A Frameshift Variant of GluN2A Identified in an Epilepsy Patient Results in NMDA Receptor Mistargeting.

N-methyl-D-aspartate receptors (NMDARs) are crucial for neuronal development and synaptic plasticity. Dysfunction of NMDARs is associated with multiple neurodevelopmental disorders, including epilepsy, autism spectrum disorder, and intellectual disability. Understanding the impact of genetic variants of NMDAR subunits can shed light on the mechanisms of disease. Here, we characterized the functional implications of a de novo mutation of the GluN2A subunit (P1199Rfs*32) resulting in the truncation of the C-terminal domain. The variant was identified in a male patient with epileptic encephalopathy, multiple seizure types, severe aphasia, and neurobehavioral changes. Given the known role of the CTD in NMDAR trafficking, we examined changes in receptor localization and abundance at the postsynaptic membrane using a combination of molecular assays in heterologous cells and rat primary neuronal cultures. We observed that the GluN2A P1199Rfs*32-containing receptors traffic efficiently to the postsynaptic membrane but have increased extra-synaptic expression relative to WT GluN2A-containing NMDARs. Using in silico predictions, we hypothesized that the mutant would lose all PDZ interactions, except for the recycling protein Scribble1. Indeed, we observed impaired binding to the scaffolding protein postsynaptic protein-95 (PSD-95); however, we found the mutant interacts with Scribble1, which facilitates the recycling of both the mutant and the WT GluN2A. Finally, we found that neurons expressing GluN2A P1199Rfs*32 have fewer synapses and decreased spine density, indicating compromised synaptic transmission in these neurons. Overall, our data show that GluN2A P1199Rfs*32 is a loss-of-function variant with altered membrane localization in neurons and provide mechanistic insight into disease etiology.

Using Bayesian hierarchical models for controlled post hoc subgroup analysis of clinical trials: application to smoking cessation treatment in American Indians and Alaska Natives.

Clinical trials powered to detect subgroup effects provide the most reliable data on heterogeneity of treatment effect among different subpopulations. However, pre-specified subgroup analysis is not always practical and post hoc analysis results should be examined cautiously. Bayesian hierarchical modelling provides grounds for defining a controlled post hoc analysis plan that is developed after seeing outcome data for the population but before unblinding the outcome by subgroup. Using simulation based on the results from a tobacco cessation clinical trial conducted among the general population, we defined an analysis plan to assess treatment effect among American Indians and Alaska Natives (AI/AN) enrolled in the study. Patients were randomized into two arms using Bayesian adaptive design. For the opt-in arm, clinicians offered a cessation treatment plan after verifying that a patient was ready to quit. For the opt-out arm, clinicians provided all participants with free cessation medications and referred them to a Quitline. The study was powered to test a hypothesis of significantly higher quit rates for the opt-out arm at one-month post randomization. Overall, one-month abstinence rates were 15.9% and 21.5% (opt-in and opt-out arm, respectively). For AI/AN, one-month abstinence rates were 10.2% and 22.0% (opt-in and opt-out arm, respectively). The posterior probability that the abstinence rate in the treatment arm is higher is 0.96, indicating that AI/AN demonstrate response to treatment at almost the same probability as the whole population.

Leveraging National Data and Regional Innovations to Right-Size Tobacco Treatment Policy for Behavioral Health in a Midwestern State.

BACKGROUND: People with mental health (MH) and substance use disorders (SUD) have high rates of tobacco use and tobacco-related mortality. They want to stop smoking and studies have shown they can quit, but few behavioral health facilities provide tobacco treatment. The purpose of this paper is to describe how a midwestern statewide behavioral health collaboration used regional data to pinpoint strengths and weaknesses in tobacco treatment trends, identified policies in neighboring states that were associated with high rates of tobacco treatment, and worked with state leaders to implement these policies to enhance treatment. METHODS: We used publicly available data from 2 SAMHSA annual national surveys of MH/SUD facilities to describe tobacco treatment services and policies in behavioral health facilities in Kansas and 3 neighboring states (Missouri, Nebraska and Oklahoma). We interviewed neighboring state leaders to identify policies they had implemented to boost tobacco recovery services in behavioral health. We collaborated with our state behavioral health agency to encourage adoption of similar policies. RESULTS: Using 7 years of survey data (2014-2020), rates for screening, counseling, and medications for tobacco dependence were highest in Oklahoma and Missouri facilities. Oklahoma had the highest percentages of facilities reporting smoke-free campuses. In all states, rates of tobacco service provision and smoke-free campuses were lower among SUD facilities than in MH facilities. State leaders associated several policies with high performance, including (a) requiring programs contracting with the state to conduct screening, provide counseling, and adopt smoke-free campuses (Oklahoma and Missouri); (b) state-based collection of tobacco treatment service provision data (Oklahoma); (c) providing facilities with free NRT for clients (Oklahoma); (d) setting benchmarks for service provision (Oklahoma); (e) comprehensive Medicaid coverage of cessation medications (Missouri). Upon review of these findings, Kansas behavioral health officials adopted a 2-year process to implement similar policies and are integrating tobacco treatment requirements into the state Certified Community Behavioral Health Clinic program. CONCLUSIONS: Summarizing and sharing freely-available data across states laid the groundwork for cross-border networking and policy change. State and federal agencies should integrate these policies into contracts and block grants to reduce tobacco-related disparities among individuals with behavioral health conditions.

Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma.

BACKGROUND: Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma. METHODS: We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival. RESULTS: At a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.8 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P=0.04). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.73 [95% CI, 0.45 to 1.18]; P=0.20) [corrected]. All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity. CONCLUSIONS: A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin's lymphoma, with a 4.9 percentage-point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490 ; EudraCT number, 2011-005450-60 .).

The medical student's guide to pathology residency, fellowships, and careers.

Recent studies have shown that relatively few MD, DO, and underrepresented in medicine (URM) students and physicians are matching into pathology residency in the United States (US). In the 2021 Main Residency Match, just 33.6% of filled pathology residency positions were taken by senior year students at US allopathic medical schools. This has been attributed to the fact that pathology is not a required rotation in most US medical schools, pathology is often taught in an integrated curriculum in the US where is does not stand out as a distinct field, and because the COVID-19 pandemic led to a suspension of in-person pathology rotations and electives. Ultimately, many US medical students fail to consider pathology as a career pathway. The objective of this article is to provide medical students with basic information, in the form of frequently asked questions (FAQs), about pathology training and career opportunities. This was accomplished by forming a team of MD and DO pathology attendings, pathology trainees, and a medical student from multiple institutions to create a pathology guide for medical students. This guide includes information about post-sophomore fellowships, 5 major pathology residency tracks, more than 20 fellowship pathways, and allopathic and osteopathic board examinations. This guide also contains photographs and descriptions of major pathology sub-specialties, including the daily and on-call duties and responsibilities of pathology residents. The exciting future of pathology is also discussed. This guide supports the agenda of the College of American Pathologists' (CAP) Pathologist Pipeline Initiative to improve student recruitment into pathology.

Bi-allelic mutations in EGR2 cause autosomal recessive demyelinating neuropathy by disrupting the EGR2-NAB complex.

BACKGROUND AND PURPOSE: Mutations in the early growth response 2 gene (EGR2) cause demyelinating, but also axonal, neuropathies differing in severity and age of onset. Except for one family, all reported cases have autosomal dominant inheritance and mutations are localized within the three zinc finger (ZNF) DNA-binding domain. The aim of this study was to provide a clinical and molecular analysis of a novel recessive mutation in EGR2. METHODS: Clinical and electrophysiological assessments of three affected patients, from a consanguineous family, were performed. Genetic analyses of EGR2 were carried out by Sanger sequencing. Functional effects of clinical recessive mutations were assessed using a mammalian two-hybrid assay. RESULTS: A novel missense mutation (c.791C>T; p.P264L) in the homozygous state was detected outside the ZNF domains of the EGR2 gene. Three affected siblings presented with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. Respiratory compromise and cranial nerve dysfunction were also found. Our data indicate that the p.P264L mutation prevents interaction of EGR2 transcription factor with NAB corepressors, suggesting that a disruption of the NAB-EGR2 protein interactions can result in dramatic neuropathy. CONCLUSION: Mutations in, or next to, the R1 domain of EGR2 should be considered with extreme caution for genetic counseling, since these could cause a severe neuropathy with an autosomal recessive manner of transmission.

Transrectal ultrasound-guided targeted biopsy of transition zone prostate cancer under cognitive registration with prebiopsy MRI and sonographic findings.

