The Economic Burden of Severe Osteoporotic Fractures in the French Healthcare Database: The FRACTOS Study.

Osteoporosis carries a high medical, economic, and societal burden principally because of the risk of severe fractures. The objective of this cost-of-illness study was to describe health resource utilization and associated costs in all patients aged ≥50 years hospitalized for a severe osteoporotic fracture over a 6-year period (2009 to 2014) in France. Data were extracted from the French national healthcare database (SNDS) on all health care resource utilization between the index date (date of hospitalization for first fracture during the enrollment period) and study end (December 31, 2016) or until the patient died. Costing was restricted to direct costs and determined from the payer perspective. Variables related to costs were identified through multivariate logistic regression analysis. A total of 356,895 patients were included (median follow-up 39.1 months). In the year after the index fracture, 36,622 patients (10.5%) were rehospitalized for a fracture-related reason. Only 18,474 (5.3%) underwent bone densitometry and 58,220 (16.7%) received a specific treatment. The total annual per capita osteoporosis-related cost in the year after the index severe osteoporotic fracture was €18,040 (from €8598 for multiple ribs to €21,085 for hip fracture) of which €17,905 was incurred by fracture-related costs. The cost incurred by management of osteoporosis was €135. Over years 2 to 5, the mean annual per capita costs of fracture treatment (€806, mostly attributable to the treatment of refractures) continued to dominate those of osteoporosis management (€99). Total annual cost of care was €1260 million (year 2014). Variables associated with higher cost were older age, male sex, site of fracture, a history of prior osteoporotic fracture, and the number of refracture events. The 5-year cost of severe osteoporotic fractures to the French health care system is high and mostly attributable to the treatment of refractures. Improved fracture prevention measures in patients with osteoporosis is crucial to reduce the economic burden of the disease. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Excess hospitalizations and mortality associated with seasonal influenza in Portugal, 2008-2018.

BACKGROUND: Influenza can have a domino effect, triggering severe conditions and leading to hospitalization or even death. Since influenza testing is not routinely performed, statistical modeling techniques are increasingly being used to estimate annual hospitalizations and deaths associated with influenza, to overcome the known underestimation from registers coded with influenza-specific diagnosis. The aim of this study was to estimate the clinical and economic burden of severe influenza in Portugal. METHODS: The study comprised ten epidemic seasons (2008/09-2017/18) and used two approaches: (i) a direct method of estimating the seasonal influenza hospitalization incidence, based on the number of National Health Service hospitalizations with influenza-specific International Classification of Diseases (ICD) codes (ICD-9: 487-488; ICD-10: J09-J11), as primary or secondary diagnosis; (ii) an indirect method of estimating excess hospitalizations and deaths using broader groups of ICD codes in time-series models, computed for six age groups and four groups of diagnoses: pneumonia or influenza (ICD-9: 480-488, 517.1; ICD-10: J09-J18), respiratory (ICD-9: 460-519; ICD-10: J00-J99), respiratory or cardiovascular (R&C, ICD-9: 390-459, 460-519; ICD-10: I00-I99, J00-J99), and all-cause. Means are reported excluding the H1N1pdm09 pandemic (2009/10). RESULTS: The mean number of hospitalizations coded as due to influenza per season was 1,207, resulting in 11.6 cases per 100,000 people. The mean direct annual cost of these hospitalizations was €3.9 million, of which 78.6% was generated by patients with comorbidities. Mean annual influenza-associated R&C hospitalizations were estimated at 5356 (min: 456; max: 8776), corresponding to 51.5 cases per 100,000 (95% CI: 40.9-62.0) for all age groups and 199.6 (95% CI: 163.9-235.8) for the population aged ≥ 65 years. The mean direct annual cost of the estimated excess R&C hospitalizations was €15.2 million for all age groups and €12.8 million for the population aged ≥ 65 years. Mean annual influenza-associated all-cause deaths per 100,000 people were estimated at 22.7 for all age groups. CONCLUSIONS: The study findings suggest that there is an under-detection of influenza in the Portuguese population. A high burden of severe influenza remains to be addressed, not only in the elderly population but also in younger people.

Refracture and mortality following hospitalization for severe osteoporotic fractures: The Fractos Study.

