Cost-effectiveness of acupuncture versus standard care for pelvic and low back pain in pregnancy: A randomized controlled trial.

OBJECTIVE: To assess the cost-effectiveness of acupuncture for pelvic girdle and low back pain (PGLBP) during pregnancy. DESIGN: Pragmatic-open-label randomised controlled trial. SETTING: Five maternity hospitals. POPULATION: Pregnant women with PGLBP. METHOD: 1:1 randomization to standard care or standard care plus acupuncture (5 sessions by an acupuncturist midwife). MAIN OUTCOME MEASURE: Efficacy: proportion of days with self-assessed pain by numerical rating scale (NRS) ≤ 4/10. Cost effectiveness (societal viewpoint, time horizon: pregnancy): incremental cost per days with NRS ≤ 4/10. Indirect non-healthcare costs included daily compensations for sick leave and productivity loss caused by absenteeism or presenteeism. RESULTS: 96 women were allocated to acupuncture and 103 to standard care (total 199). The proportion of days with NRS ≤ 4/10 was greater in the acupuncture group than in the standard care group (61% vs 48%, p = 0.007). The mean Oswestry disability score was lower in the acupuncture group than with standard care alone (33 versus 38, Δ = 5, 95% CI: 0.8 to 9, p = 0.02). Average total costs were higher in the control group (€2947) than in the acupuncture group (€2635, Δ = -€312, 95% CI: -966 to +325), resulting from the higher indirect costs of absenteeism and presenteeism. Acupuncture was a dominant strategy when both healthcare and non-healthcare costs were included. Costs for the health system (employer and out-of-pocket costs excluded) were slightly higher for acupuncture (€1512 versus €1452, Δ = €60, 95% CI: -272 to +470). CONCLUSION: Acupuncture was a dominant strategy when accounting for employer costs. A 100% probability of cost-effectiveness was obtained for a willingness to pay of €100 per days with pain NRS ≤ 4.

Are elderly patients presenting with squamous cell carcinoma of the oral cavity given the appropriate treatment?

OBJECTIVES: There is no consensus for the specific management of elderly patients presenting with oral cavity squamous cell carcinomas (OC SCC). We report our findings in the treatment of primary OC SCC, for patients of 70 years of age or more, in a French university hospital center. PATIENTS AND METHODS: One hundred and twenty five patients diagnosed between 2000 and 2010, were included retrospectively. Independent risk factors of post-operative complications were identified using a logistic regression. The overall survival (OS) was estimated using the Kaplan Meier method. Independent factors of survival were calculated using a Cox model. RESULTS: The patient's median age was 78. Women presented significantly more premalignant lesions, less alcohol intoxication, and less tobacco consumption. Half of the population sample was staged T4 in the TNM classification. Eighty eight percent of the patients received a curative treatment. The independent risk factors for post-operative complications were T3/T4 stages (OR 4.3 [1.3-14.4]), lymph node metastasis (OR 6.9 [2.1-22.7]), and alcohol abuse (OR 3.5 [1.1-11.0]). The median OS was 14.0 months. The independent negative prognostic factors for OS for patients treated curatively were: age >79 years (HR 1.9 [1.2-3.2]), stage T2/T3/T4 tumor vs. T1 (HR = 3.0 [1.5-6.0], P = 0.001) and substandard surgery (HR = 1.8 [1.1-2.9], P = 0.03). CONCLUSIONS: The management of OC SCC in elderly patients is complex and requires collaboration among gerontologists, surgeons and oncologists. The treatment choice is related to the disease extent and preoperative morbid conditions.

Low level exercise echocardiography helps diagnose early stage heart failure with preserved ejection fraction: a study of echocardiography versus catheterization.

