Trends and predictions of metabolic risk factors for acute myocardial infarction: findings from a multiethnic nationwide cohort.

Background: Understanding the trajectories of metabolic risk factors for acute myocardial infarction (AMI) is necessary for healthcare policymaking. We estimated future projections of the incidence of metabolic diseases in a multi-ethnic population with AMI. Methods: The incidence and mortality contributed by metabolic risk factors in the population with AMI (diabetes mellitus [T2DM], hypertension, hyperlipidemia, overweight/obesity, active/previous smokers) were projected up to year 2050, using linear and Poisson regression models based on the Singapore Myocardial Infarction Registry from 2007 to 2018. Forecast analysis was stratified based on age, sex and ethnicity. Findings: From 2025 to 2050, the incidence of AMI is predicted to rise by 194.4% from 482 to 1418 per 100,000 population. The largest percentage increase in metabolic risk factors within the population with AMI is projected to be overweight/obesity (880.0% increase), followed by hypertension (248.7% increase), T2DM (215.7% increase), hyperlipidemia (205.0% increase), and active/previous smoking (164.8% increase). The number of AMI-related deaths is expected to increase by 294.7% in individuals with overweight/obesity, while mortality is predicted to decrease by 11.7% in hyperlipidemia, 29.9% in hypertension, 32.7% in T2DM and 49.6% in active/previous smokers, from 2025 to 2050. Compared with Chinese individuals, Indian and Malay individuals bear a disproportionate burden of overweight/obesity incidence and AMI-related mortality. Interpretation: The incidence of AMI is projected to continue rising in the coming decades. Overweight/obesity will emerge as fastest-growing metabolic risk factor and the leading risk factor for AMI-related mortality. Funding: This research was supported by the NUHS Seed Fund (NUHSRO/2022/058/RO5+6/Seed-Mar/03) and National Medical Research Council Research Training Fellowship (MOH-001131). The SMIR is a national, ministry-funded registry run by the National Registry of Diseases Office and funded by the Ministry of Health, Singapore.

Spatial cognition training rapidly induces cortical plasticity in blind navigation: Transfer of training effect & Granger causal connectivity analysis.

How is the cortical navigation network reorganized by the Likova Cognitive-Kinesthetic Navigation Training? We measured Granger-causal connectivity of the frontal-hippocampal-insular-retrosplenial-V1 network of cortical areas before and after this one-week training in the blind. Primarily top-down influences were seen during two tasks of drawing-from-memory (drawing complex maps and drawing the shortest path between designated map locations), with the dominant role being congruent influences from the egocentric insular to the allocentric spatial retrosplenial cortex and the amodal-spatial sketchpad of V1, with concomitant influences of the frontal cortex on these areas. After training, and during planning-from-memory of the best on-demand path, the hippocampus played a much stronger role, with the V1 sketchpad feeding information forward to the retrosplenial region. The inverse causal influences among these regions generally followed a recursive feedback model of the opposite pattern to a subset of congruent influences. Thus, this navigational network reorganized its pattern of causal influences with task demands and the navigation training, which produced marked enhancement of the navigational skills.

Bone bending strength and BMD of female athletes in volleyball, soccer, and long-distance running.

PURPOSE: The purpose of the study was to determine whether sports training comprised of (1) high-impact loading sport in volleyball (VOL), (2) odd impact loading sport in soccer (SOC), and (3) low impact sport in distance running (RUN) were associated with tibial bending strength and calcaneus bone mineral density (BMD), and ulnar bending strength and wrist BMD. METHOD: Female athletes comprised of 13 VOL, 22 SOC, and 22 RUN participated in the study. Twenty-three female non-athletes (NA) served as the comparison group. Tibial and ulnar bending strength (EI, Nm2) were assessed using a mechanical response tissue analyzer (MRTA). Calcaneus and wrist BMD were assessed using a peripheral X-ray absorptiometry. Group means differences among the study groups were determined using ANCOVA with age, weight, height, percent body fat, ethnicity/race, and training history serving as covariates. RESULTS: Tibial EI of VOL (228.3 ± 138 Nm2) and SOC (208.6 ± 115 Nm2) were greater (p < 0.05) compared to NA (101.2 ± 42 Nm2). Ulnar EI of SOC (54.9 ± 51 Nm2) was higher (p < 0.05) than NA (27.2 ± 9 Nm2). Calcaneus BMD of VOL (0.618 ± 0.12 g/cm2), SOC (0.621 ± 0.009 g/cm2), and RUN (0.572 ± 0.007 g/cm2) were higher (p < 0.05) than NA (0.501 ± 0.08 g/cm2), but not different between athletic groups. Wrist BMD of VOL (0.484 ± .06 g/cm2) and SOC (0.480 ± 0.06 g/cm2) were higher (p < 0.05) than NA (0.443 ± 0.04 g/cm2). CONCLUSIONS: Female VOL athletes exhibit greater tibial bending strength than RUN and NA, but not greater than SOC. Female SOC athletes exhibit greater ulnar bending strength and wrist BMD than NA.

