Initial Experience With SARS-CoV-2-Neutralizing Monoclonal Antibodies in Kidney or Combined Kidney-Pancreas Transplant Recipients.

Background: Antiviral drugs have shown little impact in patient infected with acute respiratory coronavirus 2 (SARS-CoV-2). Especially for immunocompromised persons positive for SARS-CoV-2, novel treatments are warranted. Recently, the U.S. FDA has granted an emergency use authorization (EUA) to two monoclonal antibodies (mAb) targeting the viral spike protein: bamlanivimab and casivirimab and imdevimab. As per the EUA, all SARS-CoV-2 positive organ transplant recipients can receive mAb treatment. Patients and methods: We queried our center's transplant registry to identify SARS-CoV-2 infected recipients treated with single doses of either Bamlanivimab or casivirimab/imdevimab up to May 31, 2021. We analyzed clinical outcomes, renal function and virus-specific antibodies. The co-primary endpoints were hospitalization due to COVID-19 and SARS-CoV-2 RT-PCR negativity. Results: Thirteen patients at a median interval of 55 (IQR, 26-110) months from transplant were treated: 8 with bamlanivimab and 5 with casivirimab/imdevimab. In all, 4/13 (31%) patients were hospitalized at some time, while 11/13 (85%) achieved PCR negativity. 2/4 hospitalized patients received mAb as rescue treatment. Overall mortality was 23%, with one death attributable to transplant-associated lymphoma. All six patients infected with the B 1.1.7 variant were alive at last contact. Conclusion: mAb treatment appears effective when administered early to SARS-CoV-2-infected transplant recipients.

Estimation of pulmonary artery pressure with transesophageal echocardiography: An observer-blinded test accuracy study.

ABSTRACT: With the declining use of the pulmonary artery catheter (PAC), transesophageal echocardiography (TEE) has become an appealing alternative to obtain pulmonary artery pressure non-invasively using the simplified Bernoulli equation. The validation of this method in the perioperative setting has been scarce with no clear recommendations about which view is the most accurate to estimate right ventricular systolic pressure (RVSP).Therefore, we performed a prospective, observer-blinded, diagnostic test accuracy study to assess the difference in systolic pulmonary artery pressure (sysPAP) measuring both, invasively sysPAP and estimated RVSP with TEE in 3 different views: the mid-esophageal (ME) 4Chamber, the ME right ventricular (RV) inflow-outflow and the ME modified bicaval view.To show a clinically significant difference of at least 10% in RVSP, we included 40 cardiac surgical patients divided into 3 subgroups: Patients with mild to moderate tricuspid regurgitation (TR) and mean PAP <25 mm Hg, patients with mild to moderate TR and mean PAP≥ 25 mm Hg, and patients with severe TR.For the whole cohort, bias of estimated RVSP compared to measured sysPAP was 5.27 mm Hg, precision was 7.96 mm Hg, limits of agreement were -10.66 to 21.19 mm Hg. The best agreement between the 2 methods was found in patients with severe TR and in the ME RV inflow-outflow and the modified bicaval view. Good Doppler signals were available in 35% and 46% in these views, and in 20% in the ME 4 chamber view.The estimation of the sysPAP by TEE cannot be considered reliable in the clinical perioperative setting. Only measurements that provide a full Doppler envelope show sufficient precision to provide accurate estimations.

The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation.

PURPOSE: Chronic kidney disease (CKD) is a major health-care burden. Increasing evidence suggests that a considerable proportion of patients are affected by a monogenic kidney disorder. METHODS: In this study, the kidney transplantation waiting list at the Charité was screened for patients with undetermined cause of CKD. By next-generation sequencing (NGS) we targeted all 600 genes described and associated with kidney disease or allied disorders. RESULTS: In total, 635 patients were investigated. Of these, 245 individuals had a known cause of CKD (38.5%) of which 119 had a proven genetic disease (e.g., ADPKD, Alport). The other 340 patients (53.5%) were classified as undetermined diagnosis, of whom 87 had kidney failure (KF) onset <40 years. To this latter group genetic testing was offered as well as to those patients (n = 29) with focal segmental glomerulosclerosis (FSGS) and all individuals (n = 21) suspicious for thrombotic microangiopathy (TMA) in kidney biopsy. We detected diagnostic variants in 26 of 126 patients (20.6%) of which 14 of 126 (11.1%) were pathogenic or likely pathogenic. In another 12 of 126 (9.5%) patients, variants of unknown significance (VUS) were detected. CONCLUSION: Our study demonstrates the diagnostic value of comprehensive genetic testing among patients with undetermined CKD.

Carotid artery blood flow velocities during open-heart surgery and its association with delirium: A prospective, observational pilot study.

