Analysis of blood stream infections, antibiograms and clinical outcomes in haematological patients with febrile neutropenia: data from a tertiary care haematology institute in India.

Timely administration of appropriate empirical antibiotics in febrile neutropenia is crucial for favourable patient outcomes. There are guidelines in place recommending such antibiotics. However, regional variations and local epidemiological data must be evaluated to tailor the antibiotics for best possible and rational use. In this study, we audited the clinical and microbiological data of febrile neutropenic episodes occurring at a tertiary care haematology institution. Three hundred and ninety-three febrile neutropenic episodes occurring in 123 patients over a 1-year period were analysed for microbial profile, sensitivity and resistance patterns, and finally clinical outcomes. Gram-negative bacilli (GNB) blood stream infections (46.9%) were more prevalent as compared to gram-positive infections (41.9%). Overall mortality due to complicated neutropenic sepsis was 19.5% (24/123 patients). Increased resistance to carbapenems, beta-lactam beta-lactamase inhibitor combinations, aminoglycosides, fluoroquinolones, and cephalosporins were observed. Cefepime and tigecycline resistance were seen in 20% and 15% GNB isolates, respectively. Chest was the most frequent focus of infection, and acute myeloid leukaemia (AML) was the most common underlying disorder which correlated with the likelihood of death (p < 0.01). Multidrug-resistant GNB (esp. Klebsiella sp.) are still most worrisome isolates in neutropenic patients. Single-agent cefepime or piperacillin-tazobactam/tigecycline combination may be considered empirical agents. Chest infections and AML were independent predictors of poor clinical outcome in neutropenic patients. Regular audit of infections and antibiotic susceptibility data is needed to improve clinical outcomes in patients with febrile neutropenia.

The Presence of Cyclooxygenase 2, Tumor-Associated Macrophages, and Collagen Alignment as Prognostic Markers for Invasive Breast Carcinoma Patients.

Inflammation, and the organization of collagen in the breast tumor microenvironment, is an important mediator of breast tumor progression. However, a direct link between markers of inflammation, collagen organization, and patient outcome has yet to be established. A tumor microarray of 371 invasive breast carcinoma biopsy specimens was analyzed for expression of inflammatory markers, including cyclooxygenase 2 (COX-2), macrophages, and several collagen features in the tumor nest (TN) or the tumor-associated stroma (TS). The tumor microarray cohort included females, aged 18 to 80 years, with a median follow-up of 8.4 years. High expression of COX-2 (TN), CD68 (TS), and CD163 (TN and TS) predicted worse patient overall survival (OS). This notion was strengthened by the finding from the multivariate analysis that high numbers of CD163+ macrophages in the TS is an independent prognostic factor. Overall collagen deposition was associated with high stromal expression of COX-2 and CD163; however, total collagen deposition was not a predictor for OS. Conversely, local collagen density, alignment and perpendicular alignment to the tumor boundary (tumor-associated collagen signature-3) were predictors of OS. These results suggest that in invasive carcinoma, the localization of inflammatory cells and aligned collagen orientation predict poor patient survival. Additional clinical studies may help validate whether therapy with selective COX-2 inhibitors alters expression of CD68 and CD163 inflammatory markers.

Endovascular Versus Open Revascularization for Peripheral Arterial Disease.

OBJECTIVE: The aim of this study was to determine whether endovascular or open revascularization provides an advantageous approach to symptomatic peripheral arterial disease (PAD) over the longer term. SUMMARY OF BACKGROUND DATA: The optimal revascularization strategy for symptomatic lower extremity PAD is not established. METHODS: We evaluated amputation-free survival, overall survival, and relative rate of subsequent vascular intervention after endovascular or open lower extremity revascularization for propensity-score matched cohorts of Medicare beneficiaries with PAD from 2006 through 2009. RESULTS: Among 14,685 eligible patients, 5928 endovascular and 5928 open revascularization patients were included in matched analysis. Patients undergoing endovascular repair had improved amputation-free survival compared with open repair at 30 days (7.4 vs 8.9%, P = 0.002). This benefit persisted over the long term: At 4 years, 49% of endovascular patients had died or received major amputation compared with 54% of open patients (P < 0.001). An endovascular procedure was associated with a risk-adjusted 16% decreased risk of amputation or death compared with open over the study period (hazard ratio: 0.84; 95% confidence interval, 0.79-0.89; P < 0.001). The amputation-free survival benefit associated with an endovascular revascularization was more pronounced in patients with congestive heart failure or ischemic heart disease than in those without (P = 0.021 for interaction term). The rate of subsequent intervention at 30 days was 7.4% greater for the endovascular vs the open revascularization cohort. At 4 years, this difference remained stable at 8.6%. CONCLUSIONS: Using population-based data, we demonstrate that an endovascular approach is associated with improved amputation-free survival over the long term with only a modest relative increased risk of subsequent intervention.

