Methylene blue dose-dependently induces cutaneous inflammation and heat hyperalgesia in a novel rat model.

Methylene blue (MB) has been shown to reduce mortality and morbidity in vasoplegic patients after cardiac surgery. Though MB is considered to be safe, extravasation of MB leading to cutaneous toxicity has been reported. In this study, we sought to characterize MB-induced cutaneous toxicity and investigate the underlying mechanisms. To induce MB-induced cutaneous toxicity, we injected 64 adult male Sprague-Dawley rates with 200 µL saline (vehicle) or 1%, 0.1%, or 0.01% MB in the plantar hind paws. Paw swelling, skin histologic changes, and heat and mechanical hyperalgesia were measured. Injection of 1%, but not 0.1% or 0.01% MB, produced significant paw swelling compared to saline. Injection of 1% MB produced heat hyperalgesia but not mechanical hyperalgesia. Pain behaviors were unchanged following injections of 0.1% or 0.01% MB. Global transcriptomic analysis by RNAseq identified 117 differentially expressed genes (111 upregulated, 6 downregulated). Ingenuity Pathway Analysis showed an increased quantity of leukocytes, increased lipids, and decreased apoptosis of myeloid cells and phagocytes with activation of IL-1ß and Fos as the two major regulatory hubs. qPCR showed a 16-fold increase in IL-6 mRNA. Thus, using a novel rat model of MB-induced cutaneous toxicity, we show that infiltration of 1% MB into cutaneous tissue causes a dose-dependent pro-inflammatory response, highlighting potential roles of IL-6, IL-1ß, and Fos. Thus, anesthesiologists should administer dilute MB intravenously through peripheral venous catheters. Higher concentrations of MB (1%) should be administered through a central venous catheter to minimize the risk of cutaneous toxicity.

When to Consider Coronary Revascularization for Stable Coronary Artery Disease.

Revascularization is an effective adjunct to medical therapy for some patients with chronic coronary disease. Despite numerous randomized trials, there remains significant uncertainty regarding if and how to revascularize many patients. Coronary artery bypass grafting is a class I indication for patients with significant left main stenosis or multivessel disease with ejection fraction ≤ 35%. For other patients, clinicians must carefully consider the potential benefits of symptom improvement and reduction of future myocardial infarction or CV death against the risk and cost of revascularization. Although guidelines provide a framework for these decisions, each individual patient will have distinct coronary anatomy, clinical factors, and preferences.

A Rare Complication of Maxillomandibular Advancement Surgery: Postoperative Plate Bending Following Emergency Intubation.

Maxillomandibular advancement surgery is a recognized technique for the management of obstructive sleep apnea. Complications for this surgery are not well-documented in the literature. The authors report an unusual case of mandibular plate bending following unplanned postoperative airway management using an oral endotracheal tube in a 65-year-old male. The bent mandibular plate and airway concern required a return to the theater for the replacement of bent plates and tracheostomy placement. This case documents the importance of multidisciplinary team planning for airway-related surgery as well as the need for multidisciplinary team management of postoperative airway management following orthognathic surgery.

Nurse and Social Worker Palliative Telecare Team and Quality of Life in Patients With COPD, Heart Failure, or Interstitial Lung Disease: The ADAPT Randomized Clinical Trial.

