Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Association Between Surgeon Gender and Maternal Morbidity After Cesarean Delivery.

Importance: The stereotype that men perform surgery better than women is ancient. Surgeons have long been mainly men, but in recent decades an inversion has begun; the number of women surgeons is increasing, especially in obstetrics and gynecology. Studies outside obstetrics suggest that postoperative morbidity and mortality may be lower after surgery by women. Objective: To evaluate the association between surgeons' gender and the risks of maternal morbidity and postpartum hemorrhage (PPH) after cesarean deliveries. Design, Setting, and Participants: This prospective cohort study was based on data from the Tranexamic Acid for Preventing Postpartum Hemorrhage after Cesarean Delivery (TRAAP2) trial, a multicenter, randomized, placebo-controlled trial that took place from March 2018 through January 2020 (23 months). It aimed to investigate whether the administration of tranexamic acid plus a prophylactic uterotonic agent decreased PPH incidence after cesarean delivery compared with a uterotonic agent alone. Women having a cesarean delivery before or during labor at or after 34 weeks' gestation were recruited from 27 French maternity hospitals. Exposures: Self-reported gender (man or woman), assessed by a questionnaire immediately after delivery. Main Outcomes and Measures: The primary end point was the incidence of a composite maternal morbidity variable, and the secondary end point was the incidence of PPH (the primary outcome of the TRAAP2 trial), defined by a calculated estimated blood loss exceeding 1000 mL or transfusion by day 2. Results: Among 4244 women included, men surgeons performed 943 cesarean deliveries (22.2%) and women surgeons performed 3301 (77.8%). The rate of attending obstetricians was higher among men (441 of 929 [47.5%]) than women (687 of 3239 [21.2%]). The risk of maternal morbidity did not differ for men and women surgeons: 119 of 837 (14.2%) vs 476 of 2928 (16.3%) (adjusted risk ratio, 0.92 [95% CI, 0.77-1.13]). Interaction between surgeon gender and level of experience on the risk of maternal morbidity was not statistically significant. Similarly, the groups did not differ for PPH risk (adjusted risk ratio, 0.98 [95% CI, 0.85-1.13]). Conclusions and Relevance: Risks of postoperative maternal morbidity and of PPH exceeding 1000 mL or requiring transfusion by day 2 did not differ by the surgeon's gender.

Tranexamic acid for the prevention of blood loss after cesarean among women with twins: a secondary analysis of the TRAnexamic Acid for Preventing Postpartum Hemorrhage Following a Cesarean Delivery randomized clinical trial.

BACKGROUND: Although prophylactic tranexamic acid administration after cesarean delivery resulted in a lower incidence of calculated estimated blood loss of >1000 mL or red cell transfusion by day 2, its failure to reduce the incidence of hemorrhage-related secondary clinical outcomes (TRAnexamic Acid for Preventing Postpartum Hemorrhage Following a Cesarean Delivery trial) makes its use questionable. The magnitude of its effect may differ in women at higher risk of blood loss, including those with multiple pregnancies. OBJECTIVE: This study aimed to compare the effect of tranexamic acid vs placebo to prevent blood loss after cesarean delivery among women with multiple pregnancies. STUDY DESIGN: This was a secondary analysis of the TRAnexamic Acid for Preventing Postpartum Hemorrhage Following a Cesarean Delivery trial data, a double-blind, randomized controlled trial from March 2018 to January 2020 in 27 French maternity hospitals, that included 319 women with multiple pregnancies. Women with a cesarean delivery before or during labor at ≥34 weeks of gestation were randomized to receive intravenously 1 g of tranexamic acid (n=160) or placebo (n=159), both with prophylactic uterotonics. The primary outcome was a calculated estimated blood loss of >1000 mL or a red blood cell transfusion by 2 days after delivery. The secondary outcomes included clinical and laboratory blood loss measurements. RESULTS: Of the 4551 women randomized in this trial, 319 had a multiple pregnancy and cesarean delivery, and 298 (93.4%) had primary outcome data available. This outcome occurred in 62 of 147 women (42.2%) in the tranexamic acid group and 67 of 152 (44.1%) receiving placebo (adjusted risk ratio, 0.97; 95% confidence interval, 0.68-1.38; P=.86). No significant between-group differences occurred for any hemorrhage-related clinical outcomes: gravimetrically estimated blood loss, provider-assessed clinically significant hemorrhage, additional uterotonics, postpartum blood transfusion, arterial embolization, and emergency surgery (P>.05 for all comparisons). CONCLUSION: Among women with a multiple pregnancy and cesarean delivery, prophylactic tranexamic acid did not reduce the incidence of any blood loss-related outcomes.

