Twenty-year trajectories of cardio-metabolic factors among people with type 2 diabetes by dementia status in England: a retrospective cohort study.

To assess 20-year retrospective trajectories of cardio-metabolic factors preceding dementia diagnosis among people with type 2 diabetes (T2D). We identified 227,145 people with T2D aged > 42 years between 1999 and 2018. Annual mean levels of eight routinely measured cardio-metabolic factors were extracted from the Clinical Practice Research Datalink. Multivariable multilevel piecewise and non-piecewise growth curve models assessed retrospective trajectories of cardio-metabolic factors by dementia status from up to 19 years preceding dementia diagnosis (dementia) or last contact with healthcare (no dementia). 23,546 patients developed dementia; mean (SD) follow-up was 10.0 (5.8) years. In the dementia group, mean systolic blood pressure increased 16-19 years before dementia diagnosis compared with patients without dementia, but declined more steeply from 16 years before diagnosis, while diastolic blood pressure generally declined at similar rates. Mean body mass index followed a steeper non-linear decline from 11 years before diagnosis in the dementia group. Mean blood lipid levels (total cholesterol, LDL, HDL) and glycaemic measures (fasting plasma glucose and HbA1c) were generally higher in the dementia group compared with those without dementia and followed similar patterns of change. However, absolute group differences were small. Differences in levels of cardio-metabolic factors were observed up to two decades prior to dementia diagnosis. Our findings suggest that a long follow-up is crucial to minimise reverse causation arising from changes in cardio-metabolic factors during preclinical dementia. Future investigations which address associations between cardiometabolic factors and dementia should account for potential non-linear relationships and consider the timeframe when measurements are taken.

Prevalence of Familial Hypercholesterolemia Among the General Population and Patients With Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Contemporary studies suggest that familial hypercholesterolemia (FH) is more frequent than previously reported and increasingly recognized as affecting individuals of all ethnicities and across many regions of the world. Precise estimation of its global prevalence and prevalence across World Health Organization regions is needed to inform policies aiming at early detection and atherosclerotic cardiovascular disease (ASCVD) prevention. The present study aims to provide a comprehensive assessment and more reliable estimation of the prevalence of FH than hitherto possible in the general population (GP) and among patients with ASCVD. METHODS: We performed a systematic review and meta-analysis including studies reporting on the prevalence of heterozygous FH in the GP or among those with ASCVD. Studies reporting gene founder effects and focused on homozygous FH were excluded. The search was conducted through Medline, Embase, Cochrane, and Global Health, without time or language restrictions. A random-effects model was applied to estimate the overall pooled prevalence of FH in the general and ASCVD populations separately and by World Health Organization regions. RESULTS: From 3225 articles, 42 studies from the GP and 20 from populations with ASCVD were eligible, reporting on 7 297 363 individuals/24 636 cases of FH and 48 158 patients/2827 cases of FH, respectively. More than 60% of the studies were from Europe. Use of the Dutch Lipid Clinic Network criteria was the commonest diagnostic method. Within the GP, the overall pooled prevalence of FH was 1:311 (95% CI, 1:250-1:397; similar between children [1:364] and adults [1:303], P=0.60; across World Health Organization regions where data were available, P=0.29; and between population-based and electronic health records-based studies, P=0.82). Studies with ≤10 000 participants reported a higher prevalence (1:200-289) compared with larger cohorts (1:365-407; P<0.001). The pooled prevalence among those with ASCVD was 18-fold higher than in the GP (1:17 [95% CI, 1:12-1:24]), driven mainly by coronary artery disease (1:16; [95% CI, 1:12-1:23]). Between-study heterogeneity was large (I2>95%). Tests assessing bias were nonsignificant (P>0.3). CONCLUSIONS: With an overall prevalence of 1:311, FH is among the commonest genetic disorders in the GP, similarly present across different regions of the world, and is more frequent among those with ASCVD. The present results support the advocacy for the institution of public health policies, including screening programs, to identify FH early and to prevent its global burden.

Stereotactic body radiotherapy for bone oligometastatic disease in prostate cancer.

