Publications by authors named "Martin Risch"

92 Publications

Investigation of the use of a sensor bracelet for the presymptomatic detection of changes in physiological parameters related to COVID-19: an interim analysis of a prospective cohort study (COVI-GAPP).

BMJ Open 2022 Jun 21;12(6):e058274. Epub 2022 Jun 21.

Dr Risch Medical Laboratory, Vaduz, Liechtenstein

Objectives: We investigated machinelearningbased identification of presymptomatic COVID-19 and detection of infection-related changes in physiology using a wearable device.

Design: Interim analysis of a prospective cohort study.

Setting, Participants And Interventions: Participants from a national cohort study in Liechtenstein were included. Nightly they wore the Ava-bracelet that measured respiratory rate (RR), heart rate (HR), HR variability (HRV), wrist-skin temperature (WST) and skin perfusion. SARS-CoV-2 infection was diagnosed by molecular and/or serological assays.

Results: A total of 1.5 million hours of physiological data were recorded from 1163 participants (mean age 44±5.5 years). COVID-19 was confirmed in 127 participants of which, 66 (52%) had worn their device from baseline to symptom onset (SO) and were included in this analysis. Multi-level modelling revealed significant changes in five (RR, HR, HRV, HRV ratio and WST) device-measured physiological parameters during the incubation, presymptomatic, symptomatic and recovery periods of COVID-19 compared with baseline. The training set represented an 8-day long instance extracted from day 10 to day 2 before SO. The training set consisted of 40 days measurements from 66 participants. Based on a random split, the test set included 30% of participants and 70% were selected for the training set. The developed long short-term memory (LSTM) based recurrent neural network (RNN) algorithm had a recall (sensitivity) of 0.73 in the training set and 0.68 in the testing set when detecting COVID-19 up to 2 days prior to SO.

Conclusion: Wearable sensor technology can enable COVID-19 detection during the presymptomatic period. Our proposed RNN algorithm identified 68% of COVID-19 positive participants 2 days prior to SO and will be further trained and validated in a randomised, single-blinded, two-period, two-sequence crossover trial. ISRCTN51255782; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2021-058274DOI Listing
June 2022

Comparison of an automated DNA extraction and 16S rDNA real time PCR/sequencing diagnostic method using optimized reagents with culture during a 15-month study using specimens from sterile body sites.

BMC Microbiol 2022 05 2;22(1):119. Epub 2022 May 2.

Dr Risch, 3097, Liebefeld, Switzerland.

Background: 16S rDNA-PCR for the identification of a bacterial species is an established method. However, the DNA extraction reagents as well as the PCR reagents may contain residual bacterial DNA, which consequently generates false-positive PCR results. Additionally, previously used methods are frequently time-consuming. Here, we describe the results obtained with a new technology that uses DNA-free reagents for automated DNA extraction and subsequent real time PCR using sterile clinical specimens.

Results: In total, we compared 803 clinical specimens using real time PCR and culturing. The clinical specimens were mainly of orthopedic origin received at our diagnostic laboratory. In 595 (74.1%) samples, the results were concordant negative, and in 102 (12.7%) the results were concordant positive. A total of 170 (21.2%) clinical specimens were PCR-positive, of which 62 (36.5% from PCR positive, 7.7% in total) gave an additional benefit to the patient since only the PCR result was positive. Many of these 62 positive specimens were strongly positive based on crossingpoint values (54% < Cp 30), and these 62 positive clinical specimens were diagnosed as medically relevant as well. Thirty-eight (4.2%) clinical specimens were culture-positive (25 of them were only enrichment culture positive) but PCR-negative, mainly for S. epidermidis, S. aureus and C. acnes. The turnaround times for negative specimens were 4 hours (automated DNA extraction and real time PCR) and 1 working day for positive specimens (including Sanger sequencing). Melting-curve analysis of SYBR Green-PCR enables the differentiation of specific and unspecific PCR products. Using Ripseq, even mixed infections of 2 bacterial species could be resolved.

Conclusions: For endocarditis cases, the added benefit of PCR is obvious. The crucial innovations of the technology enable timely reporting of explicit reliable results for adequate treatment of patients. Clinical specimens with truly PCR-positive but culture-negative results represent an additional benefit for patients. Very few results at the detection limit still have to be critically examined.
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http://dx.doi.org/10.1186/s12866-022-02542-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9063205PMC
May 2022

Impact of retrograde intrarenal surgery on biomarkers that are associated with renal parenchyma injury, a preliminary study.

World J Urol 2022 Mar 23;40(3):841-847. Epub 2022 Jan 23.

Departement of Urology, Kantonsspital Graubünden, Loëstrasse 170, 7000, Chur, Switzerland.

Purpose: The primary objective of this preliminary study was to assess the changes in concentration of biomarkers, which indicate renal injury, after RIRS.

Materials And Methods: Within this prospective study, we included 21 patients with nephrolithiasis requiring treatment with RIRS. From each patient, blood and urine samples were taken at fixed intervals before and after RIRS. Kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), calbindin, albumin, clusterin, gluthation S-transferase-π (GST-π), beta-2-microglobulin (B2M), osteopontin, cystatin c, and trefoil-factor-3 (TFF3) were measured in urine. Creatinine, cystatin c and uric acid were analyzed in the blood samples.

Results: A significant increase of the biomarkers clusterin, GST-π, B2M, NGAL and cystatin c was observed after RIRS. However, the biomarkers gradually normalized during the first 14 postoperative days. The parameters surgery time, cumulative stone volume, and BMI did not significantly influence the biomarker concentrations. In the case of GST-π and NGAL a significant positive, yet minuscule effect of age was observed.

Conclusions: With our study, we identified 5 out of 12 assessed renal injury biomarkers that showed a significant increase after RIRS. The increase was only temporary and all markers normalized within 14 days. Further studies are needed to determine the clinical value of these identified markers to assess the long-term impact of intrarenal pressure elevation during RIRS.
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http://dx.doi.org/10.1007/s00345-021-03909-wDOI Listing
March 2022

Healthcare institutions' recommendation regarding the use of FFP-2 masks and SARS-CoV-2 seropositivity among healthcare workers: a multicenter longitudinal cohort study.

Antimicrob Resist Infect Control 2022 01 10;11(1). Epub 2022 Jan 10.

Division of Infectious Diseases, Cantonal Hospital of Grisons, 7000, Chur, Switzerland.

Background: Health care workers (HCW) are heavily exposed to SARS-CoV-2 from the beginning of the pandemic. We aimed to analyze risk factors for SARS-CoV-2 seroconversion among HCW with a special emphasis on the respective healthcare institutions' recommendation regarding the use of FFP-2 masks.

Methods: We recruited HCW from 13 health care institutions (HCI) with different mask policies (type IIR surgical face masks vs. FFP-2 masks) in Southeastern Switzerland (canton of Grisons). Sera of participants were analyzed for the presence of SARS-CoV-2 antibodies 6 months apart, after the first and during the second pandemic wave using an electro-chemiluminescence immunoassay (ECLIA, Roche Diagnostics). We captured risk factors for SARS-CoV-2 infection by using an online questionnaire at both time points. The effects of individual COVID-19 exposure, regional incidence and FFP-2 mask policy on the probability of seroconversion were evaluated with univariable and multivariable logistic regression.

