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Background: COVID-19 disproportionately affects those with preexisting conditions, but little research has determined whether those with chronic diseases view the pandemic itself differently - and whether there are differences between chronic diseases. We theorized that while individuals with respiratory disease or autoimmune disorders would perceive greater threat from COVID-19 and be more supportive of non-pharmaceutical interventions (NPIs), those with autoimmune disorders would be less likely to support vaccination-based interventions. Methods: We conducted a two-wave online survey conducted in February and November 2021 asking respondents their beliefs about COVID-19 risk perception, adoption and support of interventions, willingness to be vaccinated against COVID-19, and reasons for vaccination. Regression analysis was conducted to assess the relationship of respondents reporting a chronic disease and COVID-19 behaviors and attitudes, compared to healthy respondents adjusting for demographic and political factors. Results: In the initial survey, individuals reporting a chronic disease had both stronger feelings of risk from COVID-19 as well as preferences for NPIs than healthy controls. The only NPI that was still practiced significantly more compared to healthy controls in the resample was limiting trips outside of the home. Support for community-level NPIs was higher among individuals reporting a chronic disease than healthy controls and remained high among those with respiratory diseases in sample 2. Vaccine acceptance produced more divergent results: those reporting chronic respiratory diseases were 6% more willing to be vaccinated than healthy controls, while we found no significant difference between individuals with autoimmune diseases and healthy controls. Respondents with chronic respiratory disease and those with autoimmune diseases were more likely to want to be vaccinated to protect themselves from COVID-19, and those with an autoimmune disease were more likely to report fear of a bad vaccine reaction as the reason for vaccine hesitancy. In the resample, neither those with respiratory diseases nor autoimmune diseases reported being more willing to receive a booster vaccine than healthy controls. Conclusions: It is not enough to recognize the importance of health in determining attitudes: nuanced differences between conditions must also be recognized. [ABSTRACT FROM AUTHOR]

A locus on human chromosome 11q23 tagged by marker rs3802842 was associated with colorectal cancer (CRC) in a genome-wide association study; this finding has been replicated in case-control studies worldwide. In order to identify biologic factors at this locus that are related to the etiopathology of CRC, we used microarray-based target selection methods, coupled to next-generation sequencing, to study 103 kb at the 11q23 locus. We genotyped 369 putative variants from 1,030 patients with CRC (cases) and 1,061 individuals without CRC (controls) from the Ontario Familial Colorectal Cancer Registry. Two previously uncharacterized genes, COLCA1 and COLCA2, were found to be co-regulated genes that are transcribed from opposite strands. Expression levels of COLCA1 and COLCA2 transcripts correlate with rs3802842 genotypes. In colon tissues, COLCA1 co-localizes with crystalloid granules of eosinophils and granular organelles of mast cells, neutrophils, macrophages, dendritic cells and differentiated myeloid-derived cell lines. COLCA2 is present in the cytoplasm of normal epithelial, immune and other cell lineages, as well as tumor cells. Tissue microarray analysis demonstrates the association of rs3802842 with lymphocyte density in the lamina propria ( p = 0.014) and levels of COLCA1 in the lamina propria ( p = 0.00016) and COLCA2 (tumor cells, p = 0.0041 and lamina propria, p = 6 × 10-5). In conclusion, genetic, expression and immunohistochemical data implicate COLCA1 and COLCA2 in the pathogenesis of colon cancer. Histologic analyses indicate the involvement of immune pathways. [ABSTRACT FROM AUTHOR]

Azacitidine and decitabine are cytidine analogues that inhibit DNA methylation, and are used to treat myeloid haematological malignancies. Hydroxycarbamide (HC) (also known as hydroxyurea), a ribonucleotide reductase (RR) inhibitor, blocks the conversion of ribonucleotides to deoxyribonucleotides, and is also used to treat leukaemia and sickle-cell disease. Azacitidine is a ribonucleoside and decitabine is a deoxyribonucleoside; therefore, we hypothesized that inhibition of RR by HC would be antagonistic to azacitidine and synergistic to decitabine. HL-60 and T24 cancer cell lines were treated with azacitidine or decitabine in combination with HC and DNA methylation of LRE1, MAGEA1 and CDKN2A was quantitatively measured by bisulphite-polymerase chain reaction pyrosequencing. Surprisingly, we found that HC blocked the ability of both azacitidine and decitabine to inhibit DNA methylation and this antagonistic effect was attributable to the arrest of the cell cycle induced by HC. However, this antagonism could be avoided with sequential treatment of HC followed by azacitidine or decitabine. This data suggest that concurrent combination of HC blocks the ability of azacitidine and decitabine to inhibit DNA methylation and therefore these drugs should be used sequentially. [ABSTRACT FROM AUTHOR]

