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BACKGROUND: Nonadherence and nonpersistence to antidepressants in major depressive disorder (MDD) are common and associated with poor clinical and functional outcomes and increased health care reso...

Long-term opioid therapy (LTOT) is associated with increased risk for depression. It is not known if the frequency of opioid use during LTOT is associated with new-onset depression. We used Optum's de-identified Integrated Claims-Clinical dataset (2010-2018) to create a cohort of 5146 patients, 18 to 80 years of age, with an encounter or claims in the year before new LTOT. New LTOT was defined by90-day opioid use after remaining opioid free for 6 months. Opioid use frequency during the first 90 days of LTOT was categorized into occasional use (50% days covered), intermittent use (50% to80% days covered), frequent use (80% to90% days covered), and daily use (≥90% days covered). Propensity scores and inverse probability of exposure weighting controlled for confounding in models estimating risk for new-onset depression. Patients were on average 54.5 (SD ± 13.6) years of age, 55.7% were female, 72.5% were White, and 9.5% were African American. After controlling for confounding, daily users (hazard ratio = 1.40; 95% confidence interval: 1.14-1.73) and frequent users (hazard ratio = 1.34; 95% confidence interval: 1.05-1.71) were significantly more likely to develop new-onset depression compared with occasional users. This association remained after accounting for the contribution of post-index pain diagnoses and opioid use disorder. In LTOT, risk for new depression episodes is up to 40% greater in near-daily users compared with occasional users. Patients could reduce depression risk by avoiding opioid use on as many low pain days as possible. Repeated screening for depression during LTOT is warranted.

SARS-CoV-2 and its variants continue to infect hundreds of thousands every day despite the rollout of effective vaccines. Therefore, it is essential to understand the levels of protection that these vaccines provide in the face of emerging variants. Here, we report two demographically balanced cohorts of BNT162b2 vaccine recipients and COVID-19 patients, from which we evaluate neutralizing antibody titers against SARS-CoV-2 as well as the B.1.1.7 (alpha) and B.1.351 (beta) variants. We show that both B.1.1.7 and B.1.351 are less well neutralized by serum from vaccinated individuals, and that B.1.351, but not B.1.1.7, is less well neutralized by convalescent serum. We also find that the levels of variant-specific anti-spike antibodies are proportional to neutralizing activities. Together, our results demonstrate the escape of the emerging SARS-CoV-2 variants from neutralization by serum antibodies, which may lead to reduced protection from re-infection or increased risk of vaccine breakthrough., Here, the authors show that neutralization of human sera from both BNT162b2 vaccine recipients and from convalescent COVID-19 patients is less efficient against SARS- CoV-2 variants B.1.1.7 and B.1.351 and negatively associated with patient age.

Summary: People with Down syndrome (DS; trisomy 21) display a different disease spectrum relative to the general population, including lower rates of solid malignancies and higher incidence of neurological and autoimmune conditions. However, the mechanisms driving this unique clinical profile await elucidation. We completed a deep mapping of the immune system in adults with DS using mass cytometry to evaluate 100 immune cell types, which revealed global immune dysregulation consistent with chronic inflammation, including key changes in the myeloid and lymphoid cell compartments. Furthermore, measurement of interferon-inducible phosphorylation events revealed widespread hypersensitivity to interferon-α in DS, with cell-type-specific variations in downstream intracellular signaling. Mechanistically, this could be explained by overexpression of the interferon receptors encoded on chromosome 21, as demonstrated by increased IFNAR1 surface expression in all immune lineages tested. These results point to interferon-driven immune dysregulation as a likely contributor to the developmental and clinical hallmarks of DS. : Waugh et al. undertook deep mapping of the immune system in adults with trisomy 21, revealing global immune dysregulation reminiscent of inflammatory states, concurrent with widespread hypersensitivity to IFN-α. These data highlight immune dysregulation and IFN hyperactivity as contributors to the comorbidities more common in people with Down syndrome. Keywords: Down syndrome, trisomy 21, mass cytometry, CyTOF, immune dysregulation, single cell, interferon, JAK/STAT, autoimmunity, inflammation

Background Merkel cell carcinoma (MCC) is a rare and aggressive type of cancer with poor outcomes. Objective To describe treatment patterns, overall survival, and healthcare costs associated with advanced MCC (aMCC) using data from Medicare enrollees who received an aMCC diagnosis in the USA States between 2006 and 2013. Methods Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 2006 to 2013 were used to describe treatment patterns, 1- and 5-year overall survival, and total healthcare costs for the periods 12 months before aMCC diagnosis and 4–12 months afterward in patients aged ≥ 65 years. Results We identified 257 patients with an aMCC diagnosis, of whom 51% had stage IIIb disease and 49% had stage IV. Within 4 months after diagnosis, 84% of patients (n = 216) received treatment; 45% (n = 115) received surgery, 48% (n = 124) radiation therapy, and 31% (n = 80) chemotherapy. Second-line chemotherapy was administered in 33% of patients (n = 26) receiving first-line chemotherapy. Median overall survival was 27 months in patients whose aMCC was diagnosed at stage IIIb and 12 months in patients whose aMCC was diagnosed at stage IV. Median total 12-month direct healthcare costs were US$48,006 (25th–75th percentile range = US$30,594–US$69,797) per patient. Total costs were highest in patients receiving chemotherapy, either alone or combined with radiation and/or surgery (US$52,854; 25th–75th percentile range = US$34,473–US$71,987). Conclusion Most patients with aMCC received initial treatment, including surgery, radiation, and/or chemotherapy, and approximately one-third of those receiving chemotherapy received second-line chemotherapy. Total 12-month direct healthcare costs were highest in patients who received chemotherapy alone or combined with radiation and/or surgery. These poor survival results and high treatment costs highlight the need for effective new aMCC therapies. Electronic supplementary material The online version of this article (10.1007/s40258-019-00492-5) contains supplementary material, which is available to authorized users.

ImportanceColony-stimulating factors are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia. Research suggests that 55% to 95% of colony-stimulating factor prescribing is inconsistent with national guidelines.ObjectiveTo examine whether a guideline-based standing order for primary prophylactic colony-stimulating factors improves use and reduces the incidence of febrile neutropenia.Design, Setting, and ParticipantsThis cluster randomized clinical trial, the Trial Assessing CSF Prescribing Effectiveness and Risk (TrACER), involved 32 community oncology clinics in the US. Participants were adult patients with breast, colorectal, or non–small cell lung cancer initiating cancer therapy and enrolled between January 2016 and April 2020. Data analysis was performed from July to October 2021.InterventionsSites were randomized 3:1 to implementation of a guideline-based primary prophylactic colony-stimulating factor standing order system or usual care. Automated orders were added for high-risk regimens, and an alert not to prescribe was included for low-risk regimens. Risk was based on National Comprehensive Cancer Network guidelines.Main Outcomes and MeasuresThe primary outcome was to find an increase in colony-stimulating factor use among high-risk patients from 40% to 75%, a reduction in use among low-risk patients from 17% to 7%, and a 50% reduction in febrile neutropenia rates in the intervention group. Mixed model logistic regression adjusted for correlation of outcomes within a clinic.ResultsA total of 2946 patients (median [IQR] age, 59.0 [50.0-67.0] years; 2233 women [77.0%]; 2292 White [79.1%]) were enrolled; 2287 were randomized to the intervention, and 659 were randomized to usual care. Colony-stimulating factor use for patients receiving high-risk regimens was high and not significantly different between groups (847 of 950 patients [89.2%] in the intervention group vs 296 of 309 patients [95.8%] in the usual care group). Among high-risk patients, febrile neutropenia rates for the intervention (58 of 947 patients [6.1%]) and usual care (13 of 308 patients [4.2%]) groups were not significantly different. The febrile neutropenia rate for patients receiving high-risk regimens not receiving colony-stimulating factors was 14.9% (17 of 114 patients). Among the 585 patients receiving low-risk regimens, colony-stimulating factor use was low and did not differ between groups (29 of 457 patients [6.3%] in the intervention group vs 7 of 128 patients [5.5%] in the usual care group). Febrile neutropenia rates did not differ between usual care (1 of 127 patients [0.8%]) and the intervention (7 of 452 patients [1.5%]) groups.Conclusions and RelevanceIn this cluster randomized clinical trial, implementation of a guideline-informed standing order did not affect colony-stimulating factor use or febrile neutropenia rates in high-risk and low-risk patients. Overall, use was generally appropriate for the level of risk. Standing order interventions do not appear to be necessary or effective in the setting of prophylactic colony-stimulating factor prescribing.Trial RegistrationClinicalTrials.gov Identifier: NCT02728596

