Machine learning for multidimensional response and survival after cardiac resynchronization therapy using features from cardiac magnetic resonance.

Background: Cardiac resynchronization therapy (CRT) response is complex, and better approaches are required to predict survival and need for advanced therapies. Objective: The objective was to use machine learning to characterize multidimensional CRT response and its relationship with long-term survival. Methods: Associations of 39 baseline features (including cardiac magnetic resonance [CMR] findings and clinical parameters such as glomerular filtration rate [GFR]) with a multidimensional CRT response vector (consisting of post-CRT left ventricular end-systolic volume index [LVESVI] fractional change, post-CRT B-type natriuretic peptide, and change in peak VO2) were evaluated. Machine learning generated response clusters, and cross-validation assessed associations of clusters with 4-year survival. Results: Among 200 patients (median age 67.4 years, 27.0% women) with CRT and CMR, associations with more than 1 response parameter were noted for the CMR CURE-SVD dyssynchrony parameter (associated with post-CRT brain natriuretic peptide [BNP] and LVESVI fractional change) and GFR (associated with peak VO2 and post-CRT BNP). Machine learning defined 3 response clusters: cluster 1 (n = 123, 90.2% survival [best]), cluster 2 (n = 45, 60.0% survival [intermediate]), and cluster 3 (n = 32, 34.4% survival [worst]). Adding the 6-month response cluster to baseline features improved the area under the receiver operating characteristic curve for 4-year survival from 0.78 to 0.86 (P = .02). A web-based application was developed for cluster determination in future patients. Conclusion: Machine learning characterizes distinct CRT response clusters influenced by CMR features, kidney function, and other factors. These clusters have a strong and additive influence on long-term survival relative to baseline features.

Cardiac magnetic resonance defines mechanisms of sex-based differences in outcomes following cardiac resynchronization therapy.

Background: Mechanisms of sex-based differences in outcomes following cardiac resynchronization therapy (CRT) are poorly understood. Objective: To use cardiac magnetic resonance (CMR) to define mechanisms of sex-based differences in outcomes after CRT and describe distinct CMR-based phenotypes of CRT candidates based on sex and non-ischemic/ischemic cardiomyopathy type. Materials and methods: In a prospective study, sex-based differences in three short-term CRT response measures [fractional change in left ventricular end-systolic volume index 6 months after CRT (LVESVI-FC), B-type natriuretic peptide (BNP) 6 months after CRT, change in peak VO2 6 months after CRT], and long-term survival were evaluated with respect to 39 baseline parameters from CMR, exercise testing, laboratory testing, electrocardiograms, comorbid conditions, and other sources. CMR was also used to quantify the degree of left-ventricular mechanical dyssynchrony by deriving the circumferential uniformity ratio estimate (CURE-SVD) parameter from displacement encoding with stimulated echoes (DENSE) strain imaging. Statistical methods included multivariable linear regression with evaluation of interaction effects associated with sex and cardiomyopathy type (ischemic and non-ischemic cardiomyopathy) and survival analysis. Results: Among 200 patients, the 54 female patients (27%) pre-CRT had a smaller CMR-based LVEDVI (p = 0.04), more mechanical dyssynchrony based on the validated CMR CURE-SVD parameter (p = 0.04), a lower frequency of both late gadolinium enhancement (LGE) and ischemic cardiomyopathy (p < 0.0001), a greater RVEF (p = 0.02), and a greater frequency of LBBB (p = 0.01). After categorization of patients into four groups based on cardiomyopathy type (ischemic/non-ischemic cardiomyopathy) and sex, female patients with non-ischemic cardiomyopathy had the lowest CURE-SVD (p = 0.003), the lowest pre-CRT BNP levels (p = 0.01), the lowest post-CRT BNP levels (p = 0.05), and the most favorable LVESVI-FC (p = 0.001). Overall, female patients had better 3-year survival before adjustment for cardiomyopathy type (p = 0.007, HR = 0.45) and after adjustment for cardiomyopathy type (p = 0.009, HR = 0.67). Conclusion: CMR identifies distinct phenotypes of female CRT patients with non-ischemic and ischemic cardiomyopathy relative to male patients stratified by cardiomyopathy type. The more favorable short-term response and long-term survival outcomes in female heart failure patients with CRT were associated with lower indexed CMR-based LV volumes, decreased presence of scar associated with prior myocardial infarction and ICM, and greater CMR-based dyssynchrony with the CURE-SVD.

