Monitoring SARS-CoV-2 genetic variability: A post-market surveillance workflow for combined bioinformatic and laboratory evaluation of commercial RT-PCR assay performance.

OBJECTIVE: The speed at which Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is mutating has made it necessary to frequently assess how these genomic changes impact the performance of diagnostic real-time polymerase chain reaction (RT-PCR) assays. Herein, we describe a generic three-step workflow to assess the effect of genomic mutations on inclusivity and sensitivity of RT-PCR assays. METHODS: Sequences collected from the Global Initiative on Sharing All Influenza Data (GISAID) were mapped to a SARS-CoV-2 reference genome to evaluate the position and prevalence of mismatches in the oligonucleotide-binding sites of the QIAstat-Dx, an RT-PCR panel designed to detect SARS-CoV-2. The frequency of mutations and their impact on melting temperature were assessed, and sequences flagged by risk-based criteria were examined in vitro. RESULTS: Out of 8,900,393 SARS-CoV-2 genome sequences analyzed, only 173 (0.0019%) genomes contained potentially critical mutations for the QIAstat-Dx; follow-up in-vitro testing confirmed no impact on the assays' performance. CONCLUSIONS: The current study demonstrates that SARS-CoV-2 genetic variants do not affect the performance of the QIAstat-Dx device. It is recommended that manufacturers incorporate this workflow into obligatory post-marketing surveillance activities, as this approach could potentially enhance genetic monitoring of their product.

Artificial intelligence / machine-learning tool for post-market surveillance of in vitro diagnostic assays.

The study compares an artificial intelligence technology with traditional manual search of literature databases to assess the accuracy and efficiency of retrieving relevant articles for post-market surveillance of in vitro diagnostic and medical devices under the Medical Device Regulation and In Vitro Diagnostic Medical Device Regulation. Over a 3-year period, literature searches and technical assessment searches were performed manually or using the Huma.AI platform to retrieve relevant articles related to the safety and performance of selected in vitro diagnostic and medical devices. The manual search involved refined keyword searches, screening of titles/abstracts / full text, and extraction of relevant information. The Huma.AI search utilized advanced caching techniques and a natural language processing system to identify relevant reports. Searches were conducted on PubMed and PubMed Central. The number of identified relevant reports, precision rates, and time requirements for each approach were analyzed. The Huma.AI system outperformed the manual search in terms of the number of identified relevant articles in almost all cases. The average precision rates per year were significantly higher and more consistent with the Huma.AI search compared with the manual search. The Huma.AI system also took significantly less time to perform the searches and analyze the outputs than the manual search. The study demonstrated that the Huma.AI platform was more effective and efficient in identifying relevant articles compared with the manual approach.

Detecting zoonotic Influenza A using QIAstat-Dx Respiratory SARS-CoV-2 panel for pandemic preparedness.

Recent reports from the World Health Organization regarding Influenza A cases of zoonotic origin in humans (H1v and H9N2) and publications describing emergence swine Influenza A cases in humans together with "G4" Eurasian avian-like H1N1 Influenza A virus have drawn global attention to Influenza A pandemic threat. Additionally, the current COVID-19 epidemic has stressed the importance of surveillance and preparedness to prevent potential outbreaks. One feature of the QIAstat-Dx Respiratory SARS-CoV-2 panel is the double target approach for Influenza A detection of seasonal strains affecting humans using a generic Influenza A assay plus the three specific human subtype assays. This work explores the potential use of this double target approach in the QIAstat-Dx Respiratory SARS-Co-V-2 Panel as a tool to detect zoonotic Influenza A strains. A set of recently recorded H9 and H1 spillover strains and the G4 EA Influenza A strains as example of recent zoonotic Flu A strains were subjected to detection prediction with QIAstat-Dx Respiratory SARS-CoV-2 Panel using commercial synthetic dsDNA sequences. In addition, a large set of available commercial human and non-human influenza A strains were also tested using QIAstat-Dx Respiratory SARS-CoV-2 Panel for a better understanding of detection and discrimination of Influenza A strains. Results show that QIAstat-Dx Respiratory SARS-CoV-2 Panel generic Influenza A assay detects all the recently recorded H9, H5 and H1 zoonotic spillover strains and all the G4 EA Influenza A strains. Additionally, these strains yielded negative results for the three-human seasonal IAV (H1, H3 and H1N1 pandemic) assays. Additional non-human strains corroborated those results of Flu A detection with no subtype discrimination, whereas human Influenza strains were positively discriminated. These results indicate that QIAstat-Dx Respiratory SARS-CoV-2 Panel could be a useful tool to diagnose zoonotic Influenza A strains and differentiate them from the seasonal strains commonly affecting humans.

