A precisely humanized FCRN transgenic mouse for preclinical pharmacokinetics studies.

Monoclonal antibodies (mAbs) are one of the fastest-growing classes of drugs and have been approved to treat several diseases, including cancers and autoimmune disorders. Preclinical pharmacokinetics studies are performed to determine the therapeutically meaningful dosages and efficacy of candidate drugs. These studies are typically performed in non-human primates; however, using primates is costly and raises ethical considerations. As a result, rodent models that better mimic human-like pharmacokinetics have been generated and remain an area of active investigation. Pharmacokinetic characteristics of a candidate drug, such as half-life, are partly controlled by antibody binding to the human neonatal receptor hFCRN. Due to the abnormally high binding of human antibodies to mouse FCRN, traditional laboratory rodents do not accurately model the pharmacokinetics of human mAbs. In response, humanized rodents expressing hFCRN have been generated. However, these models generally use large inserts randomly integrated into the mouse genome. Here, we report the production and characterization of a CRISPR/Cas9-mediated hFCRN transgenic mouse termed SYNB-hFCRN. Using CRISPR/Cas9-assisted gene targeting, we prepared a strain with a simultaneous knockout of mFcrn and insertion of a hFCRN mini-gene under the control of the endogenous mouse promoter. These mice are healthy and express hFCRN in the appropriate tissues and immune cell subtypes. Pharmacokinetic evaluation of human IgG and adalimumab (Humira®) demonstrate hFCRN-mediated protection. These newly generated SYNB-hFCRN mice provide another valuable animal model for use in preclinical pharmacokinetics studies during early drug development.

Age at diagnosis of type 2 diabetes and cardiovascular risk factor profile: A pooled analysis.

BACKGROUND: The diagnosis of type 2 diabetes (T2D) in younger adults, an increasingly common public health issue, is associated with a higher risk of cardiovascular complications and mortality, which may be due to a more adverse cardiovascular risk profile in individuals diagnosed at a younger age. AIM: To investigate the association between age at diagnosis and the cardiovascular risk profile in adults with T2D. METHODS: A pooled dataset was used, comprised of data from five previous studies of adults with T2D, including 1409 participants of whom 196 were diagnosed with T2D under the age of 40 years. Anthropometric and blood biomarker measurements included body weight, body mass index (BMI), waist circumference, body fat percentage, glycaemic control (HbA1c), lipid profile and blood pressure. Univariable and multivariable linear regression models, adjusted for diabetes duration, sex, ethnicity and smoking status, were used to investigate the association between age at diagnosis and each cardiovascular risk factor. RESULTS: A higher proportion of participants diagnosed with T2D under the age of 40 were female, current smokers and treated with glucose-lowering medications, compared to participants diagnosed later in life. Participants diagnosed with T2D under the age of 40 also had higher body weight, BMI, waist circumference and body fat percentage, in addition to a more adverse lipid profile, compared to participants diagnosed at an older age. Modelling results showed that each one year reduction in age at diagnosis was significantly associated with 0.67 kg higher body weight [95% confidence interval (CI): 0.52-0.82 kg], 0.18 kg/m2 higher BMI (95%CI: 0.10-0.25) and 0.32 cm higher waist circumference (95%CI: 0.14-0.49), after adjustment for duration of diabetes and other confounders. Younger age at diagnosis was also significantly associated with higher HbA1c, total cholesterol, low-density lipoprotein cholesterol and triglycerides. CONCLUSION: The diagnosis of T2D earlier in life is associated with a worse cardiovascular risk factor profile, compared to those diagnosed later in life.

Clinical associations with stage B heart failure in adults with type 2 diabetes.

