Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD) depends on environmental and heritable factors, with remarkable differences evident between individuals at the molecular level. Here we present a transcriptomic survey of AD using spatial transcriptomics (ST) and single-nucleus RNA-seq in cortical samples from early-stage AD, late-stage AD, and AD in Down Syndrome (AD in DS) donors. Studying AD in DS provides an opportunity to enhance our understanding of the AD transcriptome, potentially bridging the gap between genetic mouse models and sporadic AD. Our analysis revealed spatial and cell-type specific changes in disease, with broad similarities in these changes between sAD and AD in DS. We performed additional ST experiments in a disease timecourse of 5xFAD and wildtype mice to facilitate cross-species comparisons. Finally, amyloid plaque and fibril imaging in the same tissue samples used for ST enabled us to directly link changes in gene expression with accumulation and spread of pathology.

Comparative effectiveness of glycemic control in patients with type 2 diabetes treated with GLP-1 receptor agonists: a network meta-analysis of placebo-controlled and active-comparator trials.

BACKGROUND: Clinical studies of patients with type 2 diabetes show that GLP-1 receptor agonists (GLP-1 RAs) improve glycemic control and promote weight loss. We conducted a Bayesian network meta-analysis (NMA) of placebo- and active-controlled randomized trials to assess the comparative effectiveness of liraglutide, albiglutide, dulaglutide, and exenatide twice daily and once weekly, with a focus on glycemic control. MATERIALS AND METHODS: We searched Medline, Embase, and the Cochrane Library (up to December 2014) for core registration programs for US-approved GLP-1 RAs. Patients reaching an A1C target of <7% were analyzed with a binomial model and change in A1C from baseline with a normal model. A covariate analysis assessed the impact of baseline A1C and treatment background on outcomes. RESULTS: The base-case NMA used 23 trials reporting A1C outcomes at ~6 month follow-up. The results, unadjusted and adjusted for baseline A1C, indicated that all GLP-1 RAs resulted in statistically significantly lower A1C at follow-up compared with placebo. The odds of reaching the <7% target were also significantly better compared with placebo. With dulaglutide, exenatide once weekly, and liraglutide, the absolute reduction in A1C at 6 months was 0.9%-1.4%, and was significantly better than exenatide twice daily. Albiglutide was not significantly different from exenatide twice daily. We estimate that ~50% of patients will meet the <7% A1C target within 6 months of commencing GLP-1 RAs. CONCLUSION: This was a comprehensive assessment of the comparative effectiveness of GLP-1 RAs and A1C outcome. GLP-1 RAs are a viable addition to oral antidiabetes therapy, and dulaglutide, exenatide once weekly, and liraglutide are the most effective.

Analysis of Glycemic Control of a Pharmacist-Led Medication Management Program in Patients with Type 2 Diabetes.

BACKGROUND: An integrated health care system with its own regional health plan located in Texas implemented a pharmacist-led diabetes medication management program (MMP) to treat type 2 diabetic patients (baseline A1c > 7.5%). The MMP formed collaborative practice agreements with the system's physicians to allow ambulatory care pharmacists to modify and adjust diabetic drug regimens when appropriate. Enrolled MMP patients received personalized visits with ambulatory care pharmacists and a copay waiver on diabetes medications. OBJECTIVE: To study the outcomes of an outpatient, pharmacist-led MMP, along with a copay waiver on diabetes drugs, in treating adults with type 2 diabetes mellitus over a 2-year period compared with standard care practice. METHODS: This retrospective study employed a quasi-experimental design and used medical claims, pharmacy claims, eligibility data, and electronic medical records. Patients aged 18 to 62 years, who were diagnosed with type 2 diabetes mellitus, and had at least 1 diabetes-related pharmacy claim in the year before the MMP, as well as continuous enrollment in the health plan, were included. Patients enrolled in the pharmacist-led MMP for at least 2 years (n =75) were matched to standard care patients (n =75) on age, gender, baseline A1c, insulin use, and physical comorbidity. The primary outcome was the 2-year change in A1c. Secondary outcomes included inpatient costs, outpatient costs, and pharmacy costs from the baseline period (year before enrollment) compared with the follow-up period (second year of enrollment). RESULTS: After matching MMP patients (n = 75) to control patients (n = 75), the baseline A1c (9.30 and 9.26), the mean age (53.0 and 53.3, respectively), the Selim Physical Score (3.32 and 3.26, respectively), and the use of insulin (56.0% and 56.0%, respectively) were similar in both groups. MMP patients had a greater mean reduction in A1c compared with standard care patients (-1.24 vs. -0.59, P = 0.009) from baseline to after 2 years. After 2 years, the A1c for MMP patients was significantly lower compared with control patients (8.06 vs.8.67, respectively, P = 0.014). There was also a difference in A1c after 1 year for MMP patients versus control patients (8.18 and 8.69, respectively, P = 0.012). CONCLUSIONS: A pharmacist-led diabetes MMP, combined with a diabetes drug copay waiver, was effective in significantly reducing A1c over a 2-year period for type 2 diabetic patients in this regional health plan.

