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Background: Decisions on medication treatment in children dying from cancer are often complex and may result in polypharmacy and increased medication burden. There is no information on medication burden in pediatric cancer patients at the end of life (EOL)., Objectives: To characterize medication burden during the last hospitalization in children dying from cancer., Methods: We performed a retrospective cohort study based on medical records of 90 children who died from cancer in hospital between 01 January 2010 and 30 December 2018. Demographic and clinical information were collected for the last hospitalization. We compared medication burden (number of medication orders) at hospitalization and at time of death and examined whether changes in medication burden were associated with clinical and demographic parameters., Results: Median medication burden was higher in leukemia/lymphoma patients (6 orders) compared to solid (4 orders) or CNS tumor patients (4 orders, P = 0.006). Overall, the median number of prescriptions per patient did not change until death (P = 0.42), while there was a significant reduction for some medication subgroups (chemotherapy [P = 0.035], steroids [P = 0.010]).Patients dying in the ICU (n=15) had a higher medication burden at death (6 orders) than patients dying on wards (3 orders, P = 0.001). There was a trend for a reduction in medication burden in patients with "Do not resuscitate" (DNR) orders (P = 0.055)., Conclusions: Polypharmacy is ubiquitous among pediatric oncology patients at EOL. Disease type and DNR status may affect medication burden and deprescribing during the last hospitalization.

Members of societies involved in an intractable conflict usually consider costs that stem from the continuation of the conflict as unavoidable and even justify for their collective existence. This perception is well-anchored in widely shared conflict-supporting narratives that motivate them to avoid information that challenges their views about the conflict. However, since providing information about such major costs as a method for moderating conflict-related views has not been receiving much attention, in this research, we explore this venue. We examine what kind of costs, and under what conditions, exposure to major costs of a conflict affects openness to information and conciliatory attitudes among Israeli Jews in the context of the intractable Israeli-Palestinian conflict. Study 1 ( N = 255) revealed that interventions based on messages providing information on mental health cost, economic cost, and cost of the conflict to Israeli democracy had (almost) no significant effect on perceptions of the participants of these prices, openness to new information about the conflict, or support for conciliatory policies. However, the existing perceptions that participants had about the cost of the conflict to Israeli democracy were positively associated with openness to alternative information about the conflict and support for conciliatory policies. Therefore, in Study 2 ( N = 255), we tested whether providing information about future potential costs to the two fundamental characteristics of Israel, a democracy or a Jewish state, created by the continuation of the conflict, will induce attitude change regarding the conflict. The results indicate that information on the future cost to the democratic identity of Israel significantly affected the attitude of the participants regarding the conflict, while the effect was moderated by the level of religiosity. For secular participants, this manipulation created more openness to alternative information about the conflict and increased support for conciliatory policies, but for religious participants, it backfired. We discuss implications for the role of information about losses and the relationship between religiosity and attitudes regarding democracy and conflict., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rosler, Hameiri, Bar-Tal, Christophe and Azaria-Tamir.)

Background: Elite athletes may suffer from impaired immune function and gastro-intestinal (GI) symptoms, which may affect their health and may impede their performance. These symptoms may be reduced by multi-strain probiotic supplementation. Therefore, the aim of the current study is to examine the effects of probiotic supplementation on aerobic fitness characteristics, inflammatory markers and incidence and severity of GI symptoms in elite cyclists., Methods: Twenty-seven male cyclists, ranked elite or category 1 level competitions, were randomly assigned to a multi-strain probiotic-supplemented group (E, n = 11) or placebo group (C, n = 16). All participants visited the laboratory at the beginning of the study and following 90 d of supplementation/placebo. Prior to testing, all participants completed a GI symptoms questionnaire and underwent physical and medical examination, and anthropometric measurements. Venous blood was drawn for inflammatory markers analysis. The cyclists then underwent maximal oxygen consumption (VO 2 max) test and time-to-fatigue (TTF) test at 85 % of maximal power, 3 h following the VO 2 max test. All testing procedures were repeated after 90 d of probiotic / placebo treatment (double blind design)., Results: Lower incidence of nausea, belching, and vomiting (P < 0.05) at rest, and decreased incidence of GI symptoms during training were found in E group vs. C Group, respectively (∆GI -0.27 ± 0.47 % vs. 0.08 ± 0.29 %, P = 0.03), no significant changes were observed in the incidence of total overall GI symptoms (∆GI -5.6 ± 14.7 % vs. 2.6 ± 11.6 %, P = 0.602) Mean rate of perceived exertion (RPE) values during the TTF were lower in E group (∆RPE: -0.3 ± 0.9 vs. 0.8 ± 1.5, P = 0.04). No significant changes were measured between and within groups in VO 2 max and TTF values, mean levels of C-reactive protein (CRP), IL-6-and tumor necrosis factor alpha (TNFα) values following treatment., Conclusions: Probiotics supplementation may have beneficial effects on GI symptoms in elite cyclists. Future studies, using higher doses and during different training seasons, might help understanding the effects of probiotic supplementation on elite athletes' health and performance., Trial Registration: NIH clinicaltrial.gov #NCT02756221 Registered 25 April 2016.

Circadian disruptions precede high-fat diet (HFD)-induced obesity (DIO). Deviation of the endogenous circadian rhythm period length ( tau ) from 24 hours correlates with mice inter-strain DIO under the 24-hour light-dark cycle (T-cycle). Additionally, entrainment to a tau -resembling T-cycle attenuates DIO, to some extent, in muted mice. These phenomena suggest that entrainment to a 24-hour T-cycle promotes DIO beyond that expected from the HFD-induced metabolic disruptions. However, the hypothesis that entrainment to a tau -resembling T-cycle attenuates DIO has not been tested in wild-type mice. Therefore, we examined, in newborn female FVB/N mice, whether DIO found under their 'regular' 24-hour T-cycle is attenuated under a T-cycle oscillating at their tau -resembling period of 23.7 h, which is diverted from 24 hours by only 0.3 h. Compared to mice fed a low-fat diet, those fed an HFD under the 24-hour T-cycle showed a disrupted pattern of circadian locomotor activity prior to DIO onset. Both these phenomena were absent under the tau -like T-cycle. DIO developed under the 24-hour T-cycle despite similar caloric intake, and was associated with the lower locomotor activity of HFD-fed mice compared to the other mouse groups. These results demonstrated that DIO is secondary to HFD-induced circadian disruptions that are not harmonized by the strongest Zeitgeber (light-dark cycle) when oscillating at a period that diverts by as little as ca. 0.3-h from tau . More importantly, imposing a light-dark cycle oscillating at a tau -like period length, which enhances entrainment and presumably reinforces endogenous circadian rhythms, prevented HFD-induced circadian disruptions and enabled tighter control of energy homeostasis, as manifested by the absence of DIO, even under ad-lib HFD feeding. These results support the identification of tau- related biomarkers, which may be considered as risk-factors for DIO. Moreover, these findings may promote the development of clock-related pharmaceutical interventions that will reduce the gap between tau and 24 hours, and increase the robustness of the endogenous and entrained circadian rhythms. This will enable reducing DIO, even without caloric restriction or time-restricted feeding.

In the prostate, water diffusion is faster when moving parallel to duct and gland walls than when moving perpendicular to them, but these data are not currently utilized in multiparametric magnetic resonance imaging (mpMRI) for prostate cancer (PCa) detection. Diffusion tensor imaging (DTI) can quantify the directional diffusion of water in tissue and is applied in brain and breast imaging. Our aim was to determine whether DTI may improve PCa detection. We scanned patients undergoing mpMRI for suspected PCa with a DTI sequence. We calculated diffusion metrics from DTI and diffusion weighted imaging (DWI) for suspected lesions and normal-appearing prostate tissue, using specialized software for DTI analysis, and compared predictive values for PCa in targeted biopsies, performed when clinically indicated. DTI scans were performed on 78 patients, 42 underwent biopsy and 16 were diagnosed with PCa. The median age was 62 (IQR 54.4-68.4), and PSA 4.8 (IQR 1.3-10.7) ng/mL. DTI metrics distinguished PCa lesions from normal tissue. The prime diffusion coefficient (λ 1 ) was lower in both peripheral-zone ( p < 0.0001) and central-gland ( p < 0.0001) cancers, compared to normal tissue. DTI had higher negative and positive predictive values than mpMRI to predict PCa (positive predictive value (PPV) 77.8% (58.6-97.0%), negative predictive value (NPV) 91.7% (80.6-100%) vs. PPV 46.7% (28.8-64.5%), NPV 83.3% (62.3-100%)). We conclude from this pilot study that DTI combined with T2-weighted imaging may have the potential to improve PCa detection without requiring contrast injection.

