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.).

Cost-effectiveness and budget impact of decentralising childhood tuberculosis diagnosis in six high tuberculosis incidence countries: a mathematical modelling study.

Background: The burden of childhood tuberculosis remains high globally, largely due to under-diagnosis. Decentralising childhood tuberculosis diagnosis services to lower health system levels could improve case detection, but there is little empirically based evidence on cost-effectiveness or budget impact. Methods: In this mathematical modelling study, we assessed the cost-effectiveness and budget impact of decentralising a comprehensive diagnosis package for childhood tuberculosis to district hospitals (DH-focused) or primary health centres (PHC-focused) compared to standard of care (SOC). The project was conducted in Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Sierra Leone, and Uganda between August 1st, 2018 and September 30th, 2021. A mathematical model was developed to assess the health and economic outcomes of the intervention from a health system perspective. Estimated outcomes were tuberculosis cases, deaths, disability-adjusted life years (DALYs) and incremental cost-effectiveness ratios (ICERs). We also calculated the budget impact of nationwide implementation. The TB-Speed Decentralization study is registered with ClinicalTrials.gov, NCT04038632. Findings: For the DH-focused strategy versus SOC, ICERs ranged between $263 (Cambodia) and $342 (Côte d'Ivoire) per DALY averted. For the PHC-focused strategy versus SOC, ICERs ranged between $477 (Cambodia) and $599 (Côte d'Ivoire) per DALY averted. Results were sensitive to TB prevalence and the discount rate used. The additional costs of implementing the DH-focused strategy ranged between $12.8 M (range 10.8-16.4) (Cambodia) and $50.4 M (36.5-74.4) (Mozambique), and between $13.9 M (12.6-15.6) (Sierra Leone) and $134.6 M (127.1-143.0) (Uganda) for the PHC-focused strategy. Interpretation: The DH-focused strategy may be cost-effective in some countries, depending on the cost-effectiveness threshold used for policy making. Either intervention would require substantial early investment. Funding: Unitaid.

Association between Dental Scores and Saliva Uremic Toxins.

Dental health is frequently altered in patients with chronic kidney disease. We conducted a prospective study on dental health in CKD patients with a specific interest in the association between dental health issues and the accumulation of uremic toxins in the saliva. A total of 88 patients were included in the study, with chronic kidney disease stage 2 to 5 (without kidney replacement). We analysed the total concentrations of eight uremic toxins (trimethylamine N-oxide -TMAO-, Indoxyl Sulfate, P-cresyl-sulfate, Indole 3-acetic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid -CMPF-, Kynurenine, Hippuric acid and Phenylacetylglutamine) and three precursors of uremic toxins (Tyrosine, Phenylalanine and Tryptophan) in the saliva using LC-MS/MS. We observed, for the first time, the association between various dental scores: DMFT, FST, CPITN, and OHIS, and saliva uremic toxins and precursors: TMAO, indoxyl sulfate, or hippuric acid. Further prospective interventional studies are required to confirm our results.

Effects of mechanical in-exsufflation in preventing postextubation acute respiratory failure in intensive care acquired weakness patients: a randomized controlled trial.

OBJECTIVE: We hypothesized that the use of mechanical insufflation-exsufflation can reduce the incidence of acute respiratory failure within the 48-hour post-extubation period in intensive care unit-acquired weakness patients. METHODS: This was a prospective randomized controlled open-label trial. Patients diagnosed with intensive care unit-acquired weakness were consecutively enrolled based on a Medical Research Council score ≤ 48/60. The patients randomly received two daily sessions; in the control group, conventional chest physiotherapy was performed, while in the intervention group, chest physiotherapy was associated with mechanical insufflation-exsufflation. The incidence of acute respiratory failure within 48 hours of extubation was evaluated. Similarly, the reintubation rate, intensive care unit length of stay, mortality at 28 days, and survival probability at 90 days were assessed. The study was stopped after futility results in the interim analysis. RESULTS: We included 122 consecutive patients (n = 61 per group). There was no significant difference in the incidence of acute respiratory failure between treatments (11.5% control group versus 16.4%, intervention group; p = 0.60), the need for reintubation (3.6% versus 10.7%; p = 0.27), mean length of stay (3 versus 4 days; p = 0.33), mortality at Day 28 (9.8% versus 15.0%; p = 0.42), or survival probability at Day 90 (21.3% versus 28.3%; p = 0.41). CONCLUSION: Mechanical insufflation-exsufflation combined with chest physiotherapy seems to have no impact in preventing postextubation acute respiratory failure in intensive care unit-acquired weakness patients. Similarly, mortality and survival probability were similar in both groups. Nevertheless, given the early termination of the trial, further clinical investigation is strongly recommended. CLINICAL TRIALS REGISTER: NCT01931228.

