Empiric vs Preemptive Antifungal Strategy in High-Risk Neutropenic Patients on Fluconazole Prophylaxis: A Randomized Trial of the European Organization for Research and Treatment of Cancer.

BACKGROUND: Empiric antifungal therapy is considered the standard of care for high-risk neutropenic patients with persistent fever. The impact of a preemptive, diagnostic-driven approach based on galactomannan screening and chest computed tomography scan on demand on survival and on the risk of invasive fungal disease (IFD) during the first weeks of high-risk neutropenia is unknown. METHODS: Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and allogeneic hematopoietic cell transplant recipients were randomly assigned to receive caspofungin empirically (arm A) or preemptively (arm B), while receiving fluconazole 400 mg daily prophylactically. The primary end point of this noninferiority study was overall survival (OS) 42 days after randomization. RESULTS: Of 556 patients recruited, 549 were eligible: 275 in arm A and 274 in arm B. Eighty percent of the patients had AML or MDS requiring high-dose chemotherapy, and 93% of them were in the first induction phase. At day 42, the OS was not inferior in arm B (96.7%; 95% confidence interval [CI], 93.8%-98.3%) when compared with arm A (93.1%; 95% CI, 89.3%-95.5%). The rates of IFDs at day 84 were not significantly different, 7.7% (95% CI, 4.5%-10.8%) in arm B vs 6.6% (95% CI, 3.6%-9.5%) in arm A. The rate of patients who received caspofungin was significantly lower in arm B (27%) than in arm A (63%; P < .001). CONCLUSIONS: The preemptive antifungal strategy was safe for high-risk neutropenic patients given fluconazole as prophylaxis, halving the number of patients receiving antifungals without excess mortality or IFDs. Clinical Trials Registration. NCT01288378; EudraCT 2010-020814-27.

Mental disorders, COVID-19-related life-saving measures and mortality in France: A nationwide cohort study.

BACKGROUND: Meta-analyses have shown that preexisting mental disorders may increase serious Coronavirus Disease 2019 (COVID-19) outcomes, especially mortality. However, most studies were conducted during the first months of the pandemic, were inconclusive for several categories of mental disorders, and not fully controlled for potential confounders. Our study objectives were to assess independent associations between various categories of mental disorders and COVID-19-related mortality in a nationwide sample of COVID-19 inpatients discharged over 18 months and the potential role of salvage therapy triage to explain these associations. METHODS AND FINDINGS: We analysed a nationwide retrospective cohort of all adult inpatients discharged with symptomatic COVID-19 between February 24, 2020 and August 28, 2021 in mainland France. The primary exposure was preexisting mental disorders assessed from all discharge information recorded over the last 9 years (dementia, depression, anxiety disorders, schizophrenia, alcohol use disorders, opioid use disorders, Down syndrome, other learning disabilities, and other disorder requiring psychiatric ward admission). The main outcomes were all-cause mortality and access to salvage therapy (intensive-care unit admission or life-saving respiratory support) assessed at 120 days after recorded COVID-19 diagnosis at hospital. Independent associations were analysed in multivariate logistic models. Of 465,750 inpatients with symptomatic COVID-19, 153,870 (33.0%) were recorded with a history of mental disorders. Almost all categories of mental disorders were independently associated with higher mortality risks (except opioid use disorders) and lower salvage therapy rates (except opioid use disorders and Down syndrome). After taking into account the mortality risk predicted at baseline from patient vulnerability (including older age and severe somatic comorbidities), excess mortality risks due to caseload surges in hospitals were +5.0% (95% confidence interval (CI), 4.7 to 5.2) in patients without mental disorders (for a predicted risk of 13.3% [95% CI, 13.2 to 13.4] at baseline) and significantly higher in patients with mental disorders (+9.3% [95% CI, 8.9 to 9.8] for a predicted risk of 21.2% [95% CI, 21.0 to 21.4] at baseline). In contrast, salvage therapy rates during caseload surges in hospitals were significantly higher than expected in patients without mental disorders (+4.2% [95% CI, 3.8 to 4.5]) and lower in patients with mental disorders (-4.1% [95% CI, -4.4; -3.7]) for predicted rates similar at baseline (18.8% [95% CI, 18.7-18.9] and 18.0% [95% CI, 17.9-18.2], respectively). The main limitations of our study point to the assessment of COVID-19-related mortality at 120 days and potential coding bias of medical information recorded in hospital claims data, although the main study findings were consistently reproduced in multiple sensitivity analyses. CONCLUSIONS: COVID-19 patients with mental disorders had lower odds of accessing salvage therapy, suggesting that life-saving measures at French hospitals were disproportionately denied to patients with mental disorders in this exceptional context.

