First-in-man report of transsubclavian venous implantation of the Aveir leadless cardiac pacing system.

INTRODUCTION: Transsubclavian venous implantation of the Aveir leadless cardiac pacemaker (LCP) has not been previously reported. METHODS AND RESULTS: Three cases of transsubclavian implantation of the Aveir LCP are reported. Two cases were postbilateral orthotopic lung transplant, without appropriate femoral or jugular access due to recent ECMO cannulation and jugular central venous catheters. In one case, there was strong patient preference for same-day discharge. Stability testing confirmed adequate fixation and electrical testing confirmed stable parameters in all cases. All patients tolerated the procedure well without significant immediate complications. CONCLUSIONS: We demonstrate the feasibility of transsubclavian implantation of the Aveir LCP.

Relapse Prevention with Tyrosine Kinase Inhibitors after Allogeneic Transplantation for Philadelphia Chromosome-Positive Acute Lymphoblast Leukemia: A Systematic Review.

Relapse after stem cell transplantation for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) remains a significant challenge. In this systematic review, we compare survival outcomes of second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib with first-generation TKI imatinib when these agents are used after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Ph+ ALL. In addition, we review the literature on TKI use to prevent relapse in patients who proceed to allo-HSCT beyond first complete response (>CR1). We performed database searches (inception to January 2018) using PubMed, Cochrane Library, and Embase. After exclusions, 17 articles were included in this analysis. Imatinib was used post-transplant either prophylactically or preemptively in 12 studies, 7 prospective studies and 5 retrospective studies. Overall survival (OS) for most prospective studies at 1.5 to 3 and 5 years ranged between 62% to 92% and 74.5% to 86.7%. Disease-free survival at 1.5 to 5 years was 60.4% to 92%. Additionally, imatinib failed to show survival benefit in patients who were >CR1 at the time of allo-HSCT. The cumulative OS for most retrospective studies using imatinib at 1 to 2 and 3 to 5 years was 42% to 100% and 33% to 40% respectively. Event-free survival at 1 to 2 and 3 to 5 years was 33.3% to 67% and 20% to 31% respectively. Dasatinib was used as maintenance treatment in 3 retrospective studies (n = 34). The OS for patients with Ph+ ALL using dasatinib as maintenance regimen after allo-HSCT at 1.4 to 3 years was 87% to 100% and disease-free survival at 1.4 to 3 years was 89% to 100%. Ninety-three percent of patients with minimal residual disease (MRD) positive status after allo-HSCT became MRD negative. Three prospective studies used nilotinib. In 2 studies where investigators studied patients with advanced chronic myeloid leukemia and Ph+ ALL, the cumulative OS and event-free survival at 7.5 months to 2 years were 69% to 84% and 56% to 84%, respectively. In the third study (n = 5) in patients with Ph+ ALL, nilotinib use resulted in OS at 5 years of 60%. Our review showed that use of TKIs (all generations) after allo-HSCT for patients in CR1 improved OS when given as a prophylactic or preemptive regimen. Limited data suggest that second-generation TKIs (ie, dasatinib) have a better OS, especially in patients with MRD-positive status. Imatinib did not improve OS in patients who were >CR1 at the time of allo-HSCT; for this population, no data were available with newer generation TKIs. The evaluation of survival benefit with newer generation TKIs and their efficacy in patients in >CR1 needs further study in large randomized clinical trials.