Psoriasis disease severity affects patient satisfaction with treatment.

BACKGROUND: Patients with psoriasis are often dissatisfied with available treatments, but contributing factors are not well defined. OBJECTIVE: Examine relationships between psoriasis severity, patient characteristics, and treatment satisfaction. METHODS: Patients with psoriasis were classified into mild and moderate-to-severe groups based on self-reported data. Demographics, comorbidities, symptoms, and multiple treatment satisfaction outcomes were compared between groups. Predictors of patient satisfaction with treatment were examined using linear regression models. RESULTS: The analyses included 773 patients (407 mild; 366 moderate-to-severe). The percentage of patients reporting satisfaction with treatment was low overall, ranging from 8.6% to 61.7% for the mild and 13.9% to 49.5% for the moderate-to-severe group. Satisfaction among biologics users was also low (≤53%; 50% of satisfaction rates <40%). Regression results consistently showed greater dissatisfaction with current treatment among moderately to severely affected patients. CONCLUSION: Many psoriasis patients were dissatisfied with their treatment; moderate-to-severe patients expressed significantly less satisfaction than mild patients.

Evaluating the economic burden of psoriasis in the United States.

BACKGROUND: Psoriasis has significant economic impact on patients. However, its total economic burden has not been fully quantified. OBJECTIVES: To assess the annual economic burden of psoriasis in the United States. METHODS: A systematic literature review was conducted to obtain estimates of the components of the economic burden of psoriasis. Prevalence estimates were used to estimate the 2013 psoriasis population. Incremental medical costs were calculated based on studies that compared psoriasis patients and controls. Productivity loss was estimated using measures of presenteeism, absenteeism, and unemployment. Reductions in health-related quality of life (HRQOL) were calculated from survey responses. RESULTS: The prevalence of psoriasis in the US was estimated to be 7.4 million in 2013. Comparatively, psoriasis patients incurred incremental medical costs of $2284, experienced a $2203 reduction in HRQOL, and a $1935 reduction in productivity. The total burden of psoriasis was estimated as $35.2 billion, with $12.2 billion in incremental medical costs (35%), $11.8 billion from reduced HRQOL (34%), and $11.2 billion from productivity losses (32%). LIMITATIONS: This study is constrained by the scope and populations of the existing literature. CONCLUSIONS: The economic burden of psoriasis in the US is significant, with a majority of it coming from indirect costs.

Patterns of medication utilization and costs associated with the use of etanercept, adalimumab, and ustekinumab in the management of moderate-to-severe psoriasis.

BACKGROUND: Dose escalations of biologic agents may be attempted in the management of moderate-to-severe psoriasis. This has implications for the real-world cost of treatment. OBJECTIVE: To examine the utilization patterns and costs associated with the use of etanercept, adalimumab, and ustekinumab among patients with moderate-to-severe psoriasis. METHODS: This was a retrospective cross-sectional study. Patients with 2 or more medical claims with a diagnosis of psoriasis (excluding psoriatic arthritis) who were enrolled in large employer-sponsored health plans (including a pharmacy benefit) in the United States from January 2007 to March 2012 were identified and extracted from the MarketScan Commercial Encounters Database. Patients aged at least 18 years were required to have 2 or more pharmacy claims for etanercept, adalimumab, or ustekinumab; the index date was the first biologic fill date. Demographics and comorbidities were identified during the 1-year pre-index period, and medication utilization and costs were evaluated in the 1-year post-index period after a titration period according to the product prescribing information (2 weeks to 12 weeks). Medication utilization parameters such as dose escalation, dose reduction, persistence, switching, discontinuation, and restarts were assessed at 6, 9, and 12 months from the end of the dose titration window. RESULTS: A total of 4,309 patients were included with a mean average age of 46 years, and 55% were male. Fifty-seven percent of the patients were started on etanercept, 39% on adalimumab, and 5% on ustekinumab. Patients had substantial dose escalation rates (etanercept: 41%; adalim-umab: 37%; ustekinumab: 36%, P less than 0.05) and discontinuation rates (etanercept: 35%; adalimumab: 27%; ustekinumab: 16%, P less than 0.05) over the 12-month post-titration period. Many patients also restarted the same biologic (etanercept: 37%; adalimumab: 10%; ustekinumab: 6%, P less than 0.05) or switched to another biologic (etanercept: 15%; adalimumab: 10%; ustekinumab: 5%, P less than 0.05) over the 12-month post-titration period. The persistence rates over 12 months were 19%, 53%, and 71% for etanercept, adalimumab, and ustekinumab, respectively (P less than 0.05). Close to one-third of the patients at 6 months and 39% at 12 months postdose titration experienced a dose escalation. Approximately half of the patients who experienced a dose escalation also had a discontinuation or a dose reduction over the 12-month post-titration period. CONCLUSIONS: Over one-third of psoriasis patients experienced a dose escalation of their biologic agents, and most of the dose escalation occurred during the first 6 months. Restarting, switching, and discontinuing index biologics were also common.

