Targeting appetite and satiety in diabetes and obesity, via G protein-coupled receptors.

Type 2 diabetes and obesity have reached pandemic proportions throughout the world, so much so that the World Health Organisation coined the term "Globesity" to help encapsulate the magnitude of the problem. G protein-coupled receptors (GPCRs) are highly tractable drug targets due to their wide involvement in all aspects of physiology and pathophysiology, indeed, GPCRs are the targets of approximately 30% of the currently approved drugs. GPCRs are also broadly involved in key physiologies that underlie type 2 diabetes and obesity including feeding reward, appetite and satiety, regulation of blood glucose levels, energy homeostasis and adipose function. Despite this, only two GPCRs are the target of approved pharmaceuticals for treatment of type 2 diabetes and obesity. In this review we discuss the role of these, and select other candidate GPCRs, involved in various facets of type 2 diabetic or obese pathophysiology, how they might be targeted and the potential reasons why pharmaceuticals against these targets have not progressed to clinical use. Finally, we provide a perspective on the current development pipeline of anti-obesity drugs that target GPCRs.

Dopamine and ghrelin receptor co-expression and interaction in the spinal defecation centers.

BACKGROUND: Dopamine receptor 2 (DRD2) and ghrelin receptor (GHSR1a) agonists both stimulate defecation by actions at the lumbosacral defecation center. Dopamine is in nerve terminals surrounding autonomic neurons of the defecation center, whereas ghrelin is not present in the spinal cord. Dopamine at D2 receptors generally inhibits neurons, but at the defecation center, its effect is excitatory. METHODS: In vivo recording of defecation and colorectal propulsion was used to investigate interaction between DRD2 and GHSR1a. Localization studies were used to determine sites of receptor expression in rat and human spinal cord. KEY RESULTS: Dopamine, and the DRD2 agonist, quinpirole, directly applied to the lumbosacral cord, caused defecation. The effect of intrathecal dopamine was inhibited by the GHSR1a antagonist, YIL781, given systemically, but YIL781 was not an antagonist at DRD2. The DRD2 agonist, pramipexole, administered systemically caused colorectal propulsion that was prevented when the pelvic nerves were cut. Drd2 and Ghsr were expressed together in autonomic preganglionic neurons at the level of the defecation centers in rat and human. Behaviorally induced defecation (caused by water avoidance stress) was reduced by the DRD2 antagonist, sulpiride. We had previously shown it is reduced by YIL781. CONCLUSIONS AND INFERENCES: Our observations imply that dopamine is a transmitter of the defecation pathways whose actions are exerted through interacting dopamine (D2) and ghrelin receptors on lumbosacral autonomic neurons that project to the colorectum. The results explain the excitation by dopamine agonists and the conservation of GHSR1a in the absence of ghrelin.

Design, synthesis and characterization of a fluorescently labeled functional analog of full-length human ghrelin.

Human ghrelin receptor (GHSR) is a recognized prospective target in the diagnosis and therapy of multiple cancer types. To gain a better understanding of this receptor signaling system, we have synthesized a novel full-length ghrelin analog that is fluorescently labeled at the side-chain of a C-terminal cysteine extension. This analog exhibited nanomolar affinity and potency for the ghrelin receptor. It shows comparable efficacy with that of endogenous ghrelin. The fluorescently-labeled ghrelin analog is a valuable tool for in vitro imaging of cell lines that express ghrelin receptor.

Medical foster home is less costly than traditional nursing home care.

OBJECTIVE: To compare the costs of Community Nursing Homes (CNHs) to Medical Foster Homes (MFHs) at Veteran Health Administration (VHA) Medical Centers that established MFH programs. DATA SOURCES: Episode and costs data were derived from VA and Medicare files (inpatient, outpatient, emergency room, skilled nursing facility, dialysis, and hospice). STUDY DESIGN: Propensity scores matched 354 MFH to 1693 CNH Veterans on demographics, clinical characteristics, health care utilization, and costs. DATA EXTRACTION METHODS: Data were retrieved for years 2010-2011 from the VA Corporate Data Warehouse, VA Health Data Repository, and the VA MFH Program through the VA Informatics and Computing Infrastructure (VINCI). PRINCIPAL FINDINGS: After matching on unique characteristics of MFH Veterans, costs were $71.28 less per day alive compared to CNH care. Home-based and mental health care costs increased with savings largely attributable to avoiding CNH residential care. When average out-of-pocket payments by Veterans of $74/day are considered, MFH is at least cost neutral. Mortality was 12 percent higher among matched Veterans in CNHs. CONCLUSIONS: MFHs may serve as alternatives to traditional CNH care that do not increase total costs with mortality benefits. Future work should examine the differences for functional disability subgroups.

