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Objective To evaluate the association between dose of skin-to-skin contact (SSC) per day and initiation time with the occurrence of deaths in newborns with weight up to 1800g. Method Multicentric cohort in five Brazilian neonatal units, including newborns with a birth weight of ≤1800g. The time of SSC was registered in individual file, by the team or family during the hospitalization. Maternal and newborn data were obtained through questionnaires applied to mothers and in medical records. Classification Tree was used for data analysis. Results The performance of the first SSC after 206h was significantly associated with death (p = 0.02). Although there was no association between SSC/day and death (p = 0.09), the number of deaths among those who performed more than 146.9 minutes/day was lower (3;1.5%) than among those who performed this practice for a shorter time (13;6.4%), a fact considered of great clinical importance. Early and late infections present statistically significant associations with the outcome. The chance of death was equal to zero when there was no early infection in the group with the longest duration of SSC. This probability was also equal to zero in the absence of late sepsis for the group with less than 146.9 minutes/day of SSC. Conclusions The first SSC before 206 hours of life is recommended in order to observe a reduction in the risk of neonatal death. Staying in SSC for more than 146.9 min/day seems to be clinically beneficial for these neonates mostly when it was associated with the absence of infection.

Aims Maximal exercise capacity as measured by peak oxygen consumption (pVO2) in cardiopulmonary exercise testing (CPET) of heart transplant recipients (HTR) is limited to a 50–70% level of healthy age‐matched controls. This study investigated the relationship between body composition and pVO2 during the first decade post‐transplant. Methods and results Body composition was determined by dual‐energy X‐ray absorptiometry (DXA) and pVO2 by CPET in 48 HTR (n = 38 males; mean age 51 ± 12 years). A total of 95 assessments were acquired 1–9 years post‐transplant, and the results of four consecutive periods were compared [Period 1: 1–2 years (n = 25); 2: 3–4 years (n = 23); 3: 5–6 years (n = 23); 4: 7–9 years (n = 24)]. Linear regression analysis analysed the correlation between pVO2 and pairs of appendicular lean mass (ALM) and fat mass (FM). The relation between ALM and daily dose of calcineurin inhibitor (CNI) was explored using partial correlation controlling for age, gender, and height. pVO2 increased from 0.98 (0.34) to 1.35 (0.35) L/min (P 8.8 kg/m2). ALM normalized to body mass index increased from 0.690 (0.188) to 0.848 (0.204) m2 (P = 0.02) between Periods 1 and 4, explaining 45% of the variance of pVO2 (R 2 = 0.455; P

Take Home Message Four promising biomarkers were found to be predictive for intravesical mitomycin C in non–muscle-invasive bladder cancer patients. Prospective validation is needed., Background Currently, no biomarkers of response to mitomycin C have been identified in non–muscle-invasive bladder cancer patients. Predictive biomarkers could improve the treatment outcome and eliminate adverse events from unnecessary treatment. Objective To identify and validate predictive biomarkers of chemoresection with mitomycin C. Design, setting, and participants The intervention group of a randomised controlled trial was identified for analyses. The study was conducted between January 2018 and June 2019 in two major urological departments in Denmark. Patients had a history of Ta low-grade/high-grade disease and were included upon recurrence. The intervention group (58 patients) received chemoresection with mitomycin C. Tumour and reference germline DNA from prior tumours were analysed by whole exome sequencing. Predictive biomarkers were validated in the context of Ta low-grade tumours from the UROMOL study. Outcome measurements and statistical analysis Response to chemotherapy (intervention group from the randomised controlled trial) and recurrence-free survival (UROMOL cohort) were measured. Groups were compared using Fisher’s exact test and Wilcoxon rank sum test. Results and limitations Chemoresponse was associated with the mutation status of SPTAN1, APC, and FGFR3, and the level of APOBEC signature contribution (p = 0.035, p = 0.034, p = 0.055, and p = 0.035, respectively). The main limitations include no biopsy for biomarker discovery immediately prior to chemoresection and the unmatched validation cohort. Conclusions Mutation status of APC, SPTAN1, and FGFR3 and the level of mutational contribution from APOBEC-related signatures were identified as potential predictive biomarkers for chemoresection with mitomycin C in non–muscle-invasive bladder cancer patients. A prospective validation study is however needed. Patient summary We investigated DNA from noninvasive bladder tumours in order to predict treatment response to chemotherapy. Four biomarkers showed promising results, which should be tested in future studies.

Few data have been published on the management of patients with synchronous head-and-neck cancer (HNC) and lung cancer (LC). This observational study was undertaken to describe the management of these patients in multiple centers.All patients consecutively diagnosed with synchronous HNC and LC in 26 French centers were included. Information was collected on patients' clinical characteristics, management, and outcomes. Those characteristics and treatments were analyzed descriptively. Kaplan-Meier progression-free and overall survival probabilities were estimated.The study included 132 patients: 83% male; median age: 63.7 (range: 62.1-65.4) years; all current or former smokers; Eastern Cooperative Oncology Group performance status: 0 or 1 for 21.9% or 65.9% of the patients, respectively; cardiovascular comorbidities: 63%; chronic obstructive pulmonary disease: 33%; and previous cancer: 11%. HNC histology was 98% squamous: 23.5% oral cavity, 26.5% oropharyngeal, 22.0% hypopharyngeal, and 28.0% laryngeal. LCs were mainly localized (47.7% Stage I and 9.9% Stage II): 38% squamous, 49% adenocarcinomas, and 13% others. LC diagnosis impacted HNC management for 38% of the patients, with a median time from HNC diagnosis to first HNC treatment of 40 days. HNC impacted LC management for 48% of the patients, with a median time from LC diagnosis-to-LC treatment interval of 41 days.Synchronous LC at HNC diagnosis impacted management and outcomes of both cancers. Specific recommendations should be elaborated to improve the management of these patients.

Left atrial (LA) imaging is still not routinely used for diagnosis and risk stratification, although recent studies have emphasized its importance as an imaging biomarker. Cardiovascular magnetic resonance is able to evaluate LA structure and function, metrics that serve as early indicators of disease, and provide prognostic information, e.g. regarding diastolic dysfunction, and atrial fibrillation (AF). MR angiography defines atrial anatomy, useful for planning ablation procedures, and also for characterizing atrial shapes and sizes that might predict cardiovascular events, e.g. stroke. Long-axis cine images can be evaluated to define minimum, maximum, and pre-atrial contraction LA volumes, and ejection fractions (EFs). More modern feature tracking of these cine images provides longitudinal LA strain through the cardiac cycle, and strain rates. Strain may be a more sensitive marker than EF and can predict post-operative AF, AF recurrence after ablation, outcomes in hypertrophic cardiomyopathy, stratification of diastolic dysfunction, and strain correlates with atrial fibrosis. Using high-resolution late gadolinium enhancement (LGE), the extent of fibrosis in the LA can be estimated and post-ablation scar can be evaluated. The LA LGE method is widely available, its reproducibility is good, and validations with voltage-mapping exist, although further scan–rescan studies are needed, and consensus regarding atrial segmentation is lacking. Using LGE, scar patterns after ablation in AF subjects can be reproducibly defined. Evaluation of ‘pre-existent’ atrial fibrosis may have roles in predicting AF recurrence after ablation, predicting new-onset AF and diastolic dysfunction in patients without AF. LA imaging biomarkers are ready to enter into diagnostic clinical practice.

Background: Acute kidney injury (AKI) affects up to 30% of patients undergoing cardiac surgery, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA that temporarily inhibits p53-mediated cell death that underlies AKI. Methods: This prospective, multicenter, double-blind, randomized, controlled phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran versus placebo (1:1), in reducing the incidence, severity, and duration of AKI after cardiac surgery in high-risk patients. The primary end point was the proportion of patients who developed AKI determined by serum creatinine by postoperative day 5. Other end points included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite end point of major adverse kidney events at day 90, including death, renal replacement therapy, and ≥25% reduction of estimated glomerular filtration rate was assessed. Both serum creatinine and serum cystatin-C were used for estimated glomerular filtration rate assessments. Results: A total of 360 patients were randomly assigned in 41 centers; 341 dosed patients were 73±7.5 years of age (mean±SD), 72% were men, and median European System for Cardiac Operative Risk Evaluation score was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran- versus 50% for placebo-treated patients, a 12.8% absolute risk reduction, P =0.02; odds ratio, 0.58 (95% CI, 0.37–0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran- versus 6.7% of placebo-treated patients had grade 3 AKI; 7% teprasiran- versus 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the major adverse kidney events at day 90 composite in the overall population. No safety issues were identified with teprasiran treatment. Conclusions: The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced after teprasiran administration. A phase 3 study with a major adverse kidney event at day 90 primary outcome that has recently completed enrollment was designed on the basis of these findings (NCT03510897). Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02610283.