AIM: To evaluate retrospectively the diagnostic usefulness of transrectal ultrasound (TRUS)-guided targeted biopsy (TB) for transition zone (TZ) prostate cancer (PCa) in patients with prebiopsy magnetic resonance imaging (MRI). MATERIALS AND METHODS: A consecutive series of 38 patients who underwent TRUS-guided TB of TZ lesions were evaluated. TB (mean core number, 2.4±0.6; range, 2-4) was performed by a single experienced radiologist under cognitive registration between prebiopsy MRI and TRUS. Tumour echogenicity on TRUS and Prostate Imaging-Reporting and Data System version 2 (PI-RADSv2) scoring on MRI for targeted TZ lesions were assessed. The interrupted midline sign was defined as a focal lesion traversing the midline of the TZ leading to discontinuity of the midline on both MRI and TRUS. TZ PCa with a Gleason score of 7 or greater was defined as clinically significant PCa (csPCa). RESULTS: The cancer detection rate of TRUS-guided TB for TZ lesions was 78.9% (30/38) for any PCa and 42.1% (16/38) for csPCa. Echogenicity of TZ PCa on TRUS was various and half did not show low echogenicity (low, 50%; intermediate, 26.7%; and high, 23.3%). The interrupted midline sign was identified in 50% (19/38) of patients, which was highly predictive of TZ PCa (94.7%, 18/19). CONCLUSION: TRUS-guided TB under cognitive registration based on prebiopsy MRI findings is useful to detect TZ PCa. Knowledge of the sonographic features of TZ PCa may help to target TZ PCa accurately under cognitive registration.

Probiotic effects of mixture of Groenewaldozyma salmanticensis and Gluconacetobacter liquefaciens on growth and immune responses in Paralichthys olivaceus.

This study was performed to evaluate the effects of dietary probiotics on growth, non-specific immune responses and disease resistance in olive flounder, Paralichthys olivaceus. During 8 weeks, the fish were fed the five experimental diets such as a basal commercial diet (CON), oxytetracycline (OTC) and three basal diets containing Bacillus subtilis (BS), a commercial microbial product (CES) and a mixture of yeast and bacterium (PI), respectively. Fish fed all the probiotics diets and OTC showed a significantly higher growth than fish-fed CON (P < 0·05). Fish-fed PI had a significantly higher nitroblue tetrazolium activity, whereas fish-fed CES showed a higher lysozyme level (P < 0·05). A 7-day challenge test also showed that fish-fed PI had a cumulative survival rate equivalent to that of fish-fed OTC (P < 0·05). Moreover, the diet (PI) appeared to increase the diversity of microbial community in the fish. All these results suggest that the probiotics diet could function as a potential antibiotic replacer in the olive flounder. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is unique in revealing that a diet mixture of yeast, Groenewaldozyma salmanticensis and bacterium Gluconacetobacter liquefaciens can enhance growth, innate immunity and diversity of microbial community including dominant species in the olive flounder. All these indicate that the diet mixture could function as a potential antibiotic replacer in one of the most commercially important fisheries in South Korea.

Baseline characteristics of American Indian smokeless tobacco users participating in two pilot cessation studies.

American Indians have higher rates of smokeless tobacco (SLT) use than other racial/ethnic groups in the US, yet no efficacious cessation program exists for them. Because tobacco is a sacred plant to many American Indians, it is imperative that a program respect the scared nature of tobacco while encouraging quitting recreational use. All Nations Snuff Out Smokeless (ANSOS) was designed to help American Indian SLT users quit recreational tobacco use while still using it for traditional purposes. We pilot tested the ANSOS 6-month group-based counseling program (N = 48) and a shortened version consisting of a one-time education session (N = 80). Here, we discuss the tobacco characteristics of participants at baseline in both studies. Participants across studies were more likely to be male (74.2%) and have at least a college education (65%). Participants in the one-time education sessions were younger (age 35 vs age 39) and used SLT fewer days per week (4.9 vs 5.7). Two-thirds of those in the full program reported that they often substitute SLT in locations where smoking is not allowed compared to 26%. Participants in the education sessions were more likely to report daily use of traditional tobacco (20% versus 0%). Results suggest that dual use of SLT and cigarettes needs to be addressed, as does the use of SLT to circumvent public smoking rules. The role of traditional tobacco and its relationship to lower SLT use also warrants further investigation.

One-Time Education Sessions to Help American Indian Smokeless Tobacco Users Quit.

