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Background: Crohn′s disease is being increasingly reported from Saudi Arabia and information about its pattern is still accumulating. Aim of the study: To describe and classify the disease and assess the response to therapy in patients referred to a tertiary care centre in Gassim region, Kingdom of Saudi Arabia (KSA). Patients and Methods: Fifteen Saudi patients found to have Crohn′s disease over an eight-year period were studied. The presenting symptoms, area of involvement and the response to therapy were assessed. Results: There were five males and ten females. The age of 14 patients was less than 40 years. Symptoms had existed for more than one year before diagnosis in 14 patients. Common symptoms were diarrhea, pain during defecation, blood in stool and weight loss. The ileum was involved in three patients, the colon in four and the involvement was ileocolonic in eight patients. The behavior of the disease was non-stricturing nonpenetrating in eight, stricturing in two, penetrating in one and stricturing as well as penetrating in four patients. Three patients presented as acute appendicitis, four as intestinal obstruction and five with perianal disease. Histological diagnosis was possible in 12 patients. Thrombocytosis was present in seven patients and three had episodes of deep vein thrombosis. Eight patients responded to medical therapy. Surgical intervention was necessary in seven patients and three had multiple operations. One patient died during a median follow-up period of 18 months (range: 6 months to 8 years). Conclusion: Crohn′s disease occurs more commonly in young Saudi females. Patients are symptomatic for almost a year prior to diagnosis. The presentation is variable and response to therapy is satisfactory. Surgery is necessary in a high number of patients

Background: Ulcerative colitis (UC) is being reported more frequently among the Arabs. Information on the clinical severity, endoscopic and histological grading is scanty. Aim: To assess the severity of the disease and its response to therapy in patients referred to a tertiary care referral centre in Gassim region, Kingdom of Saudi Arabia (KSA). Patients and Method: Hospital records of thirty-four patients found to have UC from 1990-2002 were analyzed. The study included clinical severity, endoscopical and histological assessment, response to therapy and frequency of complications. Results: There were 21 males and 13 females with median age 35 (range: 18-76) years. The disease was clinically mild in seven patients (21%), moderate in 11 (32%) and severe in 16 (47%). Endoscopically UC was graded as 2 in three patients (9%), 3 in 21 patients (59%) and 4 in ten patients (29%). Histologically UC was mild to moderate in 11 patients (32%) and severe in 23 (68%). Extent of UC was total in nine patients (26%), up to transverse colon in six (18%), splenic flexure in 14 (41%), rectosigmoid region in four (12%) and only up to the rectum in one (3%). Twenty-nine patients (85%) were treated with salazopyrine and five patients (15%); (two of them were hypersensitive to salazopyrine) received 5-aminosalicylic acid. Proctocolectomy was performed in two with a focus of malignancy. No patient died during the median follow-up period of 48 months (range: 4 months to 12 years). Conclusion: Ulcerative colitis presented with varying severity, more frequently in males in the population studied. Most of the patients responded to salazopyrine and surgery was necessary when malignancy was detected

Background: Hybrid Convergent ablation for atrial fibrillation (AF) combines minimally invasive surgical (epicardial) and catheter (endocardial) ablation. The procedural goal is to achieve more extensive, enduring ablation of AF substrate around the pulmonary veins, posterior wall, and vestibule of the posterior wall left atrium., Objective: To perform a systematic review and meta-analysis on safety and effectiveness of contemporary Hybrid Convergent procedures., Methods: PubMed, Embase, and manual searches identified primary research articles on Hybrid Convergent. Inclusion criteria focused on contemporary practices (epicardial ablation device and lesions). Clinical outcomes at 1 year or later follow-up, patient population, procedural details, and major adverse events (MAE) were recorded., Results: Of 249 records, 6 studies (5 observational, 1 randomized controlled trial) including 551 patients were included. Endocardial energy sources included radiofrequency and cryoballoon. Hybrid Convergent ablation was mostly performed in patients with drug-refractory persistent and longstanding persistent AF. Mean preprocedural AF duration ranged between 2 and 5.1 years. Most patients (∼92%) underwent Hybrid Convergent in a single hospitalization. At 1 year follow-up or later, 69% (95% confidence interval [CI]: 61%-78%, n = 523) were free from atrial arrhythmias and 50% (95% CI: 42%-58%, n = 343) were free from atrial arrhythmias off antiarrhythmic drugs. Thirty-day MAE rate was 6% (95% CI: 3%-8%, n = 551)., Conclusion: Hybrid Convergent ablation is an effective ablation strategy for persistent and longstanding persistent AF. Contemporary procedural approaches and published strategies aim to mitigate complications reported in early experience and address delayed inflammatory effusions., (© 2022 Heart Rhythm Society. Published by Elsevier Inc.)