Prevalence and Prognostic Implications of Moderate or Severe Mitral Regurgitation in Patients with Bicuspid Aortic Valve.

BACKGROUND: Significant (moderate or greater) mitral regurgitation (MR) could augment the hemodynamic effects of aortic valvular disease in patients with bicuspid aortic valve (BAV), imposing a greater hemodynamic burden on the left ventricle and atrium, possibly culminating in a faster onset of left ventricular dilation and/or symptoms. The aim of this study was to determine the prevalence and prognostic implications of significant MR in patients with BAV. METHODS: In this large, multicenter, international registry, a total of 2,932 patients (mean age, 48 ± 18 years; 71% men) with BAV were identified. All patients were evaluated for the presence of significant primary or secondary MR by transthoracic echocardiography and were followed up for the end points of all-cause mortality and event-free survival. RESULTS: Overall, 147 patients (5.0%) had significant primary (1.5%) or secondary (3.5%) MR. Significant MR was associated with all-cause mortality (hazard ratio [HR], 2.80; 95% CI, 1.91-4.11; P < .001) and reduced event-free survival (HR, 1.97; 95% CI, 1.58-2.46; P < .001) on univariable analysis. MR was not associated with all-cause mortality (adjusted HR, 1.33; 95% CI, 0.85-2.07; P = .21) or event-free survival (adjusted HR, 1.10; 95% CI, 0.85-1.42; P = .49) after multivariable adjustment. However, sensitivity analyses demonstrated that significant MR not due to aortic valve disease retained an independent association with mortality (adjusted HR, 1.81; 95% CI, 1.04-3.15; P = .037). Subgroup analyses demonstrated an independent association between significant MR and all-cause mortality for individuals with significant aortic regurgitation (HR, 2.037; 95% CI, 1.025-4.049; P = .042), although this association was not observed for subgroups with significant aortic stenosis or without significant aortic valve dysfunction. CONCLUSIONS: Significant MR is uncommon in patients with BAV. Following adjustment for important confounding variables, significant MR was not associated with adverse prognosis in this large study of patients with BAV, except for the patient subgroup with moderate to severe aortic regurgitation. In addition, significant MR not due to aortic valve disease demonstrated an independent association with all-cause mortality.

Impact of Left Ventricular Ejection Fraction on Clinical Outcomes in Bicuspid Aortic Valve Disease.

BACKGROUND: The prognostic impact of left ventricular ejection fraction (LVEF) in patients with bicuspid aortic valve (BAV) disease has not been previously studied. OBJECTIVES: The purpose of this study was to determine the prognostic impact of LVEF in BAV patients according to the type of aortic valve dysfunction. METHODS: We retrospectively analyzed the data collected in 2,672 patients included in an international registry of patients with BAV. Patients were classified according to the type of aortic valve dysfunction: isolated aortic stenosis (AS) (n = 749), isolated aortic regurgitation (AR) (n = 554), mixed aortic valve disease (MAVD) (n = 190), or no significant aortic valve dysfunction (n = 1,179; excluded from this analysis). The study population was divided according to LVEF strata to investigate its impact on clinical outcomes. RESULTS: The risk of all-cause mortality and the composite endpoint of aortic valve replacement or repair (AVR) and all-cause mortality increased when LVEF was <60% in the whole cohort as well as in the AS and AR groups, and when LVEF was <55% in MAVD group. In multivariable analysis, LVEF strata were significantly associated with increased rate of mortality (LVEF 50%-59%: HR: 1.83 [95% CI: 1.09-3.07]; P = 0.022; LVEF 30%-49%: HR: 1.97 [95% CI: 1.13-3.41]; P = 0.016; LVEF <30%: HR: 4.20 [95% CI: 2.01-8.75]; P < 0.001; vs LVEF 60%-70%, reference group). CONCLUSIONS: In BAV patients, the risk of adverse clinical outcomes increases significantly when the LVEF is <60%. These findings suggest that LVEF cutoff values proposed in the guidelines to indicate intervention should be raised from 50% to 60% in AS or AR and 55% in MAVD.

Left ventricular remodelling in bicuspid aortic valve disease.