The JAK2 V617F somatic variant is a well-known driver of myeloproliferative neoplasms (MPN) associated with an increased risk for athero-thrombotic cardiovascular disease. Recent studies have demonstrated its role in the development of thoracic aortic aneurysm (TAA). However, limited clinical information and level of JAK2 V617F burden have been provided for a comprehensive evaluation of potential confounders. A retrospective genotype-first study was conducted to identify carriers of the JAK2 V617F variant from an internal exome sequencing database in Yale DNA Diagnostics Lab. Additionally, the overall incidence of somatic variants in the JAK2 gene across various tissue types in the healthy population was carried out based on reanalysis of SomaMutDB and data from the UK Biobank (UKBB) cohort to compare our dataset to the population prevalence of the variant. In our database of 12,439 exomes, 594 (4.8%) were found to have a thoracic aortic aneurysm (TAA), and 12 (0.049%) were found to have a JAK2 V617F variant. Among the 12 JAK2 V617F variant carriers, five had a TAA (42%), among whom four had an ascending TAA and one had a descending TAA, with a variant allele fraction ranging from 11.2% to 20%. Among these five patients, 60% were female, and average age at diagnosis was 70 (49–79). The mean ascending aneurysm size was 5.05 cm (range 4.6–5.5 cm), and four patients had undergone surgical aortic replacement or repair. UKBB data revealed a positive correlation between the JAK2 V617F somatic variant and aortic valve disease (effect size 0.0086, p = 0.85) and TAA (effect size = 0.004, p = 0.92), although not statistically significant. An unexpectedly high prevalence of TAA in our dataset (5/594, 0.84%) is greater than the prevalence reported before for the general population, supporting its association with TAA. JAK2 V617F may contribute a meaningful proportion of otherwise unexplained aneurysm patients. Additionally, it may imply a potential JAK2-specific disease mechanism in the developmental of TAA, which suggests a possible target of therapy that warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: Recently, there have been concerted efforts to improve racial and ethnic diversity in the physician-scientist workforce. Identifying factors associated with career choices among those underrepresented in medicine and science is a necessary first step to advance this objective. The aim of the present study was to assess the attitudes and factors associated with academic and research career interests among underrepresented predoctoral physician-scientists. Methods: A cross-sectional 70-question survey was distributed to all predoctoral single degree (MD or DO) and dual degree (MD/PhD or DO/PhD) trainees at 32 medical schools in the United States from 2012 to 2014. Main outcomes included factors important to advancement in academic medicine, intended medical specialty, and future career plans. To test the post-hoc hypothesis of whether trainees from underrepresented groups have differing perceptions of career trajectories and obstacles than their counterparts, we evaluated responses according to self-identified race/ethnic status using Chi-square and Fisher's exact tests. All tests were two-sided and significance level of < 0.05 was used. Results: There were a total of 4433 responses representing all predoctoral training stages. The response rate was 27%. Most respondents were single degree trainees (MD/DO 79% vs MD/DO-PhD 21%). Most respondents self-identified as White (67%), followed by Multi-racial or Other (14.3%), Asian or Pacific Islander (10.4%), Hispanic (6%), and Black or African American (4.1%). Desired career sector, career intention, and clinical specialty interest differed across race/ethnic groups. With respect to career selection factors, anticipated non-work related responsibilities during residency were also significantly different between these groups. By multivariable regression analysis, Black or African American trainees were significantly less likely than White trainees to indicate a career in academia (OR 0.496, 95% CI 0.322–0.764) and basic research (OR 0.314, 95% CI 0.115–0.857), while Multi-racial or Other trainees were also less likely than White trainees to indicate a career in academia (OR 0.763, 95% CI 0.594–0.980). Conclusions: These data represent the first in-depth survey of career aspirations, perceptions, and interests between demographically underrepresented and non-underrepresented predoctoral physician-scientist trainees. Our results identify key differences between these cohorts, which may guide efforts to improve diversity within the physician-scientist workforce. [ABSTRACT FROM AUTHOR]

Cardiac troponin (Tn) plays a central role in the evaluation of patients with angina presenting with acute coronary syndrome. The advent of high-sensitivity assays has improved the analytic sensitivity and precision of serum Tn measurement, but this advancement has come at the cost of poorer specificity. The role of clinical judgment is of heightened importance because, more so than ever, the interpretation of serum Tn elevation hinges on the careful integration of findings from electrocardiographic, echocardiographic, physical exam, interview, and other imaging and laboratory data to formulate a weighted differential diagnosis. A thorough understanding of the epidemiology, mechanisms, and prognostic implications of Tn elevations in each cardiac and non-cardiac etiology allows the clinician to better distinguish between presentations of myocardial ischemia and myocardial injury—an important discernment to make, as the treatment of acute coronary syndrome is vastly different from the workup and management of myocardial injury and should be directed at the underlying cause. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 28-year-old female with a history of left breast lumpectomy and diagnosed with desmoid fibromatosis or aggressive fibromatosis after ultrasound-guided core biopsy. Topics discussed include her clinical examination identifies swelling in right iliac fossa close to the right iliac crest, without any regional lymphadenopathy, her Immunohistochemistry detected smooth muscle actin and cytoplasmic expression of b-catenin, and treatment with radiotherapy.

