Ganciclovir exposure under a 450mg daily dosage of valganciclovir for cytomegalovirus prevention in kidney transplantation: a prospective study.

Manuel O, Pascual M, Perrottet N, Lamoth F, Venetz J-P, Decosterd LA, Buclin T, Meylan PR. Ganciclovir exposure under a 450 mg daily dosage of valganciclovir for cytomegalovirus prevention in kidney transplantation: a prospective study. 
Clin Transplant 2010: 24: 794-800. Abstract:  This prospective study aimed at determining the ganciclovir exposure observed under a daily dosage of 450 mg valganciclovir routinely applied to kidney transplant recipients with a GFR above 25 mL/min at risk for cytomegalovirus (CMV) disease. Ganciclovir levels at trough (C(trough) ) and at peak (C(3 h) ) were measured monthly. Ganciclovir exposure (area under the curve [AUC(0-24) ]) was estimated using Bayesian non-linear mixed-effect modeling (NONMEM). Thirty-six patients received 450 mg of valganciclovir daily for three months. Median ganciclovir C(3 h) was 3.9 mg/L (range: 1.3-7.1), and C(trough) was 0.4 mg/L (range 0.1-2.7). Median AUC(0-24) of ganciclovir was 59.3 mg h/L (39.0-85.3) in patients with GFR(MDRD) 26-39 mL/min, 35.8 mg h/L (24.9-55.8) in patients with GFR(MDRD) 40-59 mL/min, and 29.6 mg h/L (22.0-43.2) in patients with GFR(MDRD)  ≥ 60 mL/min. No major differences in adverse events according to ganciclovir exposure were observed. CMV viremia was not detected during prophylaxis. After discontinuing prophylaxis, CMV viremia was seen in 8/36 patients (22%), and 4/36 patients (11%) developed CMV disease. Ganciclovir exposure after administration of valganciclovir 450 mg daily in recipients with GFR ≥60 mL/min was comparable to those previously reported with oral ganciclovir. A routine daily dose of 450 mg valganciclovir appears to be acceptable for CMV prophylaxis in most kidney transplant recipients.

Occurrence, risk factors, diagnosis and treatment of syphilis in the prospective observational Swiss HIV Cohort Study.

BACKGROUND: Annual syphilis testing was reintroduced in the Swiss HIV Cohort Study (SHCS) in 2004. We prospectively studied occurrence, risk factors, clinical manifestations, diagnostic approaches and treatment of syphilis. METHODS: Over a period of 33 months, participants with positive test results for Treponema pallidum hemagglutination assay were studied using the SHCS database and an additional structured case report form. RESULTS: Of 7244 cohort participants, 909 (12.5%) had positive syphilis serology. Among these, 633 had previously been treated and had no current signs or symptoms of syphilis at time of testing. Of 218 patients with newly detected untreated syphilis, 20% reported genitooral contacts as only risk behavior and 60% were asymptomatic. Newly detected syphilis was more frequent among men who have sex with men (MSM) [adjusted odds ratio (OR) 2.8, P < 0.001], in persons reporting casual sexual partners (adjusted OR 2.8, P < 0.001) and in MSM of younger age (P = 0.05). Only 35% of recommended cerebrospinal fluid (CFS) examinations were performed. Neurosyphilis was diagnosed in four neurologically asymptomatic patients; all of them had a Venereal Disease Research Laboratory (VDRL) titer of 1:>or=32. Ninety-one percent of the patients responded to treatment with at least a four-fold decline in VDRL titer. CONCLUSION: Syphilis remains an important coinfection in the SHCS justifying reintroduction of routine screening. Genitooral contact is a significant way of transmission and young MSM are at high risk for syphilis. Current guidelines to rule out neurosyphilis by CSF analysis are inconsistently followed in clinical practice. Serologic treatment response is above 90% in the era of combination antiretroviral therapy.

A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

BACKGROUND Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown. METHODS AND FINDINGS The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed. CONCLUSIONS These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.

Blood pressure and cognitive function: a prospective analysis among adolescents in Seychelles.

