Patient Perspectives on Seeking Emergency Care for Acute Low Back Pain and Access to Physical Therapy in the Emergency Department.

STUDY OBJECTIVE: Low back pain is a common reason for visiting the emergency department (ED), yet little is known about patient motivations for seeking emergency care. The purpose of this study was to explore patient perspectives on visiting the ED for low back pain to inform a more patient-centered approach to emergency care. METHODS: We conducted focus group discussions and individual interviews among patients visiting an urban academic ED for acute low back pain. We recruited participants from an ongoing prospective study of 101 patients receiving either ED-initiated physical therapy or usual care. We conducted discussions, and interviews using an a priori developed discussion guide. We audio recorded, transcribed, and iteratively content analyzed the data using a consensual qualitative approach until thematic saturation was reached. RESULTS: We conducted 4 focus group discussions among 18 participants (median age 46.5 years, 66.7% women, 61.1% Black) and individual interviews with 27 participants (median age 45 years, 55.6% women, 44.4% White). No new themes emerged during the fourth and final focus group. We identified 5 summary themes: (1) the decision to seek emergency care for low back pain is motivated by severe pain, resulting disability, and fears about a catastrophic diagnosis, (2) participants sought various goals from their ED visit but emphasized the primacy of pain control, (3) participants were reluctant to use pain medications but also acknowledged their benefit, (4) participants perceived a number of benefits from direct access to an ED physical therapist in the ED, and (5) participation in physical therapy ultimately facilitated recovery, but the pain was a barrier to performing exercises. CONCLUSIONS: These patient perspectives and resulting themes may be used to inform a more patient-centered emergency care experience and contextualize quantitative research findings on ED care for low back pain.

Barriers and Best Practices for the Use of Patient-Reported Outcome Measures in Emergency Medicine.

Patient-reported outcome measures are commonly used in clinical trials and have been incorporated into routine clinical care in select specialties but have not been widely implemented in emergency medicine research and clinical care. We describe measurement-related barriers to patient-reported outcome measure use in the emergency department; administrative and practical considerations; implications of developing novel emergency medicine-specific patient-reported outcome measures; and key considerations for the use of patient-reported outcome measures in emergency medicine research and clinical care. Despite the unique barriers of the ED environment, potential solutions include the use of ED-validated patient-reported outcome measures when available; adapting existing short-form, multidimensional patient-reported outcome measures previously validated in diverse populations, ideally using computer-adapted testing; and collecting responses during anticipated wait times. With this work, we aim to inform barriers and best practices to the use of patient-reported outcome measures in emergency medicine research and clinical care to support future, more widespread implementation of patient-reported outcome measures within emergency care. The successful adoption of patient-reported outcome measures for diverse ED patient populations within the unique constraints of the acute care environment may help researchers, clinicians, and policymakers improve the quality and patient-centeredness of acute care.

Impact of the COVID pandemic on emergency department CT utilization: where do we go from here?

PURPOSE: To analyze the impact of the coronavirus disease (COVID) pandemic on emergency department (ED) computed tomography (CT) utilization. METHODS: A retrospective observational study was conducted assessing seven hospitals' ED imaging volumes between Jan. 6, 2019, and Feb. 27, 2021. Weekly CT utilization is reported as CTs ordered per 100 ED visits. Utilization was ascertained in aggregate and by body area. Interrupted time series analysis was performed to assess significance of utilization change. Prespecified sensitivity analysis was performed for influenza-like or COVID-like illness (ILI/CLI). RESULTS: Weekly ED CT utilization increased from 35.9 CTs per 100 visits (95% confidence interval [95% CI] 35.8-36.1) to 41.8 per 100 visits (95% CI 41.7-42.0) in pre- and post-pandemic periods. Weekly ED CT chest utilization increased immediately following the pandemic declaration (+ 0.52 chest CTs per 100 ED visits, 95% CI 0.01-1.03, p < 0.05) and compared to pre-pandemic period (+ 0.02 per 100 ED visits, 95% CI 0.02-0.05, p < 0.02). For both CT abdomen/pelvis and CT head, there was neither an immediate effect (+ 0.34 CT-AP per 100 ED visits, 95% CI - 0.74 to 1.44, p = 0.89; - 0.42 CT-H per 100 ED visits, 95% CI - 1.53 to 0.70, p = 0.46) nor a change in weekly CT utilization (+ 0.03 CT-AP per 100 ED visits, 95% CI - 0.01 to 0.05, p = 0.09; + 0.03 CT-H per 100 ED visits, 95% CI - 0.01 to 0.06, p = 0.10).  CONCLUSION: These data may help formulate future strategies for resource utilization and imaging operations as we envision a future with COVID and other federal mandates affecting imaging utilization and appropriateness.

