The Health Resources and Services Administration (HRSA), Federal Office of Rural Health Policy (FORHP) funded the Evidence-Based Tele-Emergency Network Grant Program (EB TNGP) to serve the dual ...purpose of providing telehealth services in rural emergency departments (teleED) and systematically collecting data to inform the telehealth evidence base. This provided a unique opportunity to examine trends across multiple teleED networks and examine heterogeneity in processes and outcomes.
Six health systems received funding from HRSA under the EB TNGP to implement teleED services and they did so to 65 hospitals (91% rural) in 11 states. Three of the grantees provided teleED services to a general patient population while the remaining three grantees provided teleED services to specialized patient populations (i.e., stroke, behavioral health, critically ill children). Over a 26-month period (November 1, 2015 -December 31, 2017), each grantee submitted patient-level data for all their teleED encounters on a uniform set of measures to the data coordinating center. The six grantees reported a total of 4,324 teleED visits and 99.86% were technically successful. The teleED patients were predominantly adult, White, not Latinx, and covered by Medicare or private insurance. Across grantees, 7% of teleED patients needed resuscitation services, 58% were rated as emergent, and 30% were rated as urgent. Across grantees, 44.2% of teleED patients were transferred to another inpatient facility, 26.0% had a routine discharge, and 24.5% were admitted to the local inpatient facility. For the three grantees who served a general patient population, the most frequent presenting complaints for which teleED was activated were chest pain (25.7%), injury or trauma (17.1%), stroke symptoms (9.9%), mental/behavioral health (9.8%), and cardiac arrest (9.5%). The teleED consultation began before the local clinician exam in 37.8% of patients for the grantees who served a general patient population, but in only 1.9% of patients for the grantees who provided specialized services.
Grantees used teleED services for a representative rural population with urgent or emergent symptoms largely resulting in transfer to a distant hospital or inpatient admission locally. TeleED was often available as the first point of contact before a local provider examination. This finding points to the important role of teleED in improving access for rural ED patients.
Between 1990 and 2013, maternal mortality nearly doubled in the United States and rural residents experienced decreasing access to obstetric care. To improve maternal health, many states have ...established maternal mortality and morbidity review committees (MMRCs). We assessed the extent of rural representation in state policy efforts related to MMRCs.
We reviewed publicly available information on MMRCs (websites, statutes, bills, media) in all 50 states and the District of Columbia, separately identifying highly rural states (with >30% of the population being rural residents). We assessed whether each state 1) had established an MMRC, 2) had passed legislation requiring an MMRC, 3) had considered, but not passed, legislation requiring an MMRC, 4) mentioned rural populations in MMRC legislation, 5) required representation on the MMRC from any particular groups, and 6) required rural representation on the MMRC.
As of December 2018, MMRCs were established in 45 states and the District of Columbia, an increase from 23 in 2010. Legislation was in place in 27 states, up from 6 in 2010. Only three states specifically mentioned rurality in legislation (including one highly rural state), and only two states required rural representation among their MMRC members (neither of which were highly rural states).
Recent growth in MMRCs has had a limited focus on rural residents, despite their worse health outcomes and more limited access to health care, including obstetric services. Lack of rural representation may hamper geographically tailored efforts to reverse rising rates of maternal morbidity and mortality nationally.
We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and ...glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1-mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.
Glucagon-like peptide-1 (GLP-1) is released from endocrine L-cells lining the gut in response to food ingestion. However, GLP-1 is also produced in the nucleus of the solitary tract, where it acts as ...an anorectic neurotransmitter and key regulator of many autonomic and neuroendocrine functions. The expression and projections of GLP-1-producing neurons is highly conserved between rodent and primate brain, although a few key differences have been identified. The GLP-1 receptor (GLP-1R) has been mapped in the rodent brain, but no studies have described the distribution of GLP-1Rs in the nonhuman primate central nervous system. Here, we characterized the distribution of GLP-1R mRNA and protein in the adult macaque brain using in situ hybridization, radioligand receptor autoradiography, and immunohistochemistry with a primate specific GLP-1R antibody. Immunohistochemistry demonstrated that the GLP-1R is localized to cell bodies and fiber terminals in a very selective distribution throughout the brain. Consistent with the functional role of the GLP-1R system, we find the highest concentration of GLP-1R-immunoreactivity present in select hypothalamic and brainstem regions that regulate feeding, including the paraventricular and arcuate hypothalamic nuclei, as well as the area postrema, nucleus of the solitary tract, and dorsal motor nucleus of the vagus. Together, our data demonstrate that GLP-1R distribution is highly conserved between rodent and primate, although a few key species differences were identified, including the amygdala, where GLP-1R expression is much higher in primate than in rodent.
