Neurological outcomes in immune checkpoint inhibitor-related neurotoxicity.

While the spectrum of neurological immune checkpoint inhibitor-related adverse events is expanding, patients' outcomes are not well documented. This study aimed to assess outcomes of neurological immune-related adverse events and to identify prognostic factors. All patients experiencing grade ≥2 neurological immune-related adverse events identified at two clinical networks (French Reference Center for Paraneoplastic Neurological Syndromes, Lyon; and OncoNeuroTox, Paris) over five years were included. Modified Rankin scores were assessed at onset, 6, 12, 18 months, and last visit. A multi-state Markov model was used to estimate the transition rates between minor disability (mRS <3), severe disability (mRS 3-5), and death (mRS 6), over the study period. The state-to-state transition rates were estimated using maximum likelihood and variables were introduced into the different transitions to study their effects. A total of 147 patients were included out of 205 patients with a suspicion of neurological immune-related adverse events. The median age was 65 years (range 20-87) and 87/147 patients (59.2%) were male. Neurological immune-related adverse events involved the peripheral nervous system in 87/147 patients (59.2%), the central nervous system in 51/147 (34.7%), and both systems in 9/147 (6.1%). Paraneoplastic-like syndromes were observed in 30/147 patients (20.4%). Cancers included lung cancers (36.1%), melanoma (30.6%), urological cancers (15.6%), and others (17.8%). Patients were treated with programmed cell death protein (ligan) 1 (PD(L)1) inhibitors (70.1%), CTLA4 inhibitors (3.4%) or both (25.9%). Severe disability was reported in 108/144 patients (75.0%) at onset and in 33/146 patients (22.6%) at last visit (median follow-up duration: 12 months, range 0.5-50); 48/147 (32.7%) patients died, from cancer progression (17/48, 35.4%), neurological toxicity (15/48, 31.2%), other causes (10/48, 20.8%) or unknown causes (6/48, 12.5%). The rate of transition from severe to minor disability independently increased with melanoma [compared to lung cancer, hazard ratio = 3.26, 95%CI (1.27; 8.41)] and myositis/neuromuscular junction disorders [hazard ratio = 8.26, 95%CI (2.90; 23.58)], and decreased with older age [hazard ratio = 0.68, 95%CI (0.47; 0.99)] and paraneoplastic-like syndromes [hazard ratio = 0.29, 95%CI (0.09; 0.98)]. In patients with neurological immune-related adverse events, myositis/neuromuscular junction disorders and melanoma increase the transition rate from severe to minor disability, while older age and paraneoplastic-like syndromes result in poorer neurological outcomes; future studies are needed to optimize the management of such patients.

Stronger Impact of COVID-19 in Nursing Homes of a French Region During the Second Pandemic Wave.

OBJECTIVES: Quantify the effects of characteristics of nursing homes and their surroundings on the spread of COVID-19 outbreaks and assess the changes in resident protection between the first 2 waves (March 1 to July 31 and August 1 to December 31, 2020). DESIGN: An observational study was carried out on data on COVID-19 outbreaks extracted from a database that monitored the spread of the virus in nursing homes. SETTING AND PARTICIPANTS: The study concerned all 937 nursing homes with >10 beds in Auvergne-Rhône-Alpes region, France. METHODS: The rate of nursing homes with at least 1 outbreak and the cumulative number of deaths were modeled for each wave. RESULTS: During the second (vs the first wave), the proportion of nursing homes that reported at least 1 outbreak was higher (70% vs 56%) and the cumulative number of deaths more than twofold (3348 vs 1590). The outbreak rate was significantly lower in public hospital-associated nursing homes than in private for-profit ones. During the second wave, it was lower in public and private not-for-profit nursing homes than in private for-profit ones. During the first wave, the probability of outbreak and the mean number of deaths increased with the number of beds (P < .001). During the second wave, the probability of outbreak remained stable in >80-bed institutions and, under proportionality assumption, the mean number of deaths was less than expected in >100-bed institutions. The outbreak rate and the cumulative number of deaths increased significantly with the increase in the incidence of hospitalization for COVID-19 in the surrounding populations. CONCLUSIONS AND IMPLICATIONS: The outbreak in the nursing homes was stronger during the second than the first wave despite better preparedness and higher availabilities of tests and protective equipment. Solutions for insufficient staffing, inadequate rooming, and suboptimal functioning should be found before future epidemics.