COX-2 modulates mammary tumor progression in response to collagen density.

BACKGROUND: High breast density is linked to an increased risk of breast cancer, and correlates with changes in collagen. In a mouse model of mammary carcinoma in the context of increased collagen deposition, the MMTV-PyMT/Col1a1 (tm1jae) , there is accelerated mammary tumor formation and progression. Previous gene expression analysis suggests that increased collagen density elevates expression of PTGS2 (prostaglandin-endoperoxide synthase 2), the gene for cyclooxygenase-2 (COX-2). METHODS: To understand the role of COX-2 in tumor progression within a collagen-dense microenvironment, we treated MMTV-PyMT or MMTV-PyMT/Col1a1 (tm1jae) tumors prior to and after tumor formation. Animals received treatment with celecoxib, a specific COX-2 inhibitor, or placebo. Mammary tumors were examined for COX-2, inflammatory and stromal cell components, and collagen deposition through immunohistochemical analysis, immunofluorescence, multiplex cytokine ELISA and tissue imaging techniques. RESULTS: PyMT/Col1a1 (tm1jae) tumors were larger, more proliferative, and expressed higher levels of COX-2 and PGE2 than PyMT tumors in wild type (WT) mice. Treatment with celecoxib significantly decreased the induced tumor size and metastasis of the PyMT/Col1a1 tumors, such that their size was not different from the smaller PyMT tumors. Celecoxib had minimal effect on the PyMT tumors. Celecoxib decreased expression levels of COX-2, PGE2, and Ki-67. Several cytokines were over-expressed in PyMT/Col1a1 compared to PyMT, and celecoxib treatment prevented their over-expression. Furthermore, macrophage and neutrophil recruitment were enhanced in PyMT/Col1a1 tumors, and this effect was inhibited by celecoxib. Notably, COX-2 inhibition reduced overall collagen deposition. Finally, when celecoxib was used prior to tumor formation, PyMT/Col1a1 tumors were fewer and smaller than in untreated animals. CONCLUSION: These findings suggest that COX-2 has a direct role in modulating tumor progression in tumors arising within collagen-dense microenvironments, and suggest that COX-2 may be an effective therapeutic target for women with dense breast tissue and early-stage breast cancer.

Increased tumor response to neoadjuvant therapy among rectal cancer patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensive medications that have been reported to affect aberrant angiogenesis and the dysregulated inflammatory response. Because of such mechanisms, it was hypothesized that these medications might affect the tumor response to neoadjuvant radiation in patients with rectal cancer. METHODS: One hundred fifteen patients who were treated with neoadjuvant radiation at the University of Wisconsin (UW) between 1999 and 2012 were identified. Univariate analyses were performed with anonymized patient data. In a second independent data set, 186 patients with rectal cancer who were treated with neoadjuvant radiation at the Queen's Medical Center of the University of Hawaii (UH) between 1995 and 2010 were identified. These data were independently analyzed as before. Multivariate analyses were performed with aggregate data. RESULTS: Among patients taking ACEIs/ARBs in the UW data set, a significant 3-fold increase in the rate of pathologic complete response (pCR) to neoadjuvant therapy (52% vs 17%, P = .001) was observed. This finding was confirmed in the UH data set, in which a significant 2-fold-increased pCR rate (24% vs 12%, P = .03) was observed. Identified patient and treatment characteristics were otherwise balanced between patients taking and not taking ACEIs/ARBs. No significant effect was observed on pCR rates with other medications, including statins, metformin, and aspirin. Multivariate analyses of aggregate data identified ACEI/ARB use as a strong predictor of pCR (odds ratio, 4.02; 95% confidence interval, 2.06-7.82; P < .001). CONCLUSIONS: The incidental use of ACEIs/ARBs among patients with rectal cancer is associated with a significantly increased rate of pCR after neoadjuvant treatment. Cancer 2016;122:2487-95. © 2016 American Cancer Society.

