Sexual dysfunction in cystic fibrosis.

BACKGROUND: Sexual dysfunction (erectile dysfunction in males, sexual dissatisfaction, sexual interest/arousal disorders, and dyspareunia in females) has not been the subject of indepth research in people with cystic fibrosis (CF). This study aimed to determine the prevalence of sexual dysfunction in adults with CF, factors associated with sexual dysfunction, and the impact of sexual dysfunction on quality of life. METHOD: We conducted a multicentre study in adults with cystic fibrosis followed in specialist centres in Western France. We assessed erectile dysfunction and its severity using the IIEF5 self-questionnaire (International Index of Erectile Function); the FSFI (Female Sexual Function Index) was used to assess sexual function in females, and we evaluated quality of life in both sexes using the CFQ-R14+ questionnaire. RESULTS: In total, 77 males and 74 females completed the sexual function questionnaire (mean age 32+/- 10 and 25+/- 8,5 years respectively). Among them, 21 % of males and 30 % of females reported sexual dysfunction. CFQ-R14+ score was significantly lower in males with erectile dysfunction than those without (p < 0.001). Faecal incontinence was associated with more frequent sexual dysfunction in females and higher severity of erectile dysfunction in males. CONCLUSION: The prevalence of sexual disorders is relatively high in males and females with cystic fibrosis. Therefore, it seems important to train specialist teams to address the issue of sexuality without embarrassment, and to encourage them to seek out and treat faecal incontinence, which is associated with greater severity or frequency of these symptoms.

Concordance and agreement between different activity scores in polymyalgia rheumatica.

OBJECTIVE: The C reactive protein polymyalgia rheumatica activity score (CRP-PMR-AS) is a composite index that includes CRP levels and was developed specifically for PMR. As treatments such as interleukin-6 antagonists can normalise CRP levels, the erythrocyte sedimentation rate (ESR) of PMR-AS, the clinical (clin)-PMR-AS and the imputed-CRP (imp-CRP)-PMR-AS have been developed to avoid such bias. Our primary objective was to measure the correlation of these activity scores. Our secondary objective was to evaluate the concordance between different cutoffs of the PMR-ASs. METHOD: Data from the Safety and Efficacy of tocilizumab versus Placebo in Polymyalgia rHeumatica With glucocORticoid dEpendence (SEMAPHORE) trial, a superiority randomised double-blind placebo-controlled trial, were subjected to post hoc analysis to compare the efficacy of tocilizumab versus placebo in patients with active PMR. The CRP-PMR-AS, ESR-PMR-AS, clin-PMR-AS and imp-CRP-PMR-AS were measured at every visit. The concordance and correlation between these scores were evaluated using kappa correlation coefficients, Bland-Altman correlations, intraclass correlation coefficients (ICCs) and scatter plots. RESULTS: A total of 101 patients were included in the SEMAPHORE trial, and 100 were analysed in this study. The correlation between the PMR-ASs was excellent, as the ICC and kappa were >0.85 from week 4 until week 24 (CRP-PMR-AS ≤10 or >10). Bland-Altman plots revealed that the differences between the CRP-PMR-AS and the other threescores were low. The cut-off values for the clin-PMR-AS were similar to those for the CRP-PMR-AS 86% of the time. CONCLUSION: The correlation between all the PMR-ASs was excellent, reflecting the low weight of CRP. In clinical trials using drugs that have an impact on CRP, the derived activity scores can be used. TRIAL REGISTRATION NUMBER: NTC02908217.

[18F]FDG PET/CT for therapeutic assessment of Abatacept in early-onset polymyalgia rheumatica.

PURPOSE: Evaluate the benefit of 2-deoxy-2-[18F]-fluoro-D-glucose ([18F] FDG) positron emission tomography/computed tomography (PET/CT) for the therapeutic assessment of Abatacept (ABA) as first-line therapy in early-onset polymyalgia rheumatica (PMR) patients. METHODS: This was an ancillary study of ALORS trial (Abatacept in earLy Onset polymyalgia Rheumatica Study) assessing the ability of ABA versus placebo to achieve low disease activity (C-Reactive Protein PMR activity score (CRP PMR-AS) ≤ to 10) without glucocorticoid (GC) at week 12 in patients with early-onset PMR. The patients underwent [18F] FDG PET/CT at baseline and after 12 weeks of treatment. Responses to treatments were evaluated according to CRP PMR-AS, Erythrocyte Sedimentation Rate (ESR) PMR-AS, Clin PMR-AS, and CRP-Imputed (Imput-CRP) PMR-AS. Quantitative score by maximal standardized uptake value (SUVmax) and combined qualitative scores according to liver uptake (Leuven, Leuven/Groningen, and Besançon Scores) were used for assessment of [18F] FDG uptake in regions of interest (ROI) usually affected in PMR. Student's t-test was applied to evaluate the clinical, biological, and [18F] FDG uptake variation difference in ABA and placebo groups between W0 and W12. Subgroup analysis by GC rescue was performed. RESULTS: At W12, there was no significant difference according to SUVmax between the ABA and the placebo groups in all ROI. Subgroup analysis according to GC administration demonstrated a significant (p 0.047) decrease in SUVmax within the left sternoclavicular joint ROI in the ABA group (- 0.8) compared to the placebo group (+ 0.6) without GC rescue. Other results did not reveal any significant difference between the ABA and placebo groups. According to combined qualitative scores, there was no significant difference between ABA and placebo groups for the direct comparison analysis and subgroup analysis according to GC rescue. CONCLUSION: [18F] FDG PET/CT uptake did not decrease significantly after ABA compared to placebo in anatomical areas usually affected in PMR patients. These results are correlated with the clinical-biological therapeutic assessment. CLINICAL TRIAL REGISTRATION: The study was approved by the appropriate ethics committee (CPP Sud-Est II Ref CPP: 2018-33), and all patients gave their written informed consent before study enrollment. The protocol was registered on Clinicaltrials.gov (NCT03632187).