We studied interscapular brown adipose tissue (iBAT) activity in wild-type (WT) and glucagon-like peptide 1 receptor (GLP-1R)-deficient mice after the administration of the proglucagon-derived ...peptides (PGDPs) glucagon-like peptide (GLP-1), glucagon (GCG), and oxyntomodulin (OXM) directly into the brain. Intracerebroventricular injection of PGDPs reduces body weight and increases iBAT thermogenesis. This was independent of changes in feeding and insulin responsiveness but correlated with increased activity of sympathetic fibers innervating brown adipose tissue (BAT). Despite being a GCG receptor agonist, OXM requires GLP-1R activation to induce iBAT thermogenesis. The increase in thermogenesis in WT mice correlates with increased expression of genes upregulated by adrenergic signaling and required for iBAT thermogenesis, including PGC1a and UCP-1. In spite of the increase in iBAT thermogenesis induced by GLP-1R activation in WT mice, Glp1r(-/-) mice exhibit a normal response to cold exposure, demonstrating that endogenous GLP-1R signaling is not essential for appropriate thermogenic response after cold exposure. Our data suggest that the increase in BAT thermogenesis may be an additional mechanism whereby pharmacological GLP-1R activation controls energy balance.
Abstract
Background
Deposition of amyloid beta (Aβ) and hyperphosphorylated tau along with glial cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimer’s disease (AD). In ...recent years, impairment of autophagy has been identified as another important feature contributing to AD progression. Therefore, the potential of the autophagy activator spermidine, a small body-endogenous polyamine often used as dietary supplement, was assessed on Aβ pathology and glial cell-mediated neuroinflammation.
Results
Oral treatment of the amyloid prone AD-like APPPS1 mice with spermidine reduced neurotoxic soluble Aβ and decreased AD-associated neuroinflammation. Mechanistically, single nuclei sequencing revealed AD-associated microglia to be the main target of spermidine. This microglia population was characterized by increased AXL levels and expression of genes implicated in cell migration and phagocytosis. A subsequent proteome analysis of isolated microglia confirmed the anti-inflammatory and cytoskeletal effects of spermidine in APPPS1 mice. In primary microglia and astrocytes, spermidine-induced autophagy subsequently affected TLR3- and TLR4-mediated inflammatory processes, phagocytosis of Aβ and motility. Interestingly, spermidine regulated the neuroinflammatory response of microglia beyond transcriptional control by interfering with the assembly of the inflammasome.
Conclusions
Our data highlight that the autophagy activator spermidine holds the potential to enhance Aβ degradation and to counteract glia-mediated neuroinflammation in AD pathology.
There is accumulating evidence for a link between trauma exposure, posttraumatic stress disorder (PTSD) and diminished health status. To assess PTSD-related biological burden, we measured biological ...factors that comprise metabolic syndrome, an important established predictor of morbidity and mortality, as a correlate of long-term health risk in PTSD.
We analyzed clinical data from 253 male and female veterans, corresponding to five factors linked to metabolic syndrome (systolic and diastolic blood pressure, waist-to-hip ratio and fasting measures of high-density lipoprotein (HDL) cholesterol, serum triglycerides and plasma glucose concentration). Clinical cut-offs were defined for each biological parameter based on recommendations from the World Health Organization and the National Cholesterol Education Program. Controlling for relevant variables including sociodemographic variables, alcohol/substance/nicotine use and depression, we examined the impact of PTSD on metabolic syndrome using a logistic regression model.
