reported on their performance for three cerebrovascular phenotypes, namely, ischaemic stroke, small vessel disease (SVD), and atrophy. Clinical experts from the EdIE-R team defined phenotypes using labelling techniques developed in the development of EdIE-R, in conjunction with an expert researcher who read underlying images.ResultsEdIE-R obtained the highest F1 score in both cohorts for ischaemic stroke, ≥93%, followed by ALARM+, ≥87%. The F1 score of ESPRESSO was ≥74%, whilst that of Sem-EHR is ≥66%, although ESPRESSO had the highest precision in both cohorts, 90% and 98%. For F1 scores for SVD, EdIE-R scored ≥98% and ALARM+ ≥90%. ESPRESSO scored lowest with ≥77% and Sem-EHR ≥81%. In NHS Fife, F1 scores for atrophy by EdIE-R and ALARM+ were 99%, dropping in Generation Scotland to 96% for EdIE-R and 91% for ALARM+. Sem-EHR performed lowest for atrophy at 89% in NHS Fife and 73% in Generation Scotland. When comparing NLP tool output with brain image reads using F1 scores, ALARM+ scored 80%, outperforming EdIE-R at 66% in ischaemic stroke. For SVD, EdIE-R performed best, scoring 84%, with Sem-EHR 82%. For atrophy, EdIE-R and both ALARM+ versions were comparable at 80%.ConclusionsThe four NLP tools show varying F1 (and precision/recall) scores across all three phenotypes, although more apparent for ischaemic stroke. If NLP tools are to be used in clinical settings, this cannot be performed “out of the box.” It is essential to understand the context of their development to assess whether they are suitable for the task at hand or whether further training, re-training, or modification is required to adapt tools to the target task.

IntroductionPeople with aphasia have been shown to benefit from rhythmic elements for language production during aphasia rehabilitation. However, it is unknown whether rhythmic processing is associated with such benefits. Cortical tracking of the speech envelope (CTenv) may provide a measure of encoding of speech rhythmic properties and serve as a predictor of candidacy for rhythm-based aphasia interventions.MethodsElectroencephalography was used to capture electrophysiological responses while Spanish speakers with aphasia (n = 9) listened to a continuous speech narrative (audiobook). The Temporal Response Function was used to estimate CTenv in the delta (associated with word- and phrase-level properties), theta (syllable-level properties), and alpha bands (attention-related properties). CTenv estimates were used to predict aphasia severity, performance in rhythmic perception and production tasks, and treatment response in a sentence-level rhythm-based intervention.ResultsCTenv in delta and theta, but not alpha, predicted aphasia severity. Neither CTenv in delta, alpha, or theta bands predicted performance in rhythmic perception or production tasks. Some evidence supported that CTenv in theta could predict sentence-level learning in aphasia, but alpha and delta did not.ConclusionCTenv of the syllable-level properties was relatively preserved in individuals with less language impairment. In contrast, higher encoding of word- and phrase-level properties was relatively impaired and was predictive of more severe language impairments. CTenv and treatment response to sentence-level rhythm-based interventions need to be further investigated.

Background: This study assessed the potential cost-effectiveness of high (80–100%) vs low (21–35%) fraction of inspired oxygen (FiO2) at preventing surgical site infections (SSIs) after abdominal surgery in Nigeria, India, and South Africa. Methods: Decision-analytic models were constructed using best available evidence sourced from unbundled data of an ongoing pilot trial assessing the effectiveness of high FiO2, published literature, and a cost survey in Nigeria, India, and South Africa. Effectiveness was measured as percentage of SSIs at 30 days after surgery, a healthcare perspective was adopted, and costs were reported in US dollars ($). Results: High FiO2 may be cost-effective (cheaper and effective). In Nigeria, the average cost for high FiO2 was $216 compared with $222 for low FiO2 leading to a −$6 (95% confidence interval [CI]: −$13 to −$1) difference in costs. In India, the average cost for high FiO2 was $184 compared with $195 for low FiO2 leading to a −$11 (95% CI: −$15 to −$6) difference in costs. In South Africa, the average cost for high FiO2 was $1164 compared with $1257 for low FiO2 leading to a −$93 (95% CI: −$132 to −$65) difference in costs. The high FiO2 arm had few SSIs, 7.33% compared with 8.38% for low FiO2, leading to a −1.05 (95% CI: −1.14 to −0.90) percentage point reduction in SSIs. Conclusion: High FiO2 could be cost-effective at preventing SSIs in the three countries but further data from large clinical trials are required to confirm this.

The current study employed interrupted time series (ITS) models to analyze all available (published and unpublished) Abstract Semantic Associative Network Training (AbSANT) data. AbSANT is a semantically focused anomia treatment that targets not only concrete but abstract words, unique among existing anomia treatments. However, evidence to date for the positive effects of AbSANT comes only from small-sample, single-subject design studies, limiting the strength of this evidence and the inferences that can be drawn from it. The statistical power and greater representativeness afforded by this larger aggregated sample enabled us to look for group-level efficacy evidence for AbSANT, examine specific questions about AbSANT's direct training and generalization effects, and identify potential predictors and mechanisms of AbSANT treatment response. We found that across 33 participants from four different data sources, AbSANT appears to be a robust word retrieval therapy protocol, with overall direct training and generalization effects that were more meaningful than exposure effects. Similar to previous smaller-sample study conclusions, we found that in this large sample, training abstract words results not only in larger direct training effects than training concrete words, but also larger generalization effects, suggesting that while AbSANT successfully improves both abstract and concrete word retrieval, it may be better suited for training abstract words. In general, direct training effects were more persistent after treatment ended than generalization effects and effects for concrete words were more persistent than for abstract words. Additionally, the effects of generalization appear to be distinct from the effects of simple exposure to words, and generalization effects are consistent with AbSANT's hypothesized mechanism of action: spreading activation from directly trained concepts to related concepts. Also consistent with this mechanism, we found that milder aphasia and both conceptual and lexical semantic processing ability predicted both direct training and generalization gains, and that executive function was predictive of generalization effects. These factors are thus important to consider when evaluating the appropriateness of AbSANT for individual clients.

Ultrathin (sub-2 nm) Al _2 O _3 /MgO memristors were recently developed using an in vacuo atomic layer deposition (ALD) process that minimizes unintended defects and prevents undesirable leakage current. These memristors provide a unique platform that allows oxygen vacancies (V _O ) to be inserted into the memristor with atomic precision and study how this affects the formation and rupture of conductive filaments (CFs) during memristive switching. Herein, we present a systematic study on three sets of ultrathin Al _2 O _3 /MgO memristors with V _O -doping via modular MgO atomic layer insertion into an otherwise pristine insulating Al _2 O _3 atomic layer stack (ALS) using an in vacuo ALD. At a fixed memristor thickness of 17 Al _2 O _3 /MgO atomic layers (∼1.9 nm), the properties of the memristors were found to be affected by the number and stacking pattern of the MgO atomic layers in the Al _2 O _3 /MgO ALS. Importantly, the trend of reduced low-state resistance and the increasing appearance of multi-step switches with an increasing number of MgO atomic layers suggests a direct correlation between the dimension and dynamic evolution of the conducting filaments and the V _O concentration and distribution. Understanding such a correlation is critical to an atomic-scale control of the switching behavior of ultrathin memristors.