PURPOSE: There are sparse data describing outcomes of bone-only oligometastatic prostate cancer in comparison with lymph node disease treated with stereotactic body radiotherapy (SBRT). The primary aim of this study was to report progression-free survival (PFS) data for patients with bone-only disease. Influence of hormone sensitivity and androgen deprivation therapy use was also assessed. METHODS: This is a single-centre retrospective cohort study. Hormone-sensitive and castrate-resistant patients with oligometastatic (≤ 3) bone-only prostate cancer treated with SBRT were included. Data were collected using electronic records. Kaplan-Meier survivor function, log rank test, as well as Cox regression were used to calculate PFS and overall survival. RESULTS: In total, 51 patients with 64 bone metastases treated with SBRT were included. Nine patients were castrate resistant and 42 patient's hormone sensitive at the time of SBRT. Median follow-up was 23 months. Median PFS was 24 months in hormone-sensitive patients and 3 months in castrate-resistant patients. No patients experienced grade 3 or 4 toxicities. There were three in-field recurrences. CONCLUSIONS: In this study, patients with bone oligometastatic disease showed potential benefit from SBRT with a median PFS of 11 months. Hormone-sensitive patients showed the greatest benefit, with results similar to that published for oligometastatic pelvic nodal disease treated with SBRT. Prospective randomised control trials are needed to determine the survival benefit of SBRT in oligometastatic bone-only prostate cancer and to determine prognostic indicators.

Improving the Detection of Potential Cases of Familial Hypercholesterolemia: Could Machine Learning Be Part of the Solution?

BACKGROUND: Familial hypercholesterolemia (FH), while highly prevalent, is a significantly underdiagnosed monogenic disorder. Improved detection could reduce the large number of cardiovascular events attributable to poor case finding. We aimed to assess whether machine learning algorithms outperform clinical diagnostic criteria (signs, history, and biomarkers) and the recommended screening criteria in the United Kingdom in identifying individuals with FH-causing variants, presenting a scalable screening criteria for general populations. METHODS AND RESULTS: Analysis included UK Biobank participants with whole exome sequencing, classifying them as having FH when (likely) pathogenic variants were detected in their LDLR, APOB, or PCSK9 genes. Data were stratified into 3 data sets for (1) feature importance analysis; (2) deriving state-of-the-art statistical and machine learning models; (3) evaluating models' predictive performance against clinical diagnostic and screening criteria: Dutch Lipid Clinic Network, Simon Broome, Make Early Diagnosis to Prevent Early Death, and Familial Case Ascertainment Tool. One thousand and three of 454 710 participants were classified as having FH. A Stacking Ensemble model yielded the best predictive performance (sensitivity, 74.93%; precision, 0.61%; accuracy, 72.80%, area under the receiver operating characteristic curve, 79.12%) and outperformed clinical diagnostic criteria and the recommended screening criteria in identifying FH variant carriers within the validation data set (figures for Familial Case Ascertainment Tool, the best baseline model, were 69.55%, 0.44%, 65.43%, and 71.12%, respectively). Our model decreased the number needed to screen compared with the Familial Case Ascertainment Tool (164 versus 227). CONCLUSIONS: Our machine learning-derived model provides a higher pretest probability of identifying individuals with a molecular diagnosis of FH compared with current approaches. This provides a promising, cost-effective scalable tool for implementation into electronic health records to prioritize potential FH cases for genetic confirmation.

Association of the retail food environment, BMI, dietary patterns, and socioeconomic position in urban areas of Mexico.

The retail food environment is a key modifiable driver of food choice and the risk of non-communicable diseases (NCDs). This study aimed to assess the relationship between the density of food retailers, body mass index (BMI), dietary patterns, and socioeconomic position in Mexico. Cross-sectional dietary data, BMI and socioeconomic characteristics of adult participants came from the nationally representative 2012 National Health and Nutrition Survey in Mexico. Geographical and food outlet data were obtained from official statistics. Densities of food outlets per census tract area (CTA) were calculated. Dietary patterns were determined using exploratory factor analysis and principal component analysis. The association of food environment variables, socioeconomic position, BMI, and dietary patterns was assessed using two-level multilevel linear regression models. Three dietary patterns were identified-the healthy, the unhealthy and the carbohydrates-and-drinks dietary pattern. Lower availability of fruit and vegetable stores was associated with an unhealthier dietary pattern whilst a higher restaurant density was associated with a carbohydrates-and-drinks pattern. A graded and inverse association was observed for fruit and vegetable store density and socioeconomic position (SEP)-lower-income populations had a reduced availability of fruit and vegetable stores, compared with higher-income populations. A higher density of convenience stores was associated with a higher BMI when adjusting for unhealthy dietary patterns. Upper-income households were more likely to consume healthy dietary patterns and middle-upper-income households were less likely to consume unhealthy dietary patterns when exposed to high densities of fruit and vegetable stores. When exposed to a high concentration of convenience stores, lower and upper-lower-income households were more likely to consume unhealthy dietary patterns. Food environment and sociodemographic conditions within neighbourhoods may affect dietary behaviours. Food environment interventions and policies which improve access to healthy foods and restrict access to unhealthy foods may facilitate healthier diets and contribute to the prevention of NCDs.