Standardized technique for ejaculation preservation during prostatic endoscopic ablative surgery.

PURPOSE: Ejaculatory dysfunction is the most common side effect of benign prostatic hyperplasia surgery. Modified techniques have emerged with the aim of preserving antegrade ejaculation without compromising obstruction relief. None are standardized or validated. The PARTURP study is a randomized study investigating partial versus complete prostate resection. We conducted an investigator consensus meeting to define the ideal surgical technique to achieve both correct obstruction relief with ejaculation preservation. METHODS: An expert consensus meeting involving all investigators of the PARTURP study took place to define a common technique using the nominal group methodology. The objectives were to define the areas to be resected and the areas to be preserved; to define the criteria for proper obstruction relief; to define the criteria for proper ejaculation preservation. RESULTS: All investigators (n = 15) attended the consensus meeting, and agreement between all the participants was obtained. The anatomical landmarks to be preserved are located around the verumontanum and along the posterior part of the prostatic urethra. These structures must be preserved up to 2 cm from the verumontanum. The participants agreed on the need to preserve the urethral mucosa in all the areas to be preserved and to reach the enucleation plane in the areas of resection. CONCLUSIONS: Anatomical landmarks for ejaculation-sparing surgery have been defined by the investigators of the PARTURP randomized study. These landmarks will be used during the study, and the clinical outcomes of this ejaculation-sparing technique will be compared with complete resection with up to 3 years follow-up.

Tranexamic acid for reduction of blood loss after Caesarean delivery: a cost-effectiveness analysis of the TRAAP2 trial.

BACKGROUND: Prophylactic administration of tranexamic acid is associated with a reduction of blood loss after Caesarean delivery, but cost-effectiveness for this indication has not been assessed. METHODS: We used data from the TRAAP2 trial, a multicentre, double-blinded, RCT aimed at estimating the efficacy of tranexamic acid for preventing postpartum haemorrhage among women undergoing Caesarean delivery. Women recruited at 27 French maternity hospitals from 2018 to 2020 were enrolled before the procedure if they had a Caesarean delivery before or during labour at 34 or more weeks of gestation. The main outcomes were the cost of hospital stay for delivery and the incremental cost per delivery without complication within 90 days after delivery with tranexamic acid compared with placebo. Differences in costs and the incremental net monetary benefit (INMB) were estimated using linear regression models, and the cost-effectiveness probability of tranexamic acid compared with placebo was estimated through the parametric distribution of the INMB. RESULTS: The proportion of women without complications at day 90 was 70.7% in the tranexamic acid group and 66.0% in the placebo group. Mean total costs until occurrence of a complication of interest were €3321 in the tranexamic acid group and €3260 in the placebo group, resulting in a difference between the two groups of 7.2% and €55 after multiple imputation. The adjusted incremental cost-effectiveness ratio was €762 per additional Caesarean delivery without a complication at 90 days after delivery. At a cost-effectiveness threshold of €10,000, the cost-effectiveness probability of tranexamic acid compared with placebo was 99.9%, varying from 5.8% to 100.0% for thresholds from €0 to €10,000 per additional delivery without a complication at day 90. CONCLUSION: Tranexamic acid for the prevention of blood loss is cost-effective in reducing complications after Caesarean delivery at day 90 postpartum. However, the effect size (in cost and effectiveness) is very low. CLINICAL TRIAL REGISTRATION: NCT03431805.

Factors associated with the author-reported cost-effectiveness threshold in high-income countries: systematic review and multivariable modelling.

