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Elite Military Cues and Public Opinion on Racism

This study considers whether leaders’ domestic actions can influence their reputation for international resolve. We use a conjoint design to examine this possibility empirically.

Purpose To better understand diagnostic delay and doctor–patient communication during the diagnosis of systemic lupus erythematous in patients without malar rash, we conducted a qualitative study of primary care providers’ perceptions. Methods We conducted in-depth interviews with a purposive sample of eight primary care physicians in Kaiser Permanente Northern California. Telephone interviews were recorded, transcribed, reviewed, and coded for domains and themes. Results We identified five domains related to diagnosis: initial assessment and tests, initial diagnosis and empiric treatment, timeliness of diagnosis, communicating with the patient, and opportunities for improvement. In the absence of malar rash, the lupus manifestations are common while the disease is rare. Once the primary care provider believes that the disease may be autoimmune, they work with a rheumatologist, but this could take months. Initially, the physician assesses whether the condition is self-limiting or responds to empiric treatments. Over time, as empiric treatments fail or additional lupus manifestations emerge, the primary care provider makes a referral. Doctor–patient communication is critical to help the physician make sense of the symptoms, maintain trust, and assure the patient that he or she is receiving appropriate care. Patient persistence and communication are critically important. Continuing education was deemed essential by each physician. Conclusion In the absence of malar rash, a lupus diagnosis can be difficult. Enhanced doctor–patient communication, patient persistence, physician access to rheumatology and continuing education of primary care might improve time to diagnosis and the patient’s experience with primary care. This knowledge is transferable to other rare, complex diseases.

Objective.Hydroxychloroquine (HCQ) is a cornerstone to managing systemic lupus erythematosus (SLE), yet adherence to medication is poor. We sought to measure the association of adherence with 5 “dimensions of adherence” as articulated by the World Health Organization for chronic conditions: the patient’s socioeconomic status, and patient-, condition-, therapy-, and healthcare system–related factors. Our longterm goal is to generate evidence to design effective interventions to increase adherence.Methods.The retrospective cohort study included Kaiser Permanente Northern California patients ≥ 18 years old during 2006–2014, with SLE and ≥ 2 consecutive prescriptions for HCQ. Adherence was calculated from the medication possession ratio and dichotomized as < 80% versus ≥ 80%. Predictor variables were obtained from the electronic medical record and census data. We used multivariable logistic regression to estimate adjusted OR and 95% CI.Results.The study included 1956 patients. Only 58% of patients had adherence ≥ 80%. In adjusted analyses, socioeconomic variables did not predict adherence. Increasing age (65–89 yrs compared with ≤ 39 yrs: OR 1.44, 95% CI 1.07–1.93), white race (p < 0.05), and the number of rheumatology visits in the year before baseline (≥ 3 compared with 0 or 1: OR 1.47, 95% CI 1.18–1.83) were positively associated with adherence. The rheumatologist and medical center providing care were not associated with adherence.Conclusion.At our setting, as in other settings, about half of patients with SLE were not adherent to HCQ therapy. Differences in adherence by race/ethnicity suggest the possibility of using tailored interventions to increase adherence. Qualitative research is needed to elucidate patient preferences for adherence support.

Purpose We validated an algorithm to detect frequency errors in computerized healthcare data and estimated the incidence of these errors in an integrated healthcare system. Methods We applied Sentinel System analytic tools on the electronic health records of Kaiser Permanente, Northern California, January 1, 2010, through May 30, 2015,to identify rheumatoid arthritis (RA) patients with new use of methotrexate (365-day baseline period). We identified potential methotrexate frequency errors using ICD-9 code 995.20 (adverse drug event), Current Procedural Terminology (CPT) code 96409 for injection of leucovorin and prescription refill patterns. We performed chart review to confirm the frequency errors, assessed performance for detecting frequency errors, and estimated the incidence of chart-confirmed errors. Results The study included 24,529 methotrexate dispensings among 3,668 RA patients. Among these, 722 (3%) had one dispensing and 23,807 (97.1%) had ≥2 dispensings during 1-year follow-up period. We flagged 653 (2.7%) with a potential medication error (46 with one dispensing and 607 with ≥2 dispensings). We sampled 94 for chart review, and confirmed three methotrexate errors. All three confirmed frequency errors involved a first methotrexate dispensing followed by injected rescue therapy, leucovorin, (positive predictive value, 60%; 95% confidence interval [CI], 15-95%). No potential errors were found among patients with ≥2 dispensings. We estimated the frequency error incidence among one methotrexate dispensing to be 0.4% (95%CI, 0.1% to 1.2%). Conclusion Rescue therapy is a specific indicator of methotrexate overdose among first methotrexate dispensings. This method is generalizable to other medications with serious adverse events treated with antidotes.