A cost-effectiveness evaluation of latent tuberculosis infection screening of a migrant population in Malaysia.

To estimate the costs and benefits of screening for latent tuberculosis infection (LTBI) in a migrant population in Malaysia. An economic model was developed from a Malaysian healthcare perspective to compare QuantiFERON-TB Gold Plus (QuantiFERON) with the tuberculin skin test (TST). A decision tree was used to capture outcomes relating to LTBI screening followed by a Markov model that simulated the lifetime costs and benefits of the patient cohort. The Markov model did not capture the impact of secondary infections. The model included an R shiny interactive interface to allow adaptation to other scenarios and settings. QuantiFERON is both more effective and less costly than TST (dominant). Compared with QuantiFERON, the lifetime risk of developing active TB increases by approximately 40% for TST due to missed LTBI cases during screening (i.e. a higher number of false negative cases for TST). For a migrant population in Malaysia, QuantiFERON is cost-effective when compared with TST. Further research should consider targeted LTBI screening for migrants in Malaysia based on common risk factors.

Systematic Review on the Correlation Between SARS-CoV-2 Real-Time PCR Cycle Threshold Values and Epidemiological Trends.

BACKGROUND: The ability to proactively predict the epidemiological dynamics of infectious diseases such as coronavirus disease 2019 (COVID-19) would facilitate efficient public health responses and may help guide patient management. Viral loads of infected people correlate with infectiousness and, therefore, could be used to predict future case rates. AIM: In this systematic review, we determine whether there is a correlation between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) real-time reverse-transcription polymerase chain reaction (RT-PCR) cycle threshold (Ct) values (a proxy for viral load) and epidemiological trends in patients diagnosed with COVID-19, and whether Ct values are predictive of future cases. METHODS: A PubMed search was conducted on August 22 2022, based on a search strategy of studies reporting correlations between SARS-CoV-2 Ct values and epidemiological trends. RESULTS: Data from 16 studies were relevant for inclusion. RT-PCR Ct values were measured from national (n = 3), local (n = 7), single-unit (n = 5), or closed single-unit (n = 1) samples. All studies retrospectively examined the correlation between Ct values and epidemiological trends, and seven evaluated their prediction model prospectively. Five studies used the temporal reproduction number (Rt) as the measure of the population/epidemic growth rate. Eight studies reported a prediction time in the negative cross-correlation between Ct values and new daily cases, with seven reporting a prediction time of ~1-3 weeks, and one reporting 33 days. CONCLUSION: Ct values are negatively correlated with epidemiological trends and may be useful in predicting subsequent peaks in variant waves of COVID-19 and other circulating pathogens.

A systematic review of cost-utility analyses of screening methods in latent tuberculosis infection in high-risk populations.

BACKGROUND: The World Health Organisation (WHO) recommends that testing and treatment for latent tuberculosis infection (LTBI) should be undertaken in high-risk groups using either interferon gamma release assays (IGRAs) or a tuberculin skin test (TST). As IGRAs are more expensive than TST, an assessment of the cost-effectiveness of IGRAs can guide decision makers on the most appropriate choice of test for different high-risk populations. This current review aimed to provide the most up to date evidence on the cost-effectiveness evidence on LTBI testing in high-risk groups-specifically evidence reporting the costs per QALY of different testing strategies. METHODS: A comprehensive search of databases including MEDLINE, EMBASE and NHS-EED was undertaken from 2011 up to March 2021. Studies were screened and extracted by two independent reviewers. The study quality was assessed using the Bias in Economic Evaluation Checklist (ECOBIAS). A narrative synthesis of the included studies was undertaken. RESULTS: Thirty-two studies reported in thirty-three documents were included in this review. Quality of included studies was generally high, although there was a weakness across all studies referencing sources correctly and/or justifying choices of parameter values chosen or assumptions where parameter values were not available. Inclusions of IGRAs in testing strategies was consistently found across studies to be cost-effective but this result was sensitive to underlying LTBI prevalence rates. CONCLUSION: While some concerns remain about uncertainty in parameter values used across included studies, the evidence base since 2010 has grown with modelling approaches addressing the weakness pointed out in previous reviews but still reaching the same conclusion that IGRAs are likely to be cost-effective in high-income countries for high-risk populations. Evidence is also required on the cost-effectiveness of different strategies in low to middle income countries and countries with high TB burden.