State Opioid Limits and Volume of Opioid Prescriptions Received by Medicaid Patients.

BACKGROUND: Since early 2016, an increasing number of states passed legislations that limit the duration and/or dosage of initial opioid prescriptions or opioids for acute pain. OBJECTIVE: The objective of this study was to assess changes in the number of opioid prescriptions covered by Medicaid and received by Medicaid patients associated with state implementation of legislative limits on initial opioid prescriptions. RESEARCH DESIGN: We explored the natural experiment resulting from the staggered implementation of state legislative limits. The analysis adopted a Difference-in-Differences framework and controlled for other major state policies bearing implications for prescription opioid use. The main analysis included 26 states that implemented limits from early 2016 to late 2018. A secondary analysis included all 50 states and the District of Columbia. MEASURES: Population-adjusted state-quarter level counts of Schedule II and III opioid prescriptions received by Medicaid patients, based on data from the Medicaid State Drug Utilization Data and state Medicaid enrollment reports for 2013-2018. RESULTS: Implementation of legislative limits on initial opioid prescriptions was associated with a 7% reduction in the number of opioid prescriptions per 100 Medicaid enrollees. Such reduction was largely attributable to a reduction in Schedule II opioid prescriptions. Secondary analysis by including all jurisdictions and sensitivity checks supported the robustness of results. CONCLUSION: The recent implementation of state legislative limits on initial opioid prescriptions was associated with meaningful reductions in the volume of Schedule II opioid prescriptions received by Medicaid patients.

Lytic transglycosylases RlpA and MltC assist in Vibrio cholerae daughter cell separation.

The cell wall is a crucial structural feature in the vast majority of bacteria and comprises a covalently closed network of peptidoglycan (PG) strands. While PG synthesis is important for survival under many conditions, the cell wall is also a dynamic structure, undergoing degradation and remodeling by 'autolysins', enzymes that break down PG. Cell division, for example, requires extensive PG remodeling, especially during separation of daughter cells, which depends heavily upon the activity of amidases. However, in Vibrio cholerae, we demonstrate that amidase activity alone is insufficient for daughter cell separation and that lytic transglycosylases RlpA and MltC both contribute to this process. MltC and RlpA both localize to the septum and are functionally redundant under normal laboratory conditions; however, only RlpA can support normal cell separation in low-salt media. The division-specific activity of lytic transglycosylases has implications for the local structure of septal PG, suggesting that there may be glycan bridges between daughter cells that cannot be resolved by amidases. We propose that lytic transglycosylases at the septum cleave PG strands that are crosslinked beyond the reach of the highly regulated activity of the amidase and clear PG debris that may block the completion of outer membrane invagination.

Genetic Determinants of Penicillin Tolerance in Vibrio cholerae.

Many bacteria are resistant to killing (tolerant) by typically bactericidal antibiotics due to their ability to counteract drug-induced cell damage. Vibrio cholerae, the cholera agent, displays an unusually high tolerance to diverse inhibitors of cell wall synthesis. Exposure to these agents, which in other bacteria leads to lysis and death, results in a breakdown of the cell wall and subsequent sphere formation in V. cholerae Spheres readily recover to rod-shaped cells upon antibiotic removal, but the mechanisms mediating the recovery process are not well characterized. Here, we found that the mechanisms of recovery are dependent on environmental conditions. Interestingly, on agarose pads, spheres undergo characteristic stages during the restoration of rod shape. Drug inhibition and microscopy experiments suggest that class A penicillin binding proteins (aPBPs) play a more active role than the Rod system, especially early in sphere recovery. Transposon insertion sequencing (TnSeq) analyses revealed that lipopolysaccharide (LPS) and cell wall biogenesis genes, as well as the sigma E cell envelope stress response, were particularly critical for recovery. LPS core and O-antigen appear to be more critical for sphere formation/integrity and viability than lipid A modifications. Overall, our findings demonstrate that the outer membrane is a key contributor to beta lactam tolerance and suggest a role for aPBPs in cell wall biogenesis in the absence of rod-shape cues. Factors required for postantibiotic recovery could serve as targets for antibiotic adjuvants that enhance the efficacy of antibiotics that inhibit cell wall biogenesis.