COVID-19 pathology involves dysregulation of diverse molecular, cellular, and physiological processes. To expedite integrated and collaborative COVID-19 research, we completed multi-omics analysis of hospitalized COVID-19 patients, including matched analysis of the whole-blood transcriptome, plasma proteomics with two complementary platforms, cytokine profiling, plasma and red blood cell metabolomics, deep immune cell phenotyping by mass cytometry, and clinical data annotation. We refer to this multidimensional dataset as the COVIDome. We then created the COVIDome Explorer, an online researcher portal where the data can be analyzed and visualized in real time. We illustrate herein the use of the COVIDome dataset through a multi-omics analysis of biosignatures associated with C-reactive protein (CRP), an established marker of poor prognosis in COVID-19, revealing associations between CRP levels and damage-associated molecular patterns, depletion of protective serpins, and mitochondrial metabolism dysregulation. We expect that the COVIDome Explorer will rapidly accelerate data sharing, hypothesis testing, and discoveries worldwide., Graphical Abstract, Sullivan et al. describe the development of a multidimensional dataset for the study of COVID-19 known as the COVIDome, which includes diverse clinical, transcriptome, proteome, metabolome, and immune cell datasets. A researcher portal known as the COVIDome Explorer was created to enable global data access and analysis.

Higher arousal is linked to simple decision strategies and an increased preference for immediate rewards in younger adults, but little is known about the influence of arousal on decision making in older adults. In light of age-related locus coeruleus-norepinephrine system declines, we predicted a reduced association between arousal and decision behavior in older adults. Younger and older participants made a series of choices between smaller, higher-probability and larger, lower-probability financial gains. Each choice was preceded by the presentation of a high-arousal or low-arousal sound. Pupil dilation was continuously recorded as an index of task-evoked arousal. Both age groups showed significant modulation of pupil dilation as a function of arousal condition. Higher-arousal sounds were associated with shorter response times, particularly in younger adults. Furthermore, higher-arousal sounds were associated with greater risk aversion in younger adults and greater risk seeking in older adults, in line with an arousal-related amplification of baseline preferences in both age groups. Jointly, these findings help inform current theories of the effects of arousal on information processing in younger and older adults.

BACKGROUND: Approximately 5%-10% of patients with diabetes are diagnosed with type 1 diabetes mellitus (T1DM), the incidence and prevalence of which is projected to increase through 2050. Despite this, T1DM-related health care resource utilization (HCRU) and economic burden in the United States have not been adequately assessed, since previous studies used various cost definitions and underlying methods to examine these outcomes. OBJECTIVE: To assess HCRU and costs incurred by patients with T1DM in the United States. METHODS: This retrospective cohort study used IBM Watson MarketScan data from 2011 to 2015 and Optum's electronic medical record (EMR) and integrated data (i.e., linked EMR and administrative claims data) from 2011 to 2016. Included patients had ≥ 1 T1DM diagnosis (the earliest diagnosis date was designated as the index date), were continuously enrolled for ≥ 6 months during their pre-index baseline periods, and had ≥ 1 pharmacy claim for insulin or an insulin pump within ± 90 days of the index date. Baseline demographic and clinical characteristics were summarized descriptively. Average monthly HCRU and costs per patient per month (PPPM) paid by the health plan and patient were assessed. Costs were adjusted for inflation to 2018 U.S. dollars. RESULTS: We identified 181,423 patients with T1DM who met the selection criteria in MarketScan, 84,759 in the Optum EMR, and 8,948 in the Optum integrated databases. Most patients were male (range across databases: 52.6%-53.1%), relatively young (medians: 33-35 years, overall range: 0-100 years), and had a Charlson Comorbidity Index score of 1 (69.2%-73.0%) across all databases. Total all-cause and diabetes-related costs ranged from $1,482 to $1,522 and $733 to $780 PPPM, respectively, during the follow-up period. Pharmacy costs contributed most to the total cost of care, accounting for 55.3% ($431) to 61.1% ($448) of total diabetes-related costs. On an annualized basis, patients had an average of 0.2-0.9 all-cause hospitalizations and 0.1-0.3 diabetes-related hospitalizations during follow-up. The median costs per diabetes-related hospitalization ranged from $6,548 to $8,439, accounting for 4%-7% of total monthly diabetes-related costs. Patients had an average of 0.4-0.5 all-cause and 0.1-0.2 diabetes-related emergency department (ED) visits annually; the median costs of ED visits were $972-$1,499, contributing about 2% of monthly diabetes-related costs during follow-up. CONCLUSIONS: In this large, retrospective, observational study of pediatric and adult patients with T1DM, diabetes-related costs totaled nearly $800 per month. Pharmacy costs contributed to over half of diabetes-related costs, indicating the substantial economic burden associated with the treatment of T1DM. Additional research is needed to determine risk factors associated with costly events (e.g., hospitalizations and ED visits) and indirect costs associated with T1DM. DISCLOSURES: JDRF International provided funding for this project and manuscript. JDRF International also contracted with Evidera, a research and consulting firm for the biopharma industry, for its participation in the project and in the development of this manuscript. The Leona M. and Harry B. Helmsley Charitable Trust provided JDRF International with funding. Simeone, Shah, and Ganz are employed by Evidera and do not receive any payment or honoraria directly from Evidera's clients. LeGrand is an employee of JDRF International. Bushman was employed by JDRF International during the conduct of the study and development of this manuscript. Sullivan and Koralova are employees of The Leona M. and Harry B. Helmsley Charitable Trust.

BackgroundSpinal epidural abscess (SEA) is increasing in incidence; this not-to-miss diagnosis can cause significant morbidity and mortality, particularly if diagnoses are delayed. While some risk factors for SEA and subsequent mortality have been identified, the SEA patient population is clinically heterogeneous and sub-populations have not yet been characterized in the literature. The primary objective of this project was to identify characteristics of subgroups of patients with SEA. The secondary objective was to identify associations between subgroups and three clinical outcomes: new onset paralysis, in-hospital mortality, and 180-day readmission.MethodsDemographics and comorbid diagnoses were collected for patients diagnosed with SEA at an academic health center between 2015 and 2019. Latent class analysis was used to identify clinical subgroups. Chi-squared tests were used to compare identified subgroups with clinical outcomes.ResultsWe identified two subgroups of patients in our analysis. Group 1 had a high rate of medical comorbidities causing immunosuppression, requiring vascular access, or both. Group 2 was characterized by a high proportion of people with substance use disorders. Patients in Group 2 were more likely to be readmitted within 6 months than patients in Group 1 (p = 0.03). There was no difference between groups in new paralysis or mortality.DiscussionWhile prior studies have examined the SEA patient population as a whole, our research indicates that there are at least two distinct subgroups of patients with SEA. Patients who are younger, with substance use disorder diagnoses, may have longer hospital courses and are at higher risk of readmission within six months. Future research should explore how to best support patients in both groups, and additional implications for subgroup classification on health outcomes, including engagement in care.