Increased Prevalence of Obesity and Metabolic Syndrome in Patients with Alcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Obesity and diabetes are risk factors for advanced alcoholic liver disease, and both are components of the metabolic syndrome. We aimed to assess the prevalence of metabolic syndrome and its components in a contemporary US cohort of adults with alcoholic liver disease and compare it to a historic cohort to assess changes over time. METHOD: Individuals 18 years or older who participated in the National Health and Nutrition Examination Survey during 2009-2014 and 1999-2001 were used as the contemporary and historic cohort, respectively. Alcoholic liver disease was defined as excessive alcohol consumption (men: ≥ 3 drinks/day; women: ≥ 2 drinks/day) and elevated alanine aminotransferase. Metabolic syndrome definition was based on the updated International Diabetes Federation criteria. Data are presented as mean ± standard error or unweighted frequency. A logistic regression analysis was performed to assess differences in metabolic syndrome components between the two period cohorts while adjusting for central obesity. RESULTS: The mean age for our contemporary cohort was 41.9, 66.1% being male. Central obesity was present in 66.3%, type 2 diabetes in 18.7%, low high-density lipoprotein in 28.3%, hypertriglyceridemia in 44.8%, and hypertension in 54.7%. 36.9% met the criteria for metabolic syndrome. Compared to the historic cohort, patients in the contemporary cohort were more likely to have central obesity (50% vs. 66%, p = 0.002), metabolic syndrome (26% vs. 37%, p = 0.044), and type 2 diabetes (12% vs. 19%, p = 0.099). CONCLUSIONS: Prevalence of both obesity and metabolic syndrome is increasing in alcoholic liver disease patients. Further studies are required to investigate effective interventions to avoid disease progression in these high-risk patients.

Indolylkojyl methane analogue IKM5 potentially inhibits invasion of breast cancer cells via attenuation of GRP78.

PURPOSE: More than 90% of the breast cancer deaths occur due to the metastasis of the cancer cells to secondary organ sites. Increased Glucose-regulated protein 78 (GRP78) expression is critical for epithelial-mesenchymal transition (EMT) and invasion in breast cancer resulting in poor patient survival outcomes. Therefore, there is an urgent need of potential inhibitors of GRP78 for the abrogation of invasion and metastasis in breast cancer. METHODS: We investigated the effect of IKM5 (2-(1-(1H-indol-3-yl)octyl)-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one) (a novel Indolylkojyl methane analogue) on invasion abilities of human breast cancer cells employing invadopodia formation, Matrigel invasion assays, and mouse models for metastasis. The mechanism underlying the anti-invasive effect of IKM5 was examined through molecular docking, immunoblotting, immunocytochemistry, co-immunoprecipitation analysis, siRNA silencing, and sub-cellular fractionation studies. RESULTS: Treatment with IKM5 at its sub-toxic concentration (200 nM) suppressed invasion and invadopodia formation, and growth factor-induced cell scattering of aggressive human breast cancer MDA-MB-231, MDA-MB-468, and MCF7 cells. IKM5 spontaneously binds to GRP78 (Ki = 1.35 µM) and downregulates its expression along with the EMT markers MMP-2, Twist1, and Vimentin. Furthermore, IKM5 amplified the expression and nuclear translocation of tumor suppressor Par-4 to control NF-kB-mediated pro-EMT activities. Interestingly, IKM5 disrupts the interaction between GRP78 and TIMP-1 by inhibiting GRP78 in a Par-4-dependent manner. Moreover, IKM5 inhibited tumor growth and lung metastasis at a safe dose of 30 mg/kg/body weight. CONCLUSION: Our study warrants IKM5, a potential anticancer agent that can abrogate invasion and metastasis, suggesting its clinical development for the treatment of patients with advanced breast cancer.

Par-4 dependent modulation of cellular ß-catenin by medicinal plant natural product derivative 3-azido Withaferin A.

Here, we provide evidences that natural product derivative 3-azido Withaferin A (3-AWA) abrogated EMT and invasion by modulating ß-catenin localization and its transcriptional activity in the prostate as well as in breast cancer cells. This study, for the first time, reveals 3-AWA treatment consistently sequestered nuclear ß-catenin and augmented its cytoplasmic pool as evidenced by reducing ß-catenin transcriptional activity in these cells. Moreover, 3-AWA treatment triggered robust induction of pro-apoptotic intracellular Par-4, attenuated Akt activity and rescued Phospho-GSK3ß (by Akt) to promote ß-catenin destabilization. Further, our in vitro studies demonstrate that 3-AWA treatment amplified E-cadherin expression along with sharp downregulation of c-Myc and cyclin D1 proteins. Strikingly, endogenous Par-4 knock down by siRNA underscored 3-AWA mediated inhibition of nuclear ß-catenin was Par-4 dependent and suppression of Par-4 activity, either by Bcl-2 or by Ras transfection, restored the nuclear ß-catenin level suggesting Par-4 mediated ß-catenin regulation was not promiscuous. In vivo results further demonstrated that 3-AWA was effective inhibitor of tumor growth and immunohistochemical studies indicated that increased expression of total ß-catenin and decreased expression of phospho-ß-catenin and Par-4 in breast cancer tissues as compared to normal breast tissue suggesting Par-4 and ß-catenin proteins are mutually regulated and inversely co-related in normal as well as cancer condition. Thus, strategic regulation of intracellular Par-4 by 3-AWA in diverse cancers could be an effective tool to control cancer cell metastasis. Conclusively, this report puts forward a novel approach of controlling deregulated ß-catenin signaling by 3-AWA induced Par-4 protein.

