The Importance of Registries in the Postmarketing Surveillance of Surgical Meshes

Objective: To assess the role of registries in the postmarketing surveillance of surgical meshes. Background: To date, surgical meshes are classified as group II medical devices. Class II devices do not require premarket clearance by clinical studies. Ethicon initiated a voluntary market withdrawal of Physiomesh for laparoscopic use after an analysis of unpublished data from the 2 large independent hernia registries—Herniamed German Registry and Danish Hernia Database. This paper now presents the relevant data from the Herniamed Registry. Methods: The present analysis compares the prospective perioperative and 1-year follow-up data collected for all patients with incisional hernia who had undergone elective laparoscopic intraperitoneal onlay mesh repair either with Physiomesh (n = 1380) or with other meshes recommended in the guidelines (n = 3834). Results: Patients with Physiomesh repair had a markedly higher recurrence rate compared with the other recommended meshes (12.0% vs 5.0%; P

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R0 Versus R1 Resection Matters after Pancreaticoduodenectomy, and Less after Distal or Total Pancreatectomy for Pancreatic Cancer

Objective: The aim of this study was to decipher the true importance of R0 versus R1 resection for survival in pancreatic ductal adenocarcinoma (PDAC). Summary of Background Data: PDAC is characterized by poor survival, even after curative resection. In many studies, R0 versus R1 does not result in different prognosis and does not affect the postoperative management. Methods: Pubmed, Embase, and Cochrane databases were screened for prognostic studies on the association between resection status and survival. Hazard ratios (HRs) were pooled in a meta-analysis. Furthermore, our prospective database was retrospectively screened for curative PDAC resections according to inclusion criteria (n = 254 patients) between July 2007 and October 2014. Results: In the meta-analysis, R1 was associated with a decreased overall survival [HR 1.45 (95% confidence interval, 95% CI 1.37–1.52)] and disease-free survival [HR 1.44 (1.30–1.59)] in PDAC when compared with R0. Importantly, this effect held true only for pancreatic head resection both in the meta-analysis [R0 ≥0 mm: HR 1.21 (1.05–1.39) vs R0 ≥1 mm: HR 1.66 (1.46–1.89)] and in our cohort (R0 ≥0 mm: 31.8 vs 14.5 months, P

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Proteomic Analysis of Liver from Human Lipoprotein(a) Transgenic Mice Shows an Oxidative Stress and Lipid Export Response

Background. Mouse models of hypercholesterolaemia have been used to identify arterial proteins involved in atherosclerosis. As the liver is extremely sensitive to dyslipidemia, one might expect major changes in the abundance of liver proteins in these models even before atherosclerosis develops. Methods. Lipid levels were measured and a proteomic approach was used to quantify proteins in the livers of mice with an elevated low-density lipoprotein (LDL) and the presence of lipoprotein(a) [Lp(a)] but no atherosclerosis. Results. The livers of Lp(a) mice showed an increased triglyceride but reduced phospholipid and oxidised lipid content. Two-dimensional gel electrophoresis and mass spectrometry analysis identified 24 liver proteins with significantly increased abundance in Lp(a) mice (P

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Thromboelastography and Thromboelastometry in Assessment of Fibrinogen Deficiency and Prediction for Transfusion Requirement: A Descriptive Review

Fibrinogen is crucial for the formation of blood clot and clinical outcomes in major bleeding. Both Thromboelastography (TEG) and Rotational Thromboelastometry (ROTEM) have been increasingly used to diagnose fibrinogen deficiency and guide fibrinogen transfusion in trauma and surgical bleeding patients. We conducted a comprehensive and comparative review on the technologies and clinical applications of two typical functional fibrinogen assays using TEG (FF TEG) and ROTEM (FIBTEM) for assessment of fibrinogen level and deficiency, and prediction of transfusion requirement. Clot strength and firmness of FF TEG and ROTEM FIBTEM were the most used parameters, and their associations with fibrinogen levels as measured by Clauss method ranged from 0 to 0.9 for FF TEG and 0.27 to 0.94 for FIBTEM. A comparison of the interchangeability and clinical performance of the functional fibrinogen assays using the two systems showed that the results were correlated, but are not interchangeable between the two systems. It appears that ROTEM FIBTEM showed better associations with the Clauss method and more clinical use for monitoring fibrinogen deficiency and predicting transfusion requirements including fibrinogen replacement than FF TEG. TEG and ROTEM functional fibrinogen tests play important roles in the diagnosis of fibrinogen-related coagulopathy and guidance of transfusion requirements. Despite the fact that high-quality evidence is still needed, the two systems are likely to remain popular for the hemostatic management of bleeding patients.

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Efficient Sensitivity Based Reconstruction Technique to Accomplish Breast Hyperelastic Elastography

Hyperelastic models have been acknowledged as constitutive equations which reliably model the nonlinear behaviors observed from soft tissues under various loading conditions. Among them, the Mooney-Rivlin, Yeoh, and polynomial models have been proved capable of accurately modeling responses of breast tissues to applied compressions. Hyperelastic elastography technique takes advantage of the disparities between hyperelastic parameters of varied tissues and the change in hyperelastic parameters in pathological processes. The precise reconstruction of hyperelastic parameters of a completely unknown pathology in the breast in a noninvasive and nondestructive way using the ultrasound elastography has been scrutinized in this paper. In the ultrasound elastography, tissue displacement field is extracted from radio frequency signals or images recorded using the ultrasound medical imaging system; hence the exact displacement field might not be obtained. Our results indicate that the parameters estimated by manipulating the iterative sensitivity-matrix based method converge to tissue's real hyperelastic parameters providing appropriate parameters are assigned to the hypothetical hyperelastic and regularization parameters. Iterative methods have therefore been proposed to compute proper hypothetical hyperelastic and regularization parameters. Accurate estimates of hyperelastic parameters of obscure breast pathology have been achieved even from imprecise measurements of displacements induced in the tissue by the ramp excitation.

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Financial gain‐ and loss‐related BOLD signals in the human ventral tegmental area and substantia nigra pars compacta

Abstract

Neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) play central roles in reward‐related behaviours. Non‐human animal studies suggest that these neurons also process aversive events. However, our understanding of how the human VTA and SNC responds to such events is limited and has been hindered by the technical challenge of using fMRI (functional magnetic resonance imaging) to investigate a small structure where the signal is particularly vulnerable to physiological noise. Here we show, using methods optimised specifically for the midbrain (including high resolution imaging, a novel registration protocol, and physiological noise modelling), a BOLD (blood oxygen level dependent) signal to both financial gain and loss in the VTA and SNC, along with a response to nil outcomes that are better or worse than expected in the VTA. Taken together, these findings suggest that the human VTA and SNC are involved in the processing of both appetitive and aversive financial outcomes in humans.

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Non‐hypoxic pharmacological stabilisation of Hypoxia Inducible Factor 1α: effects on dopaminergic differentiation of human neural stem cells

Abstract

Parkinson's disease is a neurodegenerative disease resulting in degeneration of midbrain dopaminergic neurons. Exploratory studies using human fetal tissue or predifferentiated stem cells have suggested that intracerebral transplantation of dopaminergic precursor cells may become an effective treatment for patients with Parkinson's disease. However, strategies for dopaminergic stem cell differentiation vary widely in efficiency, and better methods still need to be developed.

Hypoxia Inducible Factor 1 (HIF‐1) is a transcription factor involved in the regulation of genes important for cellular adaption to hypoxia and low glucose supply. HIF‐1 is to a large degree regulated by the availability of oxygen as in its presence, the subunit HIF‐1α is degraded by HIF prolyl hydroxylase enzymes (HPHs). Stabilisation of HIF‐1α through inhibition of HPHs has been shown to increase dopaminergic differentiation of stem cells and to protect dopaminergic neurons against neurotoxins.

This study investigated the effects of non‐competitive (FG‐0041) and competitive (Compound A and JNJ‐42041935) HIF‐1α stabilising compounds on the dopaminergic differentiation of human neural stem cells. Treatment with all HPH inhibitors at high oxygen tension (20%) resulted in HIF‐1α stabilisation as assessed by immunocytochemistry for HIF‐1α and detection of increased levels of vascular endothelial growth factor in the conditioned culture medium. Following 10 days of HIF‐1α stabilisation, the cultures displayed a slightly reduced proliferative activity and significantly increased relative levels of tyrosine hydroxylase‐positive dopaminergic neurons.

In conclusion, HIF‐1α stabilisation may represent a promising strategy for the generation of dopaminergic neurons intended for use in experimental in vitro studies and cell replacement therapies.

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Insulin in the ventral tegmental area reduces cocaine‐evoked dopamine in the nucleus accumbens in vivo

Abstract

Mesolimbic dopamine circuits, implicated in incentive motivation, are sensitive to changes in metabolic state such as weight loss and diet‐induced obesity. These neurons are important targets for metabolic hormones such as leptin, glucagon‐like peptide‐1, ghrelin and insulin. Insulin receptors are located on dopamine neurons in the ventral tegmental area (VTA) and we have previously demonstrated that insulin induces long‐term depression of excitatory synapses onto VTA dopamine neurons. While insulin can decrease dopamine concentration in somatodendritic regions, it can increase dopamine in striatal slices. Whether insulin directly targets the VTA to alter dopamine release in projection areas, such as the nucleus accumbens (NAc), remains unknown. The main goal of the present experiments was to examine NAc dopamine concentration following VTA administration of insulin. Using in‐vivo fast‐scan cyclic voltammetry (FSCV) to detect rapid fluctuations in dopamine concentration, we showed that intra‐VTA insulin via action at insulin receptors reduced pedunculopontine nucleus (PPTg)‐evoked dopamine release in the NAc. Furthermore, intra‐VTA insulin reduced cocaine‐potentiated NAc dopamine. Finally, intra‐VTA or intranasal insulin decreased locomotor responses to cocaine, an effect blocked by an intra‐VTA administered insulin receptor antagonist. Together, these data demonstrate that mesolimbic dopaminergic projections are important targets of the metabolic hormone, insulin.

