Early menstrual cycle impacts of oestrogen and progesterone on the timing of the fertile window.

STUDY QUESTION: What is the effect of oestrogen and progesterone at the beginning of the menstrual cycle in delaying entry into the fertile window? SUMMARY ANSWER: Both oestrogen and progesterone contribute to a delay in the onset of the fertile window. WHAT IS KNOWN ALREADY: Oestrogen enhances cervical mucus secretion while progesterone inhibits it. STUDY DESIGN, SIZE, DURATION: Observational study. Daily observation of 220 menstrual cycles contributed by 88 women with no known menstrual cycle disorder. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women recorded cervical mucus daily and collected first-morning urine samples for analysis of oestrone-3-glucuronide, pregnanediol-3-alpha-glucuronide (PDG), FHS, and LH. They underwent serial ovarian ultrasound examinations. The main outcome measure was the timing within the cycle of the onset of the fertile window, as identified by the appearance of mucus felt or seen at the vulva. MAIN RESULTS AND THE ROLE OF CHANCE: Low oestrogen secretion and persistent progesterone secretion during the first week of the menstrual cycle both negatively affect mucus secretion. Doubling oestrogen approximately doubled the odds of entering the fertile window (OR: 1.82 95% CI=1.23; 2.69). Increasing PDG from below 1.5 to 4 µg/mg creatinine was associated with a 2-fold decrease in the odds of entering the fertile window (OR: 0.51 95% CI=0.31; 0.82). Prolonged progesterone secretion during the first week of the menstrual cycle was also statistically significantly associated with higher LH secretion. Finally, the later onset of the fertile window was associated with statistically significant persistently elevated LH secretion during the luteal phase of the previous menstrual cycle. LIMITATIONS, REASONS FOR CAUTION: This post hoc study was conducted to assess the potential impact of residual progesterone secretion at the beginning of the menstrual cycle. It was conducted on an existing data set because of the scarcity of data available to answer the question. Analysis with other datasets with similar hormone results would be useful to confirm these findings. WIDER IMPLICATIONS OF THE FINDINGS: This study provides evidence for residual progesterone secretion in the early latency phase of some menstrual cycles, which may delay the onset of the fertile window. This progesterone secretion may be supported by subtly increased LH secretion during the few days before and after the onset of menses, which may relate to follicular waves in the luteal phase. Persistent progesterone secretion should be considered in predicting the onset of the fertile window and in assessing ovulatory dysfunction. STUDY FUNDING/COMPETING INTEREST(S): The authors declare no conflicts of interest. No funding was provided for this secondary data analysis. TRIAL REGISTRATION NUMBER: N/A.

Urinary gonadotropin assay on 24-h collections as a tool to detect early central puberty onset in girls: determination of predictive thresholds.

STUDY QUESTION: Is the 24-h urinary gonadotropin assay an effective diagnostic tool in central precocious puberty (CPP) in girls? SUMMARY ANSWER: This study is the first to provide 24-h urinary gonadotropin assay data, using an electrochemiluminescent immunoassay (CMIA), and to report its usefulness as a tool for the diagnosis of CPP. WHAT IS KNOWN ALREADY: Data about the GnRH test in the diagnosis of CPP are variable and there is no consensus regarding its interpretation. The measurement of FSH and LH in urines was previously reported to be an alternative biological tool. STUDY DESIGN, SIZE, DURATION: This is a retrospective two-cohort study, involving a setting and a validation cohort. A total of 516 girls, included between October 2012 and July 2015, and 632 urinary collections were analyzed in the setting cohort. In the validation cohort, 39 girls were included between January 2021 and May 2023, and 49 urinary collections were analyzed. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included girls who consulted for an investigation of disturbed growth rate or a clinical suspicion of puberty onset in different medical centres across France (setting cohort). Girls with a suspicion of precocious puberty onset were addressed at the expert centre of paediatric endocrinology of the Groupement Hospitalier Lyon Est (validation cohort). Pelvic ultrasonography was performed and enabled their classification according to clinical and morphologic changes criteria (prepubertal or pubertal groups). The parents collected 24-h urine samples (u24) according to standardized instructions. FSH and LH (urinary or plasmatic) were measured using a current and automated CMIA. MAIN RESULTS AND THE ROLE OF CHANCE: The area under the ROC curves for CPP prediction was 0.709 for u24FSH (P < 0.001), 0.767 for u24LH (P < 0.001), and 0.753 for the u24LH/u24FSH ratio (P < 0.001). We retained all possible combinations of the four thresholds in the validation cohort (u24FSH = 1.1 or 2.0 IU/24 h; u24LH = 0.035 or 0.08 IU/24 h). The combination of u24FSH > 1.1 IU/24 h and u24LH > 0.08 IU/24 h had a positive PV of 85.7% and a negative PV of 94.3%, a sensitivity of 85.7% and a specificity of 94.3%, for classifying prepubertal and pubertal girls in this cohort. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study, in which a margin of error remains due to the inherent uncertainty regarding the clinical assessment of pubertal onset. It must be considered that the thresholds can only apply to the used reagents; measurements without extractions using other reagents are likely to show important heterogeneity. WIDER IMPLICATIONS OF THE FINDINGS: The assay performed herein is a simple, non-invasive, and analytically robust technique meeting the criteria for an alternative to the GnRH test which could be used to supplement its lack of sensitivity. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used. All authors declared no conflict of interest. TRIAL REGISTRATION NUMBER: In-house #23-5214 registered study.

