Recent work suggests personality affects the subjective psychological weight one attaches to an identity. This study extends prior findings showing a static effect on European identification in a ...single country by investigating whether a similar systematic relationship exists for a wider range of political-territorial identities (regional, national, supranational, and exclusively nationalist) across different country contexts (Germany, Poland, and the United Kingdom) and over time (2012–2018). Original cross-national and panel survey data show that different traits predict both the type and degree of inclusivity of individuals’ identity attachments. These results contribute to the growing scholarship surrounding personality’s effects on EU support while underscoring the impact predispositions have on citizens’ sociopolitical orientations. They especially illuminate the contrasting profiles associated with those who identify as exclusively nationalist versus supranational European.
Full text
Available for:
NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Thioredoxin-interacting protein (Txnip) inhibits thioredoxin NADPH-dependent reduction of protein disulfides. Total Txnip knockout (TKO) mice adapted inappropriately to prolonged fasting by shifting ...fuel dependence of skeletal muscle and heart from fat and ketone bodies to glucose. TKO mice exhibited increased Akt signaling, insulin sensitivity, and glycolysis in oxidative tissues (skeletal muscle and hearts) but not in lipogenic tissues (liver and adipose tissue). The selective activation of Akt in skeletal muscle and hearts was associated with impaired mitochondrial fuel oxidation and the accumulation of oxidized (inactive) PTEN, whose activity depends on reduction of two critical cysteine residues. Whereas muscle- and heart-specific Txnip knockout mice recapitulated the metabolic phenotype exhibited by TKO mice, liver-specific Txnip knockout mice were similar to WT mice. Embryonic fibroblasts derived from knockout mice also accumulated oxidized (inactive) PTEN and had elevated Akt phosphorylation. In addition, they had faster growth rates and increased dependence on anaerobic glycolysis due to impaired mitochondrial fuel oxidation, and they were resistant to doxorubicin-facilitated respiration-dependent apoptosis. In the absence of Txnip, oxidative inactivation of PTEN and subsequent activation of Akt attenuated mitochondrial respiration, resulting in the accumulation of NADH, a competitive inhibitor of thioredoxin NADPH-reductive activation of PTEN. These findings indicate that, in nonlipogenic tissues, Txnip is required to maintain sufficient thioredoxin NADPH activity to reductively reactivate oxidized PTEN and oppose Akt downstream signaling.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The clinical management of neuropathic pain is particularly challenging. Current therapies for neuropathic pain modulate nerve impulse propagation or synaptic transmission; these therapies are of ...limited benefit and have undesirable side effects. Injuries to peripheral nerves result in a host of pathophysiological changes associated with the sustained expression of abnormal pain. Here we show that systemic, intermittent administration of artemin produces dose- and time-related reversal of nerve injury-induced pain behavior, together with partial to complete normalization of multiple morphological and neurochemical features of the injury state. These effects of artemin were sustained for at least 28 days. Higher doses of artemin than those completely reversing experimental neuropathic pain did not elicit sensory or motor abnormalities. Our results indicate that the behavioral symptoms of neuropathic pain states can be treated successfully, and that partial to complete reversal of associated morphological and neurochemical changes is achievable with artemin.
Full text
Available for:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Low back pain is a costly healthcare problem and the leading cause of disability among adults in the United States. Primary care providers urgently need effective ways to deliver evidence-based, ...nonpharmacological therapies for chronic low back pain. Guidelines published by several government and national organizations have recommended nonpharmacological and nonopioid pharmacological therapies for low back pain.
The Pain eHealth Platform (PEP) pilot trial aims to test the feasibility of a highly innovative intervention that (1) uses an electronic health record (EHR) query to systematically identify a phenotype of obese, older adults with chronic low back pain who may benefit from Web-based behavioral treatments; (2) delivers highly tailored messages to eligible older adults with chronic low back pain via the patient portal; (3) links affected patients to a Web app that provides education on the efficacy of evidence-based, nonpharmacological, behavioral pain treatments; and (4) directs patients to existing Web-based health treatment tools.
