OBJECTIVE: Perfluoroalkyl chemicals (PFCs) have been used worldwide in a variety of consumer products. The effect of PFCs on glucose homeostasis is not known. RESEARCH DESIGN AND METHODS: We examined ...474 adolescents and 969 adults with reliable serum measures of metabolic syndrome profile from the National Health and Nutrition Examination Survey 1999-2000 and 2003-2004. RESULTS: In adolescents, increased serum perfluorononanoic acid (PFNA) concentrations were associated with hyperglycemia (odds ratio OR 3.16 95% CI 1.39-7.16, P < 0.05). Increased serum PFNA concentrations also have favorable associations with serum HDL cholesterol (0.67 0.45-0.99, P < 0.05). Overall, increased serum PFNA concentrations were inversely correlated with the prevalence of the metabolic syndrome (0.37 0.21-0.64, P < 0.005). In adults, increased serum perfluorooctanoic acid concentrations were significantly associated with increased β-cell function (β coefficient 0.07 ± 0.03, P < 0.05). Increased serum perfluorooctane sulfate (PFOS) concentrations were associated with increased blood insulin (0.14 ± 0.05, P < 0.01), homeostasis model assessment of insulin resistance (0.14 ± 0.05, P < 0.01), and β-cell function (0.15 ± 0.05, P < 0.01). Serum PFOS concentrations were also unfavorably correlated with serum HDL cholesterol (OR 1.61 95% CI 1.15-2.26, P < 0.05). CONCLUSIONS: Serum PFCs were associated with glucose homeostasis and indicators of metabolic syndrome. Further clinical and animal studies are warranted to clarify putative causal relationships.
Leber's hereditary optic neuropathy (LHON) is a rare inherited blindness caused by mutations in the mitochondrial DNA (mtDNA). The disorder is untreatable and tricky, as the existing chemotherapeutic ...agent Idebenone alleviates symptoms rather than overcoming the underlying cause. Although some studies have made progress on allotopic expression for LHON, in situ mitochondrial gene therapy remains challenging, which may simplify delivery procedures to be a promising therapeutic for LHON. LHON becomes more difficult to manage in the changed mitochondrial microenvironment, including increasing reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP). Herein, a pathologically responsive mitochondrial gene delivery vector named triphenylphosphine‐terminated poly(sulfur‐containing thioketal undecafluorohexylamine histamine) and Ide‐terminated poly(sulfur‐containing thioketal undecafluorohexylamine histamine) (TISUH) is reported to facilitate commendable in situ mitochondrial gene therapy for LHON. TISUH directly targets diseased mitochondria via triphenylphosphine and fluorination addressing the decreasing MMP. In addition, TISUH can be disassembled by high mitochondrial ROS levels to release functional genes for enhancing gene transfection efficiency and fundamentally correcting genetic abnormalities. In both traditional and gene‐mutation‐induced LHON mouse models, TISUH‐mediated gene therapy shows satisfactory curative effect through the sustained therapeutic protein expression in vivo. This work proposes a novel pathologically responsive in situ mitochondrial delivery platform and provides a promising approach for refractory LHON as well as other mtDNA mutated diseases treatments.
A pathologically responsive mitochondrial gene therapy referred to as “TISUH” in an allotopic expression‐independent manner achieves accurately in situ mitochondrial gene delivery. It is a novel nanomedicine harnessing pathological characteristics to import exogenous gene into mitochondria for Leber's hereditary optic neuropathy treatment, a capability that has potential to model mitochondrial DNA (mtDNA) mutated disorders and correct genetic abnormalities in other mtDNA mutated diseases.
Background
Atrial fibrillation (AF) recurrence rates in 1 year after cryoballoon ablation catheter (CBCA) are still high. We purposed to identify strong predictors for AF recurrence after the ...successful CBCA procedure and develop a new scoring system based only on pre‐procedural parameters.
Methods
In the derivation phase, a systematic review and meta‐analysis identified the strong predictors of AF recurrence after the CBCA. The pooled hazard ratio (HR) was used to create the new scoring system. The second phase validated the new scoring system in the cohort population.
Results
A meta‐analysis including 29 cohort studies with 16196 participants confirmed that persistent AF, stroke, heart failure, and left atrial diameter (LAD) >40 mm were powerful predictors for AF recurrence after the CBCA procedure. The HeLPS‐Cryo (heart failure 1, left atrial dilatation 1, persistent AF 2, and stroke 2) was developed based on those pre‐procedural predictors. It was validated in 140 patients receiving CBCA procedures and revealed excellent predictive performance for 1‐year AF recurrence (AUC = 0.8877; 95% CI = 0.8208 to 0.9546). The HeLPS‐Cryo score of ≥3 could predict 1‐year AF recurrence with sensitivity and specificity of 78.9% and 87.9%, respectively. The positive predictive value was 66.7%, and the negative predictive value was 93.1%.
