Work Environment Differences Between Outpatient and Inpatient Surgery: A Pilot Study on the Vascular Surgeons' Perceptions.

BACKGROUND: In France, outpatient endovascular surgical procedures have been slowly implemented in hospitals since 2015. Their development has been heterogeneous across France and is not yet the standard of care despite their benefits concerning patients' outcomes and healthcare professionals' satisfaction. However, since the COVID-19 pandemic, the demand for patient beds has been increasing, while human resources have been decreasing. This encouraged the surgery service reorganization and accelerated the shift from inpatient to outpatient surgery. Consequently, services had to adapt rapidly and this may have caused some strain on the hospital medical workforce. The objectives of this pilot study were to document and analyze the nursing staff (nurses and certified assistant nurses) well-being and workload as perceived by the vascular surgeons working with them. It also wanted to assess the link between the nursing staff's psychosocial stress and the surgeons' concentration and serenity in their workplace, based on the assumption that the well-being of both parties is inextricably linked. METHODS: An observational study was conducted using an online questionnaire distributed to the senior members of the French society of vascular and endovascular surgery (n = 490) between October 10 and October 18, 2022. RESULTS: In total, 125 surgeons completed the questionnaire (25% response rate). The main finding was that according to 68% of vascular surgeons, the nursing staff's psychosocial stress significantly impaired their serenity and concentration at work and this frequently affected the surgical procedure safety. The main sources of psychosocial stress were the high work pace (64%), demand for flexibility (56%), lack of anticipation of schedule changes (82%), and difficulties encountered in relaying these concerns to hospital managers (44.6%). CONCLUSIONS: This study demonstrated that concomitantly with the forced acceleration of outpatient activity implementation, the vascular surgeons' perceptions of their working environment are deteriorating, especially in conventional (inpatient) surgery wards where the workload is increasing and patients have more comorbidities. The worsened psychosocial stress of surgeons and staff affects the care provided.

Geographical Ambulatory Endovascular Revascularisation Disparities in France From 2015 to 2019.

OBJECTIVE: Despite efficiency and safety evidence, ambulatory endovascular revascularisation for lower extremity arterial disease (LEAD) accounted for only 5% of interventions in France in 2016. Such a low rate suggests temporal and geographical space disparities. The aim of this study was to describe the space-time development of ambulatory endovascular revascularisation for LEAD in France and to investigate the contributions of healthcare services and population characteristics as potential determinants. METHODS: A retrospective study of discharge data from French hospitals that performed endovascular procedures for LEAD between 2015 and 2019 was conducted. Space-time analyses with Moran's Index, zero inflated Poisson regression, and clustering approaches were applied. Spatial clusters were compared on the basis of healthcare services and population characteristics (including poverty and single man household as proxies of social isolation). RESULTS: Between 2015 and 2019, the number of ambulatory interventions tripled (1 104 vs.3 130). Of the 86 French departments, the proportion with >5% of ambulatory interventions increased from 10.7% to 28.7% over the study period. In 2019, ambulatory activity in French departments ranged from 0% to 39%. This change was accompanied by a northwest to northeast spatial trend. The clusters of 27 departments with substantial ambulatory activity differed from the others notably by the mortality rate of lower limb arterial thromboembolic diseases in males (OR 3.15, 95% CI 1.2-8.1), the proportion of single man households of age ≥75 (OR 0.37, 95% CI 0.2-0.8), and the poverty rate of people aged 50-59 years (OR 0.69, 95% CI 0.5-0.9). CONCLUSIONS: The development of ambulatory interventions for LEAD in France is encouraging but heterogeneous. Some determinants of this evolution are clearly population based, with a positive impact of needs to take care of the burden of LEAD but negative effects of social isolation and poverty. Research should be conducted to overcome some patient constraints such as isolation.

Premature mortality attributable to COVID-19: potential years of life lost in 17 countries around the world, January-August 2020.

