Search

Background: Despite some recent advances, pancreatic ductal adenocarcinoma (PDAC) remains a growing oncological challenge. New drugs capable of targeting more than one oncogenic pathway may be one way to improve patient outcomes. This study characterizes the effectiveness of Metavert a first-in-class dual inhibitor of GSK3-β and histone deacetylase in treating PDAC as a single agent or in combination with standard cytotoxics., Methods: Thirty-six Patient-Derived Organoids (hPDOs) characterised by RNASeq and whole exome sequencing were treated with Metavert alone or in combination with standard cytotoxics. Transcriptomic signatures (TS) representing sensitivity to Metavert alone or sensitivity to Metavert + irinotecan (IR) were evaluated in 47 patient samples, chemo-naïve in 26 and post-chemotherapy in 21 (gemcitabine=5; FOLFIRINOX=14, both=2) with companion multiplexed immunofluorescence and RNASeq data., Results: Metavert combined with gemcitabine, irinotecan, 5FU, oxaliplatin, and paclitaxel was synergistic in the hPDOs. Basal-subtype hPDOs were more sensitive to Metavert alone whereas the Metavert+IR combination exhibited synergy in Classical-subtype hPDOs with increased apoptosis and autophagy. hPDO-derived TS evaluated in PDAC tissues demonstrated that Metavert-TS Hi samples were enriched for mRNA splicing and DNA repair processes; they were associated with Basal-like tissues but also with GATA6 +ve -chemo-naïve samples and were higher following gemcitabine but not FOLFIRINOX treatment. In contrast, Metavert+IR-TS HI samples were enriched for TP53 pathways; they were associated with Classical-like pretreatment samples and with GATA6 +ve /KRT17 +ve hybrid cell types following FOLFIRINOX, but not gemcitabine treatment, and were unrelated to transcriptional subtypes., Conclusions: Metavert as a single agent and in combination with irinotecan offers novel strategies for treating pancreatic cancer., Competing Interests: Declaration of competing interest ME and SP are involved in clinical development of Metavert with Avenzoar Pharmaceuticals. The remaining authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Background: Cefiderocol may potentially be used to treat skin and soft tissue infections (SSTIs). However, the pharmacokinetics of cefiderocol in human soft tissues have not yet been determined. The objective of the present PK study was to investigate whether target-site concentrations of cefiderocol are sufficiently high for the treatment of SSTIs., Methods: In this pharmacokinetic study, a single intravenous dose of 2 g cefiderocol was administered to eight healthy male volunteers. Drug concentrations were determined in plasma, muscle and subcutis over 8 h. Free plasma concentrations were calculated using the plasma protein binding determined with ultrafiltration. Free tissue concentrations were obtained using microdialysis. Penetration ratios were calculated as AUC0-8h_free_tissue/AUC0-8h_free_plasma. A population pharmacokinetic model was developed, and the probability of target attainment (PTA) was determined using Monte Carlo simulations., Results: Cefiderocol showed good tissue penetration, with mean penetration ratios ± standard deviation of 0.99 ± 0.33 and 0.92 ± 0.30 for subcutis and muscle, respectively. Cefiderocol pharmacokinetics in plasma were best described with a two-compartment model, and tissue concentrations were described by scaling the tissue concentrations to concentrations in the peripheral compartment of the plasma model. For a thrice-daily regimen with 2 g doses intravenously infused over 3 h, PTA was ≥90% for MIC values up to 4 mg/L, both based on free plasma and soft tissue pharmacokinetics., Conclusions: This study indicates that a dose of 2 g cefiderocol achieves concentrations in plasma considered sufficient for treating relevant bacterial species. Assuming a comparable PK/PD target for soft tissues, sufficiently high concentrations would also be achieved in soft tissues., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Objective: We aimed to investigate the association of electrocardiogram (ECG) findings with outcomes in patients with chronic coronary syndrome., Methods: This secondary analysis of the ISCHEMIA and ISCHEMIA-CKD trials divided patients with chronic coronary syndrome into two groups, those with a normal ECG tracing and abnormal ECG tracing. Repolarization abnormalities included ST-segment depression ≥ 0.5 mm and T-wave inversion ≥ 1 mm; conduction abnormalities included left and right bundle branch block (LBBB and RBBB). The primary endpoint was cardiovascular death. Outcomes were assessed using a covariate-adjusted Cox-regression model., Results: Of 5876 patients, 2901 (49.4%) had a normal and 2975 (50.6%) an abnormal ECG tracing. An abnormal ECG tracing at baseline, compared with a normal ECG tracing, was associated with an increased risk of cardiovascular death (257 of 2975 [8.6%] vs. 97 of 2901 [3.3%], adjusted hazard ratio [aHR] 2.01, 95% CI 1.58-2.55) over a median follow-up period of 3.1 years (IQR 2.1-4.2). This finding was consistent across subgroups except for patients with black skin color and current smokers, in whom an abnormal ECG was not significantly associated with increased risk of cardiovascular death. Individual ECG abnormalities (ST-segment depression [aHR 2.0, 95% CI 1.52-2.63], T-wave inversion [aHR 1.89, 95% CI 1.40-2.54], LBBB [aHR 1.74, 95% CI 1.05-2.90], and RBBB [aHR 1.52, 95% CI 1.04-2.22]) were independently associated with an increased risk of cardiovascular death., Conclusion: In patients with chronic coronary syndrome, an abnormal ECG tracing was associated with an increased risk of cardiovascular death. Our findings underscore the importance of the ECG in cardiovascular risk stratification and prognostication., Trial Registration: NCT01471522, BioLINCC ID 14539., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Here, we report about a patient with a full-thickness burn injury of the left lower extremity with approximately 8% of total BSA affected. Initial therapy consisted of necrosectomy and wound coverage with split-thickness graft. The patient developed a wound infection with Pseudomonas aeruginosa, resulting in the failure of the skin graft to achieve complete healing. The case was further complicated by the patient's concurrent presentation of anemia, characterized by a hematocrit level of 19.8% on 11th day after admission. Additionally, the patient refused acceptance of any blood transfusion, adding a significant layer of complexity to the management strategy. In summary, the patient's critical state required an immediate intervention. Due to the contraindication for a further surgical debridement and autograft, we changed the treatment strategy to a conservative approach. First, the wound was debrided employing maggot therapy 17 days after admission. Subsequently, free soft tissue coverage was accomplished using decellularized fish skin dressings on 45th day. This approach yielded satisfactory wound closure. Following an approximately 2-month hospitalization period (52nd day after admission), the patient was discharged with a stable wound condition, nearing complete healing., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Burn Association.)

Purpose: Severe burn injuries are often accompanied by infections and associated with high morbidity and mortality. This study aimed to compare the prevalence and clinical impact of bacteremia between patients receiving intensive care with and without burns., Methods: This single-center retrospective cohort study at the University Hospital Vienna, Austria, analyzed blood cultures from intensive care unit (ICU) patients with and without burns (2012-2022) to assess the prevalence of bacteremia, the associated pathogen distribution and the 60-day all-cause mortality., Results: In 1170 ICU patients, 303 with burns and 867 without, the prevalence of bacteremia was similar among patients with at least one blood culture (31/157 [19.7%] versus 44/213 [20.7%], OR [95%CI] = 0.95 [0.57-1.57]). Burn patients exhibited a significantly higher frequency of microbiological sampling (51.5% versus 24.5%, p < 0.001), resulting in a higher overall prevalence of bacteremia (10.2% versus 5.1%, p = 0.002). 16.2% of all identified pathogens were multidrug-resistant (MDR). The 60-day all-cause mortality was higher in patients with MDR pathogens than in patients without bacteremia (41.7% versus 10.6%, p = 0.026)., Conclusion: Bacteremia prevalence was similar in burn and non-burn patients, with high rates of multidrug-resistant Gram-negative pathogens. The 60-day all-cause mortality was significantly higher in patients with MDR pathogens than in patients without bacteremia., (© 2024. The Author(s).)