Neoadjuvant therapy (NAT) is increasingly used in breast cancer (BC), yet, the recommended time interval between NAT completion, preoperative imaging assessment, and breast surgery is not clearly defined. This single-center retrospective study investigated tumor growth between NAT completion and surgery. The analysis included 106 BC patients who received NAT (69% chemotherapy alone, 31% chemotherapy plus anti-HER2 therapy), had post-NAT breast MRI, and definitive surgery between 2012 and 2019. The median time interval between end-of-treatment and surgery was 6 weeks; 90% had surgery within 8 weeks of NAT completion, and 10% had surgery 8-12 weeks after NAT completion. No significant correlation was found between any of the time intervals (i.e., NAT completion-to-surgery, NAT completion-to-MRI, post-NAT MRI to surgery) and the tumor size as captured in the pathology report. The only parameter that was significantly correlated with pathological tumor size was tumor size as measured on the post NAT MRI (P < .0001). The difference in tumor size between post NAT MRI and surgical pathology did not correlate with the time interval between end-of-treatment and surgery. The ratio between residual tumor size on post-NAT MRI and the time interval from the end-of-treatment to surgery, significantly correlated with the tumor size on surgical pathology (P < .0001) suggesting that NAT has a beneficial effect weeks after end-of-treatment. In conclusion, our results suggest that for patients undergoing neoadjuvant chemotherapy, surgery within 4-8 weeks of completing NAT is reasonable, and is unlikely to result in a clinically significant change in residual tumor size., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Insomnia is a disorder characterized by difficulty falling asleep and poor sleep continuity and is associated with increased risks for physical and cognitive decline. Insomnia with short sleep duration is considered the most biologically severe phenotype of the disorder. Evidence suggests that short-chain fatty acids (SCFAs), the main byproducts of fiber fermentation in the gut, may affect sleep via gut-brain communications. This study explores associations between SCFAs and sleep continuity and compares SCFA concentrations in short vs. normal sleep insomnia phenotypes in older adults. Fifty-nine participants with insomnia symptoms (≥ 65 years), completed 2 weeks of objective sleep monitoring (actigraphy), and were divided into short and normal sleep duration phenotypes via cluster analysis. Sleep measures included total sleep time (TST), sleep onset latency (SOL), sleep efficiency (SE), and wake after sleep onset (WASO). Stool samples were collected and fecal SCFA concentrations were determined by gas-chromatography-mass-spectrometry (GCMS). Higher concentrations of acetate, butyrate, and propionate, and total SCFAs, were associated with lower SE and longer SOL after controlling for Body Mass Index (BMI). Concentrations were higher in the short sleep duration phenotype. Age, BMI, TST, and SOL explained 40.7% of the variance in total SCFAs. Findings contribute to understanding pathways along the gut-brain axis and may lead to the use of SCFAs as biomarkers of insomnia phenotypes.

Background: Patients with type 2 diabetes mellitus (T2DM) have a high rate of cardiovascular disease (CVD). The Mediterranean diet is preferred for CVD prevention. Endothelial dysfunction is demonstrated early in T2DM., Objectives: To study the effects of dietary intervention of T2DM patients without known CVD on endothelial function and vascular inflammation., Methods: A prospective study enrolled 22 patients with T2DM. Patients were divided randomly into two groups: an intervention group with 12 patients (55 ± 7 years old, 6 women) and a control group with 10 patients (59 ± 10 years old, 5 women). Clinical evaluation included body mass index (BMI) and endothelial function measured by the flow mediated percent change (FMD%). Fasting blood was drawn on entry to the study and 3 months later, measuring C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), total cholesterol, triglycerides, and glycosylated hemoglobin (HbA1C%). The intervention was based on weekly telephone calls by a clinical dietitian for 3 months., Results: In the intervention group CRP and ICAM-1 were reduced (from 4.2 ± 3.3 mg/dl to 0.4 ± 0.5 mg/dl, P = 0.01 and from 258.6 ± 98.3 ng/ml to 171.6 ± 47.7 ng/ml, P = 0.004). Endothelial function (FMD%) was improved (from 0.5 ± 8.0% to 9.5 ± 11.5%, P = 0.014). No change was observed in BMI, HbA1C%, total cholesterol, and triglycerides levels in either group., Conclusions: Patients with T2DM on the Mediterranean diet who received a weekly telephone call for 3 months improved their endothelial function with reduction of markers of inflammation.

Objectives: We examined the effect of loneliness and the role of two mediating factors, depressive symptoms and malnutrition on subjective age among older adults during the 2020 COVID-19 pandemic, and explored how the pandemic is affecting subjective age. Design: A convenience sample of 201 older adults aged 65 and over was interviewed. Using bootstrapping, we tested the strength and significance of the indirect effect of depressive symptoms and malnutrition (mediators) on the relationship between feelings of loneliness and subjective age. Results: The relationship between feelings of loneliness and subjective age during the COVID-19 pandemic was mediated by malnutrition, but not by depressive symptoms. In addition, the participants felt older during the COVID-19 pandemic compared with the preceding period. Conclusions : An association was found among feelings of loneliness, malnutrition, and subjective age. To overcome these feelings in times of crisis like the pandemic, it is essential to develop new communication methods (technologies for managing and addressing the needs of the older population; technologies to encourage social engagement, and technologies for managing and providing remote medical services) for and with older adults that are effective in reducing loneliness, and to promote good nutrition. Possible practical solutions include new social network technologies for reducing loneliness combined with continued reliance on phone communication as an intervention of psychological support to promote a healthy lifestyle and prevent malnutrition.

Background: Multiple studies suggest a key role for gut microbiota in IgE-mediated food allergy (FA) development, but to date, none has studied it in the persistent state., Methods: To characterize the gut microbiota composition and short-chain fatty acid (SCFAs) profiles associated with major food allergy groups, we recruited 233 patients with FA including milk (N = 66), sesame (N = 38), peanut (N = 71), and tree nuts (N = 58), and non-allergic controls (N = 58). DNA was isolated from fecal samples, and 16S rRNA gene sequences were analyzed. SCFAs in stool were analyzed from patients with a single allergy (N = 84) and controls (N = 31)., Results: The gut microbiota composition of allergic patients was significantly different compared to age-matched controls both in α-diversity and β-diversity. Distinct microbial signatures were noted for FA to different foods. Prevotella copri (P. copri) was the most overrepresented species in non-allergic controls. SCFAs levels were significantly higher in the non-allergic compared to the FA groups, whereas P. copri significantly correlated with all three SCFAs. We used these microbial differences to distinguish between FA patients and non-allergic healthy controls with an area under the curve of 0.90, and for the classification of FA patients according to their FA types using a supervised learning algorithm. Bacteroides and P. copri were identified as taxa potentially contributing to KEGG acetate-related pathways enriched in non-allergic compared to FA. In addition, overall pathway dissimilarities were found among different FAs., Conclusions: Our results demonstrate a link between IgE-mediated FA and the composition and metabolic activity of the gut microbiota.

Primary Objective: We tested whether KPT-350, a novel selective inhibitor of nuclear export, could attenuate cortical network hyperexcitability, a major risk factor for developing post-traumatic epilepsy (PTE) following traumatic brain injury (TBI)., Research Design: All mice in this study underwent TBI and were subsequently treated with either KPT-350 or vehicle during the post-injury latent period. Half of the animal cohort was used for electrophysiology while the other half was used for immunohistochemical analysis., Methods and Procedures: TBI was induced using the controlled cortical impact (CCI) model. Cortical network activity was recorded by evoking field potentials from deep layers of the cortex and analyzed using Matlab software. Immunohistochemistry coupled with fluorescence microscopy and Image J analysis detected changes in neuronal and glial markers., Main Outcomes and Results: KPT-350 attenuated TBI-associated epileptiform activity and restored disrupted input-output responses in cortical brain slices. In vivo KPT-350 treatment reduced the loss of parvalbumin-(+) GABAergic interneurons after CCI but did not significantly change CCI-induced loss of somatostatin-(+) GABAergic interneurons, nor did it reduce reactivity of GFAP and Iba1 glial markers., Conclusion: KPT-350 can prevent cortical hyperexcitability and reduce the loss of parvalbumin-(+) GABAergic inhibitory neurons, making it a potential therapeutic option for preventing PTE.