Abstract Background Genetic testing (GT) for hereditary cancer predisposition is traditionally performed on selected genes based on established guidelines for each cancer type. Recently, expanded GT (eGT) using large hereditary cancer gene panels uncovered hereditary predisposition in a greater proportion of patients than previously anticipated. We sought to define the diagnostic yield of eGT and its clinical relevance in a broad cancer patient population over a 5-year period. Methods A total of 17,523 cancer patients with a broad range of solid tumors, who received eGT at Memorial Sloan Kettering Cancer Center between July 2015 to April 2020, were included in the study. The patients were unselected for current GT criteria such as cancer type, age of onset, and/or family history of disease. The diagnostic yield of eGT was determined for each cancer type. For 9187 patients with five common cancer types frequently interrogated for hereditary predisposition (breast, colorectal, ovarian, pancreatic, and prostate cancer), the rate of pathogenic/likely pathogenic (P/LP) variants in genes that have been associated with each cancer type was analyzed. The clinical implications of additional findings in genes not known to be associated with a patients’ cancer type were investigated. Results 16.7% of patients in a broad cancer cohort had P/LP variants in hereditary cancer predisposition genes identified by eGT. The diagnostic yield of eGT in patients with breast, colorectal, ovarian, pancreatic, and prostate cancer was 17.5%, 15.3%, 24.2%, 19.4%, and 15.9%, respectively. Additionally, 8% of the patients with five common cancers had P/LP variants in genes not known to be associated with the patient’s current cancer type, with 0.8% of them having such a variant that confers a high risk for another cancer type. Analysis of clinical and family histories revealed that 74% of patients with variants in genes not associated with their current cancer type but which conferred a high risk for another cancer did not meet the current GT criteria for the genes harboring these variants. One or more variants of uncertain significance were identified in 57% of the patients. Conclusions Compared to targeted testing approaches, eGT can increase the yield of detection of hereditary cancer predisposition in patients with a range of tumors, allowing opportunities for enhanced surveillance and intervention. The benefits of performing eGT should be weighed against the added number of VUSs identified with this approach.

Manatees (Antillean-, Amazonian, and African-) and dugongs belong to the Order Sirenia, and when combined with elephants and rock hyraxes, form the Paenungulata. A bilobed mononuclear cell has previously been identified in elephants and rock hyraxes, but not in manatees and dugongs, with cytochemical staining identifying these cells as bilobed monocytes in elephants. The objective of this study was to characterize leukocytes (white blood cells, WBC) and platelets in blood films of Florida manatees (Trichechus manatus latirostris; n = 8) using one routine hematological (Wright-Giemsa) and eight cytochemical stains: alkaline phosphatase (ALP), α-naphthyl butyrate esterase (ANBE), chloroacetate esterase (CAE), Luna, myeloperoxidase (MPx), periodic acid-Schiff (PAS), Sudan black B (SBB), and toluidine blue (TB). Heterophils and lymphocytes comprised most of the WBC, with low numbers of eosinophils, basophils, and monocytes. Additionally, 1–3% of the WBC were bilobed mononuclear cells. Bilobed mononuclear cell proportions were similar to rock hyraxes, but lower than elephants (approximate range 20–60%). Heterophils and eosinophils were positive for MPx, ALP, SBB, and PAS, with heterophils also being positive for CAE. Most of the lymphocytes were positive for ANBE and they were variably positive for CAE. Monocytes and bilobed mononuclear cells had similar cytochemical staining reactions (variably positive for all stains, except Luna and TB), supporting a monocytic origin, like elephants. Platelets were ANBE- and PAS-positive. Luna stain was useful for identifying eosinophils and TB was uninformative. This study provides new information on the morphological features and cytochemical staining characteristics of WBC and platelets and will aid in obtaining accurate hematological data of Florida manatees.

Background: Administrative data are used in studies of hemodialysis care to report cardiovascular-related hospitalizations. Showing recorded events are associated with significant health care resource use and poor outcomes would confirm that administrative data algorithms identify clinically meaningful events. Objective: The objective of this study was to describe the 30-day health service use and outcomes when a hospital admission with myocardial infarction, congestive heart failure, or ischemic stroke is recorded in administrative databases. Design: This is a retrospective review of linked administrative data. Patients and Setting: Patients receiving maintenance in-center hemodialysis in Ontario, Canada, between April 1, 2013, and March 31, 2017, were included. Measurements: Records from linked health care databases at ICES in Ontario, Canada were considered. We identified hospital admission with the most responsible diagnosis recorded as myocardial infarction, congestive heart failure, or ischemic stroke. We then assessed the frequency of common tests, procedures, consultations, post-discharge outpatient drug prescriptions, and outcomes within 30 days following the hospital admission. Methods: We used descriptive statistics to summarize results using counts and percentages for categorical variables and means with standard deviations or medians with quartile ranges for continuous variables. Results: There were 14 368 patients who received maintenance hemodialysis between April 1, 2013, and March 31, 2017. The number of events per 1000 person-years was 33.5 for hospital admissions with myocardial infarction, 34.2 for congestive heart failure, and 12.9 for ischemic stroke. The median (25th, 75th percentile) duration of hospital stay was 5 (3-10) days for myocardial infarction, 4 (2-8) days for congestive heart failure, and 9 (4-18) days for ischemic stroke. The chance of death within 30 days was 21% for myocardial infarction, 11% for congestive heart failure, and 19% for ischemic stroke. Limitations: Events, procedures, and tests recorded in administrative data can be misclassified compared with medical charts. Conclusions: In patients receiving maintenance hemodialysis, hospital admissions of major cardiovascular events routinely recorded in health administrative databases are associated with significant use of health service resources and poor health outcomes.

Introduction: Patients with end-stage renal disease (ESRD) requiring hemodialysis (HD) have an increased risk of thrombotic events and bleeding. Antisense reduction of factor XI (FXI) with IONIS-FXIRx is a novel strategy that may safely reduce the risk of thrombotic events. Methods: This multicenter study enrolled 49 patients receiving HD in 2 parts. First, 6 participants (pharmacokinetics [PK] cohort) received 1 open-label 300 mg dose of IONIS-FXIRx both before and after HD. Subsequently, 43 participants were treated in a double-blind, randomized design with 200 mg or 300 mg IONIS-FXIRx or placebo for 12 weeks. The PK, pharmacodynamics (PD), and adverse events of IONIS-FXIRx were evaluated (ClinicalTrials.gov: NCT02553889). Results: The PK of IONIS-FXIRx was consistent with previous studies and similar whether injected before or after HD. No accumulation of IONIS-FXIRx was observed after repeat administration. By day 85, mean levels of FXI activity fell 56.0% in the 200 mg group, 70.7% in the 300 mg group, and 3.9% in the placebo group compared with baseline. FXI antigen levels paralleled FXI activity. Dose-dependent prolongation of activated partial thromboplastin time (aPTT) was observed, with no changes in international normalized ratio (INR). IONIS-FXIRx was not associated with drug-related serious adverse events. In the randomized phase of the study, major bleeding events occurred in 0 (0.0%; 200 mg), 1 (6.7%; 300 mg), and 1 (7.7%; placebo) patients and were not considered related to treatment. Conclusion: IONIS-FXIRx reduced FXI activity in patients with ESRD receiving HD. Further studies are needed to determine the benefit-risk profile of FXI as a therapeutic target for patients who require HD.