Burden of liver disease progression in hospitalized patients with type 2 diabetes mellitus.

BACKGROUND & AIMS: There are uncertainties regarding the burden of liver disease in patients with type 2 diabetes (T2D). Thus, we aimed to quantify the burden of liver disease, identify risk factors, and estimate attributable risks in patients with T2D. METHODS: We measured adjusted hazard ratios of liver disease progression to hepatocellular carcinoma and/or decompensated cirrhosis in a 2010-2020 retrospective, bicentric, longitudinal, cohort of 52,066 hospitalized patients with T2D. RESULTS: Mean age was 64±14 years and 58% were men. Alcohol use disorders accounted for 57% of liver-related complications and were associated with all liver-related risk factors. Non-metabolic liver-related risk factors accounted for 37% of the liver burden. T2D control was not associated with liver disease progression. The incidence (95% CI) of liver-related complications and of competing mortality were 3.9 (3.5-4.3) and 27.8 (26.7-28.9) per 1,000 person-years at risk, respectively. The cumulative incidence of liver disease progression exceeded the cumulative incidence of competing mortality only in the presence of well-identified risk factors of liver disease progression, including alcohol use. The incidence of hepatocellular carcinoma was 0.3 (95% CI 0.1-0.5) per 1,000 person-years in patients with obesity and it increased with age. The adjusted hazard ratios of liver disease progression were 55.7 (40.5-76.6), 3.5 (2.3-5.2), 8.9 (6.9-11.5), and 1.5 (1.1-2.1), for alcohol-related liver disease, alcohol use disorders without alcohol-related liver disease, non-metabolic liver-related risk factors, and obesity, respectively. The attributable fractions of alcohol use disorders, non-metabolic liver-related risk factors, and obesity to the liver burden were 55%, 14%, and 7%, respectively. CONCLUSIONS: In this analysis of data from 2 hospital-based cohorts of patients with T2D, alcohol use disorders, rather than obesity, contributed to most of the liver burden. These results suggest that patients with T2D should be advised to drink minimal amounts of alcohol. LAY SUMMARY: There is uncertainty on the burden of liver-related complications in patients with type 2 diabetes. We studied the risks of liver cancer and complications of liver disease in over 50,000 patients with type 2 diabetes. We found that alcohol was the main factor associated with complications of liver disease. This finding has major implications on the alcohol advice given to patients with type 2 diabetes.

Estimating health state utility from activities of daily living in the French National Hospital Discharge Database: a feasibility study with head and neck cancer.

BACKGROUND: Health state utility (HSU) is a core component of QALYs and cost-effectiveness analysis, although HSU is rarely estimated among a representative sample of patients. We explored the feasibility of assessing HSU in head and neck cancer from the French National Hospital Discharge database. METHODS: An exhaustive sample of 53,258 incident adult patients with a first diagnosis of head and neck cancer was identified in 2010-2012. We used a cross-sectional approach to define five health states over two periods: three "cancer stages at initial treatment" (early, locally advanced or metastatic stage); a "relapse state" and otherwise a "relapse-free state" in the follow-up of patients initially treated at early or locally advanced stage. In patients admitted in post-acute care, a two-parameter graded response model (Item Response Theory) was estimated from all 144,012 records of six Activities of Daily Living (ADLs) and the latent health state scale underlying ADLs was calibrated with the French EQ-5D-3 L social value set. Following linear interpolation between all assessments of the patient, daily estimates of utility in post-acute care were averaged by health state, patient and month of follow-up. Finally, HSU was estimated by health state and month of follow-up for the whole patient population after controlling for survivorship and selection in post-acute care. RESULTS: Head and neck cancer was generally associated with poor HSU estimates in a real-life setting. As compared to "distant metastasis at initial treatment", mean HSU was higher in other health states, although numerical differences were small (0.45 versus around 0.54). It was primarily explained by the negative effects on HSU of an older age (38.4% aged ≥70 years in "early stage at initial treatment") and comorbidities (> 50% in other health states). HSU estimates significantly improved over time in the "relapse-free state" (from 8 to 12 months of follow-up). CONCLUSIONS: HSU estimates in head and neck cancer were primarily driven by age at diagnosis, comorbidities, and time to assessment of cancer survivors. This feasibility study highlights the potential of estimating HSU within and across severe conditions in a systematic way at the national level.

