Hypertriglyceridemia-induced acute necrotizing pancreatitis: Poor clinical outcomes requiring revisiting management modalities.

Hypertriglyceridemia-induced acute pancreatitis (HTG-AP) is the third most common cause of AP after gallstones and alcohol. Supportive measures, intravenous insulin, and plasmapheresis are possible treatment modalities for HTG-AP; however, definitive guidelines evaluating the best therapeutic approach are not clearly established. We present a rare case of a 42-year-old male without known comorbidities who was found to have HTG-AP. Despite early initiation of intravenous insulin and plasmapheresis and the initial decline in his triglycerides level, his condition was complicated by necrotizing pancreatitis and subsequent multi-organ failure. Future studies are warranted to evaluate the role of plasmapheresis in HTG-AP and its efficacy.

A Semiautonomous Deep Learning System to Reduce False Positives in Screening Mammography.

Purpose To evaluate the ability of a semiautonomous artificial intelligence (AI) model to identify screening mammograms not suspicious for breast cancer and reduce the number of false-positive examinations. Materials and Methods The deep learning algorithm was trained using 123 248 two-dimensional digital mammograms (6161 cancers) and a retrospective study was performed on three nonoverlapping datasets of 14 831 screening mammography examinations (1026 cancers) from two U.S. institutions and one U.K. institution (2008-2017). The stand-alone performance of humans and AI was compared. Human plus AI performance was simulated to examine reductions in the cancer detection rate, number of examinations, false-positive callbacks, and benign biopsies. Metrics were adjusted to mimic the natural distribution of a screening population, and bootstrapped CIs and P values were calculated. Results Retrospective evaluation on all datasets showed minimal changes to the cancer detection rate with use of the AI device (noninferiority margin of 0.25 cancers per 1000 examinations: U.S. dataset 1, P = .02; U.S. dataset 2, P < .001; U.K. dataset, P < .001). On U.S. dataset 1 (11 592 mammograms; 101 cancers; 3810 female patients; mean age, 57.3 years ± 10.0 [SD]), the device reduced screening examinations requiring radiologist interpretation by 41.6% (95% CI: 40.6%, 42.4%; P < .001), diagnostic examinations callbacks by 31.1% (95% CI: 28.7%, 33.4%; P < .001), and benign needle biopsies by 7.4% (95% CI: 4.1%, 12.4%; P < .001). U.S. dataset 2 (1362 mammograms; 330 cancers; 1293 female patients; mean age, 55.4 years ± 10.5) was reduced by 19.5% (95% CI: 16.9%, 22.1%; P < .001), 11.9% (95% CI: 8.6%, 15.7%; P < .001), and 6.5% (95% CI: 0.0%, 19.0%; P = .08), respectively. The U.K. dataset (1877 mammograms; 595 cancers; 1491 female patients; mean age, 63.5 years ± 7.1) was reduced by 36.8% (95% CI: 34.4%, 39.7%; P < .001), 17.1% (95% CI: 5.9%, 30.1%: P < .001), and 5.9% (95% CI: 2.9%, 11.5%; P < .001), respectively. Conclusion This work demonstrates the potential of a semiautonomous breast cancer screening system to reduce false positives, unnecessary procedures, patient anxiety, and medical expenses. Keywords: Artificial Intelligence, Semiautonomous Deep Learning, Breast Cancer, Screening Mammography Supplemental material is available for this article. Published under a CC BY 4.0 license.

Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair.

Homology Directed Repair (HDR) enables precise genome editing, but the implementation of HDR-based therapies is hindered by limited efficiency in comparison to methods that exploit alternative DNA repair routes, such as Non-Homologous End Joining (NHEJ). In this study, we develop a functional, pooled screening platform to identify protein-based reagents that improve HDR in human hematopoietic stem and progenitor cells (HSPCs). We leverage this screening platform to explore sequence diversity at the binding interface of the NHEJ inhibitor i53 and its target, 53BP1, identifying optimized variants that enable new intermolecular bonds and robustly increase HDR. We show that these variants specifically reduce insertion-deletion outcomes without increasing off-target editing, synergize with a DNAPK inhibitor molecule, and can be applied at manufacturing scale to increase the fraction of cells bearing repaired alleles. This screening platform can enable the discovery of future gene editing reagents that improve HDR outcomes.

