Biomarker variability and cardiovascular disease residual risk.

PURPOSE OF REVIEW: A number of cohorts and clinical trials have reported observing associations between intraindividual variation of biomarkers and manifestations of cardiovascular disease (CVD). RECENT FINDINGS: Intraindividual (or 'visit-to-visit') variability of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and triglyceride have all been found to associate with CVD outcomes, independent of their mean absolute levels, independent of each other, and independent of other traditional risk factors. These findings have been confirmed recently in large cohort studies in different populations, and in post-hoc analyses of clinical trial data. Lipoprotein variability has been associated with myocardial infarction, other arterial disease including cerebrovascular, and with cardiovascular and overall mortality. The association of higher variability of LDL-C with atheroma progression has also been assessed directly using intravascular ultrasound and carotid intima-media thickness. The lipoprotein variability of an individual contributes to their residual risk of CVD, although the mechanism remains unclear. SUMMARY: There is compelling evidence that lipoprotein variability contributes to residual risk; however, a more standardized approach is required before the risk attributable to variability can be assessed effectively.

Looking to the future: predicting renal replacement outcomes in a large community cohort with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is common and important due to poor outcomes. An ability to stratify CKD care based on outcome risk should improve care for all. Our objective was to develop and validate 5-year outcome prediction tools in a large population-based CKD cohort. Model performance was compared with the recently reported 'kidney failure risk equation' (KFRE) models. METHODS: Those with CKD in the Grampian Laboratory Outcomes Mortality and Morbidity Study-I (3396) and -II (18 687) cohorts were used to develop and validate a renal replacement therapy (RRT) prediction tool. The discrimination, calibration and overall performance were assessed. The net reclassification index compared performance of the developed model and the 3- and 4-variable KFRE model to predict RRT in the validation cohort. RESULTS: The developed model (with measures of age, sex, excretory renal function and proteinuria) performed well with a C-statistic of 0.938 (0.918-0.957) and Hosmer-Lemeshow (HL) χ(2) statistic 4.6. In the validation cohort (18 687), the developed model falsely identified fewer as high risk (414 versus 3278 individuals) compared with the KFRE 3-variable model (measures of age, sex and excretory renal function), but had more false negatives (58 versus 21 individuals). The KFRE 4-variable model could only be applied to 2274 individuals because of a lack of baseline urinary albumin creatinine ratio data, thus limiting its use in routine clinical practice. CONCLUSIONS: CKD outcome prediction tools have been developed by ourselves and others. These tools could be used to stratify care, but identify both false positives and -negatives. Further refinement should optimize the balance between identifying those at increased risk with clinical utility for stratifying care.

Definitions of progression in chronic kidney disease--predictors and relationship to renal replacement therapy in a population cohort with a 6 year follow-up.

BACKGROUND: Chronic kidney disease (CKD) is common, important and associated with increased healthcare needs due to CKD progression. Definitions of renal disease progression are multiple, and not always comparable. A measure of 'progression' directly comparable with renal replacement therapy (RRT) initiation would identify 'progressors' in research and for healthcare planning. METHODS: The Grampian Laboratory Outcomes Morbidity and Mortality Study (GLOMMS-I) is a community cohort with CKD from 2003, followed up to June 2009 for (i) RRT initiation and (ii) 'progression': sustained reduction in estimated glomerular filtration rate (eGFR) by 15 mL/min/1.73 m2 (equivalent to CKD stage change), or to <10 mL/min/1.73 m2, whichever occurs first. Predictors were baseline demographics and comorbidity. The use of the Kidney Disease: Improving Global Outcomes-2012 progression definition was also explored. RESULTS: Two thousand two hundred and eighty-nine and 1044 had Stage 3 and 4 CKD, 44% were males. Overall, RRT initiation and progression rates were 0.97 and 3.50 per 100 patient-years (py). Females had significantly lower progression and RRT initiation rates. The progression rate was not dependent on CKD stage [incidence rate ratio (IRR) for Stage 4 (versus Stage 3) 0.9 (95% CI 0.8-1.2)], whereas the RRT initiation rate was [IRR 5.6 (95% CI 3.8-8.2)]. Increased proteinuria was associated with both greater RRT initiation and progression rates. CONCLUSIONS: Progression and RRT initiation rate ratios allow comparison of predictors of these outcomes. Higher rates of both in males suggest that greater RRT initiation rate is biological rather than due to preferential treatment. Similar progression but very different RRT initiation rates in Stage 3 and 4 CKD suggests that CKD stage effect on RRT initiation is a function of endpoint proximity rather than faster renal function deterioration.