Background: Various SARS-CoV-2 variants of concerns (VOCs) characterized by higher transmissibility and immune evasion have emerged. Despite reduced vaccine efficacy against VOCs, currently available vaccines provide protection. Population-based evidence on the humoral immune response after booster vaccination is crucial to guide future vaccination strategies and in preparation for imminent COVID-19 waves., Methods: This multicenter, population-based cohort study included 4697 individuals ≥18 years of age who received a booster vaccination. Antibody levels against SARS-CoV-2 receptor binding domain (RBD) and neutralizing antibodies against wild-type (WT) virus and Omicron variants were assessed at baseline (day of booster vaccination) and after four weeks. Safety was evaluated daily within the first week using a participant-completed electronic diary. Antibody levels were compared across different vaccination strategies, taking into account individual host factors., Results: Our main model including 3838 participants revealed that individuals who received a booster with mRNA-1273 compared to BNT162b2 vaccine had a significantly higher increase (95 %CI) in anti-RBD-antibody levels (37,707 BAU/mL [34,575-40,839] vs. 27,176 BAU/mL [26,265-28,087]), and of neutralization levels against WT (1,681 [1490-1872] vs. 1141 [1004-1278] and Omicron variant (422 [369-474] vs. 329 [284-374]). Neutralizing antibody titres highly correlated with anti-RBD antibodies, with neutralizing capacity 4.4 fold higher against WT compared to Omicron. No differences in safety were found between the two booster vaccines., Conclusion: Our study underlines the superiority of a booster vaccination with mRNA-1273, independent of the primary vaccination and therefore provides guidance on the vaccination strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objective: The key characteristics of light propagation are the average penetration depth, average maximum penetration depth, average maximum lateral spread, and average path length of photons. These parameters depend on tissue optical properties and, thus, on the pathological state of the tissue. Hence, they could provide diagnostic information on tissue integrity. This study investigates these parameters for articular cartilage which has a complex structure., Methods: We utilize Monte Carlo simulation to simulate photon trajectories in articular cartilage and estimate the average values of the light propagation parameters (penetration depth, maximum penetration depth, maximum lateral spread, and path length) in the spectral band of 400-1400 nm based on the optical properties of articular cartilage zonal layers and bulk tissue., Results: Our findings suggest that photons in the visible band probe a localized small volume of articular cartilage superficial and middle zones, while those in the NIR band penetrate deeper into the tissue and have larger lateral spread. In addition, we demonstrate that a simple model of articular cartilage tissue, based on the optical properties of the bulk tissue, is capable to provide an accurate description of the light-tissue interaction in articular cartilage., Conclusion: The results indicate that as the photons in the spectral band of 400-1400 nm can reach the full depth of articular cartilage matrix, they can provide viable information on its pathological state. Therefore, diffuse optical spectroscopy holds significant importance for objectively assessing articular cartilage health., Significance: In this study, for the first time, we estimate the light propagation parameters in articular cartilage.

Introduction: Lipopolysaccharide (LPS) stimulation of human whole blood ex vivo has been widely used to investigate human innate immune responses. However, there are uncertainties regarding the reproducibility and reliability of this assay., Methods: In this prospective, single-center study, cytokine responses (interleukin 8, interferon-α, interferon-γ, interleukin 10, interleukin 1-β, interleukin 6, and tumor necrosis factor-α) to ex vivo whole blood LPS stimulation were assessed in 12 healthy volunteers. Cytokine levels were measured at 0, 2, and 4 h using a multiplex immunoassay (Luminex ® ). Stimulation was repeated after six weeks. We examined reproducibility across technical and biological replicates at baseline and between repeated experiments after 6 weeks based on the area under the curve (AUC) of the individual cytokines using Pearson's correlation coefficient and the mean coefficient of variation., Results: The lowest mean coefficients of variation were observed for the technical replicates (5.4 to 9.2%), followed by the biological replicates (8.1 to 24.8%), and the repeated experiments after 6 weeks (17 to 31.2%). Between the baseline and 6-week AUCs, the following Pearson correlation coefficients R were observed: interleukin 10, 0.97; interferon-α, 0.84; interleukin 1-β, 0.83; interleukin 8, 0.79; interleukin 6, 0.73; interferon-γ, 0.73; and tumor necrosis factor-α, 0.63., Discussion: The level of agreement between the baseline and week-6 cytokine response to ex vivo LPS stimulation was high across the seven cytokines analyzed. While interleukin 10 exhibited the lowest level of variability over time, tumor necrosis factor-α showed the highest variability in repeated experiments, which should be considered in the design and interpretation of future studies., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Jorda et al.)

Background: Early fluid management in patients with advanced chronic kidney disease (CKD) and sepsis-induced hypotension is challenging with limited evidence to support treatment recommendations. We aimed to compare an early restrictive versus liberal fluid management for sepsis-induced hypotension in patients with advanced CKD., Methods: This post-hoc analysis included patients with advanced CKD (eGFR of less than 30 mL/min/1.73 m 2 or history of end-stage renal disease on chronic dialysis) from the crystalloid liberal or vasopressor early resuscitation in sepsis (CLOVERS) trial. The primary endpoint was death from any cause before discharge home by day 90., Results: Of 1563 participants enrolled in the CLOVERS trial, 196 participants had advanced CKD (45% on chronic dialysis), with 92 participants randomly assigned to the restrictive treatment group and 104 assigned to the liberal fluid group. Death from any cause before discharge home by day 90 occurred significantly less often in the restrictive fluid group compared with the liberal fluid group (20 [21.7%] vs. 41 [39.4%], HR 0.5, 95% CI 0.29-0.85). Participants in the restrictive fluid group had more vasopressor-free days (19.7 ± 10.4 days vs. 15.4 ± 12.6 days; mean difference 4.3 days, 95% CI, 1.0-7.5) and ventilator-free days by day 28 (21.0 ± 11.8 vs. 16.5 ± 13.6 days; mean difference 4.5 days, 95% CI, 0.9-8.1)., Conclusions: In patients with advanced CKD and sepsis-induced hypotension, an early restrictive fluid strategy, prioritizing vasopressor use, was associated with a lower risk of death from any cause before discharge home by day 90 as compared with an early liberal fluid strategy., Trial Registration: NCT03434028 (2018-02-09), BioLINCC 14149., (© 2024. The Author(s).)

Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Purpose: Pancreatic cancer (PDAC) is characterized by infiltrative, spiculated tumor growth into the surrounding non-neoplastic tissue. Clinically, its diagnosis is often established by magnetic resonance imaging (MRI). At the invasive margin, tumor buds can be detected by histology, an established marker associated with poor prognosis in different types of tumors., Methods: We analyzed PDAC by determining the degree of tumor spiculation on T2-weighted MRI using a 3-tier grading system. The grade of spiculation was correlated with the density of tumor buds quantified in histological sections of the respective surgical specimen according to the guidelines of the International Tumor Budding Consensus Conference (n = 28 patients)., Results: 64% of tumors revealed intermediate to high spiculation on MRI. In over 90% of cases, tumor buds were detected. We observed a significant positive rank correlation between the grade of radiological tumor spiculation and the histopathological number of tumor buds (r s = 0.745, p < 0.001). The number of tumor buds was not significantly associated with tumor stage, presence of lymph node metastases, or histopathological grading (p ≥ 0.352)., Conclusion: Our study identifies a readily available radiological marker for non-invasive estimation of tumor budding, as a correlate for infiltrative tumor growth. This finding could help to identify PDAC patients who might benefit from more extensive peripancreatic soft tissue resection during surgery or stratify patients for personalized therapy concepts., (© 2024. The Author(s).)