Congenital Pseudoarthrosis of Tibia With Anterolateral Bowing Treated With Ilizarov Ring Fixator: A Case Report.

Congenital pseudarthrosis of the tibia (CPT) is a rare, dysplastic condition that is characterized by a "false joint" in the tibia, leading to potential disability. We present a rare case report of a 12-year-old male from India with a history of neurofibromatosis type 1 (NF1) and anterolateral bowing of the tibia since birth. He sustained a tibial fracture during play. X-ray evaluation confirmed the fracture, and a clinical diagnosis of CPT was established. The treatment involved corticotomy for deformity correction and stabilization using Ilizarov's ring fixation. The procedure was successful, with post-operative radiological evaluations showing significant improvement in the center of rotation of angulation (CORA) from 60° pre-operatively to 25° post-operatively. The patient was discharged with an external fixator and after seven months, transitioned to full weight-bearing ambulation with a specialized brace. The Ilizarov procedure proved to be a safe and effective treatment for CPT, offering benefits such as limb lengthening and ankle stabilization.

The Utility of Leadless Atrioventricular Synchronous Pacemaker Implantation as a Novel Alternative to a Traditional Pacemaker During Pregnancy.

The Micra™ leadless pacemaker (Medtronic, Minneapolis, MN, USA) is indicated for the management of symptomatic bradycardia and advanced heart block. However, the safety of this procedure during pregnancy has not been studied. Here, we present a unique case of Micra™ leadless pacemaker implantation (MLP) in a 31 weeks pregnant patient with intermittent complete heart block who presented with multiple syncopal episodes. The patient underwent an MLP implantation with <40 mGy radiation exposure (about 0.6 min of total fluoroscopy time), which is deemed a negligible dose of radiation exposure during pregnancy. Her subsequent hospital course was uneventful, and she was safely discharged home and was able to continue her pregnancy and delivery without further syncopal episodes or incidence of heart block.

Bradycardia, Renal Failure, Atrioventricular Nodal Blockade, Shock and Hyperkalaemia Syndrome Involving Digoxin Toxicity: A Case Report.

Bradycardia, renal failure, atrioventricular nodal blockade, shock and hyperkalemia (BRASH) syndrome is named after the pentad of symptoms experienced by patients with this clinical entity, and is propagated via a synergistic mechanism. Herein, we describe a case of an 81-year-old male who presented with bradycardia, dyspnoea on exertion, and confusion. He was also initially found to be in cardiogenic shock. In a setting of elevated digoxin levels, acute renal failure and hyperkalemia, he was diagnosed with BRASH syndrome. Prompt interventions of continuous renal replacement therapy and digoxin antibody administration were performed to treat this patient. His renal function improved and his hyperkalemia and bradycardia resolved over the course of 4 days, and the patient was discharged to a subacute rehabilitation facility after stabilization. BRASH syndrome is a clinical entity requiring prompt diagnosis for life-saving treatment, including renal replacement therapy, vasoactive medications, transvenous pacing, and reversing agents, when appropriate.

Differential Rates of Lower Gastrointestinal Bleeding and Other Outcomes in Colorectal Cancer Patients With Aortic Stenosis.

Background Aortic stenosis (AS) has been established as a precipitating factor in the development of colonic angiodysplasia, resulting in lower gastrointestinal bleeding (LGIB). While the association between AS and LGIB, termed "Heyde syndrome," has been examined extensively, few studies assess the impact of comorbid AS on rates of LGIB in patients with colorectal cancer (CRC). Our goal is to examine this association.  Methods Patients hospitalized from 2001 to 2013 diagnosed with CRC were identified via ICD-9 codes, further stratified by a diagnosis of AS. Continuous and categorical variables were analyzed by independent sample t-tests and chi-squared analyses respectively. Assessed outcomes included mortality, length of stay (LOS), hospital costs, rates of LGIB, colonic obstruction, colonic perforation, iron-deficiency anemia (IDA), and colectomy. Multivariate analysis via binary logistic regression was utilized to control confounding variables. Results Patients with CRC and AS had higher rates of mortality, lower gastrointestinal bleeding, iron deficiency anemia, and colectomy, while those without AS had higher rates of colonic obstruction. Length of stay and total hospital charges were higher in patients with AS.  Discussion CRC outcomes were worse in patients with AS. This could be due to higher rates of LGIB secondary to the prevalence of angiodysplasia among AS patients. More retrospective studies are required to assess the impact of comorbid AS in patients with CRC.

