Πέμπτη, 17 Ιανουαρίου 2019

Disparities in Health Care Coverage Among U.S. Born and Mexican/Central American Born Labor Workers in the U.S.

Abstract

We examined health insurance coverage among U.S. and Mexican/Central American (M/CA) born labor workers living in the U.S. Using data from the 2010–2015 National Health Interview Survey, we employed logistic regression models to examine health insurance coverage and covariates among U.S. and M/CA born labor workers. Prevalence ratios between U.S. and M/CA born workers were also obtained. U.S. born workers had double the prevalence of insurance coverage. Regarding private insurance coverage, U.S. born workers had a higher prevalence of coverage compared to their M/CA born counterparts. Among foreign born workers with U.S. citizenship, the odds of having insurance coverage was greater than that of noncitizens. Additionally, those who had lived in the U.S. for 10 or more years had higher odds of having health insurance coverage. Disparities in health care coverage exist between U.S. born and foreign born labor workers.



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Differences Between U.S.-Born and Non-U.S.-Born Black Adults Reported with Diagnosed HIV Infection: United States, 2008–2014

Abstract

Despite improvements in its treatment, HIV infection continues to affect Blacks disproportionally. Using National HIV Surveillance System data from 50 U.S. states and the District of Columbia, we examined demographic and epidemiologic differences between U.S.-born and non-U.S.-born Black adults. Of 110,452 Black adults reported with diagnosed HIV during 2008–2014 with complete country of birth information, 11.1% were non-U.S.-born. Non-U.S.-born were more likely to be older, female, have HIV infection attributed to heterosexual contact, have been diagnosed late, and live in the northeastern U.S. region. During 2014, the HIV diagnosis rate among African-born Black females was 1.4 times the rate of U.S.-born Black males, 2 times the rate of African-born Black males, and 5.3 times the rate of U.S.-born Black females. We elucidate the differences between U.S.-born and non-U.S.-born Blacks on which to base culturally appropriate HIV-prevention programs and policies.



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Lessons Learned in Clinical Research Recruitment of Immigrants and Minority Group Members with First-Episode Psychosis

Abstract

Recruitment of immigrants and racial and ethnic minorities with first-episode psychosis (FEP) for research studies presents numerous challenges. We describe methods used to recruit 43 U.S. Latinos with FEP and their family caregivers (n = 41) participating in a study to reduce duration of untreated psychosis. A key challenge was that patients were not continuing treatment at an outpatient clinic, as initially expected. To facilitate identification of patients prior to outpatient care, we collaborated with clinic and hospital administrators. Many patients and families were grappling with the aftermath of a hospitalization or adjusting to a diagnosis of a serious mental illness. A considerable amount of time was devoted to addressing participants' concerns and when possible, facilitating needed services. Our experience underscores the importance of establishing long-term relationships through multiple contacts with patients, families, and stakeholders to address recruitment barriers among underserved groups with FEP.



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Stress and Resilience: Key Correlates of Mental Health and Substance Use in the Hispanic Community Health Study of Latino Youth

Abstract

This study examined associations of immigrant generation, acculturation, and sources of stress and resilience with four outcomes—depression symptoms, anxiety symptoms, alcohol susceptibility, and smoking susceptibility. We used data from 1466 youth (ages 8–16) enrolled in the Hispanic Community Health Study of Latino Youth (SOL Youth), a probability sample of Hispanic/Latino youth living in Chicago (IL), Miami (FL), Bronx (NY), and San Diego (CA). We found no evidence of an immigrant paradox. Greater children's acculturative stress was associated with depression/anxiety symptoms; greater parent's acculturative stress was associated with smoking susceptibility. Family functioning and children's ethnic identity were associated with fewer depression/anxiety symptoms and lower alcohol/smoking susceptibility. Although acculturation-related stressors increase youths' risks for poor mental health and substance use, the development of positive ethnic identities and close, well-functioning family support systems can help protect Latino/Hispanic children from the negative behavioral and health-related consequences of stress.



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Refugee Health: A Moral Discussion



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Racial Disparities in Type of Heart Failure and Hospitalization

Abstract

Heart failure (HF) is one of the leading causes of hospitalization and readmissions. Our study aimed to examine racial disparities in heart failure patients including onset, mortality, length of stay (LOS), direct costs, and readmission rates. This is a secondary data analysis. We analyzed the risk-adjusted inpatient data of all patients admitted with HF to one health academic center. We compared five health outcomes among three racial groups (white, black, and Hispanic). There were 1006 adult patients making 1605 visits from 10/01/2011 to 09/30/2015. Most black patients were admitted in younger age than other racial groups which indicates the needs for more public health preventions. With risk adjustments, the racial differences in LOS and readmission rates remain. We stratified health outcomes by race/ethnic and type of HF. The findings suggest that further studies to uncover underlying causes of these disparities are necessary. Using risk-adjusted hospitalization data allows for comparisons of quality of care across three racial groups. The study suggests that more prevention and protection services are needed for African American patients with heart failure.



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Neighborhood Racial Diversity and Metabolic Syndrome: 2003–2008 National Health and Nutrition Examination Survey

Abstract

This study investigated the independent association between neighborhood racial/ethnic diversity and metabolic syndrome among US adults, and focused on how this association differed across individual and neighborhood characteristics (i.e., race/ethnicity, sex, age, urbanity, neighborhood poverty). Objectively-measured biomarker data from 2003 to 2008 National Health and Nutrition Examination Survey were linked to census-tract profiles from 2000 decennial census (N = 10,122). Multilevel random intercept logistic regression models were estimated to examine the contextual effects of tract-level racial/ethnic diversity on individual risks of metabolic syndrome. Overall, more than 20% of the study population were identified as having metabolic syndrome, although the prevalence also varied across demographic subgroups and specific biomarkers. Multilevel analyses showed that increased racial/ethnic diversity within a census tract was associated with decreased likelihood of having metabolic syndrome (OR 0.71, 95% CI 0.52–0.96), particularly among female (OR 0.64; 95% CI 0.43–0.96), young adults (OR 0.60; 95% CI 0.39–0.93), and residents living in urban (OR 0.67; 95% CI 0.48–0.93) or poverty neighborhoods (OR 0.54; 95% CI 0.31–0.95). The findings point to the potential benefits of neighborhood racial/ethnic diversity on individual health risks.



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The Impact of Acculturation and Racialization on Self-Rated Health Status Among U.S. Latinos

Abstract

We investigate the Hispanic paradox by examining the relationship between acculturation and health status of Latinos to understand nuances among this growing heterogeneous population using a 2011 Latino Decisions survey. We find that acculturation remains an important determinant of Latino health; however, this varies based on whether the sample is restricted to immigrants or includes all Latino adults and on the measures of acculturation employed. We find Latino citizens reported better health than non-citizens; however, other acculturation measures, such as language use and time in the U.S. do not have a marked effect. Furthermore, skin color matters only for U.S.-born Latinos. Racialization is therefore important to consider within the context of the Hispanic paradox. Our findings suggest that some of the disadvantages stemming from minority status in the U.S. are more prominent among Latinos who have greater experience with the racial hierarchy of the U.S. and greater acculturation more broadly.



