Nucleotide-Binding Oligomerization Domain 1 (NOD1) Agonists Prevent SARS-CoV-2 Infection in Human Lung Epithelial Cells through Harnessing the Innate Immune Response.

The lung is prone to infections from respiratory viruses such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). A challenge in combating these infections is the difficulty in targeting antiviral activity directly at the lung mucosal tract. Boosting the capability of the respiratory mucosa to trigger a potent immune response at the onset of infection could serve as a potential strategy for managing respiratory infections. This study focused on screening immunomodulators to enhance innate immune response in lung epithelial and immune cell models. Through testing various subfamilies and pathways of pattern recognition receptors (PRRs), the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family was found to selectively activate innate immunity in lung epithelial cells. Activation of NOD1 and dual NOD1/2 by the agonists TriDAP and M-TriDAP, respectively, increased the number of IL-8+ cells by engaging the NF-κB and interferon response pathways. Lung epithelial cells showed a stronger response to NOD1 and dual NOD1/2 agonists compared to control. Interestingly, a less-pronounced response to NOD1 agonists was noted in PBMCs, indicating a tissue-specific effect of NOD1 in lung epithelial cells without inducing widespread systemic activation. The specificity of the NOD agonist pathway was confirmed through gene silencing of NOD1 (siRNA) and selective NOD1 and dual NOD1/2 inhibitors in lung epithelial cells. Ultimately, activation induced by NOD1 and dual NOD1/2 agonists created an antiviral environment that hindered SARS-CoV-2 replication in vitro in lung epithelial cells.

Spanish translation, cultural adaptation and validation of the SarQoL®: a specific health-related quality of life questionnaire for sarcopenia.

BACKGROUND: In 2015, a specific health-related quality of life questionnaire for sarcopenia, SarQoL®, was developed and validated in French. Since then, SarQoL® has been adapted and validated in different languages. We prepared a translation, cultural adaptation and validation of the psychometric properties of the SarQoL® into Spanish. METHODS: A cross-sectional study with 86 participants. The translation and adaptation followed international guidelines with two direct translations, a synthesized version of the direct translations, two reverse translations, consensus by an expert committee of a pre-final version, pre-test by end users and final version. The discriminative power (logistic regression analyses), construct validity (Pearson and Spearman´s correlation), internal consistency (Cronbach´s alpha coefficient), test-retest reliability (intraclass correlation coefficient) and ceiling and floor effects were analyzed. RESULTS: The Spanish version showed good construct validity (high correlation with comparable domains of the SF-36), high internal consistency (Cronbach's alpha coefficient: 0.84) and excellent test-retest reliability (ICC: 0.967, 95%, CI 0.917 - 0.989). However, it had no discriminative power between sarcopenic and non-sarcopenic participants defined with the EWGSOP and FNIH diagnostic criteria of sarcopenia. It did show discriminative power between patients with decreased vs normal muscle strength (54.9 vs. 62.6, p 0.009) and low vs. normal physical performance (57.3 vs. 70.2; p 0.005). No ceiling or floor effect was found. CONCLUSIONS: The Spanish version of SarQoL® has similar psychometric properties to those of the original version of the instrument. It did not discriminate between sarcopenic and non-sarcopenic patients diagnosed according to the EWGSOP or FNIH criteria, but it did with those with low muscle strength and low physical performance.

Oropharyngeal dysphagia in older patients with hip fracture.

BACKGROUND: oropharyngeal dysphagia (OD) and hip fracture are common problems in older patients, both associated with important complications. OBJECTIVE: the aim of this study was to measure the prevalence and identify the main risk factors of dysphagia in older patients with hip fracture. DESIGN: a prospective study in an orthogeriatric unit of a university hospital over 10 months. METHODS: a total of 320 patients (mean age 86.2 years, 73.4% women) were assessed for dysphagia within 72 hours post-surgery using the Volume-Viscosity Swallow Test. Geriatric assessment, hip fracture management and complications were examined to determine their relationship with the presence of OD. RESULTS: dysphagia was present in 176 (55%) patients. Multivariate logistic regression analysis showed that the presence of delirium during hospitalization and the inability to perform instrumental activities of daily living before admission were associated with OD. CONCLUSIONS: the prevalence of OD is high in hip fracture patients. Objective dysphagia assessment should be routinely included as part of the geriatric assessment of such patients.

