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.

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.

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).

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.

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.

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.

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.

Primary repair versus surgical and transcatheter palliation in infants with tetralogy of Fallot.

OBJECTIVES: Treatment of infants with tetralogy of Fallot (ToF) has evolved in the last two decades with increasing use of primary surgical repair (PrR) and transcatheter right ventricular outflow tract palliation (RVOTd), and fewer systemic-to-pulmonary shunts (SPS). We aim to report contemporary results using these treatment options in a comparative study. METHODS: This a retrospective study using data from the UK National Congenital Heart Disease Audit. All infants (n=1662, median age 181 days) with ToF and no other complex defects undergoing repair or palliation between 2000 and 2013 were considered. Matching algorithms were used to minimise confounding due to lower age and weight in those palliated. RESULTS: Patients underwent PrR (n=1244), SPS (n=311) or RVOTd (n=107). Mortality at 12 years was higher when repair or palliation was performed before the age of 60 days rather than after, most significantly for primary repair (18.7% vs 2.2%, P<0.001), less so for RVOTd (10.8% vs 0%, P=0.06) or SPS (12.4% vs 8.3%, P=0.2). In the matched groups of patients, RVOTd was associated with more right ventricular outflow tract (RVOT) reinterventions (HR=2.3, P=0.05 vs PrR, HR=7.2, P=0.001 vs SPS) and fewer pulmonary valve replacements (PVR) (HR=0.3 vs PrR, P=0.05) at 12 years, with lower mortality after complete repair (HR=0.2 versus PrR, P=0.09). CONCLUSIONS: We found that RVOTd was associated with more RVOT reinterventions, fewer PVR and fewer deaths when compared with PrR in comparable, young infants, especially so in those under 60 days at the time of the first procedure.

A randomised controlled trial of Caphosol mouthwash in management of radiation-induced mucositis in head and neck cancer.

PURPOSE: This phase III, non-blinded, parallel-group, randomised controlled study evaluated the efficacy of Caphosol mouthwash in the management of radiation-induced oral mucositis (OM) in patients with head and neck cancer (HNC) undergoing radical (chemo)radiotherapy. PATIENTS AND METHODS: Eligible patients were randomised at 1:1 to Caphosol plus standard oral care (intervention) or standard oral care alone (control), stratified by radiotherapy technique and use of concomitant chemotherapy. Patients in the intervention arm used Caphosol for 7weeks: 6weeks during and 1-week post-radiotherapy. The primary endpoint was the incidence of severe OM (CTCAE ⩾grade 3) during and up to week 8 post-radiotherapy. Secondary endpoints include pharyngeal mucositis, dysphagia, pain and quality of life. RESULTS: The intervention (n=108) and control (n=107) arms were well balanced in terms of patient demographics and treatment characteristics. Following exclusion of patients with missing data, 210 patients were available for analysis. The incidence of severe OM did not differ between the intervention and control arms (64.1% versus 65.4%, p=0.839). Similarly, no significant benefit was observed for other secondary endpoints. Overall, compliance with the recommended frequency of Caphosol was low. CONCLUSION: Caphosol did not reduce the incidence or duration of severe OM during and after radiotherapy in HNC.

Long-term survival after surgical aortic valve replacement among patients over 65†years of age.

OBJECTIVE: Surgical aortic valve replacement (AVR) remains the gold standard therapy for severe aortic stenosis. Long-term survival data following AVR is required. Our objective was to provide a detailed contemporary benchmark of long-term survival following AVR among elderly patients (≥65 years) in the UK. METHODS: We conducted a retrospective cohort study of 1815 adult patients undergoing surgical AVR± coronary artery bypass graft (CABG) surgery at a single UK centre between 1996 and 2011. Our main outcome was patient survival, which was assessed by linkage to census records at the Office for National Statistics. RESULTS: The mean age of the cohort was 75 (±5.6) years. Patients in the AVR alone group had a slightly higher median survival of 10.9 (95% CI 10.5 to 11.8) years than the AVR+CABG group which had a median survival of 9.6 (95% CI 8.7 to 10.1) years (p=0.001 of log-rank test (LRT) for equality of survivor functions). The presence of chronic kidney disease, severely impaired left ventricular function or being a current smoker were each associated with a ≥50% increased risk of long-term mortality. Comparison of our study cohort patients and the reference (operation year, age and gender matched) UK population suggested no difference in survival probability up to 8 years (p=0.55). However, for longer periods of follow-up, the difference became increasingly significant (p<0.0001). CONCLUSIONS: Long-term survival following surgical AVR in patients over 65 years of age is excellent and up to 8 years is comparable to the matched general population.