The aim of this prospective observational single-centre pilot study was to evaluate the association between alterations in carotid artery blood flow velocities during cardiac surgery and postoperative delirium.Carotid artery blood flow velocity was determined perioperatively at 5 different timepoints by duplex sonography in 36 adult cardiac surgical patients. Delirium was assessed using the Confusion Assessment Method for the ICU and the Intensive Care Delirium Screening Checklist. Additionally, blood flow velocities in the middle cerebral arteries, differences in regional cerebral tissue oxygenation and quantity and quality of microemboli were measured.Delirium was detected in 7 of 36 patients. After cardiopulmonary bypass carotid artery blood flow velocities increased by +23 cm/second (95% confidence interval (CI) 9-36 cm/second) in non-delirious patients compared to preoperative values (P = .002), but not in delirious patients (+3 cm/second [95% CI -25 to 32 cm/second], P = .5781). Middle cerebral artery blood flow velocities were higher at aortic de-cannulation in non-delirious patients (29 cm/second [inter-quartile range (IQR), 24-36 cm/second] vs 12 cm/second [IQR, 10-19 cm/second]; P = .017). Furthermore, brain tissue oxygenation was higher in non-delirious patients during surgery.Our results suggest that higher cerebral blood flow velocities after aortic de-clamping and probably also improved brain oxygenation might be beneficial to prevent postoperative delirium.

Hemoadsorption does not Have Influence on Hemolysis During Cardiopulmonary Bypass.

Cardiopulmonary bypass (CPB) induces hemolysis, which manifests as plasma free hemoglobin. We investigated in a post hoc analysis of a single-center, blinded, controlled study whether the use of a novel hemoadsorption device (CytoSorb, CytoSorbents Europe GmbH, Berlin, Germany) affects hemolysis during CPB. A total of 35 patients undergoing elective CPB surgery with an expected CPB duration of more than 120 min were included in the analysis. The hemoadsorption device was used in 17 patients (intervention group) and not used in 18 patients (control group). The primary outcome was differences of postoperative free hemoglobin and haptoglobin levels. As secondary outcomes, we investigated differences in postoperative lactate dehydrogenase and bilirubin levels. Postoperative free hemoglobin levels were not significantly different between the groups. However, there were statistically significant differences between the treatment and control groups in the median levels of haptoglobin (58.4 vs. 17.9 mg/dL, respectively; P < 0.01) and lactate dehydrogenase (353.0 vs. 432.0 U/L, respectively; P < 0.05) on postoperative day 1. Thus, in this study, we did not find an effect on hemolysis in patients treated with hemoadsorption, though lower haptoglobin level and higher secondary hemolysis markers on postoperative day 1 in patients not treated with the hemoadsorber may be an indication of some moderate effect of the device. Studies with larger samples are needed to clarify the significance of the small differences detected in this study.

A Pilot Assessment of Carotid and Brachial Artery Blood Flow Estimation Using Ultrasound Doppler in Cardiac Surgery Patients.

OBJECTIVES: To estimate carotid and brachial artery blood flow with Doppler ultrasound in cardiac surgery patients and relate such estimates to cardiac index, lactate levels, and markers of renal function. DESIGN: A prospective observational study. SETTING: A teaching hospital. PARTICIPANTS: Twenty-five elective cardiac surgery patients. INTERVENTIONS: The authors measured bilateral carotid and brachial artery blood flows using Doppler ultrasound and, simultaneously, cardiac index using a pulmonary artery catheter; lactate and serum creatinine levels; and urine output. The relationship between these indices and biomarkers was assessed statistically. MEASUREMENTS AND MAIN RESULTS: Median carotid arterial blood flow was estimated at 0.323 L/min (interquartile ratio [IQR], 0.256-0.429 L/min) on the right and 0.308 L/min (IQR, 0.247-0.376 L/min) on the left at baseline. Median brachial arterial blood flow was estimated at 0.063 L/min (IQR, 0.039-0.115 L/min) on the right and 0.063 L/min (IQR, 0.039-0.081 L/min) on the left at baseline. There was a weak correlation between right- and left-sided flows (brachial: rho = 0.285; carotid: rho = 0.384) and between brachial and carotid flow (right: rho = 0.135, left: rho = 0.225). There also was a weak correlation between cardiac index and brachial flow (right: rho = 0.215; left: rho = 0.320) and carotid flow (left: rho = 0.159) immediately after surgery, and no correlation 1 day after surgery (right brachial: rho = -0.010; left brachial: rho = -0.064; left carotid: rho = -0.060). There were no significant correlations between carotid or brachial flows and lactate and serum creatinine levels or urine output. CONCLUSIONS: In cardiac surgery patients, Doppler-estimated carotid and brachial arterial blood flows have only a weak correlation with cardiac index and no correlation with lactate or creatinine levels or urine output. Thus, Doppler estimation of these blood flows cannot be used to provide noninvasive estimates of cardiac index in patients after cardiac surgery.

