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The COVID-19 pandemic, caused by SARS-CoV-2, demonstrated that zoonotic transmission of animal sarbecoviruses threatens human health but the determinants of transmission are incompletely understood. Here, we show that most spike (S) proteins of horseshoe bat and Malayan pangolin sarbecoviruses employ ACE2 for entry, with human and raccoon dog ACE2 exhibiting broad receptor activity. The insertion of a multibasic cleavage site into the S proteins increased entry into human lung cells driven by most S proteins tested, suggesting that acquisition of a multibasic cleavage site might increase infectivity of diverse animal sarbecoviruses for the human respiratory tract. In contrast, two bat sarbecovirus S proteins drove cell entry in an ACE2-independent, trypsin-dependent fashion and several ACE2-dependent S proteins could switch to the ACE2-independent entry pathway when exposed to trypsin. Several TMPRSS2-related cellular proteases but not the insertion of a multibasic cleavage site into the S protein allowed for ACE2-independent entry in the absence of trypsin and may support viral spread in the respiratory tract. Finally, the pan-sarbecovirus antibody S2H97 enhanced cell entry driven by two S proteins and this effect was reversed by trypsin while trypsin protected entry driven by a third S protein from neutralization by S2H97. Similarly, plasma from quadruple vaccinated individuals neutralized entry driven by all S proteins studied, and availability of the ACE2-independent, trypsin-dependent pathway reduced neutralization sensitivity. In sum, our study reports a pathway for entry into human cells that is ACE2-independent, can be supported by TMPRSS2-related proteases and may be associated with antibody evasion.

Background Severe hypoperfusion can cause lung damage. We studied the effects of regional perfusion block in normal lungs and in the lungs that had been conditioned by lavage with 500 ml saline and high V T (20 ml kg −1 ) ventilation. Methods Nineteen pigs (61.2 ± 2.5 kg) were randomized to five groups: controls ( n  = 3), the right lower lobe block alone ( n  = 3), lavage and high V T ( n  = 4), lung lavage, and high V T plus perfusion block of the right ( n  = 5) or left ( n  = 4) lower lobe. Gas exchange, respiratory mechanics, and hemodynamics were measured hourly. After an 8-h observation period, CT scans were obtained at 0 and 15 cmH 2 O airway pressure. Results Perfusion block did not damage healthy lungs. In conditioned lungs, the left perfusion block caused more edema in the contralateral lung (777 ± 62 g right lung vs 484 ± 204 g left; p  < 0.05) than the right perfusion block did (581 ± 103 g right lung vs 484 ± 204 g left; p n.s.). The gas/tissue ratio, however, was similar (0.5 ± 0.3 and 0.8 ± 0.5; p n.s.). The lobes with perfusion block were not affected (gas/tissue ratio right 1.6 ± 0.9; left 1.7 ± 0.5, respectively). Pulmonary artery pressure, PaO 2 /FiO 2 , dead space, and lung mechanics were more markedly affected in animals with left perfusion block, while the gas/tissue ratios were similar in the non-occluded lobes. Conclusions The right and left perfusion blocks caused the same “intensity” of edema in conditioned lungs. The total amount of edema in the two lungs differed because of differences in lung size. If capillary permeability is altered, increased blood flow may induce or increase edema.

PurposeTo investigate whether (1 → 3)-β-d-Glucan (BDG)-guidance shortens time to antifungal therapy and thereby reduces mortality of sepsis patients with high risk of invasive Candida infection (ICI).MethodsMulticenter, randomized, controlled trial carried out between September 2016 and September 2019 in 18 intensive care units enrolling adult sepsis patients at high risk for ICI. Patients in the control group received targeted antifungal therapy driven by culture results. In addition to targeted therapy, patients in the BDG group received antifungals if at least one of two consecutive BDG samples taken during the first two study days was ≥ 80 pg/mL. Empirical antifungal therapy was discouraged in both groups. The primary endpoint was 28-day-mortality.Results339 patients were enrolled. ICI was diagnosed in 48 patients (14.2%) within the first 96 h after enrollment. In the BDG-group, 48.8% (84/172) patients received antifungals during the first 96 h after enrollment and 6% (10/167) patients in the control group. Death until day 28 occurred in 58 of 172 patients (33.7%) in the BDG group and 51 of 167 patients (30.5%) in the control group (relative risk 1.10; 95% confidence interval, 0.80–1.51; p = 0.53). Median time to antifungal therapy was 1.1 [interquartile range (IQR) 1.0–2.2] days in the BDG group and 4.4 (IQR 2.0–9.1, p < 0.01) days in the control group.ConclusionsSerum BDG guided antifungal treatment did not improve 28-day mortality among sepsis patients with risk factors for but unexpected low rate of IC. This study cannot comment on the potential benefit of BDG-guidance in a more selected at-risk population.

