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BackgroundProne positioning has a beneficial role in coronavirus disease 2019 (COVID-19) patients receiving ventilation but lacks evidence in awake non-ventilated patients, with most studies being retrospective, lacking control populations and information on subjective tolerability.MethodsWe conducted a prospective, single-centre study of prone positioning in awake non-ventilated patients with COVID-19 and non-COVID-19 pneumonia. The primary outcome was change in peripheral oxygenation in prone versus supine position. Secondary outcomes assessed effects on end-tidal CO2, respiratory rate, heart rate and subjective symptoms. We also recruited healthy volunteers to undergo proning during hypoxic challenge.Results238 hospitalised patients with pneumonia were screened; 55 were eligible with 25 COVID-19 patients and three non-COVID-19 patients agreeing to undergo proning – the latter insufficient for further analysis. 10 healthy control volunteers underwent hypoxic challenge. Patients with COVID-19 had a median age of 64 years (interquartile range 53–75). Proning led to an increase in oxygen saturation measured by pulse oximetry (SpO2) compared to supine position (difference +1.62%; p=0.003) and occurred within 10 min of proning. There were no effects on end-tidal CO2, respiratory rate or heart rate. There was an increase in subjective discomfort (p=0.003), with no difference in breathlessness. Among healthy controls undergoing hypoxic challenge, proning did not lead to a change in SpO2 or subjective symptom scores.ConclusionIdentification of suitable patients with COVID-19 requiring oxygen supplementation from general ward environments for awake proning is challenging. Prone positioning leads to a small increase in SpO2 within 10 min of proning though is associated with increased discomfort.

Introduction Orthostatic hypotension (OH) is associated with cardiovascular mortality and morbidity. Non-pharmacological and pharmacological therapies are employed in the management of OH. The aim of this systematic review and meta-analysis is to provide an up-to-date review of the efficacy parameters of pharmacological therapies. Methods Medline, Embase, Cochrane Library, and Scopus were searched (inception-July 2021), and published articles with randomized control trials, meeting inclusion and exclusion criteria were quality assessed (Risk of Bias 2 tool). Assessment for trends in patient-related outcome measures and postural blood pressure improvement was undertaken. Studies reporting postural systolic blood pressure (SBP) before and after intervention in comparison to placebo were included in a meta-analysis using inverse -variance in a random-effects model. Results 19 articles were included in the systematic review. The orthostatic symptoms questionnaire (OHQ) was the most common patient-related outcome measure utilized in trials. Six studies included in the meta-analysis demonstrated that pharmacological therapies (pyridostigmine, midodrine, atomoxetine, yohimbine) improved postural SBP compared to placebo, with a mean rise of 12.50 mmHg [95% CI: 6.01, 18.98; p value

AimsPulmonary hypertension (PH) is dichotomized into pre- and post-capillary physiology by invasive catheterization. Imaging, particularly strain assessment, may aid in classification and be helpful with ambiguous haemodynamics. We sought to define cardiac MRI (CMR) feature tracking biatrial peak reservoir and biventricular peak systolic strain in pre- and post-capillary PH and examine the performance of peak left atrial strain in distinguishing the 2 groups compared to TTE.Methods and resultsRetrospective cross-sectional study from 1 Jan 2015 to 31 Dec 2020; 48 patients (22 pre- and 26 post-capillary) were included with contemporaneous TTE, CMR and catheterization. Mean pulmonary artery pressures were higher in the pre-capillary cohort (55 + 14 mmHg vs 42 + 9 mmHg; p+ 22 ml/m2 vs 25 + 9 ml/m2; p+ 21 ml/m2 vs 61 + 29 ml/m2; p=0.694), however peak RA strain was lower in post-capillary PH patients (8.9 + 5.5% vs 18.8 + 7.0%; p+ 5.8%, RA strain 8.9 + 5.5%). CMR LAVi and peak LA strain had a multivariate AUC of 0.98 (95% CI 0.89-1.00; pConclusionCMR volumetric and deformation assessment of the left atrium can highly accurately distinguish post- from pre-capillary PH.