The association between oral health and nutritional status in older adults: a cross-sectional study.

OBJECTIVES: This work aimed to describe the nutritional status of French older adults (age ≥ 90 years) and studied the association between oral health and nutritional status. METHODS: A cross-sectional study was carried out in 2014 among the participants of a cohort on cerebral and functional aging in France at their 25-year follow up (the PAQUID cohort). Nutritional status (Mini Nutritional Assessment [MNA]) and oral health status (number of decayed, missing, and filled teeth [DMFT], number of posterior occluding pairs, xerostomia [Xerostomia Inventory], and prosthetic rehabilitation) were recorded at the participants' living places by two dentists. Univariate and multivariate logistic regressions were used to explore the association between oral health and nutritional status, with adjustments for potential confounders. Odds ratios (OR) were estimated with their 95% confidence interval (CI). RESULTS: 87 participants were included in the analyses: 74.7% were females and the mean age was 94.1 years (± 3.0). Malnutrition or risk of malnutrition (MNA < 24) was present in 23 participants (26.4%), with only one having malnutrition. The mean DMFT score was 26.5 (± 5.3). The mean number of posterior occluding pairs was 1.5 (± 2.3). Twenty-one participants had xerostomia (24.1%). Only 8.1% of the participants had all their teeth or adequate dentures; 47.1% had inadequate dentures, while 44.8% had no dentures despite tooth loss. After adjustment, xerostomia (OR = 8.79; 95% CI = 2.38-39.10; p = 0.002) was found to be associated with malnutrition or risk of malnutrition. CONCLUSION: Being at risk of malnutrition was common among people ≥ 90 years old and was associated with xerostomia. NCT04065828.

Tranexamic Acid for the Prevention of Blood Loss after Cesarean Delivery.

BACKGROUND: Prophylactic administration of tranexamic acid has been associated with reduced postpartum blood loss after cesarean delivery in several small trials, but evidence of its benefit in this clinical context remains inconclusive. METHODS: In a multicenter, double-blind, randomized, controlled trial, we assigned women undergoing cesarean delivery before or during labor at 34 or more gestational weeks to receive an intravenously administered prophylactic uterotonic agent and either tranexamic acid (1 g) or placebo. The primary outcome was postpartum hemorrhage, defined as a calculated estimated blood loss greater than 1000 ml or receipt of a red-cell transfusion within 2 days after delivery. Secondary outcomes included gravimetrically estimated blood loss, provider-assessed clinically significant postpartum hemorrhage, use of additional uterotonic agents, and postpartum blood transfusion. RESULTS: Of the 4551 women who underwent randomization, 4431 underwent cesarean delivery, 4153 (93.7%) of whom had primary outcome data available. The primary outcome occurred in 556 of 2086 women (26.7%) in the tranexamic acid group and in 653 of 2067 (31.6%) in the placebo group (adjusted risk ratio, 0.84; 95% confidence interval [CI], 0.75 to 0.94; P = 0.003). There were no significant between-group differences in mean gravimetrically estimated blood loss or in the percentage of women with provider-assessed clinically significant postpartum hemorrhage, use of additional uterotonic agents, or postpartum blood transfusion. Thromboembolic events in the 3 months after delivery occurred in 0.4% of women (8 of 2049) who received tranexamic acid and in 0.1% of women (2 of 2056) who received placebo (adjusted risk ratio, 4.01; 95% CI, 0.85 to 18.92; P = 0.08). CONCLUSIONS: Among women who underwent cesarean delivery and received prophylactic uterotonic agents, tranexamic acid treatment resulted in a significantly lower incidence of calculated estimated blood loss greater than 1000 ml or red-cell transfusion by day 2 than placebo, but it did not result in a lower incidence of hemorrhage-related secondary clinical outcomes. (Funded by the French Ministry of Health; TRAAP2 ClinicalTrials.gov number, NCT03431805.).

