Interfacial Compatibilization into PLA/Mg Composites for Improved In Vitro Bioactivity and Stem Cell Adhesion.

The present work highlights the crucial role of the interfacial compatibilization on the design of polylactic acid (PLA)/Magnesium (Mg) composites for bone regeneration applications. In this regard, an amphiphilic poly(ethylene oxide-b-L,L-lactide) diblock copolymer with predefined composition was synthesised and used as a new interface to provide physical interactions between the metallic filler and the biopolymer matrix. This strategy allowed (i) overcoming the PLA/Mg interfacial adhesion weakness and (ii) modulating the composite hydrophilicity, bioactivity and biological behaviour. First, a full study of the influence of the copolymer incorporation on the morphological, wettability, thermal, thermo-mechanical and mechanical properties of PLA/Mg was investigated. Subsequently, the bioactivity was assessed during an in vitro degradation in simulated body fluid (SBF). Finally, biological studies with stem cells were carried out. The results showed an increase of the interfacial adhesion by the formation of a new interphase between the hydrophobic PLA matrix and the hydrophilic Mg filler. This interface stabilization was confirmed by a decrease in the damping factor (tanδ) following the copolymer addition. The latter also proves the beneficial effect of the composite hydrophilicity by selective surface localization of the hydrophilic PEO leading to a significant increase in the protein adsorption. Furthermore, hydroxyapatite was formed in bulk after 8 weeks of immersion in the SBF, suggesting that the bioactivity will be noticeably improved by the addition of the diblock copolymer. This ceramic could react as a natural bonding junction between the designed implant and the fractured bone during osteoregeneration. On the other hand, a slight decrease of the composite mechanical performances was noted.

Treatment tolerance and patient-reported outcomes favor online hemodiafiltration compared to high-flux hemodialysis in the elderly.

Large cohort studies suggest that high convective volumes associated with online hemodiafiltration may reduce the risk of mortality/morbidity compared to optimal high-flux hemodialysis. By contrast, intradialytic tolerance is not well studied. The aim of the FRENCHIE (French Convective versus Hemodialysis in Elderly) study was to compare high-flux hemodialysis and online hemodiafiltration in terms of intradialytic tolerance. In this prospective, open-label randomized controlled trial, 381 elderly chronic hemodialysis patients (over age 65) were randomly assigned in a one-to-one ratio to either high-flux hemodialysis or online hemodiafiltration. The primary outcome was intradialytic tolerance (day 30-day 120). Secondary outcomes included health-related quality of life, cardiovascular risk biomarkers, morbidity, and mortality. During the observational period for intradialytic tolerance, 85% and 84% of patients in high-flux hemodialysis and online hemodiafiltration arms, respectively, experienced at least one adverse event without significant difference between groups. As exploratory analysis, intradialytic tolerance was also studied, considering the sessions as a statistical unit according to treatment actually received. Over a total of 11,981 sessions, 2,935 were complicated by the occurrence of at least one adverse event, with a significantly lower occurrence in online hemodiafiltration with fewer episodes of intradialytic symptomatic hypotension and muscle cramps. By contrast, health-related quality of life, morbidity, and mortality were not different in both groups. An improvement in the control of metabolic bone disease biomarkers and ß2-microglobulin level without change in serum albumin concentration was observed with online hemodiafiltration. Thus, overall outcomes favor online hemodiafiltration over high-flux hemodialysis in the elderly.

Health outcomes and the transition experience of HIV-infected adolescents after transfer to adult care in Québec, Canada.

