Comprehensive Stress Stability Studies Reveal the Prominent Stability of the Liquid-Formulated Biotherapeutic Asymmetric Monovalent Bispecific IgG1 Monoclonal Antibody Format.

The developed asymmetric monovalent bispecific IgG1 or Duet monoclonal antibody (Duet mAb) has two distinct fragment antigen-binding region (Fab) subunits that target two different epitope specificities sequentially or simultaneously. The design features include unique engineered disulfide bridges, knob-into-hole mutations, and kappa and lambda chains to produce Duet mAbs. These make it structurally and functionally complex, so one expects challenging developability linked to instability, degradation of products and pathways, and limited reports available. Here, we have treated the product with different sources of extreme stress over a lengthy period, including varying heat, pH, photo stress, chemical oxidative stress, accelerated stress in physiological conditions, and forced glycation conditions. The effects of different stress conditions on the product were assessed using various analytical characterization tools to measure product-related substances, post-translational modifications (PTMs), structural integrity, higher-order disulfide linkages, and biological activity. The results revealed degradation products and pathways of Duet mAb. A moderate increase in size, charge, and hydrophobic variants, PTMs, including deamidation, oxidation, isomerization, and glycation were observed, with most conditions exhibiting biological activity. In addition, the characterization of fractionated charge variants, including deamidated species, showed satisfactory biological activity. This study demonstrated the prominent stability of the Duet mAb format comparable to most marketed mAbs.

Incorporating Acute Conditions into Risk-Adjustment for Provider Profiling: The Case of the US News and World Report Best Hospitals Rankings Methodology.

Several years ago, the US News and World Report changed their risk-adjustment methodology, now relying almost exclusively on chronic conditions for risk adjustment. The impacts of adding selected acute conditions like pneumonia, sepsis, and electrolyte disorders ("augmented") to their current risk models ("base") for 4 specialties-cardiology, neurology, oncology, and pulmonology-on estimates of hospital performance are reported here. In the augmented models, many acute conditions were associated with substantial risks of mortality. Compared to the base models, the discrimination and calibration of the augmented models for all specialties were improved. While estimated hospital performance was highly correlated between the 2 models, the inclusion of acute conditions in risk-adjustment models meaningfully improved the predictive ability of those models and had noticeable effects on hospital performance estimates. Measures or conditions that address disease severity should always be included when risk-adjusting hospitalization outcomes, especially if the goal is provider profiling.

Development of an interactive dashboard for gun violence pattern analysis and intervention design at the local level.

Introduction: Gun violence remains a concerning and persistent issue in our country. Novel dashboards may integrate and summarize important clinical and non-clinical data that can inform targeted interventions to address the underlying causes of gun violence. Methods: Data from various clinical and non-clinical sources were sourced, cleaned, and integrated into a customizable dashboard that summarizes and provides insight into the underlying factors that impact local gun violence episodes. Results: The dashboards contained data from 7786 encounters and 1152 distinct patients from our Emergency Department's Trauma Registry with various patterns noted by the team. A multidisciplinary executive team, including subject matter experts in community-based interventions, epidemiology, and social sciences, was formed to design targeted interventions based on these observations. Conclusion: Targeted interventions to reduce gun violence require a multimodal data sourcing and standardization approach, the inclusion of neighborhood-level data, and a dedicated multidisciplinary team to act on the generated insights.

A Comparison of Oxidative Lactate Metabolism in Traumatically Injured Brain and Control Brain.