Results: SARS-CoV-2 antibodies were detected in 99 of 2794 (3.5%) HCW at baseline and in 376 of 2315 (16.2%) participants 6 months later. In multivariable analyses the strongest association for seroconversion was exposure to a household member with known COVID-19 (aOR: 19.82, 95% CI 8.11-48.43, p < 0.001 at baseline and aOR: 8.68, 95% CI 6.13-12.29, p < 0.001 at follow-up). Significant occupational risk factors at baseline included exposure to COVID-19 patients (aOR: 2.79, 95% CI 1.28-6.09, p = 0.010) and to SARS-CoV-2 infected co-workers (aOR: 2.50, 95% CI 1.52-4.12, p < 0.001). At follow up 6 months later, non-occupational exposure to SARS-CoV-2 infected individuals (aOR: 2.54, 95% CI 1.66-3.89 p < 0.001) and the local COVID-19 incidence of the corresponding HCI (aOR: 1.98, 95% CI 1.30-3.02, p = 0.001) were associated with seroconversion. The healthcare institutions' mask policy (surgical masks during usual exposure vs. general use of FFP-2 masks) did not affect seroconversion rates of HCW during the first and the second pandemic wave.

Conclusion: Contact with SARS-CoV-2 infected household members was the most important risk factor for seroconversion among HCW. The strongest occupational risk factor was exposure to COVID-19 patients. During this pandemic, with heavy non-occupational exposure to SARS-CoV-2, the mask policy of HCIs did not affect the seroconversion rate of HCWs.
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http://dx.doi.org/10.1186/s13756-021-01047-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8744038PMC
January 2022

Multicenter Technical Validation of 30 Rapid Antigen Tests for the Detection of SARS-CoV-2 (VALIDATE).

Microorganisms 2021 Dec 15;9(12). Epub 2021 Dec 15.

Coordination Commission of Clinical Microbiology, Swiss Society of Microbiology, 1033 Cheseaux, Switzerland.

During COVID19 pandemic, SARS-CoV-2 rapid antigen tests (RATs) were marketed with minimal or no performance data. We aimed at closing this gap by determining technical sensitivities and specificities of 30 RATs prior to market release. We developed a standardized technical validation protocol and assessed 30 RATs across four diagnostic laboratories. RATs were tested in parallel using the Standard Q (SD Biosensor/Roche) assay as internal reference. We used left-over universal transport/optimum media from nasopharyngeal swabs of 200 SARS-CoV-2 PCR-negative and 100 PCR-positive tested patients. Transport media was mixed with assay buffer and applied to RATs according to manufacturer instructions. Sensitivities were determined according to viral loads. Specificity of at least 99% and sensitivity of 95%, 90%, and 80% had to be reached for 10, 10, 10 virus copies/mL, respectively. Sensitivities ranged from 43.5% to 98.6%, 62.3% to 100%, and 66.7% to 100% at 10, 10, 10 copies/mL, respectively. Automated assay readers such as ExDia or LumiraDx showed higher performances. Specificities ranged from 88.8% to 100%. Only 15 of 30 (50%) RATs passed our technical validation. Due to the high failure rate of 50%, mainly caused by lack of sensitivity, we recommend a thorough validation of RATs prior to market release.
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http://dx.doi.org/10.3390/microorganisms9122589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704317PMC
December 2021

Presence of autoantibodies in serum does not impact the occurrence of immune checkpoint inhibitor-induced hepatitis in a prospective cohort of cancer patients.

J Cancer Res Clin Oncol 2022 Mar 7;148(3):647-656. Epub 2021 Dec 7.

Institute of Immunobiology, Kantonsspital St. Gallen, Rorschacher Strasse 95, 9007, St. Gallen, Switzerland.

Purpose: Immune checkpoint inhibitor (ICI)-induced hepatitis belongs to the frequently occurring immune-related adverse events (irAEs), particularly with the combination therapy involving ipilimumab and nivolumab. However, predisposing factors predicting the occurrence of ICI-induced hepatitis are barely known. We investigated the association of preexisting autoantibodies in the development of ICI-induced hepatitis in a prospective cohort of cancer patients.

Methods: Data from a prospective biomarker cohort comprising melanoma and non-small cell lung cancer (NSCLC) patients were used to analyze the incidence of ICI-induced hepatitis, putatively associated factors, and outcome.

Results: 40 patients with melanoma and 91 patients with NSCLC received ICI between July 2016 and May 2019. 11 patients developed ICI-induced hepatitis (8.4%). Prior to treatment, 45.5% of patients in the hepatitis cohort and 43.8% of the control cohort showed elevated titers of autoantibodies commonly associated with autoimmune liver diseases (p = 0.82). We found two nominally significant associations between the occurrence of ICI-induced hepatitis and HLA alleles associated with autoimmune liver diseases among NSCLC patients. Of note, significantly more patients with ICI-induced hepatitis developed additional irAEs in other organs (p = 0.0001). Neither overall nor progression-free survival was affected in the hepatitis group.

Conclusion: We found nominally significant associations of ICI-induced hepatitis with two HLA alleles. ICI-induced hepatitis showed no correlation with liver-specific autoantibodies, but frequently co-occurred with irAEs affecting other organs. Unlike other irAEs, ICI-induced hepatitis is not associated with a better prognosis.
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http://dx.doi.org/10.1007/s00432-021-03870-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8881258PMC
March 2022

Quantification of the spread of SARS-CoV-2 variant B.1.1.7 in Switzerland.

Epidemics 2021 12 9;37:100480. Epub 2021 Aug 9.

Functional Genomics Center Zurich, ETH Zürich and University of Zurich, Zurich, Switzerland.

Background: In December 2020, the United Kingdom (UK) reported a SARS-CoV-2 Variant of Concern (VoC) which is now named B.1.1.7. Based on initial data from the UK and later data from other countries, this variant was estimated to have a transmission fitness advantage of around 40-80 % (Volz et al., 2021; Leung et al., 2021; Davies et al., 2021).

Aim: This study aims to estimate the transmission fitness advantage and the effective reproductive number of B.1.1.7 through time based on data from Switzerland.

Methods: We generated whole genome sequences from 11.8 % of all confirmed SARS-CoV-2 cases in Switzerland between 14 December 2020 and 11 March 2021. Based on these data, we determine the daily frequency of the B.1.1.7 variant and quantify the variant's transmission fitness advantage on a national and a regional scale.

Results: We estimate B.1.1.7 had a transmission fitness advantage of 43-52 % compared to the other variants circulating in Switzerland during the study period. Further, we estimate B.1.1.7 had a reproductive number above 1 from 01 January 2021 until the end of the study period, compared to below 1 for the other variants. Specifically, we estimate the reproductive number for B.1.1.7 was 1.24 [1.07-1.41] from 01 January until 17 January 2021 and 1.18 [1.06-1.30] from 18 January until 01 March 2021 based on the whole genome sequencing data. From 10 March to 16 March 2021, once B.1.1.7 was dominant, we estimate the reproductive number was 1.14 [1.00-1.26] based on all confirmed cases. For reference, Switzerland applied more non-pharmaceutical interventions to combat SARS-CoV-2 on 18 January 2021 and lifted some measures again on 01 March 2021.