Background: Magnetic resonance imaging (MRI) and ultrasound (US) fusion prostate-biopsies can be performed in a transrectal (TR-fusion) or transperineal (TP-fusion) approach. Prospective comparative evidence is limited. In this study we compared the detection rate of clinically-significant prostate-cancer (csPCa) within an index lesion between TR and TP-fusion., Patients and Methods: This was a prospective, noninferiority, and within-person trial. Men scheduled for MRI-US-fusion with a discrete MRI PI-RRAD ≥ 3 lesion were included. A dominant index lesion was determined for each subject and sampled by TR and TP-fusion during the same session. The order of biopsies was randomized and equipment was reset to avoid chronological and incorporation bias. For each subject, the index lesion was sampled 4-6 times in each approach. All biopsies were performed using Navigo fusion software (UC-Care, Yokneam, Israel). csPCa was defined as: Grade Group ≥ 2 or cancer-core length ≥ 6 mm. We used a noninferiority margin of 10% and a one-sided alpha level of 5%., Results: Seventy-seven patients completed the protocol. Median age was 68.2 years (IQR:64.2-72.2), median PSA was 8.9 ng/ml (IQR:6.18-12.2). Ten patients (13%) were biopsy naive, others (87%) had a previous biopsy. csPCa was detected in 32 patients (42%). All of these cases were detected by TP-fusion, while only 20 (26%) by TR-fusion. Absolute difference for csPCa diagnosis was 15.6 (CI 90% 27.9-3.2%) in favor of TP-fusion (p = 0.029). TP-fusion was noninferior to TR-fusion. The lower boundary of the 90% confidence-interval between TP-fusion and TR-fusion was greater than zero, therefore TP-fusion was also found to be superior. Exploratory subgroup analyses showed TP-fusion was consistently associated with higher detection rates of csPCa compared with TR-fusion in patient and index-lesion derived subgroups (size, location, PI-RADS, PSA, and biopsy history)., Conclusions: In this study, TP-fusion biopsies were found to be noninferior and superior to TR-fusion biopsies in detecting csPCa within MRI-visible index lesion. Centers experienced in both TP and TR-fusion should consider these results when choosing biopsy method.

Objectives: Prehospital protocols vary across local emergency medical service (EMS) agencies in California. We sought to develop evidence-based recommendations for the out-of-hospital evaluation and treatment of pediatric respiratory distress, and we evaluated the protocols for pediatric respiratory distress used by the 33 California local EMS agencies., Methods: Evidence-based recommendations were developed through an extensive literature review of the current evidence regarding out-of-hospital treatment of pediatric patients with respiratory distress. The authors compared the pediatric respiratory distress protocols of each of the 33 California local EMS agencies with the evidence-based recommendations. Our focus was on the treatment of 3 main pediatric respiratory complaints by presentation: stridor (croup), wheezing < 24 months (bronchiolitis), and wheezing > 24 months (asthma)., Results: Protocols across the 33 California local EMS agencies varied widely. Stridor (croup) had the highest protocol variability of the 3 presentations we evaluated, with no treatment having uniform use among all agencies. Only 3 (9.1%) of the local EMS agencies differentiated wheezing in children < 24 months of age, referencing this as possible bronchiolitis. All local EMS agencies included albuterol and epinephrine (intravenous/intramuscular) in their pediatric wheezing (asthma) treatment protocols. The least common treatments for wheezing (asthma) included nebulized epinephrine (3/33) and magnesium (2/33). No agencies included steroids in their treatment protocols (0/33)., Conclusion: Protocols for pediatric respiratory distress vary widely across the state of California, especially among those for stridor (croup) and wheezing in < 24 months (bronchiolitis). The evidence-based recommendations that we present for the prehospital treatment of these conditions may be useful for EMS medical directors tasked with creating and revising these protocols., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of the American College of Emergency Physicians.)

Objective: To study the hypothesis that children scheduled for ventilation tube insertion (VTI), a surrogate procedure reflecting otitis media (OM) presence, are overweight or obese., Patients and Methods: Charts of Israeli children aged 0 to 9 years undergoing VTI with or without adenoidectomy between 9/1/17 and 3/31/19 in a secondary level hospital were retrospectively identified. We compared their mean body mass index (BMI, kg/m 2 ) to the mean BMI of a control group comprised of children who underwent surgeries unrelated to OM (fracture fixation/reduction, inguinal/umbilical hernia repair, meatotomy, appendectomy). BMI measurements were plotted on gender- and age-matched curves to determine BMI percentile, and were also compared to the national pediatric overweight/obesity data. Normal weight was defined as BMI percentile <85%, overweight was BMI percentile between 85% and 97%, and obesity was BMI percentile >97%., Results: The VTI group included 83 children (mean age: 3.5 ± 1.8 years). The control group included 77 children (mean age: 6.3 ± 1.9 years). No statistically significant difference was found in the mean BMI values between both groups ( P  = .22). When compared to age- and gender-adjusted 50th BMI percentile of the general pediatric population, the mean BMI of the VTI group was significantly higher: for boys, 16.9 versus 15.2 ( P  < .01), and for girls, 16.6 versus 15.3 ( P  = .03), but not in the control group: P  = .16 (boys) and P  = .11 (girls)., Conclusion: Children undergoing VTI were overweight when compared to their age- and gender-matched peers. This observation was more noticeable in boys.

Background: Cardiovascular disease (CVD) is more frequent in patients with systemic lupus erythematosus (SLE) compared with age- and sex-matched healthy subjects. SLE is an autoimmune disease that is more prevalent in women (9:1). Women tend to develop CVD in post-menopausal years; however, women with SLE may develop endothelial dysfunction and CVD at a younger age in the pre-menopausal years., Objectives: To study the endothelial function of adult-onset SLE patients from the north of Israel (the Galilee region) and to determine whether modern management (including biological treatments) changes the risk of developing CVD., Methods: Thirteen females with adult-onset SLE without renal involvement were recruited to this prospective study. Clinical parameters (age, height, body mass index [BMI]), laboratory parameters (C-reactive protein [CRP] and hemoglobin level), and vascular responsiveness (flow mediated diameter percent change [FMD%]) were evaluated and compared to 11 age-matched healthy females. Student's t-test was used to find differences between the two groups., Results: No difference was observed in adult-onset SLE female patients and their age- and sex-matched controls with regard to age (42.1 ± 11.8 years vs. 36.6 ± 10.8 years, P = NS), BMI (25 ± 1.8 kg/m2 vs. 25 ± 2.5 kg/m2, P = NS), and hemoglobin level (11.9 ± 0.9 gr% vs. 12.7 ± 1.2 gr%, P = NS). However, a significant difference was found in CRP (2.57 ± 2.2 mg vs. 0.60 ± 0.37 mg, P = 0.001), vascular responsiveness (0.94 ± 6.6 FMD% vs. 9.2 ± 8.1 FMD%, P = 0.012), and height (165.7 ± 4.5 cm vs. 171.6 ± 5.8 cm, P = 0.009)., Conclusions: Adult-onset SLE females had impaired endothelial function even though they were treated by modern protocols.

