The frequency of COPD exacerbations during treatment with a triple inhaler — delivering a long-acting beta-agonist (LABA), a long-acting muscarinic antagonist (LAMA), and an inhaled glucocorticoid — ...was compared with that with a LABA–LAMA or LABA–inhaled glucocorticoid.
In the IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial, fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) significantly reduced exacerbations ...compared with FF/VI or UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease and a history of exacerbations.
To understand whether inhaled corticosteroid (ICS) withdrawal affected IMPACT results, given direct transition from prior maintenance medication to study medication at randomization.
Exacerbations and change from baseline in trough FEV
and St. George's Respiratory Questionnaire results were analyzed by prior ICS use. Exacerbations were also analyzed while excluding data from the first 30 days.
FF/UMEC/VI significantly reduced the annual moderate/severe exacerbation rate compared with UMEC/VI in prior ICS users (29% reduction;
< 0.001), but only a numerical reduction was seen among prior ICS nonusers (12% reduction;
= 0.115). To minimize impact from ICS withdrawal, in an analysis excluding the first 30 days, FF/UMEC/VI continued to significantly reduce the annual on-treatment moderate/severe exacerbation rate (19%;
< 0.001) compared with UMEC/VI. The benefit of FF/UMEC/VI compared with UMEC/VI was seen for severe exacerbation rates, regardless of prior ICS use (prior ICS users, 35% reduction;
< 0.001; non-ICS users, 35% reduction;
= 0.018), and overall when excluding the first 30 days (29%;
< 0.001). Improvements from baseline with FF/UMEC/VI compared with UMEC/VI were also maintained throughout the study for both trough FEV
and St. George's Respiratory Questionnaire, regardless of prior ICS use.
These data support the important treatment effects of FF/UMEC/VI combination therapy on exacerbation reduction, lung function, and quality of life that do not appear to be related to abrupt ICS withdrawal.Clinical trial registered with www.clinicaltrials.gov (NCT02164513).
Cancer cells adapt metabolically to proliferate under nutrient limitation. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support ...glucose-independent tumor cell proliferation. We found that glucose deprivation stimulated re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote glucose-independent cell proliferation. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine via the activity of mitochondrial PEP-carboxykinase (PCK2). Under these conditions, glutamine-derived PEP was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. PCK2 expression was required to maintain tumor cell proliferation under limited-glucose conditions in vitro and tumor growth in vivo. Elevated PCK2 expression is observed in several human tumor types and enriched in tumor tissue from non-small-cell lung cancer (NSCLC) patients. Our results define a role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.
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•Tumor cell metabolic flexibility enables glucose-independent cell proliferation•PCK2 helps generate glycolytic intermediates under low-glucose conditions•PCK2 expression is regulated by glucose and required for in vivo tumor growth•PCK2 expression is elevated in non-small-cell lung carcinoma (NSCLC)
Cancer cells adapt metabolically to maintain proliferation under nutrient limitation. Vincent et al. demonstrate that cancer cells can engage the early steps of gluconeogenesis—a process regulated by mitochondrial PEPCK (PCK2)—to generate biosynthetic intermediates required for tumor cell proliferation.