Clinical value of procalcitonin in critically ill patients infected by SARS-CoV-2.

Background Blood procalcitonin (PCT) levels usually increase during infectious diseases and might be helpful to differentiate bacterial from non-bacterial origin. COVID-19 patients could present co-infections at initial presentation in the Emergency Department and nosocomial infections during stay in the ICU. However, the published literature has not established whether PCT changes could aid in the diagnosis of infectious complication during the COVID-19 pandemic. Methods Retrospective, single-center, cohort study, including COVID-19 patients admitted between March and May 2020. The data were prospectively collected for department purposes; laboratory results were collected automatically at admission and during the whole patient admission. Results 56 patients were analyzed (female 32%, male 68%), 35 were admitted to ICU, and 21 received general ward care. 21 ICU patients underwent mechanical ventilation (88%), and 9 died during admission (26%). Non-survivors had higher initial blood PCT levels than survivors at ICU admission (p.

The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.

BACKGROUND & AIMS: Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF. METHODS: A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. RESULTS: Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). CONCLUSIONS: Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. CLINICALTRIALS. GOV NUMBER: NCT03056612. LAY SUMMARY: Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death - termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD - patients in this group rarely require hospital admission and have a much lower 1-year mortality risk.

Rebleeding and mortality risk are increased by ACLF but reduced by pre-emptive TIPS.

BACKGROUND & AIMS: The relationship between acute-on-chronic liver failure (ACLF) and acute variceal bleeding (AVB) is poorly understood. Specifically, the prevalence and prognosis of ACLF in the context of AVB is unclear, while the role of transjugular intrahepatic portosystemic shunt (TIPS) in the management in patients with ACLF has not been described to date. METHODS: A multicenter, international, observational study was conducted in 2,138 patients from 34 centers between 2011 and 2015. ACLF was defined and graded according to the EASL-CLIF consortium definition. Placement of pre-emptive TIPS (pTIPS) was based on individual center policy. Patients were followed-up for 1 year, until death or liver transplantation. Cox regression and competing risk models (Gray's test) were used to identify independent predictors of rebleeding or mortality. RESULTS: At admission, 380/2,138 (17.8%) patients had ACLF according to EASL-CLIF criteria (grade 1: 38.7%; grade 2: 39.2%; grade 3: 22.1%). The 42-day rebleeding (19% vs. 10%; p <0.001) and mortality (47% vs. 10%; p <0.001) rates were higher in patients with ACLF and increased with ACLF grades. Of note, the presence of ACLF was independently associated with rebleeding and mortality. pTIPS placement improved survival in patients with ACLF at 42 days and 1 year. This effect was also observed in propensity score matching analysis of 66 patients with ACLF, of whom 44 received pTIPs and 22 did not. CONCLUSIONS: This large multicenter international real-life study identified ACLF at admission as an independent predictor of rebleeding and mortality in patients with AVB. Moreover, pTIPS was associated with improved survival in patients with ACLF and AVB. LAY SUMMARY: Acute variceal bleeding is a deadly complication of liver cirrhosis that results from severe portal hypertension. This study demonstrates that the presence of acute-on-chronic liver failure (ACLF) is the strongest predictor of mortality in patients with acute variceal bleeding. Importantly, patients with ACLF and acute variceal (re)bleeding benefit from pre-emptive (early) placement of a transjugular intrahepatic portosystemic shunt.

Efficacy of Albumin Treatment for Patients with Cirrhosis and Infections Unrelated to Spontaneous Bacterial Peritonitis.