BACKGROUND: There is a high prevalence of asymptomatic (American Heart Association Stage B) heart failure (SBHF) in people with type 2 diabetes (T2D). We aimed to identify associations between clinical characteristics and markers of SBHF in adults with T2D, which may allow therapeutic interventions prior to symptom onset. METHODS: Adults with T2D from a multi-ethnic population with no prevalent cardiovascular disease [n = 247, age 52 ± 12 years, glycated haemoglobin A1c (HbA1c) 7.4 ± 1.1% (57 ± 12 mmol/mol), duration of diabetes 61 (32, 120) months] underwent echocardiography and adenosine stress perfusion cardiovascular magnetic resonance imaging. Multivariable linear regression analyses were performed to identify independent associations between clinical characteristics and markers of SBHF. RESULTS: In a series of multivariable linear regression models containing age, sex, ethnicity, smoking history, number of glucose-lowering agents, systolic blood pressure (BP) duration of diabetes, body mass index (BMI), HbA1c, serum creatinine, and low-density lipoprotein (LDL)-cholesterol, independent associations with: left ventricular mass:volume were age (ß = 0.024), number of glucose-lowering agents (ß = 0.022) and systolic BP (ß = 0.027); global longitudinal strain were never smoking (ß = -1.196), systolic BP (ß = 0.328), and BMI (ß = -0.348); myocardial perfusion reserve were age (ß = -0.364) and male sex (ß = 0.458); and aortic distensibility were age (ß = -0.629) and systolic BP (ß = -0.348). HbA1c was not independently associated with any marker of SBHF. CONCLUSIONS: In asymptomatic adults with T2D, age, systolic BP, BMI, and smoking history, but not glycaemic control, are the major determinants of SBHF. Given BP and BMI are modifiable, these may be important targets to reduce the development of symptomatic heart failure.

Effect of metformin on biomarkers of placental- mediated disease: A systematic review and meta-analysis.

Metformin reduces the incidence of placental-mediated disease (PMD) in pregnancies with and without diabetes, but the mechanism through which it exerts these effects is not yet fully understood. We performed a systematic review and meta-analysis to examine the effect of metformin on biomarkers implicated in the pathogenesis of PMD. We searched Medline, Embase and the Cochrane Library for studies of metformin and biomarkers of PMD in pregnancy. Meta-analysis was undertaken where comparable data were obtained from two or more studies. 12 studies were included in the final review. Meta-analysis of 2 studies including 323 pregnant women showed significantly reduced CRP levels following treatment with metformin compared to placebo [mean difference = -1.72, 95% CI (-2.97; -0.48); p = 0.007]. Metformin exposure was also associated with decreased levels of the inflammatory cytokines TNFα, IL-1a, IL-1b and IL-6 in serum, placenta and omental tissue taken from pregnant women. Metformin significantly decreased the release of anti-angiogenic factors sFlt-1 and sEng from ex-vivo placental and umbilical vein tissue, and increased maternal serum levels of non-phosphorylated IGFBP-1. Overall, our findings show that metformin mediates several molecular pathways implicated in the pathogenesis of pre-eclampsia and intrauterine growth retardation. Metformin therefore has exciting potential as a therapeutic, as well as preventative, agent in the treatment of PMD, which warrants further investigation.

Effects of liraglutide versus sitagliptin on circulating cardiovascular biomarkers, including circulating progenitor cells, in individuals with type 2 diabetes and obesity: Analyses from the LYDIA trial.

The mechanisms behind the beneficial cardiovascular effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) compared with dipeptidyl peptidase-4 inhibitors (DPP4is) remain largely unknown, despite both targeting the incretin pathway to improve glycaemic control. In these prespecified secondary analyses of the LYDIA trial, we examined the impact of the GLP-1RA liraglutide (1.8 mg once-daily) and the DPP4i sitagliptin (100 mg once-daily) on circulating cardiovascular biomarkers associated with atherosclerotic risk, including circulating progenitor cells (CPCs). LYDIA was a 26-week, randomized, active-comparator trial in 61 adults with type 2 diabetes and obesity (mean ± SD: age 43.8 ± 6.5 years, body mass index 35.3 ± 6.4 kg/m2 , HbA1c 7.5% ± 0.83% [58.5 ± 9.1 mmol/mol]). Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1-alpha (SDF-1ɑ), both of which are implicated in endothelial function, were higher at 26 weeks with liraglutide therapy compared with sitagliptin (mean between-group difference [95% CI]: 77.03 [18.29, 135.77] pg/mL, p = .010; and 996.25 [818.85, 1173.64] pg/mL, p < .001, respectively). There were no between-group differences in CPCs, nitric oxide, C-reactive protein, interleukin-6, tumour necrosis factor alpha and advanced glycation end-products. These analyses suggest a favourable impact of liraglutide on VEGF and SDF-1ɑ levels compared with sitagliptin. These factors may therefore be implicated in the differential cardiovascular effects observed between these agents in large cardiovascular outcome trials. However, these are secondary analyses from a previous trial and thus hypothesis-generating. Purposive trials are required to examine these findings further.