The impact of perioperative ß blocker use on patient outcomes after primary cytoreductive surgery in high-grade epithelial ovarian carcinoma.

OBJECTIVE: To quantify the impact of perioperative ß blocker use on survival after primary cytoreductive surgery for epithelial ovarian cancer. METHODS: We conducted a multi-center retrospective study of all women who underwent primary cytoreductive surgery for ovarian cancer (2000-2010). One institution had routinely used perioperative ß blockers for patients "at risk" for coronary events. The other institution did not routinely use perioperative ß blockers. Demographic, operative, and follow up data were collected. Cox proportional hazards models were used to assess the effect of ß blockers on progression-free interval (PFI) as well as overall survival (OS). RESULTS: Out of 185 eligible patients, 70 received ß blockers and 115 underwent cytoreductive surgery without perioperative ß blockers. Both groups were similar in demographics. A history of hypertension was present more often in the ß blocker group compared to the group that did not receive ß blockers (22% and 6%, p=0.002). PFI in ß blocker group was greater at 18.2 vs. 15.8months (p=0.66). The OS in the ß blocker group was significantly higher at 44.2 vs. 39.3months (p=0.01). In multivariate analysis, perioperative ß blocker use was associated with significant improvement in OS (HR 0.68 (0.46-0.99); p=0.046). CONCLUSION: Our study showed an association between perioperative ß blocker use and longer overall survival in patients undergoing primary ovarian cancer cytoreductive surgery. A prospective randomized clinical trial in this population would further validate these results.

A phase 2 study of weekly temsirolimus and bortezomib for relapsed or refractory B-cell non-Hodgkin lymphoma: A Wisconsin Oncology Network study.

BACKGROUND: Proteasome inhibitors and mammalian target of rapamycin inhibitors each have activity in various B-cell malignancies and affect distinct cellular pathways. Their combination has demonstrated synergy in vitro and in mouse models. METHODS: The authors conducted a single-arm, phase 2 trial of combined temsirolimus and bortezomib in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (NHL) using a dosing scheme that was previously tested in multiple myeloma. The patients received bortezomib and temsirolimus weekly on days 1, 8, 15, and 22 of a 35-day cycle. RESULTS: Of 39 patients who received treatment, 3 achieved a complete response (7.7%; 95% confidence interval [CI], 1.6%-21%), and 9 had a partial response (PR) (23%; 95% CI, 11%-39%). Thus, the overall response rate (12 of 39 patients) was 31% (95% CI, 17%-48%), and the median progression-free survival was 4.7 months (95% CI, 2.1-7.8 months; 2 months for patients with diffuse large B-cell lymphoma [n = 18], 7.5 months for those with mantle cell lymphoma [n = 7], and 16.5 months for those with follicular lymphoma [n = 9]). Two extensively treated patients with diffuse large B-cell lymphoma achieved a complete response. There were no unexpected toxicities from the combination. CONCLUSIONS: The current results demonstrate that the combination of a mammalian target of rapamycin inhibitor and a proteasome inhibitor is safe and has activity in patients with heavily pretreated B-cell NHL. Further studies with this combination are warranted in specific subtypes of NHL.

Predictors of surgical site infection after hospital discharge in patients undergoing major vascular surgery.

