Hepatic glucose production (HGP) is crucial for glucose homeostasis, but the underlying mechanisms have not been fully elucidated. Here, we show that a calcium-sensing enzyme, CaMKII, is activated in ...a calcium- and IP3R-dependent manner by cAMP and glucagon in primary hepatocytes and by glucagon and fasting in vivo. Genetic deficiency or inhibition of CaMKII blocks nuclear translocation of FoxO1 by affecting its phosphorylation, impairs fasting- and glucagon/cAMP-induced glycogenolysis and gluconeogenesis, and lowers blood glucose levels, while constitutively active CaMKII has the opposite effects. Importantly, the suppressive effect of CaMKII deficiency on glucose metabolism is abrogated by transduction with constitutively nuclear FoxO1, indicating that the effect of CaMKII deficiency requires nuclear exclusion of FoxO1. This same pathway is also involved in excessive HGP in the setting of obesity. These results reveal a calcium-mediated signaling pathway involved in FoxO1 nuclear localization and hepatic glucose homeostasis.
Display omitted
► Fasting and glucagon activate hepatic CaMKII in a PKA-IP3R1-Ca2+i-dependent manner ► CaMKII promotes fasting/glucagon-induced hepatic glucose production (HGP) ► CaMKII promotes nuclear FoxO1, which is required for CaMKII-mediated stimulation of HGP ► The CaMKII-FoxO1 pathway is also involved in excessive HGP in the setting of obesity
Cancer is a disease of aging and, as the world's population ages, the number of older persons with cancer is increasing and will make up a growing share of the oncology population in virtually every ...country. Despite this, older patients remain vastly underrepresented in research that sets the standards for cancer treatments. Consequently, most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients, and effective strategies to improve clinical trial participation of older adults with cancer remain sparse. For this systematic review, the authors evaluated published studies regarding barriers to participation and interventions to improve participation of older adults in cancer trials. The quality of the available evidence was low and, despite a literature describing multifaceted barriers, only one intervention study aimed to increase enrollment of older adults in trials. The findings starkly amplify the paucity of evidence‐based, effective strategies to improve participation of this underrepresented population in cancer trials. Within these limitations, the authors provide their opinion on how the current cancer research infrastructure must be modified to accommodate the needs of older patients. Several underused solutions are offered to expand clinical trials to include older adults with cancer. However, as currently constructed, these recommendations alone will not solve the evidence gap in geriatric oncology, and efforts are needed to meet older and frail adults where they are by expanding clinical trials designed specifically for this population and leveraging real‐world data.
To develop a map of cell-cell communication mediated by extracellular RNA (exRNA), the NIH Extracellular RNA Communication Consortium created the exRNA Atlas resource (https://exrna-atlas.org). The ...Atlas version 4P1 hosts 5,309 exRNA-seq and exRNA qPCR profiles from 19 studies and a suite of analysis and visualization tools. To analyze variation between profiles, we apply computational deconvolution. The analysis leads to a model with six exRNA cargo types (CT1, CT2, CT3A, CT3B, CT3C, CT4), each detectable in multiple biofluids (serum, plasma, CSF, saliva, urine). Five of the cargo types associate with known vesicular and non-vesicular (lipoprotein and ribonucleoprotein) exRNA carriers. To validate utility of this model, we re-analyze an exercise response study by deconvolution to identify physiologically relevant response pathways that were not detected previously. To enable wide application of this model, as part of the exRNA Atlas resource, we provide tools for deconvolution and analysis of user-provided case-control studies.
Display omitted
•The exRNA Atlas provides access to human exRNA profiles and web-accessible tools•Atlas analysis reveals six exRNA cargo types present across five human biofluids•Five of the cargo types associate with specific vesicular and non-vesicular carriers•These findings and resources empower studies of extracellular RNA communication
An extracellular RNA atlas from five human biofluids (serum, plasma, cerebrospinal fluid, saliva, and urine) reveals six extracellular RNA cargo types, including both vesicular and non-vesicular carriers.
The prevalence of agitation among emergency department (ED) patients is increasing. Physical restraints are routinely used to prevent self-harm and to protect staff, but are associated with serious ...safety risks. To date, characterization of physical restraint use in the emergency setting has been limited. We thus aim to describe restraint patterns in the general ED to guide future investigation in the management of behavioral disorders.
