Notes

Chemoradiation induced a number of sclerosis-like demyelination.
60 ± 0.25 μg L-1 MC-RR and 3.83 ± 0.22 μg L-1 MC-YR. These bioaccessibility results should be considered for a more accurate risk assessment related to these cyanotoxins in mussels, including the fact that the steaming waters could also represent a risk after human consumption. Repairing a large tracheoesophageal fistula with an extensive involvement of membranous wall of the trachea is sometimes troublesome, due to a lack of ideal replacement for the large defect. We report a case of successful use a pedicled sternocleidomastoid musculocutaneous flap to repair a large tracheoesophageal fistula, in which the cutaneous component was applied to the defect of membranous trachea after tracheal resection, and the muscular component was interposed between the tracheal and esophageal walls. Several studies have been published describing the clinical and radiographic findings on the novel coronavirus (COVID-19) pneumonia. Therefore, there is currently a lack of pathologic data about its effects in intubated patients. Pneumothorax may occur rarely and results from a combination of fibrotic parenchyma with prolonged high-pressure ventilation. Chest drain represent the first line treatment. However, in case of persistent pneumothorax, thoracoscopy and bleb resection may be a feasible option to reduce air leak and improve ventilation. We report the cases of two COVID-19 patients successfully treated with thoracoscopy, bleb resection, and pleurectomy for persistent pneumothorax. The COVID-19 pandemic necessitates aggressive infection mitigation strategies to reduce the risk to patients and healthcare providers. This document is intended to provide a framework for the adult cardiac surgeon to consider in this rapidly changing environment. Pre, intra, and post-operative detailed protective measures are outlined. These are guidance recommendations during a pandemic surge to be utilized for ALL patients while local COVID-19 disease burden remains elevated. Truncus arteriosus with interrupted aortic arch (TA/IAA) represents a complex lesion with high rates of reintervention. We present a novel technique of a composite flap, made possible by aberrant right subclavian anatomy. Truncus arteriosus with interrupted aortic arch (TA/IAA) was previously believed to portend a significantly worse outcome[1], however more recent series have shown improved survival [2], likely due to improved surgical, perfusion, and anesthetic techniques. Despite improvements in mortality, rates of re-operation for aortic arch related complications remain high [3]. Therefore, techniques to reduce the rate of reintervention, particularly involving increased utilization of autologous tissue would seem beneficial. BACKGROUND Although open reduction and internal fixation (ORIF) is an accepted treatment for a proportion of acute rib fractures, there is paucity of literature on its potential to treat chronic, non-union fractures. This study evaluates the outcomes and quality of life of patients who underwent ORIF for chronic, symptomatic non-union rib fractures. METHODS Thirty two patients were explored for possible ORIF of non-union rib fractures (> 6 months after injury). After excluding non-English speaking patients (n=1), those where no instability was noted at surgery (n=3), and those deceased at the time of study (n=4), 24 patients were eligible. Telephone interviews were conducted using a previously published rib fracture pain questionnaire. RESULTS Seventy percent (19/24) of eligible patients consented and completed the questionnaire at a median time from surgery of 55 months (interquartile range [IQR] 24-62 months). Injuries were classified as multi-system trauma (n=4) or isolated rib fractures (n=15). The median pain severity (on a scale of 1 [none/mild] -10 [severe]) significantly decreased from preoperatively (9, IQR 7-10) to postoperatively (1, IQR 0-2); p less then 0.001. The majority of patients returned to daily activities, were able to work at their pre-injury level, were satisfied with their surgery and would undergo operative management again. CONCLUSIONS Patients who underwent ORIF reported a significant decrease in fracture-associated symptoms and pain severity postoperatively. The majority returned to daily activities, work at pre-injury levels and were satisfied with surgery. ORIF should be considered as an option to help patients with symptomatic non-union rib fractures. BACKGROUND Although lobectomy remains the standard of care for early-stage non-small cell lung cancer (NSCLC), several studies suggest equipoise between lobectomy and stereotactic body radiation therapy (SBRT). However, randomized evidence is lacking. We compared outcomes of early-stage NSCLC patients treated with lobectomy or SBRT. METHODS We included clinical T1-2N0 NSCLC treated with lobectomy or SBRT to a biologically effective dose (BED) of ≥ 100 Gy10. We used Cox proportional hazards and nearest-neighbor propensity score (21) matching to adjust for confounders. Kaplan-Meier curves were used to assess survival and recurrence. RESULTS We identified 554 patients treated with lobectomy (n = 389) or SBRT (n = 165) at our institution between 2008 and 2018. After propensity score matching, there were 132 and 85 lobectomy and SBRT patients, respectively. SBRT was associated with increased local recurrence (HR = 6.80; 95% CI 1.92- 24.10; p = 0.003) and regional nodal recurrence (HR = 2.58; 95% CI 1.17 - 5.68; p = 0.018), as well as worse overall survival (HR = 2.00; 95% CI 1.21 - 3.32; p = 0.007) and progression-free survival (HR = 2.34; 95% CI 1.50 - 3.67; p less then 0.001).There was no difference in distant recurrence (HR = 1.19; 95% CI 0.57 - 2.52; p = 0.64). CONCLUSIONS We found superior outcomes in patients with early-stage NSCLC treated with lobectomy compared to SBRT, including locoregional control. These findings should be interpreted with caution, due to selection bias, but underscore the importance of robust randomized prospective data to clarify the relative efficacy of these modalities. The presence of parenchymal or intra-bronchial endometrial tissue is rare and has been reported in less then 6% of women of childbearing age with thoracic endometriosis. Hemoptysis during the menstrual cycle is the most common clinical presentation. We report a case of pulmonary endometriosis, treated concurrently with the patient's menstrual period, with wedge resection by video assisted thoracoscopy