ADPKD: a human disease altering Golgi function and basolateral exocytosis in renal epithelia.
Epithelial cells explanted from autosomal dominant polycystic kidney disease (ADPKD) tissue exhibit impaired exocytosis, specifically between the Golgi and basolateral membrane (Charron A, Nakamura B, Bacallo R, Wandinger-Ness A. Compromised cytoarchitecture and polarized trafficking in autosomal dominant polycystic kidney disease cells. J Cell Biol 2000; 148: 111-124.). Here the defect is shown to result in the accumulation of the basolateral transport marker vesicular stomatitis virus (VSV) G protein in the Golgi complex. Golgi complex morphology is consequently altered in the disease cells, evident in the noticeable fenestration and dilation of the cisternae. Further detailed microscopic evaluation of normal kidney and ADPKD cells revealed that ineffective basolateral exocytosis correlated with modulations in the localization of select post-Golgi transport effectors. The cytosolic coat proteins p200/myosin II and caveolin exhibited enhanced association with the cytoskeleton or the Golgi of the disease cells, respectively. Most cytoskeletal components with known roles in vesicle translocation or formation were normally arrayed with the exception of Golgi beta-spectrin, which was less prevalent on vesicles. The rab8 GTPase, important for basolateral vesicle targeting, was redistributed from the perinuclear Golgi region to disperse vesicles in ADPKD cells. At the basolateral membrane of ADPKD cells, there was a notable loss of the exocyst components sec6/sec8 and an unidentified syntaxin. It is postulated that dysregulated basolateral transport effector function precipitates the disruption of basolateral exocytosis and dilation of the ADPKD cell Golgi as basolateral cargo accumulates within the cisternae.


Pharmacological methods to reduce disease recurrence.
Allogeneic stem cell transplantation is an increasingly important treatment option in patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Although there has been substantial progress in reducing transplantation-related mortality (TRM), little progress has been made in reducing the risk of disease relapse, which continues to represent the major cause of treatment failure in patients allografted for AML and MDS. Experience with myeloablative conditioning regimens has demonstrated that, although intensification of the preparative regimen reduces relapse risk, any survival benefit is blunted by a concomitant increase in TRM. A similar inverse correlation between relapse risk and TRM is observed in patients allografted using a reduced-intensity conditioning regimen. However, the markedly lower toxicity of such regimens has permitted the design of novel conditioning strategies aimed at maximizing antitumor activity without excessive transplant toxicity. Coupled with recent advances in drug delivery and design, this has allowed the development of a spectrum of new conditioning regimens in patients with high-risk AML and MDS. At the same time, the optimization of a graft-versus-leukemia (GVL) effect by minimizing posttransplantation immunosuppression, with or without the infusion of donor lymphocytes, is essential if the risk of disease relapse is to be reduced. Recently, the delivery of adjunctive posttransplantation therapies has emerged as a promising method of augmenting antileukemic activity, either through a direct antitumor activity or consequent upon pharmacological manipulation of the alloreactive response. Taken together these advances present a realistic possibility of delivering improved outcome in patients allografted for high-risk AML or MDS.


Effective number of breeding adults in Bufo bufo estimated from age-specific variation at minisatellite loci.
Estimates of the effective number of breeding adults were derived for three semi-isolated populations of the common toad Bufo bufo based on temporal (i.e. adult-progeny) variance in allele frequency for three highly polymorphic minisatellite loci. Estimates of spatial variance in allele frequency among populations and of age-specific measures of genetic variability are also described. Each population was characterized by a low effective adult breeding number (Nb) based on a large age-specific variance in minisatellite allele frequency. Estimates of Nb (range 21-46 for population means across three loci) were approximately 55-230-fold lower than estimates of total adult census size. The implications of low effective breeding numbers for long-term maintenance of genetic variability and population viability are discussed relative to the species' reproductive ecology, current land-use practices, and present and historical habitat modification and loss. The utility of indirect measures of population parameters such as Nb and Ne based on time-series data of minisatellite allele frequencies is discussed relative to similar measures estimated from commonly used genetic markers such as protein allozymes.


Molecular basis of phytochemical-gut microbiota interactions.
Dysbiosis-associated molecular pathology is significantly involved in developing and perpetuating metabolic disorders, disrupting host energy regulation, and triggering inflammatory signaling cascades, insulin resistance, and metabolic dysfunction. Concurrently, numerous phytoconstituents are able to interact with the gut microbiota and produce bioactive metabolites that influence host cellular pathways, inflammation, and metabolic processes. These effects include improved insulin sensitivity, lipid metabolism regulation, and suppression of chronic inflammation, highlighting the therapeutic potential of phytoconstituents against metabolic abnormalities. Understanding this symbiotic relationship and the underlying molecular cascades offers innovative strategies for tailored interventions and promising therapeutic approaches to address the growing burden of metabolic disease.


2020 Alzheimer's disease facts and figures.
This article describes the public health impact of Alzheimer's disease (AD), including incidence and prevalence, mortality and morbidity, use and costs of care, and the overall impact on caregivers and society. The Special Report discusses the future challenges of meeting care demands for the growing number of people living with Alzheimer's dementia in the United States with a particular emphasis on primary care. By mid-century, the number of Americans age 65 and older with Alzheimer's dementia may grow to 13.8 million. This represents a steep increase from the estimated 5.8 million Americans age 65 and older who have Alzheimer's dementia today. Official death certificates recorded 122,019 deaths from AD in 2018, the latest year for which data are available, making Alzheimer's the sixth leading cause of death in the United States and the fifth leading cause of death among Americans age 65 and older. Between 2000 and 2018, deaths resulting from stroke, HIV and heart disease decreased, whereas reported deaths from Alzheimer's increased 146.2%. In 2019, more than 16 million family members and other unpaid caregivers provided an estimated 18.6 billion hours of care to people with Alzheimer's or other dementias. This care is valued at nearly $244 billion, but its costs extend to family caregivers' increased risk for emotional distress and negative mental and physical health outcomes. Average per-person Medicare payments for services to beneficiaries age 65 and older with AD or other dementias are more than three times as great as payments for beneficiaries without these conditions, and Medicaid payments are more than 23 times as great. Total payments in 2020 for health care, long-term care and hospice services for people age 65 and older with dementia are estimated to be $305 billion. As the population of Americans living with Alzheimer's dementia increases, the burden of caring for that population also increases. These challenges are exacerbated by a shortage of dementia care specialists, which places an increasing burden on primary care physicians (PCPs) to provide care for people living with dementia. Many PCPs feel underprepared and inadequately trained to handle dementia care responsibilities effectively. This report includes recommendations for maximizing quality care in the face of the shortage of specialists and training challenges in primary care.


Assessment of intrauterine growth retardation by diagnostic ultrasound.
In the first 1,000 cases referred to the Department of Diagnostic Ultrasound for Obstetrics and Gynaecology, 200 patients with singleton pregnancies were examined by this modality for possible intrauterine growth retardation (IUGR). Inclusion in this study was based on one or more of the following criteria: past history of IUGR, present clinical impression of IUGR, present high risk of developing IUGR, and unsuspected IUGR evidenced by diagnostic ultrasound. In 34 per cent of cases, serial examinations indicated that the date of confinement had to be recalculated. Ultrasound was in agreement with delivery results in 82 per cent of cases. Sixteen per cent of cases in this study resulted in growth-retarded infants. Ultrasound correctly diagnosed 70 per cent of these.


Effective suppression of human immunodeficiency virus type 1 through a combination of short- or long-hairpin RNAs targeting essential sequences for retroviral integration.
Small interfering RNA (siRNA) could provide a new therapeutic approach to treating human immunodeficiency virus type 1 (HIV-1) infection. For long-term suppression of HIV-1, emergence of siRNA escape variants must be controlled. Here, we constructed lentiviral vectors encoding short-hairpin RNAs (shRNA) corresponding to conserved target sequences within the integrase (int) and the attachment site (att) genes, both of which are essential for HIV-1 integration. Compared to shRNA targeting of the HIV-1 transcription factor tat (shTat), shRNA against int (shIN) or the U3 region of att (shU3) showed a more potent inhibitory effect on HIV-1 replication in human CD4+ T cells. Infection with a high dose of HIV-1 resulted in the emergence of escape mutants during long-term culture. Of note, limited genetic variation was observed in the viruses resistant to shIN. A combination of shINs against wild-type and escape mutant sequences had a negative effect on their antiviral activities, indicating a potentially detrimental effect when administering multiple shRNA targeting the same region to combat HIV-1 variants. The combination of shIN and shU3 att exhibited the strongest anti-HIV-1 activity, as seen by complete abrogation of viral DNA synthesis and viral integration. In addition, a modified long-hairpin RNA spanning the 50 nucleotides in the shIN target region effectively suppressed wild-type and shIN-resistant mutant HIV-1. These results suggest that targeting of incoming viral RNA before proviral DNA formation occurs through the use of nonoverlapping multiple siRNAs is a potent approach to achieving sustained, efficient suppression of highly mutable viruses, such as HIV-1.


Additional gastroduodenal stent placement: retrospective evaluation of 68 consecutive patients with malignant gastroduodenal obstruction.
Self-expandable metallic stent placement is widely used to manage malignant gastroduodenal obstructions. However, the techniques and effectiveness of additional gastroduodenal stent placement have not been evaluated until now. To evaluate the technical feasibility, clinical effectiveness, and complications of additional gastroduodenal stent placement in patients with recurrent obstructive symptoms after primary gastroduodenal stenting. We retrospectively analyzed data from 68 consecutive patients who had additional gastroduodenal stents placed for recurrent obstruction. Clinical effectiveness was assessed using technical and clinical success rates, gastric outlet obstruction score improvement after primary and additional stent placement, and complications. Additional stent placement was technically successful in 66 of the 68 patients (97%) and symptomatic improvement was achieved in 58 (85%). The gastric outlet obstruction score improved after primary stent placement (0.3 to 1.4) and additional stent placement (0.2 to 1.4). Complications occurred in 12 of 68 patients (18%) and were caused by tumor overgrowth (n = 7), stent collapse (n = 2), food impaction (n = 1), jaundice (n = 1), and duodenal perforation (n = 1). Additional gastroduodenal stent placement is technically feasible and clinically effective for patients with recurrent gastric outlet obstruction after stent placement.