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Reduced Late Mismatch Negativity and Auditory Sustained Potential to Rule‐Based Patterns in Schizophrenia

Abstract

Complex rule‐based auditory processing is abnormal in individuals with long‐term schizophrenia (SZ), as demonstrated by reduced mismatch negativity (MMN) to deviants in rule‐based patterns and reduced auditory sustained potential (ASP) that appears when grouping tones together. Together this suggests deficits later in the auditory processing hierarchy in Sz. Here, MMN and ASP were elicited by deviations from a complex zig‐zag pitch pattern that cannot be predicted by simple linear rules. Twenty‐seven SZ and 26 matched healthy controls (HC) participated. Frequent groups of patterns contained eight tones that zig‐zagged in a two‐up one‐down pitch‐based paradigm. There were two deviant patterns: the final tone was either higher in pitch than expected (creating a jump in pitch) or was repeated. Simple MMN to pitch‐deviants among repetitive tones was measured for comparison. Sz exhibited a smaller pitch MMN compared to HC as expected. HC produced a late MMN in response to the repeat and jump‐deviant and a larger ASP to the standard group of tones, all of which were significantly blunted in SZ. In Sz, the amplitude of the late complex MMN was related to neuropsychological functioning, whereas ASP was not. ASP and late MMN did not significantly correlate in HC or in Sz, suggesting that they are not dependent on one another and may originate within distinct processing streams. Together this suggests multiple deficits later in the auditory sensory‐perceptual hierarchy in Sz, with impairments evident in both segmentation and deviance detection abilities.

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ILC2s — resident lymphocytes pre-adapted to a specific tissue or migratory effectors that adapt to where they move?

Ronald N Germain | Yuefeng Huang

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Toxicological and Biochemical Analyses of an Autopsy Case Involving Oral Overdose of Multiple Antidiabetic and Antihypertensive Drugs

Oral antidiabetics can cause fatal hypoglycemia; although they can be chemically identified and quantified, biochemical investigations are important for assessing the biological consequences of an overdose. Such cases of overdose involving oral antidiabetics may involve other drugs for treating lifestyle-related diseases, particularly antihypertensives. Here, we report a toxicological and biochemical investigation of drugs and biochemical profiles in a fatal overdose involving multiple oral antidiabetics and antihypertensives. A 55-year-old woman died about 2 days after the ingestion of around 110 tablets of antidiabetics and antihypertensives that had been prescribed for her husband. A forensic autopsy and histological analysis demonstrated no evident pathology as the cause of death. A toxicological analysis suggested hypoglycemia and an overdose of antihypertensives as well as the retention of antidiabetics and diuretics in the pericardial fluid. A relatively low pericardial amlodipine concentration was observed, which may have been the result of its long half-life (slower distribution and reduction rate) and/or possible affinity with the myocardium. In addition, a biochemical analysis indicated hypoglycemia, without increased serum insulin and C-peptide, but with increased glucagon levels, as the possible influence of glibenclamide overdose. These observations suggest the usefulness of a combination of toxicological and biochemical analyses in postmortem investigations involving a fatal overdose of such drugs.

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A Network Pharmacology Analysis to Explore the Effect of Astragali Radix-Radix Angelica Sinensis on Traumatic Brain Injury

Traumatic brain injury (TBI) is a critical public health and socioeconomic problem worldwide. The herb pair Astragali Radix (AR)-Radix Angelica Sinensis (RAS) is a common prescribed herbal formula or is added to other Chinese medicine prescriptions for traumatic brain injury (TBI) treatment. However, the underlying mechanisms are unclear. In this study, we aimed to explore the active ingredients and action targets of AR-RAS based on the combined methods of network pharmacology prediction and experimental verification. Furthermore, the corresponding potential mechanisms of "multicomponents, multitargets, and multipathways" were disclosed. Methods. A network pharmacology approach including ADME (absorption, distribution, metabolism, and excretion) filter analysis, target prediction, known therapeutic targets collection, Gene Ontology (GO), pathway enrichment analysis, and network construction was used in this study. Further verification experiments were performed to reveal the therapeutic effects of AR-RAS in a rat model of TBI. Results. The comprehensive systematic approach was to successfully identify 14 bioactive ingredients in AR-RAS, while 33 potential targets hit by these ingredients related to TBI. Based on GO annotation analysis, multiple biological processes were significantly regulated by AR-RAS. In addition, 89 novel signaling pathways (P

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Costus afer Protects Cardio-, Hepato-, and Reno-Antioxidant Status in Streptozotocin-Intoxicated Wistar Rats

Medicinal plants are efficient modulators of oxidative stress associated with diabetes mellitus. This study evaluated the cardio-, reno-, and hepato-antioxidant status of hydroethanolic extract of Costus afer on streptozotocin-intoxicated diabetic rats. Experimental animals were daily administered with hydroethanolic extract of C. afer by oral intubation for eight weeks (60 days), after which the levels of catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), and lipid peroxidation marker (MDA) were evaluated in the heart, liver, and kidney homogenates. Plasma biochemical parameters such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total protein, creatinine, and urea were determined. Meanwhile, parts of the heart, kidneys, and liver were histopathologically examined. Streptozotocin administration induced toxicity in the cardiac, hepatic, and renal tissues by stimulating significant increases (p

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Successful treatment of pleural empyema caused by an intrathoracic esophageal fistula after iatrogenic esophageal perforation with polyglycolic acid sheets

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Pulmonary metastasis of mesonephric‐like adenocarcinoma arising from the uterine body: a striking mimicry of follicular thyroid carcinoma

Abstract

Mesonephric adenocarcinoma (MNAC) is a rare neoplasm that presumably develops from the mesonephric remnants, occurring mostly in the uterine cervix and, to a lesser extent, the vagina, uterine body, ovary, and para‐adnexal soft tissues. Histologically, MNAC exhibits a variety of architectural growth patterns, even within the same tumour, including tubular, glandular, papillary, solid, and retiform, and therefore may be confused with more common carcinomas of Müllerian origin. Moreover, the tubules with luminal eosinophilic secretions, a common characteristic of MNACs, may result in consideration of thyroidal carcinoma when tumours spread beyond the pelvis. Immunohistochemistry can identify the mesonephric nature of the tumour, that is, negative for hormone receptors and positive for CD10, calretinin, and GATA binding protein 3 (GATA3) in variable degrees

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Motor Unit Number Index (MUNIX) of hand muscles is a disease biomarker for adult spinal muscular atrophy

5q spinal muscular atrophy (SMA) is a monogenetic, autosomal-recessive, lower motoneuron disease caused by deletion or mutation of SMN1 (survival of motoneuron 1) which results in reduced expression of full-length SMN protein. Although no systematic data exist on treatment effects in adult SMA patients, the antisense-oligonucleotide Nusinersen was recently approved by the FDA and EMA as a disease modifying drug for SMA patients, including adults (Mercuri et al., 2018). As only limited data are available on adult SMA and because adult SMA include clinical stages from slightly to severely affected, reliable determination of disease progression, definition of treatment goals and establishment of suitable disease (progression) biomarkers are needed for a comprehensive high quality health care.

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Atypical presentation of pediatric BRAF RASopathy with acute encephalopathy

We report a 9‐year‐old girl with hypotonia, severe motor delay, absent speech, and facial dysmorphism who developed acute encephalopathy with severe neurological outcome. Trio‐based whole exome sequencing (WES) analysis detected a de novo heterozygous mutation in the BRAF gene leading to the diagnosis of an atypical presentation of cardiofaciocutaneous (CFC) syndrome. This is the second case of CFC syndrome complicated with acute encephalopathy reported in the literature and supports the hypothesis that acute encephalopathy might be one of the complications of the syndrome due to an intrinsic susceptibility to this acute event. The report furthermore highlights the role of WES in providing a fast diagnosis in patients in critical conditions with atypical presentation of rare genetic syndromes.

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First reported adult patient with TARP syndrome: A case report

TARP syndrome (talipes equinovarus, atrial septal defect, Robin sequence, and persistence of the left superior vena cava) is a rare X‐linked syndrome often resulting in pre‐ or post‐natal lethality in affected males. In 2010, RBM10 was identified as the disease‐causing gene, and we describe the first adult patient with TARP syndrome at age 28 years, hereby expanding the phenotypic spectrum. Our patient had Robin sequence, atrial septal defect, intellectual disability, scoliosis, and other findings previously associated with TARP syndrome. In addition, he had a prominent nose and nasal bridge, esotropia, displacement of lacrimal points in the cranial direction, small teeth, and chin dimple, which are the findings that have not previously been associated with TARP syndrome. Our patient was found to carry a hemizygous c.273_283delinsA RBM10 mutation in exon 4, an exon skipped in three of five protein‐coding transcripts, suggesting a possible explanation for our patient surviving to adulthood. Direct sequencing of maternal DNA indicated possible mosaicism, which was confirmed by massive parallel sequencing. One of two sisters were heterozygous for the mutation. Therefore, we recommend sisters of patients with TARP syndrome be carrier tested before family planning regardless of carrier testing results of the mother. Based on our patient and previously reported patients, we suggest TARP syndrome be considered as a possible diagnosis in males with severe or profound intellectual disability combined with septal heart defect, and Robin sequence, micrognathia, or cleft palate.

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Japanese patient with Cole‐carpenter syndrome with compound heterozygous variants of SEC24D

Cole‐Carpenter syndrome is a rare skeletal dysplasia associated with low‐bone mass or an osteogenesis imperfecta (OI)‐like syndrome. Only 3 and 6 variants in SEC24D have been reported in patients with Cole‐Carpenter syndrome type 2 and autosomal recessive OI, respectively. We describe a 15‐year‐old Japanese boy with short stature of the short‐trunk type and craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia. These features were consistent with a diagnosis of Cole‐Carpenter syndrome. He had low‐bone mineral density and basilar impression. Whole exome sequencing analysis identified biallelic variants in SEC24D (p.Arg484* and p.Arg313His) in the patient. We will report a patient with compound heterozygous variants of SEC24D causing Cole‐Carpenter syndrome type 2.

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Unmasking familial CPX by WES and identification of novel clinical signs

Mutations in the T‐Box transcription factor gene TBX22 are found in X‐linked Cleft Palate with or without Ankyloglossia syndrome (CPX syndrome). In addition to X‐linked inheritance, ankyloglossia, present in the majority of CPX patients, is an important diagnostic marker, but it is frequently missed or unreported, as it is a "minor" feature. Other described anomalies include cleft lip, micro and/or hypodontia, and features of CHARGE syndrome. We conducted whole exome sequencing (WES) on 22 individuals from 17 "a priori" non‐syndromic cleft lip and/or cleft palate (CL/P) families. We filtered the data for heterozygous pathogenic variants within a set of predefined candidate genes. Two canonical splice‐site mutations were found in TBX22. Detailed re‐phenotyping of the two probands and their families unravelled orofacial features previously not associated with the CPX phenotypic spectrum: choanal atresia, Pierre‐Robin sequence, and overgrowths on the posterior edge of the hard palate, on each side of the palatal midline. This study emphasizes the importance of WES analysis in familial CLP cases, combined with deep (reverse) phenotyping in "a priori" non‐syndromic clefts.