BACKGROUND & AIMS: We performed a randomized trial to determine whether albumin should be administered to patients with infections unrelated to spontaneous bacterial peritonitis (SBP). METHODS: We performed a multicenter, open-label trial in which 118 patients with cirrhosis, non-SBP infections, and additional risk factors for poor outcome were randomly assigned to receive antibiotics plus albumin (study group; n = 61) or antibiotics alone (control group; n = 57). The primary outcome was in-hospital mortality; secondary outcomes were effect of albumin on disease course. RESULTS: There were no significant differences at baseline between groups in results from standard laboratory tests, serum markers of inflammation, circulatory dysfunction, or liver severity scores. However, the combined prevalence of acute on chronic liver failure (ACLF) and kidney dysfunction was significantly higher in the study group (44.3% vs 24.6% in the control group; P = .02), indicating greater baseline overall severity. There was no significant difference in the primary outcome between groups (13.1% in the study group vs 10.5% in the control group; P = .66). Circulatory and renal functions improved in only the study group. A significantly higher proportion of patients in the study group had resolution of ACLF (82.3% vs 33.3% in the control group; P = .03). A significantly lower proportion of patients in the study group developed nosocomial infections (6.6% vs 24.6% in the control group; P = .007). CONCLUSIONS: In a randomized trial of patients with advanced cirrhosis and non-SBP infections, in-hospital mortality was similar between those who received albumin plus antibiotics vs those who received only antibiotics (controls). However, patients given albumin were sicker at baseline and, during the follow-up period, a higher proportion had ACLF resolution and a lower proportion had nosocomial infections. ClinicalTrials.gov no: NCT02034279.

The impact of frailty in aortic valve surgery.

BACKGROUND: Frailty is a geriatric syndrome that diminishes potential functional recovery after any surgical procedure. Preoperative surgical risk assessment is crucial to calibrate the risk and benefit of cardiac surgery. The aim of this study was to test usefulness of FRAIL Scale and other surgical-risk-scales and individual features of frailty in cardiac aortic valve surgery. METHODS: Prospective study. From May-2014 to February-2016, we collected 200 patients who underwent aortic valve replacement, either surgically or transcatheter. At 1-year follow-up, quality of life measurements were recorded using the EQ-5D (EuroQol). Univariate and multivariate analyses correlated preoperative condition, features of frailty and predicted risk scores with mortality, morbidity and quality of life at 1 year of follow-up. RESULTS: Mean age 78.2y, 56%male. Mean-preoperative-scores: FRAIL scale 1.5(SD 1.02), STS 2.9(SD 1.13), BI 93.8(SD 7.3), ESlog I 12.8(SD 8.5) and GS 7.3 s (SD 1.9). Morbidity at discharge, 6 m and 1 year was 51, 14 and 28%. Mortality 4%. Survival at 6 m/ 1-y was 97% / 88%. Complication-rate was higher in TAVI group due to-vascular complications. Renal dysfunction, anemia, social dependence and GS slower than 7 s were associated with morbidity. On multivariate analysis adjusted STS, BI and GS speed were statistically significant. Quality of life at 1-year follow-up adjusted for age and prosthesis type showed a significant association with STS and FRAIL scale scores. CONCLUSIONS: Frailty increases surgical risk and is associated with higher morbidity. Preoperative GS slower 7 s, and STS and FRAIL scale scores seem to be reliable predictors of quality of life at 1-year follow-up.

Multidrug-resistant bacterial infections in patients with decompensated cirrhosis and with acute-on-chronic liver failure in Europe.

