Subclinical carotid artery atherosclerosis and cognitive function in older adults.

BACKGROUND: The combined effects of increased life expectancy and the considerable number of persons reaching old age will magnify the dementia epidemic in the USA. Demonstration that subclinical atherosclerosis precedes and is associated with cognitive impairment suggests a modifiable risk factor for age-associated cognitive impairment and dementia. The purpose of this study is to determine whether subclinical atherosclerosis as measured by carotid artery intima-media thickness (CIMT) is associated with changes in cognitive function over time in older adults. METHODS: This study combined longitudinal data from three clinical trials conducted between 2000 and 2013: the B-Vitamin Atherosclerosis Intervention Trial (BVAIT), the Women's Isoflavone Soy Health (WISH) trial, and the Early versus Late Intervention Trial with Estradiol (ELITE). Participants were recruited from the general population in the Greater Los Angeles area and were free of cardiovascular disease and diabetes; no cognitive or psychiatric exclusion criteria were specified. The same standardized protocol for ultrasound image acquisition and measurement of CIMT was used in all trials. CIMT measurements performed at baseline and 2.5 years were used in these analyses. Cognitive function was assessed at baseline and 2.5 years using a battery of 14 standardized cognitive tests. All clinical trials were conducted at the University of Southern California Atherosclerosis Research Unit, Los Angeles, and had at least 2.5 years of cognitive follow-up. RESULTS: A total of 308 men and 1187 women, mean age of 61 years, were included in the combined longitudinal dataset for the primary analysis. No associations were found between CIMT and cognitive function at baseline or at 2.5 years. There was a weak inverse association between CIMT measured at baseline and change in global cognition assessed over 2.5 years (ß (SE) = - 0.056 (0.028) units per 0.1 mm CIMT, 95% CI - 0.110, - 0.001, p = 0.046). No associations between CIMT at baseline and changes in executive function, verbal memory, or visual memory were found. CONCLUSIONS: In this sample of healthy older adults, our findings suggest an association between subclinical atherosclerosis and change in global cognitive function over 2.5 years. Stronger associations were observed longitudinally over 2.5 years than cross-sectionally. When analysis was stratified by age group (<65 and ≥65 years old), the inverse association remained statistically significant for participants in the older age group. Subclinical atherosclerosis of the carotid artery may be a modifiable correlate of cognitive decline in middle and older age. TRIAL REGISTRATION: BVAIT, NCT00114400 . WISH, NCT00118846 . ELITE, NCT00114517 .

Cardiogenic Shock Due to Multisystem Inflammatory Syndrome in a Young Adult Female.

Multisystem inflammatory syndrome in adults (MIS-A) was initially described by pediatricians after reporting a temporal association of a mimicker of Kawasaki disease shortly after the resolution of a COVID-19 illness. Since June 2020, there have been an increased amount of reports of adults and adolescents above the age of 18 presenting with the syndrome. We report a case of a 20-year-old female with no medical history who presented with cardiogenic shock and was found to have MIS-A.

Emergence of multidrug-resistant, community-associated, methicillin-resistant Staphylococcus aureus clone USA300 in men who have sex with men.