Changes Induced by Early Hand-Arm Bimanual Intensive Therapy Including Lower Extremities in Young Children With Unilateral Cerebral Palsy: A Randomized Clinical Trial.

Importance: Intensive interventions are provided to young children with unilateral cerebral palsy (UCP), classically focused on the upper extremity despite the frequent impairment of gross motor function. Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) effectively improves manual dexterity and gross motor function in school-aged children. Objective: To verify if HABIT-ILE would improve manual abilities in young children with UCP more than usual motor activity. Design, Setting, and Participants: This prospective randomized clinical trial (November 2018 to December 2021), including 2 parallel groups and a 1:1 allocation, recruitment took place at European university hospitals, cerebral palsy specialized centers, and spontaneous applications at 3 sites: Brussels, Belgium; Brest, France; and Pisa, Italy. Matched (age at inclusion, lesion type, cause of cerebral palsy, and affected side) pairs randomization was performed. Young children were assessed at baseline (T0), 2 weeks after baseline (T1), and 3 months after baseline (T2). Health care professionals and assessors of main outcomes were blinded to group allocation. At least 23 young children (in each group) aged 12 to 59 months with spastic/dyskinetic UCP and able to follow instructions were needed. Exclusion criteria included uncontrolled seizures, scheduled botulinum toxin injections, orthopedic surgery scheduled during the 6 months before or during the study period, severe visual/cognitive impairments, or contraindications to magnetic resonance imaging. Interventions: Two weeks of usual motor activity including usual rehabilitation (control group) vs 2 weeks (50 hours) of HABIT-ILE (HABIT-ILE group). Main Outcomes and Measures: Primary outcome: Assisting Hand Assessment (AHA); secondary outcomes: Gross Motor Function Measure-66 (GMFM-66), Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), and Canadian Occupational Performance Measure (COPM). Results: Of 50 recruited young children (26 girls [52%], median age; 35.3 months for HABIT-ILE group; median age, 32.8 months for control group), 49 were included in the final analyses. Change in AHA score from T0 to T2 was significantly greater in the HABIT-ILE group (adjusted mean score difference [MD], 5.19; 95% CI, 2.84-7.55; P < .001). Changes in GMFM-66 (MD, 4.72; 95% CI, 2.66-6.78), PEDI-CAT daily activities (MD, 1.40; 95% CI, 0.29-2.51), COPM performance (MD, 3.62; 95% CI, 2.91-4.32), and satisfaction (MD, 3.53; 95% CI, 2.70-4.36) scores were greater in the HABIT ILE group. Conclusions and Relevance: In this clinical trial, early HABIT-ILE was shown to be an effective treatment to improve motor performance in young children with UCP. Moreover, the improvements had an impact on daily life activities of these children. Trial registration: ClinicalTrials.gov Identifier: NCT04020354.

Prevalence and severity of functional urinary and anorectal disorders and their impact on quality of life in cystic fibrosis.

BACKGROUND: In cystic fibrosis (CF), coughing is associated with a risk of pelvic floor dysfunction. However, data on the prevalence of symptoms (stress urinary incontinence, bladder overactivity, dysuria, and faecal incontinence) are lacking in males and females with CF. The impact of incontinence on adherence to respiratory care has not been studied. METHODS: We conducted a multicentre study in adults with CF followed in the North-West French CF network. Urinary disorders and their severity were assessed using the Urinary Symptom Profile (USP) self-report questionnaire; the impact of urinary disorders on general quality of life was measured using the SF-Qualiveen questionnaire; faecal incontinence was assessed using the Wexner self-report questionnaire; and the CFQ-R14+ questionnaire was used to assess quality of life. A self-administered questionnaire developed for the study assessed the impact of symptoms on respiratory care. RESULTS: Of the 178 people with CF included, 34 % reported stress urinary incontinence, with a large female predominance (63.5 % of females vs. 7.5 % of males), 65 % bladder overactivity (including 16 % urge incontinence) and 50 % faecal incontinence, also with a female predominance. Neither urinary nor faecal incontinence were related to the severity of the respiratory impairment (FEV1). Quality of life was particularly affected in women. Stress urinary Incontinence symptoms affected respiratory care in both sexes. CONCLUSION: The prevalence of functional urinary and faecal disorders was high in adults with CF and impacted on quality of life and respiratory care. Therefore, multidisciplinary teams must have knowledge of symptoms, the diagnostic tools and management strategies to provide specific treatment.

