OBJECTIVES:To describe the frequency of co-occurring newly acquired cognitive impairment, disability in activities of daily livings, and depression among survivors of a critical illness and to ...evaluate predictors of being free of post-intensive care syndrome problems.
DESIGN:Prospective cohort study.
SETTING:Medical and surgical ICUs from five U.S. centers.
PATIENTS:Patients with respiratory failure or shock, excluding those with preexisting cognitive impairment or disability in activities of daily livings.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:At 3 and 12 months after hospital discharge, we assessed patients for cognitive impairment, disability, and depression. We categorized patients into eight groups reflecting combinations of cognitive, disability, and mental health problems. Using multivariable logistic regression, we modeled the association between age, education, frailty, durations of mechanical ventilation, delirium, and severe sepsis with the odds of being post-intensive care syndrome free. We analyzed 406 patients with a median age of 61 years and an Acute Physiology and Chronic Health Evaluation II of 23. At 3 and 12 months, one or more post-intensive care syndrome problems were present in 64% and 56%, respectively. Nevertheless, co-occurring post-intensive care syndrome problems (i.e., in two or more domains) were present in 25% at 3 months and 21% at 12 months. Post-intensive care syndrome problems in all three domains were present in only 6% at 3 months and 4% at 12 months. More years of education was associated with greater odds of being post-intensive care syndrome free (p < 0.001 at 3 and 12 mo). More severe frailty was associated with lower odds of being post-intensive care syndrome free (p = 0.005 at 3 mo and p = 0.048 at 12 mo).
CONCLUSIONS:In this multicenter cohort study, one or more post-intensive care syndrome problems were present in the majority of survivors, but co-occurring problems were present in only one out of four. Education was protective from post-intensive care syndrome problems and frailty predictive of the development of post-intensive care syndrome problems. Future studies are needed to understand better the heterogeneous subtypes of post-intensive care syndrome and to identify modifiable risk factors.
Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin’s role in ...cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.
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•Metformin enhances antitumor CTL immunity by blocking PD-L1/PD-1 axis•Metformin-activated AMPK directly binds to and phosphorylates PD-L1 at S195•Abnormal PD-L1 glycosylation induced by pS195 leads to PD-L1 degradation by ERAD•Combination therapy with metformin and anti-CTLA4 has a synergistic antitumor effect
Cha et al. elucidated a mechanism to show that metformin-activated AMPK phosphorylates PD-L1 at S195 to induce abnormal glycosylation and degrades PD-L1 through an ERAD pathway. This study suggests the potential to use metformin as an adjuvant with various non-PD-L1/PD-1-targeting immune therapies.
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•LC50s of PFAA decreased with the increase in chain length.•PFOA caused hyperactivity and PFBA hypoactivity.•PFOA, PFHxA, and PFBA exposure caused morphological alterations specific ...to each.•Unique transcriptome profiles were observed for each PFAA.•Transcriptomics at end of embryogenesis predicted adverse human health outcomes.
Perfluoroalkyl substances (PFAS) are a class of synthetic chemicals that are persistent in the environment. Due to adverse health outcomes associated with longer chain PFAS, shorter chain chemicals were used as replacements, but developmental toxicity assessments of the shorter chain chemicals are limited. Toxicity of three perfluoroalkyl acids (PFAAs) perfluorooctanoic acid (PFOA), composed of 8 carbon (C8), perfluorohexanoic acid (PFHxA, C6), and perfluorobutanoic acid (PFBA, C4) was compared in developing zebrafish (Danio rerio). LC50s at 120 h post fertilization (hpf) assessed potency of each PFAA by exposing developing zebrafish (1–120 hpf) to range of concentrations. Zebrafish were then exposed to sublethal concentrations (0.4–4000 ppb, µg/L) throughout embryogenesis (1–72 hpf). Effects of the embryonic exposure on locomotor activities was completed with the visual motor response test at 120 hpf. At 72 hpf, morphological changes (total body length, head length, head width) and transcriptome profiles to compare altered molecular and disease pathways were determined. The LC50 ranking followed trend as expected based on chain length. PFOA caused hyperactivity and PFBA hypoactivity, while PFHxA did not change behavior. PFOA, PFHxA, and PFBA caused morphological and transcriptomic alterations that were unique for each chemical and were concentration-dependent indicating different toxicity mechanisms. Cancer was a top disease for PFOA and FXR/RXR activation was a top canonical pathway for PFBA. Furthermore, comparison of altered biological and molecular pathways in zebrafish exposed to PFOA matched findings reported in prior epidemiological studies and other animal models, supporting the predictive value of the transcriptome approach and for predicting adverse health outcomes associated with PFHxA or PFBA exposure.