Background Vasopressin stimulates cyst growth in autosomal dominant polycystic kidney disease (ADPKD) and is a key therapeutic target. Evaluation of high water intake as an alternative to pharmacological vasopressin blockade is supported by patients. However feasibility, safety and adherence-promoting strategies required to deliver this remain unknown. Aims Assess the feasibility of a definitive randomized high water intake trial in ADPKD. Methods In this prospective open-label randomized trial, adult ADPKD patients with eGFR ≥ 20 ml/min/1.73 m2 were randomized to prescribed high water (HW) intake targeting urine osmolality (UOsm) ≤270 mOsm/kg, or ad libitum (AW) intake (UOsm >300 mOsm/kg). Self-management strategies including home-monitoring of urine-specific gravity (USG) were employed to promote adherence. Results We enrolled 42 participants, baseline median eGFR (HW 68.4 [interquartile range (IQR) 35.9–107.2] vs. AW 75.8 [IQR 59.0–111.0 ml/min/1.73 m2, P = 0.22) and UOsm (HW 353 [IQR 190–438] vs. AW 350 [IQR 240–452] mOsm/kg, P = 0.71) were similar between groups. After 8 weeks, 67% in the HW vs. 24% in AW group achieved UOsm ≤270 mOsm/kg, P = 0.001. HW group achieved lower UOsm (194 [IQR 190–438] vs. 379 [IQR 235–503] mOsm/kg, P = 0.01) and higher urine volumes (3155 [IQR 2270–4295] vs. 1920 [IQR 1670–2960] ml/day, P = 0.02). Two cases of hyponatraemia occurred in HW group. No acute GFR effects were detected. In total 79% (519/672) of USG were submitted and 90% (468/519) were within target. Overall, 17% withdrew during the study. Conclusion DRINK demonstrated successful recruitment and adherence leading to separation between treatment arms in primary outcomes. These findings suggest a definitive trial assessing the impact of high water on kidney disease progression in ADPKD is feasible.

Objective: Whether reducing low density lipoprotein cholesterol (LDL-C) is associated with cardiovascular benefits in low risk normocholesterolaemic subjects is unknown. The INTENSITY LOW [Investig...

IntroductionElevated low-density lipoprotein cholesterol (LDL-C) is a strong independent risk predictor of cardiovascular (CV) events, while interventions to reduce it remain the only evidence-based approach to reduce CV morbidity and mortality. Secondary prevention statin trials in combination with ezetimibe and/or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors showed that there is no ‘J shaped curve’ in LDL-C levels with regard to CV outcomes. The lowest threshold beyond which reduction of LDL-C confers no further CV benefits has not been identified.The INTENSITY-HIGH study seeks to explore physiological mechanisms mediating CV benefits of LDL-C lowering by PCSK9 inhibition in patients with established cardiovascular disease (CVD). The study examines the changes in measures of endothelial function and vascular inflammation imaging following intervention with PCSK9 and against standard of care.Methods and analysisThis is a single-centre, randomised, open label, parallel group, mechanistic physiological study. It will include approximately 60 subjects with established CVD, with LDL-C of Ethics and disseminationThe study received a favourable opinion from the Wales Research Ethics Committee 4, was registered on clinicaltrials.gov and conformed to International Conference for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice. The results of this study will be reported through peer-reviewed journals and conference presentations.Trial registration numberNCT03355027.

Radiomics, quantitative feature extraction from radiological images, can improve disease diagnosis and prognostication. However, radiomic features are susceptible to image acquisition and segmentation variability. Ideally, only features robust to these variations would be incorporated into predictive models, for good generalisability. We extracted 93 radiomic features from carotid artery computed tomography angiograms of 41 patients with cerebrovascular events. We tested feature robustness to region-of-interest perturbations, image pre-processing settings and quantisation methods using both single- and multi-slice approaches. We assessed the ability of the most robust features to identify culprit and non-culprit arteries using several machine learning algorithms and report the average area under the curve (AUC) from five-fold cross validation. Multi-slice features were superior to single for producing robust radiomic features (67 vs. 61). The optimal image quantisation method used bin widths of 25 or 30. Incorporating our top 10 non-redundant robust radiomics features into ElasticNet achieved an AUC of 0.73 and accuracy of 69% (compared to carotid calcification alone [AUC: 0.44, accuracy: 46%]). Our results provide key information for introducing carotid CT radiomics into clinical practice. If validated prospectively, our robust carotid radiomic set could improve stroke prediction and target therapies to those at highest risk.