surgery (VATS). Bronchoscopy, immediately before the start of the surgical procedure, allowed us to identify the pulmonary segment that had active bleeding, which made the surgical procedure feasible. Limited lower detection ranges associated with traditional immunoassay techniques have prevented the use of brain-specific proteins as blood biomarkers of stroke in the acute phase of care, as these proteins are often only present in circulation at low concentrations. Digital ELISA is a newly developed technique with allows for quantification of proteins in biofluids with up to 1000 times greater sensitivity than conventional ELISA techniques. The purpose of this study was to determine whether the extended lower limits of detection associated with digital ELISA could enable the use of brain-specific proteins as blood biomarkers of ischemic stroke during triage. Blood was sampled from ischemic stroke patients (n = 14) at emergency department admission, as well as from neurologically normal controls matched in terms of risk factors for cardiovascular disease (n = 33). Plasma levels of two brain-specific axonal proteins, neurofilament light chain (NfL) and tau, were measured via digital ELISA, and receiver-operating characteristic analysis was used to determine their ability to discriminate between groups. Plasma levels of NfL and tau were both significantly elevated in stroke patients versus controls, and could respectively discriminate between groups with 92.9% sensitivity / 84.9% specificity, and 85.7% sensitivity / 54.6% specificity. Furthermore, adjustment of measured NfL and Tau levels according to the lower-limits of detection associated with commercially-available conventional ELISA assays resulted in a dramatic and statistically significant decrease in diagnostic performance. Collectively, our results suggest that the increased analytical sensitivity of digital ELISA could enable the use of brain-specific proteins as blood biomarkers of ischemic stroke during triage. V.Remote ischemic perconditioning (RIPerC) results in collateral enhancement and a reduction in middle cerebral artery occlusion (MCAO) induced ischemia. RIPerC likely activates multiple metabolic protective mechanisms, including effects on matrix metalloproteinases (MMPs) and protein kinases. Here we explore if RIPerC improves neuroprotection and collateral flow by modifying the activities of MMP-9 and AMPK/e-NOS. Age matched adult male Sprague Dawley rats were subjected to MCAO followed one hour later by RIPerC (3 cycles of 15 min ischemia). Animals were euthanized 24 h post-MCAO. Haematoxylin and Eosin (H&E) staining 24 h post-MCAO revealed a significant (p less then 0.02) reduction in the infarction volume in RIPerC treated animals (24.9 ± 5.4%) relative to MCAO controls (42.5 ± 4.2, %). TUNEL staining showed a 42.6% reduction in the apoptotic cells with RIPerC treatment (p less then 0.01). Immunoblotting in congruence with RT-PCR and Zymography showed that RIPerC significantly reduced MMP-9 expression and activity in RIPerC + MCAO group compared to MCAO group (218.3 ± 19.1% vs. 148.9 ± 12.05% (p less then 0.01). Immunoblotting revealed that RIPerC was associated with a significant 2.5-fold increase in activation of p-AMPK compared to the MCAO group (p less then 0.01) which was also associated with a significant increase in the e-NOS activity (p less then 0.01). RIPerC resulted in reduction of infarction volume, decreased apoptotic cell death and attenuated MMP-9 activity. This together with the increased activity of p-AMPK and increase in p-eNOS may, in part explain the neuroprotection and sustained increase in blood flow observed with RIPerC following acute stroke. Western diet (WD) consumption induces chronic mild inflammation in the hypothalamus. However, metabolic consequences of increased hypothalamic inflammatory cytokines remain unclear. This research first aimed to examine whether increased proinflammatory cytokines in the brain influenced feeding or metabolism. Rats that received an intracerebroventricular third ventricle injection (i3vt) of 0.5 pg TNFα daily for six days consumed significantly more calories than saline-injected rats, with no differences between treatment groups in terms of body weight, blood triglycerides nor glucose regulation. Continuously infusing TNFα for three weeks decreased hepatic fatty acid synthase (FAS) and increased body weight and the epididymal adipose sterol regulatory element-binding protein 1c (SREBP-1c) gene expression. Differences were not due to food intake nor voluntary wheel running activity. The second aim of this research was to examine whether inhibition of inflammation signaling in the brain at early stage of switching from chow to WD would affect diet-induced obesity development. WD-fed rats with i3vt NFκB inhibitor had greater caloric intake than rats given i3vt saline. These studies suggest elevated inflammatory cytokines in the brain induce food intake acutely and favor fat storage and weight gain in the long term. However, in the early stage of WD consumption, hypothalamic inflammatory signaling inhibits caloric intake and may serve as a warning signal of energy imbalance. BACKGROUND Very little is known about the role inflammation and mechanism(s) that enables the tumor to evade host's anti-tumor immune function during very initial days of tumor establishment. Our study focuses on the immune response and local inflammation specially the pro-inflammatory and immune modifier components that are responsible for tumor-induced immune-suppression, tumor-associated macrophages (TAM) at tumor microenvironment in mouse model from very early to late phase of tumor progression. METHODS 1 × 105 Ascites tumor, EAC in Swiss albino or Sarcoma-180 (S-180) in Balb c mice strain were inoculated intra-peritonially and grouped into Control (0 day or no tumor), initial phase (3 day tumor), early (7 Day), Late (14 day) and terminal (21 day tumor) sets. T cell activity, tumor niche macrophage, inflammatory signatures were studied using Confocal microscopy, flowcytometry, ELISA, q-RT PCR and Western blot. RESULTS We observed increased T cell infiltration at a very early stage of tumorigenesis in the umor site macrophages. AIMS Studies indicate that the pattern of shear stress determines the direction of endothelial progenitor cells (EPCs) differentiation. However, the mechanism remains largely unknown. Herein, we try to identify the role of oscillatory shear stress (OSS) in the