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Background Aging is one of the most important prognostic factors increasing the risk of clinical severity and mortality of COVID-19 infection. However, among patients over 75 years, little is known about post-acute functional decline. Objective The aim of this study was to identify factors associated with functional decline 3 months after COVID-19 onset, to identify long term COVID-19 symptoms and transitions between frailty statesafter COVID-19 onset in older hospitalized patients. Methods This prospective observational study included COVID-19 patients consecutively hospitalized from March to December 2020 in Acute Geriatric Ward in Nantes University Hospital. Functional decline, frailty status and long term symptoms were assessed at 3 month follow up. Functional status was assessed using the Activities of Daily Living simplified scale (ADL). Frailty status was evaluated using Clinical Frailty Scale (CFS). We performed multivariable analyses to identify factors associated with functional decline. Results Among the 318 patients hospitalized for COVID-19 infection, 198 were alive 3 months after discharge. At 3 months, functional decline occurred in 69 (36%) patients. In multivariable analysis, a significant association was found between functional decline and stroke (OR = 4,57, p  = 0,003), history of depressive disorder (OR = 3,05, p  = 0,016), complications (OR = 2,24, p  = 0,039), length of stay (OR = 1,05, p  = 0,025) and age (OR = 1,08, p  = 0,028). At 3 months, 75 patients described long-term symptoms (49.0%). Of those with frailty (CFS scores ≥5) at 3-months follow-up, 30% were not frail at baseline. Increasing frailty defined by a worse CFS state between baseline and 3 months occurred in 41 patients (26.8%). Conclusions This study provides evidence that both the severity of the COVID-19 infection and preexisting medical conditions correlates with a functional decline at distance of the infection. This encourages practitioners to establish discharge personalized care plan based on a multidimensional geriatric assessment and in parallel on clinical severity evaluation.

Given the prevalence of non-valvular atrial fibrillation in the geriatric population, thromboembolic prevention by means of vitamin K antagonists (VKA) is one of the most frequent daily concerns of practitioners. The effectiveness and safety of treatment with VKA correlates directly with maximizing the time in therapeutic range, with an International Normalized Ratio (INR) of 2.0-3.0. The older population concentrates many of factors known to influence INR rate, particularly concomitant medications and concurrent medical conditions, also defined as comorbidities. Determine whether a high burden on comorbidities, defined by a Charlson Comorbidity Index (CCI) of 3 or greater, is associated a lower quality of INR control. Cross-sectional study. French geriatric care units nationwide. 2164 patients aged 80 and over and treated with vitamin K antagonists. Comorbidities were assessed using the Charlson Comorbidity Index (CCI). The recorded data included age, sex, falls, kidney failure, hemorrhagic event, VKA treatment duration, and the number and type of concomitant medications. Quality of INR control, defined as time in therapeutic range (TTR), was assessed using the Rosendaal method. 487 patients were identified the low-quality control of INR group. On multivariate logistic regression analysis, low-quality control of INR was independently associated with a CCI ≥3 (OR = 1.487; 95% CI [1.15; 1.91]). The other variables associated with low-quality control of INR were: hemorrhagic event (OR = 3.151; 95% CI [1.64; 6.07]), hospitalization (OR = 1.614, 95% CI [1.21; 2.14]). An elevated CCI score (≥3) was associated with low-quality control of INR in elderly patients treated with VKA. Further research is needed to corroborate this finding.