AIMS: Characterization of left ventricular (LV) geometric pattern and LV mass could provide an important insight into the pathophysiological adaptations of the LV to pressure and/or volume overload in patients with bicuspid aortic valve (BAV) and significant (≥moderate) aortic valve (AV) disease. This study aimed to characterize LV remodelling and its prognostic impact in patients with BAV according to the predominant type of valvular dysfunction. METHODS AND RESULTS: In this international, multicentre BAV registry, 1345 patients [51.0 (37.0-63.0) years, 71% male] with significant AV disease were identified. Patients were classified as having isolated aortic stenosis (AS) (n = 669), isolated aortic regurgitation (AR) (n = 499) or mixed aortic valve disease (MAVD) (n = 177). LV hypertrophy was defined as a LV mass index >115 g/m2 in males and >95 g/m2 in females. LV geometric pattern was classified as (i) normal geometry: no LV hypertrophy, relative wall thickness (RWT) ≤0.42, (ii) concentric remodelling: no LV hypertrophy, RWT >0.42, (iii) concentric hypertrophy: LV hypertrophy, RWT >0.42, and (iv) eccentric hypertrophy: LV hypertrophy, RWT ≤0.42. Patients were followed-up for the endpoints of event-free survival (defined as a composite of AV repair/replacement and all-cause mortality) and all-cause mortality. Type of AV dysfunction was related to significant variations in LV remodelling. Higher LV mass index, i.e. LV hypertrophy, was independently associated with the composite endpoint for patients with isolated AS [hazard ratio (HR) 1.08 per 25 g/m2, 95% confidence interval (CI) 1.00-1.17, P = 0.046] and AR (HR 1.19 per 25 g/m2, 95% CI 1.11-1.29, P < 0.001), but not for those with MAVD. The presence of concentric remodelling, concentric hypertrophy and eccentric hypertrophy were independently related to the composite endpoint in patients with isolated AS (HR 1.54, 95% CI 1.06-2.23, P = 0.024; HR 1.68, 95% CI 1.17-2.42, P = 0.005; HR 1.59, 95% CI 1.03-2.45, P = 0.038, respectively), while concentric hypertrophy and eccentric hypertrophy were independently associated with the combined endpoint for those with isolated AR (HR 2.49, 95% CI 1.35-4.60, P = 0.004 and HR 3.05, 95% CI 1.71-5.45, P < 0.001, respectively). There was no independent association observed between LV remodelling and the combined endpoint for patients with MAVD. CONCLUSIONS: LV hypertrophy or remodelling were independently associated with the composite endpoint of AV repair/replacement and all-cause mortality for patients with isolated AS and isolated AR, although not for patients with MAVD.

Prognostic implications of left atrial dilation in aortic regurgitation due to bicuspid aortic valve.

OBJECTIVE: To investigate the prognostic value of left atrial volume index (LAVI) in patients with moderate to severe aortic regurgitation (AR) and bicuspid aortic valve (BAV). METHODS: 554 individuals (45 (IQR 33-57) years, 80% male) with BAV and moderate or severe AR were selected from an international, multicentre registry. The association between LAVI and the combined endpoint of all-cause mortality or aortic valve surgery was investigated with Cox proportional hazard regression analyses. RESULTS: Dilated LAVI was observed in 181 (32.7%) patients. The mean indexed aortic annulus, sinus of Valsalva, sinotubular junction and ascending aorta diameters were 13.0±2.0 mm/m2, 19.4±3.7 mm/m2, 16.5±3.8 mm/m2 and 20.4±4.5 mm/m2, respectively. After a median follow-up of 23 (4-82) months, 272 patients underwent aortic valve surgery (89%) or died (11%). When compared with patients with normal LAVI (<35 mL/m2), those with a dilated LAVI (≥35 mL/m2) had significantly higher rates of aortic valve surgery or mortality (43% and 60% vs 23% and 36%, at 1 and 5 years of follow-up, respectively, p<0.001). Dilated LAVI was independently associated with reduced event-free survival (HR=1.450, 95% CI 1.085 to 1.938, p=0.012) after adjustment for LV ejection fraction, aortic root diameter, LV end-diastolic diameter and LV end-systolic diameter. CONCLUSIONS: In this large, multicentre registry of patients with BAV and moderate to severe AR, left atrial dilation was independently associated with reduced event-free survival. The role of this parameter for the risk stratification of individuals with significant AR merits further investigation.

Synthesis of Quaternary Carbon Stereogenic Centers by Diastereoselective Conjugate Addition of Boron-Stabilized Allylic Nucleophiles to Enones.