Duchenne muscular dystrophy (DMD) is an X-linked muscle wasting disease that is caused by the loss of functional dystrophin protein in cardiac and skeletal muscles. DMD patient muscles become weakened, leading to eventual myofiber breakdown and replacement with fibrotic and adipose tissues. Inflammation drives the pathogenic processes through releasing inflammatory cytokines and other factors that promote skeletal muscle degeneration and contributing to the loss of motor function. Selective inhibitors of nuclear export (SINEs) are a class of compounds that function by inhibiting the nuclear export protein exportin 1 (XPO1). The XPO1 protein is an important regulator of key inflammatory and neurological factors that drive inflammation and neurotoxicity in various neurological and neuromuscular diseases. Here, we demonstrate that SINE compound KPT-350 can ameliorate dystrophic-associated pathologies in the muscles of DMD models of zebrafish and mice. Thus, SINE compounds are a promising novel strategy for blocking dystrophic symptoms and could be used in combinatorial treatments for DMD., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

To test the hypothesis that microRNAs may play a role in diabetic retinopathy, we measured the levels of different markers [microRNAs, vascular endothelial growth factor (VEGF), nitric oxide (NO), and total antioxidant capacity (TAO)] in patients with type 2 diabetes mellitus (T2DM) and microvascular complications. Sixty-nine patients were recruited: 22 healthy subjects, ten T2DM patients without retinopathy, 22 with nonproliferative diabetic retinopathy, and 15 with proliferative diabetic retinopathy (PDR). Serum levels of NO, VEGF, TAO and 16 candidate microRNAs were measured. Additionally, the mRNA levels of endothelial nitric oxide synthase (eNOS), induced NOS (iNOS), C reactive protein (CRP), VEGF, tumor necrosis factor α (TNFα), PON2, p22, and SOD2 were measured in human vascular endothelial cells cultured in the presence of pooled sera from the subject groups. Plasma miR-423 levels showed a significant ~ twofold decrease in patients with PDR compared to controls. P lasma NO levels were significantly higher in retinopathy, VEGF levels were significantly lower, and TAO was significantly decreased. eNOS mRNA levels were lower in the cells of T2DM patients without retinopathy, but higher in PDR. PON2, p22, and SOD2 mRNA levels were all significantly lower in PDR. CRP, TNFα, iNOS, and VEGF mRNA levels showed no significant association with disease status. Lowered miR-423 levels in diabetic patients showed a correlation with VEGF and an inverse correlation between NO and eNOS expression. Our findings suggest a cross talk between miR-423 and VEGF signaling, affecting eNOS function. miR-423 may be involved in the regulation of diabetic vascular retinal proliferation.

Objective: The objective of this study was to identify radiological and clinical factors associated with early mortality in malignant superior vena cava syndrome (SVCS)., Materials and Methods: Chest computed tomography studies of 127 patients with malignancy-associated SVCS were retrospectively reviewed. Involvement of SVC and tributaries, pleural and pericardial effusions, pulmonary artery involvement, and ancillary findings were documented. Univariate and multivariate models determined associations between radiological and clinical variables, and 30-day mortality., Results: Thirty-day mortality rate was 16.5% (n = 21). Factors associated with 30-day mortality on univariate analysis included age, cancer stage, SVCS clinical severity, left jugular vein obstruction, number of involved veins, pulmonary arteries involvement, and presence of pleural effusions. Age, SVCS clinical severity, number of veins involved, and pleural effusions were positively associated with 30-day mortality on multivariate analysis., Conclusions: Selected clinical and radiological variables are associated with early death in malignant SVCS. These factors may identify a subgroup of patients who may benefit from treatment escalation.

Perturbations in postnatal leptin signaling have been associated with altered susceptibility to diet-induced obesity (DIO) under high-fat-diet (HFD), albeit with contradicting evidence. Previous studies have shown that alpha murine urokinase-type plasminogen activator (αMUPA) mice have a higher and longer postnatal leptin surge compared with their wild types (WTs) as well as lower body weight and food intake under regular diet (RD). Here we explored αMUPA's propensity for DIO and the effect of attenuating postnatal leptin signaling with leptin antagonist (LA) on energy homeostasis under both RD and HFD. Four-day-old αMUPA pups were treated on alternate days until postnatal day 18 with either vehicle or LA (10 or 20 mg·day -1 ·kg -1 ) and weaned into RD or HFD. Compared with RD-fed αMUPA males, HFD-fed αMUPA males showed higher energy intake, even when corrected for body weight difference, and became hyperinsulinemic and obese. Additionally, HFD-fed αMUPA males gained body weight at a higher rate than their WTs mainly because of strain differences in energy expenditure. LA administration did not affect strain differences under RD but attenuated αMUPA's hyperinsulinemia and DIO under HFD, most likely by mediating energy expenditure. Together with our previous findings, these results suggest that αMUPA's leptin surge underlies its higher susceptibility to obesity under HFD, highlighting the role of leptin-related developmental processes in inducing obesity in a postweaning obesogenic environment, at least in αMUPA males. This study therefore supports the use of αMUPA mice for elucidating developmental mechanisms of obesity and the efficacy of early-life manipulations via leptin surge axis in attenuating DIO.

Background: Erectile dysfunction (ED) is a syndrome associated with endothelial dysfunction, which may predict cardiovascular events in men presenting with this syndrome. It has been shown to be associated with a higher rate of acute myocardial infarction and cardiovascular mortality, vascular inflammation, and impaired endothelial function. In this review we present the literature findings and describe the mechanistic pathways that are known to be involved in this syndrome and its related clinical consequences.

Background: It is currently expected that about 20% of children with cancer will ultimately die. Writing advanced life directives sufficiently long before the actual death of a child ensues allows both parents and medical staff to develop optimal treatment plans in the best interests of the child., Aim of the Study: The aim of the study was to evaluate factors that may influence the process of decision-making regarding Do-Not-Resuscitate (DNR) status., Methods: Retrospective single institution study., Results: Totally, 79 patients died between September 01, 2011 and August 31, 2017. Median age of the children was 10.5 years (range, 1 to 24 y). Forty-five were males. There were 37 Muslims, 27 Jews, 9 Druze, and 6 Christians. Twenty-one patients had sarcomas, 20 had CNS tumors, 10 had neuroblastoma, 17 had leukemias/lymphomas, 11 had carcinomas, and other rare tumors as well as nonmalignant diseases. No statistically significant association between all evaluated factors and DNR order status was found., Conclusions: It is possible that, other than demographic, clinical-associated, or therapy-associated factors play an important role in the process of decision-making regarding DNR. We feel that sincere communication between parents, their child (when appropriate) and medical and psychosocial staff may have a more crucial role when such decisions have to be made.

Introduction: Heparin-induced thrombocytopenia (HIT) is the most important non-hemorrhagic complication of heparin treatment. We report a case of a major thromboembolic event accompanied by thrombocytopenia following heparin exposure during coronary artery bypass graft surgery. Thrombocytopenia was documented one month after the surgery, and a major thromboembolic event which led to the patient's death diagnosed 6 weeks after heparin exposure. We discuss the pathophysiology and clinical aspects of heparin-induced thrombocytopenia, focusing on the unique features of this patient, including late persistent thrombocytopenia.

Introduction: Paraoxonase 1 (PON1) is a high density lipoprotein (HDL)-associated lactonase, which is known for its antiatherogenic properties. Previous studies in PON1 knockout (PON1KO) mice revealed that PON1KO mice have low blood pressure, which is inversely correlated with the renal levels of the cytochrome P450 -derived arachidonic acid metabolite 5,6-epoxyeicosatrienoic acid (5,6-EET). Our previous studies revealed that 5,6-EET is unstable, transforming to the δ-lactone isomer 5,6-δ-DHTL, an endothelium-derived hyperpolarizing factor (EDHF) that mediates vasodilation, and it is a potential substrate for PON1., Aim: To elucidate the role of PON1 in the modulation of vascular resistance via the regulation of the lactone-containing metabolite 5,6-δ-DHTL., Results: In mouse resistance arteries, PON1 was found to be present and active in the endothelial layer. Vascular reactivity experiments revealed that 5,6-δ-DHTL dose-dependently dilates PON1KO mouse mesenteric arteries significantly more than wild type (w.t.) resistance arteries. Pre-incubation with HDL or rePON1 reduced 5,6-δ-DHTL-dependent vasodilation. FACS analyses and confocal microscopy experiments revealed that fluorescence-tagged rePON1 penetrates into human endothelial cells' (ECs') in both dose- and time- dependent manner, accumulate in the perinuclear compartment, and retains its lactonase activity in the cells. The presence of rePON1, but not the presence of PON1 loss-of-lactonase-activity mutant, reduced the Ca 2+ influx in the ECs mediated by 5,6-δ-DHTL., Conclusion: PON1 lactonase activity in the endothelium affects vascular dilation by regulating Ca 2+ influx mediated by the lactone-containing EDHF 5,6-δ-DHTL., (Copyright © 2018. Published by Elsevier B.V.)

Background: Multiple sclerosis (MS) is a multifactorial disease with unknown etiology. It is assumed to result from interplay between genetic and environmental factors, including nutrition. We hypothesized that there are differences in nutritional parameters between MS patients and healthy controls., Methods: We examined 63 MS patients and 83 healthy controls. Nutritional status was determined by a dietary questionnaire, blood tests, quantification of cell membrane fatty acids, and serum antioxidant capacity., Results: We found that MS patients consumed a more limited diet compared with the healthy group, indicated by a lower average of 31 nutrients and by consumption levels of zinc and thiamine below the recommended daily intake. Both consumption and measured iron values were significantly lower in MS patients, with the lowest measures in the severe MS group. Long saturated fatty acids (>C16) were significantly lower in MS patients, while palmitic and palmitoleic acids were both higher. Serum total antioxidant capacity was significantly lower in the MS group compared with healthy controls, with the lowest measures in patients with severe MS., Conclusions: This study points to a possible correlation between nutritional status and MS. Understanding the clinical meaning of these findings will potentially allow for the development of future personalized dietary interventions as part of MS treatment.