Effect of Preload Alterations on Left Ventricular Systolic Parameters Including Speckle-Tracking Echocardiography Radial Strain During General Anesthesia.

OBJECTIVES: Frequently used parameters for evaluation of left ventricular systolic function are load-sensitive. However, the impact of preload alterations on speckle-tracking echocardiographic parameters during anesthesia has not been validated. Therefore, two-dimensional (2D) speckle-tracking echocardiography radial strain (RS) was assessed during general anesthesia, simulating 3 different preload conditions. DESIGN: Single-center prospective observational study. SETTING: University hospital. PARTICIPANTS: Thirty-three patients with normal left ventricular systolic function undergoing major surgery. INTERVENTIONS: Transgastric views of the midpapillary level of the left ventricle were acquired at 3 different positions. MEASUREMENTS AND MAIN RESULTS: Fractional shortening (FS), fractional area change (FAC), and 2D speckle-tracking echocardiography RS were analyzed in the transgastric midpapillary view. Considerable correlation above 0.5 was found for FAC and FS in the zero and Trendelenburg positions (r = 0.629, r = 0.587), and for RS and FAC in the anti-Trendelenburg position (r = 0.518). In the repeated-measures analysis, significant differences among the values measured at the 3 positions were found for FAC and FS. For FAC, there were differences up to 2.8 percentage points between the anti-Trendelenburg position and the other 2 positions. For FS, only the difference between position zero and anti-Trendelenburg was significant, with an observed change of 1.66. Two-dimensional RS was not significantly different at all positions, with observed changes below 1 percentage point. CONCLUSIONS: Alterations in preload did not result in clinically relevant changes of RS, FS, or FAC. Observed changes for RS were smallest; however, the variation of RS was larger than that of FS or FAC.

(Eco)toxicity and biodegradability of selected protic and aprotic ionic liquids.

Ionic liquids (ILs) are a promising group of compounds with a large variety of possible structures and uses. They are considered as a potential "green" replacement for traditional volatile organic solvents, but their impact on the environment is often neglected or not studied enough. In the present study, selected representatives of two ILs groups were analyzed: a new family of protic ILs (derived from aliphatic amines and organic acids) and some frequently used aprotic ILs (substituted imidazolium and piridinium chlorides). The aquatic toxicity (test organisms Vibrio fischeri, Pseudokirchneriella subcapitata and Lemna minor) and biodegradability tests were carried out. The additional tests with enzyme (acetylcholinesterase) and leukemia rat cells (IPC-81) provided more in-depth evaluation of toxicity. In our comparative hazard assessment protic ILs have EC50 values >100 mg L(-1) in all of the tests performed, except in the case of three representatives toward Lemna minor. They also show good biodegradability rates. The EC50 values for aprotic ILs are various orders of magnitude lower than the ones for protic ILs in most of the tests and they show a lower biodegradability potential. These findings indicate that protic ILs can be considered as environmentally safer alternatives for more toxic ILs and organic solvents.

The effect of a bolus dose of intravenous lidocaine on the minimum alveolar concentration of sevoflurane: a prospective, randomized, double-blinded, placebo-controlled trial.

BACKGROUND: The anesthetic effect of volatile anesthetics can be quantified by the minimum alveolar concentration (MAC) of the drug that prevents movement in response to a noxious stimulus in 50% of patients. The underlying mechanism regarding how immobilization is achieved by volatile anesthetics is not thoroughly understood, but several drugs affect MAC. In this study, we investigated the effect of a single IV bolus dose of lidocaine on the MAC of sevoflurane in humans. METHODS: We determined the MAC for sevoflurane using the Dixon "up-and-down" method in 3 groups of patients, aged 30 to 65 years, who underwent elective surgery (30 patients per group). Study medication (placebo, 0.75 mg·kg(-1) lidocaine or 1.5 mg·kg(-1) lidocaine) was administered 3 minutes before skin incision after a 15-minute equilibration period and the response to skin incision was recorded (movement versus no movement). RESULTS: MAC was 1.86% ± 0.40% in the placebo and 1.87% ± 0.45% in the 0.75 mg·kg(-1) lidocaine group (P = 1.00). MAC was 1.63% ± 0.24% in the 1.5 mg·kg(-1) lidocaine group, which was significantly lower than that of the placebo group (mean difference of 0.23% sevoflurane [95% adjusted confidence interval {CI}, 0.03-0.43]; P = 0.022). No significant difference was observed between the 0.75 mg·kg(-1) lidocaine and the placebo groups (mean difference of -0.01% sevoflurane [95% adjusted CI, -0.27 to 0.25]; P = 1). CONCLUSIONS: IV 1.5 mg·kg(-1) lidocaine decreased the MAC by at least 0.03% sevoflurane (mean difference 0.23% sevoflurane [95% adjusted CI, 0.03-0.43]). We did not observe a significant reduction in the MAC of sevoflurane with the IV administration of 0.75 mg·kg(-1) lidocaine.

