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Background: Whether a conservative strategy of medical therapy alone or a strategy of medical therapy plus invasive treatment is more beneficial in older adults with non-ST-segment elevation myocardial infarction (NSTEMI) remains unclear., Methods: We conducted a prospective, multicenter, randomized trial involving patients 75 years of age or older with NSTEMI at 48 sites in the United Kingdom. The patients were assigned in a 1:1 ratio to a conservative strategy of the best available medical therapy or an invasive strategy of coronary angiography and revascularization plus the best available medical therapy. Patients who were frail or had a high burden of coexisting conditions were eligible. The primary outcome was a composite of death from cardiovascular causes (cardiovascular death) or nonfatal myocardial infarction assessed in a time-to-event analysis., Results: A total of 1518 patients underwent randomization; 753 patients were assigned to the invasive-strategy group and 765 to the conservative-strategy group. The mean age of the patients was 82 years, 45% were women, and 32% were frail. A primary-outcome event occurred in 193 patients (25.6%) in the invasive-strategy group and 201 patients (26.3%) in the conservative-strategy group (hazard ratio, 0.94; 95% confidence interval [CI], 0.77 to 1.14; P = 0.53) over a median follow-up of 4.1 years. Cardiovascular death occurred in 15.8% of the patients in the invasive-strategy group and 14.2% of the patients in the conservative-strategy group (hazard ratio, 1.11; 95% CI, 0.86 to 1.44). Nonfatal myocardial infarction occurred in 11.7% in the invasive-strategy group and 15.0% in the conservative-strategy group (hazard ratio, 0.75; 95% CI, 0.57 to 0.99). Procedural complications occurred in less than 1% of the patients., Conclusions: In older adults with NSTEMI, an invasive strategy did not result in a significantly lower risk of cardiovascular death or nonfatal myocardial infarction (the composite primary outcome) than a conservative strategy over a median follow-up of 4.1 years. (Funded by the British Heart Foundation; BHF SENIOR-RITA ISRCTN Registry number, ISRCTN11343602.)., (Copyright © 2024 Massachusetts Medical Society.)

Conventional G-banded karyotype is an essential tool for detecting chromosomal variants in patients undergoing fertility evaluation. In Australia, 15 cells are traditionally analysed or counted, to enhance detection of mosaic chromosomal variants. However, this protocol is not backed by clinical evidence. This study aims to assess the test performance of an abbreviated 5-cell karyotype analysis protocol in adult patients undergoing fertility evaluation. A retrospective review of 53,293 blood karyotype tests, performed between 2019 and 2023, was conducted on a patient cohort primarily referred by reproductive endocrinology specialists. There were 513 variants reported in this cohort. Low level mosaic variants, where the variant was observed in less than 40% of cells, were reported in 13 cases, or one in 4,100 patients. Due to reduced sensitivity for low level mosaic variants, a 5-cell protocol is estimated to have a test sensitivity of 97.3% and a negative predictive value of 99.97%. A decision-making flowchart is proposed and we show that additional chromosome analysis and/or counts would be triggered in fewer than one in 10 cases using a 5-cell protocol, whilst remaining appropriate for detecting clinically significant mosaicism. A 5-cell karyotype analysis protocol therefore maintains analytical and clinical validity in adult patients undergoing fertility-related blood karyotyping. Future research is recommended to validate these findings across laboratories and to explore their application to other clinical contexts., (Copyright © 2024 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

An 11-year-old neutered male large crossbreed dog was presented for investigation because of a 10-day history of progressive lethargy, hyporexia, and pyrexia. Physical and dermatological examinations were unremarkable. Blood biochemical analysis identified a marked total and ionized hypercalcemia and increased C-reactive protein concentration. Bicavitary computed tomography screening for causes of the dog's clinical and biochemical abnormalities identified a diffuse panniculitis. Histopathological examination of full-thickness skin biopsies was consistent with pyogranulomatous inflammation. Extensive histochemical staining revealed no infectious etiology. Complete clinical and biochemical remissions were observed after starting immunosuppressive, followed by tapering, doses of prednisolone, supporting an immune-mediated etiology. Key clinical message: Sterile, immune-mediated pyogranulomatous inflammation should remain a differential diagnosis for hypercalcemia in dogs. Significant dermatological disease may occur without visible abnormalities., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

Background: The rising number of dementia diagnoses and imminent adoption of disease-modifying treatments necessitate innovative approaches to identify individuals at risk, monitor disease course and intervene non-pharmacologically earlier in the disease course. Digital assessments of dementia risk and cognitive function have the potential to outperform traditional in-person assessments in terms of their affordability, accuracy and longitudinal tracking abilities. However, their accessibility and reliability in older adults is unclear., Aims: To evaluate the usability and reliability of a smartphone assessment of lifestyle and cognitive factors relevant to dementia risk in a group of UK-based older adults., Method: Cognitively healthy adults ( n = 756) recruited through the Dementias Platform UK Great Minds volunteer register completed three assessments of cognitive function and dementia risk over a 3-month period and provided usability feedback on the Five Lives smartphone application (app). We evaluated cognitive test scores for age, gender and higher education effects, normality distributions, test-retest reliability and their relationship with participants' lifestyle dementia risk factors., Results: Participants found the app 'easy to use', 'quick to complete' and 'enjoyable'. The cognitive tests showed normal or near-to-normal distributions, variable test-retest reliabilities and age-related effects. Only tests of verbal ability showed gender and education effects. The cognitive tests did not correlate with lifestyle dementia risk scores., Conclusions: The Five Lives assessment demonstrates high usability and reliability among older adults. These findings highlight the potential of digital assessments in dementia research and clinical practice, enabling improved accessibility and better monitoring of cognitive health on a larger scale than traditional in-person assessments.

Meme-making is an effective method for engaging students and enhancing the learning environment. Memes are a social media cultural phenomenon that the majority of those in Higher Education are exposed to on an almost daily occurrence. This research examined the use of meme-making within the forensic sciences to allow students to reflect on their knowledge. Students studying modules in forensic science across six universities in the UK and USA participated in the study. At the end of a teaching session, students produced a meme (using Meme Generator) to reflect on what they had learned; memes were then shared with the class anonymously via Padlet. This allowed all class members to see and engage with the memes created. At the end of the activity students were anonymously surveyed on their experience using Microsoft Forms and analysis of the results were undertaken using SPSS software. Meme-making was found to be an inclusive learning activity with no limitations, including age (part-time, distance learning and visually impaired students were not part of the study parameters). Results showed that not only did students find the practice fun, but it also helped with the retention of the class content suggesting that the meme-making process is an effective way to enhance the learning environment while engaging students. Student feedback suggests that to maximise participation the educator should stress reflection and learning as the key purpose of generating a meme, rather than being witty or entertaining. The forensic science educator should be mindful of selecting appropriate subject matter for this often-humorous activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Takotsubo syndrome is an increasingly common cardiac emergency with no known evidence-based treatment., Objectives: The purpose of this study was to investigate cardiovascular mortality and medication use after takotsubo syndrome., Methods: In a case-control study, all patients with takotsubo syndrome in Scotland between 2010 and 2017 (n = 620) were age, sex, and geographically matched to individuals in the general population (1:4, n = 2,480) and contemporaneous patients with acute myocardial infarction (1:1, n = 620). Electronic health record data linkage of mortality outcomes and drug prescribing were analyzed using Cox proportional hazard regression models., Results: Of the 3,720 study participants (mean age, 66 years; 91% women), 153 (25%) patients with takotsubo syndrome died over the median of 5.5 years follow-up. This exceeded mortality rates in the general population (N = 374 [15%]; HR: 1.78 [95% CI: 1.48-2.15], P < 0.0001), especially for cardiovascular (HR: 2.47 [95% CI: 1.81-3.39], P < 0.001) but also noncardiovascular (HR: 1.48 [95% CI: 1.16-1.87], P = 0.002) deaths. Mortality rates were lower for patients with takotsubo syndrome than those with myocardial infarction (31%, 195/620; HR: 0.76 [95% CI: 0.62-0.94], P = 0.012), which was attributable to lower rates of cardiovascular (HR: 0.61 [95% CI: 0.44-0.84], P = 0.002) but not non-cardiovascular (HR: 0.92 [95% CI: 0.69-1.23], P = 0.59) deaths. Despite comparable medications use, cardiovascular therapies were consistently associated with better survival in patients with myocardial infarction but not in those with takotsubo syndrome. Diuretic ( P = 0.01), anti-inflammatory ( P = 0.002), and psychotropic ( P < 0.001) therapies were all associated with worse outcomes in patients with takotsubo syndrome., Conclusions: In patients with takotsubo syndrome, cardiovascular mortality is the leading cause of death, and this is not associated with cardiovascular therapy use.

