Rational and design of the REMOTE trial: An exploratory, pilot study to analyze REtinal MicrOcirculaTion in wEightlessness.

BACKGROUND: "Spaceflight associated neuro-ocular syndrome" (SANS) represents a challenging health condition in modern space medicine. Forty-eight percent of astronauts are diagnosed with SANS after long-term space missions. The pathophysiological mechanism seems to be multifactorial, and yet remains unknown. In this proof-of-concept study we plan to investigate retinal microcirculatory changes in weightlessness and aim to identify their role in the development of SANS. METHODS AND DESIGN: Healthy individuals will take part in a parabolic flight campaign, which recreates fractioned total weightlessness periods. The airplane is specifically equipped, and designed for the execution of parabolic flight maneuvers and scientific research in microgravity. Retinal microcirculation will be assessed with a modified fundus camera, which allows dynamic vessel analysis. We will additionally measure intra-ocular pressure and hemodynamic changes during each phase of the flight. Blood samples will be analyzed at baseline, one hour and 24 hours after exposure to weightlessness. CONCLUSIONS: This pilot study aims to investigate the feasibility of retinal microcirculation assessment during varying gravity. Results of this study may generate insights whether venous stasis in the eye, surrogated by the dilatation of retinal vessels and increase in intraocular pressure as signs of venous insufficiency, may potentially contribute to the development of SANS.

The association of prior paracetamol intake with outcome of very old intensive care patients with COVID-19: results from an international prospective multicentre trial.

BACKGROUND: In the early COVID-19 pandemic concerns about the correct choice of analgesics in patients with COVID-19 were raised. Little data was available on potential usefulness or harmfulness of prescription free analgesics, such as paracetamol. This international multicentre study addresses that lack of evidence regarding the usefulness or potential harm of paracetamol intake prior to ICU admission in a setting of COVID-19 disease within a large, prospectively enrolled cohort of critically ill and frail intensive care unit (ICU) patients. METHODS: This prospective international observation study (The COVIP study) recruited ICU patients ≥ 70 years admitted with COVID-19. Data on Sequential Organ Failure Assessment (SOFA) score, prior paracetamol intake within 10 days before admission, ICU therapy, limitations of care and survival during the ICU stay, at 30 days, and 3 months. Paracetamol intake was analysed for associations with ICU-, 30-day- and 3-month-mortality using Kaplan Meier analysis. Furthermore, sensitivity analyses were used to stratify 30-day-mortality in subgroups for patient-specific characteristics using logistic regression. RESULTS: 44% of the 2,646 patients with data recorded regarding paracetamol intake within 10 days prior to ICU admission took paracetamol. There was no difference in age between patients with and without paracetamol intake. Patients taking paracetamol suffered from more co-morbidities, namely diabetes mellitus (43% versus 34%, p < 0.001), arterial hypertension (70% versus 65%, p = 0.006) and had a higher score on Clinical Frailty Scale (CFS; IQR 2-5 versus IQR 2-4, p < 0.001). Patients under prior paracetamol treatment were less often subjected to intubation and vasopressor use, compared to patients without paracetamol intake (65 versus 71%, p < 0.001; 63 versus 69%, p = 0.007). Paracetamol intake was not associated with ICU-, 30-day- and 3-month-mortality, remaining true after multivariate adjusted analysis. CONCLUSION: Paracetamol intake prior to ICU admission was not associated with short-term and 3-month mortality in old, critically ill intensive care patients suffering from COVID-19. TRIAL REGISTRATION: This prospective international multicentre study was registered on ClinicalTrials.gov with the identifier "NCT04321265" on March 25, 2020.

Sex-specific treatment characteristics and 30-day mortality outcomes of critically ill COVID-19 patients over 70 years of age-results from the prospective COVIP study.