Clustering of trajectories with mixed effects classification model: Inference taking into account classification uncertainties.

Classifying patient biomarker trajectories into groups has become frequent in clinical research. Mixed effects classification models can be used to model the heterogeneity of longitudinal data. The estimated parameters of typical trajectories and the partition can be provided by the classification version of the expectation maximization algorithm, named CEM. However, the variance of the parameter estimates obtained underestimates the true variance because classification uncertainties are not taken into account. This article takes into account these uncertainties by using the stochastic EM algorithm (SEM), a stochastic version of the CEM algorithm, after convergence of the CEM algorithm. The simulations showed correct coverage probabilities of the 95% confidence intervals (close to 95% except for scenarios with high bias in typical trajectories). The method was applied on a trial, called low-cyclo, that compared the effects of low vs standard cyclosporine A doses on creatinine levels after cardiac transplantation. It identified groups of patients for whom low-dose cyclosporine may be relevant, but with high uncertainty on the dose-effect estimate.

Delaying testicular sperm extraction in 47,XXY Klinefelter patients does not impair the sperm retrieval rate, and AMH levels are higher when TESE is positive.

STUDY QUESTION: Should testicular sperm extraction (TESE) in non-mosaic 47,XXY Klinefelter syndrome (KS) patients be performed soon after puberty or could it be delayed until adulthood? SUMMARY ANSWER: The difference in sperm retrieval rate (SRR) in TESE was not significant between the 'Young' (15-22 years old) cohort and the 'Adult' (23-43 years old) cohort of non-mosaic KS patients recruited prospectively in parallel. WHAT IS KNOWN ALREADY: Several studies have tried to define predictive factors for TESE outcome in non-mosaic KS patients, with very heterogeneous results. Some authors have found that age was a pejorative factor and recommended performing TESE soon after puberty. To date, no predictive factors have been unanimously recognized to guide clinicians in deciding to perform TESE in azoospermic KS patients. STUDY DESIGN, SIZE, DURATION: Two cohorts (Young: 15-22 years old; Adult: 23-43 years old) were included prospectively in parallel. A total of 157 non-mosaic 47,XXY KS patients were included between 2010 and 2020 in the reproductive medicine department of the University Hospital of Lyon, France. However 31 patients gave up before TESE, four had cryptozoospermia and three did not have a valid hormone assessment; these were excluded from this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data for 119 patients (61 Young and 58 Adult) were analyzed. All of these patients had clinical, hormonal and seminal evaluation before conventional TESE (c-TESE). MAIN RESULTS AND THE ROLE OF CHANCE: The global SRR was 45.4%. SRRs were not significantly different between the two age groups: Young SRR=49.2%, Adult SRR = 41.4%; P = 0.393. Anti-Müllerian hormone (AMH) and inhibin B were significantly higher in the Young group (AMH: P = 0.001, Inhibin B: P < 0.001), and also higher in patients with a positive TESE than in those with a negative TESE (AMH: P = 0.001, Inhibin B: P = 0.036). The other factors did not differ between age groups or according to TESE outcome. AMH had a better predictive value than inhibin B. SRRs were significantly higher in the upper quartile of AMH plasma levels than in the lower quartile (or in cases with AMH plasma level below the quantification limit): 67.7% versus 28.9% in the whole population (P = 0.001), 60% versus 20% in the Young group (P = 0.025) and 71.4% versus 33.3% in the Adult group (P = 0.018). LIMITATIONS, REASONS FOR CAUTION: c-TESE was performed in the whole study; we cannot rule out the possibility of different results if microsurgical TESE had been performed. Because of the limited sensitivity of inhibin B and AMH assays, a large number of patients had values lower than the quantification limits, preventing the definition a threshold below which negative TESE can be predicted. WIDER IMPLICATIONS OF THE FINDINGS: In contrast to some studies, age did not appear as a pejorative factor when comparing patients 15-22 and 23-44 years of age. Improved accuracy of inhibin B and AMH assays in the future might still allow discrimination of patients with persistent foci of spermatogenesis and guide clinician decision-making and patient information. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by a grant from the French Ministry of Health D50621 (Programme Hospitalier de Recherche Clinical Régional 2008). The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: NCT01918280.