Distinguishing primary liver cancer (PLC), namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), from liver metastases is of crucial clinical importance. Histopathology remains the gold standard, but differential diagnosis may be challenging. While absent in most epithelial, the expression of the adherens junction glycoprotein N-cadherin is commonly restricted to neural and mesenchymal cells, or carcinoma cells that undergo the phenomenon of epithelial-to-mesenchymal transition (EMT). However, we recently established N- and E-cadherin expression as hallmarks of normal hepatocytes and cholangiocytes, which are also preserved in HCC and iCCA. Therefore, we hypothesized that E- and/or N-cadherin may distinguish between carcinoma derived from the liver vs carcinoma of other origins. We comprehensively evaluated E- and N-cadherin in 3359 different tumors in a multicenter study using immunohistochemistry and compared our results with previously published 882 cases of PLC, including 570 HCC and 312 iCCA. Most carcinomas showed strong positivity for E-cadherin. Strong N-cadherin positivity was present in HCC and iCCA. However, except for clear cell renal cell carcinoma (23.6% of cases) and thyroid cancer (29.2%), N-cadherin was only in some instances faintly expressed in adenocarcinomas of the gastrointestinal tract (0%-0.5%), lung (7.1%), pancreas (3.9%), gynecological organs (0%-7.4%), breast (2.2%) as well as in urothelial (9.4%) and squamous cell carcinoma (0%-5.6%). As expected, N-cadherin was detected in neuroendocrine tumors (25%-75%), malignant melanoma (46.2%) and malignant mesothelioma (41%). In conclusion, N-cadherin is a useful marker for the distinction of PLC vs liver metastases of extrahepatic carcinomas (P < .01)., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remain limited., Materials and Methods: We conducted a prospective single-centre pharmacokinetic (PK) study in 12 healthy volunteers. Subjects received seven doses of 200 mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12 h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12 h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12 h. The AUC/MIC was calculated for an MIC value of 1 mg/L, which marks the EUCAST susceptibility breakpoint for Aspergillus fumigatus and Aspergillus flavus., Results: C max and AUC0-24h of isavuconazole in plasma under assumed steady-state conditions were 6.57 ± 1.68 mg/L (mean ± SD) and 106 ± 32.1 h·mg/L, respectively. The average concentrations measured in CSF, ELF and in PBMCs were 0.07 ± 0.03, 0.94 ± 0.46 and 27.1 ± 17.8 mg/L, respectively. The AUC/MIC in plasma, CSF, ELF and in PBMCs under steady-state conditions were 106 ± 32.1, 1.68 ± 0.72, 22.6 ± 11.0 and 650 ± 426 mg·h/L, respectively., Conclusion: Isavuconazole demonstrated moderate penetration into ELF, low penetrability into CSF and high accumulation in PBMCs. Current dosing regimens resulted in sufficient plasma exposure in all subjects to treat isolates with MICs ≤ 1 mg/L., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: APN01 is a soluble recombinant human angiotensin-converting enzyme 2 (rhACE2), a key player in the renin-aldosterone-angiotensin system (RAAS). In clinical studies, APN01 was administered intravenously only, so far. The aim of this study (ClinicalTrials.gov: NCT05065645) was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of inhaled APN01., Methods: This was a phase I, double-blind, placebo-controlled, dose-escalation study. Inhalation was conducted via a nebuliser over 15 min in three single ascending dose (SAD) cohorts (n=24) and two multiple ascending dose (MAD) cohorts (n=16: every 12 h for 7 days). Doses in the SAD cohort were 1.25, 2.5 and 5 mg·mL -1 ; doses in the MAD cohort were 2.5 and 5 mg·mL -1 . Safety (including adverse events (AEs), laboratory findings and lung function results), PK and PD data were assessed., Results: In the SAD and MAD cohorts, treatment-related AEs were slightly more frequent in the active treatment group than in the placebo group. AEs were mild to moderate, with no dose-limiting toxicities. No clinically relevant changes in lung function and laboratory results were observed. The mean maximum observed plasma concentration ( C max ) values after single and multiple doses of 5 mg·mL -1 APN01 were 1.88 and 6.61 ng·mL -1 , respectively. Among the PD variables, significance was found for ACE2 and angiotensin 1-5., Conclusions: The application of aerosolised APN01 is safe and well tolerated after single and multiple doses. By achieving a high local concentration in the lungs and low systemic bioavailability, inhaled rhACE2 may present a therapeutic option in ACE2-related diseases., Competing Interests: Conflict of interest: This work was supported by Apeiron Biologics and conducted as contract research at the Medical University of Vienna, Department of Pulmology and Department of Clinical Pharmacology. The funder did not have any role in the execution of the study or interpretation of data. The academic authors declare no conflict of interest., (Copyright ©The authors 2024.)

Background: Bacterial co-infections are believed to be less frequent in patients with Covid-19 than influenza, but frequencies varied between studies., Methods: This single-center retrospective, propensity score-matched analysis included adult patients with Covid-19 or influenza admitted to normal-care wards between 02/2014 and 12/2021. Covid-19 cases were propensity score matched to influenza cases at a 2:1 ratio. Community-acquired and hospital-acquired bacterial co-infections were defined as positive blood or respiratory cultures ≤ 48 h or > 48 h after hospital admission, respectively. The primary outcome was comparison of community-acquired and hospital-acquired bacterial infections between patients with Covid-19 and influenza in the propensity score-matched cohort. Secondary outcomes included frequency of early and late microbiological testing., Results: A total of 1337 patients were included in the overall analysis, of which 360 patients with Covid-19 were matched to 180 patients with influenza. Early (≤ 48 h) microbiological sampling was performed in 138 (38.3%) patients with Covid-19 and 75 (41.7%) patients with influenza. Community-acquired bacterial co-infections were found in 14 (3.9%) of 360 patients with Covid-19 and 7 (3.9%) of 180 patients with influenza (OR 1.0, 95% CI 0.3-2.7). Late (> 48 h) microbiological sampling was performed in 129 (35.8%) patients with Covid-19 and 74 (41.1%) patients with influenza. Hospital-acquired bacterial co-infections were found in 40 (11.1%) of 360 patients with Covid-19 and 20 (11.1%) of 180 patients with influenza (OR 1.0, 95% CI 0.5-1.8)., Conclusion: The rate of community-acquired and hospital-acquired bacterial co-infections was similar in hospitalized Covid-19 and influenza patients. These findings contrast previous literature reporting that bacterial co-infections are less common in Covid-19 than influenza., (© 2023. The Author(s).)

Background: Pathophysiological changes in severely burned patients alter the pharmacokinetics (PK) of anti-infective agents, potentially leading to subtherapeutic concentrations at the target site. Albumin supplementation, to support fluid resuscitation, may affect pharmacokinetic properties by binding drugs. This study aimed to investigate the PK of piperacillin/tazobactam in burn patients admitted to the ICU before and after albumin substitution as total and unbound concentrations in plasma., Patients and Methods: Patients admitted to the ICU and scheduled for 4.5 g piperacillin/tazobactam administration and 200 mL of 20% albumin substitution as part of clinical routine were included. Patients underwent IV microdialysis, and simultaneous arterial plasma sampling, at baseline and multiple timepoints after drug administration. PK analysis of total and unbound drug concentrations under steady-state conditions was performed before and after albumin supplementation., Results: A total of seven patients with second- to third-degree burns involving 20%-60% of the total body surface were enrolled. Mean (SD) AUC0-8 (h·mg/L) of total piperacillin/tazobactam before and after albumin substitution were 402.1 (242)/53.2 (27) and 521.8 (363)/59.7 (32), respectively. Unbound mean AUC0-8 before and after albumin supplementation were 398.9 (204)/54.5 (25) and 456.4 (439)/64.5 (82), respectively., Conclusions: Albumin supplementation had little impact on the PK of piperacillin/tazobactam. After albumin supplementation, there was a numerical increase in mean AUC0-8 of total and unbound piperacillin/tazobactam, whereas similar Cmax values were observed. Future studies may investigate the effect of albumin supplementation on drugs with a higher plasma protein binding., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

To assess changes in treatment modalities for supracondylar humerus fractures (SCHFs) at a large pediatric university hospital, we analyzed patient data from 2014 to 2022. A total of 233 SCHFs treated surgically at our hospital were included. To evaluate postoperative outcome and quality of life, DASH and EuroQol-5D-Y questionnaires were sent to patients. In addition to a significant fluctuation in fracture severity, we found an increase in training interventions (more surgeries were performed by trainees) and a significant decrease in surgery times after 2016. From 2020, there was a significant shift in the type of surgical method away from closed reduction with elastic stable intramedullary nailing (ESIN) and towards closed reduction and crossed K-wire osteosynthesis (CRK). Surgeries performed in the morning and evening hours increased, while those performed in the afternoon and after midnight decreased. After a mean follow-up of 4 years, there was no difference in elbow function between ESIN and open reduction and K-wires (ORK). Treatment with ESIN was equivalent to ORK in terms of function, at least in the medium-term follow-up. In summary, the combination of shifting treatment from SCHF to daytime hours, increasing trainee participation and using cross K-wire fixation instead of ESIN had no negative impact on surgery times. In our setting, these measures have reduced resource utilization and increased efficiency without compromising patient care.