BACKGROUND & AIMS: Antibiotic resistance has been increasingly reported in patients with decompensated cirrhosis in single-center studies. Prospective investigations reporting broad epidemiological data are scarce. We aimed to analyze epidemiological changes in bacterial infections in patients with decompensated cirrhosis. METHODS: This was a prospective evaluation of 2 series of patients hospitalized with decompensated cirrhosis. The Canonic series included 1,146 patients from Northern, Southern and Western Europe in 2011. Data on epidemiology, clinical characteristics of bacterial infections, microbiology and empirical antibiotic schedules were assessed. A second series of 883 patients from Eastern, Southern and Western Europe was investigated between 2017-2018. RESULTS: A total of 455 patients developed 520 infections (39.7%) in the first series, with spontaneous bacterial peritonitis, urinary tract infections and pneumonia the most frequent infections. Nosocomial episodes predominated in this series. Nearly half of the infections were culture-positive, of which 29.2% were caused by multidrug-resistant organisms (MDROs). MDR strains were more frequently isolated in Northern and Western Europe. Extended-spectrum beta-lactamase-producing Enterobacteriaceae were the most frequent MDROs isolated in this series, although prevalence and type differed markedly among countries and centers. Antibiotic resistance was associated with poor prognosis and failure of antibiotic strategies, based on third-generation cephalosporins or quinolones. Nosocomial infection (odds ratio [OR] 2.74; p < 0.001), intensive care unit admission (OR 2.09; p = 0.02), and recent hospitalization (OR 1.93; p = 0.04) were identified as independent predictors of MDR infection. The prevalence of MDROs in the second series (392 infections/284 patients) was 23%; 38% in culture-positive infections. A mild increase in the rate of carbapenem-resistant Enterobacteriaceae was observed in this series. CONCLUSIONS: MDR bacterial infections constitute a prevalent, growing and complex healthcare problem in patients with decompensated cirrhosis and acute-on-chronic liver failure across Europe, negatively impacting on prognosis. Strategies aimed at preventing the spread of antibiotic resistance in cirrhosis should be urgently evaluated. LAY SUMMARY: Infections caused by bacteria resistant to the main antibiotic families are prevalent in patients with cirrhosis. This study demonstrates that this healthcare problem is increasing and extends through all European regions. Infections caused by these difficult to treat bacteria resolve less frequently and often cause the death of the patient. The type of resistant bacteria varies markedly among different hospitals.

Plasma cystatin C is a predictor of renal dysfunction, acute-on-chronic liver failure, and mortality in patients with acutely decompensated liver cirrhosis.

The development of acute-on-chronic liver failure (ACLF) in patients with liver cirrhosis is associated with high mortality rates. Renal failure is the most significant organ dysfunction that occurs in ACLF. So far there are no biomarkers predicting ACLF. We investigated whether cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) can predict development of renal dysfunction (RD), hepatorenal syndrome (HRS), ACLF, and mortality. We determined the plasma levels of CysC and NGAL in 429 patients hospitalized for acute decompensation of cirrhosis in the EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study. The patients were followed for 90 days. Patients without RD or ACLF at inclusion but with development of either had significantly higher baseline concentrations of CysC and NGAL compared to patients without. CysC, but not NGAL, was found to be predictive of RD (odds ratio, 9.4; 95% confidence interval [CI], 1.8-49.7), HRS (odds ratio, 4.2; 95% CI, 1.2-14.8), and ACLF (odds ratio, 5.9; 95% CI, 1.3-25.9). CysC at day 3 was not found to be a better predictor than baseline CysC. CysC and NGAL were both predictive of 90-day mortality, with hazard ratios for CysC of 3.1 (95% CI, 2.1-4.7) and for NGAL of 1.9 (95% CI, 1.5-2.4). CONCLUSION: Baseline CysC is a biomarker of RD, HRS, and ACLF and an independent predictor of mortality in patients with acutely decompensated liver cirrhosis, though determining CysC at day 3 did not provide any benefit; while NGAL is also associated with short-term mortality, it fails to predict development of RD, HRS, and ACLF. Baseline CysC may help to identify patients at risk earlier and improve clinical management. (Hepatology 2017;66:1232-1241).

Assessment of dry eye in a GVHD murine model: Approximation through tear osmolarity measurement.

