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Blood Sugar Control May Aid Stroke Recovery in Diabetes Patients

Title: Blood Sugar Control May Aid Stroke Recovery in Diabetes Patients
Category: Health News
Created: 3/30/2020 12:00:00 AM
Last Editorial Review: 3/31/2020 12:00:00 AM




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Patch Pump Device Could Offer Cheaper Insulin Delivery

Title: Patch Pump Device Could Offer Cheaper Insulin Delivery
Category: Health News
Created: 4/1/2020 12:00:00 AM
Last Editorial Review: 4/2/2020 12:00:00 AM




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Vitamin D Might Aid Seniors' Recovery From Hip Fracture: Study

Title: Vitamin D Might Aid Seniors' Recovery From Hip Fracture: Study
Category: Health News
Created: 4/2/2020 12:00:00 AM
Last Editorial Review: 4/3/2020 12:00:00 AM




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Metabolite Sequestration Enables Rapid Recovery from Fatty Acid Depletion in Escherichia coli

ABSTRACT

Microbes adapt their metabolism to take advantage of nutrients in their environment. Such adaptations control specific metabolic pathways to match energetic demands with nutrient availability. Upon depletion of nutrients, rapid pathway recovery is key to release cellular resources required for survival under the new nutritional conditions. Yet, little is known about the regulatory strategies that microbes employ to accelerate pathway recovery in response to nutrient depletion. Using the fatty acid catabolic pathway in Escherichia coli, here, we show that fast recovery can be achieved by rapid release of a transcriptional regulator from a metabolite-sequestered complex. With a combination of mathematical modeling and experiments, we show that recovery dynamics depend critically on the rate of metabolite consumption and the exposure time to nutrients. We constructed strains with rewired transcriptional regulatory architectures that highlight the metabolic benefits of negative autoregulation over constitutive and positive autoregulation. Our results have wide-ranging implications for our understanding of metabolic adaptations, as well as for guiding the design of gene circuitry for synthetic biology and metabolic engineering.

IMPORTANCE Rapid metabolic recovery during nutrient shift is critical to microbial survival, cell fitness, and competition among microbiota, yet little is known about the regulatory mechanisms of rapid metabolic recovery. This work demonstrates a previously unknown mechanism where rapid release of a transcriptional regulator from a metabolite-sequestered complex enables fast recovery to nutrient depletion. The work identified key regulatory architectures and parameters that control the speed of recovery, with wide-ranging implications for the understanding of metabolic adaptations as well as synthetic biology and metabolic engineering.




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Historical Geography and Health Equity: An Exploratory View of North Carolina Slavery and Sociohealth Factors

Current health inequities are rooted in more than simple systems failures and inefficiencies. Historical legacy has corrupted health outcomes, and resolution requires both acknowledgment and intention.




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Very large convergent multi-fluted glacigenic deposits in the NW Highlands, Scotland

We describe two large convergent multi-fluted glacigenic deposits in the NW Highlands, Scotland, and point out their resemblance to a number of landforms emerging from presently deglaciating areas of Greenland and Antarctica. We suggest that they all result from locally sourced sediment being deposited by local ice-flow, which was laterally confined by the margins of much larger adjacent glaciers or ice-streams. The NW Highlands features thus seem likely to be the result of processes active during the latter part of the Devensian Glaciation. One of these deposits, on the peninsula between Loch Broom and Little Loch Broom, is evidently sourced from the west-facing Coire Dearg of Beinn Ghobhlach, but was emplaced in a WNW direction rather than along the WSW fall-line. This suggests that the ice that emplaced it was confined by the margins of large glaciers then occupying the adjacent valleys of Loch Broom and Little Loch Broom. The second much larger and more prominent deposit, in Applecross, is composed of bouldery Torridonian sandstone till emplaced on to glacially scoured bedrock; the only feasible source location for this material is about 12 km distant, which requires that the deposit was carried by ice across the trough of Strath Maol Chalum and emplaced while active ice-streams confined it laterally to its present-day location. This, in turn, requires that ice lay in the Inner Sound between Applecross and Skye to an elevation 400–500 m above present-day sea-level. The Wester Ross Re-advance of 15–14 ka left a fragment of lateral moraine against the most easterly flute and buried the distal end of the flutes with hummocky moraine. We hypothesize that the fluted deposits reflect the locations of the ice-stream margins that constrained deposition of locally derived ice-transported sediment, rather than the flow-lines of the ice-stream itself.