IMPACT, a 52-week, randomised, double-blind trial, assessed the efficacy and safety of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy
FF/VI or UMEC/VI in patients with ...symptomatic COPD and a history of exacerbations.Subgroup analyses assessed whether the efficacy of FF/UMEC/VI
FF/VI or UMEC/VI and UMEC/VI
FF/VI varies according to prior exacerbation history, and the combined effects of exacerbation history and blood eosinophil counts. Three subgroups were defined: single moderate (1 moderate/no severe; n=3056 (30%)), frequent moderate (≥2 moderate/no severe; n=4628 (45%)) and severe (≥1 severe/any moderate; n=2671 (26%)). End-points included annual on-treatment moderate/severe exacerbation rate (pre-specified), lung function and health status (both post-hoc).Moderate/severe exacerbation rates (reduction % (95% CI)) were reduced in the FF/UMEC/VI group
FF/VI (single moderate 20% (10-29), frequent moderate 11% (2-19), severe 17% (7-26)) and
UMEC/VI (single moderate 18% (5-29), frequent moderate 29% (21-37), severe 26% (14-35)). Moderate/severe exacerbation rates were reduced in the FF/VI group
UMEC/VI in the frequent moderate subgroup; a numerical reduction was observed in the severe subgroup (single moderate 2% (-12-18), frequent moderate 21% (11-29), severe 11% (-3-22)). Moderate/severe exacerbation rates were lower in the FF/VI group compared with UMEC/VI in patients with higher eosinophil counts. FF/UMEC/VI improved lung function and health status
both dual therapies irrespective of exacerbation subgroup. UMEC/VI improved lung function
FF/VI in all subgroups.Triple therapy was more effective than dual regardless of exacerbation history, consistent with results in the intent-to-treat population. Comparisons between dual therapies were influenced by prior exacerbation history and eosinophil counts.
Spontaneous reports from patients able to report vascular sequelae in real time, and recognition that serum non transferrin bound iron may reach or exceed 10μmol/L in the blood stream after iron ...tablets or infusions, led us to hypothesize that conventional iron treatments may provoke acute vascular injury. This prompted us to examine whether a phenotype could be observed in normal human endothelial cells treated with low dose iron.
Confluent primary human endothelial cells (EC) were treated with filter-sterilized iron (II) citrate or fresh media for RNA sequencing and validation studies. RNA transcript profiles were evaluated using directional RNA sequencing with no pre-specification of target sequences. Alignments were counted for exons and junctions of the gene strand only, blinded to treatment types.
Rapid changes in RNA transcript profiles were observed in endothelial cells treated with 10μmol/L iron (II) citrate, compared to media-treated cells. Clustering for Gene Ontology (GO) performed on all differentially expressed genes revealed significant differences in biological process terms between iron and media-treated EC, whereas 10 sets of an equivalent number of randomly selected genes from the respective EC gene datasets showed no significant differences in any GO terms. After 1 hour, differentially expressed genes clustered to vesicle mediated transport, protein catabolism, and cell cycle (Benjamini p = 0.0016, 0.0024 and 0.0032 respectively), and by 6 hours, to cellular response to DNA damage stimulus most significantly through DNA repair genes FANCG, BLM, and H2AFX. Comet assays demonstrated that 10μM iron treatment elicited DNA damage within 1 hour. This was accompanied by a brisk DNA damage response pulse, as ascertained by the development of DNA damage response (DDR) foci, and p53 stabilization.
These data suggest that low dose iron treatments are sufficient to modify the vascular endothelium, and induce a DNA damage response.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The ongoing pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health
and the medical ...countermeasures available so far are limited
. Moreover, we currently lack a thorough understanding of the mechanisms of humoral immunity to SARS-CoV-2
. Here we analyse a large panel of human monoclonal antibodies that target the spike (S) glycoprotein
, and identify several that exhibit potent neutralizing activity and fully block the receptor-binding domain of the S protein (S
) from interacting with human angiotensin-converting enzyme 2 (ACE2). Using competition-binding, structural and functional studies, we show that the monoclonal antibodies can be clustered into classes that recognize distinct epitopes on the S
, as well as distinct conformational states of the S trimer. Two potently neutralizing monoclonal antibodies, COV2-2196 and COV2-2130, which recognize non-overlapping sites, bound simultaneously to the S protein and neutralized wild-type SARS-CoV-2 virus in a synergistic manner. In two mouse models of SARS-CoV-2 infection, passive transfer of COV2-2196, COV2-2130 or a combination of both of these antibodies protected mice from weight loss and reduced the viral burden and levels of inflammation in the lungs. In addition, passive transfer of either of two of the most potent ACE2-blocking monoclonal antibodies (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on the S
and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutic agents.
The IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial demonstrated a significant reduction in all-cause mortality (ACM) risk with fluticasone ...furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus UMEC/VI in patients with chronic obstructive pulmonary disease (COPD) at risk of future exacerbations. Five hundred seventy-four patients were censored in the original analysis owing to incomplete vital status information.
Report ACM and impact of stepping down therapy, following collection of additional vital status data.
Patients were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 μg, FF/VI 100/25 μg, or UMEC/VI 62.5/25 μg following a run-in on their COPD therapies. Time to ACM was prespecified. Additional vital status data collection and subsequent analyses were performed
.
We report vital status data for 99.6% of the intention-to-treat population (
= 10,355), documenting 98 (2.36%) deaths on FF/UMEC/VI, 109 (2.64%) on FF/VI, and 66 (3.19%) on UMEC/VI. For FF/UMEC/VI, the hazard ratio for death was 0.72 (95% confidence interval, 0.53-0.99;
= 0.042) versus UMEC/VI and 0.89 (95% confidence interval, 0.67-1.16;
= 0.387) versus FF/VI. Independent adjudication confirmed lower rates of cardiovascular and respiratory death and death associated with the patient's COPD.
In this secondary analysis of an efficacy outcome from the IMPACT trial, once-daily single-inhaler FF/UMEC/VI triple therapy reduced the risk of ACM versus UMEC/VI in patients with symptomatic COPD and a history of exacerbations.
Telehealth services complement in-person neurologic care. The American Academy of Neurology supports patient access to telehealth services regardless of location, coverage for telehealth services by ...all subscriber benefits and insurance, equitable provider reimbursement, simplified state licensing requirements easing access to virtual care, and expanding telehealth research and quality initiatives. The roles and responsibilities of providers should be clearly delineated in telehealth service models.
OBJECTIVETo examine age and sex differences in burnout, career satisfaction, and well-being in US neurologists.
METHODSQuantitative and qualitative analyses of menʼs (n = 1,091) and womenʼs (n = 580) ...responses to a 2016 survey of US neurologists.
RESULTSEmotional exhaustion in neurologists initially increased with age, then started to decrease as neurologists got older. Depersonalization decreased as neurologists got older. Fatigue and overall quality of life in neurologists initially worsened with age, then started to improve as neurologists got older. More women (64.6%) than men (57.8%) met burnout criteria on univariate analysis. Women respondents were younger and more likely to work in academic and employed positions. Sex was not an independent predictive factor of burnout, fatigue, or overall quality of life after controlling for age. In both men and women, greater autonomy, meaning in work, reasonable amount of clerical tasks, and having effective support staff were associated with lower burnout risk. More hours worked, more nights on call, higher outpatient volume, and higher percent of time in clinical practice were associated with higher burnout risk. For women, greater number of weekends doing hospital rounds was associated with higher burnout risk. Women neurologists made proportionately more negative comments than men regarding workload, work–life balance, leadership and deterioration of professionalism, and demands of productivity eroding the academic mission.
CONCLUSIONSWe identified differences in burnout, career satisfaction, and well-being in neurologists by age and sex. This may aid in developing strategies to prevent and mitigate burnout and promote professional fulfillment for different demographic subgroups of neurologists.
Antibodies are a principal determinant of immunity for most RNA viruses and have promise to reduce infection or disease during major epidemics. The novel coronavirus SARS-CoV-2 has caused a global ...pandemic with millions of infections and hundreds of thousands of deaths to date
. In response, we used a rapid antibody discovery platform to isolate hundreds of human monoclonal antibodies (mAbs) against the SARS-CoV-2 spike (S) protein. We stratify these mAbs into five major classes on the basis of their reactivity to subdomains of S protein as well as their cross-reactivity to SARS-CoV. Many of these mAbs inhibit infection of authentic SARS-CoV-2 virus, with most neutralizing mAbs recognizing the receptor-binding domain (RBD) of S. This work defines sites of vulnerability on SARS-CoV-2 S and demonstrates the speed and robustness of advanced antibody discovery platforms.
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