OBJECTIVE: Surgical site infection (SSI) is one of the most common postoperative complications after vascular reconstruction, producing significant morbidity and hospital readmission. In contrast to SSI that develops while patients are still hospitalized, little is known about the cohort of patients who develop SSI after discharge. In this study, we explore the factors that lead to postdischarge SSI, investigate the differences between risk factors for in-hospital vs postdischarge SSI, and develop a scoring system to identify patients who might benefit from postdischarge monitoring of their wounds. METHODS: Patients who underwent major vascular surgery from 2005 to 2012 for aneurysm and lower extremity occlusive disease were identified from the American College of Surgeons National Surgical Quality Improvement Program Participant Use Files. Patients were categorized as having no SSI, in-hospital SSI, or SSI after hospital discharge. Predictors of postdischarge SSI were determined by multivariable logistic regression and internally validated by bootstrap resampling. Risk scores were assigned to all significant variables in the model. Summative risk scores were collapsed into quartile-based ordinal categories and defined as low, low/moderate, moderate/high, and high risk. Multivariable logistic regression was used to determine predictors of in-hospital SSI. RESULTS: Of the 49,817 patients who underwent major vascular surgery, 4449 (8.9%) were diagnosed with SSI (2.1% in-hospital SSI; 6.9% postdischarge SSI). By multivariable analysis, factors significantly associated with increased odds of postdischarge SSI include female gender, obesity, diabetes, smoking, hypertension, coronary artery disease, critical limb ischemia, chronic obstructive pulmonary disease, dyspnea, neurologic disease, prolonged operative time >4 hours, American Society of Anesthesiology class 4 or 5, lower extremity revascularization or aortoiliac procedure, and groin anastomosis. The model exhibited moderate discrimination (bias-corrected C statistic, 0.691) and excellent internal calibration. The postdischarge SSI rate was 2.1% for low-risk patients, 5.1% for low/moderate-risk patients, 7.8% for moderate/high-risk patients, and 14% for high-risk patients. In a comparative analysis, comorbidities were the primary driver of postdischarge SSI, whereas in-hospital factors (operative time, emergency case status) and complications predicted in-hospital SSI. CONCLUSIONS: The majority of SSIs after major vascular surgery develop following hospital discharge. We have created a scoring system that can select a cohort of patients at high risk for SSI after discharge. These patients can be targeted for transitional care efforts focused on early detection and treatment with the goal of reducing morbidity and preventing readmission secondary to SSI.

Patient and tumor characteristics predictive of primary parotid gland malignancy: A 20-year experience at the University of Wisconsin.

PURPOSE: To identify patient and tumor characteristics predictive of primary parotid malignancy. MATERIALS AND METHODS: Records were reviewed for patients who underwent parotidectomy at the University of Wisconsin from 1994 to 2013. Patients with primary parotid neoplasms were separated into benign or malignant subgroups. A multivariate logistic regression model was employed to compare categorical (gender, lesion side, nature of presentation, recurrence) and numerical variables (age, tumor size) between the benign and malignant groups. Mean BMI was compared between the groups by univariate analysis. RESULTS: 771 patients underwent parotidectomy from 1994 to 2013, and 474 had a primary parotid neoplasm. No relationship existed between malignancy and gender (p=0.610), lesion side (p=0.110), or BMI (p=0.196). Mean age (p=0.015) and tumor size (p=0.011) were significantly different between the benign and malignant groups. Patient presentation was classified into three categories: symptomatic (n=109), palpable and asymptomatic (n=303), and incidentally noted on imaging (n=57). From all patients with symptomatic, asymptomatic or incidentally noted masses, 41.3%, 10.6% and 5.3%, respectively, were diagnosed with malignant disease. There was a significant relationship between the patient's initial presentation and malignancy (p<0.001), and patients with facial nerve dysfunction or skin involvement had the greatest likelihood of malignancy. Finally, there was a significant association between malignancy and recurrence (p=0.001). CONCLUSIONS: In this study, age, tumor size, and nature of presentation were all associated with primary parotid malignancy. Understanding the impact of these features on the probability of malignancy is valuable in decision making and counseling of patients presenting with a newly diagnosed parotid neoplasm.

Prevalence of human papillomavirus in oropharyngeal squamous cell carcinoma in the United States across time.

