A MUC5B Gene Polymorphism, rs35705950-T, Confers Protective Effects Against COVID-19 Hospitalization but Not Severe Disease or Mortality.

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in severe acute respiratory syndrome coronavirus 2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with coronavirus disease (COVID-19) infection among participants in the Million Veteran Program (MVP). Methods: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by transancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (body mass index, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease, and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects. Measurements and Main Results: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations in transancestry meta-analyses within the MVP (Ncases = 4,325; Ncontrols = 507,640; OR = 0.89 [0.82-0.97]; P = 6.86 × 10-3) and joint meta-analyses with the HGI (Ncases = 13,320; Ncontrols = 1,508,841; OR, 0.90 [0.86-0.95]; P = 8.99 × 10-5). The rs35705950-T allele was not associated with reduced COVID-19 positivity in transancestry meta-analysis within the MVP (Ncases = 19,168/Ncontrols = 492,854; OR, 0.98 [0.95-1.01]; P = 0.06) but was nominally significant (P < 0.05) in the joint meta-analysis with the HGI (Ncases = 44,820; Ncontrols = 1,775,827; OR, 0.97 [0.95-1.00]; P = 0.03). Associations were not observed with severe outcomes or mortality. Among individuals of European ancestry in the MVP, rs35705950-T was associated with fewer post-COVID-19 pneumonia events (OR, 0.82 [0.72-0.93]; P = 0.001). Conclusions: The MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations.

Routine on-site evaluation of specimen adequacy during initial ultrasound-guided fine needle aspiration of thyroid nodules: a cost-effectiveness analysis.

BACKGROUND: On-site evaluation (OSE) of specimen adequacy during fine needle aspiration (FNA) of thyroid nodules reduces unsatisfactory results but adds cost. We hypothesized that the addition of routine OSE to initial ultrasound-guided FNA of thyroid nodules is not cost-effective. METHODS: Formal cost-effectiveness analysis was performed using a decision model to compare strategies of routine initial OSE versus restriction of OSE to cases of prior inadequate FNA. Adequacy rates for FNA without OSE and detriment to quality-adjusted life expectancy (QALE) for undergoing repeat FNA were estimated on the basis of literature review and institutional experience. Costs were estimated using Medicare limiting charges and Bureau of Labor Statistics wage rates. Sensitivity analysis was used to examine the uncertainty of the model variable estimates. RESULTS: The routine OSE strategy produced a gain of 0.00007 quality-adjusted life-years (QALYs) at an additional cost of $43.75 for an incremental cost-effectiveness ratio of $639,143/QALY when compared to restriction of OSE to cases with prior inadequate results. During sensitivity analysis, routine OSE became cost-effective if FNA adequacy rate without OSE decreased from 90 to 85 %, cost of OSE decreased from $116 to $75, cost of FNA increased from $366 to $735, hourly wage increased from $23 to $123, or QALE detriment for repeat FNA increased from 0.25 to 1.6 days. CONCLUSIONS: OSE for initial ultrasound-guided FNA of thyroid nodules is not cost-effective unless the adequacy rate without OSE is less than 85 %. When operator performance exceeds this rate, OSE should be reserved for cases with previous inadequate results.

Rapid on-site evaluation of endoscopic ultrasound core biopsy specimens has excellent specificity and positive predictive value for gastrointestinal lesions.