Increased risk of acute arterial events in young patients and severely active IBD: a nationwide French cohort study.

OBJECTIVE: Magnitude and independent drivers of the risk of acute arterial events in IBD are still unclear. We addressed this question in patients with IBD compared with the general population at a nationwide level. DESIGN: Using the French National Hospital Discharge Database from 2008 to 2013, all patients aged 15 years or older and diagnosed with IBD were identified and followed up until 31 December 2013. The rates of incident acute arterial events were calculated and the impact of time with active disease (period around hospitalisation for IBD flare or IBD-related surgery) on the risk was assessed by Cox regression adjusted for traditional cardiovascular risk factors. RESULTS: Among 210 162 individuals with IBD (Crohn's disease (CD), n=97 708; UC, n=112 454), 5554 incident acute arterial events were identified. Both patients with CD and UC had a statistically significant overall increased risk of acute arterial events (standardised incidence ratio (SIR) 1.35; 95% CI 1.30 to 1.41 and SIR 1.10; 95 CI 1.06 to 1.13, respectively). The highest risk was observed in patients under the age of 55 years, both in CD and UC. The 3-month periods before and after IBD-related hospitalisation were associated with an increased risk of acute arterial events in both CD and UC (HR 1.74; 95 CI 1.44 to 2.09 and 1.87; 95% CI 1.58 to 2.22, respectively). CONCLUSION: Patients with IBD are at increased risk of acute arterial events, with the highest risk in young patients. Disease activity may also have an independent impact on the risk.

Prognosis of patients with chronic hepatitis B in France (2008-2013): A nationwide, observational and hospital-based study.

BACKGROUND & AIMS: How risk factors associated with chronic hepatitis B (CHB) modify liver disease progression and mortality has been scarcely reported outside of Asia. We aimed to evaluate these risk factors in a French population between 2008 and 2013. METHODS: All individuals discharged with CHB from acute and post-acute care hospitals in Metropolitan France between January 2008 and December 2013 were selected. Associations between liver- and non-liver-related risk factors and both liver disease progression (end-stage liver disease or hepatocellular carcinoma) and mortality were assessed by multivariate Cox proportional hazard models. RESULTS: Overall, liver disease progression, liver transplantation and death were recorded in 7479 (15.5%), 433 (8.2%) and 5299 (11.0%) patients, respectively. An additional liver-related risk factor was recorded in 5426 (72.6%) patients with liver disease progression and 2699 (75.5%) patients with liver transplantation or liver death. Adjusted hazard ratios (95% confidence interval) for liver disease progression of hepatitis D virus co-infection, hepatitis C virus co-infection, alcohol use disorders, diabetes mellitus, and other rare causes of chronic liver disease were 1.44 (1.35-1.53), 1.77 (1.68-1.87), 3.37 (3.20-3.55), 1.40 (1.32-1.48), and 2.19 (1.98-2.42), respectively. All liver-related risk factors increased the risk of all-cause mortality, especially after liver disease progression. Adjusted hazard ratios for liver disease progression and in-hospital mortality of HIV co-infection without acquired immune deficiency syndrome (AIDS) were 0.60 (0.52-0.70) and 0.63 (0.51-0.78), respectively. CONCLUSIONS: In France, 2008-2013, liver disease progression among patients with CHB was closely related to other risk factors. HIV co-infected patients without AIDS had better outcomes, suggesting better care in this group of patients. LAY SUMMARY: In France, 2008-2013, about three-quarters of patients with chronic hepatitis B who progressed to a liver-related complication, including liver transplantation and liver-related death, had an additional liver-related risk factor. Despite a higher prevalence of liver-related risk factors, HIV co-infected patients without AIDS had better outcomes. Prognosis of patients with chronic hepatitis B is closely related to other risk factors. Treatment of patients with chronic hepatitis B, including control of chronic hepatitis B-associated risk factors, is more efficient in HIV co-infected patients.

Contribution of alcohol use disorders on the burden of chronic hepatitis C in France, 2008-2013: A nationwide retrospective cohort study.

