Genome-wide CRISPR screening identifies a role for ARRDC3 in TRP53-mediated responses.

Whole-genome screens using CRISPR technologies are powerful tools to identify novel tumour suppressors as well as factors that impact responses of malignant cells to anti-cancer agents. Applying this methodology to lymphoma cells, we conducted a genome-wide screen to identify novel inhibitors of tumour expansion that are induced by the tumour suppressor TRP53. We discovered that the absence of Arrestin domain containing 3 (ARRDC3) increases the survival and long-term competitiveness of MYC-driven lymphoma cells when treated with anti-cancer agents that activate TRP53. Deleting Arrdc3 in mice caused perinatal lethality due to various developmental abnormalities, including cardiac defects. Notably, the absence of ARRDC3 markedly accelerated MYC-driven lymphoma development. Thus, ARRDC3 is a new mediator of TRP53-mediated suppression of tumour expansion, and this discovery may open new avenues to harness this process for cancer therapy.

Development of a risk score to identify patients at high risk for a severe course of COVID-19.

Aim: We aimed to develop a risk score to calculate a person's individual risk for a severe COVID-19 course (POINTED score) to support prioritization of especially vulnerable patients for a (booster) vaccination. Subject and methods: This cohort study was based on German claims data and included 623,363 individuals with a COVID-19 diagnosis in 2020. The outcome was COVID-19 related treatment in an intensive care unit, mechanical ventilation, or death after a COVID-19 infection. Data were split into a training and a test sample. Poisson regression models with robust standard errors including 35 predefined risk factors were calculated. Coefficients were rescaled with a min-max normalization to derive numeric score values between 0 and 20 for each risk factor. The scores' discriminatory ability was evaluated by calculating the area under the curve (AUC). Results: Besides age, down syndrome and hematologic cancer with therapy, immunosuppressive therapy, and other neurological conditions were the risk factors with the highest risk for a severe COVID-19 course. The AUC of the POINTED score was 0.889, indicating very good predictive validity. Conclusion: The POINTED score is a valid tool to calculate a person's risk for a severe COVID-19 course. Supplementary Information: The online version contains supplementary material available at 10.1007/s10389-023-01884-7.

Soluble CD83 improves and accelerates wound healing by the induction of pro-resolving macrophages.

To facilitate the recovery process of chronic and hard-to-heal wounds novel pro-resolving treatment options are urgently needed. We investigated the pro-regenerative properties of soluble CD83 (sCD83) on cutaneous wound healing, where sCD83 accelerated wound healing not only after systemic but also after topical application, which is of high therapeutic interest. Cytokine profile analyses revealed an initial upregulation of inflammatory mediators such as TNFα and IL-1ß, followed by a switch towards pro-resolving factors, including YM-1 and IL-10, both expressed by tissue repair macrophages. These cells are known to mediate resolution of inflammation and stimulate wound healing processes by secretion of growth factors such as epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), which promote vascularization as well as fibroblast and keratinocyte differentiation. In conclusion, we have found strong wound healing capacities of sCD83 beyond the previously described role in transplantation and autoimmunity. This makes sCD83 a promising candidate for the treatment of chronic- and hard-to-heal wounds.

Effect of therapeutic drug monitoring-based dose optimization of piperacillin/tazobactam on sepsis-related organ dysfunction in patients with sepsis: a randomized controlled trial.

PURPOSE: Insufficient antimicrobial exposure is associated with worse outcomes in sepsis. We evaluated whether therapeutic drug monitoring (TDM)-guided antibiotic therapy improves outcomes. METHODS: Randomized, multicenter, controlled trial from January 2017 to December 2019. Adult patients (n = 254) with sepsis or septic shock were randomly assigned 1:1 to receive continuous infusion of piperacillin/tazobactam with dosing guided by daily TDM of piperacillin or continuous infusion with a fixed dose (13.5 g/24 h if eGFR ≥ 20 mL/min). Target plasma concentration was four times the minimal inhibitory concentration (range ± 20%) of the underlying pathogen, respectively, of Pseudomonas aeruginosa in empiric situation. Primary outcome was the mean of daily total Sequential Organ Failure Assessment (SOFA) score up to day 10. RESULTS: Among 249 evaluable patients (66.3 ± 13.7 years; female, 30.9%), there was no significant difference in mean SOFA score between patients with TDM (7.9 points; 95% CI 7.1-8.7) and without TDM (8.2 points; 95% CI 7.5-9.0) (p = 0.39). Patients with TDM-guided therapy showed a lower 28-day mortality (21.6% vs. 25.8%, RR 0.8, 95% CI 0.5-1.3, p = 0.44) and a higher rate of clinical (OR 1.9; 95% CI 0.5-6.2, p = 0.30) and microbiological cure (OR 2.4; 95% CI 0.7-7.4, p = 0.12), but these differences did not reach statistical significance. Attainment of target concentration was more common in patients with TDM (37.3% vs. 14.6%, OR 4.5, CI 95%, 2.9-6.9, p < 0.001). CONCLUSION: TDM-guided therapy showed no beneficial effect in patients with sepsis and continuous infusion of piperacillin/tazobactam with regard to the mean SOFA score. Larger studies with strategies to ensure optimization of antimicrobial exposure are needed to definitively answer the question.

