very Blood Sugar Control May Aid Stroke Recovery in Diabetes Patients By www.medicinenet.com Published On :: Tue, 31 Mar 2020 00:00:00 PDT Title: Blood Sugar Control May Aid Stroke Recovery in Diabetes PatientsCategory: Health NewsCreated: 3/30/2020 12:00:00 AMLast Editorial Review: 3/31/2020 12:00:00 AM Full Article
very Patch Pump Device Could Offer Cheaper Insulin Delivery By www.medicinenet.com Published On :: Thu, 2 Apr 2020 00:00:00 PDT Title: Patch Pump Device Could Offer Cheaper Insulin DeliveryCategory: Health NewsCreated: 4/1/2020 12:00:00 AMLast Editorial Review: 4/2/2020 12:00:00 AM Full Article
very Vitamin D Might Aid Seniors' Recovery From Hip Fracture: Study By www.medicinenet.com Published On :: Fri, 3 Apr 2020 00:00:00 PDT Title: Vitamin D Might Aid Seniors' Recovery From Hip Fracture: StudyCategory: Health NewsCreated: 4/2/2020 12:00:00 AMLast Editorial Review: 4/3/2020 12:00:00 AM Full Article
very Metabolite Sequestration Enables Rapid Recovery from Fatty Acid Depletion in Escherichia coli By mbio.asm.org Published On :: 2020-03-17T01:30:15-07:00 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. Full Article
very Historical Geography and Health Equity: An Exploratory View of North Carolina Slavery and Sociohealth Factors By www.ncmedicaljournal.com Published On :: 2020-05-04T06:50:30-07:00 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. Full Article
very Very large convergent multi-fluted glacigenic deposits in the NW Highlands, Scotland By sjg.lyellcollection.org Published On :: 2019-11-29T02:21:48-08:00 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. Full Article
very Every Child Counts: The Importance of the 2020 Census for Pediatric Health Equity By pediatrics.aappublications.org Published On :: 2020-05-01T01:00:46-07:00 Full Article
very All for One and One Delivery Room Approach for All? By pediatrics.aappublications.org Published On :: 2020-05-01T01:00:46-07:00 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. Full Article
very Rates and Stability of Mental Health Disorders in Children Born Very Preterm at 7 and 13 Years By pediatrics.aappublications.org Published On :: 2020-05-01T01:00:46-07:00 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. Full Article
very Complexes between C-Reactive Protein and Very Low Density Lipoprotein Delay Bacterial Clearance in Sepsis [INFECTIOUS DISEASE AND HOST RESPONSE] By www.jimmunol.org Published On :: 2020-05-04T13:00:27-07:00 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. Full Article
very A New Gorilla Adenoviral Vector with Natural Lung Tropism Avoids Liver Toxicity and Is Amenable to Capsid Engineering and Vector Retargeting [Gene Delivery] By jvi.asm.org Published On :: 2020-05-04T08:00:46-07:00 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. Full Article
very Complexities in Integrating Social Risk Assessment into Health Care Delivery By www.jabfm.org Published On :: 2020-03-16T09:31:37-07:00 Full Article
very Inner Ear Arginine Vasopressin-Vasopressin Receptor 2-Aquaporin 2 Signaling Pathway Is Involved in the Induction of Motion Sickness [Drug Discovery and Translational Medicine] By jpet.aspetjournals.org Published On :: 2020-04-21T06:02:31-07:00 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. Full Article
very The Endocannabinoid System Alleviates Pain in a Murine Model of Cancer-Induced Bone Pain [Drug Discovery and Translational Medicine] By jpet.aspetjournals.org Published On :: 2020-04-13T13:53:50-07:00 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. Full Article
very Translational Pharmacokinetic-Pharmacodynamic Modeling for an Orally Available Novel Inhibitor of Epigenetic Regulator Enhancer of Zeste Homolog 2 [Drug Discovery and Translational Medicine] By jpet.aspetjournals.org Published On :: 2020-04-13T13:53:50-07:00 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. Full Article
very 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] By jpet.aspetjournals.org Published On :: 2020-04-13T13:53:50-07:00 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. Full Article
very A Mechanistic and Translational Pharmacokinetic-Pharmacodynamic Model of Abicipar Pegol and Vascular Endothelial Growth Factor Inhibition [Drug Discovery and Translational Medicine] By jpet.aspetjournals.org Published On :: 2020-04-13T13:53:50-07:00 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. Full Article
very Protein Engineering in the Ubiquitin System: Tools for Discovery and Beyond [Review Articles] By pharmrev.aspetjournals.org Published On :: 2020-02-27T12:11:24-08:00 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. Full Article
very Every Fifth Individual With Type 1 Diabetes Suffers From an Additional Autoimmune Disease: A Finnish Nationwide Study By care.diabetesjournals.org Published On :: 2020-04-20T12:00:32-07:00 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. Full Article