Background: Radiofrequency catheter ablation (CA) is an efficient antiarrhythmic treatment with a class I indication for idiopathic ventricular arrhythmia (IVA), only when drugs are ineffective or have unacceptable side effects. The accurate prediction of the origins of IVA can significantly increase the operation success rate, reduce operation duration and decrease the risk of complications. The present work proposes an artificial intelligence-enabled ECG analysis algorithm to estimate possible origins of idiopathic ventricular arrhythmia at a clinical-grade level accuracy., Method: A total of 18,612 ECG recordings extracted from 545 patients who underwent successful CA to treat IVA were proportionally sampled into training, validation and testing cohorts. We designed four classification schemes responding to different hierarchical levels of the possible IVA origins. For every classification scheme, we compared 98 distinct machine learning models with optimized hyperparameter values obtained through extensive grid search and reported an optimal algorithm with the highest accuracy scores attained on the testing cohorts., Results: For classification scheme 4, our pioneering study designs and implements a machine learning-based ECG algorithm to predict 21 possible sites of IVA origin with an accuracy of 98.24% on a testing cohort. The accuracy and F1-score for the left three schemes surpassed 99%., Conclusion: In this work, we developed an algorithm that precisely predicts the correct origins of IVA (out of 21 possible sites) and outperforms the accuracy of all prior studies and human experts., Competing Interests: JZ and HC are the inventors of intellectual property in the field of ventricular arrhythmia origins identification methods. HC has served as a consultant for Biosense Webster, Boston Scientific, and Abbott. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zheng, Fu, Struppa, Abudayyeh, Contractor, Anderson, Chu and Rakovski.)

Background: Perioperative anticoagulation management with uninterrupted or minimally interrupted anticoagulation during atrial fibrillation (AF) ablation is thought to be critical to minimize thromboembolic complications. Protamine is often administered to neutralize the effects of heparin and expedite vascular hemostasis post-procedure., Objective: We performed a systematic review and meta-analysis to determine the effectiveness of protamine to expedite vascular hemostasis and ambulation in patients undergoing AF ablation., Methods: Electronic searches on PubMed, The Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases from the inception through August 7, 2021, were performed. The primary outcomes included-time to hemostasis (minutes) and time to ambulation (minutes). The secondary outcomes included - any vascular complications (excluding minor hematoma), minor hematoma, or cerebrovascular accidents (CVA)., Results: A total of 5 eligible studies (3 retrospective cohort studies and two randomized trials) consisting of 1012 patients (515 patients received protamine group and 497 patients did not receive protamine group) were included in the meta-analysis. There was a significant reduction in time to ambulation [weighted mean difference (WMD) -176.6 minutes, 95% Confidence interval (CI) -266.9 to -86.3; p < 0.01] and time to hemostasis (WMD -13.72 minutes, 95% CI -22 to -5.4, p < 0.01) in the protamine group compared to the contrary. At a follow-up up to 3 months, there was no statistical difference between the two groups with regards to vascular complications (2.9% vs. 7.4%; Risk ratio (RR) 0.46 95% CI 0.17 to 1.24; p = 0.12), minor hematoma (2.1% vs. 5.8%; RR 0.43, 95% CI 0.16 to 1.2; p = 0.11) or CVA (0 vs. 0.3%; RR 0.62, 95% CI 0.08 to 4.98; p = 0.65)., Conclusion: Protamine administration was associated with reduced time to ambulation (176 minutes reduction) and time to hemostasis (13 minutes reduction) without an increase in any adverse events., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Introduction: Accuracy of fluoroscopy in predicting septal placement of the right ventricular (RV) leads is poor. This pilot study evaluated the feasibility and impact of real-time transthoracic echocardiogram (TTE) during RV lead placement., Method: Consecutive patients undergoing transvenous RV lead placement and had a point of care ultrasound team available for TTE guidance were included in the study. TTE was performed to confirm or refute the septal position of RV lead initially positioned using fluoroscopy; leads were repositioned until a septal position was confirmed on TTE. The primary outcome measured was whether the use of TTE resulted in lead repositioning., Result: Among the 26 patients included in the study, real-time TTE during RV lead placement resulted in reposition of the lead to a septal position in 38.5% of patients., Conclusion: Use of real-time TTE guidance during fluoroscopic RV lead placement is feasible and can aid in confirming a septal position., Competing Interests: None., (© 2021 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.)

