Rapid antigen tests for SARS-CoV-2-a synopsis of the medical evidence.

SARS-CoV-2, the causative agent of the COVID-19 pandemic, continues to influence health, economy, and stability worldwide. Diagnostic testing for SARS-CoV-2 is important to contain the COVID-19 pandemic. With the commercial availability of certified antigen (Ag) rapid diagnostic tests (RDTs), which can be used to identify an infection with SARS-CoV-2 an easy-to-use tool was introduced. Self-tests can offer advantages to complement professionally administered rapid antigen detection or nucleic acid amplification testing (NAAT). Compared to real-time polymerase chain reaction (RT-PCR), Ag-RDTs are cost inexpensive, do not need specialized laboratory equipment, facilitating high-throughput testing. However, Ag-RDT sensitivities are strongly dependent on the viral load within the specimen, which has limited their application in clinical settings so far. The methodical limitations of Ag-RDTs may produce false negative test results, particularly when specimens with low viral loads are examined. This may facilitate viral transmissions if protective measurements are lifted mistakenly.

Diagnostic Performance of Rapid Antigen Testing for SARS-CoV-2: The COVid-19 AntiGen (COVAG) study.

Background: Rapid diagnostic testing for SARS-Cov-2 antigens is used to combat the ongoing pandemic. In this study we aimed to compare two RDTs, the SD Biosensor Q SARS-CoV-2 Rapid Antigen Test (Roche) and the Panbio COVID-19 Ag Rapid Test (Abbott), against rRT-PCR. Methods: We included 2,215 all-comers at a diagnostic center between February 1 and March 31, 2021. rRT-PCR-positive samples were examined for SARS-CoV-2 variants. Findings: Three hundred and thirty eight participants (15%) were rRT-PCR-positive for SARS-CoV-2. The sensitivities of Roche-RDT and Abbott-RDT were 60.4 and 56.8% (P < 0.0001) and specificities 99.7% and 99.8% (P = 0.076). Sensitivity inversely correlated with rRT-PCR-Ct values. The RDTs had higher sensitivities in individuals referred by treating physicians (79.5%, 78.7%) than in those referred by health departments (49.5%, 44.3%) or tested for other reasons (50%, 45.8%), in persons without any comorbidities (74.4%, 71%) compared to those with comorbidities (38.2%, 34.4%), in individuals with COVID-19 symptoms (75.2%, 74.3%) compared to those without (31.9%, 23.3%), and in the absence of SARS-CoV-2 variants (87.7%, 84%) compared to Alpha variant carriers (77.1%, 72.3%). If 10,000 symptomatic individuals are tested of which 500 are truly positive, the RDTs would generate 38 false-positive and 124 false-negative results. If 10,000 asymptomatic individuals are tested, including 50 true positives, 18 false-positives and 34 false-negatives would be generated. Interpretation: The sensitivities of the two RDTs for asymptomatic SARS-CoV-2 carriers are unsatisfactory. Their widespread use may not be effective in the ongoing SARS-CoV-2 pandemic. The virus genotype influences the sensitivity of the two RDTs. RDTs should be evaluated for different SARS-CoV-2 variants.

Evaluation of five widely used serologic assays for antibodies to SARS-CoV-2.

Reliable diagnostic technologies are pivotal to the fight against COVID-19. While real-time reverse transcription-polymerase chain reaction (rRT-PCR) remains the gold standard, commercial assays for antibodies against (SARS-CoV-2) have emerged. We sought to examine 5 widely used commercial methods. We measured antibodies against SARS-CoV-2 with assays, Abbott-IgG, Roche-IgT (total antibodies, isotype-unspecific), EUROIMMUN-IgG, EUROIMMUN-IgA, DiaSorin-IgG, in 191 serum samples from patients with rRT-PCR proven COVID-19 between days 0 and 47 after the onset of clinical symptoms and in biobank samples collected in 2018. The assays were calibrated using the manufacturers' instructions; results are in multiples of the assay specific cut-offs (Abbott, Roche, EUROIMMUN) or in arbitrary units (AU/mL, DiaSorin). The assays for IgG and IgT have approximately the same sensitivity and specificity for detecting seroconversion which starts at approximately day 3 after symptom onset, sensitivity reached 93% on day 16 and was 100% for each assay on day 20. The assay for IgA antibodies was superior in sensitivity and had a lower specificity than the others. Bivariate non-parametric correlation coefficients ranged between 0.738 and 0.991. Commercial assays for IgG or total antibodies against SARS-CoV-2 are largely equivalent for establishing seroconversion but differ at high antibody titres. Increased sensitivity to detect seroconversion is afforded by including IgA antibodies. Further international efforts to harmonise assays for antibodies against SARS-CoV-2 are urgently needed.