OBJECTIVE: The cost-effectiveness threshold (CET) is a key parameter to guide objective reimbursement decisions, yet very few countries have defined a reference CET, and there is no reference method for defining it. Our objective was to determine the factors explaining the author-reported CETs in the literature. METHODS: Our systematic review targeted original articles referenced in EMBASE and published between 2010 and 2021. Selected studies had to use Quality-Adjusted Life-Year (QALY), and being conducted in high-income countries. Our explanatory variables were: estimated cost-effectiveness ratio (ICER), region of the world, source of funding, type of intervention, disease, year of publication, justification of the author-reported Cost-Effectiveness Threshold (ar-CET), economic perspective, and declaration of interest. Multivariable linear regression models implemented on R software were used, guided by a Directed Acyclic Graph. RESULTS: Two hundred and fifty four studies were included. The mean ar-CET was €63,338/QALY (standard deviation (SD) 34,965) overall, and €37,748/QALY (SD 20,750) in studies conducted in the British Commonwealth. The ar-CET increased slightly with the ICER (+ 66€/QALY for each additional 10,000€/QALY in the ICER, 95% confidence interval (IC) [31-102], p < 0.001), was higher in the United States (+ 36,225€/QALY; IC [25,582; 46,869]) and Europe (+ 10,352€/QALY; IC [72; 20,631]) compared to the British Commonwealth (p < 0.001), and was higher when the ar-CET was not defined a priori (+ 22,393€/QALY; [5809; 38,876]) compared to state recommendations defined ar-CET (p < 0.001). CONCLUSIONS: Our results underline the virtuous role of state recommendations in the choice of a low and homogeneous CET. We also highlight the need to integrate the a priori justification of the CET into good publishing guidelines.

Cost Utility and Value of Information Analysis of Femtosecond Laser-Assisted Cataract Surgery.

Importance: The efficacy and safety of femtosecond laser-assisted cataract surgery is well documented. An important requirement for decision makers is the evaluation of the cost-effectiveness of femtosecond laser-assisted cataract surgery (FLACS) over a sufficiently long horizon. Evaluating the cost-effectiveness of this treatment was a preplanned secondary objective of the Economic Evaluation of Femtosecond Laser Assisted Cataract Surgery (FEMCAT) trial. Objective: To estimate the cost utility of FLACS compared with phacoemulsification cataract surgery (PCS) on a 12-month time horizon. Design, Setting, and Participants: This multicenter randomized clinical trial compared FLACS with PCS in parallel groups. All FLACS procedures were performed using the CATALYS precision system. Participants were recruited and treated in ambulatory surgery settings in 5 university-hospital centers in France. All consecutive patients eligible for a unilateral or bilateral cataract surgery 22 years or older with written informed consent were included. Data were collected from October 2013 to October 2018, and data were analyzed from January 2020 to June 2022. Interventions: FLACS or PCS. Main Outcomes and Measures: Utility was measured through the Health Utility Index questionnaire. Costs of cataract surgery were estimated by microcosting. All inpatient and outpatient costs were collected from the French National Health Data System. Results: Of 870 randomized patients, 543 (62.4%) were female, and the mean (SD) age at surgery was 72.3 (8.6) years. A total of 440 patients were randomized to receive FLACS and 430 to receive PCS; the rate of bilateral surgery was 63.3% (551 of 870). The mean (SD) costs of cataract surgery were €1124.0 (€162.2; US $1235) for FLACS and €565.5 (€61.4; US $621) for PCS. The total mean (SD) cost of care at 12 months was €7085 (€6700; US $7787) in participants treated with FLACS and €6502 (€7323; US $7146) in participants treated with PCS. FLACS yielded a mean (SD) of 0.788 (0.009) quality-adjusted life-years (QALYs), and PCS yielded 0.792 (0.009) QALYs. The difference in mean costs was €545.9 (95% CI, -434.1 to 1525.8; US $600), and the difference in QALYs was -0.004 (95% CI, -0.028 to 0.021). The incremental cost-effectiveness ratio (ICER) was -€136 476 (US $150 000) per QALY. The cost-effectiveness probability of FLACS compared with PCS was 15.7% for a cost-effectiveness threshold of €30 000 (US $32 973) per QALY. At this threshold, the expected value of perfect information was €246 139 079 (US $270 530 231). Conclusions and Relevance: The ICER of FLACS compared with PCS was not within the $50 000 to $100 000 per QALY range frequently cited as cost-effective. Additional research and development on FLACS is needed to improve its effectiveness and lower its price. Trial Registration: ClinicalTrials.gov Identifier: NCT01982006.

Quick Epidural Top-up with Alkalinized Lidocaine for emergent caesarean delivery (QETAL study): protocol for a randomized, controlled, bicentric trial.