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Every Child Counts: The Importance of the 2020 Census for Pediatric Health Equity




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All for One and One Delivery Room Approach for All?

Multiple births are increasing in frequency related to advanced maternal age and fertility treatments, and they have an increased risk for congenital anomalies compared to singleton births. However, twins have the same congenital anomalies <15% of the time. Thus, having multiple births with discordant anomalies is a growing challenge for neonatologists. Although external anomalies can often be spotted quickly at delivery or sex differences between multiples can rapidly identify those with internal anomalies described on prenatal ultrasound, we present a case of male multiples, who would optimally receive different initial resuscitation strategies on the basis of the presence or absence of an internal anomaly. The similar size of 4 extremely preterm quadruplets raises concern for whether accurate, immediate identification of 1 neonate with a congenital diaphragmatic hernia will be reliable in the delivery room. Clinicians discuss the ethical considerations of an "all for one" approach to this resuscitation.




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Rates and Stability of Mental Health Disorders in Children Born Very Preterm at 7 and 13 Years

OBJECTIVES:

Children born very preterm (VPT) are at an increased risk of developing mental health (MH) disorders. Our aim for this study was to assess rates of MH disorders in children born VPT and term at 13 years of age and stability of MH disorders between ages 7 and 13 years by using a diagnostic measure.

METHODS:

Participants were from the Victorian Infant Brain Study longitudinal cohort and included 125 children born VPT (<30 weeks’ gestational age and/or <1250 g) and 49 children born term (≥37 weeks’ gestational age) and their families. Participants were followed-up at both 7 and 13 years, and the Development and Well-Being Assessment was administered to assess for MH disorders.

RESULTS:

Compared with term peers, 13-year-olds born VPT were more likely to meet criteria for any MH disorder (odds ratio 5.9; 95% confidence interval 1.71–20.03). Anxiety was the most common disorder in both groups (VPT = 14%; term = 4%), whereas attention-deficit/hyperactivity disorder carried the greatest differential elevated risk (odds ratio 5.6; 95% confidence interval 0.71–43.80). Overall rates of MH disorders remained stable between 7 and 13 years, although at an individual level, many participants shifted in or out of diagnostic categories over time.

CONCLUSIONS:

Children born VPT show higher rates of MH disorders than their term peers, with changing trajectories over time. Findings highlight the importance of early identification and ongoing assessment to support those with MH disorders in this population.




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Complexes between C-Reactive Protein and Very Low Density Lipoprotein Delay Bacterial Clearance in Sepsis [INFECTIOUS DISEASE AND HOST RESPONSE]

Key Points

  • Kupffer cells phagocytose both bacteria and CRP–VLDL complexes.

  • High levels of CRP–VLDL complexes delay bacterial clearance.

  • Pch disrupts CRP–VLDL complexes to improve bacterial clearance.




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    A New Gorilla Adenoviral Vector with Natural Lung Tropism Avoids Liver Toxicity and Is Amenable to Capsid Engineering and Vector Retargeting [Gene Delivery]

    Human adenoviruses have many attractive features for gene therapy applications. However, the high prevalence of preexisting immunity against these viruses in general populations worldwide has greatly limited their clinical utility. In addition, the most commonly used human adenovirus, human adenovirus subgroup C serotype 5 (HAd5), when systemically administered, triggers systemic inflammation and toxicity, with the liver being the most severely affected organ. Here, we evaluated the utility and safety of a new low-seroprevalence gorilla adenovirus (GAd; GC46) as a gene transfer vector in mice. Biodistribution studies revealed that systemically administered GAd had a selective and robust lung endothelial cell (EC) tropism with minimal vector expression throughout many other organs and tissues. Administration of a high dose of GAd accomplished extensive transgene expression in the lung yet elicited no detectable inflammatory histopathology in this organ. Furthermore, GAd, unlike HAd5, did not exhibit hepatotropism or induce liver inflammatory toxicity in mice, demonstrating the exceptional safety profile of the vector vis-à-vis systemic utility. We further demonstrated that the GAd capsid fiber shared the flexibility of the HAd5 equivalent for permitting genetic modification; GAd with the pan-EC-targeting ligand myeloid cell-binding peptide (MBP) incorporated in the capsid displayed a reduced lung tropism and efficiently retargeted gene expression to vascular beds in other organs.

