Publications by authors named "Alan Wu"

440 Publications

Adequate Antibody Response to COVID-19 Vaccine in Patients with Monoclonal Gammopathies and Light Chain Amyloidosis.

Lab Med 2022 Jan 13. Epub 2022 Jan 13.

Department of Laboratory Medicine, University of California, San Francisco, California, US.

Objective: Determine the COVID-19 seroconversion rate for patients with multiple myeloma receiving a COVID-19 vaccine.

Materials And Methods: After 45 patients received their second COVID-19 vaccine dose, their serum IgG antibodies were measured: 22 with monoclonal gammopathy (MG) of unknown significance, 3 with smoldering myeloma, 2 with light chain amyloidosis, and 18 with MG (9 in remission, 6 out of remission, and 3 with free light-chain gammopathy alone). A second serum specimen was retained for 16 patients with MG. Their antibody levels were compared to those of 78 uninfected healthy vaccinated control patients.

Results: Three patients with MG had low antibody levels on blood collected 98, 100, and 113 days after the initial vaccine dose (2 with MG of unknown significance and 1 with hypogammaglobulemia). The other 40 patients with MG (seroconversion rate 93%) and both patients with amyloidosis produced antibodies. Relative to days after vaccination, patients with MG had lower antibody levels than control patients.

Conclusion: After receiving a COVID-19 vaccine, most patients with MG produce anti-SARS-CoV-2 antibodies comparable to levels in uninfected vaccinated healthy control patients.
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http://dx.doi.org/10.1093/labmed/lmab113DOI Listing
January 2022

Evaluation of neutralizing antibodies against SARS-CoV-2 variants after infection and vaccination using a multiplexed surrogate virus neutralization test.

Clin Chem 2022 Jan 9. Epub 2022 Jan 9.

Department of Laboratory Medicine, University of California, San Francisco, CA, USA.

Background: The SARS-CoV-2 virus has mutated and evolved since the inception of the COVID-19 pandemic bringing into question the future effectiveness of current vaccines and antibody therapeutics. With evolution of the virus updated methods for the evaluation of the immune response in infected and vaccinated individuals are required to determine the durability of the immune response to SARS-CoV-2 variants.

Methods: We developed a multiplexed surrogate virus neutralization test (plex-sVNT) that simultaneously measures the ability of antibodies in serum to inhibit binding between angiotensin converting enzyme-2 (ACE2) and 7 SARS-CoV-2 trimeric spike protein variants, including wild type, B.1.1.7(α), B.1.351(β), P.1(γ), B.1.617.2(δ), B.1.617.1(κ), and B.1.429(ε). The assay was validated against a plaque reduction neutralization test (PRNT).We evaluated 170 samples from 97 COVID-19 patients and 281 samples from 188 individuals that received the Pfizer-BioNTech or Moderna mRNA vaccines.

Results: The plex-sVNT demonstrated >96% concordance with PRNT. Antibody neutralization activity was significantly reduced for all SARS-CoV-2 variants compared to wild type in both the infected and vaccinated cohorts. There was a decline in overall antibody neutralization activity, within both cohorts, out to 5 months post infection or vaccination, with the rate of decline being more significant for the vaccinated.

Conclusions: The plex-sVNT provides a correlative measure to PRNT and a convenient approach for evaluating antibody neutralization against SARS-CoV-2 variants. Neutralization of SARS-CoV-2 variants is reduced compared to wild type and declines over the ensuing months after exposure or vaccination within each cohort, however it is still unknown what degree of neutralizing capacity is protective.
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http://dx.doi.org/10.1093/clinchem/hvab283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755391PMC
January 2022

Pediatric Epilepsy Learning Healthcare System Quality of Life (PELHS-QOL-2): A novel health-related quality of life prompt for children with epilepsy.

Epilepsia 2021 Dec 31. Epub 2021 Dec 31.

Department of Population Health Sciences, Weill Cornell Medicine, New York, New York, USA.

Objective: Pediatric epilepsy is often associated with diminished health-related quality of life (HRQOL). Our aim was to establish the validity of the Pediatric Epilepsy Learning Healthcare System Quality of Life (PELHS-QOL-2) questions, a novel two-item HRQOL prompt for children with epilepsy, primarily for use in clinical care.

Methods: We performed a multicenter cross-sectional study to validate the PELHS-QOL-2. Construct validity was established through bivariate comparisons with four comparator measures and known drivers of quality of life in children with epilepsy, as well as by creating an a priori multivariable model to predict the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55). Validity generalization was established through bivariate comparisons with demographic and clinical information. Content validity and clinical utility were established by assessing how well the PELHS-QOL-2 met eight design criteria for an HRQOL prompt established by a multistakeholder group of experts.

Results: The final participant sample included 154 English-speaking caregivers of children with epilepsy (mean age = 9.7 years, range = .5-18, 49% female, 70% White). The PELHS-QOL-2 correlated with the four comparator instruments (ρ = .44-.56), was significantly associated with several known drivers of quality of life in children with epilepsy (p < .05), and predicted QOLCE-55 scores in the multivariate model (adjusted R = .54). The PELHS-QOL-2 item was not associated with the age, sex, and ethnicity of the children nor with the setting and location of data collection, although PELHS-QOL-Medications was significantly associated with race (worse for White race). Following both quantitative and qualitative analysis, the PELHS-QOL-2 met seven of eight design criteria.

Significance: The PELHS-QOL-2 is a valid HRQOL prompt and is well suited for use in clinical care as a mechanism to routinely initiate conversations with caregivers about quality of life in children with epilepsy. The association of PELHS-QOL-Medications with race merits further study.
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http://dx.doi.org/10.1111/epi.17156DOI Listing
December 2021

Evaluation of transplacental transfer of mRNA vaccine products and functional antibodies during pregnancy and early infancy.

medRxiv 2021 Dec 13. Epub 2021 Dec 13.

