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Few studies can address how adulthood cognitive trajectories relate to brain health in 70-year-olds. Participants (n = 468, 49% female) from the 1946 British birth cohort underwent 18F-Florbetapir PET/MRI. Cognitive function was measured in childhood (age 8 years) and across adulthood (ages 43, 53, 60–64 and 69 years) and was examined in relation to brain health markers of β-amyloid (Aβ) status, whole brain and hippocampal volume, and white matter hyperintensity volume (WMHV). Taking into account key contributors of adult cognitive decline including childhood cognition, those with greater Aβ and WMHV at age 70 years had greater decline in word-list learning memory in the preceding 26 years, particularly after age 60. In contrast, those with smaller whole brain and hippocampal volume at age 70 years had greater decline in processing search speed, subtly manifest from age 50 years. Subtle changes in memory and processing speed spanning 26 years of adulthood were associated with markers of brain health at 70 years of age, consistent with detectable prodromal cognitive effects in early older age.

Background: Endovascular thrombectomy (EVT) access in remote areas is limited. Preliminary data suggest that long distance transfers for EVT may be beneficial; however, the magnitude and best imaging strategy at the referring center remains uncertain. We hypothesized that patients transferred >300 miles would benefit from EVT, achieving rates of functional independence (modified Rankin Scale [mRS] score of 0–2) at 3 months similar to those patients treated at the comprehensive stroke center in the randomized EVT extended window trials and that the selection of patients with computed tomography perfusion (CTP) at the referring site would be associated with ordinal shift toward better outcomes on the mRS. Methods: This is a retrospective analysis of patients transferred from 31 referring hospitals >300 miles (measured by the most direct road distance) to 9 comprehensive stroke centers in Australia and New Zealand for EVT consideration (April 2016 through May 2021). Results: There were 131 patients; the median age was 64 [53–74] years and the median baseline National Institutes of Health Stroke Scale score was 16 [12–22]. At baseline, 79 patients (60.3%) had noncontrast CT+CT angiography, 52 (39.7%) also had CTP. At the comprehensive stroke center, 114 (87%) patients underwent cerebral angiography, and 96 (73.3%) proceeded to EVT. At 3 months, 62 patients (48.4%) had an mRS score of 0 to 2 and 81 (63.3%) mRS score of 0 to 3. CTP selection at the referring site was not associated with better ordinal scores on the mRS at 3 months (mRS median of 2 [1–3] versus 3 [1–6] in the patients selected with noncontrast CT+CT angiography, P =0.1). Nevertheless, patients selected with CTP were less likely to have an mRS score of 5 to 6 (odds ratio 0.03 [0.01–0.19]; P Conclusions: In selected patients transferred >300 miles, there was a benefit for EVT, with outcomes similar to those treated in the comprehensive stroke center in the EVT extended window trials. Remote hospital CTP selection was not associated with ordinal mRS improvement, but was associated with fewer very poor 3-month outcomes.

Chronic kidney disease is common in patients with atrial fibrillation (AF) and is associated with heightened risks of stroke/systemic embolisation and bleeding. In this review we outline the evidence for AF stroke prevention in kidney disease, identify current knowledge gaps, and give recommendations for anticoagulation at various stages of chronic kidney disease. Overall, anticoagulation is underused. Warfarin use becomes increasingly difficult with advancing kidney disease, with difficulty maintaining international normalised ratio (INR) in therapeutic range, increased risk of intracranial and fatal bleeding compared to non-vitamin K oral anticoagulants (NOACs), and high rates of discontinuation. Similarly, the direct thrombin inhibitor dabigatran is not recommended as it is predominantly renally excreted with consequent increased plasma levels and bleeding risk with advanced kidney disease. The Factor Xa inhibitors apixaban and rivaroxaban have less renal excretion (25-35%), modest increases in plasma levels with advancing kidney disease, and are the preferred first line choice for anticoagulation in moderate kidney disease based on strong evidence from randomised clinical trials (RCTs). In severe kidney disease there is a paucity of RCT data, but extrapolation of the pharmacokinetic and RCT data for moderate kidney disease, and observational studies, support the considered use of dose-adjusted Factor Xa inhibitors unless the bleeding risk is prohibitive. In Australia, apixaban is approved for creatinine clearance down to 25 mL/min, and rivaroxaban down to 15 mL/min. For end-stage kidney disease warfarin is the only agent approved, but we recommend against anticoagulation (except in selected cases) due to high bleeding risk, multiple co-morbidities, and questionable benefit.

Background: Patients who had a cryptogenic stroke (CS) suspected to be causally related to a patent foramen ovale (PFO) are candidates for percutaneous PFO closure. In such patients, it is important to screen for atrial fibrillation (AF). Limited guidance is available regarding AF monitoring strategies in CS patients with PFO addressing optimal monitoring technology and duration. Aim: To provide a narrative review of cardiac rhythm monitoring in CS patients considered for PFO closure, including current practices, stroke recurrences after CS, findings from monitoring studies in CS patients, and predictors for AF detection published in the literature. To propose a personalized strategy for cardiac monitoring in CS patients, accounting for aspects predicting AF detection. Summary of review: AF detection in CS patients is predicted by age, left atrial enlargement, prolonged PR interval, frequent premature atrial contractions, interatrial conduction block, diabetes, prior brain infarctions, leukoaraiosis, elevated B-type natriuretic peptide (BNP)/N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, and a family history of AF, as well as composed scores (e.g. CHA2DS2-VASc, atrial fibrillation in embolic stroke of undetermined source (AF-ESUS)). The causal role of the PFO may be accounted for by the risk of paradoxical embolism (RoPE) score and/or the PFO-Associated Stroke Causal Likelihood (PASCAL) classification. Conclusion: A personalized approach to AF detection in CS patients is proposed, accounting for the likelihood of AF detection and aimed at obtaining sufficient confidence regarding the absence of AF in patients considered for PFO closure. In addition, the impact of high-risk PFO features on the monitoring strategy is discussed.