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Acculturation and Adherence to Physical Activity Recommendations Among Chinese American and Non-Hispanic White Breast Cancer Survivors

Abstract

Chinese American breast cancer survivors' adherence to recommended physical activity (PA) guidelines has been understudied. This study investigated their PA adherence by acculturation level (vs. non-Hispanic White (NHW) survivors). One hundred ninety five Chinese and 202 NHW breast cancer survivors (stage 0–III) responded to a cross-sectional survey including a self-reported PA questionnaire. PA adherence referred to meeting PA recommendations for cancer survivors. Acculturation among Chinese was defined by proxies of U.S. residency, English proficiency, and interview language. Logistic regression was performed to examine factors associated with PA adherence. More-acculturated Chinese survivors' PA adherence rate was 76%. Less-acculturated Chinese survivors' adherence rate (60%) was significantly lower than that of NHWs (80%) (OR 0.38, 95%CI 0.19, 0.75). Less-acculturated Chinese survivors were also less likely to engage in vigorous-intensity PA than NHWs (p < 0.01). Future research on less-acculturated Chinese survivors' motivation for PA to promote their adherence is needed.



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Acculturation and Unmet Health Needs Among Refugees in Omaha, Nebraska

Abstract

This study assessed the association between acculturation and unmet health needs among refugees. Based on data from the Refugee Health Needs Assessment Survey (n = 291) recently conducted in Omaha, Nebraska, Chi square tests and multivariate logistic regressions were estimated to examine how acculturation among refugees was related to their unmet health needs. Relative to refugees who had been in the U.S. for less than 3 years, refugees who had been in the U.S. for 3–5 years were more likely to report lack of health insurance coverage (AOR 2.87, 95% CI 1.19, 6.92) and delaying to see a health care provider due to cost during the 12 months prior to the survey (AOR 4.01, 95% CI 1.18, 13.67). Acculturation among refugees did not necessarily alleviate their unmet health needs. Addressing these needs calls for sustainable medical assistance to refugees that well go beyond the 8-month health insurance coverage currently provided to newly arrived refugees.



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Using the Children with Special Health Care Needs Screener with Immigrant Families: An Analysis of the National Survey of Children’s Health

Abstract

Children in immigrant families are less likely to screen positive with the Children with Special Health Care Needs Screener (CSHCN-S). This may indicate that children in immigrant families are healthier or require fewer health services than non-immigrant peers. Alternatively, the screener may under-identify special healthcare needs in this population. Using the 2011–2012 National Survey of Children's Health, we examined the prevalence of a positive CSHCN-S among children from first, second, and third generation households with an equivalent number of currently diagnosed chronic conditions (0, 1, 2+). Multivariate analyses controlled for sociodemographic factors. Among children with an equivalent number of chronic conditions, fewer children from first and second generation households screened positive with the CSHCN-S relative to children from third generation households. This association remained after adjusting for covariates. The CSHCN Screener may under-identify children from immigrant households, allowing for missed opportunities to allocate health resources.



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polyRAD: Genotype Calling with Uncertainty from Sequencing Data in Polyploids and Diploids

Low or uneven read depth is a common limitation of genotyping-by-sequencing (GBS) and restriction site-associated DNA sequencing (RAD-seq), resulting in high missing data rates, heterozygotes miscalled as homozygotes, and uncertainty of allele copy number in heterozygous polyploids. Bayesian genotype calling can mitigate these issues, but previously has only been implemented in software that requires a reference genome or uses priors that may be inappropriate for the population. Here we present several novel Bayesian algorithms that estimate genotype posterior probabilities, all of which are implemented in a new R package, polyRAD. Appropriate priors can be specified for mapping populations, populations in Hardy-Weinberg equilibrium, or structured populations, and in each case can be informed by genotypes at linked markers. The polyRAD software imports read depth from several existing pipelines, and outputs continuous or discrete numerical genotypes suitable for analyses such as genome-wide association and genomic prediction.



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2D versus 3D laparoscopic total mesorectal excision: a developmental multicentre randomised controlled trial

Abstract

Aims

The role of laparoscopy in rectal cancer has been questioned. 3D laparoscopic systems are suggested to aid optimal surgical performance but have not been evaluated in advanced procedures. We hypothesised that stereoscopic imaging could improve the performance of laparoscopic total mesorectal excision (TME).

Methods

A multicentre developmental randomised controlled trial comparing 2D and 3D laparoscopic TME was performed (ISRCTN59485808). Trial surgeons were colorectal consultants that had completed their TME proficiency curve and underwent stereoscopic visual testing. Patients requiring elective laparoscopic TME with curative intent were centrally randomised (1:1) to 2D or 3D using Karl Storz IMAGE1 S D3-Link™ and 10-mm TIPCAM®1S 3D passive polarising laparoscopic systems. Outcomes were enacted adverse events as assessed by the observational clinical human reliability analysis technique, intraoperative data, 30-day patient outcomes, histopathological specimen assessment and surgeon cognitive load.

Results

88 patients were included. There were no differences in patient or tumour demographics, surgeon stereopsis, case difficulty, cognitive load, operative time, blood loss or conversion between the trial arms. 1377 intraoperative adverse events were identified (median 18 per case, IQR 14–21, range 2–49) with no differences seen between the 2D and 3D arms (18 (95% CI 17–21) vs. 17 (95% CI 16–19), p = 0.437). 3D laparoscopy had non-significantly higher mesorectal fascial plane resections (94 vs. 77%, p = 0.059; OR 0.23 (95% CI 0.05–1.16)) but equal lymph node yield and circumferential margin distance and involvement. 30-day morbidity, anastomotic leak, re-operation, length of stay and readmission rates were equal between the 2D and 3D arms.

Conclusion

Feasibility of performing multicentre 3D laparoscopic multicentre trials of specialist performed complex procedures is shown. 3D imaging did not alter the number of intraoperative adverse events; however, a potential improvement in mesorectal specimen quality was observed and should form the focus of future 3D laparoscopic TME trials.



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Effect of structural training on surgical outcomes of residents’ first operative laparoscopy: a randomized controlled trial

Abstract

Background

Gynecological surgery and resident education have changed during recent decades, thus impacting surgical training. Training on simulators must begin before operating on patients. The objective of this study was to evaluate the effect of a simple curriculum on the surgical outcome of the participants' first operative laparoscopy.