Long-term effects of intensive multifactorial therapy in individuals with screen-detected type 2 diabetes in primary care: 10-year follow-up of the ADDITION-Europe cluster-randomised trial.

BACKGROUND: The multicentre, international ADDITION-Europe study investigated the effect of promoting intensive treatment of multiple risk factors among people with screen-detected type 2 diabetes over 5 years. Here we report the results of a post-hoc 10-year follow-up analysis of ADDITION-Europe to establish whether differences in treatment and cardiovascular risk factors have been maintained and to assess effects on cardiovascular outcomes. METHODS: As previously described, general practices from four centres (Denmark, Cambridge [UK], Leicester [UK], and the Netherlands) were randomly assigned by computer-generated list to provide screening followed by routine care of diabetes, or screening followed by intensive multifactorial treatment. Population-based stepwise screening programmes among people aged 40-69 years (50-69 years in the Netherlands), between April, 2001, and December, 2006, identified patients with type 2 diabetes. Allocation was concealed from patients. Following the 5-year follow-up, no attempts were made to maintain differences in treatment between study groups. In this report, we did a post-hoc analysis of cardiovascular and renal outcomes over 10 years following randomisation, including a 5 years post-intervention follow-up. As in the original trial, the primary endpoint was a composite of first cardiovascular event, including cardiovascular mortality, cardiovascular morbidity (non-fatal myocardial infarction and non-fatal stroke), revascularisation, and non-traumatic amputation, up to Dec 31, 2014. Analyses were based on the intention-to-treat principle. ADDITION-Europe is registered with ClinicalTrials.gov, NCT00237549. FINDINGS: 343 general practices were randomly assigned to routine diabetes care (n=176) or intensive multifactorial treatment (n=167). 317 of these general practices (157 in the routine care group, 161 in the intensive treatment group) included eligible patients between April, 2001, and December, 2006. Of the 3233 individuals with screen-detected diabetes, 3057 agreed to participate (1379 in the routine care group, 1678 in the intensive treatment group), but at the 10-year follow-up 14 were lost to follow-up and 12 withdrew, leaving 3031 to enter 10-year follow-up analysis. Mean duration of follow-up was 9·61 years (SD 2·99). Sustained reductions over 10 years following diagnosis were apparent for bodyweight, HbA1c, blood pressure, and cholesterol in both study groups, but between-group differences identified at 1 and 5 years were attenuated at the 10-year follow-up. By 10 years, 443 participants had a first cardiovascular event and 465 died. There was no significant difference between groups in the incidence of the primary composite outcome (16·1 per 1000 person-years in the routine care group vs 14·3 per 1000 person-years in the intensive treatment group; hazard ratio [HR] 0·87, 95% CI 0·73-1·04; p=0·14) or all-cause mortality (15·6 vs 14·3 per 1000 person-years; HR 0·90, 0·76-1·07). INTERPRETATION: Sustained reductions in glycaemia and related cardiovascular risk factors over 10 years among people with screen-detected diabetes managed in primary care are achievable. The differences in prescribed treatment and cardiovascular risk factors in the 5 years following diagnosis were not maintained at 10 years, and the difference in cardiovascular events and mortality remained non-significant. FUNDING: National Health Service Denmark, Danish Council for Strategic Research, Danish Research Foundation for General Practice, Novo Nordisk, Novo Nordisk Foundation, Danish Centre for Evaluation and Health Technology Assessment, Danish National Board of Health, Danish Medical Research Council, Aarhus University Research Foundation, Astra, Pfizer, GlaxoSmithKline, Servier, HemoCue, Wellcome Trust, UK Medical Research Council, UK National Institute for Health Research, UK National Health Service, Merck, Julius Center for Health Sciences and Primary Care, UK Department of Health, and Nuts-OHRA.