Dry eye disease is one of the most frequent pathological events that take place in the course of the graft versus host disease (GVHD), and is the main cause of deterioration in quality of life for patients. Thus, demonstration of dry eye signs in murine models of oGVHD is crucial for the validation of these models for the study of the disease. Given the increasing evidence that tear osmolarity is an important player of dry eye disease, our purpose in this study was to validate the use of a reliable method to assess tear osmolarity in mice: the electrical impedance method. Then, we wanted to test its utility with an oGVHD model. Tear volume assessment was also performed, using the phenol red thread test. We found differences in tear osmolarity in mice that received a transplant with cells from bone marrow and spleen (the GVHD group) when compared with mice that only received bone marrow cells (the BM group) at day 7 (362 ± 8 mOsm/l and 345 ± 9 mOsm/l respectively; P < 0.01) and day 21 (348 ± 19 mOsm/l vs. 326 ± 15 mOsm/l; P < 0.05). We found also differences in tear volume at day 14 (2.30 ± 0.61 mm in oGVHD group and 2.89 ± 0.62 mm in BM group; P = 0.06) and at day 21 (2.10 ± 0.30 mm in oGVHD group and 2.89 ± 0.32 mm in BM group; P < 0.01). Besides this, we observed reduction in epithelial thickness between the GVHD and BM groups (37.0 ± 6.2 µm and 43.6 ± 3.3 µm respectively; P < 0.05). These data show the usefulness of the electrical impedance method to measure tear osmolarity in mice. We can also conclude that this oGVHD model mimics the tear film alterations found in human dry eye disease, what contributes to give relevance to this model for the study of GVHD.

Manganese redistribution by calcium-stimulated vesicle trafficking bypasses the need for P-type ATPase function.

Regulation of intracellular ion homeostasis is essential for eukaryotic cell physiology. An example is provided by loss of ATP2C1 function, which leads to skin ulceration, improper keratinocyte adhesion, and cancer formation in Hailey-Hailey patients. The yeast ATP2C1 orthologue PMR1 codes for a Mn(2+)/Ca(2+) transporter that is crucial for cis-Golgi manganese supply. Here, we present evidence that calcium overcomes the lack of Pmr1 through vesicle trafficking-stimulated manganese delivery and requires the endoplasmic reticulum Mn(2+) transporter Spf1 and the late endosome/trans-Golgi Nramp metal transporter Smf2. Smf2 co-localizes with the putative Mn(2+) transporter Atx2, and ATX2 overexpression counteracts the beneficial impact of calcium treatment. Our findings suggest that vesicle trafficking promotes organelle-specific ion interchange and cytoplasmic metal detoxification independent of calcineurin signaling or metal transporter re-localization. Our study identifies an alternative mode for cis-Golgi manganese supply in yeast and provides new perspectives for Hailey-Hailey disease treatment.

Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure (ACLF).

BACKGROUND & AIMS: Activation of liver macrophages plays a key role in liver and systemic inflammation and may be involved in development and prognosis of acute-on-chronic liver failure (ACLF). We therefore measured the circulating macrophage activation markers soluble sCD163 and mannose receptor (sMR) and related them to the short-(1-3 months) and long-term (6 months) mortality in the cirrhosis patients of the CANONIC study. METHODS: Eighty-six cirrhosis patients had no ascites and no ACLF, 580 had ascites but no ACLF; 100, 66, and 19 had ACLF-grade-I (ACLF-I), ACLF-II, and ACLF-III, respectively. The patients' clinical course was registered and their MELD, CLIF-C Acute Decompensation (AD), and CLIF-C ACLF-scores computed at inclusion. RESULTS: We found a stepwise increase (p<0.001) in median sCD163 (5.68 (IQR: 3.86-9.60); 8.26 (5.02-12.34); 9.50 (5.37-17.91); 15.68 (10.12-19.42); 20.18 (15.26-32.20) mg/L) and sMR (0.60 (0.40-0.84); 0.81 (0.57-1.12); 0.81 (0.61-1.26); 1.17 (0.89-1.62); 1.41 (1.14-1.79)mg/L) with increasing grades of ACLF. Both sCD163 and sMR were independently associated with short and long-term mortality and showed equal or higher predictive accuracy than MELD, CLIF-C ACLF and CLIF-C AD scores. Addition of the macrophage markers to the clinical scores improved the prognostic efficacy: In ACLF patients sCD163 improved prediction of short-term mortality (C-index: 0.74 (0.67-0.80)) and in patients without ACLF sMR improved prediction of long-term mortality (C-index: 0.80 (0.76-0.85)). CONCLUSIONS: The severity related increase in sCD163 and sMR and close association with mortality suggest a primary importance of inflammatory activation of liver macrophages in the emergence and course of ACLF. Accordingly, supplementation of the macrophage biomarkers to the platform of the clinical scores improved the prognostic performance beyond that of the original scores.

Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.

UNLABELLED: Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis, organ failure(s), and high 28-day mortality. We investigated whether assessments of patients at specific time points predicted their need for liver transplantation (LT) or the potential futility of their care. We assessed clinical courses of 388 patients who had ACLF at enrollment, from February through September 2011, or during early (28-day) follow-up of the prospective multicenter European Chronic Liver Failure (CLIF) ACLF in Cirrhosis study. We assessed ACLF grades at different time points to define disease resolution, improvement, worsening, or steady or fluctuating course. ACLF resolved or improved in 49.2%, had a steady or fluctuating course in 30.4%, and worsened in 20.4%. The 28-day transplant-free mortality was low-to-moderate (6%-18%) in patients with nonsevere early course (final no ACLF or ACLF-1) and high-to-very high (42%-92%) in those with severe early course (final ACLF-2 or -3) independently of initial grades. Independent predictors of course severity were CLIF Consortium ACLF score (CLIF-C ACLFs) and presence of liver failure (total bilirubin ≥12 mg/dL) at ACLF diagnosis. Eighty-one percent had their final ACLF grade at 1 week, resulting in accurate prediction of short- (28-day) and mid-term (90-day) mortality by ACLF grade at 3-7 days. Among patients that underwent early LT, 75% survived for at least 1 year. Among patients with ≥4 organ failures, or CLIF-C ACLFs >64 at days 3-7 days, and did not undergo LT, mortality was 100% by 28 days. CONCLUSIONS: Assessment of ACLF patients at 3-7 days of the syndrome provides a tool to define the emergency of LT and a rational basis for intensive care discontinuation owing to futility.

Carotenoids exclusively synthesized in red pepper (capsanthin and capsorubin) protect human dermal fibroblasts against UVB induced DNA damage.

Photoprotection by dietary carotenoids has been linked to their antioxidant properties, in particular quenching of singlet molecular oxygen and scavenging of peroxyl radicals. Here, we compared the DNA-protection and antioxidant effects of selected carotenoids exclusively synthesized in red pepper (capsanthin and capsorubin) to the xanthophyll lutein. Preincubation of human dermal fibroblasts (hdf) with capsanthin and capsorubin significantly counteracted UVB induced cytotoxicity at doses between 0 and 300 mJ cm(-2). Pretreatment of hdf with capsanthin, capsorubin or lutein (1 µM) significantly decreased the formation of DNA strand breaks following irradiation with UVB light. All carotenoids studied decreased caspase-3 cleavage (a marker for UVB-induced apoptosis), however, caspase dependent PARP-1 cleavage was not affected suggesting that the remaining caspase activity is sufficient to promote UVB-induced apoptosis. It is conceivable that carotenoids selectively interfere with cellular responses activated by UVB-mediated damage. Our findings indicate that capsanthin and capsorubin exhibit similar properties to lutein and could be used as a dietary supplement to improve natural photoprotection.

Acute kidney injury and acute-on-chronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis.