Methods

This randomized prospective interventional study was carried out in Helsinki University Hospital and Hyvinkää Hospital. We recruited twenty junior residents in Obstetrics and Gynecology, of which half formed a control group and the rest completed the intervention with a theoretical and a practical part. The participants' first laparoscopic salpingectomy was assessed from video recordings by using Objective Structured Assessment of Technical Skills (OSATS) forms and the Numeric Rating Scale (NRS). The surgical outcome and assessed scores were compared between the groups.

Results

We found no differences in operative time, blood loss, or complications, nor in OSATS or NRS scores. In the intervention group, participants with the weakest performances in the simulator, seemed to benefit from the training program more than the participants with the best performances (skill level elevation 29.2–31.6% vs. 21.1–23.3%, respectively). The participants with the best performances in the simulator were scored among the best in the recorded operations as well.

Conclusion

In this study, we found no difference in the surgical outcome between the groups. However, the participants with low starting levels in the simulator could elevate their skill levels more, though they did not reach the skill level of those with a high starting level. Consequently, we found elevation in skills levels in the simulator tasks, but not in the surgical outcome. Likely, our simple training program with a fixed number of repetitions was insufficient to reach a plateau in the learning curve, and thus the training program in such a curriculum should be proficiency based.



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Selection Pressures of Vancomycin Powder Use in Spine Surgery: A Meta-analysis

Surgical site infection (SSI) is a serious and costly complication of spine surgery. Many surgeons apply vancomycin powder to the surgical wound to prevent SSIs. While multiple studies have reported reduced rates of SSI, others have suggested that widespread use of intra-wound vancomycin may increase the incidence of vancomycin-resistant, gram-negative, or polymicrobial spinal infections.

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Prospective evaluation of ERCP performance in an Italian regional database study

Prospective studies about endoscopic retrograde cholangio-pancreatography (ERCP) in a community setting are rare.

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Lesson from epidemiology of paediatric crohn’s Disease



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Clinical outcomes of endoscopic treatment for gastric epithelial neoplasm in remnant stomach after distal gastrectomy

We aimed to evaluate the feasibility of endoscopic treatment for gastric epithelial neoplasm in the remnant stomach after distal gastrectomy and compared the clinical outcomes by tumor location and endoscopic treatment modality.

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Necrotic ulcer on the chin

Necrotic ulcer on the chin of a previously healthy 38-year-old woman.

Simonsen S, Winther C, Zachariae C, Skov L.

Int J Dermatol. 2019 Jan 10. doi: 10.1111/ijd.14378. [Epub ahead of print] No abstract available.

PMID:
 
30632142


Persisting ulcer on the chin
Meij V1, Kuijpers KC.
Author information
1
St. Antonius Ziekenhuis, Afd. Heelkunde, Nieuwegein, the Netherlands. v.meij@antoniusziekenhuis.nl
Abstract
A 62-year-old woman presented with an ulcerative lesion on the chin. She had not visited tropical regions, but she had been in Cyprus. A skin biopsy revealed coccoid micro-organisms resembling Leishmania. Subsequently a PCR was performed which showed Leishmania donovani and Leishmania infantum complex and the diagnose 'cutaneous leishmaniasis' was confirmed.

PMID: 22129807

Promoter cross-talk affects the inducible expression of intronic shRNAs from the tetracycline response element

Abstract

Background

RNA interference (RNAi), defined as double-stranded, RNA-mediated gene silencing, is a useful tool for functional genomic studies. Along with increasing information about genomic sequences due to the innovative development of genome-sequencing technologies, functional genomic technologies are needed to annotate the genome and determine the processes by which each gene is regulated. Lentiviral vectors have been used to efficiently deliver reagents, such as small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs), into cells and tissues for functional genomic analyses.

Objective

We developed a lentiviral vector that efficiently expresses intronic shRNA from the tetracycline regulatory element (TRE) promoter in a doxycycline-dependent manner.

Methods

We developed a lentiviral vector system that contains reverse tetracycline-controlled transactivator 3 (rtTA3) and the TRE promoter, which are necessary for the doxycycline-inducible expression of shRNAs that are expressed as intronic miR-30a precursors. We then measured the cross-talk between the cytomegalovirus (CMV) and TRE promoters in the vector.

Results

We found that nearby promoters influence each other and that the TRE promoter should be located far from other promoters, such as the CMV promoter, in a vector. The orientation of a promoter with respect to other promoters also influences its transcriptional activity. A head-to-head orientation of the CMV and TRE promoters maintains the lowest level of transcription from TRE in the absence of doxycycline, compared to the tail-to-tail and head-to-tail orientations.

Conclusion

Based on these findings, we were able to construct a lentiviral vector that faithfully expresses intronic miR-30a shRNA precursors in a doxycycline-inducible manner.



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Enhancement of gene knockdown efficiency by CNNC motifs in the intronic shRNA precursor

Abstract

Background

Short hairpin RNAs (shRNAs) expressed from vectors have been used as an effective means of exploiting the RNA interference (RNAi) pathway in mammalian cells. Of several methods to express shRNA, a method of transcribing shRNAs embedded in microRNA precursors has been more widely used than the one that directly expresses shRNA from RNA polymerase III promoters because the microRNA precursor form of shRNA is known to cause lower levels of cytotoxicity and off-target effects than the overexpressed shRNAs from the RNA polymerase III promoters.

Objective

We study the primary sequence features of microRNA precursors, which enhance their processing into mature form, helps design more potent shRNA precursors embedded in microRNA precursors.

Methods

We measure the enhancement of gene knockdown efficiency by adding CNNC motifs in the 3′ flanking region of shRNA precursor embedded in the human miR-30a microRNA precursor.

Results

By systemically adding three CNNC motifs in the 3′ flanking region of shRNA precursor, we found that addition of two CNNC motifs saturates their enhanced knockdown ability of shRNA and that the CNNC motif in the + 17 to + 20 from the drosha cleavage site is most important for the shRNA-mediated target gene knock down. We also did see little knockdown of target gene expression by the shRNA precursor lacking CNNC motif.

Conclusion

Since genetic studies generally require techniques that could reduce gene expression at different degrees, the findings in this study will allow us to use RNAi for genetic studies of reducing gene expression at different degrees.



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Amyotrophic lateral sclerosis and anesthesia: a case series and review of the literature

Abstract

Purpose

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to death due to respiratory failure. This report describes the perioperative characteristics of ALS patients who underwent procedures with anesthesia at our institution.

Methods

We reviewed perioperative records of ALS patients who underwent procedures with anesthesia from January 1, 2014, through December 31, 2015.

Results

Seventy-eight patients underwent 89 procedures (71 procedures with monitored anesthesia care and 18 with general anesthesia), including 45 gastrostomy tube placements and 18 bone marrow biopsies. Three patients had prolonged duration of postoperative intubation related to preexisting respiratory muscle weakness, and one patient with bilateral pneumothorax required tracheal reintubation for respiratory distress. Four patients had prolonged duration of hospitalization. Three patients were hospitalized for ALS-related complications, and one patient was hospitalized for respiratory distress when pneumoperitoneum developed after gastrostomy tube placement. Three of these patients died of complications attributable to ALS within 30 days of the procedure. Twenty-nine (32.6%) procedures required minimal sedation (e.g., bone marrow biopsy, cataract surgery) and were performed on an ambulatory basis.