Sand flies are often collected in urban areas, which has several implications for the risk of transmission of Leishmania Ross, 1903, to humans and other mammals. Given this scenario, we describe the sand fly fauna of caves and their surroundings in Mangabeiras Municipal Park (MMP) and Paredão Serra do Curral Park (PSCP), both located in the urban area of Belo Horizonte, Minas Gerais, Brazil, an endemic focus of visceral and cutaneous leishmaniasis. Collections were conducted monthly from November 2011 to October 2012, using CDC light traps exposed for two consecutive nights in four caves and their surroundings. Nonsystematized collections using Shannon traps and active searches were also performed around the caves. The presence of Leishmania DNA in collected female sand flies was evaluated by ITS1-PCR. A total of 857 sand flies representing fourteen species were collected in MMP, of which Evandromyia edwardsi (Mangabeira, 1941) was the most abundant. Leishmania amazonensis was detected in Brumptomyia nitzulescui (Costa Lima, 1932) and Ev. edwardsi, with the latter also having Leishmania braziliensis, Leishmania infantum, and Leishmania sp. A total of 228 sand flies representing four species were collected in PSCP, of which Sciopemyia microps (Mangabeira, 1942) was the most abundant. No females from PSCP were positive for Leishmania-DNA. Studies aimed at describing sand fly faunas of cave environments and detecting Leishmania are essential to understanding the relationship between these insects and this ecotope and assessing and monitoring areas that may pose risks to the health of visitors and employees.

Recent decades have been marked by a wave drug treatment research in autism spectrum disorder (ASD). This work has resulted in improved ability to treat commonly occurring behavioral challenges associated with ASD including most prominently irritability marked by aggression, self-injurious behavior, and severe tantrums. While treatment of interfering behavior has progressed in our field, there remain several areas of unmet medical need including most prominently a lack of any approved drug therapies for the core, defining symptoms of autism. We outline the progress to date in the field of autism drug treatment while taking a future look forward into how decades of work can inform better future steps in this field.

Background: Perioperative atrial fibrillation (POAF) after cardiac surgery has been associated with an increased risk of stroke in some studies. However, the exact magnitude of this association during short-term and long-term follow-up remains unclear. Methods: We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) for the time period from database inception to October 2020. We included observational studies with ≥ 100 patients that reported data on short-term or long-term stroke risk in patients with and without POAF after cardiac surgery. Data were pooled using random-effects models. We reported summary risk ratios (RRs) for studies reporting multivariable adjusted results and calculated absolute risk differences (ARDs) with 95% confidence intervals (CIs). Results: A total of 55 studies with 540,209 patients were included. POAF was associated with both an increased relative risk (RR 1.69; 95% CI, 1.41-2.03; I2 = 82%; 9 studies) and absolute risk of short-term stroke (4.5% vs 2.5%; ARD 2.0%; 95% CI, 1.28-2.89). POAF was associated with an increased relative risk (RR 1.20; 95% CI, 1.12-1.29; I2 = 16%; 10 studies) and absolute risk of long-term stroke (1.06 vs 0.88 per 100 patient-years; ARD 0.18 per 100 patient-years; 95% CI, 0.07-0.26). Sensitivity analyses of high-quality studies and studies reporting either ischemic or embolic strokes yielded similar findings. Conclusions: POAF after cardiac surgery was associated with an increased risk of both short-term and long-term stroke. However, the long-term stroke ARD was small, and whether these patients will benefit from long-term oral anticoagulation therapy is unclear. Résumé: Contexte: La fibrillation auriculaire périopératoire (FAPO) après une chirurgie cardiaque a été associée à un risque accru d’accident vasculaire cérébral (AVC) dans certaines études. Cependant, l’ampleur exacte de cette association durant le suivi à court et à long terme reste incertaine. Méthodologie: Nous avons effectué des recherches dans les bases de données PubMed, Embase et CENTRAL (Cochrane Central Register of Controlled Trials) pour la période allant de la création de ces bases à octobre 2020. Nous avons inclus des études d’observation comptant ≥ 100 patients et rapportant des données sur le risque d’AVC à court ou à long terme chez les patients ayant présenté ou non une FAPO après une chirurgie cardiaque. Les données ont été regroupées à l’aide de modèles à effets aléatoires. Nous avons consigné les rapports de risque (RR) sommaires pour les études rapportant des résultats corrigés multivariables et calculé les différences de risque absolu (DRA) avec des intervalles de confiance (IC) à 95 %. Résultats: Au total, 55 études portant sur 540 209 patients ont été incluses. La FAPO était associée à une augmentation tant du risque relatif (RR : 1,69; IC à 95 % : 1,41 à 2,03; I2 = 82 %; 9 études) que du risque absolu d’AVC à court terme (4,5 % vs 2,5 %; DRA : 2,0 %; IC à 95 % : 1,28 à 2,89). La FAPO était également associée à une augmentation du risque relatif (RR : 1,20; IC à 95 % : 1,12 à 1,29; I2 = 16 %; 10 études) et du risque absolu d’AVC à long terme (1,06 vs 0,88 par 100 années-patients; DRA : 0,18 par 100 années-patients; IC à 95 % : 0,07 à 0,26). Les analyses de sensibilité des études de haute qualité et des études rapportant des AVC ischémiques ou emboliques ont donné des résultats similaires. Conclusions: La FAPO après une chirurgie cardiaque a été associée à un risque accru d’AVC à court et à long terme. Cependant, comme la différence de risque absolu d’AVC à long terme était faible, la possibilité qu’une anticoagulothérapie orale à long terme soit bénéfique pour ces patients est incertaine.

High throughput RNA sequencing, also know as RNAseq, can easily be performed on the gold-standard technique of formalin-fixed paraffin-embedded tissue, which has long been successfully used in routine practice by pathologists. For this reason, RNAseq has been fully adopted in a very short period of time in most French molecular platforms of cancer genotyping, generating "high throughput" data, both qualitative (mutations, fusions) and quantitative (gene expression profiles). This technique opens new perspectives in oncology practice: from a diagnostic point of view (some gene fusions are specific of some diagnoses, some transcriptomic signatures suggest some types of cancer), but also from a prognostic point of view (gene expression profile of an aggressive tumor, or conversely of an indolent one), and above all from a predictive point of view, guiding the choice of potential targeted therapies (example of ALK, ROS1 or NTRK translocations). This technical approach has many advantages, first and foremost it detects, at one go, a plethora of molecular alterations which were previously analyzed sequentially using heterogenous assays (immunohistochemistry, DNA genotyping, fluorescent in situ hybridization, etc.). However, it also presents several drawbacks which may easily be overcome if certain pre-analytic parameters are correctly controlled, mainly aiming at the preservation of the quality of nucleic acids. In any event, the widespread use of RNAseq has had a profound impact on the algorithms of tumor tissue processing, shaping a new, holistic era in oncology.

Cytomegalovirus (CMV) is a ubiquitous herpes virus that develops lifelong latency following primary infection and can be reactivated following immune suppression. CMV encephalopathy has been described in few reports after hematopoietic stem cell transplantation and in patients with acquired immunodeficiency syndrome. To the best of our knowledge, CMV encephalopathy following CAR-T cells infusion had not been previously reported. Initial CMV viral load and monitoring are crucial in patients with CAR-T cells to allow early intervention with aggressive antiviral treatment without delay if needed.