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Titanium dental implants with different collar design and surface modifications: a systematic review on survival rates and marginal bone levels

Abstract

Aim

To compare clinical and radiographic outcomes of dental implants with different neck characteristics.

Methods

A protocol‐oriented search aimed at the question: "In patients subjected to tooth replacement with screw‐type dental implants does the modification of the implant neck macro or micro‐geometry contribute to the improvement of survival rates and maintenance of the peri‐implant marginal bone levels?" Primary outcomes were survival and marginal bone level (MBL) changes evaluated on randomized controlled trials with >10 participants and follow‐up >1 year. Risk of bias was evaluated using the Cochrane Collaboration's tool. The review follows the PRISMA statement.

Results

Forty‐three studies compared: 1. One‐ versus two‐piece implants (N=7); 2. Two‐piece implants with different neck characteristics (machined and rough collars, microthreads, LASER microtexturing) (N=21); 3. Two‐piece implants with macrogeometry modifications (tapering, back‐tapering and scalloping) (N=6). One‐ and two‐piece implants showed similar survival (RR= 0.45, 95% CI: [0.12, 1.66], p=0.23) and MBL changes (WMD=0.09mm, 95% CI: [‐0.27, 0.45], p=0.64) at 1‐year post‐loading. Machined collar implants have higher risk of early failure than rough collar implants (RR= 3.96, 95% CI: [1.12, 13.93], p=0.03) and 0.43mm higher bone resorption (95% CI: [0.0, 0.86], p=0.05). Microthreads (WMD= 0.07mm, 95% CI: [‐0.01, 0.15], p=0.10) and LASER microtexturing (WMD=0.15mm, 95% CI: [‐0.35, 0.65], p=0.56) do not reduce bone resorption. Scalloped implants have 1.26mm higher resorption (95% CI: [0.72, 2.00], p<0.001).

Conclusions

One‐ and two‐piece implants have similar survival and MBL changes. Rough collar implants have lower MBL changes than machined collar implants. Additional modifications to rough collars are irrelevant.

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Original vs. non‐original abutments for screw‐retained single implant crowns: an in vitro evaluation of internal fit, mechanical behaviour and screw loosening

Abstract

Objectives

To assess the internal accuracy, mechanical behaviour under static load and screw loosening before and after cyclic loading of implant‐supported crowns restored with original components or with two compatible non‐original brands.

Materials and Methods

Sixty‐three dental implants were divided into three groups (n = 21 each): Group 1 used original components, and Groups 2 and 3 used non‐original components.

Internal accuracy was measured throughout a cross section of the sample groups (n = 8) using scanning electron microscopy (SEM) to evaluate the fit for implant‐abutments, implant‐crowns and crown‐abutments.

To evaluate load‐bearing capacity, 8 samples from each group were loaded until fracture according to ISO Norm 14801. The removal torque value (RTV) was evaluated in the screws connecting the crown with the abutment and the abutment with the implant before and after cyclic loading in 5 samples from each group. The data were analysed using the Kruskal Wallis test (p < 0.05).

Results

Statistically significant differences were found among the mean crown‐abutment gaps measured in Group 1 (9.3 μm), Group 2 (45.4 μm) and Group 3 (44.9 μm).

Higher values for mean load‐bearing capacity were found in Group 1 (1098 N) than in Groups 2 and 3 (1057 N and 973 N, respectively); however, these differences were not statistically significant.

Original abutment‐implant screws exhibited lower percentages of torque reduction than the non‐originals.

Conclusions

Enhanced fit is expected when original components are used. The original abutments exhibited lower percentages of torque reduction after cyclic loading than non‐originals.

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Impact of a zoledronate coating on early post‐surgical implant stability and marginal bone resorption in the maxilla ‐ a split‐mouth randomized clinical trial

Abstract

Objectives

The objective of this clinical study was to evaluate the effect of a bisphosphonate coating on a titanium implant on the implant stability quotient (ISQ) and the radiographic marginal bone levels at implants during early healing (2 to 8 weeks).

Material and methods

In a randomized double‐blind trial with internal controls, 16 patients received a dental implant coated with zoledronate and one uncoated implant as a control. The coated and uncoated implants which were visually indistinguishable were bone level titanium implants with a moderately rough surface and a micro‐threaded neck. ISQ values were obtained at insertion and at 2, 4, 6, and 8 weeks. Radiographs were obtained at insertion and at 8 weeks. The primary outcome was the difference in ISQ values between the coated implants and the control implants at 4 and 6 weeks, corrected for insertion values. The secondary outcome was loss of marginal bone level from insertion to 8 weeks.

Results

ISQ values remained largely constant over the 8 weeks and there were no significant difference between coated and uncoated implants at any time point. There were 0.12 (SD 0.10) mm marginal bone loss at the control implants and 0.04 (SD 0.08) mm at the coated implants. The difference was 0.17 mm; SD 0.14; p<0.006). On blind qualitative scoring, 13 of the 15 control implants and 2 of 15 coated implants showed small marginal bone defects (p=0.003).

Conclusions

There were no statistically significant differences observed in ISQ values between the coated and uncoated implants during the early healing. There was less marginal bone loss at the coated implants.

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Posterior open‐wedge anterior longitudinal ligament release (POWAR): cadaveric technique analysis

Introduction

Anterior column release is a powerful surgical technique for achieving spinopelvic balance in adult patients with sagittal plane deformities. We present an alternative strategy for focal deformity correction from a posterior‐only approach. The purpose of this study was to evaluate the feasibility and efficacy of a novel surgical technique called posterior open‐wedge diskectomy and anterior longitudinal ligament (ALL) release (POWAR).

Materials and Methods

A cadaveric torso underwent POWARs at the L1‐L4 intervertebral disc spaces. Baseline measurements of end‐plate angle (EPA), anterior intervertebral disc height (ADH), and posterior intervertebral disc height (PDH) were obtained. These measurements were repeated after three stages of correction: posterior column compression alone, posterior column compression following Schwab grade 2 osteotomies, and posterior column compression following POWAR. A second cadaver underwent posterolateral spinal dissection to demonstrate the pertinent anatomical features relevant to this novel procedure.

Results

With each stage of correction, a sequential increase in EPA and ADH and a decrease in PDH were demonstrated. The large increase in ADH seen following POWAR confirmed successful release of the ALL. In situ investigation of the aorta and inferior vena cava following anterior exposure revealed no injury to the great vessels or surrounding structures. Ex vivo testing of the aorta and inferior vena cava took place at the L3‐4 level. This testing demonstrated no injury or tears to either vessel.

Conclusions

POWAR is a new surgical technique that can provide an alternative to three‐column osteotomy for surgeons performing spinal reconstructions in adults through an open, posterior‐only approach.

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A Biodegradable Stent with Surface Functionalization of Combined‐Therapy Drugs for Colorectal Cancer

Intestinal obstruction and stenosis are the main symptoms of patients with colorectal cancer. This paper describes a drug‐loaded fibrous silk fibroin (SF) membrane produced by adding curcumin and 5‐fluorouracil into the SF spinning solution for sustained drug release. The membranes as the coating of stent placement have potential in the management of cancer progress and drug‐resistance of tumor cells.

Abstract

In‐stent restenosis caused by tumor ingrowth is a major problem for patients undergoing stent placement because conventional stents often lack sustainable antitumor capabilities. The aim of this work is to develop a silk fibroin (SF)‐based nanofibrous membrane that is loaded with combined‐therapy drugs by using electrospinning technologies, which is further coated on a polydioxanone (PDO) stent and used for the treatment of colorectal cancer (CRC). In order to improve treatment effectiveness, a combination of therapeutic drugs, i.e., curcumin (CUR) and 5‐fluorouracil (5‐FU), is dissolved into SF solution and then eletrospun onto the surface of the PDO stent. The morphology, secondary structure, and in vitro drug release profiles of the membranes are characterized. The antitumor efficacy is assessed in vitro and in vivo using a human CRC cell line and normal cells, and tumor‐bearing nude mice. In vitro and in vivo studies on the nanofibrous memembrane‐coating demonstrate improved antitumor effects for the CUR/5‐FU dual drug system which can be attributed to cell cycle arrest in the S phase in association with induced apoptosis in tumor cells by blocking signal transducer and activator of transcription3 (Stat3) and nuclear factor kappa beta (NF‐kB) signaling pathways, suggesting potential in the treatment of CRC in the future.

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Multifunctional Coatings and Nanotopographies: Toward Cell Instructive and Antibacterial Implants

Incomplete material biointegration and bacterial infection are regarded as the two major causes of implant failure. Multifunctional chemical coatings and nanotopographical features are proposed as emerging solutions to simultaneously improve cell adhesion and prevent bacterial colonization on the biomaterial surface.

Abstract

In biomaterials science, it is nowadays well accepted that improving the biointegration of dental and orthopedic implants with surrounding tissues is a major goal. However, implant surfaces that support osteointegration may also favor colonization of bacterial cells. Infection of biomaterials and subsequent biofilm formation can have devastating effects and reduce patient quality of life, representing an emerging concern in healthcare. Conversely, efforts toward inhibiting bacterial colonization may impair biomaterial–tissue integration. Therefore, to improve the long‐term success of medical implants, biomaterial surfaces should ideally discourage the attachment of bacteria without affecting eukaryotic cell functions. However, most current strategies seldom investigate a combined goal. This work reviews recent strategies of surface modification to simultaneously address implant biointegration while mitigating bacterial infections. To this end, two emerging solutions are considered, multifunctional chemical coatings and nanotopographical features.

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High Modulus Conductive Hydrogels Enhance In Vitro Maturation and Contractile Function of Primary Cardiomyocytes for Uses in Drug Screening

High modulus conductive hydrogels are fabricated using carbon fibers and polyvinyl alcohol, which enhance the maturation and electrophysiological performance of neonatal rat cardiomyocytes in vitro, by activating the α5β1 integrin signaling pathway and upregulating RhoA and hypoxia inducible factor‐1α (HIF‐1α). The cell–hydrogel constructs effectively respond to drugs modulating cardiomyocytes' contraction, exhibiting high potential for uses in drug screening and cardiotoxicity assessment.