BACKGROUND: Endoscopic ultrasound (EUS) with fine needle aspiration (FNA) is a safe and effective way to sample lesions in the gastrointestinal tract. Rapid on-site specimen evaluation (ROSE) improves the accuracy of EUS-FNA. While data suggests that EUS with fine-needle biopsy (EUS-FNB) is effective, it remains unclear if ROSE is predictive of a final diagnosis when obtaining core specimens. AIM: The aim of this study was to investigate the utility of ROSE in achieving a final diagnosis for EUS-FNB core specimens. METHODS: We evaluated 60 consecutive patients referred for EUS guided sampling of lesions within or adjacent to the gastrointestinal tract. All patients underwent EUS-FNB to evaluate the additive value of ROSE to the diagnostic accuracy of specimens obtained using a core biopsy needle. EUS-FNA was also performed in a majority of cases. RESULTS: EUS-FNB was feasible in all 60 cases; on-site specimen adequacy and final diagnostic accuracy was 58 % [95 % confidence intervals (CI) 45.1-71.2] and 83 % (95 % CI 71.9-91.5), respectively. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value of ROSE for core biopsies were 65, 100, 100, and 39 %, respectively. On-site adequacy and diagnostic accuracy for EUS-FNA was 38 % (95 % CI 22.2-53.5) and 63 % (95 % CI 50.1-75.8), respectively. There were no significant complications. CONCLUSIONS: EUS-FNB is safe, feasible, and effective. ROSE of the core biopsy provides excellent PPV; however, an inadequate ROSE appears to be of limited value. Further prospective studies are needed to assess the optimal handling and onsite processing of core specimens to determine whether ROSE is beneficial for EUS-FNB.

Renal Mass Found on Imaging of Spine for Back Pain: An Incidental Finding.

A middle-aged female patient who presented with back pain was found incidentally to have a renal mass by magnetic resonance imaging (MRI). Further imaging, including computerized tomography (CT) with contrast, suggested a high likelihood of malignancy. Following surgical resection, the tumor was found to be a rare benign lesion on subsequent pathological examination. The patient had conservative treatment for her presenting spine issues and is doing very well. Prompt work-up and treatment of incidental findings by the team of primary care, physical medicine and rehabilitation physicians, radiologists, pathologists, and surgeons helped to ensure a good outcome. Residents had a learning opportunity about the disease and on timely management of incidental findings.

Association of Kidney Comorbidities and Acute Kidney Failure With Unfavorable Outcomes After COVID-19 in Individuals With the Sickle Cell Trait.

Importance: Sickle cell trait (SCT), defined as the presence of 1 hemoglobin beta sickle allele (rs334-T) and 1 normal beta allele, is prevalent in millions of people in the US, particularly in individuals of African and Hispanic ancestry. However, the association of SCT with COVID-19 is unclear. Objective: To assess the association of SCT with the prepandemic health conditions in participants of the Million Veteran Program (MVP) and to assess the severity and sequelae of COVID-19. Design, Setting, and Participants: COVID-19 clinical data include 2729 persons with SCT, of whom 353 had COVID-19, and 129 848 SCT-negative individuals, of whom 13 488 had COVID-19. Associations between SCT and COVID-19 outcomes were examined using firth regression. Analyses were performed by ancestry and adjusted for sex, age, age squared, and ancestral principal components to account for population stratification. Data for the study were collected between March 2020 and February 2021. Exposures: The hemoglobin beta S (HbS) allele (rs334-T). Main Outcomes and Measures: This study evaluated 4 COVID-19 outcomes derived from the World Health Organization severity scale and phenotypes derived from International Classification of Diseases codes in the electronic health records. Results: Of the 132 577 MVP participants with COVID-19 data, mean (SD) age at the index date was 64.8 (13.1) years. Sickle cell trait was present in 7.8% of individuals of African ancestry and associated with a history of chronic kidney disease, diabetic kidney disease, hypertensive kidney disease, pulmonary embolism, and cerebrovascular disease. Among the 4 clinical outcomes of COVID-19, SCT was associated with an increased COVID-19 mortality in individuals of African ancestry (n = 3749; odds ratio, 1.77; 95% CI, 1.13 to 2.77; P = .01). In the 60 days following COVID-19, SCT was associated with an increased incidence of acute kidney failure. A counterfactual mediation framework estimated that on average, 20.7% (95% CI, -3.8% to 56.0%) of the total effect of SCT on COVID-19 fatalities was due to acute kidney failure. Conclusions and Relevance: In this genetic association study, SCT was associated with preexisting kidney comorbidities, increased COVID-19 mortality, and kidney morbidity.

Reducing False-Positive Results With Fourth-Generation HIV Testing at a Veterans Affairs Medical Center.