Objectives: Tick-borne encephalitis virus and louping ill virus are neurotropic flaviviruses transmitted by ticks. Epidemiologically, tick-borne encephalitis is endemic in Europe whereas louping ill's predominant geographical distribution is the UK. Rarely, these flaviviruses affect dogs causing neurological signs. This case series aimed to describe the clinical, clinicopathological, and imaging findings, as well as the outcomes in six dogs with meningoencephalitis and/or meningomyelitis caused by a flavivirus in the UK in 2021., Materials and Methods: Observational retrospective case-series study. Clinical data were retrieved from medical records of dogs with positive serological or immunohistochemical results from three different institutions from spring to winter 2021., Results: Six dogs were included in the study. All dogs presented an initial phase of pyrexia and/or lethargy followed by progressive signs of spinal cord and/or intracranial disease. Magnetic resonance imaging showed bilateral and symmetrical lesions affecting the grey matter of the thalamus, pons, medulla oblongata, and thoracic or lumbar intumescences with none or mild parenchymal and meningeal contrast enhancement. Serology for tick-borne encephalitis virus was positive in five dogs with the presence of seroconversion in two dogs. The viral distinction between flaviviruses was not achieved. One dog with negative serology presented positive immunohistochemistry at post-mortem examination. Three dogs survived but presented neurological sequelae. Three dogs were euthanased due to the rapid progression of the clinical signs or static neurological signs., Clinical Significance: These cases raise awareness of the presence of tick-borne encephalitis as an emergent disease or the increased prevalence of louping ill virus affecting dogs in the UK., (© 2023 The Authors. Journal of Small Animal Practice published by John Wiley & Sons Ltd on behalf of British Small Animal Veterinary Association.)

In this chapter, we describe a method for analyzing both recombinant and plasma-derived alpha 1 antitrypsin and its oligomers by means of native ion mobility mass spectrometry. Our experimental workflow can be applied to other variants of alpha 1 antitrypsin and its oligomers as well as being used to probe their interactions with small molecules in the gas phase., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Colfax, Louisiana hosts a commercial hazardous waste thermal treatment (TT) facility, which treats fireworks, explosives, and military ordnances by open-burn/open-detonation one mile from the edge of the nearest community. Seventy-one percent of Colfax's residents are Black, and forty-six percent live below poverty, indicating the community's structural vulnerability. This community-based study originated at the behest of Colfax community members. We hypothesized that the close relationships among members of this enclave may have enhanced the community's ability to mobilize in opposition to the TT facility. We conducted semi-structured oral history interviews with nineteen community members and examined the social and interorganizational networks used by the Colfax community to claim its role in decision-making regarding the TT facility after years of exclusion from this process. Interview transcripts were analyzed through the lens of community capacity theory to gain insight into how interactions among community members about the environmental hazards led to social mobilization and improved participation in the decision-making process using codes for communication, organization, and outcome. Additionally, we reviewed Louisiana Department of Environmental Quality records for complaints about the facility to gauge public participation. One notable theme across several interviews was exclusion from the initial decision-making process related to the facility. However, interviewees noted a sustained effort was made among community members to educate themselves about the facility, organize a response through neighbor-to-neighbor contact, and take action by submitting formal complaints and participating in public hearings. Through the lens of environmental justice, this study illustrates an evolving condition of procedural justice.

Background: Discontinuation of treatment in people with first episode psychosis (FEP) is common, but the extent to which this is related to specific adverse effects of antipsychotic medications is unclear., Objectives: To investigate whether antipsychotic discontinuation is associated with the prescription of particular antipsychotics and particular adverse effects., Design: Retrospective cohort study., Methods: We assembled de-identified electronic health record (EHR) data from 2309 adults with FEP who received care from the South London and Maudsley NHS Foundation Trust between 1st April 2008 and 31st March 2019. Associations between antipsychotic medications, clinician-recorded side effects and treatment discontinuation were investigated across a mean follow-up period of 34.2 months using Cox regression., Results: The mean age of patients was 26.7 years and 1492 (64.6%) were male. Among first prescribed antipsychotic medications, discontinuation occurred earlier with haloperidol [hazard ratio (HR) = 2.78, 95% CI = 1.69-4.60] and quetiapine (HR = 1.43, 95% CI = 1.16-1.80) than with olanzapine. Discontinuation occurred sooner when there was evidence of extrapyramidal symptoms (HR = 1.33, 95% CI = 1.08-1.64) or sexual dysfunction (HR = 1.59, 95% CI = 1.03-2.46). Among antipsychotics prescribed at any point during treatment, lurasidone (HR = 1.40, 95% CI = 1.10-1.78) and aripiprazole (HR = 1.09, 95% CI = 1.01-1.19) were associated with earlier discontinuation than olanzapine. Conversely, clozapine (HR = 0.55, 95% CI = 0.41-0.73) and paliperidone 1-monthly (PP1M) long-acting injectable (HR = 0.80, 95% CI = 0.68-0.94) were associated with later discontinuation. Unexpectedly, for antipsychotics prescribed at any stage of treatment, sedation (HR = 0.89, 95% CI = 0.81-0.97), weight gain (HR = 0.73, 95% CI = 0.64-0.83), and multiple side effects (HR = 0.83, 95% CI = 0.76-0.90) were associated with later discontinuation., Conclusion: Earlier treatment discontinuation associated with sexual or extrapyramidal side effects could be related to their rapid onset and poor tolerability. Later treatment discontinuation associated with clozapine and PP1M could be related to the relative efficacy of these treatments. These findings merit consideration when selecting antipsychotic therapy for people with FEP., (© The Author(s), 2023.)

Serine protease inhibitors, SERPINS, are a highly conserved family of proteins that regulate serine proteases in the central coagulation and immune pathways, representing 2-10% of circulating proteins in the blood. Serine proteases form cascades of sequentially activated enzymes that direct thrombosis (clot formation) and thrombolysis (clot dissolution), complement activation in immune responses and also programmed cell death (apoptosis). Virus-derived serpins have co-evolved with mammalian proteases and serpins, developing into highly effective inhibitors of mammalian proteolytic pathways. Through interacting with extracellular and intracellular serine and cysteine proteases, viral serpins provide a new class of highly active virus-derived coagulation-, immune-, and apoptosis-modulating drug candidates. Viral serpins have unique characteristics: (1) function at micrograms per kilogram doses; (2) selectivity in targeting sites of protease activation; (3) minimal side effects at active concentrations; and (4) the demonstrated capacity to be modified, or fine-tuned, for altered protease targeting. To date, the virus-derived serpin class of biologics has proven effective in a wide range of animal models and in one clinical trial in patients with unstable coronary disease. Here, we outline the known viral serpins and review prior studies with viral serpins, considering their potential for application as new sources for immune-, coagulation-, and apoptosis-modulating therapeutics.

Wastewater-based epidemiology (WBE) is a valuable tool for monitoring the circulation of COVID-19. However, while variations in population size are recognised as major sources of uncertainty, wastewater SARS-CoV-2 measurements are not routinely population-normalised. This paper aims to determine whether dynamic population normalisation significantly alters SARS-CoV-2 dynamics observed through wastewater monitoring, and whether it is beneficial or necessary to provide an understanding of COVID-19 epidemiology. Data from 394 sites in England are used, and normalisation is implemented based on ammoniacal nitrogen and orthophosphate concentrations. Raw and normalised wastewater SARS-CoV-2 metrics are evaluated at the site and spatially aggregated levels are compared against indicators of prevalence based on the Coronavirus Infection Survey and Test and Trace polymerase chain reaction test results. Normalisation is shown, on average, to have a limited impact on overall temporal trends. However, significant variability in the degree to which it affects local-level trends is observed. This is not evident from previous WBE studies focused on single sites and, critically, demonstrates that while the impact of normalisation on SARS-CoV-2 trends is small on average, this may not always be the case. When averaged across many sites, normalisation strengthens the correlation between wastewater SARS-CoV-2 data and prevalence indicators; however, confidence in the improvement is low.