Patterns of dietary intake and serum carotenoid and tocopherol status are associated with biomarkers of chronic low-grade systemic inflammation and cardiovascular risk.

Dietary modification may affect inflammatory processes and protect against chronic disease. In the present study, we examined the relationship between dietary patterns, circulating carotenoid and tocopherol concentrations, and biomarkers of chronic low-grade systemic inflammation in a 10-year longitudinal study of Scottish postmenopausal women. Diet was assessed by FFQ during 1997-2000 (n 3237, mean age 54·8 (SD 2·2) years). Participants (n 2130, mean age 66·0 (SD 2·2) years) returned during 2007-11 for follow-up. Diet was assessed by FFQ (n 1682) and blood was collected for the analysis of serum high-sensitivity C-reactive protein (hs-CRP), IL-6, serum amyloid A, E-selectin, lipid profile and dietary biomarkers (carotenoids, tocopherols and retinol). Dietary pattern and dietary biomarker (serum carotenoid) components were generated by principal components analysis. A past 'prudent' dietary pattern predicted serum concentrations of hs-CRP and IL-6 (which decreased across the quintiles of the dietary pattern; P= 0·002 and P= 0·001, respectively; ANCOVA). Contemporary dietary patterns were also associated with inflammatory biomarkers. The concentrations of hs-CRP and IL-6 decreased across the quintiles of the 'prudent' dietary pattern (P= 0·030 and P= 0·006, respectively). hs-CRP concentration increased across the quintiles of a 'meat-dominated' dietary pattern (P= 0·001). Inflammatory biomarker concentrations decreased markedly across the quintiles of carotenoid component score (P< 0·001 for hs-CRP and IL-6, and P= 0·016 for E-selectin; ANCOVA). Prudent dietary pattern and carotenoid component scores were negatively associated with serum hs-CRP concentration (unstandardised ß for prudent component: -0·053, 95% CI -0·102, -0·003; carotenoid component: -0·183, 95% CI -0·233, -0·134) independent of study covariates. A prudent dietary pattern (which reflects a diet high in the intakes of fish, yogurt, pulses, rice, pasta and wine, in addition to fruit and vegetable consumption) and a serum carotenoid profile characteristic of a fruit and vegetable-rich diet are associated with lower concentrations of intermediary markers that are indicative of CVD risk reduction.

Translating chronic kidney disease epidemiology into patient care--the individual/public health risk paradox.

BACKGROUND: Applying the Kidney Disease Outcomes Quality Initiative definitions of chronic kidney disease (CKD), it appears that CKD is common. The increased recognition of CKD has brought with it the clinical challenge of translating into practice the implications for the patient and for service planning. To understand the clinical relevance and translate that into information to support individual patient care and service planning, we explored clinical outcomes in a large British CKD cohort, identified through routine opportunistic testing, with a 6-year follow-up (≈ 13,000 patient-years). METHODS: A cohort had previously been identified with CKD-sustained reduced eGFR over at least 3 months and case note review. Six-year (13,339 patient-years) follow-up for renal replacement therapy (RRT) initiation and death was achieved through data linkage. Age- and sex-specific mortality rates were compared to the general population. RESULTS: Of 3414 individuals (most Stage 3b-5), median age 78.6 years, followed for 13 339 patient-years, 170 (5%) initiated RRT and 2024 (59%) died without initiating RRT. RRT initiation rates decreased with age from 14.33 to 0.65 per 100 patient-years among those aged 15-25 and 75-85 years at baseline but the actual numbers initiating RRT increased from 6 to 34, respectively. RRT initiation rates were lower for female sex, absence of macroalbuminuria and less advanced CKD stage. Mortality rates increased with age from 2 to 34 per 100 patient-years for those aged 15-45 and > 85 years at baseline, an excess of 2 and 17 per 100 patient-years over that of the general population, respectively. However, the increase in relative risk was 19-fold for those aged 15-45 years and just 2-fold in those > 85 years. These data have been converted into simple tools for considering individual patients' risk and informing service planning. CONCLUSIONS: The contrast between relative and absolute risk for both RRT initiation and mortality by age group illustrates the difficulties for planning services. The challenge that now faces clinicians is how to appropriately identify which elderly patients with CKD are at high risk of poor outcome.