Abstract The use of a fallow phase is an important tool for maximizing crop yield potential in moisture limited agricultural environments, with a focus on removing weeds to optimize fallow efficiency. Repeated whole field herbicide treatments to control low-density weed populations is expensive and wasteful. Site-specific herbicide applications to low-density fallow weed populations is currently facilitated by proprietary, sensor-based spray booms. The use of image analysis for fallow weed detection is an opportunity to develop a system with potential for in-crop weed recognition. Here we present OpenWeedLocator (OWL), an open-source, low-cost and image-based device for fallow weed detection that improves accessibility to this technology for the weed control community. A comprehensive GitHub repository was developed, promoting community engagement with site-specific weed control methods. Validation of OWL as a low-cost tool was achieved using four, existing colour-based algorithms over seven fallow fields in New South Wales, Australia. The four algorithms were similarly effective in detecting weeds with average precision of 79% and recall of 52%. In individual transects up to 92% precision and 74% recall indicate the performance potential of OWL in fallow fields. OWL represents an opportunity to redefine the approach to weed detection by enabling community-driven technology development in agriculture.

Abstract Background Patients receiving intermittent hemodialysis have variable times of recovery to feeling better after dialysis. QT prolongation, a precursor to clinical and subclinical cardiovascular events, may contribute to delayed recovery time. We hypothesized that abnormal electrocardiographic parameters indicating perturbations in ventricular action are associated with longer recovery times thus impacting a patient-centered quality of life. Methods Among 242 incident in-center hemodialysis participants from the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study, corrected QT interval (QTc), QRST angle and heart rate variance were measured on non-dialysis days using a standard 5-min electrocardiograph recording. Left ventricular hypertrophy (LVH) was defined using the Cornell voltage product. Recovery time was ascertained during a phone interview with a standardized validated questionnaire. Associations between QTc, QRST angle, heart rate variance, and LVH and natural log-transformed recovery time were examined using linear regression adjusted for participant characteristics and electrolytes. Results Mean age was 55 (standard deviation 13) years, 55% were male, 72% were African American. Longer QTc interval was associated with increased recovery time (per 10 ms increase in QTc, recovery time increased by 6.2%; 95% confidence interval: 0.0–10.5). QRST angle, heart rate, heart rate variability and LVH were not significantly associated with recovery time. Conclusion Longer QTc intervals are associated with longer recovery time independent of serum electrolytes. This supports a relationship between a patient’s underlying arrhythmic status and time to recovery after hemodialysis. Future studies will determine if maneuvers to reduce QTc improves recovery time and quality of life of patients on hemodialysis.

Rationale & Objective: We sought to elicit patient preferences regarding the use of plasma exchange in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and its tradeoffs of risk of kidney failure and risk of serious infection. Study Design: Patient survey. Setting & Participants: The online survey was circulated to adults with AAV via kidney and vasculitis networks in Canada, the United Kingdom, and the United States. Outcomes: Respondents reviewed the estimated 1-year risks of kidney failure and serious infection in AAV with and without plasma exchange across 5 serum creatinine categories (150, 250, 350, 450, and 600 μmol/L). For each scenario, participants indicated whether or not they would choose plasma exchange. Analytical Approach: Responses were assessed with multilevel multivariable logistic regression models to identify predictors of respondent choice regarding treatment with plasma exchange. Results: The 470 respondents from the 13 countries (United States 61.7%, United Kingdom 20.0%, Canada 13.8%, and other countries 4.5%) had a mean age of 58.6 (SD 14.3) years, 70.2% women. Respondents were more likely to choose plasma exchange in scenarios at high risk of kidney failure and serious infection (creatinine level of 350 or 450 μmol/L) compared with lower risk scenarios or the highest risk scenario. However, 145 (30.9%) chose plasma exchange across all scenarios, whereas 80 (17.0%) declined plasma exchange across all scenarios. Respondents from the United Kingdom (OR, 2.61; 95% CI, 1.09-6.22) who received previous dialysis (OR, 2.70; 95% CI, 1.12-6.52) or received previous plasma exchange (OR, 5.62; 95% CI, 2.72-11.61) were more likely to choose plasma exchange, whereas older respondents (OR, 0.98; 95% CI, 0.96-0.99 per 1 year increase) were less likely. Limitations: Unclear generalizability to non–English-speaking, older, and less health literate adults, possible responder bias, survivor bias, lack of individualized risk assessments for kidney failure, and serious infection. Conclusions: Patients with AAV do not express a consistent choice for plasma exchange, which highlights the need for shared decision making.

Abstract Background We aimed to describe (1) depressive and anxiety symptom burdens reported by adults on in-centre hemodialysis in Northern Alberta, Canada and (2) patients’ and nurses’ perceptions of managing such symptoms using routine patient-reported outcome measures (PROMs). Methods A longitudinal mixed methods approach was employed. Cluster randomized controlled trial data exposed the prevalence of positive screens (scores ≥ 3) for depressive (PHQ-2) and anxiety (GAD-2) symptoms. A descriptive qualitative approach was used to understand patients’ and nurses’ perceptions of managing these symptoms using the ESAS-r: Renal and EQ-5D-5L. Using purposeful sampling, patients and nurses were invited for interviews. Field notes were documented from 6 dialysis unit observations. Patients’ responses to open-ended survey questions and nurses’ electronic chart notes related to mental health were compiled. Thematic and content analyses were used. Results Average age of patients (n = 408) was 64.0 years (SD 15.4), 57% were male, and 87% were not working; 29% screened positive for depressive symptoms, 21% for anxiety symptoms, and 16% for both. From patient (n = 10) and nurse (n = 8) interviews, unit observations, patient survey responses (n = 779) and nurses’ chart notes (n = 84), we discerned that PROMs (ESAS-r: Renal/EQ-5D-5L) had the potential to identify and prompt management of mental health concerns. However, opinions differed about whether mental health was within kidney care scope. Nonetheless, participants agreed there was a lack of mental health resources. Conclusions Prevalence of depressive and anxiety symptoms aligned with existing literature. Tensions regarding mental health management highlight the need for systemic decisions about how routine PROM use, including mental health assessment, may be optimized to meet patients’ needs.