CD44 Receptor-Mediated/Reactive Oxygen Species-Sensitive Delivery of Nanophotosensitizers against Cervical Cancer Cells.

Stimulus-sensitive, nanomedicine-based photosensitizer delivery has an opportunity to target tumor tissues since oxidative stress and the expression of molecular proteins, such as CD44 receptors, are elevated in the tumor microenvironment. The aim of this study is to investigate the CD44 receptor- and reactive oxygen species (ROS)-sensitive delivery of nanophotosensitizers of chlorin e6 (Ce6)-conjugated hyaluronic acid (HA) against HeLa human cervical cancer cells. For the synthesis of nanophotosensitizers, thioketal diamine was conjugated with the carboxyl group in HA and then the amine end group of HA-thioketal amine conjugates was conjugated again with Ce6 (Abbreviated as HAthCe6). The HAthCe6 nanophotosensitizers were of small diameter, with sizes less than 200. Their morphology was round-shaped in the observations using a transmission electron microscope (TEM). The HAthCe6 nanophotosensitizers responded to oxidative stress-induced changes in size distribution when H2O2 was added to the nanophotosensitizer aqueous solution, i.e., their monomodal distribution pattern at 0 mM H2O2 was changed to dual- and/or multi-modal distribution patterns at higher concentrations of H2O2. Furthermore, the oxidative stress induced by the H2O2 addition contributed to the disintegration of HAthCe6 nanophotosensitizers in morphology, and this phenomenon accelerated the release rate of Ce6 from nanophotosensitizers. In a cell culture study using HeLa cells, nanophotosensitizers increased Ce6 uptake ratio, ROS generation and PDT efficacy compared to free Ce6. Since HA specifically bonds with the CD44 receptor of cancer cells, the pretreatment of free HA against HeLa cells decreased the Ce6 uptake ratio, ROS generation and PDT efficacy of HAthCe6 nanophotosensitizers. These results indicated that intracellular delivery of HAthCe6 nanophotosensitizers can be controlled by the CD44 receptor-mediated pathway. Furthermore, these phenomena induced CD44 receptor-controllable ROS generation and PDT efficacy by HAthCe6 nanophotosensitizers. During in vivo tumor imaging using HeLa cells, nanophotosensitizer administration showed that the fluorescence intensity of tumor tissues was relatively higher than that of other organs. When free HA was pretreated, the fluorescence intensity of tumor tissue was relatively lower than those of other organs, indicating that HAthCe6 nanophotosensitizers have CD44 receptor sensitivity and that they can be delivered by receptor-specific manner. We suggest that HAthCe6 nanophotosensitizers are promising candidates for PDT in cervical cancer.

Patient-Reported Opioid Pill Consumption After an ED Visit: How Many Pills Are People Using?