Severe osteoporotic fractures (hip, proximal humerus, pelvic, vertebral and multiple rib fractures) carry an increased risk of mortality. This retrospective cohort study in the French national healthcare database aimed to estimate refracture and mortality rates after severe osteoporotic fractures at different sites, and to identify mortality-related variables. A total of 356,895 patients hospitalized for severe osteoporotic fracture between 2009 and 2014 inclusive were analyzed. The cohort was followed for 2 to 8 years up to the study end or until the patient died. Data were extracted on subsequent hospitalizations, refracture events, treatments, comorbidities of interest and survival. Time to refracture and survival were described using Kaplan-Meier analysis by site of fracture and overall. Mortality risk factors were identified using a Cox model. Hip fractures accounted for 60.4% of the sample (N = 215,672). In the 12 months following fracture, 58,220 patients (16.7%) received a specific osteoporosis treatment, of whom 21,228 were previously treatment-naïve. The 12-month refracture rate was 6.3% (95% confidence interval [CI], 6.2%-6.3%), ranging from 4.0% (95% CI, 3.7%-4.3%) for multiple rib fractures to 7.8% (95% CI, 7.5%-8.1%) for pelvic fractures. Twelve-month all-cause mortality was 12.8% (95% CI, 12.7%-12.9%), ranging from 5.0% (95% CI, 4.7%-5.2%) for vertebral fractures to 16.6% (95% CI, 16.4%-16.7%) for hip fractures. Osteoporosis-related mortality risk factors included fracture site, previous osteoporotic fracture (hazard ratio 1.21; 95% CI, 1.18-1.23), hip refracture (1.74; 95% CI, 1.71-1.77), and no prior osteoporosis treatment (1.24; 95% CI, 1.22-1.26). Comorbid cancer (3.15; 95% CI, 3.09-3.21) and liver disease (2.54; 95% CI, 2.40-2.68) were also strongly associated with mortality. In conclusion, severe osteoporotic fractures, including certain non-hip nonvertebral fractures, carry a high burden in terms of mortality and refracture risk. However, most patients received no anti-osteoporotic treatment. The findings emphasize the importance of better management of patients with severe fractures, and of developing effective strategies to reduce fracture risk in patients with osteoporosis. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Prescribing Pathways to Triple Therapy: A Multi-Country, Retrospective Observational Study of Adult Patients with Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Maintenance treatment strategies in COPD recommend inhaled corticosteroid (ICS) + long-acting muscarinic antagonist (LAMA) + long-acting ß2-agonist (LABA) triple therapy after initial dual therapy. Little is known about how treatment pathways to triple therapy vary across countries in clinical practice. METHODS: This multi-country, retrospective cohort study (conducted 1 January 2005-1 May 2016) included patients with a COPD diagnosis, and (UK only) evidence of smoking history, or (France, Italy, Germany, and Australia) an indicator confirming COPD diagnosis, a first instance of triple therapy recorded during the study period and ≥ 12 months of data prior to this date. Treatment pathways to triple therapy were analyzed in patients whose first instance of triple therapy was on or after the initial COPD diagnosis. The proportion of patients who initiated triple therapy prior to initial COPD diagnosis was also estimated. Meta-analyses of the main results were performed. RESULTS: In 130,729 patients across all countries, mean age (standard deviation) ranged from 63.4 (10.4) years (Germany) to 69.8 (9.9) years (Italy), and median time (interquartile range) from initial COPD diagnosis to first prescription of triple therapy ranged from 16.9 (5.7-36.2) months (Australia) to 42.5 (13.9-87.4) months (UK). ICS + LABA was the most common treatment pathway prior to triple therapy in the UK, Germany, and Italy (27.3%-31.6%); no previous maintenance therapy prior to triple therapy was the most common pathway in France and Australia (32.5% and 37.9%, respectively). Meta-analyses provided a pooled estimate of 20.4% (95% confidence interval: 13.8%-29.1%) for the proportion of patients initiating triple therapy at or before initial COPD diagnosis. CONCLUSIONS: In this retrospective cohort study, treatment pathways to triple therapy were diverse within and between countries. The differing impact of treatments may affect quality of life and disease control in patients with COPD. Further analyses should investigate factors influencing pathways to triple therapy.