BACKGROUND In severe obesity, left ventricular (LV) and right ventricular (RV) remodeling and contractile dysfunction have been documented, but less is known regarding left atrial (LA) dysfunction and its association with LV/RV remodeling, especially in children. PURPOSE To assess the effects of severe childhood obesity on cardiac function by using multichamber strain analysis with MRI. STUDY TYPE Prospective. SUBJECTS Forty-five children aged 7-18 years (including 20 with severe obesity, defined as a body mass index values above the 99th percentile). FIELD STRENGTH 5 T. SEQUENCE Steady-state-free-precession (SSFP) images in short-axis views and longitudinal two- and four-chamber views. ASSESSMENT Cardiac strain measurements were derived from standard SSFP cine images by using a dedicated MR imaging feature tracking software. Inter- and intra-rater reliability were evaluated. STATISTICAL TESTS Independent sample t test, Spearman's correlation coefficient, principal component analysis, Bland-Altman analysis, and intra-class correlation coefficients (ICC). A P value

A rebound of osteoclast activity during the 2 years after a treatment or prevention of osteoporosis with denosumab (Dmab) leads to an increased risk of vertebral fractures (VFs). We attempted to identify the risk factors for these VF and to examine the protective role of bisphosphonates. For that, 22 specialists in Switzerland provided data of unselected patients, treated with denosumab for osteoporosis or breast cancer without metastases under aromatase inhibitors, who have received at least two injections of Dmab, with at least 1 year of follow‐up after discontinuation. The questionnaire covered separately the periods before, during, and after Dmab treatment, and registered clinical, radiological, and lab data. For the analysis of the risk factors, the main outcomes were the time to the first VF after the treatment, the presence of multiple VFs (MVFs), and the number of VFs. The incidence of VF was 16.4% before, 2.2% during, and 10.3% after the treatment with Dmab. The risk of VF after Dmab discontinuation was associated with an increased risk of non‐vertebral fractures. The pretreatment predictors of the post‐treatment fracture risk were a parental hip fracture and previous VFs. Further risk factors appeared later, such as low total hip bone mineral density (BMD) during and after denosumab, increased bone resorption markers, and the loss of total hip BMD after the denosumab. Treatment with bisphosphonates, especially after Dmab, had a protective effect. Bisphosphonates given before Dmab did not further decrease the risk of VF in cases who got bisphosphonates after Dmab. This study shows that the risk of VF is poorly predictable before the prescription of denosumab. But during and after the treatment, bone resorption markers and BMD have a significant predictive value. Bisphosphonates after the treatment with denosumab are protective against VFs. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

This article explains how making a disease notifiable by law is a core component of a robust and well‐functioning health system. Mechanisms to rapidly detect and report existing or emerging infectious diseases in a timely manner are key to disease control and elimination. Using malaria in Asia‐Pacific as a case in point, we explore different policy considerations involved in making malaria a notifiable disease. These include the timing of legislative changes at different stages of elimination, investing in adequate infrastructure for a robust surveillance system that can support targeted interventions, and the importance of involving all sectors in the delivery of malaria services to detect, report and respond to every case. The article explains how frameworks to report on notifiable diseases, in this case malaria, contribute to improved regional health security.

Rituximab plus polychemotherapy is the standard of care in diffuse large B-cell lymphoma (DLBCL). GAINED, a randomized phase 3 trial, compared obinutuzumab to rituximab. Transplant-eligible patients (18-60 years) with an untreated age-adjusted International Prognostic Index (aaIPI) score ≥1 DLBCL were randomized (1:1) between obinutuzumab or rituximab and stratified by aaIPI (1; 2-3) and chemotherapy regimen (doxorubicin, cyclophosphamide, prednisone plus vindesine, bleomycin [ACVBP] or vincristine [CHOP]). Consolidation treatment was determined according to response to interim positron emission tomography (PET). Responders after cycle 2 and 4 (PET2−/PET4−) received immunochemotherapy. Responders after only cycle 4 (PET2+/4−) received transplantation. The primary objective was an 8% improvement (hazard ratio [HR] = 0.73; 80% power; α risk, 2.5%; 1-sided) in 2-year event-free survival (EFS) in the obinutuzumab arm. From September 2012, 670 patients were enrolled (obinutuzumab, n = 336; rituximab, n = 334). A total of 383 (57.2%) were aaIPI 2-3, 339 (50.6%) received CHOP. Median follow-up was 38.7 months. The 2-year EFS was similar in both groups (59.8% vs 56.6%; P = .123; HR = 0.88). The 2-year PFS in the whole cohort was 83.1% (95% confidence interval, 80% to 85.8%). PET2−/4− and PET2+/4− had similar 2-year progression-free survival (PFS) and overall survival (OS): 89.9% vs 83.9% and 94.8% vs 92.8%. The 2-year PFS and OS for PET4+ patients were 62% and 83.1%. Grade 3-5 infections were more frequent in the obinutuzumab arm (21% vs 12%). Obinutuzumab is not superior to rituximab in aaIPI ≥1 DLBCL transplant-eligible patients. This trial was registered at www.clinicaltrials.gov as #NCT01659099.

Aim: To compare healthcare resource utilization (HRU) and healthcare costs (HC) for every-2-week (Q2W) versus weekly (Q1W) cetuximab in metastatic colorectal cancer (mCRC). Patients & methods: Patients with mCRC receiving cetuximab plus chemotherapy in a line-agnostic setting. Cohort study of patients with mCRC treated with cetuximab and chemotherapy in IBM MarketScan. Analyses were weighted by inverse probability of treatment based on propensity score. Results: HRU was numerically lower with the Q2W versus Q1W regimen (weighted mean, 8.1 vs 9.5 encounters per-patient-per-month). The weighted average of HC was $17,653 and $16,469 per-patient-per-month for the Q2W and Q1W regimens, respectively; the difference between regimens decreased when restricting to CRC-related claims. Conclusion: HRU was lower and HC were similar between the Q2W and Q1W regimens.

Autosomal dominant polycystic kidney disease is the most frequent genetic kidney disease. Cardiovascular disorders associated with autosomal dominant polycystic kidney disease are multiple and may occur early in life. In autosomal dominant polycystic kidney disease cardiovascular morbidity and mortality are related both to the nonspecific consequences of chronic kidney disease and to the particular phenotype of autosomal dominant polycystic kidney disease. Compared to the general population, patients with autosomal dominant polycystic kidney disease present an increased prevalence of hypertension, left ventricular hypertrophy, atrial fibrillation, valvular diseases, aneurisms and arterial dissections. This review article provides an update on cardiovascular disorders associated with autosomal dominant polycystic kidney disease and recent pathophysiological developments.

Background and Purpose— The TST trial (Treat Stroke to Target) evaluated the benefit of targeting a LDL (low-density lipoprotein) cholesterol of 4 mm, in a French and Korean population. The follow-up lasted a median of 5.3 years in French patients (similar to the median follow-up time in the SPARCL trial [Stroke Prevention by Aggressive Reduction in Cholesterol Level]) and 2.0 years in Korean patients. Exposure duration to statin is a well-known driver for cardiovascular risk reduction. We report here the TST results in the French cohort. Methods— One thousand seventy-three French patients were assigned to Results— After a median follow-up of 5.3 years, the achieved LDL cholesterol was 66 (1.69 mmol/L) and 96 mg/dL (2.46 mmol/L) on average, respectively. The primary end point occurred in 9.6% and 12.9% of patients, respectively (HR, 0.74 [95% CI, 0.57–0.94]; P =0.019). Cerebral infarction or urgent carotid revascularization following transient ischemic attack was reduced by 27% ( P =0.046). Cerebral infarction or intracranial hemorrhage was reduced by 28% ( P =0.023). The primary outcome or intracranial hemorrhage was reduced by 25% ( P =0.021). Intracranial hemorrhages occurred in 13 and 11 patients, respectively (HR, 1.17 [95% CI, 0.53–2.62]; P =0.70). Conclusions— After an ischemic stroke of documented atherosclerotic origin, targeting a LDL cholesterol of Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01252875.

Background: The prevalence of diabetic patients is increasing over the years. It will increase the incidence of microvascular complications due to prolonged hyperglycemia in diabetic patient. Diabetic retinopathy is one of microvascular complication which is one of the leading causes of blindness in the world. Prolonged hyperglycemia in diabetic patient cause toxicity to the retina which cause nerve and vascular damage and death to the retina. In this study was analyzed the association of diabetes duration with the severity of diabetic retinopathy associated with many cases of delay in diagnosing diabetes recentlyObjective: This study aims to investigate the association of diabetes duration with the severity of diabetic retinopathyMethods: A cross-sectional design was performed by collecting data from the medical records of diabetic patients who were diagnosed with diabetic retinopathy in Diponegoro National Hospital in July-December 2019 using purposive sampling method. Research subjects were 51 patients who fulfilled the inclusion and exclusion criteria. The data were analyzed using non-parametric Chi Square test with p < 0.05 was considered statistically significant.Results: Prevalence was more in the age group of 51-60 years (45,1%), female (58,8%), diabetics

Background: The aetiology and pattern of maxillofacail injuries vary in different parts of the world and even the same country. The purpose of the study was to determine the epidemiology of maxillofacial injuries at a tertiary Hospital in Ghana. Methodology: This is a six-month (January to June 2015) prospective study. Information on age, sex, aetiology, injury type etc. was collected using a specialized design data collection form. Data was analyzed using the SPSS 17th version. Ethical approval was obtained. Result: The total study sample was 111 with a male to female ratio of 2.5:1. Majority (34.2%) were within the ages of 21 to 30 years. Majority of the victims were urban dwellers. Most of the injuries occurred on the highway (42.3%) and in the evening (35.2%). Only a small percentage (5.4%) of the road traffic crashes (RTC) victims were in some form of protection. Twenty-one (18.9%) of the injuries were intentional, of which 18 (85.7%) were assault. The commonest maxillofacial injury was a combination of soft and hard tissues 72 (64.7%). The commonest cause of maxillofacial soft tissue injuries was RTC, 72.8%. Laceration (55.6%) was the most common soft tissue injury recorded. Mandibular fractures constituted the commonest hard tissue injuries. Conclusion: This study has shown that road traffic crashes are the most common cause of injuries to the maxillofacial region. The mandible is the most frequent site of fracture, while the commonest soft tissue injury is laceration. Majority of the victims were young energetic males and adherence to road traffic regulations was very low.