Infant acute lymphoblastic leukemia (ALL) with KMT2A-gene rearrangements (KMT2A-r) have few mutations and a poor prognosis. To uncover mutations that are below the detection of standard next-generation sequencing (NGS), a combination of targeted duplex sequencing and NGS was applied on 20 infants and 7 children with KMT2A-r ALL, 5 longitudinal and 6 paired relapse samples. Of identified nonsynonymous mutations, 87 had been previously implicated in cancer and targeted genes recurrently altered in KMT2A-r leukemia and included mutations in KRAS, NRAS, FLT3, TP53, PIK3CA, PAX5, PIK3R1, and PTPN11, with infants having fewer such mutations. Of identified cancer-associated mutations, 62% were below the resolution of standard NGS. Only 33 of 87 mutations exceeded 2% of cellular prevalence and most-targeted PI3K/RAS genes (31/33) and typically KRAS/NRAS. Five patients only had low-frequency PI3K/RAS mutations without a higher-frequency signaling mutation. Further, drug-resistant clones with FLT3D835H or NRASG13D/G12S mutations that comprised only 0.06% to 0.34% of diagnostic cells, expanded at relapse. Finally, in longitudinal samples, the relapse clone persisted as a minor subclone from diagnosis and through treatment before expanding during the last month of disease. Together, we demonstrate that infant and childhood KMT2A-r ALL harbor low-frequency cancer-associated mutations, implying a vast subclonal genetic landscape.

Background: Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes. Objectives: We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease. Design: This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab. Setting: Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated. Participants: Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of

Elucidating genetic aberrations in pediatric acute myeloid leukemia (AML) provides insight in biology and may impact on risk-group stratification and clinical outcome. This study aimed to detect such aberrations in a selected series of samples without known (cyto)genetic aberration using molecular profiling. A cohort of 161 patients was selected from various study groups: DCOG, BFM, SJCRH, NOPHO and AEIOP. Samples were analyzed using RNA sequencing (n=152), whole exome (n=135) and/or whole genome sequencing (n=100). In 70 of 156 patients (45%), of whom RNA sequencing or whole genome sequencing was available, rearrangements were detected, 22 of which were novel; five involving ERG rearrangements and four NPM1 rearrangements. ERG rearrangements showed self-renewal capacity in vitro, and a distinct gene expression pattern. Gene set enrichment analysis of this cluster showed upregulation of gene sets derived from Ewing sarcoma, which was confirmed comparing gene expression profiles of AML and Ewing sarcoma. Furthermore, NPM1-rearranged cases showed cytoplasmic NPM1 localization and revealed HOXA/B gene overexpression, as described for NPM1 mutated cases. Single-gene mutations as identified in adult AML were rare. Patients had a median of 24 coding mutations (range, 7-159). Novel recurrent mutations were detected in UBTF (n=10), a regulator of RNA transcription. In 75% of patients an aberration with a prognostic impact could be detected. Therefore, we suggest these techniques need to become standard of care in diagnostics.

We report a human case of ocular filariasis, caused by a species of Breinlia nematode, from Queensland, Australia. Morphological and molecular evidence indicated that the nematode Breinlia (Johnstonema) annulipapillata, or a closely related taxon, likely transmitted from a macropodid marsupial host was involved, which might represent an accidental finding or an emerging zoonosis.

Abstract Background Kidney failure requiring dialysis is associated with poor health outcomes and health-related quality of life (HRQL). Patient-reported outcome measures (PROMs) capture symptom burden, level of functioning and other outcomes from a patient perspective, and can support clinicians to monitor disease progression, address symptoms, and facilitate patient-centered care. While evidence suggests the use of PROMs in clinical practice can lead to improved patient experience in some settings, the impact on patients’ health outcomes and experiences is not fully understood, and their cost-effectiveness in clinical settings is unknown. This study aims to fill these gaps by evaluating the effectiveness and cost-effectiveness of routinely measuring PROMs on patient-reported experience, clinical outcomes, HRQL, and healthcare utilization. Methods The EMPATHY trial is a pragmatic multi-centre cluster randomized controlled trial that will implement and evaluate the use of disease-specific and generic PROMs in three kidney care programs in Canada. In-centre hemodialysis units will be randomized into four groups, whereby patients: 1) complete a disease-specific PROM; 2) complete a generic PROM; 3) complete both types of PROMs; 4) receive usual care and do not complete any PROMs. While clinical care pathways are available to all hemodialysis units in the study, for the three active intervention groups, the results of the PROMs will be linked to treatment aids for clinicians and patients. The primary outcome of this study is patient-provider communication, assessed by the Communication Assessment Tool (CAT). Secondary outcomes include patient management and symptoms, use of healthcare services, and the costs of implementing this intervention will also be estimated. The present protocol fulfilled the Standard Protocol Items: Recommendations for Intervention Trials (SPIRIT) checklist. Discussion While using PROMs in clinical practice is supported by theory and rationale, and may engage patients and enhance their role in decisions regarding their care and outcomes, the best approach of their use is still uncertain. It is important to rigorously evaluate such interventions and investments to ensure they provide value for patients and health systems. Trial registration Protocol version (1.0) and trial registration data are available on www.clinicaltrials.gov , identifier: NCT03535922 , registered May 24, 2018.

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), “bright spotty” (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.

Background: Electrophysiological measures can predict and reflect substance use treatment response. Veterans are disproportionately affected by disorders of addiction; cocaine use disorder (CUD) being particularly problematic due to high relapse rates and the absence of approved pharmacotherapies. Prize-based Contingency Management (PBCM) is an evidence-based behavioral intervention for CUD, involving incentives for cocaine abstinence but treatment response is variable. Measurement-based adaptation of PBCM has promise to improve effectiveness but remains to be usefully developed. Methods: This trial aims to determine if individuals with distinct neurocognitive profiles differentially benefit from one of two existing versions of PBCM. CUD patients will be randomized into treatment-as-usual or 12-weeks of PBCM using either monetary or tangible prize incentives. Prior to randomization, EEG will be used to assess response to monetary versus tangible reward; EEG and cognitive-behavioral measures of working memory, cognitive control, and episodic future thinking will also be acquired. Substance use and treatment engagement will be monitored throughout the treatment interval and assessments will be repeated at post-treatment. Discussion: Results of this trial may elucidate individual differences contributing to PBCM treatment response and reveal predictors of differential benefits from existing treatment variants. The design also affords the opportunity to evaluate treatment-related changes in neurocognitive functioning over the course of PBCM. Our model posits that PBCM scaffolds future-oriented goal representation and self-control to support abstinence. Individuals with poorer functioning may be less responsive to abstract monetary reward and will therefore achieve better outcomes with respect to abstinence and treatment engagement when tangible incentives are utilized.

