Dilated cardiomyopathy

Dilated cardiomyopathy: A disorder in which the chambers of the heart are dilated (enlarged) because the heart muscle is weakened and cannot pump effectively. There are many causes, the most common being myocardial ischemia (not enough oxygen supplied to the heart muscle) due to coronary artery disease.

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Postoperative brachial artery entrapment associated with pediatric supracondylar fracture of the humerus: a case report

Severely displaced supracondylar fractures of the humerus in children are frequently associated with complications including neurovascular injuries, non-union, or compartment syndrome. In the current literatur...

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Prescriptions for adrenaline devices in children are rising faster than anaphylaxis

Researchers have called for clarity on when adrenaline auto injectors (AAIs) should be prescribed for children with allergies and how many devices they should be given after finding that...

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The PD-L1/PD-1 pathway promotes dysfunction, but not “exhaustion”, in tumor-responding T cells from pleural effusions in lung cancer patients

Abstract

Malignant pleural effusions are frequent in patients with advanced stages of lung cancer and are commonly infiltrated by lymphocytes and tumor cells. CD8+ T cells from these effusions have reduced effector functions. The programmed death receptor 1(PD-1)/programmed death ligand 1 (PD-L1) pathway is involved in T-cell exhaustion, and it might be responsible for T-cell dysfunction in lung cancer patients. Here, we show that PD-L1 is expressed on tumor cell samples from malignant effusions, on lung cancer cell lines, and, interestingly, on MRC-5 lung fibroblasts. PD-L1 was up-regulated in lung cancer cell lines upon treatment with IFN-gamma, but not under hypoxic conditions, as detected by RT-qPCR and flow cytometry. Blockade of PD-L1 on tumor cells restored granzyme-B expression in allogenic CD8+ T cells in vitro. Remarkably, pleural effusion CD8+ T cells that responded to the tumor antigens MAGE-3A and WT-1 (identified as CD137+ cells) were lower in frequency than CMV pp65-responding CD8+ T cells and did not have an exhausted phenotype (PD-1+ TIM-3+). Nonetheless, tumor-responding CD8+ T cells had a memory phenotype and expressed higher levels of PD-1. A PD-L1 blocking antibody increased the expression of granzyme-B and perforin on polyclonal- and tumor-stimulated CD8+ T cells. Taken together, our data show that rather than being exhausted, tumor-responding CD8+ T cells are not completely differentiated into effector cells and are prone to negative regulation by PD-L1. Hence, our study provides evidence that lung cancer patients respond to immunotherapy due to blockade of the PD-L1/PD-1 pathway.

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Expression patterns of programmed death-ligand 1 in esophageal adenocarcinomas: comparison between primary tumors and metastases

Abstract

Expression analysis of programmed death-ligand 1 (PD-L1) may be helpful in guiding clinical decisions for immune checkpoint inhibition therapy, but testing by immunohistochemistry may be hampered by heterogeneous staining patterns within tumors and expression changes during metastatic course. PD-L1 expression (clone SP142) was investigated in esophageal adenocarcinomas using tissue microarrays (TMA) from 112 primary resected tumors, preoperative biopsies and full slide sections from a subset of these cases (n = 24), corresponding lymph node (n = 55) and distant metastases (n = 17). PD-L1 expression was scored as 0.1–1, >1, >5, >50% positive membranous staining of tumor cells and any positive staining of tumor-associated inflammatory infiltrates and/or stroma cells. There was a significant correlation with overall PD-L1 expression between the full slide sections and the TMA (p = 0.001), but not with the corresponding biopsies. PD-L1 expression in tumor cells >1% was detected in 8.0% of cases (9/112) and 51.8% of cases (58/112) in tumor-associated inflammatory infiltrates and/or stroma cells of primary tumors. Epithelial expression in metastases was found in 5.6% of cases (4/72) and immune cell expression in 18.1% of cases (13/72), but did not correlate with the expression pattern in the primary tumor. Overall PD-L1 expression in the primary tumor did not influence survival. However, PD-L1 expression was correlated with the number of CD3⁺ tumor-infiltrating lymphocytes in the tumor center, and a combinational score of PD-L1 status/CD3⁺ tumor-infiltrating lymphocytes was correlated with patients’ overall survival.

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Human Cytomegalovirus v-CDK UL97 Phosphorylates and Inactivates the Retinoblastoma Protein-Related p107 and p130 Proteins [Microbiology]

The human cytomegalovirus (HCMV)-encoded viral cyclin-dependent kinase (v-CDK) UL97 phosphorylates the retinoblastoma (Rb) tumor suppressor. Here we identify the other Rb family members p107 and p130 as novel targets of UL97. UL97 phosphorylates p107 and p130 thereby inhibiting their ability to repress the E2F-responsive E2F1 promoter. As with Rb, this phosphorylation, and the rescue of E2F-responsive transcription, is dependent on the L1 LXCXE motif in UL97 and its interacting clefts on p107 and p130. Interestingly, UL97 does not induce the disruption of all p107-E2F or p130-E2F complexes, as it does to Rb-E2F complexes. UL97 strongly interacts with p107 but not Rb or p130. Thus the inhibitory mechanisms of UL97 for Rb family protein-mediated repression of E2F-responsive transcription appear to differ for each of the Rb family proteins. The immediate early 1 (IE1) protein of HCMV also rescues p107- and p130-mediated repression of E2F-responsive gene expression, but does not induce their phosphorylation and does not disrupt p107-E2F or p130-E2F complexes. The unique regulation of Rb family proteins by HCMV UL97 and IE1 attests to the importance of modulating Rb family protein function in HCMV-infected cells.

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Multiple roles of filopodial dynamics in particle capture and phagocytosis, and phenotypes of Cdc42 and Myo10 deletion [Cell Biology]

Macrophage filopodia, finger-like membrane protrusions, were first implicated in phagocytosis more than 100 years ago, but little is still known about the involvement of these actin-dependent structures in particle clearance. Using spinning disk confocal microscopy to image filopodial dynamics in mouse resident Lifeact-EGFP macrophages, we show that filopodia, or filopodia-like structures, support pathogen clearance by multiple means. Filopodia supported the phagocytic uptake of bacterial (Escherichia coli) particles by (i) capturing along the filopodial shaft and surfing towards the cell body, the most common mode of capture; (ii) capturing via the tip followed by retraction; (iii) combinations of surfing and retraction; or (iv) sweeping actions. In addition, filopodia supported the uptake of zymosan (Saccharomyces cerevisiae) particles by (i) providing fixation, (ii) capturing at the tip and filopodia-guided actin anterograde flow with phagocytic cup formation, and (iii) the rapid growth of new protrusions. To explore the role of filopodia-inducing Cdc42, we generated myeloid-restricted Cdc42 knockout mice. Cdc42-deficient macrophages exhibited rapid phagocytic cup kinetics, but reduced particle clearance, which could be explained by the marked rounded-up morphology of these cells. Macrophages lacking Myo10, thought to act downstream of Cdc42, had normal morphology, motility, and phagocytic cup formation, but displayed markedly reduced filopodia formation. In conclusion, live-cell imaging revealed multiple mechanisms involving macrophage filopodia in particle capture and engulfment. Cdc42 is not critical for filopodia or phagocytic cup formation, but plays a key role in driving macrophage lamellipodial spreading.