Ct values as a diagnostic tool for monitoring SARS-CoV-2 viral load using the QIAstat-Dx® Respiratory SARS-CoV-2 Panel.

OBJECTIVES: Qualitative real-time polymerase chain reaction tests are not designed to provide quantitative or semiquantitative results because cycle threshold (Ct) values are not normalized to standardized controls of known concentration. The aim of this study was to characterize SARS-CoV-2 viral loads based on Ct values, using the QIAstat-Dx® Respiratory SARS-CoV-2 Panel. METHODS: Different lineages of SARS-CoV-2 clinical samples and the World Health Organization international standard were used to assess the linearity of the QIAstat-Dx Respiratory SARS-CoV-2 Panel. Limit of detection for the different lineages was characterized. RESULTS: Comparable efficiencies and linearity for all samples resulted in R2 ≥0.99, covering a dynamic range of 1,000,000-100 copies/mL for the SARS-CoV-2 assay, showing linear correlation between Ct values and viral load down to 300 copies/mL. CONCLUSION: The SARS-CoV-2 Ct values provided by the QIAstat-Dx® Respiratory SARS-CoV-2 Panel could be used as a surrogate for viral load given the linear correlation between Ct values and viral concentration down to limit of detection. This panel allows to obtain reproducible Ct values for SARS-CoV-2 ribonucleic acid downstream of the sample collection, reducing the sample-to-Ct workflow variability. Ct values can help provide a reliable assessment and comparison of viral loads in patients when tested with the QIAstat-Dx Respiratory SARS-CoV-2 Panel.

Epidemiology, Outcomes and Resource Utilisation in Patients with Carbapenem Non-susceptible Gram-Negative Bacteria in the UK: A Retrospective, Observational Study (CARBAR UK).

INTRODUCTION: Antimicrobial resistance is an urgent medical challenge. In this two-part study, we investigated the epidemiology and management of carbapenem non-susceptible (Carb-NS) Gram-negative bacteria (GNB) in the UK. METHODS: We conducted a retrospective review of data from UK hospitals (ten in part 1, nine in part 2). In part 1, epidemiological data were collected from patients hospitalised between April 2017 and March 2018 with any laboratory detection of Carb-NS GNB, encompassing both colonisation and infection. In part 2, diagnosis and management pathways in a randomly selected population of adults from part 1 with confirmed Carb-NS GNB infection were assessed. Data were obtained from a detailed medical chart review for ≥ 3 months from index (collection date of first positive Carb-NS GNB sample). RESULTS: Of 42,340 GNB isolates from 36,098 patients colonised/infected with GNB in part 1, 7% were Carb-NS. In 157 patients included in part 2, 234 GNB index samples were collected, of which 197 (82%) were Carb-NS (median number of Carb-NS pathogens per patient, 1; range 1-3). The most frequent Carb-NS isolates were Pseudomonas aeruginosa (36%), Stenotrophomonas maltophilia (29%) and Klebsiella pneumoniae (10%). Median length of hospitalisation was 34 days. Median time from index to appropriate therapy was 3 days, with empirical therapy initiated a median of 1 day before index. Carb-NS infection was believed to contribute to 21 (28%) of 76 deaths during the study. CONCLUSIONS: This study highlights the high incidence of Carb-NS GNB colonisation and infection in the UK and the need for improved management of patients with Carb-NS GNB infection.

Accuracy of interferon gamma release assays for the COVID-19 immunity assessment.