Family history of postpartum hemorrhage is a risk factor for postpartum hemorrhage after vaginal delivery: results from the French prospective multicenter Haemorrhages and Thromboembolic Venous Disease of the Postpartum cohort study.

BACKGROUND: Postpartum hemorrhage is a major component of perinatal morbidity and mortality that affects young women worldwide and is still often unpredictable. Reducing the incidence of postpartum hemorrhage is a major health issue and identifying women at risk for postpartum hemorrhage is a key element in preventing this complication. OBJECTIVE: This study aimed to estimate postpartum hemorrhage prevalence after vaginal delivery and to identify postpartum hemorrhage risk factors. STUDY DESIGN: Unselected pregnant women ≥16 years of age admitted to 1 of 6 maternity wards in Brittany (France) for vaginal birth after 15 weeks of gestation were recruited in this prospective, multicenter cohort study between June 1, 2015, and January 31, 2019. Postpartum hemorrhage was defined as blood loss ≥500 mL in the 24 hours following delivery. Independent risk factors for postpartum hemorrhage were determined using logistic regression. Missing data were imputed using the Multivariate Imputation by Chained Equations method. RESULTS: Among 16,382 included women, the postpartum hemorrhage prevalence was 5.37%. A first-degree family history of postpartum hemorrhage (adjusted odds ratio, 1.63; 95% confidence interval, 1.24-2.14) and a personal transfusion history (adjusted odds ratio, 1.90; 95% confidence interval, 1.23-2.92) were significantly associated with postpartum hemorrhage. The use of oxytocin during labor was also a risk factor for postpartum hemorrhage (adjusted odds ratio, 1.24; 95% confidence interval, 1.06-1.44). Inversely, smoking during pregnancy and intrauterine growth restriction were associated with a reduced risk for postpartum hemorrhage (adjusted odds ratio, 0.76; 95% confidence interval, 0.63-0.91, and 0.34; 95% confidence interval, 0.13-0.87, respectively). CONCLUSION: In addition to classical risk factors, this study identified a family history of postpartum hemorrhage and personal transfusion history as new characteristics associated with postpartum hemorrhage after vaginal delivery. The association of postpartum hemorrhage with a family history of postpartum hemorrhage suggests a hereditary hemorrhagic phenotype and calls for genetic studies. Identifying women at risk for postpartum hemorrhage is a key element of being prepared for this complication.

Evaluation of the efficacy of HEMO2life®, a marine OXYgen carrier for Organ Preservation (OxyOp2) in renal transplantation: study protocol for a multicenter randomized trial.

BACKGROUND: Preventing ischemia‒reperfusion injury (IRI) is a major issue in kidney transplantation, particularly for transplant recipients receiving a kidney from extended criteria donors (ECD). The main consequence of IRI is delayed graft function (DGF). Hypoxia is one of the key factors in IRI, suggesting that the use of an oxygen carrier as an additive to preservation solution may be useful. In the OxyOp trial, we showed that the organs preserved using the oxygen carrier HEMO2life® displayed significantly less DGF. In the OxyOp2 trial, we aim to definitively test and quantify the efficacy of HEMO2life® for organ preservation in a large population of kidney grafts. METHODS: OxyOp2 is a prospective, multicenter, randomized, comparative, single-blinded, parallel-group study versus standard of care in renal transplantation. After the selection of a suitable donor according to the inclusion/exclusion criteria, both kidneys will be used in the study. Depending on the characteristics of the donor, both kidneys will be preserved either in static cold storage (standard donors) or on machine perfusion (for ECD and deceased-after-cardiac-death donors (DCD)). The kidneys resulting from one donor will be randomized: one to the standard-of-care arm (organ preserved in preservation solution routinely used according to the local practice) and the other to the active treatment arm (HEMO2life® on top of routinely used preservation solution). HEMO2life® will be used for ex vivo graft preservation at a dose of 1 g/l preservation solution. The primary outcome is the occurrence of DGF, defined as the need for renal replacement therapy during the first week after transplantation. DISCUSSION: The use of HEMO2life® in preservation solutions is a novel approach allowing, for the first time, the delivery of oxygen to organs. Improving graft survival by limiting ischemic lesions is a major public-health goal in the field of organ transplantation. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT04181710 . registered on November 29, 2019.

Clinical risk factors for vasculo-placental disorders: results from a prospective case-control study nested in HEMOTHEPP French cohort study.