Cardiovascular, cancer and mortality events after bariatric surgery in people with and without pre-existing diabetes: A nationwide study.

BACKGROUND: Bariatric surgery reduces cardiovascular events and mortality risk in obese individuals. However, it is unclear whether diabetes modifies this effect. This study examined mortality, cardiovascular, and cancer risk following bariatric surgery in adults with and without pre-existing diabetes. METHODS: Using mortality-linked Hospital Episodes Statistics (2006-14) from England, the risk of death, myocardial infarction, stroke, unstable angina, heart failure, and cancer following bariatric surgery was examined; the risk of death in people undergoing surgery was also compared with mortality rates of the general population. RESULTS: Of the 35 887 people undergoing bariatric surgery, 9175 (25.6%) had pre-existing diabetes. During a mean follow-up of 5.3 years, 801 people died, of whom 293 (36.6%) had pre-existing diabetes. The risk of all-cause mortality was 26% higher in people with than without diabetes (adjusted hazard ratio [aHR] 1.26, 95% confidence interval [CI] 1.08-1.46), whereas the risk of cancer was 21% higher (aHR 1.21; 95% CI 1.14-1.77). The risk of cardiovascular events was higher for patients with than without diabetes (aHRs [95% CIs] 2.08 [1.42-3.05], 1.80 [1.29-2.52], 1.61 [1.18-2.19], and 1.42 [1.14-1.77] for myocardial infarction, unstable angina, stroke, and heart failure, respectively). Compared with the general population, the age-standardized mortality rate ratio was 1.70 (1.52-1.91) and 1.35 (1.23-1.48) in people with and without pre-existing diabetes, respectively. CONCLUSIONS: For patients with pre-existing diabetes, the risk of death, cardiovascular events, and cancer after bariatric surgery was higher than for those without diabetes, whose mortality risk after surgery remains 35% higher than that of the general population.

Mini PCNL for renal calculi: does size matter?

OBJECTIVE: To evaluate the minimally invasive percutaneous nephrolithotomy (MIP) system for renal calculi. PATIENTS AND METHODS: Consecutive patients undergoing mini-percutaneous nephrolithotomy (mPCNL) procedures with the MIP system were enrolled. Patient position, American Society of Anesthesiologists classification, puncture location, stone clearance, postoperative drainage and complications were recorded, and features unique to MIP were noted. RESULTS: In all, 30 patients underwent 32 mPCNL procedures. The mean stone size was 17 (10.75-21.25) mm and the mean number of stones was 1 (1-2). The median stone clearance rate was 96.5 (95-100)%. The complication rate was 9.3%. No patient required a transfusion. In addition to these outcomes, we noted that the MIP system has many advantages over conventional PCNL (cPCNL). It is easy to learn and can be performed in both supine and prone positions. It is safe for supracostal puncture, provides excellent access to nearly all calyces and upper ureter, has multiple stone treatment options, can be used as an adjunct to cPCNL, and can be performed as a tubeless procedure. CONCLUSION: Our experience with the MIP system has shown several advantages over cPCNL. mPCNL with the MIP system has several features that suggest it should be considered as an alternative or adjunct to cPCNL, ureteroscopy and extracorporeal shockwave lithotripsy.

Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A systematic review and mixed-treatment comparison analysis.