A method for the site-selective and diastereoselective conjugate addition of boron-stabilized allylic nucleophiles to α,ß-unsaturated ketones is disclosed. Transformations involve easily prepared γ,γ-disubstituted allyldiboron reagents and proceed in the presence of a fluoride activator at 80 °C. Reactions proceed with a wide variety of enones and allyldiboron reagents efficiently to deliver ketone products that contain otherwise difficult-to-access vicinal ß-tertiary and γ-quaternary carbon stereogenic centers and an alkenylboron moiety. The utility of the method is highlighted by several transformations, including cross-coupling and carbocyclizations.

The Impact of Different Modes of Exercise Training on Bone Mineral Density in Older Postmenopausal Women: A Systematic Review and Meta-analysis Research.

Effectiveness of exercise on bone mass is closely related to the mode of exercise training regimen, as well as the study design. This study aimed to determine the effect of different modes of exercise training on lumbar spine and femoral neck bone mineral density (BMD) in older postmenopausal women (PMW). PubMed, CINAHL, Medline, Google Scholar, and Scopus databases and reference lists of included studies were searched up until March 25, 2019 for randomized controlled trials (RCTs) that evaluated the effectiveness of various modes of exercise training in PMW. Sixteen RCTs with 1624 subjects were included. Our study found no significant change in both lumbar spine and femoral neck BMD following exercise training (MD: 0.01 g/cm2; 95% confidence interval (CI) [- 0.01, 0.02] and MD: 0.00 g/cm2; 95% CI [- 0.01, 0.01], respectively). However, subgroup analysis by type of exercise training revealed that lumbar spine BMD (MD: 0.01; 95% CI [0.00, 0.02]) raised significantly when whole-body vibration (WBV) was employed as intervention compared with RCTs that utilized aerobic (MD: - 0.01; 95% CI [- 0.02, - 0.01]), resistance (MD: 0.01; 95% CI [- 0.04, 0.06]), and combined training (MD: 0.03; 95% CI [- 0.01, 0.08]). On the other hand, lumbar spine BMD (MD: - 0.01; 95% CI [- 0.02, - 0.01]) reduced significantly when aerobic exercise training was used as intervention compared with RCTs that utilized resistance training, combined training, and WBV. By contrast, these analyses did not have significant effect on change in femoral neck BMD. WBV is an effective method to improve lumbar spine BMD in older PMW.

Prognostic implications of left ventricular global longitudinal strain in patients with bicuspid aortic valve disease and preserved left ventricular ejection fraction.

AIMS: In patients with bicuspid aortic valve (BAV) and preserved left ventricular (LV) ejection fraction (EF), the frequency of impaired LV global longitudinal strain (GLS) and its prognostic implications are unknown. The present study evaluated the proportion and prognostic value of impaired LV GLS in patients with BAV and preserved LVEF. METHODS AND RESULTS: Five hundred and thirteen patients (68% men; mean age 44 ± 18 years) with BAV and preserved LVEF (>50%) were divided into five groups according to the type of BAV dysfunction: (i) normal function BAV, (ii) mild aortic stenosis (AS) or aortic regurgitation (AR), (iii) ≥moderate isolated AS, (iv) ≥moderate isolated AR, and (v) ≥moderate mixed AS and AR. LV systolic dysfunction based on 2D speckle-tracking echocardiography was defined as a cut-off value of LVGLS (-13.6%). The primary outcome was aortic valve intervention or all-cause mortality. The proportion of patients with LVGLS ≤-13.6% was the highest in the normal BAV group (97%) and the lowest in the group with moderate and severe mixed AS and AR (79%). During a median follow-up of 10 years, 210 (41%) patients underwent aortic valve replacement and 17 (3%) died. Patients with preserved LV systolic function (LVGLS ≤ -13.6%) had significantly better event-free survival compared to those with impaired LV systolic function (LVGLS > -13.6%). LVGLS was independently associated with increased risk of events (mainly aortic valve replacement): hazard ratio 1.09; P < 0.001. CONCLUSION: Impaired LVGLS in BAV with preserved LVEF is not infrequent and was independently associated with increased risk of events (mainly aortic valve replacement events).

A Novel Surgical Aid to Achieve Optimal Positioning of Adjacent Implants in Fully Edentulous Mandibular Cases.