transdifferentiation of EPCs into mesenchymal cells and the mechanism involved. MATERIALS AND METHODS OSS was applied to EPCs using the flow chamber system in vitro. Matrigel, Boyden chamber, and healing assay were used to observe the changes in EPCs function. Further, 2',7'-dichlorofluorescein diacetate (DCFH-DA) probe and/or western blot were performed to detect the expression of reactive oxygen species (ROS), p53 and PKCζ in EPCs. EPCs transduced with Lentivirus carrying Tp53 were implanted into the arterial vessel in the balloon injured rat model, and neointimal thickening was verified by HE staining. KEY FINDINGS OSS enhanced the expression of mesenchymal cell markers alpha-smooth muscle actin (α-SMA) and smooth muscle 22 alpha (SM22α) on EPCs. In the meantime, OSS time-dependently decreased p53 expression in EPCs, which was partially abolished by treatment with ROS scavenger N-acetylcysteine (NAC) or protein kinase C zeta (PKCζ) inhibitor Go6983. Moreover, the p53 agonist tenovin-1 attenuated the changes of OSS-mediated the mesenchymal cell markers and EPCs function. Besides, we also found that transplanting EPCs transfected with LV-Tp53 significantly inhibited neointimal thickening and promoted reendothelialization in vivo. SIGNIFICANCE This study demonstrates OSS-induced EPC transdifferentiation into mesenchymal cells and ROS/PKCζ/p53 pathway play an essential role in it. It may serve as a promising therapeutic target for cardiovascular disease in the future. Population aging, as well as the handling of age-associated diseases, is a worldwide increasing concern. Among them, Alzheimer's disease stands out as the major cause of dementia culminating in full dependence on other people for basic functions. However, despite numerous efforts, in the last decades, there was no new approved therapeutic drug for the treatment of the disease. Calcium-activated potassium channels have emerged as a potential tool for neuronal protection by modulating intracellular calcium signaling. Their subcellular localization is determinant of their functional effects. When located on the plasma membrane of neuronal cells, they can modulate synaptic function, while their activation at the inner mitochondrial membrane has a neuroprotective potential via the attenuation of mitochondrial reactive oxygen species in conditions of oxidative stress. Here we review the dual role of these channels in the aging phenotype and Alzheimer's disease pathology and discuss their potential use as a therapeutic tool. Previously, we have shown that Tfap2b, the gene encoding transcription factor AP-2β, is needed for normal mouse eye development. Specifically, targeted loss of Tfap2b in neural crest cells (NCCs)1 and their derivatives, particularly the periocular mesenchyme (POM), resulted in anterior segment defects affecting the cornea and angle tissue. These defects were further associated with an increase in intraocular pressure (IOP). The present study investigates the underlying changes in embryonic and postnatal POM cell development and differentiation caused by loss of AP-2β in the NCCs, particularly in the structures that control aqueous outflow, using Wnt1Cre+/-; Tfap2b-/lox; tdTomatolox/+ mice (AP-2β neural crest cell knockout or AP-2β NCC KO). Toluidine blue-stained sections and ultrathin sections stained with uranyl acetate and lead citrate were used to assess morphology and ultrastructure, respectively. Immunohistochemistry of KO and control eyes was performed at embryonic day (E) 15.5, E18.5, postnatal day (P) 1, P7 and P14 using phospho-histone H3 (PH3), α-smooth muscle actin (α-SMA), myocilin and endomucin antibodies, as well as a TUNEL assay. Conditional deletion of AP-2β in the NCC-derived POM resulted in defects that appeared during both embryogenesis and postnatal stages. Fate mapping of the knockout cells in the mutants revealed that the POM migrated appropriately into the eye during embryogenesis. However, during postnatal stages a significant reduction in POM proliferation in the angle region was observed in the mutants compared to controls. This was accompanied by a lack of expression of appropriate trabecular meshwork and Schlemm's canal markers. This is the first study to show that AP-2β is required for development and differentiation of the trabecular meshwork and Schlemm's canal. Together, these defects likely contributed to the elevated intraocular pressure (IOP) previously reported in the AP-2β NCC KO mice. Axonal transport blockade is an initial step in retinal ganglion cell (RGC) degeneration in glaucoma and targeting maintenance of normal axonal transport could confer neuroprotection. We present an objective, quantitative method for assessing axonal transport blockade in mouse glaucoma models. Intraocular pressure (IOP) was elevated unilaterally in CD1 mice for 3 days using intracameral microbead injection. Longitudinal sections of optic nerve head (ONH) were immunofluorescently labeled for myelin basic protein (MBP) and amyloid precursor protein (APP), which is transported predominantly orthograde by neurons. The beginning of the myelin transition zone, visualized with the MBP label, was more posterior with elevated IOP, 288.8 ± 40.9 μm, compared to normotensive control eyes, 228.7 ± 32.7 μm (p = 0.030, N = 6 pairs). Glaucomatous regional APP accumulations in retina, prelaminar ONH, unmyelinated ONH, and myelinated optic nerve were identified by objective qualification of pixels with fluorescent intensity grmpared to glaucoma alone. The method provides a short-term assessment of axonal injury for use in initial tests of neuroprotective therapies that may beneficially affect RGC transport in animal models of glaucoma. The purpose of this study was to evaluate the optic nerve head, lamina cribrosa, retina, and choroid in school age children using spectral domain optical coherence tomography (SD-OCT) and to assess these structural parameters in relation to age, axial length, and refractive error. Healthy children, ages 11.15 ± 2.62 years (range 6-15 years, n = 53), underwent cycloplegic autorefraction, biometry, and SD-OCT imaging in both eyes. Images were analyzed using custom written programs in MATLAB, after adjustment for lateral magnification. Peripapillary retinal nerve fiber layer (RNFL) thickness, retinal and choroidal thicknesses, Bruch's membrane opening (BMO) area, minimum rim width (MRW), and anterior lamina cribrosa surface depth (ALCSD) were determined and analyzed with age, axial length, and