Mean Corpuscular Volume to White Blood Cell Ratio for Thiopurine Monitoring in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Thiopurines, commonly used to treat inflammatory bowel disease, cause lymphopenia and red blood cell macrocytosis, requiring therapeutic monitoring. Mean corpuscular volume/white blood cell (MCV/WBC) ratio has been proposed as a surrogate for therapeutic monitoring. Our aim was to investigate MCV/WBC ratio for assessing clinical response to thiopurines among pediatric patients with inflammatory bowel disease. METHODS: We performed a retrospective cross-sectional study at a tertiary care center using laboratory results and standardized physician global assessments (PGA) among pediatric patients taking thiopurines. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fecal calprotectin, and 6-thioguanine nucleotides were assessed when available. The primary outcome was association between MCV/WBC ratio and clinical remission assessed by ESR, CRP, calprotectin, or PGA. We also used a composite outcome requiring all available data to be normal. Analyses were limited to 1 occurrence per patient, >60 days after starting thiopurine, and comparators were required to be within 14 days of one another. RESULTS: A total of 471 patients met inclusion criteria. MCV/WBC ratio poorly predicted quiescent disease as defined by PGA (area under receiver operating characteristic curve [AuROC] 0.55, 95% confidence interval [CI] 0.43-0.66). MCV/WBC ratio better predicted quiescent disease defined as normal CRP (AuROC 0.64, 95% CI 0.58-0.70) or normal ESR (AuROC 0.59, 95% CI 0.52-0.66). When the composite outcome measure was used, MCV/WBC ratio had an AuROC of 0.65 (95% CI 0.59-0.70), indicating it is reasonably accurate in discriminating between clinical remission and active disease. CONCLUSIONS: MCV/WBC ratio is a noninferior, easy, and low-cost alternative to thiopurine metabolite monitoring.

Insurance Among Young Adults With Inflammatory Bowel Disease: Changes Under the Affordable Care Act Dependent Provision.

BACKGROUND: A total of 20% to 30% of patients with inflammatory bowel disease (IBD) present before age 18 years, eventually requiring transfer to adult care. Vulnerability during transfer may be exacerbated by loss of insurance. A provision of the Affordable Care Act (ACA) allows young adults (YAs) to remain on parental private insurance through age 25 years. There has been a decrease in uninsured YAs since its implementation in 2010. Little is known about whether insurance coverage of YAs with IBD has been affected. OBJECTIVE: The aim of the present study was to determine whether the proportion of uninsured YAs with IBD has changed following the implementation of extended dependent eligibility under the ACA. METHODS: We conducted a cross-sectional analysis of hospitalized patients with IBD, identified in the Nationwide Inpatient Sample (NIS) using diagnostic codes, to estimate proportions of insurance coverage during the years 2006-2013. We compared 19 to 25 year olds to 2 to 18 and 26 to 35 year olds, unaffected by the provision, to account for underlying trends. RESULTS: From 2006 to 2010, 19 to 25 year olds had the highest proportion of uninsured, peaking at 14.1% in 2010. In 2011, the proportion decreased to 10.1%, below the proportion of uninsured 26 to 35 year olds (13.1%), remaining in this range through 2013. Private coverage increased in 2011 for 19 to 25 year olds, remaining stable for 26 to 35 year olds. DISCUSSION: Previous research cited 5% uninsured among all hospitalized patients with IBD. Our study indicates a higher proportion for YAs, decreasing after the ACA. Lack of insurance increases vulnerability during transfer but may be modifiable through policy change. Furthermore, research should analyze the effects of Medicaid expansion and health care exchanges.

Medical Foster Homes: Can the Adult Foster Care Model Substitute for Nursing Home Care?