Emerging evidence suggests that T-cells play a significant role in COVID-19 immunity both in the context of natural infection and vaccination. Easy to use IGRA assays including QFN SARS are considered attractive alternatives to more "traditional" but laborious methods for detection of SARS-CoV-2-specific T-cell responses. In our Letter we are proposing explanations to an apparently lower than expected T-cell responses (44 % reactive individuals) reported by Krüttgen et al in a small cohort of healthy double vaccinated individuals. These results could have been affected by reporting raw optical density values instead of calculated Interferon-É£ concentrations which is supported by unexpectedly low mitogen responses in healthy individuals. This study highlights an importance of adhering to good laboratory practice principles as well as overall importance of accurate T-cell immunity assessment using IGRA assays.

Systematic Review on the Correlation of Quantitative PCR Cycle Threshold Values of Gastrointestinal Pathogens With Patient Clinical Presentation and Outcomes.

Background: Quantitative (q) polymerase chain reaction (PCR) cycle threshold (Ct) values represent the number of amplification cycles required for a positive PCR result and are a proxy of pathogen quantity in the tested sample. The clinical utility of Ct values remains unclear for gastrointestinal infections. Objectives: This systematic review assesses the global medical literature for associations between Ct values of gastrointestinal pathogens and patient presentation and clinical outcomes. Data Sources: MEDLINE, EMBASE, Cochrane library databases: searched January 14-17, 2020. Study Eligibility Criteria: Studies reporting on the presence or absence of an association between Ct values and clinical outcomes in adult and pediatric populations were included. Animal studies, reviews, meta-analyses, and non-English language studies were excluded. Participants: Humans infected with gastrointestinal pathogens, detected with qPCR. Interventions: Diagnostics assessing Ct values. Extracted data were reported narratively. Results: Thirty-three eligible studies were identified; the most commonly studied pathogens were Clostridioides difficile (n = 15), norovirus (n = 10), and rotavirus (n = 9). Statistically significant associations between low C. difficile Ct values and increased symptom severity or poor outcome were reported in 4/8 (50%) studies, and increased risk of death in 1/2 (50%) studies; no significant associations were found between Ct value and duration of symptoms or length of hospital stay. Among studies of norovirus, 5/7 (71%), mainly genogroup II, reported symptomatic cases with significantly lower median Ct values than controls. Significantly lower rotavirus Ct values were also observed in symptomatic cases vs. controls in 3/7 (43%) studies, and associated with more severe symptoms in 2/2 studies. Contradictory associations were identified for non-C. difficile bacterial and parasitic pathogens. Conclusions: In conclusion, some studies reported clinically useful associations between Ct values and patient or healthcare outcomes; additional, well-designed, large-scale trials are warranted based on these findings. Systematic Review Registration: [PROSPERO], identifier [CRD42020167239].

Systematic review on the association between respiratory virus real-time PCR cycle threshold values and clinical presentation or outcomes.

OBJECTIVES: It is unclear whether real-time (rt)-PCR cycle threshold (Ct) values can be utilized to guide clinical and infection-control decisions. This systematic review assesses the association between respiratory pathogen rt-PCR Ct values and clinical presentation or outcomes. METHODS: We searched MEDLINE, EMBASE and Cochrane library databases on 14-17 January 2020 for studies reporting the presence or absence of an association between Ct values and clinical presentation or outcomes, excluding animal studies, reviews, meta-analyses, and non-English language studies. RESULTS: Among 33 studies identified (reporting on between 9 and 4918 participants by pathogen), influenza (n = 11 studies; 4918 participants), human rhinovirus (HRV, n = 11; 2012) and respiratory syncytial virus (RSV, n = 8; 3290) were the most-studied pathogens. Low influenza Ct values were associated with mortality in 1/3 studies, with increased disease severity/duration or ICU admission in 3/9, and with increased hospitalization or length of hospital stay (LOS) in 1/6. Low HRV Ct values were associated with increased disease severity/duration or ICU admission in 3/10 studies, and with increased hospitalization or LOS in 1/3. Low RSV Ct values were associated with increased disease severity/duration or ICU admission in 3/6 studies, and with increased hospitalization or LOS in 4/4. Contradictory associations were also identified for other respiratory pathogens. CONCLUSIONS: Respiratory infection Ct values may inform clinical and infection-control decisions. However, the study heterogeneity observed in this review highlights the need for standardized workflows to utilize Ct values as a proxy of genomic load and confirm their value for respiratory infection management.