Importance: Many patients with chronic obstructive pulmonary disease (COPD), heart failure (HF), and interstitial lung disease (ILD) endure poor quality of life despite conventional therapy. Palliative care approaches may benefit this population prior to end of life. Objective: Determine the effect of a nurse and social worker palliative telecare team on quality of life in outpatients with COPD, HF, or ILD compared with usual care. Design, Setting, and Participants: Single-blind, 2-group, multisite randomized clinical trial with accrual between October 27, 2016, and April 2, 2020, in 2 Veterans Administration health care systems (Colorado and Washington), and including community-based outpatient clinics. Outpatients with COPD, HF, or ILD at high risk of hospitalization or death who reported poor quality of life participated. Intervention: The intervention involved 6 phone calls with a nurse to help with symptom management and 6 phone calls with a social worker to provide psychosocial care. The nurse and social worker met weekly with a study primary care and palliative care physician and as needed, a pulmonologist, and cardiologist. Usual care included an educational handout developed for the study that outlined self-care for COPD, ILD, or HF. Patients in both groups received care at the discretion of their clinicians, which could include care from nurses and social workers, and specialists in cardiology, pulmonology, palliative care, and mental health. Main Outcomes and Measures: The primary outcome was difference in change in quality of life from baseline to 6 months between the intervention and usual care groups (FACT-G score range, 0-100, with higher scores indicating better quality of life, clinically meaningful change ≥4 points). Secondary quality-of-life outcomes at 6 months included disease-specific health status (Clinical COPD Questionnaire; Kansas City Cardiomyopathy Questionnaire-12), depression (Patient Health Questionnaire-8) and anxiety (Generalized Anxiety Disorder-7) symptoms. Results: Among 306 randomized patients (mean [SD] age, 68.9 [7.7] years; 276 male [90.2%], 30 female [9.8%]; 245 White [80.1%]), 177 (57.8%) had COPD, 67 (21.9%) HF, 49 (16%) both COPD and HF, and 13 (4.2%) ILD. Baseline FACT-G scores were similar (intervention, 52.9; usual care, 52.7). FACT-G completion was 76% (intervention, 117 of 154; usual care, 116 of 152) at 6 months for both groups. Mean (SD) length of intervention was 115.1 (33.4) days and included a mean of 10.4 (3.3) intervention calls per patient. In the intervention group, 112 of 154 (73%) patients received the intervention as randomized. At 6 months, mean FACT-G score improved 6.0 points in the intervention group and 1.4 points in the usual care group (difference, 4.6 points [95% CI, 1.8-7.4]; P = .001; standardized mean difference, 0.41). The intervention also improved COPD health status (standardized mean difference, 0.44; P = .04), HF health status (standardized mean difference, 0.41; P = .01), depression (standardized mean difference, -0.50; P < .001), and anxiety (standardized mean difference, -0.51; P < .001) at 6 months. Conclusions and Relevance: For adults with COPD, HF, or ILD who were at high risk of death and had poor quality of life, a nurse and social worker palliative telecare team produced clinically meaningful improvements in quality of life at 6 months compared with usual care. Trial Registration: ClinicalTrials.gov Identifier: NCT02713347.

Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Fibroblast growth factor 21 (FGF21) regulates metabolism and protects cells against stress. Efruxifermin is a bivalent Fc-FGF21 analogue that replicates FGF21 agonism of fibroblast growth factor receptor 1c, 2c, or 3c. The aim of this phase 2b study was to assess its efficacy and safety in patients with non-alcoholic steatohepatitis (NASH) and moderate (F2) or severe (F3) fibrosis. METHODS: HARMONY is a multicentre, randomised, double-blind, placebo-controlled, 96-week, phase 2b trial that was initiated at 41 clinics in the USA. Adults with biopsy-confirmed NASH, defined by a non-alcoholic fatty liver disease activity score (NAS) of 4 or higher and scores of 1 or higher in each of steatosis, ballooning, and lobular inflammation, with histological stage F2 or F3 fibrosis, were randomly assigned (1:1:1), via an interactive response system, to receive placebo or efruxifermin (28 mg or 50 mg), subcutaneously once weekly. Patients, investigators, pathologists, site staff, and the sponsor were masked to group assignments during the study. The primary endpoint was the proportion of patients with improvement in fibrosis of at least 1 stage and no worsening of NASH, based on analyses of baseline and week 24 biopsies (liver biopsy analysis set [LBAS]). A sensitivity analysis evaluated the endpoint in the full analysis set (FAS), for which patients with missing biopsies were considered non-responders. This trial is registered with ClinicalTrials.gov, NCT04767529, and is ongoing. FINDINGS: Between March 22, 2021, and Feb 7, 2022, 747 patients were assessed for eligibility and 128 patients (mean age 54·7 years [SD 10·4]; 79 [62%] female and 49 male [38%]; 118 [92%] white; and 56 [41%] Hispanic or Latino) were enrolled and randomly assigned to receive placebo (n=43), efruxifermin 28 mg (n=42; two randomised patients were not dosed because of an administrative error), or efruxifermin 50 mg (n=43). In the LBAS (n=113), eight (20%) of 41 patients in the placebo group had an improvement in fibrosis of at least 1 stage and no worsening of NASH by week 24 versus 15 (39%) of 38 patients in the efruxifermin 28 mg group (risk ratio [RR] 2·3 [95% CI 1·1-4·8]; p=0·025) and 14 (41%) of 34 patients in the efruxifermin 50 mg group (2·2 [1·0-5·0]; p=0·036). Based on the FAS (n=128), eight (19%) of 43 patients in the placebo group met this endpoint versus 15 (36%) of 42 in the efruxifermin 28 mg group (RR 2·2 [95% CI 1·0-4·8]; p=0·033) and 14 (33%) of 43 in the efruxifermin 50 mg group (1·9 [0·8-4·3]; p=0·123). The most frequent efruxifermin-related adverse events were diarrhoea (16 [40%] of 40 patients in the efruxifermin 28 mg group and 17 [40%] of 43 patients in efruxifermin 50 mg group vs eight [19%] of 43 patients in the placebo group; all events except one were grade 1-2) and nausea (11 [28%] patients in the efruxifermin 28 mg group and 18 [42%] patients in the efruxifermin 50 mg group vs ten [23%] patients in the placebo group; all grade 1-2). Five patients (two in the 28 mg group and three in the 50 mg group) discontinued due to adverse events. Serious adverse events occurred in four patients in the 50 mg group; one was defined as drug related (ulcerative esophagitis in a participant with a history of gastro-oesophageal reflux disease). No deaths occurred. INTERPRETATION: Efruxifermin improved liver fibrosis and resolved NASH over 24 weeks in patients with F2 or F3 fibrosis, with acceptable tolerability, supporting further assessment in phase 3 trials. FUNDING: Akero Therapeutics.

Impact of exercise on pulmonary artery pressure in patients with heart failure using an ambulatory pulmonary artery pressure monitor.

Background: In this multicenter prospective study, we explored the relationship between pulmonary artery pressure (PAP) at rest and in response to a 6-min walk test (6MWT) in ambulatory patients with heart failure (HF) with an implantable PAP sensor (CardioMEMS, Abbott). Methods: Between 5/2019 and 2/2021, HF patients with a CardioMEMS sensor were recruited from seven sites. PAP was recorded in the supine and seated position at rest and in the seated position immediately post-exercise. Results: In our cohort of 66 patients, mean age was 70 ± 12 years, 67% male, left ventricular ejection fraction (LVEF) < 50% in 53%, mean 6MWT distance was 277 ± 95 meters. Resting seated PAPs were 31 ± 15 mmHg (systolic), 13 ± 8 mmHg (diastolic), and 20 ± 11 mmHg (mean). The pressures were lower in the seated rather than the supine position. After 6MWT, the pressures increased to PAP systolic 37 ± 19 mmHg (p < 0.0001), diastolic 15 ± 10 mmHg (p = 0.006), and mean 24 ± 13 mmHg (p < 0.0001). Patients with elevated PAP diastolic at rest (>15 mmHg) demonstrated a greater increase in post-exercise PAP. Conclusion: The measurement of PAP with CardioMEMS is feasible immediately post-exercise. Despite being well-managed, patients had severely limited functional capacity. We observed a significant increase in PAP with ambulation which was greater in patients with higher baseline pressures.

A randomized, double-blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis.