PURPOSE: Older critically ill patients with COVID-19 have been the most vulnerable during the ongoing pandemic, with men being more prone to hospitalization and severe disease than women. We aimed to explore sex-specific differences in treatment and outcome after intensive care unit (ICU) admission in this cohort. METHODS: We performed a sex-specific analysis in critically ill patients ≥ 70 yr of age with COVID-19 who were included in the international prospective multicenter COVIP study. All patients were analyzed for ICU admission and treatment characteristics. We performed a multilevel adjusted regression analysis to elucidate associations of sex with 30-day mortality. RESULTS: A total of 3,159 patients (69.8% male, 30.2% female; median age, 75 yr) were included. Male patients were significantly fitter than female patients as determined by the Clinical Frailty Scale (fit, 67% vs 54%; vulnerable, 14% vs 19%; frail, 19% vs 27%; P < 0.001). Male patients more often underwent tracheostomy (20% vs 14%; odds ratio [OR], 1.57; P < 0.001), vasopressor therapy (69% vs 62%; OR, 1.25; P = 0.02), and renal replacement therapy (17% vs 11%; OR, 1.96; P < 0.001). There was no difference in mechanical ventilation, life-sustaining treatment limitations, and crude 30-day mortality (50% male vs 49% female; OR, 1.11; P = 0.19), which remained true after adjustment for disease severity, frailty, age and treatment limitations (OR, 1.17; 95% confidence interval, 0.94 to 1.45; P = 0.16). CONCLUSION: In this analysis of sex-specific treatment characteristics and 30-day mortality outcomes of critically ill patients with COVID-19 ≥ 70 yr of age, we found more tracheostomy and renal replacement therapy in male vs female patients, but no significant association of patient sex with 30-day mortality. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT04321265); registered 25 March 2020).

RéSUMé: OBJECTIF: Les patients âgés gravement malades atteints de la COVID-19 ont été les plus vulnérables pendant la pandémie actuelle, les hommes étant plus sujets à l'hospitalisation et aux maladies graves que les femmes. Nous avons cherché à explorer les différences spécifiques au sexe dans le traitement et les devenirs après l'admission à l'unité de soins intensifs (USI) dans cette cohorte. MéTHODE: Nous avons effectué une analyse spécifique au sexe chez des patients gravement malades âgés de ≥ 70 ans atteints de COVID-19 qui ont été inclus dans l'étude prospective multicentrique internationale COVIP. Tous les patients ont été analysés pour connaître les détails de leur admission à l'USI et les caractéristiques de leur traitement. Nous avons réalisé une analyse de régression ajustée à plusieurs niveaux pour élucider les associations entre le sexe et la mortalité à 30 jours. RéSULTATS: Au total, 3159 patients (69,8 % d'hommes, 30,2 % de femmes; âge médian, 75 ans) ont été inclus. Les patients de sexe masculin étaient significativement plus en forme que les patientes, tel que déterminé par l'échelle de fragilité clinique (bonne santé, 67 % vs 54 %; vulnérables, 14 % vs 19 %; fragiles, 19 % vs 27 %; P < 0,001). Les patients de sexe masculin ont plus souvent bénéficié d'une trachéostomie (20 % vs 14 %; rapport de cotes [RC], 1,57; P < 0,001), d'un traitement vasopresseur (69 % vs 62 %; RC, 1,25; P = 0,02) et d'un traitement substitutif de l'insuffisance rénale (17 % vs 11 %; RC, 1,96; P < 0,001). Il n'y avait aucune différence en matière de ventilation mécanique, de limites des traitements de maintien en vie et de mortalité brute à 30 jours (50 % d'hommes vs 49 % de femmes; RC, 1,11; P = 0,19), ce qui est demeuré le cas après ajustement pour tenir compte de la gravité de la maladie, de la fragilité, de l'âge et des limites du traitement (RC, 1,17 ; intervalle de confiance à 95 %, 0,94 à 1,45; P = 0,16). CONCLUSION: Dans cette analyse des caractéristiques de traitement spécifiques au sexe et des résultats de mortalité à 30 jours des patients gravement malades atteints de COVID-19 de ≥ 70 ans, nous avons noté un nombre plus élevé de trachéotomies et de traitements substitutifs de l'insuffisance rénale chez les hommes vs les femmes, mais aucune association significative entre le sexe des patients et la mortalité à 30 jours. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT04321265); enregistré le 25 mars 2020.