Endometrial carcinoma (EC) can be divided into 4 prognostic molecular subtypes, and no specific molecular profile (NSMP) type is the most commonly occurring type (∼50%). Although described as having an intermediate to favorable prognosis, this subtype encompasses pathologically and molecularly diverse tumors. We aimed to identify factors associated with outcomes within the NSMP ECs that might be used to stratify prognosis and direct treatment. Clinicopathologic, immunohistochemical, and genetic features of a large series of NSMP EC were used to identify parameters that could identify the subset associated with a very favorable outcome (disease-specific death rate <5% at 5 years, termed low-risk NSMP). A total of 1110 NSMP ECs were profiled. In a univariate analysis, stage, grade, lymphovascular invasion, estrogen receptor (ER) and progesterone receptor (PR) expression, L1CAM overexpression, and mutations in PIK3CA were associated with disease-specific survival. Two critical features, grade and ER expression, identified a low-risk NSMP subset (grade 1-2, ER-positive [>1%], 84% of cases), which showed a 5-year disease-specific death rate of 1.6% across all stages and 1.4% within stage I. The remaining cases (high-risk NSMPs, grade 3, and/or ER-negative status) were responsible for most of the disease-specific deaths (disease-specific death rate at 5 years, 22.9%; hazard ratio compared with that of low-risk NSMPs: 16.3; 95% CI, 8.4-31.7). Within NSMP EC, the low-risk and high-risk categories were of prognostic significance independent of the stage on a multivariate analysis. Low-grade and ER-positive NSMP ECs are a homogeneous low-risk group associated with an exceptionally favorable prognosis in which de-escalation and/or endocrine therapy strategies can be applied. Grade 3 and/or ER-negative status identifies a high-risk NSMP subset, including rare high-grade histotypes (eg, clear cell, dedifferentiated, and mesonephric-like), responsible for most NSMP-related deaths. Subclassification of NSMPs allows for the category of low-risk EC molecular subtypes to be dramatically expanded because it now includes both POLEmut and the much more common low-risk NSMP EC., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: Recent data support the predictive implications of molecular subtype assignment in endometrial cancer (EC). Our objective was to retrospectively assess clinical outcomes according to adjuvant treatment received within EC molecular subtypes., Methods: Clinical outcomes (disease-specific and progression-free survival DSS/PFS) of EC patients from a single institution and population-based cohorts that had undergone molecular classification were assessed with respect to adjuvant therapy received and 2016 ESMO risk group., Results: 2472 ECs were assessed; 184 (7.4%) POLEmut, 638 (25.8%) MMRd, 1223 (49.5%) NSMP and 427 (17.3%) p53abn. N = 774 (34.6%) of the cohort were ESMO 2016 high risk and 109 (4.8%) were advanced or metastatic. In patients with MMRd EC, assessed across and within stage, there was no observed benefit in DSS or PFS with the addition of chemotherapy +/- radiation compared to radiation alone in ESMO high risk (p = 0.694) or ESMO high, advanced, metastatic risk groups combined (p = 0.852). In patients with p53abn EC, adjuvant chemotherapy given with radiation was associated with significantly longer DSS compared to radiation alone in ESMO high risk (p = 0.007) and ESMO high, advanced and metastatic risk groups combined (p = 0.015), even when restricted to stage I disease (p < 0.001) and when compared in serous vs. non-serous histotypes (p = 0.009)., Conclusions: Adjuvant chemotherapy is associated with more favorable outcomes for patients with p53abn EC, including stage I disease and non-serous histotypes, but does not appear to add benefit within MMRd ECs for any stage of disease, consistent with PORTEC-3 molecular subanalysis. Prospective trials, assessing treatment efficacy within molecular subtype are needed, however these 'real-world' data should be considered when discussing adjuvant treatment with patients., Competing Interests: Declaration of Competing Interest Dr. McConechy is an employee and Dr. Huntsman is a founder and Chief Medical Officer of Imagia Canexia Health., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: To estimate the prevalence of COVID-19 among occupants of North Dunedin student flats between Flat Orientation Week (Flo-Week, week starting 14 February 2022) and the end of Semester 1 (week starting 30 May 2022); to investigate the potential under-reporting of cases to the University of Otago and under-recording of positive rapid antigen test (RAT) results in My Covid Record; to explore the COVID-related experiences of students during the above period., Methods: Randomly selected households in the North Dunedin area were visited at the end of Semester 1 and oral consent was sought for a short interview comprising closed- and open-ended questions. Households were eligible for inclusion if at least one resident was a University of Otago student., Results: One hundred and thirty-five (96.4%) of 140 eligible households participated, and in 94.1% of these households at least one resident tested positive for COVID-19 between the start of Flo-Week and the date of the interview (a mean period of 109 days [standard deviation 3.6]). In total, 73.6% of the occupants in the participating households tested positive. Of the cases who were University of Otago students, 60.4% reported their positive status to the University. Of all cases diagnosed via a RAT, 66.9% uploaded their result to My Covid Record. Students reported various academic, financial and mental health stresses associated with the general COVID-19 situation during the study period., Conclusions: These findings suggest that the number of COVID-19 cases reported to the University of Otago between Flo-Week and the end of Semester 1 was a substantial underestimate of the true number, as was the number of cases recorded in My Covid Record. The findings also highlight the considerable impact that COVID-19 had on students during Semester 1., Competing Interests: Nil, (© PMA.)

We assessed the landscape of diagnostic pathology practice and how molecular classification could potentially impact management of patients with endometrial cancer by collecting patient samples, clinicopathologic data, and patient outcomes from EC patients diagnosed in 2016 at 10 Canadian tertiary cancer centers and 19 community hospitals. ProMisE molecular subtype (POLEmut, MMRd, p53abn, No Specific Molecular Profile (NSMP)) was assigned retrospectively. 1357 patients were fully evaluable including 85 POLEmut (6.3%), 380 MMRd (28.0%), 643 NSMP (47.4%), and 249 p53abn ECs (18.3%). Immunohistochemistry (IHC) for MMR proteins was undertaken at the time of primary diagnosis in 2016 in only 42% of the cohort (570/1357; range 3.5-95.4%/center). p53 IHC had only been performed in 21.1% of the cohort (286/1357; range 10.1-41.9%/center). Thus, based on the retrospective molecular subtype assignment, 54.7% (208/380) of MMRd EC had not been tested with MMR IHC (or MSI) and 48.2% (120/249) of p53abn ECs were not tested with p53 IHC in 2016. Molecular subtype diversity within histotypes was profound; most serous carcinomas were p53abn (91.4%), but only 129/249 (51.8%) p53abn EC were serous. Low-grade (Gr1-2) endometrioid carcinomas were mostly NSMP (589/954, 61.7%) but included all molecular subtypes, including p53abn (19/954, 2.0%). Molecular subtype was significantly associated with clinical outcomes (p < 0.001) even in patients with stage I disease (OS p = 0.006, DSS p < 0.001, PFS p < 0.001). Assessment of national pathologic practice in 2016 shows highly variable use of MMR and p53 IHC and demonstrates significant opportunities to improve and standardize biomarker reporting. Inconsistent, non-reflexive IHC resulted in missed opportunities for Hereditary Cancer Program referral and Lynch Syndrome diagnosis, and missed potential therapeutic implications (e.g., chemotherapy in p53abn EC, immune blockade for MMRd EC). Routine integration of molecular subtyping into practice can improve the consistency of EC pathology assessment and classification., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Adenoviruses cause a range of major diseases across many diverse animal species including ruminants. They are classified into six genera in the family Adenoviridae. In deer species, two adenoviruses are currently recognized: deer adenovirus 1 in the Atadenovirus genus, and deer adenovirus 2 in the Mastadenovirus genus. Deer adenovirus 1 causes adenovirus haemorrhagic disease with high fatality in black-tailed and mule deer in North America. Conversely, deer adenovirus 2 was incidentally detected from a healthy white-tailed deer fawn, but experimentally it has been shown to cause pyrexia, cough and moderate to severe haemorrhage. Here, we detected a novel adenovirus, reindeer adenovirus 1, from lung lesions of a 5-year-old male reindeer (Rangifer tarandus). This animal presented with aspiration pneumonia and necrotizing bronchiolitis following a period of clinical weakness, nasal discharge and wasting. Histopathological examination of the lung revealed large intranuclear basophilic inclusions associated with the areas of necrotizing bronchiolitis. Next generation sequencing of the lung tissue identified a novel mastadenovirus with close similarity to deer adenovirus 2 and bovine adenovirus 3. To our knowledge, this is the first report of a deer mastadenovirus associated with necrotizing bronchiolitis in captive reindeer., (© 2021 Crown copyright. Transboundary and Emerging Diseases published by Wiley-VCH GmbH. This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.)