OBJECTIVE: An inverse relationship between blood pressure (BP) and cognitive function has been found in adults, but limited data are available in adolescents and young adults. We examined the prospective relation between BP and cognitive function in adolescence. METHODS: We examined the association between BP measured at the ages of 12-15 years in school surveys and cognitive endpoints measured in the Seychelles Child Development Study at ages 17 (n = 407) and 19 (n = 429) years, respectively. We evaluated multiple domains of cognition based on subtests of the Cambridge Neurological Test Automated Battery (CANTAB), the Woodcock Johnson Test of Scholastic Achievement (WJTA), the Finger Tapping test (FT) and the Kaufman Brief Intelligence Test (K-BIT). We used age, sex and height-specific z-scores of SBP, DBP and mean arterial pressure (MAP). RESULTS: Six out of the 21 cognitive endpoints tested were associated with BP. However, none of these associations were found to hold for both males and females or for different subtests within the same neurodevelopmental domain or for both SBP and DBP. Most of these associations disappeared when analyses were adjusted for selected potential confounding factors such as socio-economic status, birth weight, gestational age, BMI, alcohol consumption, blood glucose, and total n-3 and n-6 polyunsaturated fats. CONCLUSIONS: Our findings do not support a consistent association between BP and subsequent performance on tests assessing various cognitive domains in adolescents.

Safety and efficacy in gamma knife radiosurgery for trigeminal neuralgia due to megadolichbasilar artery compression: a prospective series of 29 consecutive patients

Purpose: To analyse prospectively the long-term results of Gamma Knife surgery (GKS) in patients with trigeminal neuralgia secondary to megadolichobasilar artery (MBA). Methods: Between December 1992 and November 2010, 33 consecutive patients presenting with ITN secondary to MBA were operated by GKS and followed prospectively in Timone University Hospital. The follow up is at least of 1 year in 29 patients. The median age was 74.90 years (range 51 to 90). The GKS typically was performed using MR and CT imaging guidance and a single 4 mm isocenter. The median of the prescription dose (at the 100%) was 90 Gy (range 80 to 90). The target was placed on the cisternal portion of the Vth nerve. Clinical and dosimetric parameters were analyzed. GKS was the first surgical procedure in 23 patients (79.31%). Results: The median follow- up period was 46.12 months (range 12.95 to 157.93). All the 29 patients (100%) were initially pain free in a median time of 13.5 days (range 0 to 240). The probability of remaining pain free at 0.5, 1, 2 years was 93.1%, 79.3% and 75.7% respectively, reaching at this time the flat part of the curve. Seven patients (24.13%) experienced a recurrence with a median delay of 10.75 months (range 3.77 to 12.62). The actuarial rate of recurrence was not higher than in our population with essential TN although atypical pain was associated with a much higher risk of recurrence (HR= 6.92, p= 0.0117). The hypoesthesia actuarial rates at 0.5 years was 4.3% and at 1 year reach 13% and remains stable till 12 years with a median delay of onset of 7 (5, 12) months. Female patients had a statistically much lower probability of developing a facial numbness (p of 0.03). No patient reported a bothersome hypoesthesia. Conclusion: Retrogaserian, high dose GKS, turned out to be very safe with only 13.04% hypoesthesia, which was never disabling (0%), while achieving high quality pain control. The majority of the patients demonstrated a prolonged effect of radiosurgery in absence of any trigeminal nerve disturbance.

Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery International Cooperation Study (BASICS): a prospective registry study.