Human papillomaviruses (HPVs) are involved in approximately 5% of all human cancer. Although initially recognized for causing nearly all cases of cervical carcinoma, much data has now emerged implicating HPVs as a causal factor in other anogenital cancers as well as a subset of head and neck squamous cell carcinomas (HNSCCs), most commonly oropharyngeal cancers. Numerous clinical trials have demonstrated that patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) have improved survival compared to patients with HPV- cancers. Furthermore, epidemiological evidence shows the incidence of OPSCC has been steadily rising over time in the United States. It has been proposed that an increase in HPV-related OPSCCs is the driving force behind the increasing rate of OPSCC. Although some studies have revealed an increase in HPV+ head and neck malignancies over time in specific regions of the United States, there has not been a comprehensive study validating this trend across the entire country. Therefore, we undertook this meta-analysis to assess all literature through August 2013 that reported on the prevalence of HPV in OPSCC for patient populations within the United States. The results show an increase in the prevalence of HPV+ OPSCC from 20.9% in the pre-1990 time period to 51.4% in 1990-1999 and finally to 65.4% for 2000-present. In this manner, our study provides further evidence to support the hypothesis that HPV-associated OPSCCs are driving the increasing incidence of OPSCC over time in the United States.

Cytogenetic Alterations and Correlation with Age and Gender in Patients of Multiple Myeloma: A Study from a Tertiary Care Center in Eastern India.

Karuna JhaBackground Multiple myeloma is a cytogenetically heterogeneous, evolving, and incurable disease. Differences in prevalence of myeloma already exist in Indian subcontinent as compared with Western world countries. This study attempts to investigate differences in incidence of cytogenetic abnormalities (CA) in Eastern Indian patients and study differences in incidence with respect to age and gender. Materials and Methods Interphase fluorescence in situ hybridization (FISH) was applied on purified plasma cells of 280 newly diagnosed myeloma cases using specific probes. Statistical Analysis Data was analyzed using SPSS software version 25. Results Note that 51.07% patients were FISH positive. Del13q was the most common CA. Significant association of del 13q with t(4;14), del 17p, and gain of 1q was seen. The frequencies of FISH positive and negative groups differed in the different age groups; higher number of cases in 41 to 50 years group in FISH positive group ( p < 0.05) and lower number of cases in FISH positive group in 61 to 70 years ( p < 0.05) as compared with FISH negative group. Del 17p had higher number of cases in age group 41 to 50 years and 51 to 60 years as compared with other age groups. Incidence of t(11;14) was in 5th to 7th decade while del 13q and t(4;14) had the widest range of age at presentation. Gender disparities were seen in high-risk cytogenetics like del 17p and 1q gain. Conclusion The differences in incidence rate of CAs per se in myeloma cases diagnosed in Indian subcontinent and the differences in incidence with respect to age and gender warrant further multicentric studies.

Autocatalytic reaction fronts inside a porous medium of glass spheres.

We analyze experimentally chemical wave propagation in the disordered flow field of a porous medium. The reaction fronts travel at a constant velocity that drastically depends on the mean flow direction and rate. The fronts may propagate either downstream and upstream but, surprisingly, they remain static over a range of flow rate values. Resulting from the competition between the chemical reaction and the disordered flow field, these frozen fronts display a particular sawtooth shape. The frozen regime is likely to be associated with front pinning in low velocity zones, the number of which varies with the ratio of the mean flow and the chemical front velocities.

Glomerular cell death and inflammation with high-protein diet and diabetes.

BACKGROUND: Overfeeding amino acids (AAs) increases cellular exposure to advanced glycation end-products (AGEs), a mechanism for protein intake to worsen diabetic kidney disease (DKD). This study assessed receptor for AGE (RAGE)-mediated apoptosis and inflammation in glomerular cells exposed to metabolic stressors characteristic of high-protein diets and/or diabetes in vitro with proof-of-concept appraisal in vivo. METHODS: Mouse podocytes and mesangial cells were cultured under control and metabolic stressor conditions: (i) no addition; (ii) increased AAs (4-6-fold>control); (iii) high glucose (HG, 30.5 mM); (iv) AA/HG combination; (v) AGE-bovine serum albumin (AGE-BSA, 300 µg/mL); (vi) BSA (300 µg/mL). RAGE was inhibited by blocking antibody. Diabetic (streptozotocin) and nondiabetic mice (C57BL/6J) consumed diets with protein calories of 20 or 40% (high) for 20 weeks. People with DKD and controls provided 24-h urine samples. RESULTS: In podocytes and mesangial cells, apoptosis (caspase 3/7 activity and TUNEL) increased in all metabolic stressor conditions. Both inflammatory mediator expression (real-time reverse transcriptase-polymerase chain reaction: serum amyloid A, caspase-4, inducible nitric oxide synthase, and monocyte chemotactic protein-1) and RAGE (immunostaining) also increased. RAGE inhibition prevented apoptosis and inflammation in podocytes. Among mice fed high protein, podocyte number (WT-1 immunostaining) decreased in the diabetic group, and only these diabetic mice developed albuminuria. Protein intake (urea nitrogen) correlated with AGE excretion (carboxymethyllysine) in people with DKD and controls. CONCLUSIONS: High-protein diet and/or diabetes-like conditions increased glomerular cell death and inflammation, responses mediated by RAGEs in podocytes. The concept that high-protein diets exacerbate early indicators of DKD is supported by data from mice and people.