Objective: To investigate the management strategies, temporal trends, and clinical outcomes of patients with a history of coronary artery bypass graft (CABG) surgery and presenting with acute myocardial infarction (MI)., Patients and Methods: We undertook a retrospective cohort study using the National Inpatient Sample database from the United States (January 2004-September 2015), identified all inpatient MI admissions (7,250,768 records) and stratified according to history of CABG (group 1, CABG-naive [94%]; group 2, prior CABG [6%])., Results: Patients in group 2 were older, less likely to be female, had more comorbidities, and were more likely to present with non-ST-elevation myocardial infarction compared with group 1. More patients underwent coronary angiography (68% vs 48%) and percutaneous coronary intervention (PCI) (44% vs 26%) in group 1 compared with group 2. Following multivariable logistic regression analyses, the adjusted odd ratio (OR) of in-hospital major adverse cardiovascular and cerebrovascular events (OR, 0.98; 95% CI, 0.95 to 1.005; P=.11), all-cause mortality (OR, 1; 95% CI, 0.98 to 1.04; P=.6) and major bleeding (OR, 0.99; 95% CI, 0.94 to 1.03; P=.54) were similar to group 1. Lower adjusted odds of in-hospital major adverse cardiovascular and cerebrovascular events (OR, 0.64; 95% CI, 0.57 to 0.72; P<.001), all-cause mortality (OR, 0.45; 95% CI, 0.38 to 0.53; P<.001), and acute ischemic stroke (OR, 0.71; 95% CI, 0.59 to 0.86; P<.001) were observed in group 2 patients who underwent PCI compared with those managed medically without any increased risk of major bleeding (OR, 1.08; 95% CI, 0.94 to 1.23; P=.26)., Conclusions: In this national cohort, MI patients with prior-CABG had a higher risk profile, but similar in-hospital adverse outcomes compared with CABG-naive patients. Prior-CABG patients who received PCI had better in-hospital clinical outcomes compared to those who received medical management., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Aims: To study the outcomes of cancer patients undergoing cardiac implantable electronic device (CIED) implantation., Methods and Results: De novo CIED implantations (2004-15; n = 2 670 590) from the National Inpatient Sample were analysed for characteristics and in-hospital outcomes, stratified by presence of cancer (no cancer, historical and current cancers) and further by current cancer type (haematological, lung, breast, colon, and prostate). Current and historical cancer prevalence has increased from 3.3% to 7.8%, and 5.8% to 7.8%, respectively, between 2004 and 2015. Current cancer was associated with increased adjusted odds ratio (OR) of major adverse cardiovascular events (MACE) [composite of all-cause mortality, thoracic and cardiac complications, and device-related infection; OR 1.26, 95% confidence interval (CI) 1.23-1.30], all-cause mortality (OR 1.43, 95% CI 1.35-1.50), major bleeding (OR 1.38, 95% CI 1.32-1.44), and thoracic complications (OR 1.39, 95% CI 1.35-1.43). Differences in outcomes were observed according to cancer type, with significantly worse MACE, mortality and thoracic complications with lung and haematological malignancies, and increased major bleeding in colon and prostate malignancies. The risk of complications was also different according to CIED subtype., Conclusion: The prevalence of cancer patients amongst those undergoing CIED implantation has significantly increased over 12 years. Overall, current cancers are associated with increased mortality and worse outcomes, especially in patients with lung, haematological, and colon malignancies whereas there was no evidence that historical cancer had a negative impact on outcomes., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Ileal neuroendocrine tumors (I-NETs) are the most common tumors of the small intestine. Although I-NETs are known for a lack of recurrently mutated genes, a majority of tumors do show loss of one copy of chromosome 18. Among the genes on chromosome 18 is MIR1-2, which encodes a microRNA, MIR1-3p, with high complementarity to the mRNA of CDK4. Here we show that transfection of neuroendocrine cell lines with MIR1-3p lowered CDK4 expression and activity, and arrested growth at the G1 stage of the cell cycle. Loss of copy of MIR1-2 in ileal neuroendocrine tumors associated with increased expression of CDK4. Genetic events that attenuated RB activity, including loss of copy of MIR1-2 as well as loss of copy of CDKN1B and CDKN2A, were more frequent in tumors from patients with metastatic I-NETs. These data suggest that inhibitors of CDK4/CDK6 may benefit patients whose I-NETs show loss of copy of MIR1-2, particularly patients with metastatic disease.

