Notes

MiRNAs and lncRNAs throughout NK cellular chemistry as well as NK/T-cell lymphoma.
Midregional pro-adrenomedullin (MR-proADM) is a vasoactive peptide with key roles in reducing vascular hyperpermeability and thereby improving endothelial stability during infection. While MR-proADM is useful for risk stratification in patients with sepsis, clinical data about prediction accuracy in patients with severe acute respiratory syndrome coronavirus 2 disease (COVID-19) is currently missing.

We included consecutively adult patients hospitalized for confirmed COVID-19 at a tertiary care center in Switzerland between February and April 2020. We investigated the association of MR-proADM levels with in-hospital mortality in logistic regression and discrimination analyses.

Of 89 included COVID-19 patients, 19% (n=17) died while in the hospital. Median admission MR-proADM levels (nmol/L) were increased almost 1.5-fold increased in non-survivors compared to survivors (1.3 [interquartile range IQR 1.1-2.3]) vs. 0.8 [IQR 0.7-1.1]) and showed good discrimination (area under the curve 0.78). An increase of 1nmol/L of admission MR-proADM was independently associated with a more than fivefold increase in in-hospital mortality (adjusted odds ratio of 5.5, 95% confidence interval 1.4-21.4, p=0.015). An admission MR-proADM threshold of 0.93nmol/L showed the best prognostic accuracy for in-hospital mortality with a sensitivity of 93%, aspecificity of 60% and a negative predictive value of 97%. Kinetics of follow-up MR-proADM provided further prognostic information for in-hospital treatment.

Increased levels of MR-proADM on admission and during hospital stay were independently associated with in-hospital mortality and may allow a better risk stratification, and particularly rule-out of fatal outcome, in COVID-19 patients.
Increased levels of MR-proADM on admission and during hospital stay were independently associated with in-hospital mortality and may allow a better risk stratification, and particularly rule-out of fatal outcome, in COVID-19 patients.
Novel treatment options for some carbapenem-resistant Gram-negative pathogens have been identified by the World Health Organization as being of the highest priority. Ceftolozane-tazobactam is a novel cephalosporin-beta-lactamase inhibitor combination antibiotic with potent bactericidal activity against the most difficult-to-treat multi-drug resistant and extensively drug resistant Gram-negative pathogens. This study aimed to develop and validate a liquid chromatography- tandem mass spectrometry method for the simultaneous quantification of ceftolozane and tazobactam in plasma (total and unbound), renal replacement therapy effluent (RRTE), cerebrospinal fluid (CSF) and urine.

Analytes were separated using mixed-mode chromatography with an intrinsically base-deactivated C18 column and a gradient mobile phase consisting of 0.1% formic acid, 10mM ammonium formate and acetonitrile. The analytes and internal standards were detected using rapid ionisation switching between positive and negative modes with simulte-tazobactam.
Risk stratification in patients with infection is usually based on the Sequential Organ Failure Assessment-Score (SOFA score). Our aim was to investigate whether the vasoactive peptide mid-regional pro-adrenomedullin (MR-proADM) improves the predictive value of the SOFA score for 30-day mortality in patients with acute infection presenting to the emergency department (ED).

This secondary analysis of the prospective observational TRIAGE study included 657 patients with infection. The SOFA score, MR-proADM, and traditional inflammation markers were all measured at time of admission. Associations of admission parameters and 30-day mortality were investigated by measures of logistic regression, discrimination analyses, net reclassification index (NRI), and integrated discrimination index (IDI).

MR-proADM values were higher in non-survivors compared with survivors (4.5±3.5nmol/L vs. 1.7±1.8nmol/L) with an adjusted odds ratio of 26.6 (95% CI 3.92 to 180.61, p=0.001) per 1nmol/L increase in admission MR-proADM levels and an area under the receiver operator curve (AUC) of 0.86. While the SOFA score alone revealed an AUC of 0.81, adding MR-proADM further improved discrimination (AUC 0.87) and classification within predefined risk categories (NRI 0.075, p-value <0.05). An admission MR-proADM threshold of 1.75nmol/L provided the best prognostic accuracy for 30-day mortality; with a sensitivity of 81% and a specificity of 75%, and a negative predictive value of 98%.

MR-proADM improved the mortality risk stratification in patients with infection presenting to the ED beyond SOFA score alone and may further improve initial therapeutic site-of-care decisions.

ClinicalTrials.gov NCT01768494. Registered January 15, 2013.
ClinicalTrials.gov NCT01768494. Registered January 15, 2013.
Novel point-of-care antigen assays present a promising opportunity for rapid screening of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. The purpose of this study was the clinical assessment of the new Roche SARS-CoV-2 Rapid Antigen Test.

The clinical performance of Roche SARS-CoV-2 Rapid Antigen Test was evaluated vs. a reverse transcription polymerase chain reaction (RT-PCR) laboratory-based assay (Seegene AllplexTM2019-nCoV) in nasopharyngeal swabs collected from a series of consecutive patients referred for SARS-CoV-2 diagnostics to the Pederzoli Hospital (Peschiera del Garda, Verona, Italy) over a 2-week period.