Background With the lack of effective therapy, chemoprevention, and vaccination against SARS-CoV-2, focusing on the immediate repurposing of existing drugs gives hope of curbing the COVID-19 pandemic. A recent unbiased genomics-guided tracing of the SARS-CoV-2 targets in human cells identified vitamin D among the three top-scoring molecules manifesting potential infection mitigation patterns. Growing pre-clinical and epidemiological observational data support this assumption. We hypothesized that vitamin D supplementation may improve the prognosis of COVID-19. The aim of this trial is to compare the effect of a single oral high dose of cholecalciferol versus a single oral standard dose on all-cause 14-day mortality rate in COVID-19 older adults at higher risk of worsening. Methods The COVIT-TRIAL study is an open-label, multicenter, randomized controlled superiority trial. Patients aged ≥ 65 years with COVID-19 (diagnosed within the preceding 3 days with RT-PCR and/or chest CT scan) and at least one worsening risk factor at the time of inclusion (i.e., age ≥ 75 years, or SpO2 ≤ 94% in room air, or PaO2/FiO2 ≤ 300 mmHg), having no contraindications to vitamin D supplementation, and having received no vitamin D supplementation > 800 IU/day during the preceding month are recruited. Participants are randomized either to high-dose cholecalciferol (two 200,000 IU drinking vials at once on the day of inclusion) or to standard-dose cholecalciferol (one 50,000 IU drinking vial on the day of inclusion). Two hundred sixty participants are recruited and followed up for 28 days. The primary outcome measure is all-cause mortality within 14 days of inclusion. Secondary outcomes are the score changes on the World Health Organization Ordinal Scale for Clinical Improvement (OSCI) scale for COVID-19, and the between-group comparison of safety. These outcomes are assessed at baseline, day 14, and day 28, together with the serum concentrations of 25(OH)D, creatinine, calcium, and albumin at baseline and day 7. Discussion COVIT-TRIAL is to our knowledge the first randomized controlled trial testing the effect of vitamin D supplementation on the prognosis of COVID-19 in high-risk older patients. High-dose vitamin D supplementation may be an effective, well-tolerated, and easily and immediately accessible treatment for COVID-19, the incidence of which increases dramatically and for which there are currently no scientifically validated treatments. Trial registration ClinicalTrials.gov NCT04344041 . Registered on 14 April 2020 Trial status Recruiting. Recruitment is expected to be completed in April 2021.

Background To evaluate the prevalence and management of heart failure (HF) in very old patients in geriatric settings. Methods Members of the French Society of Geriatrics and Gerontology throughout France were invited to participate in a point prevalence survey and to include all patients ≥80 years old, hospitalized in geriatric settings, with HF (stable or decompensated) on June 18, 2012. General characteristics, presence of comorbidities, blood tests and medications were recorded. Results Among 7,197 patients in geriatric institution, prevalence of HF was 20.5% ( n  = 1,478): (27% in acute care, 24.2% in rehabilitation care and 18% in nursing home). Mean age was 88.2 (SD = 5.2) and Charlson co morbidity score was high (8.49 (SD = 2.21)). Left ventricular ejection fraction (LVEF) was available in 770 (52%) patients: 536 (69.6%) had a preserved LVEF (≥ 50%), 120 (15.6%) a reduced LVEF (< 40%), and 114 (14.8%) a midrange LVEF (40–49%). Prescription of recommended HF drugs was low: 42.6% (629) used Angiotensin Converting Enzyme Inhibitors (ACEI) or Angiotensin Receptor Blockers (ARBs), 48.0% (709) β-blockers, and 21.9% (324) ACEI or ARB with β-blockers, even in reduced LVEF. In multivariate analysis ACEI or ARBs were more often used in patients with myocardial infarction (1.36 (1.04–1.78)), stroke (1.42 (1.06–1.91)), and diabetes (1.54 (1.14–2.06)). β blockers were more likely used in patients with myocardial infarction (2.06 (1.54–2.76)) and atrial fibrillation (1.70 (1.28–2.28)). Conclusion In this large very old population, prevalence of HF was high. Recommended HF drugs were underused even in reduced LVEF. These results indicate that management of HF in geriatric settings can still be improved.