OBJECTIVES: Recent guidelines advise limiting opioid prescriptions for acute pain to a three-day supply; however, scant literature quantifies opioid use patterns after an emergency department (ED) visit. We sought to describe opioid consumption patterns after an ED visit for acute pain. DESIGN: Descriptive study with data derived from a larger interventional study promoting safe opioid use after ED discharge. SETTING: Urban academic emergency department (>88,000 annual visits). SUBJECTS: Patients were eligible if age >17 years, not chronically using opioids, and newly prescribed hydrocodone-acetaminophen and were included in the analysis if they returned the completed 10-day medication diary. METHODS: Patient demographics and opioid consumption are reported. Opioid use is described in daily number of pills and daily morphine milligram equivalents (MME) both for the sample overall and by diagnosis. RESULTS: Two hundred sixty patients returned completed medication diaries (45 [17%] back pain, 52 [20%] renal colic, 54 [21%] fracture/dislocation, 40 [15%] musculoskeletal injury [nonfracture], and 69 [27%] "other"). The mean age (SD) was 45 (15) years, and 59% of the sample was female. A median of 12 pills were prescribed. Patients with renal colic used the least opioids (total pills: median [interquartile range {IQR}] = 3 [1-7]; total MME: median [IQR] = 20 [10-50]); patients with back pain used the most (total pills: median [IQR] = 12 [7-16]; total MME: median [IQR] = 65 [47.5-100]); 92.5% of patients had leftover pills. CONCLUSIONS: In this sample, pill consumption varied by illness category; however, overall, patients were consuming low quantities of pills, and the majority had unused pills 10 days after their ED visit.

Take-Home Naloxone Program Implementation: Lessons Learned From Seven Chicago-Area Hospitals.

Despite consensus recommendations from the American College of Emergency Physicians (ACEP), the Centers for Disease Control and Prevention, and the surgeon general to dispense naloxone to discharged ED patients at risk for opioid overdose, there remain numerous logistic, financial, and administrative barriers to implementing "take-home naloxone" programs at individual hospitals. This article describes the recent collective experience of 7 Chicago-area hospitals in implementing take-home naloxone programs. We highlight key barriers, such as hesitancy from hospital administrators, lack of familiarity with relevant rules and regulations in regard to medication dispensing, and inability to secure a supply of naloxone for dispensing. We also highlight common facilitators of success, such as early identification of a "C-suite" champion and the formation of a multidisciplinary team of program leaders. Finally, we provide recommendations that will assist emergency departments planning to implement their own take-home naloxone programs and will inform policymakers of specific needs that may facilitate dissemination of naloxone to the public.

Who Is Keeping Their Unused Opioids and Why?

OBJECTIVE: To better understand patients' reasoning for keeping unused opioid pills. METHODS: As part of a larger study, patients were asked their plans for their unused opioids. Responses were categorized as "dispose," "keep," and "don't know." Baseline characteristics were compared between the "keep" and "dispose" groups. Verbatim responses categorized as "keep" were analyzed qualitatively using a team-based inductive approach with constant comparison across cases. RESULTS: One hundred patients planned to dispose of their pills; 117 planned to keep them. There were no differences in demographics between the groups. Among patients who planned to keep their pills, the mean age was 43 years and 47% were male. Analysis revealed four categories of patient responses: 1) plans to keep their pills "just in case," with reference to a medical condition (e.g., kidney stone); 2) plans to keep pills "just in case" without reference to any medical condition; 3) plans to dispose in delayed fashion (e.g., after pill expiration) or unsure of how to dispose; and 4) no identified plans, yet intended to keep pills. In this sample, there were no differences in characteristics of those reporting planning to keep vs dispose of pills; however, there were diverse reasons for keeping opioids. CONCLUSIONS: This manuscript describes a sample of patients who kept their unused opioids and presents qualitative data detailing their personal reasoning for keeping the unused pills. Awareness of the range of motivations underpinning this behavior may inform the development of tailored education and risk communication messages to improve opioid disposal.

Efficacy of auditory evoked potential follow-up in viral meningitis of infants.

