Citations

Cell surface receptors control how cells respond to their environment. Many cell surface receptors recycle from endosomes to the plasma membrane via a recently discovered pathway, which includes sorting-nexin SNX17, Retriever, WASH, and CCC complexes. Here, using mammalian cells, we discover that PIKfyve and its upstream PI3-kinase VPS34 positively regulate this pathway. VPS34 produces phosphatidylinositol 3-phosphate (PI3P), which is the substrate for PIKfyve to generate PI3,5P 2 . We show that PIKfyve controls recycling of cargoes including integrins, receptors that control cell migration. Furthermore, endogenous PIKfyve colocalizes with SNX17, Retriever, WASH, and CCC complexes on endosomes. Importantly, PIKfyve inhibition results in displacement of Retriever and CCC from endosomes. In addition, we show that recruitment of SNX17 is an early step and requires VPS34. These discoveries suggest that VPS34 and PIKfyve coordinate an ordered pathway to regulate recycling from endosomes and suggest how PIKfyve functions in cell migration.

PurposeTo improve the estimation of coil sensitivity functions from limited auto‐calibration signals (ACS) in SENSE‐based reconstruction for brain imaging.MethodsWe propose to use deep learning to estimate coil sensitivity functions by leveraging information from previous scans obtained using the same RF receiver system. Specifically, deep convolutional neural networks were designed to learn an end‐to‐end mapping from the initial sensitivity to the high‐resolution counterpart. Sensitivity alignment was further proposed to reduce the geometric variation caused by different subject positions and imaging FOVs. Cross‐validation with a small set of datasets was performed to validate the learned neural network. Iterative SENSE reconstruction was adopted to evaluate the utility of the sensitivity functions from the proposed and conventional methods.ResultsThe proposed method produced improved sensitivity estimates and SENSE reconstructions compared to the conventional methods in terms of aliasing and noise suppression with very limited ACS data. Cross‐validation with a small set of data demonstrated the feasibility of learning coil sensitivity functions for brain imaging. The network learned on the spoiled GRE data can be applied to predict sensitivity functions for spin‐echo and MPRAGE datasets.ConclusionA deep learning‐based method has been proposed for improving the estimation of coil sensitivity functions. Experimental results have demonstrated the feasibility and potential of the proposed method for improving SENSE‐based reconstructions especially when the ACS data are limited.

Background Women are less likely to receive primary percutaneous coronary intervention (pPCI) than men. A potential reason is risk aversion because of the worse outcomes with pPCI among women. However, whether pPCI is associated with a comparable mortality benefit in men and women remains unknown. Methods and Results We selected patients admitted with a principal diagnosis of ST‐segment–elevation myocardial infarction in the National Inpatient Sample (2016–2018). We used propensity‐score matching to calculate average treatment effects of pPCI for in‐hospital mortality, major complications, length of stay, and cost. As a sensitivity analysis, we used logit models followed by a marginal command to calculate the average marginal effect. We included 413 500 weighted hospitalizations (30.7% women, 69.3% men). Women had more comorbidities except smoking and prior sternotomy. Compared with men, women were less likely to undergo angiography (81.0% versus 87.0%; adjusted odds ratio [OR], 0.77; 95% CI, 0.74–0.81; P <0.001) or pPCI (74.0% versus 82.0%; adjusted OR, 0.76; 95% CI, 0.73–0.79; P <0.001). There were no significant differences in average treatment effects of pPCI on mortality between men (−8.4% [−9.3% to −7.6%], P <0.001), and women (−9.5% [−10.8% to −8.3%], P <0.001) ( P interaction=0.16). This persisted in age‐stratified analyses (≥85, 65–84, 45–64, <45 years) and sensitivity analysis, excluding emergent admissions. The average treatment effects of pPCI on major complications were comparable except for acute stroke, leaving against medical advice, and palliative encounter. There were no differences in the average treatment effects of pPCI on length of stay, but the proportional increase in cost with pPCI was higher in women. Conclusions pPCI results in a comparable reduction in in‐hospital mortality in men and women. Nonetheless, risk‐adjusted rates of pPCI remain lower in women in contemporary US practice.

Palliative care has evolved to be an integral part of comprehensive cancer care with the goal of early intervention to improve quality of life and patient outcomes. The NCCN Guidelines for Palliative Care provide recommendations to help the primary oncology team promote the best quality of life possible throughout the illness trajectory for each patient with cancer. The NCCN Palliative Care Panel meets annually to evaluate and update recommendations based on panel members’ clinical expertise and emerging scientific data. These NCCN Guidelines Insights summarize the panel’s recent discussions and highlights updates on the importance of fostering adaptive coping strategies for patients and families, and on the role of pharmacologic and nonpharmacologic interventions to optimize symptom management.