BACKGROUND: In 2006, the Centers for Disease Control and Prevention issued guidelines advocating routine HIV screening for all patients. However, false-positive results are a potential patient care threat for low-risk populations even with accurate screening assays. A reduction in HIV false-positive screening results can potentially be seen by switching from the third-generation to a more sensitive and specific fourth-generation screening assay. METHODS: We studied the impact on the false-positive screening rate of a change to a fourth-generation assay at a regional US Department of Veteran Affairs Medical Center. HIV screening tests performed by the laboratory from March 1, 2016 to February 28, 2017, prior to implementation of the new assay were compared with fourth-generation HIV screening tests performed from March 1, 2017 to February 28, 2018. RESULTS: Of 7,516 third-generation HIV screening tests reviewed, 52 were reactive on the screening assay; 24 were true positives, 28 were false positives. The following year 7,802 fourth-generation HIV screening tests were performed and 23 were reactive on the screening assay; 16 were true positives and 7 were false positives. The positive predictive value for the third-generation test was 46% and 70% for the fourth-generation test. CONCLUSIONS: There were fewer false-positive results with testing with the more specific fourth- vs third-generation assay (0.09% vs 0.37%, respectively), which was statistically significant (P = .002). This reduction in false-positive screening would reduce the laboratory workload and would save an estimated $3,875 yearly and reduce the adverse effects of false-positive screening results for patients.

Liquid Biopsies in a Veteran Patient Population With Advanced Prostate and Lung Non-Small Cell Carcinomas: A New Paradigm and Unique Challenge in Personalized Medicine.

INTRODUCTION: Liquid biopsy in solid tumors is a major milestone in the field of precision oncology by analyzing circulating tumor cells in peripheral blood and genomic alterations. DNA damage repair gene (DDR) mutations have been reported in 25 to 40% of prostatic cancers and > 50% of non-small cell lung cancers (NSCLC). Tp53 mutation has been found to be associated with a poor prognosis and increased germline mutations. We herein present a quality assurance study for the utility of liquid biopsies with frequency of DDR, Tp53, and androgen receptor (AR) mutations and the clinical impact in advanced lung and prostate cancers in the veteran patient population; these quality assurance observations are the study endpoints. METHODS: We reviewed documentation from advanced cancer biomarker tests on liquid biopsies performed at the Corporal Michael J. Crescenz Veteran Affairs Medical Center in Philadelphia, Pennsylvania, from May 2019 to April 15, 2020. RESULTS: Mutations were detected in 29 of 31 (93.5%) liquid biopsies, hence, 29 liquid biopsies had sufficient ctDNA for analysis. Notable mutations were found in 23 cases (79.3%), irrespective of the cancer type showed. Of 21 prostate cancers biopsies 4 (19.0%) biomarker test directed the targeted therapy to driver mutations of the AR gene. Gene mutations from the DDR gene family were detected in 8 of 23 (34.7%) advanced prostate and lung cancer liquid biopsies, and in 6 of 21 (28.5%) prostate cancer cases indicating poor outcome and possible resistance to the current therapy. Irrespective of the cancer type, 15 of 23 (65.2%) patients harbored Tp53 mutations, which is much more frequent than is documented in the literature. Of 31 patients, 15 (48.4%) were Vietnam era veterans with the potential of Agent Orange exposure and, 20 of 31 (64.5%) had a smoking history. Seven (46.6%) of the Vietnam era veterans with potential exposure to Agent Orange were positive for Tp53 mutations irrespective of the cancer type. CONCLUSION: The minimally invasive liquid biopsy shows a great promise as a diagnostic and prognostic tool in the personalized clinical management of advanced prostate and NSCLC in veteran patient population with unique demographic characteristics. Difference in frequency of the genetic mutations (DDR, TP53, AR) in this cohort provides valuable information for disease progression, lack of response, mechanism of resistance to the implemented therapy and clinical decision making. Precision oncology can be further tailored for this cohort by focusing on DNA repair genes and Tp53 mutations in future for personalized targeted therapy.

Criticality of In-House Preparation of Viral Transport Medium in Times of Shortage During COVID-19 Pandemic.

