Factors Associated With Successful Enrollment in a Community Paramedicine Program for Heart Failure.

Introduction Participation in community paramedicine (CP) programs, sometimes referred to as Mobile Integrated Healthcare (MIH), may improve patient-centered outcomes and reduce hospital readmissions. The objective of this study was to correlate patient and system-specific factors with successful enrollment in a CP program for heart failure.  Methods We conducted a retrospective review of patients enrolled in a CP program after hospitalization for a heart failure-related diagnosis. All patients greater than 18 years of age referred to the CP program with a heart-failure-related diagnosis were included. Factors including age, sex, hospital length of stay, enrollment method, concurrent use of transitional care services, care team, and service line referral were collected. The primary outcome was successful enrollment which led to an initial home visit. Chi-square and t-tests were performed to determine if the outcome differed between cohorts.  Results A total of 908 patients met the inclusion criteria, and 677 (74.7%) received home visits. Increased participation was noted in patients enrolled in person (81.1% vs. 66%, p<0.01) and those also receiving transitional care services (78.9% vs. 62.5%, p<0.01).  Conclusion We conclude that efforts should be made to contact patients in person, prior to hospital discharge, who are eligible for CP services.

Autophagy is required for self-incompatible pollen rejection in two transgenic Arabidopsis thaliana accessions.

Successful reproduction in the Brassicaceae is mediated by a complex series of interactions between the pollen and the pistil, and some species have an additional layer of regulation with the self-incompatibility trait. While the initial activation of the self-incompatibility pathway by the pollen S-locus protein 11/S locus cysteine-rich protein and the stigma S Receptor Kinase is well characterized, the downstream mechanisms causing self-pollen rejection are still not fully understood. In previous studies, we detected the presence of autophagic bodies with self-incompatible (SI) pollinations in Arabidopsis lyrata and transgenic Arabidopsis thaliana lines, but whether autophagy was essential for self-pollen rejection was unknown. Here, we investigated the requirement of autophagy in this response by crossing mutations in the essential AUTOPHAGY7 (ATG7) and ATG5 genes into two different transgenic SI A. thaliana lines in the Col-0 and C24 accessions. By using these previously characterized transgenic lines that express A. lyrata and Arabidopsis halleri self-incompatibility genes, we demonstrated that disrupting autophagy weakened their SI responses in the stigma. When the atg7 or atg5 mutations were present, an increased number of SI pollen was found to hydrate and form pollen tubes that successfully fertilized the SI pistils. Additionally, we confirmed the presence of GFP-ATG8a-labeled autophagosomes in the stigmatic papillae following SI pollinations. Together, these findings support the requirement of autophagy in the self-incompatibility response and add to the growing understanding of the intracellular mechanisms employed in the transgenic A. thaliana stigmas to reject self-pollen.

The Effects of Hyperbaric Oxygen Therapy in Patients with Central Retinal Artery Occlusion: A Retrospective Study, Systematic Review, and Meta-analysis.

PURPOSE: Central retinal artery occlusion (CRAO) is a vision-threatening condition with a potentially poor visual prognosis. Many different treatment modalities are suggested but controversy remains regarding effectiveness of these treatments. The purpose of this study is to perform a systematic review and meta-analysis in addition to analyzing retrospective data at our own tertiary care center regarding effectiveness of hyperbaric oxygen therapy (HBOT) in treatment of CRAO. METHODS: The PubMed, Scopus, and the Cochrane Library are searched from the date of database inception to September 2021 to conduct a review based on the PRISMA (preferred reporting items for systematic review and meta-analysis), evaluating the role of HBOT in visual recovery of CRAO patients. In addition, a retrospective chart review of patients clinically diagnosed with CRAO at our university-based hospital (University of Texas Health, San Antonio, TX, USA) from year 2011 to 2021 was conducted. RESULTS: After a review of 376 articles, three articles met the inclusion criteria for meta-analysis, where a total of 207 patients received HBOT versus 89 patients that did not receive any form of oxygen therapy. Analysis of these results demonstrate that HBOT in CRAO patients does not enhance the final visual outcome (p = 0.83). Similar conclusion was also drawn from retrospective analysis of 48 patients (15 HBOT versus 33 controls) at our tertiary care center, where no visual benefit was observed in the HBOT group. CONCLUSIONS: HBOT does not appear to improve final visual outcome and concerns remain regarding adverse reactions such as barotrauma and generalized seizures. Large, randomized studies are required for further understanding of the role of HBOT in treatment of CRAO.