Objetivo: Descrever características demográficas, socioeconômicas, de hábitos de vida e de saúde mental de mães residentes em São Luís - Maranhão. Métodos: Este estudo utilizou dados de 3.215 mães que participaram da coorte BRISA, avaliadas na ocasião do nascimento e seguimento de crianças entre 15 e 36 meses de vida. Foi utilizado questionário para coletar dados demográficos, socioeconômicos e de hábitos de vida, além de três instrumentos para avaliação da saúde mental materna: Escala de Depressão Pós-Parto de Edimburgo (EPDS), Escala de Estresse Percebido (Perceived Stress Scale – PSS 14) e a versão brasileira do Self Reporting Questionnaire (SRQ-20). A análise estatística descritiva foi realizada pelo Stata 12.0. Resultados: A taxa de resposta do estudo foi de 62,2%. Predominaram mães de 20-34 anos, cor da pele parda, que possuíam companheiro, cursaram entre o segundo grau incompleto a superior completo e que recebiam até três salários mínimos. Verificou-se que 17,8% das entrevistadas apresentaram sintomas de estresse e 7,5% de depressão. Sofrimento psicológico esteve presente em 22,7% das mulheres avaliadas ao longo do segundo e terceiro anos de vida de seus filhos. Conclusão: Os dados refletem características relevantes sobre a saúde mental das mães de São Luís-Maranhão, ressaltando a importância da incorporação pelos serviços de saúde, de ações regulares de prevenção, detecção precoce e tratamento relacionados à saúde mental desse público.

Jean-Bernard Auliac,1 Florian Guisier,2 Acya Bizieux,3 Pascal Assouline,4 Marie Bernardini,5 Régine Lamy,6 Grégoire Justeau,7 Geraldine François,8 Diane Damotte,9,10 Christos Chouaïd1,11 1Pneumology Department, Centre Hospitalier Intercommunal de Créteil, Créteil, France; 2Pulmonology, Thoracic Oncology and Respiratory Department, Rouen University Hospital, Rouen, France; 3Pneumology Department, Centre Hospitalier de Vendée, La Roche-sur-Yon, France; 4Pneumology Department, Centre Hospitalier de Bligny, Bligny, France; 5Pneumology Department, Centre Hospitalier d’Aix-En-Provence, Aix-en-Provence, France; 6Pneumology Department, Centre Hospitalier de Bretagne-Sud, Lorient, France; 7Pneumology Department, Centre Hospitalier Universitaire d’Angers, Angers, France; 8Pneumology Department, Centre Hospitalier Universitaire d’Amiens, Amiens, France; 9Department of Pathology, Hôpital Cochin, APHP, Paris, France; 10University Paris Descartes, Paris, France; 11Inserm U955, UPEC, IMRB, Équipe CEpiA, Créteil, FranceCorrespondence: Jean-Bernard AuliacService de Pneumologie, CHI Créteil, 40, Avenue de Verdun, Créteil Cedex 94010, FranceEmail jean-bernard.auliac@chicreteil.frBackground: Few data have been published on the clinical and histopathological characteristics of advanced non-small–cell lung cancer (NSCLC) patients with high PD-L1 expression versus intermediate or none and the prognostic value of PD-L1 expression for patients treated with chemotherapy is unknown. This study was undertaken to prospectively assess the prognostic value of tumor-cell (TC) and immune-cell (IC) PD-L1 expressions for advanced NSCLC patients.Methods: It was a prospective, multicenter study on advanced NSCLC patients, with performance status 0/1, scheduled, consecutively, to receive first-line platin-based chemotherapy. PD-L1 expression was determined immunochemically (Dako Autostainer and monoclonal antibody 22C3) and its impact on progression-free survival (PFS) and overall survival (OS) assessed.Results: Among 198 patients screened in 19 centers, 140 were included median age: 66.5 ± 10 years; 76.4% men; 79.3% Caucasians; 10.7% nonsmokers; 63.6% adenocarcinomas; < 1%, 1– 50% and ≥ 50% TC PD-L1–expression rates were 47.1%, 25.7% and 27.2% of patients, respectively; respective null, intermediate and high rates on ICs were 35.7%, 38.6% and 25.7%. Second- and third-line chemotherapies were administered to 58.6% and 26.4% of the patients, respectively. None received immunotherapy. First-, second- and third-line median (95% CI) PFS lasted 4.6 (3.6– 5.2), 3.7 (2.3– 4.7) and 2.2 (1.5– 4.3) months, respectively; median OS was 16.9 (11.4– 19.9) months. No significant PFS and OS differences were observed according to TC or IC PD-L1 expression.Conclusion: According to the results of this prospective, multicenter study, neither TC nor IC PD-L1 expression appears to be prognostic for chemotherapy-managed advanced NSCLC patients.Keywords: chemotherapy, immunotherapy, non-small–cell lung cancer, PD-L1, prognostic

Objectives Covert stroke is a complication of coronary artery bypass graft surgery that is increasingly recognized as a serious problem. In noncardiac surgery settings, covert stroke is associated with the development of delirium, long-term cognitive decline, and future clinical stroke. Therefore, we sought to determine the feasibility of conducting a large, prospective cohort study of the influence of covert stroke on neurocognitive outcomes in patients undergoing coronary artery bypass graft surgery. Methods NeuroVISION Cardiac pilot was a prospective cohort study enrolling patients aged ≥21 years undergoing isolated coronary artery bypass graft surgery to receive diffusion-weighted magnetic resonance imaging of the brain after surgery to identify patients with covert stroke. Patients were screened for postoperative delirium in-hospital and were administered questionnaires of cognitive and global function (once before and twice after surgery). Regional cerebral oxygen saturation was recorded during surgery using near-infrared spectroscopy. Results Between March 27, 2017, and February 11, 2018, 50 of 66 patients enrolled (76%) completed the brain magnetic resonance imaging (1 patient per week). Among the 49 patients included in the analysis, 19 (39%; 95% confidence interval, 26%-53%) experienced perioperative covert stroke and 3 (6%) had a clinical stroke within 30 days of surgery. Postoperative delirium occurred in 5 (26%) patients with covert stroke and in 3 (10%) patients who did not experience covert stroke. Conclusions The NeuroVISION Cardiac pilot study established the feasibility of conducting a large, prospective cohort study of the determinants and consequences of covert stroke in patients undergoing coronary artery bypass graft surgery.

In Alzheimer’s disease, the tauopathy is known as a major mechanism responsible for the development of cognitive deficits. Early biomarkers of such affectations for diagnosis/stratification are crucial in Alzheimer’s disease research, and brain connectome studies increasingly show their potential establishing pathology fingerprints at the network level. In this context, we conducted an in vivo multimodal MRI study on young Thy-Tau22 transgenic mice expressing tauopathy, performing resting state functional MRI and structural brain imaging to identify early connectome signatures of the pathology, relating with histological and behavioural investigations. In the prodromal phase of tauopathy, before the emergence of cognitive impairments, Thy-Tau22 mice displayed selective modifications of brain functional connectivity involving three main centres: hippocampus (HIP), amygdala (AMG) and the isocortical areas, notably the somatosensory (SS) cortex. Each of these regions showed differential histopathological profiles. Disrupted ventral HIP-AMG functional pathway and altered dynamic functional connectivity were consistent with high pathological tau deposition and astrogliosis in both hippocampus and amygdala, and significant microglial reactivity in amygdalar nuclei. These patterns were concurrent with widespread functional hyperconnectivity of memory-related circuits of dorsal hippocampus—encompassing dorsal HIP-SS communication—in the absence of significant cortical histopathological markers. These findings suggest the coexistence of two intermingled mechanisms of response at the functional connectome level in the early phases of pathology: a maladaptive and a likely compensatory response. Captured in the connectivity patterns, such first responses to pathology could further be used in translational investigations as a lead towards an early biomarker of tauopathy as well as new targets for future treatments.

