Citations

Introduction: Pulmonary arterial hypertension (PAH) is a fatal disease and vasodilators are the mainstay for its therapy. However, they offer restricted advancement opportunities for the control and treatment of PAH. Thus, the PAH field needs a paradigm-shifting strategy for its successful management and control. Objective: To test the hypothesis that gut microbial dysbiosis and its increased permeability are associated with PAH. Methods: Healthy control subjects and patients with PAH were recruited from two hospitals in the Americas to ascertain the wider applicability of our hypothesis. Fecal samples of PAH patients (n=19) and control, reference subjects (n=16) were obtained at the Hospital de Clinicas de Porto Alegre, Brazil, for microbiota analysis. Plasma/serum samples were collected from PAH patients (n=22) and control, reference subjects (n=19) at the Mayo Clinic, Jacksonville, Florida, USA, for analysis of gut leakiness and inflammatory biomarkers. Results: In PAH patients, a significant decrease in abundance, diversity and evenness of gut microbial population was observed as measured by 16S ribosomal DNA analyses of fecal samples. Analysis of fecal bacteria populations also demonstrated significant increases in gram-positive, facultative-anaerobic genera, such as Actinomyces, Bifidobacterium Slackia, and Streptococcus in PAH patients. Further, plasma zonulin and iFABP, the biomarkers for gut leakiness increased by 40.3% (p=0.0018) and 81% (p=0.0012), respectively in PAH patients. High plasma LPS, HMGB1, and TIMP1 levels are involved in increased gut inflammation and gut mucosal injury. We also observed LPS, HMGB1, and TIMP1 levels were increased by 363% (p=0.0096), 20.5% (p=0.0027), and 213% (p<0.0001), respectively in PAH patients. Conclusions: PAH patients demonstrate profound gut microbial dysbiosis and increased permeability and inflammation. Further characterization of PAH specific microbial species holds novel management potential with the use of pre- and probiotics, designer antibiotics, appropriate fecal/bacterial transplantation, on top of background proven therapies.

Introduction: The estimated prevalence of diabetes mellitus (DM) is 8.4% among adults in the U.S. Cardiovascular disease is a major complication of DM. We have observed that diabetic mice, but not non-diabetic mice, undergoing 2kidney-1clip (2K1C) surgery inducing renovascular hypertension had high mortality attributed to ruptured aortic aneurysm. However, the effect of diabetes on formation of aortic aneurysm remains unclear. Method: In our previous experiment, 163 mice were divided into 4 groups: leptin KO 2K1C (db 2K1C, n=52), leptin KO Sham (db Sham, n=20), wild type 2K1C (dbc 2K1C, n=62), and wild type Sham (dbc Sham, n=29), respectively. We found that 42% (22/52) of db 2K1C died, from ruptured aortic aneurysms examined by gross examination, within 120 days, while others survived 100%. In this study, available H&E aortic sections of survived mice (n=74): db 2K1C (n=30), db Sham (n=15), dbc 2K1C (n=20), and dbc Sham (n=9) were examined 2K1C surgery in a blinded fashion. Aortic lesions defined as necrosis, thrombosis and dropped-out smooth muscle cells, which are signs of early formation of aortic aneurysm, were identified. Inflammation was graded as mild, moderate and severe inflammation. Result: The db 2K1C mice had a significantly greater aortic lesions (16/30, 53%) compared to the db Sham (13/15, 20%); and dbc 2K1C mice (1/20, 5%), p=0.002 and 0.0001, respectively. The number of aortic lesions in the dbc 2K1C group was not statistically different from that of the dbc Sham group (p=0.5). Similarly, the number of aortic lesions in the db Sham group was not statistically different from that of the dbc Sham group (0/9, 0%), p=0.125. Moderate-to-severe inflammation in the tunica media was more prevalence in db mice than the dbc mice. Conclusion: We report for the first time an increased incidence of aortic lesions in db 2K1C compared to dbc and sham groups. This finding suggests that diabetes contributes to aortic aneurysm formation in mice with renal artery stenosis, potentially due to induction of inflammation. Further studies to confirm a mechanism are warranted.