Impact of Persistent Versus Paroxysmal Preoperative Atrial Fibrillation on In-Hospital, One-Year, and Late Clinical Outcomes Following Transcatheter Aortic Valve Implantation.

Previous reports on the impact of preexisting atrial fibrillation (AF) on clinical outcomes after transcatheter aortic valve implantation (TAVI) have presented limited data on the relative impact of paroxysmal versus persistent AF subtypes. We compared in-hospital, 1-year, and late clinical outcomes in 1,098 patients who underwent TAVI with preoperative AF (556 paroxysmal, 542 persistent) versus 1,787 patients without AF. The propensity-matched cohorts with AF (n = 643) and without AF (n = 686) did not differ with respect to baseline clinical characteristics, operative technique, or in-hospital TAVI complications. At 1-year, patients with AF had higher all-cause mortality (9.0% vs 6.1%, p = 0.046) and readmission rates (13.1 vs 8.8%, p = 0.014), with lower Kansas City cardiomyopathy questionnaire scores (77.8 ± 21.8 vs 84.3 ± 17.1, p <0.001). Echocardiographic follow-up (mean time 455 ± 285 days) demonstrated no significant intergroup differences in hemodynamic findings other than a progressive increase in left atrial volume index in patient subgroups (without AF: 37.4 ± 14.7 ml/m2 vs paroxysmal AF: 46.4 ± 21.4 ml/m2 vs persistent AF: 60.5 ± 26.3 ml/m2, p <0.001). On late follow-up (mean time 49.0 [45.1 to 52.9] months), patients with persistent AF had worse all-cause mortality than patients without AF (hazard ratio 1.55, 95% confidence interval 1.17 to 2.06, p = 0.003), with no significant survival differences between the paroxysmal AF and without AF subgroups. In conclusion, patients with preexisting AF and patients without AF who underwent TAVI had similar in-hospital outcomes but worse 1-year mortality, hospital readmission, and quality of life outcomes. Compared with patients without AF, patients with persistent but not paroxysmal preexisting AF have higher late all-cause mortality at a mean follow-up of 49 months. Patients with persistent AF have higher levels of left atrial volume index than patients with paroxysmal AF and patients without AF on intermediate echocardiographic follow-up.

Acute aortic dissection in the Marfan syndrome during the COVID-19 epidemic.

A 17-year-old boy with a recent diagnosis of COVID-19 infection was admitted with acute chest pain due to type A aortic dissection and was subsequently diagnosed with the Marfan syndrome. Literature shows an increased rate of aortic dissection during flu season. The hypothesis is that a cytokine storm triggers the dissection.

Impact of the Miocene orogenesis on Kaloula spp. radiation and implication of local refugia on genetic diversification.

The phylogeography of the Kaloula genus in East Asia is still poorly understood. One of the difficulties is the absence of fossils to corroborate molecular dating estimates. Here, we examined the mitochondrial structure of Kaloula spp. in East Asia and focused on the impact of glaciations on the northernmost species: Kaloula borealis. We determined the phylogenetic relationships, molecular dating, and genetic connectivity assessments within the genus from 1211 bp of concatenated mitochondrial 12S and 16S. The relaxed clock analyses reveal the emergence of Kaloula spp. common ancestor in East and Southeast Asia between the Eocene and Oligocene, c. 38.47 Ma (24.69-53.65). The genetic diversification of lineages then increased on the East Asian Mainland during the Lower Miocene, c. 20.10 (8.73-30.65), most likely originating from the vicariance and radiation triggered by the orogeny of the Qinghai-Tibetan Plateau. Later, the dispersal towards the North East Asian Mainland during the Upper Miocene drove the population diversification of K. borealis c. 9.01 Ma (3.66-15.29). Finally, the central mainland population became isolated following orogenesis events and diverged into K. rugifera during the Pliocene, c. 3.06 Ma (0.02-10.90). The combination of population genetic and barrier analyses revealed a significant genetic isolation between populations of Kaloula spp. matching with the massive Qinling-Daba Mountain chain located in south-central China. Finally, we highlight a young divergence within the Eastern Mainland population of K. borealis, possibly attributed to refugia in south eastern China from which populations later expanded.