Elevated tyrosine results in the cytosolic retention of 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase in Arabidopsis thaliana.

The shikimate pathway plays a central role in the biosynthesis of aromatic amino acids and specialized metabolites in plants. The first enzyme, 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAHPS) serves as a key regulatory point for the pathway in various organisms. These enzymes are important in regulating the shikimate pathway in multiple microbial systems. The mechanism of regulation of DAHPS is poorly understood in plants, and the role of tyrosine (Tyr) with respect to the three DAHPS isozymes from Arabidopsis thaliana was investigated. In vitro enzymatic analyses established that Tyr does not function as an allosteric regulator for the A. thaliana DAHPS isozymes. In contrast, Arabidopsis T-DNA insertional mutants for the DAHPS1 locus, dahps1, are hypersensitive to elevated Tyr. Tyr hypersensitivity can be reversed with tryptophan and phenylalanine supplementation, indicating that Tyr is affecting the shikimate pathway flux in the dahps1 mutant. Tyr treatment of Arabidopsis seedlings showed reduced accumulation of overexpressed DAHPS2 in the chloroplast. Further, bimolecular fluorescence complementation studies revealed that DAHPS2 interacts with a 14-3-3 protein in the cytosol, and this interaction is enhanced with Tyr treatment. This interaction with 14-3-3 may retain DAHPS2 in the cytosol, which prevents its ability to function in the chloroplast with elevated Tyr.

Assessing End-of-Life Care across Settings in an Integrated Health Care Delivery System.

Objective: To systematically capture patient- and family-centered data to understand variability and opportunities in end-of-life care delivery across settings in an integrated health care delivery system. Background: Improving the quality of end-of-life care requires assessing patient and family experiences across settings where care occurs, but we found no existing instrument suitable for this purpose. Methods: We conducted a cross-sectional survey with 10,308 surviving respondents (usually next of kin) of decedents in five Kaiser Permanente operating regions. The survey included eight items from an existing validated survey and three original items. Results: The overall response rate was 26% (2631). Most respondents reported that they were knowledgeable about decedents' end-of-life care and preferences. Across regions, 80% of respondents reported overall end-of-life care as excellent or very good. The proportion of excellent and very good responses was 74-84% across regions for items assessing attributes of end-of-life care, with statistically significant differences (p < 0.05). The proportion of positive responses was 69-89%. Overall, end-of-life care was rated as excellent or very good for a greater proportion of patients who received palliative care, hospice care, or both (78-82%), compared to those who did not (69%, p < 0.05 for all). Discussion: Regions are using data to inform end-of-life care initiatives. Assessing patient and family experiences of end-of-life care across settings with a single survey was feasible and provided valuable information supporting quality improvement. The survey met our need for a general purpose survey on end-of-life care experience.

Efficacy and Outcomes of a Music-Based Emotion Regulation Mobile App in Distressed Young People: Randomized Controlled Trial.

BACKGROUND: Emotion dysregulation increases the risk of depression, anxiety, and substance use disorders. Music can help regulate emotions, and mobile phones provide constant access to it. The Music eScape mobile app teaches young people how to identify and manage emotions using music. OBJECTIVE: This study aimed to examine the effects of using Music eScape on emotion regulation, distress, and well-being at 1, 2, 3, and 6 months. Moderators of outcomes and user ratings of app quality were also examined. METHODS: A randomized controlled trial compared immediate versus 1-month delayed access to Music eScape in 169 young people (aged 16 to 25 years) with at least mild levels of mental distress (Kessler 10 score>17). RESULTS: No significant differences between immediate and delayed groups on emotion regulation, distress, or well-being were found at 1 month. Both groups achieved significant improvements in 5 of the 6 emotion regulation skills, mental distress, and well-being at 2, 3, and 6 months. Unhealthy music use moderated improvements on 3 emotion regulation skills. Users gave the app a high mean quality rating (mean 3.8 [SD 0.6]) out of 5. CONCLUSIONS: Music eScape has the potential to provide a highly accessible way of improving young people's emotion regulation skills, but further testing is required to determine its efficacy. Targeting unhealthy music use in distressed young people may improve their emotion regulation skills. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000051549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365974.

