Liver and cardiovascular disease outcomes in metabolic syndrome and diabetic populations: Bi-directional opportunities to multiply preventive strategies.

The incidence and prevalence of metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are rising globally. MetS and T2DM are associated with significant morbidity and mortality, which is partly related to liver and cardiovascular disease. Insulin resistance is central to MetS and T2DM pathophysiology, and drives ectopic fat deposition in the liver, also known as metabolic dysfunction-associated steatotic liver disease (MASLD). MetS and T2DM are not only risk factors for developing MASLD but are also independently associated with disease progression to steatohepatitis, cirrhosis, and hepatocellular carcinoma. In addition to the risk of liver disease, MetS and T2DM are independent risk factors for cardiovascular disease (CVD), including coronary artery disease (CAD) and heart failure (HF). Importantly, there is a bidirectional relationship between liver and CVD due to shared disease pathophysiology in patients with MetS and T2DM. In this review, we have described studies exploring the relationship of MetS and T2DM with MASLD and CVD, independently. Following this we discuss studies evaluating the interplay between liver and cardiovascular risk as well as pragmatic risk mitigation strategies in this patient population.

Addressing Social Determinants of Health in Maternal Cardiovascular Health.

Cardiovascular diseases (CVDs) remain the number-one cause of maternal mortality, with over two-thirds of cases being preventable. Social determinants of health (SDoH) encompass the nonmedical social and environmental factors that an individual experiences that have a significant impact on their health. These stressors disproportionately affect socially disadvantaged and minority populations. Pregnancy is a physiologically stressful state that can unmask underlying CVD risk factors and lead to adverse pregnancy outcomes (APOs). Disparities in APOs are particularly pronounced among individuals of color and those from economically disadvantaged backgrounds. This variation underscores healthcare inequity and access, a failure of the healthcare system. Besides short-term negative effects, APOs also are associated strongly with long-term CVDs. APOs therefore must be identified as a cue for early intervention, for the prevention and management of CVD risk factors. This review explores the intricate relationship among maternal morbidity and mortality, SDoH, and cardiovascular health, and the implementation of health policy efforts to reduce the negative impact of SDoH in this patient population. The review emphasizes the importance of comprehensive strategies to improve maternal health outcomes.

Etiology of orbital fractures at a level I trauma center in a large metropolitan city.

BACKGROUND/PURPOSE: Orbital fractures are a common facial fracture managed by multiple surgical specialties. Methods: A retrospective review of the electronic medical records of patients (age, 18-85 years) presenting to Northwestern Memorial Hospital and Northwestern Medical Faculty Foundation in Chicago, IL, USA with International Classification of Diseases, Ninth Revision codes for facial fractures or CPT (Current Procedural Terminology) codes for orbital fracture repair. RESULTS: A review of the electronic medical records identified 504 individual incidents of orbital fractures with available imaging for review. The most common location for an orbital fracture was a floor fracture (48.0%) followed by a medial wall fracture (25.2%). Left-sided orbital fractures were statistically significantly more common than right-sided orbital fractures (99% confidence interval). Orbital fractures were more prevalent in younger age groups. The mean patient age was 39.3 years. The most common cause of all orbital fractures was assault followed by falls. However, falls were the most common cause of orbital fractures in women and in patients aged 50 years and older. Evaluation by an ophthalmologist occurred in 62.8% of orbital fracture patients, and evaluation by a team comprising the facial trauma service (Otolaryngology, Plastic Surgery, and Oral and Maxillofacial Surgery) occurred in 81.9% of orbital fracture patients. CONCLUSION: Assault was the largest cause of all orbital fractures, and occurred most commonly in young males. Assaulted patients were more likely to have left-sided fractures compared to nonassaulted patients. In patients aged 50 years and older, falls were the most common cause of orbital fractures.

Statin therapy across the lifespan: evidence in major age groups.

This review provides needed perspective on statin efficacy and safety in individuals under 40, 40-75, and > 75 years of age. Starting with the 2013 ACC-AHA cholesterol guidelines extensive evidence base on randomized controlled trials (RCTs) we added references in the past 5 years that discussed statin efficacy and safety over the life span. In those under 40, statins are primarily used for treatment of severe hypercholesterolemia, often familial, and they are well tolerated. In middle-aged adults, statins have strong evidence for benefit in primary and secondary prevention trials; however, in primary prevention, a clinician-patient risk discussion should precede statin prescription in order to determine appropriate treatment. In those over 75, issues of statin intensity and net benefit loom large as associated comorbidity, polypharmacy, and potential for adverse effects impact the decision to use statins with RCT data strongest in support of use in secondary prevention. Statin drugs have been studied by RCTs in a large number of individuals. In those groups shown to benefit, statins have reduced the risk of atherosclerotic cardiovascular disease with few side effects as compared to controls. This review has detailed considerations that should occur when statins are given to individuals in different age groups.

Evidence for Clinical Implementation of Pharmacogenomics in Cardiac Drugs.