PURPOSE: To examine the rate of occurrence of hearing impairments among the infants who had recovered from viral meningitis under 1 year of age through auditory evoked potential (AEP) test and to investigate the efficacy of the follow-up AEP test in viral meningitis infants. METHODS: Two hundred twenty infants (440 ears) were examined through AEP test once, and 47 (94 ears) of them went back for a second examination and were diagnosed with viral meningitis. The first AEP tests were compared with the second results in 47 infants. I latency, V latency, I-III interpeak latency (IPL), and III-V IPL were checked. RESULTS: In the first AEP test conducted on 440 ears, the average values of I and V latency and I-III IPL were delayed as compared with normal values. The second AEP results were conducted on 47 infants 92.36 days after the first exam. I latency and V latency of second exam were improved significantly (p < 0.05), but I-III and III-V IPL showed no significant changes. Two hearing impaired patients (4 ears) were confirmed through chart reviews. CONCLUSION: The AEP test is a helpful study for early detection of hearing problem. However, in this study, AEP test was too sensitive in acute period, and later, the incidence rate of hearing impairment was relatively low. Therefore, age of onset, severity of neurologic symptom, and clinical examination must be considered before the AEP test.

Development of a take-home naloxone program at an urban academic emergency department.

OBJECTIVE: To describe the development of an ED-based take-home naloxone (THN) program in which naloxone kits are dispensed directly to patients during ED discharge. PRACTICE DESCRIPTION: Our THN program was carried out at an urban academic hospital in downtown Chicago, IL. The THN kits consisted of 3 vials of 0.4-mg naloxone and 3 sterile syringes and needles for intramuscular delivery. Any member of the ED team (e.g., physician, pharmacist, or nurse) could recommend naloxone dispensing for a patient; however only the treating ED physician served as the prescriber for record. The ED pharmacist provided bedside education on recognizing opioid overdose and administering naloxone. The naloxone kit was dispensed to the patient at no cost. PRACTICE INNOVATION: This ED pharmacist-led naloxone dispensing model bypasses barriers to naloxone filling and ensures that patients walk out of the emergency department with naloxone in hand. EVALUATION METHODS: We report key metrics from the first 16 months of program implementation, including the number of ED visits for opioid overdose and THN kits dispensed. We further describe the key facilitators and barriers to program development. RESULTS: Over 16 months, our emergency department had 669 unique visits for opioid overdose, and we dispensed 168 THN kits (10.5 per month). We are aware of at least 3 cases in which our THN kits were used to reverse opioid overdose. We faced key informational barriers to program development, such as a lack of knowledge regarding the allowability of ED medication dispensing, as well as financial barriers, such as the need to obtain a supply of naloxone. We also recognized the key facilitators of success, such as early engagement with hospital leadership. CONCLUSION: Implementing a successful THN program is possible in the ED setting, and individual hospital emergency departments seeking to build their own program may benefit from our report.

Priapism from Recreational Intracavernosal Injections in a High-Risk Metropolitan Community.