Studies are needed to evaluate the safety and effectiveness of mRNA SARS-CoV-2 vaccination during pregnancy, and the levels of protection provided to their newborns through placental transfer of antibodies. We evaluated the transplacental transfer of mRNA vaccine products and functional anti-SARS-CoV-2 antibodies during pregnancy and early infancy in a cohort of 20 individuals vaccinated during pregnancy. We found no evidence of mRNA vaccine products in maternal blood, placenta tissue, or cord blood at delivery. However, we found time-dependent efficient transfer of IgG and neutralizing antibodies to the neonate that persisted during early infancy. Additionally, using phage immunoprecipitation sequencing, we found a vaccine-specific signature of SARS-CoV-2 Spike protein epitope binding that is transplacentally transferred during pregnancy. In conclusion, products of mRNA vaccines are not transferred to the fetus during pregnancy, however timing of vaccination during pregnancy is critical to ensure transplacental transfer of protective antibodies during early infancy.
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http://dx.doi.org/10.1101/2021.12.09.21267423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8687468PMC
December 2021

Evaluation of transplacental transfer of mRNA vaccine products and functional antibodies during pregnancy and early infancy.

Res Sq 2021 Dec 15. Epub 2021 Dec 15.

Studies are needed to evaluate the safety and effectiveness of mRNA SARS-CoV-2 vaccination during pregnancy, and the levels of protection provided to their newborns through placental transfer of antibodies. We evaluated the transplacental transfer of mRNA vaccine products and functional anti-SARS-CoV-2 antibodies during pregnancy and early infancy in a cohort of 20 individuals vaccinated during pregnancy. We found no evidence of mRNA vaccine products in maternal blood, placenta tissue, or cord blood at delivery. However, we found time-dependent efficient transfer of IgG and neutralizing antibodies to the neonate that persisted during early infancy. Additionally, using phage immunoprecipitation sequencing, we found a vaccine-specific signature of SARS-CoV-2 Spike protein epitope binding that is transplacentally transferred during pregnancy. In conclusion, products of mRNA vaccines are not transferred to the fetus during pregnancy, however timing of vaccination during pregnancy is critical to ensure transplacental transfer of protective antibodies during early infancy.
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http://dx.doi.org/10.21203/rs.3.rs-1150427/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8687466PMC
December 2021

Serum iron concentrations in non-iron induced acute liver injury.

Clin Chim Acta 2022 Jan 11;525:12-14. Epub 2021 Dec 11.

Department of Emergency Medicine, UCSF, 1001 Potrero Avenue, Suite 6A, San Francisco, CA 94110, United States. Electronic address:

Acute liver injury (ALI) is seen in conjunction with elevated iron concentrations in the setting of acute iron toxicity. However, occult or delayed presentations of iron toxicity can be difficult to identify clinically and there is limited data describing iron concentrations in ALI without a confirmed history of iron overdose. This was a single center observational before-and-after study of adult patients who developed acute liver injury during hospitalization. Patients with a serum ALT > 500 U/L were identified by a daily hospital laboratory report and met inclusion if the ALT< 80 U/L at the time of admission, no history of overdose (iron, acetaminophen, or other ingestion), and no underlying liver disease. Serum AST, iron, and ferritin concentrations were obtained from blood samples at the time of admission and at peak serum ALT. Ten patients met inclusion criteria. The median age was 69 years old and 60% were male. There was a significant difference in serum AST (p = 0.005), serum ALT (p = 0.005), and ferritin (p = 0.005) before and after development of ALI. Serum iron concentrations were not clinically or significantly different (median: 23 mcg/dL vs 27 mcg/dL, p = 0.8). In this cohort of patients with non-iron induced acute liver injury, serum iron concentrations did not significantly change with the observed rise in aminotransferases. These data help to further characterize patterns of serum iron concentrations in patients with ALI.
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http://dx.doi.org/10.1016/j.cca.2021.12.008DOI Listing
January 2022

COVID-19 mRNA Vaccination in Lactation: Assessment of Adverse Events and Vaccine Related Antibodies in Mother-Infant Dyads.

Front Immunol 2021 3;12:777103. Epub 2021 Nov 3.

Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Francisco, San Francisco, CA, United States.

Background: Data regarding symptoms in the lactating mother-infant dyad and their immune response to COVID-19 mRNA vaccination during lactation are needed to inform vaccination guidelines.

Methods: From a prospective cohort of 50 lactating individuals who received mRNA-based vaccines for COVID-19 (mRNA-1273 and BNT162b2), blood and milk samples were collected prior to first vaccination dose, immediately prior to 2nd dose, and 4-10 weeks after 2nd dose. Symptoms in mother and infant were assessed by detailed questionnaires. Anti-SARS-CoV-2 antibody levels in blood and milk were measured by Pylon 3D automated immunoassay and ELISA. In addition, vaccine-related PEGylated proteins in milk were measured by ELISA. Blood samples were collected from a subset of infants whose mothers received the vaccine during lactation (4-15 weeks after mothers' 2nd dose).

Results: No severe maternal or infant adverse events were reported in this cohort. Two mothers and two infants were diagnosed with COVID-19 during the study period before achieving full immune response. PEGylated proteins were not found at significant levels in milk after vaccination. After vaccination, levels of anti-SARS-CoV-2 IgG and IgM significantly increased in maternal plasma and there was significant transfer of anti-SARS-CoV-2-Receptor Binding Domain (anti-RBD) IgA and IgG antibodies to milk. Milk IgA levels after the 2nd dose were negatively associated with infant age. Anti-SARS-CoV-2 IgG antibodies were not detected in the plasma of infants whose mothers were vaccinated during lactation.

Conclusions: COVID-19 mRNA vaccines generate robust immune responses in plasma and milk of lactating individuals without severe adverse events reported.
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http://dx.doi.org/10.3389/fimmu.2021.777103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595828PMC
November 2021

The Clinical Utility of Two High-Throughput 16S rRNA Gene Sequencing Workflows for Taxonomic Assignment of Unidentifiable Bacterial Pathogens in Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry.

J Clin Microbiol 2022 Jan 17;60(1):e0176921. Epub 2021 Nov 17.

