Regulation of CXCR4 by the Notch ligand delta-like 4 in endothelial cells.
Gene-targeting studies have shown that Delta-like 4 (Dll4) is required for normal embryonic vascular remodeling, but the mechanisms underlying Dll4 regulatory functions are not well defined. We generated primary human umbilical vascular endothelial cells that express Dll4 protein to study Dll4 function and previously showed that Dll4 down-regulates vascular endothelial growth factor (VEGF) receptor 2 and NRP1 expression and inhibits VEGF function. We now report that expression of Dll4 in endothelial cells inhibited attachment and migration to stromal-derived growth factor 1 (SDF1) chemokine. Cell surface, total protein, and mRNA levels of CXCR4, principal signaling receptor for SDF1, were significantly decreased in Dll4-transduced endothelial cells, attributable to a significant reduction of CXCR4 promoter activity. An immobilized recombinant extracellular portion of Dll4 (rhDLL4) was sufficient to down-regulate CXCR4 mRNA and protein, whereas protein levels of SDF1, VEGF, and RDC1 were unchanged. The gamma-secretase inhibitor L-685,458 significantly reconstituted CXCR4 mRNA in rhDLL4-stimulated endothelial cells. CXCR4 mRNA levels were significantly reduced in mouse xenografts of Dll4-transduced human gliomas compared with control gliomas, and vascular CXCR4 was not detected by immunohistochemistry in the enlarged vessels within the Dll4 gliomas. Thus, Dll4 may contribute to vascular differentiation and inhibition of the angiogenic response by regulating multiple receptor pathways.


Osteoarthritis: epidemiology.
Osteoarthritis (OA) is the most common joint disorder in the world. In Western populations it is one of the most frequent causes of pain, loss of function and disability in adults. Radiographic evidence of OA occurs in the majority of people by 65 years of age and in about 80% of those aged over 75 years. In the US it is second only to ischaemic heart disease as a cause of work disability in men over 50 years of age, and accounts for more hospitalizations than rheumatoid arthritis (RA) each year. Despite this public health impact, OA remains an enigmatic condition to the epidemiologist. In this chapter, we will review the definition and classification of OA, its prevalence, incidence, risk factors and natural history.


Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity.
Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon-glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon-glia metabolic coupling serves a physiological function.


Brief Report: Implementation of a Specific Carbohydrate Diet for a Child with Autism Spectrum Disorder and Fragile X Syndrome.
This brief report examines the implementation of dietary intervention utilizing the specific carbohydrate diet (SCD) for the management of gastrointestinal issues in a 4 year old boy diagnosed with Autism Spectrum Disorder (ASD) and Fragile X Syndrome (FXS). Data relating to anthropometrics, dietary intake, blood markers, gastrointestinal (GI) symptoms, sleep issues, and behavioral concerns were gathered at baseline and after 4 months of dietary intervention. The dietary intervention was well tolerated. Improvements in nutrient status, GI symptoms, and behavioral domains were reported. The use of the SCD protocol in children with ASD/FXS and GI symptoms warrants further investigation.


Maternal effects on anogenital distance in a wild marmot population.
In mammals, prenatal exposure to sex steroid hormones may have profound effects on later behavior and fitness and have been reported under both laboratory and field conditions. Anogenital distance is a non-invasive measure of prenatal exposure to sex steroid hormones. While we know that intra-uterine position and litter sex ratio influence anogenital distance, there are other, heretofore unstudied, factors that could influence anogenital distance, including maternal effects. We capitalized on a long-term study of wild yellow-bellied marmots (Marmota flaviventris) to study the importance of maternal effects on explaining variation in anogenital distance and found significant effects. The strength of these effects varied annually. Taken together, our data highlights the strong variability due to environmental effects, and illustrates the importance of additive genetic and maternal genetic effects on neonatal anogenital distance. We suspect that, as others apply recently popularised quantitative genetic techniques to study free-living populations, such effects will be identified in other systems.


Kdm6b Regulates the Generation of Effector CD8+ T Cells by Inducing Chromatin Accessibility in Effector-Associated Genes.
The transcriptional and epigenetic regulation of CD8+ T cell differentiation is critical for balancing pathogen eradication and long-term immunity by effector and memory CTLs, respectively. In this study, we demonstrate that the lysine demethylase 6b (Kdm6b) is essential for the proper generation and function of effector CD8+ T cells during acute infection and tumor eradication. We found that cells lacking Kdm6b (by either T cell-specific knockout mice or knockdown using short hairpin RNA strategies) show an enhanced generation of memory precursor and early effector cells upon acute viral infection in a cell-intrinsic manner. We also demonstrate that Kdm6b is indispensable for proper effector functions and tumor protection, and that memory CD8+ T cells lacking Kdm6b displayed a defective recall response. Mechanistically, we identified that Kdm6b, through induction of chromatin accessibility in key effector-associated gene loci, allows for the proper generation of effector CTLs. Our results pinpoint the essential function of Kdm6b in allowing chromatin accessibility in effector-associated genes, and identify Kdm6b as a potential target for therapeutics in diseases with dysregulated effector responses.


Spreaders, igniters, and burning shrubs: plant flammability explains novel fire dynamics in grass-invaded deserts.
Novel fire regimes are an important cause and consequence of global environmental change that involve interactions among biotic, climatic, and human components of ecosystems. Plant flammability is key to these interactions, yet few studies directly measure flammability or consider how multiple species with different flammabilities interact to produce novel fire regimes. Deserts of the southwestern United States are an ideal system for exploring how novel fire regimes can emerge when fire-promoting species invade ecosystems comprised of species that did not evolve with fire. In these deserts, exotic annual grasses provide fuel continuity across landscapes that did not historically burn. These fires often ignite a keystone desert shrub, the fire-intolerant creosote bush, Larrea tridentata (DC.) Coville. Ignition of Larrea is likely catalyzed by fuels produced by native plants that grow beneath the shrubs. We hypothesize that invasive and native species exhibit distinct flammability characteristics that in combination determine spatial patterns of fire spread and intensity. We measured flammability metrics of Larrea, two invasive grasses, Schismus arabicus and Bromus madritensis, and two native plants, the sub-shrub Ambrosia dumosa and the annual herb Amsinckia menziesii. Results of laboratory experiments show that the grasses carry fire quickly (1.32 cm/s), but burn for short duration (0.5 min) at low temperatures. In contrast, native plants spread fire slowly (0.12 cm/s), but burn up to eight times longer (4 min) and produced hotter fires. Additional experiments on the ignition requirements of Larrea suggest that native plants burn with sufficient temperature and duration to ignite dead Larrea branches (time to ignition, 2 min; temperature at ignition 692°C). Once burning, these dead branches ignite living branches in the upper portions of the shrub. Our study provides support for a conceptual model in which exotic grasses are "spreaders" of fire and native plants growing beneath shrubs are "igniters" of dead Larrea branches. Once burning, flames produced by dead branches engulf the entire shrub, resulting in locally intense fires without historical precedent in this system. We suggest that fire models and conservation-focused management could be improved by incorporating the distinct flammability characteristics and spatial distributions of spreaders, igniters, and keystone shrubs.


Dendritic cell-mediated, DNA-based vaccination against hepatitis C induces the multi-epitope-specific response of humanized, HLA transgenic mice.
Hepatitis C virus (HCV) is the etiologic agent of chronic liver disease, hepatitis C. Spontaneous resolution of viral infection is associated with vigorous HLA class I- and class II-restricted T cell responses to multiple viral epitopes. Unfortunately, only 20% of patients clear infection spontaneously, most develop chronic disease and require therapy. The response to chemotherapy varies, however; therapeutic vaccination offers an additional treatment strategy. To date, therapeutic vaccines have demonstrated only limited success. Vector-mediated vaccination with multi-epitope-expressing DNA constructs alone or in combination with chemotherapy offers an additional treatment approach. Gene sequences encoding validated HLA-A2- and HLA-DRB1-restricted epitopes were synthesized and cloned into an expression vector. Dendritic cells (DCs) derived from humanized, HLA-A2/DRB1 transgenic (donor) mice were transfected with these multi-epitope-expressing DNA constructs. Recipient HLA-A2/DRB1 mice were vaccinated s.c. with transfected DCs; control mice received non-transfected DCs. Peptide-specific IFN-γ production by splenic T cells obtained at 5 weeks post-immunization was quantified by ELISpot assay; additionally, the production of IL-4, IL-10 and TNF-α were quantified by cytokine bead array. Splenocytes derived from vaccinated HLA-A2/DRB1 transgenic mice exhibited peptide-specific cytokine production to the vast majority of the vaccine-encoded HLA class I- and class II-restricted T cell epitopes. A multi-epitope-based HCV vaccine that targets DCs offers an effective approach to inducing a broad immune response and viral clearance in chronic, HCV-infected patients.


Exposure to violence among women with unwanted pregnancies and the association with post-traumatic stress disorder, symptoms of anxiety and depression.
The objective was to examine lifetime exposure to violence, physical and sexual, among women seeking termination of pregnancy (TOP) and its association with socio-demographic factors, PTSD, symptoms of anxiety and depression. The design of the study was a Swedish multi-centre study targeting women requesting TOP. All women requesting TOP with a gestational length less than 12 pregnancy weeks were approached for participation in the study. The questionnaire comprised the following research instruments: Screen Questionnaire-Post traumatic Stress Disorder (SQ-PTSD) and Hospital Anxiety and Depression Scale (HADS). The response rate was 57% and the final sample was 1514 women. Descriptive and analytic statistics were applied. Lifetime exposure to violence was common among women seeking abortion. Exposure to violence was associated with low education, single marital status, smoking and high alcohol consumption. Exposure to violence was associated with the occurrence of signs of PTSD and symptoms of anxiety and depression. Among those having PTSD, all had been exposed to sexual violence and almost all had been exposed to physical violence, while for those with symptoms of anxiety and depression almost half had been exposed to either physical or sexual violence. Exposure to physical and sexual abuse was common among women requesting TOP, and was strongly associated with the occurrence of PTSD, symptoms of anxiety and depression. This underscores the importance for health professionals to recognize and offer support to those women exposed to violence.