[Whooping cough: a diagnosis one shouldn't forget].
Reports of whooping cough, due to Bordetella pertussis, have been increasing worldwide for the last two decades in all age groups. Infants are especially at risk for severe disease, but older children and adolescents can have a great disease burden as well. Diagnosing pertussis is difficult due to atypical symptoms, and frequent lack of laboratory confirmation. This article reviews the reasons for epidemiologic changes, clinical manifestations, diagnostic tools, treatment and prevention strategies, especially vaccination which will most certainly focus in the future on decreasing susceptible pools by immunizing adolescents and young adults. This strategy would not only protect these individuals from whooping cough, but most importantly protect, by herd immunity, the infants too young to be (fully) immunized.


Correlated Disruption of Resting-State fMRI, LFP, and Spike Connectivity between Area 3b and S2 following Spinal Cord Injury in Monkeys.
This study aims to understand how functional connectivity (FC) between areas 3b and S2 alters following input deprivation and the neuronal basis of disrupted FC of resting-state fMRI signals. We combined submillimeter fMRI with microelectrode recordings to localize the deafferented digit regions in areas 3b and S2 by mapping tactile stimulus-evoked fMRI activations before and after cervical dorsal column lesion in each male monkey. An average afferent disruption of 97% significantly reduced fMRI, local field potential (LFP), and spike responses to stimuli in both areas. Analysis of resting-state fMRI signal correlation, LFP coherence, and spike cross-correlation revealed significantly reduced functional connectivity between deafferented areas 3b and S2. The degrees of reductions in stimulus responsiveness and FC after deafferentation differed across fMRI, LFP, and spiking signals. The reduction of FC was much weaker than that of stimulus-evoked responses. Whereas the largest stimulus-evoked signal drop (∼80%) was observed in LFP signals, the greatest FC reduction was detected in the spiking activity (∼30%). fMRI signals showed mild reductions in stimulus responsiveness (∼25%) and FC (∼20%). The overall deafferentation-induced changes were quite similar in areas 3b and S2 across signals. Here we demonstrated that FC strength between areas 3b and S2 was much weakened by dorsal column lesion, and stimulus response reduction and FC disruption in fMRI covary with those of LFP and spiking signals in deafferented areas 3b and S2. These findings have important implications for fMRI studies aiming to probe FC alterations in pathological conditions involving deafferentation in humans.SIGNIFICANCE STATEMENT By directly comparing fMRI, local field potential, and spike signals in both tactile stimulation and resting states before and after severe disruption of dorsal column afferent, we demonstrated that reduction in fMRI responses to stimuli is accompanied by weakened resting-state fMRI functional connectivity (FC) in input-deprived and reorganized digit regions in area 3b of the S1 and S2. Concurrent reductions in local field potential and spike FC validated the use of resting-state fMRI signals for probing neural intrinsic FC alterations in pathological deafferented cortex, and indicated that disrupted FC between mesoscale functionally highly related regions may contribute to the behavioral impairments.


Surgery combined with photodynamic therapy for the treatment of Hidradenitis Suppurativa: A report of 7 cases.
Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease in the area of the apocrine sweat glands. The treatment of HS is relatively difficult. Therefore, surgery combined with PDT was applied to treat 7 cases of patients in this study, and treatment efficacy was observed. Simple surgical incisions and drainage were performed for patients with Hurley grade I. Surgical incisions and drainage as well as the removal of necrotic tissues were performed for patients with grades II and III. Immediately after surgery, PDT was performed. Their average Dermatology Life Quality Index (DLQI) was 24.14±4.26 before the surgery and 4.86±2.79 5 months after treatment, respectively. Scale (VSS) scores for evaluating scar formation were low to moderate after surgery and PDT. The experience of treating these 7 patients suggests that surgery combined with PDT might have a more pronounced effect, with the possible advantages of faster healing and less scarring.


Caregiver and Employee Experience Among Big Hospices-Ranking of the Largest US Hospices by Three Quality Indicators.
Several studies chronicle profit-making negatively impacting US hospice care quality. However, no study has reported on caregiver satisfaction expressed online by hospice. Assess the relationship between online caregiver sentiment, market share, profit status, and Consumer Assessment of Healthcare Providers and Systems (CAHPS®) scores among the 50 largest US hospices. Retrospective mixed methods of sentiment and multivariate regression analysis. Data sources were online caregiver reviews, provider CAHPS hospice survey data. Being a larger, for-profit predicted diminished caregiver and employee satisfaction. Caregiver Sentiment and CAHPS Composite were so highly associated (r = .862, P < .001), that they are converging on overall caregiver satisfaction. With large effect, CAHPS Star Rating was significantly higher than Review Star Rating. For-profits had significantly higher overall Emotional Intensity than non-profit hospices, again with large effect. Caregiver Sentiment, Review Star Rating, and Glassdoor Composite each predicted CAHPS Composite. Lack of staffing was more frequent among for-profits (13%) than non-profits (6%). Out-of-scope expectations prevalence was 9%. Caregiver and employees had better experiences with non-profits than for-profits. Anger and frustration was expressed toward large, for-profit providers more focused on admissions, profiteering, and paying dividends than actual care. The CAHPS appears to draw more satisfied caregivers. Whereas, online reviewing provides open-ended, real-time voicing of care quality concerns. Even with distinct methods, CAHPS survey and review sentiment analysis converge on caregiver satisfaction, yet CAHPS paints a much rosier picture of hospice quality than online reviews. Future research should explore sentiments by topic and hospice to increase customer advocacy.


C-terminal-binding protein corepresses epithelial and proapoptotic gene expression programs.
The genesis of carcinoma cells often involves epithelial-to-mesenchymal transitions and the acquisition of apoptosis resistance, but it is unclear whether these alterations are controlled coordinately or independently. Our previously reported effects of adenovirus E1a in human tumor cells raised the possibility that the E1a-interacting corepressor protein C-terminal-binding protein (CtBP) might selectively repress epithelial cell adhesion and proapoptotic genes. Here, we report that CtBP-knockout cells were hypersensitive to apoptosis. Correspondingly, microarray analysis of CtBP-knockout vs. CtBP-rescued mouse embryo fibroblasts revealed that many epithelial-specific and proapoptotic genes were indeed regulated by CtBP. Neither the apoptosis nor the repression activities of CtBP required histidine-315, suggesting that the proposed dehydrogenase activity is not essential for CtBP function. The results presented herein establish two functional roles of CtBP: to corepress epithelial genes, thus permitting epithelial-to-mesenchymal transitions, and to modulate the cellular threshold for apoptotic responses.


Functional characterization of PETIOLULE-LIKE PULVINUS (PLP) gene in abscission zone development in Medicago truncatula and its application to genetic improvement of alfalfa.
Alfalfa (Medicago sativa L.) is one of the most important forage crops throughout the world. Maximizing leaf retention during the haymaking process is critical for achieving superior hay quality and maintaining biomass yield. Leaf abscission process affects leaf retention. Previous studies have largely focused on the molecular mechanisms of floral organ, pedicel and seed abscission but scarcely touched on leaf and petiole abscission. This study focuses on leaf and petiole abscission in the model legume Medicago truncatula and its closely related commercial species alfalfa. By analysing the petiolule-like pulvinus (plp) mutant in M. truncatula at phenotypic level (breakstrength and shaking assays), microscopic level (scanning electron microscopy and cross-sectional analyses) and molecular level (expression level and expression pattern analyses), we discovered that the loss of function of PLP leads to an absence of abscission zone (AZ) formation and PLP plays an important role in leaflet and petiole AZ differentiation. Microarray analysis indicated that PLP affects abscission process through modulating genes involved in hormonal homeostasis, cell wall remodelling and degradation. Detailed analyses led us to propose a functional model of PLP in regulating leaflet and petiole abscission. Furthermore, we cloned the PLP gene (MsPLP) from alfalfa and produced RNAi transgenic alfalfa plants to down-regulate the endogenous MsPLP. Down-regulation of MsPLP results in altered pulvinus structure with increased leaflet breakstrength, thus offering a new approach to decrease leaf loss during alfalfa haymaking process.


Host Gene Expression to Predict Sepsis Progression.
Sepsis causes significant mortality. However, most patients who die of sepsis do not present with severe infection, hampering efforts to deliver early, aggressive therapy. It is also known that the host gene expression response to infection precedes clinical illness. This study seeks to develop transcriptomic models to predict progression to sepsis or shock within 72 hours of hospitalization and to validate previously identified transcriptomic signatures in the prediction of 28-day mortality. Retrospective differential gene expression analysis and predictive modeling using RNA sequencing data. Two hundred seventy-seven patients enrolled at four large academic medical centers; all with clinically adjudicated infection were considered for inclusion in this study. Sepsis progression was defined as an increase in Sepsis 3 category within 72 hours. Transcriptomic data were generated using RNAseq of whole blood. Least absolute shrinkage and selection operator modeling was used to identify predictive signatures for various measures of disease progression. Four previously identified gene signatures were tested for their ability to predict 28-day mortality. There were no significant differentially expressed genes in 136 subjects with worsened Sepsis 3 category compared with 141 nonprogressor controls. There were 1,178 differentially expressed genes identified when sepsis progression was defined as ICU admission or 28-day mortality. A model based on these genes predicted progression with an area under the curve of 0.71. Validation of previously identified gene signatures to predict sepsis mortality revealed area under the receiver operating characteristic values of 0.70-0.75 and no significant difference between signatures. Host gene expression was unable to predict sepsis progression when defined by an increase in Sepsis-3 category, suggesting this definition is not a useful framework for transcriptomic prediction methods. However, there was a differential response when progression was defined as ICU admission or death. Validation of previously described signatures predicted 28-day mortality with insufficient accuracy to offer meaningful clinical utility.


Increased UDP-glucuronosyltransferase activity and UDP-glucuronic acid concentration in the small intestine of butylated hydroxyanisole-treated mice.
Butylated hydroxyanisole (BHA) has been shown to decrease the toxicological and carcinogenic potential of a variety of chemicals. One possible mechanism for chemoprotection is that BHA increases intestinal UDP-glucuronosyltransferase activity and thereby enhances the elimination of the toxicants. Given that oral ingestion is a major route of xenobiotic exposure, we have investigated the actions of BHA on the glucuronidation capacity in the upper small intestine of female mice. Ingestion of high dosages of BHA (600-800 mg/kg/day) for 10 days produced a significant increase in in vitro microsomal acetaminophen glucuronidation but not in diethylstilbestrol conjugation. Furthermore, the concentration of UDP-glucuronic acid, the co-substrate required for glucuronidation reactions, was increased almost 2-fold in small intestine. Ingestion of BHA also increased UDP-glucose concentration and UDP-glucose dehydrogenase activities approximately 2-fold. These findings show that BHA ingestion increases intestinal glucuronidation capacity and suggest that BHA may enhance the intestinal first-pass biotransformation of xenobiotics.