The two most common types of pancreatic neuroendocrine tumors (PanNETs) are insulinomas and nonfunctioning PanNETs (NF-PanNETs). Insulinomas are small, rarely metastatic tumors that secrete high amounts of insulin, and nonfunctioning PanNETs are larger tumors that are frequently metastatic but that do not secrete hormones. Insulinomas are modeled by the highly studied RIP1-Tag2 (RT2) transgenic mice when bred into a C57Bl/6 (B6) genetic background (also known as RT2 B6 mice). But there has been a need for an animal model of nonfunctioning PanNETs, which in the clinic are a more common and severe disease. Here we show that when bred into a hybrid AB6F1 genetic background, RT2 mice make nonfunctioning PanNETs. Compared to insulinomas produced by RT2 B6 mice, the tumors produced by RT2 AB6F1 mice were larger and more metastatic, and the animals did not suffer from hypoglycemia or hyperinsulinemia. Genetic crosses revealed that a locus in mouse chromosome 2qG1 was linked to liver metastasis and to lack of insulin production. This locus was tightly linked to the gene encoding Insm1, a beta cell transcription factor that was highly expressed in human insulinomas but unexpressed in other types of PanNETs due to promoter hypermethylation. Insm1-deficient human cell lines expressed stem cell markers, were more invasive in vitro, and metastasized at higher rates in vivo when compared to isogenic Insm1-expressing cell lines. These data demonstrate that expression of Insm1 can determine whether a PanNET is a localized insulinoma or a metastatic nonfunctioning tumor.

In a mouse model for neuroendocrine tumors of the pancreas (PanNETs), liver metastasis occurred at a higher frequency in males. Male mice also had higher serum and intratumoral levels of the innate immunity protein complement C5. In mice that lost the ability to express complement C5, there was a lower frequency of metastasis, and males no longer had a higher frequency of metastasis than females. Treatment with PMX53, a small molecule antagonist of C5aR1/CD88, the receptor for complement C5a, also reduced metastasis. Mice lacking a functional gene for complement C5 had smaller primary tumors, which were less invasive and lacked the CD68+ macrophages that have previously been associated with metastasis in this type of tumor. This is the first report of a gene that causes sexual dimorphism of metastasis in a mouse model. In the human disease, which also shows sexual dimorphism for metastasis, clinically advanced tumors expressed more complement C5 than less advanced tumors., Competing Interests: Shinta Kobayashi is an appointee of the Institute for Advanced Study and an employee of Chugai Pharmaceuticals Co., LTD.