The 3-dimensional implant position is critical in achieving a successful surgical and prosthetic outcome for an implant-supported restoration. In an edentulous mandibular arch, the lack of neighboring reference points and the nature of the resorptive process make ideal surgical implant placement difficult to achieve. As the edentulous mandibular ridge resorbs lingually and apically, the ideal prosthetic tooth positions often may be located facial to the ridge crest. Achieving proper implant position requires use of a guide that takes into consideration the location of the existing ridge in addition to ideal tooth position. This article describes the use of an adaptable, metal, linked implant position guide that utilizes interimplant spacing of 5 mm, 7 mm, or 9 mm between adjacent tooth positions throughout the arch to aid in keeping adjacent implants parallel and symmetrical to the contralateral side while also respecting the ideal natural tooth dimensions and occlusion. The use of the guide is demonstrated in three cases of mandibular edentulism.

Catalytic Enantioselective Synthesis of 1,4-Keto-Alkenylboronate Esters and 1,4-Dicarbonyls.

A catalytic enantioselective method for the synthesis of 1,4-keto-alkenylboronate esters by a rhodium-catalyzed conjugate addition pathway is disclosed. A variety of novel, bench-stable alkenyl gem-diboronate esters are synthesized. These easily accessible reagents react smoothly with a collection of cyclic α,ß-unsaturated ketones, generating a new C-C bond and stereocenter. Products are isolated in up to 99 % yield with greater than 20:1 E/Z and greater than 99:1 e.r. Mechanistic studies show the site-selectivity of transmetalation and reactivity is ligand dependent. The utility of the approach is highlighted by gram-scale synthesis of enantioenriched cyclic 1,4-diketones, and stereoselective transformations of the products by hydrogenation, allylation, and isomerization.

Analysis of Vascular Event Risk After Herpes Zoster From 2007 to 2014 US Insurance Claims Data.

OBJECTIVE: To estimate the risk of transient ischemic attack (TIA), stroke, and myocardial infarction in periods covering 4 weeks before to 52 weeks after herpes zoster (HZ) diagnosis in US adults. PATIENTS AND METHODS: This retrospective study (GSK study identifier: HO-15-15771) with matched cohorts used the Truven Health MarketScan Commercial and Medicare claims data set linked with obesity and smoking status information. Patients 18 years and older at the date of HZ diagnosis and 1-year pre- and post-HZ diagnosis continuous insurance enrollment (from January 1, 2007, through December 31, 2014) were propensity score matched to controls in terms of demographic characteristics, risk factors for vascular events, other comorbid disorders, general health, obesity, and smoking status. A post hoc sensitivity analysis was performed not matching for obesity and smoking status information. Adjusted incidence rate ratios (IRRs) were estimated using multivariate Poisson models during an aggregate period (1-month before and after the index date). RESULTS: A total of 23,339 patients with HZ were matched to 46,378 controls (mean age, 56 years; 45,173 [65%] women). During the aggregate period, patients with HZ were statistically significantly more likely to suffer a TIA: IRRs for all patients and patients aged 18 to 49 years were 1.56 (95% confidence interval [CI], 1.13-2.15) and 5.12 (95% CI, 1.37-19.10), respectively (P<.05); the respective IRRs for stroke were 1.40 (95% CI, 0.93-2.11) and 8.12 (95% CI, 0.93-71.27). In the sensitivity analysis, IRRs for TIA and stroke were statistically significantly increased regardless of age. CONCLUSION: Herpes zoster was associated with an increased risk of composite events, TIA, and stroke in adults in the period around diagnosis. More research on the HZ and vascular risk association is needed. GSK STUDY IDENTIFIER: HO-15-15771.

A Novel Multi-Biomarker Assay for Non-Invasive Quantitative Monitoring of Kidney Injury.