A Case of Cerebellar Hippocampal and Basal Nuclei Transient Edema With Restricted Diffusion Syndrome With Poor Clinical Outcome.

Cerebellar hippocampal and basal nuclei transient edema with restricted diffusion (CHANTER) syndrome is a specific pattern of restricted diffusion in the hippocampi and cerebellum identified on brain imaging by clinicians in patients who present with altered mental status in the context of substance intoxication. These patients developed obstructive hydrocephalus a couple of days into their hospitalization that required therapy with osmotic agents and/or surgical interventions (i.e., drains and decompressive craniectomy). In prior cases published, many of the patients had good recovery. The case we present is of a woman who presented after polysubstance use and was found to have brain imaging findings supportive of CHANTER syndrome. Although she was treated with aggressive osmotic therapy and surgical interventions, she ultimately developed irreversible brain damage leading to an overall poor prognosis for recovery. Our case suggests variability in the progression of the syndrome and demonstrates the need for further studies to examine whether the substance of use and the patient's chronic medical conditions may contribute to the degree of recovery.

Sibutramine-Induced Nonischemic Cardiomyopathy.

Within the past 20 years, the global pandemic of obesity and associated life-threatening comorbidities significantly promoted the development and intervention of anti-obesity pharmacotherapy. Sibutramine hydrochloride monohydrate, formerly sold under the brand name Meridia and Reductil among others, is an anti-obesity, selective serotonin, and norepinephrine reuptake inhibitor drug that suppresses appetite and reduces body weight in conjunction with lifestyle modifications. However, since 2010, it has been discontinued in a majority of countries such as the United States and European Union due to an associated increase in cardiovascular events such as hypertension, tachycardia, arrhythmias, and myocardial infarction. Thus, this article illustrates a case of sibutramine-induced nonischemic cardiomyopathy, including details of evaluation, management, and monitoring of patient progress. Herein, we present a case report of a 19-year-old male with no prior medical conditions who presented to the emergency department after being found in a state of cardiac arrest (pulseless ventricular fibrillation) with consequent intubation in the field. Upon admission, cardiac catheterization and echocardiography revealed patent coronary arteries with a reduced ejection fraction of approximately 15%-20%. Acute systolic heart failure secondary to nonischemic cardiomyopathy was treated with standard medical management. In addition, due to continued episodes of non-sustained ventricular tachycardia, the patient also underwent a subcutaneous implantable cardioverter-defibrillator (ICD) placement.

Post-cardiac Injury Syndrome Following Permanent Dual-Chamber Pacemaker Implantation.

Post-cardiac injury syndrome is a heterogeneous group of conditions that result from autoimmune-mediated inflammation of the pericardium, epicardium, and myocardium. Interventions such as pacemaker lead insertions, percutaneous coronary interventions, radiofrequency ablations, cardiac surgeries, and Swan-Ganz catheterizations can cause myocardial injury leading to post-traumatic pericarditis. This phenomenon can lead to chest pain, recurrent effusions, and fever along with possible complications of heart failure, arrhythmias, conduction abnormalities as well as cardiac tamponade. Herein, we present a case report of a 64-year-old female with a history of sick sinus syndrome managed with a dual-chamber pacemaker who presented with post-cardiac injury syndrome after three months of pacemaker implantation. She developed a recurrent syndrome of fever, chest discomfort, tachycardia with weakness, hemodynamic instability, hemorrhagic serositis, and cardiac tamponade. The mechanism of exudative inflammatory effusions initially remained inconclusive, as the workup for infectious and malignant processes was negative. However, post-cardiac injury syndrome akin to the Dressler syndrome related to screw-in dual-chamber pacemaker implantation remained a possibility. Her condition was acutely managed with a combination of colchicine and glucocorticoid therapy. She was placed on long-term aspirin and colchicine therapy to prevent any recurrences. This article illustrates a case of post-cardiac injury syndrome after dual-chamber pacemaker implantation, including details of evaluation, management, complications and monitoring of patient progress.