Prior SARS-CoV-2 infection enhances and reshapes spike protein-specific memory induced by vaccination.

The diversity of vaccination modalities and infection history are both variables that have an impact on the immune memory of individuals vaccinated against SARS-CoV-2. To gain more accurate knowledge of how these parameters imprint on immune memory, we conducted a long-term follow-up of SARS-CoV-2 spike protein-specific immune memory in unvaccinated and vaccinated COVID-19 convalescent individuals as well as in infection-naïve vaccinated individuals. Here, we report that individuals from the convalescent vaccinated (hybrid immunity) group have the highest concentrations of spike protein-specific antibodies at 6 months after vaccination. As compared with infection-naïve vaccinated individuals, they also display increased frequencies of an atypical mucosa-targeted memory B cell subset. These individuals also exhibited enhanced TH1 polarization of their SARS-CoV-2 spike protein-specific follicular T helper cell pool. Together, our data suggest that prior SARS-CoV-2 infection increases the titers of SARS-CoV-2 spike protein-specific antibody responses elicited by subsequent vaccination and induces modifications in the composition of the spike protein-specific memory B cell pool that are compatible with enhanced functional protection at mucosal sites.

Lack of reproducibility of histopathological features in MYC-rearranged large B cell lymphoma using digital whole slide images: a study from the Lunenburg lymphoma biomarker consortium.

AIMS: Subclassification of large B cell lymphoma (LBCL) is challenging due to the overlap in histopathological, immunophenotypical and genetic data. In particular, the criteria to separate diffuse large B cell lymphoma (DLBCL) and high-grade B cell lymphoma (HGBL) are difficult to apply in practice. The Lunenburg Lymphoma Biomarker Consortium previously reported a cohort of over 5000 LBCL that included fluorescence in-situ hybridisation (FISH) data. This cohort contained 209 cases with MYC rearrangement that were available for a validation study by a panel of eight expert haematopathologists of how various histopathological features are used. METHODS AND RESULTS: Digital whole slide images of haematoxylin and eosin-stained sections allowed the pathologists to visually score cases independently as well as participate in virtual joint review conferences. Standardised consensus guidelines were formulated for scoring histopathological features and included overall architecture/growth pattern, presence or absence of a starry-sky pattern, cell size, nuclear pleomorphism, nucleolar prominence and a range of cytological characteristics. Despite the use of consensus guidelines, the results show a high degree of discordance among the eight expert pathologists. Approximately 50% of the cases lacked a majority score, and this discordance spanned all six histopathological features. Moreover, none of the histological variables aided in prediction of MYC single versus double/triple-hit or immunoglobulin-partner FISH-based designations or clinical outcome measures. CONCLUSIONS: Our findings indicate that there are no specific conventional morphological parameters that help to subclassify MYC-rearranged LBCL or select cases for FISH analysis, and that incorporation of FISH data is essential for accurate classification and prognostication.

Effective dose of ephedrine for treatment of hypotension after induction of general anaesthesia in neonates and infants less than 6 months of age: a multicentre randomised, controlled, open label, dose escalation trial.

BACKGROUND: The recommended dose of ephedrine in adults (0.1 mg kg-1) frequently fails to treat hypotension after induction of general anaesthesia in neonates and infants less than 6 months of age. The aim of this study was to determine the optimal dose of ephedrine in this population for the treatment of hypotension after induction of general anaesthesia with sevoflurane. METHODS: We conducted a multicentre, prospective, randomised, open-label, controlled, dose-escalation trial. Subjects were randomised if presenting a >20% change from baseline in MAP. Six cohorts of 20 subjects each were enrolled. Ten subjects in the first cohort received 0.1 mg kg-1 i. v. (reference dose). For each subsequent cohort, 10 subjects were assigned to the next higher dose (consecutively 0.6, 0.8, 1, 1.2, and 1.4 mg kg-1 i. v.), and the other subjects were assigned to one or more doses already investigated in previous cohorts. The primary outcome was the return of MAP to >80% of baseline at least once within 10 min after ephedrine administration. RESULTS: A total of 119 infants (25% females), with a mean age (standard deviation) of 2.7 (1.3) months, received their allocated dose of ephedrine. The optimal dose of ephedrine was 1.2 mg kg-1, with a percentage of success of 65.5% (95% confidence interval, 35.6-86.4). The doses of ephedrine investigated did not induce adverse events. CONCLUSIONS: Doses of ephedrine much higher (∼10-fold) than those used in adults are necessary in neonates and infants for the treatment of hypotension after induction of general anaesthesia with sevoflurane. CLINICAL TRIAL REGISTRATION: NCT02384876.