Background & Aims: Efruxifermin has shown clinical efficacy in patients with non-alcoholic steatohepatitis (NASH) and F1-F3 fibrosis. The primary objective of the BALANCED Cohort C was to assess the safety and tolerability of efruxifermin in patients with compensated NASH cirrhosis. Methods: Patients with NASH and stage 4 fibrosis (n = 30) were randomized 2:1 to receive efruxifermin 50 mg (n = 20) or placebo (n = 10) once-weekly for 16 weeks. The primary endpoint was safety and tolerability of efruxifermin. Secondary and exploratory endpoints included evaluation of non-invasive markers of liver injury and fibrosis, glucose and lipid metabolism, and changes in histology in a subset of patients who consented to end-of-study liver biopsy. Results: Efruxifermin was safe and well-tolerated; most adverse events (AEs) were grade 1 (n = 7, 23.3%) or grade 2 (n = 19, 63.3%). The most frequent AEs were gastrointestinal, including transient, mild to moderate diarrhea, and/or nausea. Significant improvements were noted in key markers of liver injury (alanine aminotransferase) and glucose and lipid metabolism. Sixteen-week treatment with efruxifermin was associated with significant reductions in non-invasive markers of fibrosis including Pro-C3 (least squares mean change from baseline [LSMCFB] -9 µg/L efruxifermin vs. -3.4 µg/L placebo; p = 0.0130) and ELF score (-0.4 efruxifermin vs. +0.4 placebo; p = 0.0036), with a trend towards reduced liver stiffness (LSMCFB -5.7 kPa efruxifermin vs. -1.1 kPa placebo; n.s.). Of 12 efruxifermin-treated patients with liver biopsy after 16 weeks, 4 (33%) achieved fibrosis improvement of at least one stage without worsening of NASH, while an additional 3 (25%) achieved resolution of NASH, compared to 0 of 5 placebo-treated patients. Conclusions: Efruxifermin appeared safe and well-tolerated with encouraging improvements in markers of liver injury, fibrosis, and glucose and lipid metabolism following 16 weeks of treatment, warranting confirmation in larger and longer term studies. Lay summary: Cirrhosis resulting from non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease, represents a major unmet medical need. Currently there are no approved drugs for the treatment of NASH. This proof-of-concept randomized, double-blind clinical trial demonstrated the potential therapeutic benefit of efruxifermin treatment compared to placebo in patients with cirrhosis due to NASH. Clinical Trial Number: NCT03976401.

Biventricular Repair in Interrupted Aortic Arch and Ventricular Septal Defect With a Small Left Ventricular Outflow Tract.

BACKGROUND: In patients with interrupted aortic arch and ventricular septal defect (VSD) with a small left ventricular outflow tract (LVOT), either aortopulmonary amalgamation or a Ross-Konno type procedure can be performed to create stable systemic outflow. We sought to analyze factors associated with these different surgical approaches. METHODS: We retrospectively identified patients who underwent surgical repair for interrupted aortic arch/VSD at our institution between 1998 and 2017. Of these, 43 patients had a small, native LVOT that was unsuitable for systemic outflow. Patient data were retrospectively collected for this cohort and analyzed. RESULTS: Aortopulmonary amalgamation was performed at 7 days (interquartile range [IQR], 5-10) in 30 patients (group I). Within group I a primary Yasui repair with ventricular septation was performed in 3 patients and a Norwood-type repair in the other 27. Of these 27, 19 underwent subsequent biventricular conversion at 9 months (IQR, 7-11). In contrast 13 patients underwent a Ross procedure at 12 days (IQR, 6-27) (group II). Compared with group I, group II patients had a smaller VSD (3.5 vs 5.1 mm, P < .001) that was more often remote from the semilunar valves (38% vs 13%, P = .02). Operative mortality occurred in 1 group I patient (4%) at the time of biventricular conversion and 2 group II patients (15%) during the Ross procedure. After a 5.2-year (IQR, 3.2-7.4) follow-up there were 2 additional mortalities in each group, all unrelated to cardiac disease. CONCLUSIONS: When native LVOT in interrupted aortic arch/VSD is unsuitable for systemic outflow, size and location of the VSD can be used to tailor the surgical approach to establish biventricular circulation with favorable intermediate-term outcomes.

Progression in Fontan conduit stenosis and hemodynamic impact during childhood and adolescence.