Ensemble machine learning methods in screening electronic health records: A scoping review.

Background: Electronic health records provide the opportunity to identify undiagnosed individuals likely to have a given disease using machine learning techniques, and who could then benefit from more medical screening and case finding, reducing the number needed to screen with convenience and healthcare cost savings. Ensemble machine learning models combining multiple prediction estimates into one are often said to provide better predictive performances than non-ensemble models. Yet, to our knowledge, no literature review summarises the use and performances of different types of ensemble machine learning models in the context of medical pre-screening. Method: We aimed to conduct a scoping review of the literature reporting the derivation of ensemble machine learning models for screening of electronic health records. We searched EMBASE and MEDLINE databases across all years applying a formal search strategy using terms related to medical screening, electronic health records and machine learning. Data were collected, analysed, and reported in accordance with the PRISMA scoping review guideline. Results: A total of 3355 articles were retrieved, of which 145 articles met our inclusion criteria and were included in this study. Ensemble machine learning models were increasingly employed across several medical specialties and often outperformed non-ensemble approaches. Ensemble machine learning models with complex combination strategies and heterogeneous classifiers often outperformed other types of ensemble machine learning models but were also less used. Ensemble machine learning models methodologies, processing steps and data sources were often not clearly described. Conclusions: Our work highlights the importance of deriving and comparing the performances of different types of ensemble machine learning models when screening electronic health records and underscores the need for more comprehensive reporting of machine learning methodologies employed in clinical research.

Systematic review of comorbidity indices for administrative data.

BACKGROUND: Adjustment for comorbidities is common in performance benchmarking and risk prediction. Despite the exponential upsurge in the number of articles citing or comparing Charlson, Elixhauser, and their variants, no systematic review has been conducted on studies comparing comorbidity measures in use with administrative data. We present a systematic review of these multiple comparison studies and introduce a new meta-analytical approach to identify the best performing comorbidity measures/indices for short-term (inpatient + ≤ 30 d) and long-term (outpatient+>30 d) mortality. METHODS: Articles up to March 18, 2011 were searched based on our predefined terms. The bibliography of the chosen articles and the relevant reviews were also searched and reviewed. Multiple comparisons between comorbidity measures/indices were split into all possible pairs. We used the hypergeometric test and confidence intervals for proportions to identify the comparators with significantly superior/inferior performance for short-term and long-term mortality. In addition, useful information such as the influence of lookback periods was extracted and reported. RESULTS: Out of 1312 retrieved articles, 54 articles were eligible. The Deyo variant of Charlson was the most commonly referred comparator followed by the Elixhauser measure. Compared with baseline variables such as age and sex, comorbidity adjustment methods seem to better predict long-term than short-term mortality and Elixhauser seems to be the best predictor for this outcome. For short-term mortality, however, recalibration giving empirical weights seems more important than the choice of comorbidity measure. CONCLUSIONS: The performance of a given comorbidity measure depends on the patient group and outcome. In general, the Elixhauser index seems the best so far, particularly for mortality beyond 30 days, although several newer, more inclusive measures are promising.

Left main coronary artery compression by dilated pulmonary artery in pulmonary arterial hypertension: a systematic review and meta-analysis.