Subgroups of patients with young-onset type 2 diabetes in India reveal insulin deficiency as a major driver.

AIM/HYPOTHESIS: Five subgroups were described in European diabetes patients using a data driven machine learning approach on commonly measured variables. We aimed to test the applicability of this phenotyping in Indian individuals with young-onset type 2 diabetes. METHODS: We applied the European-derived centroids to Indian individuals with type 2 diabetes diagnosed before 45 years of age from the WellGen cohort (n = 1612). We also applied de novo k-means clustering to the WellGen cohort to validate the subgroups. We then compared clinical and metabolic-endocrine characteristics and the complication rates between the subgroups. We also compared characteristics of the WellGen subgroups with those of two young European cohorts, ANDIS (n = 962) and DIREVA (n = 420). Subgroups were also assessed in two other Indian cohorts, Ahmedabad (n = 187) and PHENOEINDY-2 (n = 205). RESULTS: Both Indian and European young-onset type 2 diabetes patients were predominantly classified into severe insulin-deficient (SIDD) and mild obesity-related (MOD) subgroups, while the severe insulin-resistant (SIRD) and mild age-related (MARD) subgroups were rare. In WellGen, SIDD (53%) was more common than MOD (38%), contrary to findings in Europeans (Swedish 26% vs 68%, Finnish 24% vs 71%, respectively). A higher proportion of SIDD compared with MOD was also seen in Ahmedabad (57% vs 33%) and in PHENOEINDY-2 (67% vs 23%). Both in Indians and Europeans, the SIDD subgroup was characterised by insulin deficiency and hyperglycaemia, MOD by obesity, SIRD by severe insulin resistance and MARD by mild metabolic-endocrine disturbances. In WellGen, nephropathy and retinopathy were more prevalent in SIDD compared with MOD while the latter had higher prevalence of neuropathy. CONCLUSIONS /INTERPRETATION: Our data identified insulin deficiency as the major driver of type 2 diabetes in young Indians, unlike in young European individuals in whom obesity and insulin resistance predominate. Our results provide useful clues to pathophysiological mechanisms and susceptibility to complications in type 2 diabetes in the young Indian population and suggest a need to review management strategies.

COVID-19 associated mucormycosis: A Descriptive Multisite Study from India.

BACKGROUND AND AIMS: Mucormycosis is an invasive fungal infection and carries a significant morbidity and mortality. A number of cases of mucormycosis have been reported in association with COVID-19. In this study, a consortium of clinicians from various parts of India studied clinical profile of COVID-19 associated mucormycosis (CAM) and this analysis is presented here. METHODS: Investigators from multiple sites in India were involved in this study. Clinical details included the treatment and severity of COVID-19, associated morbidities, as well as the diagnosis, treatment and prognosis of mucormycosis. These data were collected using google spreadsheet at one centre. Descriptive analysis was done. RESULTS: There were 115 patients with CAM. Importantly, all patients had received corticosteroids. Diabetes was present in 85.2% of patients and 13.9% of patients had newly detected diabetes. The most common site of involvement was rhino-orbital. Mortality occurred in 25 (21.7%) patients. On logistic regression analysis, CT scan-based score for severity of lung involvement was associated with mortality. CONCLUSION: Universal administration of corticosteroids in our patients is notable. A large majority of patients had diabetes, while mortality was seen in ∼1/5th of patients, lower as compared to recently published data.

Shared Care to Destination Therapy Left Ventricular Assist Device Site: a Novel Strategy to Start a Successful Mechanical Circulatory Support Program.

