Association between proactive esophageal cooling and increased lab throughput.

INTRODUCTION: Proactive esophageal cooling has been FDA cleared to reduce the likelihood of ablation-related esophageal injury resulting from radiofrequency (RF) cardiac ablation procedures. Data suggest that procedure times for RF pulmonary vein isolation (PVI) also decrease when proactive esophageal cooling is employed instead of luminal esophageal temperature (LET) monitoring. Reduced procedure times may allow increased electrophysiology (EP) lab throughput. We aimed to quantify the change in EP lab throughput of PVI cases after the introduction of proactive esophageal cooling. METHODS: EP lab throughput data were obtained from three EP groups. We then compared EP lab throughput over equal time frames at each site before (pre-adoption) and after (post-adoption) the adoption of proactive esophageal cooling. RESULTS: Over the time frame of the study, a total of 2498 PVIs were performed over a combined 74 months, with cooling adopted in September 2021, November 2021, and March 2022 at each respective site. In the pre-adoption time frame, 1026 PVIs were performed using a combination of LET monitoring with the addition of esophageal deviation when deemed necessary by the operator. In the post-adoption time frame, 1472 PVIs were performed using exclusively proactive esophageal cooling, representing a mean 43% increase in throughput (p < .0001), despite the loss of two operators during the post-adoption time frame. CONCLUSION: Adoption of proactive esophageal cooling during PVI ablation procedures is associated with a significant increase in EP lab throughput, even after a reduction in total number of operating physicians in the post-adoption group.

Presence of Geriatric Conditions Is Prognostic of Major Bleeding in Older Patients with Atrial Fibrillation: a Cohort Study.

BACKGROUND: In older patients with atrial fibrillation (AF), physical, cognitive, and psychosocial limitations are prevalent. The prognostic value of these conditions for major bleeding is unclear. OBJECTIVE: To determine whether geriatric conditions are prospectively associated with major bleeding in older patients with AF on anticoagulation. DESIGN: Multicenter cohort study with 2-year follow-up from 2016 to 2020 in Massachusetts and Georgia from cardiology, electrophysiology, and primary care clinics. PARTICIPANTS: Diagnosed with AF, age 65 years or older, CHA2DS2-VASc score of 2 or higher, and taking oral anticoagulant (n=1,064). A total of 6507 individuals were screened. MAIN MEASURES: A six-component geriatric assessment of frailty, cognitive function, social support, depressive symptoms, vision, and hearing. Main outcome was major bleeding adjudicated by a physician panel. KEY RESULTS: At baseline, participants were, on average, 75.5 years old and 49% were women. Mean CHA2DS2-VASc score was 4.5 and the mean HAS-BLED score was 3.3. During 2.0 (± 0.4) years of follow-up, 95 (8.9%) participants developed an episode of major bleeding. After adjusting for key covariates and accounting for competing risk from death, cognitive impairment (hazard ratio [HR] 1.62, 95% confidence interval [CI]: 1.02-2.56) and frailty (HR 2.77, 95% CI 1.38-5.58) were significantly associated with the development of major bleeding. CONCLUSIONS: In older patients with AF taking anticoagulants, cognitive impairment and frailty were independently associated with major bleeding.

Runx2 (Runt-Related Transcription Factor 2) Links the DNA Damage Response to Osteogenic Reprogramming and Apoptosis of Vascular Smooth Muscle Cells.

[Figure: see text].

Exploring the role of exposure to green and blue spaces in preventing anxiety and depression among young people aged 14-24 years living in urban settings: A systematic review and conceptual framework.