Low Reynolds number suspension gravity currents.

The extension of a gravity current in a lock-exchange problem, proceeds as square root of time in the viscous-buoyancy phase, where there is a balance between gravitational and viscous forces. In the presence of particles however, this scenario is drastically altered, because sedimentation reduces the motive gravitational force and introduces a finite distance and time at which the gravity current halts. We investigate the spreading of low Reynolds number suspension gravity currents using a novel approach based on the Lattice-Boltzmann (LB) method. The suspension is modeled as a continuous medium with a concentration-dependent viscosity. The settling of particles is simulated using a drift flux function approach that enables us to capture sudden discontinuities in particle concentration that travel as kinematic shock waves. Thereafter a numerical investigation of lock-exchange flows between pure fluids of unequal viscosity, reveals the existence of wall layers which reduce the spreading rate substantially compared to the lubrication theory prediction. In suspension gravity currents, we observe that the settling of particles leads to the formation of two additional fronts: a horizontal front near the top that descends vertically and a sediment layer at the bottom which aggrandises due to deposition of particles. Three phases are identified in the spreading process: the final corresponding to the mutual approach of the two horizontal fronts while the laterally advancing front halts indicating that the suspension current stops even before all the particles have settled. The first two regimes represent a constant and a decreasing spreading rate respectively. Finally we conduct experiments to substantiate the conclusions of our numerical and theoretical investigation.

Worldwide survey on implantation of and outcomes for conduction system pacing with His bundle and left bundle branch area pacing leads.

BACKGROUND: Adoption and outcomes for conduction system pacing (CSP), which includes His bundle pacing (HBP) or left bundle branch area pacing (LBBAP), in real-world settings are incompletely understood. We sought to describe real-world adoption of CSP lead implantation and subsequent outcomes. METHODS: We performed an online cross-sectional survey on the implantation and outcomes associated with CSP, between November 15, 2020, and February 15, 2021. We described survey responses and reported HBP and LBBAP outcomes for bradycardia pacing and cardiac resynchronization CRT indications, separately. RESULTS: The analysis cohort included 140 institutions, located on 5 continents, who contributed data to the worldwide survey on CSP. Of these, 127 institutions (90.7%) reported experience implanting CSP leads. CSP and overall device implantation volumes were reported by 84 institutions. In 2019, the median proportion of device implants with CSP, HBP, and/or LBBAP leads attempted were 4.4% (interquartile range [IQR], 1.9-12.5%; range, 0.4-100%), 3.3% (IQR, 1.3-7.1%; range, 0.2-87.0%), and 2.5% (IQR, 0.5-24.0%; range, 0.1-55.6%), respectively. For bradycardia pacing indications, HBP leads, as compared to LBBAP leads, had higher reported implant threshold (median [IQR]: 1.5 V [1.3-2.0 V] vs 0.8 V [0.6-1.0 V], p = 0.0008) and lower ventricular sensing (median [IQR]: 4.0 mV [3.0-5.0 mV] vs. 10.0 mV [7.0-12.0 mV], p < 0.0001). CONCLUSION: In conclusion, CSP lead implantation has been broadly adopted but has yet to become the default approach at most surveyed institutions. As the indications and data for CSP continue to evolve, strategies to educate and promote CSP lead implantation at institutions without CSP lead implantation experience would be necessary.

