Factors influencing the indication of coronary angiography in patients presenting with chest pain unspecified: an analysis of two decades (1994-2014).

Guidelines for cardiac catheterization in patients with non-specific chest pain (NSCP) provide significant room for provider discretion, which has resulted in variability in the utilization of invasive coronary angiograms (CAs) and a high rate of normal angiograms. The overutilization of CAs in patients with NSCP and discharged without a diagnosis of coronary artery disease is an important issue in medical care quality. As a result, we sought to identify patient demographic, socioeconomic, and geographic factors that influenced the performance of a CA in patients with NSCP who were discharged without a diagnosis of coronary artery disease. We intended to establish reference data points for gauging the success of new initiatives for the evaluation of this patient population. In this 20-year retrospective cohort study (1994-2014), we examined 107 796 patients with NSCP from the Myocardial Infarction Data Acquisition System, a large statewide validated database that contains discharge data for all patients with cardiovascular disease admitted to every non-federal hospital in NJ. Patients were partitioned into two groups: those offered a CA (CA group; n = 12 541) and those that were not (No-CA group; n = 95 255). Geographic, demographic, and socioeconomic variables were compared between the two groups using multivariable logistic regression, which determined the predictive value of each categorical variable on the odds of receiving a CA. Whites were more likely than Blacks and other racial counterparts (19.7% vs. 5.6% and 16.5%, respectively; P < .001) to receive a CA. Geographically, patients who received a CA were more likely admitted to a large hospital compared to small- or medium-sized ones (12.5% vs. 8.9% and 9.7%, respectively; P < .05), a primary teaching institution rather than a teaching affiliate or community center (16.1 % vs. 14.3% and 9.1%, respectively; P < .001), and at a non-rural facility compared to a rural one (12.1% vs. 6.5%; P < .001). Lastly from a socioeconomic standpoint, patients with commercial insurance more often received a CA compared to those having Medicare or Medicaid/self-pay (13.7% vs. 9.5% and 6.0%, respectively; P < .001). The utilization of CA in patients with NSCP discharged without a diagnosis of coronary artery disease in NJ during the study period may be explained by differences in geographic, demographic, and socioeconomic factors. Patients with NSCP should be well scrutinized for CA eligibility, and reliable strategies are needed to reduce discretionary medical decisions and improve quality of care.

Identification of constrained sequence elements across 239 primate genomes.

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3-9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

A global catalog of whole-genome diversity from 233 primate species.

The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology and is urgent given severe threats these species are facing. Here, we present high-coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families and geographic regions to be associated with climate and sociality, but not with extinction risk. Furthermore, mutation rates differ across species, potentially influenced by effective population sizes. Lastly, we identified extensive recurrence of missense mutations previously thought to be human specific. This study will open a wide range of research avenues for future primate genomic research.

The landscape of tolerated genetic variation in humans and primates.

Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.

The landscape of tolerated genetic variation in humans and primates.

Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole genome sequencing data for 809 individuals from 233 primate species, and identified 4.3 million common protein-altering variants with orthologs in human. We show that these variants can be inferred to have non-deleterious effects in human based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases. One Sentence Summary: Deep learning classifier trained on 4.3 million common primate missense variants predicts variant pathogenicity in humans.

Prevalence and predictors of myopic macular degeneration among Asian adults: pooled analysis from the Asian Eye Epidemiology Consortium.