Conclusion
The HeLPS‐Cryo score can help the physician estimate the probability of 1‐year AF recurrence after the successful CBCA procedure. Patients with HeLPS‐Cryo score <3 are good candidates for the CBCA procedure.
Neuropeptide FF (NPFF) belongs to the RFamide family and is known as a morphine-modulating peptide. NPFF regulates various hypothalamic functions through two receptors, NPFFR1 and NPFFR2. The ...hypothalamic-pituitary-adrenal (HPA) axis participates in physiological stress response by increasing circulating glucocorticoid levels and modulating emotional responses. Other RFamide peptides, including neuropeptide AF, neuropeptide SF and RFamide related peptide also target NPFFR1 or NPFFR2, and have been reported to activate the HPA axis and induce anxiety- or depression-like behaviors. However, little is known about the action of NPFF on HPA axis activity and anxiety-like behaviors, and the role of the individual receptors remains unclear. In this study, NPFFR2 agonists were used to examine the role of NPFFR2 in activating the HPA axis in rodents. Administration of NPFFR2 agonists, dNPA (intracerebroventricular, ICV) and AC-263093 (intraperitoneal, IP), time-dependently (in rats) and dose-dependently (in mice) increased serum corticosteroid levels and the effects were counteracted by the NPFF receptor antagonist, RF9 (ICV), as well as corticotropin-releasing factor (CRF) antagonist, α-helical CRF(9-41) (intravenous, IV). Treatment with NPFFR2 agonist (AC-263093, IP) increased c-Fos protein expression in the hypothalamic paraventricular nucleus and induced an anxiogenic effect, which was evaluated in mice using an elevated plus maze. These findings reveal, for the first time, that the direct action of hypothalamic NPFFR2 stimulates the HPA axis and triggers anxiety-like behaviors.
Electrocardiogram (ECG)-based intelligent screening for systolic heart failure (HF) is an emerging method that could become a low-cost and rapid screening tool for early diagnosis of the disease ...before the comprehensive echocardiographic procedure. We collected 12-lead ECG signals from 900 systolic HF patients (ejection fraction, EF < 50%) and 900 individuals with normal EF in the absence of HF symptoms. The 12-lead ECG signals were converted by continuous wavelet transform (CWT) to 2D spectra and classified using a 2D convolutional neural network (CNN). The 2D CWT spectra of 12-lead ECG signals were trained separately in 12 identical 2D-CNN models. The 12-lead classification results of the 2D-CNN model revealed that Lead V6 had the highest accuracy (0.93), sensitivity (0.97), specificity (0.89), and f1 scores (0.94) in the testing dataset. We designed four comprehensive scoring methods to integrate the 12-lead classification results into a key diagnostic index. The highest quality result among these four methods was obtained when Leads V5 and V6 of the 12-lead ECG signals were combined. Our new 12-lead ECG signal-based intelligent screening method using straightforward combination of ECG leads provides a fast and accurate approach for pre-screening for systolic HF.
This study aimed to evaluate whether quantitative analysis of wrist photoplethysmography (PPG) could detect atrial fibrillation (AF). Continuous electrocardiograms recorded using an electrophysiology ...recording system and PPG obtained using a wrist-worn smartwatch were simultaneously collected from patients undergoing catheter ablation or electrical cardioversion. PPG features were extracted from 10, 25, 40, and 80 heartbeats of the split segments. Machine learning with a support vector machine and random forest approach were used to detect AF. A total of 116 patients were evaluated. We annotated > 117 h of PPG. A total of 6475 and 3957 segments of 25-beat pulse-to-pulse intervals (PPIs) were annotated as AF and sinus rhythm, respectively. The accuracy of the 25 PPIs yielded a test area under the receiver operating characteristic curve (AUC) of 0.9676, which was significantly better than the AUC for the 10 PPIs (0.9453; P < .001). PPGs obtained from another 38 patients with frequent premature ventricular/atrial complexes (PVCs/PACs) were used to evaluate the impact of other arrhythmias on diagnostic accuracy. The new AF detection algorithm achieved an AUC of 0.9680. The appropriate data length of PPG for optimizing the PPG analytics program was 25 heartbeats. Algorithm modification using a machine learning approach shows robustness to PVCs/PACs.
Abstract
Background
Few dosimetric comparisons have been published between linear accelerator (LA)-based systems and CyberKnife (CK)-based robotic radiosurgery systems for cardiac radio-ablation in ...ventricular tachycardia. This study aimed to compare the dosimetry of noninvasive cardiac radio-ablation deliverable on LA with that on CK.
Methods
Thirteen patients who underwent noninvasive cardiac radio-ablation by LA were included. The prescribed dose was 25 Gy in 1 fraction, and the average planning target volume was 49.8 ± 31.0 cm
3
(range, 14.4–93.7 cm
3
). CK plans were generated for comparison.