BACKGROUND: Little is known on outcomes after transition to adult care among adolescents with perinatal HIV infection. Though there is data from other chronic pediatric diseases suggesting increased morbidity and mortality following transfer to adult care, this has not well been studied among the first wave of survivors of perinatal HIV infection. The primary objective of this study was to determine outcomes after transition to adult care among a cohort of HIV-infected adolescents in Québec, Canada. Secondary objectives were to document participant experiences with the transition process, identify barriers to successful transition, and potential changes to improve the transition process. METHODS: Clinic records were reviewed to identify all perinatally-infected youth who transitioned from the Centre Maternel et Infantile sur le Sida pediatric HIV clinic (Montreal) at age 18 to an adult care provider between 1999 and 2012. Transitioned patients were contacted using last available patient or parental listed phone number on hospital record, internet based telephone directory, or social media. A standardized questionnaire was administered by telephone or in-person interview, and copies of current medical records obtained from treating physicians. RESULTS: Forty-five patients were transferred between 1999 and 2012, among whom 25 consented to the study, eight were lost to follow-up, eight refused participation, and four were deceased. Overall 76 % of patients remained engaged in care, defined by at least one physician visit within 6 months of the interview. Over 50 % reported difficulty with adherence to their current drug regimens. At one-year post-transfer, there was a decrease in the proportion of patients with CD4 count >500 cells/mm(3) from 64 to 29 %, and a statistically significant decrease in absolute CD4 count (mean 370 vs 524 cells/mm(3), p = 0.04.). The majority (92 %) of participants felt that 18 was too young an age to transfer to adult care, and provided suggestions for improving the transition process. CONCLUSIONS: This group of perinatally-infected youth remained engaged in care after transition, however difficulties with adherence and assuming responsibility for their own care were identified as issues in their post-transition care. The high rate of mortality among them and the changes to their health status post-transition suggest that further work is necessary to document the health outcomes of this group in larger, more diverse cohort settings.

Early changes in body weight and blood pressure are associated with mortality in incident dialysis patients.

BACKGROUND: While much research is devoted to identifying novel biomarkers, addressing the prognostic value of routinely measured clinical parameters is of great interest. We studied early blood pressure (BP) and body weight (BW) trajectories in incident haemodialysis patients and their association with all-cause mortality. METHODS: In a cohort of 357 incident patients, we obtained all records of BP and BW during the first 90 days on dialysis (over 12 800 observations) and analysed trajectories using penalized B-splines and mixed linear regression models. Baseline comorbidities and all-cause mortality (median follow-up: 2.2 years) were obtained from the French Renal Epidemiology and Information Network (REIN) registry, and the association with mortality was assessed by Cox models adjusting for baseline comorbidities. RESULTS: During the initial 90 days on dialysis, there were non-linear decreases in BP and BW, with milder slopes after 15 days [systolic BP (SBP)] or 30 days [diastolic BP (DBP) and BW]. SBP or DBP levels at dialysis initiation and changes in BW occurring in the first month or during the following 2 months were significantly associated with survival. In multivariate models adjusting for baseline comorbidities and prescriptions, higher SBP value and BW slopes were independently associated with a lower risk of mortality. Hazard ratios of mortality and 95% confidence intervals were 0.92 (0.85-0.99) for a 10 mmHg higher SBP and 0.76 (0.66-0.88) for a 1 kg/month higher BW change on Days 30-90. CONCLUSIONS: BW loss in the first weeks on dialysis is a strong and independent predictor of mortality. Low BP is also associated with mortality and is probably the consequence of underlying cardiovascular diseases. These early markers appear to be valuable prognostic factors.

Cardiovascular risk stratification in hemodialysis patients in the era of highly sensitive troponins: should we choose between hs-troponin I and hs-troponin T?

BACKGROUND: New highly sensitive (hs) assays have challenged the interpretation of cardiac troponins (cTn). The present study was designed to evaluate simultaneously conventional cTnT and cTnI together with their corresponding highly sensitive determinations in stable hemodialysis (HD) patients. Ability of cTn to stratify HD patient risk was assessed. METHODS: A total of 224 stable HD patients was included in this observational study. cTnT and hs-cTnT were measured using Roche cTnT/hs-cTnT assays based on a Cobas e601® analyzer. cTnI and hs-cTnI were measured using Beckman AccuTnI/hs-TnI IUO assays on Access II system. Patients were followed up prospectively during 9 years. Relationship between cTn level and mortality was assessed through Cox survival analysis. RESULTS: The median cTnT and cTnI concentrations were 38.5 ng/L (IQR, 18.8-76) and 10 ng/L (IQR, 10-20), respectively. The median hs-cTnT and hs-cTnI concentrations were 62.5 ng/L (IQR, 38.8-96.3) and 13.9 ng/L (IQR, 8.4-23.6), respectively. The prevalence of values above the 99th percentile was significantly more marked with cTnT (85.3 and 97.8% for conventional and hs cTnT, respectively) than with cTnI (7.6 and 67.4% for conventional and hs cTnI, respectively). During the follow-up, 167 patients died, mainly from cardiac cause (n=77). The optimized cut-off values, determined by bootstrap method, predicting mortality were 38, 69, 20 and 11 ng/L for cTnT, hs-cTnT, cTnI and hs-cTnI, respectively. After full adjustment, elevated plasma concentrations of all troponin were significant predictors of mortality. CONCLUSIONS: A large proportion of patients free of acute coronary syndrome (ACS) has hs-cTn I or T higher than the 99th percentile which could be seen as a limiting factor for ACS screening. However, all generation and type of troponin assays could be reliable indicators of prognosis risk in HD patients.