COVID-19 outbreaks in nursing homes: A strong link with the coronavirus spread in the surrounding population, France, March to July 2020.

BACKGROUND: Worldwide, COVID-19 outbreaks in nursing homes have often been sudden and massive. The study investigated the role SARS-CoV-2 virus spread in nearby population plays in introducing the disease in nursing homes. MATERIAL AND METHODS: This was carried out through modelling the occurrences of first cases in each of 943 nursing homes of Auvergne-Rhône-Alpes French Region over the first epidemic wave (March-July, 2020). The cumulative probabilities of COVID-19 outbreak in the nursing homes and those of hospitalization for the disease in the population were modelled in each of the twelve Départements of the Region over period March-July 2020. This allowed estimating the duration of the active outbreak period, the dates and heights of the peaks of outbreak probabilities in nursing homes, and the dates and heights of the peaks of hospitalization probabilities in the population. Spearman coefficient estimated the correlation between the two peak series. RESULTS: The cumulative proportion of nursing homes with COVID-19 outbreaks was 52% (490/943; range: 22-70% acc. Département). The active outbreak period in the nursing homes lasted 11 to 21 days (acc. Département) and ended before lockdown end. Spearman correlation between outbreak probability peaks in nursing homes and hospitalization probability peaks in the population (surrogate of the incidence peaks) was estimated at 0.71 (95% CI: [0.66; 0.78]). CONCLUSION: The modelling highlighted a strong correlation between the outbreak in nursing homes and the external pressure of the disease. It indicated that avoiding disease outbreaks in nursing homes requires a tight control of virus spread in the surrounding populations.

Rituximab in combination with adapted-dose of ifosfamide and etoposide as salvage treatment in elderly refractory/relapsed diffuse large B-cell lymphoma patients non-candidate for high dose therapy: a retrospective study.

We retrospectively reviewed for 72 relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) patients ineligible for autologous stem-cell transplantation (ASCT) treated between 2004 and 2017, efficacy and safety profile of rituximab (375 mg/m2) in combination with etoposide (300 mg/m2) and ifosfamide (1500 mg/m2) at 2, 3, or 4-week intervals. Median age was 79 years (range, 64-92). The median number of previous line was 1 (range 1-8). Patients received a median of six cycles (1-12). Fourteen patients (19%) presented partial and 14 complete responses (19%). Among the 369 cycles, nine patients developed febrile neutropenia (13%), 14 a grade 3-4 neutropenia (19%), 7 a grade 3-4 thrombocytopenia (10%) without grade 3-4 non-hematological toxicity. With a median follow up of 7.8 months, the median progression-free survival, overall survival, and duration of response were 4.4 months, 9.4 months, and 12 months, respectively. This regimen represents a therapeutic option in R/R DLBCL patients ineligible to ASCT.

Coffee consumption and seizure frequency in patients with drug-resistant focal epilepsy.

OBJECTIVE: To assess the relation between coffee consumption and seizure frequency in patients with drug-resistant focal epilepsy. METHODS: Cross-sectional analysis of data collected in the SAVE study, which included patients with drug-resistant focal epilepsy during long-term EEG monitoring. Patients in whom both coffee consumption and data about seizure frequency, including focal to bilateral tonic-clonic seizures (FBTCS), were available were selected. Coffee consumption was collected using a standardized self-report questionnaire and classified into four groups: none, rare (from less than 1 cup/week to up 3 cups/week), moderate (from 4 cups/week to 3 cups/day), and high (more than 4 cups/day). RESULTS: Six hundred and nineteen patients were included. There was no relation between coffee consumption and total seizure frequency (p = 0.902). In contrast, the number of FBTCS reported over the past year was significantly associated with usual coffee consumption (p = 0.029). Specifically, number of FBCTS in patients who reported moderate coffee consumption was lower than in others. In comparison with patients with moderate coffee consumption, the odds ratio (95%CI) for reporting at least 1 FBTCS per year was 1.6 (1.03-2.49) in patients who never take coffee, 1.62 (1.02-2.57) in those with rare consumption and 2.05 (1.24-3.4) in those with high consumption. Multiple ordinal logistic regression showed a trend toward an association between coffee consumption and number of FBTCS (p = 0.08). CONCLUSIONS AND RELEVANCE: Our data suggest that effect of coffee consumption on seizures might depend on dose with potential benefits on FBTCS frequency at moderate doses. These results will have to be confirmed by prospective studies.