Background and objectives Comparative safety studies typically use hierarchical treatment categories that lump monotherapy and combination therapy. The consequence of this approach on study results is not clear. For example, studies of tumor necrosis factor inhibitors usually lump users regardless of whether they are using the drug alone or in combination with other agents. This study explored the importance of lumping vs splitting users of monotherapy and combination therapy. We also explored whether the timing of disenrollment from Health Plan membership was informative as an outcome variable when interpreting unmeasured, time-varying confounding. Methods This observational cohort study included Kaiser Permanente Northern California 2003 to 2013 members with rheumatoid arthritis who started methotrexate. The study end point was a major cardiovascular event. In Cox proportional hazards analysis, we compared treatment classifications using five lumped categories with treatment classification using nine split categories. We also studied disenrollment as an outcome. Results Among 5885 patients, 238 experienced serious cardiovascular events during an average follow-up of 4.25 years. Analysis of drug treatments using 5 lumped categories was difficult to interpret because treatment effects and drug users were mixed. In contrast, analysis of 9 drug categories that split monotherapies from combination therapy was easier to interpret, although confidence intervals were wider. Analysis of drug treatment in relation to disenrollment provided useful information with which to assess study validity, although the power of the analysis was limited. Conclusion In comparative safety studies, we recommend greater transparency in classifying treatment and evaluating disenrollment.

Objective.To compare serious infection risk for systemic lupus erythematosus (SLE) patients starting glucocorticoids (GC), antimalarials (AM), or their combination.Methods.We conducted a new-user, historical cohort study, Kaiser Permanente Northern California, 1997–2013. Cox proportional hazards analysis was used to calculate adjusted HR and 95% CI.Results.The study included 3030 patients with SLE followed an average of 4 years. Compared with patients starting AM without GC (9 infections/1461 patient-yrs), the HR for the risk of infection was 3.9 (95% CI 1.7–9.2) for those starting GC ≤ 15 mg/day without AM (14 infections/252 patient-yrs), while it was 0.0 (0 infections/128 patient-yrs) for those starting the combination. We split the 14 patients with a serious infection and with GC < 15 mg/day into 2 groups: < 7.5 and ≥ 7.5–15 mg/day. The HR for < 7.5 mg/day was 4.6 (95% CI 1.8–11.4) and for ≥ 7.5–15 mg/day, 3.1 (95% CI 1.0–9.7). For patients starting GC > 15 mg/day (reflecting more severe SLE), the risk of infection was nearly the same for the combination of GC and AM (9 infections/135 patient-yrs) and GC alone (41 infections/460 patient-yrs), but the combination users had evidence of more severe disease. Patients with SLE had a 6- to 7-fold greater risk of serious infection than the general population.Conclusion.Our findings suggest that the benefits of AM treatment for SLE may extend to preventing serious infections. Although the study included > 3000 patients, the statistical power to examine GC dosages < 15 mg/day was poor.

Polysialic acid (polySia) is a large, cell-surface linear homopolymer composed of α2,8-linked sialic acid residues. Most extensively studied in the nervous system, this unique glycan modulates development by enhancing cell migration and regulating differentiation. PolySia also functions in developing and adult immune systems and is a signature of many cancers. In this study, we demonstrated that human placental trophoblasts, an epithelial lineage, also display this glycan. Cytotrophoblasts and syncytiotrophoblasts expressed polySia in the first trimester and downregulated it during the course of pregnancy. PolySia promoted cytotrophoblast migration in an explant model of chorionic villous growth. Removal of this glycan also reduced cytotrophoblast penetration of basement membranes in an in vitro model of invasion. Finally, we showed that polySia was overexpressed in biopsies from patients with gestational trophoblastic diseases, including benign molar pregnancies and malignant choriocarcinomas. These results demonstrated, for the first time, functional roles for polySia during normal human placental development and implicated these unusual oligosaccharides in the unrestrained invasion of trophoblast tumors.