Nearly one in three people in the U.S. will develop heart failure (HF), characterized by fluid retention (edema) in the lungs and elsewhere. This leads to difficult breathing, deterioration of physical capacity, restriction of normal activities and death. There is little data about the safety and effects of sexual interactions in patients with HF. We tested whether a lack of sexual interactions affected pathophysiological outcomes in a pre-clinical mouse model of dilated cardiomyopathy that recapitulates the progressive stages of human HF. Male mice were randomly given access to, or deprived from, sexual interactions with female mice, which were confirmed by videography and generation of offspring. Cohousing with access to sexual interactions markedly prolonged survival, while cohousing without access to sexual activity did not. Sexual interactions improved systolic function, reduced HF-associated edema, altered transcription of heart contractile protein genes and decreased plasma testosterone levels. To determine whether testosterone levels contributed to survival, testosterone levels were experimentally reduced. Reduction of testosterone levels significantly prolonged survival. Taken together, in mice with dilated cardiomyopathy, sexual activity altered cardiac contractile gene transcription, improved systolic function, reduced edema and prolonged survival which may be in part due to lower testosterone levels.

Summary: Individuals with Down syndrome (DS; trisomy 21) display hyperactivation of interferon (IFN) signaling and chronic inflammation, which could potentially be explained by the extra copy of four IFN receptor (IFNR) genes encoded on chromosome 21. However, the clinical effects of IFN hyperactivity in DS remain undefined. Here, we report that a commonly used mouse model of DS overexpresses IFNR genes and shows hypersensitivity to IFN ligands in diverse immune cell types. When treated repeatedly with a TLR3 agonist to induce chronic inflammation, these animals overexpress key IFN-stimulated genes, induce cytokine production, exhibit liver pathology, and undergo rapid weight loss. Importantly, the lethal immune hypersensitivity and cytokine production and the ensuing pathology are ameliorated by JAK1 inhibition. These results indicate that individuals with DS may experience harmful hyperinflammation upon IFN-inducing immune stimuli, as observed during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, pointing to JAK1 inhibition as a strategy to restore immune homeostasis in DS.

Mild cognitive impairment (MCI) of the amnestic type is considered to be a transitionary stage between healthy aging and Alzheimer’s disease (AD). Previous studies have demonstrated that intrinsic functional connectivity of the default network (DN) is altered in normal aging and AD and impacts both within and between network connectivity. While changes within the DN have been reported in MCI, it remains uncertain how interactions with other large-scale brain networks are altered in this prodromal stage of AD. We investigated within and between network connectivity in healthy older adults (HOAs) and older adults with MCI across three canonical brain networks: DN, dorsal attention network, and frontoparietal control network. We also assessed how patterns of functional connectivity among the three networks predicted cognitive status and age using multivariate partial least squares. A total of 91 MCI and 71 HOA restingstate scans were analyzed from the Alzheimer’s Disease Neuroimaging Initiative. There were three key findings. First, a circumscribed pattern of greater between network and interhemispheric connectivity was associated with higher cognitive status in HOAs. Second, for individuals with MCI, cognitive status was positively associated with a more distributed, less differentiated pattern of intrinsic functional connectivity across the three networks. Finally, greater within network functional connectivity was positively associated with cognitive status for HOAs irrespective of age, however this compensation-like effect diminished with increasing age for MCI participants. While reliable differences between healthy aging and MCI in the intrinsic network architecture of the brain are apparent, these differences emerge as shifting associations between network interactivity, cognitive functioning and age.

A 61-year-old woman with a history of orthotopic heart transplantation for familial hypertrophic cardiomyopathy 20 years previously was admitted to the hospital with subacute, progressive, exertional dyspnoea. Quantitative assessment of the jugular venous pulse demonstrated a jugular venous pressure

Background The accuracy with which hemophilia A can be identified in claims databases is unknown. Objective Develop and validate an algorithm using predictive modeling supported by machine learning to identify patients with hemophilia A in an administrative claims database. Methods We first created a screening algorithm using medical and pharmacy claims to identify potential hemophilia A patients in the US HealthCore Integrated Research Database between January 1, 2006 and April 30, 2015. Medical records for a random sample of patients were reviewed to confirm case status. In this validation sample, we used lasso logistic regression with cross-validation to select covariates in claims data and develop a predictive model to estimate the probability of being a confirmed hemophilia A case. Results The screening algorithm identified 2,252 patients and we reviewed medical records for 400 of these patients. The screening algorithm had a positive predictive value (PPV) of 65%. The predictive model identified 18 predictors of being a hemophilia A case or noncase. The strongest predictors of case status included male sex, factor VIII therapy, office visits for hemophilia A, and hospitalizations for hemophilia A. The strongest predictors of noncase status included hospitalizations for reasons other than hemophilia A and factor VIIa therapy. A probability threshold of ≥0.6 resulted in a PPV of 94.7% (95% CI: 92.0–97.5) and sensitivity of 94.4% (95% CI: 91.5–97.2). Conclusions We developed and validated an algorithm to identify hemophilia A cases in an administrative claims database with high sensitivity and high PPV.

OBJECTIVE Group visits (GVs) are a promising intervention, but more work is needed to establish intervention effects. The objective was to evaluate the effectiveness of GVs and compare them with individual visits (INDs) for chronic care of attention deficit-hyperactivity disorder (ADHD). METHODS Caregivers and children (6-12 yrs) with ADHD participated in a comparative effectiveness trial from April 2014 to June 2015. Families were offered ADHD follow-up every 3 months as GVs versus INDs. Outcomes included ADHD core symptoms, child functioning at home, quality of life, perceived social support, and ADHD-related parenting challenges. Change scores from baseline to the study end were examined for parent and child outcomes within and between treatment conditions. RESULTS Ninety-one children from 84 families participated. Eighteen families withdrew or were lost to follow-up. GV families attended more visits over 12 months, had significant improvement in mean parental emotional health (p = 0.04), and had a greater decrease in challenges related to misbehavior compared with IND families (p < 0.03). GV families experienced significant improvements in child functioning at home (p = 0.01) and reported more time for themselves, other siblings, and routine household activities (p < 0.01). Children receiving care as INDs reported a significant drop in mean emotional health. There were no significant changes in other outcomes. CONCLUSION Families participating in GVs experienced multiple improvements related to family functioning and attended more follow-up visits. Findings confirm the effectiveness of the GV intervention in delivering critical parenting support as part of ADHD management.

Prenatal alcohol exposure often results in an array of fetal developmental abnormalities termed fetal alcohol spectrum disorders (FASDs). Despite the high prevalence of FASDs, the pathophysiology of fetal damage by alcohol remains poorly understood. One of the major obstacles in studying fetal development in response to alcohol exposure is the inability to standardize the amount, pattern of alcohol consumption, and peak blood alcohol levels in pregnant mothers. In the present study, we used Doppler ultrasonography to assess fetal growth and cardiovascular parameters in response to alcohol exposure in pregnant baboons. Baboons were subjected to gastric alcohol infusion 3 times during the second trimester equivalent to human pregnancy, with maternal blood alcohol levels reaching 80 mg/dL within 30 to 60 minutes following alcohol infusion. The control group received a drink that was isocaloric to the alcohol-containing one. Doppler ultrasonography was used for longitudinal assessment of fetal biometric parameters and fetal cardiovascular indices. Fetal abdominal and head circumferences, but not femur length, were significantly decreased in alcohol-exposed fetuses near term. Peak systolic velocity of anterior and middle cerebral arteries decreased during episodes of alcohol intoxication, but there was no difference in Doppler indices between groups near term. Acute alcohol intoxication affected fetal cerebral blood flow independent of changes in the fetal cardiac output. Unlike fetal growth parameters, changes in vascular indices did not persist over gestation. In summary, alcohol effects on fetal growth and on fetal vascular function have different time courses.