Dialysis-network variability in home dialysis use not explained by patient characteristics: a national registry-based cohort study in France.

BACKGROUND: Although associated with better quality of life and potential economic advantages, home dialysis use varies greatly internationally and appears to be underused in many countries. This study aimed to estimate the dialysis-network variability in home dialysis use and identify factors associated with (i) the uptake in home dialysis, (ii) the proportion of time spent on home dialysis and (iii) home dialysis survival (patient and technique). METHODS: All adults ≥18 years old who had dialysis treatment during 2017-2019 in mainland France were included. Mixed-effects regression models were built to explore factors including patient or residence characteristics and dialysis network associated with variation in home dialysis use. RESULTS: During 2017-2019, 7728/78 757 (9.8%) patients underwent dialysis at least once at home for a total of 120 594/1 508 000 (8%) months. The heterogeneity at the dialysis-network level and to a lesser extent the regional level regarding home dialysis uptake or total time spent was marginally explained by patient characteristics or residence and dialysis-network factors. Between-network heterogeneity was less for patient and technique survival. These results were similar when the analysis was restricted to home peritoneal dialysis or home hemodialysis. CONCLUSIONS: Variability between networks in the use of home dialysis was not fully explained by non-modifiable patient and residence characteristics. Our results suggest that to increase home dialysis use in France, one should focus on home dialysis uptake rather than survival. Financial incentives and a quality improvement programme should be implemented at the dialysis-network level to increase home dialysis use.

Understanding Long-term Evolution and Predictors of Sequelae of Ebola Virus Disease Survivors in Guinea: A 48-Month Prospective, Longitudinal Cohort Study (PostEboGui).

BACKGROUND: Longitudinal analyses are needed to better understand long-term Ebola virus disease (EVD) sequelae. We aimed to estimate the prevalence, incidence, and duration of sequelae and to identify risk factors associated with symptom occurrence among EVD survivors in Guinea. METHODS: We followed 802 EVD survivors over 48 months and recorded clinical symptoms with their start/end dates. Prevalence, incidence, and duration of sequelae were calculated. Risk factors associated with symptom occurrence were assessed using an extended Cox model for recurrent events. RESULTS: Overall, the prevalence and incidence of all symptoms decreased significantly over time, but sequelae remained present 48 months after Ebola treatment center discharge with a prevalence of 30.68% (95% confidence interval [CI] 21.40-39.96) for abdominal, 30.55% (95% CI 20.68-40.41) for neurologic, 5.80% (95% CI 1.96-9.65) for musculoskeletal, and 4.24% (95% CI 2.26-6.23) for ocular sequelae. Half of all patients (50.70%; 95% CI 47.26-54.14) complained of general symptoms 2 years' postdischarge and 25.35% (95% CI 23.63-27.07) 4 years' post-discharge. Hemorrhage (hazard ratio [HR], 2.70; P = .007), neurologic (HR 2.63; P = .021), and general symptoms (HR 0.34; P = .003) in the EVD acute phase were significantly associated with the further occurrence of ocular sequelae, whereas hemorrhage (HR 1.91; P = .046) and abdominal (HR 2.21; P = .033) symptoms were significantly associated with musculoskeletal sequelae. CONCLUSIONS: Our findings provide new insight into the long-term clinical complications of EVD and their significant association with symptoms in the acute phase, thus reinforcing the importance of regular, long-term follow-up for EVD survivors.