OBJECTIVE: Pulmonary arterial hypertension (PAH) can lead to left main coronary artery compression (LMCo), but data on the impact, screening and treatment are limited. A meta-analysis of LMCo cases could fill the knowledge gaps in this topic. METHODS: Electronic databases were searched for all LMCo/PAH studies, abstracts and case reports including pulmonary artery (PA) size. Restricted maximum likelihood meta-analysis was used to evaluate LMCo-associated factors. Specificity, sensitivity and accuracy of PA size thresholds for diagnosis of LMCo were calculated. Treatment options and outcomes were summarized. RESULTS: A total of five case-control cohorts and 64 case reports/series (196 LMCo and 438 controls) were included. LMCo cases had higher PA diameter (Hedge's g 1.46 [1.09; 1.82]), PA/aorta ratio (Hedge's g 1.1 [0.64; 1.55]) and probability of CHD (log odds-ratio 1.22 [0.54; 1.9]) compared to non-LMCo, but not PA pressure or vascular resistance. A 40 mm cut-off for the PA diameter had balanced sensitivity (80.5%), specificity (79%) and accuracy (79.7%) for LMCo diagnosis, while a value of 44 mm had higher accuracy (81.7%), higher specificity (91.5%) but lower sensitivity (71.9%). Pooled mortality after non-conservative treatment (n = 150, predominantly stenting) was 2.7% at up to 22 months of mean follow-up, with 83% survivors having no angina at follow-up. CONCLUSION: PA diameter, PA/aorta ratio and CHD are associated with LMCo, while hemodynamic parameters are not. Data from this study support that a PA diameter cut-off between 40 and 44 mm can offer optimal accuracy for LMCo screening. Preferred treatment was coronary stenting, associated with low mid-term mortality and symptom relief. Diagnosis and management of left main coronary artery compression (LMCo) in patients with pulmonary arterial hypertension (PAH).

What is the suitability of clinical vignettes in benchmarking the performance of online symptom checkers? An audit study.

OBJECTIVE: Assess the suitability of clinical vignettes in benchmarking the performance of online symptom checkers (OSCs). DESIGN: Observational study using a publicly available free OSC. PARTICIPANTS: Healthily OSC, which provided consultations in English, was used to record consultation outcomes from two lay and four expert inputters using 139 standardised patient vignettes. Each vignette included three diagnostic solutions and a triage recommendation in one of three categories of triage urgency. A panel of three independent general practitioners interpreted the vignettes to arrive at an alternative set of diagnostic and triage solutions. Both sets of diagnostic and triage solutions were consolidated to arrive at a final consolidated version for benchmarking. MAIN OUTCOME MEASURES: Six inputters simulated 834 standardised patient evaluations using Healthily OSC and recorded outputs (triage solution, signposting, and whether the correct diagnostic solution appeared first or within the first three differentials). We estimated Cohen's kappa to assess how interpretations by different inputters could lead to divergent OSC output even when using the same vignette or when compared with a separate panel of physicians. RESULTS: There was moderate agreement on triage recommendation (kappa=0.48), and substantial agreement on consultation outcomes between all inputters (kappa=0.73). OSC performance improved significantly from baseline when compared against the final consolidated diagnostic and triage solution (p<0.001). CONCLUSIONS: Clinical vignettes are inherently limited in their utility to benchmark the diagnostic accuracy or triage safety of OSC. Real-world evidence studies involving real patients are recommended to benchmark the performance of OSC against a panel of physicians.

A pilot study to investigate real-time digital alerting from wearable sensors in surgical patients.

BACKGROUND: Continuous vital sign monitoring may identify changes sooner than current standard monitoring. OBJECTIVE: To investigate if the use of real-time digital alerts sent to healthcare staff can improve the time taken to identify unwell patients and those with sepsis. DESIGN: A prospective cohort study design. SETTING: West Middlesex University Hospital, UK. PARTICIPANTS: Fifty acutely unwell surgical patients admitted to hospital. INTERVENTION: Patients wore a lightweight wearable sensor measuring heart rate (HR), respiratory rate (RR) and temperature every 2 min whilst standard intermittent ward monitoring of vital signs was performed by nurses. Digital alerts were sent to healthcare staff from the sensor to a smartphone device. All alerts were reviewed for recruited patients to identify the exact time on the sensor in which deterioration occurred. The time to acknowledgement was then reviewed for each action and an average time to acknowledgement calculated. RESULTS: There were 50 patients recruited in the pilot study, of which there were vital sign alerts in 18 patients (36%). The total number of vital sign alerts generated in these 18 patients was 51. Of these 51 alerts, there were 7 alerts for high HR (13.7%), 33 for RR (64.7%) and 11 for temperature (21.6%). Out of the 27 acknowledged alerts, there were 2 alerts for HR, 17 for RR and 8 for temperature. The average time to staff acknowledgement of the notification for all alerts was 154 min (2.6 h). There were some patients which had shown signs of deterioration in the cohort. The frequency of routine observation monitoring was increased in 2 cases, 3 patients were referred to a senior clinician and 2 patients were initiated on the sepsis pathway. CONCLUSION: This study demonstrates the evaluation of digital alerts to nurses in real time. Although not all alerts were acknowledged, deterioration on the ward observations was detected and actions were taken accordingly. Patients were started on the sepsis pathway and escalation to senior clinicians occurred. Further research is required to review why only some alerts were acknowledged and the effects of digital alerting on patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04638738.

