Establishment of a high-content compatible platform to assess effects of monocyte-derived factors on neural stem cell proliferation and differentiation.

During neuroinflammation, monocytes that infiltrate the central nervous system (CNS) may contribute to regenerative processes depending on their activation status. However, the extent and mechanisms of monocyte-induced CNS repair in patients with neuroinflammatory diseases remain largely unknown, partly due to the lack of a fully human assay platform that can recapitulate monocyte-neural stem cell interactions within the CNS microenvironment. We therefore developed a human model system to assess the impact of monocytic factors on neural stem cells, establishing a high-content compatible assay for screening monocyte-induced neural stem cell proliferation and differentiation. The model combined monocytes isolated from healthy donors and human embryonic stem cell derived neural stem cells and integrated both cell-intrinsic and -extrinsic properties. We identified CNS-mimicking culture media options that induced a monocytic phenotype resembling CNS infiltrating monocytes, while allowing adequate monocyte survival. Monocyte-induced proliferation, gliogenic fate and neurogenic fate of neural stem cells were affected by the conditions of monocytic priming and basal neural stem cell culture as extrinsic factors as well as the neural stem cell passage number as an intrinsic neural stem cell property. We developed a high-content compatible human in vitro assay for the integrated analysis of monocyte-derived factors on CNS repair.

In-hospital survival of critically ill COVID-19 patients treated with glucocorticoids: a multicenter real-world data study.

The COVID-19 pandemic has posed a major challenge to healthcare systems globally. Millions of people have been infected, and millions of deaths have been reported worldwide. Glucocorticoids have attracted worldwide attention for their potential efficacy in the treatment of COVID-19. Various glucocorticoids with different dosages and treatment durations have been studied in patients with different severities, with a suitable dosage and treatment duration not yet defined. This study aimed to investigate whether in-hospital survival differs between critically ill patients treated with low-dose glucocorticoids, high-dose glucocorticoids or no glucocorticoids. All critically ill patients admitted to the intensive care unit of the Charité Hospital-Universitätsmedizin Berlin between February 2020 and December 2021 with COVID-19 pneumonia receiving supplemental oxygen were eligible to participate in this multicenter real-world data study. Patients were retrospectively assigned to one of three groups: the high corticosteroid dose (HighC) group (receiving 6 mg parenteral dexamethasone or an equivalent corticosteroid dosage for ten days), the low corticosteroid dose (LowC) group (receiving less than 6 mg parenteral dexamethasone or an equivalent corticosteroid dosage for ten days), or the no corticosteroid (NoC) group. Overall survival and risk effects were compared among groups within the total observation period, as well as at 35 days after the onset of COVID-19 symptoms. Adjusted multivariable Cox proportional hazard regression analysis was performed to compare the risk of death between the treatment groups. Out of 1561 critically ill COVID-19 patients, 1014 were included in the baseline analysis. In the survival study, 1009 patients were assigned to the NoC (n = 346), HighC (n = 552), or LowC group (n = 111). The baseline characteristics were balanced between groups, except for age, BMI, APACHE II score, SOFA and SAPS II. While the 35-day survival did not show any differences, a landmark analysis of the patients surviving beyond 35 days revealed differences between groups. The restricted mean survival time was 112 days in the LowC group [95% CI: 97 - 128], 133 days in the HighC group [95% CI: 124 - 141] and 144 days in the NoC group [95% CI: 121 - 167]. The multivariable-adjusted Cox proportional hazard analysis indicated that, regardless of age, sex, health status or invasive oxygenation, a low-dose treatment increased the hazard of death of critically ill COVID-19 patients by a factor of 2.09 ([95% CI: 0.99, 4.4], p = 0.05) and a high-dose corticosteroid treatment increased the risk by a factor of 1.07 ([95% CI: 0.53, 2.15], p = 0.85) compared to no treatment with glucocorticoids. The analysis reveals that corticosteroid treatment does not influence the survival of critically ill COVID-19 patients in the intensive care unit within 35 days. Our evaluations further suggest that regardless of ventilation status, the decision-making process for administering corticosteroid therapy should account for the individual severity of the illness.

A prospective phase IIA multicenter double-blinded randomized placebo-controlled clinical trial evaluating the efficacy and safety of inhaled Tobramycin in patients with ventilator-associated pneumonia (iToVAP).

