Research Spotlight

Chung, J. R., Kim, S. S., Belongia, E. A., McLean, H. Q., King, J. P., Nowalk, M. P., Zimmerman, R. K., Moehling Geffel, K., Martin, E. T., Monto, A. S., Lamerato, L. E., Gaglani, M., Hoffman, E., Volz, M., Jackson, M. L., Jackson, L. A., Patel, M. M. and Flannery, B. (2022). “Vaccine effectiveness against COVID-19 among symptomatic persons aged ≥12 years with reported contact with COVID-19 cases, February-September 2021.” Influenza Other Respir Viruses.

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BACKGROUND: Individuals in contact with persons with COVID-19 are at high risk of developing COVID-19; protection offered by COVID-19 vaccines in the context of known exposure is poorly understood. METHODS: Symptomatic outpatients aged ≥12 years reporting acute onset of COVID-19-like illness and tested for SARS-CoV-2 between February 1 and September 30, 2021 were enrolled. Participants were stratified by self-report of having known contact with a COVID-19 case in the 14 days prior to illness onset. Vaccine effectiveness was evaluated using the test-negative study design and multivariable logistic regression. RESULTS: Among 2229 participants, 283/451 (63%) of those reporting contact and 331/1778 (19%) without known contact tested SARS-CoV-2-positive. Adjusted vaccine effectiveness was 71% (95% confidence interval [CI], 49%-83%) among fully vaccinated participants reporting a known contact versus 80% (95% CI, 72%-86%) among those with no known contact (p-value for interaction = 0.2). CONCLUSIONS: This study contributes to growing evidence of the benefits of vaccinations in preventing COVID-19 and support vaccination recommendations and the importance of efforts to increase vaccination coverage.

Chambergo-Michilot, D., Alur, A., Kulkarni, S. and Agarwala, A. (2022). “Mipomersen in Familial Hypercholesterolemia: An Update on Health-Related Quality of Life and Patient-Reported Outcomes.” Vasc Health Risk Manag 18: 73-80.

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Familial hypercholesterolemia (FH) is an autosomal dominant condition that leads to significantly elevated low-density lipoprotein cholesterol (LDL-C) levels and an elevated risk for cardiovascular disease. Mipomersen is an antisense oligonucleotide inhibitor targeted to apolipoprotein B-100 (apoB-100) mRNA that is administered via subcutaneous injection. Once administered, mipomersen causes selective degradation of the apoB-100 mRNA and inhibition of protein translation. This ultimately results in substantial reductions in LDL-C and other lipoprotein levels. Mipomersen is approved for the treatment of homozygous FH. In this review, we discuss its mechanism, current evidence, limitations of use including adverse events, and impact on health-related quality of life.

Brinjikji, W., Abbasi, M., Mereuta, O. M., Fitzgerald, S., Larco, J. A., Dai, D., Kadirvel, R., Nogueira, R. G., Kvamme, P., Layton, K. F., Delgado, J. E., Hanel, R. A., Pereira, V. M., Almekhlafi, M. A., Yoo, A. J., Jahromi, B. S., Gounis, M. J., Patel, B. M., Savastano, L. E., Cloft, H. J., Haussen, D. C., Al-Bayati, A., Mohammaden, M., Pisani, L., Rodrigues, G., Thacker, I. C., Kayan, Y., Copelan, A. Z., Aghaebrahim, A., Sauvageau, E., Demchuk, A. M., Bhuva, P., Soomro, J., Nazari, P., Cantrell, D. R., Puri, A. S., Doyle, K. M., Entwistle, J. and Kallmes, D. F. (2022). “Histological composition of retrieved emboli in acute ischemic stroke is independent of pre-thrombectomy alteplase use.” J Stroke Cerebrovasc Dis 31(4): 106376.