Respiratory syncytial virus (RSV) is a leading cause of hospitalization of infants and young children, causing considerable respiratory disease and repeat infections that may lead to chronic respiratory conditions such as asthma, wheezing, and bronchitis. RSV causes ∼34 million new episodes of lower respiratory tract illness (LRTI) in children younger than 5 years of age, with >3 million hospitalizations due to severe RSV-associated LRTI. The standard of care is limited to symptomatic relief as there are no approved vaccines and few effective antiviral drugs; thus, a safe and efficacious RSV therapeutic is needed. Therapeutic targeting of host proteins hijacked by RSV to facilitate replication is a promising antiviral strategy as targeting the host reduces the likelihood of developing drug resistance. The nuclear export of the RSV M protein, mediated by the nuclear export protein exportin 1 (XPO1), is crucial for RSV assembly and budding. Inhibition of RSV M protein export by leptomycin B correlated with reduced RSV replication in vitro In this study, we evaluated the anti-RSV efficacy of Verdinexor (KPT-335), a small molecule designed to reversibly inhibit XPO1-mediated nuclear export. KPT-335 inhibited XPO1-mediated transport and reduced RSV replication in vitro KPT-335 was effective against RSV A and B strains and reduced viral replication following prophylactic or therapeutic administration. Inhibition of RSV replication by KPT-335 was due to a combined effect of reduced XPO1 expression, disruption of the nuclear export of RSV M protein, and inactivation of the NF-κB signaling pathway. IMPORTANCE RSV is an important cause of LRTI in infants and young children for which there are no suitable antiviral drugs offered. We evaluated the efficacy of KPT-335 as an anti-RSV drug and show that KPT-335 inhibits XPO1-mediated nuclear export, leading to nuclear accumulation of RSV M protein and reduction in RSV levels. KPT-335 treatment also resulted in inhibition of proinflammatory pathways, which has important implications for its effectiveness in vivo ., (Copyright © 2019 American Society for Microbiology.)

Anticoagulation is often used in superior vena cava syndrome (SVCS) associated with cancer (i.e malignant SVCS), even without thrombosis, but its effect on outcomes has not been reported. We aimed to determine factors and outcomes associated with thrombosis and anticoagulation in malignant SVCS. Patients with malignant SVCS diagnosed on computerized tomography (CT) were retrospectively included, indexed at diagnosis and followed for 6 months using medical records. The cohort included 183 patients with malignant SVCS of which 153 (84%) were symptomatic. Thirty of the 127 patients (24%) with a reviewable baseline CT had thrombosis of the SVC or tributaries at diagnosis. Patients with baseline thrombosis more often had symptomatic SVCS (p < 0.01). 70% (21/30) of patients with thrombosis and 52% (49/97) of those without thrombosis at baseline received anticoagulation, most often at therapeutic doses. Thrombosis occurred in 5/39 patients with anticoagulation (13%) compared to 2/18 (11%) of those without, during follow-up (p = 0.85). Anticoagulation was associated with a reduction in risk of SVC stent placement during follow-up that did not reach statistical significance (HR 0.47, 95% CI 0.2-1.13, p = 0.09). Major bleeding occurred in 7 (4%) patients, six of whom received anticoagulation (four therapeutic and two intermediate dose). Neither thrombosis nor anticoagulation affected survival. Anticoagulation is commonly used as primary prevention but its benefit remains to be proven. The role of reduced-dose anticoagulation in non-thrombotic malignant SVCS should be prospectively assessed.

Introduction  Fish bone foreign body (FFB) impaction in the upper aerodigestive tract is a common cause for emergency department referral. Its management varies in both diagnosis and treatment paradigms. Fish bone foreign bodies are more commonly found in the oropharynx in cases of patients < 40 years old, and in the esophagus in cases of patients > 40 years old. Symptoms are typically non-indicative for the location of the FFB, with the exception of foreign body sensation at/superior to the cervical esophagus. A lack of findings during the physical examination is routinely followed by imaging, with computed tomography (CT) being the preferred modality. In practice, many patients undergo unnecessary imaging studies, including CT scans. Objectives  To identify patients with suspected fish bone impaction who do not require CT imaging and can be safely discharged. Data Synthesis  We have searched the PubMed database for the following medical subject headings (MeSH) terms: fish bone , fish foreign body AND oropharynx , hypopharynx , esophagus , flexible esophagoscopy , and rigid esophagoscopy . Our search in the English language yielded 32 papers. Case reports were included, since they highlighted rare and serious complications. Conclusion  In patients > 40 years old suspected of fish bone impaction, non-contrast CT is recommended and should be urgently performed, even in the presence of ambiguous symptoms. However, in patients < 40 years old presenting within 24 hours from ingestion, imaging has little diagnostic value due to the low probability of esophageal fish bones. For this specific subgroup, in the absence of clinical findings, discharge without imaging studies may be considered safe.

Aim: To identify the effect of hydrogen-rich water (HRW) and electrolyzed-alkaline water (EAW) on high-fat-induced non-alcoholic fatty acid disease in mice., Methods: Mice were divided into four groups: (1) Regular diet (RD)/regular water (RW); (2) high-fat diet (HFD)/RW; (3) RD/EAW; and (4) HFD/EAW. Weight and body composition were measured. After twelve weeks, animals were sacrificed, and livers were processed for histology and reverse-transcriptase polymerase chain reaction. A similar experiment was performed using HRW to determine the influence and importance of molecular hydrogen (H 2 ) in EAW. Finally, we compared the response of hepatocytes isolated from mice drinking HRW or RW to palmitate overload., Results: EAW had several properties important to the study: (1) pH = 11; (2) oxidation-reduction potential of -495 mV; and (3) H 2 = 0.2 mg/L. However, in contrast to other studies, there were no differences between the groups drinking EAW or RW in either the RD or HFD groups. We hypothesized that the null result was due to low H 2 concentrations. Therefore, we evaluated the effects of RW and low and high HRW concentrations (L-HRW = 0.3 mg H 2 /L and H-HRW = 0.8 mg H 2 /L, respectively) in mice fed an HFD. Compared to RW and L-HRW, H-HRW resulted in a lower increase in fat mass (46% vs 61%), an increase in lean body mass (42% vs 28%), and a decrease in hepatic lipid accumulation ( P < 0.01). Lastly, exposure of hepatocytes isolated from mice drinking H-HRW to palmitate overload demonstrated a protective effect from H 2 by reducing hepatocyte lipid accumulation in comparison to mice drinking regular water., Conclusion: H 2 is the therapeutic agent in electrolyzed-alkaline water and attenuates HFD-induced nonalcoholic fatty liver disease in mice., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest.

Suppression of apoptosis is a key Hallmark of cancer cells, and reactivation of apoptosis is a major avenue for cancer therapy. We reveal an interaction between the two anti-apoptotic proteins iASPP and NAF-1, which are overexpressed in many types of cancer cells and tumors. iASPP is an inhibitory member of the ASPP protein family, whereas NAF-1 belongs to the NEET 2Fe-2S protein family. We show that the two proteins are stimulated to interact in cells during apoptosis. Using peptide array screening and computational methods we mapped the interaction interfaces of both proteins to residues 764-778 of iASPP that bind to a surface groove of NAF-1. A peptide corresponding to the iASPP 764-780 sequence stabilized the NAF-1 cluster, inhibited NAF-1 interaction with iASPP, and inhibited staurosporine-induced apoptosis activation in human breast cancer, as well as in PC-3 prostate cancer cells in which p53 is inactive. The iASPP 764-780 IC 50 value for inhibition of cell death in breast cancer cells was 13 ± 1 μM. The level of cell death inhibition by iASPP 764-780 was altered in breast cancer cells expressing different levels and/or variants of NAF-1, indicating that the peptide activity is associated with NAF-1 function. We propose that the interaction between iASPP and NAF-1 is required for apoptosis activation in cancer cells. This interaction uncovers a new layer in the highly complex regulation of cell death in cancer cells and opens new avenues of exploration into the development of novel anticancer drugs that reactivate apoptosis in malignant tumors.

