Gradients of connectivity distance in the cerebral cortex of the macaque monkey.
Cortical connectivity conforms to a series of organizing principles that are common across species. Spatial proximity, similar cortical type, and similar connectional profile all constitute factors for determining the connectivity between cortical regions. We previously demonstrated another principle of connectivity that is closely related to the spatial layout of the cerebral cortex. Using functional connectivity from resting-state fMRI in the human cortex, we found that the further a region is located from primary cortex, the more distant are its functional connections with the other areas of the cortex. However, it remains unknown whether this relationship between cortical layout and connectivity extends to other primate species. Here, we investigated this relationship using both resting-state functional connectivity as well as gold-standard tract-tracing connectivity in the macaque monkey cortex. For both measures of connectivity, we found a gradient of connectivity distance extending between primary and frontoparietal regions. In the human cortex, the further a region is located from primary areas, the stronger its connections to distant portions of the cortex, with connectivity distance highest in frontal and parietal regions. The similarity between the human and macaque findings provides evidence for a phylogenetically conserved relationship between the spatial layout of cortical areas and connectivity.


Isolates of Burkholderia pseudomallei from Northern Australia are distinct by multilocus sequence typing, but strain types do not correlate with clinical presentation.
Melioidosis is the disease caused by the saprophytic organism Burkholderia pseudomallei. Previous studies have suggested some strain tropism and differential virulence. In this study, we defined strains by multilocus sequence typing (MLST) of isolates taken from the Top End of Australia's Northern Territory and compared the results with those of other strains typed worldwide. We specifically sought clinical and geographical correlates of strain types. Among 87 Australian isolates, 48 sequence types were defined. None of the sequence types in this study has been found elsewhere in the world. Strains were distributed widely throughout the region, and the different presentations of disease, including neurological and prostatic infection, were associated with many different strains. There was excellent congruence between pulsed-field gel electrophoresis and MLST, and the two typing methods had a similar level of strain discrimination. The work suggests that host and environmental factors may be more important in determining disease presentation than infecting strain type. It is possible that the distinct but diverse strain types found in this study reflect Australia's geographical isolation over many millions of years.


Functional lateralization of temporoparietal junction - imitation inhibition, visual perspective-taking and theory of mind.
Although neuroimaging studies have consistently identified the temporoparietal junction (TPJ) as a key brain region involved in social cognition, the literature is far from consistent with respect to lateralization of function. For example, during theory-of-mind tasks bilateral TPJ activation is found in some studies but only right hemisphere activation in others. Visual perspective-taking and imitation inhibition, which have been argued to recruit the same socio-cognitive processes as theory of mind, are associated with unilateral activation of either left TPJ (perspective taking) or right TPJ (imitation inhibition). The present study investigated the functional lateralization of TPJ involvement in the above three socio-cognitive abilities using transcranial direct current stimulation. Three groups of healthy adults received anodal stimulation over right TPJ, left TPJ or the occipital cortex prior to performing three tasks (imitation inhibition, visual perspective-taking and theory of mind). In contrast to the extant neuroimaging literature, our results suggest bilateral TPJ involvement in imitation inhibition and visual perspective-taking, while no effect of anodal stimulation was observed on theory of mind. The discrepancy between these findings and those obtained using neuroimaging highlight the efficacy of neurostimulation as a complementary methodological tool in cognitive neuroscience.


Portable fiber group velocity test method with a gain-switched laser.
A portable method of group velocity measurement is proposed based on a self-seeded gain-switched laser. The calculated group velocity in the optical fiber is obtained by measuring the round-trip frequencies of the gain-switched laser diode with different external cavities, and only a 2 m long fiber is needed. The measurement can be accomplished without oscilloscope or optical spectrum analyzer. The error associated with this test is within 0.65%, which is limited by the jitter of the voltage-controlled oscillator. Its spectrum resolution is 0.1 nm.


Avian malaria: a new lease of life for an old experimental model to study the evolutionary ecology of Plasmodium.
Avian malaria has historically played an important role as a model in the study of human malaria, being a stimulus for the development of medical parasitology. Avian malaria has recently come back to the research scene as a unique animal model to understand the ecology and evolution of the disease, both in the field and in the laboratory. Avian malaria is highly prevalent in birds and mosquitoes around the world and is amenable to laboratory experimentation at each stage of the parasite's life cycle. Here, we take stock of 5 years of experimental laboratory research carried out using Plasmodium relictum SGS1, the most prevalent avian malaria lineage in Europe, and its natural vector, the mosquito Culex pipiens. For this purpose, we compile and analyse data obtained in our laboratory in 14 different experiments. We provide statistical relationships between different infection-related parameters, including parasitaemia, gametocytaemia, host morbidity (anaemia) and transmission rates to mosquitoes. This analysis provides a wide-ranging picture of the within-host and between-host parameters that may bear on malaria transmission and epidemiology.


Orbital disease in neuro-ophthalmology.
Orbital disease represents a diverse spectrum of pathology and can result in a variety of neuro-ophthalmic manifestations. The aim of this review is to provide updates on recent advances in our understanding of orbital disease secondary to thyroid eye disease, myositis, IgG4-related disease, sarcoidosis, granulomatosis with polyangiitis and various tumours. With regards to thyroid eye disease, there have been recent advances in the development of steroid-sparing therapies, new modalities for objectively monitoring disease activity and increased understanding of the role of environmental risk factors. There has been interest in characterizing the clinical course and underlying mechanism of optic nerve disease secondary to orbital disorders, which has led to advances in how we monitor for and prevent permanent vision loss. Increased knowledge of orbital tumour subtype histopathology and the development of novel classification systems has had prognostic value and aided medical decision-making. Orbital disease occurs secondary to a wide variety of diseases and can lead to neuro-ophthalmic manifestations with significant morbidity. Advances in our understanding of different subtypes of orbital disease have improved our ability to treat these potentially debilitating conditions.


Hyporheic microbial community development is a sensitive indicator of metal contamination.
Accurate natural resource damage assessment necessitates monitoring organisms or communities that respond most sensitively to contaminants. Observational studies have demonstrated a correlation between fluvial heavy metal deposition and hyporheic microbial community structure. To establish a causal relationship between sediment metal content and the structure of colonizing bacterial communities, we performed a controlled field experiment River sediments of 1.75-2.36 mm in diameter with five different contaminant concentrations were collected from an environmental metal contamination gradient. Sediments were sterilized and then recolonized by incubation in the hyporheic zone of an uncontaminated river (i.e., a common garden experiment was performed). A significant correlation between hyporheic microbial community structure and heavy metal contamination (R2 = 0.81) was observed. The abundance of two phylogenetic groups was highly correlated with the level of heavy metal contamination (Group I, R2 = 0.96; Group III, R2 = 0.96, most closely affiliated with the alpha- and gamma-proteobacteria, respectively). Microbial community structural responses were detected at metal concentrations an order of magnitude lower than those previously reported to impact benthic macroinvertebrate communities. We conclude that hyporheic microbial communities could offer the most sensitive method for assessing natural resource damage in lotic ecosystems in response to fluvial heavy metal deposition.


Age-related differences in unruptured intracranial aneurysms: 1-year outcomes.
The aim of this study was to determine age-related differences in short-term (1-year) outcomes in patients with unruptured intracranial aneurysms (UIAs). Four thousand fifty-nine patients prospectively enrolled in the International Study of Unruptured Intracranial Aneurysms were categorized into 3 groups by age at enrollment: < 50, 50-65, and > 65 years old. Outcomes assessed at 1 year included aneurysm rupture rates, combined morbidity and mortality from aneurysm procedure or hemorrhage, and all-cause mortality. Periprocedural morbidity, in-hospital morbidity, and poor neurological outcome on discharge (Rankin scale score of 3 or greater) were assessed in surgically and endovascularly treated groups. Univariate and multivariate associations of each outcome with age were tested. The risk of aneurysmal hemorrhage did not increase significantly with age. Procedural and in-hospital morbidity and mortality increased with age in patients treated with surgery, but remained relatively constant with increasing age with endovascular treatment. Poor neurological outcome from aneurysm- or procedure-related morbidity and mortality did not differ between management groups for patients 65 years old and younger, but was significantly higher in the surgical group for patients older than 65 years: 19.0% (95% confidence interval [CI] 13.9%-24.4%), compared with 8.0% (95% CI 2.3%-13.6%) in the endovascular group and 4.2% (95% CI 2.3%-6.2%) in the observation group. All-cause mortality increased steadily with increasing age, but differed between treatment groups only in patients < 50 years of age, with the surgical group showing a survival advantage at 1 year. Surgical treatment of UIAs appears to be safe, prevents 1-year hemorrhage, and may confer a survival benefit in patients < 50 years of age. However, surgery poses a significant risk of morbidity and death in patients > 65 years of age. Risk of endovascular treatment does not appear to increase with age. Risks and benefits of treatment in older patients should be carefully considered, and if treatment is deemed necessary for patients older than 65 years, endovascular treatment may be the best option.


Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development.
Coronaviruses pose a serious threat to global health as evidenced by Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and COVID-19. SARS Coronavirus (SARS-CoV), MERS Coronavirus (MERS-CoV), and the novel coronavirus, previously dubbed 2019-nCoV, and now officially named SARS-CoV-2, are the causative agents of the SARS, MERS, and COVID-19 disease outbreaks, respectively. Safe vaccines that rapidly induce potent and long-lasting virus-specific immune responses against these infectious agents are urgently needed. The coronavirus spike (S) protein, a characteristic structural component of the viral envelope, is considered a key target for vaccines for the prevention of coronavirus infection. We first generated codon optimized MERS-S1 subunit vaccines fused with a foldon trimerization domain to mimic the native viral structure. In variant constructs, we engineered immune stimulants (RS09 or flagellin, as TLR4 or TLR5 agonists, respectively) into this trimeric design. We comprehensively tested the pre-clinical immunogenicity of MERS-CoV vaccines in mice when delivered subcutaneously by traditional needle injection, or intracutaneously by dissolving microneedle arrays (MNAs) by evaluating virus specific IgG antibodies in the serum of vaccinated mice by ELISA and using virus neutralization assays. Driven by the urgent need for COVID-19 vaccines, we utilized this strategy to rapidly develop MNA SARS-CoV-2 subunit vaccines and tested their pre-clinical immunogenicity in vivo by exploiting our substantial experience with MNA MERS-CoV vaccines. Here we describe the development of MNA delivered MERS-CoV vaccines and their pre-clinical immunogenicity. Specifically, MNA delivered MERS-S1 subunit vaccines elicited strong and long-lasting antigen-specific antibody responses. Building on our ongoing efforts to develop MERS-CoV vaccines, promising immunogenicity of MNA-delivered MERS-CoV vaccines, and our experience with MNA fabrication and delivery, including clinical trials, we rapidly designed and produced clinically-translatable MNA SARS-CoV-2 subunit vaccines within 4 weeks of the identification of the SARS-CoV-2 S1 sequence. Most importantly, these MNA delivered SARS-CoV-2 S1 subunit vaccines elicited potent antigen-specific antibody responses that were evident beginning 2 weeks after immunization. MNA delivery of coronaviruses-S1 subunit vaccines is a promising immunization strategy against coronavirus infection. Progressive scientific and technological efforts enable quicker responses to emerging pandemics. Our ongoing efforts to develop MNA-MERS-S1 subunit vaccines enabled us to rapidly design and produce MNA SARS-CoV-2 subunit vaccines capable of inducing potent virus-specific antibody responses. Collectively, our results support the clinical development of MNA delivered recombinant protein subunit vaccines against SARS, MERS, COVID-19, and other emerging infectious diseases.


Regulatory elements of Xenopus col2a1 drive cartilaginous gene expression in transgenic frogs.
This study characterizes regulatory elements of collagen 2 alpha 1 (col2a1) in Xenopus that enable transgene expression in cartilage-forming chondrocytes. The reporters described in this study drive strong cartilage-specific gene expression, which will be a valuable tool for further investigations of Xenopus skeletal development. While endogenous col2a1 mRNA is expressed in many embryonic tissues, its expression becomes restricted to tadpole and adult chondrocytes. This chondrocyte-specific expression is recapitulated by col2a1 reporter constructs, which were tested through I-SceI meganuclease-mediated transgenesis. These constructs contain a portion of the Xenopus tropicalis col2a1 intron, which aligns to a cartilage-specific intronic enhancer that has been well characterized in mammals. Two overlapping regions of the first intron that are 1.5-Kb and 665-bp long, both of which contain this enhancer sequence, drove EGFP expression in both larval and adult chondrocytes when connected to an upstream promoter. However, neither a truncated 155-bp region that also contains the enhancer, nor a separate 347-bp intronic region that lacks it, was able to drive cartilaginous transgene expression. The two cartilage-specific transgenes are heritable in F1 progeny, which exhibit none of the background expression observed in the injected founders. This study is the first to use the I-SceI technique to characterize an enhancer element in Xenopus, and the first to generate chondrocyte-specific gene expression in a non-mammalian vertebrate. The creation of novel cartilage-specific gene expression provides a new tool for further studies of anuran skeletal development.


A Real-Time Early Warning System for Monitoring Inpatient Mortality Risk: Prospective Study Using Electronic Medical Record Data.
The rapid deterioration observed in the condition of some hospitalized patients can be attributed to either disease progression or imperfect triage and level of care assignment after their admission. An early warning system (EWS) to identify patients at high risk of subsequent intrahospital death can be an effective tool for ensuring patient safety and quality of care and reducing avoidable harm and costs. The aim of this study was to prospectively validate a real-time EWS designed to predict patients at high risk of inpatient mortality during their hospital episodes. Data were collected from the system-wide electronic medical record (EMR) of two acute Berkshire Health System hospitals, comprising 54,246 inpatient admissions from January 1, 2015, to September 30, 2017, of which 2.30% (1248/54,246) resulted in intrahospital deaths. Multiple machine learning methods (linear and nonlinear) were explored and compared. The tree-based random forest method was selected to develop the predictive application for the intrahospital mortality assessment. After constructing the model, we prospectively validated the algorithms as a real-time inpatient EWS for mortality. The EWS algorithm scored patients' daily and long-term risk of inpatient mortality probability after admission and stratified them into distinct risk groups. In the prospective validation, the EWS prospectively attained a c-statistic of 0.884, where 99 encounters were captured in the highest risk group, 69% (68/99) of whom died during the episodes. It accurately predicted the possibility of death for the top 13.3% (34/255) of the patients at least 40.8 hours before death. Important clinical utilization features, together with coded diagnoses, vital signs, and laboratory test results were recognized as impactful predictors in the final EWS. In this study, we prospectively demonstrated the capability of the newly-designed EWS to monitor and alert clinicians about patients at high risk of in-hospital death in real time, thereby providing opportunities for timely interventions. This real-time EWS is able to assist clinical decision making and enable more actionable and effective individualized care for patients' better health outcomes in target medical facilities.


Desmophyllum dianthus (Esper, 1794) in the scleractinian phylogeny and its intraspecific diversity.
The cosmopolitan solitary deep-water scleractinian coral Desmophyllum dianthus (Esper, 1794) was selected as a representative model species of the polyphyletic Caryophylliidae family to (1) examine phylogenetic relationships with respect to the principal Scleractinia taxa, (2) check population structure, (3) test the widespread connectivity hypothesis and (4) assess the utility of different nuclear and mitochondrial markers currently in use. To carry out these goals, DNA sequence data from nuclear (ITS and 28S) and mitochondrial (16S and COI) markers were analyzed for several coral species and for Mediterranean populations of D. dianthus. Three phylogenetic methodologies (ML, MP and BI), based on data from the four molecular markers, all supported D. dianthus as clearly belonging to the "robust" clade, in which the species Lophelia pertusa and D. dianthus not only grouped together, but also shared haplotypes for some DNA markers. Molecular results also showed shared haplotypes among D. dianthus populations distributed in regions separated by several thousands of kilometers and by clear geographic barriers. These results could reflect limited molecular and morphological taxonomic resolution rather than real widespread connectivity. Additional studies are needed in order to find molecular markers and morphological features able to disentangle the complex phylogenetic relationship in the Order Scleractinia and to differentiate isolated populations, thus avoiding the homoplasy found in some morphological characters that are still considered in the literature.


What are the major drivers of outcomes in cervical deformity surgery?
Cervical deformity (CD) correction is becoming more challenging and complex. Understanding the factors that drive optimal outcomes has been understudied in CD correction surgery. The purpose of this study is to assess the factors associated with improved outcomes (IO) following CD surgery. Retrospective review of a single-center database. Sixty-one patients with CD. The primary outcomes measured were radiographic and clinical "IO" or "poor outcome" (PO). Radiographic IO or PO was assessed utilizing Schwab pelvic tilt (PT)/sagittal vertical axis (SVA), and Ames cervical SVA (cSVA)/TS-CL. Clinical IO or PO was assessed using MCID EQ5D, Neck Disability Index (NDI), and/or improvement in Modified Japanese Orthopedic Association Scale (mJOA) modifier. The secondary outcomes assessed were complication and reoperation rates. CD patients with data available on baseline (BL) and 1-year (1Y) radiographic measures and health-related quality of life s were included in our study. Patients with reoperations for infection were excluded. Patients were categorized by IO, PO, or not. IO was defined as "nondeformed" radiographic measures as well as improved clinical outcomes. PO was defined as "moderate or severe deformed" radiographic measures as well as worsening clinical outcome measures. Random forest assessed ratios of predictors for IO and PO. The categorical regression models were utilized to predict BL regional deformity (Ames cSVA, TS-CL, horizontal gaze), BL global deformity (Schwab PI-LL, SVA, PT), regional/global change (BL to 1Y), BL disability (mJOA score), and BL pain/function impact outcomes. Sixty-one patients met inclusion criteria for our study (mean age of 55.8 years with 54.1% female). The most common surgical approaches were as follows: 18.3% anterior, 51.7% posterior, and 30% combined. Average number of levels fused was 7.7. The mean operative time was 823 min and mean estimated blood loss was 1037 ml. At 1 year, 24.6% of patients were found to have an IO and 9.8% to have a PO. Random forest analysis showed the top 5 individual factors associated with an "IO" were: BL Maximum Kyphosis, Maximum Lordosis, C0-C2 Angle, L4-Pelvic Angle, and NSR Back Pain (80% radiographic, 20% clinical). Categorical IO regression model (R2 = 0.328, P = 0.007) found following factors to be significant: low BL regional deformity (β = ‒0.082), low BL global deformity (β = ‒0.099), global improve (β = 0.532), regional improve (β = 0.230), low BL disability (β = 0.100), and low BL NDI (β = 0.024). Random forest found the top 5 individual BL factors associated with "PO" (80% were radiographic): BL CL Apex, DJK angle, cervical lordosis, T1 slope, and NSR neck pain. Categorical PO regression model (R2 = 0.306, P = 0.012) found following factors to be significant: high BL regional deformity (β = ‒0.108), high BL global deformity (β = ‒0.255), global decline (β = 0.272), regional decline (β = 0.443), BL disability (β = ‒0.164), and BL severe NDI (>69) (β = 0.181). The categorical weight demonstrated radiographic as the strongest predictor of both improved (global alignment) and PO (regional deformity/deterioration). Radiographic factors carry the most weight in determining an improved or PO and can be ultimately utilized in preoperative planning and surgical decision-making to optimize the outcomes.


Evaluation of limit feeding varying levels of distillers dried grains with solubles in non-feed-withdrawal molt programs for laying hens.
An experiment was conducted with 672 Hy-Line W-36 Single Comb White Leghorn hens (69 wk of age) to evaluate the effects of feeding varying levels of corn distillers dried grains with solubles (DDGS) with corn, wheat middlings, and soybean hulls on long-term laying hen postmolt performance. The control molt treatment consisted of a 47% corn:47% soybean hulls (C:SH) diet fed ad libitum for 28 d. Hens fed the other 7 treatments were limit fed 65 g/hen per day for 16 d, and then fed 55 g/hen per day for 12 d. Hens on treatments 2 and 3 were fed 49% C:35% wheat middlings (WM) or SH:10% DDGS diets (C:WM:10DDGS, C:SH:10DDGS). Hens on treatments 4 and 5 were fed 49% C:25% WM or SH:20% DDGS diets (C:WM:20DDGS, C:SH:20DDGS). Those on treatments 6 and 7 were fed 47% C:47% DDGS (C:DDGS) or 47% WM:47% DDGS (WM:DDGS) diets. Those on treatment 8 were fed a 94% DDGS diet. At 28 d, all hens were fed a corn-soybean meal layer diet (16% CP) and production performance was measured for 36 wk. None of the hens fed the molt diets went completely out of production, and only the C:SH and C:SH:10DDGS molt diets decreased hen-day egg production to below 5% by wk 4 of the molt period. Postmolt egg production was lowest (P < 0.05) for the C:WM:20DDGS treatment. No differences (P > 0.05) in egg weights were detected among treatments throughout the postmolt period. In addition, no consistent differences were observed among treatments for egg mass throughout the postmolt period. Overall results of this study indicated that limit feeding diets containing DDGS at levels of 65 or 55 g/hen per day during the molt period did not cause hens to totally cease egg production.