Association of chronic heart failure with mortality in old intensive care patients suffering from Covid-19.

AIMS: Chronic heart failure (CHF) is a major risk factor for mortality in coronavirus disease 2019 (COVID-19). This prospective international multicentre study investigates the role of pre-existing CHF on clinical outcomes of critically ill old (≥70 years) intensive care patients with COVID-19. METHODS AND RESULTS: Patients with pre-existing CHF were subclassified as having ischaemic or non-ischaemic cardiac disease; patients with a documented ejection fraction (EF) were subclassified according to heart failure EF: reduced (HFrEF, n = 132), mild (HFmrEF, n = 91), or preserved (HFpEF, n = 103). Associations of heart failure characteristics with the 30 day mortality were analysed in univariate and multivariate logistic regression analyses. Pre-existing CHF was reported in 566 of 3917 patients (14%). Patients with CHF were older, frailer, and had significantly higher SOFA scores on admission. CHF patients showed significantly higher crude 30 day mortality [60% vs. 48%, P < 0.001; odds ratio 1.87, 95% confidence interval (CI) 1.5-2.3] and 3 month mortality (69% vs. 56%, P < 0.001). After multivariate adjustment for confounders (SOFA, age, sex, and frailty), no independent association of CHF with mortality remained [adjusted odds ratio (aOR) 1.2, 95% CI 0.5-1.5; P = 0.137]. More patients suffered from pre-existing ischaemic than from non-ischaemic disease [233 vs. 328 patients (n = 5 unknown aetiology)]. There were no differences in baseline characteristics between ischaemic and non-ischaemic disease or between HFrEF, HFmrEF, and HFpEF. Crude 30 day mortality was significantly higher in HFrEF compared with HFpEF (64% vs. 48%, P = 0.042). EF as a continuous variable was not independently associated with 30 day mortality (aOR 0.98, 95% CI 0.9-1.0; P = 0.128). CONCLUSIONS: In critically ill older COVID-19 patients, pre-existing CHF was not independently associated with 30 day mortality. TRIAL REGISTRATION NUMBER: NCT04321265.

The association of the Activities of Daily Living and the outcome of old intensive care patients suffering from COVID-19.

PURPOSE: Critically ill old intensive care unit (ICU) patients suffering from Sars-CoV-2 disease (COVID-19) are at increased risk for adverse outcomes. This post hoc analysis investigates the association of the Activities of Daily Living (ADL) with the outcome in this vulnerable patient group. METHODS: The COVIP study is a prospective international observational study that recruited ICU patients ≥ 70 years admitted with COVID-19 (NCT04321265). Several parameters including ADL (ADL; 0 = disability, 6 = no disability), Clinical Frailty Scale (CFS), SOFA score, intensive care treatment, ICU- and 3-month survival were recorded. A mixed-effects Weibull proportional hazard regression analyses for 3-month mortality adjusted for multiple confounders. RESULTS: This pre-specified analysis included 2359 patients with a documented ADL and CFS. Most patients evidenced independence in their daily living before hospital admission (80% with ADL = 6). Patients with no frailty and no disability showed the lowest, patients with frailty (CFS ≥ 5) and disability (ADL < 6) the highest 3-month mortality (52 vs. 78%, p < 0.001). ADL was independently associated with 3-month mortality (ADL as a continuous variable: aHR 0.88 (95% CI 0.82-0.94, p < 0.001). Being "disable" resulted in a significant increased risk for 3-month mortality (aHR 1.53 (95% CI 1.19-1.97, p 0.001) even after adjustment for multiple confounders. CONCLUSION: Baseline Activities of Daily Living (ADL) on admission provides additional information for outcome prediction, although most critically ill old intensive care patients suffering from COVID-19 had no restriction in their ADL prior to ICU admission. Combining frailty and disability identifies a subgroup with particularly high mortality. TRIAL REGISTRATION NUMBER: NCT04321265.

Evaluation of Therapeutic Targets in Histological Subtypes of Bladder Cancer.