BACKGROUND: Infection with multidrug-resistant, community-associated, methicillin-resistant Staphylococcus aureus (MRSA) has been reported but seems to be isolated. OBJECTIVE: To determine the incidence of a multidrug-resistant MRSA clone (USA300) in San Francisco, and to determine risk factors for the infection. DESIGN: Population-based survey and cross-sectional study using chart review. SETTING: 9 hospitals in San Francisco (population-based survey) and 2 outpatient clinics in San Francisco and Boston (cross-sectional study). PATIENTS: Persons with culture-proven MRSA infections in 2004 to 2006. MEASUREMENTS: Annual incidence, spatial clustering, and risk factors for multidrug-resistant USA300 infection. Pulsed-field gel electrophoresis, polymerase chain reaction assays, and DNA sequencing were used to characterize MRSA isolates. RESULTS: The overall incidence of multidrug-resistant USA300 infection in San Francisco was 26 cases per 100,000 persons (95% CI, 16 to 36 cases per 100,000 persons); the incidence was higher in 8 contiguous ZIP codes with a higher proportion of male same-sex couples. Male-male sex was a risk factor for multidrug-resistant USA300 infection (relative risk, 13.2 [CI, 1.7 to 101.6]; P < 0.001) independent of past MRSA infection (relative risk, 2.1 [CI, 1.2 to 3.7]; P = 0.007) or clindamycin use (relative risk, 2.1 [1.2 to 3.6]; P = 0.007). The risk seemed to be independent of HIV infection. In San Francisco, multidrug-resistant USA300 manifested most often as infection of the buttocks, genitals, or perineum. In Boston, the infection was recovered exclusively from men who had sex with men. LIMITATIONS: The study was retrospective, and sexual risk behavior was not assessed. CONCLUSION: Infection with multidrug-resistant USA300 MRSA is common among men who have sex with men, and multidrug-resistant MRSA infection might be sexually transmitted in this population. Further research is needed to determine whether existing efforts to control epidemics of other sexually transmitted infections can control spread of community-associated, multidrug-resistant MRSA.

Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus.

BACKGROUND: USA300, a clone of meticillin-resistant Staphylococcus aureus, is a major source of community-acquired infections in the USA, Canada, and Europe. Our aim was to sequence its genome and compare it with those of other strains of S aureus to try to identify genes responsible for its distinctive epidemiological and virulence properties. METHODS: We ascertained the genome sequence of FPR3757, a multidrug resistant USA300 strain, by random shotgun sequencing, then compared it with the sequences of ten other staphylococcal strains. FINDINGS: Compared with closely related S aureus, we noted that almost all of the unique genes in USA300 clustered in novel allotypes of mobile genetic elements. Some of the unique genes are involved in pathogenesis, including Panton-Valentine leucocidin and molecular variants of enterotoxin Q and K. The most striking feature of the USA300 genome is the horizontal acquisition of a novel mobile genetic element that encodes an arginine deiminase pathway and an oligopeptide permease system that could contribute to growth and survival of USA300. We did not detect this element, termed arginine catabolic mobile element (ACME), in other S aureus strains. We noted a high prevalence of ACME in S epidermidis, suggesting not only that ACME transfers into USA300 from S epidermidis, but also that this element confers a selective advantage to this ubiquitous commensal of the human skin. INTERPRETATION: USA300 has acquired mobile genetic elements that encode resistance and virulence determinants that could enhance fitness and pathogenicity.

Should women have different ECG criteria for CRT than men?

One of the key aspects of heart failure management is whether patients should be considered for device therapy. Clinical trials, which have employed QRS duration and morphology as measures of left ventricular dyssynchrony, have demonstrated the morbidity and mortality benefit of cardiac resynchronization therapy. Women, however, are underrepresented in these trials, the basis of which current guidelines and standards of care are derived. Despite low enrollment of women, several studies highlight the statistically significant improvement in risk reduction that women gain from cardiac resynchronization therapy compared to men. This review discusses the foundation for current guidelines and the building evidence that women may reap more benefit from cardiac resynchronization therapy than men. Given these data, a more individualized approach should be considered in prescribing this device therapy in the future, particularly in women.

Elevated Baseline Serum Fibrinogen: Effect on 2-Year Major Adverse Cardiovascular Events Following Percutaneous Coronary Intervention.