A novel conformal superficial high-dose-rate brachytherapy device for the treatment of nonmelanoma skin cancer and keloids.

PURPOSE: To develop a novel conformal superficial brachytherapy (CSBT) device as a treatment option for the patient-specific radiation therapy of conditions including superficial lesions, postsurgical positive margins, Dupuytren's contractures, keloid scars, and complex anatomic sites (eyelids, nose, ears, etc.). METHODS AND MATERIALS: A preliminary CSBT device prototype was designed, built, and tested using readily available radioactive seeds. Iodine-125 (125I) seeds were independently guided to the treatment surface to conform to the target. Treatment planning was performed via BrachyVision Planning System (BPS) and dose distributions measured with Gafchromic EBT3 film. Percent depth dose curves and profiles for Praseodymium-142 (142Pr), and Strontium-90/Yttrium-90 (90Sr-90Y) were also investigated as potential sources. Results achieved with 90Sr-90Y and electron external beam radiation therapy were compared and Monte Carlo N-Particle eXtended 2.6 simulations of 142Pr seeds were validated. RESULTS: BPS was able to predict clinical dose distributions for a multiple seeds matrix. Calculated and measured doses for the 125I seed matrix were 500 cGy and 473.5 cGy at 5 mm depth, and 171.0 cGy and 201.0 cGy at 10 mm depth, respectively. Results of 90Sr-90Y tests demonstrate a more conformal dose than electron EBRT (1.6 mm compared to 4.3 mm penumbra). Measured 142Pr doses were 500 cGy at surface and 17.4 cGy at 5 mm depth. CONCLUSIONS: The CSBT device provides a highly conformal dose to small surface areas. Commercially available BPS can be used for treatment planning, and Monte Carlo simulation can be used for plans using beta-emitting sources and complex anatomies. Various radionuclides may be used in this device to suit prescription depths and treatment areas.

Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane.

Chronic exposure to carcinogens represents the major risk factor for head and neck squamous cell carcinoma (HNSCC). Beverages derived from broccoli sprout extracts (BSE) that are rich in glucoraphanin and its bioactive metabolite sulforaphane promote detoxication of airborne pollutants in humans. Herein, we investigated the potential chemopreventive activity of sulforaphane using in vitro models of normal and malignant mucosal epithelial cells and an in vivo model of murine oral cancer resulting from the carcinogen 4-nitroquinoline-1-oxide (4NQO). Sulforaphane treatment of Het-1A, a normal mucosal epithelial cell line, and 4 HNSCC cell lines led to dose- and time-dependent induction of NRF2 and the NRF2 target genes NQO1 and GCLC, known mediators of carcinogen detoxication. Sulforaphane also promoted NRF2-independent dephosphorylation/inactivation of pSTAT3, a key oncogenic factor in HNSCC. Compared with vehicle, sulforaphane significantly reduced the incidence and size of 4NQO-induced tongue tumors in mice. A pilot clinical trial in 10 healthy volunteers evaluated the bioavailability and pharmacodynamic activity of three different BSE regimens, based upon urinary sulforaphane metabolites and NQO1 transcripts in buccal scrapings, respectively. Ingestion of sulforaphane-rich BSE demonstrated the greatest, most consistent bioavailability. Mucosal bioactivity, defined as 2-fold or greater upregulation of NQO1 mRNA, was observed in 6 of 9 evaluable participants ingesting glucoraphanin-rich BSE; 3 of 6 ingesting sulforaphane-rich BSE; and 3 of 9 after topical-only exposure to sulforaphane-rich BSE. Together, our findings demonstrate preclinical chemopreventive activity of sulforaphane against carcinogen-induced oral cancer, and support further mechanistic and clinical investigation of sulforaphane as a chemopreventive agent against tobacco-related HNSCC. Cancer Prev Res; 9(7); 547-57. ©2016 AACR.