Conclusion: The observed increase in B.1.1.7 frequency in Switzerland during the study period is as expected based on observations in the UK. In absolute numbers, B.1.1.7 increased exponentially with an estimated doubling time of around 2-3.5 weeks. To monitor the ongoing spread of B.1.1.7, our plots are available online.
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http://dx.doi.org/10.1016/j.epidem.2021.100480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452947PMC
December 2021

Molecular characterization of a ceftriaxone-resistant Neisseria gonorrhoeae strain found in Switzerland: a case report.

Ann Clin Microbiol Antimicrob 2021 Aug 6;20(1):52. Epub 2021 Aug 6.

Centre of Laboratory Medicine (CLM) Dr Risch, 3097, Liebefeld, Switzerland.

Background: The resistance of Neisseria gonorrhoeae to ceftriaxone is unusual in Switzerland. The underlying genotype responsible for resistance is suspected to be novel. Generally, resistance in Neisseria gonorrhoeae (Ng) involves a comprehensive set of genes with many different mutations leading to resistance to different β-lactams and fluoroquinolones.

Case Presentation: A patient had a positive result from specific PCR for Ng. We routinely culture all clinical specimens with a positive NG-PCR. In this particular case, we isolated a strain with resistance to ceftriaxone in Switzerland. A total of seven different genes (penA, ponA, porinB, mtr, gyrA, parC, 23S rRNA gene) in this strain were partially sequenced for comparison with phenotypic susceptibility testing. Interestingly, two different mutations in the porinB gene were observed, and data on this gene are limited. Information on the identified allele type of the penA gene is very limited as well. Three different mutations of parC and gyrA that correlate with ciprofloxacin resistance were found. The combination of ceftriaxone and ciprofloxacin resistance makes an appropriate treatment difficult to obtain due to multidrug resistance.

Conclusion: The combined results for all genes show the appearance of new mutations in central Europe either due to worldwide spread or the emergence of new genetic combinations of mutations.
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http://dx.doi.org/10.1186/s12941-021-00456-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349002PMC
August 2021

Elementary Laboratory Assays as Biomarkers of Ageing: Support for Treatment of COVID-19?

Gerontology 2021 2;67(5):503-516. Epub 2021 Aug 2.

Kantonsspital Graubünden, Chur, Switzerland.

Youth, working age and the elderly: On a timeline, chronological age (CA) and biological age (BA) may dissociate; nosological entities manifest themselves at different BAs. In determining which disease corresponds to a given age decade, statistical registries of causes of death are unreliable and this does not change with SARS CoV-2 infection. Beyond adolescence, ageing metrics involve estimations of changes in fitness, including prediction models to estimate the number of remaining years left to live. A substantial disparity in biomarker levels and health status of ageing can be observed: the difference in CA and BA in the large cohorts under consideration is glaring. Here, we focus more closely on ageing and senescence metrics in order to make information available for risk analysis non the least with COVID-19, including the most recent risk factors of ABO blood type and 3p21.31 chromosome cluster impacting on C5a and SC5b-9 plasma levels. From the multitude of routine medical laboratory assays, a potentially meaningful set of assays aimed to best reflect the stage of individual senescence; hence risk factors the observational prospective SENIORLABOR study of 1,467 healthy elderly performed since 2009 and similar approaches since 1958 can be instantiated as a network to combine a set of elementary laboratory assays quantifying senescence.
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http://dx.doi.org/10.1159/000517659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450824PMC
October 2021

Exploring the Global Spread of Klebsiella grimontii Isolates Possessing and .

Antimicrob Agents Chemother 2021 08 17;65(9):e0072421. Epub 2021 Aug 17.

Institute for Infectious Diseases, University of Berngrid.5734.5, Bern, Switzerland.

The spread of plasmid-mediated carbapenemases within Klebsiella oxytoca is well-documented. In contrast, data concerning the closely related species Klebsiella grimontii are scarce. In fact, despite the recent report of the first -producing , nothing is known about its clonality and antibiotic resistance patterns. In a retrospective search in our collection, we identified 2 -positive K. oxytoca strains. Whole-genome sequencing with both Illumina and Nanopore indicated that our strains actually belonged to and were of sequence type 172 (ST172) and ST189. Moreover, the two strains were associated with 297-kb IncHI2/HI2A-pST1 and 90.6-kb IncFII(Yp) plasmids carrying together with and , respectively. In the IncHI2/HI2A plasmid, was located in a class 1 integron (In), while was associated with the -like regulatory elements. Overall, this plasmid was shown to be very similar to those carried by other isolated from food and animal sources (e.g., and spp. detected in Germany and Egypt). The IncFII(Yp) plasmid was unique, and its region was associated with a rare integron (In). Mapping of In indicated a possible origin in Austria from an Enterobacter hormaechei carrying a highly similar plasmid. Core-genome phylogenies indicated that the ST172 belonged to a clone of identical Swedish and Swiss strains (≤15 single nucleotide variants [SNVs] to each other), whereas the ST189 strain was sporadic. Surveillance of carbapenemase-producing K. oxytoca strains should be reinforced to detect and prevent the dissemination of new species belonging to the genus.
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http://dx.doi.org/10.1128/AAC.00724-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370233PMC
August 2021

Autoimmune diseases - New insights into a troublesome field.

J Transl Autoimmun 2021 1;4:100108. Epub 2021 Jun 1.

Center for Laboratory Medicine Dr Risch, Vaduz, Liechtenstein.

Recent updates in the diagnosis and management of chronic inflammatory conditions can be brought together to better understand autoimmune diseases (ADs). With organ-specific or organ-limited and systemic ADs, physicians often are faced with a dilemma when making a diagnosis and may feel a kind of embarrassment when a more distinct nosological entity cannot be found. ADs often overlap with other diseases and good diagnostic procedures for ADs only become evidence-based when refined histopathologic, immunopathologic, and general laboratory analyses are available. Immunofluorescence analyses, Western blotting, CUT & RUN technology allow localization of the site of autoantibody-reactivity on the relevant DNA sequence. The Polymerase chain reaction technology and CRISPR-Cas9, the new gene editor using pools of synthetic non-coding RNAs in screening experiments, are expected to lead to advances in the diagnosis of ADs. The current use of mRNA as a vaccine against COVID-19 has increased confidence in the use of mRNA or long non-coding RNAs in the treatment strategy for ADs. The integration of new knowledge about innate immunity, the complement system, vaccinology, and senescence into the care of patients with ADs expands the therapeutic arsenal of disease-modifying drugs and allows for the repurposing of anti-cytokine monoclonal/biosimilar antibodies, originally designed for chronic inflammatory diseases, for ADs. This review article brings together some of the most relevant ideas; a case report included in this review highlights the difficulty of distinguishing between ADs, chronic inflammation, and/or granular disease.
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http://dx.doi.org/10.1016/j.jtauto.2021.100108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188057PMC
June 2021

Transition From PCR-Ribotyping to Whole Genome Sequencing Based Typing of .

Front Cell Infect Microbiol 2021 1;11:681518. Epub 2021 Jun 1.