BACKGROUND: Understanding the impact of the burden of COVID-19 is key to successfully navigating the COVID-19 pandemic. As part of a larger investigation on COVID-19 mortality impact, this study aims to estimate the Potential Years of Life Lost (PYLL) in 17 countries and territories across the world (Australia, Brazil, Cape Verde, Colombia, Cyprus, France, Georgia, Israel, Kazakhstan, Peru, Norway, England & Wales, Scotland, Slovenia, Sweden, Ukraine, and the United States [USA]). METHODS: Age- and sex-specific COVID-19 death numbers from primary national sources were collected by an international research consortium. The study period was established based on the availability of data from the inception of the pandemic to the end of August 2020. The PYLL for each country were computed using 80 years as the maximum life expectancy. RESULTS: As of August 2020, 442,677 (range: 18-185,083) deaths attributed to COVID-19 were recorded in 17 countries which translated to 4,210,654 (range: 112-1,554,225) PYLL. The average PYLL per death was 8.7 years, with substantial variation ranging from 2.7 years in Australia to 19.3 PYLL in Ukraine. North and South American countries as well as England & Wales, Scotland and Sweden experienced the highest PYLL per 100,000 population; whereas Australia, Slovenia and Georgia experienced the lowest. Overall, males experienced higher PYLL rate and higher PYLL per death than females. In most countries, most of the PYLL were observed for people aged over 60 or 65 years, irrespective of sex. Yet, Brazil, Cape Verde, Colombia, Israel, Peru, Scotland, Ukraine, and the USA concentrated most PYLL in younger age groups. CONCLUSIONS: Our results highlight the role of PYLL as a tool to understand the impact of COVID-19 on demographic groups within and across countries, guiding preventive measures to protect these groups under the ongoing pandemic. Continuous monitoring of PYLL is therefore needed to better understand the burden of COVID-19 in terms of premature mortality.

Does the edge effect impact on the measure of spatial accessibility to healthcare providers?

BACKGROUND: Spatial accessibility indices are increasingly applied when investigating inequalities in health. Although most studies are making mentions of potential errors caused by the edge effect, many acknowledge having neglected to consider this concern by establishing spatial analyses within a finite region, settling for hypothesizing that accessibility to facilities will be under-reported. Our study seeks to assess the effect of edge on the accuracy of defining healthcare provider access by comparing healthcare provider accessibility accounting or not for the edge effect, in a real-world application. METHODS: This study was carried out in the department of Nord, France. The statistical unit we use is the French census block known as 'IRIS' (Ilot Regroupé pour l'Information Statistique), defined by the National Institute of Statistics and Economic Studies. The geographical accessibility indicator used is the "Index of Spatial Accessibility" (ISA), based on the E2SFCA algorithm. We calculated ISA for the pregnant women population by selecting three types of healthcare providers: general practitioners, gynecologists and midwives. We compared ISA variation when accounting or not edge effect in urban and rural zones. The GIS method was then employed to determine global and local autocorrelation. Lastly, we compared the relationship between socioeconomic distress index and ISA, when accounting or not for the edge effect, to fully evaluate its impact. RESULTS: The results revealed that on average ISA when offer and demand beyond the boundary were included is slightly below ISA when not accounting for the edge effect, and we found that the IRIS value was more likely to deteriorate than improve. Moreover, edge effect impact can vary widely by health provider type. There is greater variability within the rural IRIS group than within the urban IRIS group. We found a positive correlation between socioeconomic distress variables and composite ISA. Spatial analysis results (such as Moran's spatial autocorrelation index and local indicators of spatial autocorrelation) are not really impacted. CONCLUSION: Our research has revealed minor accessibility variation when edge effect has been considered in a French context. No general statement can be set up because intensity of impact varies according to healthcare provider type, territorial organization and methodology used to measure the accessibility to healthcare. Additional researches are required in order to distinguish what findings are specific to a territory and others common to different countries. It constitute a promising direction to determine more precisely healthcare shortage areas and then to fight against social health inequalities.

Assessment of the spatial accessibility to health professionals at French census block level.