INTRODUCTION: Recreational use of intracavernosal injections (ICIs) is a high-risk behavior that involves sharing of these agents by men without physician regulation. AIM: To characterize the etiologies and outcomes of priapism at a Los Angeles metropolitan medical center to better understand patterns of usage of recreational ICIs and the public health implications of such practices. METHODS: With institutional review board approval, we retrospectively reviewed all cases of priapism presenting to the emergency room of a Los Angeles tertiary medical center from 2010 to 2018. We compared outcomes between patients who presented with priapism after recreational ICI and patients who presented with other etiologies. MAIN OUTCOME MEASURE: We describe patient characteristics, etiologies, and treatments of priapism at our institution. RESULTS: We identified 169 priapism encounters by 143 unique patients. Recreational ICIs accounted for 82 of the 169 priapism encounters (49%). Patients who used recreational injections were younger than those who presented with other etiologies (43.5 years vs 47.5 years; P = .048) and had delayed presentations (median, 12 hours vs 8 hours; P < .0001). There was no statistical difference across groups in the proportion of patients requiring operative intervention (14.6% of recreational ICI users vs 16.1% of all other patients; P = .23). A total of 36 out of 72 patients who used recreational ICIs (50%) were HIV+. CLINICAL IMPLICATIONS: Our study adds to the relatively sparse literature on priapism outcomes. We identify and describe a high-risk population that uses recreational intracavernosal injections. STRENGTHS & LIMITATIONS: To our knowledge, this is the largest series of priapism encounters. However, the data are retrospective from a single institution, and there is a lack of long-term follow up. CONCLUSION: A large proportion of priapism visits at our institution were attributed to recreational use of ICIs. This is a high-risk patient population that may not be aware of the risks of recreational ICIs and the consequences of priapism. Further effort should be made to increase public and physician awareness of this harmful practice. Zhao H, Berdahl C, Bresee C, et al. Priapism from Recreational Intracavernosal Injections in a High-Risk Metropolitan Community. J Sex Med 2019;16:1650-1654.

The Complex Relationship Between Lower Urinary Tract Symptoms and Sexual Health.

PURPOSE OF REVIEW: Lower urinary tract symptoms (LUTS) and sexual health have common links. Medical and surgical treatments for LUTS can significantly affect various domains of sexual health including erectile function, ejaculatory function, and libido. This review summarizes recent findings. RECENT FINDINGS: Current literature demonstrates a strong association between LUTS, sexual health, and metabolic syndrome. The role of miRNA is also being investigated. Combination medical therapy with phosphodiesterase 5 inhibitors (PDE5-I) shows promise but needs further investigation. Newer surgical therapies for benign prostatic hyperplasia (BPH) aim to preserve sexual function without sacrificing efficacy and durability. Although we are beginning to acknowledge the link between LUTS and sexual health, a better understanding of the underlying biochemistry is needed. Only then can more effective therapies be developed. Further prospective studies should focus on the long-term durability and safety of treatments for both conditions.

A comparison of analgesic prescribing among ED back and neck pain visits receiving physical therapy versus usual care.

OBJECTIVE: Physical therapy (PT) is commonly cited as a non-opioid pain strategy, and previous studies indicate PT reduces opioid utilization in outpatients with back pain. No study has yet examined whether PT is associated with lower analgesic prescribing in the ED setting. METHODS: This was a retrospective cohort study of discharged ED visits with a primary ICD-10 diagnosis relating to back or neck pain from 10/1/15 to 2/21/17 at an urban academic ED. Visits receiving a PT evaluation were matched with same-date visits receiving usual care. We compared the primary outcomes of opioid and benzodiazepine prescribing between the two cohorts using chi-squared test and multivariable logistic regression. RESULTS: 74 ED visits received PT during the study period; these visits were matched with 390 same-date visits receiving usual care. Opioid prescribing among ED-PT visits was not significantly higher compared to usual care visits on both unadjusted analysis (50% vs 42%, p = 0.19) and adjusted analysis (adjOR 1.05, 95% CI 0.48-2.28). However, benzodiazepine prescribing among ED-PT visits was significantly higher than usual care visits on both unadjusted (45% vs 23%, p < 0.001) and adjusted analysis (adjOR 3.65, 95% CI 1.50-8.83). CONCLUSIONS: In this single center study, ED back and neck pain visits receiving PT were no less likely to receive an opioid prescription and were more likely to receive a benzodiazepine than visits receiving usual care. Although prior studies demonstrate that PT may reduce opioid utilization in the subsequent year, these results indicate that analgesic prescribing is not reduced at the initial ED encounter.

Physical therapy in the emergency department: A new opportunity for collaborative care.