We conducted a cross-sectional study of adult patients presenting to 5 adult EDs within a large regional health system for 2013 to 2015, and with a physical restraint order during their visit. We undertook descriptive analyses and cluster analysis to determine unique meaningful groups within our sample.
In 956,153 total ED visits, 4,661 patients (0.5%) had associated restraint orders, representing 3,739 unique patients. The median age was 47 years (interquartile range 32 to 59 years), 66.7% of patients were men, 61.9% had a psychiatric history, and 91.1% arrived by ambulance. For chief complaints, 33.7% were alcohol or drug use, 45.4% medical, 12.3% psychiatric, and 8.5% trauma. Cluster analysis identified 2 distinct cohorts. A younger, predominantly male population presented with alcohol or drug use, whereas an older group arrived with medical complaints.
Our data found strong association of alcohol or drug use with physical restraints and identified a unique elderly population with behavioral disturbances in the ED. Further characterization of causal links and safer practices to manage agitation for these vulnerable populations are needed.
Dengue is the most important mosquito-borne viral disease. In the absence of specific drugs or vaccines, control focuses on suppressing the principal mosquito vector, Aedes aegypti, yet current ...methods have not proven adequate to control the disease. New methods are therefore urgently needed, for example genetics-based sterile-male-release methods. However, this requires that lab-reared, modified mosquitoes be able to survive and disperse adequately in the field.
Adult male mosquitoes were released into an uninhabited forested area of Pahang, Malaysia. Their survival and dispersal was assessed by use of a network of traps. Two strains were used, an engineered 'genetically sterile' (OX513A) and a wild-type laboratory strain, to give both absolute and relative data about the performance of the modified mosquitoes. The two strains had similar maximum dispersal distances (220 m), but mean distance travelled of the OX513A strain was lower (52 vs. 100 m). Life expectancy was similar (2.0 vs. 2.2 days). Recapture rates were high for both strains, possibly because of the uninhabited nature of the site.
After extensive contained studies and regulatory scrutiny, a field release of engineered mosquitoes was safely and successfully conducted in Malaysia. The engineered strain showed similar field longevity to an unmodified counterpart, though in this setting dispersal was reduced relative to the unmodified strain. These data are encouraging for the future testing and implementation of genetic control strategies and will help guide future field use of this and other engineered strains.
Abstract
Aims
To establish pre-clinical proof of concept that sustained subcutaneous delivery of the secretome of human cardiac stem cells (CSCs) can be achieved in vivo to produce significant ...cardioreparative outcomes in the setting of myocardial infarction.
Methods and results
Rats were subjected to permanent ligation of left anterior descending coronary artery and randomized to receive subcutaneous implantation of TheraCyte devices containing either culture media as control or 1 × 106 human W8B2+ CSCs, immediately following myocardial ischaemia. At 4 weeks following myocardial infarction, rats treated with W8B2+ CSCs encapsulated within the TheraCyte device showed preserved left ventricular ejection fraction. The preservation of cardiac function was accompanied by reduced fibrotic scar tissue, interstitial fibrosis, cardiomyocyte hypertrophy, as well as increased myocardial vascular density. Histological analysis of the TheraCyte devices harvested at 4 weeks post-implantation demonstrated survival of human W8B2+ CSCs within the devices, and the outer membrane was highly vascularized by host blood vessels. Using CSCs expressing plasma membrane reporters, extracellular vesicles of W8B2+ CSCs were found to be transferred to the heart and other organs at 4 weeks post-implantation. Furthermore, mass spectrometry-based proteomic profiling of extracellular vesicles of W8B2+ CSCs identified proteins implicated in inflammation, immunoregulation, cell survival, angiogenesis, as well as tissue remodelling and fibrosis that could mediate the cardioreparative effects of secretome of human W8B2+ CSCs.
Conclusions
Subcutaneous implantation of TheraCyte devices encapsulating human W8B2+ CSCs attenuated adverse cardiac remodelling and preserved cardiac function following myocardial infarction. The TheraCyte device can be employed to deliver stem cells in a minimally invasive manner for effective secretome-based cardiac therapy.