Reducing diarrhoea deaths in South Africa: costs and effects of scaling up essential interventions to prevent and treat diarrhoea in under-five children.
Diarrhoea is one of the leading causes of morbidity and mortality in South African children, accounting for approximately 20% of under-five deaths. Though progress has been made in scaling up multiple interventions to reduce diarrhoea in the last decade, challenges still remain. In this paper, we model the cost and impact of scaling up 13 interventions to prevent and treat childhood diarrhoea in South Africa. Modelling was done using the Lives Saved Tool (LiST). Using 2014 as the baseline, intervention coverage was increased from 2015 until 2030. Three scale up scenarios were compared: by 2030, 1) coverage of all interventions increased by ten percentage points; 2) intervention coverage increased by 20 percentage points; 3) and intervention coverage increased to 99%. The model estimates 13 million diarrhoea cases at baseline. Scaling up intervention coverage averted between 3 million and 5.3 million diarrhoea cases. In 2030, diarrhoeal deaths are expected to reduce from an estimated 5,500 in 2014 to 2,800 in scenario one, 1,400 in scenario two and 100 in scenario three. The additional cost of implementing all 13 interventions will range from US$510 million (US$9 per capita) to US$960 million (US$18 per capita), of which the health system costs range between US$40 million (less than US$1 per capita) and US$170 million (US$3 per capita). Scaling up 13 essential interventions could have a substantial impact on reducing diarrhoeal deaths in South African children, which would contribute toward reducing child mortality in the post-MDG era. Preventive measures are key and the government should focus on improving water, sanitation and hygiene. The investments required to achieve these results seem feasible considering current health expenditure.


The MesoVATS trial: is there a future for video-assisted thoracoscopic surgery partial pleurectomy?
Malignant pleural mesothelioma, a uniformly fatal cancer caused by prior asbestos exposure, places a major burden on society. The MesoVATS trial was a multicenter randomized controlled trial that examined the role of video-assisted thoracoscopic partial pleurectomy (VAT-PP) versus talc pleurodesis in patients with malignant pleural mesothelioma. Overall there was no difference in survival between VAT-PP and talc pleurodesis. VAT-PP resulted in more complications, longer hospital stay and was more expensive. However, there was some evidence that VAT-PP improved EQ5D measured quality of life after 6 months particularly in the European Organisation for Research and Treatment of Cancer low-risk subgroup. At present the future role of VAT-PP is uncertain and may merit further investigation but this should be within the context of clinical trials. VAT-PP may also have a role to play in the specific situation of trapped lung.


An Integrated Chemical Proteomics Approach for Quantitative Profiling of Intracellular ADP-Ribosylation.
ADP-ribosylation is integral to a diverse range of cellular processes such as DNA repair, chromatin regulation and RNA processing. However, proteome-wide investigation of its cellular functions has been limited due to numerous technical challenges including the complexity of the poly(ADP-ribose) (PAR) chains, low abundance of the modification and lack of sensitive enrichment methods. We herein show that an adenosine analogue with a terminal alkyne functionality at position 2 of the adenine (2-alkyne adenosine or 2YnAd) is suitable for selective enrichment, fluorescence detection and mass spectrometry proteomics analysis of the candidate ADP-ribosylome in mammalian cells. Although similar labelling profiles were observed via fluorescence imaging for 2YnAd and 6YnAd, a previously reported clickable NAD+ precursor, quantitative mass spectrometry analysis of the two probes in MDA-MB-231 breast cancer cells revealed a significant increase in protein coverage of the 2YnAd probe. To facilitate global enrichment of ADP-ribosylated proteins, we developed a dual metabolic labelling approach that involves simultaneous treatment of live cells with both 2YnAd and 6YnAd. By combining this dual metabolic labelling strategy with highly sensitive tandem mass tag (TMT) isobaric mass spectrometry and hierarchical Bayesian analysis, we have quantified the responses of thousands of endogenous proteins to clinical PARP inhibitors Olaparib and Rucaparib.


Deletion of the α-(1,3)-glucan synthase genes induces a restructuring of the conidial cell wall responsible for the avirulence of Aspergillus fumigatus.
α-(1,3)-Glucan is a major component of the cell wall of Aspergillus fumigatus, an opportunistic human fungal pathogen. There are three genes (AGS1, AGS2 and AGS3) controlling the biosynthesis of α-(1,3)-glucan in this fungal species. Deletion of all the three AGS genes resulted in a triple mutant that was devoid of α-(1,3)-glucan in its cell wall; however, its growth and germination was identical to that of the parental strain in vitro. In the experimental murine aspergillosis model, this mutant was less pathogenic than the parental strain. The AGS deletion resulted in an extensive structural modification of the conidial cell wall, especially conidial surface where the rodlet layer was covered by an amorphous glycoprotein matrix. This surface modification was responsible for viability reduction of conidia in vivo, which explains decrease in the virulence of triple agsΔ mutant.


Gallbladder adenocarcinoma with human chorionic gonadotropin: a case report and review of literature.
The case of adenocarcinoma with human chorionic gonadtropin (HCG), primary in the male gallbladder, is extremely rare. A Medline search has shown only a few similar cases reported. We herein describe a case of primary gallbladder adenocarcinoma associated by ectopic HCG positive tumor cells in a 79-year-old male. Pathological examination showed a mixture of moderately and poorly differentiated adenocarcinoma with ectopic HCG and placental alkaline phosphatase (PlAP) in tumor cells, though the increase of serum or urinary HCG secretion was not confirmed. The literatures were also reviewed. A case of gallbladder cancer with ectopic HCG production is quite rare in the literature, though many similar cases in other site, especially in GI tract, are reported. Embryological consideration suggests the increased frequency of similar cases more than being thought now.


Canonical Wnt signaling is required for development of embryonic stem cell-derived mesoderm.
Formation of mesoderm from the pluripotent epiblast depends upon canonical Wnt/beta-catenin signaling, although a precise molecular basis for this requirement has not been established. To develop a robust model of this developmental transition, we examined the role of Wnt signaling during the analogous stage of embryonic stem cell differentiation. We show that the kinetics of Wnt ligand expression and pathway activity in vitro mirror those found in vivo. Furthermore, inhibition of this endogenous Wnt signaling abrogates the functional competence of differentiating ES cells, reflected by their failure to generate Flk1(+) mesodermal precursors and subsequent mature mesodermal lineages. Microarray analysis at various times during early differentiation reveal that mesoderm- and endoderm-associated genes fail to be induced in the absence of Wnt signaling, indicating a lack of germ layer induction that normally occurs during gastrulation in vivo. The earliest genes displaying Wnt-dependent expression, however, were those expressed in vivo in the primitive streak. Using an inducible form of stabilized beta-catenin, we find that Wnt activity, although required, does not autonomously promote primitive streak-associated gene expression in vitro. Our results suggest that Wnt signaling functions in this model system to regulate the thresholds or stability of responses to other effector pathways and demonstrate that differentiating ES cells represent a useful model system for defining complex regulatory interactions underlying primary germ layer induction.


A Phase III randomized, double-blind, clinical trial of an investigational hexavalent vaccine given at 2, 4, and 11-12 months.
Combination vaccines simplify vaccination visits and improve coverage and timeliness. DTaP5-HB-IPV-Hib is a new investigational, fully-liquid, combination vaccine designed to protect against 6 infectious diseases, including 5 pertussis antigens and OMPC instead of PT as conjugated protein for Hib component. In this multicenter, double-blind, comparator-controlled, Phase III study (NCT01480258) conducted in Sweden, Italy, and Finland, healthy infants were randomized 1:1 to receive one two immunization regimens. The DTaP5-HB-IPV-Hib Group received the investigational hexavalent vaccine (DTaP5-HB-IPV-Hib) and the Control Group received Infanrix-hexa (DTPa3-HBV-IPV/Hib) at 2, 4 and 11-12months of age. Both groups received concomitantly Prevnar 13 (PCV13) and Rotateq (RV5) or Rotarix (RV1) at 2, 4months of age and PCV13 at 11-12months. Subjects administered RV5 received a 3rd dose at 5months of age. A total of 656 subjects were randomized to the DTaP5-HB-IPV-Hib Group and 659 subjects to Control Group. Immune responses to all vaccine antigens post-toddler dose were non-inferior in the DTaP5-HB-IPV-Hib Group as compared to the Control Group. Additionally, the post-dose 2 and pre-toddler DTaP5-HB-IPV-Hib anti-PRP responses were superior. The DTaP5-HB-IPV-Hib Group responses to concomitant RV1 were non-inferior compared to the Control Group. Solicited adverse event rates after any dose were similar in both groups, except for higher rates of pyrexia (6.4% difference; 95% CI: 1.5,11.3) and somnolence (5.8% difference; 95% CI: 1.7,9.8) in the DTaP5-HB-IPV-Hib Group. Vaccine-related serious adverse events occurred infrequently in the DTaP5-HB-IPV-Hib Group (0.3%) and the Control Group (0.5%). The safety and immunogenicity of DTaP5-HB-IPV-Hib is generally comparable to Control when administered in the 2, 4, 11-12month schedule. Early Hib responses were superior versus Control. DTaP5-HB-IPV-Hib could provide a new hexavalent option for pediatric combination vaccines, aligned with recommended immunizations in Europe. V419-008 CLINICALTRIALS.GOV identifier: NCT01480258.


Quantum-limit Chern topological magnetism in TbMn6Sn6.
The quantum-level interplay between geometry, topology and correlation is at the forefront of fundamental physics1-15. Kagome magnets are predicted to support intrinsic Chern quantum phases owing to their unusual lattice geometry and breaking of time-reversal symmetry14,15. However, quantum materials hosting ideal spin-orbit-coupled kagome lattices with strong out-of-plane magnetization are lacking16-21. Here, using scanning tunnelling microscopy, we identify a new topological kagome magnet, TbMn6Sn6, that is close to satisfying these criteria. We visualize its effectively defect-free, purely manganese-based ferromagnetic kagome lattice with atomic resolution. Remarkably, its electronic state shows distinct Landau quantization on application of a magnetic field, and the quantized Landau fan structure features spin-polarized Dirac dispersion with a large Chern gap. We further demonstrate the bulk-boundary correspondence between the Chern gap and the topological edge state, as well as the Berry curvature field correspondence of Chern gapped Dirac fermions. Our results point to the realization of a quantum-limit Chern phase in TbMn6Sn6, and may enable the observation of topological quantum phenomena in the RMn6Sn6 (where R is a rare earth element) family with a variety of magnetic structures. Our visualization of the magnetic bulk-boundary-Berry correspondence covering real space and momentum space demonstrates a proof-of-principle method for revealing topological magnets.