Conclusion

When caring for patients with ALS, the perioperative team must be prepared to treat potentially complex medical conditions that may not be directly related to the procedure and anesthetic management. However, minor procedures performed with minimal sedation may be safely performed on an ambulatory basis.



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Integrative genomic analysis predicts novel functional enhancer-SNPs for bone mineral density

Abstract

Osteoporosis is a skeletal disorder characterized by low bone mineral density (BMD) and deterioration of bone microarchitecture. To identify novel genetic loci underlying osteoporosis, an effective strategy is to focus on scanning of variants with high potential functional impacts. Enhancers play a crucial role in regulating cell-type-specific transcription. Therefore, single-nucleotide polymorphisms (SNPs) located in enhancers (enhancer-SNPs) may represent strong candidate functional variants. Here, we performed a targeted analysis for potential functional enhancer-SNPs that may affect gene expression and biological processes in bone-related cells, specifically, osteoblasts, and peripheral blood monocytes (PBMs), using five independent cohorts (n = 5905) and the genetics factors for osteoporosis summary statistics, followed by comprehensive integrative genomic analyses of chromatin states, transcription, and metabolites. We identified 15 novel enhancer-SNPs associated with femoral neck and lumbar spine BMD, including 5 SNPs mapped to novel genes (e.g., rs10840343 and rs10770081 in IGF2 gene) and 10 novel SNPs mapped to known BMD-associated genes (e.g., rs2941742 in ESR1 gene, and rs10249092 and rs4342522 in SHFM1 gene). Interestingly, enhancer-SNPs rs10249092 and rs4342522 in SHFM1 were tightly linked, but annotated to different enhancers in PBMs and osteoblasts, respectively, suggesting that even tightly linked SNPs may regulate the same target gene and contribute to the phenotype variation in cell-type-specific manners. Importantly, ten enhancer-SNPs may also regulate BMD variation by affecting the serum metabolite levels. Our findings revealed novel susceptibility loci that may regulate BMD variation and provided intriguing insights into the genetic mechanisms of osteoporosis.



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New insights into the genetics of spermatogenic failure: a review of the literature

Abstract

Genetic anomalies are known to affect about 15% of infertile patients with azoospermia or severe oligozoospermia. Despite a throughout diagnostic work-up, in up to the 72% of the male partners of infertile couples, no etiological factor can be found; hence, the cause of infertility remains unclear. Recently, several novel genetic causes of spermatogenic failure (SPGF) have been described. The aim of this review was to collect all the available evidence of SPGF genetics, matching data from in-vitro and animal models with those in human beings to provide a comprehensive and updated overview of the genes capable of affecting spermatogenesis. By reviewing the literature, we provided a list of 60 candidate genes for SPGF. Their investigation by Next Generation Sequencing in large cohorts of patients with apparently idiopathic infertility would provide new interesting data about their racial- and ethnic-related prevalence in infertile patients, likely raising the diagnostic yields. We propose a phenotype-based approach to identify the genes to look for.



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Mutations in ACTL6B , coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy

Abstract

Developmental and epileptic encephalopathies (DEEs) are genetically heterogenous conditions, often characterized by early onset, EEG interictal epileptiform abnormalities, polymorphous and drug-resistant seizures, and neurodevelopmental impairments. In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis. Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the ACTL6B gene (NM_016188:c.820C>T;p.Gln274*) coding for a subunit of the neuron-specific chromatin remodeling complex nBAF. To further support these findings, a targeted ACTL6B sequencing assay was performed on a cohort of 85 unrelated DEE individuals, leading to the identification of a homozygous missense variant (NM_016188:c.1045G>A;p.Gly349Ser) in a patient. This variant did not segregate in the unaffected siblings in this family and was classified as deleterious by several prediction softwares. Interestingly, in both families, homozygous patients shared a rather homogeneous phenotype. Very few patients with ACTL6B gene variants have been sporadically reported in WES cohort studies of patients with neurodevelopmental disorders and/or congenital brain malformations. However, the limited number of patients with incomplete clinical information yet reported in the literature did not allow to establish a strong gene–disease association. Here, we provide additional genetic and clinical data on three new cases that support the pathogenic role of ACTL6B gene mutation in a syndromic form of DEE.



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There is not an increased risk of intraocular hemorrhage associated with the use of novel antiplatelet therapy, but novel anticoagulants may decrease the hazard of bleeding compared with warfarin.

JAMA Ophthalmol. 2018 Feb; 136(2): 122–130.
Published online 2017 Dec 14. doi: 10.1001/jamaophthalmol.2017.5677
PMCID: PMC5838600
PMID: 29242919

Association of Novel Oral Antithrombotics With the Risk of Intraocular Bleeding

Katherine E. Uyhazi, MD, PhD,1 Todd Miano, PharmD, MSCE,2,3 Wei Pan, MS,3 and Brian L. VanderBeek, MD, MPH, MSCEcorresponding author1,2,3,4

Associated Data

Supplementary Materials
Supplement: eTable 1. Intraocular Bleeding ICD-9 Codes

eTable 2. Univariate Analysis of Association Between Parameters and Intraocular Bleeding for Warfarin vs Dabigatran/Rivaroxaban Comparison

eTable 3. Univariate Analysis of Association Between Parameters and Intraocular Bleeding for Clopidogrel vs Prasugrel Comparison

Introduction

Millions of patients worldwide are treated with oral anticoagulation and antiplatelet therapy to reduce the risk of thromboembolic events. Although traditional anticoagulation therapy has been with the vitamin K antagonist warfarin sodium, several newer agents have become increasingly popular. The direct thrombin inhibitor dabigatran etexilate and the direct factor Xa inhibitors rivaroxaban and apixaban have been shown to be noninferior to warfarin in the prevention of stroke in patients with atrial fibrillation. Unlike warfarin, which requires frequent blood tests and dose titration, these novel anticoagulants do not require routine monitoring. Owing to their predictable pharmacokinetics, shorter half-life, reduced drug-drug interactions, and overall ease of use, more patients are being started on these and similar agents in lieu of traditional vitamin K–based therapies.

Similarly, several novel antiplatelet agents are now available for patients who have had acute coronary syndrome or percutaneous coronary intervention. In lieu of traditional dual antiplatelet therapy with aspirin and clopidogrel bisulfate, the newer oral P2Y12 inhibitors prasugrel hydrochloride and ticagrelor are increasingly prescribed owing to improved efficacy, bioavailability, and onset of action compared with that of clopidogrel.