American Indian (AI) smokeless tobacco use rates are the highest of all racial/ethnic groups within the United States. Despite this, no effective cessation program currently exists that acknowledges the cultural significance of tobacco among many American Indian tribal nations. Participants were smokeless tobacco users, over 18 years of age, and were recruited through community partners. We modified the All Nations Snuff Out Smokeless Tobacco group-based program to be delivered as a one-time education session intervention. This was delivered to 80 participants and follow-up data was collected by self-report at 6-months. The mean age of participants was 35 and most were male (70%). A majority (69%) grew up on a AI reservation; the mean age of first smokeless tobacco use was 16 years of age. Of program completers reached for 6-month post baseline, 46% reported 0 days of SLT use; 13.5% of participants reduced; while 36% reported continued daily use. In intention to treat analysis those lost to follow-up are considered current users, the quit rate was 12.5% and among those who were still using, 4.0% reduced their use. In this study, a one-time education session intervention was effective for those who prefer an individual based approach to quitting SLT use. Follow up strategies to increase participant retention at 6-months should be explored.

Case report: electrical automated massage chair use can induce osteoporotic vertebral compression fracture.

This case report describes a case of an elderly woman diagnosed with acute osteoporotic vertebral compression fracture (OVCF) at thoracic spine after using an electrical automated massage chair (EAMC). Care should be taken when using an EAMC, especially by those with or at risk of developing osteoporosis. Osteoporotic vertebral compression fracture (OVCF) is a common problem among elderly population and presents a high burden to society. Osteoporotic fractures may occur after a minimal trauma of the vertebrae. Electrical automated massage chair (EAMC) is a device that uses a programmed algorithm to perform automated massage. The massage chair, a popular device among elderly with back pain, relies on friction and rhythmic tapping created by a motorized roller. However, research regarding the safety of this device is lacking, especially in the perspective of OVCF. We present a case of an elderly woman diagnosed with acute OVCF of the thoracic spine after using an EAMC. The patient had no risk factor for fragility fracture and experienced an abrupt onset of severe upper back pain while using EAMC. Imaging studies revealed an isolated acute compression fracture at T8 vertebra (AO classification type A1) while dual-energy X-Ray absorptiometry scan confirmed osteoporosis. The patient was treated with a plastic orthosis and oral medications for osteoporosis. After 6-months follow-up, the patient showed union of the fractured T8 vertebra and no remaining symptoms. This case highlights that OVCF can be induced by EAMC. Therefore, patients with or at risk for osteoporosis should be cautious while opting for deep tissue massage using EAMC.

Comparison of carotid and basilar bifurcation aneurysms versus non-T-angled bifurcations: the geometry is associated with the outcome.

Patients with ruptured aneurysms of carotid bifurcation artery seem to suffer less often from cerebral vasospasm and early brain injury and have a better clinical outcome. Aim of our study was to identify differences in clinical course and outcome in aneurysms of terminus segments (carotid bifurcation artery and basilar tip) compared to aneurysms of other aneurysm locations except carotid bifurcation artery and basilar tip. Patients with SAH were entered into a prospectively collected database (1999 to June 2014). A total of 471 patients ('T-shaped' aneurysms n = 63, 'non-T-shaped' aneurysms n = 408) were selected. Outcome was assessed by modified Rankin Scale (mRS) 6 months after SAH. Mean age was 53.75 years. Statistically, analysis showed a significant better outcome in 'T-shaped' aneurysms (p = 0.0001) and a significant lower mortality rate (p = 0.02) despite higher rates of Fisher 3 bleeding pattern and CVS. In 'T-shaped' aneurysms, no prognostic factors for outcome could be detected. In 'non-T-shaped' aneurysms admission status (p < 0.0001), early hydrocephalus (p < 0.0001), shunt-dependence (p = 0.001), and the occurrence of severe CVS (p = 0.01) statistically were factors influencing patients' outcome. Multivariate analysis showed 'non-T-shaped' aneurysms itself as independent prognostic factor for patients' outcome. Despite same rate of poor admission status, early hydrocephalus and shunt dependence 'T-shaped' aneurysms have a highly significantly better. Pathophysiological mechanism actually is not understood. Further studies are necessary to identify, which factors lead to the decreased outcome in "non-T-shaped"- aneurysms.

Peripheral T cell lymphoma, not otherwise specified (PTCL-NOS). A new prognostic model developed by the International T cell Project Network.