The final study population consisted of 321 consecutive patients (mean age, 46 years and IQR, 32-56 years; 181 women, 56.4%), with 149/321 (46.4%) positive forSARS-CoV-2 RNA via the Seegene AllplexTM2019-nCoV Assay, and 109/321 (34.0%) positive with Roche SARS-CoV-2 Rapid Antigen Test, respectively. The overall accuracy of Roche SARS-CoV-2 Rapid Antigen Test compared to molecular testing was 86.9%, with 72.5% sensitivity and 99.4% specificity. Progressive decline in performance was observed as cycle threshold (Ct) values of different SARS-CoV-2 gene targets increased. The sensitivity was found to range between 97-100% in clinical samples with Ct values <25, between 50-81% in those with Ct values between 25 and <30, but low as 12-18% in samples with Ct values between 30 and <37.

The clinical performance of Roche SARS-CoV-2 Rapid Antigen Test is excellent in nasopharyngeal swabs with Ct values <25, which makes it a reliable screening test in patients with high viral load. However, mass community screening would require the use of more sensitive techniques.
The clinical performance of Roche SARS-CoV-2 Rapid Antigen Test is excellent in nasopharyngeal swabs with Ct values less then 25, which makes it a reliable screening test in patients with high viral load. However, mass community screening would require the use of more sensitive techniques.While much diagnosis literature focuses on errors, our goal is to learn how to achieve diagnostic excellence. Before the explosion of cognitive psychology studies on errors, authors of fictional detectives understood the principles of arriving at the correct diagnosis (in their case the guilty party). Using quotes from many fictional detectives, we discuss a framework for diagnostic excellence. Understanding the implications of these quotes should help aspiring diagnosis experts on their path to excellence.
Development and implementation of SARS-CoV-2 serologic assays gained momentum. Laboratories keep on investigating the performance of these assays. In this study, we compared three fully automated SARS-CoV-2 antibody assays.

A total of 186 samples from 84 PCR-positive COVID-19 patients and 120 control samples taken before the SARS-CoV-2 pandemic were analyzed using commercial serologic assays from Roche, Siemens and DiaSorin. Time after the positive COVID-19 PCR result and onset of symptoms was retrieved from the medical record. An extended golden standard, using the result of all three assays was defined, judging if antibodies are present or absent in a sample. Diagnostic and screening sensitivity/specificity and positive/negative predictive value were calculated.

Diagnostic sensitivity (ability to detect a COVID-19 positive patient) ≥14days after positive PCR testing was 96.7% (95% CI 88.5-99.6%) for DiaSorin, 93.3% (95% CI 83.8-98.2%) for Roche and 100% (95% CI 94.0-100%) for Siemens. Lower diagnosticictive values for antibody detection in low seroprevalence settings.
Procalcitonin (PCT) has been proposed for differentiating viral vs. bacterial infections. Midostaurin molecular weight In COVID-19, some preliminary results have shown that PCT testing could act as a predictor of bacterial co-infection and be a useful marker for assessment of disease severity.

We studied 83 COVID-19 hospitalized patients in whom PCT was specifically ordered by attending physicians. PCT results were evaluated according to the ability to accurately predict bacterial co-infections and death in comparison with other known biomarkers of infection and with major laboratory predictors of COVID-19 severity.

Thirty-three (39.8%) patients suffered an in-hospital bacterial co-infection and 44 (53.0%) patients died. In predicting bacterial co-infection, PCT showed a relatively low accuracy (area under receiver-operating characteristic [ROC] curve [AUC] 0.757; 95% confidence interval [CI] 0.651-0.845), with a strength for detecting the outcome not significantly different from that of white blood cell count and C-reactive protein (CRP). In predicting patient death, PCT showed an AUC of 0.815 (CI 0.714-0.892), not better than those of other more common laboratory tests, such as blood lymphocyte percentage (AUC 0.874, p=0.19), serum lactate dehydrogenase (AUC 0.860, p=0.47), blood neutrophil count (AUC 0.845, p=0.59), and serum albumin (AUC 0.839, p=0.73).

Procalcitonin (PCT) testing, even when appropriately ordered, did not provide a significant added value in COVID-19 patients when compared with more consolidated biomarkers of infection and poor clinical outcome. The major application of PCT in COVID-19 is its ability, associated with a negative predictive value >90%, to exclude a bacterial co-infection when a rule-out cut-off (<0.25μg/L) is applied.
90%, to exclude a bacterial co-infection when a rule-out cut-off ( less then 0.25 μg/L) is applied.Over the last two decades, gene therapy has been successfully translated to many rare diseases. The number of clinical trials is rapidly expanding and some gene therapy products have now received market authorisation in the western world. Inherited metabolic diseases (IMD) are orphan diseases frequently associated with a severe debilitating phenotype with limited therapeutic perspective. Gene therapy is progressively becoming a disease-changing therapeutic option for these patients. In this review, we aim to summarise the development of this emerging field detailing the main gene therapy strategies, routes of administration, viral and non-viral vectors and gene editing tools. We discuss the respective advantages and pitfalls of these gene therapy strategies and review their application in IMD, providing examples of clinical trials with lentiviral or adeno-associated viral gene therapy vectors in rare diseases. The rapid development of the field and implementation of gene therapy as a realistic therapeutic option for various IMD in a short term also require a good knowledge and understanding of these technologies from physicians to counsel the patients at best.
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