    IMPORTANCE In the aggregate, our mouse studies suggest that GAd is a promising gene therapy vector that utilizes lung ECs as a source of therapeutic payload production and a highly desirable toxicity profile. Further genetic engineering of the GAd capsid holds the promise of in vivo vector tropism modification and targeting.




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    Complexities in Integrating Social Risk Assessment into Health Care Delivery




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    Inner Ear Arginine Vasopressin-Vasopressin Receptor 2-Aquaporin 2 Signaling Pathway Is Involved in the Induction of Motion Sickness [Drug Discovery and Translational Medicine]

    It has been identified that arginine vasopressin (AVP), vasopressin receptor 2(V2R), and the aquaporin 2 (AQP2) signaling pathway in the inner ear play important roles in hearing and balance functions through regulating the endolymph equilibrium; however, the contributions of this signaling pathway to the development of motion sickness are unclear. The present study was designed to investigate whether the activation of the AVP-V2R-AQP2 signaling pathway in the inner ear is involved in the induction of motion sickness and whether mozavaptan, a V2R antagonist, could reduce motion sickness. We found that both rotatory stimulus and intraperitoneal AVP injection induced conditioned taste aversion (a confirmed behavioral index for motion sickness) in rats and activated the AVP-V2R-AQP2 signaling pathway with a responsive V2R downregulation in the inner ears, and AVP perfusion in cultured epithelial cells from rat endolymphatic sacs induced similar changes in this pathway signaling. Vestibular training, V2R antagonist mozavaptan, or PKA inhibitor H89 blunted these changes in the V2R-AQP2 pathway signaling while reducing rotatory stimulus– or DDAVP (a V2R agonist)-induced motion sickness in rats and dogs. Therefore, our results suggest that activation of the inner ear AVP-V2R-AQP2 signaling pathway is potentially involved in the development of motion sickness; thus, mozavaptan targeting AVP V2Rs in the inner ear may provide us with a new application option to reduce motion sickness.

    SIGNIFICANCE STATEMENT

    Motion sickness affects many people traveling or working. In the present study our results showed that activation of the inner ear arginine vasopressin-vaspopressin receptor 2 (V2R)-aquaporin 2 signaling pathway was potentially involved in the development of motion sickness and that blocking V2R with mozavaptan, a V2R antagonist, was much more effective in reducing motion sickness in both rat and dog; therefore, we demonstrated a new mechanism to underlie motion sickness and a new candidate drug to reduce motion sickness.




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    The Endocannabinoid System Alleviates Pain in a Murine Model of Cancer-Induced Bone Pain [Drug Discovery and Translational Medicine]

    Metastatic breast cancer is prevalent worldwide, and one of the most common sites of metastasis is long bones. Of patients with disease, the major symptom is pain, yet current medications fail to adequately result in analgesic efficacy and present major undesirable adverse effects. In our study, we investigate the potential of a novel monoacylglycerol lipase (MAGL) inhibitor, MJN110, in a murine model of cancer-induced bone pain. Literature has previously demonstrated that MAGL inhibitors function to increase the endogenous concentrations of 2-arachydonylglycerol, which then activates CB1 and CB2 receptors to inhibit inflammation and pain. We demonstrate that administration of MJN110 significantly and dose dependently alleviates spontaneous pain behavior during acute administration compared with vehicle control. In addition, MJN110 maintains its efficacy in a chronic-dosing paradigm over the course of 7 days without signs of receptor sensitization. In vitro analysis of MJN110 demonstrated a dose-dependent and significant decrease in cell viability and proliferation of 66.1 breast adenocarcinoma cells to a greater extent than KML29, an alternate MAGL inhibitor, or the CB2 agonist JWH015. Chronic administration of the compound did not appear to affect tumor burden, as evidenced by radiograph or histologic analysis. Together, these data support the application for MJN110 as a novel therapeutic for cancer-induced bone pain.