PURPOSE OF REVIEW: Heart failure is an important healthcare issue because of its high prevalence, mortality, and morbidity. Advanced heart failure therapies have improved significantly over the years with improved outcomes. Heart transplantation remains an elusive treatment option for most patients; hence, the need for alternative therapy has given rise to the use of mechanical circulatory support (MCS) devices, initially as bridge to transplantation, but with more recent use as destination therapy. This review focuses on the intricacies of establishing a successful left ventricular assist device (LVAD) program for destination therapy in the setting of a growing anticipated need for wider availability of such treatment options. RECENT FINDINGS: Guidelines have established the role of MCS in patients with advanced HF refractory to optimal guideline-directed medical therapy (GDMT) and cardiac device interventions. Multiple studies have shown generational improvement in the overall safety profile of MCS devices with the use of newer devices for destination therapy showing improved outcomes. Heart failure is a growing cardiovascular problem with an anticipated growing need for advanced HF therapies including MCS devices. A model of shared care LVAD to destination therapy implanting site should be considered as a strategy to start a successful LVAD program.

A Multisite Study of a Breast Density Deep Learning Model for Full-Field Digital Mammography and Synthetic Mammography.

PURPOSE: To develop a Breast Imaging Reporting and Data System (BI-RADS) breast density deep learning (DL) model in a multisite setting for synthetic two-dimensional mammographic (SM) images derived from digital breast tomosynthesis examinations by using full-field digital mammographic (FFDM) images and limited SM data. MATERIALS AND METHODS: A DL model was trained to predict BI-RADS breast density by using FFDM images acquired from 2008 to 2017 (site 1: 57 492 patients, 187 627 examinations, 750 752 images) for this retrospective study. The FFDM model was evaluated by using SM datasets from two institutions (site 1: 3842 patients, 3866 examinations, 14 472 images, acquired from 2016 to 2017; site 2: 7557 patients, 16 283 examinations, 63 973 images, 2015 to 2019). Each of the three datasets were then split into training, validation, and test. Adaptation methods were investigated to improve performance on the SM datasets, and the effect of dataset size on each adaptation method was considered. Statistical significance was assessed by using CIs, which were estimated by bootstrapping. RESULTS: Without adaptation, the model demonstrated substantial agreement with the original reporting radiologists for all three datasets (site 1 FFDM: linearly weighted Cohen κ [κw] = 0.75 [95% CI: 0.74, 0.76]; site 1 SM: κw = 0.71 [95% CI: 0.64, 0.78]; site 2 SM: κw = 0.72 [95% CI: 0.70, 0.75]). With adaptation, performance improved for site 2 (site 1: κw = 0.72 [95% CI: 0.66, 0.79], 0.71 vs 0.72, P = .80; site 2: κw = 0.79 [95% CI: 0.76, 0.81], 0.72 vs 0.79, P < .001) by using only 500 SM images from that site. CONCLUSION: A BI-RADS breast density DL model demonstrated strong performance on FFDM and SM images from two institutions without training on SM images and improved by using few SM images.Supplemental material is available for this article.Published under a CC BY 4.0 license.

Paced or sensed conduction time to determine programming with cardiac resynchronization therapy: The PASED-CRT Trial.

BACKGROUND: Cardiac resynchronization therapy (CRT) is a well-established treatment for patients with drug refractory heart failure. OBJECTIVES: This study sought to compare the longest RVsense to LVsense activation time (sLAT) versus the longest RVpace to LVsense activation time (pLAT) as the programmed site for left ventricular (LV) pacing in CRT patients with quadripolar LV leads at 3 months. METHODS: This single site, double-blinded, prospective trial, randomized patients 1:1 into the sLAT or pLAT group to determine response. LV pacing was programmed at implant and maintained through 3 months of follow-up. The 6-minute hall walk (6MHW) test, NYHA, Minnesota living with heart failure, and clinical composite score (CCS) at the 3 months was compared. RESULTS: N = 92 patients (73M:19F age 66 ± 11.3 years) were randomized implanted and programmed per protocol. Baseline characteristics were comparable. N = 39 sLAT and N = 34 pLAT completed the 3-month visit for final analysis. Significant improvement from baseline to 3 months was seen in the sLAT group from 253.9 (+/-11.5) to 323.1 (+/-11.9) P = .001. Similarly, the pLAT group improved from 274.9 (+/-16.15) to 343.9 (+/-15.9) P = .003. The difference between these groups, however, did not reach significance (P = .86). The pLAT group demonstrated a higher responder rate of (71%) versus the sLAT group (64%) based on the CCS although not reaching significance (P = .56). CONCLUSIONS: Use of both the pLAT and sLAT method of programming demonstrated significant improvement in 6MHW distance at 3 months with pLAT demonstrating a slightly higher responder rate based on CCS (P = .56). pLAT should be considered at minimum as equivalent in patients with no intrinsic conduction.