BACKGROUND: The evaluation of geographical healthcare accessibility in residential areas provides crucial information to public policy. Traditional methods - such as Physician Population Ratios (PPR) or shortest travel time - offer only a one-dimensional view of accessibility. This paper developed an improved indicator: the Index of Spatial Accessibility (ISA) to measure geographical healthcare accessibility at the smallest available infra-urban level, that is, the Îlot Regroupé pour des Indicateurs Statistiques. METHODS: This study was carried out in the department of Nord, France. Healthcare professionals are geolocalized using postal addresses available on the French state health insurance website. ISA is derived from an Enhanced Two-Step Floating Catchment Area (E2FCA). We have constructed a catchment for each healthcare provider, by taking into account residential building centroids, car travel time as calculated by Google Maps and the edge effect. Principal Component Analyses (PCA) were used to build a composite ISA to describe the global accessibility of different kinds of health professionals. RESULTS: We applied our method to studying geographical healthcare accessibility for pregnant women, by selecting three types of healthcare provider: general practitioners, gynecologists and midwives. A total of 3587 healthcare providers are potentially able to provide care for inhabitants of the department of Nord. On average there are 92 general practitioners, 22 midwives and 21 gynecologists per 100,000 residents. The composite ISA for the three types of healthcare provider is 39 per 100,000 residents. A comparative analysis between ISA and physician-population ratios indicates that ISA represents a more even distribution whereas the physician-population ratios show an 'all-or-nothing' approach. CONCLUSION: ISA is a multidimensional and improved measure, which combines the volume of services relative to population size with the proximity of services relative to the population's location, available at the smallest feasible geographical scale. It could guide policy makers towards highlighting critical areas in need of more healthcare providers, and these areas should be earmarked for further knowledge-based policy making.

Mining care trajectories using health administrative information systems: the use of state sequence analysis to assess disparities in prenatal care consumption.

BACKGROUND: Pregnant women are a vulnerable population. Although regular follow-ups are recommended during pregnancy, not all pregnant women seek care. This pilot study wanted to assess whether the integration of data from administrative health information systems and socio-economic features allows identifying disparities in prenatal care trajectories. METHODS: Prenatal care trajectories were extracted from the permanent sample of the French health insurance information system linked to the hospital discharge information system. The records of 2518 women who gave birth without complications in France in 2009 were analyzed. State sequence data analysis was performed to identify homogeneous groups of prenatal care trajectories. Socio-economic data were used to characterize their living environment. RESULTS: We identified three groups of homogeneous prenatal care trajectories: (i) women with relatively high prenatal care consumption (~11%), (ii) women with no prenatal care (~21%), and (iii) women with an intermediate level of prenatal care (~66%). Analysis of the socio-economic data demonstrated the association between disparities in prenatal care trajectories and the women's living environment. Women with relatively high care consumption generally lived in socio-economically privileged areas (better education levels, employment status and housing conditions) compared with women with few or no prenatal care. CONCLUSIONS: Although ecological, our approach demonstrates that data from health administrative information systems could be used to describe prenatal care. However, more individual variables and an improvement of the data quality are needed to efficiently monitor the content and timing of prenatal care. Moreover, state sequence analysis, which was used in this context for the first time, proves to be an interesting approach to explore care trajectories. Finally, the integration of heterogeneous sources of data, including contextual information, might help identifying areas that require health promotion actions toward vulnerable populations, such as pregnant women.

Integrative analysis of high-throughput RNAi screen data identifies the FER and CRKL tyrosine kinases as new regulators of the mitogenic ERK-dependent pathways in transformed cells.