Designing optimal insurance is important to ensure access to care for individuals that are most likely to benefit. We examined the potential impact of lowering patient cost-sharing for bariatric procedures.After defining 10 subgroups by body mass index (BMI) and type 2 diabetes mellitus (T2DM), we analyzed the National Health and Nutrition Examination Survey datasets to estimate the prevalence of each subgroup. The MarketScan claims database provided utilization rates and costs of bariatric procedures. Using an existing cost-effectiveness model, we estimated the economic value of bariatric procedures under various cost-sharing levels (0%-25%) with 2 frameworks: (1) a traditional cost-effectiveness analysis and (2) a new approach that incorporates utilization effects across subgroups.The utilization rate was higher among individuals with T2DM than those without T2DM (90.4 vs. 59.1 cases per 100,000) for bariatric procedures, which were more cost-effective for those with T2DM and a higher BMI. After accounting for utilization effects, the economic value of bariatric surgery was $177 and $63 per individual from a lifetime and a 5-year time horizon, respectively. Under no patient cost-sharing for individuals with BMI≥40 and T2DM, utilization rates were expected to increase by 21 cases per 100,000, resulting in additional $2 realized value per patient and $7.07 million in returns at the US population level.Cost-sharing is a barrier to uptake of a clinical and cost-effective treatment for severe obesity. Reducing cost-sharing for patients with severe obesity and T2DM could potentially increase the utilization of bariatric procedures and result in greater economic value to payers.

AIMS To compare clinical outcomes in patients with type 2 diabetes (T2D) switching from insulin glargine 100 units/mL (Gla-100) or insulin detemir (IDet) to insulin glargine 300 units/mL (Gla-300) or insulin degludec (IDeg). MATERIALS AND METHODS We conducted a retrospective, observational study of electronic medical records for Gla-300/IDeg adult switchers (March 1, 2015 to January 31, 2017) with active records for 12-month baseline (glycated haemoglobin [HbA1c] used a 6-month baseline period) and 6-month follow-up periods. Gla-300 and IDeg switchers were propensity score-matched using baseline demographic and clinical characteristics. Outcomes were HbA1c change and goal attainment (among patients with HbA1c captured at follow-up), and hypoglycaemia with fixed follow-up (intention-to-treat [ITT]; 6 months) and variable follow-up (on-treatment [OT]; to discontinuation or 6 months). RESULTS Each matched cohort comprised 1592 patients. The mean decrease in HbA1c and HbA1c goal (

Background Osteoporotic fractures are associated with high morbidity, mortality, and cost. Methods We performed a post hoc analysis of the Women's Health Initiative (WHI) clinical trials data to assess osteoporosis treatment and identify participant characteristics associated with utilization of osteoporosis medication(s) after new diagnoses of osteoporosis or fracture. Information from visits prior to and immediately subsequent to the first fracture event or osteoporosis diagnosis were evaluated for medication use. A full logistic regression model was used to identify factors predictive of osteoporosis medication use after a fracture or a diagnosis of osteoporosis. Results The median length of follow-up from enrollment to the last WHI clinic visit for the study cohort was 13.9 years. Among the 13,990 women who reported new diagnoses of osteoporosis or fracture between enrollment and their final WHI visit, and also had medication data available, 21.6% reported taking an osteoporosis medication other than estrogen. Higher daily calcium intake, diagnosis of osteoporosis alone or both osteoporosis and fracture (compared with diagnosis of fracture alone), Asian or Pacific Islander race/ethnicity (compared with White/Caucasian), higher income, and hormone therapy use (past or present) were associated with significantly higher likelihood of osteoporosis pharmacotherapy. Women with Black/African American race/ethnicity (compared with White/Caucasian), body mass index ≥30 (compared with body mass index of 18.5-24.9), current tobacco use (compared with past use or lifetime nonusers), and history of arthritis were less likely to use osteoporosis treatment. Conclusion Despite well-established treatment guidelines in postmenopausal women with osteoporosis or history of fractures, pharmacotherapy use was suboptimal in this study. Initiation of osteoporosis treatment after fragility fracture may represent an opportunity to improve later outcomes in these high-risk women. Specific attention needs to be paid to increasing treatment among women with fragility fractures, obesity, current tobacco use, history of arthritis, or of Black race/ethnicity.

Context Regulation of maternal thyroid hormones during pregnancy is crucial for optimal maternal and fetal outcomes. There are no specific guidelines addressing maternal levothyroxine (LT4) dose adjustments throughout pregnancy. Objective To compare two LT4 dose-adjustment algorithms in hypothyroid pregnant women. Design Thirty-three women on stable LT4 doses were recruited at Setting Academic endocrinology clinics in Washington, DC. Main Outcome Measure Proportion of TSH values within trimester-specific goal ranges. Results Mean gestational age at study entry was 6.4 ± 2.1 weeks. Seventy-five percent of TSH values were within trimester-specific goal ranges in G1 compared with 81% in G2 (P = 0.09). Similar numbers of LT4 dose adjustments per pregnancy were required in both groups (G1, 3.1 ± 2.0 vs G2, 4.1 ± 3.2; P = 0.27). Women in G1 were more likely to have suppressed TSH Conclusions We compared two options for LT4 dose adjustment and showed that an ongoing adjustment approach is as effective as empiric dose increase for maintaining goal TSH in hypothyroid women during pregnancy.

Sleep disturbance and sexual dysfunction are common in menopause; however, the nature of their association is unclear. The present study aimed to determine whether sleep characteristics were associated with sexual activity and sexual satisfaction.Sexual function in the last year and sleep characteristics (past 4 wk) were assessed by self-report at baseline for 93,668 women age 50 to 79 years enrolled in the Women's Health Initiative (WHI) Observational Study (OS). Insomnia was measured using the validated WHI Insomnia Rating Scale. Sleep-disordered breathing (SDB) risk was assessed using questions adapted from the Berlin Questionnaire. Using multivariate logistic regression, we examined cross-sectional associations between sleep measures and two indicators of sexual function: partnered sexual activity and sexual satisfaction within the last year.Fifty-six percent overall reported being somewhat or very satisfied with their current sexual activity, and 52% reported partnered sexual activity within the last year. Insomnia prevalence was 31%. After multivariable adjustment, higher insomnia scores were associated with lower odds of sexual satisfaction (yes/no) (odds ratio [OR] 0.92, 95% CI, 0.87-0.96). Short sleep duration (7-8 h) was associated with lower odds of partnered sexual activity (yes/no) (≤5 h, OR 0.88, 95% CI, 0.80-0.96) and less sexual satisfaction (≤5 h, OR 0.88, 95% CI, 0.81-0.95).Shorter sleep durations and higher insomnia scores were associated with decreased sexual function, even after adjustment for potential confounders, suggesting the importance of sufficient, high-quality sleep for sexual function. Longitudinal investigation of sleep and its impact on sexual function postmenopause will clarify this relationship.

Prenatal alcohol exposure often results in fetal alcohol syndrome and fetal alcohol spectrum disorders. Mechanisms of fetal brain damage by alcohol remain unclear. We used baboons (Papio spp.) to study alcohol-driven changes in the fetal cerebral artery endocannabinoid system. Pregnant baboons were subjected to binge alcohol exposure via gastric infusion three times during a period equivalent to the second trimester of human pregnancy. A control group was infused with orange-flavored drink that was isocaloric to the alcohol-containing solution. Cesarean sections were performed at a time equivalent to the end of the second trimester of human pregnancy. Fetal cerebral arteries were harvested and subjected to in vitro pressurization followed by pharmacological profiling. During each alcohol-infusion episode, maternal blood alcohol concentrations (BAC) reached 80 mg/dL, that is, equivalent to the BAC considered legal intoxication in humans. Circulating anandamide (AEA) and 2-arachidonoylglycerol (2-AG) remained unchanged. Ultrasound studies on pregnant mothers revealed that fetal alcohol exposure decreased peak systolic blood velocity in middle cerebral arteries when compared to pre-alcohol levels. Moreover, ethanol-induced dilation was observed in fetal cerebral arteries pressurized in vitro. This dilation was abolished by the mixture of AM251 and AM630, which block cannabinoid receptors 1 and 2, respectively. In the presence of AM251, the cannabinoid receptor agonist AEA evoked a higher, concentration-dependent dilation of cerebral arteries from alcohol-exposed fetuses. The difference in AEA-induced cerebral artery dilation vanished in the presence of AM630. CB1 and CB2 receptor mRNA and protein levels were similar in cerebral arteries from alcohol-exposed and control-exposed fetuses. In summary, alcohol exposure dilates fetal cerebral arteries via endocannabinoid receptors and results in an increased function of CB2.