BACKGROUND: Hematopoietic stem cell (HSC) transplantation is an essential element of medical therapy, leading to cures of previously incurable hematological and nonhematological diseases. Many patients do not find matched donors in a timely manner, which has driven efforts to find alternative pools of transplantable HSCs. The use of umbilical cord blood (UCB) as a source of transplantable HSCs began more than two decades ago. However, the use of UCB as a reliable source of HSCs for transplantation still faces crucial challenges: the number of HSCs present in a unit of UCB is usually sufficient for younger children but not for adults, and the persistent delayed engraftment often seen can result in high rates of infection and mortality. STUDY DESIGN AND METHODS: We propose a new approach to a solution of these problems: a potential increase of the limited number of UCB-HSCs available by harvesting HSCs contained in the placenta and the fetal chorionic membrane available at birth. RESULTS: We investigated the presence of hematopoietic progenitors and HSCs in human placenta and chorion at different gestational ages. The characterization of these cells was performed by flow cytometry and immunolocalization, and their functional status was investigated by transplanting them into immunodeficient mice. CONCLUSION: HSCs are present in extraembryonic tissues and could be banked in conjunction to the UCB-HSCs. This novel approach could have a large impact on the field of HSC banking and, more crucially, on the outcome of patients undergoing this treatment by greatly improving the use of life-saving hematopoietic transplants.

Placental trophoblasts are key determinants of in utero development. Mouse trophoblast (TB) stem cells, which were first derived over a decade ago, are a powerful cell culture model for studying their self-renewal or differentiation. Our attempts to isolate an equivalent population from the trophectoderm of human blastocysts generated colonies that quickly differentiated in vitro. This finding suggested that the human placenta has another progenitor niche. Here, we show that the chorion is one such site. Initially, we immunolocalized pluripotency factors and TB fate determinants in the early gestation placenta, amnion, and chorion. Immunoreactive cells were numerous in the chorion. We isolated these cells and plated them in medium containing fibroblast growth factor which is required for human embryonic stem cell self-renewal, and an inhibitor of activin/nodal signaling. Colonies of polarized cells with a limited lifespan emerged. Trypsin dissociation yielded continuously self-replicating monolayers. Colonies and monolayers formed the two major human TB lineages—multinucleate syncytiotrophoblasts and invasive cytotrophoblasts (CTBs). Transcriptional profiling experiments revealed the factors associated with the self-renewal or differentiation of human chorionic TB progenitor cells (TBPCs). They included imprinted genes, NR2F1/2, HMGA2, and adhesion molecules that were required for TBPC differentiation. Together, the results of these experiments suggested that the chorion is one source of epithelial CTB progenitors. These findings explain why CTBs of fully formed chorionic villi have a modest mitotic index and identify the chorionic mesoderm as a niche for TBPCs that support placental growth.

Context Relatively few patients with gout receive appropriate treatment. Objective To determine whether a pharmacist-staffed gout management program is more effective than usual care in achieving target serum uric acid (sUA) levels in gout patients. Design A parallel-group, randomized controlled trial of a pharmacist-staffed, telephone-based program for managing hyperuricemia vs usual care. Trial duration was 26 weeks. Main outcome measures Primary outcome measure was achieving sUA levels at or below 6 mg/dL at the 26-week visit. Secondary outcome was mean change in sUA levels in the control and intervention groups. Participants were adults with recurrent gout and sUA levels above 6.0 mg/dL. Participants were randomly assigned to management by a clinical pharmacist following protocol or to monitoring of sUA levels but management of their gout by their usual treating physician. Results Of 102 patients who met eligibility criteria, 77 subjects obtained a baseline sUA measurement and were entered into the trial. Among 37 participants in the intervention group, 13 (35%) had sUA levels at or below 6.0 mg/dL at 26 weeks, compared with 5 (13%) of 40 participants in the control group (risk ratio = 2.8, 95% confidence interval [CI] = 1.1 to 7.1, p = 0.03). The mean change in sUA levels among controls was +0.1 mg/dL compared with -1.5 mg/dL in the intervention group (sUA difference = -1.6, 95% CI = -0.9 to -2.4, p Conclusions A structured pharmacist-staffed program was more effective than usual care for achieving target sUA levels. These results suggest a structured program could greatly improve gout management.