Purpose: In mice, genetic changes that inactivate the retinoblastoma tumor suppressor pathway often result in pancreatic neuroendocrine tumors (Pan-NETs). Conversely, in humans with this disease, mutations in genes of the retinoblastoma pathway have rarely been detected, even in genome-wide sequencing studies. In this study, we took a closer look at the role of the retinoblastoma pathway in human Pan-NETs., Experimental Design: Pan-NET tumors from 92 patients were subjected to immunohistochemical staining for markers of the retinoblastoma pathway. To search for amplifications of retinoblastoma pathway genes, genomic DNAs from 26 tumors were subjected to copy number analysis. Finally, a small-molecule activator of the retinoblastoma pathway was tested for effects on the growth of two Pan-NET cell lines., Results: A majority of tumors expressed high amounts of Cdk4 or its partner protein cyclin D1. High amounts of phosphorylated Rb1 were present in tumors that expressed high levels of Cdk4 or cyclin D1. The copy numbers of Cdk4 or the analogous kinase gene Cdk6 were increased in 19% of the tumors. Growth of the human Pan-NET cell line QGP1 was inhibited in a xenograft mouse model by the Cdk4/6 inhibitor, PD 0332991, which reactivates the retinoblastoma pathway., Conclusions: Inactivation of the retinoblastoma pathway was indicated for most Pan-NETs. Gene amplification and overexpression of Cdk4 and Cdk6 suggests that patients with Pan-NETs may respond strongly to Cdk4/6 inhibitors that are entering clinical trials., (©2012 AACR.)

Coronary computed tomography angiography (CCTA) has become an important part of our armamentarium for noninvasive diagnosis of coronary artery disease (CAD). Emerging technologies have produced lower radiation dose, improved spatial and temporal resolution, as well as information about coronary physiology. Although the prognostic role of coronary artery calcium scoring is known, similar evidence for CCTA has only recently emerged. Initial, small studies in various patient populations have indicated that CCTA-identified CAD may have a prognostic value. These findings were confirmed in a recent analysis of the international, prospective Coronary CT Angiography Evaluation For Clinical Outcomes: An International Multicenter (CONFIRM) registry. An incremental increase in mortality was found with a worse severity of CAD on a per-patient, per-vessel, and per-segment basis. In addition, age-, sex-, and ethnicity-based differences in mortality were also found. Whether changing our management algorithms based on these findings will affect outcomes is unclear. Large prospective studies utilizing targeted management strategies for obstructive and nonobstructive CAD are required to incorporate these recent findings into our daily practice., (© 2012 Wiley Periodicals, Inc.)

In cancer cells, the aberrant conversion of pyruvate into lactate instead of acetyl-CoA in the presence of oxygen is known as the Warburg effect. The consequences and mechanisms of this metabolic peculiarity are incompletely understood. Here we report that p53 status is a key determinant of the Warburg effect. Wild-type p53 expression decreased levels of pyruvate dehydrogenase kinase-2 (Pdk2) and the product of its activity, the inactive form of the pyruvate dehydrogenase complex (P-Pdc), both of which are key regulators of pyruvate metabolism. Decreased levels of Pdk2 and P-Pdc in turn promoted conversion of pyruvate into acetyl-CoA instead of lactate. Thus, wild-type p53 limited lactate production in cancer cells unless Pdk2 could be elevated. Together, our results established that wild-type p53 prevents manifestation of the Warburg effect by controlling Pdk2. These findings elucidate a new mechanism by which p53 suppresses tumorigenesis acting at the level of cancer cell metabolism.