Retzius-sparing robotic-assisted laparoscopic radical prostatectomy: racial considerations for 250 consecutive cases.

Our objective is to report the functional and oncologic outcomes of a cohort of 250 consecutive prostate cancer patients undergoing a Retzius-sparing approach and to assess for racial differences in continence outcomes. This was a prospective, single-center, case series of 250 consecutive prostate cancer patients who underwent a Retzius-sparing robotic-assisted laparoscopic radical prostatectomy by a single surgeon between May 2015 and April 2019. Our primary objective was to report post-operative continence outcomes of patients undergoing this technique. Continence was defined as using zero or one precautionary pad per day. Median follow-up was 24.0 months [interquartile range (IQR) 18.0-30.0 months]. Median age and body mass index were 62.0 years (IQR 57.0-67.0) and 29.0 kg/m2 (IQR 26.0-33.0), respectively. Median PSA was 8.22 ng/ml (IQR 5.74-13.31). 84.8% of patients were intermediate risk or high risk pre-operatively, as per AUA/ASTRO/SUO guidelines. 96.0% had Gleason Score 7 or worse disease on final pathologic analysis. Positive margin incidence was 18.1% and 44.4% in patients with pT2 and pT3 disease, respectively, of which 75.4% were unifocal. Immediate continence (i.e., continence achieved within 1 month post-operatively) was achieved in 45.2% of patients. Three-month and 1-year continence rates were 70.0% and 92.0%, respectively. Caucasian patients experienced earlier return of continence (77% versus 65% at 3 months) compared to African American patients. IPSS scores gradually improved from 8.0 pre-operatively to 4.0 1-year later. Median PSA level was 0.01 ng/ml (IQR 0.01-9.01) post-operatively. Retzius-sparing robotic-assisted laparoscopic radical prostatectomy is an oncologically safe surgical technique with excellent short- and long-term continence outcomes. Caucasian patients may have earlier return of continence compared to African Americans.

Parents' views of genetic testing and treatment of familial hypercholesterolemia in children: a qualitative study.

Familial hypercholesterolemia (FH) is a serious inherited disorder, which greatly increases individuals' risk of cardiovascular disease (CVD) in adult life. However, medical treatment and lifestyle adjustments can fully restore life expectancy. Whilst European guidance advises that where there is a known family mutation genetic testing is undertaken in early childhood, the majority of the at-risk population remain untested and undiagnosed. To date, only a small number of studies have explored parents' and children's experiences of testing and treatment for FH, and little is known about interactions between health professionals, parents, and children in clinic settings. In this study, in-depth interviews were undertaken with parents who had attended a genetics and/or lipid clinic for FH with their children (n = 17). A thematic analysis revealed four main themes: undertaking early prevention, postponing treatment, parental concerns, and the importance of the wider family context. The majority of parents supported genetic testing for FH in childhood. However, although some were very supportive of following early treatment recommendations, others expressed reluctance. Importantly, some parents were concerned that inappropriate information had been shared with their children and wished that more time had been given to discuss how, when, and what to tell in advance. Future research is needed to explore the long-term outcomes for children who undertake genetic testing and early treatment for FH and to trial interventions to improve the engagement, follow-up, and support of children who are at risk, or diagnosed, with this disorder.

Analysis of Suicide Risk in Patients with Penile Cancer and Review of the Literature.

