PD-L1 expression and its prognostic value in metastatic papillary renal cell carcinoma: Results from a GETUG multicenter retrospective cohort.

INTRODUCTION: Papillary renal cell carcinoma (pRCC) is a rare and aggressive cancer with no specifically established therapeutic strategy in the metastatic setting. Combinations of tyrosine kinase and immune checkpoint inhibitors (ICI) are a promising option. We aimed to study the immune landscape of metastatic pRCC, and its interactions with angiogenesis pathways, to search for potential therapeutic targets. METHODS: The expression of immune markers (PD-L1, PD-1, PD-L2, LAG-3) and angiogenic pathways (CAIX, c-MET), was analyzed by immunohistochemistry on 68 metastatic pRCC retrieved from a retrospective multicenter GETUG cohort. Our primary endpoint was to estimate the prevalence of PD-L1 expression and its prognostic impact in metastatic pRCC. Secondary endpoints included the evaluation of other immune markers (PD-1, PD-L2, and LAG-3) and their association with PD-L1. We also assessed angiogenic markers and their association with PD-L1. RESULTS: Overall, 27.9 % of tumors were PD-L1 positive. PD-L2 was more frequently expressed (45.6 %), PD-1 and LAG-3 were positive in 17.6 % and 19.1 % respectively. None of these markers was correlated with PD-L1 expression. 66 % (45/68) expressed at least one immune marker, and 43 % (29/68) were "double-positive", as they expressed both immune and angiogenic markers. OS was significantly shorter for patients with PD-L1 positive pRCC. A multivariate analysis confirmed a significant association between PD-L1 expression and shorter overall survival (HR = 4.0, p = 0.01). CONCLUSION: These results reinforce clinical data on the expected benefit of ICI in metastatic pRCC treatment, as PD-L1 expression is a factor of poor prognosis in this multicenter cohort.

Changes in cerebral connectivity and brain tissue pulsations with the antidepressant response to an equimolar mixture of oxygen and nitrous oxide: an MRI and ultrasound study.

Nitrous oxide (N2O) has recently emerged as a potential fast-acting antidepressant but the cerebral mechanisms involved in this effect remain speculative. We hypothesized that the antidepressant response to an Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) would be associated with changes in cerebral connectivity and brain tissue pulsations (BTP). Thirty participants (20 with a major depressive episode resistant to at least one antidepressant and 10 healthy controls-HC, aged 25-50, only females) were exposed to a 1-h single session of EMONO and followed for 1 week. We defined response as a reduction of at least 50% in the MADRS score 1 week after exposure. Cerebral connectivity of the Anterior Cingulate Cortex (ACC), using ROI-based resting state fMRI, and BTP, using ultrasound Tissue Pulsatility Imaging, were compared before and rapidly after exposure (as well as during exposure for BTP) among HC, non-responders and responders. We conducted analyses to compare group × time, group, and time effects. Nine (45%) depressed participants were considered responders and eleven (55%) non-responders. In responders, we observed a significant reduction in the connectivity of the subgenual ACC with the precuneus. Connectivity of the supracallosal ACC with the mid-cingulate also significantly decreased after exposure in HC and in non-responders. BTP significantly increased in the three groups between baseline and gas exposure, but the increase in BTP within the first 10 min was only significant in responders. We found that a single session of EMONO can rapidly modify the functional connectivity in the subgenual ACC-precuneus, nodes within the default mode network, in depressed participants responders to EMONO. In addition, larger increases in BTP, associated with a significant rise in cerebral blood flow, appear to promote the antidepressant response, possibly by facilitating optimal drug delivery to the brain. Our study identified potential cerebral mechanisms related to the antidepressant response of N2O, as well as potential markers for treatment response with this fast-acting antidepressant.

Cluster randomized trials in nursing homes should better be planned as open-cohort than as closed-cohort.

OBJECTIVES: Two designs are frequently used in cluster randomized trials in nursing homes: closed cohort and open cohort. The former design includes residents at the beginning of the trial and then follows them. In the latter design, participants are enrolled at the beginning of the trial or although it is ongoing; at dates of assessment, all residents present in the nursing home are assessed. The open-cohort design is much less used than the closed-cohort design, but it offers several advantages such as less exposure to individual attrition. Objective was to assess whether an open-cohort design could have been feasible in trials with a closed-cohort design. STUDY DESIGN AND SETTING: Twenty-two closed-cohort trials in nursing homes. RESULTS: An open-cohort design was considered a relevant alternative for 20 trials. For 16 trials, a resident newly admitted could not opt out of the intervention, and for all trials, the resident could benefit from an intervention effect if it existed. For two trials, newly admitted residents could not benefit from the intervention effect, if it existed. CONCLUSION: The open-cohort design is well-adapted for most of the interventions assessed in nursing homes by means of a cluster randomized trial and should be considered more often.