BACKGROUND: Increased left ventricular end-diastolic pressure (LVEDP) with exercise is an early sign of heart failure with preserved left ventricular ejection fraction (LVEF). The abnormal exercise increase in LVEDP is nonlinear, with most change occurring at low-level exercise. Data on non-invasive approach of this condition are scarce. Our objective was assessing E/e' to estimate low level exercise LVEDP using a direct invasive measurement as the reference method. METHODS AND RESULTS: Sixty patients with LVEF >50 % prospectively underwent both exercise cardiac catheterization and echocardiography. E/e' was measured at rest and during low-level exercise. Abnormal LVEDP was defined as >16 mmHg. Patients with a history of coronary artery disease and/or abnormal LV morphology were classified as having apparent cardiac disease (CD). Thirty-four (57 %) patients had elevated LVEDP only during exercise. Most of the change in LVEDP occurred since the first exercise level (25 W). There was a correlation between LVEDP and septal E/e' at rest and during exercise. Lateral E/e' and E/average e' ratio had worse correlations with LVEDP. In the whole population, exercise septal E/e' at 25 W had the best accuracy for abnormal exercise LVEDP, area under curve (AUC) = 0.79. However, while low-level exercise septal E/e' had a high accuracy in CD patients (n = 26, AUC = 0.96), E/e' was not linked to LVEDP in patients without CD (n = 34). CONCLUSION: Low-level exercise septal E/e' is valuable for predicting abnormal exercise LVEDP in patients with preserved LVEF and apparent CD. However, this new diagnosis approach appears not reliable in patients with normal LV morphology and without coronary artery disease. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov . Unique identifier: NCT01714752.

A randomized, controlled, double-blind, crossover trial of zonisamide in myoclonus-dystonia.

OBJECTIVE: To evaluate the efficacy and safety of zonisamide in patients with myoclonus-dystonia. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial of zonisamide (300 mg/d) in 24 patients with myoclonus-dystonia. Each treatment period consisted of a 6-week titration phase followed by a 3-week fixed-dose phase. The periods were separated by a 5-week washout period. The co-primary outcomes were action myoclonus severity (section 4 of the Unified Myoclonus Rating Scale [UMRS 4]) and myoclonus-related functional disability (UMRS 5). Secondary outcomes included dystonia severity, assessed with the movement and disability subscales of the Burke-Fahn-Marsden-Dystonia Rating Scale (BFM), the Clinical Global Impression-Improvement scale (CGI), and safety measures. Wilcoxon signed-rank tests for paired data were used to analyze treatment effects. RESULTS: Twenty-three patients (11 men, 12 women) were analyzed in the intention-to-treat analysis. Zonisamide significantly improved both action myoclonus (median improvement [95% confidence limits] -5 [-9.25 to -1.44], p = 0.003) and myoclonus-related functional disability (median improvement [95% confidence limits] -2 [-2.58 to -2.46], p = 0.007) compared to placebo. Zonisamide also significantly improved dystonia (BFM movement) compared to placebo (median improvement [95% confidence limits] -3 [-8.46 to 0.03], p = 0.009). No difference was found between zonisamide and placebo with respect to the CGI (median improvement [95% confidence limits] -1 [-1.31 to 0.09], p = 0.1). Zonisamide was well-tolerated. CONCLUSIONS: Zonisamide is well-tolerated and effective on the motor symptoms of myoclonus-dystonia. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that zonisamide improves myoclonus and related disability in patients with myoclonus-dystonia.

Early High-Volume Hemofiltration versus Standard Care for Post-Cardiac Surgery Shock. The HEROICS Study.

RATIONALE: Post-cardiac surgery shock is associated with high morbidity and mortality. By removing toxins and proinflammatory mediators and correcting metabolic acidosis, high-volume hemofiltration (HVHF) might halt the vicious circle leading to death by improving myocardial performance and reducing vasopressor dependence. OBJECTIVES: To determine whether early HVHF decreases all-cause mortality 30 days after randomization. METHODS: This prospective, multicenter randomized controlled trial included patients with severe shock requiring high-dose catecholamines 3-24 hours post-cardiac surgery who were randomized to early HVHF (80 ml/kg/h for 48 h), followed by standard-volume continuous venovenous hemodiafiltration (CVVHDF) until resolution of shock and recovery of renal function, or conservative standard care, with delayed CVVHDF only for persistent, severe acute kidney injury. MEASUREMENTS AND MAIN RESULTS: On Day 30, 40 of 112 (36%) HVHF and 40 of 112 (36%) control subjects (odds ratio, 1.00; 95% confidence interval, 0.64-1.56; P = 1.00) had died; only 57% of the control subjects had received renal-replacement therapy. Between-group survivors' Day-60, Day-90, intensive care unit, and in-hospital mortality rates, Day-30 ventilator-free days, and renal function recovery were comparable. HVHF patients experienced faster correction of metabolic acidosis and tended to be more rapidly weaned off catecholamines but had more frequent hypophosphatemia, metabolic alkalosis, and thrombocytopenia. CONCLUSIONS: For patients with post-cardiac surgery shock requiring high-dose catecholamines, the early HVHF onset for 48 hours, followed by standard volume until resolution of shock and recovery of renal function, did not lower Day-30 mortality and did not impact other important patient-centered outcomes compared with a conservative strategy with delayed CVVHDF initiation only for patients with persistent, severe acute kidney injury. Clinical trial registered with www.clinicaltrials.gov (NCT 01077349).