Background: Major Outcomes with Personalized Dialysate TEMPerature (MyTEMP) is a 4-year cluster-randomized clinical trial comparing the effect of using a personalized, temperature-reduced dialysate protocol versus a dialysate temperature of 36.5°C on cardiovascular-related death and hospitalization. Randomization was performed at the level of the dialysis center (“the cluster”). Objective: The objective is to outline the statistical analysis plan for the MyTEMP trial. Design: MyTEMP is a pragmatic, 2-arm, parallel-group, registry-based, open-label, cluster-randomized trial. Setting: A total of 84 dialysis centers in Ontario, Canada. Patients: Approximately 13 500 patients will have received in-center hemodialysis at the 84 participating dialysis centers during the trial period (April 3, 2017, to March 1, 2021, with a maximum follow-up to March 31, 2021). Methods: Patient identification, baseline characteristics, and study outcomes will be obtained primarily through Ontario administrative health care databases held at ICES. Covariate-constrained randomization was used to allocate the 84 dialysis centers (1:1) to the intervention group or the control group. Centers in the intervention group used a personalized, temperature-reduced dialysate protocol, and centers in the control group used a fixed dialysate temperature of 36.5°C. Outcomes: The primary outcome is a composite of cardiovascular-related death or major cardiovascular-related hospitalization (defined as a hospital admission with myocardial infarction, congestive heart failure, or ischemic stroke) recorded in administrative health care databases. The key secondary outcome is the mean drop in intradialytic systolic blood pressure, defined as the patients’ predialysis systolic blood pressure minus their nadir systolic blood pressure during the dialysis treatment. Anonymized data on patients’ predialysis and intradialytic systolic blood pressure were collected at monthly intervals from each dialysis center. Analysis plan: The primary analysis will follow an intent-to-treat approach. The primary outcome will be analyzed at the patient level as the hazard ratio of time-to-first event, estimated from a subdistribution hazards model. Within-center correlation will be accounted for using a robust sandwich estimator. In the primary analysis, patients’ observation time will end if they experience the primary outcome, emigrate from Ontario, or die of a noncardiovascular cause (which will be treated as a competing risk event). The between-group difference in the mean drop in intradialytic systolic blood pressure obtained during the dialysis sessions throughout the trial period will be analyzed at the center level using an unadjusted random-effects linear mixed model. Trial status: The MyTEMP trial period is April 3, 2017, to March 31, 2021. We expect to analyze and report results by 2023 once the updated data are available at ICES. Trial registration: MyTEMP is registered with the US National Institutes of Health at clincaltrials.gov (NCT02628366). Statistical analytic plan: Version 1.1 June 15, 2021.

Background: The incidence of acute kidney injury (AKI) in patients with COVID-19 and its association with mortality and disease severity is understudied in the Canadian population. Objective: To determine the incidence of AKI in a cohort of patients with COVID-19 admitted to medicine and intensive care unit (ICU) wards, its association with in-hospital mortality, and disease severity. Our aim was to stratify these outcomes by out-of-hospital AKI and in-hospital AKI. Design: Retrospective cohort study from a registry of patients with COVID-19. Setting: Three community and 3 academic hospitals. Patients: A total of 815 patients admitted to hospital with COVID-19 between March 4, 2020, and April 23, 2021. Measurements: Stage of AKI, ICU admission, mechanical ventilation, and in-hospital mortality. Methods: We classified AKI by comparing highest to lowest recorded serum creatinine in hospital and staged AKI based on the Kidney Disease: Improving Global Outcomes (KDIGO) system. We calculated the unadjusted and adjusted odds ratio for the stage of AKI and the outcomes of ICU admission, mechanical ventilation, and in-hospital mortality. Results: Of the 815 patients registered, 439 (53.9%) developed AKI, 253 (57.6%) presented with AKI, and 186 (42.4%) developed AKI in-hospital. The odds of ICU admission, mechanical ventilation, and death increased as the AKI stage worsened. Stage 3 AKI that occurred during hospitalization increased the odds of death (odds ratio [OR] = 7.87 [4.35, 14.23]). Stage 3 AKI that occurred prior to hospitalization carried an increased odds of death (OR = 5.28 [2.60, 10.73]). Limitations: Observational study with small sample size limits precision of estimates. Lack of nonhospitalized patients with COVID-19 and hospitalized patients without COVID-19 as controls limits causal inferences. Conclusions: Acute kidney injury, whether it occurs prior to or after hospitalization, is associated with a high risk of poor outcomes in patients with COVID-19. Routine assessment of kidney function in patients with COVID-19 may improve risk stratification. Trial registration: The study was not registered on a publicly accessible registry because it did not involve any health care intervention on human participants.

Pressure is mounting on the agricultural sector to reduce reliance on herbicides for weed control leading to increased interest in the potential of cover crops to control weeds in summer fallows. The weed suppression ability of three summer cover crop species, buckwheat, millet and teff, was evaluated in field trials at two sites near Camden, NSW in 2021. Buckwheat, millet and teff reduced weed biomass by 65%, 77% and 95%, respectively at Bringelly and by 94%, 92% and 90%, respectively at Lansdowne. Following cover crop desiccation, teff residues reduced weed emergence in subsequently planted wheat by 73% and 26% at Bringelly and Lansdowne, respectively. Overall cover crops were found to be effective in suppressing weed emergence, growth, and reproductive capacity. These studies identified teff grass as an important summer crop option for the northern grains region.

Background: While home dialysis therapies are more cost effective and may offer improved health-related quality of life, uptake compared to in-center hemodialysis remains low. Objective: To test whether a web-based interactive health communication application (IHCA) compared to usual care would increase home dialysis use. Design: Randomized control trial Setting: Patients were recruited from 3 multidisciplinary kidney clinics across Ontario, Canada (Hamilton, Kingston, London). Patients: We included adults with advanced chronic kidney disease (CKD) followed in multidisciplinary kidney clinics. Patients who had not completed dialysis modality education, who did not have access to a home computer or the internet, who had significant hearing or vision impairment, who could not read/write/speak English, who had a medical contraindication for home dialysis, or who had selected conservative kidney care were excluded. Measurements: The primary outcome was any use of home dialysis (peritoneal dialysis or home hemodialysis) within 90 days of dialysis initiation. Secondary outcomes were social support, decision conflict and dialysis knowledge measured at baseline, 6 months and 1 year. Methods: Eligible patients were randomized to either usual care or the IHCA in addition to usual care in a 1:1 ratio. As part of usual care, all patients received education about dialysis modalities and kidney transplantation delivered by clinic nurses according to local practices. Randomization was performed using a computer-generated sequence in randomly permuted block sizes, stratified by site, and allocation occurred using sequentially numbered sealed, opaque envelopes. Participants, care providers, and outcome assessors were not blinded to the intervention. All analyses were performed blinded using an intention to treat approach. We estimated the effect of the ICHA on the odds of the primary outcome using unadjusted logistic regression models. Linear mixed models for repeated measures over time were used to analyze the impact of the IHCA on the secondary outcomes of interest. Results: We randomized 140 (usual care, n = 71; IHCA, n = 69) out of a planned 264 patients (mean [SD] age 61 [14.5] years, 65% men). Among patients randomized to the IHCA group that completed 6-month and 1-year follow-up visits, 56.8% and 71.4%, respectively, had not accessed the IHCA website within the past month. There were 23 (32.4%) and 26 (37.7%) patients in the usual care and IHCA groups who received a home dialysis therapy within 90 days of dialysis initiation (odds ratio, OR = 1.3, 95% CI = [0.6-2.5], P = .5). Among the 78 patients who initiated dialysis (n = 38 usual care, n = 40 IHCA), 60.5% and 65% in the usual care and IHCA groups received a home therapy within 90 days of dialysis initiation (OR = 1.2, 95% CI = [0.5-3.0], P = .7). Secondary outcomes did not differ by intervention group over time. Limitations: The trial was underpowered due to poor recruitment and use of the IHCA was low. Conclusions: We did not find evidence of a difference in home dialysis uptake with IHCA use, but our analyses were notably underpowered. The incorporation of greater patient engagement, qualitative research and design research, and pilot implementation may help future evaluations of strategies to improve home dialysis uptake. Trial Registration: ClinicalTrials.gov # NCT01403454, registration date: Jul 21, 2011

Since the recent introduction of several viable vaccines for SARS-CoV-2, vaccination uptake has become the key factor that will determine our success in containing the COVID-19 pandemic. We argue that game theory and social network models should be used to guide decisions pertaining to vaccination programmes for the best possible results. In the months following the introduction of vaccines, their availability and the human resources needed to run the vaccination programmes have been scarce in many countries. Vaccine hesitancy is also being encountered from some sections of the general public. We emphasize that decision-making under uncertainty and imperfect information, and with only conditionally optimal outcomes, is a unique forte of established game-theoretic modelling. Therefore, we can use this approach to obtain the best framework for modelling and simulating vaccination prioritization and uptake that will be readily available to inform important policy decisions for the optimal control of the COVID-19 pandemic.