However, numerous reports of systemic hemorrhagic complications have brought the safety and adverse effect profiles of novel medications into question. Intraocular hemorrhages are a rare but potentially vision-threatening complication of systemic antithrombotic use. Previous studies have shown an increased risk for all types of intraocular hemorrhages in patients taking aspirin, clopidogrel, or warfarin, raising concerns over the safety of these medications.

An analysis using the World Health Organization's database of adverse events suggests that the odds of having a retinal or vitreous hemorrhage while taking dabigatran or rivaroxaban far exceeds that of warfarin. However, the results of this study are based strictly on voluntary physician report and do not quantify the number of patients using the medication. Contrasting these findings is a meta-analysis that found no increased risk of intraocular bleeding in patients taking novel anticoagulants vs those taking vitamin K antagonists, but this analysis was not geared toward finding eye complications.

Even less is known about the ocular risks of novel antiplatelet agents, as, to our knowledge, no studies have assessed intraocular hemorrhages in patients taking the newer oral P2Y12 inhibitors. Given the increasing number of patients using novel antithrombotics, the safety profile of these medications with regard to eye disease needs to be better understood. The goal of this study was to assess the risk of intraocular bleeding in patients taking novel oral antithrombotic agents compared with that of traditional antithrombotic agents.

Methods

Data Set

Data were abstracted from the Clinformatics Data Mart Database (OptumInsight, Eden Prairie, MN), which contains the deidentified medical claims of all beneficiaries from a large private insurance network in the United States. The database includes all outpatient medical claims (office visits and associated diagnoses), all outpatient pharmaceutical prescriptions filled, and demographic data for each beneficiary during his or her enrollment in the insurance plan. The subset of data available for this study included all patients in the database from January 1, 2010, to September 30, 2015. The University of Pennsylvania institutional review board deemed this study exempt from review owing to the deidentified nature of the data.

Cohorts

For this study, the risk of intraocular bleeding was tested through comparing multiple cohorts of patients. To best assess the potential incremental risk of the novel medications, we compared them with the older medication that the novel drug intended to replace. Two separate analyses were performed. The index date for all comparison groups was the day the patient first filled a prescription. For all cohorts, patients were required to have been enrolled in the insurance plan for 24 months or more prior to the index date without a previous prescription for any of the study medications. Patients were also excluded if they had any previous diagnosis of intraocular hemorrhages or received a prescription for the comparator study medication prior to the index date.

Antiplatelet Cohort

The first analysis examined patients older than 40 years who had received at least 1 prescription for 1 of 2 P2Y12 receptor antagonists of interest: clopidogrel (older drug) or prasugrel (novel drug) during their time in the insurance plan. In addition, specific to the antiplatelet analysis, patients were required to have a history of acute coronary syndrome or a myocardial infarction within 60 days of initiation of therapy to ensure the medications were used for similar indications. Other novel antiplatelet agents (ie, ticagrelor and cangrelor) were not included owing to their limited use within the database. Patients receiving concomitant anticoagulation were either excluded from the analysis or censored at the initiation of anticoagulation. A sensitivity analysis was also performed with removal of patients with a history of ischemic stroke and transient ischemic attacks (TIAs).

Anticoagulant Cohort

The next analysis compared patients older than 40 years who filled at least 1 prescription for either rivaroxaban or dabigatran with patients who filled at least 1 prescription for warfarin. Other novel anticoagulants (ie, apixaban and edoxaban tosylate) were not tested owing to their limited use within the data set. Patients receiving concomitant P2Y12 receptor antagonists (ie, clopidogrel and prasugrel) were not excluded from the analysis; instead, concomitant exposure to P2Y12 receptor antagonists was measured and controlled for in the analysis. The novel anticoagulants studied (dabigatran and rivaroxaban) are cleared by renal elimination and are contraindicated in patients with end stage renal disease. Accordingly, patients with end stage renal disease or undergoing dialysis were excluded from the anticoagulant cohort. In addition, because the novel anticoagulants are approved only for the treatment of nonvalvular atrial fibrillation, patients with heart valve disease or valve replacement were also excluded. These latter exclusions were not applied to the antiplatelet analysis.

Follow-up

For all study cohorts, follow-up began on the date of filling the first prescription and continued until 1 of the following: occurrence of intraocular bleeding, a prescription was filled for a comparator group (ie, alternate antithrombotic), other bleeding (eg, gastrointestinal bleeding or hemorrhagic stroke), the patient's exit from the insurance plan, the end of the observation period, or a gap of more than 14 days in prescription coverage.

Outcomes of Interest

The primary outcome of interest was evidence of new intraocular hemorrhages, defined as having an incident diagnosis code for a new vitreous hemorrhage, nontraumatic intraocular hemorrhage, hyphema, retinal hemorrhage, or expulsive choroidal hemorrhage made by an eye care professional. Subconjunctival hemorrhages were not included. (See eTable 1 in the Supplement for all International Classification of Diseases, Ninth Revision, codes used in this study.)

Covariates

Confounding by indication is any association between a drug and an outcome that is owing to reasons underlying why the drug is actually prescribed, rather than a direct effect of the drug itself, and can limit these types of studies. Although using older antithrombotics as a comparator group reduces this confounding, additional covariates were evaluated for potential inclusion in multivariate analysis. These covariates included demographic information (age, sex, and race), year of initiation of treatment, indications for treatment (acute venous thrombosis, pulmonary embolism, atrial fibrillation, or atrial flutter), comorbid conditions (hypertension, types 1 and 2 diabetes, stroke, myocardial infarction, congestive heart failure, chronic liver disease, chronic pulmonary disease, peripheral vascular disease, and any malignant neoplasm) and eye disease states that are associated with bleeding (diabetic retinopathy, age-related macular degeneration, sickle cell anemia, or retinal vein occlusions). In addition, other classes of medications are known to potentiate or inhibit the effectiveness of anticoagulants and antiplatelet drugs, including selective serotonin reuptake inhibitors, statins, prescription nonsteroidal anti-inflammatory drugs (NSAIDs), and amiodarone. Other direct modulators were grouped into cytochrome P450 inhibitors (antifungals, antibiotics, fenofibrate, and calcium channel blockers) and cytochrome P450 inducers (corticosteroids, antiepileptics, rifampin, and leukotriene receptor antagonists). To assess the potential interaction between these medications and the study drugs at the time of a possible outcome, patients were considered to be users of these medications only if they had an active prescription at the time of outcome or censoring.