Objective: To assess variations in rheumatoid arthritis treatment and outcomes at the community level from 1998 through 2009. Methods: The study used computerized data from 16 Kaiser Permanente Northern California Medical Centers. Mixed modeling was used to assess patterns across time and clinic. The analysis accounted for patient demographics, clustering of patients within Medical Centers, and repeated measures of patients over time. The metric used to measure drug use, months of use per patient per year, included both users and nonusers in the denominator, to account for both prevalence and duration of use. Results: Assessment was performed of 28,601 patients with rheumatoid arthritis, with all levels of severity. From 1998 through 2009, methotrexate use doubled in the typical patient to include 23% of the time they were observed; sulfasalazine and hydrochloroquine use declined. By 2008 through 2009, leflunomide and antitumor necrosis factor agents were used by the typical patient 4% and 9% of the time, respectively. Between 1998 and 2009, disease-modifying antirheumatic drug use increased in the typical patient from 38% to 63% of the time, and oral prednisone use declined from 23% to 15% of the time, whereas opioid use initially rose but then fell to 23% of the time. No variations over time were observed for the rate of hospitalized pneumonia or opportunistic infection. Variation across clinics, measured by the difference in drug use between clinics at the 75th and 25th percentiles, was lowest for opioids (25% vs 20% of the time) and greatest for infliximab (< 1% to 3%). Conclusion: Increased use of disease-modifying antirheumatic drugs and declines in prednisone are encouraging. Opioid use may need intervention.

© 2014 The Author(s). Epidemiological studies indicate that progestin-containing contraceptives increase susceptibility to HIV, although the underlying mechanisms involving the upper female reproductive tract are undefined. To determine the effects of depot medroxyprogesterone acetate (DMPA) and the levonorgestrel intrauterine system (LNG-IUS) on gene expression and physiology of human endometrial and cervical transformation zone (TZ), microarray analyses were performed on whole tissue biopsies. In endometrium, activated pathways included leukocyte chemotaxis, attachment, and inflammation in DMPA and LNG-IUS users, and individual genes included pattern recognition receptors, complement components, and other immune mediators. In cervical TZ, progestin treatment altered expression of tissue remodeling and viability but not immune function genes. Together, these results indicate that progestins influence expression of immune-related genes in endometrium relevant to local recruitment of HIV target cells with potential to increase susceptibility and underscore the importance of the upper reproductive tract when assessing the safety of contraceptive products.

Copyright © 2014 by the Endocrine Society Endometriosis (E), an estrogen-dependent, progesterone-resistant, inflammatory disorder, affects 10%of reproductive-age women. It is diagnosed and staged at surgery, resulting in an 11-year latency from symptom onset to diagnosis, underscoring the need for less invasive, less expensive approaches. Because the uterine lining (endometrium) in women with E has altered molecular profiles, we tested whether molecular classification of this tissue can distinguish and stage disease. We developed classifiers using genomic data from n = 148 archived endometrial samples from women with E or without E (normal controls or with other common uterine/pelvic pathologies) across the menstrual cycle and evaluated their performance on independent sample sets. Classifiers were trained separately on samples in specific hormonal milieu, using margin tree classification, and accuracies were scored on independent validation samples. Classification of samples from women with E or no E involved 2 binary decisions, each based on expression of specific genes. These first distinguished presence or absence of uterine/pelvic pathology and then no E from E, with the latter further classified according to severity (minimal/mild or moderate/severe). Best performing classifiers identified E with 9 0%-100% accuracy,were cycle phase-specific or independent, and used relatively few genes to determine disease and severity. Differential gene expression and pathway analyses revealed immune activation, altered steroid and thyroid hormone signaling/metabolism, and growth factor signaling in endometrium of women with E. Similar findings were observed with other disorders vs controls. Thus, classifier analysis of genomic data from endometrium can detect and stage pelvic E with high accuracy, dependent or independent of hormonal milieu. We propose that limited classifier candidate genes are of high value in developing diagnostics and identifying therapeutic targets. Discovery of endometrial molecular differences in the presence of E and other uterine/pelvic pathologies raises the broader biological question of their impact on the steroid hormone response and normal functions of this tissue.