Two-year clinical trial of a universal adhesive in total-etch and self-etch mode in non-carious cervical lesions.

Abstract:
OBJECTIVES
To compare the clinical performance of Scotchbond™ Universal Adhesive used in self- and total-etch modes and two-bottle Scotchbond™ Multi-purpose Adhesive in total-etch mode for Class 5 non-carious cervical lesions (NCCLs).

METHODS
37 adults were recruited with 3 or 6 NCCLs (>1.5mm deep). Teeth were isolated, and a short cervical bevel was prepared. Teeth were restored randomly with Scotchbond Universal total-etch, Scotchbond Universal self-etch or Scotchbond Multi-purpose followed with a composite resin. Restorations were evaluated at baseline, 6, 12 and 24 months for marginal adaptation, marginal discoloration, secondary caries, and sensitivity to cold using modified USPHS Criteria. Patients and evaluators were blinded. Logistic and linear regression models using a generalized estimating equation were applied to evaluate the effects of time and adhesive material on clinical assessment outcomes over the 24 month follow-up period. Kaplan-Meier method was used to compare the retention between adhesive materials.

RESULTS
Clinical performance of all adhesive materials deteriorated over time for marginal adaptation, and discoloration (p<0.0001). Both Scotchbond Universal self-etch and Scotchbond Multi-purpose materials were more than three times as likely to contribute to less satisfying performance in marginal discoloration over time than Scotchbond Universal total-etch. The retention rates up to 24 months were 87.6%, 94.9% and 100% for Scotchbond Multi-purpose and Scotchbond Universal self-etch and total-etch, respectively.

CONCLUSIONS
Scotchbond Universal in self- and total- etch modes performed similar to or better than Scotchbond Multipurpose, respectively.

CLINICAL SIGNIFICANCE
24 month evaluation of a universal adhesive indicates acceptable clinical performance, particularly in a total-etch mode.

Lawson|Nathaniel C|NC|
Robles|Augusto|A|
Fu|Chin-Chuan|CC|
Lin|Chee Paul|CP|
Sawlani|Kanchan|K|
Burgess|John O|JO|

D000134:Acid Etching, Dental
D000269:Adhesives
D003188:Composite Resins
D045662:Dental Etching
D018772:Dental Marginal Adaptation
D019232:Dental Restoration Failure
D003793:Dental Restoration, Permanent
D017220:Dentin-Bonding Agents
D005260:Female
D006801:Humans
D008297:Male
D008875:Middle Aged
D019279:Resin Cements
D019237:Tooth Cervix

Universal adhesive
Total-etch
Self-etch
Non-carious cervical lesion


Identification and Validation of Carbonic Anhydrase II as the First Target of the Anti-Inflammatory Drug Actarit.

Abstract: Background and purpose: Identifying the macromolecular targets of drug molecules is a fundamental aspect of drug discovery and pharmacology. Several drugs remain without known targets (orphan) despite large-scale in silico and in vitro target prediction efforts. Ligand-centric chemical-similarity-based methods for in silico target prediction have been found to be particularly powerful, but the question remains of whether they are able to discover targets for target-orphan drugs. Experimental Approach: We used one of these in silico methods to carry out a target prediction analysis for two orphan drugs: actarit and malotilate. The top target predicted for each drug was carbonic anhydrase II (CAII). Each drug was therefore quantitatively evaluated for CAII inhibition to validate these two prospective predictions. Key Results: Actarit showed in vitro concentration-dependent inhibition of CAII activity with submicromolar potency (IC50 = 422 nM) whilst no consistent inhibition was observed for malotilate. Among the other 25 targets predicted for actarit, RORγ (RAR-related orphan receptor-gamma) is promising in that it is strongly related to actarit's indication, rheumatoid arthritis (RA). Conclusion and Implications: This study is a proof-of-concept of the utility of MolTarPred for the fast and cost-effective identification of targets of orphan drugs. Furthermore, the mechanism of action of actarit as an anti-RA agent can now be re-examined from a CAII-inhibitor perspective, given existing relationships between this target and RA. Moreover, the confirmed CAII-actarit association supports investigating the repositioning of actarit on other CAII-linked indications (e.g., hypertension, epilepsy, migraine, anemia and bone, eye and cardiac disorders).

Ghislat|Ghita|G|
Rahman|Taufiq|T|0000-0003-3830-5160
Ballester|Pedro J|PJ|

carbonic anhydrase II
actarit
target prediction
malotilate
MolTarPred


Electrochemical sensors and biosensors based on the use of polyaniline and its nanocomposites: a review on recent advances.

Abstract: Polyaniline and its composites with nanoparticles have been widely used in electrochemical sensor and biosensors due to their attractive properties and the option of tuning them by proper choice of materials. The review (with 191 references) describes the progress made in the recent years in polyaniline-based biosensors and their applications in clinical sensing, food quality control, and environmental monitoring. A first section summarizes the features of using polyaniline in biosensing systems. A subsequent section covers sensors for clinical applications (with subsections on the detection of cancer cells and bacteria, and sensing of glucose, uric acid, and cholesterol). Further sections discuss sensors for use in the food industry (such as for sulfite, phenolic compounds, acrylamide), and in environmental monitoring (mainly pesticides and heavy metal ions). A concluding section summarizes the current state, highlights some of the challenges currently compromising performance in biosensors and nanobiosensors, and discusses potential future directions. Graphical abstract Schematic presentation of electrochemical sensor and biosensors applications based on polyaniline/nanoparticles in various fields of human life including medicine, food industry, and environmental monitoring. The simultaneous use of suitable properties polyaniline and nanoparticles can provide the fabrication of sensing systems with high sensitivity, short response time, high signal/noise ratio, low detection limit, and wide linear range by improving conductivity and the large surface area for biomolecules immobilization.

Shoaie|Nahid|N|
Daneshpour|Maryam|M|
Azimzadeh|Mostafa|M|
Mahshid|Sara|S|
Khoshfetrat|Seyyed Mehdi|SM|
Jahanpeyma|Fatemeh|F|
Gholaminejad|Alieh|A|
Omidfar|Kobra|K|
Foruzandeh|Mehdi|M|

Nanoparticles
Food quality control
Environmental monitoring
Cancer cells
Bacteria
Glucose
Uric acid
Cholesterol
Sulfite
Phenolic compounds
Acrylamide
Pesticides
Heavy metal ions
Sensing system
Clinical detection
Drugs


Automated real-time method for ventricular heartbeat classification.

Abstract:
BACKGROUND AND OBJECTIVE
In this work, we develop a fully automatic and real-time ventricular heartbeat classifier based on a single ECG lead. Single ECG lead classifiers can be especially useful for wearable technologies that provide continuous and long-term monitoring of the electrocardiogram. These wearables usually have a few non-standard leads and the quality of the signals depends on the user physical activity.

METHODS
The proposed method uses an Echo State Network (ESN) to classify ECG signals following the Association for the Advancement of Medical Instrumentation (AAMI) recommendations with an inter-patient scheme. To achieve real-time classification, the classifier itself and the feature extraction approach are fast and computationally efficient. In addition, our approach allows transferring the knowledge from one database to another without additional training.

RESULTS
The classification performance of the proposed model is validated on the MIT-BIH arrhythmia and INCART databases. The sensitivity and precision of the proposed method for MIT-BIH arrhythmia database are 95.3 and 88.8 for the modified lead II and 90.9 and 89.2 for the V1 lead. The results reported are further compared to the existing methodologies in literature. Our methodology is a competitive single lead ventricular heartbeat classifier, that is comparable to state-of-the-art algorithms using multiple leads.

CONCLUSIONS
The proposed fully automated, single-lead and real-time heartbeat classifier of ventricular heartbeats reports an improved classification accuracy in different leads of the evaluated databases in comparison with other single lead heartbeat classifiers. These results open the possibility of applying our methodology to wearable long-term monitoring devices with an unconventional placement of the electrodes.

Ortín|Silvia|S|
Soriano|Miguel C|MC|
Alfaras|Miquel|M|
Mirasso|Claudio R|CR|

Biomedical signal processing
ECG heartbeat classification
Reservoir computing
Template matching


The prognostic value of squamous differentiation in endometrioid type endometrial cancer: a matched analysis.

Abstract: We aimed to examine the effect of the squamous differentiation on survival outcomes of women with endometrioid adenocarcinoma. We retrospectively reviewed the patients with endometrioid adenocarcinoma who underwent primary surgical treatment in a tertiary referral hospital. Sixty-nine patients having squamous differentiation constituted the case group. Each woman in the case group was matched with two patients in the control group based on age, disease stage, tumour grade, lymphovascular space invasion, tumour size, myometrial invasion, type of surgery and adjuvant therapy. During the follow-up, the recurrence rates were similar between the case (5/69, 7.2%) and control (10/138, 7.2%) groups (p = 1.0). The 5-year disease-free survival rate was 90.2% for the case group and 88.6% for the control group (p = .51). The 5-year overall survival rate was 94.6% for the case group and 91.8% for the control group (p = .12). Squamous differentiation seems to have no impact on the prognosis of patients with endometrioid adenocarcinoma.IMPACT STATEMENTWhat is already known on this subject? A focus of squamous differentiation is recognised in 12.8-25% of women with endometrioid adenocarcinoma. The prognostic value of the squamous differentiation was evaluated in several previous studies. However, it could not be clarified due to the conflicting results of these studies.What do the results of this study add? The probable confounding effects of well-known prognostic factors including age at diagnosis, International Federation of Gynaecology and Obstetrics stage, tumour grade, lymphovascular space invasion, tumour size, myometrial invasion, type of surgery and adjuvant therapy were eliminated with the case-control study design in the current study. Our findings indicate that the presence of squamous differentiation does not have any prognostic effect in endometrioid type endometrial cancer.What are the implications of these findings for clinical practice and/or further research? The molecular prognosticators of endometrial cancer were extensively studied in recent years. It is likely that clinicopathological and molecular prognostic factors will be integrated for predicting prognosis as a part of routine clinical practice soon. In this context, the prognostic value of the squamous differentiation in endometrioid adenocarcinomas may further be clarified by larger and multicentric studies that utilise central pathology review.

Endometrial cancer
recurrence
survival analysis


Progranulin as a candidate biomarker for therapeutic trial in patients with ALS and FTLD.

Abstract: The loss-of-function mechanism in progranulin (PGRN) mutation carriers makes PGRN an interesting target for upregulation as a therapeutic approach in neurodegenerative diseases like frontotemporal lobar degeneration. This gives rise to several questions: (1) how stable are PGRN levels in blood and cerebrospinal fluid (CSF) in follow-up? (2) Is it necessary to measure PGRN levels in CSF to monitor a therapeutic effect? Therefore, concentrations of PGRN were measured in paired CSF and serum samples of 22 patients with behavioural variant frontotemporal dementia, including one GRN mutation carrier (c.349+1G>C), 16 patients with amyotrophic lateral sclerosis and 17 non-neurodegenerative patients, which included 22 follow-up levels. PGRN levels of 14 patients with isolated dysfunction of the blood-CSF barrier were measured and PGRN was correlated with albumin quotients as a marker for blood-CSF barrier function. The intrathecal fraction of PGRN was calculated on the basis of CSF-to-serum ratios and hydrodynamic properties. Follow-up measurements of CSF and serum PGRN levels did not show any significant change in diagnostic groups. Mean PGRN levels are 35 times higher in blood than in CSF. However, the CSF-to-serum PGRN ratio does not correlate with the albumin quotient even in patients with severe impairment of the blood-CSF barrier. The calculated intrathecal fraction of CSF PGRN levels ranged between 80 and 90 %. Assuming that CSF PGRN is either brain-derived or transported from the vascular compartment via receptor mediated mechanisms, we propose that monitoring CNS specific effects of PGRN modulating drugs should be done in CSF.