The current standard of care measures for kidney function, proteinuria, and serum creatinine (SCr) are poor predictors of early-stage kidney disease. Measures that can detect chronic kidney disease in its earlier stages are needed to enable therapeutic intervention and reduce adverse outcomes of chronic kidney disease. We have developed the Kidney Injury Test (KIT) and a novel KIT Score based on the composite measurement and validation of multiple biomarkers across a unique set of 397 urine samples. The test is performed on urine samples that require no processing at the site of collection and without target sequencing or amplification. We sought to verify that the pre-defined KIT test, KIT Score, and clinical thresholds correlate with established chronic kidney disease (CKD) and may provide predictive information on early kidney injury status above and beyond proteinuria and renal function measurements alone. Statistical analyses across six DNA, protein, and metabolite markers were performed on a subset of residual spot urine samples with CKD that met assay performance quality controls from patients attending the clinical labs at the University of California, San Francisco (UCSF) as part of an ongoing IRB-approved prospective study. Inclusion criteria included selection of patients with confirmed CKD and normal healthy controls; exclusion criteria included incomplete or missing information for sample classification, logistical delays in transport/processing of urine samples or low sample volume, and acute kidney injury. Multivariate logistic regression of kidney injury status and likelihood ratio statistics were used to assess the contribution of the KIT Score for prediction of kidney injury status and stage of CKD as well as assess the potential contribution of the KIT Score for detection of early-stage CKD above and beyond traditional measures of renal function. Urine samples were processed by a proprietary immunoprobe for measuring cell-free DNA (cfDNA), methylated cfDNA, clusterin, CXCL10, total protein, and creatinine. The KIT Score and stratified KIT Score Risk Group (high versus low) had a sensitivity and specificity for detection of kidney injury status (healthy or CKD) of 97.3% (95% CI: 94.6-99.3%) and 94.1% (95% CI: 82.3-100%). In addition, in patients with normal renal function (estimated glomerular filtration rate (eGFR) ≥ 90), the KIT Score clearly identifies those with predisposing risk factors for CKD, which could not be detected by eGFR or proteinuria (p < 0.001). The KIT Score uncovers a burden of kidney injury that may yet be incompletely recognized, opening the door for earlier detection, intervention and preservation of renal function.

The Effect of Early Response to GLP-1 RA Therapy on Long-Term Adherence and Persistence Among Type 2 Diabetes Patients in the United States.

BACKGROUND: Treatment adherence and persistence are crucial to achieve glycemic control in patients with type 2 diabetes (T2D). Early response to a new therapy may lead to improved treatment adherence and associated outcomes. OBJECTIVE: To assess the effect of early response to glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy, as indicated by reduced hemoglobin A1c (A1c) and body weight, on long-term adherence and persistence. METHODS: Adults aged ≥ 18 years with T2D initiated with GLP-1 RA therapy after January 1, 2010, were identified from the IBM Explorys Therapeutic Dataset. Patients were required to have health care utilization ≥ 6 months before and ≥ 18 months after the index prescription. Changes in A1c and body weight from baseline through 6 months were assessed for all patients; early response was defined by > 1% reduction in A1c and > 3% reduction in body weight within 3-6 months. Adherence (assessed as the proportion of days covered [PDC] ≥ 80%) and nonpersistence/discontinuation (indicated by a gap in therapy ≥ 60 days) over 18 months were evaluated among early responders versus nonresponders. Multivariable logistic regression was used to assess the effect of early response to GLP-1 RA therapy on adherence and discontinuation over 18 months. RESULTS: Among 8,329 identified patients, 33.3% and 31.2% experienced early response as indicated by reductions in A1c > 1% point and in body weight > 3% from baseline, respectively. Significantly higher proportions (P < 0.001) of early responders in both reduced A1c and body weight were adherent over 18 months compared with patients without an early response (A1c: 45.0% vs. 37.1%; body weight: 43.3% vs. 38.0%). Significantly lower proportions (P < 0.001) of early responders discontinued over 18 months compared with patients without an early response (A1c: 61.4% vs. 67.9%; body weight: 61.9% vs. 67.5%). After controlling for baseline demographic and clinical characteristics including baseline weight, baseline A1c, oral antidiabetes drug use, insulin use, and the presence of comorbidity of diabetes, patients were more likely to be adherent over 18 months if they had reductions in A1c > 1% (OR = 1.59, 95% CI = 1.36-1.85) or body weight reduction > 3% (OR = 1.18, 95% CI = 1.02-1.36) at 3-6 months compared with those without an early response. Similarly, the early responders had significantly lower likelihood of discontinuation compared with those without early response (A1c > 1%; OR = 0.62, 95% CI = 0.53-0.72; body weight > 3%; OR = 0.81, 95% CI = 0.70-0.94). CONCLUSIONS: Early response to GLP-1 RA therapy was associated with significantly increased adherence and reduced likelihood of discontinuation. DISCLOSURES: Funding to conduct this study was provided to IBM Watson Health by Novo Nordisk A/S. The analysis was conducted independently by IBM Watson Health. Novo Nordisk A/S and IBM Watson Health collaborated on study design and interpretation of results. At the time of this study, Durden and Laing were employed by IBM Watson Health and received funding from Novo Nordisk to conduct this study. Fowler is employed by IBM Watson Health. Panton and Mocevic were employed by Novo Nordisk while this study was conducted. A portion of these results were presented at the AMCP Managed Care & Specialty Pharmacy Annual Meeting 2018; April 23-26, 2018; Boston, MA, where it was awarded with a bronze ribbon.