Stigma, explanatory models and unmet needs of caregivers of children with developmental disorders in a low-income African country: a cross-sectional facility-based survey.
Understanding the perspectives of caregivers of children with developmental disorders living in low-income countries is important to inform intervention programmes. The purpose of this study was to examine the stigma experiences, explanatory models, unmet needs, preferred interventions and coping mechanisms of caregivers of children with developmental disorders in Ethiopia. Participants comprised caregivers (n = 102) of children with developmental disorders attending two child mental health clinics in Addis Ababa. The majority (66.7%; n = 68) had a diagnosis of intellectual disability (ID); 34 children (33.3%) had autism spectrum disorder (ASD) as their primary diagnosis. All caregivers were administered a structured questionnaire via a face-to-face interview, which included an adaptation of the Family Interview Schedule, closed questions about socio-demographic characteristics, explanatory models of illness, type of interventions used or desired and coping strategies, and an open ended question regarding the family's unmet needs. Most caregivers reported experience of stigma: 43.1% worried about being treated differently, 45.1% felt ashamed about their child's condition and 26.7% made an effort to keep their child's condition secret. Stigma did not depend on the type of developmental disorder, the child's age or gender, or on the age or level of education of the caregiver (all p > 0.05). Reported stigma was significantly higher in caregivers who had sought traditional help (p < 0.01), provided supernatural explanations for their child's condition (p = .02) and in caregivers of Orthodox Christian faith (p = .03). Caregivers gave a mixture of biomedical explanations (e.g. head injury (30.4%) or birth complications (25.5%)) and supernatural explanations (e.g. spirit possession (40.2%) or sinful act (27.5%)) for their child's condition. The biggest reported unmet need was educational provision for their child (74.5%), followed by treatment by a health professional (47.1%), financial support (30.4%) and expert help to support their child's development (27.5%). Most caregivers reported that talking to health professionals (86.3%) and family (85.3%) helped them to cope. Many caregivers also used support from friends (76.5%) and prayer (57.8%) as coping mechanisms. This study highlights the stigma experienced by families caring for a child with a developmental disorder. Designing interventions appropriate for low-income settings that improve awareness about developmental disorders, decrease stigma, improve access to appropriate education and strengthen caregivers' support are needed.


CLASSICA: Validating artificial intelligence in classifying cancer in real time during surgery.
Treatment pathways for significant rectal polyps differ depending on the underlying pathology, but pre-excision profiling is imperfect. It has been demonstrated that differences in fluorescence perfusion signals following injection of indocyanine green (ICG) can be analysed mathematically and, with the assistance of artificial intelligence (AI), used to classify tumours endoscopically as benign or malignant. This study aims to validate this method of characterization across multiple clinical sites regarding its generalizability, usability and accuracy while developing clinical-grade software to enable it to become a useful method. The CLASSICA study is a prospective, unblinded multicentre European observational study aimed to validate the use of AI analysis of ICG fluorescence for intra-operative tissue characterization. Six hundred patients undergoing transanal endoscopic evaluation of significant rectal polyps and tumours will be enrolled in at least five clinical sites across the European Union over a 4-year period. Video recordings will be analysed regarding dynamic fluorescence patterns centrally as software is developed to enable analysis with automatic classification to happen locally. AI-based classification and subsequently guided intervention will be compared with the current standard of care including biopsies, final specimen pathology and patient outcomes. CLASSICA will validate the use of AI in the analysis of ICG fluorescence for the purposes of classifying significant rectal polyps and tumours endoscopically. Follow-on studies will compare AI-guided targeted biopsy or, indeed, AI characterization alone with traditional biopsy and AI-guided local excision versus traditional excision with regard to marginal clearance and recurrence.


Neuroligin-4 is localized to glycinergic postsynapses and regulates inhibition in the retina.
Neuroligins (NL1-NL4) are postsynaptic adhesion proteins that control the maturation and function of synapses in the central nervous system (CNS). Loss-of-function mutations in NL4 are linked to rare forms of monogenic heritable autism, but its localization and function are unknown. Using the retina as a model system, we show that NL4 is preferentially localized to glycinergic postsynapses and that the loss of NL4 is accompanied by a reduced number of glycine receptors mediating fast glycinergic transmission. Accordingly, NL4-deficient ganglion cells exhibit slower glycinergic miniature postsynaptic currents and subtle alterations in their stimulus-coding efficacy, and inhibition within the NL4-deficient retinal network is altered as assessed by electroretinogram recordings. These data indicate that NL4 shapes network activity and information processing in the retina by modulating glycinergic inhibition. Importantly, NL4 is also targeted to inhibitory synapses in other areas of the CNS, such as the thalamus, colliculi, brainstem, and spinal cord, and forms complexes with the inhibitory postsynapse proteins gephyrin and collybistin in vivo, indicating that NL4 is an important component of glycinergic postsynapses.


Extended Multiplexing of Tandem Mass Tags (TMT) Labeling Reveals Age and High Fat Diet Specific Proteome Changes in Mouse Epididymal Adipose Tissue.
The lack of high-throughput methods to analyze the adipose tissue protein composition limits our understanding of the protein networks responsible for age and diet related metabolic response. We have developed an approach using multiple-dimension liquid chromatography tandem mass spectrometry and extended multiplexing (24 biological samples) with tandem mass tags (TMT) labeling to analyze proteomes of epididymal adipose tissues isolated from mice fed either low or high fat diet for a short or a long-term, and from mice that aged on low versus high fat diets. The peripheral metabolic health (as measured by body weight, adiposity, plasma fasting glucose, insulin, triglycerides, total cholesterol levels, and glucose and insulin tolerance tests) deteriorated with diet and advancing age, with long-term high fat diet exposure being the worst. In response to short-term high fat diet, 43 proteins representing lipid metabolism (e.g. AACS, ACOX1, ACLY) and red-ox pathways (e.g. CPD2, CYP2E, SOD3) were significantly altered (FDR < 10%). Long-term high fat diet significantly altered 55 proteins associated with immune response (e.g. IGTB2, IFIT3, LGALS1) and rennin angiotensin system (e.g. ENPEP, CMA1, CPA3, ANPEP). Age-related changes on low fat diet significantly altered only 18 proteins representing mainly urea cycle (e.g. OTC, ARG1, CPS1), and amino acid biosynthesis (e.g. GMT, AKR1C6). Surprisingly, high fat diet driven age-related changes culminated with alterations in 155 proteins involving primarily the urea cycle (e.g. ARG1, CPS1), immune response/complement activation (e.g. C3, C4b, C8, C9, CFB, CFH, FGA), extracellular remodeling (e.g. EFEMP1, FBN1, FBN2, LTBP4, FERMT2, ECM1, EMILIN2, ITIH3) and apoptosis (e.g. YAP1, HIP1, NDRG1, PRKCD, MUL1) pathways. Using our adipose tissue tailored approach we have identified both age-related and high fat diet specific proteomic signatures highlighting a pronounced involvement of arginine metabolism in response to advancing age, and branched chain amino acid metabolism in early response to high fat feeding. Data are available via ProteomeXchange with identifier PXD005953.


Hepatitis E virus infection and acute-on-chronic liver failure in West Africa: a case-control study from The Gambia.
In sub-Saharan Africa, it is unknown whether hepatitis E virus (HEV) infection is a common precipitating event of acute-on-chronic liver failure (ACLF). To estimate the prevalence of HEV infection in general population and assess whether HEV is a common trigger of ACLF in cirrhotic patients in The Gambia, West Africa. We first conducted an HEV sero-survey in healthy volunteers. We then tested cirrhotic patients with ACLF (cases) and compensated cirrhosis (controls) for anti-HEV IgG as a marker of exposure to HEV, and anti-HEV IgA and HEV RNA as a marker of recent infection. We also described the characteristics and survival of the ACLF cases and controls. In the healthy volunteers (n = 204), 13.7% (95% CI: 9.6-19.2) were positive for anti-HEV IgG, and none had positive HEV viraemia. After adjusting for age and sex, the following were associated with positive anti-HEV IgG: being a Christian, a farmer, drinking water from wells, handling pigs and eating pork. In 40 cases (median age: 45 years, 72.5% male) and 71 controls (39 years, 74.6% male), ≥70% were infected with hepatitis B virus. Although hepatitis B flare and sepsis were important precipitating events of ACLF, none had marker of acute HEV. ACLF cases had high (70.0%) 28-day mortality. Hepatitis E virus infection is endemic in The Gambia, where both faecal-oral route (contaminated water) and zoonotic transmission (pigs/pork meat) may be important. However, acute HEV was not a common cause of acute-on-chronic liver failure in The Gambia.


Radial primary percutaneous coronary intervention is independently associated with decreased long-term mortality in high-risk ST-elevation myocardial infarction patients.
To compare long-term clinical outcomes in patients with ST-elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PPCI) using radial and femoral arterial access. The present study was an observational cohort study of patients with STEMI treated consecutively with PPCI between 2004 and 2011 at a single centre. The primary end point was all-cause mortality at a median follow-up of 3 years.Among 2727 patients, 1600 (58.7%) underwent PPCI via the femoral route. The femoral group was older (64.7 vs. 61.7 years; P < 0.0001), and had higher rates of diabetes (18.6% vs. 16.0%; P < 0.0001), previous PCI (11.2 vs. 7.8%; P = 0.004), previous myocardial infarction (15.3 vs. 8.3%; P < 0.0001) and cardiogenic shock (9.8 vs. 1.3%; P < 0.0001). Bleeding complications were more frequent in the femoral group (4.7 vs. 1.2%; P < 0.0001). The 5-year death rate was significantly higher in the femoral group than in the radial group (10.4 vs. 3.0%; P < 0.0001). After adjustment for confounding variables, bleeding complications [heart rate 2.07 (95% confidence interval 1.05-4.08)] and femoral access [heart rate 1.60 (95% confidence interval 1.02-2.53)] were independent predictors of all-cause mortality. After stratification using the propensity score, excess long-term mortality in patients treated via the femoral approach was predominantly in patients with a high baseline risk of death. Patients undergoing PPCI via the femoral route are at a higher risk of adverse short-term and long-term outcomes than patients undergoing PPCI via the radial route. Patients with a high baseline risk may benefit most from radial access, and future outcome studies should focus on the most at-risk patients.