Abstract Background We evaluated the safety and efficacy of XAV-19, an antispike glyco-humanized swine polyclonal neutralizing antibody in patients hospitalized with severe coronavirus disease 2019 (COVID-19). Methods This phase 2b clinical trial enrolled adult patients from 34 hospitals in France. Eligible patients had a confirmed diagnosis of severe acute respiratory syndrome coronavirus 2 within 14 days of onset of symptoms that required hospitalization for low-flow oxygen therapy (<6 L/min of oxygen). Patients were randomly assigned to receive a single intravenous infusion of 2 mg/kg of XAV-19 or placebo. The primary end point was the occurrence of death or severe respiratory failure between baseline and day 15. Results Between January 12, 2021, and April 16, 2021, 398 patients were enrolled in the study and randomly assigned to XAV-19 or placebo. The modified intention-to-treat population comprised 388 participants who received full perfusion of XAV-19 (199 patients) or placebo (189 patients). The mean (SD) age was 59.8 (12.4) years, 249 (64.2%) individuals were men, and the median time (interquartile range) from symptom onset to enrollment was 9 (7–10) days. There was no statistically significant decrease in the cumulative incidence of death or severe respiratory failure through day 15 in the XAV-19 group vs the placebo group (53/199 [26.6%] vs 48/189 [25.4%]; adjusted risk difference, 0.6%; 95% CI, −6% to 7%; hazard ratio, 1.03; 95% CI, 0.64–1.66; P = .90). In the safety population, adverse events were reported in 75.4% of 199 patients in the XAV-19 group and in 76.3% of 190 patients in the placebo group through D29. Conclusions Among patients hospitalized with COVID-19 requiring low-flow oxygen therapy, treatment with a single intravenous dose of XAV-19, compared with placebo, did not show a significant difference in terms of disease progression at day 15.

Lymph node metastasis is a crucial prognostic parameter in many different types of cancers and a gateway for further dissemination to distant organs. Prior to metastatic dissemination, the primary tumor prepares for the remodeling of the draining (sentinel) lymph node by secreting soluble factors or releasing extracellular vesicles that are transported by lymphatic vessels. These important changes occur before the appearance of the first metastatic cell and create what is known as a pre-metastatic niche giving rise to the subsequent survival and growth of metastatic cells. In this review, the lymph node structure, matrix composition and the emerging heterogeneity of cells forming it are described. Current knowledge of the major cellular and molecular processes associated with nodal pre-metastatic niche formation, including lymphangiogenesis, extracellular matrix remodeling, and immunosuppressive cell enlisting in lymph nodes are additionally summarized. Finally, future directions that research could possibly take and the clinical impact are discussed.

Background Recent data have suggested that stroke incidence in young people may be rising. In this population-based study, we aimed to determine whether the incidence of stroke in people aged <55 years old had changed over the last three decades. Methods All cases of first-ever stroke (ischaemic stroke, spontaneous intracerebral haemorrhage, and undetermined stroke) occurring in Dijon, France, from 1985 to 2011 were prospectively collected from a population-based registry. Incidence rates were calculated and temporal trends were analysed by age groups and stroke subtypes using a Poisson regression to estimate incidence rate ratios (IRR). Risk factors and premorbid treatments were analysed. Results Over the 27-year study period, 4506 patients were recorded (53% women, mean age 74.6±14.4, 10.1% aged <55 years). An increase in overall stroke incidence was noted, as was a rise in ischaemic stroke in individuals aged <55 years (IRR 1.308; 95% CI 0.982 to 1.741, p=0.066 for period 1994–2002 vs period 1985–1993, and IRR 1.697; 95% CI 1.340 to 2.150, p<0.001 for period 2003–2011 vs period 1994–2002), which was consistent for men and women. In these young patients, smoking was the most frequent risk factor (43%). Conclusions Multiple factors may account for the increased incidence of ischaemic stroke in people aged <55 years including changes in vascular risk factors, better awareness of the disease and treatment options in the population and among practitioners leading to more frequent referrals for specialised care, and improvements in stroke diagnosis. Stroke prevention must be encouraged even in young adults.