Infection of immunocompromised individuals with normally benign opportunistic viruses is a major health burden globally. Infections with viruses such as Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), Kaposi's sarcoma virus (KSHV), adenoviruses (AdV), BK virus (BKPyV), John Cunningham virus (JCPyV), and human papillomavirus (HPV) are significant concerns for the immunocompromised, including when these viruses exist as a co-infection with human immunodeficiency virus (HIV). These viral infections are more complicated in patients with a weakened immune system, and often manifest as malignancies resulting in significant morbidity and mortality. Vaccination is not an attractive option for these immune compromised individuals due to defects in their adaptive immune response. Verdinexor is part of a novel class of small molecules known as SINE (Selective Inhibitor of Nuclear Export) compounds. These small molecules demonstrate specificity for the nuclear export protein XPO1, to which they bind and block function, resulting in sequestration of XPO1-dependent proteins in the nucleus of the cell. In antiviral screening, verdinexor demonstrated varying levels of efficacy against all of the aforementioned viruses including previously with HIV. Studies by other labs have discussed likely mechanisms of action for verdinexor (ie. XPO1-dependence) against each virus. GLP toxicology studies suggest that anti-viral activity can be achieved at a tolerable dose range, based on the safety profile of a previous phase 1 clinical trial of verdinexor in healthy human volunteers. Taken together, these results indicate verdinexor has the potential to be a broad spectrum antiviral for immunocompromised subjects for which vaccination is a poor option., Competing Interests: All authors of this manuscript are employed by, and hold stake in, Karyopharm Therapeutics, developer and marketer of SINE compounds. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives To determine the influence of educational sports nutrition programs on adolescent athlete's nutritional habits and on the general and academic self-efficacy of nutrition students who facilitated the program. MethodsAn intervention framework and a convergent mixed-methods approach were used for this study. A questionnaire to examine knowledge of sports nutrition and an eating diary were used for tracking results at 3 points in time; beginning, end of the program and 3 months follow up. Nutrition students completed questionnaires examining their general and academic self-efficacy at 4 points during the study. Participants included 49 athletes aged 13-15 (26 boys and 23 girls) and 30 nutrition students. ResultsSignificant improvements were found in knowledge and nutrition behavior of athletes and in the general and academic self-efficacy of the nutrition students. ConclusionParticipation in the intervention program led to improvements of the adolescent athletes' nutritional knowledge and behavior. Implementation of the program in the framework of an academic nutrition studies course improved the general and academic self-efficacy of the nutrition students. Use of the RRA approach transformed the students from passive learners to active teachers.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders marked in most cases by the nuclear exclusion and cytoplasmic deposition of the RNA binding protein TDP43. We previously demonstrated that ALS-associated mutant TDP43 accumulates within the cytoplasm, and that TDP43 mislocalization predicts neurodegeneration. Here, we sought to prevent neurodegeneration in ALS/FTD models using selective inhibitor of nuclear export (SINE) compounds that target exportin-1 (XPO1). SINE compounds modestly extend cellular survival in neuronal ALS/FTD models and mitigate motor symptoms in an in vivo rat ALS model. At high doses, SINE compounds block nuclear egress of an XPO1 cargo reporter, but not at lower concentrations that were associated with neuroprotection. Neither SINE compounds nor leptomycin B, a separate XPO1 inhibitor, enhanced nuclear TDP43 levels, while depletion of XPO1 or other exportins had little effect on TDP43 localization, suggesting that no single exporter is necessary for TDP43 export. Supporting this hypothesis, we find overexpression of XPO1, XPO7 and NXF1 are each sufficient to promote nuclear TDP43 egress. Taken together, our results indicate that redundant pathways regulate TDP43 nuclear export, and that therapeutic prevention of cytoplasmic TDP43 accumulation in ALS/FTD may be enhanced by targeting several overlapping mechanisms.

Background: Induction of general anesthesia and endotracheal intubation may precipitate parathyroid hormone (PTH) elevation in patients with primary hyperparathyroidism (HPT). The purposes of this study were to revisit this observation and to study its impact in healthy patients., Methods: Patients with primary HPT who underwent parathyroidectomy were retrospectively studied. The PTH was sampled and compared: before, immediately after general anesthesia and endotracheal intubation, and 15 minutes after parathyroidectomy. Healthy adults who underwent elective operations were prospectively studied. The PTH was sampled before general anesthesia and endotracheal intubation, immediately after, and 15 minutes later., Results: Thirty-one patients, aged 28-89 years (mean 60.1 ± 13 years), were retrospectively studied. The PTH was significantly elevated after general anesthesia and endotracheal intubation (P = .014). Fifty patients, aged 21-86 years (mean 54 ± 15 years), were prospectively studied. The PTH elevation after general anesthesia and endotracheal intubation was not significant., Conclusion: General anesthesia and endotracheal intubation causes an immediate, steep, and significant PTH elevation in patients with primary HPT but only a minor change in healthy adults. The difference may be attributed to an impaired adrenergic response in patients with primary HPT., (© 2017 Wiley Periodicals, Inc.)

We investigated whether long-lived weight-reduced αMUPA mice differ from their wild types in postnatal body composition and leptin level, and whether these differences are affected by maternal-borne factors. Newborn αMUPA and wild type mice had similar body weight and composition up to the third postnatal week, after which αMUPA mice maintained lower body weight due to lower fat-free mass. Both strains showed a surge in leptin levels at the second postnatal week, initiating earlier in αMUPA mice, rising higher and lasting longer than in the wild types, mainly in females. Leptin level in dams' serum and breast milk, and in their pup's stomach content were also higher in αMUPA than in the WT during the surge peak. Leptin surge preceded the strain divergence in body weight, and was associated with an age-dependent decrease in the leptin:fat mass ratio-suggesting that postnatal sex and strain differences in leptin ontogeny are strongly influenced by processes independent of fat mass, such as production and secretion, and possibly outside fat tissues. Dam removal elevated corticosterone level in female pups from both strains similarly, yet mitigated the leptin surge only in αMUPA-eliminating the strain differences in leptin levels. Overall, our results indicate that αMUPA's postnatal leptin surge is more pronounced than in the wild type, more sensitive to maternal deprivation, less related to pup's total adiposity, and is associated with a lower post-weaning fat-free mass. These strain-related postnatal differences may be related to αMUPA's higher milk-borne leptin levels. Thus, our results support the use of αMUPA mice in future studies aimed to explore the relationship between maternal (i.e. milk-borne) factors, postnatal leptin levels, and post-weaning body composition and energy homeostasis.

Objective: To investigate the correlation between cardiovascular risk factors (CVRFs) and vestibular neuritis (VN) in hospitalized adult patients., Methods: A cross-sectional retrospective study was conducted in a tertiary hospital setting. The medical records of patients (aged over 18 years old) who were hospitalized between the years 2005 and 2014 with the diagnosis of VN were retrieved. Inclusion criteria were: (1) acute vertigo lasting for at least 24 hours, (2) absence of auditory complaints, (3) horizontal unidirectional nystagmus present during physical examination, and (4) absence of neurological symptoms or signs. The ratio of CVRFs among VN patients was compared to the ratio of those among the general Israeli population., Results: A significantly higher prevalence of CVRFs was found among VN hospitalized patients in comparison to the general population ( P < .05). Furthermore, a significant correlation ( P < .001) was found between the patients' age and the number of CVRFs (r = .387). A positive correlation (r = .643) was found between the number of CVRFs and VN in each age group ( P = .119)., Conclusion: There may be a possible interrelation between CVRFs and VN. This correlation can be caused by occlusion of small blood vessels leading to labyrinthine ischemia and apparition of symptoms of VN.