refraction. Results show that axial length increased and refractive error became more myopic with increasing age (R2 = 0.25, β = 0.18, P less then 0.0001 and R2 = 0.27, β = -0.37, P less then 0.0001, respectively). Minhead parameters in school age children, and also suggest that ocular remodeling occurs in some structures in school age children with normal eye growth and during early stages of myopia development. Discovering new therapeutically active molecules is the ultimate destination in pharmaceutical research and development. Most drugs discovered are lipophilic and, hence, exhibit poor aqueous solubility, resulting in low bioavailability. Thus, there is a need to use various solubility enhancement techniques. Computational approaches enable the analysis of drug-carrier interactions or the numerous conformational changes in the carrier matrix that might establish an appropriate balance between cohesive and adhesive stability in a formulation. In this review, we discuss research approaches that provided molecular insight into drugs and their modifiers to unravel their solubility, stability, and bioavailability. Multiple sclerosis (MS) is the most popular chronic and debilitating inflammatory disease of the central nervous system (CNS) that remains incurable. Dihydroorotate dehydrogenase (DHODH) is critical to the activity of T lymphocytes and represents a potential therapeutic target for MS. Here we identify piperine, a bioactive constituent of black pepper, as a potent inhibitor of DHODH with an IC50 value of 0.88 μM. Isothermal titration calorimetry and thermofluor assay demonstrate the directly interaction between piperine and DHODH. The co-complex crystal structure of DHODH and piperine at 1.98 Å resolution further reveal that Tyr356 residue of DHODH is crucial for piperine binding. Importantly, we show that piperine can inhibit T cell overactivation in a DHODH-dependent manner in concanavalin A-triggered T-cell assay and mixed lymphocyte reaction assay. Finally, piperine exhibits strong preventive and therapeutic effect in the MOG-induced experimental allergic encephalomyelitis (EAE), a useful model for studying potential treatments for MS, by restricting inflammatory cells infiltration into the CNS and preventing myelin destruction and blood-brain barrier (BBB) disruption. Taken together, these findings highlight DHODH as a therapeutic target for autoimmune disease of the nervous system, and demonstrate a novel role for piperine in the treatment of MS. Different groups have reported the Crocin anticancer activity. We previously showed Crocin-induced apoptosis in rat model of breast and gastric cancers, through the increased Bax/Bcl-2 ratio and caspases activity, as well as the cell cycle arrest in a p53-dependent manner. Since Crocin antioxidant activity has been shown under different conditions, it is interesting to elucidate its apoptotic mechanism. Here, we treated two breast cancer cell lines, MCF-7 and MDA-MB-231, with Crocin. MTT and ROS assays, cell cycle arrest, Bax/Bcl-2 ratio and caspase3 activity were determined. PARP cleavage and expression of some proteins were studied using Western blotting and immunofluorescence. The results indicated stepwise ROS generation in cytosol and mitochondria after Crocin treatment. Attenuating the early ROS level, using diphenyleneiodonium, diminished the sequent mitochondrial damage (decreasing Δψ) and downstream apoptotic signaling. Crocin induced ROS production, FOXO3a expression and nuclear translocation, and then, elevation of the expression of FOXO3a target genes (Bim and PTEN) and caspase-3 activation. Application of N-acetylcysteine blocked AKT/FOXO3a/Bim signaling. FOXO3a knockdown resulted in a decrease of Bim, PTEN and caspase 3, after Crocin treatment. PTEN knockdown caused a decrease in FOXO3a, Bim and caspase 3, in addition to an increase in p-AKT and p-FOXO3a, after Crocin treatment. In conclusion, Crocin induced apoptosis in MCF-7 and MDA-MB-231 human breast cancer cells. The ROS-activated FOXO3a cascade plays a central role in this process. FOXO3a-mediated upregulation of PTEN exerted a further inhibition of the AKT survival pathway. These data provide a new insight into applications of Crocin for cancer therapy. Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder with complex pathogenesis. The fibrillar peptide β-amyloid (Aβ) has a chief function in the pathogenesis of AD. Emerging evidence has indicated that there is a tight relationship between inflammation, mitochondrial dysfunction and Aβ formation. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is one of the main active components extracted from Polygonum multiflorum. Recent research corroborated the beneficial roles of TSG in alleviating the learning and memory of AD models. Unfortunately, the underlying mechanism of TSG remains poorly elucidated. The purpose of the present study was to investigate the effects of TSG on LPS/ATP and Aβ25-35-induced inflammation in microglia and neurons and its underlying molecular mechanisms. Our results found that treatment with TSG significantly attenuated the secretion of inflammatory cytokines, reduced NLRP3 inflammasome, and regulated mitophagy. TSG efficiently alleviated LPS-induced inflammatory response by inhibiting the NLRP3 signaling pathway both in microglia and neuron. Meanwhile, TSG promoted autophagy involved in the AMPK/PINK1/Parkin signaling pathway, which may contribute to the protective activity. Additional mechanistic investigations to evaluate the dependence of the neuroprotective role of TSG on PINK1 revealed that a lack of PINK1 inhibited autophagy, especially mitophagy in microglia. Importantly, knockdown of PINK1 or Parkin by siRNA or CRISPR/Cas9 system abolished the protective effects of TSG. In conclusion, these phenomena suggested that TSG prevented LPS/ATP and Aβ-induced inflammation via AMPK/PINK1/Parkin-dependent enhancement of mitophagy. We found the neuroprotective effect of TSG, suggesting it may be beneficial for AD prevention and treatment by suppressing the activation of inflammation. Disordered immune regulation and persistent inflammatory damage are the key mechanisms of ventilator-induced lung injury (VILI). NLR family pyrin domain containing 3 (NLRP3) inflammasome activation causes VILI by mediating the formation of inflammatory mediators and infiltration of inflammatory cells, increasing pulmonary capillary membrane permeability, which leads to pulmonary edema and lung tissue damage. What mediates