Delays in achieving the global eradication of wild poliovirus transmission continue to postpone subsequent cessation of all oral poliovirus vaccine (OPV) use. Countries must stop OPV use to end all ...cases of poliomyelitis, including vaccine‐associated paralytic polio (VAPP) and cases caused by vaccine‐derived polioviruses (VDPVs). The Global Polio Eradication Initiative (GPEI) coordinated global cessation of all type 2 OPV (OPV2) use in routine immunization in 2016 but did not successfully end the transmission of type 2 VDPVs (VDPV2s), and consequently continues to use type 2 OPV (OPV2) for outbreak response activities. Using an updated global poliovirus transmission and OPV evolution model, we characterize outbreak response options for 2019–2029 related to responding to VDPV2 outbreaks with a genetically stabilized novel OPV (nOPV2) strain or with the currently licensed monovalent OPV2 (mOPV2). Given uncertainties about the properties of nOPV2, we model different assumptions that appear consistent with the evidence on nOPV2 to date. Using nOPV2 to respond to detected cases may reduce the expected VDPV and VAPP cases and the risk of needing to restart OPV2 use in routine immunization compared to mOPV2 use for outbreak response. The actual properties, availability, and use of nOPV2 will determine its effects on type 2 poliovirus transmission in populations. Even with optimal nOPV2 performance, countries and the GPEI would still likely need to restart OPV2 use in routine immunization in OPV‐using countries if operational improvements in outbreak response to stop the transmission of cVDPV2s are not implemented effectively.
Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic ...heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.
•Quantifiable & semi-quantifiable PFAS sampled at 38 wastewater treatment plants.•PFAS detected at the influent, effluent and biosolids at every facility sampled.•The total oxidizable precursors ...assay showed a 2- to 3-fold increase in PFAS.•Quantifiable precursor mass primarily discharging via aqueous effluent.
Both quantifiable and semi-quantifiable poly- and perfluoroalkyl substances (PFAS) were evaluated in the influent, effluent, and biosolids of 38 wastewater treatment plants. PFAS were detected in all streams at all facilities. For the means of the sums of detected, quantifiable PFAS concentrations were 98 ± 28 ng/L, 80 ± 24 ng/L, and 160,000 ± 46,000 ng/kg (dry weight basis) in the influent, effluent, and biosolids (respectively). In the aqueous influent and effluent streams this quantifiable PFAS mass was typically associated with perfluoroalkyl acids (PFAAs). In contrast, quantifiable PFAS in the biosolids were primarily polyfluoroalkyl substances that potentially serve as precursors to the more recalcitrant PFAAs. Results of the total oxidizable precursor (TOP) assay on select influent and effluent samples showed that semi-quantified (or, unidentified) precursors accounted for a substantial portion (21 to 88%) of the fluorine mass compared to that associated with quantified PFAS, and that this fluorine precursor mass was not appreciably transformed to perfluoroalkyl acids within the WWTPs, as influent and effluent precursor concentrations via the TOP assay were statistically identical. Evaluation of semi-quantified PFAS, consistent with results of the TOP assay, showed the presence of several classes of precursors in the influent, effluent, and biosolids; perfluorophosphonic acids (PFPAs) and fluorotelomer phosphate diesters (di-PAPs) occurred in 100 and 92% of biosolid samples, respectively. Analysis of mass flows showed that, for both quantified (on a fluorine mass basis) and semi-quantified PFAS, the majority of PFAS exited WWTPs through the aqueous effluent compared to the biosolids stream. Overall, these results highlight the importance of semi-quantified PFAS precursors in WWTPs, and the need to further understand the impacts of their ultimate fate in the environment.