Division of Clinical Bacteriology and Mycology, University Hospital Basel, Basel, Switzerland.

causes nosocomial outbreaks which can lead to severe and even life-threatening colitis. Rapid molecular diagnostic tests allow the identification of toxin-producing, potentially hypervirulent strains, which is critical for patient management and infection control. PCR-ribotyping has been used for decades as the reference standard to investigate transmission in suspected outbreaks. However, the introduction of whole genome sequencing (WGS) for molecular epidemiology provides a realistic alternative to PCR-ribotyping. In this transition phase it is crucial to understand the strengths and weaknesses of the two technologies, and to assess their correlation. We aimed to investigate ribotype prediction from WGS data, and options for analysis at different levels of analytical granularity. Ribotypes cannot be directly determined from short read Illumina sequence data as the rRNA operons including the ribotype-defining ISR fragments collapse in genome assemblies, and comparison with traditional PCR-ribotyping results becomes impossible. Ribotype extraction from long read Oxford nanopore data also requires optimization. We have compared WGS-based typing with PCR-ribotyping in nearly 300 clinical and environmental isolates from Switzerland, and in addition from the Enterobase database (n=1778). Our results show that while multi-locus sequence type (MLST) often correlates with a specific ribotype, the agreement is not complete, and for some ribotypes the resolution is insufficient. Using core genome MLST (cgMLST) analysis, there is an improved resolution and ribotypes can often be predicted within clusters, using cutoffs of 30-50 allele differences. The exceptions are ribotypes within known ribotype complexes such as RT078/RT106, where the genome differences in cgMLST do not reflect the ribotype segregation. We show that different ribotype clusters display different degrees of diversity, which could be important for the definition of ribotype cluster specific cutoffs. WGS-based analysis offers the ultimate resolution to the SNP level, enabling exploration of patient-to-patient transmission. PCR-ribotyping does not sufficiently discriminate to prove nosocomial transmission with certainty. We discuss the associated challenges and opportunities in a switch to WGS from conventional ribotyping for .
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http://dx.doi.org/10.3389/fcimb.2021.681518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204696PMC
July 2021

Blood Omega-3 Fatty Acids Are Inversely Associated With Albumin-Creatinine Ratio in Young and Healthy Adults (The Omega-Kid Study).

Front Cardiovasc Med 2021 27;8:622619. Epub 2021 Apr 27.

Department of Internal Medicine, Cantonal Hospital of Baden, Baden, Switzerland.

Omega-3 fatty acids are associated with a lower risk of cardiovascular disease (CVD) and with beneficial effects on CV risk factors. The albumin-creatinine ratio (ACR) is a risk factor for CVD, all-cause mortality and accelerated glomerular filtration rate (GFR) decline in the general population. We aimed to investigate the association between n-3 PUFAS and ACR in heathy individuals with preserved GFR. The present cross-sectional analysis is part of the GAPP study, a population-based cohort of healthy adults aged 25-41 years. Individuals with known CVD, diabetes, or a BMI >35 kg/m were excluded. eGFR was calculated according to the combined Creatinine/Cystatin C CKD-EPI formula. ACR was obtained from a fasting morning urine sample. The Omega-3 Index (relative amount of EPA and DHA of total fatty acids in %) was obtained from whole blood aliquots. Overall, 2001 participants (median age 37 years IQR 31; 40, 53% female) were included in this analysis. Median Omega-3 Index was 4.59 (IQR 4.06; 5.25) and median eGFR 111 ml/min/1.73 m (IQR 103; 118). Median ACR was 0.14 mg/mmol (IQR 0; 0.43). We found a significant inverse association of the Omega-3 Index with ACR (ratio 0.84, 95%CI 0.73-0.96; p = 0.011) which remained after comprehensive adjustment (ratio 0.86, 95%CI 0.74-1.00; = 0.048). No association of the Omega-3 Index with eGFR was found. The adjusted difference in eGFR per 1-unit increase in Omega3-Index was -0.21 (95%CI -0.76; 0.35; = 0.47). A higher Omega-3 Index was significantly associated with lower ACR in this young and healthy population with preserved eGFR. Omega-3 fatty acids may exhibit cardio- and nephroprotective effects in healthy individuals through modulation of ACR.
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http://dx.doi.org/10.3389/fcvm.2021.622619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110728PMC
April 2021

SARS-CoV-2 N501Y Introductions and Transmissions in Switzerland from Beginning of October 2020 to February 2021-Implementation of Swiss-Wide Diagnostic Screening and Whole Genome Sequencing.

Microorganisms 2021 Mar 25;9(4). Epub 2021 Mar 25.

Applied Microbiology Research, Department of Biomedicine, University of Basel, 4056 Basel, Switzerland.

The rapid spread of the SARS-CoV-2 lineages B.1.1.7 (N501Y.V1) throughout the UK, B.1.351 (N501Y.V2) in South Africa, and P.1 (B.1.1.28.1; N501Y.V3) in Brazil has led to the definition of variants of concern (VoCs) and recommendations for lineage specific surveillance. In Switzerland, during the last weeks of December 2020, we established a nationwide screening protocol across multiple laboratories, focusing first on epidemiological and microbiological definitions. In January 2021, we validated and implemented an N501Y-specific PCR to rapidly screen for VoCs, which are then confirmed using amplicon sequencing or whole genome sequencing (WGS). A total of 13,387 VoCs have been identified since the detection of the first Swiss case in October 2020, with 4194 being B.1.1.7, 172 B.1.351, and 7 P.1. The remaining 9014 cases of VoCs have been described without further lineage specification. Overall, all diagnostic centers reported a rapid increase of the percentage of detected VOCs, with a range of 6 to 46% between 25 to 31 of January 2021 increasing towards 41 to 82% between 22 to 28 of February. A total of 739 N501Y positive genomes were analysed and show a broad range of introduction events to Switzerland. In this paper, we describe the nationwide coordination and implementation process across laboratories, public health institutions, and researchers, the first results of our N501Y-specific variant screening, and the phylogenetic analysis of all available WGS data in Switzerland, that together identified the early introduction events and subsequent community spreading of the VoCs.
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http://dx.doi.org/10.3390/microorganisms9040677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064472PMC
March 2021

Characterisation of a new bla-carrying IncN2 plasmid from an Enterobacter hormaechei subsp. steigerwaltii.

J Glob Antimicrob Resist 2021 03 8;24:325-327. Epub 2021 Feb 8.

Institute for Infectious Diseases (IFIK), University of Bern, Friedbühlstrasse 51, CH-3001 Bern, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.jgar.2021.01.017DOI Listing
March 2021

Characteristics of Three Different Chemiluminescence Assays for Testing for SARS-CoV-2 Antibodies.

Dis Markers 2021 6;2021:8810196. Epub 2021 Jan 6.

Department of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen, Rohrschacherstrasse 95, 9007 St. Gallen, Switzerland.