AIMS: To determine the prevalence and predictors of myopic macular degeneration (MMD) in a consortium of Asian studies. METHODS: Individual-level data from 19 885 participants from four population-based studies, and 1379 highly myopic participants (defined as axial length (AL) >26.0 mm) from three clinic-based/school-based studies of the Asian Eye Epidemiology Consortium were pooled. MMD was graded from fundus photographs following the meta-analysis for pathologic myopia classification and defined as the presence of diffuse choroidal atrophy, patchy chorioretinal atrophy, macular atrophy, with or without 'plus' lesion (lacquer crack, choroidal neovascularisation or Fuchs' spot). Area under the curve (AUC) evaluation for predictors was performed for the population-based studies. RESULTS: The prevalence of MMD was 0.4%, 0.5%, 1.5% and 5.2% among Asians in rural India, Beijing, Russia and Singapore, respectively. In the population-based studies, older age (per year; OR=1.13), female (OR=2.0), spherical equivalent (SE; per negative diopter; OR=1.7), longer AL (per mm; OR=3.1) and lower education (OR=1.9) were associated with MMD after multivariable adjustment (all p<0.001). Similarly, in the clinic-based/school-based studies, older age (OR=1.07; p<0.001), female (OR=2.1; p<0.001), longer AL (OR=2.1; p<0.001) and lower education (OR=1.7; p=0.005) were associated with MMD after multivariable adjustment. SE had the highest AUC of 0.92, followed by AL (AUC=0.87). The combination of SE, age, education and gender had a marginally higher AUC (0.94). CONCLUSION: In this pooled analysis of multiple Asian studies, older age, female, lower education, greater myopia severity and longer AL were risk factors of MMD, and myopic SE was the strongest single predictor of MMD.

The role of public health versus invasive coronary interventions in the decline of coronary heart disease mortality.

PURPOSE: There has been considerable debate on the extent to which the decline in coronary heart disease (CHD) mortality has been caused by better control of coronary risk factors in the general population or is the result of invasive coronary interventions in symptomatic individuals. METHODS: Using the Myocardial Infarction Data Acquisition System, a statewide database of all cardiovascular hospital admissions in New Jersey, we examined time trends in incidence of death from CHD in the Years 2000-2014 in persons with a history of hospitalization for CHD in the previous 10 years and those without such a history. RESULTS: Over the 10-year study period, there was a marked decline in CHD-related mortality in both persons with a history of CHD and persons without a history of CHD. The decline occurred across all gender, racial, and age groups and was higher in those without a prior history of CHD. CONCLUSIONS: This adds more evidence that the decline in CHD was not only because of advanced invasive medical and surgical treatments but also equally because of improved lifestyle, pharmacologic treatment of risk factors for CHD, and public health interventions.

Choroidal Nevus and Melanoma in Patients with Oculocutaneous Albinism.

BACKGROUND: There are limited reports of uveal "melanocytic" lesions in patients with oculocutaneous albinism, with no reports from Asia. OBJECTIVES: In this study, we report 3 eyes with uveal "melanocytic" lesions in Asian patients with oculocutaneous albinism. METHODS: Retrospective small case series. Three eyes of 2 Asian patients with oculocutaneous albinism were included. Case 1 was a 54-year-old female who presented with juxtapapillary choroidal melanoma and underwent enucleation. Case 2 was a 39-year-old male with pigmented choroidal nevus in the right eye and suspicious nevus/choroidal variegation in the left eye. RESULTS: For case 1, metastatic workup including ultrasound of the abdomen, liver function test, and chest X-ray was unremarkable. Magnetic resonance imaging of the cranium ruled out extraocular extension. The left eye was enucleated due to the large tumor size and poor visual potential, and histopathological examination confirmed the diagnosis of choroidal melanoma with mixed cell type. At the last follow-up 6 months after enucleation, there was no evidence of metastasis. Case 2 was observed. CONCLUSION: Pigmented choroidal nevus and melanoma are rarely observed in patients with oculocutaneous albinism.

Trends in Hospitalization for Infective Endocarditis as a Reason for Admission or a Secondary Diagnosis.