COPD treatment pathways in France: a retrospective analysis of electronic medical record data from general practitioners.

BACKGROUND: Increasing availability of therapeutic options for COPD may drive new treatment pathways. This study describes COPD treatment in France, focusing on identifying initial treatment modifications in patients with COPD who either initiated long-acting bronchodilator (LABD)-based therapy or escalated to triple therapy (long-acting muscarinic antagonist [LAMA] + long-acting ß2-agonist [LABA] + inhaled corticosteroid [ICS]). METHODS: This retrospective analysis of patients with COPD in a large general practitioner database (IQVIA Longitudinal Patient Database) in France included two cohorts: Cohort 1 - new initiators of LABD-based therapy (LAMA, LABA, LAMA + LABA, LAMA + ICS, LABA + ICS or LAMA + LABA + ICS); Cohort 2 - patients escalating to triple therapy from mono- or dual-bronchodilator-based maintenance treatment. Both cohorts were indexed on the date of initiation/escalation (January 2008-December 2013), and the first treatment modification (at class level) within the 18-month post-index observational period was described. Five mutually exclusive outcomes were defined: continuous use (no modification), discontinuation (permanent [≥91 days with no restart] or temporary [≥91 days with subsequent restart]), switch, and augmentation (Cohort 1 only). Exploratory analysis of Cohort 1 explored potential drivers of treatment initiation. RESULTS: Overall, 5,065 patients initiated LABD-based therapy (Cohort 1), and 501 escalated to triple therapy (Cohort 2). In Cohort 1, 7.0% of patients were continuous users, 46.5% discontinued permanently, 28.5% discontinued temporarily, 2.8% augmented (added LAMA and/or LABA and/or ICS), and 15.2% switched therapy. In Cohort 2, 18.2% of patients were continuous users, 7.2% discontinued permanently, 27.9% discontinued temporarily, and 46.7% switched therapy. Exploratory analyses showed that time since COPD diagnosis was first recorded, pre-index exacerbation events, and concomitant medical conditions were potential drivers of initial maintenance treatment choices. CONCLUSION: Discontinuation among new initiators of LABD-based therapy was high in France, whereas few switched or augmented treatment. In comparison, permanent discontinuation within 18 months was low in patients escalating to triple therapy.

Methodological challenges when evaluating potential off-label prescribing of drugs using electronic health care databases: A case study of dabigatran etexilate in Europe.

PURPOSE: To report and discuss estimated prevalence of potential off-label use and associated methodological challenges using a case study of dabigatran. METHODS: Observational, cross-sectional study using 3 databases with different types of clinical information available: Cegedim Strategic Data Longitudinal Patient Database (CSD-LPD), France (cardiologist panel, n = 1706; general practitioner panel, n = 2813; primary care data); National Health Databases, Denmark (n = 28 619; hospital episodes and dispensed ambulatory medications); and Clinical Practice Research Datalink (CPRD), UK (linkable to Hospital Episode Statistics [HES], n = 2150; not linkable, n = 1285; primary care data plus hospital data for HES-linkable patients). STUDY PERIOD: August 2011 to August 2015. Two definitions were used to estimate potential off-label use: a broad definition of on-label prescribing using codes for disease indication (eg, atrial fibrillation [AF]), and a restrictive definition excluding patients with conditions for which dabigatran is not indicated (eg, valvular AF). RESULTS: Prevalence estimates under the broad definition ranged from 5.7% (CPRD-HES) to 34.0% (CSD-LPD) and, under the restrictive definition, from 17.4% (CPRD-HES) to 44.1% (CSD-LPD). For the majority of potential off-label users, no diagnosis potentially related to anticoagulant use was identified. Key methodological challenges were the limited availability of detailed clinical information, likely leading to overestimation of off-label use, and differences in the information available, which may explain the disparate prevalence estimates across data sources. CONCLUSIONS: Estimates of potential off-label use should be interpreted cautiously due to limitations in available information. In this context, CPRD HES-linkable estimates are likely to be the most accurate.

Initiation and continuation of oral anticoagulant prescriptions for stroke prevention in non-valvular atrial fibrillation: A cohort study in primary care in France.