Systems parasitology: effects of Fasciola hepatica on the neurochemical profile in the rat brain.

We characterize the integrated response of a rat host to the liver fluke Fasciola hepatica using a combination of (1)H nuclear magnetic resonance spectroscopic profiles (liver, kidney, intestine, brain, spleen, plasma, urine, feces) and multiplex cytokine markers of systemic inflammation. Multivariate mathematical models were built to describe the main features of the infection at the systems level. In addition to the expected modulation of hepatic choline and energy metabolism, we found significant perturbations of the nucleotide balance in the brain, together with increased plasma IL-13, suggesting a shift toward modulation of immune reactions to minimize inflammatory damage, which may favor the co-existence of the parasite in the host. Subsequent analysis of brain extracts from other trematode infection models (i.e. Schistosoma mansoni, and Echinostoma caproni) did not elicit a change in neural nucleotide levels, indicating that the neural effects of F. hepatica infection are specific. We propose that the topographically extended response to invasion of the host as characterized by the modulated global metabolic phenotype is stratified across several bio-organizational levels and reflects the direct manipulation of host-nucleotide balance.

Immunologic profile of excessive body weight.

The purpose of this paper is to identify immunologic hallmarks of excessive bodyweight. The analysis is based on 176 adults (106 women, 70 men) who participated in a nested case-control study in Italy. All participants were healthy at the time of blood collection and aged between 36 and 75 years. We employed multivariate analysis of variance and a nonparametric Bayesian additive regression tree approach along with a receiver operating characteristic (ROC) curve analysis to determine the immunologic signature of excessive body weight (i.e., obesity and overweight). Interleukin 8 (IL-8), IL-10, interferon γ, and inducible protein 10 were shown to be predictive of excessive body weight with an area under the ROC curve of 71% (p < 0.0002). We propose that by using this profile-based approach to define immunologic signatures, it might be possible to identify unique immunologic hallmarks of specific types of obesity.

The intake of grain fibers modulates cytokine levels in blood.

Dietary fiber may modulate the environment of the intestinal lumen, alter the intestinal microflora populations, and influence the immune response and disease risk. Epidemiological investigations have suggested that higher fiber intake is associated with lower overall mortality, in particular from cardiovascular and digestive tract diseases. Here a panel of 17 cytokines and chemokines were measured in plasma of 88 cancer-free subjects sampled within the Italian EPIC-Italy cohort. A statistically significant inverse association (p-trend = 0.01) was observed for cereal fiber and cytokines included in the main factor in factor analysis (IL-1ß, IL-4, IL-5, IL-6, IL-13, and TNF-α), which alone explained 35.5% of variance. Our study suggests that fiber intake, especially cereal fiber, may be associated with a decreased level of pro-inflammatory cytokines.

Risk of COVID-19 in shielded and nursing care home patients: a cohort study in general practice.

BACKGROUND: COVID-19 cases were first detected in the UK in January 2020 and vulnerable patients were asked to shield from March to reduce their risk of COVID-19 infection. AIM: To determine the risk and determinants of COVID-19 diagnosis in shielded versus non-shielded groups, adjusted for key comorbidities not explained by shielding. DESIGN & SETTING: Retrospective cohort study of adults with COVID-19 infection between 1 February 2020 and 15 May 2020 in west London. METHOD: Individuals diagnosed with COVID-19 were identified in SystmOne records using clinical codes. Infection risks were adjusted for sociodemographic factors, nursing home status, and comorbidities. RESULTS: Of 57 713 adults, 573 (1%) individuals were identified as shielded and 1074 adults had documented COVID-19 infections (1.9%). COVID-19 infection rate in the shielded group individuals compared with non-shielded adult individuals was 6.5% (n = 37/573) versus 1.8% (n = 1037/57 140), P<0.001. A multivariable fully adjusted Cox proportional hazards (CPH) regression identified that COVID-19 infection was increased with shielding status (adjusted hazard ratio [aHR] 1.52; 95% confidence interval [CI] = 1.00 to 2.30; P = 0.048). Other determinants of COVID-19 infection included nursing home residency (aHR 7.05; 95% CI = 4.22 to 11.77; P<0.001); Black African (aHR 2.52; 95% CI = 1.99 to 3.18; P<0.001), Other (aHR 1.74; 95% CI = 1.42 to 2.13; P<0.001), Non-stated (aHR 1.70; 95% CI = 1.02 to 2.84; P = 0.04), or South Asian ethnic group (aHR 1.46; 95% CI = 1.10 to 1.93; P = 0.01); history of respiratory disease (aHR 1.51; 95% CI = 1.06 to 2.16; P = 0.02); deprivation (third versus least deprived Index of Multiple Deprivation [IMD] quintile) (aHR 1.25 ; 95% CI = 1.01 to 1.56; P = 0.05); obesity (body mass index [BMI] >30 kg/m2) (aHR 1.39; 95% CI = 1.18 to 1.63; P<0.001); and age (aHR 1.02; 95% CI = 1.01 to 1.02; P<0.001. Male sex was associated with lower risk of COVID-19 infection (aHR 0.71; 95% CI = 0.62 to 0.82; P<0.001). CONCLUSION: Shielded individuals had a higher COVID-19 infection rate compared with non-shielded individuals, after adjusting for sociodemographic factors, nursing home status, and comorbidities.

