Comparison of transcatheter versus surgical aortic valve implantation in high-risk patients : a nationwide study in France

Objective To compare the clinical outcomes and direct costs at 5 years between transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) using real-world evidence. Methods We performed a nationwide longitudinal study using data from the French Hospital Information System from 2009 to 2015. We matched, inside hospitals, 2 cohorts of adults who underwent TAVI or SAVR during 2010 on propensity score based on patient characteristics. Outcomes analysis included mortality, morbidity, and total costs and with a maximum 60-month follow-up. Clinical outcomes were compared between cohorts using hazard ratios (HRs) estimated from a Cox proportional hazards model for all-cause death, and from Fine and Gray's competing risk model for morbidity. Results Based on a cohort of 1598 patients (799 in each group) from 27 centers, a higher risk of death was observed after 1 year with TAVI compared with SAVR (16.8% vs 12.8%, respectively; HR, 1.33; 95% confidence interval [CI], 1.02-1.72) and was sustained up to 5 years (52.4% vs 37.2%; HR, 1.56; 95% CI, 1.33-1.84). At 5 years, the risk of stroke was increased (HR, 1.64; 95% CI, 1.07-2.54) as was myocardial infarction (HR, 2.30; 95% CI, 1.12-4.69) and pacemaker implantation (HR, 2.40; 95% CI, 1.81-3.17) after TAVI. The hospitalization costs per patient at 5 years were €69,083 after TAVI and €55,687 after SAVR (P < .001). Conclusions In our study, high-risk patients harbored a greater risk of mortality and morbidity at 5 years after TAVI compared with those who underwent SAVR and higher hospitalizations costs. Those results should encourage caution before expanding the indications of TAVI

Combining the hospital frailty risk score with the Charlson and Elixhauser multimorbidity indices to identify older patients at risk of poor outcomes in acute care

Objective: The Hospital Frailty Risk Score (HFRS) can be applied to medico-administrative datasets to determine the risks of 30-day mortality and long length of stay (LOS) in hospitalized older patients. The objective of this study was to compare the HFRS with Charlson and Elixhauser comorbidity indices, used separately or combined. Design: A retrospective analysis of the French medical information database. The HFRS, Charlson index, and Elixhauser index were calculated for each patient based on the index stay and hospitalizations over the preceding 2 years. Different constructions of the HFRS were considered based on overlapping diagnostic codes with either Charlson or Elixhauser indices. We used mixed logistic regression models to investigate the association between outcomes, different constructions of HFRS, and associations with comorbidity indices. Setting: 743 hospitals in France. Participants: All patients aged 75 years or older hospitalized as an emergency in 2017 (n=1,042,234). Main outcome measures: 30-day inpatient mortality and LOS >10 days. Results: The HFRS, Charlson, and Elixhauser indices were comparably associated with an increased risk of 30-day inpatient mortality and long LOS. The combined model with the highest c-statistic was obtained when associating the HFRS with standard adjustment and Charlson for 30-day inpatient mortality (adjusted c-statistics: HFRS=0.654; HFRS + Charlson = 0.676) and with Elixhauser for long LOS (adjusted c-statistics: HFRS= 0.672; HFRS + Elixhauser =0.698). Conclusions: Combining comorbidity indices and HFRS may improve discrimination for predicting long LOS in hospitalized older people, but adds little to Charlson’s 30-day inpatient mortality risk

Increased Mortality for Elective Surgery during Summer Vacation: a Longitudinal Analysis of Nationwide Data