Different models to investigate the prognosis of peripheral T cell lymphoma not otherwise specified (PTCL-NOS) have been developed by means of retrospective analyses. Here we report on a new model designed on data from the prospective T Cell Project. Twelve covariates collected by the T Cell Project were analysed and a new model (T cell score), based on four covariates (serum albumin, performance status, stage and absolute neutrophil count) that maintained their prognostic value in multiple Cox proportional hazards regression analysis was proposed. Among patients registered in the T Cell Project, 311 PTCL-NOS were retained for study. At a median follow-up of 46 months, the median overall survival (OS) and progression-free survival (PFS) was 20 and 10 months, respectively. Three groups were identified at low risk (LR, 48 patients, 15%, score 0), intermediate risk (IR, 189 patients, 61%, score 1-2), and high risk (HiR, 74 patients, 24%, score 3-4), having a 3-year OS of 76% [95% confidence interval 61-88], 43% [35-51], and 11% [4-21], respectively (P < 0·001). Comparing the performance of the T cell score on OS to that of each of the previously developed models, it emerged that the new score had the best discriminant power. The new T cell score, based on clinical variables, identifies a group with very unfavourable outcomes.

Different functional genes of upper airway microbiome associated with natural course of childhood asthma.

BACKGROUND: Microbial colonization of the airway plays a role in the pathogenesis of asthma; however, the effect of the upper airway microbiome on childhood asthma is not fully understood. We analyzed the metagenome of airway microbiome to understand the associated role of upper airway microbiome with the natural course of childhood asthma. METHODS: Nasopharyngeal swabs were collected from children with asthma, those in asthma remission, and control groups. High-throughput sequencing was used to examine the structure and functional dynamics of the airway microbiome with respect to asthma phenotypes. RESULTS: The composition of microbiota differed among healthy control, asthma, and remission groups. The relative abundance of Streptococcus was negatively associated with FEV1% predicted (P = .023) and that of Staphylococcus was negatively associated with methacholine PC20 (P = .013). Genes related to arachidonic acid metabolites, lysine residues, and glycosaminoglycans in the microbiome could be associated with airway inflammation. In particular, genes related to synthesis of anti-inflammatory prostaglandin E2 (PGE2 ) were not detected from the airway microbiome in the asthma group. CONCLUSIONS: These data suggest that alterations in the composition and function of the upper airway microbiome could be related with the natural course of asthma in children.

Outcomes of multitarget therapy using mycophenolate mofetil and tacrolimus for refractory or relapsing lupus nephritis.

Objectives Outcomes of systemic lupus erythematosus (SLE) have significantly improved over the years. However, when there is major organ involvement, the outcomes can still be unfavorable. Outcomes of multitarget therapy using mycophenolate mofetil (MMF) and tacrolimus in patients with SLE who were refractory to standard therapy were assessed. Methods We retrospectively reviewed the Hanyang BAE lupus cohort to identify patients with biopsy-confirmed lupus nephritis (classes III, IV, or V) who failed to either achieve complete response with standard induction therapy or those who had a lupus flare after achieving a complete response with conventional induction therapy and subsequently were switched to multitarget combination therapy with MMF and tacrolimus. Outcomes, including renal response, proteinuria, glomerular filtration rate, serum albumin, anti-dsDNA antibody level, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and complements, were assessed at six and 12 months. Results Twenty-nine patients, including 12 who failed to achieve a complete response at 12 months after initial conventional induction therapy and 17 with lupus flare after achieving a complete response at 12 months and treated with multitarget therapy, were included in the analysis. At six months, 53.9% of the patients showed a response, with 15.4% of patients showing a complete response and 38.5% of patients showing a partial response. At 12 months, 55.5% of patients exhibited a response (with complete and partial response in 25.9% and 29.6%, respectively). The dosage of steroids was significantly decreased at six months compared with baseline and was maintained at 12 months. Proteinuria, anti-double-stranded DNA antibody positivity, as well as C3 and C4 levels improved after treatment and persisted until 12 months, but were not significant. SLEDAI also improved. Outcomes were significantly better in patients who had a complete response but later had a flare, resulting in the use of multitarget therapy and achieving a subsequent complete response. Conclusions Multitarget therapy with MMF and tacrolimus can be a reasonable option in refractory lupus nephritis patients who failed to show adequate response to conventional induction therapy or who had flares during maintenance therapy. This treatment can help patients achieve a renal response and reduce the use of steroids.