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Contribution of Type III Interferons to Antiviral Immunity; Location, Location, Location [Immunology]

Type I interferons (IFN-α/β) and the more recently identified type III IFNs (IFN-λ) function as the first line of defense against virus infection, and regulate the development of both innate and adaptive immune responses. Type III IFNs were originally identified as a novel ligand-receptor system acting in parallel with type I IFNs, but subsequent studies have provided increasing evidence for distinct roles for each IFN family. In addition to their compartmentalized antiviral actions, these two systems appear to have multiple levels of cross-regulation, and act coordinately to achieve effective anti-microbial protection with minimal collateral damage to the host.

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Human pregnane X receptor is activated by dibenzazepine carbamate-based inhibitors of constitutive androstane receptor

Abstract

Unintentional activation of xenosensing nuclear receptors pregnane X receptor (PXR) and/or constitutive androstane receptor (CAR) by clinical drug use is known to produce severe side effects in patients, which may be overcome by co-administering antagonists. However, especially antagonizing CAR is hampered by the lack of specific inhibitors, which do not activate PXR. Recently, compounds based on a dibenzazepine carbamate scaffold were identified as potent CAR inhibitors. However, their potential to activate PXR was not thoroughly investigated, even if the lead compound was named “CAR inhibitor not PXR activator 1” (CINPA1). Thus, we performed a comprehensive analysis of the interaction of CINPA1 and four analogs with PXR. Cellular assays were used to investigate intra- and intermolecular interactions and transactivation activity of PXR as a function of the compounds. Modulation of PXR target gene expression was analyzed in primary human hepatocytes. Ligand binding to PXR was investigated by molecular docking and limited proteolytic digestion. We show here that CINPA1 induced the assembly of the PXR ligand-binding domain, released co-repressors from and recruited co-activators to the receptor. CINPA1 and its analogs induced the PXR-dependent activation of a CYP3A4 reporter gene and CINPA1 induced the expression of endogenous cytochrome P450 genes in primary hepatocytes, while not consistently inhibiting CAR-mediated induction. Molecular docking revealed favorable binding of CINPA1 and analogs to the PXR ligand-binding pocket, which was confirmed in vitro. Altogether, our data provide consistent evidence that compounds with a dibenzazepine carbamate scaffold, such as CINPA1 and its four analogs, bind to and activate PXR.

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A miRNA signature for an environmental heterocyclic amine defined by a multi-organ carcinogenicity bioassay in the rat

Abstract

Heterocyclic amines (HCAs) produced during high-temperature cooking have been studied extensively in terms of their genotoxic/genetic effects, but recent work has implicated epigenetic mechanisms involving non-coding RNAs. Colon tumors induced in the rat by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) have altered microRNA (miRNA) signatures linked to dysregulated pluripotency factors, such as c-Myc and Krüppel-like factor 4 (KLF4). We tested the hypothesis that dysregulated miRNAs from PhIP-induced colon tumors would provide a “PhIP signature” for use in other target organs obtained from a 1-year carcinogenicity bioassay in the rat. Downstream targets that were corroborated in the rat were then investigated in human cancer datasets. The results confirmed that multiple let-7 family members were downregulated in PhIP-induced skin, colon, lung, small intestine, and Zymbal’s gland tumors, and were associated with c-myc and Hmga2 upregulation. PhIP signature miRNAs with the profile mir-21^high/mir-126^low/mir-29c^low/mir-215^low/mir-145^low were linked to reduced Klf4 levels in rat tumors, and in human pan-cancer and colorectal cancer. It remains to be determined whether this PhIP signature has predictive value, given that more than 20 different genotoxic HCAs are present in the human diet, plus other agents that likely induce or repress many of the same miRNAs. Future studies should define more precisely the miRNA signatures of other HCAs, and their possible value for human risk assessment.

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Modified FOA Applied to Parameter Extraction of Flux-Gate Core

The accuracy of the magnetic core model is important to the analysis and design of the flux-gate sensor. The Jiles-Atherton model (J-A model) is the mostly used model to describe the hysteresis characteristics of the flux-gate core. But the parameters of J-A model are difficult to identify. In this paper, Fruit Fly Optimization Algorithm (FOA) is proposed to identify the parameters of the J-A model. In order to enhance the performance of the identification, a Modified Fruit Fly Optimization Algorithm (MFOA) is applied to extract the parameters of the flux-gate core. The effectiveness of MFOA is verified through five typical test functions. The influence of variation factor on the performance of MFOA is discussed. The impact of variation factor on parameters extraction of hysteresis loop is studied. It is shown that MFOA with appropriate selection of variation factor will get better performance in the accuracy, stability, and simulation time compared to those of PSO and FOA.

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Cerium Oxide Nanoparticles in Lung Acutely Induce Oxidative Stress, Inflammation, and DNA Damage in Various Organs of Mice

CeO2 nanoparticles (CeO2 NPs) which are used as a diesel fuel additive are emitted in the particulate phase in the exhaust, posing a health concern. However, limited information exists regarding the in vivo acute toxicity of CeO2 NPs on multiple organs. Presently, we investigated the acute (24 h) effects of intratracheally instilled CeO2 NPs in mice (0.5 mg/kg) on oxidative stress, inflammation, and DNA damage in major organs including lung, heart, liver, kidneys, spleen, and brain. Lipid peroxidation measured by malondialdehyde production was increased in the lungs only, and reactive oxygen species were increased in the lung, heart, kidney, and brain. Superoxide dismutase activity was decreased in the lung, liver, and kidney, whereas glutathione increased in lung but it decreased in the kidney. Total nitric oxide was increased in the lung and spleen but it decreased in the heart. Tumour necrosis factor-α increased in all organs studied. Interleukin- (IL-) 6 increased in the lung, heart, liver, kidney, and spleen. IL-1β augmented in the lung, heart, kidney, and spleen. Moreover, CeO2 NPs induced DNA damage, assessed by COMET assay, in all organs studied. Collectively, these findings indicate that pulmonary exposure to CeO2 NPs causes oxidative stress, inflammation, and DNA damage in multiple organs.