Statistical Analysis

Baseline demographic characteristics were assessed at the index date and were analyzed using descriptive statistics. Means and ranges were used for continuous variables and percentages were used for categorical variables. Cox proportional hazards regression models were used to analyze the time from prescription index date to either an outcome of interest that occurred or when the patient was censored. Hazard ratios (HRs) were estimated for 2 observation periods: days 1 to 90 after the index date and days 1 to 365 after the index date. All covariates were first assessed in a Cox univariate analysis. Each covariate with an association (defined as P < .20) with intraocular hemorrhages was then included for multivariate analysis. Backward variable selection was used for fitting the final multivariate models for each observation window in each analysis. Each of the multivariate models was assessed for multicolinearity; none was found. Furthermore, the proportional hazard assumption was tested for all variables using log-log plots and only prescription NSAIDs violated this assumption, which was not included in the multivariate analysis. All statistical analysis was performed with SAS, version 9.4 (SAS Institute Inc), software was used for all statistical analysis. P < .05 was considered significant.

Results

A total of 146 137 patients prescribed warfarin and 64 291 patients prescribed dabigatran or rivaroxaban met the inclusion criteria (Figure). Approximately half of the patients were female in each cohort (76 714 [52.5%] in the warfarin cohort and 31 576 [49.1%] in the dabigatran or rivaroxaban cohort) and most patients were white (110 639 [75.7%] in the warfarin cohort and 50 523 [78.6%] in the dabigatran or rivaroxaban cohort) (Table 1). The mean (SD) age was 69.8 (11.8) years in the warfarin cohort and 67.6 (11.7) years in the dabigatran or rivaroxaban cohort. (See Table 1 for complete baseline demographic information.) The mean time to a censoring event (in the 365-day periods) was 124 days in the warfarin cohort and 193 days in the dabigatran or rivaroxaban cohort. The warfarin cohort had 81 incident intraocular hemorrhages at 90 days and 203 incident intraocular hemorrhages at 365 days. The novel therapeutic cohort had 33 incident intraocular hemorrhages at 90 days and 92 incident intraocular hemorrhages at 365 days. The longitudinal prevalence rate of an intraocular hemorrhage was 0.14% (205 of 146 137) among patients treated with traditional anticoagulants and was 0.14% (92 of 64 291) among patients treated with novel anticoagulants.

An external file that holds a picture, illustration, etc.  Object name is jamaophthalmol-136-122-g001.jpg
Anticoagulation and Antiplatelet Prescriptions After Exclusion Criteria

aPatients were excluded if they had previous intraocular bleeding, end-stage renal disease, a kidney transplant, mitral valve disease, or a heart valve repair or replacement. ACS indicates acute coronary syndrome; MI, myocardial infarction.

Table 1.

Baseline Characteristics of Cohorts
CharacteristicPatients, No. (%)
AnticoagulantAntiplatelet
Warfarin Sodium
(n = 146 137)
Dabigatran Etexilate or Rivaroxaban
(n = 64 291)
Clopidogrel Bisulfate
(n = 103 796)
Prasugrel Hydrochloride
(n = 8386)
Age, mean (SD), y69.8 (11.8)67.6 (11.7)68.0 (11.3)61.0 (9.6)
Female sex76 714 (52.5)31 576 (49.1)37 578 (36.2)1988 (23.7)
Race
White110 639 (75.7)50 523 (78.6)76 842 (74.0)6398 (76.3)
Black13 680 (9.4)4893 (7.6)11 407 (11.0)742 (8.8)
Other21 818 (14.9)8875 (13.8)15 547 (15.0)1246 (14.9)
Diagnosis
Types 1 and 2 diabetes47 004 (32.2)19 874 (30.9)48 987 (47.2)3354 (40.0)
Age-related macular degeneration17 269 (11.8)7612 (11.8)12 248 (11.8)543 (6.5)
Vein occlusions2111 (1.4)800 (1.2)2046 (2.0)73 (0.9)
Diabetic retinopathy3203 (2.2)1524 (2.4)3150 (3.0)203 (2.4)
Atrial fibrillation or flutter44 395 (30.4)27 714 (43.1)12 659 (12.2)607 (7.2)
Hypertension109 758 (75.1)49 849 (77.5)96 481 (93.0)7276 (86.8)
Chronic kidney disease25 998 (17.8)8665 (13.5)21 809 (21.0)948 (11.3)
Prior ischemic stroke or TIA20 936 (14.3)7194 (11.2)22 271 (21.5)609 (7.3)
Prior myocardial infarction20 610 (14.1)7232 (11.2)103 796 (100)8386 (100)
Congestive heart failure37 439 (25.6)13 856 (21.6)41 159 (39.7)2154 (25.7)
Any malignant neoplasm30 343 (20.8)11 618 (18.1)16 911 (16.3)921 (11.0)
Chronic pulmonary disease55 311 (37.8)23 513 (36.6)46 044 (44.4)2767 (33.0)
Peripheral vascular disease36 592 (25.0)13 738 (21.4)41 344 (39.8)1926 (23.0)
Acute venous thrombosis34 825 (23.8)7993 (12.4)2704 (2.6)138 (1.6)
Pulmonary embolism19 414 (13.3)3844 (6.0)1027 (1.0)45 (0.5)
Medications
Prescription NSAIDs67 359 (46.1)34 985 (54.4)42 321 (40.8)3918 (46.7)
Statins78 965 (54.0)34 338 (53.4)96 228 (92.7)8103 (96.6)
SSRIs33 700 (23.1)14 865 (23.1)24 441 (23.5)1681 (20.0)
Other metabolic inhibitors110 699 (75.8)50 838 (79.1)80 352 (77.4)6387 (76.2)
Other metabolic inducers79 921 (54.7)38 479 (59.9)54142 (52.2)4522 (53.9)
Amiodarone or dronedarone12 284 (8.4)7429 (11.6)5590 (5.4)234 (2.8)
Concurrent antiplatelet use1032 (0.7)0NANA
Index year
201032 938 (22.5)205 (0.3)45 638 (44.0)0
201128 000 (19.2)5085 (7.9)9767 (9.4)0
201227 099 (18.5)10 977 (17.1)9057 (8.7)3418 (40.8)
201326 223 (17.9)19 124 (29.7)23 681 (22.8)2518 (30.0)
201417 721 (12.1)15 808 (24.6)8537 (8.2)1489 (17.8)
201514 156 (9.7)13 092 (20.4)7116 (6.9)961 (11.5)

Abbreviations: NA, not applicable; NSAIDS, nonsteroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors; TIA, transient ischemic attack.

A total of 103 796 patients prescribed clopidogrel and 8386 patients prescribed prasugrel met the inclusion criteria (Figure). A minority of patients in both cohorts were female (37 578 [36.2%] in the clopidogrel cohort and 1988 [23.7%] in the prasugrel cohort) and most were white (76 842 [74.0%] in the clopidogrel cohort and 6398 [76.3%] in the prasugrel cohort) (Table 1). The mean (SD) age was 68.0 (11.7) years in the clopidogrel cohort and 61.0 (9.6) years in the prasugrel cohort. The mean time to a censoring event was 115 days in the clopidogrel cohort and 180 days in the prasugrel cohort. There were 68 new bleeding events in the traditional clopidogrel cohort at 90 days and 134 new bleeding events at 365 days. The novel antiplatelet cohort had 5 new bleeding events at 90 days and 16 new bleeding events at 365 days. The longitudinal prevalence rate for an intraocular hemorrhage was 0.13% (134 of 103 796) in patients treated with traditional agents and was 0.19% (16 of 8386) in patients treated with novel antiplatelet agents.