Effect of age and care organization on sources of variation in kidney transplant waiting list registration.

Despite national guidelines, medical practices and kidney transplant waiting list registration policies may differ from one dialysis/transplant unit to another. Benefit risk assessment variations, especially for elderly patients, have also been described. The aim of this study was to identify sources of variation in early kidney transplant waiting list registration in France. Among 16 842 incident patients during the period 2016-2017, 4386 were registered on the kidney transplant waiting list at the start of, or during the first year after starting, dialysis (26%). We developed various log-linear mixed effect regression models on three levels: patients, dialysis networks, and transplant centers. Variability was expressed as variance from the random intercepts (± standard error). Although patient characteristics have an important impact on the likelihood of registration, the overall magnitude of variability in registration was low and shared by dialysis networks and transplant centers. Between-transplant center variability (0.23 ± 0.08) was 1.8 higher than between-dialysis network variability (0.13 ± 0.004). Older age was associated with a lower probability of registration and greater variability between networks (0.04, 0.20, & 0.93 in the 18-64, 65-74, and 75-84 age groups). Targeted interventions should focus on elderly patients and/or certain regions with greater variability in waiting list access.

Trajectory clustering using mixed classification models.

Trajectory classification has become frequent in clinical research to understand the heterogeneity of individual trajectories. The standard classification model for trajectories assumes no between-individual variance within groups. However, this assumption is often not appropriate, which may overestimate the error variance of the model, leading to a biased classification. Hence, two extensions of the standard classification model were developed through a mixed model. The first one considers an equal between-individual variance across groups, and the second one considers unequal between-individual variance. Simulations were performed to evaluate the impact of these considerations on the classification. The simulation results showed that the first extended model gives a lower misclassification percentage (with differences up to 50%) than the standard one in case of presence of a true variance between individuals inside groups. The second model decreases the misclassification percentage compared with the first one (up to 11%) when the between-individual variance is unequal between groups. However, these two extensions require high number of repeated measurements to be adjusted correctly. Using human chorionic gonadotropin trajectories after curettage for hydatidiform mole, the standard classification model classified trajectories mainly according to their levels whereas the two extended models classified them according to their patterns, which provided more clinically relevant groups. In conclusion, for studies with a nonnegligible number of repeated measurements, the use, in first instance, of a classification model that considers equal between-individual variance across groups rather than a standard classification model, appears more appropriate. A model that considers unequal between-individual variance may find its place thereafter.

Women's dissatisfaction with inappropriate behavior by health care workers during childbirth care in France: A survey study.

BACKGROUND: Quality care during childbirth requires that health care providers have not only excellent skills but also appropriate and considerate attitudes and behavior. Few studies have examined the proportion of women in Western countries expressing dissatisfaction with such inappropriate or inconsiderate behavior. This study evaluated this proportion in a sample presumably representative of French maternity units. METHODS: This prospective multicenter study, using data from a selfadministered questionnaire, took place in 25 French maternity units during one week in September 2018. The primary outcome measure was mothers' self-reported dissatisfaction with blatantly inappropriate behavior (ie, inappropriate attitude, inadequate respect for privacy, insufficient gentleness of care, and/or inappropriate language) by health care workers in the delivery room. The secondary outcome was their self-reported dissatisfaction with these workers' inconsiderate behavior (ie, unclear and inappropriate information, insufficient participation in decision-making, or deficient consideration of pain). RESULTS: Of 803 potentially eligible women, 627 completed the questionnaire after childbirth; 5.62% (35/623, 95% CI: 3.94-7.73) reported dissatisfaction with blatantly inappropriate behaviors and 9.79% (61/623, 95% CI: 7.57-12.40) with inconsiderate behaviors. The main causes of dissatisfaction reported by women in this survey were the inadequate consideration of their pain and the failure to share decision-making. CONCLUSIONS: Most of the women were satisfied with how health care workers behaved towards them in the delivery room. Nonetheless, health care staff must be aware of women's demands for greater consideration of their expressions of pain and of their voice in decisions.