A combined index of cardiac biomarkers as a risk factor for early cardiovascular mortality in hemodialysis patients.

BACKGROUND: Cardiac biomarkers, including cardiac troponin-I (cTn-I) and N-terminal pro brain natriuretic peptide (NT-proBNP) have been associated with poor outcome in hemodialysis (HD) patients. The present study was designed to evaluate these biomarkers as biological risk factors for early and late mortality in HD patients. In addition, a multimarker approach including inflammatory index was performed in order to improve the cardiovascular risk assessment of these patients. METHODS: cTnI, NT-proBNP and C-reactive protein (CRP) were measured at baseline (October through November 2002) in 130 HD patients [median age 69.0 (23.4-87.7) years old, 76 females, 54 males]. Patients were followed during 8 years. Adjusted hazard ratios (HRs) of death and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models. RESULTS: During the follow-up, 82 patients died, mainly from cardiac cause (63.4%). Elevated cTnI, NT-proBNP or CRP were all associated with increased early (death within 2 years of follow-up) but not late mortality. Moreover, the combination of all parameters (CRP ≥10.51 mg/L and cTnI ≥0.037 µg/L and NT-proBNP ≥10,204 pg/mL) dramatically increased the short-term mortality especially the cardiovascular mortality (HR 8.58, 95% CI 1.59-46.2; p=0.0007). CONCLUSIONS: A combined index of cardiovascular risk factors could provide supplementary risk stratification in HD patients for early cardiovascular mortality, strongly supporting the annual routine determination of these biomarkers.

The Young and the Resistant: HIV-Infected Adolescents at the Time of Transfer to Adult Care.

Combined antiretroviral therapy allows children with human immunodeficiency virus (HIV) to reach adulthood. We studied 45 adolescents at the time of transfer to adult care. Despite universal healthcare access, over two-thirds of the adolescents were failing treatment, which was manifested by detectable HIV-1 viral load, CD4 counts <200 cells/ mm(3), and/or triple-class drug resistance.

Randomized equivalence study evaluating the possibility of switching hemodialysis patients receiving subcutaneous human erythropoietin directly to intravenous darbepoetin alfa.

BACKGROUND: Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) used either intravenously or subcutaneously with no dose penalty; however, the direct switch from subcutaneous recombinant human erythropoietin (rHuEPO) to intravenous darbepoetin has barely been studied. OBJECTIVE: To establish the equivalence of a direct switch from subcutaneous rHuEPO to intravenous darbepoetin versus an indirect switch from subcutaneous rHuEPO to intravenous darbepoetin after 2 months of subcutaneous darbepoetin in patients undergoing hemodialysis. METHODS: In this open, randomized, 6-month, prospective study, patients with end-stage kidney disease who were on hemodialysis were randomized into 2 groups: direct switch from subcutaneous rHuEPO to intravenous darbepoetin (group 1) and indirect switch from subcutaneous rHuEPO to intravenous darbepoetin after 2 months of subcutaneous darbepoetin (group 2). A third, nonrandomized group (control), consisting of patients treated with intravenous rHuEPO who were switched to intravenous darbepoetin, was also studied to reflect possible variations of hemoglobin (Hb) levels due to change from one type of ESA to the other. The primary outcome was the proportion of patients with stable Hb levels at month 6. Secondary endpoints included Hb stability at month 3, dosage requirements for darbepoetin, and safety of the administration route. RESULTS: Among 154 randomized patients, the percentages with stable Hb levels were equivalent in groups 1 and 2, respectively, at month 3 (86.0% vs 91.3%) and month 6 (82.1% vs 81.6%; difference -0.5 [90% CI -12.8 to 11.8]). Mean Hb levels between baseline and month 6 remained stable in both groups, with no variation in mean darbepoetin dose. Mean ferritin levels remained above 100 microg/L in the 3 groups during the whole study, and darbepoetin was well tolerated. CONCLUSIONS: This study has shown equivalent efficacy on Hb stability without the need for dosage increase in patients switched directly from subcutaneous rHuEPO to intravenous darbepoetin.