Concomitant and noncanonical JAK2 and MPL mutations in JAK2V617F- and MPLW515 L-positive myelofibrosis.

Sequential genotyping for phenotype-driver mutations in JAK2 (exon 14), CALR (exon 9), and MPL (exon 10) is recommended in patients with myeloproliferative neoplasms. Yet, atypical JAK2- and MPL-mutations were described in some triple-negative patients. Whether noncanonical and/or concomitant JAK2- and MPL-mutations exist in myelofibrosis (MF) regardless of phenotype-driver mutations is not yet elucidated. For this, next-generation sequencing (NGS) was performed using blood genomic DNA from 128 MF patients (primary MF, n = 93; post-ET-MF, n = 18; post-PV-MF, n = 17). While no atypical JAK2- or MPL-mutations were seen in 24 CALR-positive samples, two JAK2-mutations [c.3323A > G, p.N1108S; c.3188G > A, p.R1063H] were detected in two of the 21 (9.5%) triple-negative patients. Twelve of the 82 (14.6%) JAK2V617F-positive cases had coexisting germline JAK2-mutations [JAK2R1063H, n = 6; JAK2R893T, n = 1; JAK2T525A, n = 1] or at least one somatic MPL-mutation [MPLY591D, n = 3; MPLW515 L, n = 2; MPLE335K, n = 1]. Overall, MPL-mutations always coexisted with JAK2V617F and/or other MPL-mutations. None of the JAK2V617F plus a second JAK2-mutation carried a TET2-mutation but all patients with JAK2V617F plus an MPL-mutation harbored a somatic TET2-mutation. Four genomic clusters could be identified in the JAK2V617F-positive cohort. Cluster-I (10%) (noncanonical JAK2mutated (mut) + TET2wildtype (wt) ) were younger and had less proliferative disease compared with cluster-IV (5%) (TET2mut + MPLmut ). In conclusion, recurrent concomitant classical and/or noncanonical JAK2- and MPL-mutations could be detected by NGS in 15.7% of JAK2V617F- and MPLW515-positive MF patients with genotype-phenotype associations. Many of the germline and/or somatic mutations might act as "Significantly Mutated Genes" contributing to the pathogenesis and phenotypic heterogeneity. A cost-effective NGS-based approach might be an important step towards patient-tailored medicine.

Inferior vena cava thrombosis and its relationship with the JAK2V617F mutation and chronic myeloproliferative disease.

BACKGROUND: Splanchnic vein thrombosis (SVT) is a typical manifestation of polycythaemia vera (PV) or essential thrombocythaemia (ET). The recently discovered JAK2V617F somatic mutation is closely associated with chronic myeloproliferative disease (CMD). We investigated whether thrombosis involving the inferior vena cava (IVC) is also related to the JAK2V617F mutation or CMD. METHODS: Blood samples were obtained from 40 IVC thrombosis patients. Fifty-three patients with isolated lower extremity deep vein thrombosis (LE-DVT) and 20 SVT patients served as controls. The presence of the JAK2V617F mutation was assessed by real-time polymerase chain reaction (RT-PCR). RESULTS: The JAK2V617F allele was not detected in any of the IVC thrombosis patients but was detected in one patient (2%) with isolated LE-DVT. However, the mutation-carrying patient did not exhibit symptoms of CMD. Even after an observation period of 30months, the patient's complete blood cell count did not exhibit any pathology. In contrast, the JAK2V617F allele was detected in four patients with SVT (20%) and CMD. CONCLUSION: According to our data, there is no evidence that IVC thrombosis is associated with the JAK2V617F mutation or the presence of chronic myeloproliferative disease.

Oral treatment with probucol in a pharmacological dose has no beneficial effects on mortality in chronic ischemic heart failure after large myocardial infarction in rats.

Cardiac remodeling after myocardial infarction is in part triggered and maintained by reactive oxygen species. Antioxidants such as probucol have shown positive short-term effects on these cardiac interstitial changes in different experimental models after intraperitoneal administration or after per-oral administration with a long pre-treatment period or in high doses. In this study, the long-term effects on mortality and cardiac remodeling were examined after induction of a large myocardial infarction in a clinical daily-life-like setting. Male Lewis rats were randomized to the study groups. Large anterolateral myocardial infarctions were induced or sham operations performed. The oral treatment was started after 48 h either with probucol or placebo after myocardial infarction and with placebo after sham operation. Induction of large myocardial infarctions led to changes of the left ventricular stiffness constants, a dilatation of the left ventricle and an increased interstitial fibrosis in the remote non-infarcted part. These changes were in tendency, but not significantly, reversed after treatment with probucol. The 6-month survival rates were 53.1% in the group probucol-myocardial infarction, 43.2% in the group placebo-myocardial infarction and 100% in the group after sham operation. There were no significant differences at Kaplan-Meier analysis between the groups after myocardial infarctions. Oral treatment with the antioxidant probucol started after myocardial infarction in a pharmacological dose does not have favourable effects on the long-term mortality in the chronic ischemic heart failure model in the rat.