Lymphangiogenesis has gained considerable interest due to its established role in cancer progression and dissemination of metastatic cells through lymph nodes. Deciphering the molecular mechanisms that govern lymphangiogenesis within lymph nodes holds promise for revealing novel targetable molecules and pathways to inhibit metastasis. In this study, we revealed a previously unrecognized role of AXL, a tyrosine kinase receptor, in the lymphatic vessel formation. We first validated the expression of AXL in lymphatic endothelial cells (LECs), followed by functional studies using RNA interference and pharmacological inhibition with R428/Bemcentinib. These approaches provided compelling evidence that AXL promotes LEC migration in both 2D and 3D culture systems. Our findings demonstrated that AXL activation was induced by VEGF-C (Vascular Endothelial Growth Factor C) and further amplified downstream signaling via the AKT pathway. In vivo, the role of AXL in lymphatic vessel sprouting was demonstrated using R428 in a model of VEGF-C-induced lymphangiogenesis in lymph nodes. Interestingly, we discovered that AXL was predominantly expressed in MARCO + LECs. Strikingly, under metastatic conditions, there was a notable increase in the density and penetration extent of these AXL-expressing LECs into the lymph node parenchyma. Collectively, our findings pinpoint AXL as a potent enhancer of lymphangiogenesis operating through the VEGF-C/AKT pathway. Furthermore, the identification of AXL expression within a distinct LEC subpopulation, particularly in the context of metastasis, underscores the intricate interplay between AXL signaling and lymphatic dynamics within the lymph node microenvironment.

When combined with anti-PD-1, monoclonal antibodies (mAbs) against GARP:TGF-β1 complexes induced more frequent immune-mediated rejections of CT26 and MC38 murine tumors than anti-PD-1 alone. In both types of tumors, the activity of anti-GARP:TGF-β1 mAbs resulted from blocking active TGF-β1 production and immunosuppression by GARP-expressing regulatory T cells. In CT26 tumors, combined GARP:TGF-β1/PD-1 blockade did not augment the infiltration of T cells, but did increase the effector functions of already present anti-tumor T cells. Here we show that, in contrast, in MC38, combined GARP:TGF-β1/PD-1 blockade increased infiltration of T cells, as a result of increased extravasation of T cells from blood vessels. Unexpectedly, combined GARP:TGF-β1/PD-1 blockade also increased the density of GARP + blood vessels covered by pericytes in MC38, but not in CT26 tumors. This appears to occur because anti-GARP:TGF-β1, by blocking TGF-β1 signals, favors the proliferation of and expression of adhesion molecules such as E-selectin by blood endothelial cells. The resulting densification of intratumoral blood vasculature probably contributes to increased T cell infiltration and to the therapeutic efficacy of GARP:TGF-β1/PD-1 blockade in MC38. We conclude from these distinct observations in MC38 and CT26, that the combined blockades of GARP:TGF-β1 and PD-1 can exert anti-tumor activity via multiple mechanisms, including the densification and normalization of intratumoral blood vasculature, the increase of T cell infiltration into the tumor and the increase of the effector functions of intratumoral tumor-specific T cells. This may prove important for the selection of cancer patients who could benefit from combined GARP:TGF-β1/PD-1 blockade in the clinics.

Several types of cancer spread through the lymphatic system via the sentinel lymph nodes (LNs). Such LN-draining primary tumors, modified by tumor factors, lead to the formation of a metastatic niche associated with an increased number of Foxp3+ regulatory T cells (Tregs). These cells are expected to contribute to the elaboration of an immune-suppressive environment. Activated Tregs express glycoprotein A repetitions predominant (GARP), which binds and presents latent transforming growth factor beta 1 (TGF-β1) at their surface. GARP is also expressed by other non-immune cell types poorly described in LNs. Here, we mapped GARP expression in non-immune cells in human and mouse metastatic LNs. The mining of available (human and murine) scRNA-Seq datasets revealed GARP expression by blood (BEC)/lymphatic (LEC) endothelial, fibroblastic, and perivascular cells. Consistently, through immunostaining and in situ RNA hybridization approaches, GARP was detected in and around blood and lymphatic vessels, in (αSMA+) fibroblasts, and in perivascular cells associated with an abundant matrix. Strikingly, GARP was detected in LECs forming the subcapsular sinus and high endothelial venules (HEVs), two vascular structures localized at the interface between LNs and the afferent lymphatic and blood vessels. Altogether, we here provide the first distribution maps for GARP in human and murine LNs.