Graphical Abstract
Key points
Patients with mild chronic obstructive pulmonary disease (COPD) have an elevated ventilatory equivalent to CO2 production (V̇E/V̇CO2) during exercise, secondary to increased dead space ...ventilation. The reason for the increased dead space is unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism.
Despite emerging evidence that mild COPD is associated with pulmonary microvascular dysfunction, limited research has focused on experimentally modulating the pulmonary microvasculature during exercise in mild COPD.
The present study sought to examine the effect of inhaled nitric oxide (iNO), a selective pulmonary vasodilator, on V̇E/V̇CO2, dyspnoea and exercise capacity in patients with mild COPD.
Experimental iNO increased peak oxygen uptake in mild COPD, secondary to reduced V̇E/V̇CO2 and dyspnoea.
This is the first study to demonstrate that experimental manipulation of the pulmonary circulation alone, can positively impact dyspnoea and exercise capacity in mild COPD.
Patients with mild chronic obstructive pulmonary disease (COPD) have an exaggerated ventilatory response to exercise, contributing to dyspnoea and exercise intolerance. Previous research in mild COPD has demonstrated an elevated ventilatory equivalent to CO2 production (V̇E/V̇CO2) during exercise, secondary to increased dead space ventilation. The reason for the increased dead space is unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. The present study tested the hypothesis that inhaled nitric oxide (iNO), a selective pulmonary vasodilator, would lower V̇E/V̇CO2 and dyspnoea, and improve exercise capacity in patients with mild COPD. In this multigroup randomized‐control cross‐over study, 15 patients with mild COPD (FEV1 = 89 ± 11% predicted) and 15 healthy controls completed symptom‐limited cardiopulmonary exercise tests while breathing normoxic gas or 40 ppm iNO. Compared with placebo, iNO significantly increased peak oxygen uptake (1.80 ± 0.14 vs. 1.53 ± 0.10 L·min–1, P < 0.001) in COPD, whereas no effect was observed in controls. At an equivalent work rate of 60 W, iNO reduced V̇E/V̇CO2 by 3.8 ± 4.2 units (P = 0.002) and dyspnoea by 1.1 ± 1.2 Borg units (P < 0.001) in COPD, whereas no effect was observed in controls. Operating lung volumes and oxygen saturation were unaffected by iNO in both groups. iNO increased peak oxygen uptake in COPD, secondary to reduced V̇E/V̇CO2 and dyspnoea. These data suggest that mild COPD patients demonstrate pulmonary microvascular dysfunction that contributes to increased V̇E/V̇CO2, dyspnoea and exercise intolerance. This is the first study to demonstrate that experimental manipulation of the pulmonary circulation alone, can positively impact dyspnoea and exercise capacity in mild COPD.
Key points
Patients with mild chronic obstructive pulmonary disease (COPD) have an elevated ventilatory equivalent to CO2 production (V̇E/V̇CO2) during exercise, secondary to increased dead space ventilation. The reason for the increased dead space is unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism.
Despite emerging evidence that mild COPD is associated with pulmonary microvascular dysfunction, limited research has focused on experimentally modulating the pulmonary microvasculature during exercise in mild COPD.
The present study sought to examine the effect of inhaled nitric oxide (iNO), a selective pulmonary vasodilator, on V̇E/V̇CO2, dyspnoea and exercise capacity in patients with mild COPD.
Experimental iNO increased peak oxygen uptake in mild COPD, secondary to reduced V̇E/V̇CO2 and dyspnoea.
This is the first study to demonstrate that experimental manipulation of the pulmonary circulation alone, can positively impact dyspnoea and exercise capacity in mild COPD.
The most fragile skeletons produced by benthic marine calcifiers are those that larvae and juveniles make to support their bodies. Ocean warming, acidification, decreased carbonate saturation and ...their interactive effects are likely to impair skeletogenesis. Failure to produce skeleton in a changing ocean has negative implications for a diversity of marine species. We examined the interactive effects of warming and acidification on an abalone (Haliotis coccoradiata) and a sea urchin (Heliocidaris erythrogramma) reared from fertilization in temperature and pH/pCO2 treatments in a climatically and regionally relevant setting. Exposure of ectodermal (abalone) and mesodermal (echinoid) calcifying systems to warming (+2°C to 4°C) and acidification (pH 7.6–7.8) resulted in unshelled larvae and abnormal juveniles. Haliotis development was most sensitive with no interaction between stressors. For Heliocidaris, the percentage of normal juveniles decreased in response to both stressors, although a +2°C warming diminished the negative effect of low pH. The number of spines produced decreased with increasing acidification/pCO2, and the interactive effect between stressors indicated that a +2°C warming reduced the negative effects of low pH. At +4°C, the developmental thermal tolerance was breached. Our results show that projected near-future climate change will have deleterious effects on development with differences in vulnerability in the two species.