Surgical safety during vacation periods may be influenced by the interplay of several factors, including workers' leave, hospital activity, climate, and the variety of patient cases. This study aimed to highlight an annually recurring peak of surgical mortality during summer in France and explore its main predictors. We selected all elective of open surgical procedures performed in French hospitals between 2007 and 2012. Surgical mortality variation was analyzed over time in relation to workers leaving on vacation, the volume of procedures performed by hospitals, and temperature changes. We ran a multilevel logistic regression for exploring the determinants of surgical mortality, taking into account the clustering of patients within hospitals and adjusting for patient and hospital characteristics. A total of 609 French hospitals had 8,926,120 discharges related to open elective surgery. During 6 years, we found a recurring mortality peak of 1.15% (95% CI 1.09-1.20) in August compared with 0.81% (0.79-0.82, p<.001) in other months. The incidence of worker vacation was 43.0% (38.9-47.2) in August compared with 7.3% (4.6-10.1, p<.001) in other months. Hospital activity decreased substantially in August (78,126 inpatient stays, 75,298-80,954) in relation to other months (128,142, 125,697–130,586, p<.001). After adjusting for all covariates, we found an "August effect" reflecting a higher risk to patients undergoing operations at this time (OR 1.16, 95% CI 1.12-1.19, p<.001). The main study limitation was the absence of data linkage between surgical staffing and mortality at the hospital level. The observed, recurring mortality peak in August raises questions about how to maintain hospital activity and optimal staffing through better regulation of human activities

External validation of the Hospital Frailty Risk Score in France

BACKGROUND: The Hospital Frailty Risk Score (HFRS) has made it possible internationally to identify subgroups of patients with characteristics of frailty from routinely collected hospital data. OBJECTIVE: To externally validate the HFRS in France. DESIGN: A retrospective analysis of the French medical information database. SETTING: 743 hospitals in Metropolitan France. SUBJECTS: All patients aged 75 years or older hospitalised as an emergency in 2017 (n = 1,042,234). METHODS: The HFRS was calculated for each patient based on the index stay and hospitalisations over the preceding 2 years. Main outcome measures were 30-day in-patient mortality, length of stay (LOS) >10 days and 30-day readmissions. Mixed logistic regression models were used to investigate the association between outcomes and HFRS score. RESULTS: Patients with high HFRS risk were associated with increased risk of mortality and prolonged LOS (adjusted odds ratio [aOR] = 1.38 [1.35-1.42] and 3.27 [3.22-3.32], c-statistics = 0.676 and 0.684, respectively), while it appeared less predictive of readmissions (aOR = 1.00 [0.98-1.02], c-statistic = 0.600). Model calibration was excellent. Restricting the score to data prior to index admission reduced discrimination of HFRS substantially. CONCLUSIONS: HFRS can be used in France to determine risks of 30-day in-patient mortality and prolonged LOS, but not 30-day readmissions. Trial registration: Reference ID on clinicaltrials.gov: ID: NCT03905629

The Relations of Children’s Dispositional Prosocial Behavior to Emotionality, Regulation, and Social Functioning

The purpose of this study was to examine the relations of a measure of children’s dispositional prosocial behavior (i.e., peer nominations) to individual differences in children’s negative emotionality, regulation, and social functioning. Children with prosocial reputations tended to be high in constructive social skills (i.e., socially appropriate behavior and constructive coping) and attentional regulation, and low in negative emotionality. The relations of children’s negative emotionality to prosocial reputation were moderated by level of dispositional attentional regulation. In addition, the relations of prosocial reputation to constructive social skills and parent-reported negative emotionality (for girls) increased with age. Vagal tone, a marker of physiological regulation, was negatively related to girls’ prosocial reputation

Cronobacter sakazakii clinical isolates overcome host barriers and evade the immune response

Cronobacter sakazakii is the most frequently clinically isolated species of the Cronobacter genus. However the virulence factors of C. sakazakii including their ability to overcome host barriers remains poorly studied. In this study, ten clinical isolates of C. sakazakii were assessed for their ability to invade and translocate through human microvascular endothelial cells (HBMEC). Their ability to avoid phagocytosis in human macrophages U937 and human brain microglial cells was investigated. Additionally, they were tested for serum sensitivity and the presence of the Cronobacter plasminogen activation gene (cpa) gene, which is reported to confer serum resistance. Our data showed that the clinical C. sakazakii strains invaded and translocated through Caco-2 and HBMEC cell lines and some strains showed significantly higher levels of invasion and translocation. Moreover, C. sakazakii was able to persist and even multiply in phagocytic macrophage and microglial cells. All strains, except one, were able to withstand human serum exposure, the single serum sensitive strain was also the only one which did not encode for the cpa gene. These results demonstrate that C. sakazakii clinical host immune response indicating their capacity to cause diseases such as necrotizing enterocolitis (NEC) and meningitis. Our data showed for the first time the ability of C. sakazakii clinical isolates to survive and multiply within human microglial cells. Additionally, it was shown that C. sakazakii clinical strains have the capacity to translocate through the Caco-2 and HBMEC cell lines paracellularly