OBJECTIVE: To compare characteristics, healthcare use, and costs of care of veterans in the rapidly expanding Veterans Health Administration (VHA) medical foster home (MFH) with those of three other VHA long-term care (LTC) programs. DESIGN: Descriptive, unmatched study. SETTING: VHA MFHs, home-based primary care (HBPC), community living centers (CLCs), and community nursing homes (CNHs). PARTICIPANTS: Veterans newly enrolled in one of the four LTC settings in calendar years 2010 or 2011. MEASUREMENTS: Using VA and Medicare data from fiscal years 2010 and 2011, demographic characteristics, healthcare use, and costs of 388 veterans in MFHs were compared with 26,037 of those in HBPC, 5,355 in CLCs, and 5,517 in CNHs in the year before and the year after enrollment. RESULTS: Veterans enrolled in the MFH program were more likely to be unmarried than those in other LTC programs and had higher levels of comorbidity and frailty than veterans receiving HBPC but had similar levels of comorbidity, frailty, and healthcare use as those in CLCs and CNHs. MFH veterans incurred lower costs than those in CNHs and CLCs. CONCLUSION: MFHs served a distinct subset of veterans with levels of comorbidity and frailty similar to those of veterans cared for in CLCs and CNHs at costs that were comparable to or lower than those of the VHA. Propensity-matched comparisons will be necessary to confirm these findings.

Integrating Motivational Interviewing Into a Home Telehealth Program for Veterans With Posttraumatic Stress Disorder Who Smoke: A Randomized Controlled Trial.

OBJECTIVE: We evaluated integrating a motivational interviewing (MI)-based smoking cessation curricula and MI counseling into a posttraumatic stress disorder (PTSD) home telehealth care management program to determine if smoking behaviors improved. METHOD: We randomized 178 Veterans with PTSD to a 90-session MI-based home telehealth program or to usual care. Outcome measures included self-reported 24-hour quit attempts, seven-day point prevalence abstinence, progression along the stages of change, and mental health symptoms. RESULTS: Favorable smoking cessation rates were observed in both groups. There was no statistical difference in self-reported 24-hour quit attempts, seven-day point prevalence smoking abstinence or progression along the stages of change. The intervention group showed improved depression and PTSD symptoms. CONCLUSION: Integrating MI-based smoking cessation treatment into PTSD home telehealth is an effective method to help Veterans with PTSD quit smoking. Further research is needed to understand how to optimize MI integration into home telehealth to achieve sustained smoking cessation rates.

Challenges of Providing End-of-Life Care for Homeless Veterans.

OBJECTIVE: To describe challenges of caring for homeless veterans at end of life (EOL) as perceived by Veterans Affairs Medical Center (VAMC) homeless and EOL care staff. DESIGN: E-mail survey. SETTING/PARTICIPANTS: Homelessness and EOL programs at VAMCs. MEASUREMENTS: Programs and their ratings of personal, structural, and clinical care challenges were described statistically. Homelessness and EOL program responses were compared in unadjusted analyses and using multivariable models. RESULTS: Of 152 VAMCs, 50 (33%) completed the survey. The VAMCs treated an average of 6.5 homeless veterans at EOL annually. Lack of appropriate housing was the most critical challenge. The EOL programs expressed somewhat more concern about lack of appropriate care site and care coordination than did homelessness programs. CONCLUSIONS: Personal, clinical, and structural challenges face care providers for veterans who are homeless at EOL. Deeper understanding of these challenges will require qualitative study of homeless veterans and care providers.

Hospital Readmission From Post-Acute Care Facilities: Risk Factors, Timing, and Outcomes.