The COVID-19 pandemic, caused by SARS-CoV-2, demonstrated that zoonotic transmission of animal sarbecoviruses threatens human health but the determinants of transmission are incompletely understood. Here, we show that most spike (S) proteins of horseshoe bat and Malayan pangolin sarbecoviruses employ ACE2 for entry, with human and raccoon dog ACE2 exhibiting broad receptor activity. The insertion of a multibasic cleavage site into the S proteins increased entry into human lung cells driven by most S proteins tested, suggesting that acquisition of a multibasic cleavage site might increase infectivity of diverse animal sarbecoviruses for the human respiratory tract. In contrast, two bat sarbecovirus S proteins drove cell entry in an ACE2-independent, trypsin-dependent fashion and several ACE2-dependent S proteins could switch to the ACE2-independent entry pathway when exposed to trypsin. Several TMPRSS2-related cellular proteases but not the insertion of a multibasic cleavage site into the S protein allowed for ACE2-independent entry in the absence of trypsin and may support viral spread in the respiratory tract. Finally, the pan-sarbecovirus antibody S2H97 enhanced cell entry driven by two S proteins and this effect was reversed by trypsin while trypsin protected entry driven by a third S protein from neutralization by S2H97. Similarly, plasma from quadruple vaccinated individuals neutralized entry driven by all S proteins studied, and availability of the ACE2-independent, trypsin-dependent pathway reduced neutralization sensitivity. In sum, our study reports a pathway for entry into human cells that is ACE2-independent, can be supported by TMPRSS2-related proteases and may be associated with antibody evasion.

The aim of this study was to characterize the systemic cytokine signature of critically ill COVID-19 patients in a high mortality setting aiming to identify biomarkers of severity, and to explore their associations with viral loads and clinical characteristics. We studied two COVID-19 critically ill patient cohorts from a referral centre located in Central Europe. The cohorts were recruited during the pre-alpha/alpha (November 2020 to April 2021) and delta (end of 2021) period respectively. We determined both the serum and bronchoalveolar SARS-CoV-2 viral load and identified the variant of concern (VoC) involved. Using a cytokine multiplex assay, we quantified systemic cytokine concentrations and analyzed their relationship with clinical findings, routine laboratory workup and pulmonary function data obtained during the ICU stay. Patients who did not survive had a significantly higher systemic and pulmonary viral load. Patients infected with the pre-alpha VoC showed a significantly lower viral load in comparison to those infected with the alpha- and delta-variants. Levels of systemic CTACK, M-CSF and IL-18 were significantly higher in non-survivors in comparison to survivors. CTACK correlated directly with APACHE II scores. We observed differences in lung compliance and the association between cytokine levels and pulmonary function, dependent on the VoC identified. An intra-cytokine analysis revealed a loss of correlation in the non-survival group in comparison to survivors in both cohorts. Critically ill COVID-19 patients exhibited a distinct systemic cytokine profile based on their survival outcomes. CTACK, M-CSF and IL-18 were identified as mortality-associated analytes independently of the VoC involved. The Intra-cytokine correlation analysis suggested the potential role of a dysregulated systemic network of inflammatory mediators in severe COVID-19 mortality.

Background Treatment effect of high-dose intravenous selenium remains controversial in patients with sepsis or septic shock. Here, we reanalyzed data from the randomized placebo-controlled trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT) to reveal possible treatment differences according to established sepsis phenotypes. Methods In this secondary data analysis of the SISPCT trial all 1089 patients of the original study were included. Patients were assigned to one of the four phenotypes by comparing patient variables with the Sepsis Endotyping in Emergency Care (SENECA) validation cohort. Survival analyses were performed using Kaplan–Meier and log-rank tests. Results No robust effect of selenium on mortality and other outcome parameters could be determined in any sepsis phenotype. Phenotype frequencies were markedly different in our study cohort compared to previous reports ( α : 2.2%, β : 6.3%, γ : 68.0%, δ : 23.4%). Differences in mortality between the respective phenotypes were not significant overall; however, 28-day mortality showed a lower mortality for the α - (20.8%) and β -phenotype (20.3%), followed by the γ - (27.1%), and δ -phenotype (28.5%). Conclusions Application of the four sepsis phenotypes to the SISPCT study cohort showed discrete but non-significant mortality differences within 28 days. However, beneficial treatment effects of high-dose intravenous selenium were still not detectable after categorizing the SISPCT study cohort according to four phenotype criteria.