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Capturing Genomic Evolution of Lung Cancers through Liquid Biopsy for Circulating Tumor DNA

Genetic sequencing of malignancies has become increasingly important to uncover therapeutic targets and capture the tumor’s dynamic changes to drug sensitivity and resistance through genomic evolution. In lung cancers, the current standard of tissue biopsy at the time of diagnosis and progression is not always feasible or practical and may underestimate intratumoral heterogeneity. Technological advances in genetic sequencing have enabled the use of circulating tumor DNA (ctDNA) analysis to obtain information on both targetable mutations and capturing real-time Darwinian evolution of tumor clones and drug resistance mechanisms under selective therapeutic pressure. The ability to analyze ctDNA from plasma, CSF, or urine enables a comprehensive view of cancers as systemic diseases and captures intratumoral heterogeneity. Here, we describe these recent advances in the setting of lung cancers and advocate for further research and the incorporation of ctDNA analysis in clinical trials of targeted therapies. By capturing genomic evolution in a noninvasive manner, liquid biopsy for ctDNA analysis could accelerate therapeutic discovery and deliver the next leap forward in precision medicine for patients with lung cancers and other solid tumors.

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Assessment of Medication Use among University Students in Ethiopia

Background. The extent, nature, and determinants of medication use of individuals can be known from drug utilization studies. Objectives. This study intended to determine medication consumption, sharing, storage, and disposal practices of university students in Northwest Ethiopia. Methods. A descriptive cross-sectional study was conducted on 404 university students selected through stratified random sampling technique. Data were collected using self-administered questionnaire and analyzed with SPSS version 20 statistical software. Pearson’s Chi-square test of independence was conducted with taken as statistically significant. Results. At 95.3% response rate, the prevalences of medication consumption and sharing were 35.3% () and 38.2% (), respectively. One hundred (26%) respondents admitted that they often keep leftover medications for future use while the rest (, 74%) discard them primarily into toilets (, 44.2%). Evidence of association existed between medication taking and year of study (), medication sharing and sex (), and medication sharing and year of study (). Conclusion. There is a high prevalence of medication consumption, medication sharing, and inappropriate disposal practices which are influenced by sex and educational status of the university students. Thus medication use related educational interventions need to be given to students in general.

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An Efficient Multiobjective Backtracking Search Algorithm for Single Machine Scheduling with Controllable Processing Times

The scheduling problem with controllable processing times (CPT) is one of the most important research topics in the scheduling field due to its widespread application. Because of the complexity of this problem, a majority of research mainly addressed single-objective small scale problems. However, most practical problems are multiobjective and large scale issues. Multiobjective metaheuristics are very efficient in solving such problems. This paper studies a single machine scheduling problem with CPT for minimizing total tardiness and compression cost simultaneously. We aim to develop a new multiobjective discrete backtracking search algorithm (MODBSA) to solve this problem. To accommodate the characteristic of the problem, a solution representation is constructed by a permutation vector and an amount vector of compression processing times. Furthermore, two major improvement strategies named adaptive selection scheme and total cost reduction strategy are developed. The adaptive selection scheme is used to select a suitable population to enhance the search efficiency of MODBSA, and the total cost reduction strategy is developed to further improve the quality of solutions. For the assessment of MODBSA, MODBSA is compared with other algorithms including NSGA-II, SPEA2, and PAES. Experimental results demonstrate that the proposed MODBSA is a promising algorithm for such scheduling problem.

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Expression and trafficking of placental microRNAs at the feto-maternal interface [Research]

During pregnancy, placental trophoblasts at the feto-maternal interface produce a broad repertoire of microRNA (miRNA) species. These species include miRNA from the primate-specific chromosome 19 miRNA cluster (C19MC), which is expressed nearly exclusively in the placenta. Trafficking of these miRNAs among the maternal, placental, and fetal compartments is unknown. To determine miRNA expression and trafficking patterns during pregnancy, we sequenced miRNAs in triads of human placenta and of maternal and fetal blood and found large subject-to-subject variability, with C19MC exhibiting compartment-specific expression. We therefore created humanized mice that transgenically express the entire 160-kb human C19MC locus or lentivirally express C19MC miRNA members selectively in the placenta. C19MC transgenic mice expressed a low level of C19MC miRNAs in diverse organs. When pregnant, female C19MC mice exhibited a strikingly elevated (>40-fold) expression of C19MC miRNA in the placenta, compared with other organs, that resembled C19MC miRNAs patterns in humans. Our mouse models showed that placental miRNA traffic primarily to the maternal circulation and that maternal miRNA can traffic to the placenta and even into the fetal compartment. These findings define an extraordinary means of nonhormonal, miRNA-based communication between the placenta and feto-maternal compartments.—Chang, G., Mouillet, J.-F., Mishima, T., Chu, T., Sadovsky, E., Coyne, C. B., Parks, W. T., Surti, U., Sadovsky, Y. Expression and trafficking of placental microRNAs at the feto-maternal interface.

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Brain Herniation into Giant Arachnoid Granulation: An Unusual Case

Arachnoid granulations are structures filled with cerebrospinal fluid (CSF) that extend into the venous sinuses through openings in the dura mater and allow the drainage of CSF from subarachnoid space into venous system. Usually they are asymptomatic but can be symptomatic when large enough to cause sinus occlusion. We report a rare case of a brain herniation into a giant arachnoid granulation in an asymptomatic elderly male patient, which was discovered incidentally.

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Tyrosine Phosphorylation of NR2B Contributes to Chronic Migraines via Increased Expression of CGRP in Rats

Tyrosine phosphorylation of NR2B (NR2B-pTyr), a subunit of the N-methyl-D-aspartate (NMDA) receptor, has been reported to develop central sensitization and persistent pain in the spine, but its effect in chronic migraines has not been examined. We hypothesized that tyrosine phosphorylation of NR2B contributes to chronic migraines (CM) through calcitonin gene-related peptide (CGRP) in rats. Ninety-four male Sprague-Dawley rats were subjected to seven inflammatory soup (IS) injections. In a subset of animals, the time course and location of NR2B tyrosine phosphorylation were detected by western blot and immunofluorescence double staining. Another set of animals were given either genistein, vehicle, or genistein and recombinant CGRP. The mechanical threshold was measured, the expressions of NR2B-pTyr, NR2B, and CGRP were quantified using western blot, and nitric oxide (NO) was measured with the nitric acid reductase method. NR2B-pTyr expression, in neurons, peaked at 24 hours after CM. Genistein improved the mechanical threshold and reduced migraine attacks 24 and 72 hours after CM. Tyrosine phosphorylation of NR2B decreased the mechanical threshold and increased migraine attacks via upregulated CGRP expression in the rat model of CM. Thus, tyrosine phosphorylation of NR2B may be a potential therapeutic target for treatment of CM.