Fine-tuning of the prediction of mortality in hemodialysis patients by use of cytokine proteomic determination.

BACKGROUND AND OBJECTIVES: Inflammation-induced atherosclerosis and enhanced susceptibility to infection are linked to immune dysfunction and account for an important part of mortality in hemodialysis patients. This 4-yr prospective study aimed to use cytokine proteomic determination for predicting cardiovascular and noncardiovascular mortality in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Levels of 12 cytokines were measured using a proteomic biochip system in 134 patients who were on stable hemodialysis and compared with a control group of 150 healthy volunteers. Cox proportional hazards regression analysis was used to determine the relationship between cytokine and clinical outcome. RESULTS: A proinflammatory state characterized by decreased anti-/proinflammatory cytokine ratio was evidenced in hemodialysis patients compared with control subjects. After adjustment for age, gender, smoking, and high-sensitivity C-reactive protein levels, IL-6 and (IL-4+IL-10)/IL-6 ratio were associated with a significant and specific enhanced hazard ratio of cardiovascular mortality (hazard ratio 11.32 [95% confidence interval 2.52 to 50.90; P < 0.01] and hazard ratio 3.14 [95% confidence interval 1.20 to 8.22; P < 0.05], respectively, when comparing the third and first tertiles). It is interesting that (IL-4+IL-6+IL-10)/(IL-2+IFN-gamma) ratio, used as a marker of lymphocytes T helper subsets cytokine secretion, was associated only with noncardiovascular mortality (hazard ratio 4.93; 95% confidence interval 1.03 to 23.65; P < 0.05). CONCLUSION: Beyond the strong prediction of cardiovascular mortality by IL-6, determination of cytokine ratios can be useful to identify hemodialysis patients with increased noncardiovascular mortality risk.

Association of aminothiols with the clinical outcome in hemodialysis patients: comparison of chromatography and immunoassay for homocysteine determination.

BACKGROUND: Controversial results on hyperhomocysteinemia and cardiovascular risk in hemodialysis (HD) could be due in part to the methodology used for homocysteine (Hcy) determination. OBJECTIVE: The aim of this study was to compare the influence of the method used for Hcy determination (chromatography or immunoassay) with regard to the association of Hcy with cardiovascular mortality rate in HD patients in a 3-year prospective study. METHODS: A total of 162 patients undergoing HD were included in a cohort study. Baseline Hcy levels were measured by HPLC and fluorescence polarization immunoassay (FPIA). Cysteine and cysteinylglycine were determined simultaneously with Hcy measurement by HPLC. RESULTS: Hcy levels obtained with both methods were highly correlated (r(2)=0.927, p<0.0001). An increased relative risk (RR) for cardiovascular mortality (n=31) was found between the highest against lowest tertile of Hcy for both HPLC (RR 2.74, 95% CI 1.07-7.02; p<0.05) and FPIA (RR 2.76, 95% CI 0.99-7.70; p=0.05). Interestingly, increased cysteine (> or =452 micromol/L) and cysteinylglycine (> or =36.6 micromol/L) levels were associated with a decreased RR of non-cardiovascular death (n=26) (RR 0.27, 95% CI 0.09-0.79; p=0.02) for cysteine and (RR 0.28, 95% CI 0.09-0.90; p=0.03) for cysteinylglycine when compared to the first tertile. CONCLUSIONS: This study demonstrated an increased risk of cardiovascular mortality in HD patients with Hcy values in the third tertile, independent of the method used. HPLC offers the advantage of simultaneous determination of other aminothiols that appear to be associated with non-cardiovascular mortality.