Despite the growing problem of anxiety and depression amongst young people aged 14-24 years living in urban settings, reviews about the role of exposure to green and blue spaces or nature in preventing anxiety and depression tend to focus on children, adults or sometimes adolescents. This review aims to explore whether exposure to green and blue spaces reduces the risk of anxiety and depression among young people aged 14-24 years living in urban settings and provide a conceptual framework. The academic databases CINAHL plus, Global Health, MEDLINE, ProQuest: Dissertations and Theses, PsycINFO, Scopus and OpenGrey were searched for research published in English between January 2000 and June 2020. All study designs were eligible. All included studies were assessed for quality. Searches identified 9208 sources with 48 meeting the inclusion criteria for the review. Experimental studies provided evidence that walking or being in a green space improves mood and state anxiety immediately following the intervention. Non-randomised evaluations and observational studies suggest that social interaction, physical activity, and mindfulness mediate the relationship between exposure to green space and mental health. We propose that the absence of noise and restorative qualities of green spaces promotes mindfulness and interrupt rumination, which in turn reduce the risk of anxiety disorders and depression. This review and the resulting conceptual framework provide evidence to healthcare professionals about the value of contact with nature and green social prescribing. For policymakers, it provides evidence about the value of bringing the benefits of forests, vegetation and nature into cities, and ensuring that these spaces are accessible and safe for young people to use.

Contemporary procedure characteristics and outcomes of accessory atrioventricular pathway ablations in an integrated community-based health care system using a tiered approach.

BACKGROUND: Since the early descriptions of large series of accessory atrioventricular pathway ablations in adults and adolescents over 20 years ago, there have been limited published reports based on more recent experiences of large referral centers. We aimed to characterize accessory pathway distribution and features in a large community-based population that influence ablation outcomes using a tiered approach to ablation. METHODS: Retrospective analysis of 289 patients (age 14-81) who underwent accessory ablation from 2015-2019 was performed. Pathways were categorized into anteroseptal, left freewall, posteroseptal, and right freewall locations. We analyzed patient and pathway features to identify factors associated with prolonged procedure time parameters. RESULTS: Initial ablation success rate was 94.7% with long-term success rate of 93.4% and median follow-up of 931 days. Accessory pathways were in left freewall (61.6%), posteroseptal (24.6%), right freewall (9.6%), and anteroseptal (4.3%) locations. Procedure outcome was dependent on pathway location. Acute success was highest for left freewall pathways (97.1%) with lowest case times (144 ± 68 min) and fluoroscopy times (15 ± 19 min). Longest procedure time parameters were seen with anteroseptal, left anterolateral, epicardial-coronary sinus, and right anterolateral pathway ablations. CONCLUSIONS: In this community-based adult and adolescent population, majority of the accessory pathways are in the left freewall and posteroseptal region and tend to be more easily ablated. A tiered approach with initial use of standard ablation equipment before the deployment of more advance tools, such as irrigated tips and 3D mapping, is cost effective without sacrificing overall efficacy.

Extracellular Matrix Proteomics Reveals Interplay of Aggrecan and Aggrecanases in Vascular Remodeling of Stented Coronary Arteries.

BACKGROUND: Extracellular matrix (ECM) remodeling contributes to in-stent restenosis and thrombosis. Despite its important clinical implications, little is known about ECM changes post-stent implantation. METHODS: Bare-metal and drug-eluting stents were implanted in pig coronary arteries with an overstretch under optical coherence tomography guidance. Stented segments were harvested 1, 3, 7, 14, and 28 days post-stenting for proteomics analysis of the media and neointima. RESULTS: A total of 151 ECM and ECM-associated proteins were identified by mass spectrometry. After stent implantation, proteins involved in regulating calcification were upregulated in the neointima of drug-eluting stents. The earliest changes in the media were proteins involved in inflammation and thrombosis, followed by changes in regulatory ECM proteins. By day 28, basement membrane proteins were reduced in drug-eluting stents in comparison with bare-metal stents. In contrast, the large aggregating proteoglycan aggrecan was increased. Aggrecanases of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family contribute to the catabolism of vascular proteoglycans. An increase in ADAMTS-specific aggrecan fragments was accompanied by a notable shift from ADAMTS1 and ADAMTS5 to ADAMTS4 gene expression after stent implantation. Immunostaining in human stented coronary arteries confirmed the presence of aggrecan and aggrecan fragments, in particular, at the contacts of the stent struts with the artery. Further investigation of aggrecan presence in the human vasculature revealed that aggrecan and aggrecan cleavage were more abundant in human arteries than in human veins. In addition, aggrecan synthesis was induced on grafting a vein into the arterial circulation, suggesting an important role for aggrecan in vascular plasticity. Finally, lack of ADAMTS-5 activity in mice resulted in an accumulation of aggrecan and a dilation of the thoracic aorta, confirming that aggrecanase activity regulates aggrecan abundance in the arterial wall and contributes to vascular remodeling. CONCLUSIONS: Significant differences were identified by proteomics in the ECM of coronary arteries after bare-metal and drug-eluting stent implantation, most notably an upregulation of aggrecan, a major ECM component of cartilaginous tissues that confers resistance to compression. The accumulation of aggrecan coincided with a shift in ADAMTS gene expression. This study provides the first evidence implicating aggrecan and aggrecanases in the vascular injury response after stenting.