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Association between IL-4 and IL-4R Polymorphisms and Periodontitis: A Meta-Analysis

Background. Previous studies have revealed that gene polymorphisms of inflammatory factors may influence the development or progression of periodontitis, a main cause of tooth loss in adults; however, due to limitations of individual studies, inconsistent findings were reported. Objective. To meta-analytically investigate the relationship between periodontitis and the Interleukin-4 (IL-4) and Interleukin-4 receptor (IL-4R) gene polymorphisms. Methods. Databases were searched for relevant case-control studies. After study selection based on the predefined selection criteria, methodological quality assessment and data extraction were conducted independently by two reviewers, before subsequent statistical analyses. Results. 37 studies involving 4,385 patients and 5,168 controls were included. All the studied IL-4 polymorphisms were not significantly associated with periodontitis, except the -33C/T (CT versus CC: OR = 0.50, 95% CI = 0.28–0.88) associated with reduced AgP susceptibility. Positive association was found between IL-4R Q551 polymorphism and periodontitis susceptibility in three genetic models (R versus Q: OR = 1.59, 95% CI = 1.14–2.22; QR versus QQ: OR = 1.84, 95% CI = 1.21–2.80; RR + QR versus QQ: OR = 1.82, 95% CI = 1.22–2.72). Conclusions. A positive association exists between the IL-4R Q551R polymorphism and occurrence of CP. The IL-4 -33 CT genotype is negatively associated with the occurrence of AgP.

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Clinical Implications for the Timely Diagnosis of Mycobacterium marinum in the Age of Biologic Therapy: A Case Report and Review of the Literature

Mycobacterium marinum infections typically present as cutaneous nodular lesions with a sporotrichoid lymphatic spread on extensor surfaces of extremities. The natural history of this infection can be altered if the host is immunosuppressed, leading to disseminated presentations. A detailed exposure history and high degree of suspicion for this indolent pathogen are often required for the correct diagnosis of this disease. We present a case of a 67-year-old male misdiagnosed with seronegative rheumatoid arthritis presenting with rheumatic nodules. Initiation of chronic immunosuppressant therapy including biologic monoclonal antibodies resulted in the exacerbation of initially localized disease to broadly disseminated lymphatic, joint, and myotendinous granulomatous disease and led to delay in the correct diagnosis. Cessation of immunosuppressants, with a prolonged course of antimicrobial therapy and multiple surgical debridements were required for cure.

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Subthreshold Depression and Clinically Significant Depression in an Italian Population of 70–74-Year-Olds: Prevalence and Association with Perceptions of Self

Estimates of depressive disorders in the elderly vary depending on how cases are defined. We estimated the prevalence of subthreshold depression (SD) and clinically significant depression (D) in a population of 70–74-year-olds. We also looked for associations with sociodemographic factors and perceptions of self. Participants underwent a multidimensional assessment (social, medical, and neuropsychological). The estimated prevalence of SD was 15.71% (95% CI: 13.70–17.72), while that of D was 5.58% (95% CI: 4.31–6.85). Multinomial logistic regression analysis revealed that female gender and dissatisfaction with family relationships were related to SD and D. A self-perception of physical age as older than actual age (but not comorbidity) and greater self-perceived stress caused by negative life events both increased the probability of SD. The likelihood of D was decreased in those who perceived their own health as good, whereas a self-perception of mental age as older than actual age and dissatisfaction with relationships with friends were both significantly associated with D. Both SD and D emerged as key problems in our population. Female gender and self-perceptions of various characteristics, which can be explored through simple questions, are associated with late-life depression in elderly people independently of their actual physical condition and other characteristics.

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Frequency Reconfigurable Circular Patch Antenna with an Arc-Shaped Slot Ground Controlled by PIN Diodes

In this paper, a compact frequency reconfigurable circular patch antenna with an arc-shaped slot loaded in the ground layer is proposed for multiband wireless communication applications. By controlling the ON/OFF states of the five PIN diodes mounted on the arc-shaped slot, the effective length of the arc-shaped slot and the effective length of antennas current are changed, and accordingly six-frequency band reconfiguration can be achieved. The simulated and measured results show that the antenna can operate from 1.82 GHz to 2.46 GHz, which is located in DCS1800 (1.71–1.88 GHz), UMTS (2.11–2.20 GHz), WiBro (2.3–2.4 GHz), and Bluetooth (2.4–2.48 GHz) frequency bands and so forth. Compared to the common rectangular slot circular patch antenna, the proposed arc-shaped slot circular patch antenna not only has a better rotational symmetry with the circular patch and substrate but also has more compact size. For the given operating frequency at 1.82 GHz, over 55% area reduction is achieved in this design with respect to the common design with rectangular slot. Since the promising frequency reconfiguration, this antenna may have potential applications in modern multiband and multifunctional mobile communication systems.

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Three Novel Mutations in the NPHS1 Gene in Vietnamese Patients with Congenital Nephrotic Syndrome

Congenital nephrotic syndrome, a rare and severe disease, is inherited as an autosomal recessive trait. The disease manifests shortly after birth and occurs predominantly in families of Finnish origin but has now been observed in all countries and races. Mutations in the NPHS1 gene, which encodes nephrin, are the main causes of congenital nephrotic syndrome in patients. In this study, we report the first mutational analysis of the NPHS1 gene in three unrelated children from three different Vietnamese families. These patients were examined and determined to be suffering from congenital nephrotic syndrome in the Department of Pediatrics, Vietnam National Hospital of Pediatrics. All 29 exons and exon-intron boundaries of NPHS1 were analyzed by PCR and DNA sequencing. Genetic analysis of the NPHS1 gene revealed one compound heterozygous variant p.Glu117Lys, one heterozygous missense mutation p.Asp310Asn, and one heterozygous frame-shifting mutation (c.3250_3251insG causing p.Val1084Glyfs12) in patient 1. In patient 2, one heterozygous variant p.Glu117Lys and one novel heterozygous missense mutation p.Ser324Ala were identified. Finally, a novel missense mutation p.Arg802Leu and a novel nonsense mutation (c.2442C>G causing p.K792) were identified in patient 3.