Feneberg|Emily|E|
Steinacker|Petra|P|
Volk|Alexander Erich|AE|
Weishaupt|Jochen Hans|JH|
Wollmer|Marc Axel|MA|
Boxer|Adam|A|
Tumani|Hayrettin|H|
Ludolph|Albert Christian|AC|
Otto|Markus|M|

D036341:Intercellular Signaling Peptides and Proteins

Progranulin
Biomarker
Cerebrospinal fluid
Frontotemporal dementia
Amyotrophic lateral sclerosis


Abstract:
OBJECTIVES
Venous thromboembolism (VTE) is a major potential complication following orthopaedic surgery. Subcutaneously administered enoxaparin has been used as the benchmark to reduce the incidence of VTE. However, concerns have been raised regarding the long-term administration of enoxaparin and its possible negative effects on bone healing and bone density with an increase of the risk of osteoporotic fractures. New oral anticoagulants such as rivaroxaban have recently been introduced, however, there is a lack of information regarding how these drugs affect bone metabolism and post-operative bone healing.

METHODS
We measured the migration and proliferation capacity of mesenchymal stem cells (MSCs) under enoxaparin or rivaroxaban treatment for three consecutive weeks, and evaluated effects on MSC mRNA expression of markers for stress and osteogenic differentiation.

RESULTS
We demonstrate that enoxaparin, but not rivaroxaban, increases the migration potential of MSCs and increases their cell count in line with elevated mRNA expression of C-X-C chemokine receptor type 4 (CXCR4), tumor necrosis factor alpha (TNFα), and alpha-B-crystallin (CryaB). However, a decrease in early osteogenic markers (insulin-like growth factors 1 and 2 (IGF1, IGF2), bone morphogenetic protein2 (BMP2)) indicated inhibitory effects on MSC differentiation into osteoblasts caused by enoxaparin, but not by rivaroxaban.

CONCLUSIONS
Our findings may explain the adverse effects of enoxaparin treatment on bone healing. Rivaroxaban has no significant impact on MSC metabolism or capacity for osteogenic differentiation in vitro.Cite this article: Dr H. Pilge. Enoxaparin and rivaroxaban have different effects on human mesenchymal stromal cells in the early stages of bone healing. Bone Joint Res 2016;5:95-100. DOI: 10.1302/2046-3758.53.2000595.

Pilge|H|H|
Fröbel|J|J|
Prodinger|P M|PM|
Mrotzek|S J|SJ|
Fischer|J C|JC|
Zilkens|C|C|
Bittersohl|B|B|
Krauspe|R|R|

enoxaparin
rivaroxaban
bone healing
human mesenchymal stromal cells (MSCs)
low-molecular-weight heparins (LMWH)


Cytosolic chloride ion is a key factor in lysosomal acidification and function of autophagy in human gastric cancer cell.

Abstract: The purpose of the present study was to clarify roles of cytosolic chloride ion (Cl(-) ) in regulation of lysosomal acidification [intra-lysosomal pH (pHlys )] and autophagy function in human gastric cancer cell line (MKN28). The MKN28 cells cultured under a low Cl(-) condition elevated pHlys and reduced the intra-lysosomal Cl(-) concentration ([Cl(-) ]lys ) via reduction of cytosolic Cl(-) concentration ([Cl(-) ]c ), showing abnormal accumulation of LC3II and p62 participating in autophagy function (dysfunction of autophagy) accompanied by inhibition of cell proliferation via G0 /G1 arrest without induction of apoptosis. We also studied effects of direct modification of H(+) transport on lysosomal acidification and autophagy. Application of bafilomycin A1 (an inhibitor of V-type H(+) -ATPase) or ethyl isopropyl amiloride [EIPA; an inhibitor of Na(+) /H(+) exchanger (NHE)] elevated pHlys and decreased [Cl(-) ]lys associated with inhibition of cell proliferation via induction of G0 /G1 arrest similar to the culture under a low Cl(-) condition. However, unlike low Cl(-) condition, application of the compound, bafilomycin A1 or EIPA, induced apoptosis associated with increases in caspase 3 and 9 without large reduction in [Cl(-) ]c compared with low Cl(-) condition. These observations suggest that the lowered [Cl(-) ]c primarily causes dysfunction of autophagy without apoptosis via dysfunction of lysosome induced by disturbance of intra-lysosomal acidification. This is the first study showing that cytosolic Cl(-) is a key factor of lysosome acidification and autophagy.

Hosogi|Shigekuni|S| Kusuzaki|Katsuyuki|K| Inui|Toshio|T| Wang|Xiangdong|X| Marunaka|Yoshinori|Y|

chloride ion
lysosome
autophagy
pH
apoptosis


The Enterokine Fibroblast Growth Factor 15/19 in Bile Acid Metabolism.

Abstract: The endocrine fibroblast growth factors (FGFs), FGF19, FGF21, and FGF23, play a key role in whole-body homeostasis. In particular, FGF19 is a postprandial hormone regulating glucose homeostasis, glycogen and protein synthesis, and primary bile acid (BA) metabolism. In the ileum, BA-dependent farnesoid X receptor (FXR) activation induces the production of FGF19, which reaches the liver through the portal system where it represses the expression of CYP7A1, the rate-limiting enzyme of hepatic de novo BAs synthesis. Dysregulation of BA levels associated with alteration in FGF19 level has been depicted in different pathological conditions of the gut-liver axis. Furthermore, FGF19 exploits strong anti-cholestatic and anti-fibrotic activities in the liver. However, native FGF19 seems to retain peculiar hepatic pro-tumorigenic actions. Recently engineered FGF19 analogues have been recently synthetized, with fully retained BA regulatory activity but without intrinsic pro-tumoral action, thus opening bona fide novel pharmacological strategy for the treatment of gut-liver axis diseases.

Cariello|Marica|M|
Piglionica|Marilidia|M|
Gadaleta|Raffaella Maria|RM|
Moschetta|Antonio|A|

Bile acid metabolism
Cholestasis
Fibroblast growth factors 19
Hepatocellular carcinoma


Mycobacterium avium Subspecies paratuberculosis Infection Modifies Gut Microbiota under Different Dietary Conditions in a Rabbit Model.

Abstract: Mycobacterium avium subspecies paratuberculosis (MAP) the causative agent of paratuberculosis, produces a chronic granulomatous inflammation of the gastrointestinal tract of ruminants. It has been recently suggested that MAP infection may be associated with dysbiosis of intestinal microbiota in ruminants. Since diet is one of the key factors affecting the balance of microbial populations in the digestive tract, we intended to evaluate the effect of MAP infection in a rabbit model fed a regular or high fiber diet during challenge. The composition of microbiota of the cecal content and the sacculus rotundus was studied in 20 New Zealand white female rabbits. The extracted DNA was subjected to paired-end Illumina sequencing of the V3-V4 hypervariable region of the 16S rRNA gene for microbiota analysis. Microbial richness (Chao1) in the cecal content was significantly increased by MAP infection in regular diet rabbits (p = 0.0043) and marginally increased (p = 0.0503) in the high fiber group. Analysis of beta-diversity showed that MAP infection produces deeper changes in the microbiota of sacculus rotundus than in the cecal content. A lower abundance of Proteobacteria in the cecal content of infected animals fed the high fiber diet and also lower abundance of Bacteroidetes in the sacculus rotundus of infected animals fed the regular diet were observed. Based on OPLS-DA analysis, we observed that some bacteria repeatedly appear to be positively associated with infection in different samples under different diets (families Dehalobacteriaceae, Coriobacteriaceae, and Mogibacteriaceae; genus Anaerofustis). The same phenomenon was observed with some of the bacteria negatively associated with MAP infection (genera Anaerostipes and Coprobacillus). However, other groups of bacteria (Enterobacteriaceae family and ML615J-28 order) were positively associated with infection in some circumstances and negatively associated with infection in others. Data demonstrate that MAP infection and diet changes do interact and result in shifts in the microbiota of the cecal content and sacculus rotundus of rabbits.

Arrazuria|Rakel|R|
Elguezabal|Natalia|N|
Juste|Ramon A|RA|
Derakhshani|Hooman|H|
Khafipour|Ehsan|E|

Mycobacterium avium subsp. paratuberculosis


Case Report: Rapid Recognition and Immune Modulation of Secondary HLH Due to Disseminated HSV Infection.

Abstract: We describe the case of a newborn who presented with multiple organ dysfunction syndrome (MODS) and hyperferritinemia, who eventually met criteria for hemophagocytic lymphohistiocytosis (HLH) due to disseminated herpes simplex virus 1 (HSV-1). While the cytokine storm abated after administration of multiple immune modulatory therapies including dexamethasone, etoposide, intravenous immune globulin, anakinra, as well as the interferon gamma antagonist emapalumab, multiple organ dysfunction syndrome progressed. Care was withdrawn after 5 days. Subsequent genetic testing did not reveal any mutations associated with familial HLH. This case highlights that even with appropriate antiviral treatment and immune suppression, disseminated HSV is often fatal. Further study is warranted to determine whether early immune modulatory therapy including interferon gamma blockade can interrupt the HLH inflammatory cascade and prevent progression of MODS.

McKeone|Daniel J|DJ|
DeMartini|Theodore K M|TKM|
Kavanagh|Robert P|RP|
Halstead|E Scott|ES|

immune modulation
multiple organ dysfunction syndrome
hemophagocytic lymphohistiocytosis
herpes simplex virus
hyperferritinemic syndrome


Molecular cloning and characterization of TNFSF14 (LIGHT) and its receptor TNFRSF14 (HVEM) in guinea pig (Cavia porcellus).

Abstract: LIGHT (lymphotoxin-related inducible ligand that competes with herpes simplex virus (HSV) glycoprotein D for herpesvirus entry mediator on T cells) is a member of the tumor necrosis factor (TNF) ligand superfamily, which plays important roles in inflammatory and immune responses. In the present study, the cDNAs of guinea pig (Cavia porcellus) LIGHT (designated as gpLIGHT) and its receptor herpes virus entry mediator (designated as gpHVEM) were amplified from spleen by reverse transcription polymerase chain reaction (RT-PCR). The ORFs of gpLIGHT and gpHVEM cover 726 and 861 bp, encoding predicted proteins with 241 and 286 aas, respectively. The three-dimensional (3D) structure, phylogenetic relationships, and characterization of both genes were also analyzed. We also generated a 3D model to verify interaction between the two proteins. Real-time quantitative PCR (qPCR) analysis revealed that both LIGHT and HVEM are constitutively expressed in guinea pig various tissues. A fusion protein SUMO (Small Ubiquitin-like Modifier)-gpsLIGHT (the soluble mature part of gpLIGHT) was efficiently expressed in Escherichia coli BL21 (DE3) and purified using metal chelate affinity chromatography (Ni-NTA). Laser scanning confocal microscopy (LSCM) showed that gpsLIGHT can bind its receptors on T cells. The LIGHT-HVEM signaling pathway plays an important role in the immune system, and our results might provide a platform for further research into the effects of LIGHT and HVEM.

Li|Chunlan|C| Chen|Shanshan|S| Song|Jinyun|J| Liu|Hongyan|H| Gu|Wei|W| Ai|Hongxin|H| Zhao|Bo|B| Zhang|Shuangquan|S|

D053240:Receptors, Tumor Necrosis Factor, Member 14

D053326:Tumor Necrosis Factor Ligand Superfamily Member 14

lymphotoxin homolog, inducible and competes with HSV glycoprotein D for HveA and is expressed on T lymphocytes

sodium dodecyl sulfate-polyacrylamide electrophoresis

P P P P P P P P P P P P P P P P R U M U U R U U U U U U U U U M U U R U U U U M R U U M M M R U U U M M U U U U U U M M M U U U M U U


Prediction of Disease Genes Based on Stage-Specific Gene Regulatory Networks in Breast Cancer.

Abstract: Breast cancer is one of the most common malignant tumors in women, which seriously endangers women's health. Great advances have been made over the last decades, however, most studies predict driver genes of breast cancer using biological experiments and/or computational methods, regardless of stage information. In this study, we propose a computational framework to predict the disease genes of breast cancer based on stage-specific gene regulatory networks. Firstly, we screen out differentially expressed genes and hypomethylated/hypermethylated genes by comparing tumor samples with corresponding normal samples. Secondly, we construct three stage-specific gene regulatory networks by integrating RNA-seq profiles and TF-target pairs, and apply WGCNA to detect modules from these networks. Subsequently, we perform network topological analysis and gene set enrichment analysis. Finally, the key genes of specific modules for each stage are screened as candidate disease genes. We obtain seven stage-specific modules, and identify 20, 12, and 22 key genes for three stages, respectively. Furthermore, 55%, 83%, and 64% of the genes are associated with breast cancer, for example E2F2, E2F8, TPX2, BUB1, and CKAP2L. So it may be of great importance for further verification by cancer experts.

stage-specific gene regulatory networks
breast cancer
differentially expressed genes
WGCNA
DNA methylation


Targeted CGRP Small Molecule Antagonists for Acute Migraine Therapy.

Abstract: Migraine is a highly prevalent, severe, and disabling neurological condition with a significant unmet need for effective acute therapies. Patients (~50%) are dissatisfied with their currently available therapies. Calcitonin gene-related peptide (CGRP) has emerged as a key neuropeptide involved in the pathophysiology of migraines. As reviewed in this manuscript, a number of small molecule antagonists of the CGRP receptor have been developed for migraine therapy. Incredibly, the majority of the clinical trials conducted have proven positive, demonstrating the importance of this signalling pathway in migraine. Unfortunately, a number of these molecules raised liver toxicity concerns when used daily for as little as 7 days resulting in their discontinuation. Despite the clear safety concerns, clinical trial data suggests that their intermittent use remains a viable and safe alternative, with 2 molecules remaining in clinical development (ubrogepant and rimegepant). Further, these proofs of principle studies identifying CGRP as a viable clinical target have led to the development of several CGRP or CGRP receptor-targeted monoclonal antibodies that continue to show good clinical efficacy.

Holland|Philip R|PR|
Goadsby|Peter J|PJ|

D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists

Migraine
Calcitonin gene-related peptide
Neuropeptides
Gepants
Headache


Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer's disease.

Abstract: Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD), increasing risk and decreasing age of disease onset. Many studies have demonstrated the detrimental effects of apoE4 in varying cellular contexts. However, the underlying mechanisms explaining how apoE4 leads to cognitive decline are not fully understood. Recently, the combination of human induced pluripotent stem cell (hiPSC) modeling of neurological diseases in vitro and electrophysiological studies in vivo have begun to unravel the intersection between apoE4, neuronal subtype dysfunction or loss, subsequent network deficits, and eventual cognitive decline. In this review, we provide an overview of the literature describing apoE4's detrimental effects in the central nervous system (CNS), specifically focusing on its contribution to neuronal subtype dysfunction or loss. We focus on γ-aminobutyric acid (GABA)-expressing interneurons in the hippocampus, which are selectively vulnerable to apoE4-mediated neurotoxicity. Additionally, we discuss the importance of the GABAergic inhibitory network to proper cognitive function and how dysfunction of this network manifests in AD. Finally, we examine how apoE4-mediated GABAergic interneuron loss can lead to inhibitory network deficits and how this deficit results in cognitive decline. We propose the following working model: Aging and/or stress induces neuronal expression of apoE. GABAergic interneurons are selectively vulnerable to intracellularly produced apoE4, through a tau dependent mechanism, which leads to their dysfunction and eventual death. In turn, GABAergic interneuron loss causes hyperexcitability and dysregulation of neural networks in the hippocampus and cortex. This dysfunction results in learning, memory, and other cognitive deficits that are the central features of AD.

Najm|Ramsey|R|
Jones|Emily A|EA|
Huang|Yadong|Y|0000-0002-5871-4589

Inhibitory network
Selective vulnerability
GABAergic interneuron
Tau
Hyperexcitability
Alzheimer’s disease
Apolipoprotein E


Understanding the economic impact of intravascular ultrasound (IVUS).

Abstract:
AIMS
To examine the cost-effectiveness of intravascular ultrasound (IVUS) use during percutaneous coronary intervention (PCI) with drug-eluting stents (DES) in treating coronary artery disease (CAD).

METHODS AND RESULTS
A Markov model was constructed with a lifetime horizon to compare costs and health outcomes between IVUS-guided PCI and PCI guided solely by angiography from an Italian healthcare payer perspective. The population examined included CAD patients undergoing PCI with DES. From a healthcare payer perspective, the resulting incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year was negative in the base-case scenario (i.e., IVUS benefit assumed to persist beyond the first year). When IVUS benefit was assumed to be limited to the first year, the ICER increased to €9,624. This conclusion remained consistent even when scenarios varied regarding the duration of the device's effect. Furthermore, benefits of using IVUS were greater for patients with acute coronary syndrome, renal insufficiency, and diabetes.

CONCLUSIONS
Using IVUS with angiography is a dominant strategy in Italy, and results demonstrate that it is desirable to target those at a greater risk of restenosis (i.e., patients with diabetes, chronic kidney disease, and acute coronary syndrome), who tend to benefit more from accurate stent implantation. Further information is necessary regarding the long-term benefits of IVUS, however sensitivity analysis presented in this research demonstrates a strong argument supporting the cost-effectiveness of IVUS.

Alberti|Alessandro|A| Giudice|Pietro|P| Gelera|Alessandra|A| Stefanini|Luca|L| Priest|Virginia|V| Simmonds|Michael|M| Lee|Christa|C| Wasserman|Matthew|M|

Intravascular ultrasound
Percutaneous coronary intervention
Drug-eluting stent
Angiography
Cost-effectiveness analyses
Economic evaluations


Assessing the sustainability of post-Green Revolution cereals in India.

Abstract: Sustainable food systems aim to provide sufficient and nutritious food, while maximizing climate resilience and minimizing resource demands as well as negative environmental impacts. Historical practices, notably the Green Revolution, prioritized the single objective to maximize production over other nutritional and environmental dimensions. We quantitatively assess outcomes of alternative production decisions across multiple objectives using India's rice-dominated monsoon cereal production as an example. We perform a series of optimizations to maximize nutrient production (i.e., protein and iron), minimize greenhouse gas (GHG) emissions and resource use (i.e., water and energy), or maximize resilience to climate extremes. We find that increasing the area under coarse cereals (i.e., millets, sorghum) improves nutritional supply (on average, +1% to +5% protein and +5% to +49% iron), increases climate resilience (1% to 13% fewer calories lost during an extreme dry year), and reduces GHGs (-2% to -13%) and demand for irrigation water (-3% to -21%) and energy (-2% to -12%) while maintaining calorie production and cropped area. The extent of these benefits partly depends on the feasibility of switching cropped area from rice to coarse cereals. Based on current production practices in 2 states, supporting these cobenefits could require greater manure and draft power but similar or less labor, fertilizer, and machinery. National- and state-level strategies considering multiple objectives in decisions about cereal production can move beyond many shortcomings of the Green Revolution while reinforcing the benefits. This ability to realistically incorporate multiple dimensions into intervention planning and implementation is the crux of sustainable food production systems worldwide.

cereals
India
Green Revolution
sustainable agriculture
tradeoffs


Videos, Views, and Vaccines: Evaluating the Quality of COVID-19 Communications on YouTube.

Abstract:
OBJECTIVES
As the coronavirus disease 2019 (COVID-19) vaccine is introduced, it is critical to recognize that public opinion on vaccines is largely influenced by health communications, with YouTube being a major source of information and misinformation. This analysis graded the accuracy, quality, and reliability of the most viewed YouTube videos depicting COVID-19 and vaccinations over a 6-mo period.

METHODS
We collected hyperlinks for the 150 most viewed YouTube videos discussing COVID-19 from January through June 2020. Closed captioning data were searched for the term "vaccine," yielding 32 videos. This sample was evaluated for quality, accuracy, and reliability using a rubric that incorporated existing instruments: Global Quality Scale (GQS), JAMA Benchmark Criteria, and DISCERN.

RESULTS
These 32 videos had 139,764,188 views at the time of data collection. The majority of videos received low scores, with network news sources receiving the lowest scores overall.

CONCLUSIONS
The overall quality of COVID-19 YouTube videos related to vaccines may be low and raises a precautionary alert for the public consuming these videos and for health-care providers working to provide the best information to their patients. Existing scoring tools may not capture the complexities of social media. New tools could allow for a better understanding of the modern landscape of health communications.

Marwah|Harleen K|HK|
Carlson|Kyle|K|
Rosseau|Natalie A|NA|
Chretien|Katherine C|KC|
Kind|Terry|T|
Jackson|Hope T|HT|

vaccinations
quality
COVID-19
YouTube
social media


Costs of outpatient and inpatient MRSA screening and treatment strategies for patients at elective hospital admission - a decision tree analysis.

Abstract:
Background
Nosocomial infections are among the most common complications in hospitals. A major part is caused by multidrug-resistant organisms (MDRO). MRSA is still the most prominent and frequent MDRO. The early detection of carriers of multidrug-resistant bacteria is an effective measure to reduce nosocomial infections caused by MDRO. For patients who are planning to go to the hospital, an outpatient screening for MDRO and pre-hospital decolonization is recommended. However, the effectiveness of such pre-admission MDRO management in preparation for a planned hospital stay has not yet been sufficiently scientifically examined from an economic perspective.

Methods
A decision tree will be used to develop scenarios for MDRO screening and treatment in the context of the outpatient and inpatient sectors using MRSA-positive patients as an example. Subsequently, the expected costs for the respective strategy are presented.

Results
The decision tree analysis shows that the expected costs of outpatient MRSA management are €8.24 and that of inpatient MRSA management are €672.51.

Conclusion
The forward displacement of the MRSA screening to the ambulatory sector and any subsequent outpatient decolonization for patients with a planned hospitalization is the most cost-effective strategy and should become a standard benefit. Excluding opportunity costs, the expected costs of inpatient MRSA management are €54.94.

D024901:Drug Resistance, Multiple, Bacterial


Microbial cellulose dressing compared with silver sulphadiazine for the treatment of partial thickness burns: A prospective, randomised, clinical trial.

Abstract:
BACKGROUND
The current treatment for partial thickness burns at the trial site is silver sulphadiazine, as it minimises bacterial colonisation of wounds. Its deleterious effect on wound healing, together with the need for repeated, often painful, procedures, has brought about the search for a better treatment. Microbial cellulose has shown promising results that avoid these disadvantages. The aim of this study was therefore to compare microbial cellulose with silver sulphadiazine as a dressing for partial thickness burns.

METHOD
All patients who presented with partial thickness (superficial and deep dermal) burns from October 2014 to October 2016 were screened for this randomised clinical trial. Twenty patients were included in each group: the cellulose group was treated with microbial cellulose sheets and the control group with silver sulphadiazine cream 10mg/g. The wound was evaluated every third day. Pain was assessed using the Face, Legs, Activity, Cry, Consolability (FLACC) scale during and after each procedure. Other variables recorded were age, sex, percentage total body surface area burned (TBSA%), clinical signs of infection, time for epithelialisation and hospital stay. Linear multivariable regression was used to analyse the significance of differences between the treatment groups by adjusting for the size and depth of the burn, and the patient's age.

RESULTS
Median TBSA% was 9% (IQR 5.5-12.5). The median number of dressing changes was 1 (IQR 1-2) in the cellulose group, which was lower than that in the control group (median 9.5, IQR 6-16) (p<0.001). Multivariable regression analysis showed that the group treated with microbial cellulose spent 6.3 (95% CI 0.2-12.5) fewer days in hospital (p=0.04), had a mean score that was 3.4 (95% CI 2.5-4.3) points lower during wound care (p<0.001), and 2.2 (95% CI 1.6-2.7) afterwards (p<0.001). Epithelialisation was quicker, but not significantly so.

CONCLUSION
These results suggest that the microbial cellulose dressing is a better first choice for treatment of partial thickness burns than silver sulphadiazine cream. Fewer dressings of the wound were done and, combined with the low pain scores, this is good for both the patients and the health care system. The differences in randomisation of the area of burns is, however, a concern that needs to be included in the interpretation of the results.

Aboelnaga|Ahmed|A|
Elmasry|Moustafa|M|
Adly|Osama A|OA|
Elbadawy|Mohamed A|MA|
Abbas|Ashraf H|AH|
Abdelrahman|Islam|I|
Salah|Omar|O|
Steinvall|Ingrid|I|

Cellulose
Burn
Pain
Time for epithelialisation
Wound dressing


Functional reconstruction of acutely burnt achilles tendon with composite anterolateral thigh flap with fascia lata: a case report.

Abstract: Soft tissue defects in the postero-inferior aspect of the leg are still challenging, especially when they affect the Achilles tendon due to its important functional involvement in the normal movement of the ankle. Dorsiflexion and flexion may be affected if proper reconstruction is not achieved, thus limiting daily activities such as walking, climbing stairs or running. Several techniques, including local or regional flaps, combinations of tendon substitutes with free muscular or fasciocutaneous flaps, and free composite flaps with tendon have been described for the reconstruction of complex defects caused by burn sequelae, tumors, trauma, chronic ulcers, etc. The gold standard treatment for moderate to large defects is the anterolateral thigh (ALT) flap with vascularized fascia lata. The ALT flap is reliable because of a long vascular pedicle and a large donor area. Moreover, the fascia lata mimics the Achilles tendon perfectly when rolled on itself. The aim of this article is to present the application of this technique for the first time in a case of an acute burn. The timing of reconstruction with free flaps is critical in acute burns. In our case, it was performed on the 24th day post-burn and no microsurgical complications appeared. More than six months after surgery, the patient showed a normal gait, was able to lift his own weight against gravity and no complications were detected in the donor area.

Andreu-Sola|V|V|
Aguilera-Sáez|J|J|
Rivas-Nicolls|D|D|
Bosacoma Roura|P|P|
Barret|J P|JP|

Achilles tendon
anterolateral thigh flap
fascia lata
acute burn


Comparison of segmentation and identification of swietenia mahagoni wood defects with augmentation images.

Abstract: The largest income for Southeast Asian countries comes from the export activities of wood production. The potential for timber exports in Indonesia continues to increase each year. This soaring potential needs to be continually improved by maintaining quality so that trust and good cooperation can continue to be established with partner countries. Wood quality is closely related to wood defects. The faster the detection of wood defects is, the faster the quality of the wood will be determined. The wood industry which is still manual is also very susceptible to human eye fatigue. Technology is currently developing rapidly to help human productive activities and image processing is a breakthrough to detect wood defects. This study aims to identify swietenia mahagoni wood defects using the euclidean distance method from the extraction of 6 texture and shape features GLCM (Gray Level Co-Occurance Method) including metric, eccentricity, contrast, correlation, energy, and homogeneity, which was previously segmented with the best segmentation from the comparison results of thresholding and k-means segmentation and produced an average accuracy of 95.33% with an F1 score value of 0.95. The dataset used is the primary dataset with a total of 54 images on 3 types of wood defects, namely growing skin defects on wood ends, rotten wood eye on the body, and healthy wood eye on the body. Cross validation is also applied to test the reliability of the proposed model. By using 3-fold cross validation, the optimal average accuracy is 88.90%. Validation with other similar datasets was also carried out by identifying potato leaf defects resulting in an average accuracy of 92.86% with the most optimal 3-fold cross validation value achieved an average accuracy of 83.33%. Image augmentation is also carried out in order to reproduce the image so that the reliability test of the proposed method can be carried out, namely by rotating the image 45 degrees,90 degrees,120 degrees,180 degrees which produces 84 images of augmentation, so that the total image is 138 images and gets an average accuracy from the image augmentation is 80%.

Riana|Dwiza|D| Rahayu|Sri|S| Hasan|Muhamad|M| Anton|||

Swietenia mahagoni
Wood defects
Euclidean distance
GLCM
Thresholding
K-means


Circumscribed plantar hypokeratosis responding to topical calcipotriol.

Abstract:
BACKGROUND
Circumscribed palmar or plantar hypokeratosis defines a benign condition clinically presented as a well-defined depressed area on the skin. It is characterized by a peculiar histopathological picture with the abrupt thinning of the horny layer of the epidermis.

MAIN OBSERVATIONS
We present a case of a 17-year-old man, who presented with a one-year history of an occasionally painful lesion on his right sole. The diagnosis of circumscribed plantar hypokeratosis was confirmed by histopathology. The lesion was successfully treated with calcipotriol ointment.

CONCLUSIONS
Circumscribed palmar or plantar hypokeratosis is a benign condition that typically affects the hands. Different therapeutic approaches have been unsuccessful. In our patient the lesion was at a less frequent plantar location and the lesion responded to topical calcipotriol.

plantar hypokeratosis palmar atrophy hyperkeratosis keratin


Long-term Response to First-line Pazopanib Therapy in mRCC Patients: A Multicenter Italian Experience.

Abstract:
BACKGROUND/AIM
The specific characteristics of patients who are most likely to benefit from pazopanib therapy are still uncertain. We report on the results of an Italian multicenter, retrospective analysis investigating the factors associated with longer response to first-line pazopanib in patients with metastatic renal cell carcinoma.

PATIENTS AND METHODS
Adult patients were considered if they had received treatment with pazopanib (800 mg/day) for >12 months in the first-line setting.

RESULTS
In total, 112 patients were evaluated. Median duration of pazopanib treatment was 22.6 months (IQR 17.8 months). Median PFS was 22.6 months (95%CI= 20.2-25.0). Eighty-three patients (74.1%) had a PFS ≥18 months. Median OS was 32.9 months (95%CI=30.2-35.6). At statistical analysis, only PS score (1+ vs. 0) was significantly associated with PFS (HR=1.76; 95%CI=1.02-3.05; p=0.04).

CONCLUSION
Pazopanib therapy may be suitable for all patients with mRCC, and especially in those with PS 0.

Sbrana|Andrea|A|
Biasco|Elisa|E|
Paolieri|Federico|F|
Palesandro|Erica|E|
Caserta|Claudia|C|
Iacovelli|Roberto|R|
Detti|Beatrice|B|
Santini|Daniele|D|
Mosca|Alessandra|A|
Morelli|Franco|F|
Fornarini|Giuseppe|G|
De Giorgi|Ugo|U|
Masini|Cristina|C|
Galli|Luca|L|

D040262:Receptors, Vascular Endothelial Growth Factor


Comparison of the effect of multicomponent and resistance training programs on metabolic health parameters in the elderly.

Abstract:
UNLABELLED
Physical activity interventions such as resistance training (RT) and multicomponent (MCT) exercise training are known to improve functional mobility and reduce the risk of disability among the elderly. Less evidence exists regarding the effectiveness of such exercises to improve metabolic risk factors for age related conditions. This study aimed to compare the effects of MCT and RT programs on metabolic health parameters in healthy elderly.

METHODS
Twenty one and 18 subjects completed a 12-week MCT and RT program respectively. Before and after intervention, body composition, functional ability, aerobic fitness and metabolic health parameters including lipid profile, inflammatory markers, glucose metabolism, hormones and growth markers were examined. Circulating concentrations of epidermal growth factor increased significantly in the MCT group from 35.8 ± 29.4 to 56.1 ± 35 pg/ml. High molecular weight adiponectin decreased significantly in the RT group from 4.7 ± 2.9 to 4.2 ± 2.3 μg/ml (p=0.03). No other biochemical parameter was significantly altered within either group. A significant between group difference was found for both ferritin (p=0.02) and EGF (p=0.01), with concentrations of ferritin decreasing in the MCT group and increasing in the RT group and concentration of EGF increasing in the MCT group yet decreasing in the RT group. The MCT program improved results of functional tests including chair stand and habitual walking speed. Present findings suggest that although both the MCT and RT interventions were enough to produce functional and physical benefits, different training programs and/or exercise dose are required to improve metabolic health in healthy older adults.

Leite|Joao Costa|JC|
Forte|Roberta|R|
de Vito|Giuseppe|G|
Boreham|Colin A G|CA|
Gibney|Michael J|MJ|
Brennan|Lorraine|L|
Gibney|Eileen R|ER|

Resistance training
Metabolic health
Elderly
Healthy aging
Multicomponent training


CXCR5+ CD8 T Cells: Protective or Pathogenic?

Abstract: CD8 T cells are infrequently considered part of germinal center reactions. Yet, a distinct CXCR5+ CD8 T cell subset identified within the B cell follicle and germinal center in situations of chronic antigen has recently been defined. CXCR5+ CD8 T cells maintain transcriptional and phenotypic features consistent with the CD8 T cell nomenclature of a non-exhausted, effector memory population. CD8 T cell localization to the B cell follicle suggests a functional profile similar to CD4 T follicular helper cells that are licensed to promote B cell responses. The functional mechanisms defined under different immune settings, while largely similar, differentially control disease pathogenesis. CXCR5+ CD8 T cells control viral load during infection, and also promote antibody-mediated autoimmune disease progression. The existence of this novel CXCR5+ CD8 T cell subset in human and murine models of disease may provide a paradigm shift in our understanding of germinal center reactions.

Valentine|Kristen M|KM|
Hoyer|Katrina K|KK|

CD8 T cells
germinal center
B cell follicle
autoimmune disease
cancer
chronic viral infection


Molecular Targeting of VEGF with a Suramin Fragment-DOCA Conjugate by Mimicking the Action of Low Molecular Weight Heparins.

Abstract: Molecular targeting of growth factors has shown great therapeutic potential in pharmaceutical research due to their roles in pathological conditions. In the present study, we developed a novel suramin fragment and deoxycholic acid conjugate (SFD) that exhibited the potential to bind to the heparin-binding site (HBD) of vascular endothelial growth factor (VEGF) and to inhibit its pathogenic action for the first time. Notably, SFD was optimally designed for binding to the HBD of VEGF using the naphthalenetrisulfonate group, allowing to observe its excellent binding efficacy in a surface plasmon resonance (SPR) study, showing remarkable binding affinity (KD = 3.8 nM) as a small molecule inhibitor. In the tubular formation assay, it was observed that SFD could bind to HBD and exhibit antiangiogenic efficacy by inhibiting VEGF, such as heparins. The cellular treatment of SFD resulted in VEGF-inhibitory effects in human umbilical vein endothelial cells (HUVECs). Therefore, we propose that SFD can be employed as a novel drug candidate to inhibit the pathophysiological action of VEGF in diseases. Consequently, SFD, which has a molecular structure optimized for binding to HBD, is put forward as a new chemical VEGF inhibitor.

Park|Jooho|J| Kang|Tae-Bong|TB|0000-0003-1441-9470 Lim|Ji-Hong|JH| Won|Hyung-Sik|HS|

D061307:Human Umbilical Vein Endothelial Cells

D042461:Vascular Endothelial Growth Factor A

molecular targeting
VEGF
suramin
heparin
drug development


Anterior Gradient Protein 3 and S100 Calcium-Binding Protein P Levels in Different Endometrial Epithelial Compartments May Play an Important Role in Recurrent Pregnancy Failure.

Abstract: Recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) are distressing conditions without effective treatments. The luminal epithelium (LE) is integral in determining receptivity of the endometrium, whereas functionalis glands and stroma aid in nurturing early embryo development. Calcium signalling pathways are known to be of vital importance to embryo implantation and pregnancy establishment, and anterior gradient protein 3 (AGR3) and S100 calcium-binding protein P (S100P) are involved with these pathways. We initially examined 20 full-thickness endometrial biopsies from premenopausal women across the menstrual cycle to characterize levels of AGR3 protein in each endometrial sub-region at the cellular level. A further 53 endometrial pipelle biopsies collected in the window of implantation were subsequently assessed to determine differential endometrial AGR3 and S100P levels relevant to RIF (n = 13) and RPL (n = 10) in comparison with parous women (n = 30) using immunohistochemistry. Significantly higher AGR3 and S100P immunostaining was observed in ciliated cells of the LE of women with recurrent reproductive failure compared with parous women, suggesting aberrant subcellular location-associated pathophysiology for these conditions. The nuclear localisation of S100P may allow transcriptional regulatory function, which is necessary for implantation of a viable pregnancy. Further work is thus warranted to assess their utility as diagnostic/therapeutic targets.


Microbial P450 Enzymes in Bioremediation and Drug Discovery: Emerging Potentials and Challenges.

Abstract: Cytochrome P450 enzymes are a structurally conserved but functionally diverse group of heme-containing mixed function oxidases found across both prokaryotic and eukaryotic forms of the microbial world. Microbial P450s are known to perform diverse functions ranging from the synthesis of cell wall components to xenobiotic/drug metabolism to biodegradation of environmental chemicals. Conventionally, many microbial systems have been reported to mimic mammalian P450-like activation of drugs and were proposed as the in-vitro models of mammalian drug metabolism. Recent reports suggest that native or engineered forms of specific microbial P450s from these and other microbial systems could be employed for desired specific biotransformation reactions toward natural and synthetic (drug) compounds underscoring their emerging potential in drug improvement and discovery. On the other hand, microorganisms particularly fungi and actinomycetes have been shown to possess catabolic P450s with unusual potential to degrade toxic environmental chemicals including persistent organic pollutants (POPs). Wood-rotting basidiomycete fungi in particular have revealed the presence of exceptionally large P450 repertoire (P450ome) in their genomes, majority of which are however orphan (with no known function). Our pre- and post-genomic studies have led to functional characterization of several fungal P450s inducible in response to exposure to several environmental toxicants and demonstration of their potential in bioremediation of these chemicals. This review is an attempt to summarize the postgenomic unveiling of this versatile enzyme superfamily in microbial systems and investigation of their potential to synthesize new drugs and degrade persistent pollutants, among other biotechnological applications.

Bhattacharya|Sukanta S|SS|
Yadav|Jagjit S|JS|

bioremediation
drug discovery
Cytochrome P450
xenobiotics
drug metabolism
hydroxylation.
motifs


Can Repeat Biopsies Change the Prognoses of AUS/FLUS Nodule?

Abstract:
Objective
Experience with atypia of undetermined signiﬁcance/follicular lesions of undetermined significance (AUS/FLUS) showed that this category exhibited a marked variability in incidence and malignant outcome in resection specimens. We aimed to determine the utility of repeated fine-needle aspiration biopsies (FNABs) and ultrasonography to determine the malignancy rate in AUS/FLUS nodules.

Methods
23,587 nodules were biopsied, and 1,288 had at least one AUS/FLUS cytology. Ultrasonographic features including solid hypoechoic status, irregular margins, microcalcifications, nodule taller than wider, or an extrathyroidal extension were also recorded. Nodules for which only 1 FNAB revealed AUS/FLUS cytology were termed Group 1; nodules that underwent 2, 3, and 4 FNABs were termed Groups 2, 3 and 4, respectively. We compared these groups according to malignancy rates.

Results
576 of nodules underwent only 1 FNAB (Group 1); 505, 174, and 33 underwent 2 (Group 2), 3 (Group 3), and 4 FNABs (Group 4), respectively. Fifty-six (30.6%), 45 (27.3%), 18 (30%), and 5 (33.3%) of Groups 1-4 were malignant, respectively. The risk of malignancy was similar in each group (p > 0.05). Suspicious ultrasonographic features were encountered in malignant nodules more than benign nodules (p < 0.05, for each).

Conclusion
Repeat biopsy of AUS/FLUS nodules did not enhance the identification of malignancy. Ultrasonographic features may be a better guide for the decision of either surveillance or diagnostic surgery.

Evranos Ogmen|Berna|B|
Aydin|Cevdet|C|
Kilinc|Ibrahim|I|
Aksoy Altinboga|Aysegul|A|
Ersoy|Reyhan|R|
Cakir|Bekir|B|

Atypia of undetermined signiﬁcance/follicular lesions of undetermined significance nodules


Breast surgery under local anesthesia: second-stage implant exchange, nipple flap reconstruction, and breast augmentation.

Abstract: Breast reconstruction can be performed safely with local anesthesia. Utilization of the star flap method in conjunction with tattooing successfully provides optimal aesthetic results without the need for an additional donor site. When tissue expander to silicon implant exchange is part of the operative plan, use of triple antibiotic irrigation as well as the Keller Funnel is recommended. Breast augmentation and breast augmentation-mastopexy can also be performed with good results under local anesthetic in a private operating room setting. All other operative conditions, including sterility and sound operative surgical techniques, should be the mainstay of any practice.

Koumanis|Dimitri J|DJ|
Colque|Alex|A|
Eisemann|Michael L|ML|
Smith|Jenna|J|

Local anesthesia
Implant exchange
Nipple
Breast reconstruction
Star flap
Areola
Nipple-areola complex (NAC)
Silicon breast implant


"Won't You Be My Doctor?": Four Keys to a Satisfying Relationship in an Increasingly Virtual World.

Abstract: Despite rapid technological advances in healthcare, medicine is still largely practiced in a doctor's office one conversation at a time. This reality is changing rapidly during the COVID-19 pandemic as face-to-face conversations with primary care practitioners are being replaced by virtual visits conducted by phone or video conferencing. Communication challenges in patient-practitioner relationships exist in face-to-face visits and they are accentuated in virtual ones. Absent a physical examination and other sensory data, conversation is the primary means by which safe, satisfying care depends. We present 4 steps to help patients and practitioners work together to obtain optimal results from virtual or face-to-face visits, summarized by the acronym PREP: Prepare, Rehearse, Engage, and Persist. Based on 80 years of combined clinical practice and research, we recommend strategies to help bridge the gap between what patients want and deserve in their medical visits and practitioners' understanding of their patients' concerns.

communication
health information technology
patient engagement
patient/doctor relationship
patient/relationship centered skills


Assessing mobile food vendors (a.k.a. street food vendors)--methods, challenges, and lessons learned for future food-environment research.

Abstract:
OBJECTIVES
Mobile food vendors (also known as street food vendors) may be important sources of food, particularly in minority and low-income communities. Unfortunately, there are no good data sources on where, when, or what vendors sell. The lack of a published assessment method may contribute to the relative exclusion of mobile food vendors from existing food-environment research. A goal of this study was to develop, pilot, and refine a method to assess mobile food vendors.

STUDY DESIGN
Cross-sectional assessment of mobile food vendors through direct observations and brief interviews.

METHODS
Using printed maps, investigators canvassed all streets in Bronx County, NY (excluding highways but including entrance and exit ramps) in 2010, looking for mobile food vendors. For each vendor identified, researchers recorded a unique identifier, the vendor's location, and direct observations. Investigators also recorded vendors answers to where, when, and what they sold.

RESULTS
Of 372 identified vendors, 38% did not answer brief-interview questions (19% were 'in transit', 15% refused; others were absent from their carts/trucks/stands or with customers). About 7% of vendors who ultimately answered questions were reluctant to engage with researchers. Some vendors expressed concerns about regulatory authority; only 34% of vendors had visible permits or licenses and many vendors had improvised illegitimate-appearing set-ups. The majority of vendors (75% of those responding) felt most comfortable speaking Spanish; 5% preferred other non-English languages. Nearly a third of vendors changed selling locations (streets, neighbourhoods, boroughs) day-to-day or even within a given day. There was considerable variability in times (hours, days, months) in which vendors reported doing business; for 86% of vendors, weather was a deciding factor.

CONCLUSIONS
Mobile food vendors have a variable and fluid presence in an urban environment. Variability in hours and locations, having most comfort with languages other than English, and reluctance to interact with individuals gathering data are principal challenges to assessment. Strategies to address assessment challenges that emerged form this project may help make mobile-vendor assessments more routine in food-environment research.

Lucan|S C|SC|
Varona|M|M|
Maroko|A R|AR|
Bumol|J|J|
Torrens|L|L|
Wylie-Rosett|J|J|

Mobile food vendors/Street vendors/Street foods/Food carts


Pazopanib efficacy in recurrent central nervous system hemangiopericytomas.

Abstract:
INTRODUCTION
There is currently no treatment for solitary fibrous tumors/hemangiopericytomas (SFT/H) of the central nervous system recurring after multiple surgeries and radiotherapies. The NAB2-STAT6 gene fusion is the hallmark of these tumors, and upregulates Early Growth Factor, activating several growth pathways.

METHODS
We treated two patients presenting pluri-recurrent meningeal SFT/H with Pazopanib, a broad-spectrum tyrosine kinase inhibitor. We analyzed the exome and RNA sequencing data of one of them and, in addition to another meningeal SFT/H, compared it to the transcriptomic profiling of 5 systemic SFT/H.

RESULTS
A dramatic clinical and radiological response was observed in both cases, respectively 84 and 43% decrease after 3 months. As a comparison, Pazopanib has only a stabilizing effect in systemic SFT/H. Indeed, central nervous system SFT/H show overexpression of different tyrosine kinases targeted by Pazopanib.

CONCLUSIONS
Two consecutive patients with untreatable central nervous system SFT/H showed a spectacular partial response to Pazopanib, an unprecedented result in SFT/H. This result could be explained by differences in expression profiles and calls for a confirmation in a larger cohort of patients.

D016543:Central Nervous System Neoplasms

Pazopanib
Hemangiopericytoma
Solitary fibrous tumor
Fusion gene
NAB2
STA6


Comparison of the clinical performances of Air-Qsp and i-Gel for airway management under general anesthesia with a muscle relaxant.

Abstract:
STUDY OBJECTIVES
Recently, i-Gel intubating laryngeal airway (ILA) has been frequently used because of the ease for airway insertion by residents and young anesthesiologists. However, it sometimes fails to fit or ventilate sufficiently in Japanese patients. Use of Air-Qsp, which is a new non-inflatable cuffed ILA, in a clinical setting has become possible. The purpose of this study was to compare the clinical performance of Air-Qsp with that of i-Gel for airway management in Japanese adult patients.

DESIGN
A randomized, single-blinded, prospective study was conducted after approval from the institutional review board.

SETTING
Operating rooms at hospitals.

PATIENTS
Thirty-seven adult patients aged 20 to 69 years, with ASA physical status I or II, and scheduled for elective surgery under general anesthesia in the supine position.

INTERVENTIONS
Patients were randomly assigned to insertion with Air-Qsp (Group A: n=20) or i-Gel (Group I: n=17).

MEASUREMENTS
The number of insertions, duration of insertion, changes in systolic blood pressure and heart rate during insertion, delivered tidal volume for setting volume control ventilation, distribution of the tips of the bronchofiberscopes (BFs) on a clock face, and the number of postoperative complications was evaluated.

MAIN RESULTS
Two patients in Group A and one patient in Group I were excluded because insertion of the device failed. There were no significant differences in measured parameters between the 2 groups. The distribution of the tips of the bronchofiberscopes tended to be around the center of the glottis in Group A, whereas they were more toward the 6-o'clock position in Group I.

CONCLUSIONS
Air-Qsp is as useful as i-Gel in Japanese patients and the distributions of the tips of BFs through ILAs are different for Air-Qsp and i-Gel.

Watanabe|Asako|A| Edanaga|Mitsutaka|M| Ichinose|Hiromichi|H| Yamakage|Michiaki|M|

Non-inflatable cuffed intubating laryngeal airway


Metals in Spine.

Abstract: The treatment of spinal disorders requires the consideration of a number of factors and understanding the type of material we are implanting is important. Alloys have different mechanical properties and behave differently under different physiologic conditions. Spinal implants need to have good performance in the characteristics of biofunctionality and biocompatibility. In this review, the alloys titanium, cobalt-chrome, nitinol, and tantalum will be examined closely. Several of the important properties that are considered when selecting an alloy for use in spinal instrumentation are explored and detailed for each. This allows for an assessment and comparison of each alloy and a possible determination of which is the best alloy for specific surgery or the best alloy for use in specific situations.

Tahal|Dimitri|D|
Madhavan|Karthik|K|
Chieng|Lee Onn|LO|
Ghobrial|George M|GM|
Wang|Michael Y|MY|

Metals
Alloys
Metal implant
Spine surgery


Tailoring the supramolecular structure of aminated polyrotaxanes toward enhanced cellular internalization.

Abstract: The effects of the supramolecular polyrotaxane (PRX) structure on cellular internalization are investigated by flow cytometry and confocal laser scanning microscopy. AF-545-labeled aminated PRXs (APRXs) containing different numbers of threaded α-cyclodextrins (CDs) and amino groups are synthesized; their cellular uptakes are analyzed using HeLa cells in serum. The APRX threaded CD number is discovered to be a more critical factor for enhancing cellular internalization than the APRX amine content. Additionally, APRXs are demonstrated to be more easily internalized than conventional linear cationic macromolecules. Because increased numbers of threaded CDs are related to increased PRX rigidity, the PRX rigid frame resulting from CD molecules threaded on a poly(ethylene glycol) (PEG) chain is suitable for intracellular tools in therapy and diagnosis.

Yokoyama|Nanako|N| Seo|Ji-Hun|JH| Tamura|Atsushi|A| Sasaki|Yoshihiro|Y| Yui|Nobuhiko|N|

supramolecular structures
polyrotaxane
cellular internalization
cyclodextrin
electrostatic interaction


The future of French museums in 2030.

Abstract: The purpose of this article is to describe the possible futures of French museums up to 2030. To do this we rely on a Delphi study that took place between late 2017 and early 2018 with 99 experts from the field. We propose three scenarios. The first aims to create museums centered around youth and to democratize culture. The second corresponds to the reaction of museums facing a decrease in public funding. The third is a breakdown scenario, where museums undergo evolutions. In this latter scenario, a direct participation of nearby stakeholders is observed, unlike the other two scenarios.

Museum
Delphi
Scenario
Culture
Foresight
France, Creative industries


Trehalose as an alternative to glycerol as a glassing agent for in vivo DNP MRI.

Abstract:
PURPOSE
In dynamic nuclear polarization (DNP), the solution needs to form a glass to attain significant levels of polarization in reasonable time periods. Molecules that do not form glasses by themselves are often mixed with glass forming excipients. Although glassing agents are often essential in DNP studies, they have the potential to perturb the metabolic measurements that are being studied. Glycerol, the glassing agent of choice for in vivo DNP studies, is effective in reducing ice crystal formation during freezing, but is rapidly metabolized, potentially altering the redox and adenosine triphosphate balance of the system.

METHODS
DNP buildup curves of 13 C urea and alanine with OX063 in the presence of trehalose, glycerol, and other polyol excipients were measured as a function of concentration. T1 and Tm relaxation times for OX063 in the presence of trehalose were measured by EPR.

RESULTS
Approximately 15-20 wt% trehalose gives a glass that polarizes samples more rapidly than the commonly used 60%-wt formulation of glycerol and yields similar polarization levels within clinically relevant timeframes.

CONCLUSIONS
Trehalose may be an attractive biologically inert alternative to glycerol for situations where there may be concerns about glycerol's glucogenic potential and possible alteration of the adenosine triphosphate/adenosine diphosphate and redox balance.

glassing
dynamic nuclear polarization
OX063
relaxation
EPR


Negative affectivity and EEG asymmetry interact to predict emotional interference on attention in early school-aged children.

Abstract: Negative affectivity (NA) is a broad construct that has been associated with the development of psychopathologies, such as anxiety, and with exaggerated attention to threatening stimuli. EEG asymmetry reflects biological individual differences in emotional reactivity that may underlie the association between NA and attention to threat. The present study included a sample of 31 five-seven year olds (M age in months=74.39, SD=6.57) to test the hypothesis that greater NA, combined with greater right anterior and posterior asymmetries, predicts increased attention interference following threat stimuli. Children completed an executive attention task which presented task-irrelevant threat (angry) and non-threat (neutral) faces prior to each trial. EEG asymmetry was measured at baseline for anterior, anterior-temporal and posterior scalp regions and child NA was measured via maternal report. As predicted, children showing greater NA and greater right anterior-temporal asymmetry showed more attention interference following angry faces. Additionally, two trend-level effects emerged: children showing greater NA and greater left anterior-temporal asymmetry showed less attention interference following angry faces, and children showing greater NA and greater left posterior asymmetry showed less attention interference, but only following neutral faces. Discussion focuses on the utility of using EEG asymmetry in the study of temperament, attentional biases, and the biological processes by which temperament confers risk for psychopathology.

Solomon|Beylul|B|
O'Toole|Laura|L|
Hong|Melanie|M|
Dennis|Tracy A|TA|

Negative affectivity
EEG asymmetry
Emotion
Attention
Children


Structural characterization and antidiabetic potential of a novel heteropolysaccharide from Grifola frondosa via IRS1/PI3K-JNK signaling pathways.

Abstract: A novel heteropolysaccharide from Grifola frondosa named GFP-W has been isolated and purified by DEAE Sephadex A-52 chromatography. Gas chromatography, fourier transform infrared spectroscopy, one-dimensional (1H- and 13C-) and two-dimensional (1H-1H COSY, 1H-13C HSQC, and 1H-13C HMBC) nuclear magnetic resonance spectroscopy were used to characterize its structure. The average molecular weight of GFP-W was 66.1 kDa. GFP-W mainly contained four kinds of linkage type units as β-D-GlcpA→, 1,2,6-α-Gal, →2)-α-Manp→, and →3)-α-L-Fucp-(1→. It could significantly increase the uptake of glucose in dexamethasone induced insulin resistant HepG2 cells by improving the mRNA and protein expression of insulin receptor substrate 1, phosphatidylinositol-3-kinase, and glucose transporter 4 upregulation and c-Jun N-terminal Kinase 1 downregulation. Moreover, antidiabetic activities of GFP-W were associated with significant changes in the extent of protein lysine acetylation, crotonylation, and succinylation levels. Our results provide a new hypoglycemic therapeutic role and an in-depth analysis on molecular mechanisms upon polysaccharides from G. frondosa.

Chen|Yuqing|Y|
Liu|Yuanyuan|Y|
Sarker|Md Moklesur Rahman|MMR|
Yan|Xin|X|
Yang|Chengfeng|C|
Zhao|Lina|L|
Lv|Xucong|X|
Liu|Bin|B|
Zhao|Chao|C|

D055504:Insulin Receptor Substrate Proteins

D048055:Mitogen-Activated Protein Kinase 8

Structural characterization
Antidiabetic
Grifola frondosa polysaccharide
Insulin signaling pathway
Protein lysine modification


Antifungal Susceptibility Patterns of Vulvovaginal Candida species among Women Attending Antenatal Clinic at Mbarara Regional Referral Hospital, South Western Uganda.

Abstract:
AIMS
To identify the Candida species that cause vulvovaginal candidiasis and determine their antifungal susceptibility patterns.

STUDY DESIGN
This was a cross-sectional study.

PLACE AND DURATION OF STUDY
The study was conducted at the antenatal clinic of Mbarara Regional Referral Hospital in Mbarara Municipality, between December 2012 and February 2013.

METHODS
High vaginal swabs from 456 pregnant women were subjected to microscopy and culture on Sabouraud Dextrose Agar. Candida isolates were identified by the germ tube and Analytical profile index (API® Candida) tests. Susceptibility to fluconazole, itraconazole and voriconazole was determined by the Etest strips and for clotrimazole and nystatin by the disc diffusion method on Mueller Hinton agar supplemented with 2%w/v glucose and 0.5μg/ml methylene blue dye.

RESULTS
Of the 456 High vaginal swabs cultured, 207 grew Candida species. Species distribution was as follows: C. albicans (78.95%), C. glabrata (14.35%), C. krusei (3.35%), C. tropicalis (1.44%), C. famata (0.96%), C. parapsilosis (0.48%) and C. lusitaniae (0.48%). Resistance to nystatin was only observed in 0.61% of C.albicans. Resistance to clotrimazole was observed in 50%, 36.67% and 0.61% of C. famata, C. glabrata and C. albicans respectively. C. krusei showed a high resistance of 71.43% to fluconazole. C. glabrata, C. krusei, C. famata and C. lusitaniae exhibited 100% resistance to itraconazole. Resistance to voriconazole of less than 11% was exhibited by only C. albicans and C. glabrata.

CONCLUSION
C.albicans was susceptible to most antifungal agents tested except itraconazole and voriconazole. All isolates were susceptible to nystatin except less than 1% of Candida albicans. Non-albicans demonstrated resistance to some drugs especially itraconazole. We recommend use of Nystatin for empirical management of vulvovaginal candidiasis among pregnant women.

Mukasa|Kiguli James|KJ|
Herbert|Itabangi|I|
Daniel|Atwine|A|
Sserunkuma|Kibuka Livingstone|KL|
Joel|Bazira|B|
Frederick|Byarugaba|B|

Antifungal
susceptible
Candida species
vulvovaginal candidiasis
resistant


Relationship between Cataract Surgery and Mortality in Elderly Patients with Cataract: Nationwide Population-Based Cohort Study in South Korea.

Abstract: We aimed to investigate the relationship between cataract surgery and all-cause and cause-specific mortality in Korean elderly patients with cataract using the Korean National Health Insurance Service-Senior cohort database. Elderly patients (≥60 years) diagnosed with cataract from 2002 through 2012 were included. The baseline characteristics included demographics and systemic and ocular comorbidities. Adjusted Cox regression models with time-varying covariates for cataract surgery were used to assess the relationship between cataract surgery and mortality. The study cohort included 241,062 patients, of whom 127,941 were in the cataract surgery group and 113,121 were in the cataract diagnosis group. The incidence of all-cause mortality was 3.62 deaths/100 person-years and 3.19 deaths/100 person-years in the cataract surgery and cataract diagnosis groups, respectively. Cataract surgery was associated with a decreased hazard of all-cause mortality after adjusting for demographics as well as systemic and ocular comorbidities (hazard ratio (HR), 0.93; p < 0.001). A protective association was noted between cataract surgery and mortality from vascular (HR, 0.92; p < 0.001) or neurologic (HR, 0.64; p < 0.001) causes. Patients with cataract who were 85 years of age and older, women, those who had lower income, and a Charlson comorbidity index score of 5 or more, or those without glaucoma revealed the largest reductions in mortality hazards resulting from cataract surgery.

cataract
cataract surgery
cause-specific mortality
all-cause mortality
NHIS-senior database


Photothermal Killing of Methicillin-Resistant Staphylococcus aureus by Bacteria-Targeted Polydopamine Nanoparticles with Nano-Localized Hyperpyrexia.

Abstract: Bacterial infections caused by antibiotic-resistant pathogens have become intractable problems to public health. Therefore, there is an imperious demand for developing new approaches to effectively kill antibiotic-resistant bacteria. In this work, we report a kind of bacteria-targeted polydopamine nanoparticle exhibiting great photothermal killing ability toward methicillin-resistant Staphylococcus aureus (MRSA) by nano-localized hyperpyrexia under low-power near-infrared (NIR) light irradiation. These bacteria-targeted nanoparticles (PDA-PEG-Van) are prepared by modifying polydopamine nanoparticles with thiol-poly(ethylene glycol) (mPEG-SH) and vancomycin (Van) molecules. The PEG shell endows the nanoparticles with excellent long-term circulation stability. Due to the multivalent hydrogen-bond interactions between vancomycin and the MRSA cell wall, the vancomycin-modified polydopamine nanoparticles can specifically target MRSA rather than mammalian cells. These bacteria-targeted nanoparticles are employed as a nano-localized heat source to kill MRSA via disrupting the bacterial cell wall and membrane under irradiation of low-power NIR light. More importantly, the surrounding healthy tissues suffer bare damage, owing to the absence of any targeting effect of PDA-PEG-Van toward mammalian cells and the low power of NIR light used in the therapeutic process. Given the above advantages, the bacteria-targeted polydopamine nanoparticles proposed in this work show tremendous potential to treat MRSA infections, because they can effectively limit localized heating in the infection sites to kill bacteria and cut down damage to healthy tissues.

photothermal killing
bacteria-targeted
polydopamine nanoparticle
vancomycin
nano-localized heat


An emergency call system for patients in locked-in state using an SSVEP-based brain switch.

Abstract: Patients in a locked-in state (LIS) due to severe neurological disorders such as amyotrophic lateral sclerosis (ALS) require seamless emergency care by their caregivers or guardians. However, it is a difficult job for the guardians to continuously monitor the patients' state, especially when direct communication is not possible. In the present study, we developed an emergency call system for such patients using a steady-state visual evoked potential (SSVEP)-based brain switch. Although there have been previous studies to implement SSVEP-based brain switch system, they have not been applied to patients in LIS, and thus their clinical value has not been validated. In this study, we verified whether the SSVEP-based brain switch system can be practically used as an emergency call system for patients in LIS. The brain switch used for our system adopted a chromatic visual stimulus, which proved to be visually less stimulating than conventional checkerboard-type stimuli but could generate SSVEP responses strong enough to be used for brain-computer interface (BCI) applications. To verify the feasibility of our emergency call system, 14 healthy participants and 3 patients with severe ALS took part in online experiments. All three ALS patients successfully called their guardians to their bedsides in about 6.56 seconds. Furthermore, additional experiments with one of these patients demonstrated that our emergency call system maintains fairly good performance even up to 4 weeks after the first experiment without renewing initial calibration data. Our results suggest that our SSVEP-based emergency call system might be successfully used in practical scenarios.


INDEL variation in the regulatory region of the major flowering time gene LanFTc1 is associated with vernalization response and flowering time in narrow-leafed lupin (Lupinus angustifolius L.).

Abstract: Narrow-leafed lupin (Lupinus angustifolius L.) cultivation was transformed by 2 dominant vernalization-insensitive, early flowering time loci known as Ku and Julius (Jul), which allowed expansion into shorter season environments. However, reliance on these loci has limited genetic and phenotypic diversity for environmental adaptation in cultivated lupin. We recently predicted that a 1,423-bp deletion in the cis-regulatory region of LanFTc1, a FLOWERING LOCUS T (FT) homologue, derepressed expression of LanFTc1 and was the underlying cause of the Ku phenotype. Here, we surveyed diverse germplasm for LanFTc1 cis-regulatory variation and identified 2 further deletions of 1,208 and 5,162 bp in the 5' regulatory region, which overlap the 1,423-bp deletion. Additionally, we confirmed that no other polymorphisms were perfectly associated with vernalization responsiveness. Phenotyping and gene expression analyses revealed that Jul accessions possessed the 5,162-bp deletion and that the Jul and Ku deletions were equally capable of removing vernalization requirement and up-regulating gene expression. The 1,208-bp deletion was associated with intermediate phenology, vernalization responsiveness, and gene expression and therefore may be useful for expanding agronomic adaptation of lupin. This insertion/deletion series may also help resolve how the vernalization response is mediated at the molecular level in legumes.

D018506:Gene Expression Regulation, Plant

FLOWERING LOCUS T (FT)
cis-regulation
insertion/deletion (INDEL)
variant series


Continued Evidence of Decline in the Enzootic Activity of Western Equine Encephalitis Virus in Colorado.

Abstract: Western equine encephalitis (WEE) was once prevalent and routinely isolated from mosquitoes in Colorado; however, isolations of Western equine encephalitis virus (WEEV) have not been reported from mosquito pools since the early 1990s. The objective of the present study was to test pools of Culex tarsalis (Coquillett) mosquitoes sampled from Weld County, CO, in 2016 for evidence of WEEV infection. Over 7,000 mosquitoes were tested, but none were positive for WEEV RNA. These data indicate that WEEV either was not circulating enzootically in Northern Colorado, was very rare, and would require much more extensive mosquito sampling to detect, or was heterogeneously distributed spatially and temporally and happened to not be present in the area sampled during 2016. Even though the reported incidence of WEE remains null, screening for WEEV viral RNA in mosquito vectors offers forewarning toward the detection and prevention of future outbreaks.

Robb|Lucy L|LL|
Hartman|Daniel A|DA|
Rice|Lauren|L|
deMaria|Justin|J|
Bergren|Nicholas A|NA|
Borland|Erin M|EM|
Kading|Rebekah C|RC|

D004667:Encephalitis Virus, Western Equine


Coupling of β1-adrenergic receptor to type 5 adenylyl cyclase and its physiological relevance in cardiac myocytes.

Abstract: Myocardial β-adrenergic receptor (β-AR) β1- and β2-subtypes are highly homologous, but play opposite roles in cardiac apoptosis and heart failure, as do cardiac adenylyl cyclase (AC) subtypes 5 (AC5) and 6 (AC6): β1-AR and AC5 promote cardiac remodeling, while β2-AR and AC6 activate cell survival pathways. However, the mechanisms involved remain poorly understood. We hypothesized that AC5 is coupled preferentially to β1-AR rather than β2-AR, and we examined this idea by means of pharmacological and genetic approaches. We found that selective inhibition of AC5 with 2'5'-dideoxyadenosine significantly suppressed cAMP accumulation and cardiac apoptosis induced by selective β1-AR stimulation, but had no effect on cAMP accumulation and cardiac apoptosis in response to selective β2-AR stimulation. The results of selective stimulation of β1-AR and β2-AR in neonatal cardiac myocytes prepared from wild-type and AC5-knockout mice were also consistent with the idea that β1-AR selectively couples with AC5. We believe these results are helpful for understanding the mechanisms underlying the different roles of AR subtypes in healthy and diseased hearts.

Tsunematsu|Takashi|T| Okumura|Satoshi|S| Mototani|Yasumasa|Y| Ohnuki|Yoshiki|Y| Jin|Huiling|H| Cai|Wenqian|W| Suita|Kenji|K| Sato|Itaru|I| Umemura|Masanari|M| Yokoyama|Utako|U| Sato|Motohiko|M| Fujita|Takayuki|T| Ishikawa|Yoshihiro|Y|

D000262:Adenylyl Cyclases
D000818:Animals
D017209:Apoptosis
D002478:Cells, Cultured
D000242:Cyclic AMP
D051379:Mice
D018345:Mice, Knockout
D032383:Myocytes, Cardiac
D018342:Receptors, Adrenergic, beta-1

Adenylyl cyclase
Apoptosis
Heart
Cyclic AMP
β-receptor


Germline mutation within COL2A1 associated with lethal chondrodysplasia in a polled Holstein family.

Abstract:
BACKGROUND
The bulldog calf syndrome is a lethal form of the inherited congenital chondrodysplasias. Among the progeny of the polled Holstein bull Energy P cases of lethal chondrodysplasia were observed. Pedigrees of the cases and the frequency of 3/8 cases among the offspring of Energy P at our teaching and experimental farm Ruthe (LuFG Ruthe) supported the assumption of a germline mutation with a mosaic of normal and defective sperm.

RESULTS
All three malformed calves were examined using necropsy, histopathology and computed tomography scanning. The phenotypic appearance of the affected calves was highly similar; they presented with severe disproportionate dwarfism and reduced body weight. The syndrome was characterized by brachygnathia superior, bilateral palatoschisis, shortening and compression of the body due to malformed vertebrae, in their size reduced and malformed ribs and reduced length of the long bones of the limbs. The bones had small irregular diaphyses and enlarged epiphyses. Whole genome sequencing of one bulldog calf, sperm of its sire Energy P and a normal progeny of Energy P identified a deleterious missense mutation (g.32476082G > A, c.2986G > A, ss2019324576) within COL2A1 on bovine chromosome (BTA) 5. Sanger sequencing confirmed the ss2019324576 variant in the affected calves and sperm of Energy P. This mutation is located within the collagen triple helix repeat and causes an exchange of glycine to serine (p.996G > S) in COL2A1. This private single nucleotide variant (SNV) was present as a gonadal mosaic in sperm of the bull. All affected calves were in a heterozygous state whereas normal half-siblings and all dams of the progeny from Energy P were missing this SNV. Validation in polled Holstein bulls and normal Holstein calves randomly sampled from several herds and from the LuFG Ruthe confirmed this SNV as private.