Three-year follow-up optical coherence tomography of under-expanded drug-eluting stent in-stent restenosis treated with ABSORB bioresorbable vascular scaffold following ultra-high pressure pre-dilatation.

The management of in-stent restenosis continues to be a common challenge in modern interventional cardiology. Drug-eluting stents have emerged to be an effective treatment following bare-metal stent in-stent restenosis as compared with drug-coated balloon angioplasty and repeat bare-metal stenting. The addition of another metallic layer is however undesirable and may limit further treatment options. In the last few years, everolimus-eluting bioresorbable vascular scaffolds have become available in treating native coronary artery disease with complete hydrolysis into water and carbon dioxide within 3-5 years. To exploit this property, we successfully used it to manage a case of drug-eluting stent in-stent restenosis from a previously under-expanded stent as demonstrated in this case. Small registry series have also recently been published supporting favorable outcomes with this approach. To the best of our knowledge, this case has the longest optical coherence tomography follow-up beyond 3 years. .

Stereoselective Tandem Bis-Electrophile Couplings of Diborylmethane.

A copper-catalyzed three-component linchpin coupling method for the stereoselective union of readily available epoxides and allyl electrophiles is disclosed. Transformations employ [B(pin)]2-methane as a conjunctive reagent, resulting in the formation of two C-C bonds at a single carbon center bearing a C(sp3) organoboron functional group. Products are obtained in 42-99% yield, and up to >20:1 dr. The utility of the approach is highlighted by stereospecific transformations entailing allylation, tandem cross coupling, and application to the synthesis 1,3-polyol motifs.

Economic analysis and budget impact of clostridial collagenase ointment compared with medicinal honey for treatment of pressure ulcers in the US.

OBJECTIVES: Pressure ulcer (PU) treatment poses significant clinical and economic challenges to health-care systems. The aim of this study was to assess the cost-effectiveness and budget impact of enzymatic debridement with clostridial collagenase ointment (CCO) compared with autolytic debridement with medicinal honey (MH) for PU treatment from a US payer/Medicare perspective in the hospital outpatient department setting. METHODS: A cost-effectiveness analysis using a Markov model was developed using a 1-week cycle length across a 1-year time horizon. The three health states were inflammation/senescence, granulation/proliferation (ie, patients achieving 100% granulation), and epithelialization. Data sources included the US Wound Registry, Medicare fee schedules, and other published clinical and cost studies about PU treatment. RESULTS: In the base case analysis over a 1-year time horizon, CCO was the economically dominant strategy (ie, simultaneously conferring greater benefit at less cost). Patients treated with CCO experienced 22.7 quality-adjusted life weeks (QALWs) at a cost of $6,161 over 1 year, whereas MH patients experienced 21.9 QALWs at a cost of $7,149. Patients treated with CCO achieved 11.5 granulation weeks and 6.0 epithelization weeks compared with 10.6 and 4.4 weeks for MH, respectively. The number of clinic visits was 40.1 for CCO vs 43.4 for MH, and the number of debridements was 12.3 for CCO compared with 17.6 for MH. Probabilistic sensitivity analyses determined CCO dominant in 72% of 10,000 iterations and cost-effective in 91%, assuming a benchmark willingness-to-pay threshold of $50,000/quality-adjusted life year ($962/QALW). The budget impact analysis showed that for every 1% of patients shifted from MH to CCO, a cost savings of $9,883 over 1 year for a cohort of 1,000 patients was observed by the payer. CONCLUSION: The results of these economic analyses suggest that CCO is a cost-effective, economically dominant alternative to MH in the treatment of patients with PUs in the hospital outpatient department setting.

Comparing Medication Adherence and Persistence Among Patients with Type 2 Diabetes Using Sodium-Glucose Cotransporter 2 Inhibitors or Sulfonylureas.