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Unusual Case of Osseointegrated Dental Implant Migration into Maxillary Sinus Removed 12 Years after Insertion

Displacement of dental implants into the maxillary sinus is not an uncommon event in implant dentistry and may lead to serious complications, such as sinusitis. To avoid systemic problems, performing the removal of the foreign body as soon as possible is suggested. Despite the fact that early implants dislocation has been reported several times, late migration into maxillary sinus has been described by just a few studies. The purpose of this study was to report a rare case of dental implant migration into maxillary sinus after 12 years of function. A 61-year-old woman came to our attention in June 2015 after being visited by an otolaryngologist and being diagnosed with sinusitis and presence of a foreign body into the right maxillary sinus. A panoramic radiograph and a CT scan showed the migration of dental implant sited in 1.6 positions into the maxillary sinus. The implant was removed following a Caldwell-Luc procedure under local anesthesia. Postoperative course was uncomplicated and the patient reported no symptoms of sinusitis after 12 months of follow-up.

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Insulin Resistance and Chronic Kidney Disease in Patients with Type 1 Diabetes Mellitus

Background and Aims. Diabetes mellitus (DM) is a chronic disease which can evolve towards devastating micro- and macrovascular complications. DM is the most frequent cause of chronic kidney disease (CKD). Insulin resistance plays an important role in the natural history of type 1 diabetes. The purpose of the study was to determine the prevalence of CKD in T1DM and the correlation with insulin resistance (IR) in patients with CKD. Materials and Methods. The study was conducted over a period of three years (2010–2013) and included patients with DM registered in the Clinical Centre of Diabetes, Nutrition and Metabolic Diseases of Dolj county. The study design was an epidemiological, transversal, noninterventional type. Finally, the study group included 200 subjects with type 1 DM. Insulin resistance (IR) was estimated by eGDR. The subjects with eGDR ≤ 7.5 mg/kg/min were considered with insulin resistance. Results. CKD was found in 44% of the patients. Analyzing statistically the presence of CKD, we found highly significant differences between patients with CKD and those without CKD regarding age and sex of the patients, the duration of diabetes, glycosylated hemoglobin (HbA1c), the estimated glucose disposal rate (eGDR), and the presence of hypertension, dyslipidemia, and hyperuricaemia. In patients with CKD, age and diabetes duration are significantly higher than in those who do not have this complication. CKD is more frequent in males than in females (50.9% men versus 34.5% women, ). From the elements of metabolic syndrome, high blood pressure, hyperuricemia, and dyslipidemia are significantly increased in diabetic patients with CKD. eGDR value (expressed as mg·kg−1·min−1) is lower in patients with CKD than in those without CKD (15.92 versus 6.42, ) indicating the fact that patients with CKD show higher insulin resistance than those without CKD. Conclusions. This study has shown that insulin resistance is associated with an increased risk of CKD, but, due to the cross-sectional design, the causal relationship cannot be assessed. However, the existence of this causality and the treatment benefit of insulin resistance in type 1 diabetes are issues for further discussion.

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Advanced Implant-Prosthetic Rehabilitation: How to Obtain a Correct Restoration of Both Functions and Aesthetics in Patients with Complex Combined Dental and Maxillofacial Trauma: A Case Report and Topical Review of the Literature

Aim. This study aims to explain the main steps that characterize the implant-prosthetic rehabilitation in complex combined dental and maxillofacial trauma. Material and Methods. A 20-year-old patient reported an extensive facial trauma which also involved the alveolar process of the maxillary bone. The patient reported a maxillofacial fracture and the loss of teeth 1.3, 1.2, 1.1, and 2.1. A “Le Fort” type 2 fracture was also reported, with the malar bone involvement. After reduction and containment of bone fractures, through appropriate mounting plates, appropriate functional and aesthetic rehabilitation of the patient were replaced thanks to a temporary removable prosthesis. After 6 months, the patient performed numerous clinical investigations, aimed at a proper planning of implant-prosthetic rehabilitation of the upper dental arch. Conclusion. With the planning of the case, as well as respecting the surrounding biological structures, the surgery of implants can be carried out with the most appropriate procedure. Lastly, new dental implants with highly bioactive surfaces have been developed, providing an excellent and rapid bone integration.

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The Effect of Volume Fraction of Single-Walled Carbon Nanotubes on Natural Frequencies of Polymer Composite Cone-Shaped Shell Made from Poly(Methyl Methacrylate)

In this paper, the effect of volume fraction of single-walled carbon nanotubes on natural frequencies of polymer composite cone-shaped shells made from Poly(Methyl Methacrylate) (PMMA) is studied. In order to determine the characterization of materials reinforced with nanoparticles, the molecular dynamics and mixture rule has been used. The motion equations of composite shell based on the classical thin shells theory using Hamilton’s principle are obtained. Then, using the Ritz method, approximate analytical solution of the natural frequency is presented. Results indicate that the nanotubes have a noticeable effect on the natural frequencies.

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Analysis of Disease Activity Categories in Chronic Spontaneous/Idiopathic Urticaria

Abstract

Background

Measurement of disease activity guides treatment of chronic spontaneous urticaria (CSU). A weekly Urticaria Activity Score―here, the average of twice-daily patient assessment of itch and hives scores summed over 1 week (UAS7_TD)―measures severity from 0 to 42. Insufficient evidence exists whether disease activity states, defined by categorical UAS7_TD scores, correlate with other patient-reported outcomes and treatment response.

Objective

To evaluate and compare categorical UAS7_TD scores with selected measures of disease-related quality of life and impact.

Methods

Data from three randomised clinical trials of omalizumab in CSU were pooled. Continuous UAS7_TD scores were categorised into five disease activity states: urticaria-free, well-controlled, mild, moderate, and severe urticaria. Total scores from the Dermatology Life Quality Index (DLQI); the Chronic Urticaria Quality of Life questionnaire (CU-Q₂oL); and questions on sleep and daily activity interference, presence of angioedema, and diphenhydramine use were compared within categorised UAS7_TD disease-state scores, using one-way analyses of variance for analysis at different time points and mixed-effects regressions for analysis of all data pooled.

Results

Pooled analyses showed that categorical UAS7_TD disease states accurately predicted differences among treated CSU patients with different levels of disease activity. A consistent pattern existed between categories, with higher-activity disease states associated with significantly higher impact and an increase in angioedema frequency. Results at different treatment time points were consistent.

Conclusion

Categorical UAS7_TD disease states can discriminate between measures when considering the impact of urticaria activity. Using five categorical disease states could simplify clinical assessment and monitoring of treatment efficacy.

This article is protected by copyright. All rights reserved.

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Search strategies for finding systematic reviews

Abstract

I have read with interest the 2017 article by F Gómez-García and colleagues called “Systematic reviews and meta-analyses on psoriasis: role of funding sources, conflict of interest, and bibliometric indices as predictors of methodological quality” published in the BJD.