Background: Injectable botulinum neurotoxins are a mainstay of treatment for pediatric spasticity. AbobotulinumtoxinA and onabotulinumtoxinA are both injectable toxin therapies used to treat pediatric lower limb (PLL) spasticity in Canada. The objective of this study was to assess the cost-effectiveness of abobotulinumtoxinA vs. onabotulinumtoxinA in the treatment of PLL spasticity in Canada. Methods: A probabilistic Markov cohort model with a 2-year time horizon was developed, with health states defined by response to therapy, as characterized by the goal attainment scale (GAS). Based on randomized controlled trial evidence, response to therapy was similar or higher for abobotulinumtoxinA relative to onabotulinumtoxinA; uncertainty was incorporated into model parameters, however, as the two therapies have not been compared head-to-head. Canadian resource use and cost data were incorporated. Results: In the base case, abobotulinumtoxinA generated 1.48 quality-adjusted life years over the model time horizon, compared to 1.47 for onabotulinumtoxinA. AbobotulinumtoxinA was associated with cost savings of $123 CAD, reflecting lower costs in both medication acquisition and health services. The estimated improvement to quality of life and reduced costs result in an estimate of economic dominance for abobotulinumtoxinA over onabotulinumtoxinA. This dominant result persisted across probabilistic and scenario analyses.Key points for decision makersBased on a review of available clinical evidence, abobotulinumtoxinA was found to have significant and/or numerical efficacy benefits to onabotulinumtoxinA on functional outcomes (Goal Attainment Scale) and tone (Modified Ashworth Scale) and in the treatment of pediatric lower limb spasticityIn this cost-effectiveness analysis, abobotulinumtoxinA was found to be associated with greater quality-adjusted life years and lower costs than onabotulinumtoxinA (economically dominant)A limitation of this analysis was the uncertainty around key parameters. Specifically, the lack of head-to-head comparison data for the two therapies, and variable data regarding likely onabotulinumtoxinA dosing in PLL in clinical practice. However, across a range of plausible scenarios, the economic dominant result remained. Based on a review of available clinical evidence, abobotulinumtoxinA was found to have significant and/or numerical efficacy benefits to onabotulinumtoxinA on functional outcomes (Goal Attainment Scale) and tone (Modified Ashworth Scale) and in the treatment of pediatric lower limb spasticity In this cost-effectiveness analysis, abobotulinumtoxinA was found to be associated with greater quality-adjusted life years and lower costs than onabotulinumtoxinA (economically dominant) A limitation of this analysis was the uncertainty around key parameters. Specifically, the lack of head-to-head comparison data for the two therapies, and variable data regarding likely onabotulinumtoxinA dosing in PLL in clinical practice. However, across a range of plausible scenarios, the economic dominant result remained.

International audience; Objective: To compare real-world outcomes with newer (insulin glargine 300 U/mL; Gla-300) versus standard of care (SoC) basal insulins (BIs) in the REACH (insulin-naïve; NCT02967224) and REGAIN (basal insulin-treated; NCT02967211) studies in participants with uncontrolled type 2 diabetes (T2DM) in Europe and Brazil.Methods: In these open-label, parallel-group, pragmatic studies, patients (HbA1c > 7.0%) were randomized to Gla-300 or SoC BI for a 6-month treatment period (to demonstrate non-inferiority of Gla-300 vs SoC BIs for HbA1c change [non-inferiority margin 0.3%]) and a 6-month extension period (continuing with their assigned treatment). Insulin titration/other medication changes were at investigator/patient discretion post-randomization.Results: Overall, 703 patients were randomized to treatment in REACH (Gla-300, n = 352; SoC, n = 351) and 609 (Gla-300, n = 305, SoC, n = 304) in REGAIN. The primary outcome, non-inferiority of Gla-300 versus SoC for HbA1c change from baseline to month 6, was met in REACH (least squares [LS] mean difference 0.12% [95% CI –0.046 to 0.281]) but not REGAIN (LS mean difference 0.17% [0.015–0.329]); no between-treatment difference in HbA1c change was shown after 12 months in either study. BI dose increased minimally from baseline to 12 months in REACH (Gla-300, +0.17 U/kg; SoC, +0.15 U/kg) and REGAIN (Gla-300, +0.11 U/kg; SoC, +0.07 U/kg). Hypoglycemia incidence was low and similar between treatment arms in both studies.Conclusions: In both REACH and REGAIN, no differences in glycemic control or hypoglycemia outcomes with Gla-300 versus SoC BIs were seen over 12 months. However, the suboptimal insulin titration in REACH and REGAIN limits comparisons of outcomes between treatment arms and suggests that more titration instruction/support may be required for patients to fully derive the benefits from newer basal insulin formulations.

Humans with dilated cardiomyopathy (DCM) and heart failure (HF) develop low levels of corin, a multi-domain, cardiac-selective serine protease involved in natriuretic peptide cleavage and sodium and water regulation. However, experimental restoration of corin levels markedly attenuates HF progression. To determine whether the beneficial effects of corin in HF require catalytic activity, we engineered cardiac overexpression of an enzymatically inactive corin transgene (corin-Tg(i)). On a wild-type (WT) background, corin-Tg(i) had no evident phenotypic effects. However, in a well-established genetic model of DCM, corin-Tg(i)/DCM mice had increased survival (p &lt, 0.01 to 0.001) vs. littermate corin-WT/DCM controls. Pleural effusion (p &lt, 0.01), lung edema (p &lt, 0.05), systemic extracellular free water (p &lt, 0.01), and heart weight were decreased (p &lt, 0.01) in corin-Tg(i)/DCM vs. corin-WT/DCM mice. Cardiac ejection fraction and fractional shortening improved (p &lt, 0.01), while ventricular dilation decreased (p &lt, 0.0001) in corin-Tg(i)/DCM mice. Plasma atrial natriuretic peptide, cyclic guanosine monophosphate, and neprilysin were significantly decreased. Cardiac phosphorylated glycogen synthase kinase-3&beta, (pSer9-GSK3&beta, ) levels were increased in corin(i)-Tg/DCM mice (p &lt, 0.01). In summary, catalytically inactive corin-Tg(i) decreased fluid retention, improved contractile function, decreased HF biomarkers, and diminished cardiac GSK3&beta, activity. Thus, the protective effects of cardiac corin on HF progression and survival in experimental DCM do not require the serine protease activity of the molecule.

Significance Triplication of human chromosome 21, or trisomy 21 (T21), causes the condition known as Down syndrome (DS). People with DS show a markedly different disease spectrum relative to typical people, being highly predisposed to conditions such as Alzheimer’s disease, while being protected from other conditions, such as most solid malignancies. Interestingly, people with DS are affected by high rates of autoimmune disorders, whereby the immune system mistakenly attacks healthy tissues. This manuscript reports an exhaustive characterization of the T cells of people with DS, demonstrating many alterations in this key immune cell type that could explain their high risk of autoimmunity. These results reveal opportunities for therapeutic intervention to modulate T cell function and improve health outcomes in DS., Trisomy 21 (T21) causes Down syndrome (DS), a condition characterized by high prevalence of autoimmune disorders. However, the molecular and cellular mechanisms driving this phenotype remain unclear. Building upon our previous finding that T cells from people with DS show increased expression of interferon (IFN)-stimulated genes, we have completed a comprehensive characterization of the peripheral T cell compartment in adults with DS with and without autoimmune conditions. CD8+ T cells from adults with DS are depleted of naïve subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-γ, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-α). Conventional CD4+ T cells display increased differentiation, polarization toward the Th1 and Th1/17 states, and overproduction of the autoimmunity-related cytokines IL-17A and IL-22. Plasma cytokine analysis confirms elevation of multiple autoimmunity-related cytokines (e.g., TNF-α, IL17A–D, IL-22) in people with DS, independent of diagnosis of autoimmunity. Although Tregs are more abundant in DS, functional assays show that CD8+ and CD4+ effector T cells with T21 are resistant to Treg-mediated suppression, regardless of Treg karyotype. Transcriptome analysis of white blood cells and T cells reveals strong signatures of T cell differentiation and activation that correlate positively with IFN hyperactivity. Finally, mass cytometry analysis of 8 IFN-inducible phosphoepitopes demonstrates that T cell subsets with T21 show elevated levels of basal IFN signaling and hypersensitivity to IFN-α stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.