Metabolic abnormalities occur after traumatic brain injury (TBI). Glucose is conventionally regarded as the major energy substrate, although lactate can also be an energy source. We compared 3-13C lactate metabolism in TBI with "normal" control brain and muscle, measuring 13C-glutamine enrichment to assess tricarboxylic acid (TCA) cycle metabolism. Microdialysis catheters in brains of nine patients with severe TBI, five non-TBI brain surgical patients, and five resting muscle (non-TBI) patients were perfused (24 h in brain, 8 h in muscle) with 8 mmol/L sodium 3-13C lactate. Microdialysate analysis employed ISCUS and nuclear magnetic resonance. In TBI, with 3-13C lactate perfusion, microdialysate glucose concentration increased nonsignificantly (mean +11.9%, p = 0.463), with significant increases (p = 0.028) for lactate (+174%), pyruvate (+35.8%), and lactate/pyruvate ratio (+101.8%). Microdialysate 13C-glutamine fractional enrichments (median, interquartile range) were: for C4 5.1 (0-11.1) % in TBI and 5.7 (4.6-6.8) % in control brain, for C3 0 (0-5.0) % in TBI and 0 (0-0) % in control brain, and for C2 2.9 (0-5.7) % in TBI and 1.8 (0-3.4) % in control brain. 13C-enrichments were not statistically different between TBI and control brain, showing both metabolize 3-13C lactate via TCA cycle, in contrast to muscle. Several patients with TBI exhibited 13C-glutamine enrichment above the non-TBI control range, suggesting lactate oxidative metabolism as a TBI "emergency option."

Focally perfused succinate potentiates brain metabolism in head injury patients.

Following traumatic brain injury, complex cerebral energy perturbations occur. Correlating with unfavourable outcome, high brain extracellular lactate/pyruvate ratio suggests hypoxic metabolism and/or mitochondrial dysfunction. We investigated whether focal administration of succinate, a tricarboxylic acid cycle intermediate interacting directly with the mitochondrial electron transport chain, could improve cerebral metabolism. Microdialysis perfused disodium 2,3-13C2 succinate (12 mmol/L) for 24 h into nine sedated traumatic brain injury patients' brains, with simultaneous microdialysate collection for ISCUS analysis of energy metabolism biomarkers (nine patients) and nuclear magnetic resonance of 13C-labelled metabolites (six patients). Metabolites 2,3-13C2 malate and 2,3-13C2 glutamine indicated tricarboxylic acid cycle metabolism, and 2,3-13C2 lactate suggested tricarboxylic acid cycle spinout of pyruvate (by malic enzyme or phosphoenolpyruvate carboxykinase and pyruvate kinase), then lactate dehydrogenase-mediated conversion to lactate. Versus baseline, succinate perfusion significantly decreased lactate/pyruvate ratio (p = 0.015), mean difference -12%, due to increased pyruvate concentration (+17%); lactate changed little (-3%); concentrations decreased for glutamate (-43%) (p = 0.018) and glucose (-15%) (p = 0.038). Lower lactate/pyruvate ratio suggests better redox status: cytosolic NADH recycled to NAD+ by mitochondrial shuttles (malate-aspartate and/or glycerol 3-phosphate), diminishing lactate dehydrogenase-mediated pyruvate-to-lactate conversion, and lowering glutamate. Glucose decrease suggests improved utilisation. Direct tricarboxylic acid cycle supplementation with 2,3-13C2 succinate improved human traumatic brain injury brain chemistry, indicated by biomarkers and 13C-labelling patterns in metabolites.

Extracellular N-Acetylaspartate in Human Traumatic Brain Injury.

N-acetylaspartate (NAA) is an amino acid derivative primarily located in the neurons of the adult brain. The function of NAA is incompletely understood. Decrease in brain tissue NAA is presently considered symptomatic and a potential biomarker of acute and chronic neuropathological conditions. The aim of this study was to use microdialysis to investigate the behavior of extracellular NAA (eNAA) levels after traumatic brain injury (TBI). Sampling for this study was performed using cerebral microdialysis catheters (M Dialysis 71) perfused at 0.3 µL/min. Extracellular NAA was measured in microdialysates by high-performance liquid chromatography in 30 patients with severe TBI and for comparison, in radiographically "normal" areas of brain in six non-TBI neurosurgical patients. We established a detailed temporal eNAA profile in eight of the severe TBI patients. Microdialysate concentrations of glucose, lactate, pyruvate, glutamate, and glycerol were measured on an ISCUS clinical microdialysis analyzer. Here, we show that the temporal profile of microdialysate eNAA was characterized by highest levels in the earliest time-points post-injury, followed by a steady decline; beyond 70 h post-injury, average levels were 40% lower than those measured in non-TBI patients. There was a significant inverse correlation between concentrations of eNAA and pyruvate; eNAA showed significant positive correlations with glycerol and the lactate/pyruvate (L/P) ratio measured in microdialysates. The results of this on-going study suggest that changes in eNAA after TBI relate to the release of intracellular components, possibly due to neuronal death or injury, as well as to adverse brain energy metabolism.