Background: Immunity that limits malarial disease is acquired over time, but adults living in endemic areas continue to become infected and can require treatment for clinical illness. Gamma delta (γδ) T cells, particularly the Vδ2+ subset, have been associated with development of clinical malaria in children. In this study, the dynamics of total γδ T cells, Vδ2+ and Vδ2− T cells were measured during a malaria transmission season in Malian adults. Methods: This study explored γδ T cell dynamics and Plasmodium falciparum infection outcomes over the course of the malaria transmission season in Malian adults enrolled in the placebo arm of a double-blind randomized vaccine trial. All volunteers were treated with anti-malarial drugs prior to the start of the transmission season and blood smears were assessed for P. falciparum infection every 2 weeks from July 2014 to January 2015. The study participants were stratified as either asymptomatic infections or clinical malaria cases. Vδ2+ and Vδ2− γδ T cell frequencies and activation (as measured by CD38 expression) were measured in all study participants at baseline and then every 2 months using a whole blood flow cytometry assay. Results: Forty of the forty-three subjects became infected with P. falciparum and, of those, 21 individuals were diagnosed with clinical malaria at least once during the season. The γδ T cell percentage and activation increased over the duration of the transmission season. Both the Vδ2+ and Vδ2− γδ T cells were activated by P. falciparum infection. Conclusion: γδ T cells increased during a malaria transmission season and this expansion was noted in both the Vδ2+ and Vδ2− γδ T cells. However, neither expansion or activation of either γδ T cell subsets discriminated study participants that had asymptomatic infections from those that had clinical malaria cases. [ABSTRACT FROM AUTHOR]

Accurate measurement and interpretation of serum levels of troponin (Tn) is a central part of the clinical workup of a patient presenting with chest pain suspicious for acute coronary syndrome (ACS). Knowledge of the molecular characteristics of the troponin complex and test characteristics of troponin measurement assays allows for a deeper understanding of causes of false positive and false negative test results in myocardial injury. In this review, we discuss the molecular structure and functions of the constituent proteins of the troponin complex (TnT, TnC, and TnI); review the different isoforms of Tn and where they are from; survey the evolution of clinical Tn assays, ranging from first-generation to high-sensitivity (hs); provide a primer on statistical interpretation of assay results based on different clinical settings; and discuss potential causes of false results. We also summarize the advances in technologies that may lead to the development of future Tn assays, including the development of point of care assays and wearable Tn sensors for real-time continuous measurement. [ABSTRACT FROM AUTHOR]

Purpose: Distant metastasis (DM) is the main cause of death for patients with human papillomavirus (HPV)-related oropharyngeal cancers (OPCs); yet, there are few reliable predictors of DM in this disease. The role of quantitative imaging (ie, radiomic) analysis was examined to determine whether there are primary tumor features discernible on imaging studies that are associated with a higher risk of DM developing.Methods and Materials: Radiation therapy planning computed tomography scans were retrieved for all nonmetastatic p16-positive OPC patients treated with radiation therapy or chemoradiation therapy at a single institution between 2005 and 2010. Radiomic biomarkers were derived from each gross tumor volume. The biomarkers included 4 representative radiomic features from tumor first-order statistics, shape, texture, and wavelet groups, as well as a combined 4-feature signature. Univariable Cox proportional hazards models for DM risk were identified. The discriminative performance of prognostic univariable and multivariable models was compared using the concordance index (C-index). Subgroup analyses were performed.Results: There were 300 HPV-related OPC patients who were eligible for the analysis. A total of 36 DM events occurred within a median follow-up period of 5 years. On univariable analysis, top results included the 4 representative radiomic features (C-index, 0.670-0.686; P < .001), the radiomic signature (C-index, 0.670; P < .001), tumor stage (C-index, 0.633; P < .001), tumor diameter (C-index, 0.653; P < .001), and tumor volume (C-index, 0.674; P < .001), which demonstrated moderate discrimination of DM risk. Combined clinical-radiomic models yielded significantly improved performance (C-index, 0.701-0.714; P < .05). In subgroup analyses, the radiomic biomarkers consistently stratified patients for DM risk, particularly for those cohorts with greater risks (C-index, 0.663-0.796), such as patients with stage III disease.Conclusions: Radiomic biomarkers appear to classify DM risk for patients with nonmetastatic HPV-related OPC. Radiomic biomarkers could be used either alone or with other clinical characteristics in the assignment of DM risk in future HPV-related OPC clinical trials. [ABSTRACT FROM AUTHOR]