Prostatic injection of botulinum toxin is not inferior to optimized medical therapy in the management of lower urinary tract symptoms due to benign prostatic hyperplasia: results of a randomized clinical trial.

OBJECTIVE: To explore efficacy and safety of Botulinum Neurotoxin Type A (BoNT-A) prostatic injection in patients with lower urinary tract symptoms (LUTS) due to benign prostatic hyperperplasia. MATERIALS AND METHODS: A phase 3 multicenter open-labeled study randomised patients to receive BoNT-A prostatic injection or optimized medical therapy. BoNT-A injection consisted in trans-rectal injections of 200 UI in the transitional zone of the prostate. Optimal medical therapy consisted in oral medication with any drug patented for LUTS. One month (M1) after randomisation patients in the BoNT-A group were asked to stop any medical therapy related to LUTS. The main judgment criterion was the IPSS score at M4. Per-protocol analysis was performed with a non-inferiority hypothesis (ΔIPSS < 3). RESULTS: 127 patients were randomised to BoNT-A (n = 64) or medical therapy (n = 63). At randomisation mean IPSS was 16.9 ± 7.2 in the BoNT-A group vs 15.7 ± 7.3 in control. In the BoNT-A group, 44 patients (73.3%) could interrupt medical therapy for LUTS from M1 to M4. At M4, mean IPSS score was 12.0 ± 6.7 in the BoNT-A group vs 11.8 ± 6.9 in control. After adjustment for baseline IPSS, delta IPSS between groups was 0.01; 95% CI [- 2.14; 2.11] leading to accept the non-inferiority hypothesis. CONCLUSIONS: Four months after BoNT-A injection, most of the patients could interrupt LUTS-related medical treatments. In these patients, IPSS improvement was not inferior to optimized medical treatment, but the study design did not allow to conclude that this improvement was related with study drug rather than with sustained placebo effect. TRIAL REGISTRATION: NCT01275521.

Immunity, inflammation and reservoir in patients at an early stage of HIV infection on intermittent ART (ANRS 141 TIPI Trial).

OBJECTIVES: The objective of this study was to assess clinical and biological changes during intermittent ART (I-ART) started early, with significant time spent on versus off ART, which has never before been studied in ART-naive patients with high nadir and current CD4 cell count. PATIENTS AND METHODS: ART-naive HIV-1-infected patients with baseline CD4 ≥ 500/mm(3) and nadir CD4 ≥ 400/mm(3) received 2 years of I-ART (6 month periods on once-daily boosted-PI-based ART, alternating with 6 month periods without ART) in a 2 year, Phase II, non-comparative multicentre trial. The trial is registered with ClinicalTrials.gov, number NCT 00820118. RESULTS: The CD4 cell count remained ≥ 500/mm(3) at 2 years in all 44 patients included in the study. The mean 2 year count was higher than the mean count at baseline in 24 patients overall (55%; 95% CI 40%-69%) and in 20 (65%; 95% CI 48%-81%) of the 31 patients who fully adhered to the trial strategy. All but three of these latter patients had HIV-1 RNA concentrations below 50 copies/mL after each 6 month 'on' period. Only one strategy-related genotypic mutation (M184I) was detected. The HIV-1 DNA median load fluctuated, but it did not differ between month 0 and month 24 (2.8 versus 2.6 log10 copies/10(6) leucocytes, P = 0.29). Biomarkers of inflammation and endothelial activation remained stable between month 0 and month 24. Naive CD4, CD8+CCR5+ and CD8+CD38+ T cell numbers tended to decline. One patient developed Burkitt's lymphoma and 12 patients reported sexually transmitted infections. CONCLUSIONS: In patients with high nadir and current CD4 cell counts, 2 year I-ART maintained the CD4 cell count above 500/mm(3), with no increase in the viral reservoir. Immune activation seems related to HIV replication, while inflammation seems to evolve independently and require specific attention.