Enhanced Recovery after Robot-Assisted Partial Nephrectomy for Cancer: Is it Better for Patients to Have a Quick Discharge?

OBJECTIVES: The aim of the study was to assess the efficacy and safety of an enhanced recovery program (ERP) after robot-assisted partial nephrectomy (RAPN) for cancer. METHODS: It was a monocentric, retrospective, comparative study. An ERP after RAPN was introduced at our institution in 2015 and proposed to all consecutive patients admitted for RAPN. The control group for this study was composed of patients managed immediately before the introduction of the ERP. We collected information on patient characteristics, tumor sizes, ischemia times, biology, hospital length of stays, postoperative (≤30 days) complications, and readmission rates. Group comparisons were made using the Pearson χ2 test for qualitative data and the Student t test for quantitative data. RESULTS: Between 2015 and 2017, 112 patients were included in the ERP group. Fifty patients were included in the control group. Ninety patients in the ERP group (80.4%) were discharged at or before postoperative day (POD) 2 versus 10 patients (20%) in the control group (p < 0.001). There was no significant difference between the ERP and control groups for the urinary retention rate (respectively 3.6 vs. 2%; p = 0.593). Resumption of normal bowel function was significantly shorter in the ERP group (94.6% at POD1 vs. 69.6% in the control group, p < 0.001). There were no significant differences for postoperative complications (15.2% in the ERP group vs. 20% in the control group, p = 0.447) or readmissions within 30 days (8.04 vs. 0.2%, p = 0.140). CONCLUSIONS: ERP after RAPN seems to reduce postoperative length of stay without increasing postoperative complications or readmissions.

Men's experience of first fatherhood discovery: a descriptive study based on free hierarchical evocation by associative networks.

Objective and Background: Men's experiences of first-fatherhood discovery differ widely with various circumstances; they were examined according to the intended/unintended occurrence of partner's pregnancy.Methods: An Associative Network study targeted 44 first-time fathers and analysed their reactions to a stimulus-sentence 'In the first days after pregnancy announcement … 'Results: Word-associations formed 19 themes and 5 metathemes. The main metathemes were Emotional (30%), Cognitive (27%) and Relational (23%). Negative emotions were more frequent in unintended vs. intended pregnancies. Subthemes Chock, Feeling of unreality, Emotion control, Guilt, Denial, or Regret prevailed in unintended pregnancies. The major theme in all pregnancies was Personal advancement but subthemes Physical and psychological preparation and Responsibility prevailed in intended pregnancies vs. Acceptation and Personal progress in unintended pregnancies. Themes Relationships (with partner and others) were more frequently mentioned in unintended pregnancies vs. theme Logistics in intended pregnancies. Overall, the participants expressed opposed conflicting emotions but a desire for real involvement in pregnancy, birth, and child-raising.Conclusion: The participants proved interested and concerned. Fathers's presence and support should be solicited, accounted for, and valued by mothers-to-be and health professionals in all pregnancies. Involving fathers since pregnancy is essential for mental equilibrium, child-parent attachment, child and parent development, and family relationships.

Impact of the dialysate acid component on haemodialysis mortality rates.

BACKGROUND: No prospective study has evaluated the long-term effect on mortality of the new acid concentrates added to bicarbonate dialysate. The aim of this pharmacoepidemiological study was to evaluate the association between hydrochloric or citric acid-based dialysate and mortality on haemodialysis (HD). METHODS: This study included 117 796 patients with 3 723 887 months on HD recorded in the national French Renal Epidemiology and Information Network registry. Dialysate acid components were retrospectively reconstructed for each facility. All patients on HD were associated each month with an exposure based on that at their facility of treatment. We took each patient's time-varying exposure into account to calculate the monthly mortality rates for each exposure. Incidence rate ratios (IRRs) for mortality were calculated with a Poisson regression, with acetic acid as the reference. Regressions were adjusted for initial clinical characteristics (age, gender, previous cardiovascular events, active malignancy, diabetes, pulmonary disease, mobility), dialysis technique and location (in-centre, outpatient centre, self-care unit) and ESRD vintage, updated monthly. RESULTS: The crude mortality rate per 1000 patient-months with citric acid {11.5 [95% confidence interval (CI) 11.1-12.0]} was lower than with either acetic acid [12.9 (95% CI 12.8-13.1)] or hydrochloric acid [12.8 (95% CI 12.2-13.5)]. For the 2014-17 period, the IRR for mortality with citric acid [adjusted IRR 0.94 (95% CI 0.90-0.99)] and with hydrochloric acid [adjusted IRR 0.86 (95% CI 0.79-0.94)] were significantly lower than with acetic acid. CONCLUSION: This post-marketing study of long-term exposure to dialysate acidifiers at the patient level found the use of citric and hydrochloric acid-based dialysates, compared with acetic acid, was associated with lower mortality.