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Critical illness is associated with cognitive impairment, but mental health and functional disabilities in survivors of intensive care are inadequately characterised. We aimed to assess associations ...of age and duration of delirium with mental health and functional disabilities in this group.
In this prospective, multicentre cohort study, we enrolled patients with respiratory failure or shock who were undergoing treatment in medical or surgical ICUs in Nashville, TN, USA. We obtained data for baseline demographics and in-hospital variables, and assessed survivors at 3 months and 12 months with measures of depression (Beck Depression Inventory II), post-traumatic stress disorder (PTSD, Post-Traumatic Stress Disorder Checklist-Event Specific Version), and functional disability (activities of daily living scales, Pfeffer Functional Activities Questionnaire, and Katz Activities of Daily Living Scale). We used linear and proportional odds logistic regression to assess the independent associations between age and duration of delirium with mental health and functional disabilities. This study is registered with ClinicalTrials.gov, number NCT00392795.
We enrolled 821 patients with a median age of 61 years (IQR 51-71), assessing 448 patients at 3 months and 382 patients at 12 months after discharge. At 3 months, 149 (37%) of 406 patients with available data reported at least mild depression, as did 116 (33%) of 347 patients at 12 months; this depression was mainly due to somatic rather than cognitive-affective symptoms. Depressive symptoms were common even among individuals without a history of depression (as reported by a proxy), occurring in 76 (30%) of 255 patients with data at 3 months and 62 (29%) of 217 individuals at 12 months. Only 7% of patients (27 of 415 at 3 months and 24 of 361 at 12 months) had symptoms consistent with post-traumatic distress disorder. Disabilities in basic activities of daily living (ADL) were present in 139 (32%) of 428 patients at 3 months and 102 (27%) of 374 at 12 months, as were disabilities in instrumental ADL in 108 (26%) of 422 individuals at 3 months and 87 (23%) of 372 at 12 months. Mental health and functional difficulties were prevalent in patients of all ages. Although old age was frequently associated with mental health problems and functional disabilities, we observed no consistent association between the presence of delirium and these outcomes.
Poor mental health and functional disability is common in patients treated in intensive-care units. Depression is five times more common than is post-traumatic distress disorder after critical illness and is driven by somatic symptoms, suggesting approaches targeting physical rather than cognitive causes could benefit patients leaving critical care.
National Institutes of Health AG027472 and the Geriatric Research, Education and Clinical Center (GRECC), Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System.
Beyond clay Rasmussen, Craig; Heckman, Katherine; Wieder, William R. ...
Biogeochemistry,
02/2018, Letnik:
137, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Improved quantification of the factors controlling soil organic matter (SOM) stabilization at continental to global scales is needed to inform projections of the largest actively cycling terrestrial ...carbon pool on Earth, and its response to environmental change. Biogeochemical models rely almost exclusively on clay content to modify rates of SOM turnover and fluxes of climate-active CO₂ to the atmosphere. Emerging conceptual understanding, however, suggests other soil physicochemical properties may predict SOM stabilization better than clay content. We addressed this discrepancy by synthesizing data from over 5,500 soil profiles spanning continental scale environmental gradients. Here, we demonstrate that other physicochemical parameters are much stronger predictors of SOM content, with clay content having relatively little explanatory power. We show that exchangeable calcium strongly predicted SOM content in water-limited, alkaline soils, whereas with increasing moisture availability and acidity, iron- and aluminum-oxyhydroxides emerged as better predictors, demonstrating that the relative importance of SOM stabilization mechanisms scales with climate and acidity. These results highlight the urgent need to modify biogeochemical models to better reflect the role of soil physicochemical properties in SOM cycling.