Denosumab discontinuation is associated with a rapid increase in bone resorption and a decrease in bone mineral density. Spontaneous vertebral fractures may occur as a side effect of the rebound of bone resorption. Cases of rebound-linked hypercalcemia have also been described, moderate in women with osteoporosis and breast cancer and severe in children receiving oncological doses of denosumab. We report the case of an adult woman with primary hyperparathyroidism and moderate hypercalcemia, treated with denosumab for osteoporosis, who developed severe hypercalcemia and spontaneous vertebral fractures (SVFs) after denosumab discontinuation. An 86-year-old woman with densitometric osteoporosis was treated for 3 years with 60 mg of subcutaneous denosumab every 6 months. She was known to have primary hyperparathyroidism, with a serum albumin-corrected calcium of 2.82 mmol/l (NV 2.15-2.5) at the end of denosumab effect. Nine months after the last denosumab injection, she was hospitalized due to worsening overall health. Clinical evaluation revealed severe hypercalcemia (calcium 3.35 mmol/l). Very high values of bone turnover markers (BTMs) suggested a rebound effect due to denosumab discontinuation. An X-ray showed multiple new SVFs. After injection of denosumab 60 mg, serum calcium rapidly decreased and BTMs were dramatically reduced. A surgical approach by minimally invasive parathyroidectomy allowed for definite resolution of hyperparathyroidism and hypercalcemia. This case suggests that hypercalcemia can be a side consequence of denosumab discontinuation, which can become severe when other causes of hypercalcemia, such as primary hyperparathyroidism, are present.

Background A standard of care for pretreated, advanced non–small‐cell lung cancers (NSCLCs), nivolumab has demonstrated long‐term benefit when administered for 2 years. We aimed to better discern an optimized administration duration by retrospectively analyzing real‐life long‐term efficacy in a prospective cohort. Methods All nivolumab‐treated adults with advanced NSCLCs (01/09/2015 to 30/09/2016) from nine French centers were eligible. On 31/12/2018, patients who are alive ≥ 2 years after starting nivolumab were defined as long‐term survivors (LTSs) and were divided into three nivolumab treatment groups: 2 years. Co‐primary endpoints were LTSs’ progression‐free survival (PFS) and overall survival (OS). Results The median follow‐up was 32 months (95% CI, 31.0 to 34.0). The 3‐year OS rate for the 259 cohort patients was 16.6%. Among them, 65 were LTSs: 47 treated 2 years. Their respective characteristics were: median age: 59, 52, and 58 years; smoking history: 92.9, 100, and 100%; adenocarcinomas: 66, 57.1, and 54.5%. LTSs’ median (m)PFS was 28.4 months; mOS was not reached. LTSs’ objective response rate was 61.6%. mOS was 32.7 months for those treated 2‐year group's 3‐year OS was longer. Twenty‐eight LTSs experienced no disease progression; 7 had durable complete responses. However, LTSs had more frequent and more severe adverse events. Conclusion In real‐life, prolonged nivolumab use provided long‐term benefit with 16.6% 3‐year OS and 25% LTSs. Survival tended to be prolonged with nivolumab continued beyond 2 years. Prospective randomized trials with adequate design are needed., Phase III trials didn't provide an optimal duration of immunotherapy for responder or stable patients in advanced non‐small‐cell lung cancer. A 2 years‐fixed duration or long‐term therapy are proposed to clinicians. The results of this observational study of 65 long‐term survivor pretreated patients showed a trends toward improvement of survival outcomes when continuing nivolumab after two years.

To determine the impact of a contextual group CBT intervention for voices on the narratives of people with psychosis Narratives from 10 participants with psychosis and hearing auditory hallucinatio...

Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic. Here we perform a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converge on genomic instability driven by a high number of chromosomal alterations, indels, signature 5 mutations and/or BRCA2 mutations. Expression data identifies the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression are associated with treatment response. Through integration of genomic and transcriptomic data, we demonstrate patient stratification to groups of low and high likelihood of cisplatin-based response. This could pave the way for future patient selection following validation in prospective clinical trials., There are currently only a few biomarkers to predict the response of muscle invasive bladder cancer to therapy. Here, the authors analyse 300 tumors using exome and RNA sequencing and find that tumors with a high degree of genomic instability and a non-basal/squamous gene expression subtype are most likely to respond to treatment.

International audience; The role of brain dystrophin in muscular dystrophy: Implications for clinical care and translational research, Hoofddorp, the Netherlands, November 29 th-December 1 st 2019

Summary Background Topotecan is currently the only drug approved in Europe in a second-line setting for the treatment of small-cell lung cancer. This study investigated whether the doublet of carboplatin plus etoposide was superior to topotecan as a second-line treatment in patients with sensitive relapsed small-cell lung cancer. Methods In this open-label, randomised, phase 3 trial done in 38 hospitals in France, we enrolled patients with histologically or cytologically confirmed advanced stage IV or locally relapsed small-cell lung cancer, who responded to first-line platinum plus etoposide treatment, but who had disease relapse or progression at least 90 days after completion of first-line treatment. Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status 0–2. Enrolled patients were randomly assigned (1:1) to receive combination carboplatin plus etoposide (six cycles of intravenous carboplatin [area under the curve 5 mg/mL per min] on day 1 plus intravenous etoposide [100 mg/m2 from day 1 to day 3]) or oral topotecan (2·3 mg/m2 from day 1 to day 5, for six cycles). Randomisation was done using the minimisation method with biased-coin balancing for ECOG performance status, response to the first-line chemotherapy, and treatment centre. The primary endpoint was progression-free survival, which was centrally reviewed and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , NCT02738346 . Findings Between July 18, 2013, and July 2, 2018, we enrolled and randomly assigned 164 patients (82 in each study group). One patient from each group withdrew consent, therefore 162 patients (81 in each group) were included in the intention-to-treat population. With a median follow-up of 22·7 months (IQR 20·0−37·3), median progression-free survival was significantly longer in the combination chemotherapy group than in the topotecan group (4·7 months, 90% CI 3·9–5·5 vs 2·7 months, 2·3–3·2; stratified hazard ratio 0·57, 90% CI 0·41–0·73; p=0·0041). The most frequent grade 3–4 adverse events were neutropenia (18 [22%] of 81 patients in the topotecan group vs 11 [14%] of 81 patients in the combination chemotherapy group), thrombocytopenia (29 [36%] vs 25 [31%]), anaemia (17 [21%] vs 20 [25%]), febrile neutropenia (nine [11%] vs five [6%]), and asthenia (eight [10%] vs seven [9%]). Two treatment-related deaths occurred in the topotecan group (both were febrile neutropenia with sepsis) and no treatment-related deaths occurred in the combination group. Interpretation Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small-cell lung cancer. Funding Amgen and the French Lung Cancer Group (Groupe Francais de Pneumo-Cancerologie).

Introduction The impact of sex on the outcomes after coronary artery bypass grafting (CABG) is controversial. The majority of CABG studies are retrospectively collected clinical or registry data, women comprise only a minority, and the reported findings represent the male predominated cohort. This individual patient meta-analysis is aimed at evaluating sex-related differences in outcomes after CABG using high quality data from randomized controlled trials (RCTs). Methods and analysis A systematic literature search will be performed to identify all CABG RCTs (minimum follow-up: 5 years). Detailed specification for the minimum deidentified patient records' data requirements will be provided to RCT primary contact to request their deidentified data for pooling. The pooled analysis will follow the prospective register of systematic reviews (PROSPERO) and the preferred reporting items for systematic reviews and meta-analyses for individual patient data systematic reviews (PRISMA-IPD) recommendations and will compare sex-related outcomes after CABG. The main hypothesis is that outcomes after CABG are worse in women than in men. We will also test whether treatment effects for off-pump and the use of multiple arterial grafts are present within each sex, and also, whether there are differential treatment effects between sexes. The primary endpoint will be a composite of all-cause mortality, myocardial infarction, stroke, and repeat revascularization at long-term follow up. Ethics and dissemination Ethics approval and participant consent for the study will be obtained locally by each study team if needed. Data will be disseminated and submitted to peer-reviewed scientific journals and meetings irrespective of study outcome.