Mechanisms of hyoscine butylbromide to improve adenoma detection: A case-control study of surface visualization at simulated colonoscope withdrawal.
Antispasmodics may improve mucosal visualization during colonoscope withdrawal, potentially improving polyp and adenoma detection. Meta-analysis and case-control studies suggest a 9 % to 13 % relative increase in adenoma and polyp detection. We aimed to assess the impact of hyoscine butylbromide on the expected visualization during colonoscope withdrawal using a CT colonography (CTC) simulation. Datasets from a previous CTC study examining the effect of antispasmodic were re-analyzed with customised CTC software, adjusted to simulate a standard colonoscopic view. Eighty-six patients received intravenous (IV) hyoscine butylbromide 20 mg, 40 mg or no antispasmodic. Main outcome measurements at unidirectional flythrough, simulating colonoscope withdrawal, were percentage colonic surface visualization, numbers and sizes of unseen areas, and colonic length. Use of antispasmodic was associated with a significant relative increase in percentage surface visualization of 2.6 % to 3.9 %, compared with no antispasmodic, P < 0.006. Total numbers of missed areas and intermediate sized (300 - 1000 mm(2)) missed areas were significantly decreased, by approximately 20 %. There were no differences between the 20-mg and 40-mg doses. Mean colonic length (161 - 169 cm) was unchanged by antispasmodic. IV hyoscine butylbromide at simulated colonoscope withdrawal was associated with significant increases in surface visualization, which might explain up to half the improvement in adenoma detection seen in clinical studies.


Preferential adhesion of prostate cancer cells to a human bone marrow endothelial cell line.
In virtually all patients with advanced prostate cancer, the disease metastasizes to bone and causes osteoblastic growth. However, the mechanisms that contribute to bone metastasis are poorly understood. It has been hypothesized that the bone provides a favorable growth environment for prostate cancer cells, which nonselectively seed the bone marrow from the bloodstream. Alternatively, prostate cancer cells may preferentially bind to bone marrow endothelial cells. We developed an in vitro model of bone endothelium and tested the hypothesis that prostate cancer cells adhere preferentially to bone marrow endothelial cells. We isolated and characterized a human bone marrow endothelial (HBME-1) cell line. Cells were transfected with the simian virus 40 large T antigen for immortalization. Cell surface receptors were characterized by immunohistochemistry and flow cytometry. The adhesion of cancer cells to HBME-1 and to endothelial cell lines from other organs was tested in an in vitro binding assay as were inhibitors of adhesion. The immortalized HBME-1 cell line demonstrated many properties characteristic of endothelial cells, including positive staining for von Willibrand factor and rapid formation of tubule structures when exposed to extracellular matrices. In an in vitro assay, prostate cancer cells adhered preferentially to human bone marrow endothelium when compared with endothelium derived from other sources. Preferential adhesion was blocked, in part, by antibodies to galectin-3 and LFA-1. These data suggest that the propensity of prostate cancer cells to establish themselves in bone is due, at least in part, to their preferential adhesion to human bone marrow endothelial cells.


In vitro generated antibodies guide thermostable ADDomer nanoparticle design for nasal vaccination and passive immunization against SARS-CoV-2.
Due to COVID-19, pandemic preparedness emerges as a key imperative, necessitating new approaches to accelerate development of reagents against infectious pathogens. Here, we developed an integrated approach combining synthetic, computational and structural methods with in vitro antibody selection and in vivo immunization to design, produce and validate nature-inspired nanoparticle-based reagents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our approach resulted in two innovations: (i) a thermostable nasal vaccine called ADDoCoV, displaying multiple copies of a SARS-CoV-2 receptor binding motif derived epitope and (ii) a multivalent nanoparticle superbinder, called Gigabody, against SARS-CoV-2 including immune-evasive variants of concern (VOCs). In vitro generated neutralizing nanobodies and electron cryo-microscopy established authenticity and accessibility of epitopes displayed by ADDoCoV. Gigabody comprising multimerized nanobodies prevented SARS-CoV-2 virion attachment with picomolar EC50. Vaccinating mice resulted in antibodies cross-reacting with VOCs including Delta and Omicron. Our study elucidates Adenovirus-derived dodecamer (ADDomer)-based nanoparticles for use in active and passive immunization and provides a blueprint for crafting reagents to combat respiratory viral infections.


Diagnostic procedures in nasopharyngeal illness.
The nasopharynx contains a wide variety of different cell types. Therefore, many kinds of lesions can occur in this area, ranging from embryologic abnormalities to benign and malignant neoplasms. The challenge to the radiologist is to describe the extent and localization of inflammation, benign, and malignant tumors. The diagnostic procedures in these cases include flexible or rigid fiberoptic clinical examinations. Pantomography and plain film studies are usually done as part of the initial examination, and CT replaces pluridirectional tomography for all questions about compact bone. Soft tissue extent of lesions is better shown on MR imaging. New scientific experiences in diagnosing lesions of the area of the nasopharynx are presented.


Selection of anionic dopant for quantifying desialylation reactions with MALDI-FTMS.
Alkylsulfonates are examined as anion dopants for the matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) of neutral oligosaccharides. The anion dopants allow neutral oligosaccharides to be examined in the same mixture as acidic oligosaccharides. The alkylsulfonate dopants interact strongly with the oligosaccharide to produce a quasimolecular ion composed of the oligosaccharides and the deprotonated alkylsulfonates. Compounds as small as disaccharides to large branched oligosaccharides can all be examined. The new series of alkylsulfonates works as well as HSO4- in terms of signal-to-noise ratio, sensitivity, and ease of preparation in the negative ion mode. The alkylsulfonates are used to construct a calibration curve for obtaining the relative amounts of varying neutral and acidic oligosaccharide mixtures. With the anion dopants, the MALDI-FTMS signals are shown to have a linear relationship with the molar ratios of the neutral and sialylated oligosaccharides. The method is also used to monitor the product of a desialylation reaction by acid hydrolysis.


Prediction of Membrane Permeation of Drug Molecules by Combining an Implicit Membrane Model with Machine Learning.
Lipid membrane permeation of drug molecules was investigated with Heterogeneous Dielectric Generalized Born (HDGB)-based models using solubility-diffusion theory and machine learning. Free energy profiles were obtained for neutral molecules by the standard HDGB and Dynamic HDGB (DHDGB) to account for the membrane deformation upon insertion of drugs. We also obtained hybrid free energy profiles where the neutralization of charged molecules was taken into account upon membrane insertion. The evaluation of the predictions was done against experimental permeability coefficients from Parallel Artificial Membrane Permeability Assays (PAMPA), and effects of partial charge sets, CGenFF, AM1-BCC, and OPLS, on the performance of the predictions were discussed. (D)HDGB-based models improved the predictions over the two-state implicit membrane models, and partial charge sets seemed to have a strong impact on the predictions. Machine learning increased the accuracy of the predictions, although it could not outperform the physics-based approach in terms of correlations.


An Ancient COI1-Independent Function for Reactive Electrophilic Oxylipins in Thermotolerance.
The jasmonate signaling pathway regulates development, growth, and defense responses in plants. Studies in the model eudicot, Arabidopsis thaliana, have identified the bioactive hormone (jasmonoyl-isoleucine [JA-Ile]) and its Coronatine Insensitive 1 (COI1)/Jasmonate-ZIM Domain (JAZ) co-receptor. In bryophytes, a conserved signaling pathway regulates similar responses but uses a different ligand, the JA-Ile precursor dinor-12-oxo-10,15(Z)-phytodienoic acid (dn-OPDA), to activate a conserved co-receptor. Jasmonate responses independent of JA-Ile and COI1, thought to be mediated by the cyclopentenone OPDA, have also been suggested, but experimental limitations in Arabidopsis have hindered attempts to uncouple OPDA and JA-Ile biosynthesis. Thus, a clear understanding of this pathway remains elusive. Here, we address the role of cyclopentenones in COI1-independent responses using the bryophyte Marchantia polymorpha, which is unable to synthesize JA-Ile but does accumulate OPDA and dn-OPDA. We demonstrate that OPDA and dn-OPDA activate a COI1-independent pathway that regulates plant thermotolerance genes, and consequently, treatment with these oxylipins protects plants against heat stress. Furthermore, we identify that these molecules signal through their electrophilic properties. By performing comparative analyses between M. polymorpha and two evolutionary distant species, A. thaliana and the charophyte alga Klebsormidium nitens, we demonstrate that this pathway is conserved in streptophyte plants and pre-dates the evolutionary appearance of the COI1-dependent jasmonate pathway, which later co-opted the pre-existing dn-OPDA as its ligand. Taken together, our data indicate that cyclopentenone-regulated COI1-independent signaling is an ancient conserved pathway, whose ancestral role was to protect plants against heat stress. This pathway was likely crucial for plants' successful land colonization and will be critical for adaption to current climate warming.


Risk of incident chronic obstructive pulmonary disease in patients with rheumatoid arthritis: A systematic review and meta-analysis.
To investigate the risk of subsequent development of chronic obstructive pulmonary disease (COPD) in patients with rheumatoid arthritis (RA). We conducted a systematic review and meta-analysis of cohort studies that reported relative risk, hazard ratio or standardized incidence ratio with 95% confidence interval (CI), comparing risk of incident COPD in patients with RA versus non-RA participants. Pooled risk ratio and 95% CI were calculated using a random-effect, generic inverse variance method of DerSimonian and Laird. Four retrospective cohort studies with 32,675 patients with RA and 122,204 controls were included in the data analysis. The pooled risk ratio of incident COPD in patients with RA versus control was 1.99 (95% CI, 1.61-2.45). The statistical heterogeneity was high with an I2 of 81%. Our study demonstrated a statistically significant increased risk of subsequent development of COPD among patients with RA.


Integration of biochemical images of a tumor into frameless stereotaxy achieved using a magnetic resonance imaging/magnetic resonance spectroscopy hybrid data set.
It is often difficult to delineate the extent of invasion of high- and low-grade gliomas into normal brain tissue by using conventional T1- and T2-weighted magnetic resonance (MR) imaging. Knowledge of the relationship between the tumor infiltration zone and normal brain, however, is one of the prerequisites for performing as radical a tumor resection as possible. Proton MR spectroscopy allows noninvasive measurements of the concentrations and spatial distributions of brain metabolites and, therefore, may provide biochemical information in vivo, that is useful in distinguishing pathological from normal areas of the brain. The authors have developed a method to use the properties of MR spectroscopy to investigate intraoperatively pathological changes in the spatial distribution of choline (Cho)-containing compounds, total creatine, and N-acetylaspartate (NAA) in brain tumors with the aid of frameless stereotaxy. Maps of the Cho/NAA ratio were calculated and automatic segmentation of the tumors was performed. Spectroscopic images of the segmented tumor were matched to an anatomical three-dimensional (3D) MR imaging set by applying a fully automated mutual-information algorithm. The resulting 3D MR image can be used subsequently for neurosurgical planning, transfer to a frameless stereotactic system, and display in the navigation microscope during surgery leading to 1H-MR spectroscopy-guided navigation. This method may allow better intraoperative identification of tumor border zones based on metabolic changes due to tumor infiltration.