Cancer-Related Causes of Death among HIV-Infected Patients in France in 2010: Evolution since 2000.

OBJECTIVES: The current study aimed at describing the distribution and characteristics of malignancy related deaths in human immunodeficiency virus (HIV) infected patients in 2010 and at comparing them to those obtained in 2000 and 2005. METHODS: Data were obtained from three national surveys conducted in France in 2010, 2005 and 2000. The underlying cause of death was documented using a standardized questionnaire fulfilled in French hospital wards involved in the management of HIV infection. RESULTS: Among the 728 deaths reported in 2010, 262 were cancer-related (36%). After a significant increase from 28% in 2000 to 33% in 2005 and 36% in 2010, cancers represent the leading cause of mortality in HIV infected patients. The proportion of deaths attributed to non-AIDS/non-hepatitis-related cancers significantly increased from 2000 to 2010 (11% of the deaths in 2000, 17% in 2005 and 22% in 2010, p<0.001), while those attributed to AIDS-defining cancers decreased during the same period (16% in 2000, 13% in 2005 and 9% in 2010, p = 0.024). Particularly, the proportion of respiratory cancers significantly increased from 5% in 2000 to 6% in 2005 and 11% in 2010 (p = 0.004). Lung cancer was the most common cancer-related cause of death in 2010 (instead of non-Hodgkin lymphoma so far) and represented the leading cause of death in people living with HIV overall. CONCLUSIONS: Cancer prevention (especially smoking cessation), screening strategies and therapeutic management need to be optimized in HIV-infected patients in order to reduce mortality, particularly in the field of respiratory cancers.

Causes of death among HIV-infected patients in France in 2010 (national survey): trends since 2000.

OBJECTIVE: The Mortalité 2010 survey aimed at describing the causes of death among HIV-infected patients in France in 2010 and their evolution since 2000. DESIGN AND METHODS: A national sample of clinical sites, providing HIV care and treatment, notified and documented deaths using a standardized questionnaire. RESULTS: The 90 participating wards notified 728 deaths. Median age at death was 50 years (interquartile range 45-58) and 75% were men. The main underlying causes of death were AIDS-related (25% in 2010 vs. 36% in 2005 and 47% in 2000), non-AIDS non-viral hepatitis-related malignancy (22 vs. 17 and 11%), liver-related (11 vs. 15 and 13%), cardiovascular diseases (10 vs. 8 and 7%) and non-AIDS-related infections (9 vs. 4 and 7%). Malignancies (AIDS and non-AIDS-related) accounted for a third of all causes of death. AIDS accounted for 33% of all causes of death among patients mono-infected with HIV vs. only 13% among those co-infected with hepatitis B virus or hepatitis C virus. CONCLUSION: In 2010, 25% of the causes of death among HIV-infected patients remained AIDS-related. Improved screening and earlier HIV treatment should lead to a smaller proportion of deaths due to AIDS. The majority of patients died of various causes, whereas their HIV infection was well controlled under treatment. Improving case management of HIV-infected patients should include a multidisciplinary approach (prevention, screening, treatment), especially in oncology. Smoking cessation should be a priority goal.

Prevalence projections of chronic diseases and impact of public health intervention.

The estimation of future prevalences of chronic diseases is essential for public health policy. Using incidence estimates from cohort data and demographic projections for general mortality and population sizes, we propose a method based on a general illness-death model to make prevalence projections for chronic diseases. In contrast to previously published methods, we account for differences between global mortality and mortality of healthy subjects and compare two assumptions regarding the secular trend for mortality of diseased subjects. Then we develop a methodology to estimate changes in future disease prevalences resulting from prevention campaign to reduce the frequency or the excess risk associated with a risk factor. The methods are applied for estimating dementia prevalence in France between 2010 and 2030.