The treatment for penile cancer has been shown to cause harmful psychiatric symptoms as well as have detrimental effects on well-being. In the past several years, alternatives to total or partial penectomy have emerged, such as chemotherapy, radiation, penile sparing, and laser ablation therapies. A more specific breakdown for penile cancer is in order as the therapy has the potential for life changing surgery. We examined the Surveillance, Epidemiology, and End Results (SEER) database (1973-2013), comprising 28% of the United States population. International Classification of Diseases, Tenth revision codes C60.8-C60.9 and the International Classification of Diseases-Oncology codes 8010/2, 8010/3, 8051/2, 8051/3, 8052/2, 8052/3, 8070/2, 8070/3-8072/3, 8074/3, 8076/3, and 8083/3-8084/3 were used. Age, race, marital status, and clinicopathologic variables were studied. We used contingency tables of suicide rates; mid-P exact test was used for analysis. There were 13 suicides noted in 6155 patients with squamous cell carcinoma of the penis. All patients that committed suicide had undergone a surgical intervention. Certainly, penile cancer after treatment has a powerful effect on quality of life as increased depression and sexual anxiety have been documented in postoperative patients. This is in contrast to the observed suicide rate. Despite the reported negative psychological effects in patients with penile cancer, suicide rates are among the lowest of all urologic malignancies.

Retzius-Sparing Robotic-Assisted Laparoscopic Radical Prostatectomy: A Safe Surgical Technique with Superior Continence Outcomes.

PURPOSE: To report early operative outcomes and assess continence in 100 consecutive patients who underwent Retzius-sparing robotic-assisted laparoscopic radical prostatectomy (RALP). MATERIALS AND METHODS: This was a prospective, single-center, consecutive case series of 100 and 100 patients undergoing a Retzius-sparing and a conventional RALP, respectively, by a single surgeon between March 2015 and April 2017. RESULTS: Baseline patient characteristics were similar between the two groups. The Retzius-sparing approach required significantly less console time (120.0 minutes vs 144.0 minutes, p < 0.001). There were no differences between intra- and post-operative complication rates, and hospital length of stay was similar in the two groups. Incidence of positive surgical margins was nonsignificantly different between the two groups, with 17% and 13% of pT2 patients and 49% and 48% of pT3 patients in the Retzius-sparing and conventional groups, respectively. Patients in the Retzius-sparing group had significantly superior rates of achieving post-operative urinary continence (log-rank test: p < 0.001), with 20% of patients continent within the first month, compared with 8% of patients in the conventional group. The mean number of pads per day needed at 3, 6, 9, and 12 months post-operatively was also significantly lower in the Retzius-sparing group. CONCLUSIONS: Retzius-sparing RALP requires shorter console time, is oncologically safe, and leads to significantly superior continence outcomes compared with conventional RALP.

Maximising Acute Kidney Injury Alerts--A Cross-Sectional Comparison with the Clinical Diagnosis.

BACKGROUND: Acute kidney injury (AKI) is serious and widespread across healthcare (1 in 7 hospital admissions) but recognition is often delayed causing avoidable harm. Nationwide automated biochemistry alerts for AKI stages 1-3 have been introduced in England to improve recognition. We explored how these alerts compared with clinical diagnosis in different hospital settings. METHODS: We used a large population cohort of 4464 patients with renal impairment. Each patient had case-note review by a nephrologist, using RIFLE criteria to diagnose AKI and chronic kidney disease (CKD). We identified and staged AKI alerts using the new national NHS England AKI algorithm and compared this with nephrologist diagnosis across hospital settings. RESULTS: Of 4464 patients, 525 had RIFLE AKI, 449 had mild AKI, 2185 had CKD (without AKI) and 1305 were of uncertain chronicity. NHS AKI algorithm criteria alerted for 90.5% of RIFLE AKI, 72.4% of mild AKI, 34.1% of uncertain cases and 14.0% of patients who actually had CKD.The algorithm identified AKI particularly well in intensive care (95.5%) and nephrology (94.6%), but less well on surgical wards (86.4%). Restricting the algorithm to stage 2 and 3 alerts reduced the over-diagnosis of AKI in CKD patients from 14.0% to 2.1%, but missed or delayed alerts in two-thirds of RIFLE AKI patients. CONCLUSION: Automated AKI detection performed well across hospital settings, but was less sensitive on surgical wards. Clinicians should be mindful that restricting alerts to stages 2-3 may identify fewer CKD patients, but including stage 1 provides more sensitive and timely alerting.

Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation.

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remains undetected and current treatment is often suboptimal.To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed.This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgment and be adjusted for country-specific and local healthcare needs and resources.

Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation.