BACKGROUND: Elevated fibrinogen is associated with short-term major adverse cardiovascular events (MACE) after percutaneous coronary intervention, but the relation with late MACE is unknown. METHODS AND RESULTS: Baseline demographics and 2-year MACE were recorded among subjects undergoing nonemergent percutaneous coronary intervention. A total of 332 subjects (66.6±19.5 years, 69.9% male, 25.3% acute coronary syndrome) were enrolled. Two-year MACE (periprocedural myocardial infarction 9.0%, rehospitalization 6.3%, revascularization 12.7%, non-periprocedural myocardial infarction 4.5%, stent thrombosis 0.9%, stroke 1.8%, and death 0.6%) were associated with higher fibrinogen (352.8±123.4 mg/dL versus 301.6±110.8 mg/dL; P<0.001), longer total stent length (40.1±25.3 mm versus 32.1±19.3 mm; P=0.004), acute coronary syndrome indication (38.7% versus 17.8%; P<0.001), number of bare-metal stents (0.5±1.1 versus 0.2±0.5; P=0.002), and stent diameter ≤2.5 mm (55.8% versus 38.4%, P=0.003). No relation between platelet reactivity and 2-year MACE was observed. Fibrinogen ≥280 mg/dL (odds ratio [OR] 3.0, confidence interval [CI], 1.6-5.4, P<0.001), total stent length ≥32 mm (OR 2.2, CI, 1.3-3.8, P<0.001), acute coronary syndrome indication (OR 4.1, CI, 2.3-7.5, P<0.001), any bare-metal stents (OR 3.2, CI, 1.6-6.1, P<0.001), and stent diameter ≤2.5 mm (OR 2.0, CI, 1.2-3.5, P=0.010) were independently associated with 2-year MACE. Following a landmark analysis excluding periprocedural myocardial infarction, fibrinogen ≥280 mg/dL remained strongly associated with 2-year MACE (37.0% versus 17.4%, log-rank P<0.001). CONCLUSIONS: Elevated baseline fibrinogen level is associated with 2-year MACE after percutaneous coronary intervention. Acute coronary syndrome indication for percutaneous coronary intervention, total stent length implanted, and use of bare-metal stents or smaller-diameter stents are also independently associated with 2-year MACE, while measures of on-thienopyridine platelet reactivity are not.

Exploratory study on the impact of switching to nilotinib in 18 patients with chronic myeloid leukemia in chronic phase with suboptimal response to imatinib.

BACKGROUND: The phase II, exploratory, open-label Exploring Nilotinib BCR-ABL Effects (ENABL) study [ClinicalTrials.gov identifier: NCT00644878] assessed the impact of switching to nilotinib therapy in patients with chronic myeloid leukemia in chronic phase (CML-CP) who had a suboptimal molecular response with imatinib. METHODS: Patients with CML-CP who had previously achieved a complete cytogenetic response (CCyR), but had a suboptimal molecular response, with frontline imatinib therapy (N = 18) were assigned to receive nilotinib 300 mg twice daily. The primary endpoint was the change in BCR-ABL1 transcript levels from baseline after 12 months; rates of major molecular response (MMR) and safety were also assessed. RESULTS: At 3 months after switching to nilotinib, 10 of 17 (59%) evaluable patients had achieved MMR. At 12 months, 9 of 12 (75%) evaluable patients had achieved MMR, and the median BCR-ABL1 level among all patients remaining in the study was 0.020% on the International Scale (IS), equivalent to a 3.7-log reduction from the standardized IS baseline (primary endpoint). Adverse events (AEs) were typically grade 1/2 and manageable with dose interruptions. A total of three patients experienced serious study drug-related AEs, including pancreatitis, bradycardia, and vertigo. No deaths were reported. CONCLUSIONS: Overall, results from this exploratory study suggest that switching to nilotinib due to suboptimal molecular response with imatinib can result in improved molecular response for patients with CML-CP.

Potential new drug treatments for congestive heart failure.

INTRODUCTION: The prevalence of heart failure (HF) has increased globally in recent decades. Advances in our understanding of underlying pathophysiologic mechanisms have given rise to new therapies for treating the growing HF population. Nonetheless, morbidity and mortality associated with HF and its financial implications are daunting. Thus, novel therapies that can improve the natural history of HF patients are urgently needed. AREAS COVERED: This article reviews new investigational drugs being developed for the treatment of both acute decompensated heart failure (ADHF) and chronic heart failure with reduced ejection fraction (HFrEF). It presents the background of these drugs with a focus on their mechanism of action, their pharmacology, evidence from clinical studies and their potential role in HF management. EXPERT OPINION: The mortality benefit associated with serelaxin treatment in the RELAX-HF trial is being tested in RELAX-AHF II, while two other drugs, ularitide and TRV027, are also being evaluated in ADHF patients. Two new agents for the treatment of chronic HFrEF, LCZ696 and ivabradine, have been recently been approved for use by the FDA and four novel agents which have shown considerable promise in early studies, omecamtiv mecarbil, vericiguat, finerenone, and neuregulin, are currently being evaluated in late-phase clinical trials.