Dopaminergic denervation severity depends on COMT Val158Met polymorphism in Parkinson's disease.

BACKGROUND: Catecholamine-O-methyl-tranferase (COMT) initiates dopamine degradation. Its activity is mainly determined by a single nucleotide polymorphism in the COMT gene (Val158Met, rs4680) separating high (Val/Val, COMT(HH)), intermediate (Val/Met, COMT(HL)) and low metabolizers (Met/Met, COMT(LL)). We investigated dopaminergic denervation in the striatum in PD patients according to COMT rs4680 genotype. METHODS: Patients with idiopathic PD were assessed for motor severity (UPDRS-III rating scale in OFF-state), dopaminergic denervation using [123I]-FP-CIT SPECT imaging, and genotyped for the COMT rs4680 enzyme. [123I]-FP-CIT binding potential (BP) for each voxel was defined by the ratio of tracer-binding in the region of interest (striatum, caudate nucleus and putamen) to that in a region of non-specific activity. Genotyping was performed using TaqMan(®) SNP genotyping assay. We used a regression model to evaluate the effect of COMT genotype on the BP in the striatum and its sub-regions. RESULTS: Genotype distribution was: 11 (27.5%) COMT(HH), 26 (65%) COMT(HL) and 3 (7.5%) COMT(LL). There were no significant differences in disease severity, treatments, or motor scores between genotypes. When adjusted to clinical severity, gender and age, low and intermediate metabolizers showed significantly higher rates of striatal denervation (COMT(HL+LL) BP = 1.32 ± 0.04) than high metabolizers (COMT(HH), BP = 1.6 ± 0.08; F(1.34) = 9.0, p = 0.005). Striatal sub-regions showed similar results. BP and UPDRS-III motor scores (r = 0.44, p = 0.04) (p < 0.001) were highly correlated. There was a gender effect, but no gender-genotype interaction. CONCLUSIONS: Striatal denervation differs according to COMT-Val158Met polymorphism. COMT activity may play a role as a compensatory mechanism in PD motor symptoms.

Multicenter prospective validation of the Baveno IV and Baveno II/III criteria in cirrhosis patients with variceal bleeding.

UNLABELLED: The criteria for defining failure to control bleeding in cirrhosis patients were introduced at the Baveno II/III meetings and were widely used as endpoints in clinical trials. Because they lacked specificity, the Baveno IV criteria were proposed in 2005 and slightly modified in 2010 (Baveno V). These criteria included a new index for patients undergoing transfusion, called adjusted-blood-requirement-index (ABRI=number of blood units/(final-initial hematocrit+0.01)), with a cutoff value of 0.75. In this multicenter prospective study, we sought to 1) validate the Baveno IV/V criteria; 2) compare them to the Baveno II/III criteria; 3) assess ABRI performance using a standardized calculation. The key inclusion criteria were: 1) variceal bleeding; 2) cirrhosis; 3) no need to modify the transfusion policy. The patients were classified according to the Baveno IV, V, and II/III criteria. The gold standard for failure during a 5-day period was the clinical judgment of three independent experts, blinded to the Baveno assessments. A total of 249 patients were included. The experts' agreement in clinical judgment of the failure was 80%. Failure occurred in 20.5% of patients; the c-statistics were 0.72 versus 0.64 and 0.65 for Baveno IV versus Baveno II/III and Baveno V criteria (P=0.001 for both). ABRI did not improve the diagnostic performance of the Baveno IV criteria. The Baveno IV, but not Baveno II/III, criteria independently predicted survival. CONCLUSION: The Baveno IV criteria demonstrated a higher accuracy than the Baveno II/III and Baveno V criteria for assessing failure to control bleeding and predicted survival independently. Together, our results show that ABRI is not a useful metric, and the Baveno IV criteria should replace the Baveno II/III criteria.