The p53 protein plays a central role in the mechanism of action of epigentic drugs that alter the methylation of cytosine residues in DNA.
Both normal and cancerous cells, treated with drugs that block cytosine methylation of DNA, are preferentially killed by these drugs when they have p53 mutations and survive if they have a wild type protein. It appears that the wild type p53 protein functions to eliminate cells that undergo large epigenetic alterations and save other cells from death by this drug treatment. This has now been observed in cancerous cells in culture, tumors in animals and tumors in humans. AML cells with p53 mutations in humans treated with decitabine are killed by differentiation or senescense, but then relapse at a high rate becoming drug resistant. The mechanism of resistance to epigenetic drugs in p53 mutant cells, by possibly restoring a wild type p53 gene or restoring a defective p53 pathway, is now an interesting hypothesis to explore.


Tumor necrosis factor-like weak inducer of apoptosis induces inflammation in Graves' orbital fibroblasts.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), along with its receptor fibroblast growth factor-inducible (Fn)14, is associated with various biological activities including inflammation. However, its role in the pathogenesis of Graves' orbitopathy (GO) is unknown. In this study, we investigated the mechanism by which TWEAK regulates inflammatory signaling in orbital fibroblasts from GO patients. We found that TWEAK and tumor necrosis factor-α (TNFA) mRNA levels were upregulated in GO as compared to non-GO tissue samples. TWEAK, TNF receptor (TNFR)1, TNFR2, and TNFR superfamily member 12A mRNA, and TWEAK and Fn14 protein levels were increased by interleukin (IL)-1β and TNF-α treatment. Treatment with exogenous recombinant TWEAK increased the transcript and protein expression of the pro-inflammatory cytokines IL-6, IL-8, and monocyte chemoattractant protein-1 to a greater extent in GO than in non-GO cells, while treatment with the anti-Fn14 antibody ITEM4 suppressed TWEAK-induced pro-inflammatory cytokine release and hyaluronan production. Additionally, the serum level of TWEAK was higher in Graves' disease patients with (341.86 ± 86.3 pg/ml) as compared to those without (294.09 ± 41.44 pg/ml) GO and healthy subjects (255.33 ± 39.38 pg/ml), and was positively correlated with clinical activity score (r = 0.629, P < 0.001) and thyroid binding immunoglobulin level (r = 0.659, P < 0.001). These results demonstrate that TWEAK/Fn14 signaling contributes to GO pathogenesis. Moreover, serum TWEAK level is a potential diagnostic biomarker for inflammatory GO, and modulating TWEAK activity may be an effective therapeutic strategy for suppressing inflammation and tissue remodeling in GO.


Digging deep into Golgi phenotypic diversity with unsupervised machine learning.
The synthesis of glycans and the sorting of proteins are critical functions of the Golgi apparatus and depend on its highly complex and compartmentalized architecture. High-content image analysis coupled to RNA interference screening offers opportunities to explore this organelle organization and the gene network underlying it. To date, image-based Golgi screens have based on a single parameter or supervised analysis with predefined Golgi structural classes. Here, we report the use of multiparametric data extracted from a single marker and a computational unsupervised analysis framework to explore Golgi phenotypic diversity more extensively. In contrast with the three visually definable phenotypes, our framework reproducibly identified 10 Golgi phenotypes. They were used to quantify and stratify phenotypic similarities among genetic perturbations. The derived phenotypic network partially overlaps previously reported protein-protein interactions as well as suggesting novel functional interactions. Our workflow suggests the existence of multiple stable Golgi organizational states and provides a proof of concept for the classification of drugs and genes using fine-grained phenotypic information.


Molecular evidence that deep-branching fungi are major fungal components in deep-sea methane cold-seep sediments.
The motile cells of chytrids were once believed to be relics from the time before the colonization of land by fungi. However, the majority of chytrids had not been found in marine but freshwater environments. We investigated fungal diversity by a fungal-specific PCR-based analysis of environmental DNA in deep-sea methane cold-seep sediments, identifying a total of 35 phylotypes, 12 of which were early diverging fungi (basal fungi, ex 'lower fungi'). The basal fungi occupied a major portion of fungal clones. These were phylogenetically placed into a deep-branching clade of fungi and the LKM11 clade that was a divergent group comprised of only environmental clones from aquatic environments. As suggested by Lara and colleagues, species of the endoparasitic genus Rozella, being recently considered of the earliest branching taxa of fungi, were nested within the LKM11 clade. In the remaining 23 phylotypes identified as the Dikarya, the majority of which were similar to those which appeared in previously deep-sea studies, but also highly novel lineages associated with Soil Clone Group I (SCGI), Entorrhiza sp. and the agaricomycetous fungi were recorded. The fungi of the Dikarya may play a role in the biodegradation of lignin and lignin-derived materials in deep-sea, because the characterized fungal species related to the frequent phylotypes within the Dikarya have been reported to possess an ability to degrade lignin.


Capecitabine plus cisplatin as first-line chemotherapy for advanced biliary tract cancer: a retrospective single-center study.
Palliative chemotherapy is currently the primary therapeutic approach in the treatment of advanced biliary tract cancer (BTC). Our aim was to assess the efficacy and safety of capecitabine plus cisplatin as first-line chemotherapy for patients with advanced BTC and to analyze the relationship between the level of CA19-9 and clinical outcome. We retrospectively reviewed the records of patients who had unresectable, metastatic or recurrent BTC who were treated with capecitabine plus cisplatin. Capecitabine was administered orally at a dose of 1,000 mg/m(2) twice a day for 14 days, followed by a 1-week rest period. Cisplatin was administered intravenously on days 1 and 8 at a dose of 30 mg/m(2) for 60 min every 3 weeks. A total of 176 patients were enrolled. Among the 143 assessable patients, 24 (17%) had a partial response. A complete response was radiologically confirmed in 1 patient who had gallbladder cancer. Sixty-two patients (43%) had stable disease and 56 patients (39%) had progressive disease. With a median follow-up of 5.7 months, the median time-to-progression (TTP) was 3.7 months (95% CI 3.1-4.3) and the median overall survival (OS) was 7.4 months (95% CI 6.1-8.7). There was a significant positive correlation between CA19-9 response and TTP (r = 0.66, p = 0.01). CA19-9 response was also significantly correlated with OS (r = 0.57, p < 0.01). The most common grade 3/4 toxicities were nausea/vomiting [12 patients (6.8%)]. Our results indicate that the capecitabine/cisplatin regimen is well tolerated and has moderate activity against advanced BTC. The CA19-9 response may be a suitable surrogate marker for patients with BTC who are treated with capecitabine/cisplatin.


Gambling in Western and Eastern Europe: the example of Hungary.
The history of gambling in post-socialist countries is noticeably different from that of other countries in Europe. The goal of this study was therefore twofold: Firstly, to systematically review all European epidemiological studies related to excessive gambling in the general adult population, and secondly, to provide an overview of the state of gambling in Hungary based on the first ever nationwide representative survey, setting the results against the backdrop of the earlier European studies. A systematic review was carried out of European gambling studies which focus on a representative adult general population. Hungarian data was obtained from the National Survey on Addiction Problems in Hungary general adult population survey (N = 2,710). Pathological gambling was measured by the South Oaks Gambling Screen. Lifetime prevalence of excessive gambling (problem and pathological gambling) in the general adult population of European countries varies between 1.1% (Italy and Spain) and 6.5% (Estonia). In Hungary, the prevalence of problem gambling is 1.9%, with pathological gambling at 1.4%. The socio-demographic characteristics of the results are similar to those of other European countries. Using epidemiological data from the general adult populations of two post-socialist nations, it was possible to compare the results with data from 12 other European countries. Based on the data available, the extremely rapid liberation of the gambling market in the post-socialist countries has led to a similarly swift escalation in associated gambling problems.


Clinical, Demographic, and Imaging Correlates of Anemia in Heart Failure With Preserved Ejection Fraction (from the RELAX Trial).
Anemia is a commonly occurring comorbidity among patients of heart failure with preserved ejection fraction (HFpEF) but limited data exists on the cardiovascular phenotype of anemia in HFpEF. We sought to characterize the clinical features, exercise capacity, and outcomes in patients with HFpEF to elucidate the phenotype and pathophysiology of anemia in HFpEF. Post hoc analyses of participants enrolled in the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure) trial was performed. Anemia was defined as hemoglobin <13 g/dL in men and <12 g/dL in women. Multivariate adjusted regression modeling was done to assess for differences in peak oxygen uptake. Adjusted hazard ratios were generated to assess difference in hospitalization events using a Cox proportional hazards model. Anemic HFpEF patients were more likely to be older, male, and have worse renal function (p <0.05 for all). N-terminal pro-B-type natriuretic peptide, troponin I, pro-collagen III N-terminal peptide, C-telopeptide for type I collagen, uric acid, cystatin-c, and galectin-3 (p <0.05 for all) levels were higher in anemic HFpEF patients. In adjusted models, anemic HFpEF patients had worse exercise capacity (peak oxygen uptake: 11.3 vs 12.1 mL/kg/min; p = 0.004). The hazard for cardiac or renal cause of hospitalization in those with anemia was 2.0 (95% confidence interval: 0.9 to 4.3). Anemic HFpEF patients have worse exercise capacity and are more likely to be hospitalized. A better understanding of the physiologic phenotypes of HFpEF patients may allow for greater personalization of treatment and prognostication in HFpEF patients.