A neuroimaging-based biomarker termed the brain age is thought to reflect variability in the brain's ageing process and predict longevity. Using Insight 46, a unique narrow-age birth cohort, we aimed to examine potential drivers and correlates of brain age.Participants, born in a single week in 1946 in mainland Britain, have had 24 prospective waves of data collection to date, including MRI and amyloid PET imaging at approximately 70 years old. Using MRI data from a previously defined selection of this cohort, we derived brain-predicted age from an established machine-learning model (trained on 2001 healthy adults aged 18-90 years); subtracting this from chronological age (at time of assessment) gave the brain-predicted age difference (brain-PAD). We tested associations with data from early life, midlife, and late life, as well as rates of MRI-derived brain atrophy.Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. We included 456 participants (225 female), with a mean chronological age of 70·7 years (SD 0·7; range 69·2 to 71·9). The mean brain-predicted age was 67·9 years (8·2, 46·3 to 94·3). Female sex was associated with a 5·4-year (95% CI 4·1 to 6·8) younger brain-PAD than male sex. An increase in brain-PAD was associated with increased cardiovascular risk at age 36 years (β=2·3 [95% CI 1·5 to 3·0]) and 69 years (β=2·6 [1·9 to 3·3]); increased cerebrovascular disease burden (1·9 [1·3 to 2·6]); lower cognitive performance (-1·3 [-2·4 to -0·2]); and increased serum neurofilament light concentration (1·2 [0·6 to 1·9]). Higher brain-PAD was associated with future hippocampal atrophy over the subsequent 2 years (0·003 mL/year [0·000 to 0·006] per 5-year increment in brain-PAD). Early-life factors did not relate to brain-PAD. Combining 12 metrics in a hierarchical partitioning model explained 33% of the variance in brain-PAD.Brain-PAD was associated with cardiovascular risk, and imaging and biochemical markers of neurodegeneration. These findings support brain-PAD as an integrative summary metric of brain health, reflecting multiple contributions to pathological brain ageing, and which might have prognostic utility.Alzheimer's Research UK, Medical Research Council Dementia Platforms UK, Selfridges Group Foundation, Wolfson Foundation, Wellcome Trust, Brain Research UK, Alzheimer's Association.

TÓM TẮTĐặt vấn đề: biến chứng chảy máu não thứ cấp trong vùng nhồi máu là nguyên nhân hàng đầu gây nên diễn biến lâm sàng nặng nề sớm ở bệnh nhân thiếu máu cục bộ não. Dự báo sớm biến chứng này có ý nghĩa quan trọng trong việc lựa chọn phương pháp điều trị phù hợp, dự phòng biến chứng cũng như có kế hoạch can thiệp sớm nếu biến chứng xảy ra. Các yếu tố dự báo hiện tại chưa đáp ứng được đầy đủ yêu cầu về độ chính xác, tính thực tiễn cũng như an toàn bức xạ cho việc ứng dụng rộng rãi trên lâm sàng. Nghiên cứu này được tiến hành nhằm đánh giá vai trò sự phá vỡ hàng rào máu não trong dự đoán biến chứng chảy máu trong vùng tổn thương.Phương pháp: chỉ số thấm hàng rào máu não được tính trên hình ảnh chụp cắt lớp vi tính tưới máu não ứng dụng phương trình Gjedde-Patlak. Giá trị dự báo của chỉ số này được đánh giá thông qua mối tương quan của nó với biến chứng chảy máu.Kết quả: nghiên cứu này cho thấy chỉ số thấm hàng rào máu não cao hơn ở các tổn thương có biến chứng chảy máu. Đồng thời, có mối tương quan chặt chẽ có ý nghĩa thống kê giữa tăng chỉ số thấm hàng rào máu não với nguy cơ xảy ra biến chứng chảy máu não thứ cấp trong vùng nhồi máu. Nghiên cứu cũng đưa ra ngưỡng dự đoán chảy máu thứ phát của chỉ số thấm hàng rào máu não đo tại vùng nhồi máu là 2.7ml/100g/phút. Tại ngưỡng này giá trị dự báo của chỉ số thấm đạt cao nhất.Kết luận: tăng thấm hàng rào máu là một trong những yếu tố nguy cơ của chảy máu thứ phát sau thiếu máu cục bộ não cấp tính. Chỉ số này đo được trên chụp cắt lớp vi tính tưới máu não cũng là yếu tố dự báo của biến chứng này. Phân tích về chỉ số thấm hàng rào máu não cần được tiến hành đồng thời với phấn tích các thông số về tướimáu trên phim chụp cắt lớp đánh giá tưới máu não trên bệnh nhân thiếu máu cục bộ não cấp tính nhằm nâng cao khả năng dự báo biến chứng và có kế hoạch dự phòng và xử trí biến chứng kịp thời.

We describe a case of an elderly lady’s journey with severe dementia through a community hospital. Community hospitals play an important role in transitional care for elders with complex needs and their families to recalibrate the goals of care and optimise function after tumultuous stays in acute hospitals. We explore how the community hospital helped to break the vicious cycle of re-hospitalisation of our patient despite her dismal disease trajectory and address the complications of feeding difficulties and high caregiver burden. We also share practical advice on how a stay in a community hospital added value to the long-term care of similar elders.

An 87-year-old male, with a background of ischaemic heart disease, chronic kidney disease, hypertension, and hyperlipidaemia, was admitted for an acute right frontoparietal stroke, which progressed to recurrent cortical infarcts. He was transferred to the community hospital for step-down care and slow stream rehabilitation. Although his acute issues resolved, he continued to require a high level of nursing care. Eventually, the goal of care switched to palliative as his condition deteriorated. This case report highlights the importance of a versatile hospitalist team in managing rapid changes in care, particularly in complex cases with great difficulty fitting into a neat care plan.

A study was carried out from 10-14 November 2011 to determine the diversity, composition and distribution of aquatic insects in the streams of Kisolong, Molongis and Hatob waterfalls. Six stations were selected in each stream with one station located at the upper reach and another situated at the lower reach. A 100 metre reach of the stream was selected for each sampling site. Surber net measuring 500 micron mesh size rectangular quadrat of 30 cm X 30 cm (0.09 m2) was used. A total of 2163 individuals representing 61 families from eight orders were successfully recorded. Heptageniidae (Ephemeroptera), Perlidae and Peltoperlidae (Plecoptera) and Hydropsychidae (Trichoptera) were the most abundant families collected in each stream. Based on biotic indices, all streams were undisturbed and had good water quality.

Peer reviewed: True, Background: SARS-CoV-2 antibody levels can be used to assess humoral immune responses following SARS-CoV-2 infection or vaccination, and may predict risk of future infection. Higher levels of SARS-CoV-2 anti-Spike antibodies are known to be associated with increased protection against future SARS-CoV-2 infection. However, variation in antibody levels and risk factors for lower antibody levels following each round of SARS-CoV-2 vaccination have not been explored across a wide range of socio-demographic, SARS-CoV-2 infection and vaccination, and health factors within population-based cohorts. Methods: Samples were collected from 9,361 individuals from TwinsUK and ALSPAC UK population-based longitudinal studies and tested for SARS-CoV-2 antibodies. Cross-sectional sampling was undertaken jointly in April-May 2021 (TwinsUK, N = 4,256; ALSPAC, N = 4,622), and in TwinsUK only in November 2021-January 2022 (N = 3,575). Variation in antibody levels after first, second, and third SARS-CoV-2 vaccination with health, socio-demographic, SARS-CoV-2 infection and SARS-CoV-2 vaccination variables were analysed. Using multivariable logistic regression models, we tested associations between antibody levels following vaccination and: (1) SARS-CoV-2 infection following vaccination(s); (2) health, socio-demographic, SARS-CoV-2 infection and SARS-CoV-2 vaccination variables. Results: Within TwinsUK, single-vaccinated individuals with the lowest 20% of anti-Spike antibody levels at initial testing had 3-fold greater odds of SARS-CoV-2 infection over the next six to nine months (OR = 2.9, 95% CI: 1.4, 6.0), compared to the top 20%. In TwinsUK and ALSPAC, individuals identified as at increased risk of COVID-19 complication through the UK 'Shielded Patient List' had consistently greater odds (2- to 4-fold) of having antibody levels in the lowest 10%. Third vaccination increased absolute antibody levels for almost all individuals, and reduced relative disparities compared with earlier vaccinations. Conclusions: These findings quantify the association between antibody level and risk of subsequent infection, and support a policy of triple vaccination for the generation of protective antibodies. Funding: Antibody testing was funded by UK Health Security Agency. The National Core Studies program is funded by COVID-19 Longitudinal Health and Wellbeing - National Core Study (LHW-NCS) HMT/UKRI/MRC (MC_PC_20030 & MC_PC_20059). Related funding was also provided by the NIHR 606 (CONVALESCENCE grant COV-LT-0009). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC.