Aim To compare glycaemic control, hypoglycaemia and treatment discontinuation of insulin glargine 300 units/mL (Gla‐300) and insulin degludec (IDeg) in a real‐world study of insulin‐naïve adults with type 2 diabetes (T2D). Materials and methods DELIVER Naive D was a retrospective observational study that used electronic medical record data from the IBM Watson Health Explorys database. Insulin‐naïve adults with T2D who started Gla‐300 or IDeg between March 2015 and September 2017 were identified. Patients were active in the system for ≥12 months before and ≥6 months after starting Gla‐300 or IDeg and had HbA1c measurements during 6‐month baseline and 3‐ to 6‐month follow‐up. Outcomes were compared among 1:1 propensity score‐matched cohorts. Results In the matched cohorts (n = 638 each), the mean age was 59 years, approximately 53% were male, and mean HbA1c was 9.67% (82 mmol/mol). Mean (SD) HbA1c decreases were comparable in the Gla‐300 and IDeg cohorts (−1.67% [2.22] and −1.58% [2.20]; P = 0.51), as were HbA1c target attainment [

Compare the use of medical therapy alone (MTA) with surgical therapy (ST) for the empiric treatment of peritonsillar abscess (PTA).A consecutive cohort of patients treated for PTA at our institution from May 2013 to February 2019 was analyzed. Demographics, disease characteristics, management strategies, and treatment outcomes were compared between treatment groups. Primary outcomes included treatment failure, defined as the need for follow-up surgical intervention, and complications within 2-weeks of empiric treatment.306 patients (72.7%) received MTA while 115 (27.3%) underwent ST. There was no significant difference in the rate of treatment failure between the MTA (7.2%) and ST (6.1%) groups (p = 0.879). Complications were rare in both groups (1.6% with MTA versus 0.9% with ST; p = 0.898). Dysphagia (p = 0.011), trismus (p = 0.045), larger abscesses (p 0.001), and hospital admission (p 0.001) were more common in the ST group. Corticosteroid prescriptions were a common component of MTA (53.3%) and less often used with ST (33.9%; p = 0.001). After adjusting for abscess size, there remained no significant difference in the rate of treatment failure between groups. Univariate analyses demonstrated no significant independent predictors of treatment failure including age, sex, race, tonsillitis history, smoking history, presenting signs and symptoms, abscess size, hospital admission, and corticosteroid prescriptions.MTA may be a safe and effective alternative to surgical drainage for the empiric treatment of PTA, warranting larger-scale prospective analyses. Abscess size did not appear to influence treatment failure; however, careful patient selection is likely to optimize treatment outcomes.

In clinical trials of treatments for pulmonary arterial hypertension (PAH), objective measures, such as 6-min walk distance (6MWD) are limited in their ability to characterize the impact of PAH therapy from a patient's perspective. Few clinical studies have evaluated the primary effects of pharmacologic treatment on patient-reported outcomes, such as symptoms, health-related quality of life (HRQoL), and productivity. MOTION (NCT02191137) is a prospective, multicenter, single-arm, open-label, phase 4 trial designed to assess whether riociguat monotherapy will improve patient-reported outcomes in patients with PAH in the United States who are not currently on treatment. Following a screening period of up to 14 days, eligible subjects will receive riociguat (0.5–2.5 mg TID) during a 10-week titration phase and a 14-week maintenance phase. The primary endpoint is change from baseline in the Living with Pulmonary Hypertension (LPH) questionnaire, a disease-specific HRQoL measure, after 24 weeks of riociguat treatment. The Short Form-12 Health Survey (SF-12) and the Work Limitations Questionnaire 8 (WLQ-8) will also be utilized to assess patient-reported outcomes. Other variables include change from baseline in World Health Organization functional class, 6MWD, and modified Borg Dyspnea Index. In addition, accelerator band activity will be validated against the 6MWD test. Safety will also be assessed. The MOTION trial will provide information on the effect of riociguat on patient-reported outcomes in PAH patients in the United States who are not currently on active treatment through the use of disease-specific and generic HRQoL measures (LPH and SF-12) and a measure of worker productivity (WLQ-8).

Bilateral oophorectomy performed in women before they are menopausal induces surgical primary ovarian insufficiency (Surgical POI), an acute and chronic deficiency of the hormones normally produced by the ovaries. Without hormone replacement therapy most of these women develop severe symptoms of estrogen deficiency and are at increased risk for osteoporosis, cardiovascular disease, cognitive decline, dementia, and the associated increases in morbidity and mortality. In cases in which a hysterectomy has been performed at the time of bilateral oophorectomy transdermal or transvaginal estradiol replacement therapy without cyclic progestin replacement is the optimum hormonal management for these women. There is substantial evidence this approach even reduces the risk for breast cancer. Unfortunately, unwarranted fear of all menopausal hormone therapies has become widespread following the reports of the Women's Health Initiative studies. This fear has led to a steep decline in use of estrogen therapy even in women in whom hormone replacement therapy is clearly indicated. Discussion of possible ovarian conservation in women who are premenopausal is an integral part of the preoperative planning for any women undergoing hysterectomy. Timely and effective hormone replacement therapy for women who will experience Surgical POI is clearly indicated.

A 43-year-old woman with Crohn’s disease was admitted to the hospital with weight loss and 1 week of fever, abdominal pain and diarrhoea. At presentation, the patient was not on steroids or other immunosuppressive agents. Cross-sectional imaging of the abdomen revealed active colitis and multiple splenic and hepatic abscesses. All culture data were negative, including aspiration of purulent material from the spleen. Despite weeks of intravenous antibiotics, daily fever and abdominal pain persisted, the intra-abdominal abscesses grew, and she developed pleuritic chest pain and consolidations of the right lung. The patient was ultimately diagnosed with aseptic abscess syndrome, a rare sequelae of inflammatory bowel disease. All antimicrobials were discontinued and she was treated with high-dose intravenous steroids, resulting in rapid clinical improvement. She was transitioned to infliximab and azathioprine as an outpatient and repeat imaging demonstrated complete resolution of the deep abscesses that had involved her spleen, liver and lungs.

Cardiac dysfunction is associated with a higher mortality in exacerbations of chronic obstructive pulmonary disease (COPD). It is unknown how the heart responds to treatment of COPD exacerbations. We followed cardiac biomarker levels during hospital admissions for exacerbations of COPD and hypothesised that these biochemical markers of cardiac dysfunction might be affected the severity and treatment of exacerbations of COPD.N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponin T were measured at admission, 12 h, 72 h, and clinical stability in 176 patients. In a second cohort (n = 93), associations between blood salbutamol concentrations and biomarker changes at 12 h were analysed.NT-proBNP increased from a geometric mean of 43 pmol/L at admission to 56 pmol/L at 12 h (p 0.001), 53 pmol/L at 72 h (p = 0.045), and decreased to 25 pmol/L (p 0.001) at stability. Troponin T levels decreased at 12 h (p 0.001), but 15/174 (9%) patients had a clinically significant rise. Nebulised bronchodilator treatment and blood salbutamol concentrations were associated with greater increases in NT-proBNP rise at 12 h independently of baseline COPD or exacerbation severity and other treatments (p 0.05). Nebulised bronchodilator and blood salbutamol concentrations also predicted rises in troponin T in univariate analyses (p 0.05).NT-proBNP continues to rise after admission to hospital for COPD exacerbations and a minority of patients have clinically significant rises in cardiac troponins. These rises were associated with nebulised beta

Value-based insurance design has been suggested as an effective approach to ensure access to highvalue medications in health insurance markets. Premera Blue Cross, a large regional health plan, implemented a value-based formulary (VBF) for pharmaceuticals in 2010 that explicitly used cost-effectiveness analysis to inform medication co-payments. This study assesses the impact of a VBF on adherence and patient and health plan expenditures on 3 chronic disease states: diabetes, hypertension, and hyperlipidemia.Interrupted time series design of employer-sponsored plans from 2006 to 2013. Beneficiaries exposed to the VBF formed the intervention group, and beneficiaries in similar plans without any changes in pharmacy benefits formed the control group.We measured medication expenditures from member, health plan, and member-plus-health plan (overall) perspectives and medication adherence as proportion of days covered. We conducted an exploratory analysis of medication utilization classifying medications according to whether co-payments moved up or down in the year following VBF implementation.For the diabetes cohort, there was a statistically significant reduction in member and overall expenditures of $5 per member per month (PMPM) and $9 PMPM, respectively. For the hypertension cohort, there was a statistically significant reduction in member expenditures of $4 PMPM and an increase in health plan expenditures of $3 PMPM. There were no statistically significant effects on hyperlipidemia cohort expenditures or on medication adherence in any of the 3 disease cohorts. Exploratory analyses suggest that patients in the diabetes and hyperlipidemia cohorts were switching to higher-value medications.A VBF can ensure access to high-value medications while maintaining affordability.