Clinically Relevant Interactions with Anti-Infectives on Intensive Care Units-A Multicenter Delphi Study.

Patients in intensive care units (ICUs) are at high risk of drug-drug interactions (DDIs) due to polypharmacy. Little is known about type and frequency of DDIs within German ICUs. Clinical pharmacists' interventions (PI) recorded in a national database (ADKA-DokuPIK) were filtered for ICU patients. Binary DDIs involving ≥1 anti-infective agent with >1 database entry were selected. A modified two-step Delphi process with a group of senior hospital pharmacists was employed to evaluate selected DDIs for clinical relevance by using a five-point scale and to develop guidance for clinical practice. In total, 16,173 PI were recorded, including 1836 (11%) DDIs in the ICU setting. Of the latter, 41% (756/1836) included ≥1 anti-infective agent, 32% (590/1836) were binary DDIs, and 25% (455/1836) were listed at least twice. This translates into 88 different DDIs, 74% (65/88) of which were rated as being clinically relevant by our expert panel. The majority of DDIs (76% [67/88]) included macrolides, antifungals, or fluoroquinolones. This percentage was even higher in DDIs being rated as clinically relevant by the experts (85% [55/65]). It is noted that an inter-professional discussion and approach is needed in the individual patient management of DDIs. The guidance developed might be a tool for decision support.

Pharmacokinetics of meropenem in septic patients on sustained low-efficiency dialysis: a population pharmacokinetic study.

BACKGROUND: The aim of the study was to describe the population pharmacokinetics (PK) of meropenem in critically ill patients receiving sustained low-efficiency dialysis (SLED). METHODS: Prospective population PK study on 19 septic patients treated with meropenem and receiving SLED for acute kidney injury. Serial blood samples for determination of meropenem concentrations were taken before, during and after SLED in up to three sessions per patient. Nonparametric population PK analysis with Monte Carlo simulations were used. Pharmacodynamic (PD) targets of 40% and 100% time above the minimal inhibitory concentration (f T > MIC) were used for probability of target attainment (PTA) and fractional target attainment (FTA) against Pseudomonas aeruginosa. RESULTS: A two-compartment linear population PK model was most appropriate with residual diuresis supported as significant covariate affecting meropenem clearance. In patients without residual diuresis the PTA for both targets (40% and 100% f T > MIC) and susceptible P. aeruginosa (MIC ≤ 2 mg/L) was > 95% for a dose of 0.5 g 8-hourly. In patients with a residual diuresis of 300 mL/d 1 g 12-hourly and 2 g 8-hourly would be required to achieve a PTA of > 95% and 93% for targets of 40% f T > MIC and 100% f T > MIC, respectively. A dose of 2 g 8-hourly would be able to achieve a FTA of 97% for 100% f T > MIC in patients with residual diuresis. CONCLUSIONS: We found a relevant PK variability for meropenem in patients on SLED, which was significantly influenced by the degree of residual diuresis. As a result dosing recommendations for meropenem in patients on SLED to achieve adequate PD targets greatly vary. Therapeutic drug monitoring may help to further optimise individual dosing. TRIAL REGISTRATION: Clincialtrials.gov, NCT02287493 .

Impact of pancreatic comorbidities in patients with end-stage liver disease on outcome after liver transplantation.

BACKGROUND: Diseases leading to end-stage liver disease (ESLD), especially alcoholic liver cirrhosis cause comorbidities of the pancreas, too. The aim of this retrospective study was to determine the impact of pancreatic alterations diagnosed pretransplant on the outcome after liver transplantation (LT). METHODS: In total, data from 372 LT patients were analyzed. Patients were followed up for a mean of 4.2 years. Incidence of chronic pancreatitis (CP), pancreatic cysts (PC) and intraductal papillary mucinous neoplasm (IPMN) was acquired retrospectively from patient's charts. RESULTS: CP, IPMN and PC were rarely diagnosed in LT-recipients [CP (3.8%), PC (1.6%) and IPMN (1.6%)]. There was no significant correlation of IPMN, CP, PC and other patient characteristics. The prevalence of CP (log rank: p=0.315), PC (log rank: p=0.242) and IPMN (log rank: p=0.491) did not influence patient survival. CONCLUSION: Frequency of radiological alterations of the pancreas in LT recipients (such as CP, PC, IPMN) diagnosed by sonography, CT scan or MRI is comparable to the non-transplant population. Short term survival of LT-recipients after transplantation is not reduced for patients with CP, PC and patients with branch-duct IPMN (with a low-risk for malignancy according to international consensus guidelines).