Coccidiosis caused by Eimeria spp. incurs significant morbidity and mortality in chickens, and is thus of great economic importance. Post-mortem intestinal lesion scoring remains one of the most common means of diagnosis; therefore alternative, non-invasive methods of diagnosis and monitoring would be highly desirable. Micro-RNAs (miRNAs) have been shown to be stable in faeces of human and animal species with expression altered in gastrointestinal disease. We hypothesized that miRNA is stable in caecal content of chickens, and that differential miRNA expression patterns would be seen in Eimeria -infected versus uninfected individuals. Initially, RNA was extracted from Eimeria tenella -infected ( n  = 3; 7 days post infection) and uninfected ( n  = 3) chicken caecal content to demonstrate miRNA stability. Subsequently, next-generation miRNA sequencing was performed on caecal content from E. tenella -infected chickens with high (lesion score (LS) 3-4; n  = 3) or low (LS1; n  = 3) levels of pathology, and uninfected controls ( n  = 3). Comparative analysis identified 19 miRNAs that exhibited significantly altered expression in the caecal content of E. tenella , infected chickens versus uninfected chickens ( t -test, False Discovery Rate (FDR) < 0.05). Eight of these miRNAs showed significant up-regulation in infection (fold change of 9.8-105, FDR <0.05). Quantitative PCR was performed using separate biological replicates to confirm differential regulation in eight of these miRNA candidates in caecal and faecal content. This work has identified a panel of miRNA candidates which may be appropriate for use as non-invasive faecal markers of active caecal coccidiosis without the need for culling. RESEARCH HIGHLIGHTS E. tenella induced differential miRNA expression in caecal content and faeces.

Objectives: To examine whether depressive symptoms predict receipt of cognitive-behavioural therapy for psychosis (CBTp) in individuals with psychosis., Design: Retrospective cross-sectional analysis of electronic health records (EHRs) of a clinical cohort., Setting: A secondary National Health Service mental healthcare service serving four boroughs of south London, UK., Participants: 20 078 patients diagnosed with an International Classification of Diseases, version 10 (ICD-10) code between F20 and 29 extracted from an EHR database., Primary and Secondary Outcome Measures: Primary: Whether recorded depressive symptoms predicted CBTp session receipt, defined as at least one session of CBTp identified from structured EHR fields supplemented by a natural language processing algorithm. Secondary: Whether age, gender, ethnicity, symptom profiles (positive, negative, manic and disorganisation symptoms), a comorbid diagnosis of depression, anxiety or bipolar disorder, general CBT receipt prior to the primary psychosis diagnosis date or type of psychosis diagnosis predicted CBTp receipt., Results: Of patients with a psychotic disorder, only 8.2% received CBTp. Individuals with at least one depressive symptom recorded, depression symptom severity and 12 out of 15 of the individual depressive symptoms independently predicted CBTp receipt. Female gender, White ethnicity and presence of a comorbid affective disorder or primary schizoaffective diagnosis were independently positively associated with CBTp receipt within the whole sample and the top 25% of mentioned depressive symptoms., Conclusions: Individuals with a psychotic disorder who had recorded depressive symptoms were significantly more likely to receive CBTp sessions, aligning with CBTp guidelines of managing depressive symptoms related to a psychotic experience. However, overall receipt of CBTp is low and more common in certain demographic groups, and needs to be increased., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objectives: We measured the variation in practice across all aspects of endometrial cancer (EC) management and assessed the potential impact of implementation of molecular classification., Methods: Centers from across Canada provided representative tumor samples and clinical data, including preoperative workup, operative management, hereditary cancer program (HCP) referrals, adjuvant therapy, surveillance and outcomes, for all EC patients diagnosed in 2016. Tumors were classified into the four ProMisE molecular subtypes., Results: A total of 1336 fully evaluable EC patients were identified from 10 tertiary cancer centers (TC; n = 1022) and 19 community centers (CC; n = 314). Variation of surgical practice across TCs was profound (14-100%) for lymphadenectomy (LND) (mean 57% Gr1/2, 82% Gr3) and omental sampling (20% Gr1/2, 79% Gr3). Preoperative CT scans were inconsistently obtained (mean 32% Gr1/2, 51% Gr3) and use of adjuvant chemo or chemoRT in high risk EC ranged from 0-55% and 64-100%, respectively. Molecular subtyping was performed retrospectively and identified 6% POLEmut, 28% MMRd, 48% NSMP and 18% p53abn ECs, and was significantly associated with survival. Within patients retrospectively diagnosed with MMRd EC only 22% had been referred to HCP. Of patients with p53abn EC, LND and omental sampling was not performed in 21% and 23% respectively, and 41% received no chemotherapy. Comparison of management in 2016 with current 2020 ESGO/ESTRO/ESP guidelines identified at least 26 and 95 patients that would have been directed to less or more adjuvant therapy, respectively (10% of cohort)., Conclusion: Molecular classification has the potential to mitigate the profound variation in practice demonstrated in current EC care, enabling reproducible risk assessment, guiding treatment and reducing health care disparities., Competing Interests: Declaration of Competing Interest Dr. M McConechy, and R Aguirre- Hernandez are employees, and Dr. Huntsman is a founder and Chief Medical Officer of Canexia Health., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Introduction: Event-free survival rates at 15 years for paediatric patients with relapsed/refractory acute lymphoblastic leukaemia (ALL) are 30%-50%, with 5-year survival for adult patients only 20%. Many patients with newly diagnosed and relapsed ALL harbour somatic RAS-signalling activation mutations. Induction therapy for ALL involves steroids, with preclinical data suggesting the combination of dexamethasone with the MEK1/2 inhibitor, selumetinib (ARRY-142886) has a synergistic anticancer effect., Methods and Analysis: The SeluDex trial is an international, parallel-group, dose-finding with expansion, phase I/II trial to assess the selumetinib/dexamethasone combination in adult and paediatric patients with relapsed/refractory, RAS pathway mutant ALL. The Cancer Research UK Clinical Trials Unit at University of Birmingham is the UK Coordinating Centre, with national hubs in Copenhagen, Denmark; Monza, Italy; Münster, Germany; Paris, France; and Utrecht, Netherlands. Patients with morphologically proven relapsed/refractory or progressive B-cell precursor or T-cell ALL, with demonstrated RAS pathway activating mutations are eligible. Adult patients are > 18 years old, ECOG < 2 and paediatric <18 years old, Lansky play scale ≥60% or Karnofsky score ≥60%. Phase I primary objective is the recommended phase II dose of selumetinib as defined by occurrence/non-occurrence of dose limiting toxicities using the continual reassessment method; phase II will evaluate preliminary antileukaemic activity of the combination, as defined by morphological response 28 days post-treatment using a Bayesian approach. Target recruitment is between 26 and 42 patients (minimum 13 and maximum 21 per group), depending the number of phase I patients included in phase II., Ethics and Dissemination: Medical ethical committees of all the participating countries have approved the study protocol; initial (UK) ethics approval (17/YH/0123) was granted by Yorkshire & The Humber-Leeds West Research Ethics Committee. Participants are required to provide written informed consent/assent. Results will be disseminated through national and international presentations and peer-reviewed publications., Trial Registration Number: ISRCTN92323261., Competing Interests: Competing interests: JI has received research funding from F. Hoffmann-La Roche., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Ischemia-reperfusion injury remains a major clinical problem in patients with ST-elevation myocardial infarction (STEMI), leading to myocardial damage despite early reperfusion by primary percutaneous coronary intervention (PPCI). There are no effective therapies to limit ischemia-reperfusion injury, which is caused by multiple pathways activated by rapid tissue reoxygenation and the generation of reactive oxygen species (ROS). FDY-5301 contains sodium iodide, a ubiquitous inorganic halide and elemental reducing agent that can act as a catalytic anti-peroxidant. We tested the feasibility, safety and potential utility of FDY-5301 as a treatment to limit ischemia-reperfusion injury, in patients with first-time STEMI undergoing emergency PPCI., Methods: STEMI patients (n = 120, median 62 years) presenting within 12 h of chest pain onset were randomized at 20 PPCI centers, in a double blind Phase 2 clinical trial, to receive FDY-5301 (0.5, 1.0 or 2.0 mg/kg) or placebo prior to reperfusion, to evaluate the feasibility endpoints. Participants underwent continuous ECG monitoring for 14 days after PPCI to address pre-specified cardiac arrhythmia safety end points and cardiac magnetic resonance imaging (MRI) at 72 h and at 3 months to assess exploratory efficacy end points., Results: Intravenous FDY-5301 was delivered before re-opening of the infarct-related artery in 97% participants and increased plasma iodide levels ~1000-fold within 2 min. There was no significant increase in the primary safety end point of incidence of cardiac arrhythmias of concern. MRI at 3 months revealed median final infarct sizes in placebo vs. 2.0 mg/kg FDY-5301-treated patients of 14.9% vs. 8.5%, and LV ejection fractions of 53.9% vs. 63.2%, respectively, although the study was not powered to detect statistical significance. In patients receiving FDY-5301, there was a significant reduction in the levels of MPO, MMP2 and NTproBNP after PPCI, but no reduction with placebo., Conclusions: Intravenous FDY-5301, delivered immediately prior to PPCI in acute STEMI, is feasible, safe, and shows potential efficacy. A larger trial is justified to test the effects of FDY-5301 on acute ischemia-reperfusion injury and clinical outcomes., Clinical Trial Registration: CT.govNCT03470441; EudraCT 2017-000047-41., (Copyright © 2021. Published by Elsevier B.V.)