Factors associated with unplanned reinterventions and their relation to early mortality after pediatric cardiac surgery.

OBJECTIVE: Unplanned reintervention (uRE) is used as an indicator of patient morbidity and quality of care in pediatric cardiac surgery. We investigated associated factors and early mortality after uREs. METHODS: Morbidity data were prospectively collected in 5 UK centers between 2015 and 2017; uRE included surgical cardiac, interventional transcatheter cardiac, permanent pacemaker, and diaphragm plication procedures. Mortality (30-day and 6-month) in uRE/no-uRE patients was reported before and after matching. Predicted 30-day mortality was calculated using the Partial Risk Adjustment in Surgery score. RESULTS: A total of 3090 procedures (2861 patients) were included (median age, 228 days). There were 146 uREs, resulting in an uRE rate of 4.7%. Partial Risk Adjustment in Surgery score, 30-day mortality and 6-month mortality in uRE and no-uRE groups were 2.4% versus 1.3%, 8.9% versus 1%, and 17.1% versus 2.4%, respectively. After matching, mortality at 6 months remained higher in uRE compared with no-uRE (12.2% vs 1.4%; P = .02; 74 pairs). In the uRE group, 21 out of 25 deaths at 6 months occurred when at least 1 additional postoperative complication was present. In multivariable analysis, neonatal age (P = .002), low weight (P = .009), univentricular heart (P < .001), and arterial shunt (P < .001) were associated with increased risk of uRE, but Partial Risk Adjustment in Surgery score was not (only in univariable analysis). CONCLUSIONS: uREs are a relatively frequent complication after pediatric cardiac surgery and are associated with some patient characteristics, but not the Partial Risk Adjustment in Surgery risk score. Early mortality was higher after uRE, independent of preoperative factors, but linked to other postoperative complications.

A meta-analysis of medications directed against PCSK9 in familial hypercholesterolemia.

BACKGROUND AND AIMS: Several medications targeting PCSK9 reduce LDL-cholesterol (LDL-C) in heterozygous familial hypercholesterolemia (HeFH). We aimed to assess in patients diagnosed clinically as HeFH, whether LDL-C reduction varied by different therapeutic approaches to PCSK9-targeting or by the underlying genetic variant. METHODS: We conducted a random-effects meta-analysis of randomised clinical trials assessing PCSK9-targeting therapies, namely alirocumab, evolocumab and inclisiran, in patients with clinically diagnosed HeFH and restricted analyses to those patients in whom genotypic data were available. A search of MEDLINE and Embase identified eligible trials published between inception and June 29, 2020. We included trials of sufficient duration to allow for a stable treatment effect: ~12 weeks for monoclonal antibodies (mAbs) (alirocumab, evolocumab) and ~1 year for small interfering RNA (siRNA) (inclisiran). Single-moderator meta-regression comparing mean percentage LDL-C reduction between mAbs and siRNA as well as PCSK9-targeting therapies between different genotypes was used to assess heterogeneity. RESULTS: Eight trials of HeFH met our inclusion criteria, including 1887 genotyped patients. Among monogenic HeFH cases (N = 1347) the LDL-C reduction from baseline was 46.12% (95%CI 48.4-43.9) for siRNA and 50.4% (59.3-41.4) for mAbs compared to control, without evidence of significant heterogeneity between treatment (QM = 0.32, df = 1, p = 0.57). Irrespective of therapeutic approach to PCSK9-targeting, reductions in LDL-C were generally consistent across genetic variants (LDL-Receptor variants, LDL-Receptor variants of unknown significance, Apolipoprotein B variants, two variants and no variant) (QM = 8.3, df = 4, p = 0.08). CONCLUSIONS: Among patients with HeFH, the LDL-C-lowering effect of PCSK9-targeting medications did not show statistical heterogeneity across different drug-classes and across genetic variants.