    SIGNIFICANCE STATEMENT

    Current standard of care for metastatic breast cancer pain is opioid-based therapies with adjunctive chemotherapy, which have highly addictive and other deleterious side effects. The need for effective, non–opioid-based therapies is essential, and harnessing the endogenous cannabinoid system is proving to be a new target to treat various types of pain conditions. We present a novel drug targeting the endogenous cannabinoid system that is effective at reducing pain in a mouse model of metastatic breast cancer to bone.




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    Translational Pharmacokinetic-Pharmacodynamic Modeling for an Orally Available Novel Inhibitor of Epigenetic Regulator Enhancer of Zeste Homolog 2 [Drug Discovery and Translational Medicine]

    PF06821497 has been identified as an orally available small-molecule enhancer of zeste homolog 2 inhibitor. The objectives of the present study were to characterize pharmacokinetic-pharmacodynamic-disease relationships of PF06821497 in xenograft mouse models with diffuse large B-cell lymphoma (Karpas422). An indirect-response model reasonably fit dose-dependent pharmacodynamic responses [histone H3 on lysine 27 (H3K27) me3 inhibition] with an unbound EC50 of 76 nM, whereas a signal-transduction model sufficiently fit dose-dependent disease responses (tumor growth inhibition) with an unbound tumor stasis concentration (Tsc) of 168 nM. Thus, effective concentration for 70% of maximal effect (EC70) for H3K27me3 inhibition was roughly comparable to Tsc, suggesting that 70% H3K27me3 inhibition could be required for tumor stasis. Consistently, an integrated pharmacokinetic-pharmacodynamic-disease model adequately describing tumor growth inhibition also suggested that ~70% H3K27me3 inhibition was associated with tumor stasis. Based on these results, we would propose that an EC70 estimate for H3K27me3 inhibition corresponding to tumor stasis could be considered a minimum target efficacious concentration of PF06821497 in cancer patients.

    SIGNIFICANCE STATEMENT

    Using a mathematical modeling approach, the quantitative relationships of an orally available anticancer small-molecule enhancer of zeste homolog 2 inhibitor, PF06821497, were characterized among pharmacokinetics, pharmacodynamic biomarker inhibition, and disease responses in nonclinical xenograft models with diffuse large B-cell lymphoma. The modeling results suggest that >70% histone H3 on lysine 27 (H3K27) me3 inhibition would be required for tumor stasis (i.e., 100% tumor growth inhibition). Accordingly, we would propose that an effective concentration for 70% of maximal effect estimate for H3K27me3 inhibition could be considered a minimum target efficacious concentration of PF06821497 in cancer patients.




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    Pharmacological Characterization of Apraglutide, a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist, for the Treatment of Short Bowel Syndrome [Drug Discovery and Translational Medicine]

    Glucagon-like peptide-2 (GLP-2) agonists have therapeutic potential in clinical indications in which the integrity or absorptive function of the intestinal mucosa is compromised, such as in short bowel syndrome (SBS). Native hGLP-2, a 33–amino acid peptide secreted from the small intestine, contributes to nutritional absorption but has a very short half-life because of enzymatic cleavage and renal clearance and thus is of limited therapeutic value. The GLP-2 analog teduglutide (Revestive/Gattex; Shire Inc.) has been approved for use in SBS since 2012 but has a once-daily injection regimen. Pharmacokinetic (PK) and pharmacodynamic studies confirm that apraglutide, a novel GLP-2 analog, has very low clearance, long elimination half-life, and high plasma protein binding compared with GLP-2 analogs teduglutide and glepaglutide. Apraglutide and teduglutide retain potency and selectivity at the GLP-2 receptor comparable to native hGLP-2, whereas glepaglutide was less potent and less selective. In rat intravenous PK studies, hGLP-2, teduglutide, glepaglutide, and apraglutide had clearances of 25, 9.9, 2.8, and 0.27 ml/kg per minute, respectively, and elimination half-lives of 6.4, 19, 16, and 159 minutes, respectively. The unique PK profile of apraglutide administered via intravenous and subcutaneous routes was confirmed in monkey and minipig and translated into significantly greater in vivo pharmacodynamic activity, measured as small intestinal growth in rats. Apraglutide showed greater intestinotrophic activity than the other peptides when administered at less-frequent dosing intervals because of its prolonged half-life. We postulate that apraglutide offers several advantages over existing GLP-2 analogs and is an excellent candidate for the treatment of gastrointestinal diseases, such as SBS.