Histologically, bladder cancer is a heterogeneous group comprising urothelial carcinoma (UC), squamous cell carcinoma, adenocarcinomas (ACs), urachal carcinomas (UrCs), and small cell neuroendocrine carcinomas (SCCs). However, all bladder cancers have been treated so far uniformly, and targeted therapy options are still limited. Thus, we aimed to determine the protein expression/molecular status of commonly used cancer targets (programmed cell death 1 ligand 1 (PD-L1), mismatch repair (MMR), androgen and estrogen receptors (AR/ER), Nectin-4, tumor-associated calcium signal transducer 2 (Tacstd2, Trop-2), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and fibroblast growth factor receptor 3 (FGFR3)) to give first insights into whether patients with SCC, AC/UrCs, and squamous-differentiated carcinomas (Sq-BLCA) of the bladder could be eligible for targeted therapies. In addition, for MMR-deficient tumors, microsatellite instability was analyzed. We completed our own data with molecular data from The Cancer Genome Atlas (TCGA). We present ratios for each drug and cumulative ratios for multiple therapeutic options for each nonurothelial subtype. For example, 58.9% of SCC patients, 33.5% of AC/UrCs patients, and 79.3% of Sq-BLCA patients would be eligible for at least one of the analyzed targets. In conclusion, our findings hold promise for targeted therapeutic approaches in selected patients in the future, as various drugs could be applied according to the biomarker status.

Early evaluation of organ failure using MELD-XI in critically ill elderly COVID-19 patients.

PURPOSECritically ill elderly patients who suffer from Sars-CoV-2 disease are at high risk for organ failure. The modified MELD-XI score has not been evaluated for outcome prediction in these most vulnerable patients.METHODSThe Corona Virus disease (COVID19) in Very Elderly Intensive Care Patients study (COVIP, NCT04321265) prospectively recruited patients on intensive care units (ICU), who were = 70 years. Data were collected from March 2020 to February 2021. The MELD-XI score was calculated using the highest serum bilirubin and creatinine on ICU admission. Univariate and multivariable logistic regression analyses were performed to assess associations between the MELD-XI score and mortality. The primary outcome was 30-day-mortality, the secondary outcomes were ICU- and 3-month-mortality.RESULTSIn total, data from 2,993 patients were analyzed. Most patients had a MELD-XI <12 on admission (76%). The patients with MELD-XI = 12 had a significantly higher 30-day-, ICU- and 3-month-mortality (44%vs 64%, and 42%vs. 59%, and 57%vs. 76%, p < 0.001). After adjustment for multiple confounders, MELD-XI = 12 remained significantly associated with 30-day- (aOR 1.572, CI 1.268-1.949, p < 0.001), ICU-, and 3-month-mortality.CONCLUSIONIn critically ill elderly intensive care patients with COVID-19, the MELD-XI score constitutes a valuable tool for an early outcome prediction.

Lactate is associated with mortality in very old intensive care patients suffering from COVID-19: results from an international observational study of 2860 patients.

PURPOSE: Lactate is an established prognosticator in critical care. However, there still is insufficient evidence about its role in predicting outcome in COVID-19. This is of particular concern in older patients who have been mostly affected during the initial surge in 2020. METHODS: This prospective international observation study (The COVIP study) recruited patients aged 70 years or older (ClinicalTrials.gov ID: NCT04321265) admitted to an intensive care unit (ICU) with COVID-19 disease from March 2020 to February 2021. In addition to serial lactate values (arterial blood gas analysis), we recorded several parameters, including SOFA score, ICU procedures, limitation of care, ICU- and 3-month mortality. A lactate concentration ≥ 2.0 mmol/L on the day of ICU admission (baseline) was defined as abnormal. The primary outcome was ICU-mortality. The secondary outcomes 30-day and 3-month mortality. RESULTS: In total, data from 2860 patients were analyzed. In most patients (68%), serum lactate was lower than 2 mmol/L. Elevated baseline serum lactate was associated with significantly higher ICU- and 3-month mortality (53% vs. 43%, and 71% vs. 57%, respectively, p < 0.001). In the multivariable analysis, the maximum lactate concentration on day 1 was independently associated with ICU mortality (aOR 1.06 95% CI 1.02-1.11; p = 0.007), 30-day mortality (aOR 1.07 95% CI 1.02-1.13; p = 0.005) and 3-month mortality (aOR 1.15 95% CI 1.08-1.24; p < 0.001) after adjustment for age, gender, SOFA score, and frailty. In 826 patients with baseline lactate ≥ 2 mmol/L sufficient data to calculate the difference between maximal levels on days 1 and 2 (∆ serum lactate) were available. A decreasing lactate concentration over time was inversely associated with ICU mortality after multivariate adjustment for SOFA score, age, Clinical Frailty Scale, and gender (aOR 0.60 95% CI 0.42-0.85; p = 0.004). CONCLUSION: In critically ill old intensive care patients suffering from COVID-19, lactate and its kinetics are valuable tools for outcome prediction. TRIAL REGISTRATION NUMBER: NCT04321265.