BACKGROUND: Oral anticoagulants are prescribed in non-valvular atrial fibrillation for stroke prevention; however, little is known about the current management of anticoagulation in France, particularly given the availability of non-vitamin K antagonist oral anticoagulants in recent years. AIMS: To describe the characteristics of patients prescribed oral anticoagulants, and assess treatment persistence in French primary care. METHODS: We conducted a cohort study of patients with non-valvular atrial fibrillation, who were newly prescribed oral anticoagulants between 1 January 2014 and 31 January 2016, using French primary care data (IMS Longitudinal Patient Database). Adjusting for baseline characteristics, risk of non-persistence (switch or discontinuation) was compared using Cox regression. RESULTS: Of 4111 patients, 1710 were newly prescribed vitamin K antagonists, 1257 rivaroxaban, 744 apixaban and 400 dabigatran. The median age was 76 years, and 57.5% were male. History of hypertension was the most common co-morbidity (68.1%). Compared with vitamin K antagonists, non-persistence was higher with rivaroxaban (hazard ratio: 1.28; 95% confidence interval: 1.13-1.45) and dabigatran (hazard ratio: 1.42; 95% confidence interval: 1.20-1.69) and similar with apixaban (hazard ratio: 1.12; 95% confidence interval: 0.96-1.32). CONCLUSIONS: Non-persistence (treatment discontinuation or switch) with vitamin K antagonists was lower than with rivaroxaban and dabigatran in French primary care; however, non-persistence with the newest drug, apixaban, was similar to vitamin K antagonists. Larger studies with longer follow-up are needed to support these findings. This study is registered on ClinicalTrials.gov (NCT02488421).

Concomitant presence of Aspergillus fumigatus and Stenotrophomonas maltophilia in the respiratory tract: a new risk for patients with liver disease?

Concomitant lung colonization by Aspergillus fumigatus and Stenotrophomonas maltophilia was reported mainly in patients with cystic fibrosis (CF) and immunocompromised patients. The aim of the study was to assess the frequency of co-culture of A. fumigatus and S. maltophilia in respiratory samples of hospitalized patients, and to determine its associated factors. Between 2007 and 2011, all patients who had A. fumigatus in their respiratory samples were retrospectively enrolled in the study. Their clinical and laboratory data, including the presence of S. maltophilia in a respiratory sample, were collected within the same month. Of the 257 enrolled patients (372 respiratory samples), 71 % were immunocompromised and 32 % had chronic respiratory disease. S. maltophilia was isolated within the same month in 20 patients (7.8 %). In the univariate analysis, factors associated with concomitant culture of A. fumigatus and S. maltophilia were liver disease (P = 0.009), orotracheal intubation (P = 0.001), ventilator-associated pneumonia (P = 0.006), central venous catheter (P = 0.003), parenteral nutrition (P = 0.008) and culture of Pseudomonas aeruginosa in respiratory samples (P = 0.002). In the multivariate analysis, the simultaneous presence of P. aeruginosa in the respiratory tract (odds ratio (OR) = 3.19, 95 % confidence interval (CI) 1.11-9.14, P = 0.031), liver disease (OR = 3.92, 95 % CI 1.32-11.62, P = 0.014) and orotracheal intubation (OR = 3.42, 95 % CI 1.17-9.96, P = 0.024) were independently associated with the co-culture of S. maltophilia and A. fumigatus. Factors independently associated with the concomitant culture of A. fumigatus and S. maltophilia were identified. These results support a future prospective study focusing on liver disease and its complications.

Respective impact of lowering body temperature and heart rate on mortality in septic shock: mediation analysis of a randomized trial.