OBJECTIVE: To characterize changes in Fontan conduit size over time and determine if cross-sectional area (CSA) affects cardiac output, pulmonary artery growth, and exercise capacity. METHODS: We conducted a retrospective cross-sectional study of patients with Fontan physiology who underwent cardiac magnetic resonance imaging or cardiac catheterization between January 2013 and October 2019. We collected Fontan and pulmonary artery measurements, hemodynamic data, and cardiopulmonary exercise test data. We identified 158 patients with an extracardiac Fontan. We measured minimum and mean Fontan conduit CSA and assessed whether these correlated with Nakata index, cardiac index, or exercise capacity. RESULTS: Minimum Fontan CSA decreased by a median of 33% (24%, 40%) during a mean follow-up of 9.6 years. Median percentage decrease in Fontan CSA did not differ among 16-, 18-, and 20-mm conduits (P = .29). There was a significant decrease in the minimum Fontan CSA (33% [25%, 41%]) starting less than 1-year post-Fontan. Median Nakata index was 177.6 mm2/m2 (149.1, 210.8) and was not associated with Fontan CSA/BSA (ρ = 0.09, P = .29). Fontan CSA/BSA was not associated with cardiac index (ρ = -0.003, P = .97). A larger Fontan CSA/BSA had a modest correlation with % predicted oxygen consumption (ρ = 0.31, P = .013). CONCLUSIONS: Fontan conduit CSA decreases as early as 6 months post-Fontan. The minimum Fontan CSA/BSA was not associated with cardiac index or pulmonary artery size but did correlate with % predicted peak oxygen consumption.

Pulmonary passport: a service evaluation study of a standardised web-based procedure logbook to aid specialist respiratory training and appraisal.

INTRODUCTION: The pulmonary passport (PP) is a secure web-based procedural logbook for specialist respiratory trainees with enhanced functionality that includes automated analysis to provide key performance metrics and in-platform interactions with supervisors. METHODS: This service evaluation study used preimplementation and postimplementation online surveys in both trainees and supervisors along with analysis of recorded data within the PP to evaluate the impact of this service on data capture, training, appraisal and quality assurance. RESULTS: From August 2017 to August 2019, 69/73 (95%) specialist respiratory trainees eligible to use the PP across two UK health education deaneries registered with the system and logged 7352 procedures. 3105 thoracic ultrasound procedures identified 2145 pleural effusions and resulted in 1253 pleural procedures of which 96% were successful. 4% of ultrasounds required referral to a more expert sonographer. Iatrogenic bleeding and pneumothorax both occurred in ≤1% of all pleural procedures. 1909 basic diagnostic bronchoscopies were recorded including 1236 bronchial washes, 328 brushes and 221 endobronchial biopsies where definite tumour was identified (biopsy sensitivity 74%). Preimplementation and postimplementation survey data confirmed the PP had increased the consistency of logging procedures by trainees, the depth of data captured, the review of procedural performance metrics in appraisal and the frequency of formal supervisor feedback. DISCUSSION: In this regional project, the implementation of a web-based procedural logbook has been feasible with excellent uptake and has enhanced procedural recording, supervision and appraisal. Furthermore, it provides unprecedented quality assurance at an individual trainee, trust and deanery level and has a number of potential wider applications in the future.

Duration of Cellular and Humoral Responses after Quadrivalent Human Papillomavirus Vaccination in Healthy Female Adults with or without Prior Type 16 and/or 18 Exposure.

Human papillomavirus virus (HPV) vaccines aim to provide durable protection and are ideal to study the association of cellular with humoral responses. We assessed the duration and characteristics of immune responses provided by the quadrivalent HPV (4vHPV) vaccine in healthy female adults with or without prior exposure with type 16 and 18 HPV. In a prospective cohort, vaccine naïve females received three doses of 4vHPV vaccine and were followed for two years to assess cellular (intracellular cytokine staining, proliferation and B cell ELISpot assays) and humoral (multiplex L1/L2 viral-like particles (VLP) and M4 ELISAs) responses. Frequencies of vaccine-specific CD4+ T cells correlated with antibody responses. Higher HPV antibody titers were found at all time points in participants previously exposed to HPV, except for anti-HPV-18 at Day 187 (one week post the third vaccination). Retrospective cohorts enrolled females who had previously received two or three 4vHPV doses and tested antibody titers by M4 ELISA and pseudovirion neutralization assay along with memory B cells (MBCs). Almost all women enrolled in a retrospective cohort with two prior doses and all women enrolled in a retrospective cohort with three prior doses had sustained antibody and memory responses. Our findings indicate that HPV vaccination induces a long-lasting, robust cellular and humoral immune responses.