Using a three-step modified Delphi method, an expert panel of primary care providers will define a low back pain phenotype for an EHR query. Using the defined low back pain phenotype, an EHR query will be created to identify patients who may benefit from the PEP. Up to 15 patients with low back pain will be interviewed to refine the tailored messaging, esthetics, and content of the patient-facing Web app within the PEP. Up to 10 primary care providers will be interviewed to better understand the facilitators and barriers to implementing the PEP, given their clinic workflow. We will assess the feasibility of the PEP in a single-arm pragmatic pilot study in which secure patient portal invitations containing a hyperlink to the PEP Web app are sent to 1000 patients. The primary outcome of the study is usability as measured by the System Usability Scale.
Qualitative interviews with primary care providers were completed in April 2019. Qualitative interviews with patients will begin in December 2019.
The PEP will leverage informatics and the patient portal to deliver evidence-based nonpharmacological treatment information to adults with chronic low back pain. Results from this study may help inform the development of Web-based health platforms for other pain and chronic health conditions.
DERR1-10.2196/14525.
On September 12, 2014, CDC was notified by the Colorado Department of Public Health and Environment of a cluster of nine children evaluated at Children's Hospital Colorado with acute neurologic ...illness characterized by extremity weakness, cranial nerve dysfunction (e.g., diplopia, facial droop, dysphagia, or dysarthria), or both. Neurologic illness onsets occurred during August 8-September 15, 2014. The median age of the children was 8 years (range = 1-18 years). Other than neck, back, or extremity pain in some patients, all had normal sensation. All had a preceding febrile illness, most with upper respiratory symptoms, occurring 3-16 days (median = 7 days) before onset of neurologic illness. Seven of eight patients with magnetic resonance imaging of the spinal cord had nonenhancing lesions of the gray matter of the spinal cord spanning multiple levels, and seven of nine with magnetic resonance imaging of the brain had nonenhancing brainstem lesions (most commonly the dorsal pons). Two of five with magnetic resonance imaging of the lumbosacral region had gadolinium enhancement of the ventral nerve roots of the cauda equina. Eight children were up to date on polio vaccination. Eight have not yet fully recovered neurologically.
Full text
Available for:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
IMPORTANCE: For adults with appendicitis, several randomized clinical trials have demonstrated that antibiotics are an effective alternative to appendectomy. However, it remains unknown how the ...characteristics of patients in such trials compare with those of patients who select their treatment and whether outcomes differ. OBJECTIVE: To compare participants in the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) randomized clinical trial (RCT) with a parallel cohort study of participants who declined randomization and self-selected treatment. DESIGN, SETTING, AND PARTICIPANTS: The CODA trial was conducted in 25 US medical centers. Participants were enrolled between May 3, 2016, and February 5, 2020; all participants were eligible for at least 1 year of follow-up, with all follow-up ending in 2021. The randomized cohort included 1094 adults with appendicitis; the self-selection cohort included patients who declined participation in the randomized group, of whom 253 selected appendectomy and 257 selected antibiotics. In this secondary analysis, characteristics and outcomes in both self-selection and randomized cohorts are described with an exploratory analysis of cohort status and receipt of appendectomy. INTERVENTIONS: Appendectomy vs antibiotics. MAIN OUTCOMES AND MEASURES: Characteristics among participants randomized to either appendectomy or antibiotics were compared with those of participants who selected their own treatment. RESULTS: Clinical characteristics were similar across the self-selection cohort (510 patients; mean age, 35.8 years 95% CI, 34.5-37.1; 218 female 43%; 95% CI, 39%-47%) and the randomized group (1094 patients; mean age, 38.2 years 95% CI, 37.4-39.0; 386 female 35%; 95% CI, 33%-38%). Compared with the randomized group, those in the self-selection cohort were less often Spanish speaking (n = 99 19%; 95% CI, 16%-23% vs n = 336 31%; 95% CI, 28%-34%), reported more formal education (some college or more, n = 355 72%; 95% CI, 68%-76% vs n = 674 63%; 95% CI, 60%-65%), and more often had commercial insurance (n = 259 53%; 95% CI, 48%-57% vs n = 486 45%; 95% CI, 42%-48%). Most outcomes were similar between the self-selection and randomized cohorts. The number of patients undergoing appendectomy by 30 days was 38 (15.3%; 95% CI, 10.7%-19.7%) among those selecting antibiotics and 155 (19.2%; 95% CI, 15.9%-22.5%) in those who were randomized to antibiotics (difference, 3.9%; 95% CI, −1.7% to 9.5%). Differences in the rate of appendectomy were primarily observed in the non-appendicolith subgroup. CONCLUSIONS AND RELEVANCE: This secondary analysis of the CODA RCT found substantially similar outcomes across the randomized and self-selection cohorts, suggesting that the randomized trial results are generalizable to the community at large. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02800785