Diagnostic and prognostic value of preoperative combined GFAP, IGFBP-2, and YKL-40 plasma levels in patients with glioblastoma.

BACKGROUND: Circulating proteins released by tumor cells have recently been investigated as potential single surrogate biomarkers for glioblastoma multiforme (GBM). The aim of the current hypothesis-generating study was to evaluate the diagnostic and prognostic role of preoperative insulin-like growth factor-binding protein 2 (IGFBP-2), chitinase-3-like protein 1 (YKL-40), and glial fibrillary acidic protein (GFAP) plasma levels in patients with GBM, both as single markers and as a combined profile. METHODS: Plasma samples from 111 patients with GBM and a subset of 40 patients with nonglial brain tumors were obtained preoperatively. Plasma from 99 healthy controls was also analyzed. IGFBP-2, YKL-40, and GFAP levels were determined using enzyme-linked immunoadsorbent assay tests. Their association with histological and radiological variables was assessed. RESULTS: Circulating levels of all 3 proteins were found to be significantly higher in patients with GBM compared with healthy controls (P < .01). Only YKL-40 and GFAP were found to demonstrate significant differences between patients with GBM and nonglial brain tumors (P = .04). GFAP was undetectable (<0.02 ng/mL) in all patients without GBM. A receiver operating characteristic analysis accounting for a 2-step diagnostic procedure including the 3 biomarkers afforded an area under the curve of 0.77 for differentiating patients with GBM from those with nonglial brain tumors. There was a significant correlation between tumor volume and plasma IGFBP-2 level (Spearman Rho correlation coefficient, 0.22; P = .025) and GFAP (Spearman Rho correlation coefficient, 0.36; P < .001) among patients with GBM. Preoperative plasma IGFBP-2 levels were found to be independently associated with worse overall survival among patients with GBM (hazard ratio, 1.3; P = .05). CONCLUSIONS: A combined profile of preoperative IGFBP-2, GFAP, and YKL-40 plasma levels could serve as an additional diagnostic tool for patients with inoperable brain lesions suggestive of GBM. In addition, IGFBP-2 levels appear to constitute an independent prognostic factor in patients with GBM.

Low titers of serum antibodies inhibiting hemagglutination predict fatal fulminant influenza A(H1N1) 2009 infection.

RATIONALE: The biology of fatal pandemic influenza infection remains undefined. OBJECTIVES: To characterize the virologic and immune parameters associated with severity or death in patients who required mechanical ventilation for A(H1N1) 2009 pneumonia of various degrees of severity during the two waves of the 2009-2011 pandemic in Paris, France. METHODS: This multicenter study included 34 unvaccinated patients with very severe or fatal confirmed influenza A(H1N1) infections. It analyzed plasma A(H1N1) 2009 reverse-transcriptase polymerase chain reaction, hemagglutinin 222G viral mutation, and humoral and cellular immune responses to the virus, assessed in hemagglutination inhibition (HI), microneutralization, ELISA, lymphoproliferative, ELISpot IFN-γ, and cytokine and chemokine assays. MEASUREMENTS AND MAIN RESULTS: The patients' median age was 35 years. Influenza A(H1N1) 2009 viremia was detected in 4 of 34 cases, and a 222G hemagglutinin mutation in 7 of 17 cases, all of them with sequential organ failure assessment greater than or equal to 8. HI antibodies were detectable in 19 of 26 survivors and undetectable in all six fatal fulminant cases. ELISA and microneutralization titers were concordant. B-cell immunophenotyping and plasma levels of immunoglobulin classes did not differ between patients who survived and died. After immune complex dissociation, influenza ELISA serology became strongly positive in the bronchoalveolar lavage of the two fatal cases tested. H1N1-specific T-cell responses in lymphoproliferative and IFN-γ assays were detectable in survivors' peripheral blood, and lymphoproliferative assays were negative in the three fatal cases tested. Plasma levels of IL-6 and IL-10 were high in fatal cases and correlated with severity. Finally, a negative HI serology 4 days after the onset of influenza symptoms predicted death from fulminant influenza (P = 0.04). CONCLUSIONS: Early negative A(H1N1) 2009 HI serology can predict death from influenza. This negative serology in fatal cases in young adults reflects the trapping of anti-H1N1 antibodies in immune complexes in the lungs, associated with poor specific helper T-cell response. Clinical trial registered with www.clinicaltrials.gov (NCT 01089400).