Background Carotid artery atherosclerosis is an important cause of ischaemic stroke. In oncology, textural analysis (“radiomics”) of computed tomography (CT) images can predict the metastatic potential and prognosis of several types of malignant tumours. We investigated whether this quantitative approach could be applied in carotid artery disease. Purpose (1) To evaluate the feasibility of computed tomography angiography (CTA) texture analysis in differentiating symptomatic from asymptomatic patients. (2) To investigate whether CTA carotid texture analysis can identify culprit lesions in patients with stroke and transient ischaemic attack (TIA). Methods Carotid CTAs of consented research subjects were included in the study. Symptomatic patients had confirmed carotid artery-related ischaemic stroke or TIA in the 7 days before CTA imaging. Asymptomatic (ASX) patients had no prior stroke/TIA. Both TexRAD, a research texture analysis software, and PyRadiomics, a Python package for radiomics studies, were used to extract 99 first-order and higher-order texture features from regions-of-interest (ROI) drawn around the outer wall of the carotid artery. Single-slice analysis compared the carotid bifurcations of symptomatic and asymptomatic patients, and of culprit (CC) and non-culprit (NC) arteries in symptomatic patients. Multi-slice analysis was conducted using a 3D volume defined by ROIs drawn on 14 consecutive CT slices of 3mm thickness, covering 3cm of carotid artery. The Mann-Whitney U test was used for inter-subject comparisons (ASX vs CC; ASX vs NC) and the Wilcoxon signed-rank test was used for intra-subject comparisons (CC vs NC). A p value Results The dataset comprised 82 carotid arteries from 41 symptomatic patients (41 culprit; 41 non-culprit) and 50 carotid arteries from 25 asymptomatic patients. Single-slice analysis revealed greater homogeneity in asymptomatic carotids versus symptomatic culprit carotids (Uniformity: ASX 0.11 (0.05); CC 0.08 (0.05), p Conclusion Textural analysis of carotid CTAs reveal significant differences between symptomatic and asymptomatic patients and between culprit and non-culprit carotid arteries within symptomatic patients. This approach could be used to identify patients at high risk of further stroke for aggressive medical therapy and surveillance. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): EPVL is undertaking a PhD funded by the Cambridge School of Clinical Medicine and the Medical Research Council's Doctoral Training Partnership

Background Hypodense filling defects within the pulmonary veins on computed tomography described as pulmonary vein sign (PVS) have been noted in acute pulmonary embolism and shown to be associated with poor prognosis. We evaluated venous flow abnormalities in chronic thromboembolic pulmonary hypertension (CTEPH) to determine its usefulness in the computed tomography assessment of CTEPH. Methods and Results Blinded retrospective computed tomography analysis of 50 proximal CTEPH cases and 3 control groups—50 acute pulmonary embolism, 50 nonthromboembolic cohort, and 50 pulmonary arterial hypertension. Venous flow reduction was assessed by the following: (1) presence of a filling defect of at least 2 cm in a pulmonary vein draining into the left atrium, and (2) left atrium attenuation (>160 Hounsfield units). PVS was most prevalent in CTEPH. Compared with all controls, sensitivity and specificity of PVS for CTEPH is 78.0% and 85.3% (95% CI, 64.0–88.5 and 78.6–90.6, respectively) versus 34.0% and 70.7% (95% CI, 21.2−48.8 and 62.7–77.8) in acute pulmonary embolism, 8.0% and 62% (95% CI, 2.2–19.2 and 53.7–69.8) in nonthromboembolic and 2.0% and 60% (95% CI, 0.1−10.7 and 51.7−67.9) in pulmonary arterial hypertension. In CTEPH, lobar and segmental arterial occlusive disease was most commonly associated with corresponding absent venous flow. PVS detection was highly reproducible (Kappa=0.96, 95% CI, 0.90–1.01, P Conclusions PVS is easy to detect with higher sensitivity and specificity in CTEPH compared with acute pulmonary embolism and is not a feature of pulmonary arterial hypertension. Asymmetric enhancement of pulmonary veins may serve as an additional parameter in the computed tomography assessment of CTEPH and can be used to differentiate CTEPH from pulmonary arterial hypertension.