Importance In the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial, which found antibiotics to be noninferior, approximately half of participants randomized to receive ...antibiotics had outpatient management with hospital discharge within 24 hours. If outpatient management is safe, it could increase convenience and decrease health care use and costs. Objective To assess the use and safety of outpatient management of acute appendicitis. Design, Setting, and Participants This cohort study, which is a secondary analysis of the CODA trial, included 776 adults with imaging-confirmed appendicitis who received antibiotics at 25 US hospitals from May 1, 2016, to February 28, 2020. Exposures Participants randomized to antibiotics (intravenous then oral) could be discharged from the emergency department based on clinician judgment and prespecified criteria (hemodynamically stable, afebrile, oral intake tolerated, pain controlled, and follow-up confirmed). Outpatient management and hospitalization were defined as discharge within or after 24 hours, respectively. Main Outcomes and Measures Outcomes compared among patients receiving outpatient vs inpatient care included serious adverse events (SAEs), appendectomies, health care encounters, satisfaction, missed workdays at 7 days, and EuroQol 5-dimension (EQ-5D) score at 30 days. In addition, appendectomy incidence among outpatients and inpatients, unadjusted and adjusted for illness severity, was compared. Results Among 776 antibiotic-randomized participants, 42 (5.4%) underwent appendectomy within 24 hours and 8 (1.0%) did not receive their first antibiotic dose within 24 hours, leaving 726 (93.6%) comprising the study population (median age, 36 years; range, 18-86 years; 462 63.6% male; 437 60.2% White). Of these participants, 335 (46.1%; site range, 0-89.2%) were discharged within 24 hours, and 391 (53.9%) were discharged after 24 hours. Over 7 days, SAEs occurred in 0.9 (95% CI, 0.2-2.6) per 100 outpatients and 1.3 (95% CI, 0.4-2.9) per 100 inpatients; in the appendicolith subgroup, SAEs occurred in 2.3 (95% CI, 0.3-8.2) per 100 outpatients vs 2.8 (95% CI, 0.6-7.9) per 100 inpatients. During this period, appendectomy occurred in 9.9% (95% CI, 6.9%-13.7%) of outpatients and 14.1% (95% CI, 10.8%-18.0%) of inpatients; adjusted analysis demonstrated a similar difference in incidence (−4.0 percentage points; 95% CI, −8.7 to 0.6). At 30 days, appendectomies occurred in 12.6% (95% CI, 9.1%-16.7%) of outpatients and 19.0% (95% CI, 15.1%-23.4%) of inpatients. Outpatients missed fewer workdays (2.6 days; 95% CI, 2.3-2.9 days) than did inpatients (3.8 days; 95% CI, 3.4-4.3 days) and had similar frequency of return health care visits and high satisfaction and EQ-5D scores. Conclusions and Relevance These findings support that outpatient antibiotic management is safe for selected adults with acute appendicitis, with no greater risk of complications or appendectomy than hospital care, and should be included in shared decision-making discussions of patient preferences for outcomes associated with nonoperative and operative care. Trial Registration ClinicalTrials.gov Identifier:NCT02800785
Despite novel therapies, relapse of multiple myeloma (MM) is virtually inevitable. Amplification of chromosome 1q, which harbors the inflammation-responsive RNA editase adenosine deaminase acting on ...RNA (ADAR)1 gene, occurs in 30-50% of MM patients and portends a poor prognosis. Since adenosine-to-inosine RNA editing has recently emerged as a driver of cancer progression, genomic amplification combined with inflammatory cytokine activation of ADAR1 could stimulate MM progression and therapeutic resistance. Here, we report that high ADAR1 RNA expression correlates with reduced patient survival rates in the MMRF CoMMpass data set. Expression of wild-type, but not mutant, ADAR1 enhances Alu-dependent editing and transcriptional activity of GLI1, a Hedgehog (Hh) pathway transcriptional activator and self-renewal agonist, and promotes immunomodulatory drug resistance in vitro. Finally, ADAR1 knockdown reduces regeneration of high-risk MM in serially transplantable patient-derived xenografts. These data demonstrate that ADAR1 promotes malignant regeneration of MM and if selectively inhibited may obviate progression and relapse.
PDF