BACKGROUND: Treatment strategies for acute basilar artery occlusion (BAO) are based on case series and data that have been extrapolated from stroke intervention trials in other cerebrovascular territories, and information on the efficacy of different treatments in unselected patients with BAO is scarce. We therefore assessed outcomes and differences in treatment response after BAO. METHODS: The Basilar Artery International Cooperation Study (BASICS) is a prospective, observational registry of consecutive patients who presented with an acute symptomatic and radiologically confirmed BAO between November 1, 2002, and October 1, 2007. Stroke severity at time of treatment was dichotomised as severe (coma, locked-in state, or tetraplegia) or mild to moderate (any deficit that was less than severe). Outcome was assessed at 1 month. Poor outcome was defined as a modified Rankin scale score of 4 or 5, or death. Patients were divided into three groups according to the treatment they received: antithrombotic treatment only (AT), which comprised antiplatelet drugs or systemic anticoagulation; primary intravenous thrombolysis (IVT), including subsequent intra-arterial thrombolysis; or intra-arterial therapy (IAT), which comprised thrombolysis, mechanical thrombectomy, stenting, or a combination of these approaches. Risk ratios (RR) for treatment effects were adjusted for age, the severity of neurological deficits at the time of treatment, time to treatment, prodromal minor stroke, location of the occlusion, and diabetes. FINDINGS: 619 patients were entered in the registry. 27 patients were excluded from the analyses because they did not receive AT, IVT, or IAT, and all had a poor outcome. Of the 592 patients who were analysed, 183 were treated with only AT, 121 with IVT, and 288 with IAT. Overall, 402 (68%) of the analysed patients had a poor outcome. No statistically significant superiority was found for any treatment strategy. Compared with outcome after AT, patients with a mild-to-moderate deficit (n=245) had about the same risk of poor outcome after IVT (adjusted RR 0.94, 95% CI 0.60-1.45) or after IAT (adjusted RR 1.29, 0.97-1.72) but had a worse outcome after IAT compared with IVT (adjusted RR 1.49, 1.00-2.23). Compared with AT, patients with a severe deficit (n=347) had a lower risk of poor outcome after IVT (adjusted RR 0.88, 0.76-1.01) or IAT (adjusted RR 0.94, 0.86-1.02), whereas outcomes were similar after treatment with IAT or IVT (adjusted RR 1.06, 0.91-1.22). INTERPRETATION: Most patients in the BASICS registry received IAT. Our results do not support unequivocal superiority of IAT over IVT, and the efficacy of IAT versus IVT in patients with an acute BAO needs to be assessed in a randomised controlled trial. FUNDING: Department of Neurology, University Medical Center Utrecht.

An electronic voting platform with elliptic curve cryptography

The future of elections seems to be electronic voting systems du to its advantatges over the traditional voting. Nowadays, there are some different paradigms to ensure the security and reliability of e-voting. This document is part of a wider project which presents an e-Voting platform based on elliptic curve cryptography. It uses an hybrid combination of two of the main e-Voting paradigms to guarantee privacy and security in the counting phase, these are precisely, the mixnets and the homomorphic protocols. This document is focused in the description of the system and the maths and programming needed to solve the homomorphic part of it. In later chapters, there is a comparison between a simple mixing system and our system proposal.

Predisposing and precipitating factors of delirium after cardiac surgery: a prospective observational cohort study.

OBJECTIVE: To comprehensively assess pre-, intra-, and postoperative delirium risk factors as potential targets for intervention. BACKGROUND: Delirium after cardiac surgery is associated with longer intensive care unit (ICU) stay, and poorer functional and cognitive outcomes. Reports on delirium risk factors so far did not cover the full range of patients' presurgical conditions, intraoperative factors, and postoperative course. METHODS: After written informed consent, 221 consecutive patients ≥ 50 years scheduled for cardiac surgery were assessed for preoperative cognitive performance, and functional and physical status. Clinical and biochemical data were systematically recorded perioperatively. RESULTS: Of the 215 patients remaining for analysis, 31% developed delirium in the intensive care unit. Using logistic regression models, older age [73.3 (71.2-75.4) vs 68.5 (67.0-70.0); P = 0.016], higher Charlson's comorbidity index [3.0 (1.5-4.0) vs 2.0 (1.0-3.0) points; P = 0.009], lower Mini-Mental State Examination (MMSE) score (MMSE, [27 (23-29) vs 28 (27-30) points; P = 0.021], length of cardiopulmonary bypass (CPB) [CPB; 133 (112-163) vs 119 (99-143) min; P = 0.004], and systemic inflammatory response syndrome in the intensive care unit [25 (36.2%) vs 13 (8.9%); P = 0.001] were independently associated with delirium. Combining age, MMSE score, Charlson's comorbidity index, and length of CPB in a regression equation allowed for a prediction of postoperative delirium with a sensitivity of 71.19% and a specificity of 76.26% (receiver operating analysis, area under the curve: 0.791; 95% confidence interval: 0.727-0.845). CONCLUSIONS: Further research will evaluate if modification of these risk factors prevents delirium and improves outcomes.