Familial hypercholesterolemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remains undetected, and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment, and management of FH in adults and children and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of noncholesterol risk factors, and the safe and effective use of low-density lipoprotein-lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be used to inform clinical judgment and be adjusted for country-specific and local healthcare needs and resources.

Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation.

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remain undetected and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors, and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgement and be adjusted for country-specific and local health care needs and resources.

Effects of wheat and oat-based whole grain foods on serum lipoprotein size and distribution in overweight middle aged people: a randomised controlled trial.

INTRODUCTION: Epidemiological studies suggest three daily servings of whole-grain foods (WGF) might lower cardiovascular disease risk, at least partly by lowering serum lipid levels. We have assessed the effects of consuming three daily portions of wholegrain food (provided as wheat or a mixture of wheat and oats) on lipoprotein subclass size and concentration in a dietary randomised controlled trial involving middle aged healthy individuals. METHODS: After a 4-week run-in period on a refined diet, volunteers were randomly allocated to a control (refined diet), wheat, or wheat + oats group for 12 weeks. Our servings were determined in order to significantly increase the intakes of non starch polysaccharides to the UK Dietary Reference Value of 18 g per day in the whole grain groups (18.5 g and 16.8 g per day in the wheat and wheat + oats groups respectively in comparison with 11.3 g per day in the control group). Outcome measures were serum lipoprotein subclasses' size and concentration. Habitual dietary intake was assessed prior and during the intervention. Of the 233 volunteers recruited, 24 withdrew and 3 were excluded. RESULTS: At baseline, significant associations were found between lipoprotein size and subclasses' concentrations and some markers of cardiovascular risk such as insulin resistance, blood pressure and serum Inter cellular adhesion molecule 1 concentration. Furthermore, alcohol and vitamin C intake were positively associated with an anti-atherogenic lipoprotein profile, with regards to lipoprotein size and subclasses' distribution. However, none of the interventions with whole grain affected lipoprotein size and profile. CONCLUSION: Our results indicate that three portions of wholegrain foods, irrelevant of the type (wheat or oat-based) do not reduce cardiovascular risk by beneficially altering the size and distribution of lipoprotein subclasses. TRIAL REGISTRATION: www.Controlled-Trials.com ISRCTN 27657880.

Hip bone loss is attenuated with 1000 IU but not 400 IU daily vitamin D3: a 1-year double-blind RCT in postmenopausal women.

Few year-long vitamin D supplementation trials exist that match seasonal changes. The aim of this study was to determine whether daily oral vitamin D3 at 400 IU or 1000 IU compared with placebo affects annual bone mineral density (BMD) change in postmenopausal women in a 1-year double-blind placebo controlled trial in Scotland. White women aged 60 to 70 years (n = 305) were randomized to one of two doses of vitamin D or placebo. All participants started simultaneously in January/February 2009, attending visits at bimonthly intervals with 265 (87%) women attending the final visit and an additional visit 1 month after treatment cessation. BMD (Lunar iDXA) and 1,25-dihydroxyvitamin D[1,25(OH)2 D], N-terminal propeptide of type 1 collagen [P1NP], C-terminal telopeptide of type I collagen [CTX], and fibroblast growth factor-23 [FGF23] were measured by immunoassay at the start and end of treatment. Circulating PTH, serum Ca, and total 25-hydroxyvitamin D [25(OH)D] (latter by tandem mass spectrometry) were measured at each visit. Mean BMD loss at the hip was significantly less for the 1000 IU vitamin D group (0.05% ± 1.46%) compared with the 400 IU vitamin D or placebo groups (0.57% ± 1.33% and 0.60% ± 1.67%, respectively) (p < 0.05). Mean (± SD) baseline 25(OH)D was 33.8 ± 14.6 nmol/L; comparative 25(OH)D change for the placebo, 400 IU, and 1000 IU vitamin D groups was -4.1 ± 11.5 nmol/L, +31.6 ± 19.8 nmol/L, and +42.6 ± 18.9 nmol/L, respectively. Treatment did not change markers of bone metabolism, except for a small reduction in PTH and an increase in serum calcium (latter with 1000 IU dose only). The discordance between the incremental increase in 25(OH)D between the 400 IU and 1000 IU vitamin D and effect on BMD suggests that 25(OH)D may not accurately reflect clinical outcome, nor how much vitamin D is being stored.