A community-integrated geographic information systems (CIGIS) study assimilating qualitative and quantitative information about human exposures and health was conducted in Colfax, Louisiana, which hosts a commercial open burn/open detonation thermal treatment (TT) facility that destroys waste from Superfund sites, explosives, military ordnances, and propellants. Fifty-eight percent of residents identified as Black, and median annual income was $16,318, with 90% of the population living below the poverty line. We conducted oral history interviews of twenty-nine residents and mined public records to document the community's experiences. Interviews focused on themes of Colfax's history, changing community fabric, resident health, and air pollution. The oral histories and public comments by community members provided information about lived experiences, including several health conditions, toleration of noise and vibration, property damage, and resulting changes to activity levels. These statements provided insight into the extent of suffering experienced by the local community. We also ran dispersion models for dates in 2020 when the waste stream composition, mass, and burn/smoldering times were provided in the facility's public records. The dispersion models placed the air pollution at the homes of residents during some of the time, and waste stream records from the TT facility agree with community testimony about health effects based on the known health effects of those compounds. CIGIS integration of our community-based qualitative data and maps with quantitative air pollution dispersion model output illustrated alignment between community complaints of impacts to health and property, known toxicological information about waste stream compounds, and dispersion model output.

Objectives: Online health forums provide rich and untapped real-time data on population health. Through novel data extraction and natural language processing (NLP) techniques, we characterise the evolution of mental and physical health concerns relating to the COVID-19 pandemic among online health forum users., Setting and Design: We obtained data from three leading online health forums: HealthBoards, Inspire and HealthUnlocked, from the period 1 January 2020 to 31 May 2020. Using NLP, we analysed the content of posts related to COVID-19., Primary Outcome Measures: (1) Proportion of forum posts containing COVID-19 keywords; (2) proportion of forum users making their very first post about COVID-19; (3) proportion of COVID-19-related posts containing content related to physical and mental health comorbidities., Results: Data from 739 434 posts created by 53 134 unique users were analysed. A total of 35 581 posts (4.8%) contained a COVID-19 keyword. Posts discussing COVID-19 and related comorbid disorders spiked in early March to mid-March around the time of global implementation of lockdowns prompting a large number of users to post on online health forums for the first time. Over a quarter of COVID-19-related thread titles mentioned a physical or mental health comorbidity., Conclusions: We demonstrate that it is feasible to characterise the content of online health forum user posts regarding COVID-19 and measure changes over time. The pandemic and corresponding public response has had a significant impact on posters' queries regarding mental health. Social media data sources such as online health forums can be harnessed to strengthen population-level mental health surveillance., Competing Interests: Competing interests: RP has received funds from Janssen, Induction Healthcare and Holmusk outside the current study., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

The domestic cat is one of the most popular pets in the world. It is estimated that 89-92% of domestic cats in the UK are non-pedigree Domestic shorthair (DSH), Domestic longhair (DLH), or Domestic semi-longhair cats (DSLH). Despite their popularity, little is known of the UK non-pedigree cats' population structure and breeding dynamics. Using a custom designed single nucleotide variant (SNV) array, this study investigated the population genetics of 1344 UK cats. Principal components analysis (PCA) and fastSTRUCTURE analysis verified that the UK's DSH, DLH, and DSLH cats are random-bred, rather than admixed, mix breed, or crossbred. In contrast to pedigree cats, the linkage disequilibrium of these random-bred cats was least extensive and decayed rapidly. Homozygosity by descent (HBD) analysis showed the majority of non-pedigree cats had proportionally less of their genome in HBD segments compared to pedigree cats, and that these segments were older. Together, these findings suggest that the DSH, DLH, and DSLH cats should be considered as a population of random-bred cats rather than a crossbred or pedigree-admixed cat. Unexpectedly, 19% of random-bred cat genomes displayed a higher proportion of HBD segments associated with more recent inbreeding events. Therefore, while non-pedigree cats as a whole are genetically diverse, they are not impervious to inbreeding and its health risks.