Malaria transmission-blocking vaccines target mosquito-stage parasites and will support elimination programmes. Gamete vaccine Pfs230D1-EPA/Alhydrogel induced superior activity to zygote vaccine Pfs25-EPA/Alhydrogel in malaria-naive US adults. Here, we compared these vaccines in malaria-experienced Malians. We did a pilot safety study then double-blind, block-randomised, comparator-controlled main-phase trial in malaria-intense Bancoumana, Mali. 18–50-year-old healthy non-pregnant, non-breastfeeding consenting adult residents were randomly assigned (1:1:1:1) to receive four doses at months 0, 1, 4·5, and 16·5 of either 47 μg Pfs25, 40 μg Pfs230D1 or comparator (Twinrix or Menactra)—all co-administered with normal saline for blinding—or 47 μg Pfs25 plus 40 μg Pfs230D1 co-administered. We documented safety and tolerability (primary endpoint in the as-treated populations) and immunogenicity (secondary endpoint in the as-treated populations: ELISA, standard-membrane-feeding assay, and mosquito direct skin feed assay). This trial is registered at ClinicalTrials.gov , NCT02334462. Between March 19, and June 2, 2015, we screened 471 individuals. Of 225 enrolled for the pilot and main cohorts, we randomly assigned 25 participants to pilot safety cohort groups of five (20%) to receive a two-dose series of Pfs25-EPA/Alhydrogel (16 μg), Pfs230D1-EPA/Alhydrogel (15 μg) or comparator, followed by Pfs25-EPA/Alhydrogel (16 μg) plus Pfs230D1-EPA/Alhydrogel (15 μg) or comparator plus saline. For the main cohort, we enrolled 200 participants between May 11 and June 2, 2015, to receive a four-dose series of 47 μg Pfs25-EPA/Alhydrogel plus saline (n=50 [25%]; Pfs25), 40 μg Pfs230D1-EPA/Alhydrogel plus saline (n=49 [25%]; Pfs230D1), 47 μg Pfs25-EPA/Alhydrogel plus 40 μg Pfs230D1-EPA/Alhydrogel (n=50 [25%]; Pfs25 plus Pfs230D1), or comparator (Twinrix or Menactra) plus saline (n=51 [25%]). Vaccinations were well tolerated in the pilot safety and main phases. Most vaccinees became seropositive after two Pfs230D1 or three Pfs25 doses; peak titres increased with each dose thereafter (Pfs230D1 geometric mean: 77·8 [95% CI 56·9–106·3], 146·4 [108·3–198·0], and 410·2 [301·6–558·0]; Pfs25 geometric mean 177·7 [130·3–242·4] and 315·7 [209·9–474·6]). Functional activity (mean peak transmission-reducing activity) appeared for Pfs230D1 (74·5% [66·6–82·5]) and Pfs25 plus Pfs230D1 (68·6% [57·3–79·8]), after the third dose and after the fourth dose (88·9% [81·7–96·2] for Pfs230D1 and 85·0% [78·4–91·5] Pfs25 plus Pfs230D1) but not for Pfs25 (58·2% [49·1–67·3] after the third dose and 58·2% [48·5–67·9] after the fourth dose). Pfs230D1 transmission-reducing activity (73·7% [64·1–83·3]) persisted 10 weeks after the fourth dose. Transmission-reducing activity of 80% was estimated at 1659 ELISA units for Pfs25, 218 for Pfs230D1, and 223 for Pfs230D1 plus Pfs25. After 3850 direct skin feed assays, 35 participants (12 Pfs25, eight Pfs230D1, five Pfs25 plus Pfs230D1, and ten comparator) had transmitted parasites at least once. The proportion of positive assays in vaccine groups (Pfs25 33 [3%] of 982 [–0·013 to 0·014], Pfs230D1 22 [2%] of 954 [–0·005 to 0·027], and combination 11 [1%] of 940 [–0·024 to 0·002]) did not differ from that of the comparator (22 [2%] of 974), nor did Pfs230D1 and combination groups differ (–0·024 to 0·001). Pfs230D1 but not Pfs25 vaccine induces durable serum functional activity in Malian adults. Direct skin feed assays detect parasite transmission to mosquitoes but increased event rates are needed to assess vaccine effectiveness. Intramural Research Program of the National Institute of Allergy and Infectious Diseases and US National Institutes of Health. [ABSTRACT FROM AUTHOR]