OBJECTIVES: Hospital discharges to post-acute care (PAC) facilities have increased rapidly. This increase may lead to more hospital readmissions from PAC facilities, which are common and poorly understood. We sought to determine the risk factors and timing for hospital readmission from PAC facilities and evaluate the impact of readmission on patient outcomes. DESIGN: Retrospective analysis of Medicare Current Beneficiary Survey (MCBS) from 2003-2009. SETTING: The MCBS is a nationally representative survey of beneficiaries matched with claims data. PARTICIPANTS: Community-dwelling beneficiaries who were hospitalized and discharged to a PAC facility for rehabilitation. INTERVENTION/EXPOSURE: Potential readmission risk factors included patient demographics, health utilization, active medical conditions at time of PAC admission, and PAC characteristics. MEASUREMENTS: Hospital readmission during the PAC stay, return to community residence, and all-cause mortality. RESULTS: Of 3246 acute hospitalizations followed by PAC facility stays, 739 (22.8%) included at least 1 hospital readmission. The strongest risk factors for readmission included impaired functional status (HR 4.78, 95% CI 3.21-7.10), markers of increased acuity such as need for intravenous medications in PAC (1.63, 1.39-1.92), and for-profit PAC ownership (1.43, 1.21-1.69). Readmitted patients had a higher mortality rate at both 30 days (18.9% vs 8.6%, P < .001) and 100 days (39.9% vs 14.5%, P < .001) even after adjusting for age, comorbidities, and prior health care utilization (30 days: OR 2.01, 95% CI 1.60-2.54; 100 days: OR 3.79, 95% CI 3.13-4.59). CONCLUSIONS: Hospital readmission from PAC facilities is common and associated with a high mortality rate. Readmission risk factors may signify inadequate transitional care processes or a mismatch between patient needs and PAC resources.

Comparing Survival Following Hip Fracture Repair in VHA and Non-VHA Facilities.

INTRODUCTION: Although postsurgical outcomes are similar between Veterans Health Administration (VHA) and non-VHA hospitals for many procedures, no studies have compared 30-day and 1-year survival following hip fracture repair. Therefore, this study compared survival of veterans aged 65 years and older treated in VHA hospitals with a propensity-matched cohort of Medicare beneficiaries in non-VHA hospitals. MATERIALS AND METHODS: Retrospective cohort study of 1894 hip fracture repair patients in VHA or non-VHA hospitals between 2003 and 2005. Current Procedural Terminology codes identified 3542 male patients aged >65 years who had hip fracture repair between 2003 and 2005 in the Veterans Affairs' National Surgical Quality Improvement Program database. The Medicare comparison sample was drawn from 2003 to 2005 Medicare Part A inpatient hospital claims files. To create comparable VHA and Medicare cohorts, patients were propensity score matched on age, admission source (community vs. nursing home), repair type, comorbidity index, race, year, and region. Thirty-day and 1-year survival after surgery were compared between cohorts after further adjustment for selected comorbidities, year of surgery, and pre- and postsurgical length of hospital stay using logistic regression. RESULTS: Odds of survival were significantly better in the Medicare than the VHA cohort at 30 days (1.68, 95% CI 1.15-2.44) and 1 year (1.35, 95% CI 1.08-1.69). CONCLUSION: Medicare beneficiaries with hip fracture repair in non-VHA hospitals had better survival than veterans in VHA hospitals. Whether this is driven by unobserved patient characteristics or systematic care differences is unknown.

Transition readiness in pediatric patients with inflammatory bowel disease: patient survey of self-management skills.

OBJECTIVE: Transition may be associated with poor health outcomes, but limited data exist regarding inflammatory bowel disease (IBD). Acquisition of self-management skills is believed to be important to this process. IBD-specific checklists of such skills have been developed to aid in transition, but none has been well studied or validated. This study aimed to describe self-assessment ability to perform tasks on one of these checklists and to explore the relation between patient age and disease duration. METHODS: Patients ages 10 to 21 years with IBD were recruited. An iPad survey queried the patients for self-assessment of ability to perform specific self-management tasks. Task categories included basic knowledge of IBD, doctor visits, medications and other treatments, and disease management. Associations with age and disease duration were tested with Spearman rank correlation. RESULTS: A total of 67 patients (31 boys) with Crohn disease (n = 40), ulcerative colitis (n = 25), and indeterminate colitis (n = 2) participated in the study. Mean patient age was 15.8 ±â€Š2.5 years, with median disease duration of 5 years (2 months-14 years). The proportion of patients who self-reported ability to complete a task without help increased with age for most tasks, including "telling others my diagnosis" (ρ = 0.43, P = 0.003), "telling medical staff I do not like or am having trouble following a treatment" (ρ = 0.37, P = 0.003), and "naming my medications" (ρ = 0.28, P = 0.02). No task significantly improved with disease duration. CONCLUSIONS: Self-assessment of ability to perform some key tasks of transition appears to improve with age, but not with disease duration. More important, communication with the medical team did not improve with age, despite being of critical importance to functioning within an adult care model.