This study makes a very important point about the influence of funding sources and conflicts of interests on the methodological quality of systematic reviews.

However, I have some concerns about the search strategy used to find systematic reviews for this analysis.

This article is protected by copyright. All rights reserved.

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JDB, Vol. 5, Pages 3: Canonical Sonic Hedgehog Signaling in Early Lung Development

The canonical hedgehog (HH) signaling pathway is of major importance during embryonic development. HH is a key regulatory morphogen of numerous cellular processes, namely, cell growth and survival, differentiation, migration, and tissue polarity. Overall, it is able to trigger tissue-specific responses that, ultimately, contribute to the formation of a fully functional organism. Of all three HH proteins, Sonic Hedgehog (SHH) plays an essential role during lung development. In fact, abnormal levels of this secreted protein lead to severe foregut defects and lung hypoplasia. Canonical SHH signal transduction relies on the presence of transmembrane receptors, such as Patched1 and Smoothened, accessory proteins, as Hedgehog-interacting protein 1, and intracellular effector proteins, like GLI transcription factors. Altogether, this complex signaling machinery contributes to conveying SHH response. Pulmonary morphogenesis is deeply dependent on SHH and on its molecular interactions with other signaling pathways. In this review, the role of SHH in early stages of lung development, specifically in lung specification, primary bud formation, and branching morphogenesis is thoroughly reviewed.

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Regorafenib overcomes chemotherapeutic multidrug resistance mediated by ABCB1 transporter in colorectal cancer: In vitro and in vivo study

Chemotherapeutic multidrug resistance (MDR) is a significant challenge to overcome in clinic practice. Several mechanisms contribute to MDR, one of which is the augmented drug efflux induced by the upregulation of ABCB1 in cancer cells. Regorafenib, a multikinase inhibitor targeting the RAS/RAF/MEK/ERK pathway, was approved by the FDA to treat metastatic colorectal cancer and gastrointestinal stromal tumors. We investigated whether and how regorafenib overcame MDR mediated by ABCB1. The results showed that regorafenib reversed the ABCB1-mediated MDR and increased the accumulation of [3H]-paclitaxel in ABCB1-overexpressing cells by suppressing efflux activity of ABCB1, but not altering expression level and localization of ABCB1.

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Resistin potentiates chemoresistance and stemness of breast cancer cells: implications for racially disparate therapeutic outcomes

Breast cancer (BC) continues to be the most frequently diagnosed cancer in American women, which disproportionately affects women of African-American (AA) descent. Previously, we reported greater serum levels of resistin in AA BC patients relative to Caucasian-American (CA) patients, and established its role in growth and aggressiveness of breast tumor cells. Here we have investigated the role of resistin in BC-chemoresistance. MDA-MB-231 and MDA-MB-468 BC cells of CA and AA origin, respectively, were incubated with resistin prior to doxorubicin treatment.

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Correlating In Vitro Target-Oriented Screening and Docking: Inhibition of Matrix Metalloproteinases Activities by Flavonoids

Planta Med
DOI: 10.1055/s-0043-104775

Metalloproteases are a family of zinc-containing endopeptidases involved in a variety of pathological disorders. The use of flavonoid derivatives as potential metalloprotease inhibitors has recently increased.Particular plants growing in Sicily are an excellent yielder of the flavonoids luteolin, apigenin, and their respective glycoside derivatives (7-O-rutinoside, 7-O-glucoside, and 7-O-glucuronide).The inhibitory activity of luteolin, apigenin, and their respective glycoside derivatives on the metalloproteases MMP-1, MMP-3, MMP-13, MMP-8, and MMP-9 was assessed and rationalized correlating in vitro target-oriented screening and in silico docking.The flavones apigenin, luteolin, and their respective glucosides have good ability to interact with metalloproteases and can also be lead compounds for further development. Glycones are more active on MMP-1, -3, -8, and -13 than MMP-9. Collagenases MMP-1, MMP-8, and MMP-13 are inhibited by compounds having rutinoside glycones. Apigenin and luteolin are inactive on MMP-1, -3, and -8, which can be interpreted as a better selectivity for both -9 and -13 peptidases. The more active compounds are apigenin-7-O-rutinoside on MMP-1 and luteolin-7-O-rutinoside on MMP-3. The lowest IC50 values were also found for apigenin-7-O-glucuronide, apigenin-7-O-rutinoside, and luteolin-7-O-glucuronide. The glycoside moiety might allow for a better anchoring to the active site of MMP-1, -3, -8, -9, and -13. Overall, the in silico data are substantially in agreement with the in vitro ones (fluorimetric assay).
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Inhibitory Effects of Garcinia cambogia Extract on CYP2B6 Enzyme Activity

Planta Med
DOI: 10.1055/s-0043-104934

This study assessed the inhibitory effects of Garcinia cambogia extract on the cytochrome P450 enzymes in vitro. G. cambogia extract was incubated with cytochrome P450 isozyme-specific substrates in human liver microsomes and recombinant CYP2B6 isozyme, and the formation of the marker metabolites was measured to investigate the inhibitory potential on cytochrome P450 enzyme activities. The results showed that G. cambogia extract has significant inhibitory effects on CYP2B6 activity in a concentration-dependent manner. Furthermore, the inhibition was potentiated following preincubation with NADPH, indicating that G. cambogia extract is a time-dependent inhibitor of CYP2B6. Meanwhile, hydroxycitric acid, the major bioactive ingredient of G. cambogia extract, did not exhibit significant inhibition effects on cytochrome P450 enzyme activities. G. cambogia extract could modulate the pharmacokinetics of CYP2B6 substrate drugs and lead to interactions with those drugs. Therefore, caution may be required with respect to concomitant intake of dietary supplements containing G. cambogia extract with CYP2B6 substrates.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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The C- terminal region of the Major Outer Sheath Protein (Msp) of Treponema denticola inhibits neutrophil chemotaxis

Summary

Treponema denticola is an oral spirochete strongly associated with severe periodontal disease. A prominent virulence factor, the major outer sheath protein (Msp), disorients neutrophil chemotaxis by altering the cellular phosphoinositide balance, leading to impairment of downstream chemotactic events including actin rearrangement, Rac1 activation and Akt activation in response to chemoattractant stimulation. The specific regions of Msp responsible for interactions with neutrophils remain unknown. In this study, we investigated the inhibitory effect of truncated Msp regions on neutrophil chemotaxis and associated signaling pathways. Murine neutrophils were treated with recombinant protein truncations followed by assessment of chemotaxis and associated signal pathway activation. Chemotaxis assays indicate sequences within the C-terminal region; particularly the first 130 amino acids, have the strongest inhibitory effect on neutrophil chemotaxis. Neutrophils incubated with the C-terminal region protein also demonstrated the greatest inhibition of Rac1 activation, increased phosphoinositide phosphatase activity, and decreased Akt activation; orchestrating impairment of chemotaxis. Furthermore, incubation with antibodies specific to only the C-terminal region blocked the Msp induced inhibition of chemotaxis and denaturing the protein restored Rac1 activation. Msp from the strain OTK, with numerous amino acid substitutions throughout the polypeptide, including the C-terminal region compared to strain 35405, showed increased ability to impair neutrophil chemotaxis. Collectively, these results indicate the C-terminal region of Msp is the most potent region to modulate neutrophil chemotactic signaling and that specific sequences and structure is likely required. Knowledge of how spirochetes dampen neutrophil response is limited and Msp may represent a novel therapeutic target for periodontal disease.