AIMS: To compare efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in people with type 2 diabetes. MATERIALS AND METHODS: We electronically searched, up to June 3, 2016, published randomized clinical trials lasting between 24 and 32 weeks that compared a GLP-1RA (albiglutide, dulaglutide, twice-daily exenatide and once-weekly exenatide, liraglutide, lixisenatide, semaglutide and taspoglutide) with placebo or another GLP-1RA. Data on cardiometabolic and safety outcomes were analysed using a mixed-treatment comparison meta-analysis. RESULTS: A total of 34 trials (14 464 participants) met the inclusion criteria; no published data for semaglutide were available. Compared with placebo, all GLP-1RAs reduced glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels (reductions ranged from -0.55% and -0.73 mmol/L, respectively, for lixisenatide to -1.21% and -1.97 mmol/L, respectively, for dulaglutide). There were no differences within short-acting (twice-daily exenatide and lixisenatide) or long-acting (albiglutide, dulaglutide, once-weekly exenatide, liraglutide and taspoglutide) groups. Compared with twice-daily exenatide, dulaglutide treatment was associated with the greatest HbA1c and FPG reduction (0.51% and 1.04 mmol/L, respectively), followed by liraglutide (0.45% and 0.93 mmol/L, respectively) and once-weekly exenatide (0.38% and 0.85 mmol/L, respectively); similar reductions were found when these 3 agents were compared with lixisenatide. Compared with placebo, all GLP-1RAs except albiglutide reduced weight and increased the risk of hypoglycaemia and gastrointestinal side effects, and all agents except dulaglutide and taspoglutide reduced systolic blood pressure. When all GLP-1RAs were compared with each other, no clinically meaningful differences were observed in weight loss, blood pressure reduction or hypoglycaemia risk. Albiglutide had the lowest risk of nausea and diarrhoea and once-weekly exenatide the lowest risk of vomiting. CONCLUSIONS: The RCTs in the present analysis show that all GLP-1RAs improve glycaemic control, reduce body weight and increase the risk of adverse gastrointestinal symptoms compared with placebo. Although there were no differences when short-acting agents were compared with each other or when long-acting agents were compared with each other, dulaglutide, liraglutide and once-weekly exenatide were superior to twice-daily exenatide and lixisenatide at lowering HbA1c and FPG levels. There were no differences in hypoglycaemia between these 3 agents, whilst once-weekly exenatide had the lowest risk of vomiting. These results, along with patient's preferences and individualized targets, should be considered when selecting a GLP-1RA.

Soluble Immune Response Suppressor (SIRS): Reassessing the immunosuppressant potential of an elusive peptide.

A previously studied immunosuppressive cytokine, Soluble Immune Response Suppressor (SIRS), may have relevance to current studies of immune suppression in a variety of human disease states. Despite extensive efforts using experimental models, mainly in mice, much remains to be discovered as to how autoimmune cells in mice and humans escape normal regulation and, conversely, how tumor cells evade evoking an immune response. It is the contention of this commentary that the literature pre-2000 contain results that might inform current studies. The broadly immunosuppressive protein, SIRS, was studied extensively from the 1970s to 1990s and culminated in the determination of the n-terminal 21mer sequence of this 15kDa protein which had high homology to the short neurotoxins from sea snakes, that are canonical members of the three finger neurotoxin superfamily (3FTx). It was not until 2007 that the prophylactic administration of the synthetic N-terminal peptide of the SIRS 21mer, identical to the published sequence, was reported to inhibit or delay the development of two autoimmune diseases in mice: experimental allergic encephalomyelitis (EAE) and type I diabetes (T1D). These findings were consistent with other studies of the 3FTx superfamily as important probes in the study of mammalian pharmacology. It is the perspective of this commentary that SIRS, SIRS peptide and the anti-peptide mAb, represent useful, pharmacologically-active probes for the study of the immune response as well as in the potential treatment of autoimmune, inflammatory diseases and cancer.

Pathophysiology of type 1 and type 2 diabetes mellitus: a 90-year perspective.