OBJECTIVE: Determine clinical risk factors for vasculo-placental disorders in singleton pregnancies. DESIGN: Prospective case-control study nested in HEMOTHEPP French cohort. SETTING: Women delivered between June, 2015 and January, 2019 in any maternity ward of Finistère. POPULATION: Cases were women with vasculo-placental disorders (pre-eclampsia, intrauterine growth restriction (IUGR), placental abruption or stillbirth). Controls were women matched for age at delivery and parity. METHODS: Clinical data were collected by obstetricians or midwives during antenatal care visits and delivery, and recorded by trained research assistants. MAIN OUTCOME MEASURES: Occurrence of a vasculo-placental disorder. RESULTS: 505 women with vasculo-placental disorder (299 pre-eclampsia, 253 IUGR, 44 placental abruptions, 11 stillbirths) and 1515 matched controls were selected out of 20,075 participants. In multivariable analysis, four clinical parameters were associated with pre-eclampsia: obesity (Odd ratio (OR) = 3.11, 95%CI 2.11-4.58), French overseas origin (OR = 4.41, 95%CI 1.87-10.42), previous vasculo-placental disorder (OR = 5.14, 95%CI 2.72-9.70), aspirin during pregnancy (OR = 10.10, 95%CI 1.99-51.08). Three clinical parameters were associated with IUGR: auto-immune/inflammatory disorder (OR = 3.75, 95%CI 1.83-7.68), previous vasculo-placental disorder (OR = 3.63, 95%CI 2.06-6.41), smoking during pregnancy (OR = 2.66, 95%CI 1.91- 3.71). A previous venous thromboembolism (VTE) was associated with IUGR in univariable but not in multivariable analysis (OR = 3.72, 95%CI 0.82-17.00, p = 0.09). CONCLUSIONS: Clinical risk factors differ between IUGR and pre-eclampsia, the later, but not the former, being associated with cardiovascular risk factors.

Abatacept in early polymyalgia rheumatica (ALORS): a proof-of-concept, randomised, placebo-controlled, parallel-group trial.

BACKGROUND: Medium-dose glucocorticoids can improve symptoms in nearly all patients with polymyalgia rheumatica. According to its good safety profile, abatacept could be used instead of glucocorticoids in early polymyalgia rheumatica. We aimed to determine whether the efficacy of abatacept is sufficient to justify larger studies in early polymyalgia rheumatica. METHODS: To evaluate whether abatacept allows low disease activity without glucocorticoids in early polymyalgia rheumatica, we conducted a proof-of-concept, randomised, double-blind, placebo-controlled, parallel-group trial. Participants were recruited from five centres in France (in Brest, Le Mans, Morlaix, Dinan and Saint Malo, and Strasbourg) and were included if they had recent-onset (<6 months) polymyalgia rheumatica with a C-reactive protein (CRP) polymyalgia rheumatica activity score (PMR-AS) of more than 17 without any signs or symptoms of giant cell arteritis (clinical and [18F]fluorodeoxyglucose PET-CT evaluation). Participants were randomly assigned (1:1) to receive weekly subcutaneous abatacept (125 mg) or matching placebo, with glucocorticoid rescue therapy allowed in cases of high disease activity, for 12 weeks, and then glucocorticoid treatment based on disease activity, until week 36. Investigators, patients, outcome assessors, and sponsor personnel were masked to group assignments. The primary endpoint was low disease activity (CRP PMR-AS ≤10) at week 12 without glucocorticoids and without rescue treatment. The study was powered to demonstrate a 60% difference in response rates between groups. Open-ended adverse events were collected at each visit by clinicians and were categorised following system organ class classification after study completion. The ALORS trial is registered with ClinicalTrials.gov, NCT03632187. FINDINGS: 34 patients (22 women and 12 men) were randomly assigned between Dec 13, 2018, and Oct 21, 2021. All patients who had been randomly assigned were included in the analysis. The primary endpoint was reached by eight (50%) of 16 patients in the abatacept group and four (22%) of 18 patients in the placebo group (relative risk 2·2 [0·9-5·5]); crude p=0·15; adjusted p=0·070). Eight (50%) patients in the abatacept and 15 (83%) in the placebo group had adverse events. Four patients (one [6%] in the abatacept group and three [17%] in the placebo group) had serious adverse events. There were no deaths or new safety concerns. INTERPRETATION: This study suggests that the effect of abatacept alone is not strong enough to justify larger studies in early polymyalgia rheumatica. This is only a first step in deciding whether a larger study should be conducted in early polymyalgia rheumatica and does not exclude a potential effect of abatacept in glucocorticoid-dependent polymyalgia rheumatica. FUNDING: BMS Pharma France.

Effect of Tocilizumab on Disease Activity in Patients With Active Polymyalgia Rheumatica Receiving Glucocorticoid Therapy: A Randomized Clinical Trial.