Extracellular signal-regulated kinase 2 has duality in function between neuronal and astrocyte expression following neonatal hypoxic-ischaemic cerebral injury

Hypoxia–ischaemia (HI) is a major cause of neonatal brain injury resulting in cerebral palsy, epilepsy, cognitive impairment and other neurological disabilities. The role of extracellular signal‐regulated kinase (ERK) isoforms and their mitogen‐activated protein kinase kinase (MEK)‐dependent phosphorylation in HI has previously been explored but remains unresolved at cellular level. This is pertinent given the growing awareness of the role of non‐neuronal cells in neuroprotection. Using a modified Rice–Vannucci model of HI in the neonatal mouse we observed time‐ and cell‐dependent ERK phosphorylation (pERK), with strongly up‐regulated pERK immunoreactivity first in periventricular white matter axons within 15–45 min of HI, followed by forebrain astrocytes and neurons (1–4 h post‐HI), and return to baseline by 16 h. We explored the effects of pharmacological ERK blockade through the MEK inhibitor SL327 on neonatal HI‐brain damage following HI alone (30 or 60 min) or lipopolysaccharide (LPS)‐sensitised HI insult (30 min). Global inhibition of ERK phosphorylation with systemically applied SL327 abolished forebrain pERK immunoreactivity, and significantly reduced cell death and associated microglial activation at 48 h post‐HI. We then explored the effects of cell‐specific ERK2 deletion alone or in combination with global ERK1 knockout under the same conditions of HI insult. Neuronal ERK2 deletion strongly decreased infarct size, neuronal cell death and microglial activation in grey matter following both HI alone or LPS‐sensitised HI. ERK1 deletion attenuated the protective effect of neuronal ERK2 deletion. Removal of astroglial ERK2 produced a reverse response, with a 3‐ to 4‐fold increase in microglial activation and cell death. Our data suggest a cell‐specific and time‐dependent role of ERK in neonatal HI, with a predominant, neurotoxic effect of neuronal ERK2, which is counteracted by neuroprotection by ERK1 and astrocytic ERK2. Overall, global pharmacological inhibition of ERK phosphorylation is strongly neuroprotective

Inhibition of neuroinflammation in BV2 microglia by the biflavonoid kolaviron is dependent on the Nrf2/ARE antioxidant protective mechanism

Kolaviron is a mixture of bioflavonoids found in the nut of the West African edible seed Garcinia kola, and it has been reported to exhibit a wide range of pharmacological activities. In this study, we investigated the effects of kolaviron in neuroinflammation. The effects of kolaviron on the expression of nitric oxide/inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE2)/cyclooxygenase-2, cellular reactive oxygen species (ROS) and the pro-inflammatory cytokines were examined in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Molecular mechanisms of the effects of kolaviron on NF-B and Nrf2/ARE signalling pathways were analysed by immunoblotting, binding assay, and reporter assay. RNA interference was used to investigate the role of Nrf2 in the anti-inflammatory effect of kolaviron. Neuroprotective effect of kolaviron was assessed in a BV2 microglia/HT22 hippocampal neuron co-culture. Kolaviron inhibited the protein levels of NO/iNOS, PGE2/COX-2, cellular ROS and the proinflammatory cytokines (TNFα and IL-6) in LPS-stimulated microglia. Further mechanistic studies showed that kolaviron inhibited neuroinflammation by inhibiting IB/NF-B signalling pathway in LPS-activated BV2 microglia. Kolaviron produced antioxidant effect in BV2 microglia by increasing HO-1 via the Nrf2/ antioxidant response element (ARE) pathway. RNAi experiments revealed that Nrf2 is need for the anti-inflammatory effect of kolaviron. Kolaviron protected HT22 neurons from neuroinflammation-induced toxicity. Kolaviron inhibits neuroinflammation through Nrf2-dependent mechanisms. This compound may therefore be beneficial in neuroinflammation-related neurodegenerative disorders