Two-fifths (40%) of the sample met criteria for metabolic syndrome. Of those with PTSD (n = 139), 43% met criteria for metabolic syndrome. The model predicted metabolic syndrome well (-2 log likelihood = 316.650, chi-squared = 23.731, p = 0.005). Veterans with higher severity of PTSD were more likely to meet diagnostic criteria for metabolic syndrome (Wald = 4.76, p = 0.03).
These findings provide preliminary evidence linking higher severity of PTSD with risk factors for diminished health and increased morbidity, as represented by metabolic syndrome.
We report a case of recurrent primary intraventricular synovial sarcoma of the brain with no extracranial primary, initially reported as a haemangiopericytoma. We believe this is the first reported ...case of primary intraventricular synovial sarcoma at this site.
A 27-year-old male presented to hospital with a new onset of seizures. Imaging revealed a left ventricular trigone mass with surrounding oedema. He underwent a left occipito-temporal craniotomy and resection with the histology reported as haemangiopericytoma. Resection was followed by adjuvant radiation treatment. Seven years later follow-up imaging revealed a 4 mm contrast enhancing lesion in the previous surgical bed. The patient underwent resection. Histological analysis of the recurrence revealed a spindle cell tumour with a SS18 gene rearrangement consistent with synovial sarcoma. Retrospective fluorescent in-situ hybridisation analysis of original histology also revealed a SS18 gene rearrangement consistent with a diagnosis of synovial sarcoma.
Synovial sarcoma should be included as part of the differential diagnosis for patients presenting with intraventricular spindle cell tumours in the brain.
Heterologous prime-boost immunisation with RTS,S/AS02A and the poxvirus MVA-CS was evaluated in 18 healthy malaria-naïve subjects in Oxford. Both priming with RTS,S and boosting MVA-CS, and the ...reverse, were found to be safe and well tolerated. T cell responses as measured by IFN-γ ex vivo ELISPOT were induced, but the responses were low to moderate in both groups, with heterologous boosting yielding only small increments in T cell immunogenicity and no increased antibody response. Protection against 3D7
Plasmodium falciparum sporozoite challenge 4 weeks after the final vaccination was equal for both regimens at 33% (95% C.I. 4.3–77.7%), with one subject remaining fully protected on rechallenge at 5 months.
Aims/hypothesis
We assessed the contribution of glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) signalling to thermogenesis induced by high-fat diet (HFD) consumption. Furthermore, we determined ...whether brown adipose tissue (BAT) activity contributes to weight loss induced by chronic subcutaneous treatment with the GLP-1R agonist, liraglutide, in a model of diet-induced obesity.
Methods
Metabolic phenotyping was performed using indirect calorimetry in wild-type (WT) and
Glp1r
-knockout (KO) mice during chow and HFD feeding at room temperature and at thermoneutrality. In a separate study, we investigated the contribution of BAT thermogenic capacity to the weight lowering effect induced by GLP-1 mimetics by administering liraglutide (10 or 30 nmol kg
−1
day
−1
s.c.) to diet-induced obese (DIO) mice for 6 or 4 weeks, respectively. In both studies, animals were subjected to a noradrenaline (norepinephrine)-stimulated oxygen consumption
V
⋅
O
2
test.
Results
At thermoneutrality, HFD-fed
Glp1r-
KO mice had similar energy expenditure (EE) compared with HFD-fed WT controls. However, HFD-fed
Glp1r
-KO mice exhibited relatively less EE when housed at a cooler standard room temperature, and had relatively lower
V
⋅
O
2
in response to a noradrenaline challenge, which is consistent with impaired BAT thermogenic capacity. In contrast to the loss of function model, chronic peripheral liraglutide treatment did not increase BAT activity as determined by noradrenaline-stimulated
V
⋅
O
2
and BAT gene expression.
Conclusions/interpretation
These data suggest that although endogenous GLP-1R signalling contributes to increased BAT thermogenesis, this mechanism does not play a significant role in the food intake-independent body weight lowering effect of the GLP-1 mimetic liraglutide in DIO mice.
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