High Prevalence of Geriatric Conditions Among Older Adults With Cardiovascular Disease.

As the population ages, the global cardiovascular disease burden will continue to increase, particularly among older adults. Increases in life expectancy and better cardiovascular care have significantly reshaped the epidemiology of cardiovascular disease and have created new patient profiles. The combination of older age, multiple comorbidities, polypharmacy, frailty, and adverse noncardiovascular outcomes is challenging our routine clinical practice in this field. In this review, we examine noncardiovascular factors that statistically interact in a relevant way with health status and quality of life in older people with cardiovascular disease. We focused on specific geriatric conditions (multimorbidity, polypharmacy, geriatric syndromes, and frailty) that are responsible for a major risk of functional decline and have an important impact on the overall prognosis in this patient population.

Asymptomatic left circumflex artery stenosis is associated with higher arrhythmia recurrence after persistent atrial fibrillation ablation.

Background: The pathophysiology of persistent atrial fibrillation (AF) remains unclear. While several studies have demonstrated an association between myocardial infarction and atrial fibrillation, the role of stable coronary artery disease (CAD) is still unknown. As a result, we aimed to assess the association between CAD obstruction and AF recurrence after persistent AF ablation in patients with no history of CAD. Materials and methods: This observational retrospective study included consecutive patients who underwent routine preprocedural cardiac computed tomography (CCT) before persistent AF ablation between September 2015 and June 2018 in 5 European University Hospitals. Exclusion criteria were CAD or coronary revascularization previously known or during follow-up. Obstructive CAD was defined as luminal stenosis ≥ 50%. Results: All in all, 496 patients (mean age 61.8 ± 10.0 years, 76.2% males) were included. CHA2DS2-VASc score was 0 or 1 in 225 (36.3%) patients. Obstructive CAD was present in 86 (17.4%) patients. During the follow-up (24 ± 19 months), 207 (41.7%) patients had AF recurrence. The recurrence rate was not different between patients with and without obstructive CAD (43.0% vs. 41.5%, respectively; P = 0.79). When considering the location of the stenosis, the recurrence rate was higher in the case of left circumflex obstruction: 56% vs. 32% at 2 years (log-rank P ≤ 0.01). After Cox multivariate analysis, circumflex artery obstruction (HR 2.32; 95% CI 1.36-3.98; P < 0.01) was independently associated with AF recurrence. Conclusion: Circumflex artery obstruction detected with CCT was independently associated with 2-fold increase in the risk of AF recurrence after persistent AF ablation. Further research is necessary to evaluate this pathophysiological relationship.

Management of death-related noncompleters in cluster randomized trials carried out in nursing homes: a methodological review.

BACKGROUND: A noncompleter is defined as a participant who leaves a trial before the end of the planned follow-up. Research in nursing homes is highly exposed to this problem because of high death rates. OBJECTIVES: The aim of this trial is to assess the statistical management of noncompleters in cluster randomized trials carried out in nursing homes. STUDY DESIGN AND SETTING: A methodological review of published cluster randomized trials. RESULTS: We selected 37 articles. For 22 (59%) trials, the design was closed-cohort (i.e., participants included all at the same time when randomizing clusters). In those 22 closed-cohort trials, the median follow-up was 6.5 months (interquartile range 4-12). The median noncompleter rate was 19.5% and the median noncompletions due to death was 73.2%. In only one trial were the baseline characteristics of completers and noncompleters compared. Strategies to deal with noncompleters were an inflation of the planned sample size (11 trials), the use of repeated measurements of the outcome (12 trials), and the use of imputation methods when analyzing data (7 trials). CONCLUSION: In cluster randomized trials of nursing homes, noncompleters are managed as for any missing data, but they are essentially due to death. Methodological and statistical developments and guidance are needed.

The Role of Telemedicine in the Management of the Behavioral and Psychological Symptoms of Dementia: A Systematic Review.

The first-line management of behavioral and psychological symptoms of dementia (BPSD) is based on nonpharmacologic interventions such as the provision of guidance and medical support to caregivers. However, accessibility to specialized care and medical resources is often scarce. The ongoing COVID-19 pandemic has compromised the delivery of outpatient care (notably in order to minimize the risk of disease transmission), thus making it essential to provide other means of accessing care for these patient populations. The use of telemedicine (TM) may be a means of increasing access to specialist care for patients with disabilities and poor access to health services, such as those with BPSD. The aim of this study is to provide a review of the literature on the use of TM for treatment and follow-up of patients with BPSD and their caregivers. We searched the PUBMED, EMBASE and CINAHL for articles published between January 1st, 2000, and December 31st, 2020, on the applicability of TM support for people with BPSD and their caregivers. We included open-label studies, qualitative studies, and randomized controlled trials . We did not include studies on the use of TM during the COVID-19 pandemic. A total of 22 publications were included and reviewed. TM was found to 1) be acceptable and feasible for both patients and caregivers, 2) decrease the frequency and intensity of BPSD, and 3) improve the caregiver's perceived wellbeing and mental health. Videoconferencing was effective for patient-centered interventions in nursing homes. Telephone-based interventions were more relevant when they were targeted at caregivers. The published studies are lacking in scope and high-quality studies are now needed to confirm these findings and assess TM's cost-effectiveness and ability to improve the management of patients with BPSD. In view of the ongoing COVID-19 pandemic, remote solutions for assessing and monitoring individuals with BPSD are urgently needed - particularly those living in rural areas and so-called "medical deserts."