Seed shattering refers to the natural shedding of seeds when they ripe, a phenomenon typically observed in wild and weedy plant species. The timing and extent of this phenomenon varies considerably among plant species. Seed shattering is primarily a genetically controlled trait; however, it is significantly influenced by environmental conditions, management practices and their interactions, especially in agro-ecosystems. This trait is undesirable in domesticated crops where consistent efforts have been made to minimize it through conventional and molecular breeding approaches. However, this evolutionary trait serves as an important fitness and survival mechanism for most weeds that utilize it to ensure efficient dispersal of their seeds, paving the way for persistent soil seedbank development and sustained future populations. Weeds have continuously evolved variations in seed shattering as an adaptation under changing management regimes. High seed retention is common in many cropping weeds where weed maturity coincides with crop harvest, facilitating seed dispersal through harvesting operations, though some weeds have notoriously high seed shattering before crop harvest. However, high seed retention in some of the most problematic agricultural weed species such as annual ryegrass (Lolium rigidum), wild radish (Raphanus raphanistrum), and weedy amaranths (Amaranthus spp.) provides an opportunity to implement innovative weed management approaches such as harvest weed seed control, which aims at capturing and destroying weed seeds retained at crop harvest. The integration of such management options with other practices is important to avoid the rapid evolution of high seed shattering in target weed species. Advances in genetics and molecular biology have shown promise for reducing seed shattering in important crops, which could be exploited for manipulating seed shattering in weed species. Future research should focus on developing a better understanding of various seed shattering mechanisms in plants in relation to changing climatic and management regimes.

Objectives:. To compare different modalities of renal replacement therapy in critically ill adults with acute kidney injury. Data Sources:. We searched Medline, PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to 25 May, 2020. We included randomized controlled trials comparing the efficacy and safety of different renal replacement therapy modalities in critically ill patients with acute kidney injury. Study Selection:. Ten reviewers (working in pairs) independently screened studies for eligibility, extracted data, and assessed risk of bias. Data Extraction:. We performed random-effects frequentist network meta-analyses and used the Grading of Recommendations, Assessment, Development, and Evaluation approach to assess certainty of evidence. The primary analysis was a four-node analysis: continuous renal replacement therapy, intermittent hemodialysis, slow efficiency extended dialysis, and peritoneal dialysis. The secondary analysis subdivided these four nodes into nine nodes including continuous veno-venous hemofiltration, continuous veno-venous hemodialysis, continuous veno-venous hemodiafiltration, continuous arterio-venous hemodiafiltration, intermittent hemodialysis, intermittent hemodialysis with hemofiltration, slow efficiency extended dialysis, slow efficiency extended dialysis with hemofiltration, and peritoneal dialysis. We set the minimal important difference threshold for mortality as 2.5% (relative difference, 0.04). Data Synthesis:. Thirty randomized controlled trials (n = 3,774 patients) proved eligible. There may be no difference in mortality between continuous renal replacement therapy and intermittent hemodialysis (relative risk, 1.04; 95% CI, 0.93–1.18; low certainty), whereas continuous renal replacement therapy demonstrated a possible increase in mortality compared with slow efficiency extended dialysis (relative risk, 1.06; 95% CI, 0.85–1.33; low certainty) and peritoneal dialysis (relative risk, 1.16; 95% CI, 0.92–1.49; low certainty). Continuous renal replacement therapy may increase renal recovery compared with intermittent hemodialysis (relative risk, 1.15; 95% CI, 0.91–1.45; low certainty), whereas both continuous renal replacement therapy and intermittent hemodialysis may be worse for renal recovery compared with slow efficiency extended dialysis and peritoneal dialysis (low certainty). Peritoneal dialysis was probably associated with the shortest duration of renal support and length of ICU stay compared with other interventions (low certainty for most comparisons). Slow efficiency extended dialysis may be associated with shortest length of hospital stay (low or moderate certainty for all comparisons) and days of mechanical ventilation (low certainty for all comparisons) compared with other interventions. There was no difference between continuous renal replacement therapy and intermittent hemodialysis in terms of hypotension (relative risk, 0.92; 95% CI, 0.72–1.16; moderate certainty) or other complications of therapy, but an increased risk of hypotension and bleeding was seen with both modalities compared with peritoneal dialysis (low or moderate certainty). Complications of slow efficiency extended dialysis were not sufficiently reported to inform comparisons. Conclusions:. The results of this network meta-analysis suggest there is no difference in mortality between continuous renal replacement therapy and intermittent hemodialysis although continuous renal replacement therapy may increases renal recovery compared with intermittent hemodialysis. Slow efficiency extended dialysis with hemofiltration may be the most effective intervention at reducing mortality. Peritoneal dialysis is associated with good efficacy, and the least number of complications however may not be practical in all settings. Importantly, all conclusions are based on very low to moderate certainty evidence, limited by imprecision. At the very least, ICU clinicians should feel comfortable that the differences between continuous renal replacement therapy, intermittent hemodialysis, slow efficiency extended dialysis, and, where clinically appropriate, peritoneal dialysis are likely small, and any of these modalities is a reasonable option to employ in critically ill patients.