Background: Combined renovascular hypertension (RVH) and type II diabetes (DM II) are a major health problem. Both share common risk factors and contribute to cardiovascular morbidity and mortality. We recently observed a high mortality rate in DM II mice (dbdb) with RVH. Purpose: We sought to determine the interactions between renovascular hypertension and DM II on the cardiovascular phenotype in dbdb mice with RVH. Methods and Materials: RVH was established by placing a polytetrafluoroethylene cuff on the right renal artery of C57BL/KS (wild type, WT) or dbdb mice. We divided the mice into four groups: WT sham, WT type RAS, dbdb sham, dbdb RAS. We examined the blood pressure, plasma angiotensin I, renin, heart weight and myocyte diameter. Histologic parameters including inflammation, necrosis and fibrosis were assessed semiquantitively. Results: Blood pressure, Renin, Plasma angiotensin I: RAS produced a similar elevation in systolic blood pressure (SBP), renin mRNA expression, and plasma angiotensin I content in WT and dbdb mice with RAS. Heart weight: Despite similar elevation in SBP, db/db RAS mice showed a greater increase in heart weight than WT RAS mice (163.7 +/- 6.4 mmHg vs 145.7 +/- 2.3; n=23).. Similar trends were observed on normalization of the heart weight to tibial length. Cardiac myocyte diameter: Cardiac myocyte diameter in WT RAS (n=26) was significantly higher than in WT sham (n=15; 16.4 ± 0.3 vs. 15.0 ± 0.3 μm, p=0.0031). Myocyte diameter was higher in dbdb RAS mice (n=19, 14.76 ± 0.35) than dbdb sham (15.94 ± 0.29 μm, p= 0.0126). However, myocyte diameter was similar in dbdb RAS and WT RAS mice (16.4 ± 0.3 vs. 15.9 ± 0.3 μm, p=0.3). Histology: Sham groups had no inflammation (INF) or necrosis (NEC). Interstitial fibrous tissue was increased in dbdb RAS mice (28% by area) vs WT RAS (19% by area). Dbdb RAS mice had more severe INF (severe in 18%, mild in 82%) than WT RAS (severe in 0%, jild in 12%). Severe NEC was found in 32.1% of dbdb compared to 11.5% of WT RAS. Conclusion: The histologic changes and hypertrophy of the heart superimpose in dbdb RAS compared to WT RAS. This indicates that the risk of cardiovascular morbidity and mortality increases synergisticly in the presence of DM II and RVH.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in developed countries. Kidney injuries related to CLL can occur via several mechanisms. Approximately 30%–40% of CLL patients with a kidney biopsy have monoclonal-protein related lesions. However, such lesions mostly involve glomeruli with only rare instances of tubule-interstitial disorders. There is only a single case report of a CLL patient who presented with crystalline light chain proximal tubulopathy (LCPT). Fanconi syndrome (FS) may provide clinical clues in these patients. We report a case of a CLL patient who presented with hypokalemia in the setting of advanced kidney failure in which serum monoclonal IgG kappa was detected. The patient demonstrated typical signs and symptoms of FS. The urinary retinol binding protein was also extremely elevated (638 times upper normal limit). A kidney biopsy revealed non-crystalline LCPT with CLL infiltration. FS in CLL is an extremely rare presentation, as only four cases had been previously reported. Of these, only a single case had crystalline LCPT. Our case is the first report of non-crystalline LCPT in a CLL patient. Obinutuzumab and Venetoclax were started to address the CLL, and an improvement in kidney function was noted thereafter.

AbstractThe Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID‐19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish‐speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health‐care services and to aid caregivers of Latinos living with AD.

AbstractMagnetic resonance imaging (MRI) is routinely used for preoperative tumor staging and to assess response to therapy in rectal cancer patients. The aim of our study was to evaluate the accuracy of MRI based restaging after neoadjuvant chemoradiotherapy (CRT) in predicting pathologic response. This multicenter cohort study included adult patients with histologically confirmed locally advanced rectal adenocarcinoma treated with neoadjuvant CRT followed by curative intent elective surgery between January 2014 and December 2019 at four academic high‐volume institutions. Magnetic resonance tumor regression grade (mrTRG) and pathologic tumor regression grade (pTRG) were reviewed and compared for all the patients. The agreement between radiologist and pathologist was assessed with the weighted k test. Risk factors for poor agreement were investigated using logistic regression. A total of 309 patients were included. Modest agreement was found between mrTRG and pTRG when regression was classified according to standard five‐tier systems (k = 0.386). When only two categories were considered for each regression system, (pTRG 0‐3 vs pTRG 4; mrTRG 2‐5 vs mrTRG 1) an accuracy of 78% (95% confidence interval [CI] 0.73‐0.83) was found between radiologic and pathologic assessment with a k value of 0.185. The logistic regression model revealed that “T3 greater than 5 mm extent” was the only variable significantly impacting on disagreement (OR 0.33, 95% CI 0.15‐0.68, P = .0034). Modest agreement exists between mrTRG and pTRG. The chances of appropriate assessment of the regression grade after neoadjuvant CRT appear to be higher in case of a T3 tumor with at least 5 mm extension in the mesorectal fat at the pretreatment MRI.