Background Higher concentrations of cholesterol-containing low-density lipoprotein (LDL-C) increase the risk of cardiovascular disease (CVD). The association of LDL-C with non-CVD traits remains unclear, as are the possible independent contributions of other cholesterol-containing lipoproteins and apolipoproteins. Methods Nuclear magnetic resonance spectroscopy was used to measure the cholesterol content of high density (HDL-C), very low-density (VLDL-C), intermediate-density (IDL-C), as well as low-density lipoprotein fractions, the apolipoproteins Apo-A1 and Apo-B, as well as total triglycerides (TG), remnant-cholesterol (Rem-Chol) and total cholesterol (TC). The causal effects of these exposures were assessed against 33 outcomes using univariable and multivariable Mendelian randomization (MR). Results The majority of cholesterol containing lipoproteins and apolipoproteins affect coronary heart disease (CHD), carotid intima-media thickness, carotid plaque, C-reactive protein (CRP) and blood pressure. Multivariable MR indicated that many of these effects act independently of HDL-C, LDL-C and TG, the most frequently measured lipid fractions. Higher concentrations of TG, VLDL-C, Rem-Chol and Apo-B increased heart failure (HF) risk; often independently of LDL-C, HDL-C or TG. Finally, a subset of these exposures associated with non-CVD traits such as Alzheimer’s disease (AD: HDL-C, LDL-C, IDL-C, Apo-B), type 2 diabetes (T2DM: VLDL-C, IDL-C, LDL-C), and inflammatory bowel disease (IBD: LDL-C, IDL-C). Conclusions The cholesterol content of a wide range of lipoprotein and apolipoproteins associate with measures of atherosclerosis, blood pressure, CRP, and CHD, with a subset affecting HF, T2DM, AD and IBD risk. Many of the observed effects appear to act independently of LDL-C, HDL-C, and TG, supporting the targeting of lipid fractions beyond LDL-C for disease prevention. UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government, and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government and the British Heart Foundation. AFS is supported by British Heart Foundation (BHF) grant PG/18/5033837, PG/22/10989 and the UCL BHF Research Accelerator AA/18/6/34223. CF and AFS received additional support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre. MGM is supported by a BHF Fellowship FS/17/70/33482. ADH and DAL (NF-0616-10102) are an NIHR Senior Investigators. This work was funded by the Strategic Priority Fund “Tackling multimorbidity at scale” programme [MR/V033867/1] delivered by the Medical Research Council and the National Institute for Health and Care Research in partnership with the Economic and Social Research Council and in collaboration with the Engineering and Physical Sciences Research Council. The UCLEB Consortium is supported by a British Heart Foundation Programme Grant (RG/10/12/28456). DAL’s contribution to this research is supported by the Bristol BHF Accelerator Award (AA/18/1/34219), her BHF Chair (CH/F/20/90003) and the UK Medical Research Council (MC_UU_00011/1-6). MK is supported by the UK Medical Research Council (MRC MR/R024227/1), National Institute on Aging (NIA), US (R01AG056477), and the Wellcome Trust (221854/Z/20/Z). PC is supported by the Thailand Research Fund (MRG6280088). TRG receives funding from the UK Medical Research Council as part of the MRC Integrative Epidemiology Unit (MC_UU_00011/4). AH receives support from the British Heart Foundation (SP/F/21/150020) and UK Medical Research Council (MC_PC-20051). ADH receives support from the UK Medical Research Council (MC_UU_12019/1). NF received funding from the National Health Institutes (MD012765, DK117445). CG has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 754490—MINDED project.

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry metaanalysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) R01HL127564 R01HL142711, Wellcome Trust 201543/B/16/Z 202802/Z/16/Z, European Commission HEALTH-F2-2013-601456 608765 786833, TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation NNF15CC0018486, American Diabetes Association 1-19-ICTS-068, Academy of Finland 312062 Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, Finnish innovation fund Sitra (EW) Finska Lakaresallskapet, American Heart Association 15POST24470131 17POST33650016, University of Bristol NIHR Biomedical Research Centre BRC-1215-2001, MRC & WT 217065/Z/19/Z, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_UU_00011, CRUK Integrative Cancer Epidemiology Programme C18281/A19169, Medical Research Council UK (MRC) MC_UU_00011/1, UK National Institute for Health Research Academic Clinical Fellowship, American Heart Association 18CDA34110116, Miguel Servet contract from the ISCIII Spanish Health Institute CP17/00142, European Social Fund (ESF), Westlake Education Foundation, British Heart Foundation FS/14/66/3129 Z01HG200362 R01HL142302 R01HL105756

Patients with localized prostate cancer comprise a large volume of treatments in radiation therapy centers. Occasionally, individual patient anatomy makes the safe delivery of an effective dose of radiation therapy challenging. We describe 2 cases of patients with a small bowel deep in the pelvis within the planning target volume with subsequent suboptimal radiation therapy treatment plans. We explore how we used the GU-Lok, a prostate immobilization device, to move the small bowel away from the prostate, and tighten target volume margins to help facilitate safe and effective treatment.

Funder: Nederlandse Organisatie voor Wetenschappelijk Onderzoek; doi: http://dx.doi.org/10.13039/501100003246, Funder: ZonMw; doi: http://dx.doi.org/10.13039/501100001826, Funder: Research Institute for Diseases in the Elderly, Funder: Ministerie van Onderwijs, Cultuur en Wetenschap; doi: http://dx.doi.org/10.13039/501100003245, Funder: Health Promotion Administration, Ministry of Health and Welfare; doi: http://dx.doi.org/10.13039/100013227, Funder: Municipality of Rotterdam, Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10-8) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10-13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

OBJECTIVE This research aims to (i) identify latent subgroups of ED presentations in Australian public EDs using a data-driven approach and (ii) compare clinical, socio-demographic and time-related characteristics of ED presentations broadly using the subgroups. METHODS We examined presentations to four public hospital EDs in Queensland from 2009 to 2014. An unsupervised machine learning algorithm, Clustering Large Applications, was used to cluster ED presentations. RESULTS There were six subgroups common across the EDs, primarily distinguishable by age, and subsequently by triage category, ED length of stay, arrival mode, departure status and several time-related attributes. Around 10% to 30% of the total presentations had high resource utilisation, with half of these from older patients (55+ years). ED resource utilisation per population was highest among the oldest cohort (75+ years). Children and young adults more frequently presented to the ED outside general-practitioner hours, mostly on Sundays. Older persons were more likely to present at any time, rather than specific hours, days or seasons. ED service performance measured against commonly used access-target indicators were rarely satisfied for older people and frequently satisfied for children. CONCLUSION Clustering Large Applications is effective in finding latent groups in large-scale mixed-type data, as demonstrated in the present study. Six types of ED presentations were identified and described using clinically relevant characteristics. The present study provides evidence for policy makers in Australia to develop alternative ED models of care tailored around the care needs of the differing groups of patients and thereby supports the sustainable delivery of acute healthcare.