Background Staphylococcus saccharolyticus is a rarely encountered coagulase-negative, which grows slowly and its strictly anaerobic staphylococcus from the skin. It is usually considered a contaminant, but some rare reports have described deep-seated infections. Virulence factors remain poorly known, although, genomic analysis highlights pathogenic potential. Case presentation We report a case of Staphylococcus saccharolyticus spondylodiscitis that followed kyphoplasty, a procedure associated with a low rate but possible severe infectious complication (0.46%), and have reviewed the literature. This case specifically stresses the risk of healthcare-associated S. saccharolyticus infection in high-risk patients (those with a history of alcoholism and heavy smoking). Conclusion S. saccharolyticus infection is difficult to diagnose due to microbiological characteristics of this bacterium; it requires timely treatment, and improved infection control procedure should be encouraged for high-risk patients.

Purpose of review This review considers both pragmatic and cutting-edge approaches for predicting motor stroke recovery over the period 2017-2019. It focuses on the predictive value of clinical scores and biomarkers including Transcranial Magnetic Stimulation (TMS) and MRI as well as more innovative alternatives. Recent findings Clinical scores combined with corticospinal tract (CST) integrity as assessed by both TMS-induced motor-evoked potential (MEP) and MRI predict motor recovery with an accuracy of about 75%. Therefore, research on novel biomarkers is still needed to improve the accuracy of these models. Summary Up to date, there is no consensus about which predictive models should be used in clinical routine. Decision trees, such as the PREP2 algorithm are probably the easiest approach to operationalize the translation of predictive models from bench to bedside. However, external validation is still needed to implement current models.

Mantle cell lymphoma has a dismal prognosis at relapse or in the refractory setting. Among therapies, mTor pathway targeting by temsirolimus has been the first strategy approved for relapse in Europe. While its efficacy in monotherapy has long been demonstrated, its use remains limited. In the T3 phase Ib clinical trial, we investigated the recommended dose of temsirolimus in association with R-CHOP (R-CHOP-T), or high-dose cytarabine plus rituximab (R-DHA-T), or fludarabine, cyclophosphamide plus rituximab (R-FC-T). From November 11, 2011 to February 26, 2015, forty-one patients were enrolled. Patients presented with high MIPI (47.5%) at relapse and a median number of treatments of 1 (1–3). Patients were treated by R-CHOP-T (n = 10), R-FC-T (n = 14), or R-DHA-T (n = 17) according to the choice of local investigators. The maximum tolerated dose (MTD) was 15 mg in the R-CHOP-T arm and has not been determined in other treatment arms because of toxicities. All patients experienced ≥ Grade 3 adverse events, mainly thrombocytopenia (76%). Twenty-six patients discontinued prematurely the treatment, mostly for toxicity (n = 12) and progression of the disease (n = 8). Of note, 6 patients of the R-DHA-T arm reached complete remission (35%). Temsirolimus with immuno-chemotherapy is associated with a high rate of toxicities. Determination of MTD could only be achieved for R-CHOP-T arm. Associations between temsirolimus and other targeted therapies may be warranted for R/R MCL patients.

Background: Patients with established coronary artery disease or peripheral artery disease often have diabetes mellitus. These patients are at high risk of future vascular events. Methods: In a prespecified analysis of the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), we compared the effects of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily) versus placebo plus aspirin in patients with diabetes mellitus versus without diabetes mellitus in preventing major vascular events. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included all-cause mortality and all major vascular events (cardiovascular death, myocardial infarction, stroke, or major adverse limb events, including amputation). The primary safety end point was a modification of the International Society on Thrombosis and Haemostasis criteria for major bleeding. Results: There were 10 341 patients with diabetes mellitus and 17 054 without diabetes mellitus in the overall trial. A consistent and similar relative risk reduction was seen for benefit of rivaroxaban plus aspirin (n=9152) versus placebo plus aspirin (n=9126) in patients both with (n=6922) and without (n=11 356) diabetes mellitus for the primary efficacy end point (hazard ratio, 0.74, P =0.002; and hazard ratio, 0.77, P =0.005, respectively, P interaction =0.77) and all-cause mortality (hazard ratio, 0.81, P =0.05; and hazard ratio, 0.84, P =0.09, respectively; P interaction =0.82). However, although the absolute risk reductions appeared numerically larger in patients with versus without diabetes mellitus, both subgroups derived similar benefit (2.3% versus 1.4% for the primary efficacy end point at 3 years, Gail-Simon qualitative P interaction P interaction =0.02; 2.7% versus 1.7% for major vascular events, P interaction P interaction =0.001). Conclusions: In stable atherosclerosis, the combination of aspirin plus rivaroxaban 2.5 mg twice daily provided a similar relative degree of benefit on coronary, cerebrovascular, and peripheral end points in patients with and without diabetes mellitus. Given their higher baseline risk, the absolute benefits appeared larger in those with diabetes mellitus, including a 3-fold greater reduction in all-cause mortality. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01776424.

Background Central nervous system damage in multiple sclerosis (MS) is responsible for serious deficiencies. Current therapies are focused on the treatment of inflammation; however, there is an urgent need for innovative therapies promoting neuroregeneration, particularly myelin repair. It is demonstrated that testosterone can act through neural androgen receptors and several clinical observations stimulated an interest in the potential protective effects of testosterone treatment for MS. Here, we sought to demonstrate the effects of a testosterone supplementation in testosterone-deficient men with relapsing-remitting MS. Methods/design This report presents the rationale and methodology of TOTEM RRMS, a French, phase 2, multicenter, randomized, placebo-controlled, and double-blind trial, which aims to prevent the progression of MS in men with low testosterone levels by administration of testosterone undecanoate, who were kept under natalizumab (Tysabri®) to overcome the anti-inflammatory effect of testosterone. Forty patients will be randomized into two groups receiving either a testosterone treatment (Nebido®) or a matching placebo. The intervention period for each group will last 66 weeks (treatment will be injected at baseline, week 6, and then every 12 weeks). The main objective is to determine the neuroprotective and remyelinating effects of testosterone using tensor diffusion imaging techniques and thalamic atrophy analyses. As secondary objectives, impacts of the testosterone supplementation will be studied using other conventional and unconventional MRI parameters and with clinical outcomes. Discussion The action of testosterone is observed in different experimental autoimmune encephalomyelitis models and epidemiological studies in humans. However, despite several preclinical data and some small clinical trials in MS, clear evidence for a therapeutic effect of hormone therapy is still missing. Therefore, our goal is to demonstrate the effects of testosterone therapies in MS. As there is no effective treatment currently available on fatigue in MS, careful attention should also be paid to secondary endpoints: fatigue, cognitive functions, and other symptoms that may improve life quality. Assuming a positive outcome of the trial, this treatment could be considered as a new neuroprotective and remyelinating therapy in relapsing-remitting MS and could be applicable to other demyelinating diseases. Trial registration ClinicalTrials.gov NCT03910738. Registered on 10 April 2019.

Esse trabalho tem como objetivo investigar o impacto causado na saúde física e mental do trabalhador pelo meio ambiente artificial, influenciado por fatores como poluição sonora, poluição atmosférica, poluição hídrica, assédio moral, confinamento, esforços repetitivos, e buscar formas de mitigação desses fatores que possam, ao desequilibrar o meio ambiente, contribuir para o desenvolvimento de várias doenças, já estudadas e publicadas em diversos artigos científicos. As relações entre saúde/doença mental e vulnerabilidade social são muito complexas e exigem uma série de reflexões e contextualizações para ser compreendidas. O fato é que, nas últimas décadas, o número de pessoas expostas a acontecimentos traumáticos aumentou de maneira significativa à medida que várias formas de violência vêm engolfando as populações civis no mundo inteiro, o que constitui um ônus adicional persistente que conduz a doenças, mortes e invalidez. This paper aims to investigate the impact on the physical and mental health of workers by the artificial environment, influenced by factors such as noise pollution, air pollution, water pollution, bullying, confinement, repetitive efforts, and seek ways to mitigate these factors can, by unbalancing the environment, contribute to the development of various diseases, already studied and published in several scientific articles. The relationships between health/mental illness and social vulnerability are very complex and require a series of reflections and contextualizations to be understood. The fact is that, in recent decades, the number of people exposed to traumatic events has increased significantly as various forms of violence engulf civilian populations worldwide, thus contributing to a persistent additional burden of disease, death and disability.