Plasma osteoprotegerin is associated with mortality in hemodialysis patients.

Expression of bone proteins resulting from transdifferentiation of vascular smooth muscle cells into osteoblasts suggests that vascular calcifications are a bioactive process. Regulating molecules such as osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) could play a key role in bone-vascular calcification imbalance. This study investigated the contribution of these proteins as well as mineral metabolism disorders in hemodialysis (HD) patient outcome. A total of 185 HD patients were followed up prospectively for 2 yr. In addition to clinical characteristics, mineral metabolism markers as well as OPG and soluble RANKL (sRANKL) were measured at baseline. After 2 yr, survival rates were described with Kaplan-Meier and compared with Cox regression analyses; 50 patients died (27 from cardiovascular diseases). Calcium, phosphate, and calcium x phosphate product were not associated with mortality. Both hyperparathyroidism (parathyroid hormone > or =300 pg/ml) and hypoparathyroidism (parathyroid hormone <150 pg/ml) were poorly associated with all-cause and cardiovascular mortality. By contrast, elevated OPG levels predicted all-cause (relative risk [RR] 2.67; 95% confidence interval [CI] 1.32 to 5.41; P = 0.006) and cardiovascular mortality (RR 3.15; 95% CI 1.14 to 8.69; P = 0.03). Low levels of sRANKL were associated with a protective effect for all-cause mortality (RR 0.45; 95% CI 0.21 to 0.94; P = 0.03). The association of OPG with all-cause mortality was stronger in patients with C-reactive protein > or =12.52 mg/L. In this condition, both highest (RR 5.68; 95% CI 1.48 to 22.73; P = 0.01) and lowest tertiles (RR 5.37; 95% CI 147 to 1968; P = 0.01) significantly predicted poor outcome. These results show that regulating-bone molecules, especially OPG, are strong predictors of mortality in HD patients, suggesting that OPG is a vascular risk factor, in particular in patients who have high C-reactive protein levels. OPG determination therefore should be added to the biologic follow-up of these patients.

Association between novel indices of malnutrition-inflammation complex syndrome and cardiovascular disease in hemodialysis patients.

BACKGROUND: Inflammation and malnutrition are recognized as important risk factors for cardiovascular disease (CVD) in hemodialysis (HD) patients. Owing to substantial short-term variability of serum C-reactive protein (CRP), more reliable markers of malnutrition-inflammation complex syndrome should be sought with stronger associations with the risk of CVD in HD patients. We therefore explored the clinical relevance of a composite inflammatory index (prognostic inflammatory and nutritional index [PINI]) and of muscle protein mass indicators, derived from creatinine kinetics. METHODS: This cross-sectional study included 177 HD patients (89 women and 88 men; median age, 67.73 years). CVD and risk factors were assessed using medical charts, clinical examination, and biochemical measurements performed at inclusion. Lean body mass (LBM) was derived from creatinine kinetic modeling, whereas PINI was calculated as the ratio (CRP xalpha1-acid-glycoprotein)/(albumin x transthyretin). Patients were divided according to the presence or absence of established CVD. RESULTS: The traditional risk factors diabetes (odds ratio [OR], 5.83; p = 0.0045) and smoking (OR, 3.50; p < 0.02) were associated with an increase in prevalent CVD. Low transthyretin (OR, 3.79; p < 0.02) and high levels of CRP (OR, 2.70; p < 0.05), PINI (OR, 3.44; p < 0.02), observed LBM (OR, 3.01; p < 0.05), and the ratio of observed/expected LBM (OR, 4.24; p < 0.01) were associated with CVD after adjustment for age, sex, dialysis center, and dialysis vintage. After additional adjustment for diabetes and smoking, only PINI (OR, 2.85; p = 0.0446) and observed/expected LBM (OR, 2.96; p = 0.0361) were still significant. CONCLUSION: PINI and LBM are associated with increased relative risk for having CVD and could be used routinely to examine the degree of severity of malnutrition inflammation complex syndrome.