Drug prescription goals in primary care: a cross-sectional study.

BACKGROUND: Care goals are often implicit, although their identification is a key element of any prescription process. This study aimed to describe the clinical goals of drug prescriptions in general practice, their determinants and the agreement between physicians and patients. METHODS: This was a cross-sectional study conducted by 11 resident trainees acting as observers in 23 general practices. The residents recorded the indication and main physician's goal for all drugs prescribed during five consultation days in each practice in December 2015, and the main patient's goal for a sub-sample of consultations. We used an eight-category generic classification of prescription goals, including three specific (mortality, morbidity and cure), three non-specific (symptoms, quality of life, functioning) and two non-specified (other goal, no goal) categories. Analyses were based on a multivariable, multilevel model and on the kappa statistic applied to the sub-sample of consultations. RESULTS: The sample encompassed 2141 consultations and 5036 drugs. The main physicians' goal of drug prescriptions was to relieve symptoms (43.3%). The other goals were to decrease the risk of morbidity (22.4%), to cure disease (11.7%), to improve quality of life (10.6%), to decrease the risk of mortality (8.5%) and to improve functioning (1.8%). The choice of a specific goal was more frequent in patients with the following characteristics: over 50 (OR [1.09;1.15]), of male gender (OR [1.09;1.39]), with full financial coverage for a long-term condition (OR [1.47;1.97]), known by the physician (OR [1.19;2.23]), or with a somatic health problem (OR [2.56;4.17]). Cohen's kappa for drug prescription goals between the patients and the physicians was 0.26 (0.23-0.30). CONCLUSIONS: Physicians' goals are poorly shared with patients. It remains to be assessed whether it is possible to collect and discuss information on prescription goals on a daily basis.

Potential lethal outbreak of coronavirus disease (COVID-19) among the elderly in retirement homes and long-term facilities, France, March 2020.

Motivated by the potential devastating effect of a COVID-19 outbreak in retirement homes and long-term facilities for dependent elderly, we present the impact of worst-case scenarios in French institutions using a specific age structure and case-age fatality ratios. The death toll could equal the yearly death toll caused by seasonal influenza in those older than 65 years or could largely exceed that, depending on the final attack rate and proportion of infected institutions.

The area between ROC curves, a non-parametric method to evaluate a biomarker for patient treatment selection.

Treatment selection markers are generally sought for when the benefit of an innovative treatment in comparison with a reference treatment is considered, and this benefit is suspected to vary according to the characteristics of the patients. Classically, such quantitative markers are detected through testing a marker-by-treatment interaction in a parametric regression model. Most alternative methods rely on modeling the risk of event occurrence in each treatment arm or the benefit of the innovative treatment over the marker values, but with assumptions that may be difficult to verify. Herein, a simple non-parametric approach is proposed to detect and assess the general capacity of a quantitative marker for treatment selection when no overall difference in efficacy could be demonstrated between two treatments in a clinical trial. This graphical method relies on the area between treatment-arm-specific receiver operating characteristic curves (ABC), which reflects the treatment selection capacity of the marker. A simulation study assessed the inference properties of the ABC estimator and compared them with other parametric and non-parametric indicators. The simulations showed that the estimate of the ABC had low bias, power comparable to parametric indicators, and that its confidence interval had a good coverage probability (better than the other non-parametric indicator in some cases). Thus, the ABC is a good alternative to parametric indicators. The ABC method was applied to data of the PETACC-8 trial that investigated FOLFOX4 versus FOLFOX4 + cetuximab in stage III colon adenocarcinoma. It enabled the detection of a treatment selection marker: the DDR2 gene.