Background: Community-acquired pneumonia (CAP) is associated with high morbidity and mortality. In the present study, we aimed to assess the effect of corticosteroids on all-cause mortality in patients hospitalized with CAP., Methods: For this meta-analysis and meta-regression, we conducted a systematic search of trials that evaluated the effect of corticosteroid therapy in patients hospitalized with CAP through March 2023. We included randomized, controlled trials, comparing adjunctive corticosteroid therapy with the standard of care alone for treatment of patients hospitalized with CAP and reporting all-cause mortality. We excluded retrospective analyses, observational data, and trial protocols. The primary outcome was all-cause mortality within 30 days after hospital admission. The safety analysis included the frequency of adverse events and steroid-associated adverse events., Results: The literature search identified 35 713 citations, of which 15 studies and 3367 patients were eligible for the final analysis. The all-cause mortality at 30 days was significantly lower in the corticosteroid group (104 of 1690, 6.15%) than in the control group (152 of 1677, 9.06%; risk ratio [RR], 0.67; 95% confidence interval [CI], .53 to .85; P = .001; I2 = 0%). In 9 studies (2549 patients) that reported the occurrence of adverse events, corticosteroid therapy was not associated with an increased risk of developing any adverse event compared with standard care (RR, 0.90; 95% CI, .65 to 1.24; P = .5; I2 = 88%)., Conclusions: Adjunctive systemic corticosteroid therapy in patients hospitalized with CAP was associated with a reduction in all-cause mortality by day 30. The benefits were more pronounced in patients with severe pneumonia., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Postsurgical handover of pediatric patients from operating rooms (OR) to pediatric intensive care units (PICU) is a critical step. This transition is susceptible to errors and inefficiencies particularly if poor multidisciplinary teamwork occurs. Despite wide adoption of standardized handover interventions, comprehensive investigations into joint effects for patient care and provider outcomes are scarce. We aimed to improve OR-PICU handovers quality and sought to evaluate the intervention with particular attention to patient care effects and provider outcomes. A prospective, before-after-study design with an interrupted-series and a multi-source, mixed-methods evaluation approach was established. Drawing upon a participative plan-do-study-act approach, a standardized, checklist-based handover process was designed and implemented. For effect assessments, we observed OR-PICU handovers on site (pre implementation: n = 31, post: n = 30), respectively, with standardized expert observation and provider self-report tools (n = 111, n = 110). Setting was a tertiary Pediatric University Hospital. Supplementary qualitative, semi-structured interviews were conducted, and a general inductive content analysis approach was used to identify key facilitators and barriers on implementation. Improvement efforts focused on stepwise implementation of (1) standardized handover process and (2) a checklist for multi-professional OR-PICU handover communication. We observed significant increases in team and patient setup (pre: 79.3%, post: 98.6%, p < .01), enhanced team engagement (pre: 50%, post: 81.7%, p < .01), and comprehensive information transfer by the anesthesia sub-team (pre: 78.6%, post: 87.3%, p < .01). Expert-rated teamwork outcomes were consistently higher, yet self-reported teamwork did not change over time. Provider perceived stress and disruptions did not change, mental workload tended to decrease over time (pre: M = 3.2, post: 2.9, p = .08). Comprehensiveness of post-operative patient information reported by PICU physician increased significantly: pre: 65.9%, post: 76.2%, p < .05. After implementation, providers acknowledged the importance of standardized handover practices and associated benefits for facilitation of information transfer and comprehensiveness. Among reported barriers were obstacles during implementation as well as insufficient consideration of professionals' individual workflow after surgery., Conclusion:  A multidisciplinary intervention for postsurgical pediatric patient handovers was associated with improved expert-rated teamwork and fewer omissions of key patient information over time. Inconsistent results were obtained for provider-rated mental workload and teamwork outcomes. The findings contribute to a better understanding concerning the interplay of teamwork and provider cognitions in the course of establishing safe patient transitions in pediatric care., What Is Known: • Transfer of critically ill children conveys significant challenges for interprofessional communication and teamwork. Prospective research into interventions for safe and efficient handover practices of OR PICU patient transitions is necessary. • Checklists are assumed to facilitate cognitive load among providers in acute clinical environments., What Is New: • A standardized, checklist-based handover intervention was associated with improvements in team set-up and information transfer. Provider outcomes such as mental workload and stress did not change over time. • The combination of teamwork and provider assessments allows a more nuanced understanding of implementation barriers and sustainable effects in course of OR-PICU handover interventions., (© 2023. The Author(s).)

Significance: Articular cartilage exhibits a zonal architecture, comprising three distinct zones: superficial, middle, and deep. Collagen fibers, being the main solid constituent of articular cartilage, exhibit unique angular and size distribution in articular cartilage zones. There is a gap in knowledge on how the unique properties of collagen fibers across articular cartilage zones affect the scattering properties of the tissue., Aim: This study hypothesizes that the structural properties of articular cartilage zones affect its scattering parameters. We provide scattering coefficient and scattering anisotropy factor of articular cartilage zones in the spectral band of 400 to 1400 nm. We enumerate the differences and similarities of the scattering properties of articular cartilage zones and provide reasoning for these observations., Approach: We utilized collimated transmittance and integrating sphere measurements to estimate the scattering coefficients of bovine articular cartilage zones and bulk tissue. We used the relationship between the scattering coefficients to estimate the scattering anisotropy factor. Polarized light microscopy was applied to estimate the depth-wise angular distribution of collagen fibers in bovine articular cartilage., Results: We report that the Rayleigh scatterers contribution to the scattering coefficients, the intensity of the light scattered by the Rayleigh and Mie scatterers, and the angular distribution of collagen fibers across tissue depth are the key parameters that affect the scattering properties of articular cartilage zones and bulk tissue. Our results indicate that in the short visible region, the superficial and middle zones of articular cartilage affect the scattering properties of the tissue, whereas in the far visible and near-infrared regions, the articular cartilage deep zone determines articular cartilage scattering properties., Conclusion: This study provides scattering properties of articular cartilage zones. Such findings support future research to utilize optical simulation to estimate the penetration depth, depth-origin, and pathlength of light in articular cartilage for optical diagnosis of the tissue., (© 2023 The Authors.)

Usutu virus (USUV) is a mosquito-borne flavivirus that is widely distributed in southern and central Europe. The zoonotic virus circulates primarily between birds and mosquitoes, can, however, in rare cases infect other mammals including humans. In the past, USUV has been repeatedly associated with mass mortalities in birds, primarily blackbirds and owls. Birds commonly succumb either due to the peracute nature of the infection or due to severe encephalitis. In Germany, USUV has spread rapidly since its first detection in 2010 in mosquitoes under the presence of susceptible host and vector species. Nonetheless, there is to date limited access to whole genome sequences resulting in the absence of in-depth phylogenetic and phylodynamic analyses. In this study, 118 wild and captive birds were sequenced using a nanopore sequencing platform with prior target enrichment via amplicons. Due to the high abundancy of Europe 3 and Africa 3 in Germany an ample quantity of associated whole genome sequences was generated and the most recent common ancestor could be determined for each lineage. The corresponding clock phylogeny revealed an introduction of USUV Europe 3 and Africa 3 into Germany three years prior to their first isolation in the avifauna in 2011 and 2014, respectively. Based on the clustering and temporal history of the lineages, evidence exists for the genetic evolution of USUV within Germany as well as new introductions thereof into the country., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bergmann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily that controls bile acid (BA) homeostasis, has also been proposed as a tumor suppressor for breast and liver cancer. However, its role in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis remains controversial. We recently found that FXR attenuates acinar cell autophagy in chronic pancreatitis resulting in reduced autophagy and promotion of pancreatic carcinogenesis. Feeding Kras-p48-Cre (KC) mice with the BA chenodeoxycholic acid (CDCA), an FXR agonist, attenuated pancreatic intraepithelial neoplasia (PanIN) progression, reduced cell proliferation, neoplastic cells and autophagic activity, and increased acinar cells, elevated pro-inflammatory cytokines and chemokines, with a compensatory increase in the anti-inflammatory response. Surprisingly, FXR-deficient KC mice did not show any response to CDCA, suggesting that CDCA attenuates PanIN progression and decelerate tumorigenesis in KC mice through activating pancreatic FXR. FXR is activated in pancreatic cancer cell lines in response to CDCA in vitro. FXR levels were highly increased in adjuvant and neoadjuvant PDAC tissue compared to healthy pancreatic tissue, indicating that FXR is expressed and potentially activated in human PDAC. These results suggest that BA exposure activates inflammation and suppresses autophagy in KC mice, resulting in reduced PanIN lesion progression. These data suggest that activation of pancreatic FXR has a protective role by reducing the growth of pre-cancerous PDAC lesions in response to CDCA and possibly other FXR agonists., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Although generic medicinal products are required to have the same qualitative and quantitative composition of the active substance as their reference originator product, patients and health care professionals express concerns about their interchangeability and safety. Therefore, the present study investigated the antimicrobial activity and pathogen mutation prevention of original and generic cefepime, linezolid and piperacillin/tazobactam against Staphylococcus aureus., Methods: Two generic formulations of cefepime, linezolid and piperacillin/tazobactam were tested against their respective originator products. Susceptibility testing was performed with twenty-one clinical isolates of S. aureus and ATCC-29213 using broth microdilution. Time kill curves (TKC) were performed with ATCC-29213 at drug concentrations above and below the respective minimum inhibitory concentrations (MIC). Mutation prevention concentration was determined for each drug formulation against ATCC-29213. All experiments were performed in triplicate. Mutant colonies from mutation prevention concentration (MPC) experiments were genotypically tested by sequence analysis., Results: MIC ratios between contiguous originator and generic drugs were similar for each isolate. No visual differences were observed in TKCs between originator and generic substances. The MPC did not differ between different formulations of the same substance. Although sequence analysis of mutant colonies revealed genomic differences compared with the original ATCC-29213, no differences in mutation frequencies were observed between clinical isolates and ATCC-29213 treated with originator or generic substances., Conclusions: Similar antimicrobial activity and pathogen mutation prevention was observed between contiguous substances. These results support the interchangeability of generic and originator drug formulations with the same active ingredient., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNA sequencing (n = 97) and multiplexed immunofluorescence (n = 122) on chemo-naive and postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high-resolution mapping of whole-tissue sections identified GATA6 (classical), KRT17 (basal-like) and cytochrome P450 3A (CYP3A) coexpressing cells that were preferentially enriched in post-CTX resected samples. The persistence of GATA6 hi and KRT17 hi cells post-CTX was significantly associated with poor survival after mFOLFIRINOX (mFFX), but not gemcitabine (GEM), treatment. Analysis of organoid models derived from chemo-naive and post-CTX samples demonstrated that CYP3A expression is a predictor of chemotherapy response and that CYP3A-expressing drug detoxification pathways can metabolize the prodrug irinotecan, a constituent of mFFX. These findings identify CYP3A-expressing drug-tolerant cell phenotypes in residual disease that may ultimately inform adjuvant treatment selection., (© 2023. The Author(s).)