Several tests based on chemiluminescence immunoassay techniques have become available to test for SARS-CoV-2 antibodies. There is currently insufficient data on serology assay performance beyond 35 days after symptoms onset. We aimed to evaluate SARS-CoV-2 antibody tests on three widely used platforms. A chemiluminescent microparticle immunoassay (CMIA; Abbott Diagnostics, USA), a luminescence immunoassay (LIA; Diasorin, Italy), and an electrochemiluminescence immunoassay (ECLIA; Roche Diagnostics, Switzerland) were investigated. In a multigroup study, sensitivity was assessed in a group of participants with confirmed SARS-CoV-2 ( = 145), whereas specificity was determined in two groups of participants without evidence of COVID-19 (i.e., healthy blood donors, = 191, and healthcare workers, = 1002). Receiver operating characteristic (ROC) curves, multilevel likelihood ratios (LR), and positive (PPV) and negative (NPV) predictive values were characterized. Finally, analytical specificity was characterized in samples with evidence of the Epstein-Barr virus (EBV) ( = 9), cytomegalovirus (CMV) ( = 7), and endemic common-cold coronavirus infections ( = 12) taken prior to the current SARS-CoV-2 pandemic. The diagnostic accuracy was comparable in all three assays (AUC 0.98). Using the manufacturers' cut-offs, the sensitivities were 90%, 95% confidence interval [84,94] (LIA), 93% [88,96] (CMIA), and 96% [91,98] (ECLIA). The specificities were 99.5% [98.9,99.8] (CMIA), 99.7% [99.3,99.9] (LIA), and 99.9% [99.5,99.98] (ECLIA). The LR at half of the manufacturers' cut-offs were 60 (CMIA), 82 (LIA), and 575 (ECLIA) for positive and 0.043 (CMIA) and 0.035 (LIA, ECLIA) for negative results. ECLIA had higher PPV at low pretest probabilities than CMIA and LIA. No interference with EBV or CMV infection was observed, whereas endemic coronavirus in some cases provided signals in LIA and/or CMIA. Although the diagnostic accuracy of the three investigated assays is comparable, their performance in low-prevalence settings is different. Introducing gray zones at half of the manufacturers' cut-offs is suggested, especially for orthogonal testing approaches that use a second assay for confirmation.
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http://dx.doi.org/10.1155/2021/8810196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834819PMC
February 2021

Comparison of the Diagnostic Performance of qPCR, Sanger Sequencing, and Whole-Genome Sequencing in Determining Clarithromycin and Levofloxacin Resistance in .

Front Cell Infect Microbiol 2020 17;10:596371. Epub 2020 Dec 17.

Labormedizinisches zentrum Dr Risch, Buchs, Switzerland.

antibiotic resistance is increasing worldwide, emphasizing the urgent need for more rapid resistance detection prior to the administration of eradication regimens. Macrolides and fluoroquinolones are widely used to treat . In this study, we aimed to compare the diagnostic performance of A) 23SrDNA qPCR (with melting curve analysis) and an in-house developed qPCR followed by Sanger sequencing with a commercial IVD-marked hybridization probe assay (for 23SrDNA and ) using 142 gastric biopsies (skipping culturing) and B) the same two qPCR for 23SrDNA and (including Sanger sequencing) with whole-genome sequencing (WGS) and phenotypic characterization of clarithromycin and levofloxacin resistance using 76 cultured isolates. The sensitivity of both qPCRs was 100% compared to that of the commercial IVD-marked hybridization probe assay for the detection of in gastric biopsies (without resistance testing). The specificity of the qPCR followed by Sanger sequencing was 100%, indicating that the best sequence identity was always . The results show good agreement between molecular tests, especially between qPCR (inclusive Sanger sequencing) and WGS. Discrepancies (concerning mutated or wild type of positive gastric biopsies) were observed between Sanger sequencing of the gene and the corresponding commercial hybridization probe assay, mostly because the high sequence diversity of the gene even at positions adjacent to the relevant codons of 87 and 91 interfered with obtaining correct results from the hybridization probe assay. Interestingly, we found several mixed sequences, indicating mixed populations in the gastric biopsies (direct detection without culturing). There was a high percentage of both levofloxacin and clarithromycin resistance in gastric biopsies (both between 22% and 29%, direct detection in gastric biopsies). Therefore, we recommend analyzing both targets in parallel. We confirmed that phenotypic resistance is highly correlated with the associated mutations. We concluded that the two qPCR followed by Sanger sequencing of the gene is a fast, cost-effective and comprehensive method for resistance testing of directly in gastric biopsies.
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http://dx.doi.org/10.3389/fcimb.2020.596371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773895PMC
June 2021

Characterization of a Pan-Immunoglobulin Assay Quantifying Antibodies Directed against the Receptor Binding Domain of the SARS-CoV-2 S1-Subunit of the Spike Protein: A Population-Based Study.

J Clin Med 2020 Dec 9;9(12). Epub 2020 Dec 9.

Central Laboratory, Kantonsspital Graubünden, Loësstrasse 170, 7000 Chur, Switzerland.

Pan-immunoglobulin assays can simultaneously detect IgG, IgM and IgA directed against the receptor binding domain (RBD) of the S1 subunit of the spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 S1-RBD Ig). In this work, we aim to evaluate a quantitative SARS-CoV-2 S1-RBD Ig electrochemiluminescence immunoassay (ECLIA) regarding analytical, diagnostic, operational and clinical characteristics. Our work takes the form of a population-based study in the principality of Liechtenstein, including 125 cases with clinically well-described and laboratory confirmed SARS-CoV-2 infection and 1159 individuals without evidence of coronavirus disease 2019 (COVID-19). SARS-CoV-2 cases were tested for antibodies in sera taken with a median of 48 days (interquartile range, IQR, 43-52) and 139 days (IQR, 129-144) after symptom onset. Sera were also tested with other assays targeting antibodies against non-RBD-S1 and -S1/S2 epitopes. Sensitivity was 97.6% (95% confidence interval, CI, 93.2-99.1), whereas specificity was 99.8% (95% CI, 99.4-99.9). Antibody levels linearly decreased from hospitalized patients to symptomatic outpatients and SARS-CoV-2 infection without symptoms ( < 0.001). Among cases with SARS-CoV-2 infection, smokers had lower antibody levels than non-smokers ( = 0.04), and patients with fever had higher antibody levels than patients without fever ( = 0.001). Pan-SARS-CoV-2 S1-RBD Ig in SARS-CoV-2 infection cases significantly increased from first to second follow-up ( < 0.001). A substantial proportion of individuals without evidence of past SARS-CoV-2 infection displayed non-S1-RBD antibody reactivities (248/1159, i.e., 21.4%, 95% CI, 19.1-23.4). In conclusion, a quantitative SARS-CoV-2 S1-RBD Ig assay offers favorable and sustained assay characteristics allowing the determination of quantitative associations between clinical characteristics (e.g., disease severity, smoking or fever) and antibody levels. The assay could also help to identify individuals with antibodies of non-S1-RBD specificity with potential clinical cross-reactivity to SARS-CoV-2.
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http://dx.doi.org/10.3390/jcm9123989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764650PMC
December 2020

Oral glucose tolerance test does not affect degree of hemoglobin glycation as measured by routine assay.

Ann Endocrinol (Paris) 2020 Dec 2;81(6):545-550. Epub 2020 Dec 2.

Labormedizinisches Zentrum Dr. Risch, Vaduz, Liechtenstein.