Diabetes mellitus is a complex metabolic disorder associated with an increased risk of microvascular and macrovascular disease; its main clinical characteristic is hyperglycaemia. The last century has been characterised by remarkable advances in our understanding of the mechanisms leading to hyperglycaemia. The central role of insulin in glucose metabolism regulation was clearly demonstrated during the early 1920s, when Banting, Best, Collip and Macleod successfully reduced blood glucose levels and glycosuria in a patient treated with a substance purified from bovine pancreata. Later, during the mid-1930s, clinical observations suggested a possible distinction between 'insulin-sensitive' and 'insulin-insensitive' diabetes. Only during the 1950s, when a reliable measure of circulating insulin was available, was it possible to translate these clinical observations into pathophysiological and biochemical differences, and the terms 'insulin-dependent' (indicating undetectable insulin levels) and 'non-insulin-dependent' (normal or high insulin levels) started to emerge. The next 30 years were characterised by pivotal progress in the field of immunology that were instrumental in demonstrating an immune-mediated loss of insulin-secreting ß-cells in subjects with 'insulin-dependent' diabetes. At the same time, new experimental techniques allowing measurement of insulin 'impedance' showed a reduced peripheral effect of insulin in subjects with 'non-insulin-dependent' diabetes (insulin resistance). The difference between the two types of diabetes emerging from decades of observations and experiments was further formally recognised in 1979, when the definitions 'type I' and 'type II' diabetes were introduced to replace the former 'insulin-dependent' and 'non-insulin-dependent' terms. In the following years, many studies elucidated the natural history and temporal contribution of insulin resistance and ß-cell insulin secretion in 'type II' diabetes. Furthermore, a central role for insulin resistance in the development of a cluster of cardiometabolic alterations (dyslipidaemia, inflammation, high blood pressure) was suggested. Possibly as a consequence of the secular changes in diabetes risk factors, in the last 10 years the limitation of a simple distinction between 'type I' and 'type II' diabetes has been increasingly recognised, with subjects showing the coexistence of insulin resistance and immune activation against ß-cells. With the advancement of our cellular and molecular understanding of diabetes, a more pathophysiological classification that overcomes the historical and simple 'glucocentric' view could result in a better patient phenotyping and therapeutic approach.

Renal track creation for percutaneous nephrolithotomy: the history and relevance of single stage dilation.

INTRODUCTION: Percutaneous nephrolithotomy (PCNL) was described in the 1980s and revolutionized the treatment of stone disease. The crucial component to this surgery is satisfactory track creation. We examine how the development and production in the 1980s of a single stage dilator (SSD) subsequently modified for pediatric PCNL has become the ideal access tool for mini percutaneous nephrolithotomy (mPCNL) today. MATERIALS AND METHODS: The conception, production, scientific and clinical development of the original SSD is described. The pitfalls of track dilation in general according to method of dilation are also discussed and outlined. RESULTS: This study provides evidence clarifying commonly held misconceptions about the origin of SSD which is the mainstay of the mPCNL technique. CONCLUSIONS: Percutaneous renal surgery continues to evolve. In less than 40 years stone surgery has transformed from a morbid open operation to a number of minimally invasive, routine techniques. The SSD has been an innovation that has played a crucial role in this change.

Cardiorespiratory fitness and risk of type 2 diabetes mellitus: A 23-year cohort study and a meta-analysis of prospective studies.

AIMS: To investigate the association between cardiorespiratory fitness (CRF) and type 2 diabetes mellitus (T2DM) in a cohort of middle-age Finnish men and to summarise the current evidence in a meta-analysis of prospective studies. METHODS: CRF was measured at baseline in a random population-based sample of 2520 subjects by assessing oxygen uptake during maximal exercise. Cox regression analysis was used to estimate the association between CRF, expressed as metabolic equivalents (METs), and the risk of T2DM adjusted for potential confounders; this estimate was then pooled with the results of other prospective studies in a meta-analysis. RESULTS: Mean (SD) baseline age and CRF were 53 (5) years and 8.7 (2.1) METs, respectively. During 23 years of follow-up, 153 (6.1%) participants developed T2DM. The hazard ratio per 1-MET higher CRF, adjusted for age, body mass index, systolic blood pressure, serum HDL-cholesterol, and family history of T2DM, was 0.93 (95% confidence interval (CI): 0.84, 1.02; p = 0.109); further adjustment for smoking, education, and socioeconomic status did not materially change the estimate. In a random-effects meta-analysis of eight studies (92,992 participants and 8564 T2DM cases) combining maximally adjusted estimates, the pooled risk ratio of T2DM per 1-MET higher CRF level was 0.95 (95% CI: 0.93, 0.98; p = 0.003; I(2) = 81%), corresponding to 23 fewer cases per 100,000 person-years based on the assumption of a causal link between CRF and T2DM. CONCLUSIONS: These data suggest that there is an inverse relationship between CRF and T2DM that is largely independent of other risk factors.