Department of Health Technology and Informatics, The Hong Kong Polytechnic Universitygrid.16890.36, Hong Kong Special Administrative Region, China.

Bacterial pathogens that cannot be identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) are occasionally encountered in clinical laboratories. The 16S rRNA gene is often used for sequence-based analysis to identify these bacterial species. Nevertheless, traditional Sanger sequencing is laborious, time-consuming, and low throughput. Here, we compared two commercially available 16S rRNA gene sequencing tests that are based on Illumina and Nanopore sequencing technologies, respectively, in their ability to identify the species of 172 clinical isolates that failed to be identified by MALDI-TOF MS. Sequencing data were analyzed by the respective built-in programs (MiSeq Reporter software of Illumina and Epi2me of Nanopore) and BLAST+ (v2.11.0). Their agreement with Sanger sequencing on species-level identification was determined. Discrepancies were resolved by whole-genome sequencing. The diagnostic accuracy of each workflow was determined using the composite sequencing result as the reference standard. Despite the high base-calling accuracy of Illumina sequencing, we demonstrated that the Nanopore workflow had a higher taxonomic resolution at the species level. Using built-in analysis algorithms, the concordance of Sanger 16S with the Illumina and Nanopore workflows was 33.14% and 87.79%, respectively. The agreement was 65.70% and 83.14%, respectively, when BLAST+ was used for analysis. Compared with the reference standard, the diagnostic accuracy of Nanopore 16S was 96.36%, which was identical to that of Sanger 16S and better than that of Illumina 16S (69.07%). The turnaround time of the Illumina workflow and the Nanopore workflow was 78 h and 8.25 h, respectively. The per-sample cost of the Illumina and Nanopore workflows was US$28.5 and US$17.7, respectively.
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http://dx.doi.org/10.1128/JCM.01769-21DOI Listing
January 2022

Effect of HIV-1 Infection on Angiopoietin 1 and 2 Levels and Measures of Microvascular and Macrovascular Endothelial Dysfunction.

J Am Heart Assoc 2021 11 2;10(22):e021397. Epub 2021 Nov 2.

Division of Cardiology Department of Medicine Zuckerberg San Francisco General HospitalUniversity of California San Francisco San Francisco CA.

Background Individuals infected with HIV have an increased risk of developing cardiovascular disease; yet, the underlying mechanisms remain unknown. Recent evidence has implicated the Tie-2 tyrosine kinase receptor system and its associated ligands ANG1 (angiopoietin 1) and ANG2 (angiopoietin 2) in maintaining vascular homeostasis. In the general population, lower ANG1 levels and higher ANG2 levels are strongly correlated with the development of cardiovascular disease. In this study, we aim to investigate the associations of HIV infection with angiopoietin levels and endothelial dysfunction. Methods and Results In this cross-sectional study, we compared measures of ANG1, ANG2, and endothelial dysfunction using flow-mediated vasodilation of the brachial artery in 39 untreated subjects infected with HIV, 47 treated subjects infected with HIV, and 46 uninfected subjects from the SCOPE (Observational Study of the Consequences of the Protease Inhibitor Era) cohort. Compared with uninfected controls, treated individuals infected with HIV had 53.1% lower mean ANG1 levels (<0.01) and similar ANG2 levels. On the other hand, untreated individuals infected with HIV had similar ANG1 levels, and 29.2% had higher ANG2 levels (<0.01) compared with uninfected controls. When compared with individuals with untreated HIV infection, those with treated HIV infection had 56% lower ANG1 levels (<0.01) and 22% lower ANG2 levels (<0.01).Both treated and untreated HIV infection were associated with significant impairment in hyperemic velocity, a key measure of microvascular dysfunction (median 61 versus 72 cm/s, <0.01), compared with uninfected controls (median 73 cm/s). This difference persisted after adjustment for ANG1 and ANG2 levels. Interestingly, when compared with untreated individuals infected with HIV, treated individuals infected with HIV had worse hyperemic velocity (-12.35 cm/s, =0.05). In contrast, HIV status, ANG1 levels, and ANG2 levels were not associated with macrovascular dysfunction as measured by flow-mediated dilatation and brachial artery diameter, 2 other measures of vascular homeostasis. Conclusions HIV infection affects the balance between levels of ANG1 and ANG2 and may disturb endothelial homeostasis through disruption of vascular homeostasis. Individuals with treated HIV had decreased ANG1 levels and similar ANG2 levels, whereas individuals with untreated HIV had similar ANG1 levels and increased ANG2 levels, suggesting that treatment status may alter the balance between ANG1 and ANG2. HIV also promotes endothelial dysfunction via impairment of microvascular dysfunction, independent of the Tie-2 receptor system; the finding of worse microvascular dysfunction in the setting of treated HIV infection may reflect the impact of viral persistence on the microvasculature or toxicities of specific antiretroviral regimens. Further research to clarify the mechanism of HIV-mediated endothelial dysfunction is necessary to advance treatment of cardiovascular complications of HIV infection.
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http://dx.doi.org/10.1161/JAHA.121.021397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751943PMC
November 2021

Susceptibility of Typhoidal, Nontyphoidal, and Extended-Spectrum-β-Lactamase-Producing to Ceftolozane/Tazobactam.

Antimicrob Agents Chemother 2022 Jan 18;66(1):e0122421. Epub 2021 Oct 18.

Department of Microbiology, The University of Hong Konggrid.194645.b, Hong Kong, China.