Background: Renal dysfunction has emerged as an important independent prognostic factor in patients with heart failure (HF). Cardiac resynchronization therapy (CRT) improves functional status and left ventricular (LV) function in HF patients with ventricular dyssynchrony. We hypothesized that CRT would also improve glomerular filtration rate as estimated by the abbreviated MDRD equation (eGFR) in patients with reduced eGFR. Methods: This is a retrospective analysis of the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) study, which evaluated CRT in HF patients with NYHA class III–IV, ejection fraction ≤35%, QRS ≥130 ms, and stable medical regimen. Patients were evaluated before implantation and 6 months after randomization to control (CRT device OFF, n=225) or CRT (n=228). Patients were categorized according to their baseline eGFR: ≥90 (category A), 60≤eGFR<90 (category B), and 30≤eGFR<60 (category C) mL/min per 1.73m 2 . Changes in eGFR were also correlated with changes in other parameters in univariate analysis. Results: At baseline, reduced eGFR was associated with ischemic etiology, increased age, mitral regurgitation, and neurohumoral activation. CRT increased LV ejection fraction and decreased LV volumes and mitral regurgitation in all categories. Importantly, CRT improved eGFR (p=0.003) and reduced blood urea nitrogen (p=0.008) compared to control in category C, but not A (p=0.75/p=0.41) and B (p=0.43/p=0.89). In addition, only in category C did atrial natriuretic peptide decrease, suggesting reduced atrial distention and filling pressures with CRT in this group with impaired eGFR. In univariate analysis, changes in eGFR correlated weakly but significantly with changes in aldosterone (r=−0.22), plasma renin activity (r=−0.19, norepinephrine (r=−0.16), and mean blood pressure (r=+0.14), a pattern consistent with reduced neurohumoral activation due to increased systemic and renal perfusion pressure. Conclusions: CRT increased eGFR and reduced blood urea nitrogen in HF patients with reduced baseline eGFR. By improving cardiac function, CRT can indirectly improve renal function, underscoring the importance of cardiorenal interaction and providing another mechanism for the beneficial effects of CRT.

Mesenchymal stem cells (MSCs) have been shown to improve regeneration of injured tissues in vivo. Several in vitro studies and animal models have demonstrated improvement in MSCs paracrine effects under hypoxic conditions. Moreover, several studies suggested that the pro B-type natriuretic peptide (pro-BNP) could be involved in the stimulation of postischemic vascular regeneration. The purpose of this study was to investigate the effect of critical limb ischemia, in a human model, on in-situ adipose derived mesenchymal stem cells (ADMSCs) and to determine whether serum levels of N-terminal pro-BNP correlate with ADMSCs counts and associated paracrine effects. Lipoaspirate samples of ≥ 10mL were collected from ischemic limbs (ischemic group) and compared to control (without ischemia). MSCs were characterized by frequency, viability, differentiation potential, cytokines expression, and cell surface markers. Serum NT pro-BNP was measured as well. MSCs counts were 9-to-10-fold higher in patients with ischemic limbs (mean 7952 MSC/mL ± 542) than controls (mean 790 MSC/mL ± 65). Pro-BNP levels (1878-4757 pg/mL) were approximately 8-to-26-fold higher than in age- and sex-matched controls. Furthermore, there were positive correlations between pro-BNP levels and MSCs counts in the ischemic group. In conclusion, patients with critical limb ischemia (CLI) have higher levels of pro-BNP and MSCs counts than controls. Increased levels of pro-BNP and MSCs counts can be considered humoral and cellular surrogates of ischemia and hypoxia in patients with CLI. This supports recent studies that suggest that the increase production of peripheral BNP may be a stem cells-mediated response to stimulate angiogenesis in the ischemic skeletal muscles.

As genomic sequencing expands to screen larger numbers of individuals, offering genetic counseling to everyone may not be possible. One approach to managing this limitation is for a genetic counselor to communicate clinically actionable results in person or by telephone, but report other results by mail. We employed this approach in a large genomic implementation study. In this paper, we describe participants’ experiences receiving genomic screening results by mail. We conducted 50 semi-structured telephone interviews with individuals who received neutral genomic screening results by mail. Most participants were satisfied receiving neutral results by mail. Participants generally had a good understanding of results; however, a few participants had misunderstandings about their genomic screening results, including mistaken beliefs about their disease risk and the comprehensiveness of the test. No one reported plans to alter health behaviors, defer medical evaluations, or take other actions that might be considered medically problematic. Reporting neutral results by mail is unlikely to cause recipients distress or generate misunderstandings that may result in reduced vigilance in following recommended preventive health strategies. Nonetheless, some individuals may benefit from additional genetic counseling support to help situate their results in the context of personal concerns and illness experiences.