6q25.1 (TAB2) microdeletion is a risk factor for hypoplastic left heart: a case report that expands the phenotype.

INTRODUCTION: Hypoplastic left heart syndrome (HLHS) is a rare but devastating congenital heart defect (CHD) accounting for 25% of all infant deaths due to a CHD. The etiology of HLHS remains elusive, but there is increasing evidence to support a genetic cause for HLHS; in particular, this syndrome is associated with abnormalities in genes involved in cardiac development. Consistent with the involvement of heritable genes in structural heart abnormalities, family members of HLHS patients have a higher incidence of both left- and right-sided valve abnormalities, including bicuspid aortic valve (BAV). CASE PRESENTATION: We previously described (Am J Med Genet A 173:1848-1857, 2017) a 4-generation family with a 6q25.1 microdeletion encompassing TAB2, a gene known to play an important role in outflow tract and cardiac valve formation during embryonic development. Affected adult family members have short stature, dysmorphic facial features, and multiple valve dysplasia, including BAV. This follow-up report includes previously unpublished details of the cardiac phenotype of affected family members. It also describes a baby recently born into this family who was diagnosed prenatally with short long bones, intrauterine growth restriction (IUGR), and HLHS. He was the second family member to have HLHS; the first died several decades ago. Postnatal genetic testing confirmed the baby had inherited the familial TAB2 deletion. CONCLUSIONS: Our findings suggest TAB2 haploinsufficiency is a risk factor for HLHS and expands the phenotypic spectrum of this microdeletion syndrome. Chromosomal single nucleotide polymorphism (SNP) microarray analysis and molecular testing for a TAB2 loss of function variant should be considered for individuals with HLHS, particularly in those with additional non-cardiac findings such as IUGR, short stature, and/or dysmorphic facial features.

Lithium and GADL1 regulate glycogen synthase kinase-3 activity to modulate KCTD12 expression.

Potassium channel tetramerization domain containing 12 (KCTD12), the auxiliary GABAB receptor subunit, is identified as a susceptibility gene for bipolar I (BPI) disorder in the Han Chinese population. Moreover, the single-nucleotide polymorphism (SNP) rs17026688 in glutamate decarboxylase-like protein 1 (GADL1) is shown to be associated with lithium response in Han Chinese BPI patients. In this study, we demonstrated for the first time the relationship among lithium, GADL1, and KCTD12. In circulating CD11b+ macrophage cells, BPI patients showed a significantly higher percentage of KCTD12 expression than healthy controls. Among BPI patients, carriers of the 'T' allele (i.e., CT or TT) at site rs17026688 were found to secrete lower amounts of GADL1 but higher amounts of GABA b receptor 2 (GABBR2) in the plasma. In human SH-SY5Y neuroblastoma cells, lithium treatment increased the percentage of KCTD12 expression. Through inhibition of glycogen synthase kinase-3 (GSK-3), lithium induced cyclic AMP-response element binding protein (CREB)-mediated KCTD12 promoter activation. On the other hand, GADL1 overexpression enhanced GSK-3 activation and inhibited KCTD12 expression. We found that lithium induced, whereas GADL1 inhibited, KCTD12 expression. These findings suggested that KCTD12 may be an important gene with respect to neuron excitability and lithium response in BPI patients. Therefore, targeting GSK-3 activity and/or KCTD12 expression may constitute a possible therapeutic strategy for treating patients with BPI disorder.

Advancing Symptom Alleviation with Palliative Treatment (ADAPT) trial to improve quality of life: a study protocol for a randomized clinical trial.