Relative prognostic impact of nutrition, anaemia, bone metabolism and cardiovascular comorbidities in elderly haemodialysis patients.

BACKGROUND: The prognostic impact of nutrition and chronic kidney disease (CKD) complications has already been described in elderly haemodialysis patients but their relative weights on risk of death remain uncertain. Using structural equation models (SEMs), we aimed to model a single variable for nutrition, each CKD complication and cardiovascular comorbidities to compare their relative impact on elderly haemodialysis patients' survival. METHODS: This prospective study recruited 3165 incident haemodialysis patients ≥75 years of age from 178 French dialysis units. Using SEMs, the following variables were computed: nutritional status, anaemia, mineral and bone disorder and cardiovascular comorbidities. Systolic blood pressure was also used in the analysis. Survival analyses used Poisson models. RESULTS: The population average age was 81.9 years (median follow-up 1.51 years, 35.5% deaths). All variables were significantly associated with mortality by univariate analysis. Nutritional status was the variable most strongly associated with mortality in the multivariate analysis, with a negative prognostic impact of low nutritional markers {incidence rate ratio [IRR] 1.42 per 1 standard deviation [SD] decrement [95% confidence interval (CI) 1.32-1.53]}. The 'cardiovascular comorbidities' variable was the second variable associated with mortality [IRR 1.19 per 1 SD increment (95% CI 1.11-1.27)]. A trend towards low intact parathyroid hormone and high serum calcium and low values of systolic blood pressure were also associated with poor survival. The variable 'anaemia' was not associated with survival. CONCLUSIONS: These findings should help physicians prioritize care in elderly haemodialysis patients with CKD complications, with special focus on nutritional status.

Unequal intra-group variance in trajectory classification.

Classifying patients into groups according to longitudinal series of measurements (ie, trajectory classification) has become frequent in clinical research. Most classification models suppose an equal intra-group variance across groups. This assumption is sometimes inappropriate because measurements in diseased subjects are often more heterogeneous than in healthy ones. We developed a new classification model for trajectories that uses unequal intra-group variance across groups and evaluated its impact on classification using simulations and a clinical study. The classification and typical trajectories were estimated using the classification Expectation Maximization (EM) algorithm to maximize the classification likelihood, the log-likelihood being profiled during the Maximization (M) step of the algorithm. The simulations showed that assuming equal intra-group variance resulted in a high misclassification rate (up to 50%) when the real intra-group variances were different. This rate was greatly reduced by allowing intra-group variances to be different. Similar classification was obtained when the real intra-group variances were equal, except when the total sample size and the number of repeated measurements were small. In a randomized trial that compared the effect of low vs standard cyclosporine A dose on creatinine levels after cardiac transplantation, the classification model with unequal intra-group variance led to more meaningful groups than with equal intra-group variance and showed distinct benefits of low dose. In conclusion, we recommend the use of a classification model for trajectories that allows for unequal intra-group variance across groups except when the number of repeated measurements and total sample size are small.

Multiple Micronutrient Plasma Level Changes Are Related to Oxidative Stress Intensity in Critically Ill Children.

OBJECTIVES: Micronutrient supplementation in critically ill adults remains controversial. In the pediatric setting, the impact of oxidative stress on the overall micronutrient status has been poorly explored, due to the limited number of studies and to confounding factors (i.e., malnutrition or extra losses). In order to better understand this phenomenon, we aim to describe micronutrient status, focusing on seven micronutrients, in well-nourished critically ill children presenting with severe oxidative stress. DESIGN: Prospective, transversal, observational, single-center study. SETTING: PICU, and anesthesiology department, Lyon, France. PATIENTS: Three groups of patients were clinically defined: severe oxidative stress PICU group (at least two organ dysfunctions), moderate oxidative stress PICU group (single organ dysfunction), and healthy control group (prior to elective surgery); oxidative stress intensity was controlled by measuring plasma levels of glutathione peroxidase and glutathione. Children presenting any former condition leading to micronutrient deficiency were excluded (malnutrition, external losses). INTERVENTIONS: Plasma levels of selenium, zinc, copper, vitamin A, vitamin E, vitamin C, and ß-carotene were measured in PICU oxidative stress conditions and compared with those of healthy children. MEASUREMENTS AND MAIN RESULTS: Two hundred one patients were enrolled (51, 48, and 102 in severe, moderate, and healthy control groups, respectively). Median age was 7.1 years (interquartile range, 2.1-13.8 yr). There was a significant trend (p < 0.02) toward plasma level decrease of six micronutrients (selenium, zinc, copper, vitamin E, vitamin C, and ß-carotene) while oxidative stress intensity increased. Biological markers of oxidative stress (glutathione peroxidase and glutathione) were in accordance with the clinical definition of the three groups. CONCLUSIONS: A multiple micronutrient deficiency or redistribution occurs in critically ill children presenting with severe oxidative stress. These findings will help to better identify children who might benefit from micronutrient supplementation and to design adapted supplementation trials in this particular setting.