Aortic Valve Replacement and the Ross Operation in Children and Young Adults.

BACKGROUND: There are several options available for aortic valve replacement (AVR), with few comparative reports in the literature. The optimal choice for AVR in each age group is not clear. OBJECTIVES: The study sought to report and compare outcomes after AVR in the young using data from a national database. METHODS: AVR procedures were compared after advanced matching, both in pairs and in a 3-way manner, using a Bayesian dynamic survival model. RESULTS: A total of 1,501 patients who underwent AVR in the United Kingdom between 2000 and 2012 were included. Of these, 47.8% had a Ross procedure, 37.8% a mechanical AVR, 10.9% a bioprosthesis AVR, and 3.5% a homograft AVR, with Ross patients being significantly younger when compared to the other groups. Overall survival at 12 years was 94.6%. In children, the Ross procedure had a 12.7% higher event-free probability (death or any reintervention) at 10 years when compared to mechanical AVR (p = 0.05). We also compared all procedures except the homograft in a matched population of young adults, where the bioprosthesis had the lowest event-free probability of 78.8%, followed by comparable results in mechanical AVR and Ross, with 86.3% and 89.6%, respectively. Younger age was associated with mortality and pulmonary reintervention in the Ross group and with aortic reintervention in the mechanical AVR. Of all 3 options, only the patients undergoing the Ross procedure approached the survival of the general population. CONCLUSIONS: AVR in the young achieves good results, with the Ross being overall better suited for this age group, especially in children. Although freedom from aortic valve reintervention is superior after the Ross procedure, the need for homograft reinterventions is an issue to take into account. All methods have advantages and limitations, with reinterventions being an issue in the long term for all, more crucially in smaller children.

Feasibility and safety of minimized cardiopulmonary bypass in major aortic surgery.

OBJECTIVES: Conventional cardiopulmonary bypass causes haemodilution and is a trigger of systemic inflammatory reactions, coagulopathy and organ failure. Miniaturized cardiopulmonary bypass has been proposed as a way to reduce these deleterious effects of conventional cardiopulmonary bypass and to promote a more physiological state. The use of miniaturized cardiopulmonary bypass has been reported in low-risk patients undergoing valve and coronary artery bypass graft (CABG) surgery. However, little is known about its application in major aortic surgery. METHODS: From February 2007 to September 2010, 49 patients underwent major aortic surgery using the Hammersmith miniaturized cardiopulmonary bypass (ECCO, Sorin). Data were extracted from medical records to characterize preoperative comorbidities (EuroSCORE), perioperative complications and the use of blood products. The same data were collected and described for 328 consecutive patients having similar surgery with conventional cardiopulmonary bypass at the Bristol Heart Institute, our twinned centre, during the same period. RESULTS: The miniaturized cardiopulmonary bypass group had a median EuroSCORE of 8 [inter-quartile range (IQR): 5-11], 13% had preoperative renal dysfunction and 20% of operations were classified as emergency or salvage. Thirty-day mortalities were 6.4; and 69, 67 and 74% had ≥ 1 unit of red cells, fresh frozen plasma (FFP) and platelets transfused, respectively. Eight percent of patients experienced a renal complication, and 8% a neurological complication. The conventional cardiopulmonary bypass group was similar, with a EuroSCORE of 8 (IQR: 6-10); 30-day mortalities were 9.4; and 68, 62 and 74% had ≥ 1 unit of red cells, FFP and platelets transfused, respectively. The proportions experiencing renal and neurological complications were 14 and 5%. CONCLUSIONS: Our experience suggests that miniaturized cardiopulmonary bypass is safe and feasible for use in major aortic cardiac surgery. A randomized trial is needed to evaluate miniaturized cardiopulmonary bypass formally.