Analyzing cytotoxic effects of selected isothiazol-3-one biocides using the toxic ratio concept and structure-activity relationship considerations.

To demonstrate how baseline toxicity can be separated from other more specific modes of toxic action and to address possible pitfals when dealing with hydrophobic substances, the four isothiazol-3-one biocides N-methylisothiazol-3-one (MIT), 5-chloro-N-methylisothiazol-3-one (CIT), N-octylisothiazol-3-one (OIT), and 4,5-dichloro-N-octylisothiazol-3-one (DCOIT) as an example for reactive electrophilic xenobiotics were tested for their cytotoxic effects on the human hepatoblastoma cell line Hep G2, on the marine bacterium Vibrio fischeri, and on the limnic green alga Scenedesmus vacuolatus. In each of the three test systems, toxic effects were observed in a consistent pattern. The two chlorinated compounds and OIT were found to be significantly more toxic than MIT. As compared to baseline toxicants, the small and polar MIT and CIT exhibited pronounced excess toxicity in each of the three test systems that is presumably triggered by their intrinsic reactivity toward cellular thiols. In contrast, OIT and DCOIT showed mainly toxicities that could be explained by their hydrophobicity. Analyzing and comparing these results using the toxic ratio concept and with data that indicate a dramatic depletion of cellular glutathione levels after incubation with DCOIT reveals that for highly hydrophobic substances, baseline level toxicity in an assay for acute toxicity can lead to an oversight of other more specific modes of toxic action that may cause significant effects that might be less reversible than those caused by unreactive baseline toxicants. This possibility should be taken into account in the hazard assessment of chemicals that are both hydrophobic and reactive.

Structure-activity relationships for the impact of selected isothiazol-3-one biocides on glutathione metabolism and glutathione reductase of the human liver cell line Hep G2.

To investigate the toxic mode of action of isothiazol-3-one biocides the four compounds N-methylisothiazol-3-one (MIT), 5-chloro-N-methylisothiazol-3-one (CIT), N-octylisothiazol-3-one (OIT) and 4,5-dichloro-N-octylisothiazol-3-one (DCOIT) were purified and tested as single chemical entities for their effects on the human hepatoblastoma cell line Hep G2 and on isolated and cellular glutathione reductase GR). The two chlorinated substances CIT and DCOIT significantly decreased the amount of total cellular glutathione (GSx) in a dose and time dependent manner. Concomitantly, an increase in the level of oxidised glutathione (GSSG) was observed. The resulting shift in the GSH/GSSG ratio entailing the breakdown of the cellular thiol reduction potential was accompanied by necrotic morphological changes like swelling of the plasma membrane and subsequent lysis of the cells. Additionally, CIT and DCOIT were found to inhibit cellular GR in the cells in a concentration dependent manner. The T-SAR-based (thinking in terms of structure-activity relationships) comparison of the chlorine-substituted structures CIT and DCOIT with their non-chlorinated and less active analogues MIT and OIT identified the chlorine substituents and the resulting reaction mechanisms to be the key structural mediators of the observed toxic effects. Furthermore, differences in the activity of both chlorinated substances could be explained using the T-SAR approach to link the lipophilicity and the intrinsic glutathione-reactivity of the compounds to the expected target site concentrations inside the cells.

Lipophilicity parameters for ionic liquid cations and their correlation to in vitro cytotoxicity.

Regarding the great structural variability of the currently expanding group of ionic liquids, it is highly desirable to understand the basic factors affecting their toxicity in different biological systems. The present study of a set of 74 ionic liquids with imidazolium, pyrrolidinium, pyridinium, quinolinium, quaternary phosphonium and quaternary ammonium cations and the comparatively small anions Cl(-), Br(-), BF(4)(-), or PF(6)(-) demonstrates the influence of the cation lipophilicity on the cytotoxicity in IPC-81 leukemia cells from rats. The scope of this correlation is limited to ionic liquids with these or similarly small anions that are sufficiently nonreactive under physiological and chromatographic conditions and whose cation lipophilicity does not exceed a certain threshold.