Novel nesprin-1 mutations associated with dilated cardiomyopathy cause nuclear envelope disruption and defects in myogenesis.

Nesprins-1 and -2 are highly expressed in skeletal and cardiac muscle and together with SUN (Sad1p/UNC84)-domain containing proteins and lamin A/C form the LInker of Nucleoskeleton-and-Cytoskeleton (LINC) bridging complex at the nuclear envelope (NE). Mutations in nesprin-1/2 have previously been found in patients with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) as well as dilated cardiomyopathy (DCM). In this study, three novel rare variants (R8272Q, S8381C and N8406K) in the C-terminus of the SYNE1 gene (nesprin-1) were identified in seven DCM patients by mutation screening. Expression of these mutants caused nuclear morphology defects and reduced lamin A/C and SUN2 staining at the NE. GST pull-down indicated that nesprin-1/lamin/SUN interactions were disrupted. Nesprin-1 mutations were also associated with augmented activation of the ERK pathway in vitro and in hearts in vivo. During C2C12 muscle cell differentiation, nesprin-1 levels are increased concomitantly with kinesin light chain (KLC-1/2) and immunoprecipitation and GST pull-down showed that these proteins interacted via a recently identified LEWD domain in the C-terminus of nesprin-1. Expression of nesprin-1 mutants in C2C12 cells caused defects in myoblast differentiation and fusion associated with dysregulation of myogenic transcription factors and disruption of the nesprin-1 and KLC-1/2 interaction at the outer nuclear membrane. Expression of nesprin-1α2 WT and mutants in zebrafish embryos caused heart developmental defects that varied in severity. These findings support a role for nesprin-1 in myogenesis and muscle disease, and uncover a novel mechanism whereby disruption of the LINC complex may contribute to the pathogenesis of DCM.

Physical, cognitive, and psychosocial conditions in relation to anticoagulation satisfaction among elderly adults with atrial fibrillation: The SAGE-AF study.

BACKGROUND: Successful anticoagulation is critical for stroke prevention in adults with atrial fibrillation (AF). Anticoagulation satisfaction is a key indicator of treatment success. While physical, cognitive, and psychosocial limitations are common in elderly AF patients, their associations with anticoagulation satisfaction are unknown. OBJECTIVE: Examine whether anticoagulation satisfaction differs among AF patients with and without physical, cognitive, and psychosocial conditions. METHODS: The study comprised AF patients greater than or equal to 65 years old who were prescribed an oral anticoagulant (warfarin 57%; direct oral anticoagulant [DOAC] 43%). Frailty, cognitive function, social support, depressive symptoms, vision, hearing, and anxiety were assessed using validated measures. Anticoagulation satisfaction was measured using the anticlot treatment scale. RESULTS: Participants (n = 1037, 50% female) were on average 76 years old. The following conditions were prevalent: frailty (14%), cognitive impairment (42%), social isolation (13%), vision impairment (35%), hearing impairment (36%), depression (29%), and anxiety (24%). Average anticlot treatment burden scale was 55 out of 60 (lower burden scales indicating higher perceived burden). Patients with high perceived burden were older, more likely to be female, and receive warfarin. After adjusting for confounders, visual impairment (adjusted odds ratio [95% confidence interval]: 1.7 [1.2-2.4]), depressive symptoms (2.4 [1.6-3.7]), and anxiety (1.8 [1.2-2.7]) were significantly associated with high perceived burden. Different conditions were associated with high perceived burden in warfarin vs DOAC users. CONCLUSION: Physical, cognitive, and psychosocial limitations are prevalent and associated with high perceived anticoagulation burden among elderly AF adults. These conditions merit consideration in anticoagulation prescribing.