Although electronic behavioral alerts are placed as an alert flag in the electronic health record to notify staff of previous behavioral and/or violent incidents in emergency departments (EDs), they ...have the potential to reinforce negative perceptions of patients and contribute to bias. We provide characterization of ED electronic behavioral alerts using electronic health record data across a large, regional health care system.
We conducted a retrospective cross-sectional study of adult patients presenting to 10 adult EDs within a Northeastern United States health care system from 2013 to 2022. Electronic behavioral alerts were manually screened for safety concerns and then categorized by the type of concern. In our patient-level analyses, we included patient data at the time of the first ED visit where an electronic behavioral alert was triggered or, if a patient had no electronic behavioral alerts, the earliest visit in the study period. We performed a mixed-effects regression analysis to identify patient-level risk factors associated with safety-related electronic behavioral alert deployment.
Of the 2,932,870 ED visits, 6,775 (0.2%) had associated electronic behavioral alerts across 789 unique patients and 1,364 unique electronic behavioral alerts. Of the encounters with electronic behavioral alerts, 5,945 (88%) were adjudicated as having a safety concern involving 653 patients. In our patient-level analysis, the median age for patients with safety-related electronic behavioral alerts was 44 years (interquartile range 33 to 55 years), 66% were men, and 37% were Black. Visits with safety-related electronic behavioral alerts had higher rates of discontinuance of care (7.8% vs 1.5% with no alert; P<.001) as defined by the patient-directed discharge, left-without-being-seen, or elopement-type dispositions. The most common topics in the electronic behavioral alerts were physical (41%) or verbal (36%) incidents with staff or other patients. In the mixed-effects logistic analysis, Black non-Hispanic patients (vs White non-Hispanic patients: adjusted odds ratio 2.60; 95% confidence interval CI 2.13 to 3.17), aged younger than 45 (vs aged 45-64 years: adjusted odds ratio 1.41; 95% CI 1.17 to 1.70), male (vs female: adjusted odds ratio 2.09; 95% CI 1.76 to 2.49), and publicly insured patients (Medicaid: adjusted odds ratio 6.18; 95% CI 4.58 to 8.36; Medicare: adjusted odds ratio 5.63; 95% CI 3.96 to 8.00 vs commercial) were associated with a higher risk of a patient having at least 1 safety-related electronic behavioral alert deployment during the study period.
In our analysis, younger, Black non-Hispanic, publicly insured, and male patients were at a higher risk of having an ED electronic behavioral alert. Although our study is not designed to reflect causality, electronic behavioral alerts may disproportionately affect care delivery and medical decisions for historically marginalized populations presenting to the ED, contribute to structural racism, and perpetuate systemic inequities.
With recent rapid advances in genomic technologies, precise delineation of structural chromosome rearrangements at the nucleotide level is becoming increasingly feasible. In this era of ...“next-generation cytogenetics” (i.e., an integration of traditional cytogenetic techniques and next-generation sequencing), a consensus nomenclature is essential for accurate communication and data sharing. Currently, nomenclature for describing the sequencing data of these aberrations is lacking. Herein, we present a system called Next-Gen Cytogenetic Nomenclature, which is concordant with the International System for Human Cytogenetic Nomenclature (2013). This system starts with the alignment of rearrangement sequences by BLAT or BLAST (alignment tools) and arrives at a concise and detailed description of chromosomal changes. To facilitate usage and implementation of this nomenclature, we are developing a program designated BLA(S)T Output Sequence Tool of Nomenclature (BOSToN), a demonstrative version of which is accessible online. A standardized characterization of structural chromosomal rearrangements is essential both for research analyses and for application in the clinical setting.
PDF
