Objectives The purpose of this study was to characterize operative outcomes for ascending aorta and arch replacement on a national scale and to develop risk models for mortality and major morbidity. ...Background Contemporary outcomes for ascending aorta and arch replacement in North America are unknown. Methods We queried the Society of Thoracic Surgeons Database for patients undergoing ascending aorta (with or without root) with or without arch replacement from 2004 to 2009. The database captured 45,894 cases, including 12,702 root, 22,048 supracoronary ascending alone, 6,786 ascending plus arch, and 4,358 root plus arch. Baseline characteristics and clinical outcomes were analyzed. A parsimonious multivariable logistic regression model was constructed to predict risks of mortality and major morbidity. Results Operative mortality was 3.4% for elective cases and 15.4% for nonelective cases. A risk model for operative mortality (c-index 0.81) revealed a risk-adjusted odds ratio for death after emergent versus elective operation of 5.9 (95% confidence interval: 5.3 to 6.6). Among elective patients, end-stage renal disease and reoperative status were the strongest predictors of mortality (adjusted odds ratios: 4.0 95% confidence interval: 2.6 to 6.4 and 2.3 (95% confidence interval: 1.9 to 2.7, respectively; p < 0.0001). Conclusions Current outcomes for ascending aorta and arch replacement in North America are excellent for elective repair; however, results deteriorate for nonelective status, suggesting that increased screening and/or lowering thresholds for elective intervention could potentially improve outcomes. The predictive models presented may serve clinicians in counseling patients.
In an iceberg-choked fjord, meltwater can drive circulation. Down-fjord of the ice, buoyancy and rotation lead to an outflowing surface coastal current hugging one side of the fjord with an inflowing ...counter-current below. To predict the structure and evolution of these currents, we develop an analytical model – complemented by numerical simulations – that involves a rectangular fjord initially at rest. Specifically, we (i) start with the so-called Rossby adjustment problem; (ii) reconfigure it for a closed channel with stratification; and (iii) generalize the conventional “dam-break” scenario to a gradual-release one that mimics the continual, slow injection of meltwater. Implicit in this description is the result that circulation is mediated by internal Kelvin waves. The analytical model shows that if the total meltwater flux increases (e.g., a larger mélange, warmer water, or enhanced ice–ocean turbulence) then circulation strength increases as would be expected. For realistic parameters, a given meltwater flux induces an exchange flow that is ∼50 times larger. This factor decreases with increasing water column stratification and vice versa. Overall, this paper is a step toward making Greenland-wide predictions of fjord inflows and outflows induced by icebergs.
Astrocytes extend highly branched processes that form functionally isolated microdomains, facilitating local homeostasis by redistributing ions, removing neurotransmitters, and releasing factors to ...influence blood flow and neuronal activity. Microdomains exhibit spontaneous increases in calcium (Ca2+), but the mechanisms and functional significance of this localized signaling are unknown. By developing conditional, membrane-anchored GCaMP3 mice, we found that microdomain activity that occurs in the absence of inositol triphosphate (IP3)-dependent release from endoplasmic reticulum arises through Ca2+ efflux from mitochondria during brief openings of the mitochondrial permeability transition pore. These microdomain Ca2+ transients were facilitated by the production of reactive oxygen species during oxidative phosphorylation and were enhanced by expression of a mutant form of superoxide dismutase 1 (SOD1 G93A) that causes astrocyte dysfunction and neurodegeneration in amyotrophic lateral sclerosis (ALS). By localizing mitochondria to microdomains, astrocytes ensure local metabolic support for energetically demanding processes and enable coupling between metabolic demand and Ca2+ signaling events.
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•Membrane-anchored GCaMP3 mice facilitate detection of microdomain Ca2+ transients•Mitochondria are localized to microdomains in astrocyte processes•Permeability transition pore opening causes microdomain mitochondrial Ca2+ events•Mitochondria-induced events are enhanced by neuronal activity and mutant SOD1
Agarwal et al. show that mitochondria in the fine processes of astrocytes produce spatially localized Ca2+ transients through brief openings of the mitochondrial transition pore, linking microdomain Ca2+ signaling in these ubiquitous glial cells to metabolic demand and mitochondrial stress.