very 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 By www.haematologica.org Published On :: 2020-05-01T00:05:42-07:00 Full Article
very THE EVERYONE PROJECT UNVEILS IMPLICIT BIAS TRAINING GUIDE [Family Medicine Updates] By www.annfammed.org Published On :: 2020-03-09T14:00:11-07:00 Full Article
very Predicting Opioid Use Following Discharge After Cesarean Delivery [Original Research] By www.annfammed.org Published On :: 2020-03-09T14:00:11-07:00 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. Full Article
very Intratumoral Delivery of a PD-1-Blocking scFv Encoded in Oncolytic HSV-1 Promotes Antitumor Immunity and Synergizes with TIGIT Blockade By cancerimmunolres.aacrjournals.org Published On :: 2020-05-01T00:05:25-07:00 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. Full Article
very 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] By aac.asm.org Published On :: 2020-04-21T08:01:10-07:00 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.) Full Article
very A Biosynthetic Platform for Antimalarial Drug Discovery [Chemistry; Biosynthesis] By aac.asm.org Published On :: 2020-04-21T08:01:09-07:00 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. Full Article
very New Drug-Discovery Assay Identifies Novel Mutant-EGFR Inhibitors [Drug Discovery] By cancerdiscovery.aacrjournals.org Published On :: 2020-05-01T00:05:26-07:00 The MaMTH-DS assay detected inhibitors of mutant EGFR in non–small cell lung cancer cells. Full Article
very Studio for rent at Garden Gate building - New and Very Nice By batdongsan.com.vn Published On :: Sat, 09 May 2020 22:47:42 GMT 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... Full Article
very How to Measure Video Marketing Impact + KPIs for Every Team’s Video Program By feedproxy.google.com Published On :: Sat, 09 May 2020 14:50:03 +0000 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. Full Article eLearning Software Blog Webcasts Webinar
very Xbox Series X News Planned for Every Month of 2020, Starts With Inside Xbox Gameplay Reveals on May 7 By feedproxy.google.com Published On :: Tue, 05 May 2020 17:31:18 GMT 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: Facebook Mixer Twitch Twitter YouTube (4K stream) 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/ Full Article Analysis Charts Industry
very Everything You Need to Start Your Own Podcast on the Cheap By feedproxy.google.com Published On :: Sat, 09 May 2020 11:00:05 +0000 If you think you’ve got something of value to share with the world – or maybe you just want a project to tackle to fill the hours – then we’ll take you through what you need to know. Full Article
very Google Pixel 4a: Everything We Know So Far By feeds.gizmodo.com.au Published On :: Mon, 04 May 2020 11:22:12 +1000 Last year the release of Google's Pixel 3a heralded a shift in the mid-range phone market. Coming in at $649 and packing some flagship specs, it changed what people should expect from a a phone at that price. Other brands followed suit, including Apple with its recently released iPhone SE. Suffice to say, the arrival of Googles new budget device, the Pixel 4a, is cause for some excitedment. Here's what we know about it so far. More » Full Article
very Mervyn King's brutal analysis of banking sector exposed in blow to coronavirus recovery By feedproxy.google.com Published On :: Sat, 09 May 2020 08:46:00 +0100 MERVYN KING, the former governor of the Bank of England, once issued a brutal analysis of the global banking system and argued for its reinvention, it can be revealed as the Government fine-tunes its economic response to the coronavirus pandemic. Full Article
very A star exploded into a supernova but it weirdly isn't very bright By www.newscientist.com Published On :: Mon, 03 Feb 2020 14:57:48 +0000 Astronomers have spotted a star that is exploding with a brightness 100 times less than expected – and it’s a mystery exactly why the explosion is so dim Full Article
very The Ultimate Optimization Problem: How to Best Use Every Square Meter of the Earth's Surface By feedproxy.google.com Published On :: Fri, 20 Sep 2019 21:08:00 GMT Lucas Joppa, founder of Microsoft's AI for Earth program, is taking an engineering approach to environmental issues Full Article energy energy/environment
very AI Faces Speed Bumps and Potholes on Its Road From the Research Lab to Everyday Use By feedproxy.google.com Published On :: Tue, 01 Oct 2019 15:00:00 GMT Rigid IT departments and job-hopping data scientists are just two of the challenges that make implementing machine learning harder than you might think Full Article robotics robotics/artificial-intelligence