Objectives: A weak correlation between symptom severity and antibody levels after primary immunization against COVID-19 has already been shown. This study aimed to describe the association between reactogenicity and immunogenicity after booster vaccination., Methods: This secondary analysis of a prospective cohort study included 484 healthcare workers who received a booster vaccination with BNT162b2. Anti-receptor binding domain (RBD) antibodies were assessed at baseline and 28 days after booster vaccination. Side effects were graded (none, mild, moderate, or severe) and reported daily for 7 days after booster vaccination. Spearman correlation coefficient (rho) was used to determine the correlations between the severity of each symptom and anti-RBD levels before vaccination and 28 days after. The Bonferroni method was used to adjust p values for multiple comparisons., Results: Most of the 484 participants reported at least one local (451 [93.2%]) or systemic (437 [90.3%]) post-booster symptom. No correlations between the severity of local symptoms and antibody levels were found. Except for nausea, systemic symptoms showed weak but statistically significant correlations with 28-day anti-RBD levels (fatigue [rho = 0.23, p < 0.01], fever [rho = 22, p < 0.01], headache [rho = 0.15, p 0.03], arthralgia [rho = 0.2, p < 0.01], myalgia [rho = 0.17, p < 0.01]). There was no association between post-booster symptoms and pre-booster antibody levels., Discussion: This study showed only a weak correlation between the severity of systemic post-booster symptoms and anti-SARS-CoV-2 antibody levels at 28 days. Therefore, self-reported symptom severity cannot be used to predict immunogenicity after booster vaccination., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Traumatic hip dislocations are very rare in childhood and adolescence. The aim of this multi-centre study is to analyse the current epidemiology and injury morphology of a large number of traumatic hip dislocations in children. This can provide a better understanding of childhood hip dislocations and contribute to the development of a therapeutic approach in order to prevent long-term impacts., Methodology: This retrospective, anonymised multi-centre study included patients, aged up to 17 years, with acute traumatic hip dislocations and open growth plates. The patients came from 16 German hospitals. Exclusion criteria included insufficient data, a positive history of hip dysplasia, or an association with syndromal, neurological or connective tissue diseases predisposing to hip dislocation. An analysis was carried out on the patients' anthropometric data and scans (X-ray, MRI, CT), which were collected between 1979 and 2021. Gender, age at the time of dislocation, associated fractures, mechanism of injury, initial treatment including time between dislocation and reduction, method of reduction, treatment algorithm following reduction and all documented complications and concomitant injuries were evaluated., Results: Seventy-six patients met the inclusion criteria. There were two age peaks at 4-8 years and 11-15 years. There was an increased incidence of girls in the under-eight age group, who had mild trauma, and in the group of over-eights there were more boys, who had moderate and severe trauma. Dorsal dislocation occurred in 89.9% of cases. Mono-injuries dominated across all age groups. Concomitant injuries rarely occurred before the age of eight; however, they increased with increasing ossification of the acetabulum and appeared as avulsion injuries in 32% of 11-15-year-olds. Of the 76 patients, 4 underwent a spontaneous, 67 a closed and 5 a primary open reduction. A reduction was performed within 6 h on 84% of the children; however, in around 10% of cases a reduction was not performed until after 24 h. Concomitant injuries needing intervention were identified in 34 children following reduction. Complications included nerve irritation in the form of sensitivity disorders (n = 6) as well as avascular necrosis (AVN) of the femoral head in 15.8% of the patients (n = 12)., Conclusions: Traumatic hip dislocations are rare in childhood and adolescence and have high complication rates. The most severe complication, femoral head necrosis, occurred in 16% of cases. Minor injuries, especially in younger children, are enough to cause a dislocation. Posterior dislocation was more frequent and primarily occurred as a mono-injury; however, concomitant injuries must be considered with increasing age. Children continue to experience delayed reductions. The length of time until reduction, age and the severity of the concomitant injury play a role in the development of femoral head necrosis; however, this topic requires additional investigation., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Usutu virus (USUV) and West Nile virus (WNV) are closely related pathogens circulating between mosquitoes and birds, but also infecting mammals as dead-end hosts. Both viruses share the same susceptible hosts, vectors, and even distribution areas in Central Europe. The aim of the study was, therefore, to understand their amplification potential and interference upon a successive infection. Two-week old geese were initially infected with an USUV isolate from Germany and with a German WNV isolate17 days later. The geese were susceptible to the USUV and the WNV infections, as evidenced by specific flavivirus antibodies in all of the birds. Furthermore, in half of the USUV-inoculated geese, USUV genomes were detected in the blood and swab samples 2-4 days post-infection. Additionally, most of the examined organs contained USUV genomes and showed signs of encephalitis and ganglioneuritis. Interestingly, upon a sequential infection with WNV, the genome copy numbers in all of the examined samples were significantly lower and less frequent than after a WNV mono-infection. Similarly, the histopathological lesions were less severe. Therefore, it can be concluded that a previous USUV infection can protect birds from clinical disease in a subsequent WNV infection.

There is increasing research on the potential application of diffuse optical spectroscopy and hyperspectral imaging for characterizing the health of the connective tissues, such as articular cartilage, during joint surgery. These optical techniques facilitate the rapid and objective diagnostic assessment of the tissue, thus providing unprecedented information toward optimal treatment strategy. Adaption of optical techniques for diagnostic assessment of musculoskeletal disorders, including osteoarthritis, requires precise determination of the optical properties of connective tissues such as articular cartilage. As every indirect method of tissue optical properties estimation consists of a measurement step followed by a computational analysis step, there are parameters associated with these steps that could influence the estimated values of the optical properties. In this study, we report the absorption and reduced scattering coefficients of articular cartilage in the spectral band of 400-1400 nm. We assess the impact of the experimental setup parameters, including surrounding medium, sample volume, and scattering anisotropy factor on the reported optical properties. Our results suggest that the absorption coefficient of articular cartilage is sensitive to the variation in the surrounding medium, whereas its reduced scattering coefficient is invariant to the experimental setup parameters., Competing Interests: The Authors declare no conflict of interest., (Published by Optica Publishing Group under the terms of the Creative Commons Attribution 4.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.)