Validation of a GPU-Based 3D dose calculator for modulated beams.

A superposition/convolution GPU-accelerated dose computation algorithm (the Calculator) has been recently incorporated into commercial software. The algorithm requires validation prior to clinical use. Three photon energies were examined: conventional 6 MV and 15 MV, and 10 MV flattening filter free (10 MVFFF). For a set of IMRT and VMAT plans based on four of the five AAPM Practice Guideline 5a downloadable datasets, ion chamber (IC) measurements were performed on the water-equivalent phantoms. The average difference between the Calculator and IC was -0.3 ± 0.8% (1SD). The same plans were projected on a phantom containing a biplanar diode array. We used the forthcoming criteria for routine gamma analysis, 3% dose-error (global (G) normalization, 2 mm distance to agreement, and 10% low dose cutoff). The γ (3%G/2 mm) average passing rate was 98.9 ± 2.1%. Measurement-guided three-dimensional dose reconstruction on the patient CT dataset (excluding the Lung) resulted in a similar average agreement rate with the Calculator: 98.2 ± 2.0%. The mean γ (3%G/2 mm) passing rate comparing the Calculator to the TPS (again excluding the Lung) was 99.0 ± 1.0%. Because of the significant inhomogeneity, the Lung case was investigated separately. The calculator has an alternate heterogeneity correction mode that can change the results in the thorax for higher-energy beams (15 MV). As this correction is nonphysical and was optimized for simple slab geometries, its application leads to mixed results when compared to the TPS and independent Monte Carlo calculations, depending on the CT dataset and the plan. The Calculator vs. TPS 15 MV Guideline 5a IMRT and VMAT plans demonstrate 96.3% and 93.4% γ (3%G/2 mm) passing rates respectively. For the lower energies, which should be predominantly used in the thoracic region, the passing rates for the same plans and criteria range from 98.6 to 100%. Overall, the Calculator accuracy is sufficient for the intended use.

CRAF autophosphorylation of serine 621 is required to prevent its proteasome-mediated degradation.

The CRAF protein kinase regulates proliferative, differentiation, and survival signals from activated RAS proteins to downstream effectors, most often by inducing MEK/ERK activation. A well-established model of CRAF regulation involves RAS-mediated translocation of CRAF to the plasma membrane, where it is activated by a series of events including phosphorylation. Here we have discovered a new mode of regulation that occurs prior to this step. By creating a kinase-defective version of CRAF in mice or by use of the RAF inhibitor sorafenib, we show that CRAF must first undergo autophosphorylation of serine 621 (S621). Autophosphorylation occurs in cis, does not involve MEK/ERK activation, and is essential to ensure the correct folding and stability of the protein. In the absence of S621 phosphorylation, CRAF is degraded by the proteasome by mechanisms that do not uniquely rely on the E3 ubiquitin ligase CHIP.

Benefits and challenges of EMR implementations in low resource settings: a state-of-the-art review.

BACKGROUND: The intent of this review is to discover the types of inquiry and range of objectives and outcomes addressed in studies of the impacts of Electronic Medical Record (EMR) implementations in limited resource settings in sub-Saharan Africa. METHODS: A state-of-the-art review characterized relevant publications from bibliographic databases and grey literature repositories through systematic searching, concept-mapping, relevance and quality filter optimization, methods and outcomes categorization and key article analysis. RESULTS: From an initial population of 749 domain articles published before February 2015, 32 passed context and methods filters to merit full-text analysis. Relevant literature was classified by type (e.g., secondary, primary), design (e.g., case series, intervention), focus (e.g., processes, outcomes) and context (e.g., location, organization). A conceptual framework of EMR implementation determinants (systems, people, processes, products) was developed to represent current knowledge about the effects of EMRs in resource-constrained settings and to facilitate comparisons with studies in other contexts. DISCUSSION: This review provides an overall impression of the types and content of health informatics articles about EMR implementations in sub-Saharan Africa. Little is known about the unique effects of EMR efforts in slum settings. The available reports emphasize the complexity and impact of social considerations, outweighing product and system limitations. Summative guides and implementation toolkits were not found but could help EMR implementers. CONCLUSION: The future of EMR implementation in sub-Saharan Africa is promising. This review reveals various examples and gaps in understanding how EMR implementations unfold in resource-constrained settings; and opportunities for new inquiry about how to improve deployments in those contexts.

RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors.

BACKGROUND: Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors. METHODS: We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed. RESULTS: Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L-mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)-pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L-mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor. CONCLUSIONS: Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann-La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.).

Sudden death due to nonarrhythmic cause in a patient with L-TGA.

We report a case of sudden death in a clinically stable adult with l-transposition of the great arteries (l-TGA). Sudden death has been reported to be the leading cause of death in l-TGA and is often attributed to arrhythmias in the absence of another identifiable cause. However, the contribution of nonarrhythmic causes to the burden of sudden death in this population is unknown. Comprehensive postmortem investigation, including autopsy and pacemaker interrogation, demonstrated that the cause of death was massive pulmonary hemorrhage due to stenosis of the patient's mechanical tricuspid (systemic AV) valve. This report highlights the important contribution of nonarrhythmic causes of sudden death in this population and the value of autopsy and device interrogation in determining true cause of death.

Differential effect of anticoagulation according to cognitive function and frailty in older patients with atrial fibrillation.

BACKGROUND: In older patients with atrial fibrillation (AF), cognitive impairment and frailty are prevalent. It is unknown whether the risk and benefit of anticoagulation differ by cognitive function and frailty. METHODS: A total of 1244 individuals with AF with age ≥65 years and a CHADSVASC score ≥2 were recruited from clinics in Massachusetts and Georgia between 2016 and 18 and followed until 2020. At baseline, frailty status and cognitive function were assessed. Hazard ratios of anticoagulation on physician adjudicated outcomes were adjusted by the propensity for receiving anticoagulation and stratified by cognitive function and frailty status. RESULTS: The average age was 75.5 (± 7.1) years, 49% were women, and 86% were prescribed oral anticoagulants. At baseline, 528 (42.4%) participants were cognitively impaired and 172 (13.8%) were frail. The adjusted hazard ratios of anticoagulation for the composite of major bleeding or death were 2.23 (95% confidence interval: 1.08-4.61) among cognitively impaired individuals and 0.94 (95% confidence interval: 0.49-1.79) among cognitively intact individuals (P for interaction = 0.08). Adjusted hazard ratios for anticoagulation were 1.84 (95% confidence interval: 0.66-5.13) among frail individuals and 1.39 (95% confidence interval: 0.84-2.40) among not frail individuals (P for interaction = 0.67). CONCLUSION: Compared with no anticoagulation, anticoagulation is associated with more major bleeding episodes and death in older patients with AF who are cognitively impaired.

Filamentous nuclear actin regulation of PML NBs during the DNA damage response is deregulated by prelamin A.

Nuclear actin participates in a continuously expanding list of core processes within eukaryotic nuclei, including the maintenance of genomic integrity. In response to DNA damage, nuclear actin polymerises into filaments that are involved in the repair of damaged DNA through incompletely defined mechanisms. We present data to show that the formation of nuclear F-actin in response to genotoxic stress acts as a scaffold for PML NBs and that these filamentous networks are essential for PML NB fission and recruitment of microbodies to DNA lesions. Further to this, we demonstrate that the accumulation of the toxic lamin A precursor prelamin A induces mislocalisation of nuclear actin to the nuclear envelope and prevents the establishment of nucleoplasmic F-actin networks in response to stress. Consequently, PML NB dynamics and recruitment to DNA lesions is ablated, resulting in impaired DNA damage repair. Inhibition of nuclear export of formin mDia2 restores nuclear F-actin formation by augmenting polymerisation of nuclear actin in response to stress and rescues PML NB localisation to sites of DNA repair, leading to reduced levels of DNA damage.

