Citations

Spontaneous coronary artery dissection (SCAD) is increasingly recognized as an important cause of acute coronary syndrome (ACS) and myocardial infarction (MI) in individuals with few or no known atherosclerotic risk factors. While systemic autoimmune inflammatory disorders are associated with precipitating SCAD, the role of infection-induced systemic inflammation in SCAD is not well defined. We present the case of a 49-year-old Caucasian woman with ST-elevation myocardial infarction (STEMI) diagnosed as SCAD from a severe systemic inflammatory response related to disseminated blastomycosis. Punch biopsy of a skin lesion and synovial fluid culture confirmed Blastomyces dermatitidis. This case suggests the possibility of systemic infection-induced inflammation as a precipitating factor in SCAD pathogenesis similar to autoimmune inflammatory disorders.

Abstract Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values<5x10-8 as genome-wide significant, and p-values<1x10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values<1x105. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.

Abstract Coccidioidomycosis is an endemic fungal infection that is typically asymptomatic or associated with pulmonary disease. Extrapulmonary disease may involve the skin, bones, or central nervous system, yet endovascular infections are exceedingly rare. We report the first case, to our knowledge, of coccidioidomycosis of the native aorta in an immunocompromised host.

Introduction: The mechanisms linking obesity to increased mortality in patients with coronavirus-disease 2019 (COVID-19) are unclear. Hypothesis: We hypothesised that obesity would be associated with adverse right ventricular (RV) remodelling and function which might be further exacerbated by COVID-19 associated increases in RV afterload/demand. Methods: We used echocardiography and computed tomography to establish links between RV dimensions and function and bodyweight in patients with severe COVID-19. In obese and non-obese participants without COVID-19, we used cardiovascular magnetic resonance to define the effects of obesity upon RV volumes, energetics, systolic function and stress reserve. Results: In patients with severe COVID-19, increasing bodyweight was associated with disproportionate RV dilatation (n=26, echocardiography, R=0.42, P=0.03, CT n=34, R=0.23, P=0.004) and impairment of RV systolic function (fractional area change (FAC) R=-0.45, P=0.04); obesity (BMI >30kg/m2) was associated with a 32% reduction in RV FAC (P=0.03). Similar associations were seen in a validation cohort (n=91, all P<0.05). In participants without COVID-19, class III obesity (n=54, BMI 47±4 kg/m 2 ) was associated with RV remodelling, impaired cardiac energetics (PCr/ATP ratio 23% lower, P<0.001) and reduction in RV systolic function at rest (by 3±1%, P=0.01), which was related to reduced energetics (R=0.3, P=0.04). Participants with class I-II obesity (BMI 35±5 kg/m 2 , n=27) had impaired RV diastolic filling rate at rest (P<0.001) and blunted RV dobutamine stress systolic response (by 68%, P=0.03) and diastolic response (by 78%, P=0.008). Surgical weight loss in patients obesity (n=37, 34±15kg weight loss) was associated with improvement in RV volume (12±26 ml lower, P=0.006) and function (ejection fraction 2±5% higher, P=0.03). Conclusions: Increasing body weight is associated with both significant alterations in RV volumes, systolic function and stress responses which are mitigated with weight loss and also with disproportionate RV dilatation and dysfunction in severe COVID-19. RV dysfunction is a modifiable mechanism which might link obesity to adverse outcomes in patients with COVID-19 and other disorders stressing the right heart.

Objective Effective medical therapy and validated trial outcomes are lacking for small bowel Crohn’s disease (CD) strictures. Histopathology of surgically resected specimens is the gold standard for correlation with imaging techniques. However, no validated histopathological scoring systems are currently available for small bowel stricturing disease. We convened an expert panel to evaluate the appropriateness of histopathology scoring systems and items generated based on panel opinion. Design Modified RAND/University of California Los Angeles methodology was used to determine the appropriateness of 313 candidate items related to assessment of CD small bowel strictures. Results In this exercise, diagnosis of naïve and anastomotic strictures required increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa. Specific definitions for stricture features and technical sampling parameters were also identified. Histopathologically, a stricture was defined as increased thickness of all layers of the bowel wall, fibrosis of the submucosa and bowel wall, and muscularisation of the submucosa. Active mucosal inflammatory disease was defined as neutrophilic inflammation in the lamina propria and any crypt or intact surface epithelium, erosion, ulcer and fistula. Chronic mucosal inflammatory disease was defined as crypt architectural distortion and loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, plasmacytosis and fibrosis, or prominent lymphoid aggregates at the mucosa/submucosa interface. None of the scoring systems used to assess CD strictures were considered appropriate for clinical trials. Conclusion Standardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development.

Background and purpose: In-hospital stroke-onset assessment and management present numerous challenges, especially in community hospitals. Comprehensive analysis of key stroke care metrics in community-based primary stroke centers is under-studied. Methods: Medical records were reviewed for patients admitted to a community hospital for non-cerebrovascular indications and for whom a stroke alert was activated between 2013 and 2019. Demographic, clinical, radiologic and laboratory information were collected for each incident stroke. Descriptive statistical analysis was employed. When applicable, Kruskal-Wallis and Chi-Square tests were used to compare median values and categorical data between pre-specified groups. Statistical significance was set at alpha = 0.05. Results: There were 192 patients with in-hospital stroke-alert activation; mean age (SD) was 71.0 years (15.0), 49.5% female. 51.6% (99/192) had in-hospital ischemic and hemorrhagic stroke. The most frequent mechanism of stroke was cardioembolism. Upon stroke activation, 45.8% had ischemic stroke while 40.1% had stroke mimics. Stroke team response time from activation was 26 minutes for all in-hospital activations. Intravenous thrombolysis was utilized in 8% of those with ischemic stroke; 3.4% were transferred for consideration of endovascular thrombectomy. In-hospital mortality was 17.7%, and the proportion of patients discharged to home was 34.4% for all activations. Conclusion: The in-hospital stroke mortality was high, and the proportions of patients who either received or were considered for acute intervention were low. Quality improvement targeting increased use of acute stroke intervention in eligible patients and reducing hospital mortality in this patient cohort is needed.