Altered function of intracortical networks in chronic lateral epicondylalgia.
Lateral epicondylalgia (LE) is a musculotendinous condition characterized by persistent pain, sensorimotor dysfunction and motor cortex reorganization. Although there is evidence linking cortical reorganization with clinical symptoms in LE, the mechanisms underpinning these changes are unknown. Here we investigated activity in motor cortical (M1) intracortical inhibitory and facilitatory networks in individuals with chronic LE and healthy controls. Surface electromyography was recorded bilaterally from the extensor carpi radialis brevis (ECRB) muscle of 14 LE (4 men, 41.5 ± 9.9 years) and 14 control participants (4 men, 42.1 ± 11.1 years). Transcranial magnetic stimulation of M1 was used to evaluate resting and active motor threshold, corticomotor output, short- (SICI) and long-latency intracortical inhibition (LICI) and intracortical facilitation (ICF) of both hemispheres. In individuals with LE, SICI (p = 0.005), ICF (p = 0.026) and LICI (p = 0.046) were less in the M1 contralateral to the affected ECRB muscle compared with healthy controls. Motor cortical threshold (rest: p = 0.57, active: p = 0.97) and corticomotor output (p = 0.15) were similar between groups. No differences were observed between individuals with LE and healthy controls for the M1 contralateral to the unaffected ECRB muscle. These data provide evidence of less intracortical inhibition mediated by both GABAA and GABAB receptors, and less intracortical facilitation in the M1 contralateral to the affected ECRB in individuals with LE compared with healthy controls. Similar changes were not present in the M1 contralateral to the unaffected ECRB. These changes may provide the substrate for M1 reorganization in chronic LE and could provide a target for future therapy. Lateral epicondylalgia (LE) is a common musculoskeletal condition characterized by elbow pain and sensorimotor dysfunction. The excitability and organization of the motor cortical representation of the wrist extensor muscles is altered in LE, but the mechanisms that underpin these changes are unknown. evidence of less intracortical inhibition mediated by both GABAA and GABAB receptors, and less intracortical facilitation mediated by NMDA receptors, in the M1 contralateral to the affected extensor carpi radialis brevis muscle in chronic LE compared with healthy controls. Altered activity in intracortical networks may contribute to altered motor cortex organization in LE and could provide a potential target for future treatments.


Expectancy of stress-reducing aromatherapy effect and performance on a stress-sensitive cognitive task.
Objective. Stress-reducing therapies help maintain cognitive performance during stress. Aromatherapy is popular for stress reduction, but its effectiveness and mechanism are unclear. This study examined stress-reducing effects of aromatherapy on cognitive function using the go/no-go (GNG) task performance and event related potentials (ERP) components sensitive to stress. The study also assessed the importance of expectancy in aromatherapy actions. Methods. 81 adults were randomized to 3 aroma groups (active experimental, detectable, and undetectable placebo) and 2 prime subgroups (prime suggesting stress-reducing aroma effects or no-prime). GNG performance, ERPs, subjective expected aroma effects, and stress ratings were assessed at baseline and poststress. Results. No specific aroma effects on stress or cognition were observed. However, regardless of experienced aroma, people receiving a prime displayed faster poststress median reaction times than those receiving no prime. A significant interaction for N200 amplitude indicated divergent ERP patterns between baseline and poststress for go and no-go stimuli depending on the prime subgroup. Furthermore, trends for beneficial prime effects were shown on poststress no-go N200/P300 latencies and N200 amplitude. Conclusion. While there were no aroma-specific effects on stress or cognition, these results highlight the role of expectancy for poststress response inhibition and attention.


Disease surveillance during a large religious mass gathering in India: The Prayagraj Kumbh 2019 experience.
Mass gathering (MG) events are associated with public health risks. During the period January 14 to March 4, 2019, Kumbh Mela in Prayagraj, India was attended by an estimated 120 million visitors. An onsite disease surveillance was established to identify and respond to disease outbreaks. A health coordination committee was established for planning. Disease surveillance was prioritized and risk assessment was done to identify diseases/conditions based on epidemic potential, severity of illness, and reporting requirement under the International Health Regulations (IHR) of 2005. A daily indicator and event-based disease surveillance was planned. The indicator-based surveillance (IBS) manually and electronically recorded data from patient hospital visits and collected MG area water testing data to assess trends. The event-based surveillance (EBS) helped identify outbreak signals based on pre-identified event triggers from the media, private health facilities, and the food safety department. Epidemic intelligence was used to analyse the data and events to detect signals, verify alerts, and initiate the response. At Kumbh Mela, disease surveillance was established for 22 acute diseases/syndromes. Sixty-five health facilities reported 156 154 illnesses (21% of a total 738 526 hospital encounters). Among the reported illnesses, 95% (n = 148 834) were communicable diseases such as acute respiratory illness (n = 52 504, 5%), acute fever (n = 41 957, 28%), and skin infections (n = 27 094, 18%). The remaining 5% (n = 7300) were non-communicable diseases (injuries n = 6601, 90%; hypothermia n = 224, 3%; burns n = 210, 3%). Water samples tested inadequate for residual chlorine in 20% of samples (102/521). The incident command centre generated 12 early warning signals from IBS and EBS: acute diarrheal disease (n = 8, 66%), vector-borne disease (n = 2, 16%), vaccine-preventable disease (n = 1, 8%), and thermal event (n = 1, 8%). There were two outbreaks (acute gastroenteritis and chickenpox) that were investigated and controlled. This onsite disease surveillance imparted a public health legacy by successfully implementing an epidemic intelligence enabled system for early disease detection and response to monitor public health risks. Acute respiratory illnesses emerged as a leading cause of morbidity among visitors. Future MG events should include disease surveillance as part of planning and augment capacity for acute respiratory illness diagnosis and management.


Antiulcer Effect of Honey in Nonsteroidal Anti-Inflammatory Drugs Induced Gastric Ulcer Model in Rats: A Systematic Review.
Peptic ulcer is a basic term for ulcers on the lower oesophagus, stomach, or jejunum. The specific term for ulcer in the stomach is gastric ulcer. The extensive use of honey around the globe helps researchers to study the usefulness of honey. Many studies had already been conducted and proved the effectiveness of honey in treating gastric ulcer. A systematic review of the literature was conducted to identify relevant studies on honey used as an alternative treatment of gastric ulcer cause by NSAIDs. A comprehensive search was conducted in Medline, SCOPUS, and Ebscohost. The main criteria used were articles published in English and using NSAIDs-induced gastric ulcer in rat's model and those reporting the effectiveness of honey. Articles published between 2001 and 2014 were identified to be relevant in studies related to the inclusion criteria. The literature search found 30 potential and closely related articles in this review, but only 5 articles were taken which meet the criteria needed to be fulfilled. All studies in this review reported the efficacy of honey for gastric ulcer based on its antioxidant and cytoprotective activities. Most of the studies conducted used different types of honey at various doses on rats. Future studies should be conducted to identify the appropriate dose for humans to achieve similar gastroprotective effects.


A simple genetic incompatibility causes hybrid male sterility in mimulus.
Much evidence has shown that postzygotic reproductive isolation (hybrid inviability or sterility) evolves by the accumulation of interlocus incompatibilities between diverging populations. Although in theory only a single pair of incompatible loci is needed to isolate species, empirical work in Drosophila has revealed that hybrid fertility problems often are highly polygenic and complex. In this article we investigate the genetic basis of hybrid sterility between two closely related species of monkeyflower, Mimulus guttatus and M. nasutus. In striking contrast to Drosophila systems, we demonstrate that nearly complete hybrid male sterility in Mimulus results from a simple genetic incompatibility between a single pair of heterospecific loci. We have genetically mapped this sterility effect: the M. guttatus allele at the hybrid male sterility 1 (hms1) locus acts dominantly in combination with recessive M. nasutus alleles at the hybrid male sterility 2 (hms2) locus to cause nearly complete hybrid male sterility. In a preliminary screen to find additional small-effect male sterility factors, we identified one additional locus that also contributes to some of the variation in hybrid male fertility. Interestingly, hms1 and hms2 also cause a significant reduction in hybrid female fertility, suggesting that sex-specific hybrid defects might share a common genetic basis. This possibility is supported by our discovery that recombination is reduced dramatically in a cross involving a parent with the hms1-hms2 incompatibility.


Improving population health by reducing poverty: New York's Earned Income Tax Credit.
Despite the established relationship between adverse health outcomes and low socioeconomic status, researchers rarely test the link between health improvements and poverty-alleviating economic policies. New research, however, links individual-level health improvements to the Earned Income Tax Credit (EITC), a broad-based income support policy. We build on these findings by examining whether the EITC has ecological, neighborhood-level health effects. We use a difference-in-difference analysis to measure child health outcomes in 90 low- and middle- income neighborhoods before and after the expansion of New York State and New York City's EITC policy between 1997-2010. Our study takes advantage of the relatively exogenous source of income variation supplied by the EITC-legislative changes to EITC policy parameters. This feature minimizes the endogeneity problem in studying the relationship between income and health. Our estimates link a 15-percentage-point increase in EITC benefit rates to a 0.45 percentage-point reduction in the low birthweight rate. We do not observe any measurable link between EITC benefits and prenatal health or asthma-related pediatric hospitalization. The magnitude of the EITC's impact on low birthweight rates suggests ecological effects, and an additional channel through which anti-poverty measures can serve as public health interventions.