Late-onset systemic lupus erythematosus: Is it "mild lupus"?

Objective The objective of this paper is to investigate the clinical characteristics and prognosis of patients with late-onset systemic lupus erythematosus (SLE) using a prospective observational cohort. Methods Late-onset SLE (≥50 years old) was compared with adult-onset SLE (≥18 and <50 years old) using 1997 ACR classification criteria for SLE, autoantibodies, disease activity measured by Adjusted Mean SLE Disease Activity Index (AMS), and damage measured by Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI). The standardized mortality ratio (SMR) was calculated. Results A total of 917 patients with SLE were enrolled. The mean number of cumulative ACR criteria in late-onset SLE ( n = 32, 3.5%) was lower than that in adult-onset SLE (4.6 ± 1.2 vs. 5.5 ± 1.4, p < 0.05). The percentage of patients with low complement was lower in late-onset SLE than adult-onset SLE ( p < 0.05). AMS was also lower in late-onset SLE (2.7 ± 2.1 vs. 4.3 ± 2.6, p < 0.01), but SDI was similar between the two groups (50% vs. 43.4%, p = 0.58). The SMR of late-onset SLE was 1.58 (95% CI 0.58-3.43), while the SMR of adult-onset SLE was 3.34 (2.34-4.63). Conclusion Compared with adult-onset SLE, late-onset SLE has a lower number of ACR criteria and lower disease activity. Organ damage is not different, but prognosis and mortality are more favorable.

Factors associated with development and mortality of pulmonary hypertension in systemic lupus erythematosus patients.

Objectives This study aims to identify the factors associated with the development and mortality of pulmonary hypertension (PH) in systemic lupus erythematosus (SLE) patients. Methods We conducted a prospective study of SLE patients in a single tertiary center. PH was defined as a systolic pulmonary arterial pressure ≥30 mmHg on transthoracic echocardiography. We assessed potential associated factors contributing to the development and mortality of PH in SLE patients. Results Of 1110 patients with SLE, 48 patients were identified to have PH. Multivariable analysis indicated that pleuritis or pericarditis (odds ratio (OR) = 4.62), anti-RNP antibody (OR = 2.42), interstitial lung disease (ILD) (OR = 8.34) and cerebro-cardiovascular disease (OR = 13.37) were independently associated with the development of PH in SLE. Subgroup analysis among patients with PH demonstrated that there were no statistically significant factors associated with PH mortality in SLE. Conclusions The prevalence of PH was 4.3% in our cohort. There were significant associations with pleuritis or pericarditis, anti-RNP antibody, ILD, and cerebro-cardiovascular disease in SLE, which may contribute to the development of PH. However, there were no statistically significant factors associated with PH mortality in SLE.

Synergistic effect of cumulative corticosteroid dose and immunosuppressants on avascular necrosis in patients with systemic lupus erythematosus.

Objectives Avascular necrosis (AVN) is one of the most common causes of organ damage in patients with systemic lupus erythematosus (SLE) and often causes serious physical disability. The aims of this study were to investigate clinical risk factors associated with symptomatic AVN and to analyze their synergistic effects in a large SLE cohort in Korea. Methods Patients with SLE were enrolled and followed from 1998 to 2014 in the Hanyang BAE Lupus cohort, and damage was measured annually according to the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). AVN was confirmed by imaging study if patients had symptoms. To determine risk factors for AVN, clinical, laboratory and therapeutic variables were analyzed by logistic regression. Relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S) were calculated to measure interactions between significant variables. Results Among 1219 SLE patients, symptomatic AVN was the most common type of musculoskeletal damage (10.8%, n = 132). SLE patients with AVN showed an earlier onset age, demonstrated AVN more commonly in conjunction with certain other clinical manifestations such as renal and neuropsychiatric disorders, and received significantly higher total cumulative corticosteroid dose and immunosuppressive agents than did patients without AVN. However, in multivariable analysis, only two variables including use of a cumulative corticosteroid dose greater than 20 g (odds ratio (OR) 3.62, p = 0.015) and use of immunosuppressants including cyclophosphamide or mycophenolate mofetil (OR 4.51, p < 0.001) remained as significant risk factors for AVN. Patients with cumulative corticosteroid dose > 20 g and immunosuppressant use had a 15.44-fold increased risk for AVN, compared with patients without these risk factors ( p < 0.001). RERI, AP and S, which define the strength of interactions between two risk factors, were 9.01 (95% confidence interval (CI) 1.30-16.73), 0.58 (95% CI 0.36-0.81) and 2.66 (95% CI 1.42-4.99), respectively, supporting the presence of synergistic interactions in the development of symptomatic AVN in our Korean lupus cohort. Conclusions An individual risk assessment for AVN development should be made prior to and during treatment for SLE, especially in patients with high-dose corticosteroid and immunosuppressant use regardless of clinical manifestations and disease activity.