BACKGROUND: General anesthesia in pregnant women can be associated with significant maternal and fetal morbidity. Emergency caesarean section can be performed by converting labor epidural analgesia to surgical anesthesia by injecting high-dose short-acting local anesthetics through the epidural catheter. The effectiveness and the delay to obtain surgical anesthesia depends upon the protocol used. Data indicate that alkalinization of local anesthetics may shorten their onset of action and increase their effectiveness. This study investigates whether alkalinization of adrenalized lidocaine could increase the efficacy and decrease the delay of onset of surgical anesthesia via an indwelling epidural catheter, thus decreasing the necessity to resort to general anesthesia for emergency caesarean deliveries. METHODS: This study will be a bicentric, double-blind, randomized, controlled trial with two parallel groups of 66 women who require emergency caesarian deliveries and who have been receiving epidural labor analgesia. The number of subjects in groups will be unbalanced with a 2:1 ratio of experimental:control. In both groups, all eligible patients will have had an epidural catheter placed for labor analgesia with levobupicaine or ropivacaine. Patient randomization will occur when the decision is made by the surgeon that an emergency caesarean delivery is indicated. Surgical anesthesia will be obtained by injecting 20 mL of 2% lidocaine with epinephrine 1:200,000, or 10 mL 2% lidocaine with epinephrine 1:200,000 plus 2 mL sodium bicarbonate 4.2% (total of 12 mL). The primary outcome will be the rate of conversion to general anesthesia for failure of the epidural to provide adequate analgesia. This study will be powered to detect a 50% reduction in the incidence of general anesthesia, from 80 to 40%, with a confidence ratio of 90%. DISCUSSION: Sodium bicarbonate could be used to avoid general anesthesia for emergency caesarean deliveries by providing reliable and effective surgical anesthesia in women with pre-existing labor epidural catheters is promising. This randomized controlled trial seeks to determine the optimal local anesthetic mixture for converting epidural analgesia to surgical anesthesia for emergency caesarean sections. This may decrease the need for general anesthesia for emergency caesarian section, shorten the time to fetal extraction, and improve safety and patient satisfaction. TRIAL REGISTRATION: ClinicalTrials.gov NCT05313256. Registered on 6 April 2022.

Early non-invasive ventilation and high-flow nasal oxygen therapy for preventing endotracheal intubation in hypoxemic blunt chest trauma patients: the OptiTHO randomized trial.

BACKGROUND: The benefit-risk ratio of prophylactic non-invasive ventilation (NIV) and high-flow nasal oxygen therapy (HFNC-O2) during the early stage of blunt chest trauma remains controversial because of limited data. The main objective of this study was to compare the rate of endotracheal intubation between two NIV strategies in high-risk blunt chest trauma patients. METHODS: The OptiTHO trial was a randomized, open-label, multicenter trial over a two-year period. Every adult patients admitted in intensive care unit within 48 h after a high-risk blunt chest trauma (Thoracic Trauma Severity Score ≥ 8), an estimated PaO2/FiO2 ratio < 300 and no evidence of acute respiratory failure were eligible for study enrollment (Clinical Trial Registration: NCT03943914). The primary objective was to compare the rate of endotracheal intubation for delayed respiratory failure between two NIV strategies: i) a prompt association of HFNC-O2 and "early" NIV in every patient for at least 48 h with vs. ii) the standard of care associating COT and "late" NIV, indicated in patients with respiratory deterioration and/or PaO2/FiO2 ratio ≤ 200 mmHg. Secondary outcomes were the occurrence of chest trauma-related complications (pulmonary infection, delayed hemothorax or moderate-to-severe ARDS). RESULTS: Study enrollment was stopped for futility after a 2-year study period and randomization of 141 patients. Overall, 11 patients (7.8%) required endotracheal intubation for delayed respiratory failure. The rate of endotracheal intubation was not significantly lower in patients treated with the experimental strategy (7% [5/71]) when compared to the control group (8.6% [6/70]), with an adjusted OR = 0.72 (95%IC: 0.20-2.43), p = 0.60. The occurrence of pulmonary infection, delayed hemothorax or delayed ARDS was not significantly lower in patients treated by the experimental strategy (adjusted OR = 1.99 [95%IC: 0.73-5.89], p = 0.18, 0.85 [95%IC: 0.33-2.20], p = 0.74 and 2.14 [95%IC: 0.36-20.77], p = 0.41, respectively). CONCLUSION: A prompt association of HFNC-O2 with preventive NIV did not reduce the rate of endotracheal intubation or secondary respiratory complications when compared to COT and late NIV in high-risk blunt chest trauma patients with non-severe hypoxemia and no sign of acute respiratory failure. CLINICAL TRIAL REGISTRATION: NCT03943914, Registered 7 May 2019.