Abstract

Effective and quick screening and cardiotoxicity assessment are very crucial for drug development. Here, a novel composite hydrogel composed of carbon fibers (CFs) with high conductivity and modulus with polyvinyl alcohol (PVA) is reported. The conductivity of the composite hydrogel PVA/CFs is similar to that of natural heart tissue, and the elastic modulus is close to that of natural heart tissue during systole, due to the incorporation of CFs. PVA/CFs remarkably enhance the maturation of neonatal rat cardiomyocytes (NRCM) in vitro by upregulating the expression of α‐actinin, troponin T, and connexin‐43, activating the signaling pathway of α5 and β1 integrin‐dependent ILK/p‐AKT, and increasing the level of RhoA and hypoxia‐inducible factor‐1α. As a result, the engineered cell sheet–like constructs NRCM@PVA/CFs display much more synchronous, stable, and robust beating behavior than NRCM@PVA. When exposed to doxorubicin or isoprenaline, NRCM@PVA/CFs can retain effective beating for much longer time or change the contractile rate much faster than NRCM@PVA, respectively, therefore representing a promising heart‐like platform for in vitro drug screening and cardiotoxicity assessment.

https://ift.tt/2DSmkIc

Enhancing the Accumulation of Polymer Micelles by Selectively Dilating Tumor Blood Vessels with NO for Highly Effective Cancer Treatment

A tumor vascular‐targeted multifunctional hybrid polymeric micelle, which is capable of augmenting the EPR effect of nanoparticles by in situ production of NO to selectively dilate tumor blood vessels, is successfully fabricated. The augmented EPR effect can significantly enhance the accumulation of the micelles in tumors, with a high cumulative content of DOX, causing a highly effective cancer treatment.

Abstract

The accumulation of nanoparticles in tumors by the enhanced permeability and retention (EPR) effect is effective and well known. However, how to maximize accumulation is still a bottleneck in the development of nanomedicine. Herein, a tumor vascular‐targeted hybrid polymeric micelle, which has a great capacity to selectively augment the EPR effect of nanoparticles by dilating tumor blood vessels via the activity of nitric oxide (NO), is presented. Under neutral conditions, the micelle is stable, with a long blood circulation half‐life due to the carboxylated poly(ethylene glycol) (PEG) layer; in mildly acidic tumor tissues, the micelle can selectively target the tumor blood vessels by the exposed cyclic Arg‐Gly‐Asp peptide (cRGD) peptides, which is realized with a pH‐dependent hydrolysis of the monomethoxy PEG layer. Simultaneously, exposed copper ions catalyze the decomposition of endogenous NO donors, which generates NO in situ, leading to vasodilation and increased tumor vascular permeability. As a result, the accumulation of nanoparticles is significantly enhanced, and a high accumulation of doxorubicin in tumors is achieved at 48 h after injection. This high dose of therapeutic agent produces a large inhibition of tumor growth (94%) in cancer treatment, and shows no general toxicity, with 100% of the mice surviving the treatment regimen.

https://ift.tt/2SbSyBg

Dendritic Cell Membrane Vesicles for Activation and Maintenance of Antigen‐Specific T Cells

Nanosized dendritic cell membrane vesicles (DC‐MVs) are examined as a platform to promote T cell responses. DC‐MVs activate DCs and promote cross‐priming of CD8+ T cells in vitro. DC‐MVs potently amplify the expansion of adoptively transferred CD8+ T cells in vivo. DC‐MVs may serve as a potential peptide delivery system for augmenting adoptive T cell therapy.

Abstract

Cell membranes have recently gained attention as a promising drug delivery system. Here, dendritic cell membrane vesicles (DC‐MVs) are examined as a platform to promote T cell responses. Nanosized DC‐MVs are derived from DCs pretreated with monophosphoryl lipid A (MPLA), a FDA‐approved immunostimulatory adjuvant. These "mature" DC‐MVs activate DCs in vitro and increase their expression of costimulatory markers. DC‐MVs also promote cross‐priming of antigen‐specific T cells in vitro, increasing their survival and CD25 expression. In addition, these mature DC‐MVs potently augment the expansion of adoptively transferred CD8+ T cells in vivo, generating twofold to fourfold higher frequency of antigen‐specific T cells, compared with other control formulations, including "immature" DC‐MVs obtained without the MPLA pretreatment. Taken together, these results suggest that DC‐MVs are an effective delivery platform for T cell activation and may serve as a potential delivery system for improving adoptive T cell therapy.

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A Microwell‐Assisted Multiaptamer Immunomagnetic Platform for Capture and Genetic Analysis of Circulating Tumor Cells

A new and simple microwell‐assisted multiaptamer immunomagnetic platform is developed for the detection and gene analysis of circulating tumor cells (CTCs). Magnetic nanoparticles modified with the aptamers having high affinity to drug‐sensitive and drug‐resistant lung cancer cells are used to capture heterogeneous CTCs. Purity of CTCs is further improved by microwell chip for mutation analysis of CTCs from clinical samples.

Abstract

Detection of circulating tumor cells (CTCs) in peripheral blood is of paramount significance for cancer diagnosis, progress evaluation, and individualized therapy. However, the rareness and heterogeneity of CTCs introduces significant challenges in the capture of cancer cells as well as downstream genetic analysis. In this work, a microwell‐assisted multiaptamer immunomagnetic platform (MMAIP) is proposed for highly efficient capture of CTCs with minimum influence of heterogeneity. Assisted by a microwell chip, the purity of CTCs is greatly improved, thus meeting the requirement of downstream gene analysis. This is, as far as is known, the first aptamer based platform enabling mutation analysis of the captured CTCs from cancer patients, which will contribute to the practical application of aptamers in clinics.

https://ift.tt/2SbTbuC

3D‐Printed Hydrogel Composites for Predictive Temporal (4D) Cellular Organizations and Patterned Biogenic Mineralization

Temporal (4D) attributes of cellular decision‐making (short‐term attachment and long‐term biomineralization) in 2D and 3D microscaffolds are reported. Underlying materials chemistries—consisting of 2‐hydroxyethyl methacrylate (HEMA)‐based hydrogels with nanoclay additives—require no activating treatments to promote specific cellular biocompliance patterns. Taken together these data point toward key concepts for controllable cell growth on 4D scaffolds.

Abstract

Materials chemistries for hydrogel scaffolds that are capable of programming temporal (4D) attributes of cellular decision‐making in supported 3D microcultures are described. The scaffolds are fabricated using direct‐ink writing (DIW)—a 3D‐printing technique using extrusion to pattern scaffolds at biologically relevant diameters (≤ 100 µm). Herein, DIW is exploited to variously incorporate a rheological nanoclay, Laponite XLG (LAP), into 2‐hydroxyethyl methacrylate (HEMA)‐based hydrogels—printing the LAP–HEMA (LH) composites as functional modifiers within otherwise unmodified 2D and 3D HEMA microstructures. The nanoclay‐modified domains, when tested as thin films, require no activating (e.g., protein) treatments to promote robust growth compliances that direct the spatial attachment of fibroblast (3T3) and preosteoblast (E1) cells, fostering for the latter a capacity to direct long‐term osteodifferentiation. Cell‐to‐gel interfacial morphologies and cellular motility are analyzed with spatial light interference microscopy (SLIM). Through combination of HEMA and LH gels, high‐resolution DIW of a nanocomposite ink (UniH) that translates organizationally dynamic attributes seen with 2D gels into dentition‐mimetic 3D scaffolds is demonstrated. These analyses confirm that the underlying materials chemistry and geometry of hydrogel nanocomposites are capable of directing cellular attachment and temporal development within 3D microcultures—a useful material system for the 4D patterning of hydrogel scaffolds.

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Intracellular Delivery of His‐Tagged Genome‐Editing Proteins Enabled by Nitrilotriacetic Acid–Containing Lipidoid Nanoparticles

Nitrilotriacetic acid–containing noncationic lipidoids are synthesized and formulated with helper lipids to form the lipidoid nanoparticles for intracellular delivery of the His‐tagged genome‐editing proteins, which take advantage of the coordination interaction between divalent nickel ion–immobilized lipidoids and the imidazole groups present on the histidine residues.

Abstract

Protein‐ and peptide‐based therapeutics with high tolerance and specificity along with low off‐target effects and genetic risks have attracted tremendous attention over the last three decades. Herein, a new type of noncationic lipidoid nanoparticle (LNP) is reported for His‐tagged protein delivery. Active lipidoids are synthesized by conjugating a nitrilotriacetic acid group with hydrophobic tails (EC16, O16B, and O17O) and nanoparticles are formulated in the presence of nickel ions and helper lipids (cholesterol, 1,2‐dioleoyl‐sn‐glycero‐3‐phosphoethanolamine, and 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐N‐[methoxy(polyethylene glycol)‐2000]). It is demonstrated that the newly developed LNPs are capable of delivering various His‐tagged proteins including green fluorescent protein (GFP), (−30)GFP‐Cre recombinase, and CRISPR/Cas9 ribonucleoprotein into mammalian cells.

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Masthead: (Adv. Healthcare Mater. 22/2018)

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BioEssays 12∕2018

Amphioxus represents the most basally divergent group in chordates and probably the best extant proxy to the ancestor of all chordates including vertebrates. The amphioxus, or lancelets, are benthic filter feeding marine animals and their interest as a model in research is due to their phylogenetic position and their anatomical and genetic stasis throughout their evolutionary history. In article number 1800130, Hector Escriva reviews the discovery and development of amphioxus as a superb model organism in evolutionary and evolutionary‐developmental biology.

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On the State of Scientific English and How to Improve it − Part 12: Keeping it Simple When Under Time Pressure…

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Pharmacogenetics of artemether‐lumefantrine influence on nevirapine disposition: clinically significant drug‐drug interaction?

Abstract

Aims

In this study the influence of first‐line antimalarial drug artemether‐lumefantrine on the pharmacokinetics of the antiretroviral drug nevirapine was investigated in the context of selected single nucleotide polymorphisms (SNPs) in a cohort of adult HIV‐infected Nigerian patients.

Methods

This was a two‐period, single sequence crossover study conducted in two stages. In stage 1, 150 HIV‐infected patients receiving nevirapine‐based antiretroviral regimens were enrolled and genotyped for 7 SNPs. Sparse pharmacokinetic sampling was conducted to identify SNPs independently associated with nevirapine plasma concentration. Patients were categorised as poor, intermediate and extensive metabolisers based on the numbers of alleles of significantly associated SNPs. Intensive sampling was conducted in selected patients from each group. In stage 2, patients received standard artemether‐lumefantrine treatment with nevirapine and intensive pharmacokinetic sampling was conducted on day 3.

Results

No clinically significant changes were observed in key nevirapine pharmacokinetic parameters, the 90% confidence interval for the measured changes falling completely within the 0.80‐1.25 no‐effect boundaries. However, the number of patients with trough plasma nevirapine concentration below the 3,400 ng ml^‐1 minimum effective concentration increased from 10% without artemether‐lumefantrine (all extensive metabolisers) to 21% with artemether‐lumefantrine (14% extensive, 4% intermediate, and 3% poor metabolisers).