BACKGROUND: Cell proliferation is a hallmark of cancer and depends on complex signaling networks that are chiefly supported by protein kinase activities. Therapeutic strategies have been used to target specific kinases but new methods are required to identify combined targets and improve treatment. Here, we propose a small interfering RNA genetic screen and an integrative approach to identify kinase networks involved in the proliferation of cancer cells. RESULTS: The functional siRNA screen of 714 kinases in HeLa cells identified 91 kinases implicated in the regulation of cell growth, most of them never being reported in previous whole-genome siRNA screens. Based on gene ontology annotations, we have further discriminated between two classes of kinases that, when suppressed, result in alterations of the mitotic index and provoke cell-cycle arrest. Extinguished kinases that lead to a low mitotic index mostly include kinases implicated in cytosolic signaling. In contrast, extinguished kinases that result in a high mitotic index mostly include kinases implicated in cell division. By mapping hit kinases in the PhosphPOINT phosphoprotein database, we generated scale-free networks consisting of 449 and 661 protein-protein interactions for kinases from low MI and high MI groups, respectively. Further analyses of the kinase interactomes revealed specific modules such as FER- and CRKL-containing modules that connect three members of the epidermal growth factor receptor (EGFR) family, suggesting a tight control of the mitogenic EGF-dependent pathway. Based on experimental studies, we confirm the involvement of these two kinases in the regulation of tumor cell growth. CONCLUSION: Based on a combined approach of large kinome-wide siRNA screens and ontology annotations, our study identifies for the first time two kinase groups differentially implicated in the control of cell proliferation. We further demonstrate that integrative analysis of the kinase interactome provides key information which can be used to facilitate or optimize target design for new therapeutic strategies. The complete list of protein-protein interactions from the two functional kinase groups will provide a useful database for future investigations.

Magnitude and determinants of excess total, age-specific and sex-specific all-cause mortality in 24 countries worldwide during 2020 and 2021: results on the impact of the COVID-19 pandemic from the C-MOR project.

INTRODUCTION: To examine the impact of the COVID-19 pandemic on mortality, we estimated excess all-cause mortality in 24 countries for 2020 and 2021, overall and stratified by sex and age. METHODS: Total, age-specific and sex-specific weekly all-cause mortality was collected for 2015-2021 and excess mortality for 2020 and 2021 was calculated by comparing weekly 2020 and 2021 age-standardised mortality rates against expected mortality, estimated based on historical data (2015-2019), accounting for seasonality, and long-term and short-term trends. Age-specific weekly excess mortality was similarly calculated using crude mortality rates. The association of country and pandemic-related variables with excess mortality was investigated using simple and multilevel regression models. RESULTS: Excess cumulative mortality for both 2020 and 2021 was found in Austria, Brazil, Belgium, Cyprus, England and Wales, Estonia, France, Georgia, Greece, Israel, Italy, Kazakhstan, Mauritius, Northern Ireland, Norway, Peru, Poland, Slovenia, Spain, Sweden, Ukraine, and the USA. Australia and Denmark experienced excess mortality only in 2021. Mauritius demonstrated a statistically significant decrease in all-cause mortality during both years. Weekly incidence of COVID-19 was significantly positively associated with excess mortality for both years, but the positive association was attenuated in 2021 as percentage of the population fully vaccinated increased. Stringency index of control measures was positively and negatively associated with excess mortality in 2020 and 2021, respectively. CONCLUSION: This study provides evidence of substantial excess mortality in most countries investigated during the first 2 years of the pandemic and suggests that COVID-19 incidence, stringency of control measures and vaccination rates interacted in determining the magnitude of excess mortality.

A statistical procedure to create a neighborhood socioeconomic index for health inequalities analysis.

INTRODUCTION: In order to study social health inequalities, contextual (or ecologic) data may constitute an appropriate alternative to individual socioeconomic characteristics. Indices can be used to summarize the multiple dimensions of the neighborhood socioeconomic status. This work proposes a statistical procedure to create a neighborhood socioeconomic index. METHODS: The study setting is composed of three French urban areas. Socioeconomic data at the census block scale come from the 1999 census. Successive principal components analyses are used to select variables and create the index. Both metropolitan area-specific and global indices are tested and compared. Socioeconomic categories are drawn with hierarchical clustering as a reference to determine "optimal" thresholds able to create categories along a one-dimensional index. RESULTS: Among the twenty variables finally selected in the index, 15 are common to the three metropolitan areas. The index explains at least 57% of the variance of these variables in each metropolitan area, with a contribution of more than 80% of the 15 common variables. CONCLUSIONS: The proposed procedure is statistically justified and robust. It can be applied to multiple geographical areas or socioeconomic variables and provides meaningful information to public health bodies. We highlight the importance of the classification method. We propose an R package in order to use this procedure.