OBJECTIVE: With the COVID-19 pandemic, there have been supply challenges necessitating that laboratories must prepare their own viral transport medium (VTM), which provides stability for clinical specimens for diagnostic viral testing. METHODS: Within a veteran affairs medical center clinical laboratory, VTM was prepared with a Hanks Balanced Salt Solution (HBSS) 500 mL bottle with phenol red, sterile heat-inactivated fetal bovine serum (FBS), gentamicin sulfate (50 mg/mL), and amphotericin B (250 µg/mL). An antimicrobial mixture was made of 50 mL each of amphotericin B and gentamicin sulfate. Ten mL of FBS and 2 mL of the antimicrobial mixture were mixed into the HBSS bottle, from which 3 mL aliquots were made. Sterility and efficacy check were assessed. These preparations were conducted at our VAMC's clinical laboratory to assure adequate VTM supply during the COVID-19 shortage. RESULTS: The VTM was successfully prepared in-house, supporting uninterrupted testing for the facility and other affiliated medical facilities/centers and community living centers. CONCLUSION: This quality assurance/improvement report represents the first published manuscript on feasible VTM preparation exclusively within a clinical microbiology laboratory during the COVID-19 pandemic.

Gonorrhea and Chlamydia Specimen Positivity Rate by Polymerase Chain Reaction at a Regional Veteran Affairs Medical Center.

OBJECTIVE: Sexually transmitted infections because of Neisseria gonorrhoeae (NG) and/or Chlamydia trachomatis (CT) remain a major public health problem. Although the literature describes the population-based epidemiology of CT/NG, it does not appear to contain reference points for the statistical analyses of specimen positivity rates by nucleic acid testing (NAT) with polymerase chain reaction (PCR) that would be collected by a laboratory following best laboratory and regulatory practice. For facilities that diagnose NG and CT by a real-time PCR assay, an understanding of the expected specimen positivity rate of gonorrhea and chlamydia would be helpful for monitoring the assay for quality assurance. Therefore, on behalf of the Michael J. Crescenz Veteran Affairs Medical Center (VAMC), we present this novel quality assurance study on its CT/NG specimen positivity rates conducted by NAT with PCR. METHODS: Quality assurance/improvement quarterly data from April 1, 2012 to September 30, 2019 were reviewed to obtain both the test volume of PCR for CT/NG and the number of positive test results at the VAMC to collate and perform statistical analyses. Testing had been performed using the Abbott m2000 RealTime System (Abbott Park, IL). RESULTS: A total of 22,709 PCR tests for CT/NG had been performed on the veteran population; of these, 502 tests were positive for NG and 744 were positive for CT. Quarterly percentage rates ranged from 1.67% to 5.30% for CT and from 1.00% to 3.25% for NG, with average rates of 3.35% and 2.22% for CT and NG, respectively. CONCLUSION: The establishment of an expected rate of specimen positivity of CT/NG by NAT with PCR at the VAMC is a significant novel reference point in the quality assurance (QA) literature and provides a benchmark that aids tremendously in QA for the microbiology/molecular laboratory.

Schwannoma with Psammoma Body.

We present a case of a 59-year-old male veteran with a chronic history of right foot soft-tissue mass that was causing pain in his shoes, but not functional or neurologic symptoms. Excision of the mass and pathologic evaluation resulted in multidisciplinary involvement and evaluation. In this example, the mass was found to be either an unusual schwannoma that happens to be psammoma body-rich or an unusual psammomatous melanocytic schwannoma that deviates from conventional examples, as a diagnostic consensus was unable to be reached. Schwannomas are an uncommon finding in the foot, and even more uncommon are those that contain psammoma bodies. Although rare, these tumors can be concerning for more systemic, life-altering diseases such as Carney complex, for which our patient refused genetic testing.

Unusual presentation of poorly differentiated primary pulmonary synovial sarcoma (PD-PPSS) diagnosed by EBUS-TBNA with cytogenetic confirmation-A diagnostic challenge.