PURPOSE: We previously showed that external cooling decreases day 14 mortality in febrile septic shock. Because cooling may participate in heart rate control, we studied the respective impact of heart rate and temperature lowering on mortality. METHODS: Post hoc analysis of the Sepsiscool randomized controlled trial database (NCT00527007). Cooling was applied to maintain normothermia (36.5-37 °C) during 48 h. We assessed the time spent below different thresholds of temperature and heart rate on day 14 mortality. The best threshold was selected by AUC-ROC and tested as a potential mediator of mortality reduction. Mediation analysis was adjusted for severity and treatments influencing temperature and heart rate evolution. Sensitivity analysis was done using only patients with appropriate antimicrobial therapy. RESULTS: A total of 197/200 patients with adequate heart rate and temperature monitoring were analyzed. The best threshold differentiating survivors and nonsurvivors was 38.4 °C for temperature and 95 b/min for heart rate. During the 48 h of intervention, cooling significantly increased the time spent with a temperature below 38.4 °C, p = 0.001, and with a heart rate below 95 b/min, p < 0.01. The longer was the time spent with a temperature below 38.4 °C, the lower was the mortality [adjOR 0.17 (0.06-0.49), p = 0.001]. The time spent with a heart rate below 95 b/min was similar in survivors and nonsurvivors [adjOR 0.68 (0.27-1.72), p = 0.42]. Mediation analysis showed that the time spent with a temperature below 38.4 °C was a significant mediator of mortality. CONCLUSION: The time spent with a temperature below 38.4 °C was independently associated with patient's outcome and explained 73% of the effect of the randomization on the day 14 mortality. Heart rate lowering was not a mediator of mortality.

Clinical evaluation of two dental implant macrostructures on peri-implant bone loss: a comparative, retrospective study.

OBJECTIVES: To compare the effect of two implant macrostructures on peri-implant bone level. MATERIAL AND METHODS: This retrospective cohort study was conducted in a private practice. Patients received test (Nobel Speedy Groovy implants) or control implants (Mk III implants) or both. Baseline and corresponding follow-up radiographs, taken with a long-cone technique, were analyzed to evaluate mean bone level changes around implants during a mean follow-up of 69 ± 19 months. A chi-squared test was performed to compare the bone level changes between the two types of implants. A multivariate analysis was used to explain the difference between the two groups. RESULTS: After controlling for inclusion and exclusion criteria, 144 dental implants corresponding to 68 implants in the test group and 76 implants in the control group were placed in 59 patients. Nine dental implants (6.25%) were lost during the observation period: five implants in the test group and four implants in the control group. Consequently, a total of 135 implants placed in 58 patients were available for analysis. Our study shows a significant difference of peri-implant bone level overtime between the test and control groups (P < 0.01). At the end of the observation period, a bone growth was observed in the control group (0.02 ± 0.80 mm), whereas a bone loss was found in the test group (-0.43 ± 1.11 mm). The mean bone level at baseline and the type of periodontal therapy and the maintenance care program were involved in this difference (P < 0.001, P = 0.035, P < 0.001, respectively). CONCLUSION: Our study demonstrates a significant difference in peri-implant bone level between test and control groups. The mean bone level at baseline, the type of periodontal therapy, and the maintenance program may explain peri-implant bone level changes overtime.

Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer.

RATIONALE: It is now well established that immune responses can take place outside of primary and secondary lymphoid organs. We previously described the presence of tertiary lymphoid structures (TLS) in patients with non-small cell lung cancer (NSCLC) characterized by clusters of mature dendritic cells (DCs) and T cells surrounded by B-cell follicles. We demonstrated that the density of these mature DCs was associated with favorable clinical outcome. OBJECTIVES: To study the role of follicular B cells in TLS and the potential link with a local humoral immune response in patients with NSCLC. METHODS: The cellular composition of TLS was investigated by immunohistochemistry. Characterization of B-cell subsets was performed by flow cytometry. A retrospective study was conducted in two independent cohorts of patients. Antibody specificity was analyzed by ELISA. MEASUREMENTS AND MAIN RESULTS: Consistent with TLS organization, all stages of B-cell differentiation were detectable in most tumors. Germinal center somatic hypermutation and class switch recombination machineries were activated, associated with the generation of plasma cells. Approximately half of the patients showed antibody reactivity against up to 7 out of the 33 tumor antigens tested. A high density of follicular B cells correlated with long-term survival, both in patients with early-stage NSCLC and with advanced-stage NSCLC treated with chemotherapy. The combination of follicular B cell and mature DC densities allowed the identification of patients with the best clinical outcome. CONCLUSIONS: B-cell density represents a new prognostic biomarker for NSCLC patient survival, and makes the link between TLS and a protective B cell-mediated immunity.