Both typhoidal and nontyphoidal salmonellae are included in the top 15 drug-resistant threats described by the U.S. Centers for Disease Control and Prevention. There is an urgent need to look for alternative antibiotics for the treatment of infections. We used the broth microdilution test to examine the susceptibilities of typhoidal and nontyphoidal salmonellae, including isolates positive for extended-spectrum β-lactamase (ESBL), to ceftolozane/tazobactam and six other antibiotics. Of the 313 (52 typhoidal and 261 nontyphoidal) isolates tested, 98.7% were susceptible to ceftolozane/tazobactam. Based on the overall MIC values, isolates were more susceptible to ceftolozane/tazobactam (0.25/0.5 mg/L) than all the comparator agents: ampicillin (≥64/≥64 mg/L), levofloxacin (0.25/1 mg/L), azithromycin (4/16 mg/L), ceftriaxone (≤0.25/4 mg/L), chloramphenicol (8/≥64 mg/L), and trimethoprim/sulfamethoxazole (1/≥8 mg/L). Comparison of the activities of the antimicrobial agents against nontyphoidal isolates according to their serogroups showed that ceftolozane/tazobactam had the highest activity (100%) against serogroup D, G, I, and Q isolates, whereas the lowest activity (85.7%) was observed against serogroup E isolates. All 10 ESBL-producing isolates (all nontyphoidal), of which 8 were CTX-M-55 producers and 2 were CTX-M-65 producers, were sensitive to ceftolozane/tazobactam, albeit with MIC values higher (1/2 mg/L) than those for non-ESBL producers (0.25/0.5 mg/L). In summary, our data indicate that ceftolozane/tazobactam is active against most strains of both typhoidal and nontyphoidal salmonellae and also against ESBL-producing salmonellae.
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http://dx.doi.org/10.1128/AAC.01224-21DOI Listing
January 2022

Rate of Serum SARS-CoV-2 Antibody Decline for two mRNA Vaccines.

J Appl Lab Med 2021 Oct 14. Epub 2021 Oct 14.

University of California, San Francisco, San Francisco, CA, 94110.

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http://dx.doi.org/10.1093/jalm/jfab137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524641PMC
October 2021

Non-invasive Urine Test for Molecular Classification of Clinical Significance in Newly Diagnosed Prostate Cancer Patients.

Front Med (Lausanne) 2021 14;8:721554. Epub 2021 Sep 14.

Department of Molecular Biology, Umeå University, Umeå, Sweden.

To avoid over-treatment of low-risk prostate cancer patients, it is important to identify clinically significant and insignificant cancer for treatment decision-making. However, no accurate test is currently available. To address this unmet medical need, we developed a novel gene classifier to distinguish clinically significant and insignificant cancer, which were classified based on the National Comprehensive Cancer Network risk stratification guidelines. A non-invasive urine test was developed using quantitative mRNA expression data of 24 genes in the classifier with an algorithm to stratify the clinical significance of the cancer. Two independent, multicenter, retrospective and prospective studies were conducted to assess the diagnostic performance of the 24-Gene Classifier and the current clinicopathological measures by univariate and multivariate logistic regression and discriminant analysis. In addition, assessments were performed in various Gleason grades/ISUP Grade Groups. The results showed high diagnostic accuracy of the 24-Gene Classifier with an AUC of 0.917 (95% CI 0.892-0.942) in the retrospective cohort ( = 520), AUC of 0.959 (95% CI 0.935-0.983) in the prospective cohort ( = 207), and AUC of 0.930 (95% 0.912-CI 0.947) in the combination cohort ( = 727). Univariate and multivariate analysis showed that the 24-Gene Classifier was more accurate than cancer stage, Gleason score, and PSA, especially in the low/intermediate-grade/ISUP Grade Group 1-3 cancer subgroups. The 24-Gene Classifier urine test is an accurate and non-invasive liquid biopsy method for identifying clinically significant prostate cancer in newly diagnosed cancer patients. It has the potential to improve prostate cancer treatment decisions and active surveillance.
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http://dx.doi.org/10.3389/fmed.2021.721554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476767PMC
September 2021

Characterization of Hemorrhagic and Ischemic Stroke in a Diverse Cohort of COVID-19 Patients.

Neurohospitalist 2021 Oct 5;11(4):295-302. Epub 2021 Feb 5.

Department of Neurosurgery, Weill Cornell Medicine, New York, NY, USA.

Background And Purpose: COVID-19 is a known risk factor for stroke. There is limited data on the influence of demographics, risk factors, and hematologic function on outcomes in COVID-19 stroke patients.

Methods: All patients with acute ischemic or hemorrhagic stroke tested for COVID-19 and treated from March 13 through May 19, 2020 were retrospectively analyzed. COVID+ patients were compared to COVID- patients and a historical cohort from 2019.

Results: 84 patients with radiographic acute stroke from the 2020 study period and 152 patients in the historical cohort were included. Stroke incidence in COVID+ patients was 1.5%, with a significant decline in total stroke presentations during this period compared to 2019. 37 patients were COVID+ and 47 patients were COVID-. 32% of COVID+ stroke patients were Hispanic compared to 15% and 18% in the COVID- and 2019 cohorts respectively (p = 0.069 and 0.07). COVID+ stroke patients were younger, had higher rates of hemorrhagic conversion (p = 0.034), higher initial NIHSS (p < 0.001), increased cryptogenic stroke mechanism (p = 0.02), and higher mortality independent of COVID-19 severity. COVID+ patients had higher rates of thrombocytopenia (p = 0.02), and were less likely to be on antiplatelet therapy (p = 0.025). In multivariable analysis, only COVID-19 status independently predicted mortality.

Conclusions: COVID status, independent of severity, was significantly associated with higher mortality in stroke patients. COVID+ stroke patients were younger and less likely to be on antiplatelets, with higher rates of thrombocytopenia, suggesting a possible role for antiplatelet use in this population.
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http://dx.doi.org/10.1177/1941874421990545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442153PMC
October 2021

Kappa/Lambda Ratio for Early Detection of Multiple Myeloma Relapse Using the Reference Change Value from Biological Variation Studies.

Authors:
Alan H B Wu

J Appl Lab Med 2021 11;6(6):1683-1687

Department of Laboratory Medicine, University of California, San Francisco, CA, USA.

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http://dx.doi.org/10.1093/jalm/jfab093DOI Listing
November 2021

The Reference Range for the Anion Gap Is Dependent on the Instrument's Electrolyte Assay.

J Appl Lab Med 2021 11;6(6):1697-1699

Department of Laboratory Medicine, University of California, San Francisco, CA, USA.