Doxycycline in Creutzfeldt-Jakob disease: a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a fatal, untreatable prion encephalopathy. Previous studies showed that doxycycline is effective in in-vitro and in-vivo models of disease, and patients with CJD who received compassionate treatment with doxycycline showed increased survival time compared with historical series. We therefore did a randomised, double-blind study of doxycycline versus placebo in CJD. METHODS: We recruited patients older than 18 years old who had a diagnosis of definite or probable sporadic CJD or genetic forms of the disease via Italian reference centres and the French national referral system. Patients were randomly assigned (ratio 1:1) to receive oral doxycycline (100 mg daily) or placebo under double-blind conditions from the day of randomisation to death. Centralised randomisation was done independently of enrolment or evaluation of patients using a minimisation method in Italy and a simple randomisation in France. Participants, caregivers, and clinicians were masked to group assignment. The primary efficacy variable was the survival time from randomisation. Interim analyses were planned to detect a significant effect of treatment as early as possible. This trial is registered with EudraCT, 2006-001858-27 for the Italian study and 2007-005553-34 for the French study. FINDINGS: From April 12, 2007, to Aug 19, 2010, in Italy, and from Jan 30, 2009, to Jan 10, 2012, in France, 121 patients with CJD were enrolled in the study, 62 of whom were randomly assigned to the treatment group and 59 to the placebo group. The first interim analysis showed absence of superiority of doxycycline compared with placebo, and the trial was stopped for futility. Efficacy analyses did not show significant differences between patients treated with doxycycline and placebo with regard to survival times (HR 1.1, 95% CI 0.8-1.7, p=0.50). Serious adverse events were judged not to be related to treatment, whereas a relation was deemed probable or possible for five non-serious adverse events that occurred in each treatment group. INTERPRETATION: Doxycycline at a dose of 100 mg per day was well tolerated but did not significantly affect the course of CJD, at variance with the results of previous observational studies. Our experience could be useful in the design of large multinational controlled trials of potential anti-prion molecules in this rare disease. FUNDING: Agenzia Italiana Farmaco, Italian Ministry of Health, AIEnP, and French Ministry of Health.

Comparable humoral response after two doses of adjuvanted influenza A/H1N1pdm2009 vaccine or natural infection in allogeneic stem cell transplant recipients.

BACKGROUND: The present study evaluated immunogenicity and tolerance of two-dose influenza A/H1N1pdm09 vaccination in allogeneic hematopoietic stem cell transplantation (HSCT) recipients, and compared the vaccine-induced humoral response to that triggered by natural infection in another group of HSCT patients. METHODS: Adult allogeneic HSCT recipients vaccinated with two doses of influenza A/H1N1pdm09 vaccine, separated by 3 weeks, and patients with proven influenza A/H1N1pdm09 infection were included. Antibody responses were measured by hemagglutination-inhibition assay 1) on days 0, 21, 42 and 6 months after the first vaccine injection in vaccinated patients and 2) before pandemic and after influenza A/H1N1pdm09 infection, in patients presented natural infection. RESULTS: At baseline, 3% of 59 recipients of adjuvanted vaccine and 0% of 20 infected patients were seroprotected (antibody titer≥1/40). Seroprotection rate observed 42 days after vaccination was not different from that observed after natural infection (66% and 60% respectively, p=0.78). In vaccinated patients, seroprotection rate increased significantly from 54% to 66% between day 21 and 42 (p=0.015). Moreover, after 6 months, seroprotection rate in 21 vaccinated patients was similar to that observed in 10 infected patients evaluated at least 76 days after infection (D76-217) (60% and 81% respectively, p=0.2). In multivariate analysis, no immunosuppressive treatment or chronic graft-versus-host disease (GVHD) and longer time between transplantation and vaccination/infection were associated with a stronger humoral response. The adjuvanted vaccine was safe with low rate of GVHD worsening. CONCLUSION: In HSCT recipients, two doses of influenza A/H1N1pdm09 adjuvanted vaccine were safe and induced a humoral response comparable to that triggered by natural infection in these patients.