    SIGNIFICANCE STATEMENT

    Apraglutide is a potent and selective GLP-2 agonist with an extremely low clearance and prolonged elimination half-life, which differentiates it from teduglutide (the only approved GLP-2 agonist). The enhanced pharmacokinetics of apraglutide will benefit patients by enabling a reduced dosing frequency and removing the need for daily injections.




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    A Mechanistic and Translational Pharmacokinetic-Pharmacodynamic Model of Abicipar Pegol and Vascular Endothelial Growth Factor Inhibition [Drug Discovery and Translational Medicine]

    Abicipar pegol (abicipar) is a novel DARPin therapeutic and highly potent vascular endothelial growth factor (VEGF) inhibitor intended for the treatment of neovascular age-related macular degeneration (nAMD). Here we develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for abicipar to guide dosing regimens in the clinic. The model incorporated abicipar-VEGF binding kinetics, VEGF expression levels, and VEGF turnover rates to describe the ocular and systemic PK data collected from the vitreous, aqueous humor (AH), choroid, retina, and serum of rabbits after a 1-mg abicipar intravitreal (IVT) dose. The model was translated to humans using human-specific mechanistic parameters and refitted to human serum and AH concentrations from patients with diabetic macular edema and nAMD. The model was then used to simulate 8-, 12- (quarterly), and 16-week dosing intervals in the clinic. Simulations of 2 mg abicipar IVT at 8-week or quarterly dosing in humans indicates minimum steady-state vitreal concentrations are maintained above both in vitro IC50 and in vivo human IC50 values. The model predicted virtually complete VEGF inhibition for the 8-week and quarterly dosing schedule during the 52-week treatment period. In the 16-week schedule, clinically significant VEGF inhibition was maintained during the 52-week period. The model quantitatively described abicipar-VEGF target engagement leading to rapid reduction of VEGF and a long duration of VEGF inhibition demonstrating the clinical feasibility of up to a 16-week dosing interval. Abicipar is predicted to reduce IVT dosing compared with other anti-VEGF therapies with the potential to lessen patient treatment burden.

    SIGNIFICANCE STATEMENT

    Current anti-VEGF treatments for neovascular age-related macular degeneration require frequent (monthly) intravitreal injections and monitoring, which increases patient burden. We developed a mechanistic pharmakinetic/pharmadynamic model to describe the interaction between abicipar (a novel VEGF inhibitor) and VEGF to evaluate the duration of action. The model demonstrates extended abicipar-VEGF target engagement leading to clinical feasibility of up to a 16-week dosing interval. Our model predicted that abicipar 8-week and quarterly dosing schedules maintain virtually complete VEGF inhibition during the 52-week period.




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    Protein Engineering in the Ubiquitin System: Tools for Discovery and Beyond [Review Articles]

    Ubiquitin (UB) transfer cascades consisting of E1, E2, and E3 enzymes constitute a complex network that regulates a myriad of biologic processes by modifying protein substrates. Deubiquitinating enzymes (DUBs) reverse UB modifications or trim UB chains of diverse linkages. Additionally, many cellular proteins carry UB-binding domains (UBDs) that translate the signals encoded in UB chains to target proteins for degradation by proteasomes or in autophagosomes, as well as affect nonproteolytic outcomes such as kinase activation, DNA repair, and transcriptional regulation. Dysregulation of the UB transfer pathways and malfunctions of DUBs and UBDs play causative roles in the development of many diseases. A greater understanding of the mechanism of UB chain assembly and the signals encoded in UB chains should aid in our understanding of disease pathogenesis and guide the development of novel therapeutics. The recent flourish of protein-engineering approaches such as unnatural amino acid incorporation, protein semisynthesis by expressed protein ligation, and high throughput selection by phage and yeast cell surface display has generated designer proteins as powerful tools to interrogate cell signaling mediated by protein ubiquitination. In this study, we highlight recent achievements of protein engineering on mapping, probing, and manipulating UB transfer in the cell.

    Significance Statement

    The post-translational modification of proteins with ubiquitin alters the fate and function of proteins in diverse ways. Protein engineering is fundamentally transforming research in this area, providing new mechanistic insights and allowing for the exploration of concepts that can potentially be applied to therapeutic intervention.