A guide to diagnosing and managing ascites in cirrhosis.

Combined serum and ascites fluid measurements point to the cause of ascites. For patients with modest edema, a reduced weight-loss target with diuresis may be acceptable.

Role of platelet-albumin-bilirubin score in predicting re-bleeding after band ligation for acute variceal hemorrhage.

Platelet-albumin-bilirubin (PALBI) score was proposed by Roayaie et al with modification of previously studied albumin-bilirubin score to include platelet as an indicator of portal hypertension in 2015. Predictive value of this score was recently tested by Elshaarawy et al for re-bleeding in patients presenting with acute variceal hemorrhage. We did a similar study at our center (n = 170) to look at incidence of re-bleeding after band ligation defined as drop in 2 units of hemoglobin and witnessed melena or hematemesis within 2 wk of the procedure. We calculated PALBI scores for all patients based on lab values prior to the procedure. Of 25.3% had re-bleeding episodes, area under receiver operating characteristic curve for PALBI as predictor of re-bleeding was 0.601 (95% confidence interval: 0.502-0.699). PALBI score showed moderate accuracy at predicting re-bleeding in our population.

Medications in type-2 diabetics and their association with liver fibrosis.

BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NAFLD) is significantly rising worldwide. Type-2 diabetes (T2D) is a major risk factor for NAFLD progression. AIM: To assess the association of commonly used medications to advanced fibrosis (AF) in patients with biopsy-proven NAFLD and T2D. METHODS: We used the International Classification of Disease 9th Revision Clinical Modification coding system to identify patients with T2D and included patients who underwent liver biopsy for suspected NAFLD between January 1, 2000 to December 31, 2015. We compared demographics, clinical characteristics, and differences in pattern of medication use in patients who had biopsy-proven AF to those without it. A univariate and multivariate analysis was performed to assess the association of different classes of medication with the presence of AF. RESULTS: A total of 1183 patients were included in the final analysis, out of which 32% (n = 381) had AF on liver biopsy. Mean age of entire cohort was 52 years and majority were females (65%) and Caucasians (85%). Among patients with AF, 51% were on oral hypoglycemics, 30% were on insulin, 66% were on antihypertensives and 27% were on lipid lowering agents for the median duration of 19 mo, 10 mo, 26 mo, and 24 mo respectively. Medications associated with decreased risk of AF included metformin, liraglutide, lisinopril, hydrochlorothiazide, atorvastatin and simvastatin while the use of furosemide and spironolactone were associated with higher prevalence of AF. CONCLUSION: In our cohort of T2D with biopsy proven NAFLD, the patients who were receiving metformin, liraglutide, lisinopril, hydrochlorothiazide, atorvastatin and simvastatin were less likely to have AF on biopsy, while patients who were receiving furosemide and spironolactone had a higher likelihood of having AF when they underwent liver biopsy. Future studies are needed to confirm these findings and to establish measures for prevention of NAFLD progression in patients with T2D.

Stress Cardiomyopathy in Association with Severe Agitation in Dementia.

Stress cardiomyopathy is a reversible left ventricular systolic dysfunction in the setting of intense emotional and physical trauma. It has rarely been described in association with the agitated state of dementia. We describe the case of a 78-year-old female with dementia who was diagnosed with stress cardiomyopathy in the setting of worsening agitation. This case underscores the importance of recognizing the non-specific manifestations of stress cardiomyopathy in this subset of patient population.

Stage IV Non-small Cell Lung Cancer Presenting as Supraventricular Tachycardia.