Consensus statement from the 2014 International Microdialysis Forum.

Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.

Systemic, local, and imaging biomarkers of brain injury: more needed, and better use of those already established?

Much progress has been made over the past two decades in the treatment of severe acute brain injury, including traumatic brain injury and subarachnoid hemorrhage, resulting in a higher proportion of patients surviving with better outcomes. This has arisen from a combination of factors. These include improvements in procedures at the scene (pre-hospital) and in the hospital emergency department, advances in neuromonitoring in the intensive care unit, both continuously at the bedside and intermittently in scans, evolution and refinement of protocol-driven therapy for better management of patients, and advances in surgical procedures and rehabilitation. Nevertheless, many patients still experience varying degrees of long-term disabilities post-injury with consequent demands on carers and resources, and there is room for improvement. Biomarkers are a key aspect of neuromonitoring. A broad definition of a biomarker is any observable feature that can be used to inform on the state of the patient, e.g., a molecular species, a feature on a scan, or a monitoring characteristic, e.g., cerebrovascular pressure reactivity index. Biomarkers are usually quantitative measures, which can be utilized in diagnosis and monitoring of response to treatment. They are thus crucial to the development of therapies and may be utilized as surrogate endpoints in Phase II clinical trials. To date, there is no specific drug treatment for acute brain injury, and many seemingly promising agents emerging from pre-clinical animal models have failed in clinical trials. Large Phase III studies of clinical outcomes are costly, consuming time and resources. It is therefore important that adequate Phase II clinical studies with informative surrogate endpoints are performed employing appropriate biomarkers. In this article, we review some of the available systemic, local, and imaging biomarkers and technologies relevant in acute brain injury patients, and highlight gaps in the current state of knowledge.

Building the pipeline: the creation of a residency training pathway for future physician leaders in health care quality.

PROBLEM: Many health care organizations seek physicians to lead quality improvement (QI) efforts, yet struggle to find individuals with the necessary expertise. Although most residency programs incorporate QI and patient safety principles into their curricula, few provide a specialized training program for residents exploring careers as physician leaders in quality. APPROACH: Recognizing this training void, the authors designed and implemented the Healthcare Leadership in Quality (HLQ) track for residents at the University of Pennsylvania Health System in 2010. This longitudinal, two-year graduate medical education (GME) track aligns with the quality goals of the University of Pennsylvania Health System and includes a core curriculum, integration into an interprofessional health care leadership team that is accountable for quality and safety outcomes on a hospital unit, a capstone QI project, and mentorship. OUTCOMES: Early evaluation has demonstrated the feasibility and efficacy of the track diverse graduate medical education training programs. Using Yardley and Dornan's interpretation of the Kirkpatrick framework, the authors have demonstrated the track's impact on four levels of educational and organizational outcomes. NEXT STEPS: Building on their early experiences, the authors are integrating project and time management skills into the core curriculum, and they are focusing more effort on faculty development in QI mentorship. Additionally, the authors plan to follow HLQ track graduates to determine whether they seek leadership roles in quality and safety and to assess the influence of the program on their careers.

Mechanisms of type 2 diabetes resolution after Roux-en-Y gastric bypass.

BACKGROUND: Bariatric surgery is the most effective treatment for the reduction of weight and resolution of type 2 diabetes mellitus (T2 DM). The objective of this study was to longitudinally assess hormonal and tissue responses after RYGB. METHODS: Eight patients (5 with T2 DM) were studied before and after RYGB. A standardized test meal (STM) was administered before and at 1, 3, 6, 9, 12, and 15 months. Separately, a 2-hour hyperinsulinemic-euglycemic clamp (E-clamp) and a 2-hour hyperglycemic clamp (H-clamp) were performed before and at 1, 3, 6, and 12 months. Glucagon-like peptide-1 (GLP-1) was infused during the last hour of the H-clamp. Body composition was assessed with DXA methodology. RESULTS: Enrollment body mass index was 49±3 kg/m(2) (X±SE). STM glucose and insulin responses were normalized by 3 and 6 months. GLP-1 level increased dramatically at 1, 3, and 6 months, normalizing by 12 and 15 months. Insulin sensitivity (M of E-clamp) increased progressively at 3-12 months as fat mass decreased. The insulin response to glucose alone fell progressively over 12 months but the glucose clearance/metabolism (M of H-clamp) did not change significantly until 12 months. In response to GLP-1 infusion, insulin levels fell progressively throughout the 12 months. CONCLUSION: The early hypersecretion of GLP-1 leads to hyperinsulinemia and early normalization of glucose levels. The GLP-1 response normalizes within 1 year after surgery. Enhanced peripheral tissue sensitivity to insulin starts at 3 months and is associated with fat mass loss. ß-cell sensitivity improves at 12 months and after the loss of ≈33% of excess weight. There is a tightly controlled feedback loop between peripheral tissue sensitivity and ß-cell and L-cell (GLP-1) responses.

