Association of Atrial Fibrillation Burden and Mortality Among Patients With Cardiac Implantable Electronic Devices.

BACKGROUND: Current estimates of atrial fibrillation (AF)-associated mortality rely on claims- or clinical-derived diagnoses of AF, limit AF to a binary entity, or are confounded by comorbidities. The objective of the present study is to assess the association between device-recognized AF and mortality among patients with cardiac implantable electronic devices capable of sensitive and continuous atrial arrhythmia detection. Secondary outcomes include relative mortality among cohorts with no AF, paroxysmal AF, persistent AF, and permanent AF. METHODS: Using the deidentified Optum Clinformatics US claims database (2015 to 2020) linked to the Medtronic CareLink database, we identified individuals with a cardiac implantable electronic device who transmitted data ≥6 months after implantation. AF burden was assessed during the first 6 months after implantation (baseline period). Subsequent mortality, assessed from claims data, was compared between patients with and those without AF, with adjustment for age, geographic region, insurance type, Charlson Comorbidity Index, and implantation year. RESULTS: Of 21 391 patients (age, 72.9±10.9 years; 56.3% male) analyzed, 7798 (36.5%) had device-recognized AF. During a mean of 22.4±12.9 months (median, 20.1 [12.8-29.7] months) of follow-up, the overall incidence of mortality was 13.5%. Patients with AF had higher adjusted all-cause mortality than patients without AF (hazard ratio, 1.29 [95% CI, 1.20-1.39]; P<0.001). Among those with AF, patients with nonparoxysmal AF had the greatest risk of mortality (persistent AF versus paroxysmal AF: hazard ratio, 1.36 [95% CI, 1.18-1.58]; P<.001; permanent AF versus paroxysmal AF: hazard ratio, 1.23 [95% CI, 1.14-1.34]; P<.001). CONCLUSIONS: After adjustment for potential confounding factors, presence of AF was associated with higher mortality than no AF in our cohort of patients with cardiac implantable electronic devices. Among those with AF, nonparoxysmal AF was associated with the greatest risk of mortality.

Moving the Paradigm Forward for Prediction and Risk-Based Primary Prevention of Heart Failure in Special Populations.

PURPOSE OF REVIEW: Heart failure (HF) treatment paradigms increasingly recognize the importance of primary prevention. This review explores factors that enhance HF risk, summarizes evidence supporting the pharmacologic primary prevention of HF, and notes barriers to the implementation of primary prevention of HF with a focus on female and sexual and gender minority patients. RECENT FINDINGS: HF has pathophysiologic sex-specific distinctions, suggesting that sex-specific preventive strategies may be beneficial. Pharmacologic agents that have shown benefit in reducing the risk of HF address the pathobiology underpinning these sex-specific risk factors. The implementation of pharmacologic therapies for primary prevention of HF needs to consider a risk-based model. Current pharmacotherapies hold mechanistic promise for the primary prevention of HF in females and gender and sexual minorities, although research is needed to understand the specific populations most likely to benefit. There are significant systemic barriers to the equitable provision of HF primary prevention.

Cell cycle-dependent adaptor complex for ClpXP-mediated proteolysis directly integrates phosphorylation and second messenger signals.

The cell-division cycle of Caulobacter crescentus depends on periodic activation and deactivation of the essential response regulator CtrA. Although CtrA is critical for transcription during some parts of the cell cycle, its activity must be eliminated before chromosome replication because CtrA also blocks the initiation of DNA replication. CtrA activity is down-regulated both by dephosphorylation and by proteolysis, mediated by the ubiquitous ATP-dependent protease ClpXP. Here we demonstrate that proteins needed for rapid CtrA proteolysis in vivo form a phosphorylation-dependent and cyclic diguanylate (cdG)-dependent adaptor complex that accelerates CtrA degradation in vitro by ClpXP. The adaptor complex includes CpdR, a single-domain response regulator; PopA, a cdG-binding protein; and RcdA, a protein whose activity cannot be predicted. When CpdR is unphosphorylated and when PopA is bound to cdG, they work together with RcdA in an all-or-none manner to reduce the Km of CtrA proteolysis 10-fold. We further identified a set of amino acids in the receiver domain of CtrA that modulate its adaptor-mediated degradation in vitro and in vivo. Complex formation between PopA and CtrA depends on these amino acids, which reside on alpha-helix 1 of the CtrA receiver domain, and on cdG binding by PopA. These results reveal that each accessory factor plays an essential biochemical role in the regulated proteolysis of CtrA and demonstrate, to our knowledge, the first example of a multiprotein, cdG-dependent proteolytic adaptor.