BACKGROUND & AIMS: Hepatitis C virus (HCV) patients are at risk of alcohol use disorders (AUDs). We measured the contribution of AUDs on the burden of chronic HCV infection in French HCV patients. METHODS: The hospital trajectory of 97,347 French HCV patients aged 18-65 in January 2008 were tracked and followed until in-hospital death or December 2013. Primary outcome was the frequency of liver-related complications. Secondary outcomes were the frequency of liver transplantation and otherwise cause-specific mortality. Adjusted odds ratios (OR), population attributable risks of AUDs and other cofactors of liver disease progression associated with HCV transmission were measured. RESULTS: The 28,101 (28.9%) individuals with AUDs had the highest odds for liver-related complications (OR=7.19; 95% confidence interval [CI], 6.90 to 7.50), liver transplantation (OR=4.28; 95% CI, 3.80 to 4.82), and liver death (OR=6.20; 95% CI, 5.85 to 6.58). Alcohol rehabilitation and abstinence were associated with 60% (95% CI, 57% to 63%) and 78% (95% CI, 76% to 80%) reduction of liver-related complications, respectively. The attributable risk of AUDs was 71.8% (95% CI, 66.0 to 76.8) of 17,669 liver-related complications, 67.4% (95% CI, 61.6 to 72.4) of 1,599 liver transplantations, and 68.8% (95% CI, 63.4 to 73.5) of 6,677 liver deaths. The number of liver transplantations remained stable and the number of liver deaths increased, at a faster rate for individuals with AUDs, over the observational period. CONCLUSION: In France, AUDs contributed to more than two-thirds of the burden of chronic HCV infection in young and middle-aged adults over 2008-2013. LAY SUMMARY: This study tracked liver-related complications and mortality of all 97,347 young and middle-aged patients (18-65years old) discharged with chronic HCV infection from French hospitals over 2008-2013. About 30% patients were recorded with alcohol use disorders (AUDs) and had the highest odds for liver-related complications (i.e. decompensated cirrhosis and liver cancer). AUDs contributed to more than two-thirds of 1,599 liver transplantations and 6,677 liver deaths recorded in patients with chronic HCV infection over 2008-2013 in France. Alcohol rehabilitation and abstinence were associated with above a 50% risk reduction of liver-related complications. Promoting alcohol abstinence should receive high priority to reduce the burden of chronic HCV infection.

Alcohol use disorders and associated chronic disease - a national retrospective cohort study from France.

BACKGROUND: Evidence on diseases caused by or associated with alcohol use disorders (AUDs) has been based on two meta-analyses including rather dated studies. The objective of this contribution was to estimate the risks of all-cause mortality and alcohol-attributable disease categories depending on a diagnosis of AUDs in a national sample for France. METHODS: In a national retrospective cohort study on all inpatient acute and rehabilitation care patients in Metropolitan France 2008-2012 (N = 26,356,361), AUDs and other disease categories were identified from all discharge diagnoses according to standard definitions, and we relied on in-hospital death for mortality (57.4% of all deaths). RESULTS: 704,803 (2.7%) patients identified with AUDs had a threefold higher risk of death (HR = 2.98; 95% CI: 2.96-3.00) and died on average 12.2 years younger (men: 10.4, 95% CI: 10.3-10.5; women: 13.7, 95% CI: 13.6-13.9). AUDs were associated with significantly higher risks of hospital admission for all alcohol-attributable disease categories: digestive diseases, cancers (exception: breast cancer), cardiovascular diseases, dementia, infectious diseases, and injuries. Elevated risks were highest for liver diseases that were associated with about two-third of deaths in patients with AUDs (men: 64.3%; women: 71.1%). CONCLUSIONS: AUDs were associated with marked premature mortality and higher risks of alcohol-attributable disease categories. Our results support the urgent need of measures to reduce the burden of AUDs.

Effect of nucleoside and nucleotide analogues on renal function in patients with chronic hepatitis B virus monoinfection.