OBJECTIVE: Treatment of ventilated pneumonia is often unsuccessful, even when patients are treated according to current guidelines. Therefore, we aimed to investigate the efficacy of the adjunctive inhaled Tobramycin in patients with pneumonia caused by Gram-negative pathogens in addition to the standard systemic treatment. DESIGN: Prospective, multicenter, double-blinded, randomized, placebo-controlled clinical trial. SETTING: 26 patients in medical and surgical ICUs. PATIENTS: Patients with ventilator-associated pneumonia caused by Gram-negative pathogens. MEASUREMENT AND MAIN RESULTS: Fourteen patients were assigned to the Tobramycin Inhal group and 12 patients to the control group. The microbiological eradication of the Gram-negative pathogens was significantly higher in the intervention group than in the control group (p < 0.001). The probability of eradication was 100% in the intervention group [95% Confidence Interval: 0.78-1.0] and 25% in the control group [95% CI: 0.09-0.53]. The increased eradication frequency was not associated with increased patient survival. CONCLUSION: Inhaled aerosolized Tobramycin demonstrated clinically meaningful efficacy in patients with Gram-negative ventilator-associated pneumonia. The probability of eradication in the intervention group was 100%. However, the successful eradication was not associated with a reduction in systemic anti-infective therapy, a shorter ICU stay, or even a survival benefit. In the presence of multidrug-resistant Gram-negative pathogens that are sensitive only to colistin and/or aminoglycosides, supplemental inhaled therapy with nebulizers suitable for this purpose should be considered in addition to systemic antibiotic therapy.

Causal Model Building in the Context of Cardiac Rehabilitation: A Systematic Review.

Randomization is an effective design option to prevent bias from confounding in the evaluation of the causal effect of interventions on outcomes. However, in some cases, randomization is not possible, making subsequent adjustment for confounders essential to obtain valid results. Several methods exist to adjust for confounding, with multivariable modeling being among the most widely used. The main challenge is to determine which variables should be included in the causal model and to specify appropriate functional relations for continuous variables in the model. While the statistical literature gives a variety of recommendations on how to build multivariable regression models in practice, this guidance is often unknown to applied researchers. We set out to investigate the current practice of explanatory regression modeling to control confounding in the field of cardiac rehabilitation, for which mainly non-randomized observational studies are available. In particular, we conducted a systematic methods review to identify and compare statistical methodology with respect to statistical model building in the context of the existing recent systematic review CROS-II, which evaluated the prognostic effect of cardiac rehabilitation. CROS-II identified 28 observational studies, which were published between 2004 and 2018. Our methods review revealed that 24 (86%) of the included studies used methods to adjust for confounding. Of these, 11 (46%) mentioned how the variables were selected and two studies (8%) considered functional forms for continuous variables. The use of background knowledge for variable selection was barely reported and data-driven variable selection methods were applied frequently. We conclude that in the majority of studies, the methods used to develop models to investigate the effect of cardiac rehabilitation on outcomes do not meet common criteria for appropriate statistical model building and that reporting often lacks precision.

Clinical characteristics, treatments, outcome, and prognostic factors of severe autoimmune encephalitis in the intensive care unit: Standard treatment and the value of additional plasma cell-depleting escalation therapies for treatment-refractory patients.

BACKGROUND AND PURPOSE: To investigate severe autoimmune encephalitis (AE) in the intensive care unit (ICU) with regard to standard treatment in responsive patients and additional escalation therapies for treatment-refractory cases. METHODS: This retrospective, single-center study analyzed medical records of ICU-dependent AE patients for clinical characteristics, treatments, prognostic factors, and neurological outcome as quantified by modified Rankin Scale (mRS) and Clinical Assessment Scale for Autoimmune Encephalitis (CASE). RESULTS: From 40 enrolled patients (median age = 52 years; range = 16-89 years) with AE mediated by neuronal surface antibodies (nsAb; 90%) and AE with onconeuronal antibodies (10%), 98% received first-line therapy. Of those, 62% obtained additional second-line therapy, and 33% received escalation therapy with bortezomib and/or daratumumab. Good neurological outcome, defined as mRS = 0-2, was observed in 47% of AE with nsAb (CASE = 5), 77% of anti-N-methyl D-aspartate receptor encephalitis patients (CASE = 1), whereas AE patients with onconeuronal antibodies had the poorest outcome (mRS = 6, 100%). Treatment-refractory AE patients with nsAb requiring escalation therapy achieved similarly good recovery (mRS = 0-2, 39%, CASE = 3) as patients improving without (mRS = 0-2, 54%, CASE = 4), although they presented a higher disease severity at disease maximum (mRS = 5 100% versus 68%, CASE = 24 versus 17; p = 0.0036), had longer ICU stays (97 versus 23 days; p = 0.0002), and a higher survival propability during follow-up (p = 0.0203). Prognostic factors for good recovery were younger age (p = 0.025) and lack of preexisting comorbidities (p = 0.011). CONCLUSIONS: Our findings suggest that treatment-refractory AE patients with nsAb in the ICU can reach similarly good outcomes after plasma cell-depleting escalation therapy as patients already responding to standard first- and/or second-line therapies.