Estimation of urinary stone composition by automated processing of CT images.

The objective of this article was developing an automated tool for routine clinical practice to estimate urinary stone composition from CT images based on the density of all constituent voxels. A total of 118 stones for which the composition had been determined by infrared spectroscopy were placed in a helical CT scanner. A standard acquisition, low-dose and high-dose acquisitions were performed. All voxels constituting each stone were automatically selected. A dissimilarity index evaluating variations of density around each voxel was created in order to minimize partial volume effects: stone composition was established on the basis of voxel density of homogeneous zones. Stone composition was determined in 52% of cases. Sensitivities for each compound were: uric acid: 65%, struvite: 19%, cystine: 78%, carbapatite: 33.5%, calcium oxalate dihydrate: 57%, calcium oxalate monohydrate: 66.5%, brushite: 75%. Low-dose acquisition did not lower the performances (P < 0.05). This entirely automated approach eliminates manual intervention on the images by the radiologist while providing identical performances including for low-dose protocols.

Non-invasive diagnosis of coronary artery disease using cardiogoniometry performed at rest.

PRINCIPLES: Cardiogoniometry is a non-invasive technique for quantitative three-dimensional vectorial analysis of myocardial depolarization and repolarization. We describe a method of surface electrophysiological cardiac assessment using cardiogoniometry performed at rest to detect variables helpful in identifying coronary artery disease. METHODS: Cardiogoniometry was performed in 793 patients prior to diagnostic coronary angiography. Using 13 variables in men and 10 in women, values from 461 patients were retrospectively analyzed to obtain a diagnostic score that would identify patients having coronary artery disease. This score was then prospectively validated on 332 patients. RESULTS: Cardiogoniometry showed a prospective diagnostic sensitivity of 64%, and a specificity of 82%. ECG diagnostic sensitivity was significantly lower, with 53% and a similar specificity of 75%. CONCLUSIONS: Cardiogoniometry is a new, noninvasive, quantitative electrodiagnostic technique which is helpful in identifying patients with coronary artery disease. It can easily be performed at rest and delivers an accurate, automated diagnostic score.

Neurological, cardiological, and oculomotor progression in 104 patients with Friedreich ataxia during long-term follow-up.

BACKGROUND: Friedreich ataxia (FA) is the most frequent autosomal recessive cerebellar ataxia. Although the phenotype is well known, disease progression has not been evaluated in a prospective manner. OBJECTIVE: To perform a long-term prospective follow-up of neurological, cardiological, and oculomotor function in patients with FA (FA patients). DESIGN: In this open-labeled prospective survey, we examined 104 FA patients every 6 months during a median period of 5 years (range, 6 months to 7 years), with a systematic standardized protocol. Data are reported as mean +/- SD. SETTING: Neurological examinations were performed at the Federation of Neurology and the Department of Genetics of the Salpêtrière Hospital, Paris, France. Cardiological follow-up was performed at the Department of Cardiology; oculomotor examinations were performed at the Institut National de la Santé et de la Récherche Médicale Unit 679, at the same hospital. Patients We studied 104 FA patients with a confirmed molecular diagnosis. None were receiving antioxidant therapy at baseline; 88 accepted treatment with the coenzyme Q(10) analogue idebenone (5 mg/kg per day). Sixteen preferred not to be treated. INTERVENTIONS: Neurological status was evaluated with the International Cooperative Ataxia Rating Scale (ICARS) and a quantitative writing test. Cardiological evaluations included echocardiography, electrocardiography, and Holter monitoring. Oculomotor function was evaluated by electro-oculography to determine the frequency of square wave jerks. RESULTS: The total ICARS score worsened during follow-up, whether or not the patients were treated with idebenone (1.93 +/- 0.25 and 4.43 +/- 1.56 points per year, respectively). The total ICARS score increased faster in patients with onset before age 15 years compared with the others (2.6 +/- 0.4 [n = 51] vs 1.1 +/- 0.3 [n = 37]; P = .05). The posture subscore increased faster in patients able to stand at baseline, who also had shorter disease durations than patients unable to stand (1.25 +/- 0.12 vs 0.47 +/- 0.22 point per year; P<.001). Neurological progression was underestimated, however, by the ICARS scores, which reached a plateau in patients with long disease durations. Oculomotor function slightly deteriorated (0.09 +/- 0.02 Hz per year; P<.001). Left ventricular mass index decreased (-4.1 +/- 1.5 g/m(2) per year; P = .008), as did ejection fraction (-1.32% +/- 0.29% per year; P<.001). CONCLUSIONS: The neurological condition of FA patients deteriorated slowly over time, even with idebenone treatment. Although cardiac hypertrophy decreased under treatment, cardiac function did not improve. The ICARS scale is not appropriate to evaluate the progression of FA in patients with long disease durations. Additional quantitative measures may improve the reliability of this scale.