Pregnancy outcomes following use of escitalopram: a prospective comparative cohort study.

Escitalopram is a serotonin reuptake inhibitor prescribed for depression and anxiety. There is a paucity of information regarding safety in pregnancy. The objective of this study was to determine whether escitalopram is associated with an increased risk for major malformations or other adverse outcomes following use in pregnancy. The authors analyzed pregnancy outcomes in women exposed to escitalopram (n = 212) versus other antidepressants (n = 212) versus nonteratogenic exposures (n = 212) and compared the outcomes. Among the escitalopram exposures were 172 (81%) live births, 32 (15%) spontaneous abortions, 6 (2.8%) therapeutic abortions, 3 stillbirths (1.7%), and 3 major malformations (1.7%). The only significant differences among groups was the rate of low birth weight (<2500 g) and overall mean birth weight (P = .225). However, spontaneous abortion rates were higher in both antidepressant groups (15% and 16%) compared with controls (8.5%; P = .066). There were lower rates of live births (P = .006), lower overall birth weight (P < .001), and increased rates of low birth weight (<2500 g; P = .009) with escitalopram. Spontaneous abortion rates were nearly double in both antidepressant groups (15% and 16%) compared with controls (8.5%) but not significant (P = .066). Escitalopram does not appear to be associated with an increased risk for major malformations but appears to increase the risk for low birth weight, which was correlated with the increase in infants weighing <2500 g. In addition, the higher rates of spontaneous abortions in both antidepressant groups confirmed previous findings.

Pancreatic stone protein as an early biomarker predicting mortality in a prospective cohort of patients with sepsis requiring ICU management.

ABSTRACT: INTRODUCTION: Biomarkers, such as C-reactive protein [CRP] and procalcitonin [PCT], are insufficiently sensitive or specific to stratify patients with sepsis. We investigate the prognostic value of pancreatic stone protein/regenerating protein (PSP/reg) concentration in patients with severe infections. METHODS: PSP/reg, CRP, PCT, tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL1-β), IL-6 and IL-8 were prospectively measured in cohort of patients ≥ 18 years of age with severe sepsis or septic shock within 24 hours of admission in a medico-surgical intensive care unit (ICU) of a community and referral university hospital, and the ability to predict in-hospital mortality was determined. RESULTS: We evaluated 107 patients, 33 with severe sepsis and 74 with septic shock, with in-hospital mortality rates of 6% (2/33) and 25% (17/74), respectively. Plasma concentrations of PSP/reg (343.5 vs. 73.5 ng/ml, P < 0.001), PCT (39.3 vs. 12.0 ng/ml, P < 0.001), IL-8 (682 vs. 184 ng/ml, P < 0.001) and IL-6 (1955 vs. 544 pg/ml, P < 0.01) were significantly higher in patients with septic shock than with severe sepsis. Of note, median PSP/reg was 13.0 ng/ml (IQR: 4.8) in 20 severely burned patients without infection. The area under the ROC curve for PSP/reg (0.65 [95% CI: 0.51 to 0.80]) was higher than for CRP (0.44 [0.29 to 0.60]), PCT 0.46 [0.29 to 0.61]), IL-8 (0.61 [0.43 to 0.77]) or IL-6 (0.59 [0.44 to 0.75]) in predicting in-hospital mortality. In patients with septic shock, PSP/reg was the only biomarker associated with in-hospital mortality (P = 0.049). Risk of mortality increased continuously for each ascending quartile of PSP/reg. CONCLUSIONS: Measurement of PSP/reg concentration within 24 hours of ICU admission may predict in-hospital mortality in patients with septic shock, identifying patients who may benefit most from tailored ICU management.

Isokinetic rotator muscles fatigue in glenohumeral joint instability before and after Latarjet surgery: a pilot prospective study.

