External validation of the 2-year mortality prediction tool in hemodialysis patients developed using a Bayesian network.

Background: In recent years, a number of predictive models have appeared to predict the risk of medium-term mortality in hemodialysis patients, but only one, limited to patients aged over 70 years, has undergone sufficiently powerful external validation. Recently, using a national learning database and an innovative approach based on Bayesian networks and 14 carefully selected predictors, we have developed a clinical prediction tool to predict all-cause mortality at 2 years in all incident hemodialysis patients. In order to generalize the results of this tool and propose its use in routine clinical practice, we carried out an external validation using an independent external validation database. Methods: A regional, multicenter, observational, retrospective cohort study was conducted to externally validate the tool for predicting 2-year all-cause mortality in incident and prevalent hemodialysis patients. This study recruited a total of 142 incident and 697 prevalent adult hemodialysis patients followed up in one of the eight Association pour l'Utilisation du Rein Artificiel dans la région Lyonnaise (AURAL) Alsace dialysis centers. Results: In incident patients, the 2-year all-cause mortality prediction tool had an area under the receiver curve (AUC-ROC) of 0.73, an accuracy of 65%, a sensitivity of 71% and a specificity of 63%. In prevalent patients, the performance for the external validation were similar in terms of AUC-ROC, accuracy and specificity, but was lower in term of sensitivity. Conclusion: The tool for predicting all-cause mortality at 2 years, developed using a Bayesian network and 14 routinely available explanatory variables, obtained satisfactory external validation in incident patients, but sensitivity was insufficient in prevalent patients.

Comparison of Perioperative Chemotherapy versus Postoperative Chemoradiotherapy for Operable Stomach Cancer: A Western Canadian Province Experience.

BACKGROUND: The standard approaches for resectable stomach cancer are postoperative chemoradiotherapy (PCR) or perioperative chemotherapy (PC). Limited evidence is available regarding the superiority of one of the two approaches. We aimed to compare the survival of patients with operable stomach cancer who were treated with PC or PCR. METHODS: In this retrospective cohort study, patients with operable stomach cancer diagnosed between 2005-2015 in the province of Saskatchewan were identified and, based on type of treatment, were placed into PCR and PC groups. A Cox proportional multivariate analysis was performed to assess independent prognostic variables, including survival advantage of PC over PCR. RESULTS: A total of 88 eligible patients with a median age of 66 (56-71) and a male to female ratio of 1:0.44 were identified. Seventy-three (83%) patients had pathologically node positive disease. Sixty-seven (76%) patients received PCR, while 21 (24%) patients received PC. The median overall survival of the whole group was 34 months, with 38 months (95% CI 24.6-51.3) in the PCR group vs. 30 months (14.3-45.7) in the PC group (p = 0.29). Median relapse-free survival was 34 months (20.7-47.3) in the PCR group vs. 23 months (6.7-39.3) in the PC group (p = 0.20). Toxicities were comparable. On multivariate analysis, T ≥ 3 tumor (HR, 3.57 (1.39-8.56)), neutrophil to lymphocyte ratio (LNR) > 2.8 (HR, 1.85 (1.05-3.25)), and positive resection margins (HR, 1.89 (1.06-3.37)) were independently correlated with inferior survival. CONCLUSIONS: This well-designed population based cohort study suggests a lack of survival benefit of PC over PCR. Both treatment options remain viable approaches for resectable stomach cancer.

In vitro and in silico hormonal activity studies of di-(2-ethylhexyl)terephthalate, a di-(2-ethylhexyl)phthalate substitute used in medical devices, and its metabolites.

Plasticizers added to polyvinylchloride used in medical devices can be released into patients' biological fluids. The substitution of di-(2-ethylhexyl)phthalate (DEHP) by alternative plasticizers is essential but their safety must be demonstrated. DEHP, di-(2-ethylhexyl)terephthalate (DEHT) and their metabolites were investigated using level 2 Organization for Economic Co-operation and Development bioassays to screen for in vitro hormonal changes. Differences between the DEHP and DEHT metabolites were observed. Albeit weak, the hormonal activities of DEHT-derived metabolites, e.g., 5-OH metabolite of mono-(ethylhexyl)terephthalate (5-OH-MEHT), were detected and the results of docking experiments performed on estrogen receptor alpha and androgen receptor agreed with the biological results. A co-stimulation of human estrogen receptor alpha and human androgen receptor was also observed. With regard to steroidogenesis, a 16-fold increase in estrogen synthesis was measured with 5-OH-MEHT. Therefore, even if DEHT remains an interesting alternative to DEHP because of its low migration from medical devices, it seems important to verify that multi-exposed patients in neonatal intensive care units do not have urinary levels of oxidized metabolites, in particular 5-OH-MEHT, suggesting a potential endocrine-disrupting effect.

Cardiac Rhythm Disturbances in Hemodialysis Patients: Early Detection Using an Implantable Loop Recorder and Correlation With Biological and Dialysis Parameters.