Mixture modeling for the detection of subpopulations in a pharmacokinetic/pharmacodynamic analysis.

To be able to estimate accurately parameters entering a non-linear mixed effects model taking into account that one or more subpopulations of patients can exist rather than assuming that the entire population is best described by unimodal distributions for the random effects, we proposed a methodology based on the likelihood approximation using the Gauss-Hermite quadrature. The idea is to combine the estimation of the model parameters and the detection of homogeneous subgroups of patients in a given population using a Gaussian mixture for the distribution of the random effects. As the accuracy of the likelihood approximation is likely to govern the quality of the estimation of the different parameters entering the non-linear mixed effects model, we based this approximation on the use of an adjustable Gauss-Hermite quadrature. Moreover, to complete this methodology, we propose a strategy allowing the detection and explanation of heterogeneity based on the Kullback-Leibler test, which was used to estimate the number of components in the Gaussian mixture. In order to evaluate the capability of the method to take into account heterogeneity, this strategy was performed in a PK/PD analysis using the database and the structural model selected in a previous analysis. In this analysis, non-responders were found out using NONMEM [Beal and Sheiner. NONMEM Users Guides. NONMEM Project Group, University of California, San Francisio, 1992] in a population of diabetic patients treated with a once-a-day new formulation of an antidiabetic drug. The authors looked for a subpopulation of patients for whom the therapeutic effect would vanish. In this paper, we looked for subpopulations of patients exhibiting specificities with respect to different parameters entering the description of the effect. The results obtained with our approach are compared in terms of parameter estimation and heterogeneity detection to those obtained in the previous analysis.

Mortality in patients with Parkinson's disease treated by stimulation of the subthalamic nucleus.

Subthalamic nucleus (STN) stimulation improves motor disability and quality of life in patients with advanced Parkinson's disease (PD). Short-term mortality is low, but little is known about long-term mortality. We assessed mortality and causes of death in 171 consecutive PD patients treated by STN stimulation. Surgery was performed after a median lagtime of 13 years from PD onset at a median age of 57 years. The median follow-up after surgery was 41 months. Sixteen patients died 8 to 83 months after neurosurgery. Poorer cognitive function was the only predictive factor for mortality (standardized mortality ratio = 2.9; 95% confidence interval [CI], 1.6-4.7; P < 0.0001). Based on a historical comparison of 118 operated patients with 39 nonoperated patients from a different population, survival among operated patients was not better (hazard ratio = 1.2; 95% CI, 0.7-2.1).

Renal outcome after ciclosporin-induced nephrotoxicity.