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.

Comparison of 68Ga-PSMA-617 PET/CT and 68Ga-RM2 PET/CT in Patients with Localized Prostate Cancer Who Are Candidates for Radical Prostatectomy: A Prospective, Single-Arm, Single-Center, Phase II Study.

Considering the wide range of therapeutic options for localized prostate cancer (e.g., active surveillance, radiation-beam therapy, focal therapy, and radical prostatectomy), accurate assessment of the aggressiveness and localization of primary prostate cancer lesions is essential for treatment decision making. National Comprehensive Cancer Network guidelines recognize prostate-specific membrane antigen (PSMA) PET/CT for use in initial staging of high-risk primary prostate cancer. The gastrin-releasing peptide receptor (GRP-R) is a neuropeptide receptor overexpressed by low-risk prostate cancer cells. We aimed to perform the first (to our knowledge) prospective head-to-head comparison of PSMA- and GRP-R-targeted imaging at initial staging to understand how PSMA PET and GRP-R PET can be used or combined in clinical practice. Methods: This was a prospective, single-center, diagnostic cross-sectional imaging study using anonymized, masked, and independent interpretations of paired PET/CT studies in 22 patients with 68Ga-PSMA-617 (a radiolabeled PSMA inhibitor) and 68Ga-RM2 (68Ga-DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, a radiolabeled GRP-R antagonist). We enrolled patients with newly diagnosed, biopsy-proven prostate cancer. None had received neoadjuvant hormone therapy or chemotherapy, and all underwent extended pelvic lymph node dissection. Histologic findings served as a reference. Results: On a lesion-based analysis (including lesions < 0.1 cm3), 68Ga-PSMA-617 PET/CT detected 74.3% (26/35) of all tumor lesions and 68Ga-RM2 PET/CT detected 78.1% (25/32; 1 patient could not be offered 68Ga-RM2 PET/CT). Paired examinations showed positive uptake of the 2 tracers in 21 of 32 lesions (65.6%), negative uptake in 5 of 32 lesions (15.6%), and discordant uptake in 6 of 32 lesions (18.8%). Uptake of 68Ga-PSMA-617 was higher when the International Society of Urological Pathology (ISUP) score was at least 4 versus at least 1 (P < 0.0001) or 2 (P = 0.0002). There were no significant differences in uptake between ISUP scores for 68Ga-RM2. Median 68Ga-RM2 SUVmax was significantly higher than median 68Ga-PSMA-617 SUVmax in the ISUP-2 subgroup (P = 0.01). Conclusion: 68Ga-PSMA-617 PET/CT is useful to depict higher, more clinically significant ISUP score lesions, and 68Ga-RM2 PET/CT has a higher detection rate for low-ISUP tumors. Combining PSMA PET and GRP-R PET allows for better classification of intraprostatic lesions.

Factors associated with the time from the first call to emergency medical services to puncture for mechanical thrombectomy for ischaemic stroke patients in Gironde, France, in 2017 and 2018.

BACKGROUND AND PURPOSE: When an ischaemic stroke due to a large vessel occlusion occurs, the sooner Mechanical Thrombectomy (MT) is performed, the better the functional prognosis. However, the organisation of care does not systematically allow rapid access to MT. The aim of our study was to determine the clinical and organisational factors associated with the time to access to MT. METHODS: We conducted a cohort study in Gironde County, France. Patients admitted for MT and regulated by the Gironde Emergency Medical Services (EMS) between 01/01/2017 and 31/12/2018 were included. The time to access to MT was the difference between the first call to EMS and groin puncture for MT. The main explanatory variables were: type of pathway (mothership (MS), drip and ship (DS) with cerebral imaging performed in the local hospital centre (LHC), and DS without imaging in the LHC); NIHSS score; driving distance to MT; time of stroke onset (weekend or holiday, school holidays, other); age and sex. Linear regression models were used to explain time to access to MT. Missing data were handled using a multiple imputation procedure (Full conditional specification, Mice R-Package) carried out in our multivariable linear regression model. A quantitative bias analysis was performed by weighing the imputed time to access to MT and identifying the weight changing the conclusions of our analysis. RESULTS: Among the 314 included patients, 152 were women (48.4%), and the mean NIHSS score was 16.4. Two hundred and two (64.3%) patients were managed through the MS pathway. The average time from onset to femoral puncture was 251 minutes. In the multivariate analysis, the time to MT was longer when patients were managed DS with imaging in the LHC pathway (+106 min, p = 0.03), and even longer in the DS without imaging in the LHC pathway (+197 min, p = 0.002), compared with MS. Time from onset to MT decreased with increasing NIHSS score (-6 min per NIHSS point, p <.0001). In our quantitative bias analysis, we multiplied the imputed time in access to MT in the DS pathways only (with or without imaging in the LHC) by weights varying from 0.9 to 0.2 (imputed delays reduced from 10% to 80%). With reduction of 40% or more, there was no longer any difference in time to access to MT between the three studied pathways. CONCLUSIONS: The DS pathway can be shortened by generalizing access to cerebral imaging in LHCs. Optimizing pre-admission orientation toward MT is a major issue in LVOS management.