Hypoalbuminemia of Hemodialysis (HD) patients is an independent cardiovascular risk factor, however, there is no mechanistic explanation between hypoalbuminemia and vascular injury. In the event of oxidative stress and inflammation to which HD patients are exposed, albumin is oxidized and undetected by common laboratory methods, rendering an apparent hypoalbuminemia. We wanted to show that these circulating modified oxidized albumin molecules cause direct vascular damage, mediating inflammation. Once these in-vivo albumin modifications were reduced in- vitro, the apparent hypoalbuminemia concomitantly with its inflammatory effects, were eliminated. Albumin modification profiles from 14 healthy controls (HC) and 14 HD patients were obtained by mass spectrometry (MS) analyses before and after reduction in- vitro, using redox agent 1,4 dithiothreitol (DTT). Their inflammatory effects were explored by exposing human umbilical endothelial cells (HUVEC) to all these forms of albumin. Albumin separated from hypoalbuminemic HD patients increased endothelial mRNA expression of cytokines and adhesion molecules, and augmented secretion of IL-6. This endothelial inflammatory state was almost fully reverted by exposing HUVEC to the in-vitro reduced HD albumin. MS profile of albumin modifications peaks was similar between HD and HC, but the intensities of the various peaks were significantly different. Abolishing the reversible oxidative modifications by DTT prevented endothelial injury and increased albumin levels. The irreversible modifications such as glycation and sulfonation show low intensities in HD albumin profiles and are nearly unobserved in HC. We showed, for the first time, a mechanistic link between hypoalbuminemia and the pro-inflammatory properties of in-vivo oxidized albumin, initiating vascular injury.

Background: Acute otitis media (AOM) is a common childhood disease, with an enormous economic and healthcare-related burden. Guidelines and consensus papers for AOM diagnosis and management were published in many countries. Our objective was to study the differences and similarities between these protocols in developing and developed countries., Methods: The keywords: 'acute otitis media' AND 'children' AND ['treatment' or 'management'] AND ['guideline' or 'consensus'] were used in various electronic databases between 1 January 1989 through 31 December 2015. Overall, 99 sources from 62 countries were retrieved: 53 from 22 developed countries, and 46 from 40 developing countries. Representative guidelines from America (the USA, Argentina), Europe (Italy, Moldova), Africa (South Africa, Tanzania, Ethiopia), Asia (Japan, Afghanistan, Sri Lanka),and Oceania (South Australia, Fiji) were compared., Results: Paediatric societies publish guidelines in most developed countries; in developing countries, the Ministry of Health usually initiates guideline formulation. Most guidelines use the same diagnostic criteria and offer watchful waiting in mild-moderate scenarios. Amoxicillin is the suggested first-line antibiotic, whereas options for second-line and third-line therapies vary. Duration of therapy varies and is usually age dependent: 5-7 days for children <2 years and 10 days for children >2 years in developed countries, while duration and age groups vary greatly in developing countries. Reduction of AOM risk factors is encouraged in developed countries, but rarely in developing countries., Conclusions: Guidelines for AOM from developing and developed countries are similar in many aspects, with variation in specific recommendations, due to local epidemiology and healthcare accessibility. Formulation of regional guidelines may help reduce AOM burden., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

The NEET proteins mitoNEET (mNT) and nutrient-deprivation autophagy factor-1 (NAF-1) are required for cancer cell proliferation and resistance to oxidative stress. NAF-1 and mNT are also implicated in a number of other human pathologies including diabetes, neurodegeneration and cardiovascular disease, as well as in development, differentiation and aging. Previous studies suggested that mNT and NAF-1 could function in the same pathway in mammalian cells, preventing the over-accumulation of iron and reactive oxygen species (ROS) in mitochondria. Nevertheless, it is unknown whether these two proteins directly interact in cells, and how they mediate their function. Here we demonstrate, using yeast two-hybrid, in vivo bimolecular fluorescence complementation (BiFC), direct coupling analysis (DCA), RNA-sequencing, ROS and iron imaging, and single and double shRNA lines with suppressed mNT, NAF-1 and mNT/NAF-1 expression, that mNT and NAF-1 directly interact in mammalian cells and could function in the same cellular pathway. We further show using an in vitro cluster transfer assay that mNT can transfer its clusters to NAF-1. Our study highlights the possibility that mNT and NAF-1 function as part of an iron-sulfur (2Fe-2S) cluster relay to maintain the levels of iron and Fe-S clusters under control in the mitochondria of mammalian cells, thereby preventing the activation of apoptosis and/or autophagy and supporting cellular proliferation.

Background: Biliary dilatation in the asymptomatic patient is a frequent incidental finding in the work-up for which there are no current guidelines., Objectives: The purpose of this study was to determine the yield of magnetic resonance cholangiopancreatography (MRCP) in asymptomatic patients with an incidental finding of biliary duct dilatation., Methods: The study included 68 consecutive patients for evaluation of biliary duct dilatation found incidentally on computed tomography (CT) or ultrasound (US). MRCP scans were reviewed, and data were retrospectively collected on demographics and laboratory work-up. Patients were divided by the presence of a significant or non-significant MRCP findings explaining the biliary duct dilatation and compared for normal or abnormal liver function., Results: Liver function was normal in 47 patients and abnormal in 21 patients. MRCP identified the cause of the bile duct dilatation in 41 patients (60.3%). Rates of insignificant causes were 51% in the normal-liver-function group and 7% in the abnormal-function group. Corresponding rates of significant causes were 27.7% and 61.9% ( p  = 0.007)., Conclusions: MRCP is a valuable tool in the work-up of biliary duct dilatation. Although significantly more significant causes of bile dilatation are identified in patients with abnormal liver function, almost one-third of patients with normal liver function need further work-up. This has important implications for establishing criteria for the use of MRCP in asymptomatic patients with biliary dilatation.

Introduction: The recent Israeli acute otitis media (AOM) guidelines, drafted mainly by pediatricians and family physicians in 2013, addressed diagnostic and therapeutic issues, in order to reduce over-diagnosis and treatment. These guidelines are considered as the 'standard of care' for AOM management. While the adherence rate of pediatricians to previous Israeli AOM guidelines (2004) was reported to be high (>85%), the compliance of otolaryngologists has not been studied., Methods: An anonymous 19-item questionnaire was circulated among practicing Israeli otolaryngologists (residents [n = 93], specialists [n = 283]). All the items were scored according to the number of correct answers in line with the guidelines, and summed on a 0-100 scale., Results: Response rate was 34% (n = 127). Overall, scores of correct answers of residents (n = 48, 52% of all residents) and specialists (n = 79, 28% of all specialists) were similar, and showed comparable moderate adherence to both guidelines: 55.7 vs 58.3 (p = 0.26). Residents were more likely to adhere to the U.S. guidelines, when compared to specialists (score difference 6.1 vs 2.8, p = 0.008). Responders preferred the microscope for diagnosis (48%), over the recommended (pneumatic) otoscope (62%) (p = 0.05), and were more likely to start antibiotic therapy (62%), rather than the 'watchful waiting' (38%) (p = 0.03). Concerning antibiotic treatment, 50% of otolaryngologists prescribed amoxicillin as recommended, at 60-80 mg/kg/d., Conclusion: The moderate adherence rate suggests that the guidelines were partially adopted by otolaryngologists, who use different instrumentation than recommended, and treat more severe/complicated cases. Over-treatment with antibiotics and inaccurate dosing regimens are still common. Better implementation of the AOM guidelines among otolaryngologists should be performed in designated training platforms., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The largest randomized controlled trial (RCT) on the effect of FDG-PET on surgical management for metastatic colorectal adenocarcinoma to liver ("PET-CAM") reported only a modest change in surgical management (8%)., Purpose: To explore the relationship between prior chemotherapy and detection of metastatic disease on PET in patients from PET-CAM. Secondary aim: to determine whether centralized imaging interpretation could have impacted trial results., Methods: The study included 120 patients from a single institution. Local PET interpretation (PET-L) was recorded from the original database. Retrospective PET interpretation was performed independently by at least one additional reader (PET-C). The presence of extrahepatic disease (EHD) and significant additional liver metastases (=SALM), defined as metastases not originally planned for resection, was recorded. Patients were stratified to responders to recent chemotherapy (Group R) versus all others (Group O) according to surgical pathology and RECIST criteria., Results: Thirty-seven of 50 patients who received recent chemotherapy (<90 days) were responders (Group R). EHD was present in 30/120 (25%) patients. There was no difference in detection of EHD on PET-L (7/37;18.9%), PET-C (7/37;18.9%), and CT (4/37;10.8%) for Group R (p = 0.375), but in Group O more EHD was detected on both PET-L (15/83;18.1%) and PET-C (22/83;26.5%) than CT (8/83;9.6%); p = 0.039 and p < 0.001, respectively. For the entire cohort, PET-L and PET-C detected EHD and/or SALM not reported on CT in 14 (11.7%) and 22 (18.3%) patients., Conclusion: The impact of recent chemotherapy on detection of colorectal metastases with PET suggests that the utility of PET in patient selection for liver resection in the prior PET-CAM-RCT may have been underestimated.