Cox univariate analysis revealed that, at 90 days, dabigatran and rivaroxaban were not associated with intraocular hemorrhages compared with warfarin (HR, 0.69; 95% CI, 0.46-1.04; P = .07). However, at 365 days, dabigatran and rivaroxaban were associated with a 32% decreased hazard (HR, 0.68; 95% CI, 0.53-0.87; P = .002). Univariate analysis of prasugrel at both 90 and 365 days showed no association with intraocular hemorrhages compared with clopidogrel (90-day HR, 0.72; 95% CI, 0.29-1.78; P = .47; 365-day HR, 0.98; 95% CI, 0.59-1.65; P = .95). (See eTables 2 and 3 in the Supplement for full univariate analysis results.)

Multivariate analysis again revealed no association for warfarin or dabigatran or rivaroxaban and intraocular hemorrhages in the 90-day period (HR, 0.73; 95% CI, 0.22-2.63; P = .13), but a 25% decreased hazard was seen at 365 days (HR, 0.75; 95% CI, 0.58-0.97; P = .03) (Table 2). No association was also found for developing an intraocular hemorrhage while taking clopidogrel compared with prasugrel in either of the observation windows (90-day HR, 0.75; 95% CI, 0.29-1.92; P = .55; 365-day HR, 1.19; 95% CI, 0.69-2.04; P = .53) (Table 3). A sensitivity analysis that removed all patients with a previous TIA or ischemic stroke from the antiplatelet cohorts found no difference in prasugrel's hazard for intraocular hemorrhages at either time point (90-day HR, 0.60; 95% CI, 0.19-1.93; P = .39; 365-day HR, 1.13; 95% CI, 0.63-2.02; P = .69). With the exception of retinal vein occlusions in the 90-day antiplatelet comparison, the ocular diseases most associated with bleeding (age-related macular degeneration HRs, 2.48-3.15; P < .001 for all comparisons; retinal vein occlusion HRs, 2.32-5.04; P < .009; and diabetic retinopathy HRs, 1.84-2.96; P < .04) were all found to have increased HRs for intraocular hemorrhages (Tables 2 and and33).

Table 2.

Multivariate Results for Significant Associations for Intraocular Hemorrhages in Warfarin vs Dabigatran or Rivaroxaban Comparison
CharacteristicNo. (%)HR (95% CI)P Value
Patients
(n = 210 428)
Intraocular Hemorrhagesa
90-d Analysisb
Warfarin sodium146 137 (69.4)81 (0.06)1 [Reference]NA
Dabigatran etexilate or rivaroxaban64 291 (30.6)33 (0.05)0.73 (0.22-2.63).13
Peripheral vascular disease50 330 (23.9)46 (0.09)1.60 (1.09-2.36).02
Hypertension159 607 (75.8)103 (0.06)2.13 (1.13-4.04).02
Metabolic inhibitors161 537 (76.8)83 (0.05)0.62 (0.41-0.95).03
Retinal vein occlusion2911 (1.4)14 (0.48)5.04 (2.78-9.12)<.001
Age-related macular degeneration24 881 (11.8)39 (0.16)2.48 (1.64-3.75)<.001
Diabetic retinopathy4727 (2.2)14 (0.30)2.96 (1.64-5.35)<.001
365-d Analysis
Warfarin146 137 (69.4)203 (0.14)1 [Reference]NA
Dabigatran or rivaroxaban64 291 (30.6)92 (0.14)0.75 (0.58-0.97).03
Statins114 361 (54.3)197 (0.17)1.37 (1.07-1.75).01
Previous myocardial infarction27 842 (13.2)63 (0.23)1.52 (1.14-2.02).004
Diabetic retinopathy4796 (2.3)25 (0.52)1.98 (1.29-3.04).002
Retinal vein occlusion2953 (1.4)27 (0.91)3.73 (2.46-5.64)<.001
Age-related macular degeneration25 176 (12.0)106 (0.42)3.16 (2.46-4.05)<.001
Index year
201033 143 (15.8)19 (0.06)1 [Reference]<.001
201133 085 (15.7)21 (0.06)1.14 (0.61-2.13)
201238 076 (18.1)38 (0.10)1.78 (1.03-3.10)
201345 347 (21.5)77 (0.17)1.12 (0.67-1.86)
201433 529 (15.9)102 (0.30)1.24 (0.75-2.05)
201527 248 (12.9)38 (0.14)0.54 (0.31-0.95)

Abbreviations: HR, hazard ratio; NA, not applicable.

aThere is a 1 to 1 correlation between number of patients and number of intraocular hemorrhages.
bTo prevent overfitting a model with a limited number of outcomes, a backward variable selection was used for fitting each of the final models with 1 variable per every additional 10 outcomes allowed to be included in the final model.

Table 3.

Multivariate Results for Significant Associations for Intraocular Hemorrhages in Clopidogrel vs Prasugrel Comparison
CharacteristicNo. (%)HR (95% CI)P Value
Patients
(n = 112 182)
Intraocular Hemorrhagesa
90-d Analysisb
Clopidogrel bisulfate103 796 (92.5)68 (0.07)1 [Reference]NA
Prasugrel hydrochloride8386 (7.5)5 (0.06)0.75 (0.29-1.92).55
Chronic kidney disease22 757 (20.3)26 (0.11)1.88 (1.15-3.06).01
Age-related macular degeneration12 791 (11.4)23 (0.18)2.87 (1.72-4.80)<.001
diabetic retinopathy3353 (3.0)7 (0.21)2.28 (1.03-5.08).04
Index year
201045 638 (40.6)15 (0.03)1 [Reference].05
20119767 (8.7)8 (0.08)3.15 (1.33-7.43)
201212 475 (11.1)7 (0.06)2.28 (0.91-5.72)
201326 199 (23.4)25 (0.10)2.15 (1.13-4.11)
201410 026 (8.9)10 (0.10)1.26 (0.56-2.82)
20158077 (7.2)8 (0.10)1.18 (0.50-2.81)
365-d Analysis
Clopidogrel103 796 (92.5)134 (0.13)1 [Reference]NA
Prasugrel8386 (7.5)16 (0.19)1.19 (0.69-2.04).53
Types 1 or 2 diabetes52 341 (46.7)95 (0.18)1.81 (1.29-2.54)<.001
Congestive heart failure43 313 (38.6)73 (0.17)1.43 (1.03-1.98).03
Retinal vein occlusions2146 (1.9)11 (0.51)2.32 (1.23-4.39).009
Age-related macular degeneration12 929 (11.5)51 (0.39)3.15 (1.23-4.39)<.001
Diabetic retinopathy3405 (3.0)14 (0.41)1.84 (1.04-3.26).04
Index year
201045 638 (40.6)30 (0.07)1 [Reference].03
20119767 (8.7)10 (0.10)1.93 (0.94-3.95)
201212 475 (11.1)10 (0.08)1.45 (0.70-3.04)
201326 199 (23.4)55 (0.21)1.57 (0.99-2.47)
201410 026 (8.9)30 (0.30)1.16 (0.69-1.95)
20158077 (7.2)15 (0.19)0.66 (0.35-1.24)

Abbreviations: HR, hazard ratio; NA, not applicable.

aThere is a 1 to 1 correlation between number of patients and number of intraocular hemorrhages.
bTo prevent overfitting a model with a limited number of outcomes, a backward variable selection was used for fitting each of the final models with 1 variable per every additional 10 outcomes allowed to be included in the final model.