A Rare Skeletal Dysplasia-Close Mimicker Of Juvenile Idiopathic Arthritis-Progressive Pseudorheumatoid Dysplasia.
Progressive pseudorheumatoid dysplasia or spondyloepiphyseal dysplasia tarda is caused by a mutation in Wnt1 inducible signalling pathway protein 3 (WISP3) and passes in an autosomal recessive manner. Prevalence underestimated as one per million and most of the cases remain undiagnosed or treated as Juvenile Idiopathic Arthritis (JIA). Differentiation between JIA and PPRD is really challenging however, this case is genetically confirmed from our country. 7-year-old, short stature boy, with multiple joint swellings of hands and feet, initially suspected to have JIA and had been worked up and took treatment for that for the past 2 years. He had progressive stiffness of small joints. Baseline biochemistry, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor and ANA, were within normal limits. He was moderately growth hormone deficient. Thyroid function tests and insulin-like growth factor 1 (IGF-1) were within reference ranges. Skeletal survey showed typical findings of pseudorheumatoid skeletal dysplasia. Physical therapy and genetic counselling were done.


Pharmacological Inhibition of KIT Activates MET Signaling in Gastrointestinal Stromal Tumors.
Gastrointestinal stromal tumors (GIST) are the most common adult sarcomas and the oncogenic driver is usually a KIT or PDGFRA mutation. Although GISTs are often initially sensitive to imatinib or other tyrosine kinase inhibitors, resistance generally develops, necessitating backup strategies for therapy. In this study, we determined that a subset of human GIST specimens that acquired imatinib resistance acquired expression of activated forms of the MET oncogene. MET activation also developed after imatinib therapy in a mouse model of GIST (KitV558del/+ mice), where it was associated with increased tumor hypoxia. MET activation also occurred in imatinib-sensitive human GIST cell lines after imatinib treatment in vitro. MET inhibition by crizotinib or RNA interference was cytotoxic to an imatinib-resistant human GIST cell population. Moreover, combining crizotinib and imatinib was more effective than imatinib alone in imatinib-sensitive GIST models. Finally, cabozantinib, a dual MET and KIT small-molecule inhibitor, was markedly more effective than imatinib in multiple preclinical models of imatinib-sensitive and imatinib-resistant GIST. Collectively, our findings showed that activation of compensatory MET signaling by KIT inhibition may contribute to tumor resistance. Furthermore, our work offered a preclinical proof of concept for MET inhibition by cabozantinib as an effective strategy for GIST treatment.


Genome wide array comparative genomic hybridisation analysis of premalignant lesions of the stomach.
Gastric cancer is one of the most frequent malignancies in the world, ranking fifth in the Netherlands as a cause of cancer death. Surgery is the only curative treatment for advanced cases, but results of gastrectomy largely depend on the stage of the disease. A better understanding of the mechanisms of progression from a preneoplastic condition through intraepithelial neoplasia to invasive cancer may provide information relevant to designing focused prevention strategies. Because the pattern of chromosomal aberrations in precursors of gastric cancer is unclear, 11 gastric polyps with intraepithelial neoplasia (three hyperplastic polyps and eight adenomas) were analysed by microarray comparative genomic hybridisation to study chromosomal instability in precursors of gastric cancer. Chromosomal aberrations were detected in all specimens. Adenomas showed no more chromosomal aberrations than did the hyperplastic polyps. The most frequent aberrations were gain of 7q36 and 20q12, and loss of 5q14-q21 in the adenomas, and loss of 15q11-14, 1p21-31, and 21q11-21.2 in the hyperplastic polyps. The most frequent chromosomal aberration in common to both types was loss of 9p21.3. Hyperplastic polyps showed many chromosomal aberrations, confirming that neoplastic transformation can occur in these lesions. These observations are consistent with the existence of two morphologically and genetically distinct pathways to gastric cancer-the hyperplastic polyp pathway and the (intestinal type) adenoma pathway. The relative contribution of each to gastric carcinogenesis in general, and how they compare to patterns of chromosomal aberrations in the more prevalent flat foci of intraepithelial neoplasia remain to be determined.


Development of a visually guided Raman spectroscopy probe for cervical assessment during pregnancy.
Preterm birth (PTB) is the leading cause of neonatal death, however, accurate prediction methods do not exist. Detection of early changes in the cervix, an organ that biochemically remodels to deliver the fetus, has potential to predict PTB risk. Researchers have employed light-based methods to monitor biochemical changes in the cervix during pregnancy, however, these approaches required patients to undergo a speculum examination which many patients find uncomfortable and is not standard practice during prenatal care. Herein, a visually guided optical probe is presented that measures the cervix via introduction by bimanual examination, a procedure that is commonly performed during prenatal visits and labor for tactile monitoring of the cervix. The device incorporates a Raman spectroscopy probe for biochemical monitoring and a camera for visualizing measurement location to ensure it is void of cervical mucus and blood. This probe was tested in 15 patients receiving obstetric and gynecological care, and results acquired with and without a speculum revealed similar spectra, demonstrating that the visually guided probe conserved data quality. Additionally, the majority of patients reported reduced discomfort from the device. In summary, the visual guidance probe successfully measured the cervix while integrating with standard prenatal care, reducing a barrier in clinical translation.


Nuclear expression of human apurinic/apyrimidinic endonuclease (HAP1/Ref-1) in head-and-neck cancer is associated with resistance to chemoradiotherapy and poor outcome.
HAP1/Ref-1 endonuclease is involved in the repair of DNA strand breaks and in the activation of DNA binding of several transcription factors. HAP1 is also a potent activator of wild type p53. It therefore has multiple possible roles in the response of human cancer to radiotherapy and chemotherapy. The nuclear expression of HAP1 and p53 proteins was studied by immunohistochemistry in paraffin-embedded material from 95 patients with locally advanced squamous cell head-and-neck cancer (HNC) treated with radical radiotherapy (38 cases with induction platinum-based chemotherapy and 57 with concurrent platinum chemoradiotherapy). HAP1 was present in the nuclei of normal epithelium and stromal cells. Loss of HAP1 nuclear expression was frequently noted in cancer cells. Tumors with high HAP1 nuclear expression (% of positive cells > mean; mean = 11%) were of good differentiation (p = 0.06) and presented frequently with advanced nodal disease (p = 0.01). High nuclear HAP1 expression was significantly associated with poor complete response rate (p = 0.00001), shorter local relapse-free interval (p < 0.0001), and poorer survival (p < 0.0008). HAP1 nuclear reactivity was inversely associated with p53 nuclear accumulation (p = 0.003). The inverse correlation between HAP1 expression and prognosis was independent of p53 status. HAP1 nuclear expression in HNC is inversely associated with p53 nuclear accumulation and directly related to resistance to chemoradiotherapy and poor survival. Further clinical investigation is required to confirm these findings.


A repository of protein abundance data of drug metabolizing enzymes and transporters for applications in physiologically based pharmacokinetic (PBPK) modelling and simulation.
Population factors such as age, gender, ethnicity, genotype and disease state can cause inter-individual variability in pharmacokinetic (PK) profile of drugs. Primarily, this variability arises from differences in abundance of drug metabolizing enzymes and transporters (DMET) among individuals and/or groups. Hence, availability of compiled data on abundance of DMET proteins in different populations can be useful for developing physiologically based pharmacokinetic (PBPK) models. The latter are routinely employed for prediction of PK profiles and drug interactions during drug development and in case of special populations, where clinical studies either are not feasible or have ethical concerns. Therefore, the main aim of this work was to develop a repository of literature-reported DMET abundance data in various human tissues, which included compilation of information on sample size, technique(s) involved, and the demographic factors. The collation of literature reported data revealed high inter-laboratory variability in abundance of DMET proteins. We carried out unbiased meta-analysis to obtain weighted mean and percent coefficient of variation (%CV) values. The obtained %CV values were then integrated into a PBPK model to highlight the variability in drug PK in healthy adults, taking lamotrigine as a model drug. The validated PBPK model was extrapolated to predict PK of lamotrigine in paediatric and hepatic impaired populations. This study thus exemplifies importance of the DMET protein abundance database, and use of determined values of weighted mean and %CV after meta-analysis in PBPK modelling for the prediction of PK of drugs in healthy and special populations.


Recurrence Risk After Up-to-Date Colon Cancer Staging, Surgery, and Pathology: Analysis of the Entire Swedish Population.
Developments in the quality of care of patients with colon cancer have improved surgical outcome and thus the need for adjuvant chemotherapy. To investigate the recurrence rate in a large population-based cohort after modern staging, surgery, and pathology have been implemented. This was a retrospective registry study. Data from patients included in the Swedish Colorectal Cancer Registry covering 99% of all cases and undergoing surgery for colon cancer stages I to III between 2007 and 2012 were obtained. In total, 14,325 patients who did not receive any neoadjuvant treatment, underwent radical surgery, and were alive 30 days after surgery were included. Tumor and node classification and National Comprehensive Cancer Network-defined risk factors for recurrence were used to assess overall and stage-specific 5-year recurrence rates. The median follow-up of nonrecurrent cases was 77 months (range, 47-118 mo). The 5-year recurrence rate was 5% in stage I, 12% in stage II, and 33% in stage III patients. In patients classified as having pT3N0 cancer with no or 1 risk factor, the 5-year recurrence rates were 9% and 11%. Risk factors for shorter time to recurrence were male sex, more advanced pT and pN classification, vascular and perineural invasion, emergency surgery, lack of central ligature, short longitudinal resection margin, postoperative complications, and, in stage III, no adjuvant chemotherapy. The registry does not contain some recently identified factors of relevance for recurrence rates, and some late recurrences may be missing. The recurrence rate is less than that previously observed in historical materials, but current, commonly used risk factors are still useful in evaluating recurrence risks. Stratification by pT and pN classification and the number of risk factors enables the identification of large patient groups characterized by such a low recurrence rate that it is questionable whether adjuvant treatment is motivated. See Video Abstract at http://links.lww.com/DCR/A663.