ICU-Mortality in Old and Very Old Patients Suffering From Sepsis and Septic Shock.

Purpose: Old (>64 years) and very old (>79 years) intensive care patients with sepsis have a high mortality. In the very old, the value of critical care has been questioned. We aimed to compare the mortality, rates of organ support, and the length of stay in old vs. very old patients with sepsis and septic shock in intensive care. Methods: This analysis included 9,385 patients, from the multi-center eICU Collaborative Research Database, with sepsis; 6184 were old (aged 65-79 years), and 3,201 were very old patients (aged 80 years and older). A multi-level logistic regression analysis was used to fit three sequential regression models for the binary primary outcome of ICU mortality. A sensitivity analysis in septic shock patients (n = 1054) was also conducted. Results: In the very old patients, the median length of stay was shorter (50 ± 67 vs. 56 ± 72 h; p < 0.001), and the rate of a prolonged ICU stay was lower (>168 h; 9 vs. 12%; p < 0.001) than the old patients. The mortality from sepsis was higher in very old patients (13 vs. 11%; p = 0.005), and after multi-variable adjustment being very old was associated with higher odds for ICU mortality (aOR 1.32, 95% CI 1.09-1.59; p = 0.004). In patients with septic shock, mortality was also higher in the very old patients (38 vs. 36%; aOR 1.50, 95% CI 1.10-2.06; p = 0.01). Conclusion: Very old ICU-patients suffer from a slightly higher ICU mortality compared with old ICU-patients. However, despite the statistically significant differences in mortality, the clinical relevance of such minor differences seems to be negligible.

Machine learning predicts mortality in septic patients using only routinely available ABG variables: a multi-centre evaluation.

PURPOSE: To evaluate the application of machine learning methods, specifically Deep Neural Networks (DNN) models for intensive care (ICU) mortality prediction. The aim was to predict mortality within 96 hours after admission to mirror the clinical situation of patient evaluation after an ICU trial, which consists of 24-48 hours of ICU treatment and then "re-triage". The input variables were deliberately restricted to ABG values to maximise real-world practicability. METHODS: We retrospectively evaluated septic patients in the multi-centre eICU dataset as well as single centre MIMIC-III dataset. Included were all patients alive after 48 hours with available data on ABG (n = 3979 and n = 9655 ICU stays for the multi-centre and single centre respectively). The primary endpoint was 96 -h-mortality. RESULTS: The model was developed using long short-term memory (LSTM), a type of DNN designed to learn temporal dependencies between variables. Input variables were all ABG values within the first 48 hours. The SOFA score (AUC of 0.72) was moderately predictive. Logistic regression showed good performance (AUC of 0.82). The best performance was achieved by the LSTM-based model with AUC of 0.88 in the multi-centre study and AUC of 0.85 in the single centre study. CONCLUSIONS: An LSTM-based model could help physicians with the "re-triage" and the decision to restrict treatment in patients with a poor prognosis.

Failure of Lactate Clearance Predicts the Outcome of Critically Ill Septic Patients.