Identification and characterization of TspA, a major CD4(+) T-cell- and B-cell-stimulating Neisseria-specific antigen.
In search for novel T-cell immunogens involved in protection against invasive meningococcal disease, we screened fractionated proteins of Neisseria meningitidis (strain SD, B:15:P1.16) by using peripheral blood mononuclear cells (PBMCs) and specific T-cell lines obtained from normal individuals and patients convalescing from N. meningitidis infection. Proteins of iron-depleted meningococci produced higher PBMC proliferation indices than proteins of iron-replete organisms, indicating that iron-regulated proteins are T-cell immunogens. Insoluble proteins of the iron-depleted cells, which produced better T-cell stimulation than soluble ones, were fractionated by using sodium dodecyl sulfate-polyacrylamide gels and recovered as five fractions (F1 to F5) corresponding to decreasing molecular weight ranges. The proteins were purified (by elution and precipitation) or electroblotted onto nitrocellulose membranes (dissolved and precipitated) before use in further T-cell proliferation assays. One of the fractions (F1), containing high-molecular-mass proteins (>130 kDa), consistently showed the strongest T-cell proliferation responses in all of the T-cell lines examined. F1 proteins were subdivided into four smaller fractions (F1A to F1D) which were reexamined in T-cell proliferation assays, and F1C induced the strongest responses in patients' T-cell lines. Rabbit polyclonal antibodies to F1C components were used to screen a genomic expression library of N. meningitidis. Two major clones (C1 and C24) of recombinant meningococcal DNA were identified and fully sequenced. Sequence analysis showed that C24 (1,874 bp) consisted of a single open reading frame (ORF), which was included in clone C1 (2, 778 bp). The strong CD4(+) T-cell-stimulating effect of the polypeptide product of this ORF (named TspA) was confirmed, using a patient T-cell line. Immunogenicity for B cells was confirmed by showing that convalescent patients' serum antibodies recognized TspA on Western blots. Additional genetic sequence downstream of C24 was obtained from the meningococcal genomic sequence database (Sanger Centre), enabling the whole gene of 2,761 bp to be reconstructed. The DNA and deduced amino acid sequence data for tspA failed to show significant homology to any known gene, except for a corresponding (uncharacterized) gene in Neisseria gonorrhoeae genome sequences, suggesting that tspA is unique to the genus Neisseria. The DNA and deduced amino acid sequence of the second ORF of clone C1 showed significant homology to gloA, encoding glyoxalase I enzyme, of Salmonella typhimurium and Escherichia coli. Thus, we have identified a novel neisserial protein (TspA) which proved to be a strong CD4(+) T-cell- and B-cell-stimulating immunogen with potential as a possible vaccine candidate.


Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, PPARgamma agonists, differentially regulate cigarette smoke-mediated pro-inflammatory cytokine release in monocytes/macrophages.
Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) ligands have the potential for use as anti-inflammatory agents in chronic airway diseases. We hypothesized that cigarette smoke (CS)-mediated pro-inflammatory cytokine release would be downregulated in the monocyte-macrophage cell line (MonoMac6) by synthetic and natural PPARgamma ligands. Surprisingly, treatment of MonoMac6 cells with the natural PPARgamma ligand 15-deoxy-Delta12,14-prostaglandin J2 led to increased cytokine (IL-8) release in response to either TNF-alpha or CS extract (CSE). However, exposure to rosiglitazone, a synthetic agonist, led to decreased TNF-alpha, but not CSE, mediated cytokine release. Cytokine release correlated with nuclear PPARgamma localization; CSE reduced the amount of activated PPARgamma located in the nucleus and formed aldehyde adducts as PPARgamma protein carbonyls. Furthermore, it was shown that PPARgamma interacts with the RelA/p65 subunit of NF-kappaB under TNF-alpha exposure conditions, but this interaction was disrupted by CS exposure, suggesting that CS blocks this important anti-inflammatory pathway involving PPARgamma. Thus, these new data show that activation of PPARgamma with natural or synthetic ligands have differential inhibitory effects on CS-mediated pro-inflammatory mediator release. These data have implications in designing therapies for treatment of COPD and pulmonary fibrosis.


Somatosensory disinhibition in patients with paroxysmal kinesigenic dyskinesia.
Paroxysmal kinesigenic dyskinesia (PKD) is characterized by recurrent brief episodes of chorea and dystonia induced by sudden movement. Whether the central nervous system is hyper- or hypoexcitable in PKD remains undetermined. The aim of our study was to compare the somatosensory evoked potential (SEP) recovery cycle, a marker of somatosensory system excitability, in PKD patients and controls. Twenty-four PKD patients (mean age of (20.0±5.3) years; 21 males, 3 females) and 18 control age-matched subjects (mean age of (22.0±5.0) years; 17 males, 1 female) were studied. The stimuli were delivered to the median nerve in the affected dominant arm in patients and in the dominant arm in controls. The change in SEP amplitude was measured after paired electrical stimulation at interstimulus intervals (ISIs) of 5, 20, and 40 ms. The SEPs evoked by S2 (test stimulus) were calculated by subtracting the response to S1 (the conditioning stimulus) from the response to a pair of stimuli (S1+S2), and their amplitudes were compared with those of the control response (S1) at each ISI. Analysis of variance (ANOVA) or equivalent was used for non-parametric data. In patients, the P27 amplitude after the single stimulus (S1) was significantly larger than that after the control stimulus. The (S2/S1)×100 ratio for P14 and N30 SEPs did not differ significantly between PKD patients and normal subjects at ISI of 5 ms but were significantly higher in patients at ISIs of 20 and 40 ms (P<0.05). Somatosensory system disinhibition takes place in PKD. The finding of reduced suppression of different SEPs, each thought to have a different origin, suggests an abnormality of intracortical and subcortical inhibitory circuits.


Uptake of telehealth implementation for COPD patients in a high-poverty, inner-city environment: A survey.
This study aimed to investigate computer and internet access and education attained in patients with chronic obstructive pulmonary disease (COPD) as potential barriers to implementation of telemedicine. We prospectively assessed 98 patients admitted with an acute exacerbation of COPD (mean age: 70.5 ± 9.3 years; force expired volume in the first second: 0.75 ± 0.39 L; 59% male) recording educational level attained and home computer and internet access. Hospital readmission surveillance occurred up to 2.7 (2.6-2.8) years following the index hospital admission. Only 16% of patients had a computer and only 14% had internet access; this group were younger and more educated than those without a computer. There was no difference in hospital readmissions over 2 years between those with and without access to a computer or internet. Only 12% of the whole cohort were educated to a school leaving age of 16 years and this group were more likely to be still working. School leaving age was directly associated with fewer hospital readmissions ( r = 0.251, p = 0.031). In conclusion, these data highlight the current challenges to the widespread implementation of telehealth in COPD patients as there is limited availability of computer and internet access with such patients demonstrating a lower level of education achievement.


Developing communication in adults with profound and multiple learning difficulties using objects of reference.
Objects of reference were used to develop communication in adults with profound and multiple learning difficulties (PMLD). The use of objects specific to individuals is recommended, but it makes heavy demands on care staff who implement such programmes. This study investigated the effectiveness of using a standard set of objects with a group of 13 adults with PMLD. Progress was monitored over a 20-week training period using an assessment based upon the cues provided by staff to promote the use of the objects. Results indicated that the group as a whole made significant gains, although a plateau effect was reached after the first 10 weeks of training. Some individuals within the group were near to ceiling performance after training, while others, though progressing, still made limited use of the objects. There was evidence, as suggested in the literature, that greater and more sustained progress was made with objects at the index level of representation. The views of the care staff who implemented the training programme were sought through semistructured interviews. Although the use of a standard set of objects presents a number of difficulties, it is concluded that it is desirable in situations where the use of individual objects with each client is unfeasible. It has the additional advantages that it instructs and motivates care staff and provides a means by which the use of objects of reference by individual clients may be assessed and planning for the development of their communication may be informed.


Friends and foes from an ant brain's point of view--neuronal correlates of colony odors in a social insect.
Successful cooperation depends on reliable identification of friends and foes. Social insects discriminate colony members (nestmates/friends) from foreign workers (non-nestmates/foes) by colony-specific, multi-component colony odors. Traditionally, complex processing in the brain has been regarded as crucial for colony recognition. Odor information is represented as spatial patterns of activity and processed in the primary olfactory neuropile, the antennal lobe (AL) of insects, which is analogous to the vertebrate olfactory bulb. Correlative evidence indicates that the spatial activity patterns reflect odor-quality, i.e., how an odor is perceived. For colony odors, alternatively, a sensory filter in the peripheral nervous system was suggested, causing specific anosmia to nestmate colony odors. Here, we investigate neuronal correlates of colony odors in the brain of a social insect to directly test whether they are anosmic to nestmate colony odors and whether spatial activity patterns in the AL can predict how odor qualities like "friend" and "foe" are attributed to colony odors. Using ant dummies that mimic natural conditions, we presented colony odors and investigated their neuronal representation in the ant Camponotus floridanus. Nestmate and non-nestmate colony odors elicited neuronal activity: In the periphery, we recorded sensory responses of olfactory receptor neurons (electroantennography), and in the brain, we measured colony odor specific spatial activity patterns in the AL (calcium imaging). Surprisingly, upon repeated stimulation with the same colony odor, spatial activity patterns were variable, and as variable as activity patterns elicited by different colony odors. Ants are not anosmic to nestmate colony odors. However, spatial activity patterns in the AL alone do not provide sufficient information for colony odor discrimination and this finding challenges the current notion of how odor quality is coded. Our result illustrates the enormous challenge for the nervous system to classify multi-component odors and indicates that other neuronal parameters, e.g., precise timing of neuronal activity, are likely necessary for attribution of odor quality to multi-component odors.