Conclusions

This approach highlights additional increase in the already existing risk of suboptimal trough plasma concentration, especially in extensive metabolisers when nevirapine is co‐administered with artemether‐lumefantrine.

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In Grateful Recognition of Our Editorial Board

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BioEssays 12∕2018

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A Word of Heartfelt Thanks to Our Reviewers

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Corrigendum Referring to: Getting the Message? Native Reactive Electrophiles Pass Two Out of Three Thresholds to be Bona Fide Signaling Mediators

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BioEssays 12∕2018

African trypanosomes cause human and veterinary disease throughout sub‐Saharan Africa. The parasite cycles between the insect vector, tsetse flies, and the mammalian host, where they live free in the blood and extracellular spaces. Trypanosomes use a remarkable process of antigenic variation to survive in the face of the host adaptive immune response. Further details can be found in article number 1800181 by James D. Bangs.

Photo Credits:

Trypanosome: Peter Bush, School of Dental Medicine, University at Buffalo African

Cattle: Keith Matthews, Institute of Immunology and Infection Research, University of Edinburgh

Postprandial Tsetse: Geoffrey Attardo, Department of Entomology and Nematology, University of California Davis.

https://ift.tt/2QhNvlH

Clinical and Translational Pharmacological Aspects of the Management of Fibrous Dysplasia of Bone

Abstract

Fibrous dysplasia (FD) is a genetic, non‐inheritable rare bone disease caused by a post‐zygotic activating mutation of the alpha subunit of the stimulatory G‐protein (Gαs) causing increased abnormal bone formation leading to pain, deformity and fractures. To date, no cure has been identified for FD/MAS and treatment is symptomatic and aimed at decreasing pain and/or local bone turnover. Various drugs have been used to achieve clinical improvement in FD/MAS patients including bisphosphonates and denosumab, however further translational studies are also warranted to address unresolved pathophysiological issues and explore novel pharmacological targets for the management of FD/MAS.

In this article, we review literature on the medical treatment of FD/MAS, discuss the unresolved pathophysiological issues and explore novel pharmacological targets for the management of FD/MAS.

https://ift.tt/2BuAa1d

Sirt5 is dispensable for BrafV600E‐mediated cutaneous melanoma development and growth in vivo

Abstract

Sirt5 is known to functionally regulate mitochondrial proteins by altering posttranslational modifications, including lysine desuccinylation. While roles for Sirt5 as either a tumor promoter or suppressor, or in chemoresistance, have been implicated in other cancers, the function of Sirt5 in cutaneous melanoma has not been well examined. Therefore, to determine whether Sirt5 is necessary for Braf ^V600E ‐mediated melanoma formation and/or disease progression, we crossed a genetically engineered murine melanoma model (Tyr ^{Cre ERT 2/+} ; Braf ^{LSL ‐V600E/+} ; Pten ^flox/flox ) to Sirt5 ^‐/‐ knockout animals. In addition, we tested for synergism with a selective BRAF (V600E) inhibitor in Sirt5 ^‐/‐ mouse melanoma cells. Taken together, this report demonstrates that, in these models, Sirt5 is dispensable for Braf ^V600E ‐mediated cutaneous melanoma formation and growth in vivo, and does not improve sensitivity to a selective BRAF inhibitor.

This article is protected by copyright. All rights reserved.

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c‐Rel is a cell cycle modulator in human melanoma cells

Abstract

Melanoma progression and resistance to therapy is associated with faulty regulation of signaling molecules including the central transcription factor NF‐κB. Increased expression of the c‐Rel subunit of NF‐κB has been described in progressing melanoma, though mechanistic implications of this up‐regulation remain unclear. To elucidate the functional role of c‐Rel in melanoma biology, we have assessed its expression in human melanoma as well as in melanoma cell lines. Suppression of c‐Rel expression in four melanoma cell lines resulted in reduced growth and altered cell cycle regulation, namely G2/M and polyploid phase induction. Moreover, mitotic spindle morphology was profoundly altered in three of the cell lines with a predominance of monopolar structures. These findings suggest that c‐Rel is involved in G2/M phase regulation, prevention of polyploidy and, consequently, in chromosomal stability. Our results highlight a novel tumor‐promoting function of c‐Rel in human melanoma cells through governing cell cycle regulation.

This article is protected by copyright. All rights reserved.

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Psychological and Genetic Predictors of Pain Tolerance

Abstract

Previous studies have shown associations between genetic polymorphisms and pain tolerance, but psychological evaluations are seldom measured. The objective of this study was to determine the independent effects of demographic, psychological and genetic predictors of cold noxious pain tolerance. Healthy subjects (n=89) completed the Pain Catastrophizing Scale (PCS) and Fear of Pain Questionnaire (FPQ‐III), underwent genotyping for candidate single nucleotide polymorphisms (SNPs), and completed a cold‐pressor test in a 1‐2 degrees Celsius water bath for a maximum of three minutes. The primary outcome measure was pain tolerance, defined as the maximum duration of time subjects left their non‐dominant hand in the cold‐water bath. Cox proportional hazards regression indicated that female sex, Asian race, and increasing PCS and FPQ‐III scores were associated with lower pain tolerance. No candidate SNP was significantly associated with pain tolerance. Future genetic studies should include demographic and psychological variables as confounders in experimental pain models.

This article is protected by copyright. All rights reserved.

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Computational Methods and Tools to Predict Cytochrome P450 Metabolism for Drug Discovery

This review describes important recent developments in the computational prediction of cytochrome P450 (CYP) metabolism. In silico models to predict CYP inhibitors, substrates, sites of metabolism and metabolite structures are discussed with a particular focus on freely available software for use in drug discovery.

Abstract

In this review we present important, recent developments in the computational prediction of cytochrome P450 (CYP) metabolism in the context of drug discovery. We discuss in silico models for the various aspects of CYP metabolism prediction, including CYP substrate and inhibitor predictors, site of metabolism predictors (i.e. metabolically labile sites within potential substrates) and metabolite structure predictors. We summarise the different approaches taken by these models, such as rule‐based methods, machine learning, data mining, quantum chemical methods, molecular interaction fields and docking. We highlight the scope and limitations of each method and discuss future implications for the field of metabolism prediction in drug discovery.

This article is protected by copyright. All rights reserved.

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Suitability of MMGBSA for the Selection of Correct Ligand Binding Modes from Docking Results

MMGBSA can be efficiently used to select the correct binding pose for ligands. The results are further improved by energy minimization of complexes from molecular dynamics simulations. Also, the correlation coefficient between experimental and calculated data is improved.

Abstract

The estimation of the correct binding mode and affinity of a ligand into a target protein using computational methods is challenging. However, docking can introduce poses from which the correct binding mode could be identified using other methods. Here, we analyzed the reliability of binding energy estimation using the molecular mechanics‐generalized Born surface area (MMGBSA) method without and with energy minimization to identify the likely ligand binding modes within docking results. MMGBSA workflow (1) outperformed docking in recognizing the correct binding modes of androgen receptor ligands and (2) improved the correlation coefficient of computational and experimental results of rescored docking poses to phosphodiesterase 4B. Combined with stability and atomic distance analysis, MMGBSA helped to (3) identify the binding modes and sites of metabolism of cytochrome P450 2A6 substrates. The standard deviation of estimated binding energy within one simulation was lowered by minimization in all three example cases. Minimization improved the identification of the correct binding modes of androgen receptor ligands. Although only three case studies are shown, the results are analogous and indicate that these behaviors could be generalized. Such identified binding modes could be further used, for example, with free energy perturbation methods to understand binding energetics more accurately.

This article is protected by copyright. All rights reserved.

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Issue Information

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Cover Image

The cover image, a rotating multimedia painting by master artist Pierre H. Matisse, is based on the Research Article Blueprints for the Rational Design of Therapeutic Mutacin 1140 Variants by Johan A. Kers et al., https://doi.org/10.1111/cbdd.13365. Molecular model design credit: Rudramani Pokhrel and Prem Chapagain (Florida International University).

https://ift.tt/2R66xsi

A rapid method for estimation of the efficacy of potential antimicrobials in humans and animals by agar diffusion assay

We describe a simple agar diffusion assay, which can be used as a general method for the rapid detection of antimicrobial activity of drug candidates in animal or human blood plasma for the ultimate prediction of the efficacy of potential drugs prior to clinical trials.

Abstract

Drug resistance continues to challenge traditional antimicrobial drugs and limit their clinical utility. This requires us to continue our search for new drug candidates with novel mechanisms of action against infectious diseases. We now describe a simple agar diffusion assay, which can be used as a general method for the rapid detection of antimicrobial activity of drug candidates in animal or human blood plasma for the ultimate prediction of the efficacy of potential drugs prior to clinical trials. We present an example for a clinical candidate against Mycobacterium tuberculosis.

https://ift.tt/2POoe2W

Cytopathologic characteristics of HPV‐related small cell carcinoma of the oropharynx

Abstract

Background

Human papillomavirus (HPV)–related squamous cell carcinoma (SqCC) of the oropharynx is an epidemiologically and clinically distinct form of SqCC that is associated with an improved prognosis. However, HPV‐related small cell carcinoma of the oropharynx is a rare and newly described variant that is associated with aggressive clinical behavior and poor outcomes. To date, fewer than 2 dozen reports of this entity exist in the literature, and there is no discussion of cytopathologic features. This article reports 6 cases and discusses the salient cytomorphologic findings, ancillary studies, and challenges when this entity is encountered.

Methods

Anatomic pathology archives were searched to identify patients with a diagnosis of HPV‐related small cell carcinoma of the oropharynx. Medical records were reviewed to document the following: age, sex, smoking status, other relevant clinical history, primary location, treatment, and clinical outcome. Both p16 and high‐risk HPV in situ hybridization (ISH) studies were positive in at least 1 specimen from each patient. The pathologic diagnoses, cytomorphologic characteristics, immunocytochemical stains, and HPV ISH studies were reviewed and recorded for all available cases.

Results

Six patients with 11 cytopathology specimens of HPV‐related small cell carcinoma of the oropharynx were identified. The mean age was 61.3 years, and all patients died with widely metastatic disease (mean, 23 months; range, 12‐48 months). Mixed small cell carcinoma and SqCC components were present in half of the cases.

Conclusions

The identification of a small cell component can be reliably performed with cytology preparations and is crucial because this (and not the HPV status) determines the prognosis.