Effect of Serum Fibrinogen, Total Stent Length, and Type of Acute Coronary Syndrome on 6-Month Major Adverse Cardiovascular Events and Bleeding After Percutaneous Coronary Intervention.

This study evaluated the relation between baseline fibrinogen and 6-month major adverse cardiovascular events (MACE) and bleeding after percutaneous coronary intervention (PCI). Three hundred eighty-seven subjects (65.6 ± 16.1 years, 69.5% men, 26.9% acute coronary syndrome [ACS]) who underwent PCI with baseline fibrinogen and platelet reactivity (VerifyNow P2Y12 assay, Accumetrics, San Diego, California) measured were enrolled. Fibrinogen (368.8 ± 144.1 vs 316.8 ± 114.3 mg/dl; p = 0.001), total stent length (TSL; 44.5 ± 25.0 vs 32.2 ± 20.1 mm; p <0.001), and ACS presentation (40.6% vs 23.9%; p = 0.005) were independently associated with 6-month MACE rates (17.8%: myocardial infarction 9.8%, rehospitalization for ACS 3.6%, urgent revascularization 3.6%, stroke 0.5%, and death 0.3%). Measures of platelet reactivity were not associated with 6-month MACE. After multivariate analysis, fibrinogen ≥280 mg/dl (odds ratio [OR] 2.60, 95% CI 1.33 to 5.11, p = 0.005), TSL ≥32 mm (OR 3.21, 95% CI 1.82 to 5.64, p <0.001), and ACS presentation (OR 2.58, 95% CI 1.45 to 4.61, p = 0.001) were associated with higher 6-month MACE. In 271 subjects receiving chronic P2Y12 inhibitor therapy, 6-month Thrombolysis In Myocardial Infarction bleeding after PCI was 7.0%, but no difference in fibrinogen level (338.3 ± 109.7 vs 324.3 ± 113.8 mg/dl, p = 0.60) stratified by Thrombolysis In Myocardial Infarction bleeding was observed. In conclusion, elevated serum fibrinogen, ACS presentation, and longer TSL are independently associated with higher 6-month MACE after PCI, whereas no association with on-thienopyridine platelet reactivity and 6-month MACE was observed. Post-PCI bleeding was not associated with lower fibrinogen level.

Evaluating the Impact of a Switch to Nilotinib on Imatinib-Related Chronic Low-Grade Adverse Events in Patients With CML-CP: The ENRICH Study.

BACKGROUND: Many patients with chronic myeloid leukemia in chronic phase experience chronic treatment-related adverse events (AEs) during imatinib therapy. These AEs can impair quality of life and lead to reduced treatment adherence, which is associated with poor clinical outcomes. PATIENTS AND METHODS: In the phase II ENRICH (Exploring Nilotinib to Reduce Imatinib Related Chronic Adverse Events) study (N = 52), the effect of switching patients with imatinib-related chronic low-grade nonhematologic AEs from imatinib to nilotinib was evaluated. RESULTS: Three months after switching to nilotinib, 84.6% of the patients had overall improvement in imatinib-related AEs (primary endpoint). Of 210 imatinib-related AEs identified at baseline, 62.9% had resolved within 3 months of switching to nilotinib. Of evaluable patients, most had improvements in overall quality of life after switching to nilotinib. At screening, 65.4% of evaluable patients had a major molecular response (BCR-ABL1 ≤ 0.1% on the International Scale). After switching to nilotinib, the rate of the major molecular response was 76.1% at 3 months and 87.8% at 12 months. Treatment-emergent AEs reported with nilotinib were typically grade 1 or 2; however, some patients developed more serious AEs, and 8 patients discontinued nilotinib because of new or worsening AEs. CONCLUSION: Overall, results from the ENRICH study demonstrated that switching to nilotinib can mitigate imatinib-related chronic low-grade nonhematologic AEs in patients with chronic myeloid leukemia in chronic phase, in conjunction with acceptable safety and achievement of molecular responses. This trial was registered at www.clinicaltrials.gov as NCT00980018.