Conformational comparisons of oxytocin agonists, partial agonists, and antagonists using laser Raman and circular dichroism spectroscopy. Examination of 1-penicillamine and diastereoisomeric analogues.
The biological activity of peptide hormones and analogues depends on the structural and conformational properties of these compounds. A comparative study of the conformational properties of diastereoisomeric analogues of oxytocin with weak agonist activities (fully active but low potency), partial agonist activity (only able to partially induce biological response), and of conformationally restricted 1-penicillamine analogues with potent antagonist activity (no intrinsic activity, but can block the hormone's activity) was made using circular dichroism and laser Raman spectroscopies. Conformational information regarding the peptide amide, disulfide, and tyrosine chromophores was obtained, and indicates differences in the hormone agonists and antagonists. The diastereoisomeric oxytocin analogues [1-hemi-D-cystine]-, [2-D-tyrosine]-, and [5-D-asparagine]-oxytocin, have spectral features consistent with overall backbone conformations similar to oxytocin itself, but with differences in side chain moieties. This suggests that the substantial decrease in potency of the diastereoisomeric oxytocin analogues is due to changes in the relative orientations of the side chains. In contrast, the 1-penicillamine analogues of the present study, [1-penicillamine, 4-threonine]- and [1-penicillamine, 2-phenylalanine, 4-threonine]-oxytocin, like 1-penicillamine oxytocin analogues previously examined, have different backbone and disulfide conformations than oxytocin. All the 1-penicillamine oxytocin derivatives thus far examined appear, from laser Raman and CD data, to have similar topologies. However, those of the present study seem to have more rigid conformations as evidenced by very intense amide n-pi* and tyrosine pi-pi* CD transitions.


Parietal resting-state EEG alpha source connectivity is associated with subcortical white matter lesions in HIV-positive people.
Parietal resting-state electroencephalographic (rsEEG) alpha (8-10 Hz) source connectivity is abnormal in HIV-positive persons. Here we tested whether this abnormality may be associated with subcortical white matter vascular lesions in the cerebral hemispheres. Clinical, rsEEG, and magnetic resonance imaging (MRI) datasets in 38 HIV-positive persons and clinical and rsEEG datasets in 13 healthy controls were analyzed. Radiologists visually evaluated the subcortical white matter hyperintensities from T2-weighted FLAIR MRIs (i.e., Fazekas scale). In parallel, neurophysiologists estimated the eLORETA rsEEG source lagged linear connectivity from parietal cortical regions of interest. Compared to the HIV participants with no/negligible subcortical white matter hyperintensities, the HIV participants with mild/moderate subcortical white matter hyperintensities showed lower parietal interhemispheric rsEEG alpha lagged linear connectivity. This effect was also observed in HIV-positive persons with unimpaired cognition. This rsEEG marker allowed good discrimination (area under the receiver operating characteristic curve > 0.80) between the HIV-positive individuals with different amounts of subcortical white matter hyperintensities. The parietal rsEEG alpha source connectivity is associated with subcortical white matter vascular lesions in HIV-positive persons, even without neurocognitive disorders. Those MRI-rsEEG markers may be used to screen HIV-positive persons at risk of neurocognitive disorders.


A persistent level of Cisd2 extends healthy lifespan and delays aging in mice.
The CISD2 gene, which is an evolutionarily conserved novel gene, encodes a transmembrane protein primarily associated with the mitochondrial outer membrane. Significantly, the CISD2 gene is located within the candidate region on chromosome 4q where a genetic component for human longevity has been mapped. Previously, we have shown that Cisd2 deficiency shortens lifespan resulting in premature aging in mice. Additionally, an age-dependent decrease in Cisd2 expression has been detected during normal aging. In this study, we demonstrate that a persistent level of Cisd2 achieved by transgenic expression in mice extends their median and maximum lifespan without any apparent deleterious side effects. Cisd2 also ameliorates age-associated degeneration of the skin, skeletal muscles and neurons. Moreover, Cisd2 protects mitochondria from age-associated damage and functional decline as well as attenuating the age-associated reduction in whole-body energy metabolism. These results suggest that Cisd2 is a fundamentally important regulator of lifespan and provide an experimental basis for exploring the candidacy of CISD2 in human longevity.


Toughening of Epoxy Adhesives by Combined Interaction of Carbon Nanotubes and Silsesquioxanes.
The extensive use of adhesives in many structural applications in the transport industry and particularly in the aeronautic field is due to numerous advantages of bonded joints. However, still many researchers are working to enhance the mechanical properties and rheological performance of adhesives by using nanoadditives. In this study the effect of the addition of Multi-Wall Carbon Nanotubes (MWCNTs) with Polyhedral Oligomeric Silsesquioxane (POSS) compounds, either Glycidyl Oligomeric Silsesquioxanes (GPOSS) or DodecaPhenyl Oligomeric Silsesquioxanes (DPHPOSS) to Tetraglycidyl Methylene Dianiline (TGMDA) epoxy formulation, was investigated. The formulations contain neither a tougher matrix such as elastomers nor other additives typically used to provide a closer match in the coefficient of thermal expansion in order to discriminate only the effect of the addition of the above-mentioned components. Bonded aluminium single lap joints were made using both untreated and Chromic Acid Anodisation (CAA)-treated aluminium alloy T2024 adherends. The effects of the different chemical functionalities of POSS compounds, as well as the synergistic effect between the MWCNT and POSS combination on adhesion strength, were evaluated by viscosity measurement, tensile tests, Dynamic Mechanical Analysis (DMA), single lap joint shear strength tests, and morphological investigation. The best performance in the Lap Shear Strength (LSS) of the manufactured joints has been found for treated adherends bonded with epoxy adhesive containing MWCNTs and GPOSS. Carbon nanotubes have been found to play a very effective bridging function across the fracture surface of the bonded joints.


Assessment of bagging GBLUP for whole-genome prediction of broiler chicken traits.
Bootstrap aggregation (bagging) is a resampling method known to produce more accurate predictions when predictors are unstable or when the number of markers is much larger than sample size, because of variance reduction capabilities. The purpose of this study was to compare genomic best linear unbiased prediction (GBLUP) with bootstrap aggregated sampling GBLUP (Bagged GBLUP, or BGBLUP) in terms of prediction accuracy. We used a 600 K Affymetrix platform with 1351 birds genotyped and phenotyped for three traits in broiler chickens; body weight, ultrasound measurement of breast muscle and hen house egg production. The predictive performance of GBLUP versus BGBLUP was evaluated in different scenarios consisting of including or excluding the TOP 20 markers from a standard genome-wide association study (GWAS) as fixed effects in the GBLUP model, and varying training sample sizes and allelic frequency bins. Predictive performance was assessed via five replications of a threefold cross-validation using the correlation between observed and predicted values, and prediction mean-squared error. GBLUP overfitted the training set data, and BGBLUP delivered a better predictive ability in testing sets. Treating the TOP 20 markers from the GWAS into the model as fixed effects improved prediction accuracy and added advantages to BGBLUP over GBLUP. The performance of GBLUP and BGBLUP at different allele frequency bins and training sample sizes was similar. In general, results of this study confirm that BGBLUP can be valuable for enhancing genome-enabled prediction of complex traits.


Electrochemiluminescent bioassay based on Ru@Zr-BTC-MOFs nanoparticles for determination of let-7a miRNA using the hybridization chain reaction.
Carboxyl-rich tris(4,4'-dicarboxylic acid-2,2'-bipyridyl) ruthenium(II) ([Ru(dcbpy)3]2+) and 1,3,5-phenyl tricarboxylic acid (H3BTC) were used as the organic ligand to synthesize the metal-organic frameworks by a simple one-pot hydrothermal method with ZrCl4 as metal ion source. Subsequently, the excellent electrochemiluminescence (ECL) luminophore (denoted as Ru@Zr-BTC-MOFs) was obtained. The Ru@Zr-BTC-MOFs displayed outstanding ECL properties, and a sensitive ECL bioassay based on Ru@Zr-BTC-MOFs was designed for the detection of let-7a microRNA (miRNA) using hybrid chain reaction (HCR). Under the optimal experimental conditions, the proposed bioassay exhibited a good linear relationship in the range from 50.0 fM to 5.00 × 102 pM with a detection limit of 3.71 fM. Besides, the proposed sensor exhibited satisfactory performance in real samples. The recovery was 91 ~ 108%, and the relative standard deviation was less than 5.6%. It might have potential clinical applications for detecting miRNA in biomedical research and clinical diagnosis. The schematic diagram of the preparation of Ru@Zr-BTC-MOFs (a) and ECL sensor for detecting let -7a (b).


Electroencephalographic characterization of pentylenetetrazole kindling in rats and modulation of epileptiform discharges by nitric oxide.
Epileptogenesis is a progressive process which culminates with spontaneous, recurrent and unpredictable epileptic seizures due to enhanced neuronal excitability. Well-characterized animal models of this process are needed to clarify its underlying molecular mechanisms, in which the role of nitric oxide has been a controversial component. We have used kindling with a sub-convulsive dose of pentylenetetrazole to objectively characterize early electroencephalographic changes during epileptogenesis. We used electroencephalographic recordings both during pentylenetetrazole (20 mg/kg) kindling for 20 days and then, 24 days later to quantify the number, duration and spectral power of epileptic discharges. The levels of nitric oxide were modulated locally in the cerebral cortex by pharmacological agents. The number of epileptiform discharges increased during the kindling protocol as well as 24 days later, revealing the induction of a self-sustaining epileptogenic process. Epileptic discharges were characterized by theta frequencies (4-10 Hz) that were associated with absence-like seizures. However, during kindling, the spectral power of the theta band progressively decreased, while the power of higher frequencies, in the beta band, increased. Nitric oxide in the cerebral cortex inhibited the number and amplitude of epileptic discharges. The electroencephalographic characterization of this kindling protocol provides a valuable tool to detect consequences of therapeutic interventions undertaken at initial phases of epileptogenesis, especially those targeted towards stopping this process. Increases of nitric oxide in the cerebral cortex could be a useful intervention to negatively modulate neuronal excitability, epileptic discharges and the progression of epileptogenesis.


Examining the Relationship between Infant Weight Status and Parent-Infant Interactions within a Food and Nonfood Context.
Background: Most observational research examining factors in the home environment that contribute to child adiposity has focused on feeding and physical activity, although aspects of one's nonfood home environment such as parent-child interactions can also impact body weight. The main objectives of this study were to determine if parent-infant interactions under different contexts provide a unique contribution to infants' concurrent adiposity after accounting for known obesity-related covariates. Methods: This was a cross-sectional analysis of 121 9- to 15-month-old infants using data collected at the baseline visit of an ongoing intervention study. Mother-infant interactions during a feeding episode and a free-play task were recorded and coded. Anthropometrics of infants were measured by trained research staff. We used two-step hierarchical multivariable regression models to examine the unique contribution of mother-infant interactions to weight status after accounting for known obesity-related covariates (i.e., maternal age, BMI, education, parity, and gestational age, child sex, breastfeeding duration, age of solid food introduction, and birthweight). Results: Maternal intrusiveness, child negative affect, and child responsiveness during free-play, but not feeding were significantly associated with z-weight-for-length. For every 1-U increase in maternal intrusiveness and child negative affect there was a 0.321 (p = 0.011) and 0.415 (p = 0.028) unit increase in z-weight-for-length, respectively, whereas for every 1-U increase in child responsiveness there was a decrease of 0.386 U in z-weight-for-length (p = 0.025). Conclusion: This research contributes new findings support the idea that parent-child interactions outside of the feeding context may relate to obesity. Clinical Trial Registration Number NCT02936284.