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    Every Fifth Individual With Type 1 Diabetes Suffers From an Additional Autoimmune Disease: A Finnish Nationwide Study

    OBJECTIVE

    The aim of this study was to quantify the excess risk of autoimmune hypothyroidism and hyperthyroidism, Addison disease, celiac disease, and atrophic gastritis in adults with type 1 diabetes (T1D) compared with nondiabetic individuals in Finland.

    RESEARCH DESIGN AND METHODS

    The study included 4,758 individuals with T1D from the Finnish Diabetic Nephropathy (FinnDiane) Study and 12,710 nondiabetic control individuals. The autoimmune diseases (ADs) were identified by linking the data with the Finnish nationwide health registries from 1970 to 2015.

    RESULTS

    The median age of the FinnDiane individuals at the end of follow-up in 2015 was 51.4 (interquartile range 42.6–60.1) years, and the median duration of diabetes was 35.5 (26.5–44.0) years. Of individuals with T1D, 22.8% had at least one additional AD, which included 31.6% of women and 14.9% of men. The odds ratios for hypothyroidism, hyperthyroidism, celiac disease, Addison disease, and atrophic gastritis were 3.43 (95% CI 3.09–3.81), 2.98 (2.27–3.90), 4.64 (3.71–5.81), 24.13 (5.60–104.03), and 5.08 (3.15–8.18), respectively, in the individuals with T1D compared with the control individuals. The corresponding ORs for women compared with men were 2.96 (2.53–3.47), 2.83 (1.87–4.28), 1.52 (1.15–2.02), 2.22 (0.83–5.91), and 1.36 (0.77–2.39), respectively, in individuals with T1D. Late onset of T1D and aging increased the risk of hypothyroidism, whereas young age at onset of T1D increased the risk of celiac disease.

    CONCLUSIONS

    This is one of the largest studies quantifying the risk of coexisting AD in adult individuals with T1D in the country with the highest incidence of T1D in the world. The results highlight the importance of continuous screening for other ADs in individuals with T1D.




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    Association of early disease progression and very poor survival in the GALLIUM study in follicular lymphoma: benefit of obinutuzumab in reducing the rate of early progression




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    THE EVERYONE PROJECT UNVEILS IMPLICIT BIAS TRAINING GUIDE [Family Medicine Updates]




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    Predicting Opioid Use Following Discharge After Cesarean Delivery [Original Research]

    PURPOSE

    Although cesarean delivery is the most common surgical procedure in the United States, postoperative opioid prescribing varies greatly. We hypothesized that patient characteristics, procedural characteristics, or both would be associated with high vs low opioid use after discharge. This information could help individualize prescriptions.

    METHODS

    In this prospective cohort study, we quantified opioid use for 4 weeks following hospital discharge after cesarean delivery. Predischarge characteristics were obtained from health records, and patients self-reported total opioid use postdischarge on weekly questionnaires. Opioid use was quantified in milligram morphine equivalents (MMEs). Binomial and Poisson regression analyses were performed to assess predictors of opioid use after discharge.

    RESULTS

    Of the 233 patients starting the study, 203 (87.1%) completed at least 1 questionnaire and were included in analyses (86.3% completed all 4 questionnaires). A total of 113 patients were high users (>75 MMEs) and 90 patients were low users (≤75 MMEs) of opioids postdischarge. The group reporting low opioid use received on average 44% fewer opioids in the 24 hours before discharge compared with the group reporting high opioid use (mean = 33.0 vs 59.3 MMEs, P <.001). Only a minority of patients (11.4% to 15.8%) stored leftover opioids in a locked location, and just 31 patients disposed of leftover opioids.

    CONCLUSIONS

    Knowledge of predischarge opioid use can be useful as a tool to inform individualized opioid prescriptions, help optimize nonopioid analgesia, and reduce opioid use. Additional studies are needed to evaluate the impact of implementing such measures on prescribing practices, pain, and functional outcomes.