Persistence with treatment in newly treated middle-aged patients with essential hypertension.

BACKGROUND: Antihypertensive agents have been found to decrease morbidity and/or mortality associated with cardiovascular disease (CVD). Surveys have shown that hypertension has been diagnosed in many patients but remains uncontrolled. One factor may be the lack of persistence to treatment. OBJECTIVE: To evaluate persistence with antihypertensives and its determinants among newly treated patients. METHODS: A cohort of 21,011 patients with essential hypertension was reconstructed from prescription records in the Régie de l'assurance maladie du Québec administrative database. We included subjects between 50 and 64 years of age newly treated for hypertension with diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, calcium-channel blockers, or angiotensin II receptor blockers prescribed individually or in combination. Cohort entry was from January 1, 1998, to December 31, 2000. Subjects were considered newly treated if they had not taken any antihypertensive agents in the year prior to the index date, which was defined as the date of the first prescription. Patients were followed until June 30, 2001; death; end of coverage; or occurrence of CVD. Main outcome measure was the persistence rate. The cumulative persistence rate was determined by Kaplan-Meier analysis. The rate ratio of discontinuing antihypertensive therapy was estimated using the Cox regression model. RESULTS: The mean age of patients was 58 years. Persistence with antihypertensive therapy fell to 75% in the first 6 months after treatment and continued to decline over the next 3 years to 55%. During a one-year period of follow-up, with diuretics used as the reference class and controlling for several variables, patients prescribed other antihypertensive classes or combined therapy (HR 0.71; 95% CI 0.67 to 0.75) were found to have a better rate of persistence. Having diabetes (HR 0.86; 95% CI 0.79 to 0.94) and dyslipidemia (HR 0.71; 95% CI 0.66 to 0.76) increased the rate of persistence. Similar values were observed during the 3-year period of follow-up. CONCLUSIONS: Barriers to persistence occur early in the course of therapy, and adherence continues to decline over a period of 3 years. Patients were least persistent to diuretic therapy.

Measurement of circulating troponin Ic enhances the prognostic value of C-reactive protein in haemodialysis patients.

BACKGROUND: Cardiac Troponin I (cTnI) levels are considered an important diagnostic tool in acute coronary events. They could be of predictive value in haemodialysis (HD) patients. However, the relationship between cTnI and the HD-induced inflammatory state remains unclear. The aim of this study was to explore the prognostic relevance to all-cause and cardiovascular mortalities in HD patients of cTnI, in combination with highly sensitive C-reactive protein (hs-CRP) levels. METHODS: We measured cTnI and hs-CRP at baseline (March 10 to November 16, 2001) in 191 HD patients without clinical signs of acute coronary artery disease [median age 66.7 years (range 22.3-93.5), 94 females, 97 males]. We used a cTnI concentration with a total imprecision of 10% (0.03 microg/l), determined in the laboratory, as the analytical threshold value. Patients were followed for mortality until 1 January, 2003 (median follow-up 418 days). The adjusted relative risks (RRs) of death and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models. RESULTS: A significant proportion (25.1%) of patients had elevated CTnl, > or =0.03 microg/l; 40.3% of patients had CRP concentrations > or =10 mg/l. During follow-up, 29 patients died, 44.8% due to cardiac causes. Elevated cTnI or CRP levels were associated with increased mortality [RR adjusted for age, sex and duration of dialysis 4.2 (1.9-9.0) for cTnI > or =0.03 microg/l and 3.6 (1.6-8.1) for CRP > or =10 mg/l], cTnI being particularly predictive of cardiovascular death. Moreover, the combination of elevated hs-CRP (> or =10 mg/l) and circulating cTnI (> or =0.03 microg/l) dramatically impaired the HD survival rate [adjusted RR for all-cause mortality 16.9 (4.5-63.8)]. CONCLUSION: Circulating cTnI was associated with poor prognosis, especially when combined with elevated CRP, strongly supporting the adoption of regular cTnI testing in HD patients.