Health profiles of overweight and obese youth attending general practice.
Literature suggests that overweight and obese young people use healthcare services more often, but this awaits confirmation in primary care. To identify health profiles of underweight, overweight and obese young people attending general practice and compare them to normal-weight youth and also to explore the weight-related health risks of eating and exercise behaviour in the four different weight categories. This study used a cross-sectional design with baseline data from a trial including 683 young people (14-24 years of age) presenting to general practice. Through computer-assisted telephone interviews data were obtained on number and type of health complaints and consultations, emotional distress, health-related quality of life (HRQoL) and eating and exercise behaviour. General practitioners (GPs) were consulted more often by overweight (incidence rate ratio (IRR): 1.28, 95% CI (1.04 to 1.57)) and obese youth (IRR: 1.54, 95% CI (1.21 to 1.97), but not for different health problems compared with normal-weight youth. The reason for presentation was seldom a weight issue. Obese youth reported lower physical HRQoL. Obese and underweight youth were less likely to be satisfied with their eating behaviour than their normal-weight peers. Exercise levels were low in the entire cohort. Our study highlights the need for effective weight management given that overweight and obese youth consult their GP more often. Since young people do not present with weight issues, it becomes important for GPs to find ways to initiate the discussion about weight, healthy eating and exercise with youth. ISRCTN16059206.


Associations of HLA alleles with specific language impairment.
Human leukocyte antigen (HLA) loci have been implicated in several neurodevelopmental disorders in which language is affected. However, to date, no studies have investigated the possible involvement of HLA loci in specific language impairment (SLI), a disorder that is defined primarily upon unexpected language impairment. We report association analyses of single-nucleotide polymorphisms (SNPs) and HLA types in a cohort of individuals affected by language impairment. We perform quantitative association analyses of three linguistic measures and case-control association analyses using both SNP data and imputed HLA types. Quantitative association analyses of imputed HLA types suggested a role for the HLA-A locus in susceptibility to SLI. HLA-A A1 was associated with a measure of short-term memory (P = 0.004) and A3 with expressive language ability (P = 0.006). Parent-of-origin effects were found between HLA-B B8 and HLA-DQA1*0501 and receptive language. These alleles have a negative correlation with receptive language ability when inherited from the mother (P = 0.021, P = 0.034, respectively) but are positively correlated with the same trait when paternally inherited (P = 0.013, P = 0.029, respectively). Finally, case control analyses using imputed HLA types indicated that the DR10 allele of HLA-DRB1 was more frequent in individuals with SLI than population controls (P = 0.004, relative risk = 2.575), as has been reported for individuals with attention deficit hyperactivity disorder (ADHD). These preliminary data provide an intriguing link to those described by previous studies of other neurodevelopmental disorders and suggest a possible role for HLA loci in language disorders.


The Association of Cooking Fuel Use, Dietary Intake, and Blood Pressure among Rural Women in China.
Household air pollution (HAP) from solid cooking fuels continues to affect 600 million people in China and has been associated with high blood pressure. The role of diet in HAP-associated high blood pressure has yet to be evaluated in China. The aim of this study was to estimate the impact of cooking fuel on change in blood pressure and evaluate whether intake of antioxidant- and omega-3 fatty acid-rich foods (fruits, vegetables, and seafood) attenuates any adverse effects of solid fuel use on blood pressure. We analyzed longitudinal data collected between 1991 and 2011 from nonpregnant women aged 18 to 80 years living in rural areas of China. We used linear mixed effects models to estimate the association between cooking fuel (coal or wood versus clean [electric or liquid petroleum gas]) and blood pressure. Possible mediation of the fuel effect by diet was assessed by the difference method. A total of 6671 women were included in this study. Women less than 40 years of age cooking with cleaner fuels over time had lower rates of change in systolic blood pressure compared to women cooking with coal (p = 0.004), and this effect was not mediated by dietary intake. Associations between fuel use and change in diastolic blood pressure were not significant. These findings lend further support for there being a direct effect of reducing HAP on improvements in blood pressure, independent of concurrent dietary intake.


Egg consumption and CHD and stroke mortality: a prospective study of US adults.
To evaluate the relationship between egg consumption and CHD and stroke mortality using the Third National Health and Nutrition Examination Survey 1988-1994 (NHANES III) and follow-up survey. A cross-sectional survey using a stratified, multi-stage probability sample was analysed, adjusting for survey design. Egg consumption was obtained from the FFQ and separated into categories of egg intake. Hazard ratios (HR) were calculated for CHD and stroke mortality using multivariate Cox regression models. A health and nutrition survey conducted in the USA from 1988 to 1994 with follow-up through 31 December 2000. The study population included men and women who were free of CVD and had completed a FFQ at baseline. Multivariate models adjusting for health, lifestyle and dietary factors indicated that 'high' egg consumption (≥ 7 times/week v. <1 time/week) was not associated with significantly increased CHD mortality (HR = 1·13, 95 % CI 0·61, 2·11 (men); HR = 0·92, 95 % CI 0·27, 3·11 (women)). There was a statistically significant inverse association between 'high' egg consumption and stroke mortality among men (HR = 0·27, 95 % CI 0·10, 0·73), but the estimate was imprecise because of sparse data. We did not observe a statistically significant positive association between 'high' egg consumption and CHD or stroke mortality in analyses restricted to individuals with diabetes, but these analyses may be limited due to the small number of diabetics. We did not find a significant positive association between egg consumption and increased risk of mortality from CHD or stroke in the US population. These results corroborate the findings of previous studies.


Minimizing cardiac toxicity in children with acute myeloid leukemia.
Anthracycline chemotherapy remains an integral component of modern pediatric acute myeloid leukemia (AML) regimens and is often delivered at high doses to maximize cancer survival. Unfortunately, high-dose anthracyclines are associated with a significant risk of cardiotoxicity, which may result in early and/or long-term left ventricular systolic dysfunction and heart failure. Moreover, the development of cardiotoxicity during pediatric AML therapy is associated with lower event-free and overall survival, which may be partially attributable to incomplete anthracycline delivery. A combined strategy of primary cardioprotection and close cardiac monitoring can maximize chemotherapy delivery while reducing the toxicity of intensive AML therapy. Primary cardioprotection using dexrazoxane reduces short-term cardiotoxicity without compromising cancer survival. Liposomal anthracycline formulations, which are under active investigation, have the potential to mitigate cardiotoxicity while also improving antitumor efficacy. Primary cardioprotective strategies may reduce but not eliminate the risk of cardiotoxicity; therefore, close cardiac monitoring is also needed. Standard cardiac monitoring consists of serial echocardiographic assessments for left ventricular ejection fraction decline. Global longitudinal strain has prognostic utility in cancer therapy-related cardiotoxicity and may be used as an adjunct assessment. Additional cardioprotective measures should be considered in response to significant cardiotoxicity; these include cardiac remodeling medications to support cardiac recovery and anthracycline dose interruption and/or regimen modifications. However, the withholding of anthracyclines should be limited to avoid compromising cancer survival. A careful approach to cardioprotection during AML therapy is critical to maximize the efficacy of leukemia treatment while minimizing the short- and long-term risks of cardiotoxicity.


Indian Society for Study of Pain, Cancer Pain Special Interest Group Guidelines on Pharmacological Management of Cancer Pain (Part III).
The Indian Society for Study of Pain (ISSP), Cancer Pain Special Interest Group, guidelines on pharmacological management of cancer pain in adults provide a structured, step-wise approach which will help to improve the management of cancer pain and to provide patients with a minimally acceptable quality of life. The guidelines have been developed based on the available literature and evidence, to suit the needs, patient population, and situations in India. A questionnaire based on the key elements of each sub draft addressing certain inconclusive areas where evidence was lacking, was made available on the ISSP website and circulated by E-mail to all the ISSP and Indian Association of Palliative Care members. Antidepressants and/or anticonvulsants should be used to treat neuropathic cancer pain and the dose should be titrated according to the clinical response and side effects. External beam radiotherapy should be offered to all patients with painful metastatic bone pain. There is evidence on the use of ketamine in cancer neuropathic pain, but with no beneficial effect, thus it is not recommended.


Chromosome evolution in the Thermotogales: large-scale inversions and strain diversification of CRISPR sequences.
In the present study, the chromosomes of two members of the Thermotogales were compared. A whole-genome alignment of Thermotoga maritima MSB8 and Thermotoga neapolitana NS-E has revealed numerous large-scale DNA rearrangements, most of which are associated with CRISPR DNA repeats and/or tRNA genes. These DNA rearrangements do not include the putative origin of DNA replication but move within the same replichore, i.e., the same replicating half of the chromosome (delimited by the replication origin and terminus). Based on cumulative GC skew analysis, both the T. maritima and T. neapolitana lineages contain one or two major inverted DNA segments. Also, based on PCR amplification and sequence analysis of the DNA joints that are associated with the major rearrangements, the overall chromosome architecture was found to be conserved at most DNA joints for other strains of T. neapolitana. Taken together, the results from this analysis suggest that the observed chromosomal rearrangements in the Thermotogales likely occurred by successive inversions after their divergence from a common ancestor and before strain diversification. Finally, sequence analysis shows that size polymorphisms in the DNA joints associated with CRISPRs can be explained by expansion and possibly contraction of the DNA repeat and spacer unit, providing a tool for discerning the relatedness of strains from different geographic locations.


Antibodies to periodontogenic bacteria are associated with higher disease activity in lupus patients.
Microbial infections and mucosal dysbiosis influence morbidity in patients with systemic lupus erythematosus (SLE). In the oral cavity, periodontal bacteria and subgingival plaque dysbiosis provide persistent inflammatory stimuli at the mucosal surface. This study was undertaken to evaluate whether exposure to periodontal bacteria influences disease parameters in SLE patients. Circulating antibodies to specific periodontal bacteria have been used as surrogate markers to determine an ongoing bacterial burden, or as indicators of past exposure to the bacteria. Banked serum samples from SLE patients in the Oklahoma Lupus Cohort were used to measure antibody titres against periodontal pathogens (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Treponema denticola) and commensals (Capnocytophaga ochracea, and Streptococcus gordonii) by ELISA. Correlations between anti-bacterial antibodies and different clinicalparameters of SLE including, autoantibodies (anti-dsDNA, anti-SmRNP, anti-SSA/Ro and anti-SSB/La), complement, and disease activity (SLEDAI and BILAG) were studied. SLE patients had varying amounts of antibodies to different oral bacteria. The antibody titres against A. actinomycetemcomitans, P. gingivalis, T. denticola, and C. ochracea were higher in patients positive for anti-dsDNA antibodies, and they showed significant correlations with anti-dsDNA titres and reduced levels of complement. Among the periodontal pathogens, only antibodies to A. actinomycetemcomitans were associated with higher disease activity. Our results suggest that exposure to specific pathogenic periodontal bacteria influences disease activity in SLE patients. These findings provide a rationale for assessing and improving periodontal health in SLE patients, as an adjunct to lupus therapies.