Objective To assess the causes of maternal mortality at a referral hospital in Rwanda. Methods A secondary data analysis of 217 women with recorded maternal mortality from 2017 to 2019 was conducted among 11,308 total maternal admissions. Demographics, diagnosis, management, referring hospital source, and outcomes were recorded. Results The mean (±SD) age of maternal death was 30.7±7.2 years (range 16-57 years). The overall maternal mortality rate was 1.99%, with yearly rates of 2.45%, 2.53%, and 1.84% in 2017, 2018, and 2019, respectively. A significant seasonal variation was noted. Sepsis was the most common cause of maternal death (50%), followed by hemorrhage (19%) and hypertensive disorders (15%). Causes of maternal deaths included preeclampsia (13%) and abortion (8%). Furthermore, 82% of all the deaths were referrals from smaller community hospitals. Conclusion Maternal death due to sepsis remain a major cause of maternal deaths in Rwanda. Infection prevention and the early diagnosis and management of sepsis must be a priority in reducing maternal mortality.

Intimate partner violence (IPV) is a major public health problem with adverse health and mental consequences. Patient- and clinician-related barriers to screening include underreporting, misattribution of IPV to other causes, and patients not seeking help or facing social stigmas and discrimination. Radiology may help overcome these barriers through objective imaging evaluation, noting mismatches between image findings and provided clinical history. Recognizing injury patterns specific to IPV on imaging aids early identification and intervention even when the patient is not forthcoming. This article examines the ways radiologists have adapted to meet an ever-increasing demand for diagnosis and reporting of IPV.

Background and ObjectiveWe investigated the associations between theAPOEgenotype, intracerebral hemorrhage (ICH), and neuroimaging markers of cerebral amyloid angiopathy (CAA).MethodsWe included patients from a prospective, multicenter UK observational cohort study of patients with ICH and representative UK population controls. First, we assessed the association of theAPOEgenotype with ICH (compared with controls without ICH). Second, among patients with ICH, we assessed the association ofAPOEstatus with the hematoma location (lobar or deep) and brain CT markers of CAA (finger-like projections [FLP] and subarachnoid extension [SAE]).ResultsWe included 907 patients with ICH and 2,636 controls. The mean age was 73.2 (12.4 SD) years for ICH cases vs 69.6 (0.2 SD) for population controls; 50.3% of cases and 42.1% of controls were female. Compared with controls, anyAPOEε2 allele was associated with all ICH (lobar and nonlobar) and lobar ICH on its own in the dominant model (OR 1.38, 95% CI 1.13–1.7,p= 0.002 and OR 1.50, 95% CI 1.1–2.04,p= 0.01, respectively) but not deep ICH in an age-adjusted analyses (OR 1.26, 95% CI 0.97–1.63,p= 0.08). In the cases-only analysis, theAPOEε4 allele was associated with lobar compared with deep ICH in an age-adjusted analyses (OR 1.56, 95% CI 1.1–2.2,p= 0.01). When assessing CAA markers,APOEalleles were independently associated with FLP (ε4: OR 1.74, 95% CI 1.04–2.93,p= 0.04 and ε2/ε4: 2.56, 95% CI 0.99–6.61,p= 0.05). We did not find an association betweenAPOEalleles and SAE.DiscussionWe confirmed associations betweenAPOEalleles and ICH including lobar ICH. Our analysis shows selective associations betweenAPOEε2 and ε4 alleles with FLP, a CT marker of CAA. Our findings suggest that differentAPOEalleles might have diverging influences on individual neuroimaging biomarkers of CAA-associated ICH.

Intimate partner violence (IPV) is a highly prevalent public health issue with multiple adverse health effects for affected persons. Radiologists are well suited to assess a patient's likelihood of IPV. Recognition of common IPV injury mechanisms and resulting target and defensive injury patterns on imaging, as well as understanding differences in imaging utilization between patients with and without IPV, will aid radiologists in accurate IPV diagnosis. Target injuries often involve the face and neck as a result of blunt trauma or strangulation, whereas defensive injuries often involve the extremity. Awareness of differences in injury patterns resulting from IPV-related and accidental trauma can aid radiologists in detecting a mismatch between the provided clinical history and imaging findings, to support suspicion for IPV. Radiologists should consider all available current and prior imaging in assessing the likelihood of IPV; this process may be aided by machine learning methods. Even if correctly suspecting IPV based on imaging, radiologists face challenges in acting upon that suspicion, including appropriately documenting the findings, without compromising the patient's confidentiality and safety. However, through a multidisciplinary approach with appropriate support mechanisms, radiologists may serve as effective frontline physicians for raising suspicion for IPV.

Aortoesophageal fistula (AOF) is a rare but life-threatening condition. We present a case of AOF secondary to oesophageal Squamous Cell Carcinoma (SCC) treated with Thoracic Endovascular Aortic Repair (TEVAR) and a literature review of cases of AOF secondary to oesophageal malignancies treated with TEVAR. We performed a literature review of patients with oesophageal malignancies complicated by AOF who underwent endovascular stenting as treatment. A total of 16 articles with 22 patients were found during the review. The majority (18 out of 22 patients, 82%) were male. 18 (82%) presented with haemorrhage and 9 (41%) presented with hypotension. Of the eight studies where location of oesophageal tumour was mentioned, 7 (88%) were in the mid-thoracic oesophagus. Survival at 6 months post-stenting was up to 45%. Early recognition of AOF, effective resuscitation and early intervention is critical in survival of patients with AOF. TEVAR has been shown to have good outcomes with high technical success rate.

In machine learning (ML) on relational datasets, association patterns in the data, paths in decision trees, and weights between layers of the neural network coming from multiple underlying sources are often entangled, masking the pattern-to-source relation, weakening prediction and defying explanation. This paper presents a revolutionary ML paradigm: Pattern Discovery and Disentanglement (PDD), which disentangles associations and provides an All-in-One knowledge framework and computational platform, capable of a) disentangling patterns to associate with distinct sources/classes; b) discovering rare/imbalanced groups, detecting anomalies and rectifying discrepancies to improve class association, pattern/entity clustering; c) organizing knowledge for interpretability/traceability for causal exploration with statistical support. Results from base studies validate such capabilities. The explainable knowledge reveals pattern-source relations, entity characteristics and underlying factors for causal inference, clinical study, and practice, addressing the major concern of interpretability, trust and reliability when applying ML to healthcare --- a step towards closing the AI chasm.