FGFR1 amplifications in squamous cell carcinomas of the lung: diagnostic and therapeutic implications.
Fibroblast growth factor receptor 1 (FGFR1) is a type 4 receptor tyrosine kinase. The receptor and its ligands play an important role in development and physiology. However, constitutive activation of FGFR1 by gene amplification, translocation or mutation is associated with various malignancies as, for example, breast cancer or myeloproliferative diseases. We have recently reported that FGFR1 amplification occurs in 20% of pulmonary squamous cell carcinomas, and preclinical tests have shown that these alterations are therapeutically tractable. These findings make FGFR1 amplification a potential biomarker for lung cancer treatment. Squamous cell carcinomas of the lung are characterized by an uneven FGFR1 gene copy number distribution. Therefore, fluorescence in situ hybridization assays need to address focality and heterogeneity of FGFR1 in these tumors. Here, we review our proposal for a reading and evaluation strategy. Furthermore, we highlight the emerging landscape of clinical trials with selective and unselective FGFR inhibitors and provide first response data from early clinical trials.


Measurement issues when assessing quality of life outcomes for different types of hernia mesh repair.
The NHS is required to collect data from patient reported outcome measures (PROMs) for inguinal hernia surgery. We explored the use of one such measure, the Carolinas Comfort Scale(®) (CCS), to compare long-term outcomes for patients who received two different types of mesh. The CCS questionnaire asks about mesh sensation, pain and movement limitations, and combines the answers into a total score. A total of 684 patients were treated between January 2007 and August 2008 and were followed up in November 2009. Data on 215 patients who met the inclusion criteria were available (96 patients who received Surgipro™ mesh and 119 who received Parietene™ Progrip™ mesh). Recurrence rates were similar in the Surgipro™ group (2/96, 2.1%) and Progrip™ group (3/118, 2.5%) (Fisher's exact test = 1.0). Chronic pain occurred less frequently in the Surgipro™ group (11/95, 11.6%) than in the Progrip™ group (22/118, 18.6%) (p<0.157). Overall, 90% of CCS total scores indicated a good outcome (scores of 10 or less out of 115). A principal component analysis of the CCS found that responses clustered into two subscales: 'mesh sensation' and 'pain+movement limitations'. The Progrip™ group had a slightly higher mesh sensation score (p<0.051) and similar pain+movement limitations scores (p<0.120). In this study of quality of life outcomes related to different mesh types, the CCS subscales were more sensitive to differences in outcome than the total CCS score for the whole questionnaire. Future research should consider using the CCS subscales rather than the CCS total score.


cDNA cloning, tissue distribution, and chromosomal localization of Ocp2, a gene encoding a putative transcription-associated factor predominantly expressed in the auditory organs.
We report the cloning of the Ocp2 gene encoding OCP-II from a guinea pig organ-of-Corti cDNA library. The predicted open reading frame encodes a protein of 163 amino acids with an estimated molecular mass of 18.6 kDa. A homology search revealed that Ocp2 shares significant sequence similarity with p15, a subunit of transcription factor SIII that regulates the activity of the RNA polymerase II elongation complex. The Ocp2 messenger RNA is expressed abundantly in the cochlea while not significantly in any other tissues examined, including brain, eye, heart, intestine, kidney, liver, lung, thigh muscle, and testis, demonstrating that the expression of this gene may be restricted to auditory organs. A polyclonal antiserum was raised against the N-terminal region of OCP-II. Immunohistochemical staining of paraffin-embedded sections of the cochlea showed that OCP-II is localized abundantly in nonsensory cells in the organ of Corti; in addition, it was also detected, at a lower concentration, in vestibular sensory organs, as well as auditory and vestibular brain stem nuclei. The Ocp2 gene was mapped to mouse chromosome 4 as well as 11. Our results suggest that OCP-II may be involved in transcription regulation for the development or maintenance of specialized functions of the inner ear.


A rational use of glucocorticoids in patients with early arthritis has a minimal impact on bone mass.
Glucocorticoid (GC)-induced osteoporosis is a frequent complication in patients with rheumatoid arthritis. However, little information exists about the consequences of GC use in patients with early arthritis. Here we describe the variables underlying the use of GC in early arthritis, as well as its effect on bone-mineral density. Data from 116 patients in our early arthritis register were analyzed (90 women; median age, 52.5 years, interquartile range (IQR, 38.5-66); 6-month median disease duration at entry (IQR, 4-9)). In this register, the clinical and treatment information was recorded systematically, including the cumulative GC dose. Lumbar spine, hip, and forearm bone-mineral density (BMD) measurements were performed at entry and after a 2-year follow-up. A multivariate analysis was performed to establish the variables associated with the use of GCs, as well as those associated with variations in BMD. Of the patients with early arthritis studied, 67% received GCs during the 2-year follow-up. GCs were more frequently prescribed to elderly patients, those with higher basal disease activity and disability, and patients with positive rheumatoid factor. When adjusted for these variables, GCs were less frequently prescribed to female patients. The use of GCs was associated with an increase of BMD in the ultradistal region of the forearm, although it induced a significant loss of BMD in the medial region of the forearm. No relevant effect of GC was noted on the BMD measured at other locations. The frequent use of GCs as a "bridge therapy" in patients with early arthritis does not seem to be associated with relevant loss of bone mass. Moreover, cumulative GC administration might be associated with an increase of juxtaarticular BMD.


Human dendritic cell DC-SIGN and TLR-2 mediate complementary immune regulatory activities in response to Lactobacillus rhamnosus JB-1.
The microbiota is required for optimal host development and ongoing immune homeostasis. Lactobacilli are common inhabitants of the mammalian large intestine and immunoregulatory effects have been described for certain, but not all, strains. The mechanisms underpinning these protective effects are beginning to be elucidated. One such protective organism is Lactobacillus rhamnosus JB-1 (Lb. rhamnosus JB-1). Lb. murinus has no such anti-inflammatory protective effects and was used as a comparator organism. Human monocyte-derived dendritic cells (MDDCs) were co-incubated with bacteria and analysed over time for bacterial adhesion and intracellular processing, costimulatory molecule expression, cytokine secretion and induction of lymphocyte polarization. Neutralising antibodies were utilized to identify the responsible MDDC receptors. Lb. rhamnosus JB-1 adhered to MDDCs, but internalization and intracellular processing was significantly delayed, compared to Lb. murinus which was rapidly internalized and processed. Lb. murinus induced CD80 and CD86 expression, accompanied by high levels of cytokine secretion, while Lb. rhamnosus JB-1 was a poor inducer of costimulatory molecule expression and cytokine secretion. Lb. rhamnosus JB-1 primed MDDCs induced Foxp3 expression in autologous lymphocytes, while Lb. murinus primed MDDCs induced Foxp3, T-bet and Ror-γt expression. DC-SIGN was required for Lb. rhamnosus JB-1 adhesion and influenced IL-12 secretion, while TLR-2 influenced IL-10 and IL-12 secretion. Here we demonstrate that the delayed kinetics of bacterial processing by MDDCs correlates with MDDC activation and stimulation of lymphocytes. Thus, inhibition or delay of intracellular processing may be a novel strategy by which certain commensals may avoid the induction of proinflammatory responses.


Assessing disability weights based on the responses of 30,660 people from four European countries.
In calculations of burden of disease using disability-adjusted life years, disability weights are needed to quantify health losses relating to non-fatal outcomes, expressed as years lived with disability. In 2012 a new set of global disability weights was published for the Global Burden of Disease 2010 (GBD 2010) study. That study suggested that comparative assessments of different health outcomes are broadly similar across settings, but the significance of this conclusion has been debated. The aim of the present study was to estimate disability weights for Europe for a set of 255 health states, including 43 new health states, by replicating the GBD 2010 Disability Weights Measurement study among representative population samples from four European countries. For the assessment of disability weights for Europe we applied the GBD 2010 disability weights measurement approach in web-based sample surveys in Hungary, Italy, Netherlands, and Sweden. The survey included paired comparisons (PC) and population health equivalence questions (PHE) formulated as discrete choices. Probit regression analysis was used to estimate cardinal values from PC responses. To locate results onto the 0-to-1 disability weight scale, we assessed the feasibility of using the GBD 2010 scaling approach based on PHE questions, as well as an alternative approach using non-parametric regression. In total, 30,660 respondents participated in the survey. Comparison of the probit regression results from the PC responses for each country indicated high linear correlations between countries. The PHE data had high levels of measurement error in these general population samples, which compromises the ability to infer ratio-scaled values from discrete choice responses. Using the non-parametric regression approach as an alternative rescaling procedure, the set of disability weights were bounded by distance vision mild impairment and anemia with the lowest weight (0.004) and severe multiple sclerosis with the highest weight (0.677). PC assessments of health outcomes in this study resulted in estimates that were highly correlated across four European countries. Assessment of the feasibility of rescaling based on a discrete choice formulation of the PHE question indicated that this approach may not be suitable for use in a web-based survey of the general population.