GLP-1 (7-36) amide restores myocardial insulin sensitivity and prevents the progression of heart failure in senescent beagles.

BACKGROUND: We previously demonstrated that older beagles have impaired whole body and myocardial insulin responsiveness (MIR), and that glucagon-like peptide-1 (GLP-1 [7-36] amide) improves MIR in young beagles with dilated cardiomyopathy (DCM). Here, we sought to determine if aging alone predisposes to an accelerated course of DCM, and if GLP-1 [7-36] amide would restore MIR and impact the course of DCM in older beagles. METHODS: Eight young beagles (Young-Control) and sixteen old beagles underwent chronic left ventricle (LV) instrumentation. Seven old beagles were treated with GLP-1 (7-36) amide (2.5 pmol/kg/min) for 2 weeks prior to instrumentation and for 35 days thereafter (Old + GLP-1), while other 9 served as control (Old-Control). All dogs underwent baseline metabolic determinations and LV biopsy for mitochondria isolation prior to the development of DCM induced by rapid pacing (240 min-1). Hemodynamic measurements were performed routinely as heart failure progressed. RESULTS: At baseline, all old beagles had elevated non-esterifed fatty acids (NEFA), and impaired MIR. GLP-1 reduced plasma NEFA (Old-Control: 853 ± 34; Old + GLP-1: 531 ± 33 µmol/L, p < 0.02), improved MIR (Old-Control: 289 ± 54; Old + GLP-1: 512 ± 44 mg/min/100 mg, p < 0.05), and increased uncoupling protein-3 (UCP-3) expression in isolated mitochondria. Compared to the Young-Control, the Old-Controls experienced an accelerated course of DCM (7 days versus 29 days, p < 0.005) and excess mortality, while the Old + GLP-1 experienced increased latency to the onset of DCM (7 days versus 23 days, p < 0.005) and reduced mortality. CONCLUSION: Aging is associated with myocardial insulin resistance, which predispose to an accelerated course of DCM. GLP-1 treatment is associated with increased MIR and protection against an accelerated course of DCM in older beagles.

GLP-1(32-36)amide, a novel pentapeptide cleavage product of GLP-1, modulates whole body glucose metabolism in dogs.

We have previously demonstrated in human subjects who under euglycemic clamp conditions GLP-1(9-36)amide infusions inhibit endogenous glucose production without substantial insulinotropic effects. An earlier report indicates that GLP-1(9-36)amide is cleaved to a nonapeptide, GLP-1(28-36)amide and a pentapeptide GLP-1(32-36)amide (LVKGR amide). Here we study the effects of the pentapeptide on whole body glucose disposal during hyperglycemic clamp studies. Five dogs underwent indwelling catheterizations. Following recovery, the dogs underwent a 180 min hyperglycemic clamp (basal glucose +98 mg/dl) in a cross-over design. Saline or pentapeptide (30 pmol kg(-1) min(-1)) was infused during the last 120 min after commencement of the hyperglycemic clamp in a primed continuous manner. During the last 30 min of the pentapeptide infusion, glucose utilization (M) significantly increased to 21.4±2.9 mg kg(-1) min(-1)compared to M of 14.3±1.1 mg kg(-1)min(-1) during the saline infusion (P=0.026, paired t-test; P=0.062, Mann-Whitney U test). During this interval, no significant differences in insulin (26.6±3.2 vs. 23.7±2.5 µU/ml, P=NS) or glucagon secretion (34.0±2.1 vs. 31.7±1.8 pg/ml, P=NS) were observed. These findings demonstrate that under hyperglycemic clamp studies the pentapeptide modulates glucose metabolism by a stimulation of whole-body glucose disposal. Further, the findings suggest that the metabolic benefits previously observed during GLP-1(9-36)amide infusions in humans might be due, at least in part, to the metabolic effects of the pentapeptide that is cleaved from the pro-peptide, GLP-1(9-36)amide in the circulation.