We aimed to analyze the changes in isokinetic internal (IR) and external (ER) rotator muscles fatigue (a) in patients with non-operated recurrent anterior instability, and (b) before and after shoulder surgical stabilization with the Bristow-Latarjet procedure. Thirty-seven patients with non-operated unilateral recurrent anterior post-traumatic instability (NG) were compared with 12 healthy subjects [control group (CG)]. Twenty patients with operated recurrent anterior instability group (OG) underwent isokinetic evaluation before and 3, 6, and 21 months after Bristow-Latarjet surgery. IR and ER muscles strength was evaluated with Con-Trex® dynamometer, with subjects seated and at a 45° shoulder abduction angle in scapular plane. IR and ER muscle fatigue was determined after 10 concentric repetitions at 180° · s(-1) through the fatigue index, the percent decrease in performance (DP), and the slope of peak torque decrease. There were no differences in rotator muscles fatigue between NG and CG. In OG, 3 months post-surgery, IR DP of operated shoulder was significantly (P < 0.001) higher than presurgery and 6 and 21 months post-surgery. Rotator muscles fatigability was not associated with recurrent anterior instability. After surgical stabilization, there was a significantly higher IR fatigability in the operated shoulder 3 months post-surgery, followed by recovery evidenced 6 months post-surgery and long-term maintenance over 21 months.

Reproducibility of acute mountain sickness in children and adults : a prospective study

Objectif: Alors qu'un antécédent d' AMS est couramment utilisé pour fournir des conseils et recommander une prophylaxie médicamenteuse pour les expositions ultérieures à la haute altitude, la reproductibilité intra-individuelle de l'AMS au cours d'expositions répétées n'a jamais été examinée dans une étude prospective contrôlée. Méthodes : Chez 27 enfants et 29 adultes non acclimatés, nous avons évalué la présence et la sévérité de l' AMS durant les 48 premières heures après une montée rapide à 3450m, et ceci en deux occasions distantes de 9 à 12 mois. Résultats: 18 adultes (62 %) et 6 enfants (22 %) ont souffert d'AMS durant la première exposition et 14 adultes (48 %) et 4 enfants (15 %) durant la seconde (P=O.Ol, adultes versus enfants). Mais surtout, la reproductibilité intra-individuelle de l'AMS était très différente (P < 0.001) entre les deux groupes; en effet, aucun des 6 enfants ayant souffert d'AMS au cours de la première exposition n'en n'a souffert au cours de la seconde mais 4 enfants sans AMS lors de la première exposition ont été touchés lors de la seconde exposition. Contrairement à cela, 14 des 18 adultes qui ont souffert de 1' AMS lors de la première exposition ont également présenté ce problème au cours de la seconde et aucun nouveau cas ne s'est développé dans ceux qui n'avaient pas souffert de cette affection lors de la première occasion. ConClusion : Si chez 1' adulte, un antécédent d' AMS a une bonne valeur prédictive d'un nouvel épisode durant les expositions futures dans des conditions similaires, il n'en est pas de même chez l'enfant chez lequel il n'a pas de valeur prédictive. Un antécédent d'AMS ne devrait donc pas inciter les praticiens à déconseiller la réexposition ou à prescrire une prophylaxie médicamenteuse chez l'enfant.

Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts.

BACKGROUND: American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events. METHODS AND RESULTS: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH <0.45 mIU/L, the last two with normal free thyroxine levels. Among 25 390 participants, 2068 (8.1%) had subclinical hypothyroidism and 648 (2.6%) had subclinical hyperthyroidism. In age- and sex-adjusted analyses, risks of heart failure events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01); the hazard ratio was 1.01 (95% confidence interval, 0.81-1.26) for TSH of 4.5 to 6.9 mIU/L, 1.65 (95% confidence interval, 0.84-3.23) for TSH of 7.0 to 9.9 mIU/L, 1.86 (95% confidence interval, 1.27-2.72) for TSH of 10.0 to 19.9 mIU/L (P for trend <0.01) and 1.31 (95% confidence interval, 0.88-1.95) for TSH of 0.10 to 0.44 mIU/L and 1.94 (95% confidence interval, 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors. CONCLUSION: Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH ≥10 and <0.10 mIU/L.