Abstract
Aims
Elevated apolipoprotein C-III (apoC-III) levels are associated with hypertriglyceridaemia and coronary heart disease. AKCEA-APOCIII-LRx is an N-acetyl galactosamine-conjugated antisense ...oligonucleotide targeted to the liver that selectively inhibits apoC-III protein synthesis.
Methods and results
The safety, tolerability, and efficacy of AKCEA-APOCIII-LRx was assessed in a double-blind, placebo-controlled, dose-escalation Phase 1/2a study in healthy volunteers (ages 18–65) with triglyceride levels ≥90 or ≥200 mg/dL. Single-dose cohorts were treated with 10, 30, 60, 90, and 120 mg subcutaneously (sc) and multiple-dose cohorts were treated with 15 and 30 mg weekly sc for 6 weeks or 60 mg every 4 weeks sc for 3 months. In the single-dose cohorts treated with 10, 30, 60, 90, or 120 mg of AKCEA-APOCIII-LRx, median reductions of 0, −42%, −73%, −81%, and −92% in apoC-III, and −12%, −7%, −42%, −73%, and −77% in triglycerides were observed 14 days after dosing. In multiple-dose cohorts of 15 and 30 mg weekly and 60 mg every 4 weeks, median reductions of −66%, −84%, and −89% in apoC-III, and −59%, −73%, and −66% in triglycerides were observed 1 week after the last dose. Significant reductions in total cholesterol, apolipoprotein B, non-high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol, and increases in HDL-C were also observed. AKCEA-APOCIII-LRx was well tolerated with one injection site reaction of mild erythema, and no flu-like reactions, platelet count reductions, liver, or renal safety signals.
Conclusion
Treatment of hypertriglyceridaemic subjects with AKCEA-APOCIII-LRx results in a broad improvement in the atherogenic lipid profile with a favourable safety and tolerability profile. ClinicalTrials.gov Identifier: NCT02900027.
The adult CNS contains an abundant population of oligodendrocyte precursor cells (NG2(+) cells) that generate oligodendrocytes and repair myelin, but how these ubiquitous progenitors maintain their ...density is unknown. We generated NG2-mEGFP mice and used in vivo two-photon imaging to study their dynamics in the adult brain. Time-lapse imaging revealed that NG2(+) cells in the cortex were highly dynamic; they surveyed their local environment with motile filopodia, extended growth cones and continuously migrated. They maintained unique territories though self-avoidance, and NG2(+) cell loss though death, differentiation or ablation triggered rapid migration and proliferation of adjacent cells to restore their density. NG2(+) cells recruited to sites of focal CNS injury were similarly replaced by a proliferative burst surrounding the injury site. Thus, homeostatic control of NG2(+) cell density through a balance of active growth and self-repulsion ensures that these progenitors are available to replace oligodendrocytes and participate in tissue repair.
Delirium's pathophysiology is poorly understood. We sought to determine if plasma biomarkers of inflammation, coagulation, endothelial activation, and blood brain barrier (BBB) injury were associated ...with emergency department (ED) delirium duration.
We enrolled hospitalized patients who were 65 years or older from the ED. Plasma biomarkers of inflammation (interleukin-6 IL-6, IL-8, soluble tumor necrosis factor receptor I sTNFRI), coagulation (Protein C), endothelial activation (plasminogen activating inhibitor-1 PAI-1), and BBB injury (S100B) at were measured using blood obtained at enrollment. The dependent variable was ED delirium duration which was determined by the Brief Confusion Assessment Method assessed in the ED and hospitalization. Proportional odds logistic regression analyses were performed adjusted for relevant confounders and allowing for interaction by baseline dementia status.
A total of 156 patients were enrolled. IL-6 (POR = 1.59, 95%CI: 1.09-2.32) and PAI-1 (POR = 2.96, 95%CI: 1.48 to 6.85) were independently associated with more prominent ED delirium duration in subjects without dementia only. No significant associations between IL-8, Protein C, sTNRFI, and S100B and ED delirium duration were observed.