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http://dx.doi.org/10.1093/jalm/jfab091DOI Listing
November 2021

Circulating miR-122 in patients with non-toxic acute acetaminophen ingestions.

Clin Toxicol (Phila) 2021 Sep 16:1-3. Epub 2021 Sep 16.

Department of Emergency Medicine, University of California, San Francisco, CA, USA.

MicroRNA-122 (miR-122) is a novel biomarker of liver injury and has been proposed as an early predictor of acetaminophen-associated hepatotoxicity. However, there is little data on miR-122 in patients with nontoxic acute acetaminophen ingestions. This was an observational study of patients with a history of acute acetaminophen ingestion and measured acetaminophen concentrations below the treatment nomogram and who did not receive antidotal treatment. Fold increase in miR-122 expression was measured from the remnant sample corresponding with the timed serum acetaminophen concentration used to determine need for antidotal treatment. Ten patients met inclusion criteria with a four-hour acetaminophen concentration below the nomogram line (mean: 73.4 µg/mL). There was no significant difference in mean fold change of miR-122 expression between the acetaminophen exposed patients and negative controls [(0.82, IQR: 0.27, 0.77) vs (1.24, IQR: 0.54, 1.98),  = 0.33]. miR-122 was not elevated in patients with acute acetaminophen ingestions with timed acetaminophen concentrations below the nomogram line. These data help to further characterize patterns of miR-122 in patients with acute acetaminophen exposures.
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http://dx.doi.org/10.1080/15563650.2021.1978477DOI Listing
September 2021

Improved Detection of -Mediated β-Lactam Resistance in Using a New Oxacillin Salt Agar Screen.

Front Microbiol 2021 6;12:704552. Epub 2021 Aug 6.

Department of Clinical Pathology, Tuen Mun Hospital, Hospital Authority, Hong Kong, China.

Oxacillin resistance mediated by in is emerging in some geographic areas. We evaluated cefoxitin disk diffusion (DD) and a new oxacillin agar (supplemented with 2 μg/ml oxacillin and 2% sodium chloride) screen for the detection of -mediated resistance in . A total of 300 consecutive, non-duplicated clinical isolates from diverse sources in Hong Kong in 2019 were tested. The categorical agreement and errors obtained between cefoxitin DD test, oxacillin agar screen and PCR were analyzed. Isolates with discordant results were further tested by MIC, penicillin binding protein 2a (PBP2a) assays, population analysis and molecular typing. PCR showed that 62 isolates were -positive and 238 isolates were -negative. For cefoxitin DD results interpreted using / breakpoints, the categorical agreement (CA) for two brands of Muller-Hinton agars, MH-II (Becton Dickinson) and MH-E (bioMérieux) were both 96.0%; MEs were both 0%; and VMEs were 19.4 and 12.9%, respectively. The new oxacillin agar reliably differentiated -positive and -negative isolates (100% CA) without any ME or VME results. The 8 isolates with false susceptibility in the cefoxitin DD testing had cefoxitin and oxacillin MICs in the susceptible range. The isolates showed heterogeneous oxacillin resistance with resistant subpopulations at low frequencies. All had positive PBP2a results and were typed as sequence type 27/SCC V. The findings highlight the inability of cefoxitin DD and MIC tests for reliable detection of some -positive isolates.
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http://dx.doi.org/10.3389/fmicb.2021.704552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378274PMC
August 2021

Impact of duloxetine on male fertility: A randomised controlled clinical trial.

Andrologia 2021 Nov 9;53(10):e14207. Epub 2021 Aug 9.

Department of Urology, Weill Cornell Medicine, New York, NY, USA.

This study assessed the impact of duloxetine (serotonin and norepinephrine reuptake inhibitor) on semen parameters, sperm DNA fragmentation and serum hormones. We performed a double-blind, placebo-controlled, randomised clinical trial of duloxetine 60mg or placebo daily for 6 weeks (5 weeks full dose and 1 week taper). The primary outcome was the proportion of men with abnormal DNA fragmentation during and after duloxetine administration. Secondary outcomes were changes in semen parameters and hormones on treatment (2 and 6 weeks) and after discontinuation (8 and 10 weeks). Sixty-eight healthy males aged 18-65 were included. Duloxetine was not associated with an increase in the proportion of participants with abnormal sperm DNA fragmentation terminal deoxynucleotidyl transferase dUTP nick-end labelling scores (>25%) on treatment (p = 0.09) or after treatment (p = 0.56), nor did median sperm DNA fragmentation increase on treatment. Compared with placebo, there were no changes in bulk semen parameters during treatment. Limited changes in hormonal values were detected. This first published human study of a serotonin and norepinephrine reuptake inhibitor on male fertility revealed no clinically meaningful effects on sperm DNA fragmentation, semen parameters or serum hormones. Duloxetine, and possibly other serotonin and norepinephrine reuptake inhibitors, may be considered for men desiring fertility who require antidepressant treatment.
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http://dx.doi.org/10.1111/and.14207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487983PMC
November 2021

COVID-19 mRNA Vaccination in Lactation: Assessment of adverse events and vaccine related antibodies in mother-infant dyads.

medRxiv 2021 Sep 16. Epub 2021 Sep 16.

Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Francisco, California, United States of America.

Background: Data regarding adverse events observed in the lactating mother-infant dyad and their immune response to COVID-19 mRNA vaccination during lactation are needed to inform vaccination guidelines.

Methods: From a prospective cohort of 50 lactating individuals who received mRNA-based vaccines for COVID-19 (mRNA-1273 and BNT162b2), blood and milk samples were collected prior to first vaccination dose, immediately prior to 2nd dose, and 4-10 weeks after 2nd dose. Symptoms in mother and infant were assessed by detailed questionnaires. Anti-SARS-CoV-2 antibody levels in blood and milk were measured by Pylon 3D automated immunoassay and ELISA. In addition, vaccine-related PEGylated proteins in milk were measured by ELISA. Blood samples were collected from a subset of infants whose mothers received the vaccine during lactation (4-15 weeks after mothers' 2nd dose).