OBJECTIVE: Prognostic stratification of patients with cirrhosis is common clinical practice. This study compares the prognostic accuracy (28-day and 90-day transplant-free mortality) of the acute-on-chronic liver failure (ACLF) classification (no ACLF, ACLF grades 1, 2 and 3) with that of acute kidney injury (AKI) classification (no AKI, AKI stages 1, 2 and 3). DESIGN: The study was performed in 510 patients with an acute decompensation of cirrhosis previously included in the European Association for the Study of the Liver-Chronic Liver Failure consortium CANONIC study. ACLF was evaluated at enrollment and 48 h after enrollment, and AKI was evaluated at 48 h according to Acute Kidney Injury Network criteria. RESULTS: 240 patients (47.1%) met the criteria of ACLF at enrollment, while 98 patients (19.2%) developed AKI. The presence of ACLF and AKI was strongly associated with mortality. 28-day transplant-free mortality and 90-day transplant-free mortality of patients with ACLF (32% and 49.8%, respectively) were significantly higher with respect to those of patients without ACLF (6.2% and 16.4%, respectively; both p<0.001). Corresponding values in patients with and without AKI were 46% and 59%, and 12% and 25.6%, respectively (p<0.0001 for both). ACLF classification was more accurate than AKI classification in predicting 90-day mortality (area under the receiving operating characteristic curve=0.72 vs 0.62; p<0.0001) in the whole series of patients. Moreover, assessment of ACLF classification at 48 h had significantly better prognostic accuracy compared with that of both AKI classification and ACLF classification at enrollment. CONCLUSIONS: ACLF stratification is more accurate than AKI stratification in the prediction of short-term mortality in patients with acute decompensation of cirrhosis.

Anti-MPER antibodies with heterogeneous neutralization capacity are detectable in most untreated HIV-1 infected individuals.

BACKGROUND: The MPER region of the HIV-1 envelope glycoprotein gp41 is targeted by broadly neutralizing antibodies. However, the localization of this epitope in a hydrophobic environment seems to hamper the elicitation of these antibodies in HIV infected individuals.We have quantified and characterized anti-MPER antibodies by ELISA and by flow cytometry using a collection of mini gp41-derived proteins expressed on the surface of 293T cells. Longitudinal plasma samples from 35 HIV-1 infected individuals were assayed for MPER recognition and MPER-dependent neutralizing capacity using HIV-2 viruses engrafted with HIV-1 MPER sequences. RESULTS: Miniproteins devoid of the cysteine loop of gp41 exposed the MPER on 293T cell membrane. Anti-MPER antibodies were identified in most individuals and were stable when analyzed in longitudinal samples. The magnitude of the responses was strongly correlated with the global response to the HIV-1 envelope glycoprotein, suggesting no specific limitation for anti-MPER antibodies. Peptide mapping showed poor recognition of the C-terminal MPER moiety and a wide presence of antibodies against the 2F5 epitope. However, antibody titers failed to correlate with 2F5-blocking activity and, more importantly, with the specific neutralization of HIV-2 chimeric viruses bearing the HIV-1 MPER sequence; suggesting a strong functional heterogeneity in anti-MPER humoral responses. CONCLUSIONS: Anti-MPER antibodies can be detected in the vast majority of HIV-1 infected individuals and are generated in the context of the global anti-Env response. However, the neutralizing capacity is heterogeneous suggesting that eliciting neutralizing anti-MPER antibodies by immunization might require refinement of immunogens to skip nonneutralizing responses.

[Multicenter cross-sectional study on the prevalence of delirium in orthogeriatric units: «DELFRA 24 study¼ protocol]. / Estudio transversal multicéntrico sobre la prevalencia de delirium en unidades de ortogeriatría: protocolo de «Estudio DELFRA 24¼.