Acute effects of systemic inflammation upon the neuro-glial-vascular unit and cerebrovascular function

Brain health relies on a tightly regulated system known as neurovascular coupling whereby the cellular constituents of the neuro-glial-vascular unit (NGVU) regulate cerebral haemodynamics in accordance with brain metabolic demand. Disruption of neurovascular coupling impairs brain health and is associated with the development of a number for neurological conditions, including Alzheimer’s disease. The NGVU is also a key site of action for neuroinflammatory responses and contributes to the transition of systemic inflammation to neuroinflammatory processes. Thus, systemic inflammatory challenges may cause a shift in NGVU operation towards prioritising neuroinflammatory action and thus altering neurovascular coupling and resultant cerebrovascular changes. To investigate this, rats were injected with lipopolysaccharide (LPS) (2 ​mg/kg) to induce a systemic inflammatory response, or vehicle, and brain haemodynamic responses to sensory and non-sensory (hypercapnia) stimuli were assessed in vivo using optical imaging techniques. Following imaging, animals were perfused and their brains extracted to histologically characterise components of the NGVU to determine the association between underlying cellular changes and in vivo blood flow regulation. LPS-treated animals showed changes in haemodynamic function and cerebrovascular dynamics 6 ​hours after LPS administration. Histological assessment identified a significant increase in astrogliosis, microgliosis and endothelial activation in LPS-treated animals. Our data shows that an acutely induced systemic inflammatory response is able to rapidly alter in vivo haemodynamic function and is associated with significant changes in the cellular constituents of the NGVU. We suggest that these effects are initially mediated by endothelial cells, which are directly exposed to the circulating inflammatory stimulus and have been implicated in regulating functional hyperaemia

Microglia activation in a model of retinal degeneration and TUDCA neuroprotective effects

Background: Retinitis pigmentosa is a heterogeneous group of inherited neurodegenerative retinal disorders characterized by a progressive peripheral vision loss and night vision difficulties, subsequently leading to central vision impairment. Chronic microglia activation is associated with various neurodegenerative diseases including retinitis pigmentosa. The objective of this study was to quantify microglia activation in the retina of P23H rats, an animal model of retinitis pigmentosa, and to evaluate the therapeutic effects of TUDCA (tauroursodeoxycholic acid), which has been described as a neuroprotective compound. Methods: For this study, homozygous P23H line 3 and Sprague-Dawley (SD) rats were injected weekly with TUDCA (500 mg/kg, ip) or vehicle (saline) from 20 days to 4 months old. Vertical retinal sections and whole-mount retinas were immunostained for specific markers of microglial cells (anti-CD11b, anti-Iba1 and anti-MHC-II). Microglial cell morphology was analyzed and the number of retinal microglial was quantified. Results: Microglial cells in the SD rat retinas were arranged in regular mosaics homogenously distributed within the plexiform and ganglion cell layers. In the P23H rat retina, microglial cells increased in number in all layers compared with control SD rat retinas, preserving the regular mosaic distribution. In addition, a large number of amoeboid CD11b-positive cells were observed in the P23H rat retina, even in the subretinal space. Retinas of TUDCA-treated P23H animals exhibited lower microglial cell number in all layers and absence of microglial cells in the subretinal space. Conclusions: These results report novel TUDCA anti-inflammatory actions, with potential therapeutic implications for neurodegenerative diseases, including retinitis pigmentosa.This research was supported by grants from the Spanish Ministry of Economy and Competitiveness-FEDER (BFU2012-36845), Instituto de Salud Carlos III (RETICS RD12/0034/0010), Organización Nacional de Ciegos Españoles (ONCE), FUNDALUCE, Asociación Retina Asturias and Fundación Jesús de Gangoiti