Results: No severe maternal or infant adverse events were reported in this cohort. Two mothers and two infants were diagnosed with COVID-19 during the study period. PEGylated proteins, were not found at significant levels in milk after vaccination. After vaccination, levels of anti-SARS-CoV-2 IgG and IgM significantly increased in maternal plasma and there was significant transfer of anti-SARS-CoV-2-Receptor Binding Domain (anti-RBD) IgA and IgG antibodies to milk. Milk IgA levels after the 2nd dose were negatively associated with infant age. Anti-SARS-CoV-2 IgG antibodies were not detected in the plasma of infants whose mothers were vaccinated during lactation.

Conclusions: COVID-19 mRNA vaccines generate robust immune responses in plasma and milk of lactating individuals without severe adverse events reported.
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http://dx.doi.org/10.1101/2021.03.09.21253241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351783PMC
September 2021

Diagnostic Value of Nucleocapsid Protein in Blood for SARS-CoV-2 Infection.

Clin Chem 2021 12;68(1):240-248

Department of Laboratory Medicine, University of California, San Francisco, CA, USA.

Background: Biomarkers have been widely explored for coronavirus disease 2019 diagnosis. Both viral RNA or antigens (Ag) in the respiratory system and antibodies (Ab) in blood are used to identify active infection, transmission risk, and immune response but have limitations. This study investigated the diagnostic utility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein (N-Ag) in serum.

Methods: We retrospectively studied 208 randomly selected cases with SARS-CoV-2 infection confirmed by viral RNA test in swabs. N-Ag concentrations were measured in remnant serum samples, compared to viral RNA or Ab results, and correlated to electronic health records for clinical value evaluation.

Results: Serum N-Ag was detected during active infection as early as day 2 from symptom onset with a diagnostic sensitivity of 81.5%. Within 1 week of symptom onset, the diagnostic sensitivity and specificity reached 90.9% (95% CI, 85.1%-94.6%) and 98.3% (95% CI, 91.1%-99.9%), respectively. Moreover, serum N-Ag concentration closely correlated to disease severity, reflected by highest level of care, medical interventions, chest imaging, and the length of hospital stays. Longitudinal analysis revealed the simultaneous increase of Abs and decline of N-Ag.

Conclusions: Serum N-Ag is a biomarker for SARS-CoV-2 acute infection with high diagnostic sensitivity and specificity compared to viral RNA in the respiratory system. There is a correlation between serum N-Ag concentrations and disease severity and an inverse relationship of N-Ag and Abs. The diagnostic value of serum N-Ag, as well as technical and practical advantages it could offer, may meet unsatisfied diagnostic and prognostic needs during the pandemic.
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http://dx.doi.org/10.1093/clinchem/hvab148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436384PMC
December 2021

Development of an LC-MS/MS Method for Measurement of Irinotecan and Its Major Metabolites in Plasma: Technical Considerations.

Lab Med 2022 Jan;53(1):47-52

Department of Laboratory Medicine, University of California and Zuckerberg San Francisco General Hospital, San Francisco, CA, US.

Objective: Irinotecan (CPT-11) is an important drug used in the treatment of several solid tumor types. To minimize its toxicity, therapeutic drug monitoring of CPT-11 and its major metabolites (SN-38, SN-38-glucuronide [SN-38G], and APC) has been proposed. We aimed to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of CPT-11 and its major metabolites in plasma.

Methods: Specimen preparation consisted of protein precipitation, evaporation, and reconstitution. Analyses were performed on a C18 column using reverse-phase gradient elution. Electrospray ionization and multiple reaction monitoring in positive mode were used for MS. The following heavy isotope-labeled internal standards were used: CPT-11 D10, SN-38 D3, SN-38G D3, and APC D3.

Results: We found that CPT-11, SN-38G, and APC eluted at ~4.6 to 4.7 minutes, and SN-38 eluted at ~5.1 to 5.2 minutes. A second peak for SN-38 was detected at ~4.6 to 4.7 minutes. Given that the structure of SN-38 is found in CPT-11, SN-38G, and APC, and in the CPT-11 D10 used here, in-source fragmentation was the likely cause. In addition, we found that a low-level SN-38 impurity was present in CPT-11 D10 and to a lesser extent in SN-38 D3.

Conclusion: When developing methods for CPT-11 and its metabolites, it is important to consider the effects of in-source fragmentation and the choice of internal standards.
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http://dx.doi.org/10.1093/labmed/lmab059DOI Listing
January 2022

Development and Evaluation of Computable Phenotypes in Pediatric Epilepsy:3 Cases.

J Child Neurol 2021 10 28;36(11):990-997. Epub 2021 Jul 28.

Department of Population Health Sciences, Weill Cornell Medicine/New York-Presbyterian Hospital, New York, NY, USA.

Introduction: Computable phenotypes allow identification of well-defined patient cohorts from electronic health record data. Little is known about the accuracy of diagnostic codes for important clinical concepts in pediatric epilepsy, such as (1) risk factors like neonatal hypoxic-ischemic encephalopathy; (2) clinical concepts like treatment resistance; (3) and syndromes like juvenile myoclonic epilepsy. We developed and evaluated the performance of computable phenotypes for these examples using electronic health record data at one center.

Methods: We identified gold standard cohorts for neonatal hypoxic-ischemic encephalopathy, pediatric treatment-resistant epilepsy, and juvenile myoclonic epilepsy via existing registries and review of clinical notes. From the electronic health record, we extracted diagnostic and procedure codes for all children with a diagnosis of epilepsy and seizures. We used these codes to develop computable phenotypes and evaluated by sensitivity, positive predictive value, and the F-measure.

Results: For neonatal hypoxic-ischemic encephalopathy, the best-performing computable phenotype (HIE and [brain magnetic resonance imaging (MRI) or electroencephalography (EEG) within 120 days of life] and absence of commonly miscoded conditions) had high sensitivity (95.7%, 95% confidence interval [CI] 85-99), positive predictive value (100%, 95% CI 95-100), and measure (0.98). For treatment-resistant epilepsy, the best-performing computable phenotype (3 or more antiseizure medicines in the last 2 years or treatment-resistant ) had a sensitivity of 86.9% (95% CI 79-93), positive predictive value of 69.6% (95% CI 60-79), and F-measure of 0.77. For juvenile myoclonic epilepsy, the best performing computable phenotype (JME ) had poor sensitivity (52%, 95% CI 43-60) but high positive predictive value (90.4%, 95% CI 81-96); the measure was 0.66.