Preliminary Evaluation of QuantiFERON SARS-CoV-2 and QIAreach Anti-SARS-CoV-2 Total Test in Recently Vaccinated Individuals.

INTRODUCTION: There is an increasing body of evidence surrounding the importance of a T cell-mediated response to SARS-CoV-2 infection and after COVID-19 vaccination. In this internal feasibility study, we evaluated both the total antibody (IgA, IgM, and IgG) and T cell responses in a cohort of COVID-19 convalescents and vaccinated individuals. METHODS: Whole blood specimens were collected weekly from 12 subjects at different time points within/after the COVID-19 mRNA vaccination regimen, and from 4 PCR-confirmed convalescent donors to measure durability of humoral and cell-mediated immune response. T cell and antibody responses were evaluated via the QuantiFERON SARS-CoV-2 research use only (QFN SARS-CoV-2) assay which is an interferon gamma release assay (IGRA) and QIAreach Anti-SARS-CoV-2 total (Anti-CoV-2) test, respectively. RESULTS: In a cohort of recently vaccinated individuals, subjects demonstrated robust total antibody and CD4+/CD8+ T cell response to SARS-CoV-2 mRNA vaccines when followed for 2 months post-2nd dose. In most individuals, T cell response declined between the 1st and 2nd doses suggesting a need for a booster or the completion of the 2-dose vaccine series. In a group of convalescent donors tested with QFN SARS-CoV-2 and Anti-CoV-2 tests, all patients had an antibody and T cell response up to 1 year after natural infection. CONCLUSION: This small feasibility study demonstrates that the QFN-SARS-CoV-2 test is able to identify CD4+ and CD8+ T cell-mediated responses in SARS-CoV-2-vaccinated subjects and those recovered from COVID-19, alongside a qualitative antibody response detectable via the QIAreach Anti-CoV2 test.

The potential clinical utility of measuring severe acute respiratory syndrome coronavirus 2-specific T-cell responses.

BACKGROUND: Both humoral and cell-mediated responses are associated with immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although our understanding of the potential role of T-cell responses in the context of coronavirus disease 2019 (COVID-19) is rapidly increasing, more information is still needed. OBJECTIVES: To provide an overview of the role of T-cell immunity in COVID-19, in the context of natural infection and post-vaccination, and discuss the potential utility of measuring SARS-CoV-2-specific T-cell responses, drawing on experience of the use of interferon-γ release assays (IGRAs) in tuberculosis (TB). SOURCES: PubMed articles up to 16 April 2021. CONTENT: T-cell responses can be detected very early in the course of COVID-19, earlier than the detection of antibody responses, and are correlated with COVID-19 outcome. Lower CD4+ and CD8+ T-cell counts are markers of more severe disease, longer duration of viral RNA positivity and increased mortality. In line with natural infection, SARS-CoV-2 vaccination stimulates robust T-cell responses, which probably play an important role in protection; data on long-term T-cell responses are currently limited. The utility of measuring T-cell responses is already well established in both aiding the diagnosis of TB infection using IGRAs, and evaluation of T-cell responses to TB vaccine candidates. A variety of assays have already been developed to measure SARS-CoV-2-specific T-cell responses, including IGRAs, intracellular cytokine staining and activation-induced markers. IGRAs based on SARS-CoV-2 antigens can distinguish between convalescent and uninfected healthy blood donors. IMPLICATIONS: Simple assays for measuring the quantity and function of T-cell responses may have utility in the prognostication of COVID-19, and for monitoring immune responses to SARS-CoV-2 vaccination and population-based immunity to SARS-CoV-2 variants of interest.

Application of the hollow fibre infection model (HFIM) in antimicrobial development: a systematic review and recommendations of reporting.