Discussion

Novel antithrombotic agents are established as safe and effective alternatives to traditional medications for the treatment of atrial fibrillation, thromboembolic disease, and acute coronary syndrome. The direct thrombin inhibitor dabigatran and the direct factor Xa inhibitor rivaroxaban are increasingly being prescribed owing to their ease of use and improved adverse effect profiles. Likewise, the oral P2Y12inhibitors prasugrel and ticagrelor are approved for use in patients with acute coronary syndrome and have demonstrated superior efficacy compared with clopidogrel.

To our knowledge, this study represents the first evaluation of the risk of intraocular bleeding with a novel antiplatelet agent. Our data suggest that prasugrel carries no additional ocular risk compared with its traditional counterpart, clopidogrel. Further inquiry will be needed on ocular safety profiles as more data become available for even newer antiplatelet and anticoagulation agents such as ticagrelor, cangrelor, apixaban, and edoxaban.

This study found a decreased hazard of intraocular hemorrhages at 365 days for dabigatran and rivaroxaban compared with warfarin. Our results, along with the recent meta-analysis of clinical trial data by Sun et alcontradict the concerns for intraocular bleeding raised by case reports and the World Health Organization adverse events database analysis. Information in the World Health Organization adverse events database results is based solely on voluntary reporting. This type of information can be misleading because it is susceptible to reporting bias and lacks the ability to control for confounding factors or to properly quantitate risk since the total number of prescriptions represented is unknown.

Although our results are similar to those reported in the meta-analysis by Sun et al, it is important to differentiate how each study arrived at its conclusions. Our study focuses on real-world use of anticoagulants, whereas the meta-analysis focused on results from clinical trial populations that may differ from our study in terms of baseline bleeding risk and how the drugs are dosed and monitored. We excluded people with a previous history of intraocular hemorrhages (to limit recurrences in those predisposed to intraocular hemorrhages) and controlled for eye diseases most frequently associated with bleeding. Unless they are specifically focused on ocular outcomes, clinical trials (and by extension, the meta-analysis by Sun et al) are unlikely to exclude patients with previous ocular bleeding or emphasize a history of diabetic retinopathy, retinal vein occlusions, or age-related macular degeneration during randomization. The importance of these risk factors is further highlighted in each of our final models, which show the significant hazard they represent for intraocular bleeding.

Furthermore, the a priori removal of patients predisposed to bleeding from our study also likely explains our lower rate of bleeding (0.14%) in the anticoagulant cohorts compared with that reported by Caldeira et al (0.21%-0.33%). Removal of these patients was needed to best equate the cohorts at baseline and allow for a direct assessment of the association of the medications with intraocular hemorrhages, independent of the underlying disease. Although this limits the generalizability of our results, our exceptionally low rate of intraocular hemorrhages throughout the study supports the safety of antithrombotics with regards to the eye in this population.

Strengths and Limitations

Other strengths of our study should be noted, including our ability to assess many other nonophthalmic factors that could mitigate or potentiate the effects of anticoagulants that may have been an issue in previous studies. In addition, the cohort design of the study minimizes the potential bias of convenience sampling that frequently occurs in case reports (and, by extension, the World Health Organization report) when rare outcomes spur publications that do not reflect the true rate seen in a larger population. Last, pharmacy records, not patient reports, determined medication use; thus, recall bias was eliminated.

Owing to the nature of our data and the inability to know if patients temporarily stopped their medication at or around the time of eye surgery, we are unable to comment on the safety profile of these drugs perioperatively. Although recent studies have shown no increased risk of perioperative vitreous hemorrhage with antithrombotic use, balancing the potentially life-threatening risk of stopping these medications and the low risk of hemorrhagic ocular complications is a difficult decision that should be made between the surgeon, the prescribing clinician, and the patient. Further work should be performed to better inform this decision.

Several limitations need to be considered when reviewing the results of our study. First, the rate of intraocular hemorrhages was exceedingly low, and the power of our study to detect subtle differences between antiplatelet cohorts was limited despite the large number of patients. In another context, however, this is reassuring, given the widespread use of antithrombotic agents. It could even be argued that since the incidence of an intraocular hemorrhage occurring while taking these medications is less than 0.2%, small differences between medication classes may not be clinically significant. Second, not all patients underwent an eye examination while taking the medications studied. Although patients with visually significant bleeding would have presumably been referred for care, it is possible that patients with clinically insignificant intraocular hemorrhages went undiagnosed, suggesting that our incidence rates may be an underestimate. Third, this study used administrative billing data that were unable to be verified with medical record–level data, nor have all the International Classification of Diseases, Ninth Revision codes used been specifically validated. Next, the database consists of claims from 1 insurance network and may not be generalizable to other patient populations.

Last, the database only includes data on prescription NSAIDs. We are unable to account for any over-the-counter use of NSAIDs or other factors that could influence the potency of the antithrombotic medications (ie, the effect of grapefruit juice on warfarin levels). Although this limitation certainly exists, the commonness of use of over-the-counter NSAIDs combined with the extremely low occurrence rate of bleeding found in this study suggest that the overall effect of this issue is likely low.

Conclusions

Owing to the increasing use of novel antithrombotic medications for the treatment of coronary artery disease and atrial fibrillation, the ocular safety profile of these medications must be understood. Our study suggests that there is not an increased risk of intraocular hemorrhage associated with the use of novel antiplatelet therapy, but novel anticoagulants may decrease the hazard of bleeding compared with warfarin.

Notes

Supplement.

eTable 1. Intraocular Bleeding ICD-9 Codes

eTable 2. Univariate Analysis of Association Between Parameters and Intraocular Bleeding for Warfarin vs Dabigatran/Rivaroxaban Comparison

eTable 3. Univariate Analysis of Association Between Parameters and Intraocular Bleeding for Clopidogrel vs Prasugrel Comparison

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