Background Gram-negative bacteremia is a major cause of morbidity and mortality in hospitalized patients. Data to guide the duration of antibiotic therapy are limited. Methods This was a randomized, multicenter, open-label, noninferiority trial. Inpatients with gram-negative bacteremia, who were afebrile and hemodynamically stable for at least 48 hours, were randomized to receive 7 days (intervention) or 14 days (control) of covering antibiotic therapy. Patients with uncontrolled focus of infection were excluded. The primary outcome at 90 days was a composite of all-cause mortality; relapse, suppurative, or distant complications; and readmission or extended hospitalization (>14 days). The noninferiority margin was set at 10%. Results We included 604 patients (306 intervention, 298 control) between January 2013 and August 2017 in 3 centers in Israel and Italy. The source of the infection was urinary in 411 of 604 patients (68%); causative pathogens were mainly Enterobacteriaceae (543/604 [90%]). A 7-day difference in the median duration of covering antibiotics was achieved. The primary outcome occurred in 140 of 306 patients (45.8%) in the 7-day group vs 144 of 298 (48.3%) in the 14-day group (risk difference, –2.6% [95% confidence interval, –10.5% to 5.3%]). No significant differences were observed in all other outcomes and adverse events, except for a shorter time to return to baseline functional status in the short-course therapy arm. Conclusions In patients hospitalized with gram-negative bacteremia achieving clinical stability before day 7, an antibiotic course of 7 days was noninferior to 14 days. Reducing antibiotic treatment for uncomplicated gram-negative bacteremia to 7 days is an important antibiotic stewardship intervention. Clinical Trials Registration NCT01737320.

Aims To assess the short‐term immunogenicity to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) mRNA vaccine in a population of heart transplant (HTx) recipients. A prospective single‐centre cohort study of HTx recipients who received a two‐dose SARS‐CoV‐2 mRNA vaccine (BNT162b2, Pfizer‐BioNTech). Methods and results Whole blood for anti‐spike IgG (S‐IgG) antibodies was drawn at days 21–26 and at days 35–40 after the first vaccine dose. Geometric mean titres (GMT) ≥50 AU/mL were interpreted positive. Included were 42 HTx recipients at a median age of 61 [interquartile range (IQR) 44–69] years. Median time from HTx to the first vaccine dose was 9.1 (IQR 2.6–14) years. Only 15% of HTx recipients demonstrated the presence of positive S‐IgG antibody titres in response to the first vaccine dose [GMT 90 (IQR 54–229) AU/mL]. Overall, 49% of HTx recipients induced S‐IgG antibodies in response to either the first or the full two‐dose vaccine schedule [GMT 426 (IQR 106–884) AU/mL]. Older age [68 (IQR 59–70) years vs. 46 (IQR 34–63) years, P = 0.034] and anti‐metabolite‐based immunosuppression protocols (89% vs. 44%, P = 0.011) were associated with low immunogenicity. Importantly, 36% of HTx recipients who were non‐responders to the first vaccine dose became S‐IgG seropositive in response to the second vaccine dose. Approximately a half of HTx recipients did not generate S‐IgG antibodies following SARS‐CoV‐2 two‐dose vaccine. Conclusions The generally achieved protection from SARS‐CoV‐2 mRNA vaccination should be regarded with caution in the population of HTx recipients. The possible benefit of additive vaccine should be further studied.

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Objectives: The pleiotropic effect of hydroxymethylglutaryl-CoA reductase inhibitors (statins) might have a beneficial effect in sepsis through several mechanisms. The aim was to assess the efficacy and safety of statins, compared with placebo, for the treatment of sepsis in adults. Methods: We searched the following databases: the Cochrane Central Register of Controlled Trials

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Background: The diagnostic yield of endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) from mediastinal lymph nodes ranges from 66%-89%. However, in many cases cytologic material is not sufficient for full molecular evaluation. A novel method of transcarinal cryobiopsy aims to provide bronchoscopically obtained, larger specimen samples from mediastinal lymph nodes. We aimed to assess the efficacy and safety of transcarinal EBUS-guided lymph node cryobiopsy. Methods: Patients referred for EBUS-TBNA, based on abnormal mediastinal clinical and radiographic findings, were enrolled into this prospective interventional study between July 2020 and August 2021. All EBUS-TBNA procedures were performed using ProCore 22G needle (Cook Medical) to create, both a transcarinal tract for the cryoprobe and to obtain TBNA samples. For EBUS guided transcarinal cryobiopsy, we used flexible 1.1 mm or 1.7 mm cryoprobe inserted into the working channel of the EBUS scope and into the target subcarinal lymph node. Results: Twenty-four patients with male predominance 2:1 and mean age of 60.12 AE 10.16 years were enrolled. All target lymph nodes had hypoechoic, homogenic consistency with demarcated borders, without central structures. Cryobiopsy provided pathological diagnosis in 20 cases (83.33%), with 1.1 mm cryoprobe in 14 and with 1.7 mm cryoprobe in 6 cases. In one case each, pathology was provided by TBNA or by cryoprobe alone. No immediate or late complications were encountered during the procedures. Conclusion: Transcarinal EBUS guided lymph node cryobiopsy following EBUS-TBNA proved to be efficient with a high diagnostic yield and can be considered safe, because no immediate or late complications occurred.

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The IPF-conditioned matrix (IPF-CM) system enables the study of matrix–fibroblast interplay. While effective at slowing fibrosis, nintedanib has limitations and the mechanism is not fully elucidated. In the current work, we explored the underlying signaling pathways and characterized nintedanib involvement in the IPF-CM fibrotic process. Results were validated using IPF patient samples and bleomycin-treated animals with/without oral and inhaled nintedanib. IPF-derived primary human lung fibroblasts (HLFs) were cultured on Matrigel and then cleared using NH4OH, creating the IPF-CM. Normal HLF-CM served as control. RNA-sequencing, PCR and western-blots were performed. HIF1α targets were evaluated by immunohistochemistry in bleomycin-treated rats with/without nintedanib and in patient samples with IPF. HLFs cultured on IPF-CM showed over-expression of ‘HIF1α signaling pathway’ (KEGG, p < 0.0001), with emphasis on SERPINE1 (PAI-1), VEGFA and TIMP1. IPF patient samples showed high HIF1α staining, especially in established fibrous tissue. PAI-1 was overexpressed, mainly in alveolar macrophages. Nintedanib completely reduced HIF1α upregulation in the IPF-CM and rat-bleomycin models. IPF-HLFs alter the extracellular matrix, thus creating a matrix that further propagates an IPF-like phenotype in normal HLFs. This pro-fibrotic loop includes the HIF1α pathway, which can be blocked by nintedanib.