BACKGROUND: People living with chronic heart failure (CHF), chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD) suffer impaired quality of life due to burdensome symptoms and depression. The Advancing Symptom Alleviation with Palliative Treatment (ADAPT) trial aims to determine the effect of a multidisciplinary, team-based intervention on quality of life in people with these common diseases. METHODS/DESIGN: The ADAPT trial is a two-site, patient-level randomized clinical trial that examines the effectiveness of the ADAPT intervention compared to usual care on patient-reported quality of life at 6 months in veterans with CHF, COPD or ILD with poor quality of life and increased risk for hospitalization or death. The ADAPT intervention involves a multidisciplinary team-a registered nurse, social worker, palliative care specialist, and primary care provider (with access to a pulmonologist and cardiologist)-who meet weekly to make recommendations and write orders for consideration by participants' individual primary care providers. The nurse and social worker interact with participants over six visits to identify and manage a primary bothersome symptom and complete a structured psychosocial intervention and advance care planning. The primary outcome is change in patient-reported quality of life at 6 months as measured by the Functional Assessment of Chronic Illness Therapy-General questionnaire. Secondary outcomes at 6 months include change in symptom distress, depression, anxiety, disease-specific quality of life hospitalizations, and advance care planning communication and documentation. Intervention implementation will be assessed using a mixed-methods approach including a qualitative assessment of participants' and intervention personnel experiences and a quantitative assessment of care delivery, resources, and cost. DISCUSSION: The ADAPT trial studies an innovative intervention designed to improve quality of life for veterans with common, burdensome illnesses by targeting key underlying factors-symptoms and depression-that impair quality of life but persist despite disease-specific therapies. Leveraging the skills of affiliate health providers with physician supervision will extend the reach of palliative care and improve quality of life for those with advanced disease within routine outpatient care. The hybrid effectiveness/implementation design of the ADAPT trial will shorten the time to broader dissemination if effective and create avenues for future research. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02713347 . Registered March 19, 2016.

The role of vasodilator-stimulated phosphoprotein (VASP) in the control of hepatic gluconeogenic gene expression.

During periods in which glucose absorption from the gastrointestinal (GI) tract is insufficient to meet body requirements, hepatic gluconeogenesis plays a key role to maintain normal blood glucose levels. The current studies investigated the role in this process played by vasodilatory-associated phosphoprotein (VASP), a protein that is phosphorylated in hepatocytes by cAMP/protein kinase A (PKA), a key mediator of the action of glucagon. We report that following stimulation of hepatocytes with 8Br-cAMP, phosphorylation of VASP preceded induction of genes encoding key gluconeogenic enzymes, glucose-6-phosphatase (G6p) and phosphoenolpyruvate carboxykinase (Pck1), and that VASP overexpression enhanced this gene induction. Conversely, hepatocytes from mice lacking VASP (Vasp-/-) displayed blunted induction of gluconeogenic enzymes in response to cAMP, and Vasp-/- mice exhibited both greater fasting hypoglycemia and blunted hepatic gluconeogenic enzyme gene expression in response to fasting in vivo. These effects of VASP deficiency were associated with reduced phosphorylation of both CREB (a key transcription factor for gluconeogenesis that lies downstream of PKA) and histone deacetylase 4 (HDAC4), a combination of effects that inhibit transcription of gluconeogenic genes. These data support a model in which VASP functions as a molecular bridge linking the two key signal transduction pathways governing hepatic gluconeogenic gene expression.

Methamphetamine-Induced Tachydysrhythmia in an Adolescent in Diabetic Ketoacidosis.

BACKGROUND: Diabetic ketoacidosis (DKA) is a common complication affecting patients with type 1 diabetes, and DKA is associated with dehydration and electrolyte abnormalities. Supraventricular tachycardia (SVT), although a common tachydysrhythmia in the pediatric population, remains a rare entity in patients presenting with DKA. CASE REPORT: We describe a case of first-time SVT in an adolescent patient with DKA and recent methamphetamine abuse, with both factors likely predisposing him to develop a tachydysrhythmia. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: SVT can be present in a patient who has concomitant recent stimulant intake and DKA. A trial of abortive therapy, such as adenosine, should be considered upon diagnosis.