Immunodominance of an antiviral cytotoxic T cell response is shaped by the kinetics of viral protein expression.
Lymphocytic choriomeningitis virus (LCMV) infection induces a protective CTL response consisting of gp- and nucleoprotein (NP)-specific CTL. We find that a small load of LCMV led to immunodominance of NP-CTL, whereas a large viral load resulted in dominance of gp-CTL. This is the first study describing that immunodominance is not fixed after infection with a given pathogen, but varies with the viral load instead. We assumed higher Ag sensitivity for NP-CTL, which would explain their preferential priming at low viral load, as well as their overstimulation resulting in selective exhaustion at high viral load. The higher Ag sensitivity of NP-CTL was due to faster kinetics of NP-epitope presentation. Thus, we uncover a novel factor that impinges upon immunodominance and is related to the kinetics of virus protein expression. We propose that CTL against early viral proteins swiftly interfere with virus replication, resulting in efficient protection. If these "early" CTL fail in immediate virus control, they are activated in the face of higher viral load compared with "late" CTL and are therefore prone to be exhausted. Thus, the observed absence of early CTL in persistent infections might not be the cause, but rather the consequence of viral persistence.


Weed seed contamination in imported seed lots entering New Zealand.
Imports of seeds for sowing are a major pathway for the introduction of contaminant seeds, and many agricultural weeds globally naturalised originally have entered through this pathway. Effective management of this pathway is a significant means of reducing future plant introductions and helps minimise agricultural losses. Using a national border inspection database, we examined the frequency, origin and identity of contaminant seeds within seed for sowing shipments entering New Zealand between 2014-2018. Our analysis looked at 41,610 seed lots across 1,420 crop seed species from over 90 countries. Overall, contamination was rare, occurring in 1.9% of all seed lots. Among the different crop types, the arable category had the lowest percentage of seed lots contaminated (0.5%) and the forage category had the highest (12.6%). Crop seeds Capsicum, Phaseolus and Solanum had the lowest contamination rates (0.0%). Forage crops Medicago (27.3%) and Trifolium (19.8%) had the highest contamination rates. Out of 191 genera recorded as contaminants, Chenopodium was the most common. Regulated quarantine weeds were the rarest contaminant type, only occurring in 0.06% of seed lots. Sorghum halepense was the most common quarantine species and was only found in vegetable seed lots. Vegetable crop seed lots accounted for approximately half of all quarantine species detections, Raphanus sativus being the most contaminated vegetable crop. Larger seed lots were significantly more contaminated and more likely to contain a quarantine species than smaller seed lots. These findings support International Seed Testing Association rules on maximum seed lot weights. Low contamination rates suggest industry practices are effective in minimising contaminant seeds. Considering New Zealand inspects every imported seed lot, utilises a working sample size 5 times larger than International Seed Testing Association rules require, trades crop seed with approximately half of the world's countries and imports thousands of crop seed species, our study provides a unique overview of contaminant seeds that move throughout the seed for sowing system.


MR of the pituitary gland postsurgery: serial MR studies following transsphenoidal resection.
To determine the MR appearance of the pituitary gland in the early and late postoperative periods in order to distinguish operative complications more effectively and to establish a postoperative baseline. Ten patients were prospectively studied with MR following transsphenoidal resection of a pituitary tumor. Early postoperative studies were obtained at 2 to 8 days following surgery, late studies at 4 to 9 months in all patients and also at 12 to 16 months in five. Major observations were height of the pituitary mass and appearance of the surgical packing. Within 8 days following surgery, the height of the pituitary mass was unchanged in two cases, increased in three, and only minimally decreased in five. All decreased in height (average 54%) by 4 to 9 months. Gelfoam packing completely (five) or nearly completely (three) resorbed leaving a normal-size, although deformed, pituitary gland. Fat-packed resection defects persisted (two). In the early postoperative period, the appearance of the pituitary gland is similar in size to its preoperative appearance. Subsequent involution with packing resorption yields a smaller, deformed pituitary gland.


Recovery of otoacoustic emissions after high-level noise exposure in the American bullfrog.
The American bullfrog (Rana catesbeiana) has an amphibian papilla (AP) that senses airborne, low-frequency sound and generates distortion product otoacoustic emissions (DPOAEs) similar to other vertebrate species. Although ranid frogs are typically found in noisy environments, the effects of noise on the AP have not been studied. First, we determined the noise levels that diminished DPOAE at 2f1-f2 using an f2 stimulus level at 80 dB SPL and that also produced morphological damage of the sensory epithelium. Second, we compared DPOAE (2f1-f2) responses with histopathologic changes occurring in bullfrogs after noise exposure. Consistent morphological damage, such as fragmented hair cells and missing bundles, as well as elimination of DPOAE responses were seen only after very high-level (>150 dB SPL) sound exposures. The morphological response of hair cells to noise differed along the mediolateral AP axis: medial hair cells were sensitive to noise and lateral hair cells were relatively insensitive to noise. Renewed or repaired hair cells were not observed until 9 days post-exposure. Following noise exposure, DPOAE responses disappeared within 24 h and then recovered to normal pre-exposure levels within 3-4 days. Our results suggest that DPOAEs in the bullfrog are sensitive to the initial period of hair cell damage. After noise-induced damage, the bullfrog AP has functional recovery mechanisms that do not depend on substantial hair cell regeneration or repair. Thus, the bullfrog auditory system might serve as an interesting model for investigation of ways to prevent noise damage.


Changes in alcohol use during the COVID-19 pandemic and previous pandemics: A systematic review.
The objective of this study is to summarize the research on the relationships between exposure to the COVID-19 pandemic or previous pandemics and changes in alcohol use. A systematic search of Medline and Embase was performed to identify cohort and cross-sectional population studies that examined changes in alcohol use during or following a pandemic compared to before a pandemic occurred. Outcomes examined included differences in the volume and frequency of alcohol consumption and the frequencies of heavy episodic drinking (HED) and alcohol-related problems during a pandemic compared to before a pandemic. Quality assessment was performed using the Cochrane Risk of Bias Tool for Nonrandomized Studies. This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search yielded 672 articles; 27 were included in the narrative review, of which 6 were cohort studies (all from high-income countries). A total of 259,188 participants were included. All cohort studies examined the impact of COVID-19 and associated pandemic-related policies, including social distancing and alcohol-specific policies, on alcohol use. Cohort studies demonstrated a consistent significant decrease in total alcohol consumption (Australia) and a significant increase in the frequency of alcohol use (United States). A significant decrease in the frequency of HED was observed in Australia and Spain but not in the United States. A significant increase in the proportion of people with problematic alcohol use was observed in the United Kingdom. Initial insights into changes in alcohol use indicate substantial heterogeneity. Alcohol use may have decreased in some countries, while HED and the proportion of people with problematic alcohol use may have increased. The lack of high-quality studies from low- and middle-income countries reflects a dearth of information from countries inhabited by most of the world's population.


Examining the impact of integrating physical activity on fluid intelligence and academic performance in an elementary school setting: a preliminary investigation.
To examine the impact of integrating physical activity with elementary curricula on fluid intelligence and academic achievement. A random sample of 3rd grade teachers integrated physical activity into their core curricula approximately 30 minutes a day, 3 days a week from January 2008 to April 2008. Noninvasive fluid intelligence cognitive measures were used along with State-mandated academic achievement tests. Experimental Group children averaged close to 1200 pedometer steps per integration day, thus averaging 3600 steps per week. Children in the Experimental Group performed significantly better on the SPM Fluid Intelligence Test. Children in the Experimental Group also performed significantly better on the Social Studies State mandated academic achievement test. Experimental Group children also received higher scores on the English/Language Arts, Math and Science achievements tests, but were not statistically significant compared with Control Group children. Children classified in Fitnessgram's Healthy Fitness Zone for BMI earned lower scores on many of the SPM Fluid Intelligence components. This investigation provides evidence that movement can influence fluid intelligence and should be considered to promote cognitive development of elementary-age children. Equally compelling were the differences in SPM Fluid Intelligence Test scores for children who were distinguished by Fitnessgram's BMI cut points.


Screening of NaCl salinity sensitivity across eight species of subterranean amphipod genus Niphargus.
Secondary salinization of freshwater is becoming a growing environmental problem. Currently, there is few data available on the effects of salinisation on subterranean crustaceans that are vital for the maintenance of groundwater ecosystem functioning. In this study, the sensitivity of subterranean Niphargus amphipods to NaCl was investigated. We expected that cave-dwelling species would be more sensitive as surface-subterranean boundary species. Eight ecologically different Niphargus species were tested: four live at the boundary between the surface and subterranean ecosystems (N. timavi, N. krameri, N. sphagnicolus, N. spinulifemur), three live in cave streams (N. stygius, N. scopicauda, N. podpecanus), and one species (N. hebereri) lives in anchialine caves and wells. The organisms were exposed to five concentrations of NaCl for 96 h and afterwards the immobility, mortality, and electron transfer system (ETS) activity (a measure for metabolic rate of animals) were evaluated. As expected, the most tolerant species was N. hebereri dwelling in naturally high-salinity habitat. However, contrary to our expectations, the species collected at the surface-subterranean boundary were more sensitive as cave stream species when their immobility and mortality were assessed. Interestingly, the majority of Niphargus tested were more NaCl tolerant as can be deduced from currently available data for subterranean and surface crustaceans. We could not observe a clear trend in ETS activity changes between groups of surface-subterranean boundary and cave streams species after exposure to NaCl stress, but it appears that osmotic stress-induced metabolic rate changes are species-specific. This study shows that amphipods Niphargus can be a valuable subterranean environmental research model and further ecotoxicity research is of interest.