2,3-Diphosphoglycerate Concentrations in Autologous Salvaged Versus Stored Red Blood Cells and in Surgical Patients After Transfusion.

BACKGROUND: Stored red blood cells (RBCs) are deficient in 2,3-diphosphoglycerate (2,3-DPG), but it is unclear how autologous salvaged blood (ASB) compares with stored blood and how rapidly 2,3-DPG levels return to normal after transfusion. Therefore, we compared levels of 2,3-DPG in stored versus ASB RBCs and in patients' blood after transfusion. METHODS: Twenty-four patients undergoing multilevel spine fusion surgery were enrolled. We measured 2,3-DPG and the oxyhemoglobin dissociation curve (P50) in samples taken from the ASB and stored blood bags before transfusion and in blood samples drawn from patients before and after transfusion. RESULTS: The mean storage duration for stored RBCs was 24 ± 8 days. Compared with fresh RBCs, stored RBCs had decreased 2,3-DPG levels (by approximately 90%; P < 0.0001) and a decreased P50 (by approximately 30%; P < 0.0001). However, ASB RBCs did not exhibit these changes. The mean 2,3-DPG concentration decreased by approximately 20% (P < 0.05) in postoperative blood sampled from patients who received 1 to 3 stored RBC units and by approximately 30% (P < 0.01) in those who received ≥4 stored RBC units. 2,3-DPG was unchanged in patients who received no stored blood or ASB alone. After surgery, 2,3-DPG levels recovered gradually over 3 postoperative days in patients who received stored RBCs. CONCLUSIONS: Stored RBCs, but not ASB RBCs, have decreased levels of 2,3-DPG and a left-shift in the oxyhemoglobin dissociation curve. Postoperatively, 2,3-DPG levels remain below preoperative baseline levels for up to 3 postoperative days in patients who receive stored RBCs but are unchanged in those who receive only ASB RBCs.

Perspectives on Advances in Tuberculosis Diagnostics, Drugs, and Vaccines.

Despite concerted efforts over the past 2 decades at developing new diagnostics, drugs, and vaccines with expanding pipelines, tuberculosis remains a global emergency. Several novel diagnostic technologies show promise of better point-of-care rapid tests for tuberculosis including nucleic acid-based amplification tests, imaging, and breath analysis of volatile organic compounds. Advances in new and repurposed drugs for use in multidrug-resistant (MDR) or extensively drug-resistant (XDR) tuberculosis have focused on development of several new drug regimens and their evaluation in clinical trials and now influence World Health Organization guidelines. Since the failure of the MVA85A vaccine 2 years ago, there have been no new tuberculosis vaccine candidates entering clinical testing. The current status quo of the lengthy treatment duration and poor treatment outcomes associated with MDR/XDR tuberculosis and with comorbidity of tuberculosis with human immunodeficiency virus and noncommunicable diseases is unacceptable. New innovations and political and funder commitment for early rapid diagnosis, shortening duration of therapy, improving treatment outcomes, and prevention are urgently required.

Dietary exposure to the endocrine disruptor tolylfluanid promotes global metabolic dysfunction in male mice.

Environmental endocrine disruptors are implicated as putative contributors to the burgeoning metabolic disease epidemic. Tolylfluanid (TF) is a commonly detected fungicide in Europe, and previous in vitro and ex vivo work has identified it as a potent endocrine disruptor with the capacity to promote adipocyte differentiation and induce adipocytic insulin resistance, effects likely resulting from activation of glucocorticoid receptor signaling. The present study extends these findings to an in vivo mouse model of dietary TF exposure. After 12 weeks of consumption of a normal chow diet supplemented with 100 parts per million TF, mice exhibited increased body weight gain and an increase in total fat mass, with a specific augmentation in visceral adipose depots. This increased adipose accumulation is proposed to occur through a reduction in lipolytic and fatty acid oxidation gene expression. Dietary TF exposure induced glucose intolerance, insulin resistance, and metabolic inflexibility, while also disrupting diurnal rhythms of energy expenditure and food consumption. Adipose tissue endocrine function was also impaired with a reduction in serum adiponectin levels. Moreover, adipocytes from TF-exposed mice exhibited reduced insulin sensitivity, an effect likely mediated through a specific down-regulation of insulin receptor substrate-1 expression, mirroring effects of ex vivo TF exposure. Finally, gene set enrichment analysis revealed an increase in adipose glucocorticoid receptor signaling with TF treatment. Taken together, these findings identify TF as a novel in vivo endocrine disruptor and obesogen in mice, with dietary exposure leading to alterations in energy homeostasis that recapitulate many features of the metabolic syndrome.