AbstractBackgroundStroke has been linked to a lack of physical activity; however, the extent of the association between inactive lifestyles and stroke risk has yet to be characterized across large populations.PurposeThis study aimed to explore the association between activity‐related behaviors and stroke incidence.MethodsData from 1999 to 2018 waves of the concurrent cross‐sectional National Health and Nutrition Examination Survey (NHANES) were extracted. We analyzed participants characteristics and outcomes for all participants with data on whether they had a stroke or not and assessed how different forms of physical activity affect the incidence of disease.ResultsOf the 102,578 individuals included, 3851 had a history of stroke. A range of activity‐related behaviors was protective against stroke, including engaging in moderate‐intensity work over the last 30 days (OR = 0.8, 95% CI = 0.7–0.9; P = 0.001) and vigorous‐intensity work activities over the last 30 days (OR = 0.6, 95% CI = 0.5–0.8; P < 0.001), and muscle‐strengthening exercises (OR = 0.6, 95% CI = 0.5–0.8; P < 0.001). Conversely, more than 4 h of daily TV, video, or computer use was positively associated with the likelihood of stroke (OR = 11.7, 95% CI = 2.1–219.2; P = 0.022).ConclusionDifferent types, frequencies, and intensities of physical activity were associated with reduced stroke incidence, implying that there is an option for everyone. Daily or every other day activities are more critical in reducing stroke than reducing sedentary behavior duration.

AbstractBackground & AimsMachine learning (ML) provides new approaches for prognostication through the identification of novel subgroups of patients. We explored whether ML could support disease sub‐phenotyping and risk stratification in primary biliary cholangitis (PBC).MethodsML was applied to an international dataset of PBC patients. The dataset was split into a derivation cohort (training set) and a validation cohort (validation set), and key clinical features were analysed. The outcome was a composite of liver‐related death or liver transplantation. ML and standard survival analysis were performed.ResultsThe training set was composed of 11,819 subjects, while the validation set was composed of 1,069 subjects. ML identified four clusters of patients characterized by different phenotypes and long‐term prognosis. Cluster 1 (n = 3566) included patients with excellent prognosis, whereas Cluster 2 (n = 3966) consisted of individuals at worse prognosis differing from Cluster 1 only for albumin levels around the limit of normal. Cluster 3 (n = 2379) included young patients with florid cholestasis and Cluster 4 (n = 1908) comprised advanced cases. Further sub‐analyses on the dynamics of albumin within the normal range revealed that ursodeoxycholic acid‐induced increase of albumin >1.2 x lower limit of normal (LLN) is associated with improved transplant‐free survival.ConclusionsUnsupervised ML identified four novel groups of PBC patients with different phenotypes and prognosis and highlighted subtle variations of albumin within the normal range. Therapy‐induced increase of albumin >1.2 x LLN should be considered a treatment goal.

Introduction : Fetal posterior cerebral artery (FPCA) occlusion is a rare but potentially disabling cause of stroke. While endovascular treatment is established for acute large vessel occlusion (LVO) stroke, FPCA occlusions were excluded from acute ischemic stroke trials. We aim to report the feasibility, safety and outcome of mechanical thrombectomy (MT) in acute FPCA occlusions. Methods : We performed a multi‐center retrospective review of consecutive patients who underwent MT of acute FPCA occlusion. Primary FPCA occlusion was defined as an occlusion that was identified on the pre‐procedure CT angiogram or baseline angiogram whereas a secondary FPCA occlusion was defined as an occlusion that occurred secondary to embolization to a new territory after recanalization of a different LVO. Demographics, clinical presentation, imaging findings, endovascular treatment and outcome were reviewed. Results : There were twenty‐five patients with acute FPCA occlusion who underwent MT, distributed across 14 centers. Median NIHSS on presentation was 16. There were 76% (19/25) of patients who presented with primary FPCA occlusion and 24% (6/25) of patients who had a secondary FPCA occlusion. The configuration of the FPCA was full in 64% patients and partial or “fetal‐type” in 36% of patients. FPCA occlusion was missed on initial CTA in 21% of patients with primary FPCA occlusion (4/19). The site of occlusion was posterior communicating artery in 52%, P2 segment in 40% and P3 in 8% of patients. TICI 2b/3 reperfusion was achieved in 96% of FPCA patients. There were no intra‐procedural complications. At 90 days, 48% (12/25) were functionally independent as defined by mRS≤2. Conclusions : Endovascular treatment of acute FPCA occlusion is safe and technically feasible. A high index of suspicion is important to detect occlusion of the fetal posterior cerebral artery in patients presenting with anterior circulation stroke syndrome and patent anterior circulation.