Chromosomal instability in the prediction of pituitary neuroendocrine tumors prognosis.

The purpose of this study was to analyze the impact of copy number variations (CNV) on sporadic pituitary neuroendocrine tumors (PitNETs) prognosis, to identify specific prognosis markers according to the known clinico-pathological classification. CGH array analysis was performed on 195 fresh-frozen PitNETs (56 gonadotroph, 11 immunonegative, 56 somatotroph, 39 lactotroph and 33 corticotroph), with 5 years post-surgery follow-up (124 recurrences), classified according to the five-tiered grading classification (invasion, Ki-67, mitotic index and p53 positivity). Effect of alterations on recurrence was studied using logistic regression models. Transcriptomic analysis of 32 lactotroph tumors was performed. The quantity of CNV was dependent on tumor type: higher in lactotroph (median(min-max) = 38% (0-97) of probes) compared to corticotroph (11% (0-77)), somatotroph (5% (0-99)), gonadotroph (0% (0-10)) and immunonegative tumors (0% (0-17). It was not predictive of recurrence in the whole cohort. In lactotroph tumors, genome instability, especially quantity of gains, significantly predicted recurrence independently of invasion and proliferation (p-value = 0.02, OR = 1.2). However, no specific CNV was found as a prognostic marker. Transcriptomic analysis of the genes included in the CNV and associated with prognosis didn't show significantly overrepresented pathway. In somatotroph and corticotroph tumors, USP8 and GNAS mutations were not associated with genome disruption or recurrence respectively. To conclude, CGH array analysis showed genome instability was dependent on PitNET type. Lactotroph tumors were highly altered and the quantity of altered genome was associated with poorer prognosis though the mechanism is unclear, whereas gonadotroph and immunonegative tumors showed the same 'quiet' profile, leaving the mechanism underlying tumorigenesis open to question.

Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features.

OBJECTIVE: Antibodies against contactin-associated protein-like 2 (CASPR2-Abs) have been described in acquired neuromyotonia, limbic encephalitis (LE) and Morvan syndrome (MoS). However, it is unknown whether these constitute one sole spectrum of diseases with the same immunopathogenesis or three distinct entities with different mechanisms. METHODS: A cluster analysis of neurological symptoms was performed in a retrospective cohort of 56 CASPR2-Abs patients. In parallel, immunological features and human leucocyte antigen (HLA) were studied. RESULTS: Cluster analysis distinguished patients with predominant limbic symptoms (n=29/56) from those with peripheral nerve hyperexcitability (PNH; n=27/56). In the limbic-prominent group, limbic features were either isolated (LE/-; 18/56, 32.1%), or combined with extralimbic symptoms (LE/+; 11/56, 19.6%). Those with PNH were separated in one group with severe PNH and extralimbic involvement (PNH/+; 16/56, 28.6%), resembling historical MoS descriptions; and one group with milder and usually isolated PNH (PNH/-; 11/56, 19.6%). LE/- and LE/+ patients shared immunogenetic characteristics demonstrating a homogeneous entity. HLA-DRB1*11:01 was carried more frequently than in healthy controls only by patients with LE (94.1% vs 18.3%; p=1.3×10-10). Patients with LE also had serum titres (median 1:40 960) and rates of cerebrospinal fluid positivity (93.1%) higher than the other groups (p<0.05). Conversely, DRB1*11:01 association was absent in PNH/+ patients, but only they had malignant thymoma (87.5%), serum antibodies against leucine-rich glioma-inactivated 1 protein (66.7%) and against netrin-1 receptor deleted in colorectal carcinoma (53.8%), and myasthenia gravis (50.0%). INTERPRETATION: Symptoms' distribution supports specific clinical phenotypes without overlap between LE and MoS. The distinct immunogenetic characteristics shared by all patients with LE and the particular oncological and autoimmune associations of MoS suggest two very different aetiopathogenesis.

Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium.

PURPOSE: MYC rearrangement (MYC-R) occurs in approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and has been associated with poor prognosis in many studies. The impact of MYC-R on prognosis may be influenced by the MYC partner gene (immunoglobulin [IG] or a non-IG gene). We evaluated a large cohort of patients through the Lunenburg Lymphoma Biomarker Consortium to validate the prognostic significance of MYC-R (single-, double-, and triple-hit status) in DLBCL within the context of the MYC partner gene. METHODS: The study cohort included patients with histologically confirmed DLBCL morphology derived from large prospective trials and patient registries in Europe and North America who were uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or the like. Fluorescence in situ hybridization for the MYC, BCL2, BCL6, and IG heavy and light chain loci was used, and results were correlated with clinical outcomes. RESULTS: A total of 5,117 patients were identified of whom 2,383 (47%) had biopsy material available to assess for MYC-R. MYC-R was present in 264 (11%) of 2,383 patients and was associated with a significantly shorter progression-free and overall survival, with a strong time-dependent effect within the first 24 months after diagnosis. The adverse prognostic impact of MYC-R was only evident in patients with a concurrent rearrangement of BCL2 and/or BCL6 and an IG partner (hazard ratio, 2.4; 95% CI, 1.6 to 3.6; P < .001). CONCLUSION: The negative prognostic impact of MYC-R in DLBCL is largely observed in patients with MYC double hit/triple-hit disease in which MYC is translocated to an IG partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further.

Centralization errors in comparative genomic hybridization array analysis of pituitary tumor samples.

Reliable interpretation of comparative genomic hybridization array (aCGH) results requires centralization and normalization of the data. We evaluated the reliability of aCGH centralization by comparing aCGH results (with classical centralization-normalization steps) to fluorescence in situ hybridization (FISH) results. In addition, we propose a method to correct centralization bias. Sixty-six pituitary tumors were analyzed (Agilent aCGH + SNP 4 × 180K microarray). For each tumor, the FISH-based log2 (ratios) of a subset of chromosomes were compared with the corresponding aCGH raw log2 (ratios). With our new normalization-centralization process, this difference was added to all log2 (ratios), before performing loess regression on non-altered probes only. Finally, the mean log2 (ratio) and the percentage of normal probes were compared between CGHnormaliter and our new FISH-based method. For 11 tumors, FISH results and raw CGH log2 (ratios) differed significantly. In addition, nine tumors showed discrepancies between results generated by CGHnormaliter and our new-method. Such discrepancies seemed to occur with tumours with many abnormalities (0%-40% normal probes), rather than in those tumours with fewer abnormalities (31%-100% normal probes). Five tumors had too few normal probes to allow normalization. In these tumors, which can exhibit many changes in DNA copy number, we found that centralization bias was frequent and uncorrected by current normalization methods. Therefore, an external control for centralization, such as FISH analysis, is required to insure reliable interpretation of aCGH data.

Restricted mean survival time over 15 years for patients starting renal replacement therapy.

Background: The restricted mean survival time (RMST) estimates life expectancy up to a given time horizon and can thus express the impact of a disease. The aim of this study was to estimate the 15-year RMST of a hypothetical cohort of incident patients starting renal replacement therapy (RRT), according to their age, gender and diabetes status, and to compare it with the expected RMST of the general population. Methods: Using data from 67 258 adult patients in the French Renal Epidemiology and Information Network (REIN) registry, we estimated the RMST of a hypothetical patient cohort (and its subgroups) for the first 15 years after starting RRT (cRMST) and used the general population mortality tables to estimate the expected RMST (pRMST). Results were expressed in three different ways: the cRMST, which calculates the years of life gained under the hypothesis of 100% death without RRT treatment, the difference between the pRMST and the cRMST (the years lost), and a ratio expressing the percentage reduction of the expected RMST: (pRMST - cRMST)/pRMST. Results: Over their first 15 years of RRT, the RMST of end-stage renal disease (ESRD) patients decreased with age, ranging from 14.3 years in patients without diabetes aged 18 years at ESRD to 1.8 years for those aged 90 years, and from 12.7 to 1.6 years, respectively, for those with diabetes; expected RMST varied from 15.0 to 4.1 years between 18 and 90 years. The number of years lost in all subgroups followed a bell curve that was highest for patients aged 70 years. After the age of 55 years in patients with and 70 years in patients without diabetes, the reduction of the expected RMST was >50%. Conclusion: While neither a clinician nor a survival curve can predict with absolute certainty how long a patient will live, providing estimates on years gained or lost, or percentage reduction of expected RMST, may improve the accuracy of the prognostic estimates that influence clinical decisions and information given to patients.

Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort.

BACKGROUND: The occurrence of familial forms of sarcoidosis (OMIM 181100) suggests a genetic predisposition. The involvement of butyrophilin-like 2 (BTNL2) gene (rs2076530 variant) has to be investigated. RESULTS: The study performed independent analyses of BTNL2 polymorphism, clinical phenotypes, and outcomes in familial vs. sporadic presentations in 256 sporadic and 207 familial cases from 140 families. The logistic multivariate model showed that a young age at diagnosis and the combination of lung and skin involvement at diagnosis may distinguish sporadic from familial sarcoidosis (p = 0.016 and p = 0.041). We observed also that Sarcoid Clinical Activity Classification (SCAC) profiles were significantly different between familial and sporadic cases (p = 0.0497). Variant rs2076530 was more frequent in patients than in controls (OR = 2.02; 95% CI: [1.32-3.09]) but showed no difference between sporadic and familial cases and no difference according to the clinical phenotype or the outcome. CONCLUSION: Despite a significant difference in BTNL2 polymorphism between sarcoid patients and controls, there was no such difference between familial and sporadic sarcoidosis cases and no correlation between BTNL2 polymorphism and disease severity or outcome. Thus, BTNL2 difference cannot be considered as a key marker for disease classification or patient management.

[Cost-effectiveness analysis of various strategies of end-stage renal disease patients' care in France]. / Évaluation médico-économique des stratégies de prise en charge de l'insuffisance rénale chronique terminale en France.

End-stage renal disease is a chronic state that may continue for many years before death. Patients may receive various modalities of renal replacement therapy that vary over time, which we describe as a treatment trajectory. The French health insurance system pays dialysis facilities and professionals various fixed fees according to the dialysis modalities they provide; fees are highest for hospital-based haemodialysis care, which treats around 58% of all dialysis patients. As in other European countries, a variety of dialysis modalities are used in France, and their weight and distribution differ from region to region. This study hypothesizes that some patients currently treated in hospital-based haemodialysis could be treated with another RRT modality without any increase in mortality risk. The aim of this study was to propose new care strategies so as to evaluate the medico-economic impact of replacing some hospital-based HD care by various other modalities for French health insurance. Care strategies were modelled using a statistical tool that predicts course and trajectories of a hypothetical cohort of news patients over a 15-year period. The results confirmed that the development of kidney transplantation in six sub-cohorts (according to age and diabetes status) is an efficient strategy, compared to all evaluated strategies. Strategies considering joint development of peritoneal dialysis and hospital-based haemodialysis are efficient for patients over 45 years but their feasibility has to be evaluated. Other alternative strategies also need to be considered because they are as effective and less costly than the current care practices.

A graphical method to assess distribution assumption in group-based trajectory models.

Group-based trajectory models had a rapid development in the analysis of longitudinal data in clinical research. In these models, the assumption of homoscedasticity of the residuals is frequently made but this assumption is not always met. We developed here an easy-to-perform graphical method to assess the assumption of homoscedasticity of the residuals to apply especially in group-based trajectory models. The method is based on drawing an envelope to visualize the local dispersion of the residuals around each typical trajectory. Its efficiency is demonstrated using data on CD4 lymphocyte counts in patients with human immunodeficiency virus put on antiretroviral therapy. Four distinct distributions that take into account increasing parts of the variability of the observed data are presented. Significant differences in group structures and trajectory patterns were found according to the chosen distribution. These differences might have large impacts on the final trajectories and their characteristics; thus on potential medical decisions. With a single glance, the graphical criteria allow the choice of the distribution that best capture data variability and help dealing with a potential heteroscedasticity problem.

Economic impact of a modification of the treatment trajectories of patients with end-stage renal disease.