Objectives The aim of this study was to examine the value of frailty to predict in-hospital major bleeding and determine its impact on mid-term mortality following transcatheter (TAVR) or surgical (SAVR) aortic valve replacement. Background Bleeding complications are harbingers of mortality and major morbidity in patients undergoing TAVR or SAVR. Despite the high prevalence of frailty in this population, little is known about its effects on bleeding risk. Methods A post hoc analysis was performed of the multinational FRAILTY-AVR (Frailty Aortic Valve Replacement) cohort study, which prospectively enrolled older adults ≥70 years of age undergoing TAVR or SAVR. Trained researchers assessed frailty using a questionnaire and physical performance battery pre-procedure and ascertained clinical data from the electronic health record. The primary endpoint was major or life-threatening bleeding during the index hospitalization, and the secondary endpoint was units of packed red blood cells transfused. Results The cohort consisted of 1,195 patients with a mean age of 81.3 ± 6.0 years. The incidence of life-threatening bleeding, major bleeding with a clinically apparent source, and major bleeding without a clinically apparent source was, respectively, 3%, 6%, and 9% in the TAVR group and 8%, 10%, and 31% in the SAVR group. Frailty measured using the Essential Frailty Toolset was an independent predictor of major bleeding and packed red blood cell transfusions in both groups. Major bleeding was associated with a 3-fold increase in 1-year mortality following TAVR (odds ratio: 3.40; 95% confidence interval: 2.22 to 5.21) and SAVR (odds ratio: 2.79; 95% confidence interval: 1.25 to 6.21). Conclusions Frailty is associated with post-procedural major bleeding in older adults undergoing TAVR and SAVR, which is in turn associated with a higher risk for mid-term mortality.

Breast cancer remains the first cause of death in women worldwide even if the average 10-year survival rate is 83%. It remains difficult to accurately evaluate the risk of recurrence, and consequently the need of chemotherapy, in estrogen receptor (ER)-positive, HER2-negative early breast cancers, at the individual level, leading to overtreatment for some patients. In that context, multigene prognostic scores are proposed in combination with clinicopathological parameters, to guide adjuvant treatment decisions. In our study, patients diagnosed with ER-positive, Her2-negative breast cancer, analyzed with the 12-gene EndoPredictTM test are prospectively included in the national SiMosein registry. The decision for Endopredict testing is determined by an oncological tumor board in expert breast cancer centers. The test is locally performed (10 national laboratories, evaluated by a national quality control exchange program). Clinicopathological parameters are recorded and the treatment decision before and after the genomic test is requested. The aim of the study is to prospectively evaluate the real-life use of the EndopredictTM test and the impact of the recurrence risk on the adjuvant treatment decision. A total of 3153 patients were included between May 2016 and December 2018. Patients are 75.6% post-menopausal (median age: 57.55y) and are mostly diagnosed as invasive ductal carcinoma not otherwise specified (81.2%) with SBR grade 2 (74.02%) and positive Ki67 staining (>14%, 66.4%). Tumor sizes are pT1ab, pT1c or pT2 in respectively 12.1%, 54.7% and 31.4% of the cases. Lymph node involvement is negative (pN0) in 70.5% of the cases. However, 29.5% of cases are pN1-3 with 5.2% of pN1mi. All cases are ER-positive, HER2-negative early breast cancers and 74.8% are progesterone receptor (PR)-positive (PR>10%) and 76.43% of the cases are of luminal B-like subtype. The population evaluated in this prospective study is in accordance to the intermediate prognostic subpopulation of luminal breast cancers where genomic signatures could contribute to guide the adjuvant treatment decision. The risk of relapse at 10 years, as reflected by the EPclin score, is of 13.16% on average, with 55.18% of high risk (positive threshold 10%). Treatment decisions before and after the test were recorded for 599 patients. The decision remains unmodified after the test in 54.59% of the cases. Conversely, change in adjuvant treatment decision was made from hormone therapy (HT) to adjunction of chemotherapy (HT+CT) in 18.20% of the cases and from (HT+CT) to (HT) leading to chemotherapy withdrawn in 27.21%. Finally, the national SiMosein registry, evaluated the utility of the test. The use of EndopredictTM is mostly restricted to the intermediate prognostic subgroup of the early luminal breast subtype as requested by the French health authority (HAS). The test is routinely used in France and clinicians need mainly the test for treatment decision. The EPclin score leads to 45.41% of modification of treatment with a majority of avoidance of chemotherapy (59.93%). Citation Format: Jacqueline Lehmann-Che, Jennifer Wong, Lucie Tixier, Ludovic Lacroix, Magali Triki-Lacroix, Pierre-Jean Lamy, Agnes Garnier, Véronique Quillien, Florence Godey, Isabelle Soubeyran, Gaëtan MacGrogan, Laurent Arnould, Juliette Haudebourg, Anne Tallet, Linda Dainese, Caroline Hugonin, Frédérique Penault-Llorca. Simosein registry, the French national real-life prospective evaluation of the impact of Endopredict® (EPclin) on treatment decision in ER-positive, HER2-negative breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-25.

Care pathways and long-term outcomes of acute stroke patients requiring mechanical ventilation have not been thoroughly studied. Stroke Prognosis in Intensive Care (SPICE) is a prospective multicenter cohort study which will be conducted in 34 intensive care units (ICUs) in the Paris, France area. Patients will be eligible if they meet all of the following inclusion criteria: (1) age of 18 years or older; (2) acute stroke (i.e., ischemic stroke, intracranial hemorrhage, or subarachnoid hemorrhage) diagnosed on neuroimaging; (3) ICU admission within 7 days before or after stroke onset; and (4) need for mechanical ventilation for a duration of at least 24 h. Patients will be excluded if they meet any of the following: (1) stroke of traumatic origin; (2) refusal to participate; and (3) privation of liberty by administrative or judicial decision. The primary endpoint is poor functional outcome at 1 year, defined by a score of 4 to 6 on the modified Rankin scale (mRS), indicating severe disability or death. Main secondary endpoints will include decisions to withhold or withdraw care, mRS scores at 3 and 6 months, and health-related quality of life at 1 year. The SPICE multicenter study will investigate 1-year outcomes, ethical issues, as well as care pathways of acute stroke patients requiring invasive ventilation in the ICU. Gathered data will delineate human resources and facilities needs for adequate management. The identification of prognostic factors at the acute phase will help to identify patients who may benefit from prolonged intensive care and rehabilitation. Trial registration: NCT03335995.

Objective: To analyze women’s desires, expectations and experiences regarding skin-to-skin contact and breastfeeding in the first hour of life of their newborns. Methods: Qualitative research carried out in a teaching hospital in the Northeast Region of Brazil. The patients were followed longitudinally during prenatal care, at birth and during the puerperium. The participants were pregnant women during normal risk prenatal care, aged over 18 years old. Structured and semi-structured interviews were carried out in the prenatal period, participant observation at the time of delivery and new interviews in the puerperium. Content analysis was applied in the thematic modality. Results: 18 women between 21 and 38 years old were enrolled in the research. Women expressed the desire for skin-to-skin contact and breastfeeding as immediate practices right after delivery and birth. However, many women did not believe it was possible, and the performance of routine procedures was considered the main obstacle. These expectations that skin-to-skin contact and early breastfeeding would not be carried out were confirmed in the experiences immediately after birth. Conclusions: The expectations and experiences brought by these women suggest a flaw that starts in prenatal care and implies difficulties in implementing the studied practices. Thus, the empowerment and participation of women can become an important tool in the humanization of birth. RESUMO Objetivo: Analisar os desejos, as expectativas e as experiências de mulheres no que diz respeito ao contato pele a pele e à amamentação na primeira hora de vida. Métodos: Pesquisa qualitativa realizada em um hospital de ensino de uma capital da Região Nordeste. As mulheres foram acompanhadas longitudinalmente, durante o pré-natal, o parto e o puerpério. As participantes eram gestantes em pré-natal de risco habitual, com idade maior de 18 anos. Foram realizadas entrevistas estruturadas e semiestruturadas no pré-natal, observação participante no momento do parto e novas entrevistas no puerpério. Fez-se a análise de conteúdo na modalidade temática. Resultados: Participaram da pesquisa 18 mulheres, entre 21 e 38 anos. Elas expressaram o desejo do contato pele a pele e da amamentação como práticas imediatas após o parto e o nascimento, contudo muitas não acreditavam que fosse possível, sendo o principal entrave a realização de procedimentos de rotina. As expectativas de impossibilidade do contato pele a pele e amamentação precoce foram confirmadas no momento do parto. Conclusões: As expectativas e experiências trazidas pelas mulheres apontam para uma falha que se inicia no pré-natal e implica dificuldades na implementação das práticas estudadas. Desse modo, o fortalecimento da participação das mulheres pode se mostrar uma ferramenta importante na humanização do nascimento.

