We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.

Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis

IL (interleukin)-6 is a pivotal cytokine of innate immunity, which enacts a broad set of physiological functions traditionally associated with host defense, immune cell regulation, proliferation, a...

Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease.

IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial.

Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells attributable to acquired leukemic mutations in genes such as DNMT3A or TET2...

https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.119.044362?download=true

Genetic Interleukin 6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis

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.

/pdf/reducing-false-positive-results-with-fourth-generation-hiv-3jru4lmyu9.pdf

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

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.

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

Abstract Introduction/Objective With the outbreak of COVID-19 caused by SARS-CoV-2, there have been challenges in the maintenance of adequate supplies both in terms of PPE and for testing. The shortage of commercial VTM for the transport of specimens for PCR testing has created a situation in which laboratories would need to manufacture their own in-house VTM as commonly used commercial VTM is unavailable. However, there is sparse literature on the emergency manufacture of VTM. Here, we describe the VAMC experience in manufacturing/quality control on its own VTM. Results VTM was manufactured by pathology and laboratory medicine using strict aseptic technique with 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 ug/ml). First, 50 ml of amphotericin B and 50 ml of gentamicin sulfate were mixed. Then 10 ml of FBS was mixed with the HBSS bottle and then 2 ml of the gentamicin/amphotericin B mixture was also mixed into the HBSS bottle. 3 ml aliquots were made from this mixture to constitute individual tubes of VTM for clinical use. Sterility for each batch (after 24-hour incubation at 37o C in the CO2 incubator) was assessed visually and by culture on a blood agar, chocolate agar, and thioglycolate mediums. An efficacy check was performed for each batch by spiking positive and negative controls into the VTM aliquots; RT-PCR for SARS-CoV-2 was executed to verify the medium did not degrade viral RNA and produced expected results for room temperature, refrigerated, and frozen samples. Previously manufactured VTM without phenol red also underwent sterility and efficacy checks. Results VTM was successfully manufactured in-house, allowing testing to continue despite the shortage. Sterility and efficacy checks on all lots and bottles from which the VTM aliquots were made passed with no growth detected and efficacy passing with all expected positives and negatives resulting as expected. Conclusion To the author’s knowledge, this represents the first published abstract on VTM manufacture in this most unprecedented crisis involving COVID-19. In this national emergency with corresponding shortage of testing supplies including commercial VTM, the in-house manufacture of VTM is both feasible and prudent to ensure continuity of testing and quality patient/laboratory care.

In-House Viral Transport Medium (VTM) Manufacture in the Time of Shortage, Supply and Crisis of COVID-19 at Veteran Affairs Medical Center (VAMC)

Abstract Introduction/Objective Due to the spread of SARS-CoV-2 – the causative pathogen behind COVID-19, a significant impact on society including significant death, morbidity, strain on the nation’s medical systems, and an economic shutdown of many sectors has come to pass. While society has been affected by this virus, it has also been documented in the mainstream news that this pandemic has disproportionately affected non-white minority groups, and that access to testing for vulnerable populations have been limited. Similarly, previously published epidemiological data by Zuvekas et al. show that populations with health insurance, higher socioeconomic class, and white in race have received significantly better access to private health care resources. As veterans represent a vulnerable population, as part of quality assurance, testing data was reviewed to verify that this trend was not also affecting the VAMC. Methods As part of a quality assurance/quality improvement project, a retrospective manual review of all SARS-CoV- 2 RT-PCR tests performed at the VAMC from March 11th, 2020 to April 13th, 2020. These tests were reviewed within the computerized medical record system to determine the age, gender, and ethnicity of the patients. The demographic data from this search was compared with the population statistics of the major metropolitan city that the VAMC is located in. Results Out of 571 patients who were tested for SARS-CoV-2, 264 (46%) had an ethnic African-Americans background, 135 (24%) had an ethnic Caucasian or white background, 8 had an ethnic Hispanic background, 3 had an ethnic native Hawaiian or other Pacific Islander background, 2 had an ethnic Asian background (0.4%), and 1 had an ethnic American Indian or Alaskan Native background. The rest had left ethnicity unanswered or was unknown/declined to state. The majority of those tested were males (392 or 69%). Ages of patients tested ranged from 24 to 98 years of age. The ethnic distribution of those tested was like the ethnic distribution within the city where the VAMC was located. Conclusion Quality healthcare to the entire population also means that healthcare should be accessible to all members who require it. The VAMC offers broad access for testing to all its patients of all ethnicities. This demonstrates, in the changing healthcare landscape, one of the many advantages of the Veteran Affairs system.

/pdf/improved-across-the-board-access-to-sars-cov-2-laboratory-8t9b6cny6m.pdf

Improved Across the Board Access to SARS-CoV-2 Laboratory Testing in an Integrated Medical System;the Veteran Affairs Medical Center (VAMC) Experience

Unicentric Castleman disease and lymphoepithelial cyst of the parotid: A case report and review of the literature

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