Hydrolysis of polysorbate in biopharmaceutical products has been ascribed to the enzymatic activity from trace levels of residual host cell proteins. In recent years, significant efforts to identify the causative enzymes typically used elaborate, material-intensive and time-consuming approaches. Therefore, the lack of fast and sensitive assays to monitor their activity remains a major bottleneck for supporting process optimization and troubleshooting activities where time and sample throughput are crucial constraints. To address this bottleneck, we developed a novel Electrochemiluminescence-based Polysorbase Activity (EPA) assay to measure hydrolytic activities in biotherapeutics throughout the drug substance manufacturing process. By combining the favorable features of an in-house designed surrogate substrate with a well-established detection platform, the method yields fast (∼36 h turnaround time) and highly sensitive readouts compatible with high-throughput testing. The assay capability for detecting substrate conversion in a precise and reliable manner was demonstrated by extensive qualification studies and by employing a number of recombinant hydrolases associated with polysorbate hydrolysis. In addition, high assay sensitivity and wide applicability were confirmed for in-process pool samples of three different antibody products by performing a head-to-head comparison between this method and an established liquid chromatography - mass spectrometry based assay for the quantification of free fatty acids. Overall, our results suggest that this new approach is well-suited to resolve differences in hydrolytic activity through all stages of purification., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: It is unclear whether thrombectomy alone is non-inferior to thrombectomy with intravenous thrombolysis in patients with acute ischemic stroke due to large-vessel occlusion., Purpose: To perform a comprehensive, trial-level data, non-inferiority meta-analysis of randomised controlled trials comparing endovascular thrombectomy with and without intravenous thrombolysis in patients with ischemic stroke due to large-vessel occlusion of anterior circulation., Methods: The prespecified primary efficacy outcome was functional independence, defined as a modified Rankin scale (mRS)score of 0 to 2 at 90 days. The two prespecified non-inferiority margins were risk differences of -10% and - 5%. The study was registered in PROSPERO (CRD42022361110) and conducted according to PRISMA guidelines., Results: Six trials were included in this analysis (DIRECT-MT, DEVT, SKIP, MR CLEAN-NO IV, DIRECT-SAFE and SWIFT DIRECT) comprising a total of 2334 patients. Functional independence at 90 days was achieved by 570 (49·0%) of 1164 patients in the thrombectomy alone group and 595 (50·9%) of 1170 patients in the thrombectomy with thrombolysis group (pooled risk difference - 0·02, [95% CI -0·06-0·02]). Combined thrombectomy and thrombolysis were associated with significantly higher rates of successful reperfusion (pooled risk ratio 0·96 [95% CI, 0·93-0·99], p = 0·006) but at the expense of a significantly increased risk of overall - but not symptomatic - intracranial haemorrhage (pooled risk ratio 0·87 [95% CI, 0·77-0·98], p = 0·02)., Conclusions: Compared with a combined treatment approach, thrombectomy alone was non-inferior at -10% non-inferiority margin, but not at a - 5% inferiority margin for functional independence. Current evidence cannot exclude clinically important differences between the two treatment approaches., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Usutu virus (USUV) and West Nile virus (WNV) are known to cause diseases and mortalities in bird populations. Since 2010/2011, USUV has circulated in Germany and spread nationwide, while WNV was only introduced into East Germany in 2018. The zoological garden investigated is located in Northern Germany, where USUV infections in wild birds have been detected for several years. In this longitudinal study conducted over a four-year period, zoo birds were sampled biannually and screened for molecular and serological evidence of USUV and WNV. USUV genomes were detected in eight of the sampled birds and whole-genome sequences revealed the circulation of USUV lineages Europe 3 and Africa 3. Of the eight birds infected with USUV during the study period, four died after the infection, while four survived without displaying clinical signs. Furthermore, in a few of the birds, a USUV (re-)infection was confirmed on a serological level with three birds producing USUV-neutralizing antibodies (nAbs) over a period of four years. Nonetheless, in two birds sampled throughout this longitudinal study, neither a USUV nor a WNV infection was evident. In 2022, WNV nAbs were detected for the first time in a juvenile zoo bird, indicating the introduction of the virus into this region.

Objective: To investigate the immunogenicity and safety of BNT162b2 booster vaccination with and without a tetravalent influenza vaccine., Methods: A prospective, open-label cohort study on immunogenicity and safety of COVID-19 booster vaccination with or without a tetravalent influenza vaccine was performed. Eight hundred thirty-eight health care workers were included in the following study arms: BNT162b2 booster-only, influenza-vaccine-only or combination of both. Levels of antibodies against SARS-CoV-2 spike receptor binding domain, and haemagglutinin inhibition tested for four different influenza strains (A(H1N1)pdm09, A(H3N2), B/Victoria, B/Yamagata) were measured at the time of vaccination and 4 weeks later., Results: After 4 weeks, median (interquartile range) levels of antibodies against the receptor binding domain of the viral spike (S) protein and relative change from baseline were high in individuals who received BNTb162b2 booster vaccination only (absolute: 16 600 [10 980-24 360] vs. 12 630 [8198-18 750] BAU/mL [p < 0.0001]; relative increase: 49% [23.6-95.3] vs. 40% [21.9-80.6] [p 0.048]; booster-only n = 521 vs. combination-arm n = 229 respectively). Results were confirmed after matching for sex, age, body mass index, baseline antibody levels and vaccine compound received for primary immunization (absolute: 13 930 [10 610-22 760] vs. 12 520 [8710-17 940]; [p 0.031]; relative increase: 55.7% [27.8-98.5] vs. 42.2% [22.9-74.5]; p 0.045). Adverse events were almost identical in the booster-only and the combination-arm, but numerically low in the influenza arm (525/536 [97.9%] vs. 235/240 [97.9%] vs. 26/33 [78.8 %])., Discussion: Although no safety concerns occurred, our study provides evidence on reduced immunogenicity of a BNT162b2 booster vaccination in combination with a tetravalent influenza vaccine. Further studies investigating new influenza variants as well as potential differences vaccine effectiveness are needed., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate the outcome of conversion surgery in patients with metastatic pancreatic cancer (mPDAC) and to identify patients who may benefit from this approach., Background: The role of conversion surgery in patients with mPDAC and exceptional response to chemotherapy remains unclear., Methods: Patients who underwent surgical exploration for mPDAC following chemotherapy between 2006 and 2019 were included. Data on demographics, oncologic treatment, pathology, and postoperative outcomes were analyzed. Univariate and multivariate survival analyses were performed., Results: Some 173 patients received preoperative chemotherapy and underwent surgical exploration. Ninety-three patients underwent resection of the primary tumor and metastatic sites, 80 patients underwent exploration only. In the resection subgroup, 45 patients had complete pathological response of metastases (ypM0) and 48 patients had residual metastases (ypM1). ypM0 status was associated with lower carcinoembryonic antigen levels and lower ypN stage. Overall survival after resection was 25.5 months in ypM0, 10.7 months in ypM1, and 8.1 months in patients without resection ( P <0.001). Additional adjuvant chemotherapy was significantly associated with prolonged survival in resected patients (29.0 vs 14.8 mo, P =0.024) as well as in ypM0 (29.1 vs 19.2 mo, P =0.047). Multivariable analysis identified conversion surgery, carbohydrate antigen 19-9 (CA19-9) and time of resection as independent prognostic markers for the entire cohort. CA19-9, ypM0 and adjuvant treatment were independent predictors of survival in the resection subgroup., Conclusion: In patients with mPDAC and ypM0 status after chemotherapy, surgical resection is associated with encouraging survival. mPDAC patients with exceptional response to chemotherapy may be candidates for exploration and for resection in ypM0. Adjuvant chemotherapy may provide an additional survival advantage., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Previous findings suggest that bacterial coinfections are less common in ICU patients with COVID-19 than with influenza, but evidence is limited., Objectives: This study aimed to compare the rate of early bacterial coinfections in ICU patients with COVID-19 or influenza., Design Setting and Participants: Retrospective propensity score matched cohort study. We included patients admitted to ICUs of a single academic center with COVID-19 or influenza (January 2015 to April 2022)., Main Outcomes and Measures: The primary outcome was early bacterial coinfection (i.e., positive blood or respiratory culture within 2 d of ICU admission) in the propensity score matched cohort. Key secondary outcomes included frequency of early microbiological testing, antibiotic use, and 30-day all-cause mortality., Results: Out of 289 patients with COVID-19 and 39 patients with influenza, 117 ( n = 78 vs 39) were included in the matched analysis. In the matched cohort, the rate of early bacterial coinfections was similar between COVID-19 and influenza (18/78 [23%] vs 8/39 [21%]; odds ratio, 1.16; 95% CI, 0.42-3.45; p = 0.82). The frequency of early microbiological testing and antibiotic use was similar between the two groups. Within the overall COVID-19 group, early bacterial coinfections were associated with a statistically significant increase in 30-day all-cause mortality (21/68 [30.9%] vs 40/221 [18.1%]; hazard ratio, 1.84; 95% CI, 1.01-3.32)., Conclusions and Relevance: Our data suggest similar rates of early bacterial coinfections in ICU patients with COVID-19 and influenza. In addition, early bacterial coinfections were significantly associated with an increased 30-day mortality in patients with COVID-19., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Introduction: Language policies are often aimed at changing language behaviours, yet it is notoriously difficult to assess their effects. This study investigates language use and competence in the Indigenous Sámi populations of Norway and Sweden in light of the national-level policies the two countries have adopted., Methods: We provide a cross-country comparison of relevant educational, linguistic and budgetary policies in Sweden and Norway. Next, we present novel data from a survey with 5,416 Sámi and non-Sámi participants in 20 northern municipalities, examining Sámi language use and proficiencies across generations and contexts. Lexical proficiency in North Sámi was tested in a small subset of participants., Results: Sámi language use has dropped considerably over the past three generations. Only a small proportion of Sámi are highly fluent and use a Sámi language with their children (around 4% in Sweden and 11% in Norway). One fifth of Sámi adults use a Sámi language at least 'occasionally', and use is most common in the home context. Sámi language knowledge remains negligible in the majority population., Discussion: The higher levels of language use and proficiency in Norway seem at least in part to reflect the more favourable policies adopted there. In both countries, more work is needed to increase speaker numbers, also in the majority population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lloyd-Smith, Bergmann, Hund and Kupisch.)