Purpose: Analysis of circulating tumor DNA (ctDNA) in the plasma of patients with retinoblastoma and simulating lesions. Design: Retrospective cross-sectional study of the association of plasma ctDNA from retinoblastoma and simulating lesions with disease course. Participants: Fifty-eight Memorial Sloan Kettering Cancer Center patients with retinoblastoma comprising 68 plasma ctDNA samples and 5 with retinoblastoma-simulating lesions. Methods: The ctDNA analyzed with hybridization capture and next-generation sequencing in blood (plasma) of patients who had retinoblastoma or simulating lesions were evaluated for association with clinical course of the disease. Main Outcome Measures: Presence or absence of molecular aberrations in the RB1 gene and correlations with clinical features. Results: RB1 cell-free DNA (cfDNA) was detected in 16 of 19 patients with newly diagnosed, untreated intraocular retinoblastoma and in 3 of 3 patients with newly diagnosed, untreated metastatic disease. It was also present in 3 patients with recurrent intraocular disease before therapy, but was not present in patients with recurrent disease who received intra-arterial chemotherapy, nor in 21 patients who had undergone enucleation for unilateral disease. In 1 patient who had delayed treatment (insurance reasons) and showed rapid growth of the intraocular tumor, the variant allele frequency increased in 1 month from 0.34% to 2.48%. No RB1 mutations were detected in the cfDNA from plasma of patients with simulating lesions (3 with Coats disease and 1 with persistent fetal vasculature [PFV]). In 2 patients, we identified 2 independent RB1 mutations in plasma. Conclusions: Mutations in RB1 were found in the cfDNA from blood of patients with newly diagnosed, untreated retinoblastoma and in patients who showed disease recurrence in the eye after prior treatment, but not in unilateral retinoblastoma after enucleation Levels of ctDNA increase in patients with progressive disease who did not receive any treatment. High plasma cfDNA levels were detected in patients with newly diagnosed metastatic disease, and these levels decreased after systemic chemotherapy was administered. Further validation is needed for measuring the somatic alterations in cfDNA from blood in retinoblastoma that could provide a promising method of monitoring patients in the future.

Increasing concern for the ongoing availability and efficacy of herbicides is driving interest in the development of alternative physical and thermal weed control methods. Fortunately, improvements in weed detection through advancements in computing hardware and deep learning algorithms are creating an opportunity to use novel weed control tools, such as lasers, in large-scale cropping systems. For alternative control options, there are two key weed control timing opportunities, early and late post-crop emergence. Weed density for the early timing is typically higher, with a shorter window for control. Conversely, late post-emergent treatment of surviving and late-emerging weeds would occur in lower densities of larger and more variably sized weeds, given a prior weed control effort, but with a longer available weed control period. Research in laser weeding to date has primarily focused on early growth stage weeds and the ability of this approach to control larger weeds remains unknown. This study used a 25 W, 975 nm fiber-coupled diode laser to evaluate the opportunity for control of annual ryegrass (Lolium rigidum Gaudin) and the influence of four different growth stages (three-leaf, seven-leaf, mid-tillering, and late-tillering). Annual ryegrass plants at each growth stage were treated using a laser-focused to a 5 mm diameter with five different irradiation durations developing energy densities of 1.3, 2.5, 6.4, 19.1, and 76.4 J mm−2. At the three-leaf stage, all plants were controlled at 76.4 J mm−2 and 93.3% controlled at 19.1 J mm−2. Complete control of seven-leaf plants was only achieved at 76.4 J mm−2. Although laser treatments did not control mid-tillering stage plants, 76.4 J mm−2 reduced biomass by 60.2%. No similar reductions in biomass were recorded for the largest plants. This initial research assists in the development of novel weed control options in the context of large-scale conservation cropping systems. Future research should investigate the influence of laser treatments on additional weed species and the impact of increased laser power on larger weeds.

The information theoretic principle of rational adaptation predicts that individuals with aphasia adapt to their language impairments by relying more heavily on comparatively unimpaired non-linguistic knowledge to communicate. This prediction was examined by assessing the extent to which adults with chronic aphasia due to left-hemisphere stroke rely more on conceptual rather than lexical information during verb retrieval, as compared to age-matched neurotypical controls. A primed verb naming task examined the degree of facilitation each participant group received from either conceptual event-related or lexical collocate cues, compared to unrelated baseline cues. The results provide evidence that adults with aphasia received amplified facilitation from conceptual cues compared to controls, whereas healthy controls received greater facilitation from lexical cues. This indicates that adaptation to alternative and relatively unimpaired information may facilitate successful word retrieval in aphasia. Implications for models of rational adaptation and clinical neurorehabilitation are discussed.

ObjectivesTo determine whether the generic and branded warfarins used as anticoagulants in Brazil are therapeutic equivalents based on their international normalized ratio (INR) results.MethodsThis crossover randomized controlled trial had four periods. We used the branded Marevan and two generic versions of warfarin sodium tablets, manufactured by União Química and Teuto laboratories, all purchased from retail drugstores. Eligible participants were outpatients from an anticoagulation clinic at a university hospital in São Paulo, Brazil. They had atrial fibrillation or flutter and had been using warfarin for at least 2 months with an INR therapeutic range of 2.0-3.0. Randomization was by numbered, opaque, sealed envelopes. Healthcare personnel and outcome assessors were blinded to treatments, but patients were not. The primary outcome was the variability in the INR (ΔINR) and secondary outcomes included mean INR. We accepted formulations as equivalent if the 95% confidence interval (CI) of the comparison of ΔINR between branded and generic formulations was within the limit of ±0.49.ResultsOne hundred patients were recruited and randomized to six sequences of treatment (four sequences with n = 17 and two sequences with n = 16). União Química generic warfarin had equivalent variability in the INR to Marevan (ΔINR +0.09 [95% CI -0.29 to +0.46], n = 84). Comparison between Teuto generic warfarin and Marevan was inconclusive (ΔINR +0.29 [95% CI -0.09 to +0.68], n = 84).ConclusionsMarevan and União Química warfarin had equivalent therapeutic effectiveness and both could be confidently used for anticoagulation. The comparison between Marevan and TW was inconclusive and does not warrant a statement of equivalence. Our methods are especially important for comparing generic and branded drugs that raise concerns and may be subject of future investigations by regulatory agents.Trial registrationClinicalTrials.gov NCT02017197.

Introduction The transition from child to adult health services is a challenging and complex process for young people with cerebral palsy (CP). Poorly managed transition is associated with deterioration in health, increased hospitalisations and reduced quality of life. While international research identifies key practices that can improve the experience and outcomes of transition, there is a paucity of data in the Irish context. This research study aims to gain an insight into the experience of transition for young people with CP in Ireland.Methods and analysis A convergent parallel mixed-methods design will be used to collect, analyse and interpret quantitative and qualitative data. Participants will be young people aged 16–22 years with CP, their parent(s)/carer(s) and service providers. Quantitative and qualitative data will be collected through questionnaires and interviews, respectively. Quantitative data will be reported using descriptive statistics. Where sufficient data are collected, we will examine associations between the experience of transition practices and sociodemographic and CP-related factors, respectively, using appropriate regression models. Associations between service provider characteristics and provision of key transition practices may also be explored using appropriate regression models. Qualitative data will be analysed using the Framework Method. A coding matrix based on key transitional practices identified from the literature will be used to identify convergence and divergence across study components at the integration stage.Ethics and dissemination The study has been approved by the RCSI University of Medicine and Health Sciences Research Ethics Committee (REC201911010). Results will be presented to non-academic stakeholders through a variety of knowledge translation activities. Results will be published in open access, peer-reviewed journals and presented at national and international scientific conferences.