Results
Both the CK and LA plans accomplished appropriate dose coverage and normal tissue sparing. Compared with the LA plans, the CK plans achieved significantly lower gradient indices (3.12 ± 0.71 vs. 3.48 ± 0.55,
p
= 0.031) and gradient measures (1.00 ± 0.29 cm vs. 1.17 ± 0.29 cm,
p
< 0.001). They had similar equivalent conformity indices (CK vs. LA: 0.84 ± 0.08 vs. 0.87 ± 0.07,
p
= 0.093) and maximum doses 2 cm from the planning target volume (PTV) in any direction (CK vs. LA: 50.8 ± 9.9% vs. 53.1 ± 5.3%,
p
= 0.423). The dosimetric advantages of CK were more prominent in patients with a PTV of ≤ 50 cm
3
or a spherical PTV. In patients with a PTV of > 50 cm
3
or a non-spherical PTV, the LA and CK plans were similar regarding dosimetric parameters. CK plans involved more beams (232.2 ± 110.8 beams vs. 10.0 ± 1.7 arcs) and longer treatment times (119.2 ± 43.3 min vs. 22.4 ± 1.6 min,
p
= 0.007).
Conclusions
Both CK and LA are ideal modalities for noninvasive cardiac radio-ablation. Upfront treatment should be considered based on clinical intent.
Aims
It has been proposed that an increase of myocardial adiposity is related to left ventricular (LV) diastolic dysfunction. The specific roles of myocardial steatosis including epicardial fat and ...intramyocardial fat for diastolic function are unknown in those patients suffering heart failure (HF) with reduced (HFrEF) or preserved ejection fraction (HFpEF). This study aims to determine the complex relationship between myocardial adiposity in patients with HFrEF or HFpEF.
Methods and results
Using cardiac magnetic resonance imaging (CMRI), myocardial steatosis was measured in 305 subjects (34 patients with HFrEF, 163 with HFpEF, and 108 non‐HF controls). We also evaluated cardiac structure and diastolic and systolic function by echocardiography and CMRI. Patients with HFpEF had significantly more intramyocardial fat than HFrEF patients or non‐HF controls intramyocardial fat content (%), 1.56 (1.26, 1.89) vs. 0.75 (0.50, 0.87) and 1.0 (0.79, 1.15), P < 0.05. Intramyocardial fat amount (%) was higher in HFpEF women than in men 1.91% (1.17%, 2.32%) vs. 1.22 (0.87%, 2.02%), P = 0.01. When estimated by CMRI (left ventricular peak filling rate), echocardiographic E/e′ level, or left atrial volume index, intramyocardial fat correlated with LV diastolic dysfunction parameters in HFpEF patients, and this was independent of age, co‐morbidities, body mass index, gender, and myocardial fibrosis (standardized coefficient: β = −0.34, P = 0.03; β = 0.29, P = 0.025; and β = 0.25, P = 0.02, respectively).
Conclusions
Patients with HFpEF had significantly more intramyocardial fat than HFrEF patients or non‐HF controls. Independent of risk factors or gender, intramyocardial fat correlated with LV diastolic dysfunction parameters in HFpEF patients.
Abstract
Background
Adding radiotherapy (RT) to systemic therapy improves progression-free survival (PFS) and overall survival (OS) in oligometastatic non-small cell lung cancer (NSCLC). Whether ...these findings translate to epidermal growth factor receptor (EGFR)–mutated NSCLC remains unknown. The SINDAS trial (NCT02893332) evaluated first-line tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated synchronous oligometastatic NSCLC and randomized to upfront RT vs no RT; we now report the prespecified interim analysis at 68% accrual.
Methods
Inclusion criteria were biopsy-proven EGFR-mutated adenocarcinoma (per amplification refractory mutation system or next generation sequencing), with synchronous (newly diagnosed, treatment naïve) oligometastatic (≤5 metastases; ≤2 lesions in any one organ) NSCLC without brain metastases. All patients received a first-generation TKI (gefitinib, erlotinib, or icotinib), and randomization was between no RT vs RT (25-40 Gy in 5 fractions depending on tumor size and location) to all metastases and the primary tumor/involved regional lymphatics. The primary endpoint (intention to treat) was PFS. Secondary endpoints included OS and toxicities. All statistical tests were 2-sided.
Results
A total of 133 patients (n = 65 TKI only, n = 68 TKI with RT) were enrolled (2016-2019). The median follow-up was 23.6 months. The respective median PFS was 12.5 months vs 20.2 months (P < .001), and the median OS was 17.4 months vs 25.5 months (P < .001) for TKI only vs TKI with RT. Treatment yielded no grade 5 events and a 6% rate of symptomatic grade 3-4 pneumonitis in the TKI with RT arm. Based on the efficacy results of this prespecified interim analysis, the ethics committee recommended premature cessation of this trial.
Conclusions
As compared with a first-line TKI alone, addition of upfront local therapy using RT statistically significantly improved PFS and OS for EGFR-mutated NSCLC.
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