West Nile virus (WNV) is known to cause disease and death in humans and various animals worldwide. WNV has circulated in Germany since 2018. In 2020, four birds tested positive for the WNV genome at Zoopark Erfurt (Thuringia). Moreover, virus neutralization assays detected neutralizing antibodies (nAb) against WNV in 28 birds. In addition, nAb against WNV and Usutu virus (USUV) were found in 14 birds. To protect valuable animals and to reduce the risk of viral transmission from birds to humans, we performed a field study on WNV vaccination at the zoo. To conduct the study, 61 birds from the zoo were categorized into three groups and subjected to a vaccination regimen, where each bird received either 1.0 mL, 0.5 mL, or 0.3 mL of a commercial inactivated WNV vaccine three times. The vaccinations were administered at three-week intervals, or as per modified vaccination schedules. Furthermore, 52 birds served as non-vaccinated controls. Adverse vaccination reactions were absent. The greatest increase in nAb titres was observed in birds that received 1.0 mL of vaccine. However, pre-existing antibodies to WNV and USUV appeared to have a major effect on antibody development in all groups and in all bird species, whereas sex and age had no effect. After vaccination, no death was detected in vaccinated birds for more than 1 year.

Background: An understanding vaccine-dependent effects on protective and sustained humoral immune response is crucial to planning future vaccination strategies against coronavirus disease 2019 (COVID-19)., Methods: In this multicenter, population-based, cohort study including 4601 individuals after primary vaccination against COVID-19 ≥ 4 months earlier we compared factors associated with residual antibody levels against severe acute respiratory syndrome coronavirus-2 receptor-binding domain (RBD) across different vaccination strategies (BNT162b2, mRNA-1273, or ChAdOx1)., Results: Our main model including 3787 individuals (2 × BNT162b2, n = 2271; 2 × mRNA-1273, n = 251; 2 × ChAdOx1, n = 1265), predicted significantly lower levels of anti-RBD antibodies after 6 months in individuals vaccinated with ChAdOx1 (392.7 binding antibody units per milliliter [BAU/mL]) compared with those vaccinated with BNT162b2 (1179.5 BAU/mL) or mRNA-1273 (2098.2 BAU/mL). Vaccine-dependent association of antibody levels was found for age with a significant predicted difference in BAU/ml per year for BNT162b2 (-21.5; 95% confidence interval [CI], -24.7 to -18.3) and no significant association for mRNA-1273 (-4.0; 95% CI, -20.0 to 12.1) or ChAdOx1 (1.7; 95% CI, .2 to 3.1). The predicted decrease over time since full immunization was highest in mRNA-1273 (-23.4; 95% CI, -31.4 to -15.4) compared with BNT162b2 (-5.9; 95% CI, -7 to -4.8)., Conclusions: Our study revealed population-based evidence of vaccine-dependent effects of age and time since full immunization on humoral immune response. Findings underline the importance of individualized vaccine selection, especially in elderly individuals., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

COVID-19-associated pulmonary aspergillosis (CAPA) is a life-threatening fungal infection that mainly affects critically ill patients. The aim of this study was to assess the incidence and clinical outcomes of putative CAPA in critically ill COVID-19 patients. This retrospective observational cohort study included 181 cases from 5 ICUs at Vienna General Hospital between January 2020 and April 2022. Patients were diagnosed with putative CAPA according to the AspICU classification, which included a positive Aspergillus culture in a bronchoalveolar lavage sample, compatible signs and symptoms, and abnormal medical imaging. The primary outcome was adjusted 60-day all-cause mortality from ICU admission in patients with vs. without putative CAPA. Secondary outcomes included time from ICU admission to CAPA diagnosis and pathogen prevalence and distribution. Putative CAPA was identified in 35 (19.3%) of 181 COVID-19 patients. The mean time to diagnosis was 9 days. Death at 60 days occurred in 18 of 35 (51.4%) patients with CAPA and in 43 of 146 (29.5%) patients without CAPA (adjusted HR (95%CI) = 2.15 (1.20-3.86, p = 0.002). The most frequently isolated Aspergillus species was Aspergillus fumigatus. The prevalence of putative pulmonary aspergillosis in critically ill COVID-19 patients was high and was associated with significantly higher mortality.

Background: Mental and neurological disorders cause a large proportion of morbidity burden and require adequate health care structures. However, deficits in the German health care system like long waiting times for access to specialized care and a lack of coordination between health care providers lead to suboptimal quality of care and elevated health care costs., Objective: To overcome these deficits, we implement and evaluate a unique stepped and coordinated model of care (the Neurologisch-psychiatrische und psychotherapeutische Versorgung [NPPV] program) for patients with mental and neurological diseases., Methods: Patients included in the program receive an appropriate treatment according to medical needs in a multiprofessional network of ambulatory health care providers. The therapy is coordinated by a managing physician and complemented by additional therapy modules, such as group therapy, internet-based cognitive behavioral therapy, and a case management. Statutory health insurance (SHI) routine data and data from a longitudinal patient survey will be used to compare the program with regular care and evaluate SHI expenditures and patient-related outcomes. A health care provider survey will evaluate the quality of structure and processes and provider satisfaction. Finally, an analysis of ambulatory claims data and drug prescription data will be used to evaluate if health care providers follow a needs-led approach in therapy. Ethics approval for this trial was obtained from the ethics committee of the chamber of physicians in North Rhine (September 13, 2017, reference No. 2017287)., Results: Patient enrollment of NPPV ended in September 2021. Data analysis has been completed in 2022. The results of this study will be disseminated through scientific publications, academic conferences, and a publicly available report to the German Federal Joint Committee, which is expected to be available in the first half of 2023., Conclusions: The NPPV program is the first intervention to implement a stepped model of care for both mental and neurological diseases in Germany. The analysis of several data sources and a large sample size (more than 14,000 patients) enable a comprehensive evaluation of the NPPV program., Trial Registration: German Clinical Trials Register DRKS00022754; https://tinyurl.com/3mx9pz5z., International Registered Report Identifier (irrid): DERR1-10.2196/37569., (©Johannes Pollmanns, Karlheinz Großgarten, Julia K Wolff, Hans-Dieter Nolting, Clarissa Graf, Frank Bergmann, Gereon Nelles. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 17.01.2023.)

Introduction: Resection margin status is a well-established prognosticator in pancreatic cancer. The prognostic impact of IPMN dysplasia at the pancreatic transection margin in IPMN-associated carcinoma (IPMN-Ca) remains unclear, hence institutional practices on additional resections vary., Methods: Patients undergoing partial pancreatectomy or attempted partial pancreatectomy converted to total pancreatectomy for IPMN-Ca between 04/2002 and 12/2018 were identified. Final pathology of the definitive pancreatic transection margin was identified. The association between the presence of IPMN dysplasia at the margin and overall survival (OS) was assessed., Results: Of 302 patients with IPMN-Ca, 181 (59.9%) patients received partial pancreatoduodenectomy, 61 (20.2%) distal pancreatectomy, and 60 (19.9%) were converted to total pancreatectomy. Median OS was 98.6 months in R0 (≥1 mm), 39.3 months in R1 (<1 mm), and 22.0 months in R1(direct) resected patients, respectively (p < 0.0001). No IPMN dysplasia at the definitive margin was present in 103 (34.1%), low-grade in 131 (43.4%), and high-grade/R1 in 8 (2.6%) patients. Low-grade dysplasia or total pancreatectomy were not associated with shorter OS compared to dysplasia-free margin across the entire cohort. Sensitivity analyses confirmed a lack of prognostic relevance of low-grade IPMN dysplasia at the pancreatic margin in R0 resected IPMN-Ca and in R0 resected UICC stage IA/IB IPMN-Ca., Conclusions: Low-grade IPMN at the transection margin is not associated with shorter overall survival after partial pancreatectomy for IPMN-Ca. Additional resections for low-grade dysplasia, up to total pancreatectomy do not result in a survival benefit and should be omitted. Due to limited sample size, high-grade dysplasia could not be analyzed., Competing Interests: Declaration of competing interest No competing interests to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study aims to study the depth of artery wall tumour invasion in patients undergoing surgery for pancreatic ductal adenocarcinoma., Methods: Specimens from 47 pancreatic cancer patients with major arterial (splenic, SA; celiac, CA; common hepatic, CHA) invasion were examined: 45 left (distal) pancreatectomies, including 11 celiac artery resections, and two total pancreatectomies. Dissection of tumour-invaded arteries in 25 fresh specimens was attempted ex vivo using the sub-adventitial dissection technique (SDT). Tumour invasion of 66 arteries was graded using the tumour-free distance (TFD) from the external elastic lamina (EEL): 0 = no arterial invasion; I = TFD ≥ 1 mm; II = TFD < 1 mm; and grade III = EEL invasion., Results: AJCC TNM staging was IA = 1 (2%), IB = 4 (9%), IIA = 5 (11%), IIB = 17(36%) and III = 20 (43%). Grade III tumour invasion was found in 17/47(36%) SAs, in 5/11 (45%) CAs and in 1/8 (13%) CHAs (p = 0.318). Attempted ex vivo SDT undertaken in 33 arteries from 25 specimens was complete in 16 and incomplete in 17 arteries. The median (IQR) TFD was 0.97 (0.11-2.54) mm in dissected and 0.14 (0.10, 0.14) mm in non-dissected SAs (p = 0.034). EEL tumour invasion occurred in 0/12 (0%) dissected compared to 7/13 (54%) non-dissected SAs (p = 0.005). Grades 0, I, II and III invasion were found in four (33%), two (17%) and six (50%), respectively, of 12 dissected SAs and grades II and III in six 6 (46%) and seven (54%), respectively, of 13 non-dissected SAs (p = 0.002)., Conclusions: The grading system described may form the basis for classification to further develop arterial dissection techniques for pancreatic cancer., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Usutu virus (USUV) is a mosquito-borne zoonotic virus and one of the causes of flavivirus encephalitis in birds and occasionally in humans. USUV rapidly disperses in a susceptible host and vector environment, as is the case in South and Central Europe. However, compared to other flaviviruses, USUV has received less research attention and there is therefore limited access to whole-genome sequences and also to in-depth phylogenetic and phylodynamic analyses. To ease future molecular studies, this study compares first- (partial sequencing via Sanger), second- (Illumina), and third-generation (MinION Nanopore) sequencing platforms for USUV. With emphasis on MinION Nanopore sequencing, cDNA-direct and target-enrichment (amplicon-based) sequencing approaches were validated in parallel. The study was based on four samples from succumbed birds commonly collected throughout Germany. The samples were isolated from various sample matrices, organs as well as blood cruor, and included three different USUV lineages. We concluded that depending on the focus of a research project, amplicon-based MinION Nanopore sequencing can be an ideal cost- and time-effective alternative to Illumina in producing optimal genome coverage. It can be implemented for an array of lab- or field-based objectives, including among others: phylodynamic studies and the analysis of viral quasispecies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Holicki, Bergmann, Stoek, Schulz, Groschup, Ziegler and Sadeghi.)