Background: Hemoglobin A1c (HbA1c) is an accurate index of fluctuation in glycemia over the 2-3 months prior to quantitative assessment. During this time, hemoglobin (Hb) slowly glycates until it shows the properties of advanced glycation end-products. Glycation kinetics is intensified by prolonged glucose exposure. In subjects undergoing oral glucose tolerance testing (OGTT), immediately after ingestion, glucose is ostensibly transported by the glucose transporter 1 (GLUT1) to erythrocyte corpuscular hemoglobin. The earliest significant measurable level of hemoglobin glycation associated with this transportation is still not clear.

Subjects And Methods: We attempted to explore the early impact of short-term glucose load on HbA1c levels, because it is now known that transmembrane GLUT1-mediated glucose transport occurs immediately. A total of 88 participants (46 patients and 42 clinically healthy controls) underwent fasting plasma glucose quantitation during an OGTT. HbA1c, revealed by a monoclonal anti-glycation epitope antibody and adiponectin, was quantitated before (T0) and 2 hours (T120) after 80 g glucose ingestion.

Results: Wilcoxon test revealed that the HbA1c values did not significantly vary (P=0.15) during the OGTT, whereas glucose concentration varied strongly between T0 and T120.

Discussion: It is well known that quantitative estimation of HbA1c is informative for clinical care, independently of glucose level. The molecular mechanisms and dynamics by which glucose enters/exits red blood cells are incompletely known and may differ between individuals. We here show, for the first time, that HbA1c levels do not significantly increase during OGTT, supporting the view that non-enzymatic glycation of hemoglobin occurs slowly and that glycation during the 2 hours of an OGTT is insignificant.
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http://dx.doi.org/10.1016/j.ando.2020.11.003DOI Listing
December 2020

Temporal Course of SARS-CoV-2 Antibody Positivity in Patients with COVID-19 following the First Clinical Presentation.

Biomed Res Int 2020 16;2020:9878453. Epub 2020 Nov 16.

Labormedizinisches Zentrum Dr. Risch, Wuhrstrasse 14, 9490 Vaduz, Liechtenstein.

Knowledge of the sensitivities of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody tests beyond 35 days after the clinical onset of COVID-19 is insufficient. We aimed to describe positivity rate of SARS-CoV-2 assays employing three different measurement principles over a prolonged period. Two hundred sixty-eight samples from 180 symptomatic patients with COVID-19 and a reverse transcription polymerase chain reaction (RT-PCR) test followed by serological investigation of SARS-CoV-2 antibodies were included. We conducted three chemiluminescence (including electrochemiluminescence assay (ECLIA)), four enzyme-linked immunosorbent assay (ELISA), and one lateral flow immunoassay (LFIA) test formats. Positivity rates, as well as positive (PPVs) and negative predictive values (NPVs), were calculated for each week after the first clinical presentation for COVID-19. Furthermore, combinations of tests were assessed within an orthogonal testing approach employing two independent assays and predictive values were calculated. Heat maps were constructed to graphically illustrate operational test characteristics. During a follow-up period of more than 9 weeks, chemiluminescence assays and one ELISA IgG test showed stable positivity rates after the third week. With the exception of ECLIA, the PPVs of the other chemiluminescence assays were ≥95% for COVID-19 only after the second week. ELISA and LFIA had somewhat lower PPVs. IgM exhibited insufficient predictive characteristics. An orthogonal testing approach provided PPVs ≥ 95% for patients with a moderate pretest probability (e.g., symptomatic patients), even for tests with a low single test performance. After the second week, NPVs of all but IgM assays were ≥95% for patients with low to moderate pretest probability. The confirmation of negative results using an orthogonal algorithm with another assay provided lower NPVs than the single assays. When interpreting results from SARS-CoV-2 tests, the pretest probability, time of blood draw, and assay characteristics must be carefully considered. An orthogonal testing approach increases the accuracy of positive, but not negative, predictions.
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http://dx.doi.org/10.1155/2020/9878453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673235PMC
December 2020

Flattening the curve in 52 days: characterisation of the COVID-19 pandemic in the Principality of Liechtenstein - an observational study.

Swiss Med Wkly 2020 10 16;150:w20361. Epub 2020 Oct 16.

Department of General Internal Medicine, Landesspital Liechtenstein, Vaduz, Liechtenstein.

Background: The principality of Liechtenstein had its first COVID-19 case at the beginning of March 2020. After exponential growth, the pandemic’s first wave was contained, with the last case being diagnosed 52 days after the initial occurrence.

Aim: To characterise the COVID-19 pandemic in Liechtenstein.

Methods: All patients diagnosed in Liechtenstein were followed up until recovery and again 6–8 weeks after symptom onset. They were contacted every 2 days to record their clinical status until the resolution of their symptoms. The diagnosis of COVID-19 was based on clinical symptoms and molecular testing. Household and close workplace contacts were included in the follow-up, which also comprised antibody testing. In addition, public health measures installed during the pandemic in Liechtenstein are summarised.

Results: During the first wave, 5% of the population obtained a reverse transcriptase polymerase chain reaction test. A total of 95 patients (median age 39 years) were diagnosed with COVID-19 (82 who resided in Liechtenstein), resulting in an incidence in Liechtenstein of 0.211%. One patient, aged 94, died (mortality rate 1%). Only 62% of patients could retrospectively identify a potential source of infection. Testing the patients’ household and close workplace contacts (n = 170) with antibody tests revealed that 25% of those tested were additional COVID-19 cases, a quarter of whom were asymptomatic. Those households which adhered to strict isolation measures had a significantly lower rate of affected household members than those who didn’t follow such measures. The national public health measures never restricted free movement of residents. Masks were only mandatory in healthcare settings. The use of home working for the general workforce was promoted. Gatherings were prohibited. Schools, universities, certain public spaces (like sports facilities and playgrounds), childcare facilities, nonessential shops, restaurants and bars were closed. Social distancing, hygienic measures, solidarity and supporting individuals who were at risk were the main pillars of the public health campaigns.

Conclusion: The close collaboration of all relevant stakeholders allowed for the complete workup of all COVID-19 patients nationwide. A multitude of factors (e.g., young age of the patients, low-threshold access to testing, close monitoring of cases, high alertness and adherence to public health measures by the population) led to the early containment of the first wave of the pandemic, with a very low rate of serious outcomes. Antibody testing for SARS-CoV-2 revealed a substantial proportion of undiagnosed COVID-19 cases among close contacts of the patients.
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http://dx.doi.org/10.4414/smw.2020.20361DOI Listing
October 2020

Diagnostic Characteristics of 3-Parameter and 2-Parameter Equations for the Calculation of a Combined Indicator of Vitamin B12 Status to Predict Cobalamin Deficiency in a Large Mixed Patient Population.

Clin Lab 2020 Oct;66(10)

Background: A combined indicator for the determination of vitamin B12 status (4cB12) that employs four markers of vitamin B12 status (i.e., holotranscobalamin, HoloTC; vitamin B12, B12; methyl malonic acid, MMA; and homocysteine, Hcy) has been proposed for the comprehensive assessment of B12 status. We aimed to compare recently published 2- (2cB12) and 3-parameter (3cB12) cB12 equations missing one or two markers of B12 status with the established four-parameter cB12 (4cB12).