Evaluation of isolated lung perfusion as neoadjuvant therapy of lung metastases using a novel in vivo pig model: II. High-dose cisplatin is well tolerated by the native lung tissue.

OBJECTIVE: Efficacy of in vivo isolated lung perfusion (ILP) with cisplatin could be shown in different rodent tumor models. Despite the use of this alternative therapeutical strategy in very few patients with lung metastases, there are no systematic studies regarding the tolerance of the native lung tissue in large animal models or humans. METHODS: In a novel ILP pig model, groups with two different concentrations of cisplatin (group CP150: 150 mg/m(2) cisplatin, n=5; group CP300: 300 mg/m(2) cisplatin, n=5) were compared with a control group (n=5) and a Sham group (n=5) concerning the influence on hemodynamic, ventilatory and gas exchange parameters as well as on structural integrity of the lung. In the additional CP300-HT group the potentially cumulative effect of hyperthermia and high-dose cisplatin perfusion was evaluated (300 mg/m(2) cisplatin, 41.5 degrees C, n=5). Following the ILP of the left lung for 40 min, right main bronchus and right pulmonary arteries were clamped and survival as well as lung function parameters were dependent on the previously perfused lung for the 6-h-reperfusion period. Quantification of histological acute lung injury was performed using the score of Chiang. ANOVA, ANOVA with repeated measures and Pearson's correlation estimation were applied for statistical evaluation. RESULTS: All animals survived ILP and the entire reperfusion period. Platinum levels of the perfusate and lung tissue showed a significant correlation with the dose given (P<0.001) but no correlation with the very low plasma levels in all groups (P=0.825). ILP resulted in a slight deterioration of most functional parameters compared to the Sham group. Although there were no differences between the perfusion groups regarding hemodynamic and ventilatory parameters, gas exchange parameters (pO(2)/FiO(2)-index, pCO(2), AADO(2)) demonstrated a trend toward dose-related functional impairment. Histological evaluation confirmed a dose-depending damage of lung tissue (P<0.001, correlation coefficient 0.670). The hyperthermic ILP with high-dose cisplatin led to improved gas exchange parameters and a reduction of morphological lung damage. CONCLUSIONS: In vivo ILP with high-dose cisplatin represents a safe procedure in this pig model. Hyperthermic perfusion up to 41.5 degrees C was beneficial to reduce the acute lung injury. The promising results of this study might be used for initiation of clinical trials as an alternative treatment in patients with a very poor prognosis.

Pharmacokinetics of oxaliplatin during chronomodulated infusion in metastatic gastrointestinal cancer patients: a pilot investigation with preliminary results.

Several clinical trials have demonstrated that the three-drug combination of oxaliplatin, 5-fluorouracil (5-FU) and leucovorin (LV) administered chronomodulated improved antitumour efficacy in the treatment of metastatic colorectal cancer and was better tolerated than constant-rate infusion. However, only a few pharmacokinetic data of 5-FU during chronomodulated infusion are available but up to now not for oxaliplatin. In this pilot study, the platinum levels of plasma ultrafiltrate (PUF) and total plasma were monitored during chronomodulated infusion of oxaliplatin, 5-FU and LV in 7 patients with metastatic gastrointestinal cancer. A cycle of the 4-day chemotherapeutic regimen consisted of 12-h infusions with sinusoidal drug delivery rate of: oxaliplatin (25 mg/m2/d, peak at 16:00 hours), 5-FU and LV (750 mg/m2/d and 150 mg/m2/d, respectively, peak at 4:00 hours), the same scheme was reinitiated on day 15. Blood samples were collected on day 1 and day 4 during different cycles. Concentration-time profiles of ultrafilterable and total platinum in plasma during chronomodulated infusion were characterised. As expected, we found residual platinum levels in total plasma but not in PUF prior next cycle. Comparing day 1 with day 4, Cmax of platinum in PUF was significantly increased (84 +/- 13 ng/ml vs. 131 +/- 22 ng/ml, P = 0.012) as well as AUC0-24h of platinum in PUF (0.97 +/- 0.29 microg x h/ml vs. 1.90 +/- 0.44 microg x h/ml, P = 0.018). The same effect was observed for total plasma platinum suggesting an accumulation within the cycle. The observed interindividual variability of Cmax, tmax, AUC0-24h, t1/2 was moderate. Because of the small sample size in this pilot investigation, the findings need to be confirmed in larger pharmacokinetic studies. In a next step individual pharmacokinetic parameters should be associated with patient specific parameters and treatment-induced toxicity.