Liver transplantation in patients with multiple organ failures: Feasibility and outcomes.
Multiple organ failures (OFs) are common in patients with cirrhosis, but the independent effect of the number or type of OFs on liver transplantation (LT) outcomes is not well defined. United Network for Organ Sharing data were analyzed from 2002 to 2016 for all adults listed for LT who received an LT within 30 days after listing. We estimated post-LT survival stratified by number and type of pre-transplant OFs before and after adjusting for confounding variables. During the study period, 4,714 (4.1%) patients died and 19,375 (16.6%) patients were transplanted within 30 days of listing. One or more OF were more common in those who were transplanted (57.4%) compared to those without LT (9.5%). The probability of staying alive more than 30 days on the waiting list without LT decreased with increasing number of OFs; while 90% were alive without OF, only 20% were alive with two OFs, and 2-8% with three or more OFs. The interval between listing and transplantation decreased with an increase in OFs, and the median time to transplant after listing was only 4-5 days with three or more OFs. Although the risk of post-LT mortality increased with increasing number of OFs, the 90-day patient survival was 90% and one-year survival was 81% in the presence of 5-6 OFs. The number of OFs was an independent predictor of survival, but the maximum difference in one-year graft or patient survival between those without OF and those with 5-6 OFs was only 9%. Additionally, the type of OF had minimal impact on outcomes. Liver transplantation is feasible with excellent outcomes, even in the presence of five or six OFs. Multiple organ failures, ranging from 1-6, are common in hospitalized patients with cirrhosis. The survival without liver transplant is dismal in the presence of three or more organ failures. Small retrospective studies have shown that liver transplant is feasible with good outcomes even in the presence of multiple organ failures. In this study, using a large national dataset, we show that survival chances for more than 30 days in those with three or more organ failures are less than 8%. However, if a liver transplant is performed quickly, the survival chances are very high with one-year survival ranging from 84% with three organ failures to 81% with 5-6 organ failures.


Dynamism in Dupuytren's contractures.
Dynamism of Dupuytren's contractures may occur if a contracture crosses over both the metacarpophalangeal (MCPJ) and proximal interphalangeal (PIPJ) joints of one finger. In this situation the extension deficit at one joint can be influenced by the position of the other. This may affect clinical measurements and introduce errors and bias into research using angular deformity as an endpoint. This study reports the dynamism encountered when measuring passive joint extension deficits in pre-operative contractures. Eighty-five digits with a contracture affecting the PIPJ or MCPJ and PIPJ on 72 hands from 70 patients were studied. Seventy-six digits showed dynamism at either the MCPJ or PIPJ (89%). Seventy-four showed dynamism at the PIPJ (87%). The mean dynamism observed was 6° at the MCPJ and 14° at the PIPJ. Previous Dupuytren's surgery to the finger did not influence the amount of dynamism seen. Dynamism is common and may be a source of error or bias in trials of Dupuytren's disease treatment.


On the optimal energy of epithermal neutron beams for BNCT.
The optimal neutron energy for the treatment of deep-seated tumours using boron neutron capture therapy is studied by analysing various figures of merit. In particular, analysis of the therapeutic gain as a function of the neutron energy indicates that, with the currently available 10B carriers, the most useful neutrons for the treatment of deep-seated tumours, in particular glioblastoma multiforme, are those with an energy of a few keV. Based on the results of the simulations, a method is presented which allows us to evaluate the quality of epithermal neutron beams of known energy spectrum, thus allowing us to compare different neutron-producing reactions and beam-shaping assembly configurations used for accelerator-based neutron sources.


Reproductive toxicity evaluation of acetaminophen in Swiss CD-1 mice using a continuous breeding protocol.
Acetaminophen (APAP) was evaluated for reproductive toxicity in Swiss CD-1 mice using a continuous breeding protocol. APAP was administered in the diet at 0, 0.25, 0.5, and 1.0% (w/w), which represented average daily intakes of 0, 357, 715, and 1430 mg APAP/kg/day, respectively. Exposure of parental (P) breeding pairs to 1% APAP in the diet for 14 weeks during cohabitation significantly decreased the number of litters per pair, and reduced, although not significantly, the number of live pups per litter. Importantly, 6 of 19 high-dose P pairs failed to produce a fifth litter, and this fully accounted for the diminished number of litters in this group. In addition, the fifth litter that was produced by the 13 high-dose P pairs averaged only about 9 live pups per litter, which correspondingly reduced the overall group average for this parameter. In comparison, the control and two lower-dose P pairs produced 11 or 12 live pups per litter on average. Although the birth weights for F1 pups in the final litter were unaffected by prenatal APAP exposure, postnatal growth was adversely affected as evidenced by retarded weight gain as measured at 28 and 74 +/- 10 days of age for all three dietary levels. At 1% APAP this weight gain effect was more pronounced at Day 28 than at Day 74 +/- 10, suggesting that nursing pups may have been exposed to higher concentrations or may be more sensitive to APAP and/or an active metabolite than were the young adults.(ABSTRACT TRUNCATED AT 250 WORDS)


Cloning and expression of cry2Aa from native Bacillus thuringiensis strain SY49-1 and its insecticidal activity against Culex pipiens (Diptera: Culicidae).
Bacillus thuringiensis (Berliner) (Bt) is well known for having toxicity against pest insects because of their ability to form endospores and broad-range activity of their parasporal inclusions. In this study, a new member of cry2A gene from previously characterized native B. thuringiensis SY49-1 strain was cloned, expressed and used for its activity against Culex pipiens (Diptera: Culicidae) larvae. The sequence analysis of the cloned cry2A gene revealed that it encodes a polypeptide of 633 aa residues with 99% identity to Cry2Aa protein with expected molecular weight of 70.7 kDa. Bacillus thuringiensis delta-endotoxin nomenclature committee designed our sequence as Cry2Aa18 being a new member of Bt toxins. Bioassays against last instar larvae of C. pipiens indicated that Cry2Aa18 has considerable toxicity with LC50 of 630 μg ml-1. In order to prevent the spread of infectious diseases mediated by C. pipiens, this newly characterized cry2Aa18 gene could constitute as an important biological control tool for controlling mosquito larvae living in freshwater systems and can be used as a good alternative for minimizing the use of chemicals.


Patterns of DNA sequence variation suggest the recent action of positive selection in the janus-ocnus region of Drosophila simulans.
Levels of nucleotide polymorphism in three paralogous Drosophila simulans genes, janusA (janA), janusB (janB), and ocnus (ocn), were surveyed by DNA sequencing. The three genes lie in tandem within a 2.5-kb region of chromosome arm 3R. In a sample of eight alleles from a worldwide distribution we found a significant departure from neutrality by several statistical tests. The most striking feature of this sample was that in a 1.7-kb region containing the janA and janB genes, 30 out of 31 segregating sites contained variants present only once in the sample, and 29 of these unique variants were found in the same allele. A restriction survey of an additional 28 lines of D. simulans revealed strong linkage disequilibrium over the janA-janB region and identified six more alleles matching the rare haplotype. Among the rare alleles, the level of DNA sequence variation was typical for D. simulans autosomal genes and showed no departure from neutrality. In addition, the rare haplotype was more similar to the D. melanogaster sequence, indicating that it was the ancestral form. These results suggest that the derived haplotype has risen to high worldwide frequency relatively recently, most likely as a result of natural selection.


Predicting the volume of distribution of drugs in humans.
Recent studies have shown that many promising new drug candidates were abandoned due to poor pharmacokinetic properties (PKs). Therefore, it is important to predict the PKs of compounds during the early stages of drug development. The volume of distribution (VD) is one of the most important PK parameters. When considered along with systemic clearance, the VD determines the biological half-life, which is used for designing suitable dosage regimens and rational formulations. At present, the methods used to predict VD include (i) the extrapolation of animal data, (ii) physiologically based pharmacokinetic (PBPK) modeling and (iii) in silico approaches that employ quantitative structure-pharmacokinetic relationships (QSPR). In this article, the latest progress in the field of VD prediction is summarized in terms of the above three areas, respectively, and these approaches are expected to be valuable for screening new drugs during the early stages of drug discovery and development.


DARK Classics in Chemical Neuroscience: NBOMes.
N-Benzylphenethylamines, commonly known as NBOMes, are synthetic psychedelic compounds derived from the phenethylamine class of psychedelics (2C-X compounds), which originally have been derived from the naturally occurring alkaloid mescaline. Analogously to their parent compounds and other classical psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), NBOMes are believed to exert their main pharmacological effects through activation of serotonin 2A (5-HT2A) receptors. Since their introduction as New Psychoactive Substances (NPSs) in 2010, NBOMes have been widely used for recreational purposes; this has resulted in numerous cases of acute toxicity, sometimes with lethal outcomes, leading to the classification of several NBOMes as Schedule I substances in 2013. However, in addition to their recreational use, the NBOMe class has yielded several important biochemical tools, including [11C]Cimbi-36, which is now being used in positron emission tomography (PET) studies of the 5-HT2A and 5-HT2C receptors in the mammalian brain, and 25CN-NBOH, one of the most selective 5-HT2A receptor agonists developed to date. In this Review, the history, chemistry, structure-activity relationships, ADME (absorption, distribution, metabolism, and excretion) properties, and safety profiles of NBOMes will be outlined and discussed.


STAG2 promotes error correction in mitosis by regulating kinetochore-microtubule attachments.
Mutations in the STAG2 gene are present in ∼20% of tumors from different tissues of origin. STAG2 encodes a subunit of the cohesin complex, and tumors with loss-of-function mutations are usually aneuploid and display elevated frequencies of lagging chromosomes during anaphase. Lagging chromosomes are a hallmark of chromosomal instability (CIN) arising from persistent errors in kinetochore-microtubule (kMT) attachment. To determine whether the loss of STAG2 increases the rate of formation of kMT attachment errors or decreases the rate of their correction, we examined mitosis in STAG2-deficient cells. STAG2 depletion does not impair bipolar spindle formation or delay mitotic progression. Instead, loss of STAG2 permits excessive centromere stretch along with hyperstabilization of kMT attachments. STAG2-deficient cells display mislocalization of Bub1 kinase, Bub3 and the chromosome passenger complex. Importantly, strategically destabilizing kMT attachments in tumor cells harboring STAG2 mutations by overexpression of the microtubule-destabilizing enzymes MCAK (also known as KIF2C) and Kif2B decreased the rate of lagging chromosomes and reduced the rate of chromosome missegregation. These data demonstrate that STAG2 promotes the correction of kMT attachment errors to ensure faithful chromosome segregation during mitosis.


[Anatomy of the body and of the mind in Francis Glisson].
In this paper I shall point out that Francis Glisson's conceptualisation of irritability must be understood by looking at the epistemological context within which it developed. The theory of irritability has to be interpreted as part of an 'analogical conception' that puts the analytical operations of mind in relation to the epistemic model provided by dissection. Establishing this relation makes it possible for Glisson to think the activity of the organs as 'empirical epistemic operations'.