Conclusion: The variable accuracy of our computable phenotypes (hypoxic-ischemic encephalopathy high, treatment resistance medium, and juvenile myoclonic epilepsy low) demonstrates the heterogeneity of success using administrative data to identify cohorts important for pediatric epilepsy research.
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http://dx.doi.org/10.1177/08830738211019578DOI Listing
October 2021

Passive and active immunity in infants born to mothers with SARS-CoV-2 infection during pregnancy: prospective cohort study.

BMJ Open 2021 07 7;11(7):e053036. Epub 2021 Jul 7.

Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.

Objective: To investigate maternal immunoglobulins' (IgM, IgG) response to SARS-CoV-2 infection during pregnancy and IgG transplacental transfer, to characterise neonatal antibody response to SARS-CoV-2 infection, and to longitudinally follow actively and passively acquired antibodies in infants.

Design: A prospective observational study.

Setting: Public healthcare system in Santa Clara County (California, USA).

Participants: Women with symptomatic or asymptomatic SARS-CoV-2 infection during pregnancy and their infants were enrolled between 15 April 2020 and 31 March 2021.

Outcomes: SARS-CoV-2 serology analyses in the cord and maternal blood at delivery and longitudinally in infant blood between birth and 28 weeks of life.

Results: Of 145 mothers who tested positive for SARS-CoV-2 during pregnancy, 86 had symptomatic infections: 78 with mild-moderate symptoms, and 8 with severe-critical symptoms. The seropositivity rates of the mothers at delivery was 65% (95% CI 0.56% to 0.73%) and the cord blood was 58% (95% CI 0.49% to 0.66%). IgG levels significantly correlated between the maternal and cord blood (Rs=0.93, p<0.0001). IgG transplacental transfer ratio was significantly higher when the first maternal positive PCR was 60-180 days before delivery compared with <60 days (1.2 vs 0.6, p<0.0001). Infant IgG seroreversion rates over follow-up periods of 1-4, 5-12, and 13-28 weeks were 8% (4 of 48), 12% (3 of 25), and 38% (5 of 13), respectively. The IgG seropositivity in the infants was positively related to IgG levels in the cord blood and persisted up to 6 months of age. Two newborns showed seroconversion at 2 weeks of age with high levels of IgM and IgG, including one premature infant with confirmed intrapartum infection.

Conclusions: Maternal SARS-CoV-2 IgG is efficiently transferred across the placenta when infections occur more than 2 months before delivery. Maternally derived passive immunity may persist in infants up to 6 months of life. Neonates are capable of mounting a strong antibody response to perinatal SARS-CoV-2 infection.
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http://dx.doi.org/10.1136/bmjopen-2021-053036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264915PMC
July 2021

Citywide serosurveillance of the initial SARS-CoV-2 outbreak in San Francisco using electronic health records.

Nat Commun 2021 06 11;12(1):3566. Epub 2021 Jun 11.

University of California San Francisco, San Francisco, CA, USA.

Serosurveillance provides a unique opportunity to quantify the proportion of the population that has been exposed to pathogens. Here, we developed and piloted Serosurveillance for Continuous, ActionabLe Epidemiologic Intelligence of Transmission (SCALE-IT), a platform through which we systematically tested remnant samples from routine blood draws in two major hospital networks in San Francisco for SARS-CoV-2 antibodies during the early months of the pandemic. Importantly, SCALE-IT allows for algorithmic sample selection and rich data on covariates by leveraging electronic health record data. We estimated overall seroprevalence at 4.2%, corresponding to a case ascertainment rate of only 4.9%, and identified important heterogeneities by neighborhood, homelessness status, and race/ethnicity. Neighborhood seroprevalence estimates from SCALE-IT were comparable to local community-based surveys, while providing results encompassing the entire city that have been previously unavailable. Leveraging this hybrid serosurveillance approach has strong potential for application beyond this local context and for diseases other than SARS-CoV-2.
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http://dx.doi.org/10.1038/s41467-021-23651-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195995PMC
June 2021

A Sensitive and Specific Competitive Enzyme-Linked Immunosorbent Assay for Serodiagnosis of COVID-19 in Animals.

Microorganisms 2021 May 10;9(5). Epub 2021 May 10.

Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.

In addition to human cases, cases of COVID-19 in captive animals and pets are increasingly reported. This raises the concern for two-way COVID-19 transmission between humans and animals. Here, we developed a SARS-CoV-2 nucleocapsid protein-based competitive enzyme-linked immunosorbent assay (cELISA) for serodiagnosis of COVID-19 which can theoretically be used in virtually all kinds of animals. We used 187 serum samples from patients with/without COVID-19, laboratory animals immunized with inactive SARS-CoV-2 virions, COVID-19-negative animals, and animals seropositive to other betacoronaviruses. A cut-off percent inhibition value of 22.345% was determined and the analytical sensitivity and specificity were found to be 1:64-1:256 and 93.9%, respectively. Evaluation on its diagnostic performance using 155 serum samples from COVID-19-negative animals and COVID-19 human patients showed a diagnostic sensitivity and specificity of 80.8% and 100%, respectively. The cELISA can be incorporated into routine blood testing of farmed/captive animals for COVID-19 surveillance.
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http://dx.doi.org/10.3390/microorganisms9051019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150753PMC
May 2021

Passive and active immunity in infants born to mothers with SARS-CoV-2 infection during pregnancy: Prospective cohort study.

medRxiv 2021 May 3. Epub 2021 May 3.

Department of Pediatrics, Division of Neonatology, Santa Clara Valley Medical Center, San Jose, CA, USA.