We postulate that the trends for infective endocarditis (IE) are different for patients admitted for this condition compared with those admitted for a different reason with IE as a secondary diagnosis. Using the Myocardial Infarction Data Acquisition System (MIDAS) database, we analyzed 21,443 records of patients hospitalized with diagnosis of IE from 1994 to 2015. There were 9,191 patients hospitalized with IE as the primary diagnosis, and 12,252 patients with IE as a secondary diagnosis. Piecewise linear models were used to detect changes in trends. A bootstrap method was used to assess the statistical significance of the slopes and break point of each model. Differences in co-morbidities and microbiological patterns were analyzed. Trend analysis showed a significant decrease in IE as the primary diagnosis starting in the year 2004 (p <0.01). Hospitalizations with IE as a secondary diagnosis showed a linear increase in incidence (p <0.001), without any change points. In primary diagnosis IE, the proportion of streptococci as a causative microorganism was higher compared with staphylococci (p <0.001). On the contrary, in secondary diagnosis IE, the proportion of staphylococci was higher than streptococci (p <0.001). The proportion of gram-negative and other organism IE was similar in both groups. In conclusion, this study showed 2 divergent temporal trends in hospitalizations for IE as a primary or secondary diagnosis starting in 2004. The profile of the microorganisms reveals a steady higher proportion of staphylococcal infection in secondary diagnosis IE compared with streptococcal infection. Different strategies are needed for the prevention of IE.

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas.

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN.

Orbital Cellulitis with Endogenous Panophthalmitis Caused by Methicillin-Sensitive Staphylococcus aureus in Pregnancy.

Orbital cellulitis along with panophthalmitis is uncommon. The causes are usually trauma-related or endogenous. The prognosis in terms of globe salvage is very poor, with most cases usually requiring enucleation or evisceration of the affected eye. Immunosuppression in some form is usually present, which accounts for the aggressive course of the infection. In this communication, we report on a case in a 25-year-old female, who in the second trimester of pregnancy had developed orbital cellulitis and panophthalmitis caused by methicillin-sensitive Staphylococcus aureus (MSSA), with the primary source of infection being cellulitis on her forearm following intravenous therapy for severe anemia. Despite intensive intravenous and topical antibiotics, she required an evisceration of the eye. However, the pregnancy continued uneventfully with the delivery of a full-term, healthy infant. Bacteremia, although rare in pregnancy, can cause endogenous panophthalmitis and orbital cellulitis, especially in a background of immunosuppresssion.

An Unusual Eyelid Mass of Cysticercosis: A Twist in the Tale.

Cysticercosis is a parasitic infestation caused by the larval form of the tapeworm, Taenia solium (T. solium). The common sites for cysticerosis include the brain, eyes, and skeletal muscle. Ocular or adnexal involvement is commonly seen with the commonest ophthalmic site being subretinal space and the vitreous cavity. However, only a handful of cases of eyelid cysticercosis have been reported in the past. We report a rare and unusual case of isolated eyelid cysticercosis in a middle-aged woman masquerading as an asymptomatic slowly growing subcutaneous painless mass in the left eyelid which was presumed to be a benign skin mass, a cyst of appendageal origin such as an epidermoid cyst. This case highlights the ubiquitous nature of cysticercosis in tropical countries and the need for a high degree of suspicion while surgically treating subcutaneous masses. We would additionally emphasize the need to rule out neurocysticercosis in such cases.

Vision Loss due to Central Retinal Artery Occlusion Following Embolization in a Case of a Giant Juvenile Nasopharyngeal Angiofibroma.

Juvenile nasopharyngeal angiofibroma (JNA) is a benign, vascular, and locally aggressive tumor that arises in the nasal cavity, extending into the nasopharynx and often in to the orbit. It may rarely present to the ophthalmologist with proptosis and optic neuropathy. Preoperative embolization of JNA is done before surgical resection. In this communication, the authors report a rare occurrence of ipsilateral central retinal artery occlusion (CRAO) following embolization with polyvinyl alcohol in a 13-year-old boy with right-sided JNA. Retrospective review of the angiograms pointed out to a suspicious communication between the external carotid artery and the ophthalmic vessels. Pre-embolization detailed study of the angiograms is necessary to avoid such devastating complications. Although rare, vision loss is a possible complication arising from embolization of nasopharyngeal and intracranial tumors, and all patients undergoing these procedures should be informed of the risk of visual loss because it has a lasting impact on the quality of life.