activation of NLRP3 inflammasome in VILI? In this study, we constructed an in vitro cyclic stretch (CS)-stimulated mouse lung epithelial (MLE-12) cell model that was transfected with NIMA-related kinase 7 (NEK7) small interfering RNA (siRNA) or scramble siRNA (sc siRNA) and pretreated with or without glibenclamide (glb). We also established a VILI mouse model, which was pretreated with glibenclamide or oridonin (Ori). Our goal was to investigate the regulatory effects of NEK7 on NLRP3 inflammasome activation and the anti-inflammatory effects of glibenclamide and oridonin on VILI. Mechanical stretch exaggerated the interaction between NEK7 and NLRP3, leading to assembly and activation of NLRP3 inflammasome downstream of potassium efflux. NEK7 depletion and treatment with glibenclamide or oridonin exerted anti-inflammatory effects that alleviated VILI by blocking the interaction between NEK7 and NLRP3, inhibiting NLRP3 inflammasome activation. NEK7 is a vital mediator of NLRP3 inflammasome activation, and glibenclamide or oridonin may be candidates for the development of new therapeutics against VILI driven by the interaction between NEK7 and NLRP3. Chronic renal failure (CRF) is a symptom of kidney damage in the terminal stages. If a patient is not treated, then CRF will progress to uremia, which greatly reduces the lifespan of the patient. However, current screening strategies, including routine urine tests and medical imaging investigations, have poor sensitivity. Therefore, exploring new and efficient diagnostic methods for CRF such as serum spectroscopy is of great significance. In this study, we first used Raman spectroscopy to classify sera from CRF patients and control subjects. A total of 47 samples from CRF patients and 54 samples from control subjects were acquired. The spectra revealed differences in the phospholipids and proteins between the CRF patients and control subjects. The differences between the CRF patients and control subjects were evaluated by building machine learning models. Subsequent principal component analysis (PCA) was first used for feature extraction. Then, back propagation (BP) neural network, extreme learning machine (ELM), genetic algorithms based on support vector machine (GA-SVM), particle swarm optimization-support vector machine (PSO-SVM), grid search-support vector machine (GS-SVM) and simulated annealing particle swarm optimization based on support vector machine (SAPSO-SVM) algorithms were employed to establish diagnostic models; the diagnostic accuracy of the six classifiers was 70.4 %, 71 %, 83.5 %, 86.9 %, 89.7 % and 82.8 %, respectively, for control subjects and CRF patients. The results show the potential of Raman spectroscopy in differentiating between the control subjects and CRF patients. Based on the limitations of current routine diagnostic methods, serum Raman spectroscopy may be an adjunct/replaceable method for the clinical diagnosis of CRF with the prospective validation of more samples. V.BACKGROUND A significant subset of breast cancer survivors experience cognitive difficulties in attention and memory, which persist for years following treatment. Transcranial direct current stimulation (tDCS) has been shown to be effective in improving working memory, attention, processing speed, and other cognitive functions in both healthy and clinical populations. To date, no studies have examined tDCS in rehabilitation of cancer-related cognitive dysfunction. OBJECTIVE/HYPOTHESIS We aimed to provide preliminary evidence for feasibility, tolerability, acceptability, and efficacy of tDCS in improving performance on a measure of sustained attention. METHODS In a within-subjects design, 16 breast cancer survivors underwent 2 consecutive days of active tDCS over the prefrontal cortex, and 2 days of sham tDCS, counterbalanced for order of stimulation condition, while performing a continuous performance test. RESULTS Stimulation was feasible and tolerable, with 89% of participants completing all sessions, and none reporting more than mild to moderate discomfort. Analyses of efficacy showed that during active stimulation, participants had significantly lower standard errors of reaction times overall, indicating better sustained attention ability, as compared to sham stimulation (p less then 0.05). Furthermore, the effect of stimulation on standard errors of reaction times differed by inter-stimulus interval (ISI) for 1 and 2 second ISIs, there was no significant difference in performance between sham and active tDCS conditions, but for 4 second ISIs, stimulation improved variability in response times relative to sham (p less then 0.05). CONCLUSIONS Results suggest that tDCS is feasible, tolerable, and may be an effective intervention to improve sustained attention difficulties in survivors with cancer-related cognitive dysfunction. BACKGROUND Fluid and vasopressor management in septic shock remains controversial. In this randomized controlled trial, we evaluated the efficacy of dynamic measures (stroke volume change during passive leg raise) to guide resuscitation and improve patient outcome. RESEARCH QUESTION Will resuscitation guided by dynamic assessments of fluid responsiveness in patients with septic shock improve patient outcomes? STUDY DESIGN and Methods Prospective, multicenter, randomized clinical trial at 13 hospitals in the United States and United Kingdom. Patients presented to Emergency Rooms with sepsis associated hypotension and anticipated Intensive Care Unit (ICU) admission. Intervention arm patients were assessed for fluid responsiveness before clinically driven fluid bolus or increase in vasopressors. The protocol included reassessment and therapy as indicated by the PLR result. The control arm received Usual Care. Primary clinical outcome was positive fluid balance at 72 hours or ICU discharge, whichever occurred first. RESULTS In modified-ITT (mITT) analysis including 83 Intervention and 41 Usual Care eligible patients, fluid balance at 72 hours or ICU discharge was significantly lower (-1.37L favoring Intervention arm, 0.65 ± 2.85L Intervention arm vs. 2.02 ± 3.44L Usual Care arm, p=0.021. Fewer patients required renal replacement therapy (5.1% vs 17.5%, p=0.04) or mechanical ventilation (17.7% vs 34.1%, p=0.04) in the Intervention arm compared to Usual Care. In the all-randomized Intent to Treat (ITT) population (102 Intervention, 48 Usual Care) there were no significant differences in safety signals. INTERPRETATION Physiologically informed