BACKGROUND: This study assumed that some patients currently treated at hospital-based haemodialysis centres can be treated with another renal replacement therapy (RRT) modality without any increase in mortality risk and sought to evaluate the monthly cost impact of replacing hospital-based haemodialysis, for which fees are highest, by different proportions of other modalities. METHODS: We used a deterministic model tool to predict the outcomes and trajectories of hypothetical cohorts of incident adult end-stage renal disease (ESRD) patients for 15 years of RRT (10 different modalities). Our estimates were based on data from 67 258 patients in the REIN registry and 65 662 patients in the French national health insurance information system. Patients were categorized into six subcohorts, stratified for age and diabetes at ESRD onset, and analyses run for each subcohort. We simulated new strategies of care by changing any or all of the following: initial distributions in treatment modalities, transition rates and some costs. Strategies were classified according to their monthly per-patient cost compared to current practices (cost-minimization analysis). RESULTS: Simulations of the status quo for the next 15 years predicted a per-patient monthly cost of €2684 for a patient aged 18-45 years without diabetes and €7361 for one older than 70 years with diabetes. All of the strategies we analysed had monthly per-patient costs lower than the status quo, except for daily home HD. None impaired expected survival. Savings varied by strategy. CONCLUSIONS: Alternative strategies may well be less expensive than current practices. The decision to implement new strategies must nonetheless consider the number of patients concerned, feasibility of renal care reorganization, and investment costs. It must also take into account the role of patients' choice and the availability of professionals.

Comparison of two next-generation sequencing kits for diagnosis of epileptic disorders with a user-friendly tool for displaying gene coverage, DeCovA.

In recent years, molecular genetics has been playing an increasing role in the diagnostic process of monogenic epilepsies. Knowing the genetic basis of one patient's epilepsy provides accurate genetic counseling and may guide therapeutic options. Genetic diagnosis of epilepsy syndromes has long been based on Sanger sequencing and search for large rearrangements using MLPA or DNA arrays (array-CGH or SNP-array). Recently, next-generation sequencing (NGS) was demonstrated to be a powerful approach to overcome the wide clinical and genetic heterogeneity of epileptic disorders. Coverage is critical for assessing the quality and accuracy of results from NGS. However, it is often a difficult parameter to display in practice. The aim of the study was to compare two library-building methods (Haloplex, Agilent and SeqCap EZ, Roche) for a targeted panel of 41 genes causing monogenic epileptic disorders. We included 24 patients, 20 of whom had known disease-causing mutations. For each patient both libraries were built in parallel and sequenced on an Ion Torrent Personal Genome Machine (PGM). To compare coverage and depth, we developed a simple homemade tool, named DeCovA (Depth and Coverage Analysis). DeCovA displays the sequencing depth of each base and the coverage of target genes for each genomic position. The fraction of each gene covered at different thresholds could be easily estimated. None of the two methods used, namely NextGene and Ion Reporter, were able to identify all the known mutations/CNVs displayed by the 20 patients. Variant detection rate was globally similar for the two techniques and DeCovA showed that failure to detect a mutation was mainly related to insufficient coverage.

Modelling treatment trajectories to optimize the organization of renal replacement therapy and public health decision-making.

BACKGROUND: Nephrologists need to better understand the impact of their decisions about long-term treatment strategies. Healthcare planning requires the anticipation of demand. Indicators from ESRD registries are especially difficult to interpret when the underlying dynamic process is not well understood. Therefore, we have developed a statistical tool to study the course of incident ESRD patient cohorts over time and to quantify, by simulations, the impact of various expected changes or new strategies. METHODS: Based on the data from 67 258 ESRD adult patients, we first estimated transition rates between 10 different modalities of treatment ('compartments') with a multistate model. In a second step, we predicted the number of patients in each compartment at each time point for a cohort of 1000 patients for 180 months after the onset of renal replacement therapy (RRT). We tested two scenarios to illustrate the possibility of simulating policy changes. RESULTS: Increased use of non-assisted automated peritoneal dialysis (PD) (from 7.7 to 19.2% at RRT onset) will not substantially influence the proportion of total RRT time in PD for patients aged 18-44 without diabetes. Improving access to kidney transplants from cadaveric donors for patients aged 45-69 with diabetes will increase the 15-year restricted mean lifetime by 5 months and the time spent with a functioning graft (34 versus 23%). CONCLUSIONS: A model based on patients' treatment trajectories can improve the description and understanding of RRT as a dynamic phenomenon. Its use for simulation may help professionals and decision-makers to optimize renal organization and care.