The coding sequence of amyloid-beta precursor protein APP contains a neural-specific promoter element.
The amyloid-beta precursor protein APP is generally accepted to be involved in the pathology of Alzheimer's disease. Since its physiological role is still unclear, we decided to study the function of APP via stable transgenesis in the amphibian Xenopus laevis. However, the application of constructs encoding (mutant) APP fused to the C-terminus of the green fluorescent protein GFP (GFP-APP), and harboring a tissue-specific or an inducible gene promoter did not result in transgene expression of APP in neuronal and neuroendocrine cells. Surprisingly, a construct encoding either Xenopus or human APP fused to the N-terminus of GFP (APP-GFP) gave fluorescence throughout the whole brain of the tadpole, despite the fact that a proopiomelanocortin gene promoter was used to target transgene expression specifically to the intermediate pituitary cells. Detailed analysis with deletion mutants revealed the presence of a neural-specific, transcriptionally active DNA element within the 3'-end of the APP-coding sequence that gave rise to an aberrant transcript and protein in the APP-GFP transgenic animals. The DNA element appears to prevent proper APP transgene expression in Xenopus neuronal and neuroendocrine cells. Thus, the coding sequences of Xenopus and human APP contain a neural-specific promoter element, the physiological significance of which is at present unclear.


Isokinetic and isometric muscle strength in a healthy population with special reference to age and gender.
Muscle strength is an excellent indicator of general health when based on reliable measurements. Muscle strength data for a healthy population are rare or non-existent. The aim of the present study was to measure a set of normal values for isometric and isokinetic muscle strength for all the major joint movements of the body and, from these data, to create a basis for comparison of the muscle strength of an individual with the expected value in a normal population. A randomly selected group, aged 20-80 years, from the Copenhagen City Heart Study were studied. The group was subgrouped according to age and gender. Isometric and isokinetic muscle strength was measured in each subject across the main joints in the body. A statistical model was developed that encompassed the three main muscle groups: upper limbs, trunk and lower limbs. Muscle strength in healthy men decreases in a linear fashion from the age of 25 years down to between 54% and 89% at the age of 75 years, and seems not highly dependent on any other parameter than age. For women, the muscle strength is dependent on weight and is only related to age from around 40 years of age. The decrease in muscle strength from the age around 40 to 75 years is 48-92%. For most muscle groups, men are 1.5-2 times stronger than women, with the oldest men having strength similar to that observed among the youngest women. We developed a model to compare the isometric and isokinetic muscle strength of all the major joint movements of an individual with values for a healthy man or woman at any age in the range of 20-80 years. In all age groups, women have lower muscle strength than men. Men's muscle strength declines with age, while women's muscle strength declines from the age of 41 years.


Protective effect of quercetin against sodium fluoride induced oxidative stress in rat's heart.
The antioxidative and cardioprotective properties of quercetin were investigated against sodium fluoride (NaF) induced oxidative stress in rat hearts. Experimental rats were divided into five groups. The first group served as the untreated (normal) control. The second group received NaF at a dose of 600 ppm through drinking water for 1 week, and served as the toxin control. The third and fourth groups were exposed to quercetin (at the dose of 10 and 20 mg kg(-1) intraperitoneally (i.p.) for 1 week) prior to NaF intoxication, and the fifth group was treated with vitamin C at a dose of 10 mg kg(-1) i.p., for 1 week prior to NaF intoxication and served as the positive control in the study. The activities of various antioxidant enzymes, superoxide dismutase and catalase, level of reduced glutathione and lipid peroxidation end product were determined in the cardiac tissues of all the experimental animals. NaF intoxication significantly altered all the indices related to the pro-oxidant-antioxidant status of the heart; treatment with the active constituents prior to NaF administration, however, prevented these alterations. The combined results suggest that quercetin protects rat hearts from NaF-induced oxidative stress, probably via its antioxidant properties.


Access to renal transplantation among American Indians and Hispanics.
African Americans have decreased access to renal transplantation compared with whites. Whether similar barriers exist for American Indians or Hispanics is not well defined. The authors identified a total of 1,335 patients ages 20 to 59 years without prior renal transplantation undergoing dialysis in December 1994 in Arizona and New Mexico. For each patient, information was collected on identification as a potential candidate for renal transplantation, referral to a renal transplantation center, completion of 4 stages in the evaluation process, and receipt of a transplant over 7 years. American Indians were more likely than whites to be identified as potential candidates (relative risk [RR] 1.30, 95% confidence interval [CI] 1.15 to 1.44) and to be referred to a transplant center (RR 1.16, 95% CI 1.09 to 1.19). There were no significant differences in candidacy or referral status between Hispanics and whites. Among potential candidates referred to a transplant center, both American Indians (RR 0.73, 95% CI 0.51 to 0.96) and Hispanics (RR 0.68, 95% CI 0.50 to 0.88) were less likely than whites to be placed on a waiting list. Both American Indians (hazard ratio [HR] 0.37, 95% CI 0.24 to 0.58) and Hispanics (HR 0.58, 95% CI 0.39 to 0.86) were much less likely than whites to undergo renal transplantation. Despite similar referral rates for renal transplantation, American Indians and Hispanics were less likely than whites to be placed on a transplant waiting list or receive a transplant. Policies to address these disparities should address specific barriers within the transplant evaluation process.


Menstrual psychosis.
This paper reviews the literature on menstrual psychosis and proposes a new classification, adapting that of v. Krafft-Ebing (1902) and Jolly (1914). The world literature consists mainly of case reports; they include a few with data good enough for a statistical demonstration of the link between onset and menses. These well-documented cases include examples of pre-menstrual, catamenial, paramenstrual and mid-cycle onsets, and continuous illnesses with phasic shifts rhythmic with the menstrual cycle. In sufferers, episodes seem to be concentrated around the menarche and after childbirth. The clinical picture resembles that of puerperal psychosis, and there are at least 20 women who have suffered both psychoses at different epochs in their lives. Both seem to fall within the manic depressive rubric, so that menstruation can be another trigger of a bipolar episode. Some work suggests an association with anovulatory cycles. Cases starting before the menarche suggest a diencephalic origin.


An RCT of acute health effects in COPD-patients after passive vape exposure from e-cigarettes.
Background: E-cigarette use has been shown to have short-term acute effects among active users but less is known of the acute passive effects, particularly among individuals with existing respiratory diseases. Objective: To investigate local and systemic effects of short-term passive vape exposure among patients with mild or moderate chronic obstructive pulmonary disease (COPD). Methods: In a double-blinded crossover study 16 non-smoking COPD-patients (mean age 68) were randomly exposed for 4 h to passive vape (median PM2.5: 18 µg/m3 (range: 8-333)) and clean air (PM2.5 < 6 µg/m3) separated by 14 days. Particles were measured using an ultrafine particle counter (P-TRAK) and a scanning mobility particle sizer (SMPS). Health effects including Surfactant Protein-A (SP-A) and albumin in exhaled air, spirometry, FeNO, and plasma proteins were evaluated before, right after, and 24 hours after exposure. Participants reported symptoms throughout exposure sessions. Data were analyzed using mixed models. Results: SP-A in exhaled air was negatively affected by exposure to vape and several plasma proteins increased significantly. Throat irritation was more pronounced during passive vape exposure, while FVC and FEV1 decreased, however, not significantly. Conclusions: SP-A in exhaled air and some plasma proteins were affected by passive vape in patients with COPD indicating inflammation, showing that passive vape exposure is potentially harmful.


Effect of acute and chronic alcohol ingestion on the rate of folate catabolism and hepatic enzyme induction in mice.
1. Folate deficiency is commonly found in alcoholic subjects although the causative mechanism is uncertain. It has been suggested that microsomal enzyme induction resulting from chronic alcohol ingestion might accelerate the rate of folate catabolism thus causing deficiency. 2. By using an experimental animal model to determine the rate of catabolism of [3H]pteroylglutamate (folic acid) by the quantitative estimation of the two urinary catabolites p-[3H]aminobenzoylglutamate and [3H]acetamidobenzoylglumate, we have measured both the rate of folate catabolism and the extent of microsomal-enzyme induction in mice after acute and chronic alcohol ingestion. 3. Despite significant evidence of enzyme induction in the chronic alcohol group, there was no difference in the rate of folate catabolism after acute or chronic alcohol ingestion when compared with that of the controls.


Microthermoforming as a novel technique for manufacturing scaffolds in tissue engineering (CellChips).
The CellChip is a microstructured polymer scaffold, which favours a three-dimensional cultivation of cells within an array of cubic microcontainers. The manufacturing process used so far is microinjection moulding combined with laser-based perforation. In a first attempt to simplify the process, costly perforation was avoided by using commercially available, inexpensive microfiltration membranes for the bottom of the microcavities. Microthermoforming is a promising novel technique which allows the CellChip to be produced from thin film. Working pressures of approximately 4000 kPa were required for the adequate moulding of 50 microm thick films from three different polymers (polystyrene, polycarbonate, cyclo-olefin polymer). Integrating drafts and chamfers in micromoulds is not going to eliminate an uneven thickness profile, but reduces demoulding forces. Microthermoformed CellChips of polycarbonate were perforated by an ion track technique to guarantee a sufficient supply of medium and gases to the cells. The prestructured CellChips were irradiated with 1460 MeV xenon ions at a fluence of a few 10(6) ions/cm2. The tracks were etched in an aqueous solution of 5 N NaOH at 30 degrees C, which resulted in cylindrical pores approximately 2 microm in diameter. Microinjection-moulded, membrane-bonded and thermoformed CellChips were subjected to comparative examination for viability in a cell culture experiment with parenchymal liver cells (HepG2). The cells stayed viable over a period of more than 20 days. No significant differences in viability between injection-moulded, membrane-bonded, and thermoformed CellChips were observed.