Trisomy 21 (T21) is the most prevalent human chromosomal disorder, causing a range of cardiovascular, musculoskeletal, and neurological abnormalities. However, the cellular processes disrupted by T21 are poorly understood. Consistent with the clinical overlap between T21 and ciliopathies, we discovered that T21 disrupts cilia formation and signaling. Cilia defects arise from increased expression of Pericentrin, a centrosome scaffold and trafficking protein encoded on chromosome 21. Elevated Pericentrin is necessary and sufficient for T21 cilia defects. Pericentrin accumulates at centrosomes and dramatically in the cytoplasm surrounding centrosomes. Centrosome Pericentrin recruits more γ-tubulin and enhances microtubules, whereas cytoplasmic Pericentrin assembles into large foci that do not efficiently traffic. Moreover, the Pericentrin-associated cilia assembly factor IFT20 and the ciliary signaling molecule Smoothened do not efficiently traffic to centrosomes and cilia. Thus, increased centrosome protein dosage produces ciliopathy-like outcomes in T21 cells by decreasing trafficking between the cytoplasm, centrosomes, and cilia.

Leptin, an appetite-regulatory hormone, is also known to act as a proinflammatory adipokine. One of the effects of increased systemic leptin concentrations may be greater sensitivity to pain. We report the results of two studies examining the association between leptin and pain: a small pilot longitudinal study, followed by a large cross-sectional study. In Study 1, three women with physician-diagnosed fibromyalgia provided blood draws daily for 25 consecutive days, as well as daily self-reported musculoskeletal pain. Daily fluctuations in serum leptin were positively associated with pain across all three participants (F (1,63) = 12.8, p

OBJECTIVE Menopause is a risk factor for fracture; thus, menopause age may affect bone mass and fracture rates. We compared bone mineral density (BMD) and fracture rates among healthy postmenopausal women with varying ages at self-reported nonsurgical menopause. METHODS We compared hazard ratios for fractures and differences in BMD among 21,711 postmenopausal women from the Women's Health Initiative Observational Study cohort who had no prior hysterectomy, oophorectomy, or hormone therapy and had varying self-reported ages at menopause (

Objectives. We sought to estimate the association between sedative hypnotic use and motor vehicle crash risk. Methods. We conducted a new user cohort study of 409 171 adults in an integrated health care system. Health plan data were linked to driver license and collision records. Participants were aged 21 years or older, licensed to drive in Washington State, had at least 1 year of continuous enrollment between 2003 and 2008, and were followed until death, disenrollment, or study end. We used proportional hazards regression to estimate the risk of crash associated with 3 sedatives. Results. We found 5.8% of patients received new sedative prescriptions, with 11 197 person-years of exposure. New users of sedatives were associated with an increased risk of crash relative to nonuse: temazepam hazard ratio (HR) = 1.27 (95% confidence interval [CI] = 0.85, 1.91), trazodone HR = 1.91 (95% CI = 1.62, 2.25), and zolpidem HR = 2.20 (95% CI = 1.64, 2.95). These risk estimates are equivalent to blood alcohol concentration levels between 0.06% and 0.11%. Conclusions. New use of sedative hypnotics is associated with increased motor vehicle crash risk. Clinicians initiating sedative hypnotic treatment should consider length of treatment and counseling on driving risk.

BACKGROUND AND OBJECTIVE: Diabetic macular edema (DME) is a leading cause of blindness for non-elderly adults; however, health care-associated burden data from this population is lacking. The authors describe health care-associated burden in non-elderly patients with DME compared to those with diabetes and no DME. PATIENTS AND METHODS: In this retrospective, large-cohort study examines enrollment and health care claims (2007 to 2011) from a national database of insured patients aged 18 to 63 years (mean: 51). Comorbidity and health care utilization differences between patients with DME (n = 24,326) and matched controls with diabetes but no DME (n = 122,710) were analyzed over 1 and 3 years. RESULTS: DME patients had significantly more baseline comorbidities, and generally developed them at a higher rate over the study. Health care resource utilization rates were significantly higher in DME patients for every category analyzed. Patients with DME averaged more than 10 health care visits more than those with diabetes but no DME (25.5 vs 14.9; P < .001). CONCLUSION: Working-age patients with DME exhibit a complicated comorbidity profile and high associated burden of health care consumption. Considering this burden is critical for managing this complex population. [ Ophthalmic Surg Lasers Imaging Retina . 2015;46:744–751.]

Triple-negative breast cancer (TNBC) is an aggressive disease with a poor prognosis. Advances in the treatment of TNBC have been hampered by the lack of novel effective targeted therapies. The primary goal of this study was to evaluate the efficacy of targeting Aurora kinase A (AurA), a key regulator of mitosis, in TNBC models. A secondary objective was to determine the role of the p53 family of transcriptional regulators, commonly mutated in TNBC, in determining the phenotypic response to the AurA inhibitor alisertib (MLN8237). Alisertib exhibited potent antiproliferative and proapoptotic activity in a subset of TNBC models. The induction of apoptosis in response to alisertib exposure was dependent on p53 and p73 activity. In the absence of functional p53 or p73, there was a shift in the phenotypic response following alisertib exposure from apoptosis to cellular senescence. In addition, senescence was observed in patient-derived tumor xenografts with acquired resistance to alisertib treatment. AurA inhibitors are a promising class of novel therapeutics in TNBC. The role of p53 and p73 in mediating the phenotypic response to antimitotic agents in TNBC may be harnessed to develop an effective biomarker selection strategy in this difficult to target disease. Mol Cancer Ther; 14(5); 1117–29. ©2015 AACR.

Interferon-gamma release assays have potentially been transformative to screening programs focused on latent tuberculosis infection (LTBI) in foreign-born persons. We sought to add to this assessment by presenting the impact of a well-established refugee screening and treatment program switching from skin testing to Quantiferon(®)-TB Gold (QFT). We completed a retrospective cohort of refugees screened for tuberculosis between November 1, 2009-April 30, 2011 (pre-QFT) and May 1, 2011-October 31, 2012 (post-QFT). Among 2244 refugees screened that met the inclusion criteria, there was a significant difference in the proportion of refugees diagnosed with LTBI between the two time periods (p =

The Old World non-human primates (NHP) - baboons (Papio spp.) share similarities with humans regarding fetal and placental development and some pregnancy-related complications. Information about the mechanism of birth and complications arising during parturition in these species is relatively sparse. In this manuscript, we add information from a series of pathological and observational cases to highlight insights and selected complications of birth in Papio spp, based on video-recording of the delivery process, X-ray, MRI, and ultrasound evaluations in pregnant baboons. Additionally, we abstracted pathology records obtained from perinatal loss in a large baboon colony during a 17 year period. The presented cases provide important information for the management of pregnancy and delivery in Papio spp.