OBJECTIVE
To review and summarize data on carfilzomib, which was approved by the Food and Drug Administration (FDA) in July 2012 for the treatment of patients with relapsed and refractory multiple ...myeloma (MM) who received prior bortezomib and thalidomide or lenalidomide.
DATA SOURCES
A literature search through PubMed was conducted through October 2012 using the terms carfilzomib, PR-171, proteasome inhibitor (PI), and MM. Data were also obtained through the American Society of Clinical Oncology and American Society of Hematology abstracts and FDA briefing documents.
STUDY SELECTION AND DATA EXTRACTION
The literature search was limited to human studies published in English. Priority was placed on trials of carfilzomib in relapsed and refractory MM.
DATA SYNTHESIS
Carfilzomib is a new PI that differs in pharmacology and pharmacokinetics from bortezomib, the first-in-class PI. The FDA approval was based on efficacy data from a Phase 2 study of carfilzomib in patients with relapsed and refractory MM (n = 266). All patients had received prior bortezomib and 80% were refractory or intolerant to both bortezomib and lenalidomide. Patients were treated with intravenous carfilzomib 20 mg/m2 (cycle 1) followed by 27 mg/m2 (cycles ≥2) on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The overall response rate was 23.7% (18.7–29.4), with a median duration of response of 7.8 (5.6–9.2) months. Safety data from an integrated analysis reported thrombocytopenia, anemia, fatigue, nausea, and diarrhea as the most common adverse events, with minimal dose-limiting neutropenia or peripheral neuropathy (PN) (n = 526). The incidence of grade 3 or higher thrombocytopenia was 24.9%, while that of neutropenia was 11.9%, and the incidence of all grades of treatment-emergent PN was 13%.
CONCLUSIONS
Carfilzomib is a safe and effective new treatment option for patients with relapsed MM refractory to bortezomib and thalidomide or lenalidomide. Randomized head-to-head trials with bortezomib will assist in formulary and treatment decisions in the context of PIs as a drug class.
OBJECTIVE:Decades-old, common ICU practices including deep sedation, immobilization, and limited family access are being challenged. We endeavoured to evaluate the relationship between ABCDEF bundle ...performance and patient-centered outcomes in critical care.
DESIGN:Prospective, multicenter, cohort study from a national quality improvement collaborative.
SETTING:68 academic, community, and federal ICUs collected data during a 20-month period.
PATIENTS:15,226 adults with at least one ICU day.
INTERVENTIONS:We defined ABCDEF bundle performance (our main exposure) in two ways1) complete performance (patient received every eligible bundle element on any given day) and 2) proportional performance (percentage of eligible bundle elements performed on any given day). We explored the association between complete and proportional ABCDEF bundle performance and three sets of outcomespatient-related (mortality, ICU and hospital discharge), symptom-related (mechanical ventilation, coma, delirium, pain, restraint use), and system-related (ICU readmission, discharge destination). All models were adjusted for a minimum of 18 a priori determined potential confounders.
MEASUREMENTS AND RESULTS:Complete ABCDEF bundle performance was associated with lower likelihood of seven outcomeshospital death within 7 days (adjusted hazard ratio, 0.32; CI, 0.17–0.62), next-day mechanical ventilation (adjusted odds ratio AOR, 0.28; CI, 0.22–0.36), coma (AOR, 0.35; CI, 0.22–0.56), delirium (AOR, 0.60; CI, 0.49–0.72), physical restraint use (AOR, 0.37; CI, 0.30–0.46), ICU readmission (AOR, 0.54; CI, 0.37–0.79), and discharge to a facility other than home (AOR, 0.64; CI, 0.51–0.80). There was a consistent dose-response relationship between higher proportional bundle performance and improvements in each of the above-mentioned clinical outcomes (all p < 0.002). Significant pain was more frequently reported as bundle performance proportionally increased (p = 0.0001).
CONCLUSIONS:ABCDEF bundle performance showed significant and clinically meaningful improvements in outcomes including survival, mechanical ventilation use, coma, delirium, restraint-free care, ICU readmissions, and post-ICU discharge disposition.
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