Reduced ventricular proarrhythmic potential of the novel combined ion-channel blocker AZD1305 versus dofetilide in dogs with remodeled hearts.

BACKGROUND: AZD1305 is an investigational antiarrhythmic agent for management of atrial fibrillation. It blocks various cardiac ion currents at different potencies and has atrial-predominant electrophysiological effects. We investigated the electrophysiological and proarrhythmic effects of AZD1305 versus dofetilide in dogs with chronic complete atrioventricular block and myocardial hypertrophic remodeling. METHODS AND RESULTS: AZD1305 was administered to anesthetized mongrel dogs before and >2 weeks after the induction of atrioventricular block and ventricular and atrial electrophysiological parameters were assessed. In all dogs, the selective I(Kr) blocker dofetilide was used to examine susceptibility to acquired torsades de pointes in chronic atrioventricular block and for comparison. At normal sinus rhythm, AZD1305 increased QT and RR intervals from 290±7 to 397±15 ms (+37%, P<0.0001) and from 603±22 to 778±32 ms (+29%, P=0.002), respectively. In the same animals at chronic atrioventricular block, AZD1305 increased the QT interval from 535±28 to 747±36 ms (+40%, P<0.0001), similar to the QT prolongation by dofetilide (511±22 to 703±45 ms [+38%, P<0.0001]). AZD1305 slightly slowed the idioventricular rhythm. Whereas all (n=14) chronic atrioventricular block animals exhibited torsades de pointes on dofetilide, the arrhythmia was induced in only 4 of 11 dogs after AZD1305. Beat-to-beat variability of left-ventricular monophasic-action-potential duration increased after dofetilide (2.3±0.2 to 6.3±0.7 ms; P<0.0001) but not after AZD1305 (2.8±0.3 to 3.7±0.3 ms; P=0.20) despite similar left-ventricular monophasic-action-potential duration prolongations. CONCLUSIONS: Despite causing similar degrees of repolarization delay as the selective I(Kr) blocker dofetilide, the combined ion-channel blocker AZD1305 induces less repolarization instability and has a lower ventricular proarrhythmic potential in the remodeled dog heart.

ATP-induced helicase slippage reveals highly coordinated subunits.

Helicases are vital enzymes that carry out strand separation of duplex nucleic acids during replication, repair and recombination. Bacteriophage T7 gene product 4 is a model hexameric helicase that has been observed to use dTTP, but not ATP, to unwind double-stranded (ds)DNA as it translocates from 5' to 3' along single-stranded (ss)DNA. Whether and how different subunits of the helicase coordinate their chemo-mechanical activities and DNA binding during translocation is still under debate. Here we address this question using a single-molecule approach to monitor helicase unwinding. We found that T7 helicase does in fact unwind dsDNA in the presence of ATP and that the unwinding rate is even faster than that with dTTP. However, unwinding traces showed a remarkable sawtooth pattern where processive unwinding was repeatedly interrupted by sudden slippage events, ultimately preventing unwinding over a substantial distance. This behaviour was not observed with dTTP alone and was greatly reduced when ATP solution was supplemented with a small amount of dTTP. These findings presented an opportunity to use nucleotide mixtures to investigate helicase subunit coordination. We found that T7 helicase binds and hydrolyses ATP and dTTP by competitive kinetics such that the unwinding rate is dictated simply by their respective maximum rates V(max), Michaelis constants K(M) and concentrations. In contrast, processivity does not follow a simple competitive behaviour and shows a cooperative dependence on nucleotide concentrations. This does not agree with an uncoordinated mechanism where each subunit functions independently, but supports a model where nearly all subunits coordinate their chemo-mechanical activities and DNA binding. Our data indicate that only one subunit at a time can accept a nucleotide while other subunits are nucleotide-ligated and thus they interact with the DNA to ensure processivity. Such subunit coordination may be general to many ring-shaped helicases and reveals a potential mechanism for regulation of DNA unwinding during replication.