Beyond glycemic control: cardiovascular effects of incretin-based therapies.

As cardiovascular (CV) disease remains the major cause of mortality and morbidity in type 2 diabetes mellitus, reducing macrovascular complications has been a major target of antiglycemic therapies. Emerging evidence suggests that incretin-based therapies are safe and may provide CV and cerebrovascular (CBV) benefits beyond those attributable to glycemic control, making the class an attractive therapeutic option. However, the mechanisms whereby the various classes of incretin-based therapies exert CV and CBV benefits may be distinct and may not necessarily lead to similar outcomes. In this chapter, we will discuss the potential mechanisms and current understanding of CV and CBV benefits of native glucagon-like peptide (GLP)-1, GLP-1 receptor agonists and analogues, and of dipeptidyl peptidase-4 inhibitor therapies as a means to better understand differences in safety and efficacy.

Monitoring vigabatrin in head injury patients by cerebral microdialysis: obtaining pharmacokinetic measurements in a neurocritical care setting.

AIMS: The aims were to determine blood-brain barrier penetration and brain extracellular pharmacokinetics for the anticonvulsant vigabatrin (VGB; γ-vinyl-γ-aminobutyric acid) in brain extracellular fluid and plasma from severe traumatic brain injury (TBI) patients, and to measure the response of γ-aminobutyric acid (GABA) concentration in brain extracellular fluid. METHODS: Severe TBI patients (n = 10) received VGB (0.5 g enterally, every 12 h). Each patient had a cerebral microdialysis catheter; two patients had a second catheter in a different region of the brain. Plasma samples were collected 0.5 h before and 2, 4 and 11.5 h after the first VGB dose. Cerebral microdialysis commenced before the first VGB dose and continued through at least three doses of VGB. Controls were seven severe TBI patients with microdialysis, without VGB. RESULTS: After the first VGB dose, the maximum concentration of VGB (Cmax ) was 31.7 (26.9-42.6) µmol l(-1) (median and interquartile range for eight patients) in plasma and 2.41 (2.03-5.94) µmol l(-1) in brain microdialysates (nine patients, 11 catheters), without significant plasma-brain correlation. After three doses, median Cmax in microdialysates increased to 5.22 (4.24-7.14) µmol l(-1) (eight patients, 10 catheters). Microdialysate VGB concentrations were higher close to focal lesions than in distant sites. Microdialysate GABA concentrations increased modestly in some of the patients after VGB administration. CONCLUSIONS: Vigabatrin, given enterally to severe TBI patients, crosses the blood-brain barrier into the brain extracellular fluid, where it accumulates with multiple dosing. Pharmacokinetics suggest delayed uptake from the blood.

Patient-centered community health worker intervention to improve posthospital outcomes: a randomized clinical trial.