BACKGROUND: Patients with type 2 diabetes treated with pharmacotherapy should be adherent to and persistent with their medications to experience glycemic control and prevent associated complications. OBJECTIVE: To compare medication adherence and persistence among patients with type 2 diabetes who are newly initiating a sodium-glucose cotransporter 2 (SGLT-2) inhibitor or a sulfonylurea. METHODS: This was a retrospective, observational cohort study using the MarketScan claims databases. The patients who were selected for the study had newly initiated treatment with an SGLT-2 inhibitor or a sulfonylurea between January 1, 2015, and December 31, 2015 (index date; class of earliest medication is defined as the index class); were aged ≥18 years on the index date; were continuously enrolled with health insurance for 12 months before and 6 months after (ie, follow-up) the index date; and had ≥1 baseline diagnoses of type 2 diabetes. Study exclusions were type 1 diabetes, pregnancy, and gestational diabetes. Medication adherence was measured by the proportion of days covered (PDC) with the index class during the follow-up period and dichotomized as adherent (PDC ≥80%) or nonadherent. Persistence was defined as the number of days from the index date until a >60-day continuous gap in days without the index drug class (ie, discontinuation) or the end of follow-up. A propensity score model was used to match patients receiving an SGLT-2 inhibitor to patients receiving a sulfonylurea in a 1:1 ratio based on patient characteristics. Logistic (ie, adherence) and Cox (ie, persistence) regression models were fit to the matched samples. RESULTS: Initially, the study included 17,724 patients who received an SGLT-2 inhibitor and 25,490 patients who received a sulfonylurea. After propensity score matching, 13,657 patients remained in each cohort. Compared with patients receiving a sulfonylurea, a statistically significantly greater percentage of patients receiving an SGLT-2 inhibitor were adherent to therapy (61.4% vs 53.9%, respectively; odds ratio of adherence, 1.364; 95% confidence interval [CI], 1.30-1.43; P <.001) and persistent (76.1% vs 68.9%, respectively; hazard ratio of discontinuation, 0.746; 95% CI, 0.71-0.78; P <.001). CONCLUSION: Maintaining adherence to and persistence with antidiabetes medication is vital to glycemic control among patients with type 2 diabetes. In this real-world study, patients who newly initiated treatment with SGLT-2 inhibitors were more likely to adhere to treatment and persist with the initiated therapy than similar patients who newly initiated treatment with sulfonylureas.

Prognostic Implications of Raphe in Bicuspid Aortic Valve Anatomy.

Importance: Little is known about the association between bicuspid aortic valve (BAV) morphologic findings and the degree of valvular dysfunction, presence of aortopathy, and complications, including aortic valve surgery, aortic dissection, and all-cause mortality. Objective: To investigate the association between BAV morphologic findings (raphe vs nonraphe) and the degree of valve dysfunction, presence of aortopathy, and prognosis (including need for aortic valve surgery, aortic dissection, and all-cause mortality). Design, Setting, and Participants: In this large international multicenter registry of patients with BAV treated at tertiary referral centers, 2118 patients with BAV were evaluated. Patients referred for echocardiography from June 1, 1991, through November 31, 2015, were included in the study. Exposures: Clinical and echocardiographic data were analyzed retrospectively. The morphologic BAV findings were categorized according to the Sievers and Schmidtke classification. Aortic valve function was divided into normal, regurgitation, or stenosis. Patterns of BAV aortopathy included the following: type 1, dilation of the ascending aorta and aortic root; type 2, isolated dilation of the ascending aorta; and type 3, isolated dilation of the sinus of Valsalva and/or sinotubular junction. Main Outcomes and Measures: Association between the presence and location of raphe and the risk of significant (moderate and severe) aortic valve dysfunction and aortic dilation and/or dissection. Results: Of the 2118 patients (mean [SD] age, 47 [18] years; 1525 [72.0%] male), 1881 (88.8%) had BAV with fusion raphe, whereas 237 (11.2%) had BAV without raphe. Bicuspid aortic valves with raphe had a significantly higher prevalence of valve dysfunction, with a significantly higher frequency of aortic regurgitation (622 [33.1%] vs 57 [24.1%], P < .001) and aortic stenosis (728 [38.7%] vs 51 [21.5%], P < .001). Furthermore, aortic valve replacement event rates were significantly higher among patients with BAV with raphe (364 [19.9%] at 1 year, 393 [21.4%] at 2 years, and 447 [24.4%] at 5 years) vs patients without raphe (30 [14.0%] at 1 year, 32 [15.0%] at 2 years, and 40 [18.0%] at 5 years) (P = .02). In addition, the all-cause mortality event rates were significantly higher among patients with BAV with raphe (77 [5.1%] at 1 year, 87 [6.2%] at 2 years, and 110 [9.5%] at 5 years) vs patients without raphe (2 [1.8%] at 1 year, 3 [3.0%] at 2 years, and 5 [4.4%] at 5 years) (P = .03). However, on multivariable analysis, the presence of raphe was not significantly associated with all-cause mortality. Conclusions and Relevance: In this large multicenter, international BAV registry, the presence of raphe was associated with a higher prevalence of significant aortic stenosis and regurgitation. The presence of raphe was also associated with increased rates of aortic valve and aortic surgery. Although patients with BAV and raphe had higher mortality rates than patients without, the presence of a raphe was not independently associated with increased all-cause mortality.