OBJECTIVES: This systematic review focuses on the use of the in vitro hollow fibre infection model (HFIM) for microbial culture. We summarize the direction of the field to date and propose best-practice principles for reporting of the applications. METHODS: Searches in six databases (MEDLINE®, EMBASE®, PubMed®, BIOSIS®, SCOPUS® and Cochrane®) up to January 2020 identified 129 studies meeting our inclusion criteria. Two reviewers independently assessed and extracted data from each publication. The quality of reporting of microbiological and technical parameters was analysed. RESULTS: Forty-seven out of 129 (36.4%) studies did not report the minimum pharmacokinetic parameters required in order to replicate the pharmacokinetic profile of HFIM experiments. Fifty-three out of 129 (41.1%) publications did not report the medium used in the HFIM. The overwhelming majority of publications did not perform any technical repeats [107/129 (82.9%)] or biological repeats [97/129 (75.2%)]. CONCLUSIONS: This review demonstrates that most publications provide insufficient data to allow for results to be evaluated, thus impairing the reproducibility of HFIM experiments. Therefore, there is a clear need for the development of laboratory standardization and improved reporting of HFIM experiments.

Performance evaluation of the QIAstat-Dx® Respiratory SARS-CoV-2 Panel.

OBJECTIVE: The aim of this study was to evaluate the QIAstat-Dx® Respiratory SARS-CoV-2 Panel (QIAstat-SARS-CoV-2), which is a closed, fully automated, multiplex polymerase chain reaction (PCR) assay that detects severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 21 other pathogens that cause respiratory disease. METHODS: Nasopharyngeal swabs from patients with or suspected of having coronavirus disease 2019 were collected and tested at Bichat-Claude Bernard Hospital, Paris, France. Using the World Health Organisation-approved real-time-PCR assay developed by the Charité Institute of Virology as the reference, positive percent agreement (PPA) and negative percent agreement (NPA) were calculated. RESULTS: In total, 189 negative and 88 positive samples were analyzed. QIAstat-SARS-CoV-2 had an NPA of 90.48% (95% confidence interval (CI), 85.37%, 94.26%) and a PPA of 94.32% (95% CI, 87.24%, 98.13%). Co-infections were detected by QIAstat-SARS-CoV-2 in 4/277 specimens. The methods exhibited comparable failure rates (23/307 [7.5%] vs. 6/298 [2.0%] for QIAstat-SARS-CoV-2 and reference methods, respectively). The turnaround time was shorter for QIAstat-SARS-CoV-2 compared with the reference method (difference in mean -14:30 h [standard error, 0:03:23; 95% CI, -14:37, -14:24]; P < 0.001). CONCLUSIONS: QIAstat-SARS-CoV-2 shows good agreement with the reference assay, providing faster and accurate results for detecting SARS-CoV-2.

Risk factors for carbapenem-resistant Gram-negative bacterial infections: a systematic review.

BACKGROUND: Rapid and widespread increases in carbapenem resistance (CR) necessitate identification of risk factors to guide appropriate interventions. OBJECTIVES: We aimed to identify risk factors for CR Gram-negative infection through a systematic literature review. DATA SOURCES: We searched MEDLINE (via OvidSP and PubMed) and Embase (via OvidSP) databases and the Cochrane Central Register of Controlled Trials. STUDY ELIGIBILITY CRITERIA: Prospective or retrospective cohort and case-control studies reporting quantitative data on risk factors associated with infections due to CR Gram-negative pathogens in hospitalized patients were eligible. PARTICIPANTS: Studies included hospitalized patients with CR infection caused by Gram-negative bacterial pathogens (Enterobacterales and non-fermenters). METHODS: Searches were conducted in January 2018/December 2019 to identify studies published since 2007. Risk factor data were extracted and grouped by factor. The primary metric was proportion of studies reporting a significant association with CR infection for each factor. RESULTS: In total, 92 studies were identified. Risk factors most frequently reported as significantly associated with CR infection (>10 studies) were previous antibiotic use (91.1%; 72/79 studies); previous carbapenem use (82.6%; 57/69); previous colonization (72.7%; 8/11); mechanical ventilation (66.7%; 36/54); previous intensive care unit stay (64.4%; 38/59); dialysis (61.1%; 11/18); catheter (58.0%; 40/69); length of stay in hospital (54.5%; 30/55); comorbidities (52.7%; 39/74); APACHE II (51.7%; 15/29); and intubation (51.4%; 18/35). Risk factors were mostly consistent across different species and sites of infection. CONCLUSIONS: Several variables, particularly previous antibiotic use, are strong risk factors for CR infection. Interventions to mitigate against CR infection should target these factors.