Economic and comorbidity burden among moderate-to-severe psoriasis patients with comorbid psoriatic arthritis.

OBJECTIVE: To compare the prevalence of comorbidities, health care utilization, and costs between moderate-to-severe psoriasis (PsO) patients with comorbid psoriatic arthritis (PsA) and matched controls. METHODS: Adults ages 18-64 years with concomitant diagnoses of PsO and PsA (PsO+PsA) were identified in the OptumHealth Reporting and Insights claims database between January 2007 and March 2012. Moderate-to-severe PsO was defined based on the use of at least one systemic or phototherapy during the 12-month study period after the index date (randomly selected date after the first PsO diagnosis). Control patients without PsO and PsA were demographically matched 1:1 with PsO+PsA patients. Multivariate regressions were employed to examine PsO/PsA-related comorbidities, medications, health care utilization, and costs between PsO+PsA patients and controls, adjusting for demographics, index year, insurance type, and non-PsO/PsA-related comorbidities. RESULTS: Among 1,230 matched pairs of PsO+PsA patients and controls, PsO+PsA patients had significantly more PsO/PsA-related comorbidities, with the top 3 most common in both groups being hypertension (35.8% versus 23.5%), hyperlipidemia (34.6% versus 28.5%), and diabetes mellitus (15.9% versus 10.0%). Compared with controls, PsO+PsA patients had a higher number of distinct prescriptions filled (incidence rate ratio 2.3, P < 0.05); were more likely to have inpatient admissions (odds ratio [OR] 1.6), emergency room visits (OR 1.3), and outpatient visits (OR 62.7) (all P < 0.05); and incurred significantly higher total, pharmacy, and medical costs (adjusted annual cost differences per patient $23,160, $17,696, and $5,077, respectively; all P < 0.01). CONCLUSION: Compared with matched PsO- and PsA-free controls, moderate-to-severe PsO patients with comorbid PsA had higher comorbidity and health care utilization and costs.

Time- and behavioral state-dependent changes in posterior hypothalamic GABAA receptors contribute to the regulation of sleep.

Sleep-wake behavior is regulated by a circadian rhythm, homeostatically and by additional mechanisms that determine the timing of slow-wave sleep and rapid eye movement sleep (REMS) episodes. The posterior hypothalamus coordinates the neural and humoral signals with the rest-activity cycle. It contains wake-active neurons, and is a site where stimulation of inhibitory GABAA receptors promotes sleep, whereas their antagonism enhances wakefulness. We explored whether GABAergic mechanisms present in the posterior hypothalamus contribute to the homeostatic and other aspects of sleep-wake regulation. Using micropunches of tissue extracted from either the perifornical (PF) or dorsomedial (DM) regions of the posterior hypothalamus of rats, we determined that mRNA levels for selected subunits of GABAA receptors (ß1, ß3 and ε) were higher at the end of the active period or following sleep deprivation, when the need for sleep is high, than after several hours of sleep, when sleep need is partially fulfilled. Such a pattern was present in the PF region only, and was consistent with changes in ß1 subunit and GABA synthesizing enzyme (GAD) protein levels. In contrast, in the DM region, the levels of GABAA receptor subunit mRNAs and proteins (α1, α2, ß1) and GAD varied with circadian time, but were not responsive to sleep deprivation. Separate experiments with sleep-wake monitoring and local perfusion of the PF region with the GABAA receptor antagonist bicuculline revealed that the antagonist had a weaker sleep-reducing effect when sleep need was enhanced by sleep deprivation and that the increased amount of REMS characteristic of the late sleep period was dependent on endogenous GABAergic inhibition. These results support the concept that a varying magnitude of GABAergic inhibition exerted within the PF region contributes to the homeostatic regulation of sleep and shapes its temporal pattern, whereas GABAergic mechanisms in the DM region contribute to circadian regulation.