Effects of GADL1 overexpression on cell migration and the associated morphological changes.

Lithium has been used for maintenance treatment of bipolar disorder, but drug response varies among patients. Single-nucleotide polymorphisms in glutamate decarboxylase-like protein 1 (GADL1) are found to be associated with lithium response in Han Chinese bipolar patients. In this study, we assessed GADL1 function using a neuroblastoma cell line that stably overexpressed GADL1. Genes encoding factors involved in cell migration, such as FN1, ITGA2, ITGAV and CCL2, were downregulated in GADL1-overexpressing cells. GADL1 overexpression indeed suppressed cell migration. Cell migration speed and perimeter length exhibited similar trends, both of which were decreased under GADL1 overexpression or lithium treatment but increased upon stimulation with CCL2. Secreted GADL1 or its enzyme product, taurine, in the conditioned medium might exert only mild effects on the observed changes. Compared with SH-SY5Y cells, GADL1-overexpressing cells were much more sensitive to CCL2 treatment but less sensitive to lithium, indicating that the level of GADL1 expression can affect cell sensitivity to lithium or  CCL2 treatment. Together, these results suggest that cell migration and related morphological changes might provide good indicators of the sensitivity toward lithium treatment, and the GADL1 stable overexpression cell line might serve as a useful platform to screen novel therapeutics for bipolar disorder.

Endoscopically Assisted Middle Cranial Fossa Reconstruction Following Traumatic Intracranial Intrusion of the Mandibular Condyle.

Traumatic intracranial intrusions of the mandibular condyle are a rare injury pattern that carries significant morbid outcomes due to potential for neurological, otological, temporomandibular joint damage, or joint ankylosis. Treatment modalities involve either closed reduction, open approaches via transcranial or subtemporal approaches, or delayed total joint replacement. This paper presents a clinical report of a traumatic intracranial intrusion of the mandibular condyle treated with an endoscopically assisted preauricular approach to reconstruct the middle cranial fossa and temporomandibular articular disc. Endoscopically assisted techniques allow for minimally invasive and less morbid surgical interventions to this pathology, with greater precision than closed reduction techniques.

Development and validation of an imaging and clinical scoring system to predict early mortality in spontaneous ruptured hepatocellular carcinoma treated with transarterial embolization.

PURPOSE: To develop and validate a scoring system using a combination of imaging and clinical parameters to predict 30-day mortality in ruptured HCC (rHCC) patients after transarterial embolization (TAE). METHODS: 98 consecutive patients with rHCC who underwent abdominal CT and subsequent TAE between January 2007 and December 2016 were retrospectively reviewed. The CT scans were reviewed by two radiologists blinded to the patient outcome. Clinical parameters including serum bilirubin, albumin, INR, creatinine, and hemoglobin were recorded. Independent risk factors for 30-day mortality after TAE were identified using multivariate binary logistic regression, for development of a scoring system. The scoring system was then validated in 20 patients between January 2017 and May 2018. RESULTS: In the development cohort, bilobar tumor distribution (OR = 29.6), clinical parameters of bilirubin > 2.5 mg/dL (OR = 5.9), and albumin < 30 g/L (OR = 4.1) were independent predictors for 30-day mortality. A 6-point score was derived and yielded area-under-the-receiver-operating-characteristic-curve (AUC) of 0.904. A score ≥ 4 resulted in sensitivity of 80.5% and specificity of 91.2% for 30-day mortality. In the validation cohort, AUC for 30-day mortality was 0.939. A score ≥ 4 resulted in sensitivity of 81.2% and specificity of 88.9%. In both development and validation cohorts, the proposed scoring system was better than biochemical components of Child-Pugh score and serum bilirubin to predict 30-day mortality. CONCLUSION: Imaging and clinical parameters can be combined into a scoring system to accurately predict 30-day mortality after TAE in rHCC patients. The score may help identify and counsel high-risk patients.