A phase III randomized trial evaluating the quality of life impact of a tailored versus systematic use of defunctioning ileostomy following total mesorectal excision for rectal cancer-GRECCAR 17 trial protocol.

AIM: The systematic use of a defunctioning ileostomy for 2-3 months postoperatively to protect low colorectal anastomosis (<7 cm from the anal verge) has been the standard practice after total mesorectal excision (TME). However, stoma-related complications can occur in 20%-60% of cases, which may lead to prolonged inpatient care, urgent reoperation and long-term definitive stoma. A negative impact on quality of life (QoL) and increased healthcare expenses are also observed. Conversely, it has been reported that patients without a defunctioning stoma or following early stoma closure (days 8-12 after TME) have a better functional outcome than patients with systematic defunctioning stoma in situ for 2-3 months. METHOD: The main objective of this trial is to compare the QoL impact of a tailored versus systematic use of a defunctioning stoma after TME for rectal cancer. The primary outcome is QoL at 12 months postoperatively using the European Organization for. Research and Treatment of Cancer QoL questionnaire QLQ-C30. Among 29 centres of the French GRECCAR network, 200 patients will be recruited over 18 months, with follow-up at 1, 4, 8 and 12 months postoperatively, in an open-label, randomized, two-parallel arm, phase III superiority clinical trial. The experimental arm (arm A) will undergo a tailored use of defunctioning stoma after TME based on a two-step process: (i) to perform or not a defunctioning stoma according to the personalized risk of anastomotic leak (defunctioning stoma only if modified anastomotic failure observed risk score ≥2) and (ii) if a stoma is fashioned, whether to perform an early stoma closure at days 8-12, according to clinical (fever), biochemical (C-reactive protein level on days 2 and 4 postoperatively) and radiological postoperative assessment (CT scan with retrograde contrast enema at days 7-8 postoperatively). The control arm (arm B) will undergo systematic use of a defunctioning stoma for 2-3 months after TME for all patients, in keeping with French national and international guidelines. Secondary outcomes will include comprehensive analysis of functional outcomes (including bowel, urinary and sexual function) again up to 12 months postoperatively and a cost analysis. Regular assessments of anastomotic leak rates in both arms (every 50 randomized patients) will be performed and an independent data monitoring committee will recommend trial cessation if this rate is excessive in arm A compared to arm B. CONCLUSION: The GRECCAR 17 trial is the first randomized trial to assess a tailored, patient-specific approach to decisions regarding defunctioning stoma use and closure after TME according to personalized risk of anastomotic leak. The results of this trial will describe, for the first time, the QoL and morbidity impact of selective use of a defunctioning ileostomy and the potential health economic effect of such an approach.

Multicenter study to assess surgical treatments of 452 sinonasal intestinal-type adenocarcinomas: A REFCOR study.

PURPOSE: The objective was to assess the local oncological outcomes of endoscopic versus external surgical treatment of sinonasal intestinal-type adenocarcinomas (ITAC) and the factors of recurrence. METHODS: a retrospective non-randomized case-control multicenter study was carried out, including 452 untreated sinonasal ITACs recruited from 10 tertiary referral centers. The tumors were re-classified according to the UICC 2017 (pT). Survival curves were obtained using the Kaplan-Meier method. Univariate analysis was done with the log-rank test. Multivariate analysis was performed with a Cox model adjusted for age, T stage, and radiotherapy. A binary logistic regression compared surgical complications and performed two supplementary analyses on positive margins. RESULTS: We compared 195 and 257 patients operated by the external and endoscopic approach, respectively. The mean follow-up was 59.2 ± 48.7 months. Post-operative margins were invaded in 30.6 versus 18.9% of patients, respectively (p = 0.007). The overall recurrence rate was 33.8 versus 24.6%, respectively (p = 0.034). There was a significant difference in favor of the endoscopic approach regarding local recurrence-free survival thanks to better surgical margins in univariate and multivariate analysis (Odd Ratio = 2.01 (1.2-3.36) p = 0.0087). The complication rate (Odds Ratio = 3.4 (1.79-6.32) p < 0.001) was significantly lower in the endoscopic group. The histological positivity of signet-ring cells shows a statistically significant difference in recurrence-free survival (p = 0.0028). CONCLUSION: the oncological control of ITAC is better through the endoscopic approach, with negative margins and the absence of signet-ring-cells, two independent factors of recurrence.