Plasma Biomarkers of systemic inflammation and endothelial activation are associated with ED delirium duration in older ED patients without dementia.
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.
In this study, patients treated in ICUs were at high risk for new cognitive impairment during 12 months of follow-up, with 24% of patients having deficits similar in severity to those in Alzheimer's ...disease. A longer duration of delirium was associated with worse cognitive scores.
Survivors of critical illness frequently have a prolonged and poorly understood form of cognitive dysfunction,
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–
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which is characterized by new deficits (or exacerbations of preexisting mild deficits) in global cognition or executive function. This long-term cognitive impairment after critical illness may be a growing public health problem, given the large number of acutely ill patients being treated in intensive care units (ICUs) globally.
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Among older adults, cognitive decline is associated with institutionalization,
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hospitalization,
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and considerable annual societal costs.
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,
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Yet little is known about the epidemiology of long-term cognitive impairment after critical illness.
Delirium, a form of acute brain . . .
The bacterial endosymbiont Wolbachia manipulates arthropod host biology in numerous ways, including sex ratio distortion and differential offspring survival. These bacteria infect a vast array of ...arthropods, some of which pose serious agricultural and human health threats. Wolbachia‐mediated phenotypes such as cytoplasmic incompatibility and/or pathogen interference can be used for vector and disease control; however, many medically important vectors and important agricultural species are uninfected or are infected with strains of Wolbachia that do not elicit phenotypes desirable for disease or pest control. The ability to transfer strains of Wolbachia into new hosts (transinfection) can create novel Wolbachia–host associations. Transinfection has two primary benefits. First, Wolbachia–host interactions can be examined to tease apart the influence of the host and bacteria on phenotypes. Second, desirable phenotypes induced by Wolbachia in a particular insect can be transferred to another recipient host. This can allow the manipulation of insect populations that transmit pathogens or detrimentally affect agriculture. As such, transinfection is a valuable tool to explore Wolbachia biology and control arthropod‐borne disease. The present review summarizes what is currently known about Wolbachia transinfection methods and applications. We also provide a comprehensive list of published successful and unsuccessful Wolbachia transinfection attempts.
Treatment options are limited for patients with recurrent and/or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC); mortality rates exceed 70% in patients with distant metastases. Here, we ...present the first interim analysis of the R/M cSCC cohort from the 2-cohort-locally advanced and R/M-phase II KEYNOTE-629 study.
Patients with R/M cSCC not amenable to surgery or radiation received pembrolizumab 200 mg every 3 weeks. The primary end point was objective response rate per RECIST v1.1. Secondary end points were duration of response, disease control rate, progression-free survival, overall survival, and safety.
At data cutoff (April 8, 2019), median follow-up of 105 enrolled patients in the R/M cohort was 11.4 months (range, 0.4 to 16.3 months). Objective response rate was 34.3% (95% CI, 25.3% to 44.2%; 4 complete responses, 32 partial responses), and disease control rate was 52.4% (95% CI, 42.4% to 62.2%). Median duration of response was not reached (range, 2.7 to 13.1+ months; '+' refers to ongoing response at data cutoff). Median progression-free survival was 6.9 months (95% CI, 3.1 months to 8.5 months). Median overall survival was not reached (95% CI, 10.7 months to not reached). Treatment-related adverse events occurred in 66.7% of patients (n = 70), the most common of which were pruritus (n = 15; 14.3%), asthenia (n = 14; 13.3%), and fatigue (n = 13; 12.4%). Grade 3 to 5 treatment-related adverse events occurred in 5.7% (n = 6) of patients. One patient died of treatment-related cranial nerve neuropathy.
Pembrolizumab demonstrated effective antitumor activity; clinically meaningful, durable responses; and acceptable safety in primarily elderly patients with R/M cSCC, supporting its use in clinical practice. Pembrolizumab adverse events in this study were consistent with its established safety profile.
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