Methods: In 3,614 routine samples in which HoloTC, B12, MMA, Hcy and serum folate were measured, cB12 was assessed with 4cB12, as well as with four 3cB12 and six 2cB12 equations. Diagnostic accuracy (AUC) curves were calculated by receiver operating characteristic (ROC) curve analysis with the four-parameter equation (4cB12) as an index. Furthermore, we investigated whether calculating cB12 in addition to a 2-step algorithm employing the same parameters would add diagnostic value for the diagnosis of vitamin B12 deficiency.

Results: HoloTC showed the highest diagnostic accuracy among the single markers (AUC = 0.94). The cB12 equation using HoloTC and MMA (2cB12HoloTC/MMA) had the highest AUC among the 2-parameter equations (0.98). Among the 3-parameter equations, 3cB12HoloTC/MMA/Hcy and 3cB12HoloTC/B12/MMA revealed an AUC of 0.99, which was significantly higher than that of 2cB12HoloTC/MMA (p < 0.01). Calculating 2cB12HoloTC/MMA in addition to using a stepwise algorithm employing HoloTC and MMA for diagnosis of vitamin B12 deficiency increased the positive likelihood ratio from 12.1 to 42.6.

Conclusions: cB12 calculated with two or three markers of B12 status provides a good approximation of the 4cB12 equation. A 2cB12 equation employing the same parameters improved diagnostic accuracy compared to the use of a 2-step diagnostic algorithm alone. Our results suggest, that laboratories should consider enriching their reports by additionally reporting a corresponding 2cB12 or 3cB12 to results obtained in stepwise diagnostic algorithms.
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http://dx.doi.org/10.7754/Clin.Lab.2020.200130DOI Listing
October 2020

A consideration of convalescent plasma and plasma derivatives in the care of Severely-ill patients with COVID-19.

Transfus Apher Sci 2020 Oct 5;59(5):102936. Epub 2020 Sep 5.

Labormedizinisches Zentrum Dr. Risch, Vaduz, Liechtenstein. Electronic address:

The pathogenesis and immunopathological damage of severe forms of COVID-19 resemble acute autoimmune disease sparked by SARS-CoV-2, including an early systemic overproduction of proinflammatory cytokines. Such immunopathological features provide a rationale for the use of passive immunotherapy with convalescent plasma as a source of neutralizing anti-viral antibodies and of anti-inflammatory plasma components. While convalescent plasma therapy is now being evaluated in prospective clinical trials, we further consider the therapeutic potential of human hyper immune globulins, and of heterologous, engineered and monoclonal neutralizing antibodies as anti-viral agents to treat COVID-19. Good medical practice procedures are still needed and is why we also discuss the potential use of polyclonal polyspecific immunoglobulins (IVIG), a therapeutic plasma derivative, with potent anti-inflammatory activity, in severe forms of Covid-19.
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http://dx.doi.org/10.1016/j.transci.2020.102936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833822PMC
October 2020

Reference Intervals for Platelet Counts in the Elderly: Results from the Prospective SENIORLAB Study.

J Clin Med 2020 Sep 3;9(9). Epub 2020 Sep 3.

Zentrallabor, Kantonsspital Graubünden, Loësstrasse 170, 7000 Chur, Switzerland.

Currently, age- and sex-independent reference limits (RLs) are frequently used to interpret platelet counts in seniors. We aimed to define and validate reference intervals (RIs) for platelet counts within the framework of the prospective SENIORLAB study. Subjectively healthy Swiss individuals aged 60 years and older were prospectively included and followed for morbidity and mortality. Participants who had circumstances known to affect platelet counts were excluded. The obtained RIs were validated with indirect statistical methods. Frequencies of abnormal platelet counts in a population-based setting, including 41.5% of the entire age-specific population of the Principality of Liechtenstein, were compared by using age- and sex-independent RIs and the RLs obtained in the present study. For males ( = 542), 95% RIs for platelet counts were defined as follows: 150-300 × 10/L (60-69 years); 130-300 × 10/L (70-79 years); and 120-300 × 10/L (80 years and above). For females ( = 661), the consolidated age-independent 95% RI was 165-355 × 10/L. These RI values were validated by indirect RI determination of 51,687 (30,392 female/21,295 male) patients of the same age. Age- and sex-independent RIs exhibited imbalanced frequencies of abnormal platelet counts between the two sexes, which were corrected by introducing age- and sex-specific RLs. In conclusion, females have higher platelet counts than males. Whereas the upper RL for males remains constant, the lower RL decreases with age. We propose to abandon the practice of employing sex- and age-independent RL for platelet counts in the elderly.
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http://dx.doi.org/10.3390/jcm9092856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564319PMC
September 2020

Frequency of serological non-responders and false-negative RT-PCR results in SARS-CoV-2 testing: a population-based study.

Clin Chem Lab Med 2020 08 31;58(12):2131-2140. Epub 2020 Aug 31.

Zentrallabor, Kantonsspital Graubünden, Chur, Switzerland.

Objectives The sensitivity of molecular and serological methods for COVID-19 testing in an epidemiological setting is not well described. The aim of the study was to determine the frequency of negative RT-PCR results at first clinical presentation as well as negative serological results after a follow-up of at least 3 weeks. Methods Among all patients seen for suspected COVID-19 in Liechtenstein (n=1921), we included initially RT-PCR positive index patients (n=85) as well as initially RT-PCR negative (n=66) for follow-up with SARS-CoV-2 antibody testing. Antibodies were detected with seven different commercially available immunoassays. Frequencies of negative RT-PCR and serology results in individuals with COVID-19 were determined and compared to those observed in a validation cohort of Swiss patients (n=211). Results Among COVID-19 patients in Liechtenstein, false-negative RT-PCR at initial presentation was seen in 18% (12/66), whereas negative serology in COVID-19 patients was 4% (3/85). The validation cohort showed similar frequencies: 2/66 (3%) for negative serology, and 16/155 (10%) for false negative RT-PCR. COVID-19 patients with negative follow-up serology tended to have a longer disease duration (p=0.05) and more clinical symptoms than other patients with COVID-19 (p<0.05). The antibody titer from quantitative immunoassays was positively associated with the number of disease symptoms and disease duration (p<0.001). Conclusions RT-PCR at initial presentation in patients with suspected COVID-19 can miss infected patients. Antibody titers of SARS-CoV-2 assays are linked to the number of disease symptoms and the duration of disease. One in 25 patients with RT-PCR-positive COVID-19 does not develop antibodies detectable with frequently employed and commercially available immunoassays.
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http://dx.doi.org/10.1515/cclm-2020-0978DOI Listing
August 2020

EDTA-Anticoagulated Whole Blood for SARS-CoV-2 Antibody Testing by Electrochemiluminescence Immunoassay (ECLIA) and Enzyme-Linked Immunosorbent Assay (ELISA).

Diagnostics (Basel) 2020 Aug 14;10(8). Epub 2020 Aug 14.

Zentrallabor, Kantonsspital Graubünden, 7000 Chur, Switzerland.