The Management of Myocardial Injury after Non-Cardiac Surgery (MANAGE) trial demonstrated that dabigatran 110 mg twice daily was more effective than placebo in preventing the primary composite outcome of vascular mortality, non-fatal myocardial infarction, non-hemorrhagic stroke, peripheral arterial thrombosis, amputation and symptomatic venous thromboembolism in patients with myocardial injury after non-cardiac surgery (MINS). The cost implications of dabigatran for this population are unknown but are important given the significant clinical implications. Hospitalized events, procedures, and study and non-study medications were documented. We applied Canadian unit costs to healthcare resources consumed for all patients in the trial, and calculated the average cost per patient in Canadian dollars for the duration of the study (median follow-up of 16 months). A sensitivity analysis was performed using only Canadian patients, and subgroup analyses were also conducted. The total study cost for the dabigatran group was $9985 per patient, compared with $10,082 for placebo, a difference of − $97 (95% confidence interval [CI] − $2128 to $3672). Savings arising from fewer clinical events and procedures in the dabigatran 110 mg twice-daily group were enough to offset the cost of the study drug. In Canadian patients, the difference was $250 (95% CI −$2848 to $4840). Both differences were considered cost neutral. Dabigatran 110 mg twice daily was cost saving or cost neutral in many subgroups that were considered. Dabigatran 110 mg twice daily was cost neutral for patients in the MANAGE trial. Our cost findings support the use of dabigatran 110 mg twice daily in patients with MINS. ClinicalTrials.gov identifier number NCT01661101.

Graphical abstract The reduction in LA and PV dimensions after ablation. Clinically successful PVI ablation decreased the PV and LA dimensions in AF patients (left panel). We make observations (right panel) that are compatible with the direct effect of ablation energy and subsequent scar formation causing the atrial downsizing., Background Ablative pulmonary vein isolation (PVI) decreases pulmonary vein (PV) and left atrial (LA) dimensions in atrial fibrillation (AF) patients. These changes are attributed to reverse structural remodeling following sinus rhythm restoration but evidence is lacking. We hypothesized that the downsizing is directly caused by the ablative energy and subsequent scar formation. Methods We studied cardiac magnetic resonance imaging in 21 paroxysmal AF patients before and 3 months after successful PVI and in healthy sheep (n = 12) before and after PVI of the right PV only. Results PVI decreased the PV diameter in patients and sheep by 11.0(10.3) and 9.2(11.0)%, (p

Parkinson’s disease (PD) evolves over an extended and variable period in humans; several years prior to the onset of classical motor symptoms, cognitive deficits as well as sleep and biological rhythm disorders develop and worsen with disease progression, significantly impacting the quality of life of patients. The gold standard MPTP macaque model of PD recapitulates the progression of motor and non-motor symptoms over contracted periods of time.Here, this multidisciplinary and multiparametric study follows, in five animals, the steady progression of motor and non-motor symptoms and describes their reversal following bilateral grafts of neural precursors in diverse functional domains of the basal ganglia.Results show unprecedented recovery from cognitive symptoms in addition to a strong clinical motor recuperation. Both motor and cognitive recovery and partial circadian rhythm recovery correlate with the degree of graft integration into the host environment as well as with in-vivo levels of striatal dopaminergic innervation and function.Given inter-individuality of disease progression and recovery the present study underlines the importance of longitudinal multidisciplinary assessments in view of clinical translation and provides empirical evidence that integration of neural precursors following transplantation efficiently restores function at multiple levels in parkinsonian non-human primates.One Sentence SummaryEmpirical evidence that cell therapy efficiently reverts cognitive and clinical motor symptoms in the non-human primate model of Parkinson’s disease.

International audience; BACKGROUND AND OBJECTIVES: Rituximab is an anti-CD20 monoclonal antibody approved in several diseases, including chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), rheumatoid arthritis (RA), and anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). The influence of underlying disease on rituximab pharmacokinetics has never been investigated for several cancer and non-cancer diseases simultaneously. This study aimed at assessing this influence using an integrated semi-mechanistic model accounting for target-mediated elimination of rituximab. METHODS: Rituximab concentration-time data from five studies previously published in patients with CLL, DLBCL, FL, RA, and AAV were described using a two-compartment model with irreversible binding of rituximab to its target antigen. Both underlying disease and target antigen measurements were assessed as covariates. RESULTS: Central volume of distribution was [95% confidence interval] 1.7-fold [1.6-1.9] higher in DLBCL than in RA, FL, and CLL, and it was 1.8-fold [1.6-2.1] higher in RA, FL, and CLL than in AAV. First-order elimination rate constants were 1.8-fold [1.7-2.0] and 1.3-fold [1.2-1.5] higher in RA, DLBCL, and FL than in CLL and AAV, respectively. Baseline latent antigen level (L(0)) was 54-fold [30-94], 20-fold [11-36], and 29-fold [14-64] higher in CLL, DLBCL, and FL, respectively, than in RA and AAV. In lymphoma, L(0) increased with baseline total metabolic tumor volume (p = 6.10(-7)). In CLL, the second-order target-mediated elimination rate constant (k(deg)) increased with baseline CD20 count on circulating B cells (CD20(cir), p = 0.0081). CONCLUSIONS: Our results show for the first time that rituximab pharmacokinetics is strongly influenced by underlying disease and disease activity. Notably, neoplasms are associated with higher antigen amounts that result in decreased exposure to rituximab compared to inflammatory diseases. Our model might be used to estimate unbound target amounts in upcoming studies.

Introduction Advanced non-squamous non-small cell lung cancer (NsqNSCLC) progressing at the induction of a first-line of platin-based chemotherapy is a subgroup of patients with poor prognosis and few second-line treatment options. Materials and Methods This single-stage phase II prospective multicenter open-label trial performed in platin-based refractory (i.e. progressing during induction phase of first-line platin-based chemotherapy) advanced NsqNSCLC assessed the efficacy of the nintedanib-docetaxel combination in second-line treatment. The primary endpoint was progression-free survival (PFS) rates at 12 weeks with a cut-off at 30% for ineffectiveness and 50% for minimal efficacy. Results A total of 59 patients from 23 centers were included (mean age, 58.5 years; male gender, 73.6%; performance status 0–1, 100%; former/current smokers, 92.5%; adenocarcinoma, 92.5%, median platin-based first-line chemotherapy, 2). Nintedanib-docetaxel combination was administered for a median of 4 cycles. The rate of PFS at 12 weeks was 39.6% (95% CI, 28.2–56.8). Median PFS was 2.7 (95% CI, 1.4–4.1) months and one-year PFS was 11.8% (95% CI, 4.8–22.2). Median overall survival (OS) was 6.9 (95% CI, 4.3–8.2) months and 12-month OS was 32.1% (95% CI, 19.8–45.0); 18-month OS was 27.6% (95% CI, 16,1–40.4). Twenty-nine (53.7%) patients reported at least one serious treatment-related adverse events leading to permanent discontinuation of at least one study drug in 12 (22.2%) patients. Conclusion The predefined minimal efficacy was not demonstrated. However, a number of NsqNSCLC patients refractory to first-line platin-based chemotherapy appeared to benefit from this combination.

Background: Adverse cardiovascular events are a leading cause of perioperative morbidity and mortality. The definitions of perioperative cardiovascular adverse events are heterogeneous. As part of the international Standardized Endpoints in Perioperative Medicine initiative, this study aimed to find consensus amongst clinical trialists on a set of standardised and valid cardiovascular outcomes for use in future perioperative clinical trials.Methods: We identified currently used perioperative cardiovascular outcomes by a systematic review of the anaesthesia and perioperative medicine literature (PubMed/Ovid, Embase, and Cochrane Library). We performed a three-stage Delphi consensus-gaining process that involved 55 clinician researchers worldwide. Cardiovascular outcomes were first shortlisted and the most suitable definitions determined. These cardiovascular outcomes were then assessed for validity, reliability, feasibility, and clarity.Results: We identified 18 cardiovascular outcomes. Participation in the three Delphi rounds was 100% (n=19), 71% (n=55), and 89% (n=17), respectively. A final list of nine cardiovascular outcomes was elicited from the consensus: myocardial infarction, myocardial injury, cardiovascular death, non-fatal cardiac arrest, coronary revascularisation, major adverse cardiac events, pulmonary embolism, deep vein thrombosis, and atrial fibrillation. These nine cardiovascular outcomes were rated by the majority of experts as valid, reliable, feasible, and clearly defined.Conclusions: These nine consensus cardiovascular outcomes can be confidently used as endpoints in clinical trials designed to evaluate perioperative interventions with the goal of improving perioperative outcomes.

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices. ispartof: EUROPEAN JOURNAL OF CANCER vol:146 pages:30-47 ispartof: location:England status: published