Inverse association between fasting plasma glucose and risk of ventricular arrhythmias.

AIMS/HYPOTHESIS: In nondiabetic individuals, low values of fasting plasma glucose (FPG) have been associated with an increased risk of cardiovascular events. Identification of the potential mechanisms behind this association could help to elucidate the relationship between glycaemia and cardiovascular disease. We aimed to determine the association between FPG and ventricular arrhythmias. METHODS: FPG and other cardiometabolic risk factors were measured in a population-based cohort of 2,482 men without a known history of type 2 diabetes mellitus at baseline. Associations between FPG levels and incident cases of ventricular arrhythmias (ventricular tachycardia or fibrillation events ascertained using the National Hospital Discharge Register) were estimated using Cox regression analysis adjusted for potential confounders. RESULTS: During a median follow-up of 23.3 (interquartile range 18.5-25.3) years, 74 (2.9%) incident events were recorded. In a multivariable analysis adjusted for age, systolic BP, smoking status, LDL- and HDL-cholesterol, and C-reactive protein, the HR for ventricular arrhythmia per 1 mmol/l higher baseline FPG was 0.58 (95% CI 0.34, 0.98); this estimate did not materially change after further adjustment for BMI, alcohol consumption, triacylglycerols and history of ischaemic heart disease (0.50 [95% CI 0.28, 0.89]). CONCLUSIONS/INTERPRETATION: In this nondiabetic male population, FPG was inversely associated with incident risk of ventricular arrhythmias. While our results could help clarify the relationship between low glucose levels and cardiovascular risk, further studies are required to confirm these findings in other populations.

Serum potassium and glucose regulation in the ADDITION-Leicester screening study.

INTRODUCTION: Previous observational studies have shown conflicting results between plasma K+ concentrations and risk of type 2 diabetes. To help clarify the evidence we aimed to determine whether an association existed between serum K+ and glucose regulation within a UK multiethnic population. METHODS: Participants were recruited as part of the ADDITION Leicester study, a population based screening study. Individuals from primary care between the age of 40 and 75 years if White European or 25 and 75 years if South Asian or Afro Caribbean were recruited. Tests for associations between baseline characteristics and K+ quartiles were conducted using linear regression models. RESULTS: Data showed individuals in the lowest K+ quartile had significantly greater 2-hour glucose levels (0.53 mmol/L, 95% CI: 0.36 to 0.70, P ≤ 0.001) than those in the highest K+ quartile. This estimation did not change with adjustment for potential confounders. Conversely, participants in the lowest K+ quartile had a 0.14% lower HbA1c (95% CI -0.19 to -0.10: P ≤ 0.001) compared to those in the highest K+ quartile. CONCLUSION: This cross-sectional analysis demonstrated that lower K+ was associated with greater 2 hr glucose. The data supports the possibility that K+ may influence glucose regulation and further research is warranted.

Advancing cancer patient care by integrating circulating tumor cell technology to understand the spatial and temporal dynamics of cancer.