Atrial Fibrillation (AF) is a common arrhythmia with an incidence that is as high as 10% in the elderly population. Given the large proportion of strokes caused by AF as well as the associated morbidity and mortality, reducing stroke burden is the most important part of AF management. While warfarin significantly reduces the risk of AF-related stroke, perceived bleeding risks and compliance limit its widespread use in the high-risk AF population. The left atrial appendage is believed to be the "culprit" for thrombogenesis in nonvalvular AF and is a new therapeutic target for stroke prevention. The purpose of this review is to explore the evolving field of percutaneous LAA occlusion. After briefly highlighting the risk of stroke with AF, problems with warfarin, and the role of the LAA in clot formation, this article discusses the feasibility and efficacy of various devices which have been developed for percutaneous LAA occlusion.

Interindividual variability in response to chemicals and drugs is a common regulatory concern. It is assumed that xenobiotic-induced adverse reactions have a strong genetic basis, but many mechanism-based investigations have not been successful in identifying susceptible individuals. While recent advances in pharmacogenetics of adverse drug reactions show promise, the small size of the populations susceptible to important adverse events limits the utility of whole-genome association studies conducted entirely in humans. We present a strategy to identify genetic polymorphisms that may underlie susceptibility to adverse drug reactions. First, in a cohort of healthy adults who received the maximum recommended dose of acetaminophen (4 g/d x 7 d), we confirm that about one third of subjects develop elevations in serum alanine aminotransferase, indicative of liver injury. To identify the genetic basis for this susceptibility, a panel of 36 inbred mouse strains was used to model genetic diversity. Mice were treated with 300 mg/kg or a range of additional acetaminophen doses, and the extent of liver injury was quantified. We then employed whole-genome association analysis and targeted sequencing to determine that polymorphisms in Ly86, Cd44, Cd59a, and Capn8 correlate strongly with liver injury and demonstrated that dose-curves vary with background. Finally, we demonstrated that variation in the orthologous human gene, CD44, is associated with susceptibility to acetaminophen in two independent cohorts. Our results indicate a role for CD44 in modulation of susceptibility to acetaminophen hepatotoxicity. These studies demonstrate that a diverse mouse population can be used to understand and predict adverse toxicity in heterogeneous human populations through guided resequencing.

Osteopontin (OPN) is both a matrix protein in mineralized tissues and a cytokine, and it has a pivotal role in osteoclast-mediated bone resorption. Here, using a proprietary hydroxyapatite substitute for bone mineral (Osteologic discs), we investigated the requirement for OPN in mineral resorption. Resorption pits formed in the Osteologic discs, revealed by staining with silver nitrite (Von Kossa stain), were analyzed using the NIH Image J program, which can determine the number of pits formed per unit area, their average size, and the fractional area resorbed. After a preincubation of bone marrow cells from OPN -/- and OPN +/+ mice with M-CSF to allow the multiplication of osteoclast precursors on cell culture plastic, osteoclast formation on both Osteologic discs and standard cell culture plates was induced with soluble receptor activator of NFkappaB ligand, sRANKL. We did not detect a dramatic difference in osteoclast formation between OPN +/+ and OPN -/- cells, as judged by staining for tartrate-resistant acid phosphatase in osteoclasts formed on cell culture plastic, nor was there a significant difference in the ability of the osteoclasts to form resorption pits in the Osteologic discs. Additionally, none of six different anti-OPN monoclonal antibodies had a significant and reproducible effect on the formation or subsequent functioning of the OPN+/+ osteoclasts. These studies suggest that, in contrast to what has been found for normal bone, the efficiency of dissolution of a ceramic, protein-free (excepting protein adsorbed from the culture medium) hydroxyapatite/tri-calcium phosphate substrate by osteoclasts is not substantially enhanced by endogenous or exogenous OPN.