Aims To provide a comprehensive evaluation of the biomedical effects of circulating concentrations of cholesterol-containing lipoproteins and apolipoproteins. Methods and Results Nuclear magnetic resonance (NMR) spectroscopy was used to measure the cholesterol content of high density (HDL-C), very low-density (VLDL-C), intermediate-density (IDL-C), and low-density (LDL-C) lipoprotein fractions; apolipoproteins Apo-A1 and Apo-B; as well as total triglycerides (TG), remnant-cholesterol (Rem-chol) and total cholesterol (TC). The causal effects of these exposures were assessed against 33 cardiovascular as well as non-cardiovascular outcomes using two-sample univariable and multivariable Mendelian randomization (MR). We observed that most cholesterol containing lipoproteins and apolipoproteins affected coronary heart disease (CHD), cIMT, carotid plaque, CRP and blood pressure. Through multivariable MR we showed that many of these exposures acted independently of the more commonly measured blood lipids: HDL-C, LDL-C and TG. We furthermore found that HF risk was increased by higher concentrations of TG, VLDL-C, Rem-Chol and Apo-B, often independently of LDL-C, HDL-C or TG. Finally, a smaller subset of these exposures could be robustly mapped to non-CVD traits such as Alzheimer’s disease (AD: HDL-C, LDL-C, IDL-C, Apo-B), type 2 diabetes (T2DM: VLDL-C, IDL-C, LDL-C), and inflammatory bowel disease (IBD: LDL-C, IDL-C). Conclusion The cholesterol content of a wide range of lipoprotein and apolipoproteins affected measures of atherosclerosis and CHD, implicating subfractions beyond LDL-C. Novel findings include cholesterol-containing lipoproteins and apolipoproteins affecting HF, blood pressure, CRP, AD and IBD. Many of the observed effects acted independently of LDL-C, HDL-C, and TG, supporting additional non-LDL-C avenues to disease prevention.

Background and ObjectivesThe goals of this work were to quantify the independent and interactive associations of β-amyloid (Aβ) and white matter hyperintensity volume (WMHV), a marker of presumed cerebrovascular disease (CVD), with rates of neurodegeneration and to examine the contributions of APOE ε4 and vascular risk measured at different stages of adulthood in cognitively normal members of the 1946 British Birth Cohort.MethodsParticipants underwent brain MRI and florbetapir-Aβ PET as part of Insight 46, an observational population-based study. Changes in whole-brain, ventricular, and hippocampal volume were directly measured from baseline and repeat volumetric T1 MRI with the boundary shift integral. Linear regression was used to test associations with baseline Aβ deposition, baseline WMHV, APOE ε4, and office-based Framingham Heart Study Cardiovascular Risk Score (FHS-CVS) and systolic blood pressure (BP) at ages 36, 53, and 69 years.ResultsThree hundred forty-six cognitively normal participants (mean [SD] age at baseline scan 70.5 [0.6] years; 48% female) had high-quality T1 MRI data from both time points (mean [SD] scan interval 2.4 [0.2] years). Being Aβ positive at baseline was associated with 0.87–mL/y faster whole-brain atrophy (95% CI 0.03, 1.72), 0.39–mL/y greater ventricular expansion (95% CI 0.16, 0.64), and 0.016–mL/y faster hippocampal atrophy (95% CI 0.004, 0.027), while each 10-mL additional WMHV at baseline was associated with 1.07–mL/y faster whole-brain atrophy (95% CI 0.47, 1.67), 0.31–mL/y greater ventricular expansion (95% CI 0.13, 0.60), and 0.014–mL/y faster hippocampal atrophy (95% CI 0.006, 0.022). These contributions were independent, and there was no evidence that Aβ and WMHV interacted in their effects. There were no independent associations of APOE ε4 with rates of neurodegeneration after adjustment for Aβ status and WMHV, no clear relationships between FHS-CVS or systolic BP and rates of neurodegeneration when assessed across the whole sample, and no evidence that FHS-CVS or systolic BP acted synergistically with Aβ.DiscussionAβ and presumed CVD have distinct and additive effects on rates of neurodegeneration in cognitively normal elderly. These findings have implications for the use of MRI measures as biomarkers of neurodegeneration and emphasize the importance of risk management and early intervention targeting both pathways.

Objectives With the increased prevalence of childhood-onset inflammatory bowel disease (IBD), there is a greater need for a planned transition process for adolescents and young adults (AYA). The Canadian IBD Transition Network and Crohn’s and Colitis Canada joined in collaborative efforts to describe a set of care consensus statements to provide a framework for transitioning AYA from pediatric to adult care. Methods Consensus statements were drafted after focus group meetings and literature reviews. An expert panel consisting of 20 IBD physicians, nurses, surgeon, adolescent medicine physician, as well as patient and caregiver representatives met, discussed and systematically voted. The consensus was reached when greater than 75% of members voted in agreement. When greater than 75% of members rated strong support, the statement was rendered a strong recommendation, suggesting that a clinician should implement the statement for all or most of their clinical practice. Results The Canadian expert panel generated 15 consensus statements (9 strong and 6 weak recommendations). Areas of focus of the statements included: transition program implementation, key stakeholders, areas of potential need and gaps in the research. Conclusions These consensus statements provide a framework for the transition process. The quality of evidence for these statements was generally low, highlighting the need for further controlled studies to investigate and better define effective strategies for transition in pediatric to adult IBD care.

ObjectiveTo investigate subjective cognitive decline (SCD) in relation to β-amyloid pathology and to test for associations with anxiety, depression, objective cognition and family history of dementia in the Insight 46 study.MethodsCognitively unimpaired ~70-year-old participants, all born in the same week in 1946 (n=460, 49% female, 18% amyloid-positive), underwent assessments including the SCD-Questionnaire (MyCog). MyCog scores were evaluated with respect to18F-Florbetapir-PET amyloid status (positive/negative). Associations with anxiety, depression, objective cognition (measured by the Preclinical Alzheimer Cognitive Composite, PACC) and family history of dementia were also investigated. The informant’s perspective on SCD was evaluated in relation to MyCog score.ResultsAnxiety (mean (SD) trait anxiety score: 4.4 (3.9)) was associated with higher MyCog scores, especially in women. MyCog scores were higher in amyloid-positive compared with amyloid-negative individuals (adjusted means (95% CIs): 5.3 (4.4 to 6.1) vs 4.3 (3.9 to 4.7), p=0.044), after accounting for differences in anxiety. PACC (mean (SD) −0.05 (0.68)) and family history of dementia (prevalence: 23.9%) were not independently associated with MyCog scores. The informant’s perception of SCD was generally in accordance with that of the participant.ConclusionsThis cross-sectional study demonstrates that symptoms of SCD are associated with both β-amyloid pathology, and more consistently, trait anxiety in a population-based cohort of older adults, at an age when those who are destined to develop dementia are still likely to be some years away from symptoms. This highlights the necessity of considering anxiety symptoms when assessing Alzheimer’s disease pathology and SCD.