Importance: Few treatments are available for patients with glucocorticoid-dependent polymyalgia rheumatica. IL-6 antagonists may reduce disease activity in patients with active glucocorticoid-dependent polymyalgia rheumatica. Objective: To compare the efficacy of tocilizumab vs placebo in patients with glucocorticoid-dependent polymyalgia rheumatica. Design, Setting, and Participants: This double-blind, parallel-group, placebo-controlled randomized clinical trial enrolled 101 patients with polymyalgia rheumatica at 17 hospitals in France from February 2017 to October 2019. Final follow-up occurred in November 2020. Inclusion criteria were persistent disease activity (polymyalgia rheumatica activity score computed using the C-reactive protein level [CRP PMR-AS] >10) and prednisone dose greater than or equal to 10 mg per day. Interventions: Patients were randomly assigned to receive intravenous tocilizumab (8 mg/kg; n = 51) or placebo (n = 50) every 4 weeks for 24 weeks, combined with predefined standardized tapering of oral prednisone. Main Outcomes and Measures: The primary efficacy end point was CRP PMR-AS less than 10 (range, 0-100; higher values indicate greater activity; no minimal clinically important difference defined) combined with either prednisone dose less than or equal to 5 mg per day or a decrease in prednisone dose greater than or equal to 10 mg from baseline at week 24. There were 11 secondary outcomes assessed at week 24 included in this report, including disease activity (measured by CRP PMR-AS) and the proportion of patients no longer taking prednisone. Results: Of the 101 randomized patients (mean age, 67.2 years; 68 [67.3%] women), 100 (99%) received at least 1 infusion and 100 completed the trial. The primary end point was achieved in 67.3% of patients in the tocilizumab group and 31.4% of patients in the placebo group (adjusted difference, 36.0% [95% CI, 19.4%-52.6%]; adjusted relative risk, 2.3 [95% CI, 1.5-3.6]; P < .001). Of 11 reported secondary end points at 24 weeks, 7 showed significant differences favoring tocilizumab, including mean CRP PMR-AS score (7.5 [95% CI, 5.4-9.6] vs 14.9 [95% CI, 11.4-18.4]; adjusted difference, -7.5 [95% CI, -11.2 to -3.8]; P < .001) and the percentage of patients no longer receiving prednisone (49.0% vs 19.6%; adjusted difference, 29.3% [95% CI, 18.9%-39.7%]; adjusted relative risk, 2.5 [95% CI, 1.8-3.5]; P < .001). The most frequent adverse events were infections, experienced by 23 patients (46.9%) in the tocilizumab group and 20 (39.2%) in the placebo group. Conclusions and Relevance: Among patients with active polymyalgia rheumatica despite prednisone therapy, tocilizumab, compared with placebo, resulted in a significantly greater percentage of patients with a CRP PMR-AS less than 10 with reduced prednisone requirements at week 24. Further research is needed to confirm efficacy and to determine the balance of potential benefits and harms. Trial Registration: ClinicalTrials.gov Identifier: NCT02908217.

Excessive gestational weight gain is an independent risk factor for gestational diabetes mellitus in singleton pregnancies: Results from a French cohort study.

OBJECTIVE: Increase in prevalence of maternal obesity worldwide raises concern among health professionals. Our purpose was to evaluate the impact of maternal obesity and of excessive gestational weight gain (GWG) on the course of singleton pregnancies in a French maternity ward. STUDY DESIGN: 3599 consecutive women who delivered from April 2013 to May 2015 at Brest University Hospital were included in HPP-IPF cohort study, a study designed to evaluate clinical and biological determinants of postpartum hemorrhage (PPH). Maternal obesity was defined by a pre-pregnancy Body Mass Index (BMI) ≥ 30 kg/m2 and excessive GWG was defined according to the Institute of Medicine 2009 guidelines. Obstetric complications(including gestational diabetes mellitus (GDM), gestational hypertension, pre-eclampsia, venous thromboembolism, PPH, cesarean section (C-section) and macrosomia) were collected prospectively in a standardized case report form. For each complication, Odd Ratios (OR) according to pre-pregnancy BMI and GWG were calculated in univariable and multivariable analyses. RESULTS: Out of the 3162 women analyzed for this report, 583 (18.4%) were overweight, 400 (12.7%) were obese and 36.6% had excessive GWG. In multivariable analysis, after adjustment for confounding factors, obese women were at increased risk of GDM (OR 5.83, 95%CI 4.37-7.79), PPH (OR 1.69, 95%CI 1.19-2.41), C-section (OR 2.50, 95%CI 1.92-3.26) and macrosomia (OR 1.90, 95%CI 1.31-2.76). Similarly, women with excessive GWG were at increased risk of GDM (OR 1.55, 95%CI 1.17-2.06), C-section (OR 1.46, 95%CI 1.16-1.83) and macrosomia (OR 2.09, 95%CI 1.50-2.91). CONCLUSIONS: Maternal obesity and excessive GWG are independent risk factors for GDM, C-section and macrosomia in singleton pregnancies. Further studies are needed to evaluate if a lifestyle intervention aiming at avoiding excessive GWG could improve clinical outcomes in pregnant women.