Performance of French medico-administrative databases in epidemiology of infectious diseases: a scoping review.

The development of medico-administrative databases over the last few decades has led to an evolution and to a significant production of epidemiological studies on infectious diseases based on retrospective medical data and consumption of care. This new form of epidemiological research faces numerous methodological challenges, among which the assessment of the validity of targeting algorithm. We conducted a scoping review of studies that undertook an estimation of the completeness and validity of French medico-administrative databases for infectious disease epidemiological research. Nineteen validation studies and nine capture-recapture studies were identified. These studies covered 20 infectious diseases and were mostly based on the evaluation of hospital claimed data. The evaluation of their methodological qualities highlighted the difficulties associated with these types of research, particularly those linked to the assessment of their underlying hypotheses. We recall several recommendations relating to the problems addressed, which should contribute to the quality of future evaluation studies based on medico-administrative data and consequently to the quality of the epidemiological indicators produced from these information systems.

Impact of the COVID-19 pandemic on total, sex- and age-specific all-cause mortality in 20 countries worldwide during 2020: results from the C-MOR project.

BACKGROUND: To understand the impact of the COVID-19 pandemic on mortality, this study investigates overall, sex- and age-specific excess all-cause mortality in 20 countries, during 2020. METHODS: Total, sex- and age-specific weekly all-cause mortality for 2015-2020 was collected from national vital statistics databases. Excess mortality for 2020 was calculated by comparing weekly 2020 observed mortality against expected mortality, estimated from historical data (2015-2019) accounting for seasonality, long- and short-term trends. Crude and age-standardized rates were analysed for total and sex-specific mortality. RESULTS: Austria, Brazil, Cyprus, England and Wales, France, Georgia, Israel, Italy, Northern Ireland, Peru, Scotland, Slovenia, Sweden, and the USA displayed substantial excess age-standardized mortality of varying duration during 2020, while Australia, Denmark, Estonia, Mauritius, Norway, and Ukraine did not. In sex-specific analyses, excess mortality was higher in males than females, except for Slovenia (higher in females) and Cyprus (similar in both sexes). Lastly, for most countries substantial excess mortality was only detectable (Austria, Cyprus, Israel, and Slovenia) or was higher (Brazil, England and Wales, France, Georgia, Italy, Northern Ireland, Sweden, Peru and the USA) in the oldest age group investigated. Peru demonstrated substantial excess mortality even in the <45 age group. CONCLUSIONS: This study highlights that excess all-cause mortality during 2020 is context dependent, with specific countries, sex- and age-groups being most affected. As the pandemic continues, tracking excess mortality is important to accurately estimate the true toll of COVID-19, while at the same time investigating the effects of changing contexts, different variants, testing, quarantine, and vaccination strategies.

Hospitalization and Death in the First 30 days After Outpatient Lower Extremity Arterial Stenting.

PURPOSE: To compare the safety of outpatient versus inpatient endovascular treatment of lower extremity arterial disease (LEAD) using real-life data. MATERIALS AND METHODS: This retrospective observational study used real-life data from the French national health data information system on adult patients who underwent stenting for LEAD between 2013 and 2016. The outcomes of interest were all-cause mortality, all-cause hospitalization, planned hospitalization, and unplanned hospitalization at day 3 and day 30 after the index endovascular intervention for LEAD revascularization. A propensity score was used to control for indication bias. Outcome rates in outpatient and inpatient settings were compared with the Poisson regression model. Sensitivity analyses were performed by varying the definition of the outcomes of interest. RESULTS: During the study period, 26,715 interventions were performed among which 2819 (10.6%) were in outpatient settings. Outpatients were slightly younger than inpatients (64.73 ± 10.68 vs. 68.10 ± 11.50, respectively). The percentage of women patients was similar: 19.8% in the outpatient group and 27.2% in the inpatient group. Within 30 days after discharge, 73 patients (.31%) and 2 (.07%) patients (p = .02) died in the inpatient group and outpatient group, respectively. The death and rehospitalization rate were similar: 3.8 and 3.5 per 1000 person-months for inpatients and outpatients, respectively. No difference was observed after adjusting for patients' case-mix in the regression model (RR = .99; 95% CI [.82-1.19]). CONCLUSIONS: Outpatient stenting for LEAD did not present any additional risk of early postoperative rehospitalization or death compared with inpatient stenting.