BACKGROUND & AIMS: There is controversy regarding whether nucleos(t)ide analogues contribute to renal impairment in patients with chronic hepatitis B virus (HBV) infection. We analyzed changes in renal function in patients with chronic HBV infection and whether these were associated with treatment or comorbidities. METHODS: We performed a longitudinal observational study to investigate factors associated with renal function in 214 patients (median age, 43 y; 69.2% men) with compensated chronic HBV monoinfection treated with 343 lines of nucleos(t)ide analogues (210 monotherapies, 133 combinations) between 1990 and 2012 (median time, 2.4 y) in France. A linear mixed-effect model was used to model variations of estimated glomerular filtration rate (eGFR, computed with the Chronic Kidney Disease Epidemiology Collaboration formula), adjusting for age, sex, geographic origin, initial liver fibrosis, level of HBV DNA, and an eGFR less than 90 mL/min/1.73 m(2). RESULTS: The eGFR decreased in patients given adefovir dipivoxil as monotherapy or in a combination (P < .0001 and P < .002, respectively), and remained stable in patients given lamivudine, tenofovir disoproxil fumarate, or entecavir. The eGFR decreased in patients with a baseline eGFR of less than 90 mL/min/1.73 m2, regardless of treatment. The eGFR remained stable or increased, regardless of treatment, in patients with a baseline eGFR of 90 mL/min/1.73 m2 or greater and with an initial HBV DNA level of 100,000 IU/mL or greater. Patients born in areas of high endemicity of HBV were more prone to increases in eGFR with treatment. CONCLUSIONS: In a real-life study, the eGFR remained stable or increased over time in patients with chronic HBV monoinfection with a baseline eGFR of 90 mL/min/1.73 m2 or higher and treated with tenofovir disoproxil fumarate or entecavir. Patients born in an area of high endemicity of HBV who had initial levels of HBV DNA of 100,000 IU/mL or greater were more likely to have increased eGFR with treatment.

HIV-serodiscordant couples desiring a child: 'treatment as prevention,' preexposure prophylaxis, or medically assisted procreation?

OBJECTIVE: We sought to assess the residual risk of HIV transmission, cost, and cost-effectiveness of various strategies that can help fertile HIV-uninfected female/HIV-1-infected male on combination antiretroviral therapy with plasma HIV RNA <50 copies/mL couples to have a child: (1) unprotected sexual intercourse (treatment as prevention); (2) treatment as prevention limited to fertile days (targeting fertile days); (3) treatment as prevention with preexposure prophylaxis (tenofovir/emtricitabine); (4) treatment as prevention and preexposure prophylaxis limited to fertile days; or (5) medically assisted procreation (MAP). STUDY DESIGN: This was a model-based, cost-effectiveness analysis performed from a French societal perspective. Input parameters derived from international literature included: 85% probability of live births in different strategies, 0.0083%/mo HIV transmission risk with unprotected vaginal intercourse, 1% HIV mother-to-child transmission rate, and 4.4% birth defect risk related to combination antiretroviral therapy when the mother is infected at conception. Targeting fertile days and preexposure prophylaxis were estimated to decrease the risk of HIV transmission by 80% and 67%, respectively, and by 93.4% for preexposure prophylaxis limited to fertile days (the relative risk of transmission considering the combination of both strategies assuming to be (1-80%)*(1-67%) = 16.6% in basecase). Tenofovir/emtricitabine monthly cost was set at €540. RESULTS: The HIV transmission risk was highest with treatment as prevention and lowest for MAP (5.4 and 0.0 HIV-infected women/10,000 pregnancies, respectively). Targeting fertile days was more effective than preexposure prophylaxis (0.9 vs 1.8) and associated with lowest costs. Preexposure prophylaxis limited to fertile days was more effective than targeting fertile days (0.3 vs 0.9) with a cost-effectiveness ratio of €1,130,000/life year saved; MAP cost-effectiveness ratio when compared with preexposure prophylaxis limited to fertile days was €3,600,000/life year saved. Results were robust to multiple sensitivity analyses. CONCLUSION: Targeting fertile days is associated with a low risk of HIV transmission in fertile HIV-uninfected female/male with controlled HIV-1 infection couples. The risk is lower with preexposure prophylaxis limited to fertile days, or MAP, but these strategies are associated with unfavorable cost-effectiveness ratios under their current costs.

Should we await IFN-free regimens to treat HCV genotype 1 treatment-naive patients? A cost-effectiveness analysis (ANRS 95141).