Transradial Repair of Type IA Endoleak.

An 81-year-old Caucasian male with a known abdominal aortic aneurysm (AAA) was referred to the endovascular clinic. One month after successful endovascular repair, surveillance CTA showed endoleak with presence of contrast within the aneurysmal sac. An elective repair was performed.

Solid-Liquid Work of Adhesion.

We establish a tool for direct measurements of the work needed to separate a liquid from a solid. This method mimics a pendant drop that is subjected to a gravitational force that is slowly increasing until the solid-liquid contact area starts to shrink spontaneously. The work of separation is then calculated in analogy to Tate's law. The values obtained for the work of separation are independent of drop size and are in agreement with Dupré's theory, showing that they are equal to the work of adhesion.

A semi-synthetic natural product blocks collagen induced arthritis by preferentially suppressing the production of IL-6.

Rheumatoid arthritis (RA), an autoimmune-inflammatory disease is characterized by dysregulation of signal transduction pathways, increased production of pro-inflammatory cytokines, enhanced leukocyte infiltration into synovial microvascular endothelium, extensive formation of hyper proliferative pannus, degradation of cartilage and bone erosion. Several compounds that abrogate cytokine production demonstrate a therapeutic effect in experimental models of arthritis. In this study, we report that a novel semi-synthetic natural product (Compound A) being a preferential IL-6 inhibitor, is efficacious in a murine model of arthritis. In vitro evaluations of pro-inflammatory cytokine production reveal that Compound A preferentially inhibits induced production of IL-6 and not TNF-α from THP-1 cells and isolated human monocytes. Furthermore, Compound A robustly inhibits the spontaneous production of IL-6 from pathologically relevant synovial tissue cells isolated from patients with active RA. In a physiologically relevant assay, Compound A selectively inhibits the activated T cell contact-mediated production of IL-6 from human monocytes. Compound A, at pharmacologically efficacious concentrations, does not significantly curtail the LPS-induced activation of p38 MAPKs. In the collagen-induced arthritis (CIA) mouse model (i) macroscopic observations demonstrate that Compound A, administered subcutaneously in a therapeutic regimen, significantly and dose-dependently inhibits disease associated increases in articular index and paw thickness; (ii) histological analyses of paw tissues reveal that Compound A prominently diminishes joint destruction, hyperproliferative pannus formation and infiltration of inflammatory cells. Collectively, these results provide direct evidence that Compound A, a novel preferential IL-6 inhibitor, suppresses collagen-induced arthritis, and may be a potential therapeutic for treating patients with active RA.

Anti-inflammatory properties of mutolide isolated from the fungus Lepidosphaeria species (PM0651419).

Mutolide an anti-inflammatory compound was isolated from the coprophilous fungus Lepidosphaeria sp. (PM0651419). The compound mitigated LPS-induced secretion of pro-inflammatory cytokines TNF-α and IL-6 from THP-1 cells as well as human peripheral blood mononuclear cells (hPBMCs). Mutolide also inhibited secretion of another pro-inflammatory cytokine IL-17 from anti-hCD3/anti-hCD28 stimulated hPBMCs. NF-κB is the major transcription factor involved in the secretion of pro-inflammatory cytokines including IL-17. Mechanistic evaluations revealed that mutolide inhibited induced NF-κB activation and translocation from cytoplasm into the nucleus. However, mutolide did not significantly affect activity of p38 MAPK enzyme, a serine/threonine kinase involved in cell cycle proliferation and cytokine secretion. These results indicate that mutolide may exert its anti-inflammatory effect via NF-κB inhibition. Oral administration of mutolide at 100 mg/kg showed significant inhibition of LPS-induced release of TNF-α from Balb/c mice in an acute model of inflammation. Our results highlight the anti-inflammatory properties of mutolide and suggest that further evaluation in a chronic model of inflammation is required to confirm the potential of mutolide as a druggable candidate for the treatment of inflammatory diseases.