IMPORTANCE Socioeconomic and behavioral factors can negatively influence posthospital outcomes among patients of low socioeconomic status (SES). Traditional hospital personnel often lack the time, skills, and community linkages required to address these factors. OBJECTIVE To determine whether a tailored community health worker (CHW) intervention would improve posthospital outcomes among low-SES patients. DESIGN, SETTING, AND PARTICIPANTS A 2-armed, single-blind, randomized clinical trial was conducted between April 10, 2011, and October 30, 2012, at 2 urban, academically affiliated hospitals. Of 683 eligible general medical inpatients (ie, low-income, uninsured, or Medicaid) that we screened, 237 individuals (34.7%) declined to participate. The remaining 446 patients (65.3%) were enrolled and randomly assigned to study arms. Nearly equal percentages of control and intervention group patients completed the follow-up interview (86.6% vs 86.9%). INTERVENTIONS During hospital admission, CHWs worked with patients to create individualized action plans for achieving patients' stated goals for recovery. The CHWs provided support tailored to patient goals for a minimum of 2 weeks. MAIN OUTCOMES AND MEASURES The prespecified primary outcome was completion of primary care follow-up within 14 days of discharge. Prespecified secondary outcomes were quality of discharge communication, self-rated health, satisfaction, patient activation, medication adherence, and 30-day readmission rates. RESULTS Using intention-to-treat analysis, we found that intervention patients were more likely to obtain timely posthospital primary care (60.0% vs 47.9%; P = .02; adjusted odds ratio [OR], 1.52; 95% CI, 1.03-2.23), to report high-quality discharge communication (91.3% vs 78.7%; P = .002; adjusted OR, 2.94; 95% CI, 1.5-5.8), and to show greater improvements in mental health (6.7 vs 4.5; P = .02) and patient activation (3.4 vs 1.6; P = .05). There were no significant differences between groups in physical health, satisfaction with medical care, or medication adherence. Similar proportions of patients in both arms experienced at least one 30-day readmission; however, intervention patients were less likely to have multiple 30-day readmissions (2.3% vs 5.5%; P = .08; adjusted OR, 0.40; 95% CI, 0.14-1.06). Among the subgroup of 63 readmitted patients, recurrent readmission was reduced from 40.0% vs 15.2% (P = .03; adjusted OR, 0.27; 95% CI, 0.08-0.89). CONCLUSIONS AND RELEVANCE Patient-centered CHW intervention improves access to primary care and quality of discharge while controlling recurrent readmissions in a high-risk population. Health systems may leverage the CHW workforce to improve posthospital outcomes by addressing behavioral and socioeconomic drivers of disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01346462.

The glucoregulatory benefits of glucagon-like peptide-1 (7-36) amide infusion during intensive insulin therapy in critically ill surgical patients: a pilot study.

OBJECTIVES: Intensive insulin therapy for tight glycemic control in critically ill surgical patients has been shown to reduce mortality; however, intensive insulin therapy is associated with iatrogenic hypoglycemia and increased variability of blood glucose levels. The incretin glucagon-like peptide-1 (7-36) amide is both insulinotropic and insulinomimetic and has been suggested as an adjunct to improve glycemic control in critically ill patients. We hypothesized that the addition of continuous infusion of glucagon-like peptide-1 to intensive insulin therapy would result in better glucose control, reduced requirement of exogenous insulin administration, and fewer hypoglycemic events. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. SETTING: Surgical or burn ICU. PATIENTS: Eighteen patients who required intensive insulin therapy. INTERVENTIONS: A 72-hour continuous infusion of either glucagon-like peptide-1 (1.5 pmol/kg/min) or normal saline plus intensive insulin therapy. MEASUREMENTS AND MAIN RESULTS: The glucagon-like peptide-1 cohort (n = 9) and saline cohort (n = 9) were similar in age, Acute Physiology and Chronic Health Evaluation score, and history of diabetes. Blood glucose levels in the glucagon-like peptide-1 group were better controlled with much less variability. The coefficient of variation of blood glucose ranged from 7.2% to 30.4% in the glucagon-like peptide-1 group and from 19.8% to 56.8% in saline group. The mean blood glucose coefficient of variation for the glucagon-like peptide-1 and saline groups was 18.0% ± 2.7% and 30.3% ± 4.0% (p = 0.010), respectively. The 72-hour average insulin infusion rates were 3.37 ± 0.61 and 4.57 ± 1.18 U/hr (p = not significant). The incidents of hypoglycemia (≤ 2.78 mmol/L) in both groups were low (one in the glucagon-like peptide-1 group, three in the saline group). CONCLUSIONS: Glucagon-like peptide-1 (7-36) amide is a safe and efficacious form of adjunct therapy in patients with hyperglycemia in the surgical ICU setting. Improved stability of blood glucose is a favorable outcome, which enhances the safety of intensive insulin therapy. Larger studies of this potentially valuable therapy for glycemic control in the ICU are justified.

Incretin-based therapies: can we achieve glycemic control and cardioprotection?