Association Between Preoperative Magnetic Resonance Imaging-based Urethral Parameters and Continence Recovery Following Robot-assisted Radical Prostatectomy.

BACKGROUND: Studies demonstrated the significance of membranous urethral length (MUL) as a predictor of continence following robot-assisted radical prostatectomy (RARP). There are other magnetic resonance imaging (MRI) parameters that might be linked to continence outcome. OBJECTIVE: To evaluate the association between preoperative urethral parameters on MRI and continence outcome, to estimate the risk of incontinence using different cut-off values, and to assess interobserver variability in measuring urethral parameters. DESIGN, SETTING, AND PARTICIPANTS: Patients with localised prostate cancer who underwent RARP were retrospectively reviewed. Baseline patient characteristics, perioperative, and pathological outcomes were assessed. Continence was defined as no pad or a safety pad with <2g/24h pad weight. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Several MRI variables were measured by a uroradiologist, a uro-oncology fellow, and a urologist. Binary logistic regression analyses were performed to identify predictors of incontinence. Interclass correlation was used to evaluate interobserver variability. RESULTS AND LIMITATIONS: A total of 190 patients met the study inclusion criteria. The mean MUL was 14.6mm. Age and MUL were significantly associated with incontinence outcome. The area under the receiver operating characteristic curve for continence based on MUL was 0.78 at 12 mo. The risk of incontinence in patients with MUL of <10mm was 27.8% (13.8% and 39.1% for patients aged <65 and >65 yr respectively). Conversely, the risk of incontinence with MUL >15mm was 2.7% (1.5% and 4.5% for patients aged <65 and >65 yr, respectively). The concordance rate between different observers was 89% for coronal MUL, but 77%, 74%, and 62% for sagittal MUL, membranous urethral thickness, and intraprostatic urethral length, respectively. CONCLUSIONS: This study confirmed the significance of MUL for the continence outcome following RARP. There was also excellent consistency in measuring MUL values between different observers. PATIENT SUMMARY: Although further studies would be required to verify our findings, we support the significance of membranous urethral length in predicting the risk of incontinence and the need to incorporate it as part of preoperative assessment and counselling. This can reliably be measured by urologists and can further facilitate a patient-tailored approach to radical treatment of prostate cancer.

Age over 35 years is associated with increased mortality after pulmonary valve replacement in repaired tetralogy of Fallot: results from the UK National Congenital Heart Disease Audit database.

OBJECTIVES: Many adults with repaired tetralogy of Fallot will require a pulmonary valve replacement (PVR), but there is no consensus on the best timing. In this study, we aim to evaluate the impact of age at PVR on outcomes. METHODS: This is a national multicentre retrospective study including all patients >15 years of age with repaired tetralogy of Fallot who underwent their first PVR between 2000 and 2013. The optimal age cut-off was identified using Cox regression and classification and regression tree analysis. RESULTS: A total of 707 patients were included, median age 26 (15-72) years. The mortality rate at 10 years after PVR was 4.2%, and the second PVR rate of 6.8%. Age at PVR of 35 years was identified as the optimal cut-off in relation to late mortality. Patients above 35 years of age had a 5.6 fold risk of death at 10 years compared with those with PVR under 35 years (10.4% vs 1.3%, P < 0.001), more concomitant tricuspid valve repair/replacement (15.1% vs 5.7%, P < 0.001) and surgical arrhythmia treatment (18.4% vs 5.9%, P < 0.001). In those under 50 years, there was an 8.7 fold risk of late death compared with the general population, higher for those with PVR after 35 than those with PVR below 35 years (hazard ratio 9.9 vs 7.4). CONCLUSIONS: Patients above 35 years of age with repaired tetralogy of Fallot have significantly worse mortality after PVR, compared with younger patients and a higher burden of mortality relative to the general population. This suggests that there are still cases where the timing of initial PVR is not optimal, warranting a re-evaluation of criteria for intervention.

Hypoxia and angiogenic biomarkers in prostate cancer after external beam radiotherapy (EBRT) alone or combined with high-dose-rate brachytherapy boost (HDR-BTb).