Characterization of Ciprofloxacin Resistance Levels: Implications for Ototopical Therapy.

HYPOTHESIS: Ciprofloxacin-resistant pathogens are inhibited by high concentrations of ciprofloxacin found in commercially-available ototopical solutions. BACKGROUND: Ciprofloxacin-resistant pathogens in otitis media are currently treated with ototopical ciprofloxacin suspensions. This is done irrespective of laboratory-reported ciprofloxacin susceptibility, under the assumption that the high concentration of ciprofloxacin applied topically is sufficient to overcome antimicrobial resistance. METHODS: We evaluated 34 ciprofloxacin-resistant isolates consisting of Staphylococcus aureus, Pseudomonas aeruginosa, Corynebacterium spp., and Turicella otitidis. Ciprofloxacin minimum inhibitory concentration (MIC) assays and clinical ototopical solution minimum bactericidal concentration (CMBC) assays were performed. RESULTS: Amongst the ciprofloxacin-resistant isolates, ciprofloxacin MICs ranged from 8 to 256 mcg/ml (mean: 87.1 mcg/ml) and CMBCs ranged from 23.4 to 1500 mcg/ml (mean: 237.0 mcg/ml). There were no significant differences with respect to MIC in comparing P. aeruginosa versus Corynebacterium spp. (mean: 53.3 versus 55.2, p = 0.86), S. aureus versus P. aeruginosa (mean: 128.0 versus 53.3, p = 0.34), and S. aureus versus Corynebacterium spp. (mean: 128.0 versus 55.2, p = 0.09). The correlation between ciprofloxacin MIC and CMBC was poor (Pearson's r = -0.08, p = 0.75). CONCLUSIONS: Ciprofloxacin-resistant pathogens commonly recovered from otitis media exhibit highly variable ciprofloxacin MIC and CMBC levels. Ciprofloxacin was able to inhibit growth in all isolates tested at MIC levels less than or equal to 256 mcg/ml; however, CMBC's up to 1500 mcg/ml were observed within that same group. The clinical relevance of these in vitro MICs is unclear due in part to higher bactericidal concentrations (CMBC) in several strains. Our results suggest that treatment failures may be due to a combination of factors rather than high-level resistance alone.

Outcomes of Neoadjuvant Chemoradiation With and Without Systemic Chemotherapy in Resectable and Borderline Resectable Pancreatic Adenocarcinoma.

Introduction: Neoadjuvant therapy is increasingly being used for localized pancreatic adenocarcinoma. While there is evidence supporting neoadjuvant systemic chemotherapy as well as chemoradiation, more evidence is needed to determine whether systemic chemotherapy with chemoradiation offers benefits over chemoradiation alone. This study compares the outcomes of neoadjuvant chemoradiation therapy with and without systemic chemotherapy in resectable and borderline resectable pancreatic cancers. Methods: This retrospective study evaluated patients with resectable and borderline resectable pancreatic adenocarcinoma who completed neoadjuvant chemoradiation therapy with and without systemic chemotherapy prior to surgical resection. 149 patients met inclusion criteria, with 75 having resectable cancer and 74 having borderline resectable cancer. Outcomes included recurrence free and overall survival rates at 6, 12, and 36 months. Results: In resectable pancreatic carcinoma, 72% of patients treated with chemoradiation alone achieved 1 year recurrence free survival compared to 78% of patients treated with systemic chemotherapy and chemoradiation (p = 0.55). 28% of patients treated with chemoradiation alone had 3 years recurrence free survival compared to 31% of patients who received systemic and chemoradiation therapy (p = 0.75). In both treatment groups, 92% of patients lived past 1 year (p = 0.92), and 44% of patients survived at least 3 years (p = 0.95). In borderline resectable pancreatic carcinoma, 50% of patients treated with chemoradiation alone achieved 1 year recurrence free survival compared to 70% of patients treated with systemic chemotherapy and chemoradiation (p = 0.079). The 3 years recurrence free survival was 26 and 29% for the chemoradiation alone group and the systemic chemotherapy plus chemoradiation group, respectively (p = 0.85). There was no significant difference in 1 year overall survival: 85% of patients treated with chemoradiation alone survived compared to 92% of patients treated with systemic chemotherapy and chemoradiation (p = 0.32). Both groups had 41% 3 years overall survival (p = 0.96). Discussion: In resectable and borderline resectable pancreatic adenocarcinoma, there was no significant difference in overall or recurrence free survival between patients treated with chemoradiation with and without systemic chemotherapy. Our findings suggest that systemic neoadjuvant chemotherapy with chemoradiation and chemoradiation alone are efficacious treatments for localized pancreatic carcinoma. This brings into question whether more effective systemic chemotherapy is necessary to increase survival benefit.