Safety of transvenous lead removal in adult congenital heart disease: a national perspective.

INTRODUCTION AND OBJECTIVES: Data are scarce on outcomes of transvenous lead removal (TLR) in adult congenital heart disease (CHD). We evaluated the safety of the TLR procedure in adult CHD patients from a 10-year national database. METHODS: We used the Healthcare Cost and Utilization Project Nationwide Inpatient Sample to identify TLR procedures in adult patients with and without CHD from 2005 to 2014. Outcomes included in-hospital mortality and complications. RESULTS: Of 132 068 adult patients undergoing TLR, 1939 had simple CHD, 657 had complex CHD, and 626 had unclassified CHD. The number of TLR procedures in adult CHD slightly increased from 236 in 2005 to 445 in 2014, with fluctuations over the study period. The overall rate of any complications in the TLR procedure was 16.6% in patients with CHD vs 10.1% in patients without CHD (P <.001). In a propensity score-matched cohort, CHD was associated with a higher risk of any complication after full adjustment vs patients without CHD (adjusted odd ratio, 1.49; 95% confidence interval, 1.11-1.99; P=.007). Simple and complex CHD were associated with 1.5- and 2.1-fold increased risks of any TLR-related complication, respectively. CHD was not associated with an increased risk of in-hospital mortality (adjusted odd ratio, 0.77; 95% confidence interval, 0.42-1.39; P=.386). CONCLUSIONS: Compared with patients without CHD, adult patients with simple and complex CHD undergoing TLR are more likely to have complications but show no increase in mortality.

Rates of Potentially Inappropriate Dosing of Direct-Acting Oral Anticoagulants and Associations With Geriatric Conditions Among Older Patients With Atrial Fibrillation: The SAGE-AF Study.

Background Direct-acting oral anticoagulant (DOAC) dosing guidelines for atrial fibrillation recommend dose alteration based on age, renal function, body weight, and drug-drug interactions. There is paucity of data describing the frequency and factors associated with prescription of potentially inappropriate doses. Methods and Results In the ongoing SAGE-AF (Systematic Assessment of Geriatric Elements in Atrial Fibrillation) study, we performed geriatric assessments (frailty, cognitive impairment, sensory impairments, social isolation, and depression) for participants with atrial fibrillation (age ≥65 years, CHA2DS2VASc ≥2, no anticoagulant contraindications). We developed an algorithm to analyze DOAC dose appropriateness accounting for drug-drug interactions, age, renal function, and body weight. We also examined whether geriatric impairments were related to inappropriate dosing. Of 1064 patients prescribed anticoagulants, 460 received a DOAC. Participants were aged 74±7 years, 49% were women, and 82% were white. A quarter (23%; n=105) of participants received inappropriate DOAC dose, of whom 82 (78%) were underdosed and 23 (22%) were overdosed. Among participants receiving an inappropriate dose, 12 (11%) were identified using the drug-drug interactions criteria and would have otherwise been misclassified. In multivariable regression analyses, older age, higher CHA2DS2VASc score, and history of renal failure were associated with inappropriate DOAC dosing (P<0.05). Geriatric conditions were not associated with inappropriate dosing. Conclusions In this cohort, over 20% of older patients with atrial fibrillation treated with DOACs were prescribed an inappropriate dose, with most being underdosed. Drug-drug interactions were common. Factors that influence prescription of guideline-nonadherent doses may be perception of higher bleeding risk or presence of renal failure in addition to lack of familiarity with dosing guidelines.

Tumor necrosis factor-alpha blocks apoptosis in melanoma cells when BRAF signaling is inhibited.