Nursing home research: the first International Association of Gerontology and Geriatrics (IAGG) research conference.

The International Association of Gerontology and Geriatrics held its first conference on nursing home research in St Louis, MO, in November 2013. This article provides a summary of the presentations.

Association of rheumatoid arthritis susceptibility gene with lipid profiles in patients with rheumatoid arthritis.

OBJECTIVE: RA patients have an increased risk of cardiovascular (CV) disease, although the mechanisms are unclear. As RA and CV disease may be associated through lipid profiles, we examined whether single nucleotide polymorphisms (SNPs) associated with RA susceptibility were associated with low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride (TG) levels in RA subjects. METHODS: Patients (n = 763) enrolled in the Veterans Affairs RA registry who were not on hydroxymethylglutaryl-CoA reductase inhibitor were genotyped for human leukocyte antigen shared epitope (HLA-DRB1-SE) and SNPs in the following genes: CTLA-4 (cytotoxic T-lymphocyte antigen 4), IL-10, PTPN22 (protein tyrosine phosphatase, non-receptor type 22), REL (c-Rel), STAT4 (signal transducer and activator of transcription protein), TNF- and TRAF1 (TNF receptor-associated factor 1). Other covariates included patient characteristics (age, gender, race, smoking status, education, BMI, modified CharlsonDeyo comorbidity index), CV characteristics (hypertension, diabetes, alcohol abuse), pharmacologic exposures (MTX, anti-TNF, glucocorticoids) and RA severity/activity markers (RA disease duration, mean DAS, CRP, RF positivity, anti-CCP positivity). Multivariate linear regression was performed to determine the factors associated with LDL, HDL and TG levels. RESULTS: The REL SNP rs9309331 homozygous minor allele was associated with higher LDL levels. Caucasian race and increasing BMI were associated with lower HDL. Factors associated with higher TG were diabetes, Caucasian race and higher BMI. CONCLUSION: The REL SNP rs9309331 was associated with LDL levels in our study. This association is a possible explanation of the increased risk of RA patients for CV disease and requires further inquiry.

Effect of a hospitalist-run postdischarge clinic on outcomes.

BACKGROUND: New post-discharge strategies to reduce adverse events are needed. OBJECTIVE: To determine whether follow-up in a hospitalist-run post-discharge clinic (PDC) decreases post-discharge adverse events when compared to follow-up in a primary care clinic (PCP) or urgent care clinic (UC). DESIGN: Retrospective cohort study using propensity scoring in multivariate analysis. PATIENTS: Consecutive Veterans discharged home after a nonscheduled admission seen in PDC, UC, or PCP within 30 days of discharge. INTERVENTIONS: Recently discharged patients are seen by housestaff who cared for them during the index admission and staffed with a rotating hospitalist in PDC; UC and PCP patients are seen by housestaff or attending ambulatory physicians. MAIN MEASURES: The primary outcome was a composite of hospital readmissions, Emergency Department visits, and mortality 30 days after discharge. KEY RESULTS: 5085 patients met criteria; 538 followed up in PDC (10.6%), 1848 with their PCP (36.3%), and 2699 in UC (53.1%). Patients following up in PDC were older and had a higher comorbidity burden. ICU exposure was similar between groups. Patients seen in PDC had shorter length of stay (LOS) (PDC, 3.8 days, UC, 5.0 days, PCP, 6.2 days; p = 0.04) and time to first post-discharge visit (PDC, 5.0 days, UC, 9.4 days, PCP, 13.7 days; p < 0.01). There were no differences between groups in the primary outcome in unadjusted or propensity-adjusted multivariate analysis. CONCLUSIONS: Patients seen in a hospitalist-run PDC had similar 30-day post-discharge adverse outcome rates despite a 2.4-day shorter LOS compared to patients seen by their PCP. Prospective testing of PDCs is warranted.