Electromyographic activity at the base and tip of the tongue across sleep-wake states in rats.

Obstructive sleep apnea (OSA) patients have elevated tonic and phasic inspiratory activity in the genioglossus and other upper airway muscles during wakefulness; this protects their upper airway from collapse. In this group, sleep-related decrements of upper airway motor tone result in sleep-related upper airway obstructions. We previously reported that in the rat, a species widely used to study the neural mechanisms of both sleep and breathing, lingual electromyographic activity (EMG) is minimal or absent during slow-wave sleep (SWS) and then gradually increases after the onset of rapid eye movement sleep (REMS) due to the appearance of large phasic bursts. Here, we investigated whether sleep-wake patterns and respiratory modulation of lingual EMG depend on the site of EMG recording within the tongue. In nine chronically instrumented rats, we recorded from 17 sites within the tongue and from the diaphragm across sleep-wake states. We quantified lingual EMG in successive 10s intervals of continuous 2h recordings (1-3 p.m.). We found that sleep-wake patterns of lingual EMG did not differ between the base and tip of the tongue, and that respiratory modulation was extremely rare regardless of the recording site. We also determined that the often rhythmic lingual bursts during REMS do not occur with respiratory rhythmicity. This pattern differs from that in OSA subjects who, unlike rats, have collapsible upper airway, exhibit prominent respiratory modulation of upper airway motor tone during quiet wakefulness, retain considerable tonic and inspiratory phasic activity during SWS, and show nadirs of activity during REMS.

Disinhibition of perifornical hypothalamic neurones activates noradrenergic neurones and blocks pontine carbachol-induced REM sleep-like episodes in rats.

Studies in behaving animals suggest that neurones located in the perifornical (PF) region of the posterior hypothalamus promote wakefulness and suppress sleep. Among such cells are those that synthesize the excitatory peptides, orexins (ORX). Lack of ORX, or their receptors, is associated with narcolepsy/cataplexy, a disorder characterized by an increased pressure for rapid eye movement (REM) sleep. We used anaesthetized rats in which pontine microinjections of a cholinergic agonist, carbachol, can repeatedly elicit REM sleep-like episodes to test whether activation of PF cells induced by antagonism of endogenous, GABA(A) receptor-mediated, inhibition suppresses the ability of the brainstem to generate REM sleep-like state. Microinjections of the GABA(A) receptor antagonist, bicuculline (20 nl, 1 mm), into the PF region elicited cortical and hippocampal activation, increased the respiratory rate and hypoglossal nerve activity, induced c-fos expression in ORX and other PF neurones, and increased c-fos expression in pontine A7 and other noradrenergic neurones. The ability of pontine carbachol to elicit any cortical, hippocampal or brainstem component of the REM sleep-like response was abolished during the period of bicuculline-induced activation. The activating and REM sleep-suppressing effect of PF bicuculline was not attenuated by systemic administration of the ORX type 1 receptor antagonist, SB334867. Thus, activation of PF neurones that are endogenously inhibited by GABA(A) receptors is sufficient to turn off the brainstem REM sleep-generating network; the effect is, at least in part, due to activation of pontine noradrenergic neurones, but is not mediated by ORX type 1 receptors. A malfunction of the pathway that originates in GABA(A) receptor-expressing PF neurones may cause narcolepsy/cataplexy.

Differential effect of sleep-wake states on lingual and dorsal neck muscle activity in rats.

Postural tone is reduced during slow-wave sleep (SWS) and absent during rapid eye movement sleep (REMS). In obstructive sleep apnea subjects, upper airway dilating muscles, including those of the tongue, show a similar pattern; this contributes to sleep-related airway obstructions. However, in healthy subjects, state-dependent changes in the activity of pharyngeal muscles are variable. In seven chronically instrumented Sprague-Dawley rats, an animal model used to study sleep and sleep-disordered breathing, we quantified lingual and postural muscle activity across the sleep-wake states by measuring the root mean square levels of the electromyograms (EMG) in successive 10s intervals collected during 2h of recording at a constant circadian time (1-3p.m.). The nuchal EMG was low and steady during SWS and further reduced with occasional twitches during REMS. In contrast, the mean lingual EMG during SWS was only 5.9+/-1.6% (S.E.) of its mean in wakefulness, and during REMS, it increased to 46+/-15% (S.E.) (p<0.03) due to the appearance of phasic bursts, the intensity of which progressively increased. The lingual and nuchal activities also had different time courses during state transitions. In obstructive sleep apnea subjects, the sleep-wake changes in the activity of pharyngeal muscles may become similar to those in postural muscles as a result of pharyngeal tone adaptations to the disorder.