Hyperlipidaemia and cardiovascular disease: do fibrates have a role?

PURPOSE OF REVIEW: Fibrates continue to be a viable treatment option for mixed atherogenic dyslipidemia, and recent reports from clinical studies have shed new light on the therapeutic utility of fibrates for the prevention of microvascular and macrovascular disease, especially in combination with statins. RECENT FINDINGS: Data from randomized placebo-controlled trials have shown that fibrates reduce nonfatal coronary events but do not confer any benefit on mortality or other adverse cardiovascular outcomes. The ACCORD Lipid trial studied the additive effect of fenofibrate therapy along with low-dose simvastatin therapy in 5,518 patients with type 2 diabetes mellitus, and found that fenofibrate did not affect any of the adverse cardiovascular outcomes, either individually or as part of a composite outcome, after 4.7 years of follow-up. An a priori subgroup analysis showed a significant benefit from fenofibrate-simvastatin combination therapy over simvastatin alone in participants with moderate hypertriglyceridemia and low HDL-cholesterol on major cardiovascular events, consistent with post-hoc analyses of previous fibrate trials. The ACCORD-Eye study adds to the sparse clinical data on the effect of fenofibrate on diabetic retinopathy, and showed that fenofibrate may be used to reduce the risk of progression of diabetic retinopathy even in patients with established disease. The combination of statin and fibrate was well tolerated. SUMMARY: Fibrate therapy does not reduce mortality but may reduce nonfatal coronary events in patients at risk for cardiovascular disease, including those with type 2 diabetes. The ACCORD Lipid study shows that the combination of low-dose simvastatin and fenofibrate is well tolerated, and is potentially cardioprotective in patients with atherogenic 'mixed' dyslipidemia.

COVID-19 and Cardiac Arrhythmias: a Contemporary Review.

Purpose of Review: A significant proportion of patients infected by the severe acute respiratory syndrome-coronavirus (SARS-CoV2) (COVID-19) also have disorders affecting the cardiac rhythm. In this review, we provide an in-depth review of the pathophysiological mechanisms underlying the associated arrhythmic complications of COVID-19 infection and provide pragmatic, evidence-based recommendations for the clinical management of these conditions. Recent Findings: Arrhythmic manifestations of COVID-19 include atrial arrhythmias such as atrial fibrillation or atrial flutter, sinus node dysfunction, atrioventricular conduction abnormalities, ventricular tachyarrhythmias, sudden cardiac arrest, and cardiovascular dysautonomias including the so-called long COVID syndrome. Various pathophysiological mechanisms have been implicated, such as direct viral invasion, hypoxemia, local and systemic inflammation, changes in ion channel physiology, immune activation, and autonomic dysregulation. The development of atrial or ventricular arrhythmias in hospitalized COVID-19 patients has been shown to portend a higher risk of in-hospital death. Summary: Arrhythmic complications from acute COVID-19 infection are commonly encountered in clinical practice, and COVID-19 patients with cardiac complications tend to have worse clinical outcomes than those without. Management of these arrhythmias should be based on published evidence-based guidelines, with special consideration of the acuity of COVID-19 infection, concomitant use of antimicrobial and anti-inflammatory drugs, and the transient nature of some rhythm disorders. Some manifestations, such as the long COVID syndrome, may lead to residual symptoms several months after acute infection. As the pandemic evolves with the discovery of new SARS-CoV2 variants, development and use of newer anti-viral and immuno-modulator drugs, and the increasing adoption of vaccination, clinicians must remain vigilant for other arrhythmic manifestations that may occur in association with this novel but potentially deadly disease.

Virtual Transformation and the Use of Social Media: Cardiac Electrophysiology Education in the Post-COVID-19 Era.