Sexually dimorphic effects of gestational endocrine-disrupting chemicals on microRNA expression in the developing rat hypothalamus.
This study examined developmental changes and sexual dimorphisms in hypothalamic microRNAs, and whether gestational exposures to environmental endocrine-disrupting chemicals (EDCs) altered their expression patterns. Pregnant rat dams were treated on gestational days 16 and 18 with vehicle, estradiol benzoate, or a mixture of polychlorinated biphenyls. Male and female offspring were euthanized on postnatal days (P) 15, 30, 45, or 90, and microRNA and mRNA targets were quantified in the medial preoptic nucleus (MPN) and ventromedial nucleus (VMN) of the hypothalamus. MicroRNAs showed robust developmental changes in both regions, and were sexually dimorphic in the MPN, but not VMN. Importantly, microRNAs in females were up-regulated by EDCs at P30, and down-regulated in males at P90. Few changes in mRNAs were found. Thus, hypothalamic microRNAs are sensitive to prenatal EDC treatment in a sex-, developmental age-, and brain region-specific manner.


[A participatory ergonomics program in a chemical company].
We describe a participatory ergonomics program that started in April 2010 in a chemical company located in the autonomous region of Valencia, Spain. The program was introduced in the company, the intervention level was agreed (two working lines, 24 workers) and a working group was established (Ergo Group, including managers, technicians and safety representatives in the company) with the aim of leading the intervention. A questionnaire was applied to collect information on ergonomic injuries and exposures in workers at the selected working lines. This information was analyzed by the Ergo Group and was later discussed at prevention circles with the direct participation of affected workers. When the present article was being drafted, 16 improvements to working conditions had already been proposed. Some of these improvements had been implemented and, in the opinion of some of the participants, were effective. To develop this kind of program, which could benefit a substantial number of workers in Spain, a firm commitment to prevention by companies is required.


Serum 25-hydroxyvitamin D and adipose tissue vitamin D receptor gene expression: relationship with obesity and type 2 diabetes.
The relationship between 25-hydroxyvitamin D [25(OH)D] and obesity and type 2 diabetes is not completely understood. Vitamin D receptor (VDR) expression in adipose tissue (AT) is related to obesity and might be regulated by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. To analyze serum 25(OH)D and VDR gene expression in AT according to body mass index (BMI) and glycemic status and the effect of 1,25(OH)2D3 on AT according to BMI. Two cohorts were studied: 1) 118 subjects classified according to their BMI (lean, overweight, obese, or morbidly obese [MO]) and their glycemic status (normoglycemic [NG] and prediabetic and diabetic [P&D]); and 2) 30 obese subjects (BMI > 30 kg/m(2)) classified as NG and P&D. VDR gene expression was analyzed during preadipocyte differentiation and in vitro stimulation with 1,25(OH)2D3 of AT explants from donors with different BMI values. University Hospital. Serum 25(OH)D, parathyroid hormone (PTH), and AT VDR gene expression. 25(OH)D levels were lower in P&D than NG subjects, significantly so in the lean and MO groups (P < .05). 25(OH)D levels correlated negatively with homeostasis model of assessment for insulin resistance (HOMA-IR) (r = -0.200; P = .032) and glucose (r = -0.295; P = .001), but not with BMI. VDR gene expression was higher in MO than in the other BMI groups (P < .05). 1,25(OH)2D3 increased VDR gene expression in AT from obese patients (P < .05) but not from lean subjects. 25(OH)D levels are diminished in P&D compared to NG subjects, independently of BMI, and are closely related to glucose metabolism variables, suggesting that vitamin D deficiency is associated more with carbohydrate metabolism than with obesity. Moreover, AT has a different response to 1,25(OH)2D3 depending on the degree of obesity.


Pattern of p53 gene mutations in breast cancers of women of the midwestern United States.
Mutation in the p53 gene is the most common genetic lesion in human cancers. The pattern of mutation in the p53 gene differs among cancers and may be a useful epidemiological tool for identification of factors contributing to carcinogenesis. Our purpose was to determine if the pattern of p53 mutation in breast carcinomas in our population of women residing in the midwestern region of the United States is similar to the pattern of p53 mutation in breast cancers in patients from other regions of the United States and Europe and in other epithelial tumors. With a technique we recently developed for the analysis of p53 mutations in genomic DNA from tumor cell clusters in touch preparations of solid tumors, we sequenced exons 5-9 and adjacent splice junctions of the gene in 44 breast cancers. Cells from each tumor were also stained with three monoclonal antibodies which recognize different epitopes of the p53 protein. We detected p53 mutations in 14 (32.6%) of 44 breast carcinomas. Only half of the mutations were missense changes. The other half included five microdeletions (three producing frame-shifts), one single-base substitution generating a stop codon, and one single-base substitution generating a splice junction abnormality. Nuclear expression of p53 antigen was present in eight of 44 cancers, including six with hemizygous missense mutations in the p53 gene. The pattern of p53 mutations in our breast cancer population differs from that reported in breast cancer populations by other investigators in which most p53 mutations were missense. Among 14 mutations in our population, at least five drastically altered the structure of p53, suggesting that a recessive mechanism of inactivation of the p53 gene may be more common than in other populations. Differences in the pattern of p53 mutation in breast cancers in Midwestern women and in breast cancers in other populations may reflect selection bias or small sample sizes currently available. However, our data are compatible with the possibility that an endogenous or exogenous factor influences p53 carcinogenesis in some women with breast cancer in the Midwest to a greater extent than in other regions of the United States and Europe.


Disruption of Rb/E2F pathway results in increased cyclooxygenase-2 expression and activity in prostate epithelial cells.
The loss of the retinoblastoma tumor suppressor gene (RB) is common in many human cancers, including prostate. We previously reported that engineered deletion of RB in prostate epithelial cells results in sustained cell growth in serum-free media, a predisposition to develop hyperplasia and dysplasia in prostate tissue recombinant grafts, and sensitization to hormonal carcinogenesis. Examining the molecular consequence of RB loss in this system, we show that cyclooxygenase-2 (COX-2) is significantly up-regulated following RB deletion in prostate tissue recombinants. To study the effect of RB deletion on COX-2 regulation, we generated wild-type (PrE) and Rb-/- (Rb-/-PrE) prostate epithelial cell lines rescued by tissue recombination. We show elevated COX-2 mRNA and protein expression in Rb-/-PrE cell lines with increased prostaglandin synthesis. We also find that loss of Rb leads to deregulated E2F activity, with increased expression of E2F target genes, and that exogenous expression of E2F1 results in elevated COX-2 mRNA and protein levels. COX-2 promoter studies reveal that E2F1 transcriptionally activates COX-2, which is dependent on the transactivation and DNA-binding domains of E2F1. Further analysis revealed that the E2F1 target gene, c-myb, is elevated in Rb-/-PrE cells and E2F1-overexpressing cells, whereas ectopic overexpression of c-myb activates the COX-2 promoter in prostate epithelial cells. Additionally, cotransfection with E2F1 and a dominant-negative c-myb inhibited E2F1 activation of the COX-2 promoter. Taken together, these results suggest activation of a transcriptional cascade by which E2F1 regulates COX-2 expression through the c-myb oncogene. This study reports a novel finding describing that deregulation of the Rb/E2F complex results in increased COX-2 expression and activity.


Complications and side-effects of foam sclerotherapy.
To describe and report incidence and frequency of side-effects and complications of sclerotherapy with foamed sclerosing agents. To explain, when possible, their pathophysiology and to indicate possible manoeuvres and techniques to limit them. Review of current literature and personal research. Complications of foam sclerotherapy include complications of sclerotherapy in general and specific complications of foamed sclerosing agents. Side-effects related to the sclerosing compounds are also taken into account. Complications and side-effects of careful foam sclerotherapy remain uncommon. However, more research is needed to understand them better and to further reduce their incidence. Their description to patients in the course of the informed consent is a prerequisite to any sclerosing treatment.


How to promote fruit consumption in children. Visual appeal versus restriction.
The prevalence of overweight is increasing dramatically in children. A protective factor against the development of overweight is a sufficient intake of fruit and vegetables. However, the consumption of fruit and vegetables in children is far from ideal these days. Therefore, it is important to examine how the intake of fruit and vegetables can be promoted. In this study, the effects of two fruit promoting techniques were evaluated in 4-7-year-old children: presenting fruit in a more visually appealing manner versus restricting the intake of fruit. Two presentations of fruit (regular and visually appealing) were offered to the participants. In a first taste session participants were either allowed to eat from both fruit presentations (no-prohibition group) or prohibited from eating one of the two presentations (regular fruit prohibited group/visually appealing fruit prohibited group). In a second taste session all participants were allowed to eat from both fruit presentations. The results indicated that visual appeal had a strong effect on consumption of the fruit. With respect to restriction, no effects were found. Parents, schools, supermarkets and food producers should take advantage of these results, and offer children fruit and vegetables that are presented in a visually appealing manner.


DREAM regulates BDNF-dependent spinal sensitization.
The transcriptional repressor DREAM (downstream regulatory element antagonist modulator) controls the expression of prodynorphin and has been involved in the modulation of endogenous responses to pain. To investigate the role of DREAM in central mechanisms of pain sensitization, we used a line of transgenic mice (L1) overexpressing a Ca(2+)- and cAMP-insensitive DREAM mutant in spinal cord and dorsal root ganglia. L1 DREAM transgenic mice showed reduced expression in the spinal cord of several genes related to pain, including prodynorphin and BDNF (brain-derived neurotrophic factor) and a state of basal hyperalgesia without change in A-type currents. Peripheral inflammation produced enhancement of spinal reflexes and increased expression of BDNF in wild type but not in DREAM transgenic mice. The enhancement of the spinal reflexes was reproduced in vitro by persistent electrical stimulation of C-fibers in wild type but not in transgenic mice. Exposure to exogenous BDNF produced a long-term enhancement of dorsal root-ventral root responses in transgenic mice. Our results indicate that endogenous BDNF is involved in spinal sensitization following inflammation and that blockade of BDNF induction in DREAM transgenic mice underlies the failure to develop spinal sensitization.