Objective To assess associations between head injury (HI) with loss of consciousness (LOC), ageing and markers of later‐life cerebral pathology; and to explore whether those effects may help explain subtle cognitive deficits in dementia‐free individuals. Methods Participants (n = 502, age = 69–71) from the 1946 British Birth Cohort underwent cognitive testing (subtests of Preclinical Alzheimer Cognitive Composite), 18F‐florbetapir Aβ‐PET and MR imaging. Measures include Aβ‐PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) microstructure, Alzheimer’s disease (AD)‐related cortical thickness, and serum neurofilament light chain (NFL). LOC HI metrics include HI occurring: (i) >15 years prior to the scan (ii) anytime up to age 71. Results Compared to those with no evidence of an LOC HI, only those reporting an LOC HI>15 years prior (16%, n = 80) performed worse on cognitive tests at age 69–71, taking into account premorbid cognition, particularly on the digit‐symbol substitution test (DSST). Smaller brain volume (BV) and adverse NAWM microstructural integrity explained 30% and 16% of the relationship between HI and DSST, respectively. We found no evidence that LOC HI was associated with Aβ load, hippocampal volume, WMH volume, AD‐related cortical thickness or NFL (all p > 0.01). Interpretation Having a LOC HI aged 50’s and younger was linked with lower later‐life cognitive function at age ~70 than expected. This may reflect a damaging but small impact of HI; explained in part by smaller BV and different microstructure pathways but not via pathology related to AD (amyloid, hippocampal volume, AD cortical thickness) or ongoing neurodegeneration (serum NFL).

Introduction: Percutaneous ultrasound-guided core needle biopsy is a well-established method in the diagnosis of musculoskeletal tumors. It is unclear which factors contribute the most to a successful biopsy. The aim of the study was to determine the value of ultrasoundguided core needle biopsy of solid lesions in the musculoskeletal system using a 16-gauge needle. Material and methods: A retrospective analysis performed at a regional sarcoma center over one year included patients referred for ultrasound-guided biopsy of musculoskeletal soft tissue lesions. At least 6 months’ clinical and radiological follow-up, results from repeat or excisional biopsy, or interventional treatment, served as outcome reference. The biopsy procedure and yield were analyzed. The biopsy was classified as ‘diagnostic’ when a definitive diagnosis could be made on the first biopsy, and ‘accurate’ when only the malignant or benign nature of the tumor could be determined. Results: From 102 referrals for biopsy of soft tissue lesions in 2019, a total of 73 biopsies of solid lesions with a 16-gauge cutting needle were included (73 patients). There were 34 males and 39 females, with a mean age of 57.7 years. The overall proportion of diagnostic biopsies was 84%, for malignant lesions 88% and benign lesions 81%. The tumor could be classified as malignant or benign in 12 patients (16%) (accurate biopsy). It was possible to discriminate between malignant and benign lesions in each case. The majority of biopsied lesions were benign 64% (n = 47). Conclusion: The diagnostic value of ultrasound-guided percutaneous core needle biopsy of musculoskeletal soft tissue lesions performed with 16-gauge needle is good, with a high rate of diagnostic biopsies, both for benign and malignant lesions.

Tumor hypoxia induces the large-scale adaptive reprogramming of cancer cells, promoting their transformation into highly invasive and metastatic species that lead to highly negative prognoses for cancer patients. We describe the synthesis and application of a hypoxia-responsive trigger derived from previously inaccessible enamine N-oxide structures. Hypoxia-dependent reduction of this motif by hemeproteins results in the concomitant activation of a caged molecule and a latent electrophile. We exploit the former in a hypoxia-activated prodrug application using a caged staurosporine molecule as a proof-of-principle. We demonstrate the latter in in vivo tumor labeling applications with enamine-N-oxide-modified near-infrared probes. Hypoxia-activated prodrug development has long been complicated by the heterogeneity of tumor hypoxia in patients. The dual drug release and imaging modalities of the highly versatile enamine N-oxide motif present an attractive opportunity for theranostic development that can address the need not only for new therapeutics but paired methods for patient stratification.

BackgroundThe optimal time to commence anticoagulation in patients with atrial fibrillation (AF) after ischaemic stroke or transient ischaemic attack (TIA) is unclear, with guidelines differing in recommendations. A limitation of previous studies is the focus on clinically overt stroke, rather than radiologically obvious diffusion-weighted imaging ischaemic lesions. We aimed to quantify silent ischaemic lesions and haemorrhages on MRI at 1 month in patients commenced on early (MethodsA prospective multicentre, observational cohort study was performed at 11 Australian stroke centres. Clinical and MRI data were collected at baseline and follow-up, with blinded imaging assessment performed by two authors. Timing of commencement of anticoagulation was at the discretion of the treating stroke physician.ResultsWe recruited 276 patients of whom 208 met the eligibility criteria. The average age was 74.2 years (SD±10.63), and 79 (38%) patients were female. Median National Institute of Health Stroke Scale score was 5 (IQR 1–12). Median baseline ischaemic lesion volume was 5 mL (IQR 2–17). There were a greater number of new ischaemic lesions on follow-up MRI in patients commenced on anticoagulation ≥4 days after index event (17% vs 8%, p=0.04), but no difference in haemorrhage rates (22% vs 32%, p=0.10). Baseline ischaemic lesion volume of ≤5 mL was less likely to have a new haemorrhage at 1 month (p=0.02). There was no difference in haemorrhage rates in patients with an initial ischaemic lesion volume of >5 mL, regardless of anticoagulation timing.ConclusionCommencing anticoagulation