Objective: To investigate maternal immunoglobulins' (IgM, IgG) response to SARS-CoV-2 infection during pregnancy and IgG transplacental transfer, to characterize neonatal antibody response to SARS-CoV-2 infection, and to longitudinally follow actively- and passively-acquired SARS-CoV-2 antibodies in infants.

Design: A prospective observational study.

Setting: A public healthcare system in Santa Clara County (CA, USA).

Participants: Women with SARS-CoV-2 infection during pregnancy and their infants were enrolled between April 15, 2020 and March 31, 2021.

Outcomes: SARS-CoV-2 serology analyses in the cord and maternal blood at delivery and longitudinally in infant blood between birth and 28 weeks of life.

Results: Of 145 mothers who tested positive for SARS-CoV-2 during pregnancy, 86 had symptomatic infections: 78 with mild-moderate symptoms, and eight with severe-critical symptoms. Of the 147 newborns, two infants showed seroconversion at two weeks of age with high levels of IgM and IgG, including one premature infant with confirmed intrapartum infection. The seropositivity rates of the mothers at delivery was 65% (95% CI 0.56-0.73) and the cord blood was 58% (95% CI 0.49-0.66). IgG levels significantly correlated between the maternal and cord blood (Rs= 0.93, p< 0.0001). IgG transplacental transfer ratio was significantly higher when the first maternal positive PCR was 60-180 days before delivery compared to <60 days (1.2 vs. 0.6, p=<0.0001). Infant IgG negative conversion rate over follow-up periods of 1-4, 5-12, and 13-28 weeks were 8% (4/48), 12% (3/25), and 38% (5/13), respectively. The IgG seropositivity in the infants was positively related to IgG levels in the cord blood and persisted up to six months of age.

Conclusions: Maternal SARS-CoV-2 IgG is efficiently transferred across the placenta when infections occur more than two months before delivery. Maternally-derived passive immunity may protect infants up to six months of life. Neonates mount a strong antibody response to perinatal SARS-CoV-2 infection.
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http://dx.doi.org/10.1101/2021.05.01.21255871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109203PMC
May 2021

Reduced pre-analytical issues for measuring troponin with use of a high sensitivity assay.

Authors:
Alan H B Wu

Clin Biochem 2021 Sep 4;95:89-90. Epub 2021 May 4.

Department of Laboratory Medicine, University of California, San Francisco, CA 94110, USA. Electronic address:

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http://dx.doi.org/10.1016/j.clinbiochem.2021.05.001DOI Listing
September 2021

A combined assay for quantifying remdesivir and its metabolite, along with dexamethasone, in serum.

J Antimicrob Chemother 2021 06;76(7):1865-1873

Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco (UCSF), San Francisco, CA, USA.

Background: As global confirmed cases and deaths from coronavirus disease 2019 (COVID-19) surpass 100 and 2.2 million, respectively, quantifying the effects of the widespread treatment of remdesivir (GS-5734, Veklury) and the steroid dexamethasone is becoming increasingly important. Limited pharmacokinetic studies indicate that remdesivir concentrations in serum decrease quickly after dosing, so its primary serum metabolite GS-441524 may have more analytical utility.

Objectives: We developed and validated a method to quantify remdesivir, its metabolite GS-441524 and dexamethasone in human serum.

Methods: We used LC-MS/MS and applied the method to 23 serum samples from seven patients with severe COVID-19.

Results: The method has limits of detection of 0.0375 ng/mL for remdesivir, 0.375 ng/mL for GS-441524 and 3.75 ng/mL for dexamethasone. We found low intra-patient variability, but significant inter-patient variability, in remdesivir, GS-441524 and dexamethasone levels.

Conclusions: The significant inter-patient variability highlights the importance of therapeutic drug monitoring of COVID-19 patients and possible dose adjustment to achieve efficacy.
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http://dx.doi.org/10.1093/jac/dkab094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083282PMC
June 2021

A SARS-CoV-2 Label-Free Surrogate Virus Neutralization Test and a Longitudinal Study of Antibody Characteristics in COVID-19 Patients.

J Clin Microbiol 2021 06 18;59(7):e0019321. Epub 2021 Jun 18.

Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.

Methods designed to measure severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) humoral response include virus neutralization tests to determine antibody neutralization activity. For ease of use and universal applicability, surrogate virus neutralization tests (sVNTs) based on antibody-mediated blockage of molecular interactions have been proposed. A surrogate virus neutralization test was established on a label-free immunoassay platform (LF-sVNT). The LF-sVNT analyzes the binding ability of SARS-CoV-2 spike protein receptor-binding domain (RBD) to angiotensin-converting enzyme 2 (ACE2) after neutralizing RBD with antibodies in serum. The LF-sVNT neutralizing antibody titers (50% inhibitory concentration [IC]) were determined from serum samples ( = 246) from coronavirus disease 2019 (COVID-19) patients ( = 113), as well as the IgG concentrations and the IgG avidity indices. Although there was variability in the kinetics of the IgG concentrations and neutralizing antibody titers between individuals, there was an initial rise, plateau, and then in some cases a gradual decline at later time points after 40 days after symptom onset. The IgG avidity indices, in the same cases, plateaued after an initial rise and did not show a decline. The LF-sVNT can be a valuable tool in research and clinical laboratories for the assessment of the presence of neutralizing antibodies to COVID-19. This study is the first to provide longitudinal neutralizing antibody titers beyond 200 days post-symptom onset. Despite the decline of IgG concentration and neutralizing antibody titer, IgG avidity index increases, reaches a plateau, and then remains constant up to 8 months postinfection. The decline of antibody neutralization activity can be attributed to the reduction in antibody quantity rather than the deterioration of antibody quality, as measured by antibody avidity.
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http://dx.doi.org/10.1128/JCM.00193-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218741PMC
June 2021

A 23-Gene Classifier urine test for prostate cancer prognosis.

Clin Transl Med 2021 03;11(3):e340

Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen Urology Minimally Invasive Engineering Centre, Shenzhen, China.

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http://dx.doi.org/10.1002/ctm2.340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919118PMC
March 2021
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