Excess all-cause mortality and COVID-19-related mortality: a temporal analysis in 22 countries, from January until August 2020.

BACKGROUND: This study aimed to investigate overall and sex-specific excess all-cause mortality since the inception of the COVID-19 pandemic until August 2020 among 22 countries. METHODS: Countries reported weekly or monthly all-cause mortality from January 2015 until the end of June or August 2020. Weekly or monthly COVID-19 deaths were reported for 2020. Excess mortality for 2020 was calculated by comparing weekly or monthly 2020 mortality (observed deaths) against a baseline mortality obtained from 2015-2019 data for the same week or month using two methods: (i) difference in observed mortality rates between 2020 and the 2015-2019 average and (ii) difference between observed and expected 2020 deaths. RESULTS: Brazil, France, Italy, Spain, Sweden, the UK (England, Wales, Northern Ireland and Scotland) and the USA demonstrated excess all-cause mortality, whereas Australia, Denmark and Georgia experienced a decrease in all-cause mortality. Israel, Ukraine and Ireland demonstrated sex-specific changes in all-cause mortality. CONCLUSIONS: All-cause mortality up to August 2020 was higher than in previous years in some, but not all, participating countries. Geographical location and seasonality of each country, as well as the prompt application of high-stringency control measures, may explain the observed variability in mortality changes.

Duration of sick leave after same-day discharge for lower extremity arterial disease and varicose vein interventions in active population of French patients, 2013-2016: observational study.

OBJECTIVE: To assess whether disparities in rates of same-day discharge for lower extremities arterial disease (5%) and varicose vein interventions (90%) are associated with the burden of postprocedural rehabilitation process, measured through the duration of sick leave. DESIGN: Retrospective observational study using French National Health Insurance data in 2012-2016. SETTING: The French National Health Data System (Système National des Données de Santé), which covers 98.8% of the 66 million people in the French population. PARTICIPANTS: French workforce population aged 18 to 65 years old who underwent a first angioplasty with stent placement for lower extremities arterial disease (LEAD, n=30 238) or a first varicose vein intervention (n=265 670) between 2013 and 2016. MAIN OUTCOME MEASURES: Duration and renewals of sick leave within 180 days after endovascular intervention, continuity of care and prescription indices to assess coordination among healthcare professionals after intervention associated with specific intervention settings: conventional (inpatient) or same-day discharge (outpatient). Association was estimated by multivariate negative binomial regressions adjusting for age, gender and comorbidities. RESULTS: Outpatient settings decrease the incidence rate ratio (IRR) of the number of cumulated days of sick leave by 14% in both interventions. The increasing variety of prescribers decreases the IRR of cumulated days of sick leave and prescription renewals for varicose interventions by 25% and 21%, respectively, but increases them for LEAD interventions by 240% and 106%. Less coordination between healthcare specialists increases the IRR of cumulative days of sick leave and renewals by 37% and 29% for varicose, and 11% and 9% for LEAD interventions. CONCLUSIONS: Low rates of outpatients in LEAD angioplasty does not seem related to the duration of sick leave. Outpatient setting reduces the duration of sick leave and their renewals, whatever the intervention. Coordination of healthcare professionals is a key element of interventions follow-up with pathology specificities.

Contrasting gene expression profiles in two canine models of atrial fibrillation.