very Zipline Deploys Medical Delivery Drones with U.S. Military By feedproxy.google.com Published On :: Tue, 22 Oct 2019 15:00:00 GMT A military exercise in Australia demonstrates how small drones can airdrop critical medical supplies to soldiers in combat Full Article robotics robotics/drones
very 13 Going on 30 Was Almost, Uh, Not Very Good By feedproxy.google.com Published On :: Fri, 08 May 2020 16:32:52 -0400 A YouTube search unearths deleted scenes shot with a different cast. Full Article 13 going on 30 friday night movie club movies fabuloso
very RPGCast – Episode 266: “It’s A SE3cret To Everybody” By feedproxy.google.com Published On :: Sat, 11 May 2013 22:36:22 +0000 What a week. First we learn what really happens at E3. Then Quin gets hungry. After that, Square Enix gets real specific. But Diablo 3... Full Article News Podcasts RPG Cast
very RPGCast – Episode 317: “Everyone Gets Tropico 4!” By feedproxy.google.com Published On :: Sat, 16 Aug 2014 22:29:11 +0000 Manny and Chris report back from their recent hunting expedition. Phil teaches us about MMOs for beginners. Anna Marie does all the picrosses. And Jon... Full Article News Podcasts RPG Cast
very RPGCast – Episode 371: “EVERYONE’S FIRED” By feedproxy.google.com Published On :: Sat, 09 Jan 2016 22:16:47 +0000 As Anna works on replacing the podcast staff, Chris tries to figure out who can twink him through FFXI RoV. Alice doesn’t deliver missiles, but... Full Article News Podcasts RPG Cast
very RPGCast – Episode 394: “Where Everyone Loves Everyone” By feedproxy.google.com Published On :: Sat, 30 Jul 2016 23:49:25 +0000 Someone forgets to take out the trash. Inazuma Eleven gets an alternate timeline. Sega gets a mini of their own. There’s a talking dog and... Full Article News Podcasts RPG Cast
very RPGCast – Episode 427: “Very Tragickarp” By feedproxy.google.com Published On :: Sat, 27 May 2017 20:19:11 +0000 Today’s episode is pretty fishy. But that doesn’t keep Alice from telling us about her music sequencer powered robot armor. It doesn’t stop Capcom from... Full Article News Podcasts RPG Cast
very RPGCast – Episode 456: “A Very Special e-PAWS-sode” By feedproxy.google.com Published On :: Sat, 17 Mar 2018 20:16:15 +0000 Anna Marie hosts this week’s Cat Fancy, as the cast tries to figure out if touching girls is OK (we discover it isn’t OK to... Full Article News Podcasts RPG Cast
very RPGCast – Episode 505: “We’ll Just Postpone It Every Week” By feedproxy.google.com Published On :: Sat, 29 Jun 2019 19:13:59 +0000 Anna Marie loses her mind as well as control of her mouth. Chris investigates the impacts of bringing Diet Coke into Mementos. Peter buys more games. Nathan finishes Final Fanatasy VIII just in time to start playing Final Fantasy VIII. And Kelley just tries to survive Bloodstained's framerate on the Switch. Full Article News Podcasts RPG Cast Atelier Lulua Bloodstained: Ritual of the Night Cadence of Hyrule Dragon Quest Builders 2 Final Fantasy V Final Fantasy VIII Final Fantasy XIV: Shadowbringers Persona Q2
very ‘Every stone will be uncovered’: how Georgia officials failed the Ahmaud Arbery case By news.yahoo.com Published On :: Sat, 09 May 2020 08:03:41 -0400 Systemic flaws within Glynn county’s district attorney offices led to a lack of action against the men involved in this ‘modern lynching’In the days and weeks after Ahmaud Arbery was shot and killed, multiple Glynn county law enforcement officials failed to thoroughly investigate his death and, in one case, refused to allow police officers to make arrests, the Guardian has learned.Arbery, 25, was jogging through the neighborhood just outside Brunswick, Georgia, on 23 February when he was shot dead by two white men. Gregory McMichael, 64, and his son Travis, 34, were charged with murder and aggravated assault on Thursday evening, after graphic video footage of the killing was released publicly and sparked national outrage.Lawyers for Arbery’s family have called the killing a “modern lynching” and decried the lack of action in the case prior to the release of the video, pointing to racial inequalities in the criminal justice system.In the police report, Gregory McMichael claimed Arbery “violently attacked” his son, who shot Arbery in self defense.Jackie Johnson, the Glynn county district attorney, refused to allow police officers who responded to arrest the two men, Glynn county commissioner Peter Murphy told the Guardian in a phone call on Friday.The police department was put in touch with one of Johnson’s assistant district attorneys after the shooting, but Johnson made the decision not to charge the father and son, the former having worked in her office for more than 20 years, Murphy said.