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Correction: An extremely severe phenotype attributed to WDR81 nonsense mutations

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Issue Information

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Annals of Neurology: Volume 84, Number 5, November 2018

A photomicrograph of HeLa cells expressing amino acids 1‐149 of the protein KCTD7 with a mutation (L108M) seen in patients who have progressive myoclonic epilepsy (EPM3) also known as neuronal ceroid lipofuscinosis (CLN14). The mutant protein has an HA tag that has been stained with red fluorescence to localize the protein, revealing red filaments in the nucleus and in the surrounding cytoplasm. Filament structures are altered by this L108M mutation in the BTB domain of KCTD7. The nucleus of each cell is stained blue. (See Metz et al., pages http://dx.doi.org/10.1002/ana.25351766–780)

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Two main focal seizure patterns revealed by intracerebral electroencephalographic biomarker analysis

Summary

Objective

Long‐term recording with intracerebral electrodes is commonly utilized to identify brain areas responsible for seizure generation (epileptogenic zone) and to tailor therapeutic surgical resections in patients with focal drug‐resistant epilepsy. This invasive diagnostic procedure generates a wealth of data that contribute to understanding human epilepsy. We analyze intracerebral signals to identify and classify focal ictal patterns.

Methods

We retrospectively analyzed stereo‐electroencephalographic (EEG) data in a cohort of patients either cryptogenic (magnetic resonance imaging negative) or presenting with noncongruent anatomoelectroclinical data. A computer‐assisted method based on EEG signal analysis in frequency and space domains was applied to 467 seizures recorded in 105 patients submitted to stereo‐EEG presurgical monitoring.

Results

Two main focal seizure patterns were identified. P‐type seizures, typical of neocortex, were observed in 73 patients (69.5%), lasted 22 ± 13 seconds (mean +SD), and were characterized by a sharp‐onset/sharp‐offset transient superimposed on low‐voltage fast activity (126 ± 19 Hz). L‐type seizures were observed in 43 patients (40.9%) and consistently involved mesial temporal structures; they lasted longer (93 ± 48 second), started with 116 ± 21 Hz low‐voltage fast activity superimposed on a slow potential shift, and terminated with large‐amplitude, periodic bursting activity. In 23 patients (21.9%), the L‐type seizure was preceded by a P seizure. Spasmlike and unclassifiable EEG seizures were observed in 11.4% of cases.

Significance

The proposed computer‐assisted approach revealed signal information concealed to visual inspection that contributes to identifying two principal seizure patterns typical of the neocortex and of mesial temporal networks.

https://ift.tt/2FCNW5K

Neurocognition in childhood epilepsy: Impact on mortality and complete seizure remission 50 years later

Summary

Objective

To study associations of the severity of impairment in childhood neurocognition (NC) with long‐term mortality and complete seizure remission.

Methods

A population‐based cohort of 245 subjects with childhood onset epilepsy was followed up for 50 years (median = 45, range = 2‐50). Childhood NC before age 18 years was assessed as a combination of formal intelligence quotient scores and functional criteria (school achievement, working history, and psychoneurological development). Impaired NC was categorized with respect to definitions of intellectual functioning in International Classification of Diseases, 10th revision (R41.83, F70‐F73). The outcome variables, defined as all‐cause mortality and 10‐year terminal remission with the 5 past years off medication (10YTR), were analyzed with Cox regression models.

Results

Of the 245 subjects, 119 (49%) had normal childhood NC, whereas 126 (51%) had various degrees of neurocognitive impairment. During the 50‐year observation period, 71 (29%) of the subjects died, 13% of those with normal and 44% of those with impaired NC. The hazard of death increased gradually in line with more impaired cognition, reaching significance in moderate, severe, and profound impairment versus normal NC (hazard ratio [Bonferroni corrected 95% confidence interval] = 3.3 [1.2‐9.2], 4.2 [1.2‐14.2], and 5.5 [2.4‐12.3], respectively). The chance for 10YTR was highest among subjects with normal NC (61%), whereas none of those with profound impairment reached 10YTR. In the intermediate categories, the chance was, however, not directly related to the increasing severity of impairment.

Significance

The severity of neurocognitive impairment during childhood shows a parallel increase in the risk of death. In comparison with normal NC, subjects with lower childhood NC are less likely to enter seizure remission. However, normal NC does not guarantee complete remission or prevent premature death in some individuals with childhood onset epilepsy.

https://ift.tt/2FCNR1W

Diagnostic and prognostic value of noninvasive long‐term video‐electroencephalographic monitoring in epilepsy surgery: A systematic review and meta‐analysis from the E‐PILEPSY consortium

Summary

Objective

The European Union–funded E‐PILEPSY network (now continuing within the European Reference Network for rare and complex epilepsies [EpiCARE]) aims to harmonize and optimize presurgical diagnostic procedures by creating and implementing evidence‐based guidelines across Europe. The present study evaluates the current evidence on the diagnostic accuracy of long‐term video‐electroencephalographic monitoring (LTM) in identifying the epileptogenic zone in epilepsy surgery candidates.

Methods

MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov were searched for relevant articles. First, we used random‐effects meta‐analytical models to calculate pooled estimates of sensitivity and specificity with respect to postsurgical seizure freedom. In a second phase, we analyzed individual patient data in an exploratory fashion, assessing diagnostic accuracy within lesional and nonlesional temporal lobe epilepsy (TLE) and extratemporal lobe epilepsy (ETLE) patients. We also evaluated seizure freedom rate in the presence of "localizing" or "nonlocalizing" LTM within each group. The quality of evidence was assessed using the QUADAS‐2 tool and the GRADE approach.

Results

Ninety‐four studies were eligible. Forty‐four were included in sensitivity meta‐analysis and 34 in specificity meta‐analysis. Pooled sensitivity was 0.70 (95% confidence interval [CI] = 0.60‐0.80) and specificity was 0.40 (95% CI = 0.27‐0.54). Subgroup analysis was based on individual data of 534 patients (41% men). In lesional TLE patients, sensitivity was 0.85 (95% CI = 0.81‐0.89) and specificity was −0.19 (95% CI = 0.13‐0.28). In lesional ETLE patients, a sensitivity of 0.47 (95% CI = 0.36‐0.58) and specificity of 0.35 (95% CI = 0.21‐0.53) were observed. In lesional TLE, if LTM was localizing and concordant with resection site, the seizure freedom rate was 247 of 333 (74%), whereas in lesional ETLE it was 34 of 56 (61%). The quality of evidence was assigned as "very low."

Significance

Long‐term video‐electroencephalographic monitoring is associated with moderate sensitivity and low specificity in identification of the epileptogenic zone. Sensitivity is remarkably higher in lesional TLE compared to lesional ETLE. Substantial heterogeneity across the studies indicates the need for improved design and quality of reporting.

https://ift.tt/2r33C8r

Prolonged status epilepticus: Early recognition and prediction of full recovery in a 12‐year cohort

Summary

Objectives

Early identification of patients who are at risk of prolonged status epilepticus (SE) and patients with high chances of full recovery despite prolonged SE may urge clinicians to intensify treatment rather than to withdraw care. We aimed to develop prediction models based on readily available clinical parameters to predict prolonged SE at seizure onset and to identify patients with high chances for full recovery.

Methods

From 2005 to 2016, all adult SE patients treated at the University Hospital Basel, a Swiss medical care center, were included. Multivariable Poisson regression was performed to identify predictors of prolonged SE (defined as SE for >12, >24, and >48 hours) and return to baseline from prolonged SE. The area under the receiver‐operating characteristic curves (AUROC) for prediction models was calculated.

Results

Of 467 patients, the median age was 66.7 years and mortality was 12%. Relative risk (RR) for death was 1.06 (P < 0.0001) with every SE day. In multivariable analysis, nonconvulsive SE with coma, SE severity score ≥3, and acute brain lesions at SE onset independently predicted prolonged SE with an AUROC of 0.68 for >12, 0.67 for >24, and 0.72 for >48 hours of SE. Absence of nonconvulsive SE with coma and a decreasing Charlson comorbidity index were independent predictors for return to baseline in prolonged SE with an AUROC of 0.82 and 0.76 following cross‐validation. Both associations remained significant despite adjustments for determinants of adverse outcome, such as anesthetics and vasopressors (nonconvulsive SE with coma RR = 0.24, 95% confidence interval [CI] 0.07‐0.86; comorbidity index RR = 0.87, 95% CI 0.76‐0.99).

Significance

Although our data indicate that identification of prolonged SE at seizure onset is unreliable, timely recognition of patients with high chances of good outcome despite prolonged SE is promising on the basis of comorbidities, type of SE, and level of consciousness. Further external validation of this prediction model is needed.

https://ift.tt/2r2H6MR

Postictal electroencephalographic (EEG) suppression: A stereo‐EEG study of 100 focal to bilateral tonic–clonic seizures

Summary

Objectives

We aimed to describe intracerebral aspects of postictal generalized electroencephalography suppression (PGES) following focal to bilateral tonic–clonic ("secondarily generalized tonic–clonic") seizures (GTCS) recorded using stereoelectroencephalographic (SEEG), and to correlate these with electroclinical features.

Methods

Three independent observers scored semiologic and SEEG features. Patient and epilepsy characteristics were collected. Descriptive statistics and multivariate analysis were performed. The operational definition of PGES on SEEG used strict criteria (absence of visible signal at 20 μV/mm amplitude, in all readable channels). Postictal regional suppression (RS) was identified if only a subset of implanted electrodes showed absence of signal.

Results

We evaluated 100 seizures in 52 patients. Interobserver agreement was good (κ 0.72 for clinical features and 0.73 for EEG features). PGES was present in 27 of 100 and RS without PGES present in 42 of 100 seizures. Region of RS included epileptogenic zone in 43 of 51 (86%). No effect of sampling (multilobar or bilateral exploration) was seen. Oral tonicity (mouth opening and/or tonic vocalization during the tonic phase of GTCS) was associated with the presence of PGES (P = 0.029; negative predictive value [NPV] 0.91). Bilateral upper limb extension during the tonic phase correlated with PGES (P = 0.041; NPV 0.85). Association of both oral tonicity and bilateral upper limb extension had a high NPV of 0.96.

Significance

SEEG recordings confirm true absence of signal during postictal EEG suppression. PGES is unlikely when both upper limb extension and oral tonicity are absent. We hypothesize that bilateral tonic seizure discharge at bulbar level brainstem regions is associated with the production of oral signs and may relate to mechanisms of PGES.

https://ift.tt/2FCNJ2s

A HS6ST2 gene variant associated with X‐linked intellectual disability and severe myopia in two male twins

X‐Linked Intellectual Disability (XLID) refers to a clinically and genetically heterogeneous neurodevelopmental disorder, in which males are more heavily affected than females. Among the syndromic forms of XLID, identified by additional clinical signs as part of the disease spectrum, the association between XLID and severe myopia has been poorly characterized.