BACKGROUND & AIMS: In treatment-naive patients mono-infected with genotype 1 chronic HCV, treatments with telaprevir/boceprevir (TVR/BOC)-based triple therapy are standard-of-care. However, more efficacious direct-acting antivirals (IFN-based new DAAs) are available and interferon-free (IFN-free) regimens are imminent (2015). METHODS: A mathematical model estimated quality-adjusted life years, cost and incremental cost-effectiveness ratios of (i) IFN-based new DAAs vs. TVR/BOC-based triple therapy; and (ii) IFN-based new DAAs initiation strategies, given that IFN-free regimens are imminent. The sustained virological response in F3-4/F0-2 was 71/89% with IFN-based new DAAs, 85/95% with IFN-free regimens, vs. 64/80% with TVR/BOC-based triple therapy. Serious adverse events leading to discontinuation were taken as: 0-0.6% with IFN-based new DAAs, 0% with IFN-free regimens, vs. 1-10% with TVR/BOC-based triple therapy. Costs were €60,000 for 12weeks of IFN-based new DAAs and two times higher for IFN-free regimens. RESULTS: Treatment with IFN-based new DAAs when fibrosis stage ⩾F2 is cost-effective compared to TVR/BOC-based triple therapy (€37,900/QALY gained), but not at F0-1 (€103,500/QALY gained). Awaiting the IFN-free regimens is more effective, except in F4 patients, but not cost-effective compared to IFN-based new DAAs. If we decrease the cost of IFN-free regimens close to that of IFN-based new DAAs, then awaiting the IFN-free regimen becomes cost-effective. CONCLUSIONS: Treatment with IFN-based new DAAs at stage ⩾F2 is both effective and cost-effective compared to TVR/BOC triple therapy. Awaiting IFN-free regimens and then treating regardless of fibrosis is more efficacious, except in F4 patients; however, the cost-effectiveness of this strategy is highly dependent on its cost.

Effectiveness and cost of quick diagnostic tests to determine tetanus immunity in patients with a wound in French emergency departments.

BACKGROUND: Tétanos Quick Stick® (TQS) is a test for tetanus immunity screening for wounded patients in emergency departments (EDs), but represents additional costs compared with a medical interview on vaccination history. The study objective was to assess the effectiveness and cost of the TQS in French EDs. METHODS: We performed a model-based analysis that simulates screening of tetanus immunity and risk of tetanus based on prophylaxis administration. Strategies compared were: i) diagnosis of tetanus immunity by "TQS"; ii) "Medical Interview" (current practice). The study population was 1,658,000 French adults seeking ED care for a wound in 2012. Model parameters were estimated based on French national surveillance data, and published literature. Outcome measures were number of tetanus cases, life years gained and costs (2012 €) from a societal perspective. RESULTS: Use of TQS had negligible impact on health outcomes (0.02 tetanus cases/year in France vs. 0.41 for "Medical Interview"), but resulted in a decrease in annual costs of €2,203,000 (-42%). Base case and sub-group analysis showed that with the same effectiveness, the average cost per patient was: €13 with "Medical Interview" vs. €11.7 with TQS for the overall cohort; €28.9 with "Medical Interview" vs. €21 with "TQS" for tetanus-prone wounds; €15 with "Medical Interview" vs. €14.1 with "TQS" for patients aged ≥65 years; and €6.2 with "Medical Interview" vs. €7.8 with "TQS" for non-tetanus-prone wounds. CONCLUSIONS: Use of TQS is as effective and less costly than "Medical Interview" when applied in ED to wounded patients with tetanus-prone wounds or aged ≥65 years. However, it is more expensive in patients with non-tetanus-prone wounds.

Alcohol rehabilitation and cancer risk: a nationwide hospital cohort study in France.

BACKGROUND: Even though alcohol consumption is an established risk factor for cancer, evidence regarding the effect of a reduction or cessation of alcohol consumption on cancer incidence is scarce. Our main study aim was to assess the effect of alcohol rehabilitation and abstinence on cancer incidence in people with alcohol dependence. METHODS: We conducted a nationwide hospital retrospective cohort study which included all adults residing in mainland France and discharged in 2018-21. Multivariable Cox proportional hazards models were used to estimate the effect of rehabilitation treatment at hospital or a history of abstinence versus alcohol dependence without rehabilitation or abstinence on the risk for incident alcohol-associated cancers by sex, controlled for potential confounding risk factors. FINDINGS: 10 260 056 men and 13 739 369 women were discharged from French hospitals in 2018-21. Alcohol dependence was identified in 645 720 (6·3%) men and 219 323 (1·6%) women. Alcohol dependence was strongly related to alcohol-associated cancer sites in both sexes (hepatocellular carcinoma and oral, pharyngeal, laryngeal, oesophageal, and colorectal cancers), except for breast cancer. Rehabilitation treatment or abstinence was associated with significantly lower risks compared with alcohol dependence without rehabilitation or abstinence (adjusted hazard ratios: 0·58, 99·89% CI 0·56-0·60 in men and 0·62, 0·57-0·66 in women). Relative risk reductions were significant for each alcohol-associated cancer site in both sexes and supported by all subgroup and sensitivity analyses. INTERPRETATION: Our study results support the clear benefits of alcohol rehabilitation and abstinence in reducing the risk for alcohol-associated cancers. As only two in five patients with alcohol dependence were recorded with a history of rehabilitation treatment or abstinence, a large untapped potential exists for reducing cancer incidence. FUNDING: European Union's EU4Health programme.