Structure and hydration of L-proline in aqueous solutions.
The structure and hydration of L-proline in aqueous solution have been investigated using a combination of neutron diffraction with isotopic substitution, empirical potential structure refinement modeling, and small-angle neutron scattering at three concentrations, 1:10, 1:15, and 1:20 proline/water mole ratios. In each solution the carboxylate oxygen atoms from proline accept less than two hydrogen bonds from the surrounding water solvent and the amine hydrogen atoms donate less than one hydrogen bond to the surrounding water molecules. The solute-solute radial distribution functions indicate relatively weak interactions between proline molecules, and significant clustering or aggregation of proline is absent at all these concentrations. The spatial density distributions for the hydration of the COO- group in proline show a similar shape to that found previously in L-glutamic acid in aqueous solution but with a reduced coordination number.


Remotely controlled nanofluidic implantable platform for tunable drug delivery.
Chronic diseases such as hypertension and rheumatoid arthritis are persistent ailments that require personalized lifelong therapeutic management. However, the difficulty of adherence to strict dosing schedule compromises therapeutic efficacy and safety. Moreover, the conventional one-size-fits-all treatment approach is increasingly challenged due to the intricacies of inter- and intra-individual variabilities. While accelerated technological advances have led to sophisticated implantable drug delivery devices, flexibility in dosage and timing modulation to tailor precise treatment to individual needs remains an elusive goal. Here we describe the development of a subcutaneously implantable remote-controlled nanofluidic device capable of sustained drug release with adjustable dosing and timing. By leveraging a low intensity electric field to modify the concentration driven diffusion across a nanofluidic membrane, the rate of drug administration can be increased, decreased or stopped via Bluetooth remote command. We demonstrate in vitro the release modulation of enalapril and methotrexate, first-line therapeutics for treatment of hypertension and rheumatoid arthritis, respectively. Further, we show reliable remote communication and device biocompatibility via in vivo studies. Unlike a pulsatile release regimen typical of some conventional controlled delivery systems, our implant offers a continuous drug administration that avoids abrupt fluctuations, which could affect response and tolerability. Our system could set the foundation for an on-demand delivery platform technology for long term management of chronic diseases.


Exotic nuclei and their decay.
Recent advances in nuclear accelerators and experimental techniques have led to an increased ability to synthesize new isotopes. As isotopes are produced with more and more extreme combinations of neutrons and protons in their nuclei, new phenomena are observed, and the versatility of the nucleus is increased as a laboratory for studying fundamental forces. Among the newly discovered decay modes are (i) proton radioactivity, (ii) triton, two-proton, two-neutron, and three-neutron decays that are beta-delayed, as well as (iii)(14)C emission in radioactive decay. Precise tests of the properties of the weak force have also been achieved.


Predictors for Depressive Mood in Geriatric Patients After Traumatic Brain Injury: A Retrospective Cross-Sectional Study.
To identify predictors for depressive mood in geriatric patients after traumatic brain injury (TBI). A retrospective review of patients' medical charts was performed in TBI patients who were older than 60 years and referred to the Department of Rehabilitation Medicine at Severance Hospital in 2002-2016. The patients were classified into two groups based on the Geriatric Depression Scale (GDS): non-depressive group (0≤GDS≤16) and depressive group (17≤GDS≤30). Data was collected on demographic, socioeconomic, comorbidities, and trauma-related factors, as well as the pathophysiology of TBI, localization of lesion, post-traumatic complications, functional level, and cognitive and linguistic function. Significant variables from univariate analysis were analyzed using logistic regression. Forty-two patients were included, of whom 64.3% displayed a depressive mood. Patients in the depressive group had higher comorbidity scores (p=0.03), lower Functional Independence Measure (FIM) totals (p=0.03) and FIM motor (p=0.03) scores, higher modified Rankin Scale scores (p=0.04), and frequently had a bilateral or left side brain lesion (p=0.002). Higher comorbidity scores (odds ratio [OR], 1.764; 95% confidence interval [CI], 1.047-2.971), bilateral lesions (OR, 13.078; 95% CI, 1.786-95.780), and left side lesions (OR, 46.074; 95% CI, 3.175-668.502) were independently associated with a depressive mood in the multiple logistic regression analysis. The risk of depressive mood in geriatric patients after TBI is associated with comorbidity, functional limitation, and the horizontal distribution of brain lesions. The most significant determining factors were comorbidity and the horizontal distribution of brain lesions. Early detection of risk factors is important to prevent and manage depressive mood in geriatric patients after TBI.


Prenatal naled and chlorpyrifos exposure is associated with deficits in infant motor function in a cohort of Chinese infants.
Organophosphate insecticides (OPs) are used worldwide, yet despite nearly ubiquitous exposure in the general population, few have been studied outside the laboratory. Fetal brains undergo rapid growth and development, leaving them susceptible to long-term effects of neurotoxic OPs. The objective here was to investigate the extent to which prenatal exposure to OPs affects infant motor development. 30 OPs were measured in umbilical cord blood using gas chromatography tandem mass spectrometry in a cohort of Chinese infants. Motor function was assessed at 6-weeks and 9-months using Peabody Developmental Motor Scales 2nd edition (PDMS-2) (n=199). Outcomes included subtest scores: reflexes, stationary, locomotion, grasping, visual-motor integration (V-M), composite scores: gross (GM), fine (FM), total motor (TM), and standardized motor quotients: gross (GMQ), fine (FMQ), total motor (TMQ). Naled, methamidophos, trichlorfon, chlorpyrifos, and phorate were detected in ≥10% of samples. Prenatal naled and chlorpyrifos were associated with decreased 9-month motor function. Scores were 0.55, 0.85, and 0.90 points lower per 1ng/mL increase in log-naled, for V-M (p=0.04), FM (p=0.04), and FMQ (p=0.08), respectively. For chlorpyrifos, scores were 0.50, 1.98, 0.80, 1.91, 3.49, 2.71, 6.29, 2.56, 2.04, and 2.59 points lower for exposed versus unexposed infants, for reflexes (p=0.04), locomotion (p=0.02), grasping (p=0.05), V-M (p<0.001), GM (p=0.007), FM (p=0.002), TM (p<0.001), GMQ (p=0.01), FMQ (p=0.07), and TMQ (p=0.008), respectively. Girls appeared to be more sensitive to the negative effects of OPs on 9-month motor function than boys. We found deficits in 9-month motor function in infants with prenatal exposure to naled and chlorpyrifos. Naled is being aerially sprayed to combat mosquitoes carrying Zika virus, yet this is the first non-occupational human study of its health effects. Delays in early-motor skill acquisition may be detrimental for downstream development and cognition.


Feature selection and activity recognition system using a single triaxial accelerometer.
Activity recognition is required in various applications such as medical monitoring and rehabilitation. Previously developed activity recognition systems utilizing triaxial accelerometers have provided mixed results, with subject-to-subject variability. This paper presents an accurate activity recognition system utilizing a body worn wireless accelerometer, to be used in the real-life application of patient monitoring. The algorithm utilizes data from a single, waist-mounted triaxial accelerometer to classify gait events into six daily living activities and transitional events. The accelerometer can be worn at any location around the circumference of the waist, thereby reducing user training. Feature selection is performed using Relief-F and sequential forward floating search (SFFS) from a range of previously published features, as well as new features introduced in this paper. Relevant and robust features that are insensitive to the positioning of accelerometer around the waist are selected. SFFS selected almost half the number of features in comparison to Relief-F and provided higher accuracy than Relief-F. Activity classification is performed using Naïve Bayes and k-nearest neighbor (k-NN) and the results are compared. Activity recognition results on seven subjects with leave-one-person-out error estimates show an overall accuracy of about 98% for both the classifiers. Accuracy for each of the individual activity is also more than 95%.


Primary assessment of a self-adhesive gutta-percha material.
To evaluate a prototype gutta-percha material (Bio-Gutta), which is claimed to work without sealer because of its incorporated ultrafine bioactive glass particles, in terms of its induction of pH and calcium phosphate (CaP) precipitates, and its self-adhesiveness in root canals. Bio-Gutta was compared with conventional gutta-percha (GP, composition: 70 wt% ZnO, 30 wt% polyisoprene). Test and control materials (N = 3) were immersed in phosphate-buffered saline (PBS) at 37 °C for 30 days. The pH in the solution was monitored. Apparent CaP formation was assessed using scanning electron microscopy (SEM). The root canals of 33 single-rooted teeth were filled by vertical compaction of heated Bio-Gutta, 33 control canals were filled with vertically compacted GP without sealer. Push-out bond strengths associated with the filling materials in root cross-sections from middle root thirds was determined 1, 8, and 30 days after root filling (N = 11 per group). These values were compared between groups using one-way anova (α < 0.05). Bio-Gutta induced a high pH in the PBS solution, which plateaued at values between 11.4 and 11.8. Apparent CaP crystals covered the Bio-Gutta material after 30 days of immersion in PBS, whilst no such structures were observed on GP. Both materials under investigation had similar initial push-out bond strength values (P > 0.05). The adherence of Bio-Gutta increased from day 1 to 8 and was significantly higher than that of conventional GP at 8 and 30 days (P < 0.05). The experimental gutta-percha material under investigation was alkaline and caused CaP precipitates on its surface. It improved its adherence to the root canal wall within 1 week.


Using GPS telemetry to validate least-cost modeling of gray squirrel (Sciurus carolinensis) movement within a fragmented landscape.
In Britain, the population of native red squirrels Sciurus vulgaris has suffered population declines and local extinctions. Interspecific resource competition and disease spread by the invasive gray squirrel Sciurus carolinensis are the main factors behind the decline. Gray squirrels have adapted to the British landscape so efficiently that they are widely distributed. Knowledge on how gray squirrels are using the landscape matrix and being able to predict their movements will aid management. This study is the first to use global positioning system (GPS) collars on wild gray squirrels to accurately record movements and land cover use within the landscape matrix. This data were used to validate Geographical Information System (GIS) least-cost model predictions of movements and provided much needed information on gray squirrel movement pathways and network use. Buffered least-cost paths and least-cost corridors provide predictions of the most probable movements through the landscape and are seen to perform better than the more expansive least-cost networks which include all possible movements. Applying the knowledge and methodologies gained to current gray squirrel expansion areas, such as Scotland and in Italy, will aid in the prediction of potential movement areas and therefore management of the invasive gray squirrel. The methodologies presented in this study could potentially be used in any landscape and on numerous species.