fluid and vasopressor resuscitation using passive leg raise-induced stroke volume change to guide management of septic shock is safe and demonstrated lower net fluid balance and reductions in the risk of renal and respiratory failure. Dynamic assessments to guide fluid administration may improve outcomes for septic shock patients compared with Usual Care. BACKGROUND Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality. We hypothesized that applying machine learning to clinical and quantitative CT imaging features would improve mortality prediction in COPD. METHODS We selected 30 clinical, spirometric, and imaging features as inputs for a random survival forest (RSF). We used top features in a Cox regression to create a machine learning mortality prediction (MLMP-COPD) model, and also assessed the performance of other statistical and machine learning models. We trained the models in moderate-to-severe COPD subjects from a subset of COPDGene, and tested prediction performance in the remainder of individuals with moderate-to-severe COPD in COPDGene and ECLIPSE. We compared our model to BODE; BODE modifications; and the age, dyspnea, obstruction (ADO) index. RESULTS We included 2,632 COPDGene and 1,268 ECLIPSE participants. The top predictors of mortality were 6-minute walk distance, FEV1 (% predicted) and age. The top imaging predictor was pulmonary artery-to-aorta ratio. MLMP-COPD resulted in a C-index of ≥ 0.7 in both COPDGene and ECLIPSE (6.4- and 7.2-year median follow up, respectively), significantly better than all tested mortality indices (p-value less then 0.05). MLMP-COPD had fewer predictors, but similar performance to other models. The group with the highest BODE scores (7-10) had 64% mortality, while the highest mortality group defined by MLMP-COPD had 77% mortality (p = 0.012). CONCLUSIONS A MLMP-COPD model outperformed 4 existing models for predicting all-cause mortality across two COPD cohorts. Performance of machine learning was similar to traditional statistical methods. The model is available online at https//cdnm.shinyapps.io/cgmortalityapp/. Various putative oxygen chemosensory cells are reported to be present throughout the vertebrate body performing pivotal roles in respiration by initiating responses during acute hypoxia. Since air-breathing fishes often are exposed to the oxygen-deficient milieu, in such conditions various chemosensory cells operate in an orchestrated fashion. The Pseudobranchial neurosecretory system (PSNS) a newly discovered system, is one of these. It has been placed in the category of "Diffuse NE systems (DNES)". It is found in all the catfish species and in some other non-catfish group of teleosts. In catfishes, it is present in close association with the carotid labyrinth- a chemosensory structure, known in fish and amphibians. The presence of this system in Glossogobius giuris, in association with the pseudobranch, a structure considered to be precursor of carotid labyrinth, is a significant finding. In an attempt to study the structure and organization of the pseudobranchial neurosecretory system in a non-catfish species of teleost, the present investigation was undertaken on a goby G. giuris. The histological observations, using a neurosecretion-specific stain, revealed the presence of this system in G. giuris. The findings are discussed in the light of the association of PSNS with pseudobranch and the type of "neurohaemal contact complex" formed between this neurosecretory system and the elements of the circulatory system. BACKGROUND Campylobacter is the most common cause of infectious diarrhea in agammaglobulinemia patients. These infections can be severe, prolonged, and recurrent in such patients. PATIENT AND METHODS We report a 29-year-old male patient with X-linked agammaglobulinemia with Campylobacter coli enterocolitis that persisted for nine months despite multiple 10- to 14-day courses of oral ciprofloxacin and azithromycin. RESULTS The isolate was highly resistant to ciprofloxacin, erythromycin, tetracycline, and fosfomycin. The patient failed to respond to intravenous ertapenem, 1.0g/day for two weeks, to which the pathogen was susceptible. He was finally cured with oral gentamicin, 80mg four times daily, and stool cultures remained negative during the seven-month follow-up. CONCLUSION Oral aminoglycoside might be the most appropriate choice for eradication of persistent Campylobacter in the intestinal tract for macrolide- and fluoroquinolone-resistant isolate in agammaglobulinemia patients with chronic diarrhea or relapsing systemic infections. Endothelial dysfunction (ED) is a critical and initiating factor in the genesis of diabetic vascular complications whose occurrence and development is closely related to the complex intravascular microenvironment. However, currently, there is no dynamic model simulating the diabetic vascular endothelial microenvironment that can be used to investigate the mechanism underlying multifactor-induced ED. Here, we developed an integrated microfluidic chip as a new methodological platform to study vascular ED. Selenoprotein S (SELENOS) was found to be involved in the defense against oxidative stress-induced vascular endothelial injury in our previous studies. However, the regulatory signaling pathway underlying this process has not been described. With this chip, we demonstrated that multifactor-induced oxidative stress injury in human aortic endothelial cells (HAECs) has a synergistic effects and upregulates SELENOS expression. Subsequently, SELENOS was found to protect HAECs against multifactor-induced oxidative stress injury by regulating the PKCα/PI3K/Akt/eNOS pathway in the diabetic vascular endothelial microenvironment. Based on these data, our diabetic vascular chip provides a promising tool for studying vascular endothelial function, and SELENOS may be a novel target for prevention and treatment of diabetic macrovascular complications. OBJECTIVES To investigate the effect of hepatitis C virus (HCV) infection treatment with direct-acting antiviral (DAA) drugs on patients' mood, sleep quality, and quality of life (QoL). METHOD Chronic HCV infected patients receiving DAAs were evaluated prospectively. Patients were evaluated before the beginning of treatment and 12 to 24 weeks after finishing their treatment duration using the Pittsburgh Sleep Quality Index, Beck depression inventory questionnaire, and SF-36 health-related QoL questionnaires. RESULTS A total of 120 patients with a mean age of 