Gene-expression changes in atrial fibrillation patients reflect both underlying heart-disease substrates and changes because of atrial fibrillation-induced atrial-tachycardia remodeling. These are difficult to separate in clinical investigations. This study assessed time-dependent mRNA expression-changes in canine models of atrial-tachycardia remodeling and congestive heart failure. Five experimental groups (5 dogs/group) were submitted to atrial (ATP, 400 bpm x 24 hours, 1 or 6 weeks) or ventricular (VTP, 240 bpm x 24 hours or 2 weeks) tachypacing. The expression of approximately 21,700 transcripts was analyzed by microarray in isolated left-atrial cardiomyocytes and (for 18 genes) by real-time RT-PCR. Protein-expression changes were assessed by Western blot. In VTP, a large number of significant mRNA-expression changes occurred after both 24 hours (2209) and 2 weeks (2720). In ATP, fewer changes occurred at 24 hours (242) and fewer still (87) at 1 week, with no statistically-significant alterations at 6 weeks. Expression changes in VTP varied over time in complex ways. Extracellular matrix-related transcripts were strongly upregulated by VTP consistent with its pathophysiology, with 8 collagen-genes upregulated >10-fold, fibrillin-1 8-fold and MMP2 4.5-fold at 2 weeks (time of fibrosis) but unchanged at 24 hours. Other extracellular matrix genes (eg, fibronectin, lysine oxidase-like 2) increased at both time-points ( approximately 10, approximately 5-fold respectively). In ATP, mRNA-changes almost exclusively represented downregulation and were quantitatively smaller. This study shows that VTP-induced congestive heart failure and ATP produce qualitatively different temporally-evolving patterns of gene-expression change, and that specific transcriptomal responses associated with atrial fibrillation versus underlying heart disease substrates must be considered in assessing gene-expression changes in man.

Categorical state sequence analysis and regression tree to identify determinants of care trajectory in chronic disease: Example of end-stage renal disease.

BACKGROUND: Patients with chronic diseases, like patients with end-stage renal disease (ESRD), have long history of care driven by multiple determinants (medical, social, economic, etc.). Although in most epidemiological studies, analyses of health care determinants are computed on single health care events using classical multivariate statistical regression methods. Only few studies have integrated the concept of treatment trajectories as a whole and studied their determinants. METHODS: All 18- to 80-year-old incident ESRD patients who started dialysis in Ile-de-France or Bretagne between 2006 and 2009 and could be followed for a period of 48 months after initiation of a renal replacement therapy were included (n = 5568). Their care trajectories were defined as categorical state sequences. Associations between patients' characteristics and care trajectories were assessed using a regression tree model together with a discrepancy analysis. RESULTS: On average, each patient experienced 1.56 different renal replacement therapies (min = 1; max = 5) during the 48 months of follow-up. About 55% of patients never changed treatment and only 1% tried three or more renal replacement therapy modalities. Twelve homogeneous care trajectory groups were identified. Covariates explained 12% of the discrepancy between groups, particularly age, regions and initiation of hemodialysis with a catheter. CONCLUSIONS: Regression tree analysis of categorical state sequence highlighted geographical disparities in the care trajectory of French patients with ESRD that cannot be observed when focusing on a single outcome, such as survival. This method is an original tool to visualize and characterize care trajectories, notably in the context of chronic condition like ESRD.

Human atrial ion channel and transporter subunit gene-expression remodeling associated with valvular heart disease and atrial fibrillation.

BACKGROUND: Valvular heart disease (VHD), which often leads to atrial fibrillation (AF), and AF both cause ion-channel remodeling. We evaluated the ion-channel gene expression profile of VHD patients, in permanent AF (AF-VHD) or in sinus rhythm (SR-VHD), in comparison with patients without AF or VHD, respectively. METHODS AND RESULTS: We used microarrays containing probes for human ion-channel and Ca2+-regulator genes to quantify mRNA expression in atrial tissues from 7 SR-VHD patients and 11 AF-VHD patients relative to 11 control patients in SR without structural heart disease (SR-CAD). From the data set, we selected for detailed analysis 59 transcripts expressed in the human heart. SR-VHD patients differentially expressed 24/59 ion-channel and Ca2+-regulator transcripts. There was significant overlap between VHD groups, with 66% of genes altered in SR-VHD patients being similarly modified in AF-VHD. Statistical differences between the AF- and SR-VHD groups identified the specific molecular portrait of AF, which involved 12 genes that were further confirmed by real-time reverse transcription-polymerase chain reaction. For example, phospholamban, the beta-subunit MinK (KCNE1) and MIRP2 (KCNE3), and the 2-pore potassium channel TWIK-1 were upregulated in AF-VHD compared with SR-VHD, whereas the T-type calcium-channel Cav3.1 and the transient-outward potassium channel Kv4.3 were downregulated. Two-way hierarchical clustering separated SR-VHD from AF-VHD patients. AF-related changes in L-type Ca2+-current and inward-rectifier current were confirmed at protein and functional levels. Finally, for 13 selected genes, SR restoration reversed ion-channel remodeling. CONCLUSIONS: VHD extensively remodels cardiac ion-channel and transporter expression, and AF alters ion-channel expression in VHD patients.