This article is protected by copyright. All rights reserved.

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Prescriptions for adrenaline devices in children are rising faster than anaphylaxis

Researchers have called for clarity on when adrenaline auto injectors (AAIs) should be prescribed for children with allergies and how many devices they should be given after finding that...

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Becoming a parent may add a year or two to your life

Tracking 1.4 million people has found that having children increases life expectancies by around 1.5 years – perhaps because adult children help elderly parents

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Reliability and validity of the Turkish CHILDREN’S voice handicap INDEX-10 (TR-CVHI-10)

During voice production, there can be some problems which are not in correspondence with age and gender and/or there can be some changes in voice quality, pitch, loudness, resonance and duration limiting individuals’ communication. Thus, all these result in dysphonia [1]. As dysphonia affects speech intelligibility, %6 of people having dysphonia have also communication problems no matter how old they are and what their gender is [2]. Therefore, treatment of pediatric dysphonia plays a key role in preventing the problems that can occur in puberty and adulthood [3].

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Branchial Arch Anomalies: Recurrence, Malignant Degeneration and Operative Complications

Branchial arch anomalies (BAA) represent one of the commonest pediatric neck masses, but large case series are lacking with none specifically examining risk of recurrence, surgical complications, and malignancy.

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A Systematic Review of Complications Associated with Direct Implants Vs. Tissue Expanders Following Wise Pattern Skin Sparing Mastectomy

With proven oncological safety and improved aesthetic outcomes, the Type IV or “Wise Pattern” skin sparing mastectomy (SSM) is a procedure that is being performed with increasing frequency. Unfortunately, it is also associated with an increased risk of complication. The purpose of this investigation is to determine the complications associated with direct-to-implant and two-step tissue-expander breast reconstruction following Wise Pattern SSM.

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Becoming a parent may add a year or two to your life

Tracking 1.4 million people has found that having children increases life expectancies by around 1.5 years – perhaps because adult children help elderly parents

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Interstitial Lung Disease Associated with Crizotinib in Patients with Advanced Non-Small-Cell Lung Cancer: Independent Review of Four PROFILE Trials

Interstitial lung disease (ILD) is a potentially serious side effect associated with crizotinib, a tyrosine kinase inhibitor for ALK-positive advanced non-small-cell lung cancer. In this retrospective review of 1669 patients who received crizotinib in four clinical trials, an expert independent review committee determined that the incidence of ILD was 1.2% overall, 1.3% in Caucasians, and 1.2% in Asians but higher at 3.7% in Japanese patients. Mortality rate due to ILD was 50%. ILD associated with crizotinib, although rare, can occur at any time and requires close monitoring.

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Ablative Therapy for Oligometastatic Non-Small-Cell Lung Cancer

The oligometastatic state represents a distinct entity amongst those with metastatic disease and consists of patients with metastases limited in number and location, representing an intermediate state between locally confined and widely metastatic cancers. Although similar, “oligorecurence” (limited number of metachronous metastases under conditions of a controlled primary lesion) and “oligoprogressive” state (disease progression at a limited number of sites with disease controlled at other sites of disease) are distinct entities.

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Molecular Testing Turnaround Time for Non-Small Cell Lung Cancer in Routine Clinical Practice Confirms Feasibility of CAP/IASLC/AMP Guideline Recommendations: a single center analysis

This study examines the feasibility of the target molecular testing turnaround time put forward by the CAP/IASLC/AMP guidelines for non-small cell lung cancer. In a retrospective review of all such cases over a one-year period sent out from a large academic institution, 81.5% of testing results were available within the recommended 10 day interval.

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Erratum to: Spectra Optia ® for Automated Red Blood Cell Exchange in Patients with Sickle Cell Disease: A NICE Medical Technology Guidance

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Economic Evaluations of Thrombophilia Screening Prior to Prescribing Combined Oral Contraceptives: A Systematic and Critical Review

Abstract

Background

Combined oral contraceptives (COCs) increase the risk of venous thromboembolism (VTE), particularly among women with inherited clotting disorders. The World Health Organization classifies combined hormonal contraception as an “unacceptable health risk” for women with thrombogenic mutations but advises against universal thrombophilia screening before prescribing COCs given the low prevalence of thrombophilia and high screening costs.

Objective

Through the lens of lifetime costs and benefits, this paper systematically and critically reviews all published economic evaluations of thrombophilia screening prior to prescribing COCs.

Methods

We searched relevant databases for economic evaluations of thrombophilia screening before prescribing COCs. After extracting the key study characteristics and economic variables, we evaluated each article using the Quality of Health Economic Studies (QHES) and the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) instruments.

Results

Seven economic evaluations of thrombophilia screening before prescribing COCs met our inclusion criteria. Only the two economic evaluations focusing exclusively on selective screening exceeded the 75-point threshold for high-quality economic studies based on the QHES instrument, whereas only one of these exceeded the 85% CHEERS threshold. Only three of the seven economic evaluations performed sensitivity analysis on key parameters. Most studies underestimated the benefits of thrombophilia screening by comparing one-time costs of genetic screening against benefits per person-year, thus implicitly assuming a 1-year duration of COC use, neglecting the long-term implications of VTE and/or neglecting the lifetime benefits of awareness of inherited thrombophilia.

Conclusion

Our review highlights the lack of methodologically rigorous economic evaluations of universal thrombophilia screening before prescribing COCs.

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A Head-to-Head Comparison of UK SF-6D and Thai and UK EQ-5D-5L Value Sets in Thai Patients with Chronic Diseases

Abstract

Purpose

Little was known about the head-to-head comparison of psychometric properties between SF-6D and EQ-5D-5L or the different value sets of EQ-5D-5L. Therefore, this study set out to compare the psychometric properties including agreement, convergent, and known-group validity between the SF-6D and the EQ-5D-5L using the real value sets from Thailand and the UK in patients with chronic diseases.