PURPOSE: To investigate angiogenic and hypoxia biomarkers to predict outcome in patients receiving external beam radiotherapy (EBRT) alone or combined with high-dose-rate brachytherapy boost (HDR-BTb) for localised prostate cancer. METHODS: Prostate biopsy samples were collected prospectively in patients entered into a phase 3 randomised controlled trial of patients receiving EBRT or EBRT + HDR-BTb. Univariate and multivariate analyses using Cox proportional hazards model were performed to identify associations between immunohistochemical staining of hypoxia inducible factor 1 alpha (HIF1α), glucose transporter 1 (GLUT1), osteopontin (OPN) and microvessel density (MVD) using CD-34 antibody with clinical outcome. The primary endpoint was biochemical relapse free survival (BRFS) and secondary endpoint was distant metastasis free survival (DMFS). RESULTS: Immunohistochemistry was available for 204 patients. Increased OPN (Hazard ratio [HR] 2.38, 95% Confidence Interval [CI] 1.06-5.34, p < 0.036) and GLUT1 (HR 2.36, 95%CI 1.39-4.01, p < 0.001) expression were predictive of worse BRFS. Increased GLUT1 expression (HR 2.22, 1.02-4.84, p = 0.045) was predictive of worse DMFS. Increased MVD (CD-34) (HR 1.82, 95%CI 1.06-3.14, p = 0.03) and OPN (HR 1.82, 95%CI 1.06-3.14, p = 0.03) but reduced GLUT1 expression (HR 0.40, 95%CI 0.20-0.79, p = 0.009) were predictive of improved BRFS in patients receiving EBRT + HDR-BTb. CONCLUSION: Our data suggest angiogenic and hypoxia biomarkers may predict outcome and benefit of dose escalation, however further validation in prospective studies including hypoxia modification is needed. Trial registration number ISRCTN98241100, registered with ISRCTN at http://www.controlled-trials.com/isrctn/.

Clinical and cost-effectiveness of the Ross procedure versus conventional aortic valve replacement in young adults.

Objectives: In young and middle-aged adults, there are three current options for aortic valve replacement (AVR), namely mechanical AVR (mechAVR), tissue AVR (biological AVR) and the Ross operation, with no clear guidance on the best option. We aim to compare the clinical effectiveness and cost-effectiveness of the Ross procedure with conventional AVR in young and middle-aged adults. Methods: This is a systematic literature review and meta-analysis of AVR options. Markov multistate model was adopted to compare cost-effectiveness. Lifetime costs, quality-adjusted life years (QALYs), net monetary benefit (NMB), population expected value of perfect information (EVPI) and expected value of partial perfect information were estimated. Results: We identified 48 cohorts with a total number of 12 975 patients (mean age 44.5 years, mean follow-up 7.1 years). Mortality, bleeding and thromboembolic events over the follow-up period were lowest after the Ross operation, compared with mechAVR and biological AVR (p<0.001). Aortic reoperation rates were lower after Ross compared with biological AVR, but slightly higher when compared with mechAVR (p<0.001). At a willingness-to-pay threshold of £20effective. At a willingness-to-pay threshold of £20, 000 per QALY000 per QALY, the Ross procedure is more cost-effective compared the Ross procedure is more cost-effective compared withwith conventional AVR, with a lifetime incremental NMB of £60 conventional AVR, with a lifetime incremental NMB of £60 952 (952 (££3030 236236 to to ££7979 464). Incremental costs were £12464). Incremental costs were £12 323 (323 (££61086108 to to ££1515 972) and incremental QALYs 3.66 (1.81972) and incremental QALYs 3.66 (1.81 to to 4.76). The population EVPI indicates that a trial costing up to £2.03 million could be cost 4.76). The population EVPI indicates that a trial costing up to £2.03 million could be cost--effective.At a willingness-to-pay threshold of £20 000 per QALY, the Ross procedure is more cost-effective compared with conventional AVR, with a lifetime incremental NMB of £60 952 (£30 236 to £79 464). Incremental costs were £12 323 (£6108 to £15 972) and incremental QALYs 3.66 (1.81 to 4.76). The population EVPI indicates that a trial costing up to £2.03 million could be cost-effective. Conclusions: In young and middle-aged adults with aortic valve disease, the Ross procedure may confer greater quality of life and be more cost-effective than conventional AVR. A high-quality randomised trial could be warranted and cost-effective.