Purpose To describe the complications that occur following biologic therapeutic injections. Methods We queried physician members of the Biologic Association, a multidisciplinary organization dedicated to providing a unified voice for all matters related to musculoskeletal biologics and regenerative medicine. Patients included in this study must have (1) received a biologic injection, (2) sustained an adverse reaction, and (3) had a minimum of 1‐year follow‐up after the injection. Patient demographic information, medical comorbidities, diagnoses, and previous treatments were recorded. The type of injection, injection setting, injection manufacturers, and specific details about the complication and outcome were collected. Results In total, 14 patients were identified across 6 institutions in the United States (mean age 63 years, range: 36‐83 years). The most common injections in this series were intra‐articular knee injections (50%), followed intra‐articular shoulder injections (21.4%). The most common underlying diagnosis was osteoarthritis (78.5%). Types of injections included umbilical cord blood, platelet‐rich plasma, bone marrow aspirate concentrate, placental tissue, and unspecified “stem cell” injections. Complications included infection (50%), suspected sterile inflammatory response (42.9%), and a combination of both (7.1%). The most common pathogen identified from infection cases was Escherichia coli (n = 4). All patients who had isolated infections underwent treatment with at least one subsequent surgical intervention (mean: 3.6, range: 1‐12) and intravenous antibiotic therapy. Conclusions This study demonstrates that serious complications can occur following treatment with biologic injections, including infections requiring multiple surgical procedures and inflammatory reactions. Level of Evidence Level IV, case series.

Abstract Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on nine of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 in families 42 and 44, 6q25.2-25.3 in families 47 and 59, and 6q24.2-25.1 in families 30, 33, and 35. Region-based logarithm of the odds scores and expression data identified the likely candidate genes for each haplotype overlap: ARID1B at 6q25.3, MAP3K4 at 6q26, and UTRN (6q24.1) and PHACTR2 (6q24.2). Further annotation was used to zero in on potential risk variants in those genes. All four genes are good candidate genes for lung cancer risk, having been linked to either lung cancer specifically or other cancers. However, this is the first time any of these genes has been implicated in germline risk. Functional analysis of these four genes is planned for future work. Significance: This study identifies four genes associated with lung cancer risk, which could help guide future lung cancer prevention and treatment approaches.

Objective: Preeclampsia is a cardiovascular complication characterised by the new onset of hypertension and proteinuria or other end-organ dysfunction. Currently there are no effective treatments for preeclampsia except delivery of the placenta and the baby, often pre-term. Administration of mesenchymal stem cells (MSCs) has shown therapeutic potential in pre-clinical models of preeclampsia. In this study, we aimed to identify novel placental miRNAs in preeclampsia which could be targeted by MSCs or their extracellular vesicles (MSC-EVs). Design and method: Human MSCs were isolated from abdominal fat tissue during caesarean section and cultured for 48 h. Human umbilical cord endothelial cells (HUVEC) were co-cultured with MSCs from pregnancies with or without preeclampsia (n = 3) up to 90 h and angiogenesis assessed using tubule formation assay in IncuCyteu live cell imaging system. Using separate patient samples, miRNA was isolated from placentae from women with and without preeclampsia (n = 2) and miRNA next generation sequencing (miRNAseq) performed. The expression of two miRNAs identified in miRNAseq (miRNA-183–5p and miRNA-203a-3p) were measured in HUVEC cells exposed to 24 h hypoxia (1%) or normoxia (21%) in the presence of MSC conditioned medium (MSC-CM) or MSC-EVs. Results: MSCs isolated from women with preeclampsia demonstrated impaired pro-angiogenic profile compared to MSCs derived from normotensive pregnancies measured by the network length (mm/m2) of HUVECs following 66 h, 72 h, 78 h, 84 h and 90 h of exposure to MSC-CM (n = 3, p = 0.001). The results of miRNAseq identified a number of aberrantly expressed miRNAs including mir-183–5p (logFC = -2.8, p = 0.001) and mir-203a-3p (logFC = -6.7, p = 0.001). Following exposure of HUVECs to hypoxia, mir-183–5p was significantly increased by approximately 8-fold (p = 0.001) whereas mir-203a-3p showed no change in expression. MSC-CM and MSC-EVs were both capable of ameliorating this increase in mir-183–5p as a result of hypoxia (p = 0.01, MSC-CM; p = 0.001, MSC-EVs). Conclusions: In patients with preeclampsia, MSCs show impaired angiogenic function, potentially leading to inappropriate placental development and angiogenesis in pregnancy. Administration of healthy MSCs or associated MSC-EVs could have a therapeutic potential in the treatment of preeclampsia and the mechanism could involve novel mir-183–5p as a treatment target.