Poorly differentiated primary pulmonary synovial sarcoma (PD-PPSS) is a rare, aggressive neoplasm, which occurs in 0.5% cases of all lung malignancies. The diagnosis of PD-PPSS can be very challenging on cytology samples. We present here an unusual case of PD-PPSS diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), in the setting of known history of diffuse large B-cell lymphoma. Diff-Quik and Papanicolaou stains showed cellular specimen with clusters of highly atypical small round blue cells admixed with lymphoid elements; and some with denuded cytoplasm. Cell block further showed molding, crush artifact and atypical mitotic figures. A differential diagnosis based on extended immunohistochemical work-up was Ewing?s sarcoma/PNET versus poorly differentiated synovial sarcoma. Fluorescent in-situ hybridization (FISH) showed SYT gene rearrangement at 18q11.2. In this report, we describe the cytomorphological features, diagnostic pitfalls, challenges, potential mimics, and importance of acquisition of adequate material for the ancillary work-up on the cell block.

C. glycolicum as the sole cause of bacteremia in a patient with acute cholecystitis.

Here we describe a case of Clostridia glycolicum (C. glycolicum) bacteremia in a bed-ridden elderly man with chronic illnesses. The bacterium was identified by the Remel RapID ANA II System. We believe that this is the fifth published report of human illness caused by this bacterium. In the four previously reported cases, C. glycolicum was found in cultures with other bacteria. This is the first reported case in which C. glycolicum was the sole causative agent of disease.

Nanoparticulate PdZn as a Novel Catalyst for ZnO Nanowire Growth.

ZnO nanowires have been grown by chemical vapour deposition (CVD) using PdZn bimetallic nanoparticles to catalyse the process. Nanocatalyst particles with mean particle diameters of 2.6 ± 0.3 nm were shown to catalyse the growth process, displaying activities that compare well with those reported for sputtered systems. Since nanowire diameters are linked to catalyst morphology, the size-control we are able to exhibit during particle preparation represents an advantage over existing approaches in terms of controlling nanowire dimensions, which is necessary in order to utilize the nanowires for catalytic or electrical applications.(See supplementary material 1).

Rapid synthesis of aligned zinc oxide nanowires.

A solution growth approach for zinc oxide (ZnO) nanowires is highly appealing because of the low growth temperature and possibility for large area synthesis. Reported reaction times for ZnO nanowire synthesis, however, are long, spanning from several hours to days. In this work, we report on the rapid synthesis of ZnO nanowires on various substrates (such as poly(ethylene terephthalate) (PET), silicon and glass) using a commercially available microwave oven. The average growth rate of our nanowires is determined to be as high as 100 nm min(-1), depending on the microwave power. Transmission electron microscopy analysis revealed a defect-free single-crystalline lattice of the nanowires. A detailed analysis of the growth characteristics of ZnO nanowires as functions of growth time and microwave power is reported. Our work demonstrates the possibility of a fast synthesis route using microwave heating for nanomaterials synthesis.

Case report: Paenibacillus thiaminolyticus: a new cause of human infection, inducing bacteremia in a patient on hemodialysis.

Paenibacilli are gram-positive, aerobic bacteria that are related to Bacilli but differ in the DNA encoding their 16S rRNA. Until recently, these organisms were not known to cause human disease. There are now several reports of human infection caused by a few members of this genus, most commonly by P. alvei. We report a human infection in a patient with a permacath for chronic hemodialysis who was found to have bacteremia caused by P. thiaminolyticus, which is an environmental bacterium that has never been found to cause human disease. We identified this bacterium by biochemical tests, cloning, sequencing the genomic DNA encoding its 16S rRNA, growth characteristics, and electron microscopic studies. This constitutes the first report of a human infection caused by this organism.

Achieving high-current carbon nanotube emitters.

When a carbon nanotube emitter is operated at high currents (typically above 1 microA per emitter), a small voltage drop ( approximately few volts) along its length or at its contact generates a reverse/canceling electric field that causes a saturation-like deviation from the classical Fowler-Nordheim behavior with respect to the applied electric field. We present a correction to the Fowler-Nordheim equation to account for this effect, which is experimentally verified using field emission and contact electrical measurements on individual carbon nanotube emitters. By using rapid thermal annealing to improve both the crystallinity of the carbon nanotubes and their electrical contact to the substrate, it is possible to reduce this voltage drop, allowing very high currents of up to 100 microA to be achieved per emitter with no significant deviation from the classical Fowler-Nordheim behavior.