While lateral flow test formats can be utilized with whole blood and low sample volumes, their diagnostic characteristics are inferior to immunoassays based on chemiluminescence immunoassay (CLIA) or enzyme-linked immunosorbent assay (ELISA) technology. CLIAs and ELISAs can be automated to a high degree but commonly require larger serum or plasma volumes for sample processing. We addressed the suitability of EDTA-anticoagulated whole blood as an alternative sample material for antibody testing against SARS-CoV-2 by electro-CLIA (ECLIA; Roche, Rotkreuz, Switzerland) and ELISA (IgG and IgA; Euroimmun, Germany). Simultaneously drawn venous serum and EDTA-anticoagulated whole blood samples from 223 individuals were included. Correction of the whole blood results for hematocrit led to a good agreement with the serum results for weakly to moderately positive antibody signals. In receiver-operating characteristic curve analysis, all three assays displayed comparable diagnostic accuracy (area under the curve (AUC)) using corrected whole blood and serum (AUCs: 0.97 for ECLIA and IgG ELISA; 0.84 for IgA ELISA). In conclusion, our results suggest that the investigated assays can reliably detect antibodies against SARS-CoV-2 in hemolyzed whole blood anticoagulated with EDTA. Correction of these results for hematocrit is suggested. This study demonstrates that the automated processing of whole blood for identification of SARS-CoV-2 antibodies with common ECLIA and ELISA methods is accurate and feasible.
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http://dx.doi.org/10.3390/diagnostics10080593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460437PMC
August 2020

Treatment of urinary tract infections in Swiss primary care: quality and determinants of antibiotic prescribing.

BMC Fam Pract 2020 07 1;21(1):125. Epub 2020 Jul 1.

Institute of Primary Care, University and University Hospital of Zurich, Pestalozzistrasse 24, 8071, Zurich, Switzerland.

Background: Urinary tract infections are one of the most common reasons for prescribing antibiotics in primary care. Current guidelines recommend fosfomycin, nitrofurantoin, or trimethoprim - sulfamethoxazol as empiric first line antimicrobial agents in uncomplicated infections. However, there is evidence that the use of fluoroquinolones, which are no longer recommended, is still inappropriate high. We determined antibiotic prescription patterns, quality and factors affecting antibiotic prescriptions in urinary tract infections in primary care in Switzerland.

Methods: From June 2017 to August 2018, we conducted a cross-sectional study in patients suffering from a urinary tract infection (UTI). Patient and general practitioners characteristics as well as antibiotic prescribing patterns were analysed.

Results: Antibiotic prescribing patterns in 1.352 consecutively recruited patients, treated in 163 practices could be analysed. In 950 (84.7%) patients with an uncomplicated UTI the prescriptions were according to current guidelines and therefore rated as appropriate. Fluoroquinolones were prescribed in 13.8% and therefore rated as inappropriate. In multivariable analysis, the age of the general practitioner was associated with increasing odds of prescribing a not guideline recommended antibiotic therapy.

Conclusions: We found a high degree of guideline conform antibiotic prescriptions in patients with an uncomplicated urinary tract infection in primary care in Switzerland. However, there is still a substantial use of fluoroquinolones in empiric therapy.
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http://dx.doi.org/10.1186/s12875-020-01201-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329427PMC
July 2020

Aldosterone-to-renin ratio and blood pressure in young adults from the general population.

Am Heart J 2020 04 29;222:199-207. Epub 2020 Jan 29.

Cardiology Division, Department of Medicine, University Hospital of Basel, Basel, Switzerland; Cardiovascular Research Institute Basel, University Hospital Basel, Basel, Switzerland; Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.

Background: The effect of the renin angiotensin system on blood pressure (BP) values in young adults from the general population is not well studied. We investigated the relationship between the aldosterone-to-renin ratio (ARR) and various BP indices in this population.

Methods: We assembled a population-based sample of adults aged 25-41 years. Conventional and 24-hour BP recordings were obtained in all patients. Direct renin concentration and plasma aldosterone concentration were measured. Multivariable regression models were constructed to assess the relationships of ARR with BP and hypertension.

Results: We included 1,353 individuals (mean age 37 years, 56% women). The median (interquartile range) ARR, direct renin concentration, and plasma aldosterone concentration were 13.8 (8.7-22.9), 7.2 ng/L (4.4-11.0) and 94 ng/L (68-134). All BP indices were higher across sex-specific ARR quartiles. Per 1-unit increase in log-transformed ARR, the multivariable-adjusted β-coefficients (95% CI) for conventional, 24-hour, daytime, and nighttime systolic BP were 1.68 (0.87-2.48), P < .0001; 2.40 (1.68-3.12), P < .0001; 2.23 (1.48-2.99), P < .0001; and 2.80 (2.03-3.58), P < .0001, respectively. Per 1-unit increase in log-transformed ARR, the multivariable-adjusted odds ratio (95% CI) for conventional, 24-hour, sustained and masked hypertension was 1.70 (1.17-2.28), P = .0004; 1.29 (1.06-1.56), P = .01; 1.82 (1.33-2.49), P = .002; and 1.14 (0.94-1.38), P = .20, respectively.

Conclusions: In young adults, ARR was strongly associated with conventional and ambulatory BP. Our data suggest that an aldosterone-driven phenomenon occurs very early in the development of hypertension.
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http://dx.doi.org/10.1016/j.ahj.2019.11.022DOI Listing
April 2020

Diagnostic Accuracy of Holotranscobalamin, Vitamin B12, Methylmalonic Acid, and Homocysteine in Detecting B12 Deficiency in a Large, Mixed Patient Population.

Dis Markers 2020 7;2020:7468506. Epub 2020 Feb 7.

Labormedizinisches zentrum Dr. Risch, Vaduz, Liechtenstein.

Four biomarkers are commonly employed to diagnose B12 deficiency: vitamin B12 (B12), holotranscobalamin (HoloTC), methylmalonic acid (MMA), and homocysteine (Hcy). 4cB12, a combined index of the B12 status, has been suggested to improve the recognition of B12 deficiency. We aimed to evaluate the four different markers for detecting B12 deficiency, as determined by 4cB12. Within a large, mixed patient population, 11,833 samples had concurrent measurements of B12, HoloTC, MMA, and Hcy. 4cB12 was calculated according to the methods described by Fedosov. Diagnostic cutoffs as well as diagnostic accuracy for the detection of B12 deficiency were assessed with receiver operating characteristic (ROC) analysis. The median age was 56 years, and women accounted for 58.8% of the samples. Overall, the area under the curve (AUC) for the detection of subclinical B12 deficiency was highest for HoloTC (0.92), followed by MMA (0.91), B12 (0.9) and Hcy (0.78). The difference between HoloTC and B12 was driven by a significantly higher AUC for HoloTC (0.93) than for B12 (0.89), MMA (0.91), and Hcy in women 50 years and older (0.79; < 0.05 for all). In the detection of subclinical B12 deficiency, there were no significant differences in the AUCs of HoloTC, B12, and MMA among men and women <50 years. In conclusion, in women < 50 years and in men, HoloTC, MMA, or Hcy do not appear superior to B12 for the detection of B12 deficiency. For women 50 years and older, HoloTC seems to be the preferred first-line marker for the detection of subclinical B12 deficiency.
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http://dx.doi.org/10.1155/2020/7468506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017578PMC
October 2020
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