The health state of France before COVID-19 pandemic between 1990 and 2019: an analysis of the Global Burden of Disease study 2019.

Background: France faces nowadays some major challenges regarding its health care system including medically underserved areas, social health inequalities, and hospital pressures. Various indicators and sources of data allow us to describe the health status of a population and, consequently, to assess the impact of these challenges. We assessed the burden of diseases before COVID-19 in France in 2019 and its evolution from 1990 to 2019, and compared it with Western European countries. Methods: We used specific Global Burden of Diseases (GBD) metrics: socio-demographic index (SDI), life expectancy (LE), healthy life expectancy (HALE), years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) with their 95% uncertainty interval (95% UI). We compared French age-standardized metrics to those for other Western European Countries for both sexes and also between 1990 and 2019. We also described the specific causes of these different metrics. Findings: We observed for life expectancy at birth in France a trend to an improvement over time from 77.2 (95% UI: 77.2-77.3) years in 1990 to 82.9 (82.7-83.1) in 2019, which represented the seventh highest life expectancy among 23 Western European countries. HALE at birth in France increased from 67.0 (64.0-69.7) to 71.5 (68.1-74.5), which represented the fourth highest HALE among 23 Western European countries. In France, the total number of DALY per 100.000 population tended to decrease from 25,192 (22,374-28,351) in 1990 to 18,782 (16,408-21,920) in 2019. As compared to other European countries, the burden due to cardiovascular diseases was lower. Neoplasms and cardio-vascular diseases were the two leading causes of YLLs. Mental and musculoskeletal disorders were the two leading causes of YLDs. Interpretation: Overall, these results highlight a clear trend of improvement in the health status in France with certain differences between western European countries. The health policy makers need to devise interventional strategies to reduce the burden of diseases and injuries, with specific attention to causes such as cancers, cardiovascular diseases, mental health and musculoskeletal disorders. Funding: Bill & Melinda Gates Foundation.

Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.

OBJECTIVE: To assess the efficacy and safety of rituximab in adults responding poorly to standard treatment for severe autoimmune thrombotic thrombocytopenic purpura. DESIGN: Open-label prospective study. Outcomes in the survivors were compared to those of 53 historical survivors who were given therapeutic plasma exchange alone or with vincristine. SETTING: Hospitals belonging to the Reference Network for Thrombotic Microangiopathies in France. PATIENTS: Twenty-two adults with either no response or a disease exacerbation when treated with intensive therapeutic plasma exchange. INTERVENTION: Add-on rituximab therapy, four infusions over 15 days. MEASUREMENTS AND MAIN RESULTS: One patient died despite two rituximab infusions. In the rituximab-treated patients, the time to a durable remission was significantly shortened (p = .03), although the plasma volume required to achieve a durable remission was not significantly different compared to the controls. Platelet count recovery occurred within 35 days in all 21 survivors, compared to only 78% of the historical controls (p < .02). Of the rituximab-treated patients, none had a relapse within the first year but three relapsed later on. In patients treated with rituximab, a rapid and profound peripheral B-cell depletion was produced, lasting for 9 months and correlating with higher a disintegrin and metalloproteinase with thrombospondin-13 activity and lower anti-a disintegrin and metalloproteinase with thrombospondin-13 antibody titers. These differences were no longer significant after 12 months. No severe side effects occurred. CONCLUSIONS: Adults with severe thrombocytopenic purpura who responded poorly to therapeutic plasma exchange and who were treated with rituximab had shorter overall treatment duration and reduced 1-yr relapses than historical controls.