Difficulties in endotracheal intubation increase morbidity and mortality in intensive care patients. We studied the problem in surgical intensive care patients with the aim of risk reduction. Patients intubated in the intensive care unit were evaluated. The intubations were performed or supervised by anaesthetists following the algorithm valid at the time of the study. Fifty percent of the 198 intubations were performed by specialist anaesthetists, 41.5% by anaesthesia trainees and 8.5% by surgical trainees. The initial attempt was by direct laryngoscopy (n=173), flexible fibrescope (n=8) or blind nasal technique (n=17). When direct laryngoscopy failed (n=7), intubation was accomplished with an intubating laryngeal mask airway (n=5), Frova stylet (n=1) or fibrescope (n=1). Thirty percent were rated as easy, 47% as moderately easy and 23% as difficult. Difficult intubations were associated with a higher incidence of anatomic anomalies, difficult bag-mask ventilation and severe oxygen desaturation. Every intubation in the ICU setting should be considered potentially difficult. The existing algorithm should be modified to incorporate the American Society of Anesthesiologists difficult airway algorithm adapted to the needs of the intensive care unit. A training program for alternative methods of airway management for difficult intubations should be established.

The COVID-19 pandemic, caused by SARS-CoV-2, demonstrated that zoonotic transmission of animal sarbecoviruses threatens human health but the determinants of transmission are incompletely understood. Here, we show that most spike (S) proteins of horseshoe bat and Malayan pangolin sarbecoviruses employ ACE2 for entry, with human and raccoon dog ACE2 exhibiting broad receptor activity. The insertion of a multibasic cleavage site into the S proteins increased entry into human lung cells driven by most S proteins tested, suggesting that acquisition of a multibasic cleavage site might increase infectivity of diverse animal sarbecoviruses for the human respiratory tract. In contrast, two bat sarbecovirus S proteins drove cell entry in an ACE2-independent, trypsin-dependent fashion and several ACE2-dependent S proteins could switch to the ACE2-independent entry pathway when exposed to trypsin. Several TMPRSS2-related cellular proteases but not the insertion of a multibasic cleavage site into the S protein allowed for ACE2-independent entry in the absence of trypsin and may support viral spread in the respiratory tract. Finally, the pan-sarbecovirus antibody S2H97 enhanced cell entry driven by two S proteins and this effect was reversed by trypsin. Similarly, plasma from quadruple vaccinated individuals neutralized entry driven by all S proteins studied, and use of the ACE2-independent, trypsin-dependent pathway reduced neutralization sensitivity. In sum, our study reports a pathway for entry into human cells that is ACE2-independent, supported by TMPRSS2-related proteases and associated with antibody evasion.

Zusammenfassung Eine auf den Thorax einwirkende Energie kann je nach Art, Lokalisation und Intensität zu Rippenserien- oder Sternumfrakturen, der Kombination aus beiden und zur Verletzung intrathorakaler Organe führen. Mitunter resultiert eine Instabilität der Thoraxwand mit hochgradiger Einschränkung der Atemmechanik. In der vergangenen Dekade hat die operative Thoraxwandrekonstruktion bei Thoraxwandinstabilität stark an Bedeutung gewonnen. Die Evidenz für ein operatives Vorgehen stützt sich mittlerweile auf prospektive randomisierte multizentrische Studien, multiple retrospektive Datenanalysen und darauf fußende Metaanalysen. einschließlich eines Cochrane-Reviews. Die Beurteilungen der Art und Schwere des einwirkenden Traumas sowie des Grads der atemmechanischen Einschränkung sind die Basis einer strukturierten Entscheidung über eine erweiterte konservative oder operativ-rekonstruktive Strategie sowie Operationszeitpunkt, -art und -umfang. Durch die frühzeitige Operation innerhalb von 72 h können Morbidität (Pneumonierate, Intensivstationsliege- und Beatmungsdauer) sowie Letalität verringert werden. Im vorliegenden Beitrag werden bereits etablierte und evidenzbasierte Algorithmen zur Thoraxwandrekonstruktion im Kontext der aktuellen Evidenz diskutiert.

Eine auf den Thorax einwirkende Energie kann je nach Art, Lokalisation und Intensität zu Rippenserien- oder Sternumfrakturen, der Kombination aus beiden und zur Verletzung intrathorakaler Organe führen. Mitunter resultiert eine Instabilität der Thoraxwand mit hochgradiger Einschränkung der Atemmechanik. In der vergangenen Dekade hat die operative Thoraxwandrekonstruktion bei Thoraxwandinstabilität stark an Bedeutung gewonnen. Die Evidenz für ein operatives Vorgehen stützt sich mittlerweile auf prospektive randomisierte multizentrische Studien, multiple retrospektive Datenanalysen und darauf fußende Metaanalysen. einschließlich eines Cochrane-Reviews. Die Beurteilungen der Art und Schwere des einwirkenden Traumas sowie des Grads der atemmechanischen Einschränkung sind die Basis einer strukturierten Entscheidung über eine erweiterte konservative oder operativ-rekonstruktive Strategie sowie Operationszeitpunkt, -art und -umfang. Durch die frühzeitige Operation innerhalb von 72 h können Morbidität (Pneumonierate, Intensivstationsliege- und Beatmungsdauer) sowie Letalität verringert werden. Im vorliegenden Beitrag werden bereits etablierte und evidenzbasierte Algorithmen zur Thoraxwandrekonstruktion im Kontext der aktuellen Evidenz diskutiert.