Mitotic motor CENP-E cooperates with PRC1 in temporal control of central spindle assembly.
Error-free cell division depends on the accurate assembly of the spindle midzone from dynamic spindle microtubules to ensure chromatid segregation during metaphase-anaphase transition. However, the mechanism underlying the key transition from the mitotic spindle to central spindle before anaphase onset remains elusive. Given the prevalence of chromosome instability phenotype in gastric tumorigenesis, we developed a strategy to model context-dependent cell division using a combination of light sheet microscope and 3D gastric organoids. Light sheet microscopic image analyses of 3D organoids showed that CENP-E inhibited cells undergoing aberrant metaphase-anaphase transition and exhibiting chromosome segregation errors during mitosis. High-resolution real-time imaging analyses of 2D cell culture revealed that CENP-E inhibited cells undergoing central spindle splitting and chromosome instability phenotype. Using biotinylated syntelin as an affinity matrix, we found that CENP-E forms a complex with PRC1 in mitotic cells. Chemical inhibition of CENP-E in metaphase by syntelin prevented accurate central spindle assembly by perturbing temporal assembly of PRC1 to the midzone. Thus, CENP-E-mediated PRC1 assembly to the central spindle constitutes a temporal switch to organize dynamic kinetochore microtubules into stable midzone arrays. These findings reveal a previously uncharacterized role of CENP-E in temporal control of central spindle assembly. Since CENP-E is absent from yeast, we reasoned that metazoans evolved an elaborate central spindle organization machinery to ensure accurate sister chromatid segregation during anaphase and cytokinesis.


PR55α regulatory subunit of PP2A inhibits the MOB1/LATS cascade and activates YAP in pancreatic cancer cells.
PP2A holoenzyme complexes are responsible for the majority of Ser/Thr phosphatase activities in human cells. Each PP2A consists of a catalytic subunit (C), a scaffold subunit (A), and a regulatory subunit (B). While the A and C subunits each exists only in two highly conserved isoforms, a large number of B subunits share no homology, which determines PP2A substrate specificity and cellular localization. It is anticipated that different PP2A holoenzymes play distinct roles in cellular signaling networks, whereas PP2A has only generally been defined as a putative tumor suppressor, which is mostly based on the loss-of-function studies using pharmacological or biological inhibitors for the highly conserved A or C subunit of PP2A. Recent studies of specific pathways indicate that some PP2A complexes also possess tumor-promoting functions. We have previously reported an essential role of PR55α, a PP2A regulatory subunit, in the support of oncogenic phenotypes, including in vivo tumorigenicity/metastasis of pancreatic cancer cells. In this report, we have elucidated a novel role of PR55α-regulated PP2A in the activation of YAP oncoprotein, whose function is required for anchorage-independent growth during oncogenesis of solid tumors. Our data show two lines of YAP regulation by PR55α: (1) PR55α inhibits the MOB1-triggered autoactivation of LATS1/2 kinases, the core member of the Hippo pathway that inhibits YAP by inducing its proteasomal degradation and cytoplasmic retention and (2) PR55α directly interacts with and regulates YAP itself. Accordingly, PR55α is essential for YAP-promoted gene transcriptions, as well as for anchorage-independent growth, in which YAP plays a key role. In summary, current findings demonstrate a novel YAP activation mechanism based on the PR55α-regulated PP2A phosphatase.


Analysis weighs issues in divestiture decisions.
Financial managers faced with the task of recommending whether diversified services should be dissolved or continued need a logical means of analysis. Their evaluations should consider not only the venture's financial results but concerns specific to the hospital and its market, as well as related social and legal issues. Failure analysis, a function of business portfolio management, helps put these variables in perspective and provides a framework for decision making.


Efficacy and safety of ginger in osteoarthritis patients: a meta-analysis of randomized placebo-controlled trials.
The aim of this study was to assess the clinical efficacy and safety of oral ginger for symptomatic treatment of osteoarthritis (OA) by carrying out a systematic literature search followed by meta-analyses on selected studies. Inclusion criteria were randomized controlled trials (RCTs) comparing oral ginger treatment with placebo in OA patients aged >18 years. Outcomes were reduction in pain and reduction in disability. Harm was assessed as withdrawals due to adverse events. The efficacy effect size was estimated using Hedges' standardized mean difference (SMD), and safety by risk ratio (RR). Standard random-effects meta-analysis was used, and inconsistency was evaluated by the I-squared index (I(2)). Out of 122 retrieved references, 117 were discarded, leaving five trials (593 patients) for meta-analyses. The majority reported relevant randomization procedures and blinding, but an inadequate intention-to-treat (ITT) analysis. Following ginger intake, a statistically significant pain reduction SMD = -0.30 ([95% CI: [(-0.50, -0.09)], P = 0.005]) with a low degree of inconsistency among trials (I(2) = 27%), and a statistically significant reduction in disability SMD = -0.22 ([95% CI: ([-0.39, -0.04)]; P = 0.01; I(2) = 0%]) were seen, both in favor of ginger. Patients given ginger were more than twice as likely to discontinue treatment compared to placebo ([RR = 2.33; 95% CI: (1.04, 5.22)]; P = 0.04; I(2) = 0%]). Ginger was modestly efficacious and reasonably safe for treatment of OA. We judged the evidence to be of moderate quality, based on the small number of participants and inadequate ITT populations. Prospero: CRD42011001777.


Genome-wide transcript profiling of endosperm without paternal contribution identifies parent-of-origin-dependent regulation of AGAMOUS-LIKE36.
Seed development in angiosperms is dependent on the interplay among different transcriptional programs operating in the embryo, the endosperm, and the maternally-derived seed coat. In angiosperms, the embryo and the endosperm are products of double fertilization during which the two pollen sperm cells fuse with the egg cell and the central cell of the female gametophyte. In Arabidopsis, analyses of mutants in the cell-cycle regulator CYCLIN DEPENDENT KINASE A;1 (CKDA;1) have revealed the importance of a paternal genome for the effective development of the endosperm and ultimately the seed. Here we have exploited cdka;1 fertilization as a novel tool for the identification of seed regulators and factors involved in parent-of-origin-specific regulation during seed development. We have generated genome-wide transcription profiles of cdka;1 fertilized seeds and identified approximately 600 genes that are downregulated in the absence of a paternal genome. Among those, AGAMOUS-LIKE (AGL) genes encoding Type-I MADS-box transcription factors were significantly overrepresented. Here, AGL36 was chosen for an in-depth study and shown to be imprinted. We demonstrate that AGL36 parent-of-origin-dependent expression is controlled by the activity of METHYLTRANSFERASE1 (MET1) maintenance DNA methyltransferase and DEMETER (DME) DNA glycosylase. Interestingly, our data also show that the active maternal allele of AGL36 is regulated throughout endosperm development by components of the FIS Polycomb Repressive Complex 2 (PRC2), revealing a new type of dual epigenetic regulation in seeds.


Prevalence of subclinical ketosis and relationships with postpartum diseases in European dairy cows.
Subclinical ketosis (SCK) is defined as concentrations of β-hydroxybutyrate (BHBA) ≥ 1.2 to 1.4 mmol/L and it is considered a gateway condition for other metabolic and infectious disorders such as metritis, mastitis, clinical ketosis, and displaced abomasum. Reported prevalence rates range from 6.9 to 43% in the first 2 mo of lactation. However, there is a dearth of information on prevalence rates considering the diversity of European dairy farms. The objectives of this study were to (1) determine prevalence of SCK, (2) identify thresholds of BHBA, and (3) study their relationships with postpartum metritis, clinical ketosis, displaced abomasum, lameness, and mastitis in European dairy farms. From May to October 2011, a convenience sample of 528 dairy herds from Croatia, Germany, Hungary, Italy, Poland, Portugal, Serbia, Slovenia, Spain, and Turkey was studied. β-Hydroxybutyrate levels were measured in 5,884 cows with a handheld meter within 2 to 15 d in milk (DIM). On average, 11 cows were enrolled per farm and relevant information (e.g., DIM, postpartum diseases, herd size) was recorded. Using receiver operator characteristic curve analyses, blood BHBA thresholds were determined for the occurrence of metritis, mastitis, clinical ketosis, displaced abomasum, and lameness. Multivariate binary logistic regression models were built for each disease, considering cow as the experimental unit and herd as a random effect. Overall prevalence of SCK (i.e., blood BHBA ≥ 1.2 mmol/L) within 10 countries was 21.8%, ranging from 11.2 to 36.6%. Cows with SCK had 1.5, 9.5, and 5.0 times greater odds of developing metritis, clinical ketosis, and displaced abomasum, respectively. Multivariate binary logistic regression models demonstrated that cows with blood BHBA levels of ≥ 1.4, ≥ 1.1 and ≥ 1.7 mmol/L during 2 to 15 DIM had 1.7, 10.5, and 6.9 times greater odds of developing metritis, clinical ketosis, and displaced abomasum, respectively, compared with cows with lower BHBA blood levels. Interestingly, a postpartum blood BHBA threshold ≥ 1.1 mmol/L increased the odds for lameness in dairy cows 1.8 (95% confidence interval: 1.3 to 2.5) times. Overall, prevalence of SCK was high between 2 to 15 DIM and SCK increased the odds of metritis, clinical ketosis, lameness, and displaced abomasum in European dairy herds.


Oncologic Accuracy of Image-guided Percutaneous Core-Needle Biopsy of Peripheral Nerve Sheath Tumors at a High-volume Sarcoma Center.
Peripheral nerve sheath tumors (PNSTs) are clinically heterogenous, comprising benign (BPNST) and malignant (MPNST) variants. BPNSTs can be managed with nerve-sparing excision or observation. MPNSTs require radical resection and multidisciplinary oncologic management (1, 15). Image-guided core-needle biopsy (IGCNBx) is the well-established standard to obtain preoperative tissue diagnosis of soft tissue tumors. However, there has been resistance to performing IGCNBx of PNSTs because of the presumed risk of nerve injury and unknown accuracy in determining malignancy. We sought to define the accuracy and safety of IGCNBx in PNSTs. All patients that underwent both IGCNBx and surgical resection of a PNST at our institution between 2002 and 2016 were analyzed. The accuracy of IGCNBx in determining malignancy was calculated, including subgroup analyses by histologic subtype and neurofibromatosis 1 status. Complication data were collected and analyzed. Among the 78 PNSTs with IGCNBx and postresection surgical pathology, 76% (n=59) had BPNST and 24% (n=19) had MPNST on postresection surgical pathology. IGCNBx accurately determined malignancy in 94% of cases. IGCNBx demonstrating schwannoma or MPNST were 100% accurate in determining malignancy. IGCNBx demonstrating neurofibroma or indeterminate results were 33% and 57% malignant on postresection surgical pathology, respectively. There were no long-term complications, including sensory or motor deficits, from IGCNBx. Percutaneous IGCNBx demonstrates 94% accuracy in differentiating benign from malignant PNSTs. IGCNBx demonstrating neurofibroma or indeterminate pathology should be interpreted with caution because of risk of malignant reclassification on surgical pathology. Our results reaffirm the safety of IGCNBx, as no patients experienced long-term complications.