Patient and Procedural Factors Associated With Increased Islet Cell Yield in Total Pancreatectomy With Islet Autotransplantation.

OBJECTIVES: Total pancreatectomy with islet autotransplantation (TPIAT) offers symptom relief to highly selected patients with recurrent acute and/or chronic pancreatitis. However, with variable clinical response, it is important to refine islet manipulation technique and patient selection criteria. This study explores the variables associated with high islet cell yield, a driver of success in TPIAT. METHODS: This study evaluated patients who underwent TPIAT at Dartmouth-Hitchcock Medical Center from 2012 to 2016. Odds ratios were calculated for various patient and procedural characteristics. The primary clinical outcome was the number of isolated islet equivalents per kilogram body weight. RESULTS: Thirty-eight patients met inclusion criteria. Patients with no computed tomography or magnetic resonance imaging evidence of chronic pancreatitis, without pancreatic duct stones, and without parenchymal stones were associated with higher odds of success (P = 0.02, P = 0.02, and P = 0.002, respectively). Patients with preoperative glycated hemoglobin greater than 5.6, with islet cell suspensions positive for cultures, and with positive gram stains were associated with lower odds of success (P = 0.02, P = 0.01, and P = 0.02, respectively). CONCLUSIONS: Factors that diminish a successful islet cell harvest during TPIAT include the presence of infected islets, an elevated preoperative glycated hemoglobin, and the presence of pancreatic duct stones.

Prediction of Atypical Ductal Hyperplasia Upgrades Through a Machine Learning Approach to Reduce Unnecessary Surgical Excisions.

PURPOSE: Surgical excision is currently recommended for all occurrences of atypical ductal hyperplasia (ADH) found on core needle biopsies for malignancy diagnoses and treatment of lesions. The excision of all ADH lesions may lead to overtreatment, which results in invasive surgeries for benign lesions in many women. A machine learning method to predict ADH upgrade may help clinicians and patients decide whether combined active surveillance and hormonal therapy is a reasonable alternative to surgical excision. METHODS: The following six machine learning models were developed to predict ADH upgrade from core needle biopsy: gradient-boosting trees, random forest, radial support vector machine (SVM), weighted K-nearest neighbors (KNN), logistic elastic net, and logistic regression. The study cohort consisted of 128 lesions from 124 women at a tertiary academic care center in New Hampshire who had ADH on core needle biopsy and who underwent an associated surgical excision from 2011 to 2017. RESULTS: The best-performing models were gradient-boosting trees (area under the curve [AUC], 68%; accuracy, 78%) and random forest (AUC, 67%; accuracy, 77%). The top five most important features that determined ADH upgrade were age at biopsy, lesion size, number of biopsies, needle gauge, and personal and family history of breast cancer. Using the random forest model, 98% of all malignancies would have been diagnosed through surgical biopsies, whereas 16% of unnecessary surgeries on benign lesions could have been avoided (ie, 87% sensitivity at 45% specificity). CONCLUSION: These results add to the growing body of support for machine learning models as useful aids for clinicians and patients in decisions about the clinical management of ADH.