Background: Treatment on risk adapted intensive pediatric protocols has improved outcome for teenagers and young adults (TYA) with T-cell acute lymphoblastic leukemia (T-ALL). Understanding the biology of disease in this age group and the genetic basis of relapse is a key goal as patients with relapsed/refractory disease have poor outcomes with conventional chemotherapy and novel molecular targets are required. This study examines the question of whether TYA T-ALL has a specific biological-molecular profile distinct from pediatric or adult T-ALL., Methods: Genomic characterization was undertaken of a retrospective discovery cohort of 80 patients aged 15-26 years with primary or relapsed T-ALL, using a combination of Genome-Wide Human SNP Array 6.0, targeted gene mutation and promoter methylation analyses. Findings were confirmed by MLPA, real-time quantitative PCR, and FISH. Whole Exome Sequencing was performed in 4 patients with matched presentation and relapse to model clonal evolution. A prevalence analysis was performed on a final data set of 1,792 individual cases to identify genetic lesions with age specific frequency patterns, including 972 pediatric (1-14 years), 439 TYA (15-24 years) and 381 adult (≥25 years) cases. These cases were extracted from 19 publications with comparable genomic data identified through a PubMed search., Results: Genomic characterization of this large cohort of TYA T-ALL patients identified recurrent isochromosome 7q i(7q) in our discovery cohort (n = 3). Prevalence analysis did not identify any age specific genetic abnormalities. Genomic analysis of 6 pairs of matched presentation - relapsed T-ALL established that all relapses were clonally related to the initial leukemia. Whole exome sequencing analysis revealed recurrent, targetable, mutations disrupting NOTCH, PI3K/AKT/mTOR, FLT3, NRAS as well as drug metabolism pathways., Conclusions: All genetic aberrations in TYA T-ALL occurred with an incidence similar or intermediate to that reported in the pediatric and adult literature, demonstrating that overall TYA T-ALL exhibits a transitional genomic profile. Analysis of matched presentation - relapse supported the hypothesis that relapse is driven by the Darwinian evolution of sub-clones associated with drug resistance (NT5C2 and TP53 mutations) and re-iterative mutation of known key T-ALL drivers, including NOTCH1., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Using novel data mining methods such as natural language processing (NLP) on electronic health records (EHRs) for screening and detecting individuals at risk for psychosis., Method: The study included all patients receiving a first index diagnosis of nonorganic and nonpsychotic mental disorder within the South London and Maudsley (SLaM) NHS Foundation Trust between January 1, 2008, and July 28, 2018. Least Absolute Shrinkage and Selection Operator (LASSO)-regularized Cox regression was used to refine and externally validate a refined version of a five-item individualized, transdiagnostic, clinically based risk calculator previously developed (Harrell's C = 0.79) and piloted for implementation. The refined version included 14 additional NLP-predictors: tearfulness, poor appetite, weight loss, insomnia, cannabis, cocaine, guilt, irritability, delusions, hopelessness, disturbed sleep, poor insight, agitation, and paranoia., Results: A total of 92 151 patients with a first index diagnosis of nonorganic and nonpsychotic mental disorder within the SLaM Trust were included in the derivation (n = 28 297) or external validation (n = 63 854) data sets. Mean age was 33.6 years, 50.7% were women, and 67.0% were of white race/ethnicity. Mean follow-up was 1590 days. The overall 6-year risk of psychosis in secondary mental health care was 3.4 (95% CI, 3.3-3.6). External validation indicated strong performance on unseen data (Harrell's C 0.85, 95% CI 0.84-0.86), an increase of 0.06 from the original model., Conclusions: Using NLP on EHRs can considerably enhance the prognostic accuracy of psychosis risk calculators. This can help identify patients at risk of psychosis who require assessment and specialized care, facilitating earlier detection and potentially improving patient outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The impact of precision psychiatry for clinical practice has not been systematically appraised. This study aims to provide a comprehensive review of validated prediction models to estimate the individual risk of being affected with a condition (diagnostic), developing outcomes (prognostic), or responding to treatments (predictive) in mental disorders., Methods: PRISMA/RIGHT/CHARMS-compliant systematic review of the Web of Science, Cochrane Central Register of Reviews, and Ovid/PsycINFO databases from inception until July 21, 2019 (PROSPERO CRD42019155713) to identify diagnostic/prognostic/predictive prediction studies that reported individualized estimates in psychiatry and that were internally or externally validated or implemented. Random effect meta-regression analyses addressed the impact of several factors on the accuracy of prediction models., Findings: Literature search identified 584 prediction modeling studies, of which 89 were included. 10.4% of the total studies included prediction models internally validated (n = 61), 4.6% models externally validated (n = 27), and 0.2% (n = 1) models considered for implementation. Across validated prediction modeling studies (n = 88), 18.2% were diagnostic, 68.2% prognostic, and 13.6% predictive. The most frequently investigated condition was psychosis (36.4%), and the most frequently employed predictors clinical (69.5%). Unimodal compared to multimodal models (β = .29, P = .03) and diagnostic compared to prognostic (β = .84, p < .0001) and predictive (β = .87, P = .002) models were associated with increased accuracy., Interpretation: To date, several validated prediction models are available to support the diagnosis and prognosis of psychiatric conditions, in particular, psychosis, or to predict treatment response. Advancements of knowledge are limited by the lack of implementation research in real-world clinical practice. A new generation of implementation research is required to address this translational gap., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Infection with Yersinia pseudotuberculosis can be difficult to diagnose and treat successfully. Twenty-four cases from the Zoological Society of London (ZSL) London Zoo and ZSL Whipsnade Zoo were identified between 2001 and 2019. Husbandry, medical, and postmortem records for six primates, 10 artiodactyls, and eight birds were reviewed to identify common clinical signs and gross lesions. Most cases occurred during the winter; however, an outbreak in four primates occurred during the summer following a period of stress associated with increased ambient noise and activity. Common clinical signs included lethargy (6/6 primates, 4/10 artiodactyls, 4/8 birds) or death without premonitory signs (3/10 artiodactyls, 4/8 birds). Once clinical signs were observed, disease progressed quickly. Poor condition was common in mammals (6/6 primates, 9/10 artiodactyls), but often went undetected until postmortem examination. Neurological signs occurred in three of six primates. Diarrhea and anorexia were uncommon in all animals. Hepatitis was observed in all groups (4/6 primates, 2/10 artiodactyls, 4/8 birds), mesenteric lymphadenomegaly was common in mammals (4/6 primates, 8/10 artiodactyls), and gastroenteritis was common in artiodactyls (7/10). Erythematous, punctate rashes, which have only been reported with yersiniosis in humans, were present in three of six primates. Bacterial cultures from the liver in primates and birds or enlarged mesenteric lymph nodes in artiodactyls were often diagnostic. All isolates were susceptible to marbofloxacin, oxytetracycline, streptomycin, ceftazidime, amoxicillin clavulanic acid, trimethoprim sulfamethoxazole, azithromycin, and doxycycline, and resistant to clindamycin. Histopathology and Perl's Prussian blue stains were performed on available liver samples ( n = 18). Intracellular hemosiderin was present in 17 of 18 cases. Additional research is needed to determine if there is a relationship between hemosiderosis and yersiniosis.

The real-world impact of psychosis prevention is reliant on effective strategies for identifying individuals at risk. A transdiagnostic, individualized, clinically-based risk calculator to improve this has been developed and externally validated twice in two different UK healthcare trusts with convincing results. The prognostic performance of this risk calculator outside the UK is unknown. All individuals who accessed primary or secondary health care services belonging to the IBM ® MarketScan ® Commercial Database between January 2015 and December 2017, and received a first ICD-10 index diagnosis of nonorganic/nonpsychotic mental disorder, were included. According to the risk calculator, age, gender, ethnicity, age-by-gender, and ICD-10 cluster diagnosis at index date were used to predict development of any ICD-10 nonorganic psychotic disorder. Because patient-level ethnicity data were not available city-level ethnicity proportions were used as proxy. The study included 2,430,333 patients with a mean follow-up of 15.36 months and cumulative incidence of psychosis at two years of 1.43%. There were profound differences compared to the original development UK database in terms of case-mix, psychosis incidence, distribution of baseline predictors (ICD-10 cluster diagnoses), availability of patient-level ethnicity data, follow-up time and availability of specialized clinical services for at-risk individuals. Despite these important differences, the model retained accuracy significantly above chance (Harrell's C = 0.676, 95% CI: 0.672-0.679). To date, this is the largest international external replication of an individualized prognostic model in the field of psychiatry. This risk calculator is transportable on an international scale to improve the automatic detection of individuals at risk of psychosis.

Objective: Administration of unfractionated heparin to STEMI patients by the ambulance service is an established practice in Scotland, but the efficacy is unknown. We studied the effects of unfractionated heparin in STEMI patients treated by primary percutaneous coronary intervention, on infarct artery patency and mortality., Methods and Results: Consecutive patients (n = 1000) admitted to Ninewells Hospital, Dundee, from 2010 to 2014 for primary percutaneous coronary intervention were allocated to 2 groups: 437 (44%) prehospital heparin (PHH) administered by paramedics, and 563 (56%) in-hospital heparin. A trained medical student assessed coronary flow at presentation and collected the data. Mortality status was ascertained at 30 days and 5 years. Cox proportional hazards regression models were generated. The patient groups were similar, although PHH had shorter symptom onset-treatment time (187 vs. 251 minutes, P < 0.001) and less cardiogenic shock (3.9% vs. 8.0%, P = 0.008). Initial coronary flow was not different between the groups. Thirty day mortality in PHH was 2.5% versus 8.3%, P < 0.001. Independent predictors of 30-day mortality were age (odds ratio 1.07, 95% CI 1.04-1.09), cardiogenic shock (5.97, 3.33-10.69), radial access (0.53, 0.28-0.98), and PHH (0.33, 0.17-0.66). Five-year mortality in PHH was 13.0% versus 21.6%, P < 0.001. Significant predictors of long-term mortality were age (1.07, 1.06-1.09), cardiogenic shock (3.40, 2.23-5.17), and PHH (0.68, 0.49-0.96)., Conclusions: PHH was associated with reduced short- and long-term mortality after adjusting for important potential confounders.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. While there are a number of well-recognized prognostic biomarkers at diagnosis, the most powerful independent prognostic factor is the response of the leukemia to induction chemotherapy (Campana and Pui: Blood 129 (2017) 1913-1918). Given the potential for machine learning to improve precision medicine, we tested its capacity to monitor disease in children undergoing ALL treatment. Diagnostic and on-treatment bone marrow samples were labeled with an ALL-discriminating antibody combination and analyzed by imaging flow cytometry. Ignoring the fluorescent markers and using only features extracted from bright-field and dark-field cell images, a deep learning model was able to identify ALL cells at an accuracy of >88%. This antibody-free, single cell method is cheap, quick, and could be adapted to a simple, laser-free cytometer to allow automated, point-of-care testing to detect slow early responders. Adaptation to other types of leukemia is feasible, which would revolutionize residual disease monitoring. © 2020 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry., (© 2020 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.)