Validation of the French translation of a self-administered questionnaire looking for a history of pre-eclampsia.

We evaluated the diagnostic performances of the French translation of a self-administered questionnaire designed by Diehl et al. looking for a history of pre-eclampsia. After a phone call, 206 women who gave birth at Brest University Hospital responded to the questionnaire online. Then, their responses were compared to their medical files. The sensitivity of the questionnaire was 95.2% and its specificity was 98.0%. This French questionnaire has then demonstrated its validity. It can now be used to explore the role of a pre-eclampsia history on various pathologies and, by this mean, to improve knowledge about women's health.

Effect of neuromuscular electrical stimulation on exercise capacity in patients with severe chronic obstructive pulmonary disease: A randomised controlled trial.

OBJECTIVE: To compare strengthening by neuromuscular electrical stimulation versus cycle ergometer training during a pulmonary rehabilitation program, in patients with severe to very severe chronic obstructive pulmonary disease. DESIGN: A prospective randomized controlled study. SETTING: Two inpatient pulmonary rehabilitation centers. SUBJECTS: Patients with severe to very severe chronic obstructive pulmonary disease and multidimensional index to predict risk of death ≥5, were randomly assigned to receive neuromuscular electrical stimulation or cycle ergometer training during pulmonary rehabilitation. MAIN MEASURES: The primary endpoint was the change in exercise capacity using 1-min sit-to-stand test Secondary endpoints were the changes in exercise capacity using 6-min walk test, quadriceps strength, quality of life and dyspnea. RESULTS: 102 patients were included. After 3 weeks, 47 patients in the neuromuscular electrical stimulation group, and 45 in the cycle ergometer training group were able to be analyzed. No significant difference was seen in the evolution of exercise capacity using 1-min sit-to-stand test (3.3 ± 3.8 and 2.6 ± 4.1) and 6-min walk test (37.8 ± 58.4 and 33.1 ± 46.7), in the evolution of quadriceps strength and endurance (9.2 ± 12.9 and 6.6 ± 16.1; 9.0 ± 13.2 and 6.2 ± 17.0), in the evolution of quality of life (St George's Respiratory Questionnaire: -11.3 ± 11.7 and -8.1 ± 11.6; COPD Assessment Test: -5.7 ± 7.1 and -4.7 ± 7.0), or in the evolution of dyspnea using Dyspnea 12 (-5.5 ± 10.2 and -5.9 ± 8.5) except using modified medical research council scale (95% confidence interval: 0.48 [0.05; 0.91], p = 0.027). CONCLUSION: We found no significant difference between the two programs on exercise capacity, quadriceps strength and quality of life.

Effectiveness of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on total and cardiovascular mortality and morbidity in primary prevention: A nationwide study based on French Health Insurance Data (SNDS).

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) both inhibit the renin-angiotensin system (RAS) but have different sites of action. Whether clinically meaningful differences exist is still debated. The authors set up a population-based nationwide retrospective cohort study with at least 5 years of follow-up based on the comprehensive French Health Insurance Database linked to the French hospital discharge database. Patients aged 50 or above, identified as ARB or ACE inhibitor new users in 2009 (at least one delivery during the year and no such delivery in 2008) were eligible. Exclusion criteria included history of cancer, cardiovascular disease, or chronic renal insufficiency. Main outcome measure was overall mortality. Secondary outcomes were cardiovascular deaths, major cardiovascular events, and major or other cardiovascular events. Out of 407 815 eligible patients, 233 682 (57%) were ARB users; two-third had no previous exposure to antihypertensive drug. Based on propensity-score based Cox model, ARB new user group had a better overall (HR: .878, 95%CI, .854 to .902), and cardiovascular (HR: .841, 95%CI, .800 to .84) survival and had a lower risk for major cardiovascular events (HR: .886, 95%CI, .868 to .905). Statistically significant quantitative interactions were detected with diabetes. Considering subgroup analyses, ARBs had a better survival than ACE inhibitors in nondiabetic patients.

Effect of Different Modalities of Purgative Preparation on the Diagnostic Yield of Small Bowel Capsule for the Exploration of Suspected Small Bowel Bleeding: A Multicenter Randomized Controlled Trial.