Systematic review on estimated rates of nephrotoxicity and neurotoxicity in patients treated with polymyxins.

BACKGROUND: Nephrotoxicity and neurotoxicity are commonly associated with polymyxin treatment; however, the emergence of multidrug-resistant Gram-negative bacteria with limited therapeutic options has resulted in increased use of polymyxins. OBJECTIVES: To determine the rates of nephrotoxicity and neurotoxicity during polymyxin treatment and whether any factors influence these. DATA SOURCES: Medline, Embase and Cochrane Library databases were searched on 2 January 2020. STUDY ELIGIBILITY CRITERIA: Studies reporting nephrotoxicity and/or neurotoxicity rates in patients with infections treated with polymyxins were included. Reviews, meta-analyses and reports not in English were excluded. PARTICIPANTS: Patients hospitalized with infections treated with systemic or inhaled polymyxins were included. For comparative analyses, patients treated with non-polymyxin-based regimens were also included. METHODS: Meta-analyses were performed using a random-effects model; subgroup meta-analyses were conducted where data permitted using a mixed-effects model. RESULTS: In total, 237 reports of randomized controlled trials, cohort and case-control studies were eligible for inclusion; most were single-arm observational studies. Nephrotoxic events in 35,569 patients receiving polymyxins were analysed. Overall nephrotoxicity rate was 0.282 (95% confidence interval (CI) 0.259-0.307). When excluding studies where >50% of patients received inhaled-only polymyxin treatment or nephrotoxicity assessment was by methods other than internationally recognized criteria (RIFLE, KDIGO or AKIN), the nephrotoxicity rate was 0.391 (95% CI 0.364-0.419). The odds of nephrotoxicity were greater with polymyxin therapies compared to non-polymyxin-based regimens (odds ratio 2.23 (95% CI 1.58-3.15); p < 0.001). Meta-analyses showed a significant effect of polymyxin type, dose, patient age, number of concomitant nephrotoxins and use of diuretics, glycopeptides or vasopressors on the rate of nephrotoxicity. Polymyxin therapies were not associated with a significantly different rate of neurotoxicity than non-polymyxin-based regimens (p 0.051). The overall rate of neurotoxicity during polymyxin therapy was 0.030 (95% CI 0.020-0.043). CONCLUSIONS: Polymyxins are associated with a higher risk of nephrotoxicity than non-polymyxin-based regimens.

First performance report of QIAreach™ Anti-SARS-CoV-2 Total Test, an innovative nanoparticle fluorescence digital detection platform.

In 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic. Disease diagnosis, appropriate clinical management and infection control are all important factors in controlling the spread of SARS-CoV-2. The QIAreach™ Anti-SARS-CoV-2 Total Test (Anti-CoV2) is a rapid, qualitative serological test, using proprietary nanoparticle fluorescence technology to detect total antibody (IgA, IgM, and IgG) against SARS-CoV-2. Here we report the results of the US Food and Drug Administration (FDA) clinical agreement study. Thirty positive plasma or serum samples were taken from consenting individuals with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection ≥14 days from symptom onset. Seventy-five samples from before the believed circulation of SARS-CoV-2 (November 1, 2019) were used to assess specificity. Positive percent agreement (PPA) and negative percent agreement (NPA) were calculated along with the corresponding exact two-sided 95 % confidence intervals (CI) using an FDA Emergency Use Authorized PCR test as the reference method. Anti-CoV2 was shown to have 100 % sensitivity (PPA; 95 % CI 88.4-100 %) and 100 % specificity (NPA; 95 % CI 95.2-100 %). Against 157 pre-pandemic samples, no cross-reactivity was observed with seasonal coronaviruses or other respiratory pathogens tested. Additionally, no interference was observed when samples were spiked with: conjugated bilirubin 0.4 mg/ml; unconjugated bilirubin 0.4 mg/ml; hemoglobin 5 mg/ml; prednisolone 0.12 mg/ml; triglycerides 15 mg/ml. In conclusion, Anti-CoV2 provides accurate qualitative detection of total antibodies against SARS-CoV-2.