Here we investigate whether the presence of germinal vesicle-stage oocytes (GV- oocytes) reflects poor oocyte developmental competence (or quality). This was a prospective, non-randomised, cohort pilot-study involving 60 patients undergoing in vitro fertilization/ intracytoplasmic sperm injection for whom complete pregnancy outcome data were available. Patients in whom GV- oocytes were retrieved (GV+) at transvaginal oocyte retrieval (TVOR) were compared with those from whom no GVs were retrieved (GV-). We found that GV+ ( n = 29) and GV- ( n = 31) patients were similarly aged (35.4 vs. 36.4 years; p = 0.446). GV+ patients had a mean of 2.41 ± 2.03 GVs and comparable yields of MII oocytes to GV- patients (11 ± 6.88 vs. 8.26 ± 4.84; p = 0.077). Compared with GV- patients, GV+ patients had markedly lower implantation rates (11.8% vs. 30.2%; p = 0.022) as well as oocyte utilisation rates for clinical pregnancy (2.3% vs. 6.8%; p = 0.018) and live-birth (1.9% vs. 5.7%; p = 0.029). DNA damage levels measured using γH2AX immunostaining were not different in oocytes from women <36 years versus those ≥36 years ( p = 0.606). Thus, patients who have GV- stage oocytes at TVOR exhibit poor oocyte quality reflected in reduced per-oocyte pregnancy success rates and uniformly high levels of oocyte DNA damage.

Despite attempts to improve the definitions of ambiguous lineage leukemia (ALAL) during the last 2 decades, general therapy recommendations are missing. Herein, we report a large cohort of children with ALAL and propose a treatment strategy. A retrospective multinational study (International Berlin-Frankfurt-Münster Study of Leukemias of Ambiguous Lineage [iBFM-AMBI2012]) of 233 cases of pediatric ALAL patients is presented. Survival statistics were used to compare the prognosis of subsets and types of treatment. Five-year event-free survival (EFS) of patients with acute lymphoblastic leukemia (ALL)-type primary therapy (80% ± 4%) was superior to that of children who received acute myeloid leukemia (AML)-type or combined-type treatment (36% ± 7.2% and 50% ± 12%, respectively). When ALL- or AML-specific gene fusions were excluded, 5-year EFS of CD19 + leukemia was 83% ± 5.3% on ALL-type primary treatment compared with 0% ± 0% and 28% ± 14% on AML-type and combined-type primary treatment, respectively. Superiority of ALL-type treatment was documented in single-population mixed phenotype ALAL (using World Health Organization and/or European Group for Immunophenotyping of Leukemia definitions) and bilineal ALAL. Treatment with ALL-type protocols is recommended for the majority of pediatric patients with ALAL, including cases with CD19 + ALAL. AML-type treatment is preferred in a minority of ALAL cases with CD19 - and no other lymphoid features. No overall benefit of transplantation was documented, and it could be introduced in some patients with a poor response to treatment. As no clear indicator was found for a change in treatment type, this is to be considered only in cases with ≥5% blasts after remission induction. The results provide a basis for a prospective trial., (© 2018 by The American Society of Hematology.)

Objective: Both Mindfulness Based Cognitive Therapy (MBCT) and Cognitive Therapy (CT) enhance self-management of prodromal symptoms associated with depressive relapse, albeit through divergent therapeutic procedures. We evaluated rates of relapse in remitted depressed patients receiving MBCT and CT. Decentering and dysfunctional attitudes were assessed as treatment-specific process markers., Method: Participants in remission from Major Depressive Disorder (MDD; N = 166) were randomized to 8 weeks of either MBCT (N = 82) or CT (N = 84) and were followed for 24 months, with process markers measured every 3 months. Attendance in both treatments was high (6.3/8 session) and treatment fidelity and competence were evaluated. Relapse was defined as a return of symptoms meeting the criteria for major depression on Module A of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (SCID)., Results: Intention-to-treat analyses indicated no differences between MBCT and CT in either rates of relapse to MDD or time to relapse across 24 months of follow up. Both groups experienced significant increases in decentering and participants in CT reported greater reductions in dysfunctional attitudes. Within both treatments, participants who relapsed evidenced lower decentering scores than those who stayed well over the follow up., Conclusions: This is the first study to directly compare relapse prophylaxis following MBCT and CT directly. The lack of group differences in time to relapse supports the view that both interventions are equally effective and that increases in decentering achieved via either treatment are associated with greater protection. These findings lend credence to Teasdale et al.'s (2002) contention that, even though they may be taught through dissimilar methods, CT and MBCT help participants develop similar metacognitive skills for the regulation of distressing thoughts and emotions. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Objectives: Percutaneous coronary intervention (PCI) of chronic total occlusion (CTO) has historically been associated with higher event rates during follow-up. The hybrid algorithm and contemporary wiring and dissection re-entry (DR) techniques can potentially improve long-term outcomes after CTO-PCI. This study assessed the long-term clinical outcomes of the hybrid CTO practice, when applied by operators with varying experience levels., Methods: We examined the 1-year clinical events after hospital discharge of the RECHARGE population, according to technical outcome and final technique. The primary endpoint was major adverse cardiac event (MACE) rate. Centers that provided ≥90% complete 12-month follow-up were included., Results: Follow-up data of 1067 out of 1165 patients (92%) were provided by 13 centers. Mean follow-up duration was 362.8 ± 0.9 days. One-year MACE-free survival rate was 91.3% (974/1067). MACE included death (1.9%; n = 20), myocardial infarction (1.4%; n = 15), target-vessel failure (5.9%; n = 63), and target-vessel revascularization (TVR) (5.5%; n = 59). Non-TVR was performed in 6.7% (n = 71). MACE was significantly in favor of successful CTO-PCI (8.0% vs 13%; P=.04), even after adjusting for baseline differences (adjusted hazard ratio, 0.59; 95% confidence interval, 0.36-0.98; P=.04). Other events, including individual MACE components, were comparable with respect to technical outcome and final technique (DR vs non-DR techniques)., Conclusions: The use of the hybrid algorithm with contemporary techniques by moderate to highly experienced operators for CTO-PCI is safe and associated with a low 1-year event rate. Successful procedures are associated with a better MACE rate. DR techniques can be used as first-line strategies alongside intimal wiring techniques without compromising clinical outcomes.

Objectives: This study sought to create a contemporary scoring tool to predict technical outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) from patients treated by hybrid operators with differing experience levels., Background: Current scoring systems need regular updating to cope with the positive evolutions regarding materials, techniques, and outcomes, while at the same time being applicable for a broad range of operators., Methods: Clinical and angiographic characteristics from 880 CTO-PCIs included in the REgistry of CrossBoss and Hybrid procedures in FrAnce, the NetheRlands, BelGium and UnitEd Kingdom (RECHARGE) were analyzed by using a derivation and validation set (2:1 ratio). Variables significantly associated with technical failure in the multivariable analysis were incorporated in the score. Subsequently, the discriminatory capacity was assessed and the validation set was used to compare with the J-CTO score and PROGRESS scores., Results: Technical success in the derivation and validation sets was 83% and 85%, respectively. Multivariate analysis identified six parameters associated with technical failure: blunt stump (beta coefficient (b) = 1.014); calcification (b = 0.908); tortuosity ≥45° (b = 0.964); lesion length 20 mm (b = 0.556); diseased distal landing zone (b = 0.794), and previous bypass graft on CTO vessel (b = 0.833). Score variables remained significant after bootstrapping. The RECHARGE score showed better discriminatory capacity in both sets (area-under-the-curve (AUC) = 0.783 and 0.711), compared to the J-CTO (AUC = 0.676) and PROGRESS (AUC = 0.608) scores., Conclusions: The RECHARGE score is a novel, easy-to-use tool for assessing the risk for technical failure in hybrid CTO-PCI and has the potential to perform well for a broad community of operators. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Purpose can provide a sense of intentionality, guide behavior to achieve personal aims and living objectives, and may offer insight into how and why certain people remain healthy over time. A review of the literature sought to identify contemporary research pertaining to purpose and older adults. Thirty-one studies were selected for evaluation based on inclusion criteria. Research outcomes suggest that greater reported purpose is related to a range of better health and well-being outcomes for older adults. With few exceptions, the literature demonstrates that purpose declines with age. Nevertheless, the potential to experience purpose persists across the life span, by providing opportunities for older adults to continue contributing roles, participate in meaningful activities, and sustain their social value and sense of relevance. Further research could explore how purpose is experienced by the oldest-old age-group, those living within noncommunity settings, and people with age-related cognitive impairment such as dementia.