INTRODUCTION: The aim of our study was to compare clear liquid diet with 2 different polyethylene glycol (PEG)-based bowel preparation methods regarding diagnostic yield of small bowel capsule endoscopy (SBCE) in patients with suspected small bowel bleeding (SBB). METHODS: In this prospective multicenter randomized controlled trial, consecutive patients undergoing SBCE for suspected SBB between September 2010 and February 2016 were considered. Patients were randomly assigned to standard regimen, that is, clear fluids only (prep 1), standard regimen plus 500 mL PEG after SBCE ingestion (prep 2), or standard regimen plus 2 L PEG plus 500 mL PEG after SBCE ingestion (prep 3). The primary outcome was the detection of at least one clinically significant lesion in the small bowel. The quality of small bowel cleansing was assessed. A questionnaire on the clinical tolerance was filled by the patients. RESULTS: We analyzed 834 patients. No significant difference was observed for detection of P1 or P2 small bowel lesions between prep1 group (40.5%), prep 2 group (40.2%), and prep 3 group (38.5%). Small bowel cleansing was improved in prep 2 and 3 groups compared with that in prep 1 group. Compliance to the preparation and tolerance was better in prep 2 group than in prep 3 group. DISCUSSION: Small bowel purgative before SBCE allowed better quality of cleansing. However, it did not improve diagnostic yield of SBCE for suspected SBB.

Hospitalization for adverse events under abiraterone or enzalutamide exposure in real-world setting: A French population-based study on prostate cancer patients.

AIMS: Safety profiles of abiraterone and enzalutamide rely mainly on Phase III clinical trials. Our objective was to estimate the incidence rate ratio (IRR) for certain adverse events leading in real life to hospitalization (atrial fibrillation, acute heart failure, ischaemic heart disease, acute kidney injury [AKI], ischaemic stroke, torsade de pointe/QT interval prolongation, hepatitis and seizure), comparing abiraterone to enzalutamide. We also set out to discuss previously identified safety signals. METHOD: Using the French National Health Insurance System database, all patients newly exposed to abiraterone or enzalutamide between 2013 and 2017 and followed until 31 December 2018 were targeted. IRRs for each event were estimated using a Poisson model in a sub-population of patients without contraindications or precautions for use for either treatment. RESULTS: Among 11 534 new users of abiraterone and enzalutamide, AKI (IRR 1.42, 95% CI: 1.01-2.00), liver monitoring suggestive of hepatic damage (IRR 3.06, 95% CI: 2.66-3.53) and atrial fibrillation (IRR 1.12, 95% CI: 1.05-1.19) were significantly more often observed with abiraterone than with enzalutamide. CONCLUSION: Our study provides knowledge on abiraterone and enzalutamide real-life safety profiles, especially for events leading to hospitalization. Despite several limitations, including the lack of clinical data, the safety signal for AKI under abiraterone is in line with results of an analysis of the French pharmacovigilance database, which requires further specific investigations. Enlightening the clinicians' therapeutic choices for patients treated for prostate cancer, our study should lead to clinicians being cautious in the use of abiraterone.

Safety and pharmacokinetics of Roscovitine (Seliciclib) in cystic fibrosis patients chronically infected with Pseudomonas aeruginosa, a randomized, placebo-controlled study.

BACKGROUND: The orally available kinase inhibitor R-roscovitine has undergone clinical trials against various cancers and is currently under clinical evaluation against Cushing disease and rheumatoid arthritis. Roscovitine displays biological properties suggesting potential benefits in CF: it partially corrects F508del-CFTR trafficking, stimulates the bactericidal properties of CF alveolar macrophages, and displays anti-inflammatory properties and analgesic effects. METHODS: A phase 2 trial study (ROSCO-CF) was launched to evaluate the safety and effects of roscovitine in Pseudomonas aeruginosa infected adult CF patients carrying two CF causing mutations (at least one F508del-CFTR mutation) and harboring a FEV1 ≥40%. ROSCO-CF was a multicenter, double-blind, placebo-controlled, dose-ranging study (200, 400, 800 mg roscovitine, orally administered daily for 4 days/week/4 weeks). RESULTS: Among the 34 volunteers enrolled, randomization assigned 11/8/8/7 to receive the 0 (placebo)/ 200/400/800 mg roscovitine doses, respectively. In these subjects with polypharmacy, roscovitine was relatively safe and well-tolerated, with no significant adverse effects (AEs) other than five serious AEs (SAEs) possibly related to roscovitine. Pharmacokinetics of roscovitine were rather variable among subjects. No significant efficacy, at the levels of inflammation, infection, spirometry, sweat chloride, pain and quality of life, was detected in roscovitine-treated groups compared to the placebo-treated group. CONCLUSION: Roscovitine was relatively safe and well-tolerated in CF patients especially at the 200 and 400 mg doses. However, there were 5 subject withdrawals due to SAEs in the roscovitine group and none in the placebo group. The lack of evidence for efficacy of roscovitine (despite encouraging cellular and animal results) may be due to high pharmacokinetics variability, short duration of treatment, and/or inappropriate dosing protocol.

Development and Validation of a Predictive Tool for Postpartum Hemorrhage after Vaginal Delivery: A Prospective Cohort Study.