Emergency department-initiated physical therapy (ED PT) is an emerging resource in the United States, with the number of ED PT programs in the United States growing rapidly over the last decade. In this collaborative model of care, physical therapists are consulted by the treating ED physician to assist in the evaluation and treatment of a number of movement and functional disorders, such as low back pain, peripheral vertigo, and various gait disturbances. Patients receiving ED PT benefit from the physical therapist's expertise in musculoskeletal and vestibular conditions and from the individualized attention provided in a typical bedside evaluation and treatment session, which includes education on expected symptom trajectory, recommendations for activity modulation, and facilitated outpatient follow-up. Early data suggest that both physicians and patients view ED PT services favorably, and that ED PT is associated with improvement of several important clinical and operational outcomes. Hospital systems interested in building their own ED PT program may benefit from the key steps outlined in this review, as well as a summary of the typical clinical volumes and practice patterns encountered at existing programs around the country.

Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription.

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.

Benzodiazepine-opioid co-prescribing in a national probability sample of ED encounters.

BACKGROUND: Benzodiazepine-opioid combination therapy is potentially harmful due to the risk of synergistic respiratory depression, and the rate of death due to benzodiazepine-opioid overdose is increasing. Little is known about the prevalence and characteristics of benzodiazepine-opioid co-prescribing from the ED setting. METHODS: Secondary analysis of data from the National Hospital Ambulatory Medical Care Survey, using sample weights to generate population estimates. The primary objective was to describe the annual prevalence of benzodiazepine-opioid co-prescribing from 2006 to 2012, using 95% confidence intervals (95% CI) to compare adjacent years. The secondary objective was to compare characteristics of ED encounters receiving a benzodiazepine-opioid co-prescription versus those receiving an opioid prescription alone, using a multivariable logistic regression. RESULTS: The prevalence of benzodiazepine-opioid co-prescribing did not significantly change from 2006 to 2012. During this period, 2.7% (95% CI: 2.5-2.8%) of ED encounters prescribed an opioid were also prescribed a benzodiazepine. Relative to encounters receiving an opioid prescription alone, encounters receiving a co-prescription were more likely to represent a follow-up rather than initial visit (Odds Ratio [OR] 1.52), receive more medications (OR 1.41) and fewer procedures (OR 0.48) while in the ED, and more likely to have a diagnosis related to mental disorder (OR 20.60) or musculoskeletal problem (OR 3.71). CONCLUSIONS: From 2006 to 2012, almost 3% of all ED encounters receiving an opioid prescription also received a benzodiazepine co-prescription. The odds of benzodiazepine-opioid co-prescribing were significantly higher in ED encounters representing a follow-up visit and in diagnoses relating to a mental disorder or musculoskeletal problem.

Combined protein- and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM.

Integrin alpha M (ITGAM; CD11b) is a component of the macrophage-1 antigen complex, which mediates leukocyte adhesion, migration and phagocytosis as part of the immune system. We previously identified a missense polymorphism, rs1143679 (R77H), strongly associated with systemic lupus erythematosus (SLE). However, the molecular mechanisms of this variant are incompletely understood. A meta-analysis of published and novel data on 28 439 individuals with European, African, Hispanic and Asian ancestries reinforces genetic association between rs1143679 and SLE [Pmeta = 3.60 × 10(-90), odds ratio (OR) = 1.76]. Since rs1143679 is in the most active region of chromatin regulation and transcription factor binding in ITGAM, we quantitated ITGAM RNA and surface protein levels in monocytes from patients with each rs1143679 genotype. We observed that transcript levels significantly decreased for the risk allele ('A') relative to the non-risk allele ('G'), in a dose-dependent fashion: ('AA' < 'AG' < 'GG'). CD11b protein levels in patients' monocytes were directly correlated with RNA levels. Strikingly, heterozygous individuals express much lower (average 10- to 15-fold reduction) amounts of the 'A' transcript than 'G' transcript. We found that the non-risk sequence surrounding rs1143679 exhibits transcriptional enhancer activity in vivo and binds to Ku70/80, NFKB1 and EBF1 in vitro, functions that are significantly reduced with the risk allele. Mutant CD11b protein shows significantly reduced binding to fibrinogen and vitronectin, relative to non-risk, both in purified protein and in cellular models. This two-pronged contribution (nucleic acid- and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE.

Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations.

Recent reports have associated NCF2, encoding a core component of the multi-protein NADPH oxidase (NADPHO), with systemic lupus erythematosus (SLE) susceptibility in individuals of European ancestry. To identify ethnicity-specific and -robust variants within NCF2, we assessed 145 SNPs in and around the NCF2 gene in 5325 cases and 21 866 controls of European-American (EA), African-American (AA), Hispanic (HS) and Korean (KR) ancestry. Subsequent imputation, conditional, haplotype and bioinformatic analyses identified seven potentially functional SLE-predisposing variants. Association with non-synonymous rs17849502, previously reported in EA, was detected in EA, HS and AA (P(EA) = 1.01 × 10(-54), PHS = 3.68 × 10(-10), P(AA) = 0.03); synonymous rs17849501 was similarly significant. These SNPs were monomorphic in KR. Novel associations were detected with coding variants at rs35937854 in AA (PAA = 1.49 × 10(-9)), and rs13306575 in HS and KR (P(HS) = 7.04 × 10(-7), P(KR) = 3.30 × 10(-3)). In KR, a 3-SNP haplotype was significantly associated (P = 4.20 × 10(-7)), implying that SLE predisposing variants were tagged. Significant SNP-SNP interaction (P = 0.02) was detected between rs13306575 and rs17849502 in HS, and a dramatically increased risk (OR = 6.55) with a risk allele at each locus. Molecular modeling predicts that these non-synonymous mutations could disrupt NADPHO complex assembly. The risk allele of rs17849501, located in a conserved transcriptional regulatory region, increased reporter gene activity, suggesting in vivo enhancer function. Our results not only establish allelic heterogeneity within NCF2 associated with SLE, but also emphasize the utility of multi-ethnic cohorts to identify predisposing variants explaining additional phenotypic variance ('missing heritability') of complex diseases like SLE.

CYP2C19 drug-drug and drug-gene interactions in ED patients.

BACKGROUND: CYP450 polymorphisms result in variable rates of drug metabolism. CYP drug-drug interactions can contribute to altered drug effectiveness and safety. STUDY OBJECTIVES: The primary objective was to determine the percentage of emergency department (ED) patients with cytochrome 2C19 (CYP2C19) drug-drug interactions. The secondary objective was to determine the prevalence of CYP2C19 polymorphisms in a US ED population. METHODS: We conducted a prospective observational study in an urban academic ED with 72,000 annual visits. Drug ingestion histories for the 48 hours preceding ED visit were obtained; each drug was coded as CYP2C19 substrate, inhibitor, inducer, or not CYP2C19 dependent. Ten percent of patients were randomized to undergo CYP2C19 genotyping using the Roche Amplichip. RESULTS: A total of 502 patients were included; 61% were female, 65% were white, and median age was 39 years (interquartile range, 22-53). One hundred thirty-one (26.1%) patients had taken at least 1 CYP2C19-dependent home drug. Eighteen (13.7%) patients who were already taking a CYP2C19-dependent drug were given or prescribed a CYP2C19-dependent drug while in the ED. Among the 53 patients genotyped, 52 (98%) were extensive metabolizers and 1 was a poor metabolizer. CONCLUSIONS: In a population of ED patients, more than a quarter had taken a CYP2C19-dependent drug in the preceding 48 hours, but few were given or prescribed another CYP2C19-dependent drug in the ED. On genotyping analysis, CYP2C19 polymorphisms were uncommon in our cohort. We conclude that changing prescribing practice due to CYP2C19 drug-drug interaction or genotype is unlikely to be useful in most US ED populations.

Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production.

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD=6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.