Effects of mechanical in-exsufflation in preventing postextubation acute respiratory failure in intensive care acquired weakness patients: a randomized controlled trial / Efeitos da insuflação-exsuflação mecânica na prevenção da insuficiência respiratória aguda pós-extubação em pacientes com fraqueza adquirida em terapia intensiva: um estudo controlado e randomizado

ABSTRACT Objective: We hypothesized that the use of mechanical insufflation-exsufflation can reduce the incidence of acute respiratory failure within the 48-hour post-extubation period in intensive care unit-acquired weakness patients. Methods: This was a prospective randomized controlled open-label trial. Patients diagnosed with intensive care unit-acquired weakness were consecutively enrolled based on a Medical Research Council score ≤ 48/60. The patients randomly received two daily sessions; in the control group, conventional chest physiotherapy was performed, while in the intervention group, chest physiotherapy was associated with mechanical insufflation-exsufflation. The incidence of acute respiratory failure within 48 hours of extubation was evaluated. Similarly, the reintubation rate, intensive care unit length of stay, mortality at 28 days, and survival probability at 90 days were assessed. The study was stopped after futility results in the interim analysis. Results: We included 122 consecutive patients (n = 61 per group). There was no significant difference in the incidence of acute respiratory failure between treatments (11.5% control group versus 16.4%, intervention group; p = 0.60), the need for reintubation (3.6% versus 10.7%; p = 0.27), mean length of stay (3 versus 4 days; p = 0.33), mortality at Day 28 (9.8% versus 15.0%; p = 0.42), or survival probability at Day 90 (21.3% versus 28.3%; p = 0.41). Conclusion: Mechanical insufflation-exsufflation combined with chest physiotherapy seems to have no impact in preventing postextubation acute respiratory failure in intensive care unit-acquired weakness patients. Similarly, mortality and survival probability were similar in both groups. Nevertheless, given the early termination of the trial, further clinical investigation is strongly recommended. Clinical Trials Register: NCT 01931228

RESUMO Objetivo: Verificar se o uso de insuflação-exsuflação mecânica pode reduzir a incidência da insuficiência respiratória aguda no período de 48 horas pós-extubação em pacientes com fraqueza adquirida em unidades de terapia intensiva. Métodos: Estudo prospectivo, randomizado, controlado e aberto. Os pacientes diagnosticados com fraqueza adquirida em unidade de terapia intensiva foram incluídos consecutivamente, com base em uma pontuação do Medical Research Council ≤ 48/60. Os pacientes receberam aleatoriamente duas sessões diárias; no grupo controle, realizou-se fisioterapia torácica convencional, enquanto no grupo intervenção, combinou-se fisioterapia torácica com insuflação-exsuflação mecânica. Avaliou-se a incidência de insuficiência respiratória aguda dentro de 48 horas após a extubação. Da mesma forma, avaliaram-se a taxa de reintubação, o tempo de permanência na unidade de terapia intensiva, a mortalidade aos 28 dias e a probabilidade de sobrevida aos 90 dias. O estudo foi interrompido após resultados de futilidade na análise intermediária. Resultados: Incluímos 122 pacientes consecutivos (n = 61 por grupo). Não houve diferença significativa na incidência de insuficiência respiratória aguda entre os tratamentos (11,5% no grupo controle versus 16,4% no grupo intervenção; p = 0,60), na necessidade de reintubação (3,6% versus 10,7%; p = 0,27), no tempo médio de internação (3 versus 4 dias; p = 0,33), na mortalidade aos 28 dias (9,8% versus 15,0%; p = 0,42) ou na probabilidade de sobrevida aos 90 dias (21,3% versus 28,3%; p = 0,41). Conclusão: A insuflação-exsuflação mecânica associada à fisioterapia torácica parece não ter impacto na prevenção da insuficiência respiratória aguda pós-extubação em pacientes com fraqueza adquirida na unidade de terapia intensiva. Da mesma forma, a mortalidade e a probabilidade de sobrevida foram semelhantes em ambos os grupos. No entanto, devido ao término precoce do estudo, recomenda-se enfaticamente uma investigação clínica mais aprofundada. Registro Clinical Trials: NCT 01931228

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.