The known interactions between the somatotropic and hypothalamic‐pituitary‐gonadal (HPG) axes have not been well delineated in older individuals. Aging‐associated decline in insulin like growth factor‐1 (IGF‐1) levels has been proposed to play a role in reproductive senescence in animals. However, the effects of GH on LH secretion are unknown in older individuals. Our objective was to determine whether GH modulates LH secretion or levels of sex steroids (SS) in healthy older (ages 65–88 years) men (n = 24) and women (n = 24) with low‐normal plasma IGF‐1 levels. In a double‐masked, placebo‐controlled (n = 24), randomized study, we evaluated the effects of GH (n = 24, 20 μg/kg sc 3×/week) for 26 weeks on nocturnal LH secretory dynamics [(8 pm to 8 am, Q20) min sampling and analyzed by multiparameter deconvolution algorithm]. Indices of LH secretion [frequency, mass per burst, pulsatile production rate, and approximate entropy (ApEn)] and fasting serum IGF‐1, SHBG, and SS (TT, fT, or E2) were measured. At baseline, all indices of LH secretion (frequency, mass per burst, pulsatile production rate) were inversely (P

Trisomy 21 (T21) causes Down syndrome (DS), but the mechanisms by which T21 produces the different disease spectrum observed in people with DS are unknown. We recently identified an activated interferon response associated with T21 in human cells of different origins, consistent with overexpression of the four interferon receptors encoded on chromosome 21, and proposed that DS could be understood partially as an interferonopathy. However, the impact of T21 on systemic signaling cascades in living individuals with DS is undefined. To address this knowledge gap, we employed proteomics approaches to analyze blood samples from 263 individuals, 165 of them with DS, leading to the identification of dozens of proteins that are consistently deregulated by T21. Most prominent among these proteins are numerous factors involved in immune control, the complement cascade, and growth factor signaling. Importantly, people with DS display higher levels of many pro-inflammatory cytokines (e.g. IL-6, MCP-1, IL-22, TNF-α) and pronounced complement consumption, resembling changes seen in type I interferonopathies and other autoinflammatory conditions. Therefore, these results are consistent with the hypothesis that increased interferon signaling caused by T21 leads to chronic immune dysregulation, and justify investigations to define the therapeutic value of immune-modulatory strategies in DS.

Background In 2012, >48000 pertussis cases were reported in the United States. Many cases occurred in vaccinated persons, showing that pertussis vaccination does not prevent all pertussis cases. However, pertussis vaccination may have an impact on disease severity. Methods We analyzed data on probable and confirmed pertussis cases reported through Enhanced Pertussis Surveillance (Emerging Infections Program Network) between 2010 and 2012. Surveillance data were collected through physician and patient interview and vaccine registries. We assessed whether having received an age-appropriate number of pertussis vaccines (AAV) (for persons aged ≥3 months) was associated with reduced odds of posttussive vomiting, a marker of more clinically significant illness, or of severe pertussis (seizure, encephalopathy, pneumonia, and/or hospitalization). Adjusted odds ratios were calculated using multivariable logistic regression. Results Among 9801 pertussis patients aged ≥3 months, 77.6% were AAV. AAV status was associated with a 60% reduction in odds of severe disease in children aged 7 months-6 years in multivariable logistic regression and a 30% reduction in odds of posttussive vomiting in persons aged 19 months-64 years. Conclusions Serious pertussis symptoms and complications are less common among AAV pertussis patients, demonstrating that the positive impact of pertussis vaccination extends beyond decreasing risk of disease.

Objective Children with attention-deficit hyperactivity disorder (ADHD) have ongoing needs that impair home and school functioning. Group visit models are a promising way to deliver timely parenting support but family and provider acceptance has not previously been examined. The objective was to describe the acceptability of ADHD group visits in busy pediatric clinics based on caregivers, child participants and facilitators. Methods Data were analyzed from school-age children and caregivers who participated in one of two 12-month long randomized controlled studies of the ADHD group visit model from 2012 to 2013 or 2014 to 2015. Feedback was obtained using semi-structured questions at each study end, by telephone or at the last group visit. Sessions were audio-recorded, transcribed and themes were extracted by participant type. Results A total of 34 caregivers, 41 children and 9 facilitators offered feedback. Caregivers enjoyed the "support group" aspect and learning new things from others. Caregivers reported improved understanding of ADHD and positive changes in the relationship with their child. Children were able to recall specific skills learned including how skills helped at home or school. Facilitators acknowledged systems-level challenges to offering group visits but felt the group format helped increase understanding of families' needs, improved overall care, and provided innovative ways to engage with families. Conclusion The majority of comments from families and facilitators highlighted a variety of benefits of the use of a group visit model for ADHD chronic care. Despite systems-level barriers to implementation, families and facilitators felt the benefits outweighed the challenges.

Colony stimulating factors (CSF) are widely prescribed to avoid febrile neutropenia (FN) among cancer patients receiving chemotherapy, but studies show their use is often not consistent with practice guidelines. In addition, there is limited high quality evidence assessing benefits and harms of primary prophylactic-CSF (PP-CSF) in the setting of chemotherapy that poses an intermediate risk of FN. To address these issues, with funding from the Patient Centered Outcomes Research Institute (PCORI) and the National Cancer Institute's Community Oncology Research Program, SWOG is sponsoring a prospective, cluster randomized controlled pragmatic trial of an automated order entry protocol for PP-CSF among patients with breast, lung and colorectal cancer receiving myelosuppressive chemotherapy, with a nested randomized controlled trial of PP-CSF for patients receiving intermediate risk chemotherapy. Primary outcomes include adherence to practice guidelines, overall rates of FN and rates of FN among persons receiving intermediate risk chemotherapy. The study, the first pragmatic trial in the National Cancer Institute's cancer cooperative clinical trials network, will provide critical evidence to inform physician and patient decision-making around PP-CSF use and practice policies regarding automated orders in cancer components.

A growing body of research has reported a bilingual advantage in performance on executive control tasks, but it is not known at what point in emerging bilingualism these advantages first appear. The present study investigated the effect of early stage second-language training on executive control. Monolingual English-speaking students were tested on a go–nogo task, sentence judgment task, and verbal fluency, before and after 6 months of Spanish instruction. The training group (n = 25) consisted of students enrolled in introductory Spanish and the control group (n = 30) consisted of students enrolled in introductory Psychology. After training, the Spanish group showed larger P3 amplitude on the go–nogo task and smaller P600 amplitude on the judgment task, indicating enhanced performance, with no changes for the control group and no differences between groups on behavioral measures. Results are discussed in terms of neural changes underlying executive control after brief second-language learning.

Objectives To compare different chronic obstructive pulmonary disease (COPD) cost-effectiveness models with respect to structure and input parameters and to cross-validate the models by running the same hypothetical treatment scenarios. Methods COPD modeling groups simulated four hypothetical interventions with their model and compared the results with a reference scenario of no intervention. The four interventions modeled assumed 1) 20% reduction in decline in lung function, 2) 25% reduction in exacerbation frequency, 3) 10% reduction in all-cause mortality, and 4) all these effects combined. The interventions were simulated for a 5-year and lifetime horizon with standardization, if possible, for sex, age, COPD severity, smoking status, exacerbation frequencies, mortality due to other causes, utilities, costs, and discount rates. Furthermore, uncertainty around the outcomes of intervention four was compared. Results Seven out of nine contacted COPD modeling groups agreed to participate. The 5-year incremental cost-effectiveness ratios (ICERs) for the most comprehensive intervention, intervention four, was €17,000/quality-adjusted life-year (QALY) for two models, €25,000 to €28,000/QALY for three models, and €47,000/QALY for the remaining two models. Differences in the ICERs could mainly be explained by differences in input values for disease progression, exacerbation-related mortality, and all-cause mortality, with high input values resulting in low ICERs and vice versa. Lifetime results were mainly affected by the input values for mortality. The probability of intervention four to be cost-effective at a willingness-to-pay value of €50,000/QALY was 90% to 100% for five models and about 70% and 50% for the other two models, respectively. Conclusions Mortality was the most important factor determining the differences in cost-effectiveness outcomes between models.