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    Intratumoral Delivery of a PD-1-Blocking scFv Encoded in Oncolytic HSV-1 Promotes Antitumor Immunity and Synergizes with TIGIT Blockade

    Oncolytic virotherapy can lead to systemic antitumor immunity, but the therapeutic potential of oncolytic viruses in humans is limited due to their insufficient ability to overcome the immunosuppressive tumor microenvironment (TME). Here, we showed that locoregional oncolytic virotherapy upregulated the expression of PD-L1 in the TME, which was mediated by virus-induced type I and type II IFNs. To explore PD-1/PD-L1 signaling as a direct target in tumor tissue, we developed a novel immunotherapeutic herpes simplex virus (HSV), OVH-aMPD-1, that expressed a single-chain variable fragment (scFv) against PD-1 (aMPD-1 scFv). The virus was designed to locally deliver aMPD-1 scFv in the TME to achieve enhanced antitumor effects. This virus effectively modified the TME by releasing damage-associated molecular patterns, promoting antigen cross-presentation by dendritic cells, and enhancing the infiltration of activated T cells; these alterations resulted in antitumor T-cell activity that led to reduced tumor burdens in a liver cancer model. Compared with OVH, OVH-aMPD-1 promoted the infiltration of myeloid-derived suppressor cells (MDSC), resulting in significantly higher percentages of CD155+ granulocytic-MDSCs (G-MDSC) and monocytic-MDSCs (M-MDSC) in tumors. In combination with TIGIT blockade, this virus enhanced tumor-specific immune responses in mice with implanted subcutaneous tumors or invasive tumors. These findings highlighted that intratumoral immunomodulation with an OV expressing aMPD-1 scFv could be an effective stand-alone strategy to treat cancers or drive maximal efficacy of a combination therapy with other immune checkpoint inhibitors.




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    A Novel Inhaled Dry-Powder Formulation of Ribavirin Allows for Efficient Lung Delivery in Healthy Participants and Those with Chronic Obstructive Pulmonary Disease in a Phase 1 Study [Antiviral Agents]

    Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition, causing progressive decline in lung function leading to premature death. Acute exacerbations in COPD patients are predominantly associated with respiratory viruses. Ribavirin is a generic broad-spectrum antiviral agent that could be used for treatment of viral respiratory infections in COPD. Using the Particle Replication In Nonwetting Templates (PRINT) technology, which produces dry-powder particles of uniform shape and size, two new inhaled formulations of ribavirin (ribavirin-PRINT-CFI and ribavirin-PRINT-IP) were developed for efficient delivery to the lung and to minimize bystander exposure. Ribavirin-PRINT-CFI was well tolerated in healthy participants after single dosing and ribavirin-PRINT-IP was well tolerated in healthy and COPD participants after single and repeat dosing. Ribavirin-PRINT-CFI was replaced with ribavirin-PRINT-IP since the latter formulation was found to have improved physicochemical properties and it had a higher ratio of active drug to excipient per unit dose. Ribavirin concentrations were measured in lung epithelial lining fluid in both healthy and COPD participants and achieved target concentrations. Both formulations were rapidly absorbed with approximately dose proportional pharmacokinetics in plasma. Exposure to bystanders was negligible based on both the plasma and airborne ribavirin concentrations with the ribavirin-PRINT-IP formulation. Thus, ribavirin-PRINT-IP allowed for an efficient and convenient delivery of ribavirin to the lungs while minimizing systemic exposure. Further clinical investigations would be required to demonstrate ribavirin-PRINT-IP antiviral characteristics and impact on COPD viral-induced exacerbations. (The clinical trials discussed in this study have been registered at ClinicalTrials.gov under identifiers NCT03243760 and NCT03235726.)




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    A Biosynthetic Platform for Antimalarial Drug Discovery [Chemistry; Biosynthesis]

    Advances in synthetic biology have enabled the production of a variety of compounds using bacteria as a vehicle for complex compound biosynthesis. Violacein, a naturally occurring indole pigment with antibiotic properties, can be biosynthetically engineered in Escherichia coli expressing its nonnative synthesis pathway. To explore whether this synthetic biosynthesis platform could be used for drug discovery, here we have screened bacterially derived violacein against the main causative agent of human malaria, Plasmodium falciparum. We show the antiparasitic activity of bacterially derived violacein against the P. falciparum 3D7 laboratory reference strain as well as drug-sensitive and -resistant patient isolates, confirming the potential utility of this drug as an antimalarial agent. We then screen a biosynthetic series of violacein derivatives against P. falciparum growth. The varied activity of each derivative against asexual parasite growth points to the need to further develop violacein as an antimalarial. Towards defining its mode of action, we show that biosynthetic violacein affects the parasite actin cytoskeleton, resulting in an accumulation of actin signal that is independent of actin polymerization. This activity points to a target that modulates actin behavior in the cell either in terms of its regulation or its folding. More broadly, our data show that bacterial synthetic biosynthesis could become a suitable platform for antimalarial drug discovery, with potential applications in future high-throughput drug screening with otherwise chemically intractable natural products.