Resuming Training in High-Level Athletes After Mild COVID-19 Infection: A Multicenter Prospective Study (ASCCOVID-19).

BACKGROUND: There is a paucity of data on cardiovascular sequelae of asymptomatic/mildly symptomatic SARS-Cov-2 infections (COVID). OBJECTIVES: The aim of this prospective study was to characterize the cardiovascular sequelae of asymptomatic/mildly symptomatic COVID-19 among high/elite-level athletes. METHODS: 950 athletes (779 professional French National Rugby League (F-NRL) players; 171 student athletes) were included. SARS-Cov-2 testing was performed at inclusion, and F-NRL athletes were intensely followed-up for incident COVID-19. Athletes underwent ECG and biomarker profiling (D-Dimer, troponin, C-reactive protein). COVID(+) athletes underwent additional exercise testing, echocardiography and cardiac magnetic resonance imaging (CMR). RESULTS: 285/950 athletes (30.0%) had mild/asymptomatic COVID-19 [79 (8.3%) at inclusion (COVID(+)prevalent); 206 (28.3%) during follow-up (COVID(+)incident)]. 2.6% COVID(+) athletes had abnormal ECGs, while 0.4% had an abnormal echocardiogram. During stress testing (following 7-day rest), COVID(+) athletes had a functional capacity of 12.8 ± 2.7 METS with only stress-induced premature ventricular ectopy in 10 (4.3%). Prevalence of CMR scar was comparable between COVID(+) athletes and controls [COVID(+) vs. COVID(-); 1/102 (1.0%) vs 1/28 (3.6%)]. During 289 ± 56 days follow-up, one athlete had ventricular tachycardia, with no obvious link with a SARS-CoV-2 infection. The proportion with troponin I and CRP values above the upper-limit threshold was comparable between pre- and post-infection (5.9% vs 5.9%, and 5.6% vs 8.7%, respectively). The proportion with D-Dimer values above the upper-limit threshold increased when comparing pre- and post-infection (7.9% vs 17.3%, P = 0.01). CONCLUSION: The absence of cardiac sequelae in pauci/asymptomatic COVID(+) athletes is reassuring and argues against the need for systematic cardiac assessment prior to resumption of training (clinicaltrials.gov; NCT04936503).

Early multidisciplinary prevention program of post-stroke shoulder pain: A randomized clinical trial.

OBJECTIVE: To evaluate if positioning the upper-limb promoting abduction, external rotation and flexion of the shoulder reduces the intensity of post-stroke shoulder pain at day-7 compared to usual clinical practice. DESIGN & SETTING: Prospective single-center randomized clinical trial using a superiority design comparing two preventive strategies of post-stroke shoulder pain in a stroke unit. SUBJECTS: Patients were included within 2 days from a first symptomatic ischemic stroke affecting shoulder motor function. INTERVENTIONS: Intervention group included specific positioning of the shoulder in abduction, external rotation and flexion in bed, chair and during mobilization. Control group referred to usual practice i.e. positioning using a standard support scarf. MAIN MEASURES: Primary outcome was the intensity of shoulder pain assessed by the visual analog scale (VAS) (0-100) at day-7 post-stroke. Other outcomes measured at day-7 and 2 months post-stroke were the VAS, motor function, spasticity, depression, functional independence and rates of complex regional Pain syndrome (CRPS). RESULTS: 76 patients (49 males; mean age = 68.3) were randomized. The shoulder pain at day-7 was not different between the control group (16.1, SD = 27.4) and the intervention group (10.3, SD = 21.5, p = 0.18) as well as at 2 months (p = 0.12). A lower rate of depression was observed in the intervention group at 2 months 36.7% (CI95% 19.9;56.1) vs 52.9% (CI95% 35.1;70.2). No between-group difference in other outcomes was observed at 2 months. CONCLUSIONS: This study failed to demonstrate the benefit of a specific positioning tool in reducing the intensity of post-stroke shoulder pain which was lower than previously reported in the literature.