Background: Restless legs syndrome (RLS) affects approximately 30% of patients with end-stage kidney disease and is associated with impaired sleep and health-related quality of life. Medications used to treat RLS in patients receiving dialysis may have an increased risk of adverse events with dose titration, and residual RLS symptoms are common despite the use of effective treatments. Randomized controlled trials of monotherapy and combination pharmacologic therapy for RLS in hemodialysis are needed. Objective: To perform a randomized, crossover, placebo-controlled blinded trial of pharmacologic therapy for RLS in hemodialysis. Design/setting: The DIalysis Symptom COntrol-Restless Legs Syndrome (DISCO-RLS) trial is a randomized, crossover, placebo-controlled blinded trial of fixed low-dose pharmacologic therapy in patients receiving hemodialysis in 10 centers across Canada. It uses patient partners in its design, conduct, and reporting. Participants: Adults receiving thrice-weekly hemodialysis for at least 3 months with RLS of at least mild symptoms defined International Restless Legs Syndrome Study Group Rating Scale (IRLS) of 10 or more will enter a double placebo run-in period to exclude nonadherent participants and those unable to tolerate double placebo. Seventy-two participants who completed the run-in period will be randomized to 1 of 8 treatment sequences based on modeling with 4 treatment periods. Methods: Each treatment period lasts 4 weeks and consists of ropinirole 0.5 mg daily and gabapentin 100 mg daily, both together or neither with a double dummy placebo control for each treatment. The primary outcome is the difference in change scores of the IRLS between study treatments. Secondary outcomes are the differences in change scores of the Restless Legs Syndrome-6 Scale, patient global impression, 5-level EQ-5D version, and safety outcomes. Results: This randomized, crossover, placebo-controlled blinded trial will evaluate the efficacy and safety of fixed low-dose combination of ropinirole and gabapentin in patients receiving hemodialysis with RLS. Limitations: Patients with chronic kidney disease not on dialysis, kidney transplant recipients and those receiving peritoneal dialysis or home hemodialysis are not included. The intervention’s long term safety and efficacy including the risk of augmentation is not captured. Conclusion: This randomized crossover placebo controlled blinded trial will evaluate the efficacy and safety of fixed low-dose combination ropinirole and gabapentin in patients receiving hemodialysis with RLS. Trial Registration: ClinicalTrials.gov (NCT03806530)

Background: Understanding how frailty affects patients listed for transplantation has been identified as a priority research need. Frailty may be associated with a high risk of death or wait-list withdrawal, but this has not been evaluated in a large multicenter cohort of Canadian wait-listed patients. Objective: The primary objective is to evaluate whether frailty is associated with death or permanent withdrawal from the transplant wait list. Secondary objectives include assessing whether frailty is associated with hospitalization, quality of life, and the probability of being accepted to the wait list. Design: Prospective cohort study. Setting: Seven sites with established renal transplant programs that evaluate patients for the kidney transplant wait list. Patients: Individuals who are being considered for the kidney transplant wait list. Measurements: We will assess frailty using the Fried Phenotype, a frailty index, the Short Physical Performance Battery, and the Clinical Frailty Scale at the time of listing for transplantation. We will also assess frailty at the time of referral to the wait list and annually after listing in a subgroup of patients. Methods: The primary outcome of the composite of time to death or permanent wait-list withdrawal will be compared between patients who are frail and those who are not frail and will account for the competing risks of deceased and live donor transplantation. Secondary outcomes will include number of hospitalizations and length of stay, and in a subset, changes in frailty severity over time, change in quality of life, and the probability of being listed. Recruitment of 1165 patients will provide >80% power to identify a relative hazard of ≥1.7 comparing patients who are frail to those who are not frail for the primary outcome (2-sided α = .05), whereas a more conservative recruitment target of 624 patients will provide >80% power to identify a relative hazard of ≥2.0. Results: Through December 2019, 665 assessments of frailty (inclusive of those for the primary outcome and all secondary outcomes including repeated measures) have been completed. Limitations: There may be variation across sites in the processes of referral and listing for transplantation that will require consideration in the analysis and results. Conclusions: This study will provide a detailed understanding of the association between frailty and outcomes for wait-listed patients. Understanding this association is necessary before routinely measuring frailty as part of the wait-list eligibility assessment and prior to ascertaining the need for interventions that may modify frailty. Trial Registration: Not applicable as this is a protocol for a prospective observational study.

This article presents the emerging transdisciplinary practice of Experimental Heritage as performed within an ongoing Irish-Swedish research project involving artists and archaeologists. The project is undertaken simultaneously in western Ireland and south-eastern Sweden. It explores the chosen Irish and Swedish landscapes of Clare and Öland, their similarities and differences, with the aid of combined and integrated artistic and archaeological practices. The starting points for common explorations are: stone and water, movement and time/the multitemporal, and the tangible and intangible aspects of landscape experience. In a transdisciplinary process, we explore new ways of combining art, archaeology and heritage within and between these landscapes.

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis (p < 0.001) and area postrema relapses (P = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS (p < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January (P = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD.

Background: Small randomized trials demonstrated that a lower compared with higher dialysate temperature reduced the average drop in intradialytic blood pressure. Some observational studies demonstrated that a lower compared with higher dialysate temperature was associated with a lower risk of all-cause mortality and cardiovascular mortality. There is now the need for a large randomized trial that compares the effect of a low vs high dialysate temperature on major cardiovascular outcomes. Objective: The purpose of this study is to test the effect of outpatient hemodialysis centers randomized to (1) a personalized temperature-reduced dialysate protocol or (2) a standard-temperature dialysate protocol for 4 years on cardiovascular-related death and hospitalizations. Design: The design of the study is a pragmatic, registry-based, open-label, cluster randomized controlled trial. Setting: Hemodialysis centers in Ontario, Canada, were randomized on February 1, 2017, for a trial start date of April 3, 2017, and end date of March 31, 2021. Participants: In total, 84 hemodialysis centers will care for approximately 15 500 patients and provide over 4 million dialysis sessions over a 4-year follow-up. Intervention: Hemodialysis centers were randomized (1:1) to provide (1) a personalized temperature-reduced dialysate protocol or (2) a standard-temperature dialysate protocol of 36.5°C. For the personalized protocol, nurses set the dialysate temperature between 0.5°C and 0.9°C below the patient’s predialysis body temperature for each dialysis session, to a minimum dialysate temperature of 35.5°C. Primary outcome: A composite of cardiovascular-related death or major cardiovascular-related hospitalization (a hospital admission with myocardial infarction, congestive heart failure, or ischemic stroke) captured in Ontario health care administrative databases. Planned primary analysis: The primary analysis will follow an intent-to-treat approach. The hazard ratio of time-to-first event will be estimated from a Cox model. Within-center correlation will be considered using a robust sandwich estimator. Observation time will be censored on the trial end date or when patients die from a noncardiovascular event. Trial Registration: www.clinicaltrials.gov ; identifier: NCT02628366.

This article is concerned with the 14th century church of St. Anne’s in the historic walled city of Famagusta, Cyprus, as a site for transdisciplinary investigation embedded in, interrogated by, and disseminated via, digital space. The principal tool to create the foundational model and database of this historic structure was HBIM (Historic Building Information Modelling), beyond which further experiments were conducted in Padua and Singapore into the scholarly and pedagogical potential of VR, AR, and curated 4D interactive historic spaces. Such non-invasive systems of analysis are most welcome in a city where the legalities of conducting work ‘in the field’ are complicated by political and economic considerations.DOI: https://doi.org/10.20365/disegnarecon.21.2018.11