Objective: Prominent among the endothelium-derived hyperpolarizing factors (EDHFs) are the Cytochrome P450 (CYP) epoxygenase-derived arachidonic acid metabolites-the epoxyeicosatrienoic acids (EETs), that are known as vasodilators in the microcirculation. Among the EET isomers, 5,6-EET undergoes rapid lactonization in aqueous solution to the more stable 5,6-δ DHTL (5,6-dihydroxytrienoic lactone) isomer. It is unclear whether this metabolic transformation maintains its vasodilator potential and what is the mechanism of action. Thus, the aim of this study was to investigate the capacity of the lactone isomer, 5,6- δ DHTL, to induce dilation of arterioles and explore the endothelial Ca 2+ response mechanism., Approach and Results: In isolated human microvessels 5,6- δ DHTL induced a dose dependent vasodilation, that was inhibited by mechanical denudation of the endothelial layer. This 5,6- δ DHTL -dependent dilation was partially reduced in the presence of L-NAME (NOS inhibitor) or the NO-scavenger, cPTIO (by 19.7%, which was not statistically significantly). In human endothelial cells, 5,6- δ DHTL induced an increase in intracellular Ca 2+ ([Ca 2+ ]i) in a dose dependent manner. This increase in [Ca 2+ ]i was similar to that induced by the 5,6-EET isomer, and significantly higher than observed by administering the hydrolytic dihydroxy isomer, 5,6-DHET. Further experiments aimed to investigate the mechanism of action revealed, that the 5,6-δ DHTL-mediated ([Ca 2+ ]i elevation was reduced by IP3 and ryanodine antagonists, but not by antagonists to the TRPV4 membrane channel. Similar to their effect on the dilation response in the arteries, NO inhibitors reduced the 5,6-δ DHTL-mediated ([Ca 2+ ]i elevation by 20%. Subsequent 5,6-δ DHTL -dependent K + ion efflux from endothelial cells, was abolished by the inhibition of small and intermediate conductance K Ca ., Conclusions: The present study shows that 5,6-δ DHTL is a potential EDHF, that dilates microvessels through a mechanism that involves endothelial dependent Ca 2+ entry, requiring endothelial hyperpolarization. These results suggest the existence of additional lactone-containing metabolites that can be derived from the PUFA metabolism and which may function as novel EDHFs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The global prevalence of obesity has increased considerably in the last two decades. Obesity is caused by an imbalance between energy intake (EI) and energy expenditure (EE), and thus negative energy balance is required to bring about weight loss, which can be achieved by either decreasing EI or increasing EE. Caffeine has been found to influence the energy balance by increasing EE and decreasing EI, therefore, it can potentially be useful as a body weight regulator. Caffeine improves weight maintenance through thermogenesis, fat oxidation, and EI. The sympathetic nervous system is involved in the regulation of energy balance and lipolysis (breakdown of lipids to glycerol and free fatty acids) and the sympathetic innervation of white adipose tissue may play an important role in the regulation of total body fat. This article reviews the current knowledge on the thermogenic properties of caffeine, and its effects on appetite and EI in relation to energy balance and body weight regulation.

In vitro growth of Pseudomonas aeruginosa biofilm on tympanostomy tubes showed that in Armstrong T-tubes, biofilm colonies were mainly located in the perpendicular junction between the body and the flanges, but in Paparella-type tube, they concentrated on the round rims. These "weakness" zones can be the future target areas for geometry changes, and can be specifically coated with antibiofilm materials.

The capsid structural protein of the New World alphavirus, Venezuelan equine encephalitis virus (VEEV), interacts with the host nuclear transport proteins importin α/β1 and CRM1. Novel selective inhibitor of nuclear export (SINE) compounds, KPT-185, KPT-335 (verdinexor), and KPT-350, target the host's primary nuclear export protein, CRM1, in a manner similar to the archetypical inhibitor Leptomycin B. One major limitation of Leptomycin B is its irreversible binding to CRM1; which SINE compounds alleviate because they are slowly reversible. Chemically inhibiting CRM1 with these compounds enhanced capsid localization to the nucleus compared to the inactive compound KPT-301, as indicated by immunofluorescent confocal microscopy. Differences in extracellular versus intracellular viral RNA, as well as decreased capsid in cell free supernatants, indicated the inhibitors affected viral assembly, which led to a decrease in viral titers. The decrease in viral replication was confirmed using a luciferase-tagged virus and through plaque assays. SINE compounds had no effect on VEEV TC83&#95;Cm, which encodes a mutated form of capsid that is unable to enter the nucleus. Serially passaging VEEV in the presence of KPT-185 resulted in mutations within the nuclear localization and nuclear export signals of capsid. Finally, SINE compound treatment also reduced the viral titers of the related eastern and western equine encephalitis viruses, suggesting that CRM1 maintains a common interaction with capsid proteins across the New World alphavirus genus., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: ST is employee of Karyopharm Therapeutics and has financial interest in this company. This does not alter our adherence to all PLOS policies on sharing data and materials.

Influenza A virus (IAV) causes seasonal epidemics of respiratory illness that can cause mild to severe illness and potentially death. Antiviral drugs are an important countermeasure against IAV; however, drug resistance has developed, thus new therapeutic approaches are being sought. Previously, we demonstrated the antiviral activity of a novel nuclear export inhibitor drug, verdinexor, to reduce influenza replication in vitro and pulmonary virus burden in mice. In this study, in vivo efficacy of verdinexor was further evaluated in two animal models or influenza virus infection, mice and ferrets. In mice, verdinexor was efficacious to limit virus shedding, reduce pulmonary pro-inflammatory cytokine expression, and moderate leukocyte infiltration into the bronchoalveolar space. Similarly, verdinexor-treated ferrets had reduced lung pathology, virus burden, and inflammatory cytokine expression in the nasal wash exudate. These findings support the anti-viral efficacy of verdinexor, and warrant its development as a novel antiviral therapeutic for influenza infection., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: SS and ST are current employees and shareholders of Karyopharm Therapeutics. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Other authors have declared that no competing interests exist.

Iron-sulfur (Fe-S) proteins are thought to play an important role in cancer cells mediating redox reactions, DNA replication, and telomere maintenance. Nutrient-deprivation autophagy factor-1 (NAF-1) is a 2Fe-2S protein associated with the progression of multiple cancer types. It is unique among Fe-S proteins because of its 3Cys-1His cluster coordination structure that allows it to be relatively stable, as well as to transfer its clusters to apo-acceptor proteins. Here, we report that overexpression of NAF-1 in xenograft breast cancer tumors results in a dramatic augmentation in tumor size and aggressiveness and that NAF-1 overexpression enhances the tolerance of cancer cells to oxidative stress. Remarkably, overexpression of a NAF-1 mutant with a single point mutation that stabilizes the NAF-1 cluster, NAF-1(H114C), in xenograft breast cancer tumors results in a dramatic decrease in tumor size that is accompanied by enhanced mitochondrial iron and reactive oxygen accumulation and reduced cellular tolerance to oxidative stress. Furthermore, treating breast cancer cells with pioglitazone that stabilizes the 3Cys-1His cluster of NAF-1 results in a similar effect on mitochondrial iron and reactive oxygen species accumulation. Taken together, our findings point to a key role for the unique 3Cys-1His cluster of NAF-1 in promoting rapid tumor growth through cellular resistance to oxidative stress. Cluster transfer reactions mediated by the overexpressed NAF-1 protein are therefore critical for inducing oxidative stress tolerance in cancer cells, leading to rapid tumor growth, and drugs that stabilize the NAF-1 cluster could be used as part of a treatment strategy for cancers that display high NAF-1 expression., Competing Interests: The authors declare no conflict of interest.

Background: Upper respiratory tract infection is the most common non-preventable cause of surgery cancellation. Consequently, surgeons and anaesthesiologists involved in elective ENT surgical procedures frequently face a dilemma of whether to proceed or to postpone surgery in affected children., Methods: A literature review was conducted and a practical assessment algorithm proposed., Conclusion: The risk-benefit assessment should take into consideration the impact of postponing the surgery intended to bring relief to the child and the risks of proceeding with general anaesthesia in an inflamed airway. The suggested algorithm for assessment may be a useful tool to support the decision of whether to proceed or to postpone surgery.