A novel method for analyzing extremely biased agonism at G protein-coupled receptors.
Seven transmembrane receptors were originally named and characterized based on their ability to couple to heterotrimeric G proteins. The assortment of coupling partners for G protein-coupled receptors has subsequently expanded to include other effectors (most notably the βarrestins). This diversity of partners available to the receptor has prompted the pursuit of ligands that selectively activate only a subset of the available partners. A biased or functionally selective ligand may be able to distinguish between different active states of the receptor, and this would result in the preferential activation of one signaling cascade more than another. Although application of the "standard" operational model for analyzing ligand bias is useful and suitable in most cases, there are limitations that arise when the biased agonist fails to induce a significant response in one of the assays being compared. In this article, we describe a quantitative method for measuring ligand bias that is particularly useful for such cases of extreme bias. Using simulations and experimental evidence from several κ opioid receptor agonists, we illustrate a "competitive" model for quantitating the degree and direction of bias. By comparing the results obtained from the competitive model with the standard model, we demonstrate that the competitive model expands the potential for evaluating the bias of very partial agonists. We conclude the competitive model provides a useful mechanism for analyzing the bias of partial agonists that exhibit extreme bias.


Advanced paternal age effects in neurodevelopmental disorders-review of potential underlying mechanisms.
Multiple epidemiological studies suggest a relationship between advanced paternal age (APA) at conception and adverse neurodevelopmental outcomes in offspring, particularly with regard to increased risk for autism and schizophrenia. Conclusive evidence about how age-related changes in paternal gametes, or age-independent behavioral traits affect neural development is still lacking. Recent evidence suggests that the origins of APA effects are likely to be multidimensional, involving both inherited predisposition and de novo events. Here we provide a review of the epidemiological and molecular findings to date. Focusing on the latter, we present the evidence for genetic and epigenetic mechanisms underpinning the association between late fatherhood and disorder in offspring. We also discuss the limitations of the APA literature. We propose that different hypotheses relating to the origins of the APA effects are not mutually exclusive. Instead, multiple mechanisms likely contribute, reflecting the etiological complexity of neurodevelopmental disorders.


Differences in Net Information Flow and Dynamic Connectivity Metrics Between Physically Active and Inactive Subjects Measured by Functional Near-Infrared Spectroscopy (fNIRS) During a Fatiguing Handgrip Task.
Twenty-three young adults (4 Females, 25.13 ± 3.72 years) performed an intermittent maximal handgrip force task using their dominant hand for 20 min (3.5 s squeeze/6.5 s release, 120 blocks) with concurrent cortical activity imaging by functional Near-Infrared Spectroscopy (fNRIS; OMM-3000, Shimadzu Corp., 111 channels). Subjects were grouped as physically active (n = 10) or inactive (n = 12) based on a questionnaire (active-exercise at least four times a week, inactive- exercise less than two times a week). We explored how motor task fatigue affected the vasomotion-induced oscillations in ΔHbO as measured by fNIRS at each hemodynamic frequency band: endothelial component (0.003-0.02 Hz) associated to microvascular activity, neurogenic component (0.02-0.04 Hz) related to intrinsic neuronal activity, and myogenic component (0.04-0.15 Hz) linked to activity of smooth muscles of arterioles. To help understand how these three neurovascular regulatory mechanisms relate to handgrip task performance we quantified several dynamic fNIRS metrics, including directional phase transfer entropy (dPTE), a computationally efficient and data-driven method used as a marker of information flow between cortical regions, and directional connectivity (DC), a means to compute directionality of information flow between two cortical regions. The relationship between static functional connectivity (SFC) and functional connectivity variability (FCV) was also explored to understand their mutual dependence for each frequency band in the context of handgrip performance as fatigued increased. Our findings ultimately showed differences between subject groups across all fNIRS metrics and hemodynamic frequency bands. These findings imply that physical activity modulates neurovascular control mechanisms at the endogenic, neurogenic, and myogenic frequency bands resulting in delayed fatigue onset and enhanced performance. The dynamic cortical network metrics quantified in this work for young, healthy subjects provides baseline measurements to guide future work on older individuals and persons with impaired cardiovascular health.


Structural correlates of mild cognitive impairment.
The structural correlates of mild cognitive impairment (MCI) were examined in 105 elderly subjects whose cognitive function ranged from intact to demented, including 38 subjects with MCI. Hippocampal volumes (left and right HcV), brain volume (BV), and grey matter volume (GMV) and white matter volume (WMV) were segmented from high resolution magnetic resonance data sets and normalised to intracranial volume (ICV). Hippocampal volume reductions, but not global brain, white or grey matter atrophy, were associated with MCI. White matter lesion severity did not differ over cognitive states. In multiple logistic regression models, normalised HcV and ICV (indicating premorbid brain volume) were significant predictors of MCI versus normality. Normalised BV and ICV significantly predicted dementia versus MCI. Absolute volumetric measures of HcV and BV yielded comparable classification accuracies. Hippocampal atrophy may be the crucial step for the transition from normality to MCI. Widespread brain atrophy may be the step to determine the transition from MCI to dementia. Brain volume reserve effects appear to be involved in both of these steps.


Reproducible research practices, openness and transparency in health economic evaluations: study protocol for a cross-sectional comparative analysis.
There has been a growing awareness of the need for rigorously and transparent reported health research, to ensure the reproducibility of studies by future researchers. Health economic evaluations, the comparative analysis of alternative interventions in terms of their costs and consequences, have been promoted as an important tool to inform decision-making. The objective of this study will be to investigate the extent to which articles of economic evaluations of healthcare interventions indexed in MEDLINE incorporate research practices that promote transparency, openness and reproducibility. This is the study protocol for a cross-sectional comparative analysis. We registered the study protocol within the Open Science Framework (osf.io/gzaxr). We will evaluate a random sample of 600 cost-effectiveness analysis publications, a specific form of health economic evaluations, indexed in MEDLINE during 2012 (n=200), 2019 (n=200) and 2022 (n=200). We will include published papers written in English reporting an incremental cost-effectiveness ratio in terms of costs per life years gained, quality-adjusted life years and/or disability-adjusted life years. Screening and selection of articles will be conducted by at least two researchers. Reproducible research practices, openness and transparency in each article will be extracted using a standardised data extraction form by multiple researchers, with a 33% random sample (n=200) extracted in duplicate. Information on general, methodological and reproducibility items will be reported, stratified by year, citation of the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement and journal. Risk ratios with 95% CIs will be calculated to represent changes in reporting between 2012-2019 and 2019-2022. Due to the nature of the proposed study, no ethical approval will be required. All data will be deposited in a cross-disciplinary public repository. It is anticipated the study findings could be relevant to a variety of audiences. Study findings will be disseminated at scientific conferences and published in peer-reviewed journals.


The grapevine-infecting vitiviruses, with particular reference to grapevine virus A.
A number of vitiviruses infect grapevine, arguably the most important fruit crop, and the host from which they derive their genus name. In contrast to most grapevine viruses, the etiological role of these viruses is unclear, albeit that they are associated with several well-known--and a number of emerging--diseases of grapevine. Here, we review the genus Vitivirus, with special reference to its most omnipresent member, grapevine virus A. We discuss the latest taxonomic status of the genus, as well as the genome and genomic organisation, replication mechanism, and genetic variability of GVA, and we also present the latest research progress with vitivirus-based vectors; the identification of a new vitivirus, GVE, the discovery of VIGG, a unique GVA-induced host protein, the molecular characterisation of hitherto unknown or puzzling genetic elements in the GVA genome, and the latest developments in vitivirus diagnostics.


The role of input noise in transcriptional regulation.
Gene expression levels fluctuate even under constant external conditions. Much emphasis has usually been placed on the components of this noise that are due to randomness in transcription and translation. Here we focus on the role of noise associated with the inputs to transcriptional regulation; in particular, we analyze the effects of random arrival times and binding of transcription factors to their target sites along the genome. This contribution to the total noise sets a fundamental physical limit to the reliability of genetic control, and has clear signatures, but we show that these are easily obscured by experimental limitations and even by conventional methods for plotting the variance vs. mean expression level. We argue that simple, universal models of noise dominated by transcription and translation are inconsistent with the embedding of gene expression in a network of regulatory interactions. Analysis of recent experiments on transcriptional control in the early Drosophila embryo shows that these results are quantitatively consistent with the predicted signatures of input noise, and we discuss the experiments needed to test the importance of input noise more generally.


Effect of Cultivation and Timing of Nitrogen Fertilization on Large Patch Disease of Zoysiagrass.
Large patch of zoysiagrass (Zoysia spp.) is caused by Rhizoctonia solani anastomosis group 2-2 LP. The effects of summer cultivation (core-aerification, verticutting, and sand topdressing) and spring and fall versus summer nitrogen (N) fertilization on large patch in fairway height 'Meyer' zoysiagrass were investigated from 2008 to 2011 in Manhattan, Haysville, and Olathe, KS. Disease was assessed by measuring patch diameters or analyzing digital images of affected plot areas to determine the percentage of non-green turfgrass within patches. Cultivation did not affect thatch temperature, soil temperature, soil water content, or turf recovery from large patch in early summer. Furthermore, cultivation did not result in overall significant reductions in patch diameters or average weekly rate of patch diameter increase among plots at the three experimental locations. In some site-year combinations, spring and fall N fertility was associated with lower percentages of non-green turf within affected plot areas in Manhattan and Haysville. In some cases, applications of N during spring and fall may alleviate large patch symptoms.


Cost-effectiveness of percutaneous coronary intervention in patients with stable coronary artery disease and abnormal fractional flow reserve.
The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) 2 trial demonstrated a significant reduction in subsequent coronary revascularization among patients with stable angina and at least 1 coronary lesion with a fractional flow reserve ≤0.80 who were randomized to percutaneous coronary intervention (PCI) compared with best medical therapy. The economic and quality-of-life implications of PCI in the setting of an abnormal fractional flow reserve are unknown. We calculated the cost of the index hospitalization based on initial resource use and follow-up costs based on Medicare reimbursements. We assessed patient utility using the EQ-5D health survey with US weights at baseline and 1 month and projected quality-adjusted life-years assuming a linear decline over 3 years in the 1-month utility improvements. We calculated the incremental cost-effectiveness ratio based on cumulative costs over 12 months. Initial costs were significantly higher for PCI in the setting of an abnormal fractional flow reserve than with medical therapy ($9927 versus $3900, P<0.001), but the $6027 difference narrowed over 1-year follow-up to $2883 (P<0.001), mostly because of the cost of subsequent revascularization procedures. Patient utility was improved more at 1 month with PCI than with medical therapy (0.054 versus 0.001 units, P<0.001). The incremental cost-effectiveness ratio of PCI was $36 000 per quality-adjusted life-year, which was robust in bootstrap replications and in sensitivity analyses. PCI of coronary lesions with reduced fractional flow reserve improves outcomes and appears economically attractive compared with best medical therapy among patients with stable angina.