PURPOSE OF REVIEW: The COVID-19 pandemic has significantly impacted the delivery of education for all specialties, including cardiac electrophysiology. This review will provide an overview of the COVID-19 spurred digital transformation of electrophysiology education for practicing clinicians and trainees in electrophysiology and cover the use of social media in these educational efforts. RECENT FINDINGS: Major international, national, and local meetings and electrophysiology fellowship-specific educational sessions have transitioned rapidly to virtual and distanced learning, enhanced by social media. This has allowed for participation in educational activities by electrophysiologists on a wider, more global scale. Social media has also allowed rapid dissemination of new advances, techniques, and research findings in real time and to a global audience, but caution must be exercised as pitfalls also exist. SUMMARY: The digital and social media transformation of cardiac electrophysiology education has arrived and revolutionized the way education is delivered and consumed. Continued hybrid in-person and virtual modalities will provide electrophysiologists the flexibility to choose the best option to suit their individual needs and preferences for continuing education.

Modulation of advanced glycation end products by candesartan in patients with diabetic kidney disease--a dose-response relationship study.

Advanced glycation end products (AGEs) are proinflammatory mediators implicated in the pathogenesis of diabetic kidney disease (DKD). In this study, dose-dependent effects of angiotensin receptor blockade on urinary AGEs were evaluated in patients with DKD. Patients with type 2 diabetes and proteinuria ≥500 mg/d (n = 11) were compared with diabetic controls without DKD (n = 10) and normal controls (n = 11). After a 2-week washout period, DKD participants were treated with candesartan doses progressively increasing from 8, 16, 32, to 64 mg/d every 3 weeks for a total of 12 weeks. Other antihypertensive agents were adjusted to maintain stable blood pressure. At baseline and after each dosing period, blood pressure measurements and 24-hour urine collections were obtained. Urinary carboxymethyl lysine, an AGE biomarker, was reduced over the 12-week dose escalation protocol (r = 0.38, P = 0.01) in DKD participants. Creatinine clearance increased slightly, but albuminuria was unaffected by candesartan administration. Baseline urinary transforming growth factor-ß1 excretion was lower in DKD participants than in controls and did not change during the study period. Reducing kidney exposure to AGEs may be a mechanism of protection by angiotensin receptor blockade in DKD. AGEs may also impact the diabetic kidney through mechanisms independent of transforming growth factor-ß1.

COVID-19 and cardiac arrhythmias: a global perspective on arrhythmia characteristics and management strategies.

BACKGROUND: Cardiovascular and arrhythmic events have been reported in hospitalized COVID-19 patients. However, arrhythmia manifestations and treatment strategies used in these patients have not been well-described. We sought to better understand the cardiac arrhythmic manifestations and treatment strategies in hospitalized COVID-19 patients through a worldwide cross-sectional survey. METHODS: The Heart Rhythm Society (HRS) sent an online survey (via SurveyMonkey) to electrophysiology (EP) professionals (physicians, scientists, and allied professionals) across the globe. The survey was active from March 27 to April 13, 2020. RESULTS: A total of 1197 respondents completed the survey with 50% of respondents from outside the USA, representing 76 countries and 6 continents. Of respondents, 905 (76%) reported having COVID-19-positive patients in their hospital. Atrial fibrillation was the most commonly reported tachyarrhythmia whereas severe sinus bradycardia and complete heart block were the most common bradyarrhythmias. Ventricular tachycardia/ventricular fibrillation arrest and pulseless electrical activity were reported by 4.8% and 5.6% of respondents, respectively. There were 140 of 631 (22.2%) respondents who reported using anticoagulation therapy in all COVID-19-positive patients who did not otherwise have an indication. One hundred fifty-five of 498 (31%) reported regular use of hydroxychloroquine/chloroquine (HCQ) + azithromycin (AZM); concomitant use of AZM was more common in the USA. Sixty of 489 respondents (12.3%) reported having to discontinue therapy with HCQ + AZM due to significant QTc prolongation and 20 (4.1%) reported cases of Torsade de Pointes in patients on HCQ/chloroquine and AZM. Amiodarone was the most common antiarrhythmic drug used for ventricular arrhythmia management. CONCLUSIONS: In this global survey of > 1100 EP professionals regarding hospitalized COVID-19 patients, a variety of arrhythmic manifestations were observed, ranging from benign to potentially life-threatening. Observed adverse events related to use of HCQ + AZM included prolonged QTc requiring drug discontinuation as well as Torsade de Pointes. Large prospective studies to better define arrhythmic manifestations as well as the safety of treatment strategies in COVID-19 patients are warranted.