Introduction Carotid atherosclerosis is the main cause of ischaemic stroke. Texture analysis is a radiomic approach used to quantify image heterogeneity which can predict tumour aggression in oncology. We investigated whether this method could be applied to carotid artery disease to differentiate symptomatic from asymptomatic patients and culprit from non-culprit plaques, and then whether machine learning (ML) could correctly classify plaques based on these features. Methods CT angiography (CTA) images from symptomatic patients with carotid artery-related cerebrovascular accidents (CVAs) and from asymptomatic (ASX) patients were studied. Regions-of-interest (ROIs) were drawn on 14 consecutive carotid artery CTA slices with 3mm slice thickness. PyRadiomics was used for isotropic image (1x1x1) resampling and normalisation prior to texture feature extraction from 6 different classes (Table 1). Asymptomatic carotids were compared to culprit carotids (CC), and non-culprit (NC) carotids using the Mann Whitney U test or Wilcoxon signed-rank tests as appropriate, with a p-value Results The dataset comprised 82 carotid arteries from 41 symptomatic patients (41 culprit; 41 non-culprit) and 50 carotid arteries from 25 asymptomatic patients. CC and NC carotids showed significant differences in both first- and second-order features (IH Median: CC 618 (61); NC 646 (97), p Conclusions Textural analysis combined with machine learning on carotid CT scans reveals highly significant differences between symptomatic and asymptomatic patients, and between culprit and non-culprit carotid arteries within symptomatic patients. This approach could help identify patients at high-risk of stroke for aggressive medical therapy and surveillance. Conflict of Interest None

Background There is a continuous relationship between low density lipoprotein cholesterol (LDL-C) and cardiovascular risk. The cardiovascular benefits of reducing LDL-C in low risk normocholesterolaemic subjects is unknown. The INTENSITY LOW study sought to determine whether lowering LDL-C by alirocumab improves endothelial function in healthy individuals. Method This was a single-centre, randomised, single-blind, placebo-controlled study. 30 healthy normocholesterolaemic participants aged 18-45 were randomized 1:1 to receive either alirocumab 150mg or placebo subcutaneously. Forearm blood flow (FBF) as measured by venous occlusion plethysmography was undertaken at baseline and again after 2 weeks therapy. Endothelium-dependent and -independent vasodilation were assessed during intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) respectively. All participants then received a further dose of their original treatment allocation, as well as atorvastatin 20mg once daily, and measurements were undertaken after a further 2 weeks. Pulse wave velocity (PWV), Augmentation Index (AIx) and carotid Intima-media thickness (CIMT), as well as LDL-C levels, were measured at each timepoint. Results Alirocumab reduced LDL-C compared to placebo by 48% (ΔLDL-C -1.00mmol/L, 95% CI 0.89-1.11, P Conclusion Alirocumab significantly reduced LDL-C compared to placebo without any change to endothelial function, as measured by forearm plethysmography, or to markers of arterial stiffness, as measured by PWV and AIx, in normocholesterolaemic healthy subjects. However, an improvement in endothelial function was seen when combination therapy was compared to statin therapy alone. Conflict of Interest None