OBJECTIVES: The aim of this study was to identify using implantable loop recorder (ILR) monitoring the mechanisms leading to sudden death (SD) in patients undergoing hemodialysis (HD). BACKGROUND: SD accounts for 11% to 25% of death in HD patients. METHODS: Continuous rhythm monitoring was performed using the remote monitoring capability of the ILR device in patients undergoing HD at 8 centers. Clinical, biological, and technical HD parameters were recorded and analyzed. RESULTS: Seventy-one patients (mean age 65 ± 9 years, 73% men) were included. Left ventricular ejection fraction was <50% in 16%. Twelve patients (17%) had histories of atrial fibrillation or flutter at inclusion. During a mean follow-up period of 21.3 ± 6.9 months, 16 patients died (14% patient-years), 7 (44%) of cardiovascular causes. Four SDs occurred, with progressive bradycardia followed by asystole. The incidence of patients presenting with significant conduction disorder and with ventricular arrhythmia was 14% and 9% patient-years, respectively. In multivariate survival frailty analyses, a higher risk for conduction disorder was associated with plasma potassium >5.0 mmol/l, bicarbonate <22 mmol/l, hemoglobin >11.5 g/dl, pre-HD systolic blood pressure >140 mm Hg, the longer interdialytic period, history of coronary artery disease, previous other arrhythmias, and diabetes mellitus. A higher risk for ventricular arrhythmia was associated with potassium <4.0 mmol/l, no antiarrhythmic drugs, and previous other arrhythmias. With ILR monitoring, de novo atrial fibrillation or flutter was diagnosed in 14 patients (20%). CONCLUSIONS: ILR may be considered in HD patients prone to significant conduction disorders, ventricular arrhythmia, or atrial fibrillation or flutter to allow early identification and initiation of adequate treatment. Therapeutic strategies reducing serum potassium variability could decrease the rate of SD in these patients. (Implantable Loop Recorder in Hemodialysis Patients [RYTHMODIAL]; NCT01252823).

Prognosis of patients with severe hyponatraemia is related not only to hyponatraemia but also to comorbidities and to medical management: results of an observational retrospective study.

BACKGROUND: The true cause of death in severe hyponatraemic patients remains controversial. The present study aimed to analyse the relationship between comorbidity, medical management and prognosis in severe hyponatraemic patients. METHODS: Medical records of all patients hospitalised in our institution in 2012 with a plasma sodium ≤120 mmol/l were retrospectively analysed. RESULTS: One hundred forty-seven of 64 723 adult patients (0.2 %) were identified with severe hyponatraemia. In-hospital mortality rate was 24.5 and 50.3 % after a median follow-up of 431 days. Patients with plasma sodium <110 mmol/l had less comorbidity (Charlson Comorbidity Index 2.2 ± 1.9 vs. 4.0 ± 3.1 (plasma sodium 110-115 mmol/l) and 4.2 ± 3.1 (plasma sodium 116-120 mmol/l); P = .02)) and a small trend for less mortality, respectively 40.0, 51.2 and 52.3 % (P = .64). At discharge, nonsurvivors and survivors had similar plasma sodium with 58.3 % of nonsurvivors being normonatraemic. Urine analysis was performed in 74.2 % of cases and associated with lower in-hospital mortality (20.2 % vs. 36.8 %, P = .05). In multivariate Cox analysis, mortality was significantly associated with plasma sodium normalisation (HR 0.35, P < 0.001), urine analysis (HR 0.48, P = .01), Charlson Comorbidity Index (HR 1.23, P < .001) and serum albumin (HR 0.88, P < .001). CONCLUSION: Mortality in severe hyponatraemia appears mainly due to comorbidities although the latter are potentiated by hyponatraemia itself and its management thereby exacerbating the risk of death.

Primum Non Nocere: A More Proactive Workplace Drug Testing Regime for Australian Medical Practitioners?

This article considers whether Australian medical practitioners should be subject to a more proactive workplace drug testing regime in order to minimise the risk of harm to patients. It first canvasses the history of workplace drug testing in the United States, the United Kingdom and Australia, before exploring whether there is a need for more proactive drug testing of Australian medical practitioners. It then considers whether workplace drug testing adequately addresses drug-related risks to patient safety, and discusses some of the privacy issues associated with workplace drug testing regimes. The article concludes that although an argument can be advanced in favour of a more proactive workplace drug testing regime for all Australian medical practitioners, the implementation of such a regime would be costly and complicated. As a result, it should only apply to practitioners assessed as working in "high-risk" roles.

Haemodialysis in patients treated with oral anticoagulant: should we heparinize?