Manhattan++: displaying genome-wide association summary statistics with multiple annotation layers.
Over the last 10 years, there have been over 3300 genome-wide association studies (GWAS). Almost every GWAS study provides a Manhattan plot either as a main figure or in the supplement. Several software packages can generate a Manhattan plot, but they are all limited in the extent to which they can annotate gene-names, allele frequencies, and variants having high impact on gene function or provide any other added information or flexibility. Furthermore, in a conventional Manhattan plot, there is no way of distinguishing a locus identified due to a single variant with very significant p-value from a locus with multiple variants which appear to be in a haplotype block having very similar p-values. Here we present a software tool written in R, which generates a transposed Manhattan plot along with additional features like variant consequence and minor allele frequency to annotate the plot and addresses these limitations. The software also gives flexibility on how and where the user wants to display the annotations. The software can be downloaded from CRAN repository and also from the GitHub project page. We present a major step up to the existing conventional Manhattan plot generation tools. We hope this form of display along with the added annotations will bring more insight to the reader from this new Manhattan++ plot.


Gastrointestinal endoscopy in patients on anticoagulant therapy and antiplatelet agents.
Periprocedural management of antithrombotics for gastrointestinal endoscopy is a common clinical issue, given the widespread use of these drugs for primary and secondary cardiovascular prevention. For diagnostic procedures, with or without biopsy, no adjustments in antithrombotics are usually needed. For operative procedures, balancing the risk of periprocedural hemorrhage with the continuation of antithrombotics against the chance of recurrent thromboembolic events with their discontinuation may be challenging. Oral anticoagulants need to be temporarily withheld, and consideration must be given to whether a periendoscopic "bridge" therapy, typically a low-molecular-weight heparin, should be used in order to minimize the risk of thromboembolic events. Although some emerging evidence has shown that patients receiving heparin bridging appear to be at increased risk of overall and major bleeding and at similar risk of thromboembolic events compared to controls, bridging therapy is still recommended for patients on vitamin K antagonists who are at high thrombotic risk. Conversely, bridging therapy is usually not needed for patients taking new oral agents, which are characterized by shorter half-lives, and a rapid offset and onset of action. Management of antiplatelet therapy requires special care in patients on secondary prevention, especially those with coronary stents. This review is intended to summarize the recommendations of updated International Guidelines designed to help the decision-making process in such an intricate field.


Efficacy of pharmacologic closure of patent ductus arteriosus in small-for-gestational-age extremely preterm infants.
Optimal management of the patent ductus arteriosus (PDA) in preterm infants remains controversial. Therefore, studies identifying infants who are most likely to benefit from PDA treatment are needed. We sought to examine if significant intrauterine growth restriction, defined by birth weight z-score, reduces the efficacy of PDA closure with indomethacin or ibuprofen and thereby increases the need for surgical closure of PDA after pharmacologic treatment. We studied infants 23-28weeks' gestation born 2006-2013 at NICHD Neonatal Research Network centers. We examined the responses to PDA treatment with indomethacin and/or ibuprofen and whether the PDA was subsequently closed surgically. Logistic regression generated adjusted odds ratios (ORs) for the associations between the z-score groups (<-2, -2 to -0.5, and >-0.5) and PDA surgery following pharmacologic treatment. 5606 infants were diagnosed with PDA; 3587 (64.0%) received indomethacin or ibuprofen or both, and 909 (25.3%) underwent PDA surgery. Mothers of infants with PDA non-closure were less likely to have hypertension (19% vs. 28%). Infants with non-closure were more likely to be female (53% vs. 49%), have lower gestational age and birth weight and to develop sepsis (42% vs. 31%). Compared to infants with z-score>-0.5, PDA surgery was increased among infants with z-score -2 to -0.5 (OR=1.23; 95% CI 1.02-1.47) but not among infants with z-score<-2. Infants with birth weight z-score -2 to -0.5 are more likely than normally grown infants to require PDA surgery following pharmacologic treatment.


Pancreatic intraepithelial neoplasia in association with intraductal papillary mucinous neoplasms of the pancreas: implications for disease progression and recurrence.
The development of pancreatic cancer (PC) several years after curative resection for noninvasive intraductal papillary mucinous neoplasm (IPMN) and the presence of PC distant from IPMN suggest that PC may develop independently of the IPMN. Here, we identified pancreatic intraepithelial neoplasia (PanIN) lesions, the putative precursors of PC, in the ducts of pancreata resected for IPMN and assessed the frequency of molecular aberrations common to PanIN and PC, within these lesions. The protein expression of p53, p21(WAF1/CIP1), cyclin D1, p16(INK4A) and DPC4/Smad4 were examined by immunohistochemistry in 267 PanIN lesions from a cohort of 23 patients with IPMN. Overexpression of p21(WAF1/CIP1) was present in PanIN-1A and -1B lesions and increased in frequency in PanIN-2 and PanIN-3. Overexpression of p53 and cyclin D1, and loss of p16(INK4A) expression were detected in PanIN-2 and PanIN-3 lesions. Loss of DPC4/Smad4 expression occurred only in the PanIN-3 lesions. PanIN lesions that were more dysplastic than the coincident IPMN were identified in 5 of 12 patients, and 2 of these contained a greater number of aberrations in protein expression than the IPMN. PanIN lesions seen in association with IPMN demonstrate molecular and histologic changes identical to PanIN lesions found in association with PC and, in some cases, are more advanced than the associated IPMN. These data suggest that PanIN lesions found in the ducts of a pancreas with IPMN may be relevant to the development of PC either coincident with IPMN or in the remnant pancreas after curative resection of IPMN.


High Amount of Organic Matter during Caries Formation Reduces Remineralization and Resin Infiltration of Enamel Caries.
The amount of organic material in the cariogenic environment correlates with the amount of organic material incorporated in carious enamel. The incorporated organic material may be expected to reduce the pore volumes available for remineralization and resin infiltration, but these expected outcomes have not yet been quantified. We tested the effect of the amount of organic content in the cariogenic agent on remineralization and the resin-occluded pore volume in artificial subsurface enamel caries. An acid gel (organic-rich; G1) and an aqueous solution (organic-poor; G2) were used to induce subsurface lesions in human enamel. Undemineralized histological sections were prepared, microradiographed, and then submitted to resin infiltration in vitro. The enamel component volumes (mineral, organic, remineralizable [total water volume], loosely and firmly bound water volumes, and resin-occluded volume) were measured (by microradiography and polarizing microscopy) at histological sites (n = 38, G1; n = 34, G2). The main outcomes were the differences between the experimental and the predicted volumes (Δremineralizable and Δresin-occluded volumes). Resin infiltration was confirmed by confocal scanning laser microscopy. Compared to G2, G1 presented more incorporated organic volume and lower Δremineralizable volume (p = 0.003; Hedges g = 0.66; power = 0.87), a lower increase in loosely bound water volume (p = 0.0013; Hedges g = 0.74; power = 0.93), a lower remineralization volume in the surface layer (p = 0.017; Hedges g = 0.68; power = 0.8), and a lower Δresin-occluded volume (p = 0.0015; Hedges g = 0.73; power = 0.92). In conclusion, the higher amount of organic matter in the cariogenic gel negatively affected remineralization and the resin-occluded volume in subsurface lesions.


The effects of combined exposure of solvents and noise on auditory function - A systematic review and meta-analysis.
Chemical substances can negatively affect the auditory system. Chemical substances alone or combined with high-level noise have recently become a major concern as a cause of occupational hearing loss. To assess the combined effect of solvents and noise versus solvents only, or noise only, on the auditory function of workers. Published articles which included noise and/or solvent exposure or combined effects of solvents and noise, studies conducted on human beings only and the use of audiological tests on participants. Thirteen papers were eligible for inclusion. The participants' ages ranged from 18 to 68 years. Results revealed that 24.5% presented with hearing loss as a result of noise exposure only; 18% presented with hearing loss owing to solvent exposure only; and a total of 43.3% presented with hearing loss owing to combined noise and solvent exposure. Furthermore, the prevalence of hearing loss in the noise and solvent group was significantly (p < 0.001) higher than the other groups in 10 out of the 13 studies analysed, with a pooled odds ratio (OR) of 2.754. Of the 178 participants (total of all participants exposed to solvents), a total of 32 participants presented with auditory pathology as a result of exposure to solvents only. There was a significantly higher pooled odds of hearing loss in noise and solvent-exposed group compared to solvent-only group (pooled OR = 2.15, 95% CI: 1.24-3.72, p = 0.006). The findings revealed significantly higher odds of acquiring hearing loss when workers were exposed to a combination of solvents and noise as opposed to solvents only, motivating for its inclusion into hearing conservation programmes.


Association of Paid Sick Leave Laws With Foodborne Illness Rates.
Previous studies suggest an association between paid sick leave (PSL) and better population health, including fewer infectious and nosocomial gastrointestinal disease outbreaks. Yet few studies examine whether laws requiring employers to offer PSL demonstrate a similar association. This mixed-methods study examined whether laws requiring employers to provide PSL are associated with decreased foodborne illness rates, particularly laws that are more supportive of employees taking leave. The four earliest PSL laws were classified by whether they were more or less supportive of employees taking leave. Jurisdictions with PSL were matched to comparison jurisdictions by population size and density. Using difference-in-differences, monthly foodborne illness rates (2000-2014) in implementation and comparison jurisdictions before and after the laws were effective were compared, stratifying by how supportive the laws were of employees taking leave, and then by disease. The empirical analysis was conducted from 2015-2017. Foodborne illness rates declined after implementation of the PSL law in jurisdictions with laws more supportive of employees taking leave, but increased in jurisdictions with laws that are less supportive. In adjusted analyses, PSL laws that were more supportive of employees taking sick leave were associated with an adjusted 22% decrease in foodborne illness rates (p=0.005). These results are driven by campylobacteriosis. Although the results suggest an association between more supportive PSL laws and decreased foodborne illness rates, they should be interpreted cautiously because the trend is driven by campylobacteriosis, which has low person-to-person transmission.