Postpartum hemorrhage (PPH) is one of the leading causes of maternal morbidity worldwide. This study aimed to develop and validate a predictive model for PPH after vaginal deliveries, based on routinely available clinical and biological data. The derivation monocentric cohort included pregnant women with vaginal delivery at Brest University Hospital (France) between April 2013 and May 2015. Immediate PPH was defined as a blood loss of ≥500 mL in the first 24 h after delivery and measured with a graduated collector bag. A logistic model, using a combination of multiple imputation and variable selection with bootstrap, was used to construct a predictive model and a score for PPH. An external validation was performed on a prospective cohort of women who delivered between 2015 and 2019 at Brest University Hospital. Among 2742 deliveries, PPH occurred in 141 (5.1%) women. Eight factors were independently associated with PPH: pre-eclampsia (aOR 6.25, 95% CI 2.35−16.65), antepartum bleeding (aOR 2.36, 95% CI 1.43−3.91), multiple pregnancy (aOR 3.24, 95% CI 1.52−6.92), labor duration ≥ 8 h (aOR 1.81, 95% CI 1.20−2.73), macrosomia (aOR 2.33, 95% CI 1.36−4.00), episiotomy (aOR 2.02, 95% CI 1.40−2.93), platelet count < 150 Giga/L (aOR 2.59, 95% CI 1.47−4.55) and aPTT ratio ≥ 1.1 (aOR 2.01, 95% CI 1.25−3.23). The derived predictive score, ranging from 0 to 10 (woman at risk if score ≥ 1), demonstrated a good discriminant power (AUROC 0.69; 95% CI 0.65−0.74) and calibration. The external validation cohort was composed of 3061 vaginal deliveries. The predictive score on this independent cohort showed an acceptable ability to discriminate (AUROC 0.66; 95% CI 0.62−0.70). We derived and validated a robust predictive model identifying women at risk for PPH using in-depth statistical methodology. This score has the potential to improve the care of pregnant women and to take preventive actions on them.

Impact of recommendations on sodium valproate prescription among women with epilepsy: An interrupted time-series study.

BACKGROUND: The European Medicines Agency (EMA) has developed risk minimization measures (RMMs) to reduce the use of the teratogenic drug, sodium valproate (VPA). The objective was to assess the impact of these RMMs among females with epilepsy in France. METHODS: We used data from the French National Health Insurance Database (SNDS), including 114,936 females aged under 50, with a reimbursement claim for an antiepileptic drug from January 2011 to December 2017, and identified as people with epilepsy. We used a controlled interrupted time series stratifying on age: girls (0-14 years old) and women of childbearing age (15-49 years), and with 129,917 males as controls. RESULTS: VPA prevalent use among girls and women of childbearing age with epilepsy decreased significantly after the issue of the RMMs (trend changes of, respectively, -5 and -4 users per 1000 females at-risk per quarter in comparison to the control group). We did not detect any significant change in VPA incident use. CONCLUSIONS: VPA use decreased over the study period among females with epilepsy but there were still 317 women and 206 girls started on VPA therapy VPA in 2017 (8 per 1000 at-risk and 18 per 1000, respectively). This suggests that either the measures should be strengthened or that the lowest level of VPA use has been reached. In this context, the introduction of a new RMM (in 2018) needs to be evaluated.

Additional, Mechanized Upper Limb Self-Rehabilitation in Patients With Subacute Stroke: The REM-AVC Randomized Trial.

Background and Purpose: Additional therapy may improve poststroke outcomes. Self-rehabilitation is a useful means to increase rehabilitation time. Mechanized systems are usual means to extend time for motor training. The primary aim was to compare the effects of self-rehabilitation using a mechanized device with control self-exercises on upper extremity impairment in patients with stroke. Methods: Phase III, parallel, concealed allocation, randomized controlled, multicenter trial, with 12-month follow-up. Patients aged 18 to 80 years, 3 weeks to 3 months poststroke with a Fugl-Meyer Assessment score of 10 to 40 points, were randomized to the Exo or control groups. All undertook two 30-minute self-rehabilitation sessions/day, 5 days/wk for 4 weeks in addition to usual rehabilitation. The Exo group performed games-based exercises using a gravity-supported mechanical exoskeleton (Armeo Spring). The control group performed stretching plus basic active exercises. Primary outcome was change in upper extremity Fugl-Meyer Assessment score at 4 weeks. Results: Two hundred fifteen participants were randomly allocated to the Exo group (107) or the control group (108). Mean age (SD), 58.3 (13.6) years; mean time poststroke, 54.8 (22.1) days; and mean baseline Fugl-Meyer Assessment score, 26.1 (9.5). There was no between-group difference in mean change in Fugl-Meyer Assessment score following the intervention: 13.3 (9.0) in the Exo group and 11.8 (8.8) in the control group (P=0.22). There were no significant between-group differences in changes for any of the other outcomes at any time point (except for perception of the self-rehabilitation). There was no between-group difference in cost utility at 12 months. Conclusions: In patients with moderate-to-severe impairment in the subacute phase of stroke, the purchase and use of complex devices to provide additional upper limb training may not be necessary: simply educating patients to regularly move and stretch their limbs appears sufficient. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01383512.