Acute Myeloid Leukemia (AML) is a heterogenous hematopoietic cancer characterized by abnormal differentiation and uncontrolled proliferation of hematopoietic progenitor cells. Recent approaches to treatment, which aim to improve outcomes in refractory AML, include strategies to molecularly target specific receptor-mediated signaling pathways which regulate cell growth and proliferation. One target-specific approach is the inhibition of fms-like tyrosine kinase 3 (FLT3). FLT3 is expressed on the surface of hematopoietic progenitor cells and plays an important role in regulating proliferation, survival, and differentiation of multipotent stem cells. The presence of internal tandem duplications (ITDs) at the juxta membrane domain within the FLT3 receptor are common driver mutations in 30% of AML patients. In this study, we utilized 3 luciferase-expressing human AML models, MV4-11, MOLM-13, and, OCI-AML3 to determine the prognostic impact of FLT3 inhibitor Gilteritinib on the allelic ratio of ITD versus wildtype allele. OCI-AML3 expresses wild-type FLT3 whereas MOLM-13 is heterozygous for FLT3-ITD mutations, and MV4-11 possesses a homozygous in-frame tandem repeat insertion in the FLT3 allele. Here we demonstrate that FLT3-ITD mutational status impacts the efficacy of Gilteritinib in both in vitro and in vivo AML models. The in vitro assays showed that treatment with Gilteritinib resulted in significant dose dependent reduction in overall cell viability and bioluminescence in the MV4-11 cell line, while MOLM-13 was only moderately sensitive, and OCI-AML3 was least sensitive to Gilteritinib treatment. Additionally, we evaluated the downstream MAPK and PI3K signaling pathways as FLT3-ITD oncogenic mutations result in ligand-independent constitutive activation of signaling pathways mediating leukemic transformation. For in vivo validation, MV4-11, MOLM-13, and OCI-AML3 luciferase expressing cells were implanted systemically into NCG mice and once tumors were established, we evaluated the survival benefit in response to Gilteritinib and various standard of care agents. In accordance with our in vitro findings, the quantification of tumor progression by bioluminescent imaging showed the highest therapeutic activity of Gilteritinib in MV4-11 tumor bearing mice through selective targeting of FLT3-ITD mutations. Taken together, our in vitro and in vivo results demonstrate that differential FLT3-ITD mutational status in AML models impacts Gilteritinib treatment response and downstream signaling events with the highest activity in MV4-11 followed by MOLM-13, and lack of activity in OCI-AML3 harboring wild-type FLT3. Citation Format: Bincy John, Pasupathi Sundaramoorthy, Elizabeth Rainbolt, Andrew Wong, Zachary Ward, Justin Avery, Savannah Todd, Shasta Kidder, Diana Gietl, Chassidy Hall, David Harris. Differential flt3 mutational status in acute myeloid leukemia predicts sensitivity to flt3 inhibitor gilteritinib in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 8.

Syngeneic tumor models provide a platform to assess novel immune-oncology therapeutics in fully immuno-competent mice. A subcutaneous flank tumor implant provides a convenient and accessible location to monitor the tumor growth and response to therapy. However, the tumor microenvironment, and therefore, the responsiveness to immuno-oncology therapies, is greatly impacted by the location in which the tumor develops (Ho 2021, Oliver 2018). Given the potential of different immuno-suppressive features driven by the specific tumor location, we wanted to compare the tumor infiltrating leukocyte populations in the subcutaneous flank and orthotopic pancreatic Pan02 syngeneic models, as well as the response to standard of care therapies. Pan02 cells were either implanted orthotopically in the pancreas or subcutaneously in the flank and allowed to establish before dosing with either vehicle, oxaliplatin, anti-CTLA-4 or the combination of therapies. Established tumors from untreated orthotopic and flank models were sampled for flow cytometry to assess infiltration by a broad range of immune cell populations. Response to therapy was clearly dependent on tumor location with flank tumors being resistant to both monotherapy and combination therapy, while the orthotopic tumors responded modestly to monotherapy but displayed synergy with the combination therapy. The results suggest that for a given syngeneic tumor cell line with identical mutational load and antigenicity, we can generate unique tumor microenvironments dependent on implant location leading to different outcomes when testing novel immune-oncology therapies. These types of models can help define the context in which novel immune-oncology therapeutics can be expected to drive an effective immune response. Citation Format: Andrew Wong, Patrick Fadden, Cara Clouse, Patrick Wood, Marianna Brown-Augustine, Fei Zhao, Elliot Ser, Joseph Kolb, Chassidy Hall, Elizabeth Rainbolt. Site specific tumor response to combination chemotherapy and immune checkpoint inhibitor in the syngeneic Pan02 pancreatic ductal adenocarcinoma model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4156.

SARS-CoV-2 antibody levels can be used to assess humoral immune responses following SARS-CoV-2 infection or vaccination, and may predict risk of future infection. From cross-sectional antibody testing of 9,361 individuals from TwinsUK and ALSPAC UK population-based longitudinal studies (jointly in April-May 2021, and TwinsUK only in November 2021-January 2022), we tested associations between antibody levels following vaccination and: (1) SARS-CoV-2 infection following vaccination(s); (2) health, socio-demographic, SARS-CoV-2 infection and SARS-CoV-2 vaccination variables.Within TwinsUK, single-vaccinated individuals with the lowest 20% of anti-Spike antibody levels at initial testing had 3-fold greater odds of SARS-CoV-2 infection over the next six to nine months, compared to the top 20%. In TwinsUK and ALSPAC, individuals identified as at increased risk of COVID-19 complication through the UK “Shielded Patient List” had consistently greater odds (2 to 4-fold) of having antibody levels in the lowest 10%. Third vaccination increased absolute antibody levels for almost all individuals, and reduced relative disparities compared with earlier vaccinations.These findings quantify the association between antibody level and risk of subsequent infection, and support a policy of triple vaccination for the generation of protective antibodies.Lay summaryIn this study, we analysed blood samples from 9,361 participants from two studies in the UK: an adult twin registry, TwinsUK (4,739 individuals); and the Avon Longitudinal Study of Parents and Children, ALSPAC (4,622 individuals). We did this work as part of the UK Government National Core Studies initiative researching COVID-19. We measured blood antibodies which are specific to SARS-CoV-2 (which causes COVID-19). Having a third COVID-19 vaccination boosted antibody levels. More than 90% of people from TwinsUK had levels after third vaccination that were greater than the average level after second vaccination. Importantly, this was the case even in individuals on the UK “Shielded Patient List”. We found that people with lower antibody levels after first vaccination were more likely to report having COVID-19 later on, compared to people with higher antibody levels. People on the UK “Shielded Patient List”, and individuals who reported that they had poorer general health, were more likely to have lower antibody levels after vaccination. In contrast, people who had had a previous COVID-19 infection were more likely to have higher antibody levels following vaccination compared to people without infection. People receiving the Oxford/AstraZeneca rather than the Pfizer BioNTech vaccine had lower antibody levels after one or two vaccinations. However, after a third vaccination, there was no difference in antibody levels between those who had Oxford/AstraZeneca and Pfizer BioNTech vaccines for their first two doses. These findings support having a third COVID-19 vaccination to boost antibodies.

IntroductionPrimary aldosteronism (PA) is associated with increased risk of cardiovascular events. However, treatment of PA has not been shown to improve left ventricular (LV) systolic function using the conventional assessment with LV ejection fraction (LVEF). We aim to use speckle-tracking echocardiography to assess for improvement in subclinical systolic function after treatment of PA.MethodsWe prospectively recruited 57 patients with PA, who underwent 24-h ambulatory blood pressure (BP) measurements and echocardiography, including global longitudinal strain (GLS) assessment of left ventricle, at baseline and 12 months post-treatment.ResultsAt baseline, GLS was low in 14 of 50 (28.0%) patients. On multivariable analysis, GLS was associated with diastolic BP (P = 0.038) and glomerular filtration rate (P = 0.026). GLS improved post-surgery by −2.3, 95% CI: −3.9 to −0.6, P = 0.010, and post-medications by −1.3, 95% CI: −2.6 to 0.03, P = 0.089, whereas there were no changes in LVEF in either group. Improvement in GLS was independently correlated with baseline GLS (P < 0.001) and increase in plasma renin activity (P = 0.007). Patients with post-treatment plasma renin activity ≥1 ng/ml/h had improvements in GLS (P = 0.0019), whereas patients with persistently suppressed renin had no improvement. Post-adrenalectomy, there were also improvements in LV mass index (P = 0.012), left atrial volume index (P = 0.002), and mitral E/e’ (P = 0.006), whereas it was not statistically significant in patients treated with medications.ConclusionTreatment of hyperaldosteronism is effective in improving subclinical LV systolic dysfunction. Elevation of renin levels after treatment, which reflects adequate reversal of sodium overload state, is associated with better systolic function after treatment.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier: NCT03174847.