PURPOSE: Early lactate clearance is an important parameter for prognosis assessment and therapy control in sepsis. Patients with a lactate clearance >0% might differ from patients with an inferior clearance in terms of intensive care management and outcomes. This study analyzes a large collective with regards to baseline risk distribution and outcomes. METHODS: In total, 3299 patients were included in this analysis, consisting of 1528 (46%) ≤0% and 1771 (54%) >0% patients. The primary endpoint was intensive care unit (ICU) mortality. Multilevel logistic regression analyses were used to compare both groups: A baseline model (model 1) with lactate clearance as a fixed effect and ICU as a random effect was installed. For model 2, patient characteristics (model 2) were included. For model 3, intensive care treatment (mechanical ventilation and vasopressors) was added to the model. Models 1 and 2 were used to evaluate the primary and secondary outcomes, respectively. Model 3 was only used to evaluate the primary outcomes. Adjusted odds ratios (aORs) with respective 95% confidence intervals (CI) were calculated. RESULTS: The cohorts had no relevant differences regarding the gender, BMI, age, heart rate, body temperature, and baseline lactate. Neither the primary infection focuses nor the ethnic background differed between both groups. In both groups, the most common infection sites were of pulmonary origin, the urinary tract, and the gastrointestinal tract. Patients with lactate clearance >0% evidenced lower sepsis-related organ failure assessment (SOFA) scores (7 ± 6 versus 9 ± 6; p < 0.001) and creatinine (1.53 ± 1.49 versus 1.80 ± 1.67; p < 0.001). The ICU mortality differed significantly (14% versus 32%), and remained this way after multivariable adjustment for patient characteristics and intensive care treatment (aOR 0.43 95% CI 0.36-0.53; p < 0.001). In the additional sensitivity analysis, the lack of lactate clearance was associated with a worse prognosis in each subgroup. CONCLUSION: In this large collective of septic patients, the 6 h lactate clearance is an independent method for outcome prediction.

[Diabetes and Heart failure]. / Diabetes und Herzinsuffizienz.

Diabetes is a very important comorbidity in patients with heart failure. When both diseases are present, mortality is greatly increased. Therefore, it is important to sufficiently diagnose and treat patients with diabetes and heart failure to improve outcome. This article provides an overview on epidemiology, pathogeneses, diagnostic and therapeutic options.

Fibroblast growth factor receptor (FGFR) alterations in squamous differentiated bladder cancer: a putative therapeutic target for a small subgroup.

Although drugable fibroblast growth factor receptor (FGFR) alterations in squamous cell carcinomas (SCC) of various entities are well known, little is known about FGFR modifications in squamous differentiated bladder cancer. Therefore, our study evaluated FGFR1-3 alterations as a putative therapeutic target in this subgroup. We analyzed 73 squamous differentiated bladder cancers (n = 10 pT2, n = 55 pT3, n = 8 pT4) for FGFR1-3 protein expression, FGFR1-3 copy number variations, FGFR3 chromosomal rearrangements (fluorescence in situ hybridization (FISH)) and FGFR3 mutations (SNapShot analysis). Only single cases displayed enhanced protein expression, most frequently FGFR3 overexpression (9.4% (6/64)). FISH showed no amplifications of FGFR1, 2 or 3. Break apart events were only slightly above the cut off in 12.1% (8/66) of cases and no FGFR3-TACC3 rearrangements could be proven by qPCR. FGFR3 mutations (p.S249C) were found in 8.5% (6/71) of tumors and were significantly associated with FGFR3 protein overexpression (p < 0.001), and unfavourable clinical outcome (p = 0.001). Our findings are consistent with the results of the TCGA data set for the "squamous-like" subtype of bladder cancer (n = 85), which revealed reduced overall expression of FGFR1 and FGFR2 in tumors compared to normal tissue, while expression of FGFR3 remained high. In the TCGA "squamous-like" subtype FGFR3 mutations were found in 4.9% and correlated with high FGFR3 RNA expression. Mutations of FGFR1 and FGFR2 were less frequent (2.4% and 1.2%). Hence, our comprehensive study provides novel insights into a subgroup of squamous differentiated bladder tumors that hold clues for novel therapeutic regimens and may benefit from FGFR3-targeted therapies.