The lethal effect of tryptone-soya broth.
Overnight cultures of V. cholerae, V. el tor, non-cholera vibrio, and Streptococcus pneumoniae in tryptone-soya broth (with 5% blood added for the last-named) failed to grow on subculture despite visible growth in all tubes. Viable counts and pH determinations of overnight cultures of various species in tryptone-soya broth, brain-heart infusion broth, and Lab-Lemco peptone broth show that death in tryptone-soya broth is associated with the drop in pH resulting from fermentation of glucose in the medium and that this drop is greater than that produced by the same amount of glucose in brain-heart infusion broth. Some strains of pneumococci failed to grow in brain-heart infusion broth and it is suggested that both these media are unsuitable for blood cultures.


Cost-effectiveness of School-Based Eye Examinations in Preschoolers Referred for Follow-up From Visual Screening.
Many preschool visual screening programs incorporate school-based comprehensive examinations, but the follow-up rates and cost-effectiveness of this approach are not well studied. To determine the follow-up rates and cost-effectiveness of referral to community-based eye care professionals vs to a mobile eye examination unit (mobile follow-up) among preschool children with failed visual screening results. This retrospective cohort cost-effectiveness study with decision analytic modeling and probabilistic sensitivity analysis included 3429 children in 37 public preschools in San Francisco, California, who underwent visual chart screening during the 2009-2012 academic years and 1524 children in the same schools who underwent autorefraction screening during the 2012-2013 academic year. One hundred seventy-five children who underwent visual chart screening were referred for community-based comprehensive eye examinations; 204 who underwent autorefractive screening were referred for preschool-based mobile follow-up. Data were collected from October 1, 2009, to May 29, 2013, and analyzed from June 30, 2013, to January 16, 2016. Cost-effectiveness of community-based vs mobile follow-up standardized for referral method. Of the 175 children referred for community-based follow-up (91 boys [52.0%]; 84 girls [48.0%]; mean [SD] age, 3.8 [0.7] years), 104 attended (59.4%). Of 204 children referred for mobile follow-up (89 boys [43.6%]; 115 girls [56.4%]; mean [SD] age, 4.1 [0.6] years), 112 attended (54.9%). Costs per case detected were $664 and $776, respectively. In univariate analysis, mobile follow-up was equally cost-effective if it increased the follow-up rate to 73% or if its costs were reduced by at least 27%. In multivariate analysis with Monte Carlo simulation, community-based follow-up was more cost-effective than mobile follow-up in 88% of simulated cases and had typical savings of $112 (95% CI, -$77 to $368) per case detected. Community-based eye care professionals may provide more cost-effective care than a mobile eye examination unit visiting the preschool among children with failed preschool-based visual screening.


Attitudes in an interpersonal context: Psychological safety as a route to attitude change.
Interpersonal contexts can be complex because they can involve two or more people who are interdependent, each of whom is pursuing both individual and shared goals. Interactions consist of individual and joint behaviors that evolve dynamically over time. Interactions are likely to affect people's attitudes because the interpersonal context gives conversation partners a great deal of opportunity to intentionally or unintentionally influence each other. However, despite the importance of attitudes and attitude change in interpersonal interactions, this topic remains understudied. To shed light on the importance of this topic. We briefly review the features of interpersonal contexts and build a case that understanding people's sense of psychological safety is key to understanding interpersonal influences on people's attitudes. Specifically, feeling psychologically safe can make individuals more open-minded, increase reflective introspection, and decrease defensive processing. Psychological safety impacts how individuals think, make sense of their social world, and process attitude-relevant information. These processes can result in attitude change, even without any attempt at persuasion. We review the literature on interpersonal threats, receiving psychological safety, providing psychological safety, and interpersonal dynamics. We then detail the shortcomings of current approaches, highlight unanswered questions, and suggest avenues for future research that can contribute in developing this field.


Association of insulin resistance and glycemic measures with major abnormal electrocardiogram in older Chinese: cross-sectional analysis based on the Guangzhou Biobank Cohort Study.
To examine whether insulin resistance (IR) and glycemic measures were associated with major abnormal electrocardiogram (MA-ECG) and its specific abnormalities in the general population. Twelve-lead ECG measurements were performed on 21,720 participants without cardiovascular disease (5,918 men) from the Guangzhou Biobank Cohort Study. The participants were aged 50 years or above (mean age 61.6, standard deviation 7.1 years). Logistic regression was used to assess the associations of IR and glycemic measures with MA-ECG and specific abnormalities. Ln-fasting insulin was significantly associated with MA-ECG and ST-T abnormalities (adjusted odds ratio=1.52, 95% confidence interval=1.15-2.02 and 1.83, 1.37-2.45, respectively, for per standard deviation), which were stronger than those of TyG index with MA-ECG (1.08, 1.04-1.13) and ST-T abnormalities (1.16, 1.11-1.22). Ln-fasting insulin had association with Q wave abnormalities (3.19, 1.52-6.67). The association of TyG index with prolonged QTc varied by sex and obesity (P for interaction ≤0.01). Participants with diabetes had stronger associations of ln-fasting plasma glucose with ECG abnormalities than those without. IR and glycemic measures were associated with MA-ECG, ischemia and prolonged QTc in older Chinese, especially in women, those with obesity, and those with diabetes. These findings underscore the importance of regular evaluations for these groups.


Surgical aspects of cochlear implantation: mechanisms of insertional trauma.
The development of hybrid electroacoustic devices has made conservation of residual hearing an important goal in cochlear implant surgery. Our laboratory has recently conducted anatomical studies directed toward better understanding mechanisms underlying loss of residual hearing associated with electrode insertion. This paper provides an overview of observations based on microdissection, scanning electron microscopy and temporal bone histology relating to inner ear injury that may occur during implant surgery. Trauma to cochlear structures including lateral wall tissues, the basilar membrane, the osseous spiral lamina and the modiolus is considered in relation to the implications of specific types of injury for hearing preservation. These findings are relevant to the design of future implant devices and to various important issues regarding the surgical technique used for implantation, including the possible use of the round window as a portal of entry for electrode insertion.


Perspectives of Nursing Students towards Schizophrenia Stigma: A Qualitative Study Protocol.
This study aims to explore fourth-year nursing students' knowledge of schizophrenia and their attitudes, empathy, and intentional behaviours towards people with schizophrenia. This will be a descriptive qualitative study using focus-group interviews. Fourth-year nursing students on clinical placement in a hospital in Hunan province will be invited for focus-group interviews. Snowball and purposive sampling will be used to recruit nursing students for this study. Five focus-group interviews, each including six participants, will be conducted to explore participants' knowledge, attitudes, intentional behaviours, and empathy towards schizophrenia. The interview will be conducted through the online Tencent video conference platform and the interview data will be collected through the same platform. All interviews will be recorded and transcribed verbatim and analysed with the approach of the content analysis supported by NVivo 12. Simultaneous data collection and analysis will be performed, and the interviews will be continued until data saturation is met. The findings of this study will be helpful in developing effective interventions to decrease the stigma toward schizophrenia among nursing students and those who study healthcare disciplines.


[Multicenter study of adherence to guidelines on surgical prophylaxis and the determinants of non-adherence in ArgentinaEstudo multicêntrico sobre a adesão a diretrizes de profilaxia cirúrgica e seus determinantes na Argentina].
Evaluate the level of adherence to guidelines on surgical prophylaxis in health facilities in Argentina and the determinants of non-adherence. Cross-sectional multicenter study in 35 centers in Argentina. The level of adherence to guidelines and the forms of non-adherence were determined and these were compared based on the characteristics of the indicated antibiotic, anesthesiologist, surgery, and facility, as well as patient age. An adjusted logistic regression model was used. A total of 1,083 surgical procedures were reviewed. Adherence to guidelines was 67%. The most frequent forms of non-adherence were: incorrect antibiotic (28.9%), unnecessary prophylaxis (25.5%), and prolonged prophylaxis (24.4%). Adherence to guidelines was higher in persons under 18 years of age (84.9% compared to 65.5%, p < 0.001). According to the type of health coverage (social welfare, private insurance, public coverage, or community coverage), adherence was 33.3%, 64.4%, 78.8%, and 83.3%, respectively; p < 0.001. According to population (maternal and child, pediatric, specific pathologies, and general pathologies), adherence was 97.9%, 97.2%, 89.4%, and 63.2%, respectively; p < 0.001. Adherence was highest in neurosurgery (91.1%), obstetrics (82.4%), and cardiovascular surgery (72.9%), and lowest in otorhinolaryngology (47.8%), ophthalmology (50%), and urology (55.9%) (p < 0.001). The adjusted analysis showed the highest adherence to guidelines in persons under 18 (odds ratio [OR]: 4.97; 95% confidence interval [CI 95]: 1.13-21.80); emergency surgery (OR: 2.18; CI 95: 1.11-4.26); and public, private, and community facilities (OR: 9.35; CI 95: 3.85-22.70). Adherence was also higher in facilities for maternal and child care and specific pathologies (OR: 10.52; CI 95, 1.30-85.12), cardiovascular surgery, neurosurgery, obstetrics (OR: 2.73; CI 95: 1.55-4.78), and facilities with programs to optimize the use of antimicrobial drugs (OR 1.95; CI 95, 1.10-3.45). Adherence to guidelines was 67%. Incorrect, unnecessary, and prolonged use of antibiotics were the most frequent forms of non-adherence. Adherence was higher with younger patients, where programs exist to optimize the use of antimicrobial drugs, where there is private or public health coverage, with the pediatric population, for specific pathologies, in emergency surgery, and in certain specialties.


Meta-analysis of sex difference in testosterone levels in umbilical cord blood.
This meta-analysis reviewed published literature comparing human male and female umbilical cord total testosterone (T) levels. A total of 18 studies using 1,229 samples from 602 male and 627 female newborns were analysed using the RevMan 5 statistical package. Analysis using the inverse variance method based on a random-effects model revealed significantly higher cord T in boys than girls at a moderate effect size (Hedges' g = 0.57). There was significant heterogeneity between the 18 studies, although the five studies using direct assays showed no heterogeneity. For studies using extraction and chromatography, those that combined T from arterial and venous cord blood found a larger sex difference than those using only cord venous samples (Hedges' g = 0.94 vs 0.32); this suggests umbilical cord venous T is of maternal/placental origin and arterial T is of fetal origin. The wide range of T values between studies suggests high cross-reactivity in the assay methods reviewed.