COVID-19 has caused a global shift in healthcare-seeking behaviour; however, presentation rates with serious conditions, such as stroke in low COVID-19-prevalence cities, has received less attention.To determine if there was a significant reduction in stroke admissions, delivery of acute reperfusion therapies, or increased delays to presentation during the first wave of the COVID-19 pandemic.A multicentre, retrospective, observational cohort study was performed across three tertiary hospitals in Brisbane, Australia. Cases were identified using ICD-10 codes and then individually reviewed for eligibility using prespecified inclusion and exclusion criteria. All metrics were compared over 3 months from 1 March to 31 May 2020 with two corresponding 3-month periods in 2018 and 2019.There was a mean of 2.15 (95% CI 1.87-2.48) stroke admissions per day in the examined pandemic months compared with 2.13 (95% CI 1.85-2.45) and 2.26 (95% CI 1.97-2.59) in March to May 2018 and 2019 respectively, with no significant difference found (P = 0.81). There was also no difference in rates of intravenous thrombolysis (P = 0.82), endovascular thrombectomy (P = 0.93) and time from last known well to presentation (P = 0.54). Conversely, daily emergency department presentations (including non-stroke presentations) significantly reduced (P 0.0001).During the early months of the COVID-19 pandemic there was no significant reduction in stroke presentations, use of acute reperfusion therapies or delays to presentation, despite a reduction in ED presentations for any cause. Our results differ from the global experience, with possible explanations, including differences in public health messaging and healthcare infrastructure.

The aim of this study was to determine the diagnostic yield of multigene panel testing among patients referred with hereditary breast and ovarian cancer (HBOC). Patients who met provincial eligibility criteria were tested at the Advanced Molecular Diagnostic Laboratory at Mount Sinai Hospital, Toronto. Gene sequencing and exon-level copy number variant (CNV) analysis was performed. The referring physician had the opportunity to choose between several different gene panels based on patient phenotype. Cases were included in the analysis based on personal and family history of cancer and the type of panel ordered. 3251 cases that received panel testing were included in this analysis. Overall, 9.1% (295) had a positive (pathogenic or likely pathogenic) result and 27.1% (882) had an inconclusive result (variant of uncertain significance). The genes with the highest prevalence of positive results were in BRCA2 (2.2%, 71/3235), BRCA1 (1.9%, 62/3235), and CHEK2 (1.4%, 40/2916). Of the positive cases, 9.8% (29) had a pathogenic or likely pathogenic variant in a gene associated with Lynch syndrome (MSH6, MSH2, MLH1, or PMS2). Our overall positive yield is similar to that reported in the literature. The yield of inconclusive results was three times that of positive results. By testing more individuals in families with HBOC and through data-sharing efforts, the clinical significance of most variants may eventually be determined and panel testing for monogenic cancer predisposition syndromes will have greater utility.

To describe the development and determine the diagnostic accuracy of the Brisbane Evidence-Based Language Test in detecting aphasia. Consecutive acute stroke admissions ( = 100; mean = 66.49y) participated in a single (assessor) blinded cross-sectional study. Index assessment was the ∼45 min Brisbane Evidence-Based Language Test. The Brisbane Evidence-Based Language Test is further divided into four 15-25 min Short Tests: two Foundation Tests (severe impairment), Standard (moderate) and High Level Test (mild). Independent reference standard included the Language Screening Test, Aphasia Screening Test, Comprehensive Aphasia Test and/or Measure for Cognitive-Linguistic Abilities, treating team diagnosis and aphasia referral post-ward discharge. Brisbane Evidence-Based Language Test cut-off score of ≤157 demonstrated 80.8% (LR+ =10.9) sensitivity and 92.6% (LR- =0.21) specificity. All Short Tests reported specificities of ≥92.6%. Foundation Tests I (cut-off ≤61) and II (cut-off ≤51) reported lower sensitivity (≥57.5%) given their focus on severe conditions. The Standard (cut-off ≤90) and High Level Test (cut-off ≤78) reported sensitivities of ≥72.6%. The Brisbane Evidence-Based Language Test is a sensitive assessment of aphasia. Diagnostically, the High Level Test recorded the highest psychometric capabilities of the Short Tests, equivalent to the full Brisbane Evidence-Based Language Test. The test is available for download from brisbanetest.org.Implications for rehabilitationAphasia is a debilitating condition and accurate identification of language disorders is important in healthcare.Language assessment is complex and the accuracy of assessment procedures is dependent upon a variety of factors.The Brisbane Evidence-Based Language Test is a new evidence-based language test specifically designed to adapt to varying patient need, clinical contexts and co-occurring conditions.In this cross-sectional validation study, the Brisbane Evidence-Based Language Test was found to be a sensitive measure for identifying aphasia in stroke.

We have previously designed a library of lentiviral vectors to generate somatic-transgenic rodents to monitor signalling pathways in diseased organs using whole-body bioluminescence imaging, in conscious, freely moving rodents. We have now expanded this technology to adeno-associated viral vectors. We first explored bio-distribution by assessing GFP expression after neonatal intravenous delivery of AAV8. We observed widespread gene expression in, central and peripheral nervous system, liver, kidney and skeletal muscle. Next, we selected a constitutive SFFV promoter and NFκB binding sequence for bioluminescence and biosensor evaluation. An intravenous injection of AAV8 containing firefly luciferase and eGFP under transcriptional control of either element resulted in strong and persistent widespread luciferase expression. A single dose of LPS-induced a 10-fold increase in luciferase expression in AAV8-NFκB mice and immunohistochemistry revealed GFP expression in cells of astrocytic and neuronal morphology. Importantly, whole-body bioluminescence persisted up to 240 days. We have validated a novel biosensor technology in an AAV system by using an NFκB response element and revealed its potential to monitor signalling pathway in a non-invasive manner in a model of LPS-induced inflammation. This technology complements existing germline-transgenic models and may be applicable to other rodent disease models. ispartof: SCIENTIFIC REPORTS vol:10 issue:1 ispartof: location:England status: published

Exosomes, derived from stem cells, have great promise in regenerative medicine due to their capabilities of ameliorating inflammation, preventing tissue damage and promoting healing, which in part are associated with the exosomal RNA/miRNA. The application of mesenchymal stem cell exosomes in treating hepatic disorders including nonalcoholic fatty liver disease has drawn much attention. In this chapter, we describe our experience in culturing human mesenchymal stem cells and isolating their exosomes from culture medium through ultracentrifugation. Methods to extract exosomal RNA/miRNA are also discussed.