We aimed to determine clinical outcomes 1 year after successful chronic total occlusion (CTO) PCI and, in particular, whether use of dissection and re-entry strategies affects clinical outcomes. Hybrid approaches have increased the procedural success of CTO percutaneous coronary intervention (PCI) but longer-term outcomes are unknown, particularly in relation to dissection and re-entry techniques. Data were collected for consecutive CTO PCIs performed by hybrid-trained operators from 7 United Kingdom (UK) centres between 2012 and 2014. The primary endpoint (death, myocardial infarction, unplanned target vessel revascularization) was measured at 12 months along with angina status. One-year follow up data were available for 96% of successful cases (n = 805). In total, 85% of patients had a CCS angina class of 2-4 prior to CTO PCI. Final successful procedural strategy was antegrade wire escalation 48%; antegrade dissection and re-entry (ADR) 21%; retrograde wire escalation 5%; retrograde dissection and re-entry (RDR) 26%. Overall, 47% of CTOs were recanalized using dissection and re-entry strategies. During a mean follow up of 11.5 ± 3.8 months, the primary endpoint occurred in 8.6% (n = 69) of patients (10.3% (n = 39/375) in DART group and 7.0% (n = 30/430) in wire-based cases). The majority of patients (88%) had no or minimal angina (CCS class 0 or 1). ADR and RDR were used more frequently in more complex cases with greater disease burden, however, the only independent predictor of the primary endpoint was lesion length. CTO PCI in complex lesions using the hybrid approach is safe, effective and has a low one-year adverse event rate. The method used to recanalize arteries was not associated with adverse outcomes. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: Small observational studies demonstrate the feasibility of transradial approach for chronic total occlusion (CTO) percutaneous coronary intervention. The aim of the current study is to assess technical success, complication rates, and procedural efficiency in fully transradial approach (fTRA) and transfemoral approach (TFA) in a large prospective European registry adopting the hybrid algorithm for CTO percutaneous coronary intervention (Registry of CrossBoss and Hybrid Procedures in France, the Netherlands, Belgium and United Kingdom, RECHARGE registry)., Methods and Results: We analyzed 1253 CTO percutaneous coronary intervention procedures performed according to the hybrid protocol in 17 European centers, comparing fTRA (single or biradial access) and TFA (single or bifemoral or combined radial and femoral access). fTRA was applied in 306 (24%) and TFA in 947 (76%) cases. The average Japanese CTO score was 2.1±1.2 in fTRA and 2.3±1.1 in TFA ( P =0.06). Technical success was achieved in 85% in fTRA and 86% in TFA ( P =0.51). Technical success was comparable for fTRA and TFA in different Japanese CTO score subgroups after multivariable analysis and after propensity adjustment. In-hospital major adverse cardiac and cerebral events occurred in 2.0% in fTRA and 2.9% in TFA ( P =0.40). Major access site bleeding occurred in 0.3% in fTRA and 0.5% in TFA ( P =0.66). fTRA compared with TFA had similar procedural duration (80 minutes [54-120 minutes] versus 90 minutes [60-121 minutes]; P =0.07), similar radiation dose (dose area product 89 Gray×cm 2 [52-163 Gray×cm 2 ] versus 101 Gray×cm 2 [59-171 Gray×cm 2 ]; P =0.06), and lower contrast agent use (200 mL [150-310 mL] versus 250 mL [200-350 mL]; P <0.01)., Conclusions: fTRA CTO percutaneous coronary intervention is a valid alternative to TFA with a high rate of success, low complication rates, and no decrease in procedural efficiency., (© 2017 American Heart Association, Inc.)

Background: Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD) are highly prevalent, comorbid, and have significant impact on morbidity, mortality, and socioeconomic burden in Canada. Combined psycho- and pharmacotherapies for both conditions promise better outcomes than treatment as usual (TAU). At the Centre for Addiction and Mental Health, Toronto, Canada, we developed and implemented an Integrated Care Pathway (ICP) specifically for treatment of concurrent MDD and AUD. The goal of the study is to assess the clinical effectiveness of the ICP approach in comparison to TAU., Materials and Methods: Non-randomized design, clinical chart review, Chi-square and t-tests, Cohen's d, Linear Mixed Effects Models, Kaplan-Meier, and log-rank analyses., Results: Eighty-one ICP patients were included, matched to 81 controls by age, sex, severity of depressive symptoms, and patterns of drinking. ICP cohort had a significantly lower dropout rate (18.5% vs 69.1%, p < .001; at 16 weeks of treatment, respectively), both cohorts demonstrated significant reduction in the number of heavy drinking days (β = .01, p < .001) and standard drinks per week (β = .15, p < .001) with a significantly higher reduction of both indicators over time in the ICP cohort. Significant reduction in depressive symptoms severity (QIDS: 14.6 vs 10.0, p < .001; BDI: 26.3 vs 16.2, p < .001) was observed in ICP cohort (no data for TAU cohort)., Conclusions: The ICP patients demonstrated improvements on several levels including depressive symptoms, and changes in alcohol drinking patterns. The study demonstrated the overall effectiveness of the ICP and apparent advantage over TAU, which must be corroborated through a randomized clinical trial. (Am J Addict 2017;26:602-609) SCIENTIFIC SIGNIFICANCE: This study is one of the first works showing the outcomes of an ICP developed in the mental health area and for co-occurring disorders. Despite the limitations, the relative advantage of the ICP methodology warrants future research in this area., (© 2017 American Academy of Addiction Psychiatry.)

In the current research, we sought to examine the role of spatial frequency on the detection of threat using a speeded visual search paradigm. Participants searched for threat-relevant (snakes or spiders) or non-threat-relevant (frogs or cockroaches) targets in an array of neutral (flowers or mushrooms) distracters, and we measured search performance with images filtered to contain different levels (high and low) of spatial frequency information. The results replicate previous work demonstrating more rapid detection of threatening versus non-threatening stimuli [e.g. LoBue, V. & DeLoache, J. S. (2008). Detecting the snake in the grass: Attention to fear-relevant stimuli by adults and young children. Psychological Science, 19, 284-289. doi:10.1111/j.1467-9280.2008.02081.x]. Most importantly, the results suggest that low spatial frequency or relatively coarse levels of visual information is sufficient for the rapid and accurate detection of threatening stimuli. Furthermore, the results also suggest that visual similarity between the stimuli used in the search tasks plays a significant role in speeded detection. The results are discussed in terms of the theoretical implications for the rapid detection of threat and methodological implications for properly accounting for similarity between the stimuli in visual search studies.

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies., (© 2016 Wiley Periodicals, Inc.)

Despite a large volume of evidence supporting the use of dual antiplatelet therapy in patients with acute coronary syndrome, there remains major uncertainty regarding the optimal duration of therapy. Clinical trials have varied markedly in the duration of therapy, both across and within trials. Recent systematic reviews and meta-analyses suggest that shorter durations of dual antiplatelet therapy are superior because the avoidance of atherothrombotic events is counterbalanced by the greater risks of excess major bleeding with apparent increases in all-cause mortality with longer durations. These findings did not show significant heterogeneity according to whether patients had stable or unstable coronary heart disease. Moreover, the potential hazards and benefits may differ when applied to the general broad population of patients encountered in everyday clinical practice who have markedly higher bleeding and atherothrombotic event rates. Clinicians lack definitive information regarding the duration of therapy in patients with acute coronary syndrome and risk scores do not appear to be sufficiently robust to address these concerns. We believe that there is a pressing need to undertake a broad inclusive safety trial of shorter durations of therapy in real world populations of patients with acute coronary syndrome. The clinical evidence would further inform future research into strategies for personalised medicine., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Gender differences exist in clinical outcomes after routine percutaneous coronary intervention (PCI), but studies reporting such outcomes after chronic total occlusion (CTO) PCI are limited. We assessed the characteristics and outcomes of female patients undergoing CTO PCI. We retrospectively analyzed a dedicated national (United Kingdom) prospective CTO database from 2011 to 2015 for outcomes and characteristics of female patients undergoing CTO PCI (unmatched and propensity matched). Female patients constituted 20.5% (n = 260 of 1,271) of the unmatched cohort and 33.3% (n = 233 of 699) of the matched cohort and were more likely to be older (women aged >70 years, 48% in the unmatched and 45% in the matched cohort). An increased inhospital complication rate was observed in female patients (unmatched: 10% women vs 4.45% men, p = 0.0012, and matched 9.87% women vs 3.86% men, p = 0.0032). Coronary perforation, bleeding, and contrast-induced nephropathy were more frequently observed in female patients. Femoral access site with >6 French sheath was associated with an increased risk of bleeding. Presence of calcification in the CTO artery was associated with coronary perforation (grade III) in female patients in the matched cohort (p = 0.007). Female patients undergoing CTO PCI were older and experienced increased of inhospital complications. Increased awareness of these complications could influence the selection of access site and sheath size, the need for prehydration, judicious choice of balloon size, collateral selection, and wire placement in female patients undergoing CTO PCI., (Copyright © 2016 Elsevier Inc. All rights reserved.)