“The police at the scene went to her, saying they were ready to arrest both of them,” Allen Booker, the Glynn county district 5 commissioner, told the Atlanta Journal-Constitution on Friday. “These were the police at the scene who had done the investigation. She shut them down to protect her friend McMichael.”Days later, Johnson recused herself. Johnson did not immediately respond to a request for comment. By 27 February, George Barnhill, the Waycross judicial district attorney, and the second of three DAs on the case, took over. Less than 24 hours after seeing the video and evidence compiled by the police, Murphy said, Barnhill decided to not charge the McMichaels.“And so within 24 hours the Glynn county police had been told by two separate DA offices not to make any arrests,” Murphy said. “And obviously, they want to assume no responsibility for their actions.”On 2 April, Barnhill sent an email to law enforcement authorities saying the 25-year-old Arbery had an “apparent aggressive nature” and that his family were “not strangers to the local criminal justice system”.“Arbery’s mental health records & prior convictions help explain his apparent aggressive nature and his possible thought pattern to attack an armed man,” Barnhill said in the email, which was first reported by the New York Times.“What it appears is he was purposely trying to assault the character of the victim and there’s just no reason why,” said Chris Stewart, one of the lawyers representing Arbery’s family.The family have pointed to the McMichaels’ connection to local law enforcement both at the district attorney’s office and police department as evidence of systemic flaws and roadblocks in their search for justice. It was only after the video of Arbery’s death was released this week that the third DA’s office requested the Georgia Bureau of Investigations (GBI) get involved.On Friday, GBI director Vic Reynolds told reporters he could not “answer what another agency did or didn’t see” in the first two months of the investigation.“But I can tell you that based on our involvement in this case and considering the fact we hit the ground running Wednesday morning and within 36 hours we had secured warrants for two individuals for felony murder, I think that speaks volumes for itself.”In a 7 April email sent to the office of Georgia attorney general Chris Carr, Barnhill recused himself because his son worked on a case involving Arbery while working in Johnson’s office.Lee Merritt, one of the lawyers who represents Arbery’s family, said Wanda Cooper-Jones, Arbery’s mother, found the connection between Barnhill’s son and her own on Facebook and brought it to the attention of his office.“She followed the links. That’s exactly how it happened,” he said to the Guardian on Friday by phone.According to a police report filed 23 February, Gregory and Travis McMichael grabbed their weapons, a .357 Magnum revolver and a shotgun, jumped into a truck and followed Arbery as he ran.In the email to Carr from early April, Barnhill references a “decent cell phone video of the entire shooting incident”, an apparent reference to the one leaked this week.Reynolds said on Friday that the investigation into the shooting, the video and the person who filmed it, would continue.“Every stone will be uncovered,” Reynolds said. Full Article
very The Nintendo Switch had a very good March By feedproxy.google.com Published On :: Tue, 21 Apr 2020 14:22:35 +0000 Nintendo is selling a lot of Switches. The convertible console has been a lifesaver for people sheltering in place around the world. COVID-19-induced travel restrictions and the long-awaited arrival of Animal Crossing: New Horizons have proven to be a perfect storm for the three-year-old platform. New numbers out from NPD this morning shed some light […] Full Article Gaming Hardware Animal Crossing Nintendo Nintendo Switch npd Switch
very Coronavirus will play out very differently in world's poorest nations By www.newscientist.com Published On :: Fri, 03 Apr 2020 15:45:43 +0000 Cases of covid-19 have been slow to appear in developing economies, but now they are ramping up. Slums and refugee camps could be particularly vulnerable Full Article
very Transatlantic slavery introduced infectious diseases to the Americas By www.newscientist.com Published On :: Thu, 30 Apr 2020 16:00:17 +0000 The remains of three slaves found in Mexico contain the earliest signs of the hepatitis B virus and yaws bacteria in the Americas, suggesting transatlantic slavery introduced these diseases Full Article
very Revisiting AC Odyssey? Find Every Tomb and Ainigmata With This Map By www.ign.com Published On :: Sat, 9 May 2020 13:32:39 +0000 This interactive map for Assassin's Creed Odyssey will help you find everything you need, like ainigmata ostraka and tombs. Full Article
very ICYMI: Every New Xbox Series X Game Shown at Inside Xbox By www.ign.com Published On :: Sat, 9 May 2020 15:01:04 +0000 All 13 games from third-party developers coming to Xbox Series X. Full Article