Objectives: The efficacy and quality of generic antibacterial drug formulations are often questioned by both healthcare specialists and patients. Therefore, the present study investigated the interchangeability of generic drugs with their originators by comparing bioequivalence parameters and stability data of generic cefepime, linezolid and piperacillin/tazobactam with their respective originator drugs., Methods: In this open-label, randomized, crossover bioequivalence study, three groups of 12 healthy volunteers each received a single intravenous infusion of either 2 g of cefepime or 4.5 g of piperacillin/tazobactam and two generic formulations, or 600 mg of linezolid and one generic formulation. Plasma sampling was performed, with a 5 day washout period between study days. Stability was tested by storing reconstituted generic and originator products according to their own storage specifications and those of the comparator products. All concentrations were measured by LC-MS., Results: Similar ratios of generic/originator (90% CI) Cmax were observed for Cefepime-MIP/Maxipime [93.7 (88.4-99.4)], Cefepime Sandoz/Maxipime [95.9 (89.1-103.2)], Linezolid Kabi/Zyvoxid [104.5 (91.1-119.9)], Piperacillin Kabi/Tazobac [95.9 (90.4-101.7)], Piperacillin Aurobindo/Tazobac [99.7 (84.9-104.7)], Tazobactam Kabi/Tazobac [93.4 (87.4-99.8)] and Tazobactam Aurobindo/Tazobac [97.4 (89.7-105.8)]. Accordingly, similar ratios of AUC0-t were observed for Cefepime-MIP/Maxipime [91.1 (87.6-94.8)], Cefepime Sandoz/Maxipime [97.9 (92.5-103.5)], Linezolid Kabi/Zyvoxid [99.7 (93.3-106.6)], Piperacillin Kabi/Tazobac [92.2 (88.3-96.3)], Piperacillin Aurobindo/Tazobac [99.9 (97.0-102.8)], Tazobactam Kabi/Tazobac [91.4 (86.4-96.7)] and Tazobactam Aurobindo/Tazobac [98.8 (94.3-103.6)]. Stable and similar concentrations were measured for all contiguous substances, regardless of storage conditions., Conclusions: Compared with their respective originator drugs, generic cefepime, linezolid and piperacillin/tazobactam met the predetermined bioequivalence criteria. All formulations were stable under the storage conditions of their respective comparators., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Clinical research relies on data from patients and volunteers, yet the target sample size is often not achieved. Here, we assessed the perception of clinical research among clinical trial participants to improve the recruitment process for future studies., Methods: We conducted a single-center descriptive and exploratory study of 300 current or former participants in various phase I-III clinical trials. Questionnaires were either distributed to current clinical trial participants or emailed to former subjects., Results: Subjects strongly agreed or agreed that contributing to improving medical care (> 81%), contributing to scientific research (> 79%), and trusting their treating physicians (> 77%) were motives for study participation. Among healthy volunteers, financial motives positively correlated with the number of clinical trials they had participated in (p < 0.05). Higher age positively correlated with expectation of best available treatment during study participation among patients (p < 0.05). Less than 8% of all subjects expressed "great concern" about the potential risks of sharing their personal information as part of the study. Subjects displayed "great trust" or "trust" in medical staff (86.6%) and in government research institutions (76.4%), and "very little trust" or "little trust" in pharmaceutical companies (35.4%) and health insurance companies (16.9%)., Conclusion: Altruistic motives and trust in treating physicians were predominant motives for clinical trial participation. Older patients expected to receive the best available treatment during participation. Healthy volunteers who reported financial motives had participated in more clinical trials. Consistent with great trust in medical staff and government research institutions, little concern was expressed about the misuse of personal data during the trial., (© 2022. The Author(s).)

Germline defects in the transcription factor GATA1 are known to cause dyserythropoiesis with(out) anemia and variable abnormalities in platelet count and function. However, damaging variants closely located to the C-terminal zinc finger domain of GATA1 are nearly unknown. In this study, a 36-year-old male index patient and his 4-year-old daughter suffered from moderate mucocutaneous bleeding diathesis since birth. Whole exome sequencing detected a novel hemizygous GATA1 missense variant, c.886A>C p.T296P, located between the C-terminal zinc finger and the nuclear localization sequence with non-random X-chromosome inactivation in the heterozygous daughter. Blood smears from both patients demonstrated large platelet fractions and moderate thrombocytopenia in the index. Flow cytometry and electron microscopy analysis supported a combined α-/δ (AN-subtype)-storage pool deficiency as cause for impaired agonist-induced platelet aggregation (light transmission aggregometry) and granule exocytosis (flow cytometry). The absence of BCAM in the index (Lu(a-b-)) and its low expression in the daughter (Lu(a-b+)) confirmed a less obvious effect of defective GATA1 also on erythrocytes. Borderline anemia, elevated HbF levels, and differential transcription of GATA1-regulated genes indicated mild dyserythropoiesis in both patients. Furthermore, a mild SLC4A1 defect associated with a heterozygous SLC4A1 c.2210C>T p.A737V variant maternally transmitted in the daughter may modify the disease to mild spherocytosis and hemolysis.

Spider silk has fascinated mankind for millennia, but it is only in recent decades that scientific research has begun to unravel all its characteristics and applications. The uniqueness of spider silk resides in its versatility, in which a combination of high strength and extensibility results in extraordinary toughness, superior to almost all natural and man-made fibers. Dragline silk consists of proteins with highly repetitive amino acid sequences, which have been correlated with specific secondary structures responsible for its physical properties. The native fiber also shows high cytocompatibility coupled with low immunogenicity, making it a promising natural biomaterial for numerous biomedical applications. Recently, novel technologies have enabled new insights into the material and biomedical properties of silk. Due to the increasing interest in spider silk, as well as the desire to produce synthetic alternatives, we present an update on the current knowledge of silk fibers produced by the spider genus Trichonephila., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Microdialysis sampling after drug microdosing may provide tissue pharmacokinetic data early in clinical drug development. However, low administered doses and small sample volumes pose an analytical challenge, particularly for highly protein-bound drugs. Materials & methods: Carbon-14 [ 14 C]diclofenac was used as a model drug to assess the technical and analytical feasibility of in vivo microdialysis after microdose administration in an in vitro setup. Results: [ 14 C]diclofenac dialysate concentrations were accurately quantified with accelerator MS. [ 14 C]diclofenac dialysate recoveries were similar in the presence and absence of therapeutic diclofenac concentrations but were considerably decreased when albumin was added to the immersion solution, suggesting high protein binding. Conclusion: These results demonstrate the feasibility of combining microdosing and microdialysis to assess tissue pharmacokinetics.