Characterization of the expression of the hypoxia-induced genes neuritin, TXNIP and IGFBP3 in cancer.

By triggering an adaptive response to hypoxia which is a common feature of tumor microenvironments, endothelial cells contribute to the onset of angiogenic responses involved in tumor growth. Therefore, identifying hypoxic markers represent a challenge for a better understanding of tumor angiogenesis and for the optimization of anti-angiogenic therapeutic strategy. Using representational difference analysis combined with microarray, we here report the identification of 133 hypoxia-induced transcripts in human microendothelial cells (HMEC-1). By Northern blot, we confirm hypoxia-induced expression of insulin-like growth factor binding protein 3 (igfbp3), thioredoxin-interacting protein (txnip), neuritin (nrn1). Finally, by performing in situ hybridization on several types of human tumors, we provide evidence for nrn1 and txnip as hypoxic perinecrotic markers and for igfbp3 as a tumor endothelial marker. We propose these hypoxia-induced genes could represent relevant prognostic tools and targets for therapeutic intervention in cancers.

Data standards for flow cytometry.

Flow cytometry (FCM) is an analytical tool widely used for cancer and HIV/AIDS research, and treatment, stem cell manipulation and detecting microorganisms in environmental samples. Current data standards do not capture the full scope of FCM experiments and there is a demand for software tools that can assist in the exploration and analysis of large FCM datasets. We are implementing a standardized approach to capturing, analyzing, and disseminating FCM data that will facilitate both more complex analyses and analysis of datasets that could not previously be efficiently studied. Initial work has focused on developing a community-based guideline for recording and reporting the details of FCM experiments. Open source software tools that implement this standard are being created, with an emphasis on facilitating reproducible and extensible data analyses. As well, tools for electronic collaboration will assist the integrated access and comprehension of experiments to empower users to collaborate on FCM analyses. This coordinated, joint development of bioinformatics standards and software tools for FCM data analysis has the potential to greatly facilitate both basic and clinical research--impacting a notably diverse range of medical and environmental research areas.

Profiling dendritic cell maturation with dedicated microarrays.

Dendritic cell (DC) maturation is the process by which immature DC in the periphery differentiate into fully competent antigen-presenting cells that initiate the T cell response. However, DC respond to many distinct maturation stimuli, and different types of mature DC induce qualitatively different T cell responses. As DC maturation involves the coordinated regulation of hundreds of genes, comprehensive assessment of DC maturation status would ideally involve monitoring the expression of all of these transcripts. However, whole-genome microarrays are not well-suited for routine phenotyping of DC, as the vast majority of genes represented on such chips are not relevant to DC biology, and their cost limits their use for most laboratories. We therefore developed a DC-dedicated microarray, or "DC Chip", incorporating probes for 121 genes up-regulated during DC maturation, 93 genes down-regulated during maturation, 14 DC-specific genes, and 90 other genes with known or probable immune functions. These microarrays were used to study the kinetics of DC maturation and the differences in maturation profiles among five healthy donors after stimulation with tumor necrosis factor-alpha + polyI:C. Results obtained with the DC Chip were consistent with flow cytometry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction, as well as previously published data. Furthermore, the coordinated regulation of a cluster of genes (indoleamine dioxygenase, kynureninase, kynurenine monoxygenase, tryptophanyl tRNA synthetase, and 3-hydroxyanthranilate 3,4-dioxygenase) involved in tryptophan metabolism was observed. These data demonstrate the use of the DC Chip for monitoring the molecular processes involved in the orientation of the immune response by DC.