Guggulsterone enhances head and neck cancer therapies via inhibition of signal transducer and activator of transcription-3.

Treatment of human head and neck squamous cell carcinoma (HNSCC) cell lines with guggulsterone, a widely available, well-tolerated nutraceutical, demonstrated dose-dependent decreases in cell viability with EC(50)s ranging from 5 to 8 microM. Guggulsterone induced apoptosis and cell cycle arrest, inhibited invasion and enhanced the efficacy of erlotinib, cetuximab and cisplatin in HNSCC cell lines. Guggulsterone induced decreased expression of both phosphotyrosine and total signal transducer and activator of transcription (STAT)-3, which contributed to guggulsterone's growth inhibitory effect. Hypoxia-inducible factor (HIF)-1alpha was also decreased in response to guggulsterone treatment. In a xenograft model of HNSCC, guggulsterone treatment resulted in increased apoptosis and decreased expression of STAT3. In vivo treatment with a guggulsterone-containing natural product, Guggulipid, resulted in decreased rates of tumor growth and enhancement of cetuximab's activity. Our results suggest that guggulsterone-mediated inhibition of STAT3 and HIF-1alpha provide a biologic rationale for further clinical investigation of this compound in the treatment of HNSCC.

Gating of the shaker potassium channel is modulated differentially by N-glycosylation and sialic acids.

N-linked glycans, including sialic acids, are integral components of ion channel complexes. To determine if N-linked sugars can modulate a rapidly inactivating K+ channel, the glycosylated Drosophila melanogaster Shaker K+ channel (ShB) and the N-glycosylation-deficient mutant (ShNQ), were studied under conditions of full and reduced sialylation. Through an apparent electrostatic mechanism, full sialylation induced uniform and significant hyperpolarizing shifts in all measured voltage-dependent ShB gating parameters compared to those measured under conditions of reduced sialylation. Steady-state gating of ShNQ was unaffected by changes in sialylation and was nearly identical to that observed for ShB under conditions of reduced sialylation, indicating that N-linked sialic acids were wholly responsible for the observed effects of sialic acid on ShB gating. Interestingly, the rates of transition among channel states and the voltage-independent rates of activation and inactivation were significantly slower for ShNQ compared to ShB. Both effects were independent of sialylation, indicating that N-linked sugars other than sialic acids alter ShB gating kinetics but have little to no effect on the steady-state distribution of channels among states. The effect of sialic acids on channel gating, particularly inactivation gating, and the impact of other N-linked sugars on channel gating kinetics are unique to the ShB isoform. Thus, ShB gating is modulated by two complementary but distinct sugar-dependent mechanisms, (1) an N-linked sialic acid-dependent surface charge effect and (2) a sialic acid-independent effect that is consistent with N-linked sugars affecting the stability of ShB among its functional states.

Psychoneuroimmune implications of type 2 diabetes.

The idea that type 2 diabetes is associated with augmented innate immune function characterized by increased circulating levels of acute phase reactants and altered macrophage biology is fairly well established, even though the mechanisms involved in this complex interaction still are not entirely clear. To date, the majority of studies investigating innate immune function in type 2 diabetes are limited to the context of wound healing, atherosclerosis, stroke, and other commonly identified comorbidities. Several important recurring themes come out of these data. First, type 2 diabetes is associated with a state of chronic, subclinical inflammation. Second, in macrophages, type 2 diabetic conditions enhance proinflammatory reactions and impair anti-inflammatory responses. Third, after acute activation of the innate immune system in type 2 diabetes, recovery or resolution of inflammation is impaired. The consequences of type 2 diabetes-associated inflammatory alterations on PNI processes have been recognized only recently. Given the impact of diminished emotional well-being on the quality of life in patients who have type 2 diabetes, diabetes-induced exacerbation of PNI responses should be considered a serious complication of type 2 diabetes that warrants further clinical attention.