BACKGROUND: Anticoagulation for the haemodialysis circuit in patients treated with oral anticoagulation poses additional haemorrhagic risk. The few available data suggest that tapering or even stopping heparinization is feasible and the HeprAN membrane with grafted heparin was developed to decrease heparin dose. The objective of our study was to evaluate the need for additional anticoagulation in patients on long-term oral anticoagulation, according to the type of membrane used. METHODS: This is a prospective, randomized, crossover bifactorial trial in haemodialysed patients on oral anticoagulation. Each patient had four haemodialysis sessions with two different membranes [HeprAN or polysulphone (PS)] and with or without enoxaparin. Clinical coagulation was evaluated by the need for premature ending and by a visual score (Janssen scale). Coagulation activation markers were also measured: d-dimers, prothrombin fragments 1 + 2, thrombin-antithrombin complexes, tissue factor pathway inhibitor and platelet factor-4. RESULTS: Ten patients were included (M/F = 4/6, mean age 63 ± 15 years). None of the 40 sessions ended prematurely. The clotting scores were similar with or without enoxaparin (dialyser: 1.49 ± 0.19 versus 1.53 ± 0.17, P = 0.97; bubble trap: 0.75 ± 0.19 versus 0.78 ± 0.22, P = 0.62) and with the polysulphone or the HeprAN membrane (dialyser: 1.54 ± 0.20 versus 1.47 ± 0.16, P = 0.65; bubble trap: 0.74 ± 0.22 versus 0.79 ± 0.19, P = 0.58). There was no significant difference in coagulation activation markers between dialysis modalities; however, dialysis efficacy was significantly greater with the PS membrane (1.58 ± 0.07 versus 1.43 ± 0.06, P = 0.02). CONCLUSIONS: These results suggest that haemodialysis without additional anticoagulation is possible in patients with oral anticoagulation. The HeprAN membrane did not provide any additional benefit compared with a PS membrane.

Pharmacokinetics of insulin aspart and glucagon in type 1 diabetes during closed-loop operation.

BACKGROUND: We assessed the pharmacokinetics of subcutaneous insulin aspart and glucagon during closed-loop operation and their relationship with body composition variables. METHODS: We retrospectively analyzed data collected from closed-loop experiments in 15 type 1 diabetes patients (age 47.1 ± 12.3 years, body mass index 25.9 ± 4.6 kg/m², glycated hemoglobin 7.9% ± 0.7%). Patients received an evening meal accompanied with prandial insulin bolus and stayed in the clinical facility until the next morning. Glucose levels were regulated by dual-hormone closed-loop delivery. Insulin and glucagon were delivered using two subcutaneous infusion pumps installed on the abdominal wall. Plasma insulin and glucagon were measured every 10-30 min. Percentage of body fat, percentage of fat in the abdominal area, and mass of abdominal fat were measured by dual X-ray absorptiometry. RESULTS: A pharmacokinetic model estimated time-to-peak plasma concentrations [t(max) insulin 51 (19) min, t(max) glucagon 19 (4) min, mean (standard deviation)], metabolic clearance rate [MCR insulin 0.019 (0.015-0.026) liter/kg/min, MCR glucagon 0.012 (0.010-0.014) liter/kg/min, median (interquartile range)], and the background plasma concentrations [I(b) insulin 10.2 (6.3-15.2) mU/liter, I(b) glucagon 50 (45-56) pg/ml, median (interquartile range)]. t(max) correlated positively between insulin and glucagon (r = 0.7; p = .007) while MCR correlated negatively (r = -0.7; p = .015). In this small sample size, t(max), MCR, and I(b) of insulin and glucagon did not correlate with percentage of body fat, percentage of fat in the abdominal area, or total mass of abdominal fat. CONCLUSIONS: Insulin and glucagon pharmacokinetics might be related during closed-loop operation. Our data suggest that slower absorption of insulin is associated with slower absorption of glucagon. Body composition does not seem to influence insulin and glucagon pharmacokinetics.

Risk factors for BK virus infection in the era of therapeutic drug monitoring.

BACKGROUND: Overimmunosuppression is a widely recognized risk factor for BK virus (BKV) infection, particularly with the combination of tacrolimus, mycophenolate mofetil (MMF), and steroids. Nevertheless, the exact impact of exposure to tacrolimus and MMF is not well understood. METHODS: We examined 240 kidney recipients between 2006 and 2008. BKV was monitored every 2 months in the urine or blood. A kidney biopsy was performed when viremia exceeded 10 copies/mL. RESULTS: Ninety-five (40%) patients had sustained viruria, 48 (20%) sustained viremia, and 17 (7%) biopsy-proven polyomavirus-associated nephropathy. The mean time-to-occurrence was 7.6, 7.9, and 9.7 months for viruria, viremia, and polyomavirus-associated nephropathy. Risk factors associated with BKV infection in univariate analyses were retransplantation, panel-reactive antibody more than 0%, cytomegalovirus D+/R-, cold ischemia time, delayed graft function, induction with antithymocyte globulins, acute rejection before month 3 (M3), tacrolimus trough levels more than 10 ng/mL, and M3 AUC0-12 hr more than 50 hr mg/L. Multivariate analyses showed that cytomegalovirus D+/R- (adjusted hazard ratio [AHR], 2.03; P=0.05), acute rejection (AHR, 5.4; P<0.001), and mycophenolic acid AUC0-12 hr more than 50 hr mg/L (AHR, 3.6; P=0.001) were risk factors for BKV. CONCLUSIONS: This study identified a link between a state of increased immunosuppression and BKV infection, especially in patients with higher MMF exposure and elevated tacrolimus trough levels at M3.