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    New Drug-Discovery Assay Identifies Novel Mutant-EGFR Inhibitors [Drug Discovery]

    The MaMTH-DS assay detected inhibitors of mutant EGFR in non–small cell lung cancer cells.




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    Studio for rent at Garden Gate building - New and Very Nice

    Nice mini studio for rent at Garden Gate building, located on 08 Hoang Minh Giam street, Phu Nhuan district nearby Tan Son Nhat airport.Fully furnished, new with nice interiors Size: 38sqm, 1wc View: Look over the pool Managed by CBRE, security 24/24 Utilities: Free Gym, Swimming...




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    How to Measure Video Marketing Impact + KPIs for Every Team’s Video Program

    window.addEventListener("message", function (message) { var msg = message.data && JSON.parse(message.data); if (msg.name === "hapyak_embedded_experience_aspect_ratio_available") { var hyIframe = document.getElementById("hapyak_embedded_experience_6432"); hyIframe.style.paddingTop = 100 * (1 / […]

    The post How to Measure Video Marketing Impact + KPIs for Every Team’s Video Program appeared first on e-Learning Feeds.




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    Xbox Series X News Planned for Every Month of 2020, Starts With Inside Xbox Gameplay Reveals on May 7

    Microsoft has announced it will share new information on the Xbox Series X every month in 2020 starting with the May 7th episode of Inside Xbox, which will showcase gameplay from third-party partners. Microsoft is calling it "Xbox 20/20." The event starts at 8am PT / 11am ET. 

    "These monthly moments will take place throughout the rest of the year and will be a way for us to engage, connect and celebrate with you about what’s in store for the next generation of gaming, including what’s next for Xbox Series X, Xbox Game Studios, Xbox Game Pass and Project xCloud," said Microsoft. "Every month will bring something different. Stay tuned to Xbox Wire for more details."

    The company did reveal the July event will be focused on upcoming first-party games from Xbox Game Studios. 

    "A number of our studio teams are looking forward to sharing first looks at new gameplay, insights from development teams being optimized for Xbox Series X, and brand-new game announcements," said Microsoft.  "We cannot wait to share this initial look at what some of those teams are working on."

    A new teaser video of the May 7 Inside Xbox event has been posted online and the closed captions reveals it is the "New Xbox Sound." It is possible it is the new bootup screen for the Xbox Series X. View the video below:

    The Inside Xbox event for May 7 can be watched from multiple streaming sites:

    Read more information below:

    This is a momentous year for Xbox, with our next-gen console paving the way for all our games and services to come together in even better ways. Here’s what 2020 looks like, just to start:

    • Our goal remains to launch Xbox Series X and Halo Infinite this Holiday
    • All 15 Xbox Game Studios teams are hard at work on next-generation games for Xbox Series X and Xbox Game Pass
    • The best development teams around the world are working hard to have their games ready to play on Xbox Series X this holiday
    • For PC players, we plan to support the community by making all our major releases at launch available with Xbox Game Pass for PC, including Halo Infinite, Wasteland 3, Minecraft Dungeons and of course, Microsoft Flight Simulator.
    • We have new updates and titles lined up for Xbox Game Pass for console and PC
    • We’re expanding Project xCloud into new countries and on new devices—and later this year Project xCloud and Xbox Game Pass will come together, enabling you and your friends to play together in more ways.

    It’s a lot – and that’s saying something in 2020, a year which could be summed up as “a lot.” With all this in mind, we set out to create new touchpoints to celebrate gaming and share what’s next with our global community.

    A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

    Full Article - https://www.vgchartz.com/article/443394/xbox-series-x-news-planned-for-every-month-of-2020-starts-with-inside-xbox-gameplay-reveals-on-may-7/




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