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BACKGROUND AND PURPOSE: Given recent evidence suggesting the clot composition may be associated with revascularization outcomes and stroke etiology, clot composition research has been a topic of growing interest. It is currently unclear what effect, if any, pre-thrombectomy thrombolysis has on clot composition. Understanding this association is important as it is a potential confounding variable in clot composition research. We retrospectively evaluated the composition of retrieved clots from ischemic stroke patients who did and did not receive pre-treatment tPA to study the effect of tPA on clot composition. MATERIALS AND METHODS: Consecutive patients enrolled in the Stroke Thromboembolism Registry of Imaging and Pathology (STRIP) were included in this study. All patients underwent mechanical thrombectomy and retrieved clots were sent to a central core lab for processing. Histological analysis was performed using Martius Scarlett Blue (MSB) staining and area of the clot was also measured on the gross photos. Student’s t test was used for continuous variables and chi-squared test for categorical variables. RESULTS: A total of 1430 patients were included in this study. Mean age was 68.4±13.5 years. Overall rate of TICI 2c/3 was 67%. A total of 517 patients received tPA (36%) and 913 patients did not (64%). Mean RBC density for the tPA group was 42.97±22.62% compared to 42.80±23.18% for the non-tPA group (P=0.89). Mean WBC density for the tPA group was 3.74±2.60% compared to 3.42±2.21% for the non-tPA group (P=0.012). Mean fibrin density for the tPA group was 26.52±15.81% compared to 26.53±15.34% for the non-tPA group (P=0.98). Mean platelet density for the tPA group was 26.22±18.60% compared to 26.55±19.47% for the non-tPA group (P=0.75). tPA group also had significantly smaller clot area compared to non-tPA group. CONCLUSIONS: Our study 1430 retrieved emboli and ischemic stroke patients shows no interaction between tPA administration and clot composition. These findings suggest that tPA does not result in any histological changes in clot composition.

Borman, S., Wilkinson, J., Meldi-Sholl, L., Johnson, C., Carter, K., Covington, K. R., Fitzgerald, A. L., Kurley, S. J., Farberg, A. S., Goldberg, M. S., Monzon, F. A., Oelschlager, K. and Cook, R. W. (2022). “Analytical validity of DecisionDx-SCC, a gene expression profile test to identify risk of metastasis in cutaneous squamous cell carcinoma (SCC) patients.” Diagn Pathol 17(1): 32.

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BACKGROUND: To improve identification of patients with cutaneous squamous cell carcinoma (SCC) at high risk for metastatic disease, the DecisionDx-SCC assay, a prognostic 40-gene expression profile (40-GEP) test, was developed and validated. The 40-GEP assay utilizes RT-PCR gene expression analysis on primary tumor biopsy tissue to evaluate the expression of 34 signature gene targets and 6 normalization genes. The test provides classifications of low risk (Class 1), moderate risk (Class 2A), and high risk (Class 2B) of metastasis within 3 years of diagnosis. The primary objective of this study was to validate the analytical performance of the 40-gene expression signature. METHODS: The repeatability and reproducibility of the 40-GEP test was evaluated by performance of inter-assay, intra-assay, and inter-operator precision experiments along with monitoring the reliability of sample and reagent stability for class call concordance. The technical performance of clinical orders from September 2020 through July 2021 for the 40-GEP test was assessed. RESULTS: Patient hematoxylin and eosin (H&E) stained slides were reviewed by a board-certified pathologist to assess minimum acceptable tumor content. Class specific controls (Class 1 and Class 2B) were evaluated with Levey-Jennings analysis and demonstrated consistent and reproducible results. Inter-assay, inter-operator and intra-assay concordance were all ≥90%, with short-term and long-term RNA stability also meeting minimum concordance requirements. Of the 2586 orders received, 93.5% remained eligible for testing, with 97.1% of all tested samples demonstrating actionable class call results. CONCLUSION: DecisionDx-SCC demonstrates a high degree of analytical precision, yielding high concordance rates across multiple performance experiments, along with exhibiting robust technical reliability on clinical samples.

Fujikawa, K., Nonaka, N., Wang, X. and Shibata, S. (2022). “An in situ hybridization study of syndecan family during the late stages of developing mouse molar tooth germ.” Anat Sci Int.

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Expression of syndecan-1, 2, 3, and 4 mRNAs during the late stages of tooth germ formation was investigated by in situ hybridization, using [(35)S]-UTP-labeled cRNA probes. Syndecan-1 mRNA was mainly expressed in the stellate reticulum and stratum intermedium as well as at the cervical region of dental papilla/dental follicle during E18.5-P3.0. Expression in the dental epithelium was enhanced during the postnatal periods, which was supported by real-time RT-PCR analysis. These spatiotemporal expression patterns may suggest specific roles of syndecan-1 in tooth formation such as tooth eruption or root formation. Syndecan-3 mRNA expression became evident in odontoblasts at E18.5, but compared to collagen type I mRNA, which was strongly expressed at this stage, syndecan-3 expression in odontoblast was restricted in mature odontoblasts beneath the cusps during the postnatal periods. This result was also supported by real-time RT-PCR analysis, and indicated that syndecan-3 may be involved in the progress of dentinogenesis rather than in the initiation of it. Syndecan-4 mRNA roughly showed comparable expression patterns to those of syndecan-3. Syndecan-2 mRNA did not show significant expression during the experimental period, but real-time RT-PCR analysis suggested that syndecan-2 expression might be enhanced with hard tissue formation.