Glucagon-like (GLP-1) is a peptide hormone secreted from the small intestine in response to nutrient ingestion. GLP-1 stimulates insulin secretion in a glucose-dependent manner, inhibits glucagon secretion and gastric emptying, and reduces appetite. Because of the short circulating half-life of the native GLP-1, novel GLP-1 receptor (GLP-1R) agonists and analogs and dipeptidyl peptidase 4 (DPP-4) inhibitors have been developed to facilitate clinical use. Emerging evidence indicates that GLP-1-based therapies are safe and may provide cardiovascular (CV) benefits beyond glycemic control. Preclinical and clinical studies are providing increasing evidence that GLP-1 therapies may positively affect CV function and metabolism by salutary effects on CV risk factors as well as via direct cardioprotective actions. However, the mechanisms whereby the various classes of incretin-based therapies exert CV effects may be mechanistically distinct and may not necessarily lead to similar CV outcomes. In this review, we will discuss the potential mechanisms and current understanding of CV benefits of native GLP-1, GLP-1R agonists and analogs, and of DPP-4 inhibitor therapies as a means to compare their putative CV benefits.

The use of participatory action research to design a patient-centered community health worker care transitions intervention.

BACKGROUND: Policymakers, patients and clinicians are increasingly eager to foster patient involvement in health care innovation. Our objective was to use participatory action research with high-risk hospitalized patients to design a post-hospital transition intervention. METHODS: We conducted qualitative interviews with sixty-five low-income, recently hospitalized patients exploring their perceptions of barriers to post-hospital recovery and ideas for improvement. We then used a modified grounded theory approach to design an intervention that would address each barrier using patients׳ suggestions. RESULTS: Five key themes were translated into design elements. First, patients wished to establish a relationship with healthcare personnel to whom they could relate. The intervention was provided by an empathic community health worker (CHW) who established rapport during hospitalization. Second, patients suggested tailoring support to their needs and goals. CHWs and patients designed individualized action plans for achieving their goals for recovery. Third, patient goals were misaligned with those of the inpatient team. CHW facilitated patient-provider discharge communication to align goals. Fourth, patients lacked post-discharge support for predominantly psychosocial or financial issues that undermined recovery. CHWs provided support tailored to patient needs. Finally, patients faced numerous barriers in obtaining post-hospital primary care. CHWs helped patients to obtain timely care with a suitable provider. CONCLUSIONS: Low-income hospitalized patients voiced needs and suggestions that were directly translated into the design of a scalable patient-centered CHW intervention. IMPLICATIONS: The approach of using participatory action research to tightly mapping patient input into intervention design is rapid and systematic strategy for operationalizing patient involvement in innovation.

Lactate uptake by the injured human brain: evidence from an arteriovenous gradient and cerebral microdialysis study.

Lactate has been regarded as a waste product of anaerobic metabolism of glucose. Evidence also suggests, however, that the brain may use lactate as an alternative fuel. Our aim was to determine the extent of lactate uptake from the circulation into the brain after traumatic brain injury (TBI) and to compare it with levels of lactate in the brain extracellular fluid. We recruited 19 patients with diffuse TBI, monitored with cerebral microdialysis and jugular bulb catheters. Serial arteriovenous (AV) concentration differences of glucose and lactate were calculated from arterial and jugular blood samples, providing a measure of net uptake or export by the brain. Microdialysis was used to measure brain extracellular glucose and lactate. In 17/19 patients studied for 5 days post-injury, there were periods of net lactate uptake into the brain, most frequently on day 3 after injury. Brain microdialysate lactate had a median (interquartile range [IQR]) concentration of 2.5 (1.5-3.2) mmol/L during lactate uptake and 2.2 (1.7-3.0) mmol/L during lactate export. Lactate uptake into the brain occurred at a median (IQR) arterial lactate concentration of 1.6 (1.0-2.2) mmol/L. Lactate uptake was associated with significantly higher AV difference in glucose values with a median (IQR) of 0.4 (0.03-0.7) mmol/L during uptake and 0.1 (-0.2-0.3) mmol/L during lactate export (Mann-Whitney U p=0.003). Despite relatively high brain lactate compared with arterial lactate concentrations, the brain appears to up-regulate lactate transport into the brain after TBI. This may serve to satisfy greater demands for energy substrate from the brain after TBI.