Spatial and temporal dynamics of cancer, studied with physical science approaches at critical transition points of the disease can provide insight into the biology of cancer and the evolutionary changes that occur both naturally and in response to therapy. A very promising development in translational cancer medicine has been the emergence of circulating tumor cells (CTC) as minimally invasive "liquid biopsies." We envision that the future utility of CTC will not simply be confined to enumeration, but also include their routine characterization using a high-content approach that investigates morphometrics, protein expression and genomic profiling. This novel approach guided by mathematical models to predict the spread of disease from the primary site to secondary site can bring the bench to the bedside for cancer patients. It is agnostic with reference to drug choice and treatment regimen, which also means that each patient is unique. The approach is Bayesian from a data collection perspective and is patient-centric rather than drug or new chemical entity-centric. The analysis of data comes from an understanding of commonalities and differences that are detected among patients with a given cancer type. Thus, patients are treated over the course of their disease with various drug regimens that reflects our real-time understanding of their evolving tumor genomics and response to treatment. This likely means that smaller cohorts of patients receive any given regimen but we hypothesize that it would lead to better patient outcomes than with the current classic approach to drug testing and development.

Algorithm for selecting men for pelvic lymph node dissection (PLND) during radical prostatectomy based on clinical risk factors in an Australian population.

OBJECTIVE: To define selection criteria for pelvic lymph node dissection (PLND) based on a contemporary Australian cohort of men with clinically localised prostate cancer undergoing radical prostatectomy (RP) with PLND, as stage migration of prostate cancer has led to re-evaluation of the role of PLND at the time of RP. PATIENTS AND METHODS: In all, 200 consecutive men treated by one surgeon between 2000 and 2005 with open RP and PLND. The clinical and pathological data were extracted by retrospective chart review. Associations between clinical predictors and LN positivity were assessed by logistic regression analysis. RESULTS: Overall, there were LN metastases were in 10 (5%) men. The LN positivity rate was significantly associated with biopsy Gleason score, preoperative prostate-specific antigen (PSA) concentration and percentage of positive cores (PPC), with respective odds ratios (OR) (95% confidence interval [CI]) of 3.70 (1.98-6.92), 1.11 (1.04-1.19) and 1.04 (1.01-1.06) Trend toward significant association with clinical stage (OR 1.75, 95% CI 0.97-3.13) On multivariate analysis, PSA concentration and biopsy Gleason score were significant predictors of LN disease. All 10 men with LN metastases came from a high-risk group of 96, identifiable by having at least one of the following: stage ≥ cT2b, biopsy Gleason score ≥ 4+3, PSA concentration of ≥ 10 ng/mL or PPC of ≥ 38%. CONCLUSIONS: The risk of LN metastases depends upon well-defined clinical risk factors of stage, biopsy Gleason score, PSA concentration and PPC. The present data suggests a simple risk-stratification method, using these risk factors, of identifying men to have PLND at the time of RP.

Predictors of positive surgical margins at open and robot-assisted laparoscopic radical prostatectomy: a single surgeon series.

Robot-assisted laparoscopic radical prostatectomy (RALRP), increasingly used to treat localized prostate cancer, has advantages over open radical prostatectomy (ORP) in terms of reduced bleeding and quicker convalescence. However, debate continues over whether RALRP provides superior or at least equivalent surgical outcomes. This study compares positive surgical margins (+SM), as a surrogate for long-term cancer control, at RALRP and ORP performed by a single experienced surgeon during the process of taking up RALRP. 400 consecutive patients undergoing surgery for prostate cancer under a single surgeon (DW) between November 1999 and July 2009 were studied. Prior to July 2005, all patients underwent ORP; after this date, most patients were treated by RALRP. Data were collected by retrospective chart review and analysed independently of the treating surgeon. +SM were defined as the presence of cancer at an inked surface. Overall, 23 (11.5%) of 200 patients undergoing RALRP had +SM, compared to 40 (20.0%) of 200 patients undergoing ORP (P < 0.05). On univariate logistic regression analysis, in addition to surgical approach (odds ratio [OR] = 1.92), patient age (OR = 1.05), pathologic stage (OR = 3.93) and specimen Gleason (GS) score (OR = 1.86) were significant predictors of +SM. On multivariate analysis, surgical approach, p-stage and specimen GS remained significant predictors of +SM. RALRP is associated with lower rates of +SM compared to ORP, even after adjusting for other known risk factors. Of note, the RALRP in this study were part of the surgeon's learning curve.