OBJECTIVE: To comprehensively assess the pharmacogenomic evidence of routinely used drugs for clinical utility. METHODS: Between January 2, 2011, and May 31, 2013, we assessed 71 drugs by identifying all drug/genetic variant combinations with published clinical pharmacogenomic evidence. Literature supporting each drug/variant pair was assessed for study design and methods, outcomes, statistical significance, and clinical relevance. Proposed clinical summaries were formally scored using a modified AGREE (Appraisal of Guidelines for Research and Evaluation) II instrument, including recommendation for or against guideline implementation. RESULTS: Positive pharmacogenomic findings were identified for 51 of 71 cardiovascular drugs (71.8%), representing 884 unique drug/variant pairs from 597 publications. After analysis for quality and clinical relevance, 92 drug/variant pairs were proposed for translation into clinical summaries, encompassing 23 drugs (32.4% of drugs reviewed). All were recommended for clinical implementation using AGREE II, with mean ± SD overall quality scores of 5.18±0.91 (of 7.0; range, 3.67-7.0). Drug guidelines had highest mean ± SD scores in AGREE II domain 1 (Scope) (91.9±6.1 of 100) and moderate but still robust mean ± SD scores in domain 3 (Rigor) (73.1±11.1), domain 4 (Clarity) (67.8±12.5), and domain 5 (Applicability) (65.8±10.0). Clopidogrel (CYP2C19), metoprolol (CYP2D6), simvastatin (rs4149056), dabigatran (rs2244613), hydralazine (rs1799983, rs1799998), and warfarin (CYP2C9/VKORC1) were distinguished by the highest scores. Seven of the 9 most commonly prescribed drugs warranted translation guidelines summarizing clinical pharmacogenomic information. CONCLUSION: Considerable clinically actionable pharmacogenomic information for cardiovascular drugs exists, supporting the idea that consideration of such information when prescribing is warranted.

Anti-angiogenic SPARC peptides inhibit progression of neuroblastoma tumors.

BACKGROUND: New, more effective strategies are needed to treat highly aggressive neuroblastoma. Our laboratory has previously shown that full-length Secreted Protein Acidic and Rich in Cysteine (SPARC) and a SPARC peptide corresponding to the follistatin domain of the protein (FS-E) potently block angiogenesis and inhibit the growth of neuroblastoma tumors in preclinical models. Peptide FS-E is structurally complex and difficult to produce, limiting its potential as a therapeutic in the clinic. RESULTS: In this study, we synthesized two smaller and structurally more simple SPARC peptides, FSEN and FSEC, that respectively correspond to the N-and C-terminal loops of peptide FS-E. We show that both peptides FSEN and FSEC have anti-angiogenic activity in vitro and in vivo, although FSEC is more potent. Peptide FSEC also significantly inhibited the growth of neuroblastoma xenografts. Histologic examination demonstrated characteristic features of tumor angiogenesis with structurally abnormal, tortuous blood vessels in control neuroblastoma xenografts. In contrast, the blood vessels observed in tumors, treated with SPARC peptides, were thin walled and structurally more normal. Using a novel method to quantitatively assess blood vessel abnormality we demonstrated that both SPARC peptides induced changes in blood vessel architecture that are consistent with blood vessel normalization. CONCLUSION: Our results demonstrate that SPARC peptide FSEC has potent anti-angiogenic and anti-tumorigenic effects in neuroblastoma. Its simple structure and ease of production indicate that it may have clinical utility in the treatment of high-risk neuroblastoma and other types of pediatric and adult cancers, which depend on angiogenesis.

Relationship of EGFR mutations, expression, amplification, and polymorphisms to epidermal growth factor receptor inhibitors in the NCI60 cell lines.

PURPOSE: The mechanism of sensitivity and resistance to epidermal growth factor receptor (EGFR) inhibitors is incompletely understood, particularly in cancers other than non-small-cell lung cancer (NSCLC). To understand the variable response to this class of drugs, we used the NCI60 cancer cell lines. We aimed to determine if there are interactions between EGFR expression, mutations, polymorphisms, and gene amplification, and whether these factors are associated with variability in response to EGFR inhibitors. EXPERIMENTAL DESIGN: The EGFRVIII and tyrosine kinase (TK) domain mutations were examined in the NCI60 cancer cell lines. Five polymorphisms, -216G/T, -191C/A, intron 1 (CA)n, R497K, and 2607A/G, were genotyped. EGFR amplification was also assessed with high-density single-nucleotide polymorphism chip and real-time PCR, respectively. The results were correlated with cytotoxicity data for erlotinib and other 11 EGFR inhibitors, as well as other publicly available data for these lines. RESULTS: All 12 inhibitors behaved similarly. No EGFRVIII but putative TK mutations in two cell lines were found. Both mutant cell lines were insensitive to all inhibitors. Meanwhile, response did not correlate with EGFR amplification but with EGFR gene expression, especially in the cell lines with relatively normal gene status. In addition, EGFR expression was associated with the -216G/T polymorphism but not with the intron 1 (CA)n polymorphism. A combination of -216G/T and R497K polymorphisms was weakly associated with drug response. CONCLUSIONS: These observations suggest that in addition to TK mutations, germ-line variability may also contribute to the pharmacodynamics of EGFR inhibitors, particularly when EGFR is genetically normal.