The protein kinase BRAF, a component of the RAS/RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway, regulates cell fate in response to extracellular signals. Activating mutations in BRAF occur in approximately 70% of human melanomas. The active proteins stimulate constitutive pathway signaling, proliferation, and survival. Thus, inhibition of BRAF signaling in melanoma cells causes cell cycle arrest and induces cell death through apoptosis, validating BRAF as an important therapeutic target. Here, we show that the apoptosis induced by inhibition of BRAF signaling in melanoma cells can be prevented if the cells are treated with tumor necrosis factor (TNF)-alpha. This allows the cells to recover from the inhibition of BRAF signaling and reenter the cell cycle. This effect occurs due to a specific TNF-alpha and BRAF interaction because TNF-alpha does not prevent cell death in the presence of cisplatin, nitrogen mustard or thapsigargin. Furthermore, the cytokines Fas ligand, TNF-related apoptosis-inducing ligand, interleukin (IL)-1, and IL-6 do not prevent cell death when BRAF signaling is inhibited. The survival mechanism requires nuclear factor-kappaB (NF-kappaB) transcription factor activity, which is strongly induced by TNF-alpha in these cells. These findings suggest that drugs that target the BRAF/MEK pathway could be combined with agents that target TNF-alpha and/or NF-kappaB signaling to provide exciting new therapeutic opportunities for the treatment of melanoma.

Clinical Outcomes During Admissions for Heart Failure Among Adults With Congenital Heart Disease.

Background Heart failure (HF) admissions in adults with congenital heart disease (CHD) are becoming more common. We compared in-hospital and readmission events among adults with and without CHD admitted for HF. Methods and Results We identified all admissions with the primary diagnosis of HF among adults in the California State Inpatient Database between January 1, 2005 and January 1, 2012. International Classification of Disease (ICD) codes identified the type of CHD lesion, comorbidities, and in-hospital and 30-day readmissions events. Adjusted odds ratio (AOR, 95% CI) was calculated after adjusting for admission year, age, sex, race, household income, primary payor, and Charlson comorbidity index. Of 203 759 patients admitted for HF, 539 had CHD other than atrial septal defect. Compared with patients admitted for HF without CHD, those with CHD were younger, more often male, and had fewer comorbidities as determined by Charlson comorbidity index. On multivariate analysis, CHD patients admitted for HF had higher odds of length of stay ≥7 days (AOR 2.5 [95% CI 2.0-3.1]), incident arrhythmias (AOR 2.8 [95% CI 1.7-4.5]), and in-hospital mortality (AOR 1.9 [95% CI 1.1-3.1]). Also, CHD patients had lower odds of readmission for HF (AOR 0.6 [95% CI 0.3-0.9]), but similar odds of other 30-day readmission events. Complex CHD patients had higher odds of length of stay ≥7 days (AOR 1.9 [95% CI 1.1-3.3]) than patients with noncomplex CHD lesions, but similar odds of all other clinical outcomes. Conclusions Among patients admitted with the primary diagnosis of HF in California, adults with CHD have substantially higher odds of longer length of stay, incident arrhythmias, and in-hospital mortality compared with non-CHD patients. These results suggest a need for HF risk stratification strategies and management protocols specific for patients with CHD.

Prelamin A mediates myocardial inflammation in dilated and HIV-associated cardiomyopathies.

Cardiomyopathies are complex heart muscle diseases that can be inherited or acquired. Dilated cardiomyopathy can result from mutations in LMNA, encoding the nuclear intermediate filament proteins lamin A/C. Some LMNA mutations lead to accumulation of the lamin A precursor, prelamin A, which is disease causing in a number of tissues, yet its impact upon the heart is unknown. Here, we discovered myocardial prelamin A accumulation occurred in a case of dilated cardiomyopathy, and we show that a potentially novel mouse model of cardiac-specific prelamin A accumulation exhibited a phenotype consistent with inflammatory cardiomyopathy, which we observed to be similar to HIV-associated cardiomyopathy, an acquired disease state. Numerous HIV protease therapies are known to inhibit ZMPSTE24, the enzyme responsible for prelamin A processing, and we confirmed that accumulation of prelamin A occurred in HIV+ patient cardiac biopsies. These findings (a) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (b) have implications for the management of HIV patients with cardiac disease, suggesting protease inhibitors should be replaced with alternative therapies (i.e., nonnucleoside reverse transcriptase inhibitors); and (c) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy.