Reproducible and fully automated testing of nocifensive behavior in mice.
Pain in rodents is often inferred from their withdrawal from noxious stimulation. Threshold stimulus intensity or response latency is used to quantify pain sensitivity. This usually involves applying stimuli by hand and measuring responses by eye, which limits reproducibility and throughput. We describe a device that standardizes and automates pain testing by providing computer-controlled aiming, stimulation, and response measurement. Optogenetic and thermal stimuli are applied using blue and infrared light, respectively. Precise mechanical stimulation is also demonstrated. Reflectance of red light is used to measure paw withdrawal with millisecond precision. We show that consistent stimulus delivery is crucial for resolving stimulus-dependent variations in withdrawal and for testing with sustained stimuli. Moreover, substage video reveals "spontaneous" behaviors for consideration alongside withdrawal metrics to better assess the pain experience. The entire process was automated using machine learning. RAMalgo (reproducible automated multimodal algometry) improves the standardization, comprehensiveness, and throughput of preclinical pain testing.


Vasomotion and transvascular exchange of fluid and plasma proteins.
The effect of spontaneous arteriolar vasomotion on the transvascular exchange of fluid and plasma proteins has been studied theoretically. The model combines fluid dynamic principles with a phenomenological approach to transvascular exchange on the basis of irreversible thermodynamics. The analytical treatment of the intravascular flow together with consideration of local changes of the morphology and vascular membrane characteristics makes it possible to determine the spatial and temporal variation of transvascular fluid and plasma protein fluxes. Since the undulations of the arteriolar diameter have low frequencies (3 to 10 per cycle), the transvascular fluxes are in phase with the vasomotion. The model combines hemodynamics, microhemorheology and mass transfer at the vessel wall and provides pressures, velocities, plasma protein concentration, hematocrit and apparent blood viscosity at any position in the microvascular bed at any time. In addition, global parameters as the total filtration rate and the total transvascular mass flow rate of plasma proteins are determined as functions of time. Numerical results are obtained for the cat mesentery with the terminal arteriole exhibiting vasomotion. The vascular arrangement studied comprised a terminal arteriole, capillaries and a venule together with appropriate side branches. The results show dramatic temporal changes in the hemodynamic parameters. Fluid filtration occurs along the entire vascular length at all times except during vasoconstriction when small absorption rates occur on the venous side. The transvascular fluxes achieve maximum values either on the arteriolar or on the venular side depending on the moment of the vasomotion cycle. The transvascular exchange rates in the mid-capillaries are generally low.


Total synthesis of neolaulimalide and isolaulimalide.
The first total syntheses of the potential antitumoral leads neolaulimalide (2) and isolaulimalide (3) have been achieved. Key steps in our convergent, fully stereocontrolled route are a Yamaguchi macrolactonization, a Julia-Lythgoe-Kocienski olefination, a Kulinkovich reaction, and a cyclopropyl-allyl rearrangement to install the exo-methylene group. Overall, we synthesized 2 in 21 linear steps (3% yield) and 3 in 24 steps (2% yield).


ETV6-NTRK3 and STRN-ALK kinase fusions are recurrent events in papillary thyroid cancer of adult population.
PTC-specific analysis identified novel fusions involving RET, BRAF, NTRK1, NTRK3, AGK and ALK genes in adults and pediatric PTCs. Although many novel fusions are PTC-specific events and, therefore, are ideal for diagnosis purposes, validation across additional and larger patient cohorts is essential for introducing these potential diagnostic or prognostic biomarkers into the clinical practice. As most of the BRAF, NTRK3 and ALK fusions were initially found in pediatric PTC or in more aggressive thyroid carcinomas, and there is a great disparity across population, in this study, we screened a large set of adult-sporadic PTC cases for the most prevalent kinase fusion lately described in the TCGA. The prevalence of the fusions was determined by RT-PCR in 71 classical PTC, 45 follicular variants of PTC (FVPTC), 19 follicular thyroid adenomas (FTAs) and 22 follicular thyroid carcinomas (FTCs). ETV6-NTRK3 was exclusively found in FVPTC, in both encapsulated and infiltrative variants, but was not found in FTAs and FTCs. STRN-ALK was found in both classical PTC and FVPTC. No AGK-BRAF fusion was identified in this series, endorsing that AGK-BRAF is a genetic event mainly associated with pediatric PTCs. The identification of kinase fusions in thyroid carcinomas helps to expand our knowledge about the landscape of oncogenic alterations in PTC. As ETV6-NTRK3 and STRN-ALK are recurrent and not identified in benign lesions, they can certainly help with diagnosis of thyroid nodules. Further analysis is needed to define if they can also be useful for prognosis and guiding therapy.


Ras signals principally via Erk in G1 but cooperates with PI3K/Akt for Cyclin D induction and S-phase entry.
Numerous studies exploring oncogenic Ras or manipulating physiological Ras signalling have established an irrefutable role for Ras as driver of cell cycle progression. Despite this wealth of information the precise signalling timeline and effectors engaged by Ras, particularly during G1, remain obscure as approaches for Ras inhibition are slow-acting and ill-suited for charting discrete Ras signalling episodes along the cell cycle. We have developed an approach based on the inducible recruitment of a Ras-GAP that enforces endogenous Ras inhibition within minutes. Applying this strategy to inhibit Ras stepwise in synchronous cell populations revealed that Ras signaling was required well into G1 for Cyclin D induction, pocket protein phosphorylation and S-phase entry, irrespective of whether cells emerged from quiescence or G2/M. Unexpectedly, Erk, and not PI3K/Akt or Ral was activated by Ras at mid-G1, albeit PI3K/Akt signalling was a necessary companion of Ras/Erk for sustaining cyclin-D levels and G1/S transition. Our findings chart mitogenic signaling by endogenous Ras during G1 and identify limited effector engagement restricted to Raf/MEK/Erk as a cogent distinction from oncogenic Ras signalling.


Surgical treatment of frontoethmoidal encephalocele: a case report.
This study reports a patient affected by congenital frontoethmoidal encephalocele. The cause of this malformation is unknown. A preoperative selective diagnosis evaluation is necessary. The workup should include an accurate clinical examination associated with radiological study (two- and three-dimensional computed tomography, magnetic resonance imaging, etc). The aim of the surgical treatment is to restore the functional brain tissue in the cranial cavity, perform dural repair, correct bone lack and other associated facial malformations (hypertelorism, orbital dystopia, etc.). A multidisciplinary team approach is necessary to resolve the brain herniation and to correct splanchnocranium malformations frequently associated with encephalocele. Cranial flap with orbital osteotomies has been performed; this operation permits correction of the hypertelorism and of the orbital dystopia associated with this malformation. In bone reconstructions, miniplates have been used as fixation devices. In adults we generally use titanium, but resorbable devices are required in children because of growing tissues. A restoration of craniofacial malformations with good aesthetic and functional results is achieved with early surgery.


Renal dysplasia characterized by prominent cartilaginous metaplasia lesions in VACTERL association: A case report.
Renal dysplasia is the most important cause of end-stage renal disease in children. The histopathological characteristic of dysplasia is primitive tubules with fibromuscular disorganization. Renal dysplasia often includes metaplastic cartilage. Metaplastic cartilage in renal dysplasia has been explained as occurring secondary to vesicoureteral reflux (VUR). Additionally, renal dysplasia is observed in renal dysplasia-associated syndromes, which are combinations of multiple developmental malformations and include VACTERL association. We observed the following multiple developmental malformations in a 108-day-old male infant during a nephrectomy: a nonfunctioning right kidney with VUR, hemidiaphragmatic eventration, a ventricular septal defect (VSD) with tetralogy of Fallot in the heart, cryptorchidism, and hyperdactylia. These developmental anomalies satisfied the diagnostic criteria for VACTERL association. A surgical specimen of the right nonfunctioning kidney revealed prominent cartilaginous metaplasia in the renal dysplasia with VUR. The densities of the ectopic cartilaginous lesions in this nonfunctioning kidney were extraordinarily high compared with other renal dysplasia cases. Giemsa banding of his genome produced normal results. The patient has not undergone further detailed genomic investigation. This case might be a novel type of VACTERL association, that is, renal dysplasia combined with prominent cartilaginous metaplasia, tetralogy of Fallot and VSD of the heart, hemidiaphragmatic eventration, and hyperdactylia.


Polypeptide-based nanogels co-encapsulating a synergistic combination of doxorubicin with 17-AAG show potent anti-tumor activity in ErbB2-driven breast cancer models.
ErbB2-driven breast cancers constitute 20-25% of the cases diagnosed within the USA. The humanized anti-ErbB2 monoclonal antibody, Trastuzumab (Herceptin™; Genentech), with chemotherapy is the current standard of treatment. Novel agents and strategies continue to be explored, given the challenges posed by Trastuzumab-resistance development in most patients. The HSP90 inhibitor, 17-allylaminodemethoxygeldanamycin (17-AAG), which induces ErbB2 degradation and attenuates downstream oncogenic signaling, is one such agent that showed significant promise in early phase I and II clinical trials. Its low water solubility, potential toxicities and undesirable side effects observed in patients, partly due to the Cremophor-based formulation, have been discouraging factors in the advancement of this promising drug into clinical use. Encapsulation of 17-AAG into polymeric nanoparticle formulations, particularly in synergistic combination with conventional chemotherapeutics, represents an alternative approach to overcome these problems. Herein, we report an efficient co-encapsulation of 17-AAG and doxorubicin, a clinically well-established and effective modality in breast cancer treatment, into biodegradable and biocompatible polypeptide-based nanogels. Dual drug-loaded nanogels displayed potent cytotoxicity in a breast cancer cell panel and exerted selective synergistic anticancer activity against ErbB2-overexpressing breast cancer cell lines. Analysis of ErbB2 degradation confirmed efficient 17-AAG release from nanogels with activity comparable to free 17-AAG. Furthermore, nanogels containing both 17-AAG and doxorubicin exhibited superior antitumor efficacy in vivo in an ErbB2-driven xenograft model compared to the combination of free drugs. These studies demonstrate that polypeptide-based nanogels can serve as novel nanocarriers for encapsulating 17-AAG along with other chemotherapeutics, providing an opportunity to overcome solubility issues and thereby exploit its full potential as an anti-cancer agent.


Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor.
The insulin-like growth factor I receptor (IGF-IR) is a transmembrane tyrosine kinase that is essential to growth and development and also thought to provide a survival signal for the maintenance of the transformed phenotype. There has been increasing interest in further understanding the role of IGF-I signaling in cancer and in developing receptor antagonists for therapeutic application. We describe herein a novel animal model that involves transgenic expression of a fusion receptor that is constitutively activated by homodimerization. Transgenic mice that expressed the activated receptor showed aberrant development of the mammary glands and developed salivary and mammary adenocarcinomas as early as 8 weeks of age. Xenograft tumors and a cell line were derived from the transgenic animals and are sensitive to inhibition by a novel small-molecule inhibitor of the IGF-IR kinase. This new model should provide new opportunities for further understanding how aberrant IGF-IR signaling leads to tumorigenesis and for optimizing novel antagonists of the receptor kinase.


BatchBMD as an Efficient and Accurate Dual-Energy X-ray Absorptiometry Report Generator.
Dual-energy X-ray absorptiometry is the gold standard for evaluating Bone Mineral Density (BMD); however, a typical BMD report is generated in a time-inefficient manner and is prone to error. We developed a rule-based automated reporting system, BatchBMD, that accelerates DXA reporting while improving its accuracy over current systems. BatchBMD generates a structured report, customized to the specific clinical purpose. To compare BatchBMD to a Web-based Reporting (WBR) system for efficiency and accuracy, 500 examinations were randomly chosen from those performed at the Taipei Municipal Wanfang Hospital from January to March 2021. The final assessment included all 2326 examinations conducted from September 2020 to March 2021. The average reporting times were 6.7 and 10.8 min for BatchBMD and the WBR system, respectively, while accuracy was 99.4% and 98.2%, respectively. Most of the errors made by BatchBMD were digit errors in the appendicular skeletal muscle index. After correcting this, 100% accuracy across all 2326 examinations was validated. This automated and accurate BMD reporting system significantly reduces report production workload for radiologists and technicians while increasing productivity and quality. Additionally, the portable software, which employs a simple framework, can reduce deployment costs in clinical practice.


[Evaluation of perioperative management of seven patients with pulmonary artery sling in recent seven years].
Pulmonary artery sling (PA sling) is a rare vascular anomaly in which the left pulmonary artery arises from the right pulmonary artery. It can cause compression of trachea. Due to its rarity, risk factors influencing postsurgical outcome are still unclear. The purpose of our study is to investigate past cases of PA sling to clarify risk factors. We investigated 7 patients who had undergone one-stage operation of PA sling from 2001 to 2007. Hospital stay, ICU stay and length of artificial ventilation are set as primary outcome. Patients' weight, range of tracheal stenosis, operation time, cardiopulmonary bypass time, presence of tracheal stenosis, bronchial anomaly, preoperative intubation, intracardiac anomaly and postoperative re-intubation were compared. In-hospital mortality was none. Two cases in patients with tracheomalacia were re-intubated. Concomitant tracheoplasty was performed in six patients. Two patients with intracardiac anomaly underwent cardiac operation. No factor except tracheomalacia affected primary outcome. We need more cases to clarify factors affecting outcome of patients with PA sling. However, existence of tracheomalacia is found to be a risk factor of longer artificial ventilation.


Evaluation of Five Image Registration Tools for Abdominal CT: Pitfalls and Opportunities with Soft Anatomy.
Image registration has become an essential image processing technique to compare data across time and individuals. With the successes in volumetric brain registration, general-purpose software tools are beginning to be applied to abdominal computed tomography (CT) scans. Herein, we evaluate five current tools for registering clinically acquired abdominal CT scans. Twelve abdominal organs were labeled on a set of 20 atlases to enable assessment of correspondence. The 20 atlases were pairwise registered based on only intensity information with five registration tools (affine IRTK, FNIRT, Non-Rigid IRTK, NiftyReg, and ANTs). Following the brain literature, the Dice similarity coefficient (DSC), mean surface distance, and Hausdorff distance were calculated on the registered organs individually. However, interpretation was confounded due to a significant proportion of outliers. Examining the retrospectively selected top 1 and 5 atlases for each target revealed that there was a substantive performance difference between methods. To further our understanding, we constructed majority vote segmentation with the top 5 DSC values for each organ and target. The results illustrated a median improvement of 85% in DSC between the raw results and majority vote. These experiments show that some images may be well registered to some targets using the available software tools, but there is significant room for improvement and reveals the need for innovation and research in the field of registration in abdominal CTs. If image registration is to be used for local interpretation of abdominal CT, great care must be taken to account for outliers (e.g., atlas selection in statistical fusion).


Tumor cell intravasation.
The process of entering the bloodstream, intravasation, is a necessary step in the development of distant metastases. The focus of this review is on the pathways and molecules that have been identified as being important based on current in vitro and in vivo assays for intravasation. Properties of the vasculature which are important for intravasation include microvessel density and also diameter of the vasculature, with increased intravasation correlating with increased vessel diameter in some tumors. TGFB signaling can enhance intravasation at least in part through induction of EMT, and we discuss other TGFB target genes that are important for intravasation. In addition to TGFB signaling, a number of studies have demonstrated that activation of EGF receptor family members stimulates intravasation, with downstream signaling through PI3K, N-WASP, RhoA, and WASP to induce invadopodia. With respect to proteases, there is strong evidence for contributions by uPA/uPAR, while the roles of MMPs in intravasation may be more tumor specific. Other cells including macrophages, fibroblasts, neutrophils, and platelets can also play a role in enhancing tumor cell intravasation. The technology is now available to interrogate the expression patterns of circulating tumor cells, which will provide an important reality check for the model systems being used. With a better understanding of the mechanisms underlying intravasation, the goal is to provide new opportunities for improving prognosis as well as potentially developing new treatments.


Treatment of Nocturnal Enuresis Using Miniaturised Smart Mechatronics With Artificial Intelligence.
Our study was designed to develop a customisable, wearable, and comfortable medical device - the text so-called "MyPAD" that monitors the fullness of the bladder, triggering an alarm indicating the need to void, in order to prevent badwetting - i.e., treating Nocturnal Enuresis (NE) at the text pre-void stage using miniaturised mechatronics with Artificial Intelligence (AI). The developed features include: multiple bespoke ultrasound (US) probes for sensing, a bespoke electronic device housing custom US electronics for signal processing, a bedside alarm box for processing the echoed pulses and generating alarms, and a phantom to mimic the human body. The validation of the system is conducted on the text tissue-mimicking phantom and volunteers using Bidirectional Long Short-Term Memory Recurrent Neural Networks (Bi-LSTM-RNN) and Reinforcement Learning (RL). A Se value of 99% and a Sp value of 99.5% with an overall accuracy rate of 99.3% are observed. The obtained results demonstrate successful empirical evidence for the viability of the device, both in monitoring bladder expansion to determine voiding need and in reinforcing the continuous learning and customisation of the device for bladder control through consecutive uses. Clinical impact: MyPAD will treat the NE better and efficiently against other techniques currently used (e.g., post-void alarms) and will i) replace those techniques quickly considering sufferers' condition while being treated by other approaches, and ii) enable children to gain control of incontinence over time and consistently have dry nights. Category: Early/Pre-Clinical Research.


POLIII-derived non-coding RNAs acting as scaffolds and decoys.
A large variety of eukaryotic small structured POLIII-derived non-coding RNAs (ncRNAs) have been described in the past. However, for only few, e.g. 7SL and H1/MRP families, cellular functions are well understood. For the vast majority of these transcripts, cellular functions remain unknown. Recent findings on the role of Y RNAs and other POLIII-derived ncRNAs suggest an evolutionarily conserved function of these ncRNAs in the assembly and function of ribonucleoprotein complexes (RNPs). These RNPs provide cellular `machineries', which are essential for guiding the fate and function of a variety of RNAs. In this review, we summarize current knowledge on the role of POLIII-derived ncRNAs in the assembly and function of RNPs. We propose that these ncRNAs serve as scaffolding factors that `chaperone' RNA-binding proteins (RBPs) to form functional RNPs. In addition or associated with this role, some small ncRNAs act as molecular decoys impairing the RBP-guided control of RNA fate by competing with other RNA substrates. This suggests that POLIII-derived ncRNAs serve essential and conserved roles in the assembly of larger RNPs and thus the control of gene expression by indirectly guiding the fate of mRNAs and lncRNAs.


Participation in society for people with a rare diagnosis.
Many rare diagnoses are syndromes that have complex consequences with a significant impact on the individuals' everyday life. Adults with rare diagnoses are a growing group and knowledge about their needs is often scarce. The objective was to investigate the experiences of adults living with different rare diagnoses, how they perceived their difficulties, needs and participation in everyday life, and to identify some common issues and problems. Individuals with four different diagnoses were interviewed in four focus groups: Artrogryposis Multiplex Congenita AMC (n = 9), Dysmelia (n = 11), 22q11 deletion syndrome (n = 10) and Klinefelter syndrome (n = 8). The interviews focused on the following topics; education, working life, daily routines, sleep, housing, health care and society support system contacts. The study was conducted as qualitative research using content analysis. The participants described their needs and perceived consequences from not having their everyday needs met. A major theme covers most of the participants' experiences: Complex and varying consequences of the condition have an impact on their participation in education, working and everyday life, mostly due to contextual barrier factors. The interviewees are affected by different rare conditions. Despite these differences they face similar challenges, due to the low prevalence of their condition and the resulting lack of both knowledge and holistic perspective of service providers. To gather, disseminate and implement information about rare conditions in society is thus a very important task. It is equally important to improve the ways to transfer information and to promote cooperation between service providers.


Pharmacologic evaluation of A23187-induced contractions of three distinct preparations of guinea pig lung parenchymal strips.
The present investigation examined the pharmacologic profiles of three distinct guinea pig lung parenchymal strips (LPS): intact LPS, denuded LPS (devoid of any lung pleura) and pleural surface strips. All three preparations responded similarly to increasing concentrations of KCl, whereas maximum contractile responses of the intact LPS and pleural surface strips to histamine, LTD4 and U46619, a thromboxane A2 mimetic, were significantly greater (P less than 0.001) than those elicited by the denuded LPS. Moreover, concentration-response curves for intact LPS and pleural surface strips to ovalbumin and ionophore A23187 challenges were equivalent to each other, which were significantly (P less than 0.001) higher in magnitude than that for the denuded LPS. The net contractile response of the denuded LPS to A23187 was significantly reduced by 35% in the presence of 1 x 10(-5) M A-64077, a 5-lipoxygenase inhibitor, and nearly abolished with the addition of 1 x 10(-6) M pyrilamine and 4 x 10(-6) M indomethacin. In contrast, the maximum contractile responses of the intact LPS and pleural surface strips were reduced by 40 and 30%, respectively, in the presence of all three inhibitors. On the other hand, morphometric analysis revealed that the density of mast cells in the smooth muscle of lung pleura was as high as that found in the bronchiolar area (2.35 +/- 0.31 vs. 2.62 +/- 0.28 per 0.05 mm2). In contrast, mast cells were scarcely identified in the alveolar parenchyma.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of fiber optic probe geometry on depth-resolved fluorescence measurements from epithelial tissues: a Monte Carlo simulation.
Developing fiber optic probe geometries to selectively measure fluorescence spectra from different sublayers within human epithelial tissues will potentially improve the endogenous fluorescence contrast between neoplastic and nonneoplastic tissues. In this study, two basic fiber optic probe geometries, which are called the variable aperture (VA) and multidistance (MD) approaches, are compared for depth-resolved fluorescence measurements from human cervical epithelial tissues. The VA probe has completely overlapping illumination and collection areas with variable diameters, while the MD probe employs separate illumination and collection fibers with a fixed separation between them. Monte Carlo simulation results show that the total fluorescence detected is significantly higher for the VA probe geometry, while the probing depth is significantly greater for the MD probe geometry. An important observation is that the VA probe is more sensitive to the epithelial layer, while the MD probe is more sensitive to the stromal layer. The effect of other factors, including numerical aperture (NA) and tissue optical properties on the fluorescence measurements with VA and MD probe geometries, are also evaluated. The total fluorescence detected with both probe geometries significantly increases when the fiber NA is changed from 0.22 to 0.37. The sensitivity to different sublayers is found to be strongly dependent on the tissue optical properties. The simulation results are used to design a simple fiber optic probe that combines both the VA and MD geometries to enable fluorescence measurements from the different sublayers within human epithelial tissues.


Discontinuous Dissolution Mechanism of Olivine Deduced from a Topography Observation Method.
Olivine dissolution plays an important role in environmental science and technology, from controlling global element circulation to carbon capture for climate change mitigation. Most studies have been focused on investigating its dissolution rates by monitoring chemical effluent changes under various conditions. However, only by observation of surface reactivity can we unravel the actual mechanism (s) of dissolution. Here, we studied the dissolution of an olivine (010) plane in a flow-through reaction cell with an acidic solution, a surface-controlled regime, and far-from-equilibrium conditions. Direct mineral surface topography measurements using vertical scanning interferometry and atomic force microscopy allowed for quantitative analyses of the spatial and temporal changes in the dissolution rate. The (010) plane dissolved discontinuously in time for different surface sites, resulting in a heterogeneously distributed rate map. Pits with different depths showed opposite dissolution rate distributions from the dislocation center to further out from the etch pit. Based on the step-wave model, we propose a mechanism of dissolution that is governed by the competition between Gibbs free energy of the dissolution process, ΔG, and the critical free energy of the opening of etch pits, i.e., ΔGcrit. The migration of step waves, the distribution of surface defects, the strain field of etch pits, and other dynamic elements, resulting in the instantaneous change of ΔGcrit on the surface, are important factors leading to the discontinuous dissolution of crystal materials. This discontinuous dissolution provides new insight into the guidance of crystalline mineral applications and the prediction of material properties regarding mineral dissolution variation.


Quality assessment of splice site annotation based on conservation across multiple species.
Despite many improvements over the years, the annotation of the human genome remains imperfect, and even the best annotations of the human reference genome sometimes contradict one another. Hence, refinement of the human genome annotation is an important challenge. The use of evolutionarily conserved sequences provides a strategy for addressing this problem, and the rapidly growing number of genomes from other species increases the power of an evolution-driven approach. Using the latest large-scale whole genome alignment data, we found that splice sites from protein-coding genes in the high-quality MANE annotation are consistently conserved across more than 400 species. We also studied splice sites from the RefSeq, GENCODE, and CHESS databases that are not present in MANE, from both protein-coding genes and lncRNAs. We trained a logistic regression classifier to distinguish between the conservation patterns exhibited by splice sites from MANE versus sites that were flanked by the standard GT-AG dinucleotides, but that were chosen randomly from a sequence not under selection. We found that up to 70% of splice sites from annotated protein-coding transcripts outside of MANE exhibit conservation patterns closer to random sequence as opposed to highly-conserved splice sites from MANE. Our study highlights potentially erroneous splice sites that might require further scrutiny.


Seasonal influenza and vaccination strategies-is a paradigm shift needed? A synopsis of the 3rd New Zealand Influenza Symposium, November 2016.
Influenza continues to be a global public health problem despite the availability of preventive vaccines and public health vaccination programmes. This paper presents a synopsis of the 3rd New Zealand Influenza Symposium (NZiS) that was hosted by the Immunisation Advisory Centre (IMAC) in November 2016. Experts and service providers convened to discuss current issues in the prevention and management of influenza. One of the key topics discussed was the use of novel vaccines, such as adjuvanted and high-dose vaccines, and antiviral prophylaxis to protect young children and the elderly. Another area of focus was on paradigms of seasonal influenza vaccination strategies that reduce community transmission and provide individual protection to reduce the burden of influenza. The need for better influenza surveillance and country-specific data to guide policy makers and healthcare providers was highlighted in order to improve population health outcomes.


Evolution of seasonal ecological niches in the Passerina buntings (Aves: Cardinalidae).
The evolution of migration has long been considered complex and recent work has demonstrated additional complexity: some species follow the same ecological conditions throughout the year, whereas others 'switch niches' between breeding and wintering ranges. Hypotheses regarding the evolution of migration would generally predict niche-following as primitive, and niche-switching as derived. However, no test has, to our knowledge, yet determined the directionality of evolution of these states within a lineage. We present an analysis of phylogenetic dimensions of seasonal niches in the Passerina buntings that indicates greater evolutionary change in the niches of breeding populations than among those of wintering populations. These results are consistent with hypotheses of (i) niche conservatism (in winter, at least) across a recently speciated lineage; and (ii) the derived state of the breeding (rather than winter) ecological niches of each species.


Guidelines for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 11: interbody techniques for lumbar fusion.
The majority of reviewed medical evidence suggests that interbody techniques are associated with higher fusion rates compared with PLF when applied to patients with low-back pain due to DDD limited to one or two levels. The evidence is generally of poor quality and retrospective in nature. Conflicting evidence exists supporting the role of interbody graft placement for improvement of functional outcomes; however, there is no Class I or II evidence to suggest that the use of an interbody graft is associated with worse outcomes, and Class II evidence exists to suggest that outcomes are improved. Complication rates of interbody graft placement, particularly of circumferential procedures, are higher in most series. Many complications, however, are associated with pedicle screw fixation and not with interbody graft placement per se. In the context of a single-level stand-alone ALIF or ALIF with posterior instrumentation, there does not appear to be a substantial benefit to the addition of a PLF. The addition of a PLF to a construct that already includes an interbody graft is, however, associated with increased costs and complications. Therefore, although the addition of supplemental fixation (a 270 degrees fusion) may be necessary for biomechanical reasons, it may not be appropriate to subject the patient to the morbidity of a full posterior exposure for placement of graft material. Significant differences in clinical outcomes between the various interbody techniques have not been convincingly demonstrated. No general recommendation can therefore be made regarding the technique that should be used to achieve interbody fusion.


A FAIR and AI-ready Higgs boson decay dataset.
To enable the reusability of massive scientific datasets by humans and machines, researchers aim to adhere to the principles of findability, accessibility, interoperability, and reusability (FAIR) for data and artificial intelligence (AI) models. This article provides a domain-agnostic, step-by-step assessment guide to evaluate whether or not a given dataset meets these principles. We demonstrate how to use this guide to evaluate the FAIRness of an open simulated dataset produced by the CMS Collaboration at the CERN Large Hadron Collider. This dataset consists of Higgs boson decays and quark and gluon background, and is available through the CERN Open Data Portal. We use additional available tools to assess the FAIRness of this dataset, and incorporate feedback from members of the FAIR community to validate our results. This article is accompanied by a Jupyter notebook to visualize and explore this dataset. This study marks the first in a planned series of articles that will guide scientists in the creation of FAIR AI models and datasets in high energy particle physics.


The transformation of HIV therapy: One pill once a day.
A co-formulated, one pill once a day antiretroviral regimen (single-tablet regimen), containing efavirenz, emtricitabine, and tenofovir disoproxyl fumarate (Atripla), revolutionized the antiretroviral therapy landscape. Single-tablet regimens provide not only dosing convenience but help optimize adherence and persistence with antiretroviral therapy to achieve durably suppressed viremia with both individual and societal benefits. Given the many excellent options available now, single-tablet regimens are the preferred choice for initiating antiretroviral therapy in almost all patients with rare exceptions for drug interactions and pregnancy, and for simplification of more complex antiretroviral therapy to a single-tablet regimen. In this special commemorative article, we celebrate this astounding advancement in antiretroviral therapy, championed by John C. Martin while CEO of Gilead Sciences, and its transformative impact on HIV care nationally and globally.


Glycosides for Peripheral Neuropathic Pain: A Potential Medicinal Components.
Neuropathic pain is a refractory disease that occurs across the world and pharmacotherapy has limited efficacy and/or safety. This disease imposes a significant burden on both the somatic and mental health of patients; indeed, some patients have referred to neuropathic pain as being 'worse than death'. The pharmacological agents that are used to treat neuropathic pain at present can produce mild effects in certain patients, and induce many adverse reactions, such as sedation, dizziness, vomiting, and peripheral oedema. Therefore, there is an urgent need to discover novel drugs that are safer and more effective. Natural compounds from medical plants have become potential sources of analgesics, and evidence has shown that glycosides alleviated neuropathic pain via regulating oxidative stress, transcriptional regulation, ion channels, membrane receptors and so on. In this review, we summarize the epidemiology of neuropathic pain and the existing therapeutic drugs used for disease prevention and treatment. We also demonstrate how glycosides exhibit an antinociceptive effect on neuropathic pain in laboratory research and describe the antinociceptive mechanisms involved to facilitate the discovery of new drugs to improve the quality of life of patients experiencing neuropathic pain.


Diversity in the Extracellular Vesicle-Derived Microbiome of Tissues According to Tumor Progression in Pancreatic Cancer.
This study was conducted to identify the composition and diversity of the microbiome in tissues of pancreatic cancer and to determine its role. First, extracellular vesicles (EVs) were obtained from the paired tumor and normal tissues, and 16s rRNA gene sequencing was performed. We identified the microbiomes, compared the diversity between groups, and found that Tepidimonas was more abundant in tumors. Second, larger tumors resulted in lower levels of Leuconostoc and Sutterella, and increased lymph node metastasis resulted in higher levels of Comamonas and Turicibacter in tumor tissues. Moreover, in the case of tumor recurrence, the levels of Streptococcus and Akkermansia were decreased in tumor tissues. Finally, with the supernatant of Tepidimonasfonticaldi, proliferation and migration of cells increased, and epithelial-mesenchymal transition and the Tricarboxylic Acid (TCA) cycle-related metabolites were enhanced. The composition and diversity of EV-derived microbiomes are important for providing novel insights into theragnostic approaches in pancreatic cancer.


Omega-3 fatty acids decreased irritability of patients with bipolar disorder in an add-on, open label study.
This is a report on a 37-patient continuation study of the open ended, Omega-3 Fatty Acid (O-3FA) add-on study. Subjects consisted of the original 19 patients, along with 18 new patients recruited and followed in the same fashion as the first nineteen. Subjects carried a DSM-IV-TR diagnosis of Bipolar Disorder and were visiting a Mood Disorder Clinic regularly through the length of the study. At each visit, patients' clinical status was monitored using the Clinical Monitoring Form. Subjects reported on the frequency and severity of irritability experienced during the preceding ten days; frequency was measured by way of percentage of days in which subjects experienced irritability, while severity of that irritability was rated on a Likert scale of 1-4 (if present). The irritability component of Young Mania Rating Scale (YMRS) was also recorded quarterly on 13 of the 39 patients consistently. Patients had persistent irritability despite their ongoing pharmacologic and psychotherapy. Omega-3 Fatty Acid intake helped with the irritability component of patients suffering from bipolar disorder with a significant presenting sign of irritability. Low dose (1 to 2 grams per day), add-on O-3FA may also help with the irritability component of different clinical conditions, such as schizophrenia, borderline personality disorder and other psychiatric conditions with a common presenting sign of irritability.


[The CAD-S, an instrument for the assessment of adaptation to divorce - separation].
The CAD-S, an Instrument for the Assessment of Adaptation to Divorce - Separation. This paper presents an instrument for the evaluation of the adaptation to divorce-separation. The CAD-S is a questionnaire created in Spanish, made up of 20 items whose aim is the evaluation of the family's adaptation to divorce-separation, using one of the parents as informant. Data were collected in four different samples of divorced persons and their children from different autonomous comunities from the Spanish state. 223 parents and 160 children from divorced families took part in this study. Four factors emerged, accounting for 52.39 percent of the total variance: psychological and emotional difficulties, conflict with the ex-partner, disposition to co-parentality, and negative outcomes of separation for children. The results suggest that CAD-S appears to be a reliable and valid instrument, with high internal consistency (Cronbach's alpha) and adequate construct validity supported by its relations with measures of satisfaction with life (SWLS), in the case of parents, and conduct problems (CBCL) for children.


Prophylactic negative-pressure wound therapy after cesarean is associated with reduced risk of surgical site infection: a systematic review and meta-analysis.
The objective of the study was to assess the effect of prophylactic negative-pressure wound therapy on surgical site infections and other wound complications in women after cesarean delivery. We searched Ovid Medline, Embase, SCOPUS, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov. We included randomized controlled trials and observational studies comparing prophylactic negative-pressure wound therapy with standard wound dressing for cesarean delivery. The primary outcome was surgical site infection after cesarean delivery. Secondary outcomes were composite wound complications, wound dehiscence, wound seroma, endometritis, and hospital readmission. Heterogeneity was assessed using Higgin's I2. Relative risks with 95% confidence intervals were calculated using random-effects models. Six randomized controlled trials and 3 cohort studies in high-risk mostly obese women met inclusion criteria and were included in the meta-analysis. Six were full-text articles, 2 published abstracts, and 1 report of trial results in ClinicalTrials.gov. Studies were also heterogeneous in the patients included and type of negative-pressure wound therapy device. The risk of surgical site infection was significantly lower with the use of prophylactic negative-pressure wound therapy compared with standard wound dressing (7 studies: pooled risk ratio, 0.45; 95% confidence interval, 0.31-0.66; adjusted risk ratio, -6.0%, 95% confidence interval, -10.0% to -3.0%; number needed to treat, 17, 95% confidence interval, 10-34). There was no evidence of significant statistical heterogeneity (I2 = 9.9%) or publication bias (Egger P = .532). Of the secondary outcomes, only composite wound complications were significantly reduced in patients receiving prophylactic negative-pressure wound therapy compared with standard dressing (9 studies: pooled risk ratio, 0.68, 95% confidence interval, 0.49-0.94). Studies on the effectiveness of prophylactic negative-pressure wound therapy at cesarean delivery are heterogeneous but suggest a reduction in surgical site infection and overall wound complications. Larger definitive trials are needed to clarify the clinical utility of prophylactic negative-pressure wound therapy after cesarean delivery.


Generation of cytotoxic T cell against HBcAg using retrovirally transduced dendritic cells.
Cytotoxic T lymphocytes (CTLs) play an important role in resolving HBV infection. In the present study, we attempted to evaluate the efficiency of bone marrow-derived dendritic cells (DCs) transduced with recombinant retroviral vector bearing hepatitis B virus (HBV) core gene and the capability of generating CTLs against HBcAg by genetically modified DCs in vivo. A retroviral vector containing HBV core gene was constructed. Replicating DC progenitor of C57BL/6 mice was transduced by retroviral vector and continually cultured in the presence of recombinant mouse granulocyte-macrophage colony-stimulating factor (rmGM-CSF) and interleukin-4(IL-4) for 6 days. LPS was added and cultured for additional two days. The efficiency of gene transfer was determined by PCR, Western blot and FACS. Transduced DCs immunized C57BL/6 mice subcutaneously 2 times at an one-week interval. Intracellular IFN-gamma and IL-4 of immunized mice lymphocytes were analyzed. Generation of CTLs in lymphocytes stimulated with mitomycin C-treated EL4-C cell which stably expresses HBcAg was determined by LDH release assays. Recombinant retroviral expression vector (pLCSN) was positively detected by PCR as well as enzyme digestion with EcoRI and BamH I. Retroviruses were generated by pLCSN transfection packing cell and the virus titer was 3 x 10(5) CFU/ml. Indirect immunofluorescence and FACS showed that HBV core gene was expressed in murine fibroblasts. Transduced bone marrow cells had capability of differentiating into DCs in vitro in the presence of rmGM-CSF and rmIL-4. The result of PCR showed that HBV core gene was integrated into the genome of transduced DCs. Western blot analysis showed that HBV core gene was expressed in DCs. The transduction rate was 28 % determined by FACS. Retroviral transduction had no influence on DCs expressions of CD80 and MHC class II. HBcAg specific CTLs and Th1 type immune responses could be generated in the mice by using transduced DCs as antigen presenting cells (APCs). Retroviral transduction of myeloid DCs progenitors expresses efficiently HBcAg, and genetically modified DCs evoke a higher CTLs response than HBcAg in vivo.


Orientation of the tox gene in the prophage of corynebacteriophage beta.
The orientation of the gene for diphtheria toxin, tox, in the prophage of converting corynebacteriophage beta has been determined. The orientation of tox in prophage and that reported simultaneously by Holmes (1976) for vegetative phage are compatible with the hypothesis that beta phage is inserted into the chromosome of its bacterial host by means of a mechanism similar to that described for lambda phage, and that the phage attachment site lies between the tox and imm genes. The position of three tox mutations that are phenotypically CRM- has also been determined. Relative to the tox-45 mutation, they are located more proximally to the end of the tox structural gene that corresponds to the amino terminal of diphtheria toxin.


Parameterization of NMR relaxation curves in terms of logarithmic moments of the relaxation time distribution.
This work addresses the problem of a compact and easily comparable representation of multi-exponential relaxation data. It is often convenient to describe such data in a few parameters, all being of physical significance and easy to interpret, and in such a way that enables a model-free comparison between different groups of samples. Logarithmic moments (LMs) of the relaxation time constitute a set of parameters which are related to the characteristic relaxation time on the log-scale, the width and the asymmetry of an underlying distribution of exponentials. On the other hand, the calculation of LMs does not require knowing the actual distribution function and is reduced to a numerical integration of original data. The performance of this method has been tested on both synthetic and experimental NMR relaxation data which differ in a signal-to-noise ratio, the sampling range and the sampling rate. The calculation of two lower-order LMs, the log-mean time and the log-variance, has proved robust against deficiencies of the experiment such as scattered data point and incomplete sampling. One may consider using them as such to monitor formation of a heterogeneous structure, e.g., in phase separation, vitrification, polymerization, hydration, aging, contrast agent propagation processes. It may also assist in interpreting frequency and temperature dependences of relaxation, revealing a crossover from slow to fast exchange between populations. The third LM was found to be a less reliable quantity due to its susceptibility to the noise and must be used with caution.


Keratin 14 is a novel interaction partner of keratinocyte differentiation regulator: receptor-interacting protein kinase 4.
The epidermis, the outer layer of the skin, is formed by stratified keratinocyte layers. The self-renewal of the epidermis is provided by sustained proliferation and differentiation of the keratinocyte stem cells localized to the basal layer of the epidermis. Receptor-interacting protein kinase 4 (RIPK4) is an important regulator of keratinocyte differentiation, mutations of which are associated with congenital ectodermal malformations. In an attempt to identify the molecular basis of RIPK4's function, we applied yeast two-hybrid screen (Y2H) and found basal layer-specific keratin filament component keratin 14 (KRT14) as a novel RIPK4-interacting partner. During keratinocyte differentiation, layer-specific keratin composition is tightly regulated. Likewise, the basal layer specific KRT14/keratin 5 (KRT5) heterodimers are replaced by keratin 1 (KRT1)/keratin 10 (KRT10) in suprabasal layers. The regulation of keratin turnover is under the control of signaling associated with posttranslational modifications in which phosphorylation plays a major role. In this study, we verified the KRT14-RIPK4 interaction, which was identified with Y2H, in mammalian cells and showed that the interaction was direct by using proteins expressed in bacteria. According to our results, the N-terminal kinase domain of RIPK4 is responsible for KRT14-RIPK4 interaction; however, the RIPK4 kinase activity is dispensable for the interaction. In accordance with their interaction, RIPK4 and KRT14 colocalize within the cells, particularly at keratin filaments associated with perinuclear ring-like structures. Moreover, RIPK4 did not show any effect on KRT14/KRT5 heterodimer formation. Our results suggest that RIPK4 may regulate the keratin turnover required for keratinocyte differentiation through interacting with KRT14.


Reaction Time-Based Cognitive Assessments in Virtual Reality - A Feasibility Study with an Age Diverse Sample.
While virtual reality (VR) is an emerging paradigm in a variety of research contexts, VR-based embodiment effects on behavior and performance still lack in sufficient evidence regarding to bias in cognitive performance assessment. In this methodological observational study, we compare the VR measurement of cognitive performance with a conventional computer-based testing approach in real life (RL) in younger and older adults. The differences between VR and RL scenarios are investigated using the background of two theoretical models from cognitive psychology. Furthermore, data assessment reliability and validity are analyzed, concerning the feasibility of technological and ergonomic aspects. A within-group comparison showed no change in information processing speed in either one of the two age groups, i.e., both groups perform equally well in RL and in a VR testing environment. The use of lifelike VR environments for cognitive performance tests seems not to lead to any performance changes compared to RL computer-based assessments, making VR suitable for similar applications. On technical concerns, we recommend the careful use of reaction time paradigms regarding to input hardware and stimuli presentation.


The Rationale for Repurposing Sildenafil for Lung Cancer Treatment.
There is now a considerable body of evidence for sildenafil possessing anticancer properties. In this article, we argue the case for testing sildenafil as a lung cancer therapy chemoadjuvant. Currently, lung cancer is a disease with insufficient treatment options, with only 20% of patients responding to systemic chemotherapy, and even incremental potential improvements should be explored. We review the literature concerning the biochemical, physiological and metabolic effects on cancer cells by sildenafil alone, and when combined with chemotherapeutic agents. Most studies have shown that sildenafil is cytotoxic to cancer cells, both as a monotherapy and as a chemoadjuvant. Sildenafil enhances cancer cell apoptosis when used as a chemoadjuvant both in vitro and in vivo. In particular, in rodent experiments sildenafil has decreased tumour size compared to chemotherapy alone. Sildenafil has also been proven as an agent to decrease drug-efflux by cancer cells and increases blood perfusion to lung tissue, which can potentially increase the dosage of chemotherapeutic agents delivered to lung cancer cells compared to healthy tissue. In addition, the proven clinical effects of sildenafil on other lung diseases suggest that it could improve other patient outcomes, such as right ventricular function and quality of life. Sildenafil may also extend the half-life of docetaxel and some small molecule inhibitors used in lung cancer treatment by acting as an inhibitor of CYP3A4. We conclude that the evidence strongly warrants clinical investigation into the use of sildenafil as an agent for the treatment of lung-cancer.


The Relationship of Health Behaviors to Childhood Cognition and Brain Health.
Physical activity and aerobic fitness have been shown to have positive implications for children's cognitive performance and brain structure and function. In addition, emerging evidence suggests that excess body mass is related to decreased cognitive performance and differential brain structure and function. Recently, several randomized controlled trials have provided causal evidence for the beneficial effects of daily physical activity on cognition and its neural underpinnings. However, the data linking excess body mass to compromised cognitive function are largely correlational since trials that manipulate body mass to determine changes in brain and cognition remain sparse. Such studies are sorely needed to provide strong evidence for the relation of childhood health behaviors to not only physical, but brain health as well. This manuscript provides a brief review of the current literature on physical activity and excess body mass on brain structure, brain function, and an aspect of cognition known as executive control, which refers to cognitive processes involved in the intentional component of environmental interaction. Generally, the findings indicate that daily physical activity or higher aerobic fitness is related to greater volume and integrity of brain structure, efficient and effective brain function, and superior executive control. Alternatively, excess body mass is related to decreased integrity of brain structure, less effective brain function, and poorer executive control. Key Messages: The findings have considerable implications for lifespan health and effective functioning, and demonstrate that childhood health behaviors have implications not only for cognitive and brain health but also for scholastic performance and educational attainment.


Passive biaxial mechanical response of aged human iliac arteries.
Inflation and extension tests of arteries are essential for the understanding of arterial wall mechanics. Data for such tests of human arteries are rare. At autopsy we harvested 10 non-diseased external iliac arteries of aged subjects (52-87 yrs). Structural homogeneity was ensured by means of ultrasound imaging, and anamneses of patients were recorded. We measured the axial in situ stretches, load-free geometries and opening angles. Passive biaxial mechanical responses of preconditioned cylindrical specimens were studied in 37 degrees C calcium-free Tyrode solution under quasistatic loading conditions. Specimens were subjected to pressure cycles varying from 0 to 33.3 kPa (250 mmHg) at nine fixed axial loads, varying from 0 to 9.90N. For the description of the load-deformation behavior we employed five "two-dimensional" orthotropic strain-energy functions frequently used in arterial wall mechanics. The associated constitutive models were compared in regard to their ability of representing the experimental data. Histology showed that the arteries were of the muscular type. In contrast to animal arteries they exhibited intimal layers of considerable thickness. The average ratio of wall thickness to outer diameter was 7.7, which is much less than observed for common animal arteries. We found a clear correlation between age and the axial in situ stretch lambda is (r = -0.72, P = 0.03), and between age and distensibility of specimens, i.e. aged specimens are less distensible. Axial in situ stretches were clearly smaller (1.07 +/- 0.09, mean +/- SD) than in animal arteries. For one specimen lambda is was even smaller than 1.0, i.e. the vessel elongated axially upon excision. The nonlinear and anisotropic load-deformation behavior showed small hystereses. For the majority of specimens we observed axial stretches smaller than 1.3 and circumferential stretches smaller than 1.1 for the investigated loading range. Data from in situ inflation tests showed a significant increase of the axial stretch with intraluminal pressure. Thus, for this type of artery the axial in situ stretch of a non-pressurized vessel is not representative of the axial in vivo stretch. None of the constitutive models were able to represent the deformation behavior of the entire loading range. For the physiological loading range, however, some of the models achieved good agreement with the experimental data.


Ca2+ channel subtypes and pharmacology in the kidney.
A large body of evidence has accrued indicating that voltage-gated Ca(2+) channel subtypes, including L-, T-, N-, and P/Q-type, are present within renal vascular and tubular tissues, and the blockade of these Ca(2+) channels produces diverse actions on renal microcirculation. Because nifedipine acts exclusively on L-type Ca(2+) channels, the observation that nifedipine predominantly dilates afferent arterioles implicates intrarenal heterogeneity in the distribution of L-type Ca(2+) channels and suggests that it potentially causes glomerular hypertension. In contrast, recently developed Ca(2+) channel blockers (CCBs), including mibefradil and efonidipine, exert blocking action on L-type and T-type Ca(2+) channels and elicit vasodilation of afferent and efferent arterioles, which suggests the presence of T-type Ca(2+) channels in both arterioles and the distinct impact on intraglomerular pressure. Recently, aldosterone has been established as an aggravating factor in kidney disease, and T-type Ca(2+) channels mediate aldosterone release as well as its effect on renal efferent arteriolar tone. Furthermore, T-type CCBs are reported to exert inhibitory action on inflammatory process and renin secretion. Similarly, N-type Ca(2+) channels are present in nerve terminals, and the inhibition of neurotransmitter release by N-type CCBs (eg, cilnidipine) elicits dilation of afferent and efferent arterioles and reduces glomerular pressure. Collectively, the kidney is endowed with a variety of Ca(2+) channel subtypes, and the inhibition of these channels by their specific CCBs leads to variable impact on renal microcirculation. Furthermore, multifaceted activity of CCBs on T- and N-type Ca(2+) channels may offer additive benefits through nonhemodynamic mechanisms in the progression of chronic kidney disease.


The economic impact of methicillin-resistant Staphylococcus aureus in Canadian hospitals.
To determine the costs associated with the management of hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA), and to estimate the economic burden associated with MRSA in Canadian hospitals. Patient-specific costs were used to determine the attributable cost of MRSA associated with excess hospitalization and concurrent treatment. Excess hospitalization for infected patients was identified using the Appropriateness Evaluation Protocol, a criterion-based chart review process to determine the need for each day of hospitalization. Concurrent treatment costs were identified through chart review for days in isolation, antimicrobial therapy, and MRSA screening tests. The economic burden to Canadian hospitals was estimated based on 3,167,521 hospital discharges for 1996 and 1997 and an incidence of 4.12 MRSA cases per 1,000 admissions. A tertiary-care, university-affiliated teaching hospital in Toronto, Ontario, Canada. Inpatients with at least one culture yielding MRSA between April 1996 and March 1998. A total of 20 patients with MRSA infections and 79 colonized patients (with 94 admissions) were identified. This represented a rate of 2.9 MRSA cases per 1,000 admissions. The mean number of additional hospital days attributable to MRSA infection was 14, with 11 admissions having at least 1 attributable day. The total attributable cost to treat MRSA infections was $287,200, or $14,360 per patient The cost for isolation and management of colonized patients was $128,095, or $1,363 per admission. Costs for MRSA screening in the hospital were $109,813. Assuming an infection rate of 10% to 20%, we determined the costs associated with MRSA in Canadian hospitals to be $42 million to $59 million annually. These results indicate that there is a substantial economic burden associated with MRSA in Canadian hospitals. These costs will continue to rise if the incidence of MRSA increases further.


Transdermal fentanyl combined with nonsteroidal anti-inflammatory drugs for analgesia in horses.
This study investigated the pharmcokinetics, efficacy, and safety of the fentanyl transdermal therapeutic system (TTS) in horses in which there was an inadequate analgesic response to nonsteroidal anti-inflammatory drugs (NSAIDs) alone. Nine horses with pain that was refractory to therapeutic doses of phenylbutazone (n = 3) or flunixin meglumine (n = 6) subsequently also received between 39 and 110 microg/kg of transdermal fentanyl. Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 12, 24, 36, 48, 60, and 72 hours after patch application, and a radioimmunoassay was used to determine serum fentanyl concentrations. Pharmacokinetic values were determined by noncompartmental analysis. Physical examination findings were recorded in all horses, and pain and lameness grading systems were used to assign scores to 8 and 6 horses, respectively. All horses tolerated the administration of fentanyl TTS, in that no clinically significant adverse effects attributable to fentanyl were observed. Use of the TTS resulted in variable serum concentrations of fentanyl, with a peak serum concentration of 2.2+/-1.1 ng/mL (mean+/-SD) and a time to peak serum concentration of 26+/-13 hours. After transdermal fentanyl administration, mean time to reach serum fentanyl concentrations consistent with analgesia in other species (1 ng/mL) was 14 hours. In addition, serum fentanyl concentrations of 1 ng/mL or greater were maintained in all but one horse for at least 18 hours. Pain scores were significantly decreased after fentanyl TTS and NSAID administration (P < .05), but lameness scores were not significantly different (P > .05). Overall, administration of fentanyl TTS had a favorable pharmacokinetic profile in horses with clinical pain, and the fentanyl TTS in combination with NSAIDs appeared to provide safe and effective analgesia in most of the horses with pain that was refractory to NSAID therapy alone.


Effect of a 12-Week Physical Activity Program on Gross Motor Skills in Children.
This study examined the effects of a 12-week Comprehensive School Physical Activity Program (CSPAP) on gross motor skill development in children from low-income families. Participants were 1,460 school-aged children (mean age = 8.4 ± 1.8 years; 730 girls, 730 boys) recruited from three schools receiving U.S. governmental financial assistance. Students were recruited from grades K-6. CSPAP was implemented over one semester during the 2014-2015 school year. Select gross motor skill items were assessed during each student's physical education class at baseline and at a 12-week follow-up using the Test for Gross Motor Development-2nd Edition (TGMD-2). Each student's TGMD-2 score was converted to a percentage of the total possible score. A 7 × 2 × 2 analysis of variance test with repeated measures was employed to examine the effects of age, sex, and time on TGMD-2 percent scores, adjusting for clustering within the data structure. There were greater TGMD-2 percent scores at follow-up compared with baseline (82.4% vs. 72.6%, mean difference = 9.8%, p < .001, Cohen's d = 0.67), and greater improvements were seen in younger children compared with older children (mean difference of change = 4.0%-7.5%, p < .01, Cohen's d = 0.30-0.55).


Diagnosis of catheter-related bloodstream infection in a total parenteral nutrition population: inclusion of sepsis defervescence after removal of culture-positive central venous catheter.
Defervescence of sepsis after removal of culture-positive central venous catheters (CVCs) has been advocated for diagnosis of catheter-related bloodstream infection (CRBSI) even without positive blood culture. However, most studies report CRBSI incidence only when blood cultures, and CVC tip, are positive (standard definition). We examined the effect of inclusion of defervescence criteria on CRBSI incidence in a total parenteral nutrition (TPN) population. The study was carried out in a 525 bed tertiary referral hospital for a period of 12 years. CRBSI incidence was compared between standard definition (positive CVC tip culture and positive blood culture) and when 'defervescence criteria' were included. Sepsis defervescence was defined as a fall in temperature, white cell count and sepsis resolution after CVC removal, with positive CVC tip culture, but negative blood cultures. CRBSI episodes in which a blood culture was omitted were excluded. The study population included 1365 patients in whom 2536 CVCs were used over a period of 15 234 CVC-days. There were 192 CRBSI episodes in 165 patients. In all, 152 CRBSI episodes met only the standard criteria for CRBSI whereas 40 episodes met the defervescence criteria. The standard definition alone resulted in a mean (+/- SD) incidence of 10.6+/-5.8 per 1000 CVC-days. This increased to 13+/-6.4 per 1000 CVC-days when defervescence criteria were included. Inclusion of defervescence criteria increased CRBSI incidence by a mean of 2.5+/-1.4 episodes per 1000 days or 27% (95% CI: 1.61-3.339; P<0.001). This study implies that the scale of CRBSI may be higher than is currently recognised and that the blood culture positivity rate for CRBSI is 79% (152/192).


Human immune response to monoclonal antibody administration is dose-dependent.
When mouse monoclonal antibodies (MAbs) are injected into patients they usually induce an immune response. The resultant human anti-mouse-immunoglobulin antibody (Hu-aMAb) limits multiple injections of these reagents. A strategy to decrease the production of Hu-aMAb was tested in 20 patients with advanced gastrointestinal carcinoma. Ten patients received 700 mg of MAb as their initial exposure to mouse immunoglobulin, while the other ten patients received 100-mg of immunoglobulin initially. Each group received the same maintenance regimen until Hu-aMAb or disease progression was detected. Six patients in the high-dose group did not produce detectable Hu-aMAb for up to five months after initial exposure. All ten of the patients who received the low initial dose developed Hu-aMAb. Allergic reaction did not occur in the absence of Hu-aMAb. This larger initial dose in vivo injection strategy may allow repetitive exposure to MAb reagents without Hu-aMAb limiting further diagnostic or therapeutic use of murine immunoglobulin.


Resource use by abused women following an intervention program: associated severity of abuse and reports of abuse ending.
Although violence against women is recognized as major public health problem, little is known about the effectiveness of interventions. To evaluate severity of abuse and use of community resources following an intervention program, 132 pregnant abused women received three counseling sessions in a prenatal setting. A comparison group of 67 abused women were offered a wallet-sized card listing community resources for violence. Resource use, severity of abuse, and reports of the abuse ending were measured for both groups at 6 and 12 months after delivery. Resource use was significantly (p < .001) related to severity of abuse, irrespective of whether the woman had received the intervention. Women using resources at 6 months were also users at 12 months. These findings indicate a "survivorship model" whereby abused women assertively and persistently seek a variety of community resources to end the abuse. The recommendation that primary care providers go beyond traditional identification and referral for abuse to coordination and evaluation of service delivery is discussed.


Importance in diagnosis of gastritis of detection by PCR of the cagA gene in Helicobacter pylori strains isolated from children.
The cagA gene has been detected by PCR and DNA hybridization in 45 Helicobacter pylori strains isolated from children. For each child, clinical symptoms, endoscopic aspect of the gastric mucosa, and histological gastritis were evaluated. Gene-positive strains were associated with hemorrhagic gastritis in 66.6% of the children, while gene-negative strains were associated with hemorrhagic gastritis in 11.2% of the children (P = 0.0001). In addition, 88.8% of gene-positive strains were associated with severe histological gastritis (scores of 3 and 4), and gene-negative strains were collected from the gastric mucosa with the same type of infiltration of neutrophils and lymphocytes in the lamina propia in 55.5% of the children. These differences were statistically significant (P = 0.017). Gene-positive strains were also isolated more frequently from children with vomiting (P = 0.04), while the absence of clinical signs was not significantly different in cagA gene-positive or -negative patients. All of these observations confirmed the role of this cagA gene as a marker of gastric inflammation in children. The detection of this gene might be helpful to determine the degree of inflammation of the gastric mucosa in the absence of abdominal symptoms. We might better understand the natural history of H. pylori infection if we studied the evolution of gastritis in children with regard to the cagA status of isolated strains.


Alcohol and tobacco use prediagnosis and postdiagnosis, and survival in a cohort of patients with early stage cancers of the oral cavity, pharynx, and larynx.
As more people begin to survive first cancers, there is an increased need for science-based recommendations to improve survivorship. For survivors of head and neck cancer, use of tobacco and alcohol before diagnosis predicts poorer survival; however, the role of continuing these behaviors after diagnosis on mortality is less clear, especially for more moderate alcohol consumption. Patients (n = 264) who were recent survivors of early stage head and neck cancer were asked to retrospectively report their tobacco and alcohol histories (before diagnosis), with information prospectively updated annually thereafter. Patients were followed for an average of 4.2 years, with 62 deaths observed. Smoking history before diagnosis dose-dependently increased the risk of dying; risks reached 5.4 [95% confidence interval (95% CI), 0.7-40.1] among those with >60 pack-years of smoking. Likewise, alcohol history before diagnosis dose-dependently increased mortality risk; risks reached 4.9 (95% CI, 1.5-16.3) for persons who drank >5 drinks/d, an effect explained by beer and liquor consumption. After adjusting for prediagnosis exposures, continued drinking (average of 2.3 drinks/d) postdiagnosis significantly increased risk (relative risk for continued drinking versus no drinking, 2.7; 95% CI, 1.2-6.1), whereas continued smoking was associated with nonsignificantly higher risk (relative risk for continued smoking versus no smoking, 1.8; 95% CI, 0.9-3.9). Continued drinking of alcoholic beverages after an initial diagnosis of head and neck cancer adversely affects survival; cessation efforts should be incorporated into survivorship care of these patients.


[Determination of the expected day of delivery--ultrasound has not been shown to be more accurate than the calendar method].
It has been claimed that the expected day of delivery (EDD) determined on the basis of an ultrasound scan is more accurate than using a calendar method. The aim of this paper is to assess the evidence in support of this claim. A critical review of the methodologically best research revealed that among women with regular cycles and know first day of the last menstrual period, Naegele's rule predicted the EDD to be 3.3 days too early, on average, whereas prediction based on ultrasound scans was 2.0 days too late. The standard deviations of the two distributions were the same. After correction for the systematic biases, the two methods of prediction were thus equally precise. It is concluded that the EDD should be calculated by adding 283 days to the date of the last period rather than by adding 280 days. For women with regular cycles and known first day of the last menstrual period, ultrasound dating does not lead to a more precise prediction.


HEARING, PSYCHOPHYSICS, AND COCHLEAR IMPLANTATION: EXPERIENCES OF OLDER INDIVIDUALS WITH MILD SLOPING TO PROFOUND SENSORY HEARING LOSS.
In a previous paper we reported the frequency selectivity, temporal resolution, nonlinear cochlear processing, and speech recognition in quiet and in noise for 5 listeners with normal hearing (mean age 24.2 years) and 17 older listeners (mean age 68.5 years) with bilateral, mild sloping to profound sensory hearing loss (Gifford et al., 2007). Since that report, 2 additional participants with hearing loss completed experimentation for a total of 19 listeners. Of the 19 with hearing loss, 16 ultimately received a cochlear implant. The purpose of the current study was to provide information on the pre-operative psychophysical characteristics of low-frequency hearing and speech recognition abilities, and on the resultant postoperative speech recognition and associated benefit from cochlear implantation. The current preoperative data for the 16 listeners receiving cochlear implants demonstrate: 1) reduced or absent nonlinear cochlear processing at 500 Hz, 2) impaired frequency selectivity at 500 Hz, 3) normal temporal resolution at low modulation rates for a 500-Hz carrier, 4) poor speech recognition in a modulated background, and 5) highly variable speech recognition (from 0 to over 60% correct) for monosyllables in the bilaterally aided condition. As reported previously, measures of auditory function were not significantly correlated with pre- or post-operative speech recognition - with the exception of nonlinear cochlear processing and preoperative sentence recognition in quiet (p=0.008) and at +10 dB SNR (p=0.007). These correlations, however, were driven by the data obtained from two listeners who had the highest degree of nonlinearity and preoperative sentence recognition. All estimates of postoperative speech recognition performance were significantly higher than preoperative estimates for both the ear that was implanted (p<0.001) as well as for the best-aided condition (p<0.001). It can be concluded that older individuals with mild sloping to profound sensory hearing loss have very little to no residual nonlinear cochlear function, resulting in impaired frequency selectivity as well as poor speech recognition in modulated noise. These same individuals exhibit highly significant improvement in speech recognition in both quiet and noise following cochlear implantation. For older individuals with mild to profound sensorineural hearing loss who have difficulty in speech recognition with appropriately fitted hearing aids, there is little to lose in terms of psychoacoustic processing in the low-frequency region and much to gain with respect to speech recognition and overall communication benefit. These data further support the need to consider factors beyond the audiogram in determining cochlear implant candidacy, as older individuals with relatively good low-frequency hearing may exhibit vastly different speech perception abilities - illustrating the point that signal audibility is not a reliable predictor of performance on supra-threshold tasks such as speech recognition.


Validation of the Japanese version of comorbid conditions questionnaire (CCQ-J) and recent physical symptoms questionnaire (RPSQ-J).
The comorbid conditions questionnaire (CCQ) and the recent physical symptoms questionnaire (RPSQ) have been validated in the US for the evaluation of comorbid physical conditions in patients with irritable bowel syndrome (IBS). A lack of instruments to assess somatization in Japanese subjects with IBS warrants development of the Japanese versions of these questionnaires. The purpose of this study was to validate the Japanese versions created, the CCQ-J and RPSQ-J. Study 1 was carried out to verify the test-retest reliability and internal consistency of the CCQ-J and RPSQ-J in 49 patients with functional bowel disorder. Study 2 was performed to confirm the construct validities of these questionnaires compared to the Cornell Medical Index (CMI) in 120 patients with psychosomatic symptoms (assigned to the somatoform disorder, anxiety disorder, depressive disorder, or IBS group) and 22 healthy subjects. In Study 1, high reproducibility and high intraclass correlation coefficients were demonstrated for these questionnaires. In Study 2, total score on the CMI was significantly associated with score on the CCQ-J and on the RPSQ-J in the IBS group. The proportion of patients with chronic back pain was significantly higher in the IBS group than in controls (27.3% vs. 18.5%, p<0.05). The CCQ-J and RPSQ-J are valid and reliable instruments for evaluating comorbid conditions in Japanese patients with IBS. Further studies are needed to confirm the direct cross-cultural comparison of the impact of somatization in IBS between different countries.


Learning regions of interest from low level maps in virtual microscopy.
Virtual microscopy can improve the workflow of modern pathology laboratories, a goal limited by the large size of the virtual slides (VS). Lately, determination of the Regions of Interest has shown to be useful in navigation and compression tasks. This work presents a novel method for establishing RoIs in VS, based on a relevance score calculated from example images selected by pathologist. The process starts by splitting the Virtual Slide (VS) into a grid of blocks, each represented by a set of low level features which aim to capture the very basic visual properties, namely, color, intensity, orientation and texture. The expert selects then two blocks i.e. A typical relevant (irrelevant) instance. Different similarity (disimilarity) maps are then constructed, using these positive (negative) examples. The obtained maps are then integrated by a normalization process that promotes maps with a similarity global maxima that largely exceeds the average local maxima. Each image region is thus entailed with an associated score, established by the number of closest positive (negative) blocks, whereby any block has also an associated score. Evaluation was carried out using 8 VS from different tissues, upon which a group of three pathologists had navigated. Precision-recall measurements were calculated at each step of any actual navigation, obtaining an average precision of 55% and a recall of about 38% when using the available set of navigations.


Adenocarcinoma of an Ileostomy in a Case of Hirschprung's Disease with Retroviral Disease.
The number of ileostomies created for benign diseases such as familial adenomatous polyposis and ulcerative colitis is increasing. Long-term ileostomies are prone to develop various complications over time. Ileostomy site carcinoma is a well-established complication in ulcerative colitis and familial adenomatous polyposis that have undergone total colectomy. However, no case of ileostomy site carcinoma has been described in a patient with Hirschprung's disease. We present the first case of adenocarcinoma at an ileostomy site in a patient with Hirschprung's disease with retroviral disease.


Overview of the main methods used to combine proteins with nanosystems: absorption, bioconjugation, and encapsulation.
The latest development of protein engineering allows the production of proteins having desired properties and large potential markets, but the clinical advances of therapeutical proteins are still limited by their fragility. Nanotechnology could provide optimal vectors able to protect from degradation therapeutical biomolecules such as proteins, enzymes or specific polypeptides. On the other hand, some proteins can be also used as active ligands to help nanoparticles loaded with chemotherapeutic or other drugs to reach particular sites in the body. The aim of this review is to provide an overall picture of the general aspects of the most successful approaches used to combine proteins with nanosystems. This combination is mainly achieved by absorption, bioconjugation and encapsulation. Interactions of nanoparticles with biomolecules and caveats related to protein denaturation are also pointed out. A clear understanding of nanoparticle-protein interactions could make possible the design of precise and versatile hybrid nanosystems. This could further allow control of their pharmacokinetics as well as activity, and safety.


Hepatocyte expression of serum response factor is essential for liver function, hepatocyte proliferation and survival, and postnatal body growth in mice.
Serum response factor (SRF) is a transcription factor that binds to a CarG box motif within the serum response element of genes that are expressed in response to mitogens. SRF plays essential roles in muscle and nervous system development; however, little is known about the role of SRF during liver growth and function. To examine the function of SRF in the liver, we generated mice in which the Srf gene was specifically disrupted in hepatocytes. The survival of mice lacking hepatic SRF activity was lower than that of control mice; moreover, surviving mutant mice had lower blood glucose and triglyceride levels compared with control mice. In addition, Srf(loxP/loxP)AlfpCre mice were smaller and had severely depressed levels of serum insulin-like growth factor 1 (IGF-1). Srf-deficient livers were also smaller than control livers, and liver cell proliferation and viability were compromised. Gene array analysis of SRF depleted livers revealed a reduction in many messenger RNAs, including those encoding components of the growth hormone/IGF-1 pathway, cyclins, several metabolic regulators, and cytochrome p450 enzymes. SRF is essential for hepatocyte proliferation and survival, liver function, and control of postnatal body growth by regulating hepatocyte gene expression.


Implementation of pharmacogenetic testing in oncology: DPYD-guided dosing to prevent fluoropyrimidine toxicity in British Columbia.
Background: Fluoropyrimidine toxicity is often due to variations in the gene (DPYD) encoding dihydropyrimidine dehydrogenase (DPD). DPYD genotyping can be used to adjust doses to reduce the likelihood of fluoropyrimidine toxicity while maintaining therapeutically effective drug levels. Methods: A multiplex QPCR assay was locally developed to allow genotyping for six DPYD variants. The test was offered prospectively for all patients starting on fluoropyrimidines at the BC Cancer Centre in Vancouver and then across B.C., Canada as well as retrospectively for patients suspected to have had an adverse reaction to therapy. Dose adjustments were made for variant carriers. The incidence of toxicity in the first three cycles was compared between DPYD variant allele carriers and non-variant carriers. Subsequent to an initial implementation phase, this test was made available province-wide. Results: In 9 months, 186 patients were tested and 14 were found to be heterozygous variant carriers. Fluoropyrimidine-related toxicity was higher in DPYD variant carriers. Of 127 non-variant carriers who have completed chemotherapy, 18 (14%) experienced severe (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Of note, 22% (3 patients) of the variant carriers experienced severe toxicity even after DPYD-guided dose reductions. For one of these carriers who experienced severe thrombocytopenia within the first week, DPYD testing likely prevented lethal toxicity. In DPYD variant carriers who tolerate reduced doses, a later 25% increase led to chemotherapy discontinuation. As a result, a recommendation was made to clinicians based on available literature and expert opinion specifying that variant carriers who tolerated two cycles without toxicity can have a dose escalation of only 10%. Conclusion: DPYD-guided dose reductions were a feasible and acceptable method of preventing severe toxicity in DPYD variant carriers. Even with dose reductions, there were variant carriers who still experienced severe fluoropyrimidine toxicity, highlighting the importance of adhering to guideline-recommended dose reductions. Following the completion of the pilot phase of this study, DPYD genotyping was made available province-wide in British Columbia.


Coexpression of MEIOTIC-TOPOISOMERASE VIB-dCas9 with guide RNAs specific to a recombination hotspot is insufficient to increase crossover frequency in Arabidopsis.
During meiosis, homologous chromosomes pair and recombine, which can result in reciprocal crossovers that increase genetic diversity. Crossovers are unevenly distributed along eukaryote chromosomes and show repression in heterochromatin and the centromeres. Within the chromosome arms, crossovers are often concentrated in hotspots, which are typically in the kilobase range. The uneven distribution of crossovers along chromosomes, together with their low number per meiosis, creates a limitation during crop breeding, where recombination can be beneficial. Therefore, targeting crossovers to specific genome locations has the potential to accelerate crop improvement. In plants, meiotic crossovers are initiated by DNA double-strand breaks that are catalyzed by SPO11 complexes, which consist of 2 catalytic (SPO11-1 and SPO11-2) and 2 noncatalytic subunits (MTOPVIB). We used the model plant Arabidopsis thaliana to coexpress an MTOPVIB-dCas9 fusion protein with guide RNAs specific to the 3a crossover hotspot. We observed that this was insufficient to significantly change meiotic crossover frequency or pattern within 3a. We discuss the implications of our findings for targeting meiotic recombination within plant genomes.


Warm partner contact is related to lower cardiovascular reactivity.
The authors investigated the relationship between brief warm social and physical contact among cohabitating couples and blood pressure (BP) reactivity to stress in a sample of healthy adults (66 African American, 117 Caucasian; 74 women, 109 men). Prior to stress, the warm contact group underwent a 10-minute period of handholding while viewing a romantic video. Followed by a 20-second hug with their partner, while the no contact group rested quietly for 10 minutes and 20 seconds. In response to a public speaking task, individuals receiving prestress partner contact demonstrated lower systolic BP diastolic BP, and heart rate increases compared with the no contact group. The effects of warm contact were comparable for men and women and were greater for African Americans compared with Caucasians. These findings suggest that affectionate relationships with a supportive partner may contribute to lower reactivity to stressful life events and may partially mediate the benefit of marital support on better cardiovascular health.


T-wave alternans phase following ventricular extrasystoles predicts arrhythmia-free survival.
The purpose of this study was to assess the value of T-wave alternans (TWA) following ventricular extrasystoles in predicting arrhythmia-free survival. Stratifying risk for sudden death in patients with coronary disease and moderate left ventricular (LV) dysfunction remains a challenge. We hypothesized that, in such patients, a discontinuity in beat-to-beat T-wave alternation (TWA phase reversal) following single ventricular extrasystoles reflects transiently exaggerated repolarization dispersion, and predicts spontaneous ventricular arrhythmias. We studied 59 patients with ischemic LV dysfunction (mean LV ejection fraction 38.7 +/- 5.3%) and nonsustained ventricular tachycardia undergoing programmed stimulation. TWA was computed spectrally from the ECG during ventricular pacing, and TWA phase reversal was reflected by a discontinuity in T-wave oscillation after single ventricular extrasystoles. Patients induced into ventricular arrhythmias (n = 36) had greater TWA magnitude (V(alt): 6.60 +/- 6.46 microV vs 2.61 +/- 1.97 microV; P = .001) and more frequent TWA phase reversal (62.1% vs 44.4%; P = .02) than those who were not (n = 23). During a mean follow-up of 36 +/- 12 months, positive TWA (V(alt) > or =1.9 microV) and TWA phase reversal both (P < .05) predicted events (all-cause mortality, ventricular tachycardia, ventricular fibrillation). Univariate predictors of arrhythmia-free survival were TWA phase reversal (P < .005), positive TWA (P < .05), age (P = .008), and LV mass index (P = .043). On multivariate analysis, only TWA phase reversal and age predicted events; if TWA phase was excluded, only positive TWA and age predicted events. Phase reversal in TWA following ventricular extrasystoles predicts spontaneous ventricular arrhythmias and all-cause mortality in patients with moderate ischemic LV dysfunction and was a better predictor than positive TWA or programmed ventricular stimulation.


The Cleanroom-Free, Cheap, and Rapid Fabrication of Nanoelectrodes with Low zM Limits of Detection.
Nanoscale electrodes have been a topic of intense research for many decades. Their enhanced sensitivities, born out of an improved signal-to-noise ratio as electrode dimensions decrease, make them ideal for the development of low-concentration analyte sensors. However, to date, nanoelectrode fabrication has typically required expensive equipment and exhaustive, time-consuming fabrication methods that have rendered them unsuitable for widespread use and commercialization. Herein, a method of nanoband electrode fabrication using low cost materials and equipment commonly found in research laboratories around the world is reported. The materials' cost to produce each nanoband is less than €0.01 and fabrication of a batch takes less than 1 h. The devices can be made of flexible plastics and their designs can be quickly and easily iterated. Facile methods of combining these nanobands into powerful devices, such as complete three-electrode systems, are also displayed. As a proof of concept, the electrodes are functionalized for the detection of a DNA sequence specific to SARS-CoV-2 and found to display single molecule sensitivity.


Fifteen years of phenotypic and genotypic surveillance and antibiotic susceptibility pattern of Actinomycetes (Mycobacterium, Nocardia, Rhodococcus, etc.) in clinical and environmental samples of Iran.
Actinomycetes, ubiquitous in the natural world, have been known to inflict infections upon both immunocompromised and healthy individuals. Interestingly enough, these species are oftentimes found residing within the microbiota of humans and animals alike. Unfortunately, these infections are frequently misdiagnosed as more sinister ailments such as malignancy or tuberculosis. Due to this issue, this review deals with 15 years of study on clinical and environmental samples to determine Actinomycetes' prevalence, isolation, identification, and antibiotic susceptibility pattern in Iran by Davood Azadi et al. According to the Davood Azadi framework, we searched the following databases: PubMed/MEDLINE, Embase, Scopus, Web of Science, SID, and Google Scholar in the period from 2007 to 2023. This review aimed to provide an overview of the most recent techniques for collecting environmental samples, cultivating them, and identifying the Actinomycetes group's members. The isolation of Actinomycetes from clinical and ecological sources is becoming more prevalent and should be a concern for health authorities in developing countries. Health centers should take action to increase awareness of diagnostic criteria and management guidelines for actinomycete diseases. Improvements in national and regional reference laboratories may also aid in accurately diagnosing these diseases.


Chemoprevention of azoxymethane/dextran sodium sulfate-induced mouse colon carcinogenesis by freeze-dried yam sanyaku and its constituent diosgenin.
The effects of sanyaku, a traditional Chinese medicine [freeze-dried powder of the yam tuber (Dioscorea)], and its major steroidal saponin constituent, diosgenin, on colon carcinogenesis were investigated. Male ICR mice were subjected to a single intraperitoneal injection of azoxymethane (AOM; 10 mg/kg body weight) followed by administration of 1.5% dextran sodium sulfate (DSS) in drinking water for 7 days to establish carcinogenesis. Commercial diosgenin or sanyaku, which contained diosgenin at 63.8 ± 1.2 mg/kg dry weight, was given in the diet at 20, 100, or 500 mg/kg for 17 weeks. Groups of mice that received diosgenin or sanyaku at all doses yielded significantly less number of colon tumors compared with the AOM/DSS-treated mice. Occurrence of colonic mucosal ulcer and dysplastic crypt induced by AOM/DSS treatment was also significantly decreased by the administration of diosgenin and sanyaku, which was in accordance with the significant reduction of AOM/DSS-mediated increases in expression of inflammatory cytokines such as IL-1β by diosgenin and sanyaku. Furthermore, elevated levels of serum triglyceride in the AOM/DSS-treated mice tended to be reduced in mice given diosgenin and sanyaku. Microarray and real-time reverse transcriptase PCR analyses revealed that diosgenin administration increased 12-fold the expression of lipoprotein lipase, which may contribute to reduced serum triglyceride levels. Other genes altered by diosgenin included those associated with antioxidative stress responses and apoptosis, such as heme oxygenase-1, superoxide dismutase-3, and caspase-6. Our results imply that the Chinese medicine sanyaku and the tubers of various yams containing diosgenin as food could be ingested to prevent colon carcinogenesis in humans.


Recent advances in edible coatings for fresh and minimally processed fruits.
The development of new edible coatings with improved functionality and performance for fresh and minimally processed fruits is one of the challenges of the post harvest industry. In the past few years, research efforts have focused on the design of new eco-friendly coatings based on biodegradable polymers, which not only reduce the requirements of packaging but also lead to the conversion of by-products of the food industry into value added film-forming components. This work reviews the different coating formulations and applications available at present, as well as the main results of the most recent investigations carried out on the topic. Traditionally, edible coatings have been used as a barrier to minimize water loss and delay the natural senescence of coated fruits through selective permeability to gases. However, the new generation of edible coatings is being especially designed to allow the incorporation and/or controlled release of antioxidants, vitamins, nutraceuticals, and natural antimicrobial agents by means of the application of promising technologies such as nanoencapsulation and the layer-by-layer assembly.


The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission.
Striking differences in Kaposi's sarcoma (KS) risk for AIDS patients who acquire HIV via homosexual activity and those whose HIV infections derive from blood product exposure suggest the presence of a sexually transmitted agent other than HIV in the development of KS. Using an immunofluorescence assay, we examined serum samples from 913 patients for the presence of antibody specific for infection by human herpesvirus 8 (HHV8), an agent whose genome is regularly found in KS tissue. The distribution of HHV8 seropositivity conforms to that expected for a sexually transmitted pathogen and tracks closely with the risk for KS development. Our data support the inference that this virus is the etiologic cofactor predicted by the epidemiology of KS.