41.03 ±7.68 years were evaluated (68.3% males). The mean follow-up duration was 141.79 ± 27.88 days after finishing the treatment. Significant improvement in the scores of sleep quality (5.13 ±1.5 vs. 3.43 ±1.35), mood (12.77 ±4.02 vs. 9.27 ±3.14), and QoL (77.49 ±5.15 vs. 83.95 ±3.39) post-treatment compared to pre-treatment were observed (P0.05). CONCLUSIONS DAAs for the treatment of HCV have a significant effect on improving their sleep, mood, and QoL. The changes in sleep quality, mood, and QoL of patients were independent and were not affected by each other. SCOPE This position paper describes the view adopted by EUCAST on the role of daptomycin in the treatment of serious infections caused by Enterococcus species. BACKGROUND High-dose daptomycin is considered effective in the treatment of enterococcal bloodstream infection (BSI) and endocarditis, although published clinical experience with the latter condition is limited. METHODS EUCAST reviewed the available published data on pharmacokinetics-pharmacodynamics (PK-PD), resistance selection, clinical efficacy and safety for the use of 10-12 mg/kg/day of daptomycin for these conditions, noting that the doses licensed by the European Medicines Agency are only 4-6 mg/kg/day, and only for infections caused by Staphylococcus aureus. FINDINGS AND RECOMMENDATIONS The PK-PD evidence shows that, even with doses of 10-12 mg/kg/day, it is not possible to treat infections caused by isolates at the upper end of the wild-type distributions of Enterococcus faecalis (with MICs of 4 mg/L) and E. faecium (with MICs of 4 or 8 mg/L). For this reason, and because there are ongoing issues with the reliability of laboratory testing, EUCAST lists daptomycin breakpoints for Enterococcus species as "IE" - insufficient evidence. EUCAST advises increased vigilance in the use of high-dose of daptomycin to treat enterococcal BSI and endocarditis. Additional PK-PD studies and prospective efficacy and safety studies of serious Enterococcal infections treated with high-dose daptomycin may permit the setting of breakpoints in the future. Endometriosis, a common benign gynecological disease, has the growth characteristics of malignant tumors, however, the pathogenesis of this disease remains unclear. It is well known that micro ribonucleic acids (miRNAs) are involved in epithelial-mesenchymal transition (EMT), associated with the development of endometriosis. This study investigated the role of a specific miRNA, miR-34c-5p, in endometriosis. High-throughput sequencing (HTS) showed that miR-34c-5p expression was reduced in ectopic endometrium (ecEM) in patients from Northeast Asia with ovarian endometriosis. A wound healing assay and a transwell invasion assay showed that miR-34c-5p inhibits the invasion and migration of Ishikawa and End1/E6E7 endocervical cells. Dual luciferase gene reporter assays revealed that miR-34c-5p specifically targets Notch1 3 'UTR, and Western blot analyses showed that miR-34c-5p promotes E-cadherin expression but inhibits Notch1, N-cadherin and vimentin expression in Ishikawa and End1/E6E7 cell lines. These results were reversed following knockdown of miR-34c-5p. Using quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot analyses, there was a significant reduction in the expression of Notch1 in ecEM compared with eutopic endometrium (euEM). The results of this study indicate that miR-34c-5p inhibits the progression of EMT and cell invasion and migration by targeting the Notch signaling pathway, specifically, Notch1. The findings of this study provide unique insights into the development of EMT in endometriosis and novel, potential therapeutic targets. Therapeutic benefits and clinical application of paclitaxel for treating non-small cell lung cancers (NSCLCs) are extremely hampered due to the chemoresistance. A recent study found that fibronectin type III domain-containing protein 5 (FNDC5) was downregulated in NSCLCs cells and negatively correlated with the clinicopathological characteristics in patients with NSCLCs. However, the role and potential molecular basis for FNDC5 in paclitaxel sensitivity of NSCLCs remain unclear. Paclitaxel-sensitive or resistant NSCLCs cell lines were exposed to small interfering RNA against FNDC5 (siFndc5) or recombinant irisin in the presence or absence of paclitaxel. NSCLCs cell lines have decreased FNDC5 expression compared with the normal human lung epithelial cells, which was further downregulated in paclitaxel-resistant cells. Irisin treatment suppressed, whereas Fndc5 silence promoted NSCLCs cells proliferation under basal conditions. Besides, we found that FNDC5 increased paclitaxel chemosensitivity in paclitaxel-sensitive or resistant NSCLCs cell lines via downregulating multidrug resistance protein 1 (MDR1). Further studies revealed that FNDC5 inhibited MDR1 expression via blocking nuclear factor-κB (NF-κB) activation. FNDC5 promotes paclitaxel sensitivity of NSCLCs cells via inhibiting NF-κB/MDR1 signaling, and FNDC5 might be a novel therapeutic target for the treatment of NSCLCs. Multiple treatment options beyond anticoagulation exist for massive and submassive pulmonary embolism to reduce mortality. For some patients, systemic thrombolytics and catheter-directed thrombolysis are appropriate interventions. For others, surgical pulmonary embolectomy can be life-saving. Extracorporeal life support and right ventricular assist devices can provide hemodynamic support in challenging cases. We propose a management algorithm for the treatment of massive and submassive pulmonary embolism, in conjunction with a multidisciplinary pulmonary embolism response team, to guide clinicians in individualizing treatment for patients in a timely manner. BACKGROUND Hypersensitivity reactions (HSR) to antineoplastic agents may lead to discontinuation of first-line treatments. Rapid drug desensitization (RDD) allows for a safe reintroduction in allergic patients. OBJECTIVE To evaluate the safety and efficacy of the Brigham and Women's Hospital's 12-step RDD in a Portuguese cancer patient population, and to identify markers associated with breakthrough reactions (BTR) to platins. METHODS We have conducted a retrospective review of desensitizations undertaken at the Immunoallergology Day-Care Unit of the Santa Maria Hospital in Lisbon from July 2008 to July 2019. Adult cancer patients with immediate HSR were included. Skin testing was performed to platins, trastuzumab and cetuximab. The 12-step protocol was used for most patients