Methods

356 adults taking a medication for at least 3 months were identified from a university hospital in Bangkok, Thailand, between July 2014 and March 2015. Agreement was assessed by intraclass correlation coefficients (ICCs) and Bland–Altman plots. Convergent validity was evaluated using Spearman’s rank correlation coefficients between SF-6D and EQ-5D-5L and EQ-VAS and SF-12v2. For known-groups validity, the Mann–Whitney U test and Kruskal–Wallis test were used to examine the associations between SF-6D and EQ-5D-5L and patient characteristics.

Results

Agreements between the SF-6D and the EQ-5D-5L using Thai and UK value sets were fair, with ICCs of 0.45 and 0.49, respectively. Bland-Altman plots showed that the majority of the SF-6D index scores were lower than the EQ-5D-5L index scores. Both the EQ-5D-5L value sets were more related to the EQ-VAS and physical health, while the SF-6D was more associated with mental health. Both EQ-5D-5L value sets were more sensitive than the SF-6D in discriminating patients with different levels of more known groups except for adverse drug reactions.

Conclusions

The SF-6D and both EQ-5D-5L value sets appeared to be valid but sensitive to different outcomes in Thai patients with chronic diseases.

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Estimating Willingness to Pay for Online Health Services with Discrete-Choice Experiments

Abstract

Background

Research has outlined the benefits and costs of online health services, but these studies have typically focused on a specific geographic region or disease. Very few studies have estimated consumer demand for online health services.

Objective

This study estimated household’s willingness to pay (WTP) for the ability to receive remote diagnosis, treatment, monitoring and consultations online (telehealth).

Methods

WTP was estimated with a random utility model and household data from a US survey employing repeated discrete-choice experiments.

Results

The representative household was willing to pay $US4.39 per month for telehealth. This valuation increased to $US5.85 for households with higher opportunity costs, as measured by income, and to $US6.22 for households living more than 20 miles away from their nearest medical facility.

Conclusion

WTP estimates offer insights into the potential benefits from policies intended to promote the expansion of online health services into underserved areas. These include the Federal Communications Commission’s Rural Healthcare Pilot Program and the Department of Agriculture’s Distance Learning and Telemedicine Grants programme.

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Non-invasive in vivo imaging of cardiac stem/progenitor cell biodistribution and retention after intracoronary and intramyocardial delivery in a swine model of chronic ischemia reperfusion injury

The safety and efficacy of cardiac stem/progenitor cells (CSC) have been demonstrated in previous preclinical and clinical assays for heart failure. However, their optimal delivery route to the ischemic heart ...

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In-Situ Formed Type I Nanocrystalline Perovskite Film for Highly Efficient Light-Emitting Diode

ACS Nano

DOI: 10.1021/acsnano.7b00608

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Unraveling Hydrophobic Interactions at the Molecular Scale Using Force Spectroscopy and Molecular Dynamics Simulations

ACS Nano

DOI: 10.1021/acsnano.6b06360

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Self-Assembly of Islands on Spherical Substrates by Surface Instability

ACS Nano

DOI: 10.1021/acsnano.6b07108

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Nanoassemblies of Tissue-Reactive, Polyoxazoline Graft-Copolymers Restore the Lubrication Properties of Degraded Cartilage

ACS Nano

DOI: 10.1021/acsnano.6b07847

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A Review of Electronic Devices to Assess Inhaler Technique

Abstract

Purpose of Review

Multiple electronic devices exist that provide feedback on the accuracy of patient inhaler technique. Our purpose is to describe the inhaler technique feedback provided by these devices, including specific technique steps measured, how feedback is displayed, target of feedback (patient, provider, researcher), and compatibility with inhaler type (metered-dose inhaler [MDI], diskus, etc.).

Recent Findings

We identified eight devices that provide feedback on inhaler technique. Only one device assessed all evidence-based MDI technique steps. Most devices provide limited real-time feedback to patients, if any feedback at all.

Summary

Technologies to assess inhaler technique are advancing and hold great potential for improving patient inhaler technique. Many devices are limited in their ability to detect all evidence-based technique steps and provide real-time user-friendly feedback to patients and providers. Usability tests with patients and providers could identify ways to improve these devices to improve their utility in clinical settings.

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Erratum to: Assessing risk of osteoporotic fractures in primary care: development and validation of the FRA-HS algorithm

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Tumor Necrosis Factor Alpha Overexpression Induces Mainly Osteoclastogenesis at the Vertebral Site

Abstract

Syndesmophyte occurrence and axial bone loss were investigated in the heterozygous Tg187 tumor necrosis factor (TNF) transgenic mouse model (Tg-huTNF) of arthritis. Female and male Tg-huTNF mice were compared to wild-type mice (WT) at 2, 4, 6, 8, and 10 weeks. Syndesmophytes, intervertebral disc space, osteoclasts, osteoid surface, and vertebra microarchitecture were assessed by histomorphometry and microcomputed tomography. No spontaneous syndesmophyte formation was detected in Tg-huTNF compared to WT mice. However, increased porosity was observed mainly in peridiscal lumbar vertebra. Accordingly, bone microarchitecture parameters were altered in Tg-huTNF mice, with decrease in bone volume fraction, and trabecular number and thickness after 6 weeks compared to WT (p < 0.05). Osteoclast count and surface were increased (p < 0.01). Moreover, the non-mineralized (osteoid) surface was also increased in Tg-huTNF after 6 weeks (p < 0.01). Despite increased osteoclast and osteoid surfaces, an imbalance between both was observed in favour of osteoid surface at the early phase and then to osteoclast surface. These results demonstrated an axial bone loss in the Tg-huTNF model, additional to the common limb arthritis, related to overexpression of TNF. However, the absence of syndesmophyte and the increase of osteoid surface suggested that chronic inflammation might block bone mineralisation. Finally, the relative increased osteoid surface was not enough to compensate the high osteoclast activity.

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Hodgkin lymphoma survivors at high risk of second cancers

Patients who are cured of Hodgkin lymphoma are at a high risk of developing a second type of cancer, particularly if they have a family history of the disease, a major new study reports. People who survived Hodgkin lymphoma were 2.4 times more likely to...

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Patients should have free and immediate access to all information related to clinical trials

Mendel and colleagues highlight the problem of unethical trials getting approved by research ethics committees while the participating patients are kept in the dark.1I agree with their proposals but...

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Science is America's Foundation--and our Future

Instead of arbitrarily slashing federal programs, Congress should continue to work on a bipartisan basis to secure long-term, sustained investments for R&D

-- Read more on ScientificAmerican.com

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