CONCLUSIONS
The identified spontaneous missense mutation within COL2A1 is most likely the cause of lethal chondrodysplasia in the progeny of Energy P through a dominant negative effect. This example suggests that it would be beneficial to conduct whole genome sequencing of sperm from bulls widely used in artificial insemination in order to detect germline mosaicism.

Reinartz|Sina|S| Mohwinkel|Hartmut|H| Sürie|Christian|C| Hellige|Maren|M| Feige|Karsten|K| Eikelberg|Deborah|D| Beineke|Andreas|A| Metzger|Julia|J| Distl|Ottmar|O|

COL2A1
Bulldog
Mosaic
Whole genome sequencing
Cattle


Novel mitral valve technologies-transcatheter mitral valve implantation: a systematic review.

Abstract:
Background
Valvular heart disease is an important cause of morbidity and mortality throughout the world; in industrialized nations, mitral regurgitation (MR) is the most common valvular lesion. Untreated, severe MR has a poor prognosis, with a 5-year mortality rate of up to 50%. Surgical repair of symptomatic, severe primary MR has been demonstrated to improve survival. The aim of this review is to assess the early outcomes of newly developed transcatheter mitral valve implantation technologies for the treatment of secondary native valve disease. Furthermore, the outcomes of patients receiving transcatheter treatment of regurgitant failure of surgically repaired or replaced mitral valve has also been addressed.

Methods
A systematic review of twenty-five studies assessing the outcomes of patients undergoing transcatheter mitral valve implantation for native mitral regurgitation or failed prior surgical repair or bioprosthetic replacement was carried out.

Results
The outcomes of 112 patients undergoing transcatheter mitral valve replacement for secondary mitral regurgitation using six different valve systems were assessed. There were 15 early deaths and 24 deaths over the follow-up period. The outcomes of 44 patients undergoing transcatheter valve-in-valve replacement were assessed with an overall mortality of ten patients. There were 20 patients included who had valve-in-ring transcatheter mitral replacement for previous failed repair. The total mortality was five patients during the follow-up period.

Conclusions
Transcatheter mitral valve implantation represents a new evolution in management of valvular disease and affords management options to patients who historically may not have been offered treatment. Early results have demonstrated some promise and improvements in technology, imaging modalities and patient selection will surely result in a reliable and durable valve.

Flynn|Campbell D|CD|
Wilson-Smith|Ashley R|AR|
Yan|Tristan D|TD|

transcatheter mitral valve implantation
Transcatheter mitral valve replacement
valve-in-valve
valve-in-ring


Complete genome sequence of Enterococcus faecalis LD33, a bacteriocin-producing strain.

Abstract: Enterococcus faecalis LD33 strain was originally isolated from traditional naturally fermented cream in Inner Mongolia of China. Its complete genome sequence was carried out using the Illumina Hiseq and the PacBio RSII platform. The genome only has a circular chromosome and a GC content of 37.58%. Other core information shown in the genome sequencing results further insight on this bacterium's genetic elements for bacteriocin production and the genes related to respiratory chain.

Yuehua|Jiao|J| Lanwei|Zhang|Z| Fei|Liu|L| Huaxi|Yi|Y| Xue|Han|H|

D001430:Bacteriocins
D001483:Base Sequence
D002876:Chromosomes, Bacterial
D004270:DNA, Circular
D013293:Enterococcus faecalis
D016680:Genome, Bacterial

Genome
Enterococcus faecalis
Bacteriocin
Respiration


Gradual extinction reduces reinstatement.

Abstract: The current study investigated whether gradually reducing the frequency of aversive stimuli during extinction can prevent the return of fear. Thirty-one participants of a three-stage procedure (acquisition, extinction and a reinstatement test on day 2) were randomly assigned to a standard extinction (SE) and gradual extinction (GE) procedure. The two groups differed only in the extinction procedure. While the SE group ran through a regular extinction process without any negative events, the frequency of the aversive stimuli during the extinction phase was gradually reduced for the GE group. The unconditioned stimulus (US) was an air blast (5 bar, 10 ms). A spider and a scorpion were used as conditioned stimuli (CS). The outcome variables were contingency ratings and physiological measures (skin conductance response, SCR and startle response). There were no differences found between the two groups for the acquisition and extinction phases concerning contingency ratings, SCR, or startle response. GE compared to SE significantly reduced the return of fear in the reinstatement test for the startle response but not for SCR or contingency ratings. This study was successful in translating the findings in rodent to humans. The results suggest that the GE process is suitable for increasing the efficacy of fear extinction.

Shiban|Youssef|Y| Wittmann|Jasmin|J| Weißinger|Mara|M| Mühlberger|Andreas|A|

gradual extinction
contingency ratings
skin conductance response
startle response
pavlovian fear conditioning
virtual reality


The oral microbiome of patients with axial spondyloarthritis compared to healthy individuals.

Abstract: Background. A loss of mucosal tolerance to the resident microbiome has been postulated in the aetiopathogenesis of spondyloarthritis, thus the purpose of these studies was to investigate microbial communities that colonise the oral cavity of patients with axial spondyloarthritis (AxSpA) and to compare these with microbial profiles of a matched healthy population. Methods. Thirty-nine participants, 17 patients with AxSpA and 22 age and gender-matched disease-free controls were recruited to the study. For patients with AxSpA, disease activity was assessed using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). All participants underwent a detailed dental examination to assess oral health, including the presence of periodontal disease assessed using probing pocket depth (PPD). Plaque samples were obtained and their bacterial populations were profiled using Ion Torrent sequencing of the V6 region of the 16S rRNA gene. Results.Patients with AxSpA had active disease (BASDAI 4.1 ± 2.1 [mean ± SD]), and a significantly greater prevalence of periodontitis (PPD ≥ 4 mm at ≥4 sites) than controls. Bacterial communities did not differ between the two groups with multiple metrics of α and β diversity considered. Analysis of operational taxonomic units (OTUs) and higher levels of taxonomic assignment did not provide strong evidence of any single taxa associated with AxSpA in the subgingival plaque. Discussion. Although 16S rRNA gene sequencing did not identify specific bacterial profiles associated with AxSpA, there remains the potential for the microbiota to exert functional and metabolic influences in the oral cavity which could be involved in the pathogenesis of AxSpA.

Bisanz|Jordan E|JE|
Suppiah|Praema|P|
Thomson|W Murray|WM|
Milne|Trudy|T|
Yeoh|Nigel|N|
Nolan|Anita|A|
Ettinger|Grace|G|
Reid|Gregor|G|
Gloor|Gregory B|GB|
Burton|Jeremy P|JP|
Cullinan|Mary P|MP|
Stebbings|Simon M|SM|

Microbiome
Axial spondyloarthritis
Oral cavity
Periodontal disease


Microtensile Bond Strength, Bonding Interface Morphology, Adhesive Resin Infiltration, and Marginal Adaptation of Bulk-fill Composites Placed Using Different Adhesives.

Abstract:
PURPOSE
This study evaluated dentin bond strength, failure mode, interface morphology, adhesive infiltration into dentin, and marginal adaptation of bulk-fill composites used with different adhesives.

MATERIALS AND METHODS
Third molars received occlusal class I cavities (4 mm x 4 mm x 4 mm) that were bulk-filled with Admira Fusion x-tra (Voco) or SonicFill 2 (Kerr) using four adhesives (Scotchbond Multipurpose, 3M Oral Care; Clearfil SE Bond, Kuraray Noritake; OptiBond All-In-One, Kerr; Futurabond U, Voco). Scotchbond was used with acid-etching, while the remaining adhesives were applied in self-etch mode. Sixty-four teeth were selected for the microtensile bond strength test (n = 8). Failure modes were analyzed with scanning electron microscopy (SEM). Interface morphology and adhesive infiltration (n = 3) were investigated using confocal laser scanning microscopy (CLSM). Marginal adaptation (n = 3) was also evaluated using SEM. Bond strength, failure mode, and adhesive infiltration data were analyzed for distribution and homocedasticity, followed by appropriate statistical analyses (α = 0.05).

RESULTS
Regarding bond strength, no differences were found among adhesives for SonicFill; Clearfil showed a significantly lower mean value than did Scotchbond (p ≤ 0.05) for Admira; the two composites did not differ. Adhesive and mixed failures were observed for all groups. Scotchbond led to thicker hybrid layers with deeper adhesive infiltration as opposed to Futurabond. The groups Admira+Futurabond, SonicFill+Clearfil, and SonicFill+Futurabond presented the highest marginal discontinuity.

CONCLUSION
The tested bulk-fill composites did not affect dentin bonding. Scotchbond and Clearfil seem to be reliable for bonding SonicFill 2 to dentin. The performance of Futurabond was questionable, given its poor-quality interface and higher percentages of marginal gaps.

Sebold|Maicon|M|
Lins|Rodrigo Barros Esteves|RBE|
Sahadi|Beatriz Ometto|BO|
Santi|Marina Rodrigues|MR|
Martins|Luís Roberto Marcondes|LRM|
Giannini|Marcelo|M|

D000269:Adhesives
D003188:Composite Resins
D001840:Dental Bonding
D003738:Dental Cements
D003804:Dentin
D017220:Dentin-Bonding Agents
D008422:Materials Testing
D008855:Microscopy, Electron, Scanning
D019279:Resin Cements
D013718:Tensile Strength

adhesive
dentin
composite resin
dental bonding
dental etching
ultrasonics


Implantation of rotary blood pumps into 115 patients: a single-centre experience.

Abstract:
OBJECTIVES
From 2004 to 2009, rotary blood pumps were implanted for heart failure as a bridge to transplant or destination therapy in 101 male and 14 female patients at our institution. We report on our experiences of these patients with a follow-up of 132 patient years.

METHODS
Seventy-four HeartMate II axial flow pumps and 41 HeartWare centrifugal pumps were implanted in patients with non-ischaemic (n = 70) or ischaemic cardiomyopathy (n = 45). The mean age of the patients was 50 ± 13 years. All patients were on inotropic support prior to implantation. Extracorporeal membrane oxygenation was used as a bridging procedure in 21 cases.

RESULTS
The perioperative mortality was 14%. Hospital discharge occurred on average after 46 ± 33 days. Twenty-two patients of this cohort received a heart transplant 492 ± 342 days after implantation of the device. Two patients died after heart transplantation. A 1-year survival of 73% and a 2-year survival of 69% were recorded, despite a low incidence of transplant procedures. The longest support time was 1686 days.

CONCLUSIONS
Modern left ventricular assist device technology can be used successfully for heart failure. The scarcity of donor hearts leads to prolonged periods on the device, and chronic ventricular assist device therapy has become a reality, although bridge to transplant was intended; therefore, sufficient support services for outpatient care of these patients are required.

Meyer|Anna L|AL|
Malehsa|Doris|D|
Bara|Christoph|C|
Haverich|Axel|A|
Strueber|Martin|M|

HeartMate II
HeartWare
Left ventricular assist device
Outcome