and a shorter protocol was used in 9 taxane-reactive patients with the aim of resuming regular infusions. RESULTS A total of 1471 RDD were performed in 272 patients to 136 platins, 124 taxanes, 13 monoclonal antibodies, and 10 other drugs. Skin testing was positive in 127 of platin-reactive patients (95.3%) and negative in cetuximab- and trastuzumabreactive patients. There were 141 BTR during RDD (9.6% of infusions), 79.4% induced by platins, the majority mild reactions (68.8%). Eight paclitaxel-reactive patients completed a shorter protocol and resumed regular infusions successfully. Multiple platin infusions (cut-off ≥10) and Total IgE≥100U/mL were identified as independent risk factors for BTR in platin-reactive patients. CONCLUSION This large singlecenter study confirms the safety and efficacy of the 12-step RDD protocol in a different cancer population, providing evidence of its universal applications. Total IgE is a potential useful biomarker to identify high-risk platin-reactive patients. Olea europaea L. is historically one of the most important trees of the Mediterranean countries. Increasing scientific interest regarding its fruits, leaves and olive oil has led to the elucidation of several phytochemical and biological characteristics. However, the phytochemical and biological studies regarding olive flowers remain limited. The aim of the present study was the phytochemical characterization of olive flowers' hydroalcoholic extract from Greek variety Lianolia, the effective isolation of the major secondary metabolites and evaluation of their inhibition activity against tyrosinase, elastase and collagenase. UPLC-HRMS/MS analysis was used to investigate the chemical composition of hydroalcoholic extract resulting in the identification of sixty-three secondary metabolites witch mainly belong to phenilethanoids, triterpenoids, flavonoids and secoiridoids. The orthogonial combination of Centrifugal Partition Chromatography and preparative HPLC in the same purification process led to the isolation of nine major compounds of the extract including two triterpenic acids, two flavonoid glycosides and five secoiridoid derivatives. From them, oleofloside A and oleofloside B are new natural products. Although, the hydroalcoholic extract and isolated secoiridoids exhibited weak or no inhibition activity towards tyrosinase and elastase, they exhibit remarkable anti-collagenase activity with 2΄-ethoxyoleuropein being the most active compound. OBJECTIVE To compare multimorbidity prevalence using self-reported and administrative data and identify factors associated with agreement between data sources. STUDY DESIGN AND SETTING Self-reported cross-sectional data from four Canadian Community Health Survey waves were linked to administrative data in Ontario, Canada. Multimorbidity prevalence was examined using two definitions, 2+ and 3+ chronic conditions (CCs). Agreement between data sources was assessed using Kappa and Phi statistics. Logistic regression was used to estimate associations between agreement and sociodemographic, health behavior, and health status variables for each multimorbidity definition. RESULTS Regardless of multimorbidity definition, prevalence was higher using administrative data (2+CCs 55.5% vs. 47.1%; 3+CCs 30.0% vs. 24.2%). Agreement between data sources was moderate (2+CCs K=0.482; 3+CCs K=0.442) and while associated with sociodemographic, health behavior, and health status factors, the magnitude and sometimes direction of association differed by multimorbidity definition. CONCLUSION A better understanding is needed of what factors influence individuals' reporting of CCs and how they align with what is in administrative data as policy makers need a solid evidence base on which to make decisions for health planning. Our results suggest that data sources may need to be triangulated to provide accurate estimates of multimorbidity for health services planning and policy. OBJECTIVE To describe agreement between administrative and self-report data on the number and type of chronic conditions (CCs) and determine whether associations between CC count and health service use differ by data source. STUDY DESIGN AND SETTING We linked Canadian Community Health Survey and administrative data for a cohort of adults aged 45+ in Ontario and identified 12 CCs from both data sources. Agreement was described by count and constituent CCs. We estimated associations between CC count (self-report and administrative data) and health service use (administrative data only) over one year. RESULTS Among 71,317 adults, 26.9% showed agreement on both count and constituent CCs but agreement declined with increasing CCs. Health service use increased with CC count but the association was stronger when CCs were measured with administrative data. For example, when measured with administrative data, the odds of a general practitioner visit for 5+ CCs vs none was 20.3 (95%CI 20.0-20.5) but when using self-report data, the estimate was 8.0 (95% CI 7.8-8.2). CONCLUSION Agreement on the number of CCs was low and resulted in different estimates on the association with health service use, illustrating the challenges in CC measurement and the ability to interpret the effects on outcomes. INTRODUCTION Life expectancy in the US is 78.6 years, and although people are living longer, they are also living with chronic diseases. As women age, they are more susceptible to chronic disease including mental health conditions and Alzheimer's Disease (AD) dementia. Therefore, practical and cost effective ways to prevent the onset of cognitive, mental and physical ailments and increase the quality of life among aging populations is timely and warranted. The purpose of this study in aging adult women was to explore if prayer is associated with electrical brain activity patterns consistent with meditation and therefore a likely pro-health behavior. MATERIALS AND METHODS A sample of 33 healthy women (Mage = 80.1, SD = 8.3) were recruited from a Midwestern Catholic Sisters community. Participants completed 6 consecutive, counterbalanced electroencephalogram (EEG) sessions three resting sessions and three praying sessions equating to 18 min of recorded EEG data for each participant. Differences in alpha power and frontal alpha asymmetry (FAA) between praying and resting conditions and the influence of age on the association between inter-individual differences in alpha power were explored.
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