INTRODUCTION: Delirium is the most common perioperative complication in older adults with hip fracture (HF), leading to a catastrophic impact on their functional recovery and cognitive status. Currently, the true prevalence of this syndrome is unknown as its detection and management are not standardized in clinical practice. METHODS: A multicenter observational cross-sectional study will be conducted nationwide, involving different orthogeriatric units in Spain. The prevalence of delirium will be assessed using the 4AT scale, along with its characteristics and its relationship with other geriatric syndromes, sociodemographic variables, surgical characteristics, and laboratory parameters. RESULTS: Data collection is scheduled to take place on World Delirium Day (Wednesday, March 13, 2024), and therefore, the results are expected during the second or third quarter of 2024. CONCLUSIONS: Understanding the real prevalence and characteristics of delirium in older adults with HF could contribute to the development of strategies for its detection and management, reducing the impact of its consequences.

The Multidimensional Prognostic Index predicts incident delirium among hospitalized older patients with COVID-19: a multicenter prospective European study.

PURPOSE: Incident delirium is a frequent complication among hospitalized older people with COVID-19, associated with increased length of hospital stay, higher morbidity and mortality rates. Although delirium is preventable with early detection, systematic assessment methods and predictive models are not universally defined, thus delirium is often underrated. In this study, we tested the role of the Multidimensional Prognostic Index (MPI), a prognostic tool based on Comprehensive Geriatric Assessment, to predict the risk of incident delirium. METHODS: Hospitalized older patients (≥ 65 years) with COVID-19 infection were enrolled (n = 502) from ten centers across Europe. At hospital admission, the MPI was administered to all the patients and two already validated delirium prediction models were computed (AWOL delirium risk-stratification score and Martinez model). Delirium occurrence during hospitalization was ascertained using the 4A's Test (4AT). Accuracy of the MPI and the other delirium predictive models was assessed through logistic regression models and the area under the curve (AUC). RESULTS: We analyzed 293 patients without delirium at hospital admission. Of them 33 (11.3%) developed delirium during hospitalization. Higher MPI score at admission (higher multidimensional frailty) was associated with higher risk of incident delirium also adjusting for the other delirium predictive models and COVID-19 severity (OR = 12.72, 95% CI = 2.11-76.86 for MPI-2 vs MPI-1, and OR = 33.44, 95% CI = 4.55-146.61 for MPI-3 vs MPI-1). The MPI showed good accuracy in predicting incident delirium (AUC = 0.71) also superior to AWOL tool, (AUC = 0.63) and Martinez model (AUC = 0.61) (p < 0.0001 for both comparisons). CONCLUSIONS: The MPI is a sensitive tool for early identification of older patients with incident delirium.

A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis.

BACKGROUND & AIMS: The Acute Kidney Injury Network (AKIN) criteria are widely used in nephrology, but information on cirrhosis is limited. We aimed at evaluating the AKIN criteria and their relationship with the cause of kidney impairment and survival. METHODS: We performed a prospective study of 375 consecutive patients hospitalized for complications of cirrhosis. One-hundred and seventy-seven (47%) patients fulfilled the criteria of Acute Kidney Injury (AKI) during hospitalization, the causes being hypovolemia, infections, hepatorenal syndrome (HRS), nephrotoxicity, and miscellaneous (62, 54, 32, 8, and 21 cases, respectively). RESULTS: At diagnosis, most patients had AKI stage 1 (77%). Both the occurrence of AKI and its stage were associated with 3-month survival. However, survival difference between stages 2 and 3 was not statistically significant. Moreover, if stage 1 patients were categorized into 2 groups according to the level of serum creatinine used in the classical definition of kidney impairment (1.5mg/dl), the two groups had a significantly different outcome. Combining AKIN criteria and maximum serum creatinine, 3 risk groups were identified: (A) patients with AKI stage 1 with peak creatinine ≤ 1.5mg/dl; (B) patients with stage 1 with peak creatinine >1.5mg/dl; and (C) patients with stages 2-3 (survival 84%, 68%, and 36%, respectively; p<0.001). Survival was independently related to the cause of kidney impairment, patients with HRS or infection-related having the worst prognosis. CONCLUSIONS: A classification that combines the AKIN criteria and classical criteria of kidney failure in cirrhosis provides a better risk stratification than AKIN criteria alone. The cause of impairment in kidney function is key in assessing prognosis in cirrhosis.