BACKGROUND: Renal outcome after ciclosporin (CsA) is not clear in most studies involving patients with many renal comorbid conditions. We first report on renal function recovery after CsA in previously healthy kidney patients. METHODS: Uveitis patients, enroled in a unique single centre cohort follow-up study initiated in 1987, were prospectively evaluated for plasma creatinine and glomerular filtration rate (GFR) before, during (>2 years) and after (>6 months) CsA therapy. We hypothesized that CsA alters renal function progressively over time according to two additive exponential components (irreversible and reversible) and used a mixed linear model with exponential speed parameters maximizing the likelihood. RESULTS: Twenty-seven patients treated for 60+/-34 months (CsA 5.1+/-2.5 mg/kg/day) were followed up for 56+/-42 months after CsA withdrawal. Baseline creatinine was 0.92+/-0.15 mg/dl. The reversible effect of CsA was quantified as a 0.11+/-0.07 mg/dl increase in creatinine/100 mg CsA/day (P<0.001) and a 6.0+/-3.7 ml/min/1.73 m(2) decrease in GFR/100 mg CsA/day (P<0.0001). The irreversible effect was quantified as a 0.03+/-0.05 mg/dl increase in creatinine/100 g cumulative CsA received (P<0.007) and a decrease of 3.3+/-3.9 ml/min/1.73 m(2) GFR/100 g CsA. CONCLUSIONS: Although significant decrease in GFR is induced by low-dose CsA therapy in previously healthy kidney patients, renal function recovery is possible after CsA withdrawal and best predicted by CsA daily dosage. Irreversible loss in GFR is correlated to cumulated CsA exposure. The lowest CsA dosage and shortest exposure time effect as well as unlimited renal monitoring are required in order to provide the best long-term renal outcome.

Phase II multi-step planning methods in oncology: comparison, recommendations and potential applications.

Phase II clinical trials in oncology are commonly used to determine whether a new treatment has a sufficient response rate to be compared with the best standard therapy in phase III. The multi-step planning methods such as Fleming's procedure and the triangular test adapted for phase II trials were elaborated to terminate phase II trials early. We compared these methods considering a fixed number of steps (4 or 5) on their statistical properties: overall type II error and observed type II error, average number of subjects necessary to conclude, probability to conclude at each step and maximum number of subjects necessary to conclude. Fleming's procedure has an actual power similar to the theoretical power for low to high response rate. In contrast, triangular test has an actual power different from the theoretical power in a few situations: it was very high in case of a very low minimum response rate and very low (<20%) in case of a very high minimum response rate (>80%). In these situations, Fleming's procedure and triangular test were not compared and triangular test cannot be recommended. For intermediate response rate, triangular test required a lower average number of subjects to conclude, a larger number of subjects at each step and thus a larger maximum number of subjects. It provided a larger probability to conclude during the first steps. These advantages should be balanced with the risk to have to include a larger number of patients. Multi-step methods, when correctly used are useful for cytotoxic development when response rate is the end point. They can also be used in trials where toxicity is the end point, and could be of great interest for cytostatic development for example with biological surrogate endpoints. An example using real phase II data is also presented.

Living donor liver transplantation in high-risk vs. low-risk patients: optimization using statistical models.

Living donors represent a recognized alternative for facilitating the access to transplantation in a period of organ shortage. However, which candidates should be preferentially considered for living-donor liver transplantation (LDLT) is debated. The aim of this study was to create statistical models to determine which strategies of selection for LDLT provide the most efficient contribution. The study included 331 patients listed for deceased-donor transplantation (DDLT) and 128 transplanted with living donors. Statistical models predicting the events following listing were created and combined in a multistate model allowing the testing of different strategies of selection for LDLT and to compare their results. Taking 3-yr survival after listing as the principal end-point, selecting the 20% patients at highest risk of death on the waiting list gave better results than selecting the 20% patients at lowest risk of death after LDLT (70% vs. 64%, respectively). These strategies resulted in waiting list mortality rates of 17% and 8%, respectively. One-year survival after LDLT was lower in high-risk patients (85%) than in low-risk patients (91%). However, the 1-yr survival benefit derived from LDLT was 75% in high-risk patients while it was nil in low-risk patients. In conclusion, LDLT is more effective for overcoming the consequences of organ shortage when performed in patients at high risk of death on the waiting list. On an individual basis, the sickest patients are those who derive the most important benefit from LDLT. This study provides incentives for considering LDLT in high-risk patients.