Prevalence, risk factors, and impact on mortality of neuropsychiatric lupus: a prospective, single-center study.

Objective The objective of this paper is to identify the prevalence, risk factors, and impact on mortality of neuropsychiatric systemic lupus erythematosus (NPSLE). Methods Patients from the Hanyang BAE lupus cohort were registered and followed from 1998 to 2015. NPSLE was defined using American College of Rheumatology (ACR) case definitions and Ainiala criteria. Demographics, autoantibodies, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and Systemic Lupus International Collaborating Clinic (SLICC)/ACR Damage Index were collected at baseline and then annually. Mortality data were derived by linking data from the Korean National Statistics Office. Multivariable logistic regression and Cox regression analysis were conducted in the inception cohort to assess the risk factors and mortality impact of NPSLE. Results Of 1121 registered patients, 429 (38.3%) had NPSLE manifestations according to ACR criteria and 216 (19.3%) by Ainiala criteria. In multivariable logistic regression analysis, higher SLEDAI (OR 1.08, CI 1.01-1.16, p = 0.02) and antiphospholipid antibody positivity (OR 1.72, CI 1.03-2.87, p = 0.04) at SLE diagnosis increased NPSLE risk, while elevated anti-dsDNA antibodies (OR 0.43, CI 0.24-0.78, p < 0.01) and greater education duration (OR 0.92, CI 0.85-1.00, p = 0.04) showed reduced risk of NPSLE. Cox proportional hazard models demonstrated that presence of NPSLE had a three-fold increased risk of mortality (HR 3.09, CI 1.03-9.21, p = 0.04), especially in patients with focal CNS NPSLE (HR = 7.83, CI 2.12-28.96, p < 0.01). Conclusion Higher SLEDAI, antiphospholipid antibody positivity, absence of anti-dsDNA antibody at SLE diagnosis, and fewer years of education are risk factors for development of NPSLE. Presence of NPSLE, especially focal CNS NPSLE, increased the risk of mortality in SLE patients.

Feasibility of Implementing the All Nations Breath of Life Culturally Tailored Smoking Cessation Program for American Indians in Multi-Tribal Urban Communities.

Introduction: Prevalence of cigarette smoking is highest among American Indians, yet few culturally appropriate smoking cessation programs have yet been developed and tested for multi-tribal American Indian adult populations. This study examined implementation of the All Nations Breath of Life culturally tailored smoking cessation program in multi-tribal urban and suburban American Indian communities in seven locations across five states (N = 312). Methods: This single-arm study used community-based participatory research to conduct a 12-week intervention whose primary purpose was to curb commercial tobacco use among American Indians. Participants were followed through month 6 in person and month 12 via telephone. The primary outcome was continuous abstinence from recreational cigarette smoking at 6 months post-baseline, verified through voluntary provision of salivary cotinine levels. Results: At program completion (12 weeks post-baseline), 53.3% of program completers remained abstinent; labeling those lost to follow-up as smokers resulted in a 41.4% quit rate. At 6 months post-baseline (primary endpoint), 31.1% of retained participants quit smoking (p < .0001 compared to the highest quit rates among multi-tribal populations reported in the literature, 7%); final quit rate was 22.1% labeling those lost to follow-up as smokers (p = .002). Retention rate at endpoint was 71.2%. 12-month follow-up was attempted with all participants and had a retention rate of 49.0%. Of those participants reached, 34.0% were smoke-free. Conclusions: All Nations Breath of Life shows promise as a smoking cessation program for multi-tribal urban American Indian communities. It can be successfully implemented in a variety of urban settings. Implications: This is the first large feasibility study of a culturally tailored smoking cessation program for American Indians with good cessation and retention rates in a multi-tribal urban American Indian population. It shows that All Nations Breath of Life can be implemented in multiple urban settings across five states. To our knowledge, this is the first program of its kind to be implemented across multiple heterogeneous urban locations and to include salivary cotinine testing for verification of self-report data across these locations.