Is Going Beyond Rasch Analysis Necessary to Assess the Construct Validity of a Motor Function Scale?

OBJECTIVE: To examine whether a Rasch analysis is sufficient to establish the construct validity of the Motor Function Measure (MFM) and discuss whether weighting the MFM item scores would improve the MFM construct validity. DESIGN: Observational cross-sectional multicenter study. SETTING: Twenty-three physical medicine departments, neurology departments, or reference centers for neuromuscular diseases. PARTICIPANTS: Patients (N=911) aged 6 to 60 years with Charcot-Marie-Tooth disease (CMT), facioscapulohumeral dystrophy (FSHD), or myotonic dystrophy type 1 (DM1). INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Comparison of the goodness-of-fit of the confirmatory factor analysis (CFA) model vs that of a modified multidimensional Rasch model on MFM item scores in each considered disease. RESULTS: The CFA model showed good fit to the data and significantly better goodness of fit than the modified multidimensional Rasch model regardless of the disease (P<.001). Statistically significant differences in item standardized factor loadings were found between DM1, CMT, and FSHD in only 6 of 32 items (items 6, 27, 2, 7, 9 and 17). CONCLUSIONS: For multidimensional scales designed to measure patient abilities in various diseases, a Rasch analysis might not be the most convenient, whereas a CFA is able to establish the scale construct validity and provide weights to adapt the item scores to a specific disease.

Effects on Mortality and Cardiovascular Events of Adherence to Guideline-Recommended Therapy 4 Years after Lower Extremity Arterial Revascularization.

BACKGROUND: All patients with lower extremity peripheral arterial disease (LE-PAD) should benefit from recommended pharmacologic therapies including antiplatelet agents, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and HMG-CoA-reductase inhibitors (statins). In the present study, this triple therapy was defined as the best medical treatment. This study was designed to determine the current risk of cardiovascular (CV) events and mortality and also to evaluate the effect of pharmacologic treatment on patient's survival, CV events, and additional vascular surgery in vascularized LE-PAD patients. This observational, cohort study analyzed prospectively collected data of 140 consecutive patients after hospitalization for LE-PAD revascularization in the vascular surgery department of our university hospital, between January 1 and June 30, 2013. METHODS: Data from guideline-recommended classes of medications (ACE, ARB, statins, and antiplatelet agents or anticoagulation) were collected at the time of discharge to hospitalization and at the end of the follow-up. Information about mortality, CV events, and additional vascular surgery was collected during follow-up. RESULTS: The mean follow-up of patients was 41 months. Mortality and CV events concerned 24% and 12% of the patients, respectively, and additional vascular surgery was performed in 33% of the patients. There was no difference in mortality and CV event rates according to pharmacologic treatment. Additional vascular surgery rate of LE-PAD patients with best medical treatment tended to be lower than without (incidence rate ratio = 0.5777; 95% confidence interval, 0.3101-1.06; P = 0.08). Best medical treatment was prescribed in 54% of patients at discharge of hospitalization. This proportion (54%) was statistically unchanged at the end of follow-up. CONCLUSIONS: In this small cohort, we failed to show that best medical treatment decreased mortality or CV event rates, but it tended to be associated with decreased additional vascular surgery rate. Further studies taking into consideration the control of CV risk factors could be interesting to demonstrate better outcome from LE-PAD patients with best medical treatment compared with LE-PAD patients without. There is an urgent need for a more effective implementation of currently recommended medication and a continued search after more effective pharmacologic treatment options in LE-PAD.