Despite numerous advancements in diagnostics and treatment, lung cancer carries a high mortality rate. This is primarily attributable to the fact that the majority of patients present with stage III or IV disease and otherwise non-specific symptoms. In this article, we discuss a rare case of stage IV lung cancer presenting as supraventricular tachycardia secondary to cardiomediastinal involvement. Unfortunately, by the time the tumor had involved the mediastinum, surgical options were limited and treatment was largely palliative.

A Large Pericardial Effusion Culminating in Left Lung Collapse.

Pericardial effusion is characterized by excess fluid accumulation in the pericardium. It can be asymptomatic or silent when the effusion is trivial in size or develops slowly. On the other hand, large rapidly developing effusions may present with hemodynamic instability or tamponade. In rare circumstances when a large effusion develops over a period of time, it may cause compression atelectasis of the surrounding bronchi and lung. We describe the case of a 70-year-old female who presented with acute respiratory insufficiency due to left lung collapse secondary to large pericardial effusion. To our knowledge, this is an extremely rare complication of large pericardial effusion.

Lambl's Excrescences: An Enigma of Modern Diagnostic Cardiology.

Lambl's excrescences were first described in 1856 by a Bohemian physician, Vilém Dusan Lambl, and since then have gained widespread attention and controversy within the medical literature. Despite numerous case reports and observational studies, consensus on the significance and management of Lambl's excrescences remains sparse. We describe the case of a 48-year-old male who presented with recurrent embolic strokes. No underlying paroxysmal arrhythmia or inter-atrial shunt was identified, and the only pathological finding was a 1-mm aortic valve strand. We managed this patient successfully using a novel oral anticoagulant.

Resection of early esophageal neoplasms: The pendulum swings from surgical to endoscopic management.

Esophageal cancer is a highly lethal disease and is the sixth leading cause of cancer related mortality in the world. The standard treatment is esophagectomy which is associated with significant morbidity and mortality. This led to development of minimally invasive, organ sparing endoscopic therapies which have comparable outcomes to esophagectomy in early cancer. These include endoscopic mucosal resection and endoscopic submucosal dissection. In early squamous cell cancer, endoscopic submucosal dissection is preferred as it is associated with cause specific 5-year survival rates of 100% for M1 and M2 tumors and 85% for M3 and SM1 tumors and low recurrence rates. In early adenocarcinoma, endoscopic resection of visible abnormalities is followed by ablation of the remaining flat Barrett's mucosa to prevent recurrences. Radiofrequency ablation is the most widely used ablation modality with others being cryotherapy and argon plasma coagulation. Focal endoscopic mucosal resection followed by radiofrequency ablation leads to eradication of neoplasia in 93.4% of patients and eradication of intestinal metaplasia in 73.1% of patients. Innovative techniques such as submucosal tunneling with endoscopic resection are developed for management of submucosal tumors of the esophagus. This review includes a discussion of various endoscopic techniques and their clinical outcomes in early squamous cell cancer, adenocarcinoma and submucosal tumors. An overview of comparison between esophagectomy and endoscopic therapy are also presented.

Differential regulation of NM23-H1 under hypoxic and serum starvation conditions in metastatic cancer cells and its implication in EMT.

Multiple stresses are prevalent inside the tumor microenvironment rendering tumor growth, neighboring invasion and metastasis of the cancer cells to distant organs. NM23-H1 is the first metastasis suppressor gene identified and known to be implicated as an important regulator of stress-induced metastasis. Herein, we demonstrated that prototypical NM23-H1 expression diminished during hypoxia and serum starvation in Panc-1/MDA-MB-231 cells, but converse invasion patterns were obtained in these two diverse stresses. Supportingly, a compelling discrete difference in mRNA and protein levels of NM23-H1 was achieved in hypoxia as well as serum starvation. Knockdown of NM23-H1 activates EMT whereas the similar effects are subdued in serum starvation where NM23-H1 down-modulation prompted E-cadherin upregulation. Stable NM23-H1 expression augmented E-cadherin levels along with retardation in invadopodea formation and invasion. In hypoxia/serum starvation excess NM23-H1 effectively modulated the Twist1 promoter activity. Thus, differential regulation of NM23-H1 may corroborate/abrogate EMT depending on the nature of stress, tumor microenvironment and cellular context.