Introduction Vasopressin stimulates cyst growth in autosomal dominant polycystic kidney disease (ADPKD) leading to enlarged kidneys, hypertension and renal failure. Vasopressin receptor blockade slows disease progression. Physiological suppression of vasopressin secretion through high water (HW) intake could achieve a similar effect, necessitating a definitive large-scale trial of HW intake in ADPKD. The objective of the DRINK trial is to answer the key design and feasibility questions required to deliver a successful definitive water intake trial. Methods and analysis We describe the design of a single-centre, open-label, prospective, randomised controlled trial. The "Determining feasibility of R andomisation to high vs. ad libitum water In take in Polycystic K idney Disease" (DRINK) trial aims to enrol 50 patients with ADPKD, over the age of 16 years with an estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2. Participants will be randomised 1:1 to HW intake based on an individualised water intake prescription, or to ad libitum (AW) water intake. The HW group will aim for a dilute urine (urine osmolality ≤270 mOsm/kg) as a surrogate marker of vasopressin suppression, and those in the AW group will target more concentrated urine. Participants will have an 8-week treatment period, and will be seen at weeks 0, 2, 4 and 8, undergoing assessments of fluid status, renal function and serum and urine osmolalities. They will receive dietary advice, and self-monitor urine specific gravity and fluid intake. The trial employs smartphone technology to permit home monitoring and remote direct data capture. The primary feasibility end points are recruitment rate and separation between arms in measured urinary osmolality. Key secondary assessments include acceptability, adherence, health-related quality of life, acute effects of HW intake on measured (51Cr-EDTA) and eGFR and ADPKD-related pain. Ethics and dissemination Ethical approval was awarded by the East of England Essex Research Ethics Committee (16/EE/0026). The results of DRINK will be submitted to peer-reviewed journals, and presented to patients via the PKD Charity. Trial registration number NCT02933268 and ISCRTN16794957

Background: Vasopressin promotes cyst growth in Autosomal Dominant Polycystic Kidney Disease (ADPKD). Vasopressin receptor antagonists slow disease progression, but their use is limited by side effects and cost. High water intake suppresses vasopressin production and may provide a viable alternative to pharmacological receptor blockade. We aimed to assess the feasibility of a definitive randomised high water intake trial in ADPKD. Methods: We conducted a phase 2, single-centre open-label randomised controlled trial (NCT02933268). Adults aged 16 years and older with ADPKD and an eGFR20ml/min/1.73m2 were randomly assigned to prescribed high water intake (HW) targeting a urine osmolality of 270mOsm/kg, or ad libitum (AW) intake. The co-primary outcomes were the proportion of participants achieving target urine osmolality and the rate of recruitment. Secondary outcomes included separation between treatment arms, changes in GFR, copeptin, and safety. Findings: 42 participants with a median baseline eGFR 75.8 (IQR 46.5-107.5) ml/min/1.73m2 and urine osmolality 352 (IQR 202-452) mOsm/Kg were enrolled over 12 months and randomised to HW (n=21) or AW (n=21). After 8 weeks, 67% in the HW compared to 24% in the AW group had a urine osmolality of 270mOsm/kg, p=0.001. The median week-8 urine osmolality was significantly higher in the AW compared to HW group (379 IQR 235-503 v 194 IQR 190-438 mOsm/kg, p=0.01). There was no difference in median week 8 plasma copeptin (AW=4.1, IQR 2.9-11.2 vs HW=3.6, IQR 2.7-5.7, p=0.25) and no evidence of acute effects of increased hydration on measured or estimated GFR. Interpretation: It is possible to recruit to and achieve separation between trial arms in urine osmolality in a randomised trial. A definitive trial assessing the effect of high water intake on kidney function in ADPKD is feasible. Clinical Trial Number: NCT02933268 Funding Statement: The study is funded by the British Renal Society and Kidney Care UK (formerly British Kidney Patient Association) grant programme, the PKD Charity, the Addenbrooke’s Charitable Trust and Kidney Research UK. Declaration of Interests: None declared Ethics Approval Statement: DRINK was approved by the East of England Essex Research Committee (16/EE/0026) and the study was overseen by the trial steering committee.