We used Whole Exome Sequencing (WES) to study two Italian male twins presenting impaired intellectual function and adaptive behavior, in association with severe myopia and mild facial dysmorphisms. WES analysis detected the novel, maternally inherited, mutation c.916G>C (G306R) in the X‐linked Heparan Sulfate 6‐O‐ Sulfotransferase 2 (HS6ST2) gene. HS6ST2 transfers sulphate from adenosine 3'‐phosphate, 5'‐phosphosulphate (PAPS) to the 6^th position of the N‐sulphoglucosamine (GlcNS) residue in Heparan Sulfate (HS) proteoglycans. Low HS sulfation levels are associated with defective optic disc and stalk morphogenesis during mammalian visual system development. The c.916G>C variant affects the HS6ST2 substrate binding site and its effect was considered "deleterious" by in‐silico tools. An In‐vitro enzymatic assay showed that the HS6ST2 mutant isoform had significantly reduced sulphotransferase activity.

Taken together, the results suggest that mutant HS6ST2 is possibly involved in the development of myopia and cognitive impairment, characteristics of the probands reported here.

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Targeted panel sequencing in adult patients with left ventricular non‐compaction reveals a large genetic heterogeneity

Left ventricular non‐compaction (LVNC) is a cardiomyopathy that may be of genetic origin, however few data are available about the yield of mutation, the spectrum of genes and allelic variations. The aim of this study was to better characterize the genetic spectrum of isolated LVNC in a prospective cohort of 95 unrelated adult patients through the molecular investigation of 107 genes involved in cardiomyopathies and arrhythmias.

Fifty‐two pathogenic or probably pathogenic variants were identified in 40 patients (42%) including 31 patients (32.5%) with single variant and 9 patients with complex genotypes (9.5%). Mutated patients tended to have younger age at diagnosis than patients with no identified mutation. The most prevalent genes were TTN, then HCN4, MYH7, and RYR2. The distribution includes 13 genes previously reported in LVNC and 10 additional candidate genes.

Our results show that LVNC is basically a genetic disease and support genetic counseling and cardiac screening in relatives. There is a large genetic heterogeneity, with predominant TTN null mutations and frequent complex genotypes. The gene spectrum is close to the one observed in dilated cardiomyopathy but with specific genes such as HCN4. We also identified new candidate genes that could be involved in this sub‐phenotype of cardiomyopathy.

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Diagnosis and treatment of alcohol use disorder in patients with end‐stage alcoholic liver disease

Abstract

Almost 14‐30% of the world's population is affected by alcohol use disorder (AUD), and excessive alcohol consumption represents the most common cause of liver disease in the western world. The clinical picture of alcoholic end‐stage liver disease is rendered extremely complex as manifestations such as alcohol withdrawal syndrome, craving and physical dependence, as well as extrahepatic alcohol‐related diseases merge with the complications of advanced cirrhosis. This makes AUD recognition and assessment difficult and its management arduous as many drugs commonly employed to treat complications such as alcohol withdrawal syndrome are often contraindicated by the presence of hepatic encephalopathy or hepatorenal syndrome.

Reaching and maintaining abstinence represent the mainstay of managing patients with AUD and end‐stage liver disease. Psychosocial interventions are an essential component of treatment to reach these goals. However, these interventions alone often prove insufficient in AUD patients and even more frequently in those with end‐stage liver disease because of inadequate adherence due to poor functional and physical status. Thus, pharmacological treatments need to be associated, but the available options are greatly limited in end‐stage liver disease because many GABA‐ergic drugs can favor the development of hepatic encephalopathy, while drugs undergoing extensive liver metabolism should be avoided or used with the greatest caution. Because of these limitations, the management of end‐stage AUD is extremely challenging and requires an integrated multidisciplinary approach.

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Sexual dysfunction and sex hormone abnormalities in patients with cirrhosis: Review of pathogenesis and management

Abstract

Healthy sexual function is important to maintain a good quality of life but is frequently impaired in patients with cirrhosis. The degree of sexual dysfunction appears to be linked with the degree of hepatic dysfunction. In men, sexual dysfunction can be related to the hyperestrogenism of portal hypertension and/or to decreased testosterone resulting from testicular dysfunction. In women, suppression of the hypothalamic‐pituitary‐gonadal axis appears to be a principal contributor, with no significant effect of portal hypertension. There is also a huge psychological barrier to breakthrough as there is a component of depression in many patients with cirrhosis. Sexual dysfunction is often underdiagnosed in the cirrhotic cohort. Management of sexual disorders in patients with cirrhosis can be challenging as they are often multifactorial. Multidisciplinary approach is the key in managing these patients. We review the current literature on the pathogenesis of sexual dysfunction in cirrhotic patients and propose a step‐wise algorithm to better manage these patients.

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New strategies for the management of decompensated cirrosis: long‐term albumin administration for everyone?

Abstract

Natural history of cirrhosis is characterized by the progression from a compensated to a decompensated state, which is defined by the development of several complications of the disease (1). Ascites is the most frequent complication of patients with decompensated cirrhosis, but other common complications include hepatic encephalopathy, GI bleeding, bacterial infections, kidney failure and hyponatremia. Decompensated cirrhosis is not only associated with poor outcome, with median survival of approximately 2 years, but also with impaired health‐related quality of life and high economic burden due to frequent hospital admissions and use of health‐care resources. Currently, management of decompensated cirrhosis is mainly based on symptomatic treatment of individual complications once they occur, rather than using a pathophysiological approach (2).

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Prevalence and clinical characteristics of stroke patients with p.R544C NOTCH3 mutation in Taiwan

Abstract

Objective

Features of cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations vary between ethnicities and regions. In Taiwan, more than 70% of CADASIL patients carry the mutation hot spot of p.R544C. We investigated the prevalence of NOTCH3 p.R544C mutation in stroke patients in Taiwan.

Methods

This prospective, multicenter study recruited acute stroke patients within 10 days of symptom onset. The p.R544C mutation was identified by polymerase chain reaction with confronting two‐pair primers and sequencing. Clinical parameters, vascular risk factors, stroke subtypes, and stroke outcomes were analyzed.

Results

Of the 1970 stroke patients (mean age 61.1 ± 13.6 years, male 69.5%) included, 1705 (86.5%) had ischemic stroke and 265 (13.5%) had intracerebral hemorrhage. The prevalence of p.R544C in the study population was 2.8% (95% confidence interval [CI] = 2.1–3.5%). The prevalence was highest in patients with small vessel occlusion type of ischemic stroke (5.6%), followed by intracerebral hemorrhage (5.3%), and infarct of undetermined etiology (2.7%), and was low in patients with cardioembolism (0.8%) and large artery atherosclerosis (0.7%). All p.R544C patients with intracerebral hemorrhage were nonlobar hemorrhage. Sibling history of stroke (odds ratio [OR] = 4.50, 95% CI = 1.67–12.14 in ischemic stroke; OR = 6.03, 95% CI = 1.03–35.47 in intracerebral hemorrhage, respectively) and small vessel occlusion (OR, 4.03, 95% CI, 1.26–12.92) were significantly associated with p.R544C.

Interpretation

p.R544C NOTCH3 mutation is underdiagnosed in stroke patients in Taiwan, especially in those with small vessel occlusion and sibling history of stroke.

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Issue Information

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Vaccines for Preventing Influenza in Healthy Individuals

Abstract

Influenza is an acute respiratory infection that imposes a heavy burden on society. The illness itself usually lasts a few days but the residual symptoms of cough and malaise can last for weeks. In addition, it can cause complications such as otitis media, pneumonia, secondary bacterial pneumonia, exacerbations of chronic respiratory disease, bronchiolitis, febrile seizures, Reye's syndrome, and myocarditis.¹ Vaccines have been developed in attempt to minimize the effects of influenza. However, given the yearly antigenic changes of the virus, a new vaccine has to be developed, produced, and administered to the population every year.² The Cochrane review discussed here assesses the efficacy of vaccines in preventing influenza in healthy adults including pregnant women.

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The 2018 Academic Emergency Medicine Consensus Conference: Aligning the Pediatric Emergency Medicine Research Agenda to Reduce Health Outcome Gaps

Abstract

Emergency care providers share a compelling interest in developing an effective patient‐centered, outcomes‐based research agenda that can decrease variability in pediatric outcomes. The 2018 Academic Emergency Medicine Consensus Conference, "Aligning the Pediatric Emergency Medicine Research Agenda to Reduce Health Outcome Gaps (AEMCC)," aimed to fulfill this role. This conference convened major thought leaders and stakeholders to introduce a research, scholarship, and innovation agenda for pediatric emergency care specifically to reduce health outcome gaps. Planning committee and conference participants included emergency physicians, pediatric emergency physicians, pediatricians, and researchers with expertise in research dissemination and translation, as well as comparative effectiveness, in collaboration with patients, patient and family advocates from national advocacy organizations, and trainees. Topics that were explored and deliberated through subcommittee breakout sessions led by content experts included: 1) pediatric emergency medical services (EMS) research, 2) pediatric emergency medicine (PEM) research network collaboration, 3) PEM education for emergency medicine providers, 4) workforce development for PEM, and 5) enhancing collaboration across emergency departments (PEM practice in non‐children's hospitals). The work product of this conference is a research agenda that aims to identify areas of future research, innovation, and scholarship in pediatric emergency medicine.

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Re: SAEM Annual Meeting Abstracts

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The current state and future perspectives of cannabinoids in cancer biology

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The prognostic significance of circulating tumor cells in head and neck and non‐small‐cell lung cancer

3D DNA FISH of circulating tumor cells demonstrates a higher resolution for genomic aberrations compared to 2D imaging modalities.

Abstract

Tumor biopsy is the gold standard for the assessment of clinical biomarkers for treatment. However, tumors change dynamically in response to therapy, and there remains a need for a more representative biomarker that can be assayed over the course of treatment. Circulating tumor cells (CTCs) may provide clinically important and comprehensive tumoral information that is predictive of treatment response and outcome. Blood samples were processed for CTCs from 56 patients using the ClearCell FX system. Captured cells were phenotyped for CTC clusters and markers for immunotherapy (PD‐L1) CTC chromosomal architecture (ALK, EGFR). CTCs were isolated in 11/23 (47.8%) of head and neck cancer (HNC) patients and 17/33 (51.5%) of non‐small‐cell lung cancer (NSCLC) patients. CTCs were determined to be PD‐L1‐positive in 6/11 (54.4%) HNC and 11/17 (64.7%) NSCLC cases, respectively. 3D chromosomal DNA FISH for ALK and EGFR molecular targets showed better resolution than in 2D when imaging CTCs. HNC CTC‐positive patients had shorter progression‐free survival (PFS) (hazard ratio[HR]: 4.946; 95% confidence internal[CI]:1.571‐15.57; P = 0.0063), and PD‐L1‐positive CTCs were found to be significantly associated with worse outcome ([HR]:5.159; 95% [CI]:1.011‐26.33; P = 0.0485). In the advanced stage NSCLC patient cohort, PFS was not found to be associated with CTCs prior to therapy ([HR]:2.246; 95% [CI]:0.9565‐5.273; P = 0.0632), nor the presence of PD‐L1 expression ([HR]:1.646; 95% [CI]:0.5128‐5.283; P = 0.4023). This study demonstrated that CTCs are predictive of poorer outcomes in HNC and provides distinct and separate utility for CTCs in HNC and NSCLC, which may be more representative of the disease burden and overall survival than the parameters used to measure them.

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JNK2 modulates the CD1d‐dependent and ‐independent activation of iNKT cells

Invariant Natural Killer T (iNKT) cells play critical roles in autoimmune, anti‐tumor and anti‐microbial immune responses, and are activated by glycolipids presented by the MHC class I‐like molecule, CD1d. How the activation of signaling pathways impacts antigen (Ag)‐dependent iNKT cell activation is not well‐known. In the current study, we found that the MAPK JNK2 not only negatively regulates CD1d‐mediated Ag presentation in APCs, but also contributes to CD1d‐independent iNKT cell activation. A deficiency in the JNK2 (but not JNK1) isoform enhanced Ag presentation by CD1d. Using a vaccinia virus (VV) infection model known to cause a loss in iNKT cells in a CD1d‐independent, but IL‐12‐dependent manner, we found the virus‐induced loss of iNKT cells in JNK2 KO mice was substantially lower than that observed in JNK1 KO or wildtype (WT) mice. Importantly, compared to WT mice, JNK2 KO mouse iNKT cells were found to express less surface IL‐12 receptors. As with a VV infection, an IL‐12 injection also resulted in a smaller decrease in JNK2 KO iNKT cells as compared to WT mice. Overall, our work strongly suggests JNK2 is a negative regulator of CD1d‐mediated Ag presentation and contributes to IL‐12‐induced iNKT cell activation and loss during viral infections.

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USP14 promotes K63‐linked RIG‐I deubiquitination and suppresses antiviral immune responses

RIG‐I is a critical RNA virus sensor that initiates antiviral immune response through K63‐linked ubiquitination. In this study, we demonstrated USP14, a deubiquitinating enzyme, as a negative regulator in antiviral responses by directly deubiquitinating K63‐linked RIG‐I. USP14 knockdown significantly enhanced RIG‐I‐triggered type I IFN signaling and inhibited VSV replication both in mouse peritoneal macrophages and THP1 cells. USP14 overexpression in HeLa cells attenuated RIG‐I‐triggered IFN‐β expression and promoted VSV replication. Besides, USP14 specific inhibitor‐IU1 increased RIG‐I‐mediated type I IFN production and antiviral responses in vitro and in vivo. In addition, USP14 could interact with RIG‐I and remove RIG‐I K63‐linked polyubiquitination chains. This paper is the first to report that USP14 acts as a negative regulator in antiviral response through deubiquitinating K63‐linked RIG‐I. These findings provide insights into a potential new therapy targeting USP14 for RNA virus related diseases.

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GM‐CSF therapy inhibits chronic graft‐versus‐host disease via expansion of regulatory T cells

Regulatory T cells (Tregs) attenuate excessive immune responses, making their expansion beneficial in immune‐mediated diseases, including allogeneic bone marrow transplantation‐associated graft‐versus‐host disease (GVHD). In addition to interleukin‐2, Tregs require T cell receptor and costimulatory signals from antigen‐presenting cells, such as dendritic cells (DCs), for their optimal proliferation. Granulocyte‐macrophage colony stimulating factor (GM‐CSF) increases DC number and may promote DC‐dependent Treg proliferation. Here, we demonstrate that GM‐CSF treatment increases CD4⁺CD8^– DCs, which is associated with Treg expansion. In a mouse model of chronic GVHD (cGVHD), GM‐CSF therapy expanded Tregs, protected against the development of skin GVHD, and regulated both T helper (Th)1 and Th17 responses in the peripheral lymph nodes, resulting in an attenuation of skin cGVHD. Notably, the expanded Tregs were instrumental to GM‐CSF‐mediated cGVHD inhibition, which was dependent upon an increased ratio of Tregs to conventional T cells rather than augmentation of suppressive function. These data suggest that GM‐CSF induces Treg proliferation by expanding CD4⁺CD8⁻ DCs which in turn regulates alloimmune responses in a cGVHD mouse model. Thus, GM‐CSF could be used as a therapeutic DC modulator to induce Treg expansion and inhibit excessive alloimmune responses in immune‐related disease.

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Quasi‐Hodgkin–Huxley Neurons with Leaky Integrate‐and‐Fire Functions Physically Realized with Memristive Devices

Quasi‐Hodgkin–Huxley (HH) neurons with leaky integrate‐and‐fire functions are physically demonstrated by W/WO₃/poly(3,4‐ethylenedioxythiophene):polystyrene sulfonate/Pt memristive devices with a battery effect; in the device, proton migration plays a key role. With the help of a neuromorphic circuit, the neuron successfully emulates the multifunction of a biological neuron, being advantageous over previously reported HH and leaky integrate‐and‐fire neurons.

Abstract

Artificial neurons with functions such as leaky integrate‐and‐fire (LIF) and spike output are essential for brain‐inspired computation with high efficiency. However, previously implemented artificial neurons, e.g., Hodgkin–Huxley (HH) neurons, integrate‐and‐fire (IF) neurons, and LIF neurons, only achieve partial functionality of a biological neuron. In this work, quasi‐HH neurons with leaky integrate‐and‐fire functions are physically demonstrated with a volatile memristive device, W/WO₃/poly(3,4‐ethylenedioxythiophene): polystyrene sulfonate/Pt. The resistive switching behavior of the device can be attributed to the migration of protons, unlike the migration of oxygen ions normally involved in oxide‐based memristors. With multifunctions similar to their biological counterparts, quasi‐HH neurons are advantageous over the reported HH and LIF neurons, demonstrating their potential for neuromorphic computing applications.

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Mitigating Chromatic Dispersion with Hybrid Optical Metasurfaces

The normal dispersion of refractive components, often revealed by sending a white light beam through a prism, is cancelled using phased gradient metasurfaces. The realization of hybrid metasurface devices enables the conception of new nondispersive broadband components.

Abstract

Metasurfaces control various properties of light via scattering across a large number of subwavelength‐spaced nanostructures. Although metasurfaces appear to be ideal photonic platforms for realizing and designing miniaturized devices, their chromatic aberrations have hindered the large‐scale deployment of this technology in numerous applications. Wavelength‐dependent diffraction and resonant scattering effects usually limit their working operation wavelengths. In refractive optics, chromatic dispersion is a significant problem and is generally treated by cascading multiple lenses into achromatic doublets, triplets, and so on. Recently, broadband achromatic metalenses in the visible have been proposed to circumvent chromatic aberration but their throughput efficiency is still limited. Here, the dispersion of refractive components is corrected by leveraging the inherent dispersion of metasurfaces. Hybrid refractive‐metasurface devices, with nondispersive refraction in the visible, are experimentally demonstrated. The dispersion of this hybrid component, characterized by using a Fourier plane imaging microscopy setup, is essentially achromatic over about 150 nm in the visible. Broadband focusing with composite plano‐convex metasurface lenses is also proposed. These devices could find applications in numerous consumer optics, augmented reality components, and all applications including imaging for which monochromatic performance is not sufficient.

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Subwavelength Artificial Structures: Opening a New Era for Engineering Optics

As one of the cornerstones of the modern information society, engineering optics is faced with great challenges resulting from classic optical theories and materials. Based on subwavelength engineered structures, it is now possible to break through traditional performance limitations by replacing bulky and costly optical devices with extremely thin and lightweight components, which lays the foundation of the next generation of engineering optics.

Abstract

In the past centuries, the scale of engineering optics has evolved toward two opposite directions: one is represented by giant telescopes with apertures larger than tens of meters and the other is the rapidly developing micro/nano‐optics and nanophotonics. At the nanoscale, subwavelength light–matter interaction is blended with classic and quantum effects in various functional materials such as noble metals, semiconductors, phase‐change materials, and 2D materials, which provides unprecedented opportunities to upgrade the performance of classic optical devices and overcome the fundamental and engineering difficulties faced by traditional optical engineers. Here, the research motivations and recent advances in subwavelength artificial structures are summarized, with a particular emphasis on their practical applications in super‐resolution and large‐aperture imaging systems, as well as highly efficient and spectrally selective absorbers and emitters. The role of dispersion engineering and near‐field coupling in the form of catenary optical fields is highlighted, which reveals a methodology to engineer the electromagnetic response of complex subwavelength structures. Challenges and tentative solutions are presented regarding multiscale design, optimization, fabrication, and system integration, with the hope of providing recipes to transform the theoretical and technological breakthroughs on subwavelength hierarchical structures to the next generation of engineering optics, namely Engineering Optics 2.0.

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Minimally Invasive and Regenerative Therapeutics

Current and future minimally invasive and regenerative therapeutics are reviewed together with delivery routes and tools. Regenerative therapeutics based on cells, biomaterials, biomolecules, and their combinations for different organs are described. The integration of minimally invasive approaches with robotics, regenerative therapeutics, and imaging techniques is also introduced. In addition, related challenges and future directions are discussed.

Abstract

Advances in biomaterial synthesis and fabrication, stem cell biology, bioimaging, microsurgery procedures, and microscale technologies have made minimally invasive therapeutics a viable tool in regenerative medicine. Therapeutics, herein defined as cells, biomaterials, biomolecules, and their combinations, can be delivered in a minimally invasive way to regenerate different tissues in the body, such as bone, cartilage, pancreas, cardiac, skeletal muscle, liver, skin, and neural tissues. Sophisticated methods of tracking, sensing, and stimulation of therapeutics in vivo using nano‐biomaterials and soft bioelectronic devices provide great opportunities to further develop minimally invasive and regenerative therapeutics (MIRET). In general, minimally invasive delivery methods offer high yield with low risk of complications and reduced costs compared to conventional delivery methods. Here, minimally invasive approaches for delivering regenerative therapeutics into the body are reviewed. The use of MIRET to treat different tissues and organs is described. Although some clinical trials have been performed using MIRET, it is hoped that such therapeutics find wider applications to treat patients. Finally, some future perspective and challenges for this emerging field are highlighted.

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