Analysis of the Impact of Selected Vitamins Deficiencies on the Risk of Disability in Older People.

Vitamin deficiencies have a serious impact on healthy aging in older people. Many age-related disorders have a direct or indirect impact on nutrition, both in terms of nutrient assimilation and food access, which may result in vitamin deficiencies and may lead to or worsen disabilities. Frailty is characterized by reduced functional abilities, with a key role of malnutrition in its pathogenesis. Aging is associated with various changes in body composition that lead to sarcopenia. Frailty, aging, and sarcopenia all favor malnutrition, and poor nutritional status is a major cause of geriatric morbidity and mortality. In the present narrative review, we focused on vitamins with a significant risk of deficiency in high-income countries: D, C, and B (B6/B9/B12). We also focused on vitamin E as the main lipophilic antioxidant, synergistic to vitamin C. We first discuss the role and needs of these vitamins, the prevalence of deficiencies, and their causes and consequences. We then look at how these vitamins are involved in the biological pathways associated with sarcopenia and frailty. Lastly, we discuss the critical early diagnosis and management of these deficiencies and summarize potential ways of screening malnutrition. A focused nutritional approach might improve the diagnosis of nutritional deficiencies and the initiation of appropriate clinical interventions for reducing the risk of frailty. Further comprehensive research programs on nutritional interventions are needed, with a view to lowering deficiencies in older people and thus decreasing the risk of frailty and sarcopenia.

A Local COVID-19 Support Platform for Nursing Homes: Feedback and Perspectives.

The COVID-19 pandemic has had a major impact on nursing homes (NHs), which were not prepared to manage infections among their at-risk patient populations. In order to comply with the French government's guidelines, we rapidly set up a local support platform (LSP) to help NHs manage their cases of COVID-19. The LSP comprised multidisciplinary decision support, a specialist phone hotline, mobile geriatric medicine teams, and videoconferences on COVID-19. We first quantified the LSP's interventions in 63 local NHs since the start of the first wave of COVID-19 (March 2020): 9 instances of multidisciplinary decision support, 275 calls to the specialist phone hotline, 84 interventions by mobile geriatric medicine teams, and 16 videoconferences. The LSP had been used during and between the first and second waves of the epidemic, and all had evolved to meet the NHs' needs.

Prognostic value of Charlson Comorbidity Index in the elderly with a cardioverter defibrillator implantation.

BACKGROUND: Elderly patients are often underrepresented in implantable cardioverter defibrillator (ICD) trials, and ICD implantation in patients ≥75 years consequently remains controversial. We aimed to evaluate mortality, appropriate ICD therapy rates and survival gain in an elderly population after risk stratification according to the Charlson Comorbidity Index (CCI). METHODS: This monocentric retrospective study included elderly ICD patients ≥75 years. They were subdivided according to their CCI score into 3 categories (0-1, 2-3 or ≥4 points). Elderly patients were matched 1:2 with younger control ICD patients on gender, type of prevention (primary or secondary) and type of device (associated cardiac resynchronization therapy or not). RESULTS: Between January 2009 and July 2017, 121 elderly patients (mean age 78 ± 3; 83% male) matched with 242 controls (mean age 66 ± 5) were included. At 5 year follow-up after ICD implantation, overall survival was 78%, 57%, and 29% (P = 0.002) in the elderly with a CCI score of 0-1, 2-3 and ≥4 respectively, and 72% in controls. There was no significant difference regarding ICD appropriate therapy between the 3 subgroups despite a trend towards lower rates of therapy in CCI ≥ 4 points patients (34.2%, 39.7% and 22.8% respectively; P = 0.45). Median potential survival gain after an appropriate therapy was >5, 4.7 and 1.4 years, with a CCI score of 0-1, 2-3 and ≥4 respectively (P = 0.01). CONCLUSION: Elderly patients with CCI score ≥ 4 had the lowest survival after ICD implantation and little survival gain in case of appropriate defibrillator therapy. More than age alone, the burden of comorbidities assessed by the CCI could be helpful to better select elderly patients for ICD implantation.