Effects of embryonic propofol exposure on axonal growth and locomotor activity in zebrafish.
Prenatal propofol exposure induced neurotoxicity in the developing brains and led to persistent learning deficits in the offspring. Our goal was to use zebrafish to explore whether the decline in learning and memory was correlated with inhibition of neuronal growth after propofol exposure. Zebrafish embryos at 6 hours postfertilization (hpf) were exposed to control or 1, 2 or 4 μg/mL propofol until 48 hpf. Spontaneous locomotor activity and swimming behavior in response to dark-to-light photoperiod stimulation were studied in zebrafish larvae at 6 days postfertilization (dpf). The adaptability to repeated stimulation was used to indicate learning and memory function of larvae. Transgenic NBT line zebrafish was used to quantitate the effect of propofol on motor neuronal growth of embryos in vivo. Six dpf transgenic zebrafish larvae went through photoperiod stimulation after their neuronal length had been analyzed during the embryonic period. Our data indicate that embryonic exposure to 1, 2 and 4 μg/mL propofol had no adverse effect on spontaneous movement in zebrafish larvae, but 2 and 4 μg/mL propofol significantly impaired the learning and memory function of larvae. Moreover, propofol significantly inhibited axonal growth of motor neurons during the embryonic stage, which was correlated with learning and memory deficiency in larvae. Our findings demonstrate that the neuronal growth was correlated with learning and memory function, indicating the relevance of zebrafish as a new model to explore the mechanisms through which propofol induces long-term learning and memory impairment.


Electrospinning of linezolid loaded PLGA nanofibers: effect of solvents on its spinnability, drug delivery, mechanical properties, and antibacterial activities.
Objective: The choice of a desirable solvent/solvent system is fundamental for optimization of electrospinning by altering the rheological and electrostatic properties of the polymer solutions.Methods: The effects of the solvents and their properties on the viscosity and spinnability of the polymer solutions and the diameter, morphology, in vitro drug release, drug release mechanisms, antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and mechanical properties of electrospun poly-(d,l-lactide-co-glycolide) (PLGA) nanofibers were investigated. Dichloromethane (DCM), dimethylformamide (DMF), various ratios of DCM:DMF, and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) were used as solvents.Results: Although solutions containing DCM/DMF alone were not spinnable, different ratios of DCM:DMF and HFIP were determined as suitable solvents to produce nanofibers because of high enough conductivity, viscosity, and low enough surface tension of the solutions. The DCM:DMF ratio was highly effective on viscosity, nanofiber diameter, morphology, and linezolid release rate. The viscosity of HFIP containing solution was higher and the obtained nanofibers were thicker and smoother with better mechanical properties. The release of nanofibers containing HFIP at a concentration of 10% w/v PLGA was more prolonged than nanofibers containing DCM:DMF mixture. The effect of linezolid content on nanofibers was also investigated. As the amount of linezolid increased, nanofiber diameter and drug release increased and bead formation was observed. While antibacterial activity with nanofibers for which DCM:DMF was used, lasted for 13 days, it was extended to 16 days in nanofibers for which HFIP was used.Conclusions: Type and ratio of the solvent system affected viscosity and spinnability of the solutions, the average nanofiber diameter, morphology, in vitro activity and mechanical properties of the obtained electrospun nanofibers.


A computational approach to identify blood cell-expressed Parkinson's disease biomarkers that are coordinately expressed in brain tissue.
Identification of genes whose regulation of expression is functionally similar in both brain tissue and blood cells could in principle enable monitoring of significant neurological traits and disorders by analysis of blood samples. We thus employed transcriptional analysis of pathologically affected tissues, using agnostic approaches to identify overlapping gene functions and integrating this transcriptomic information with expression quantitative trait loci (eQTL) data. Here, we estimate the correlation of gene expression in the top-associated cis-eQTLs of brain tissue and blood cells in Parkinson's Disease (PD). We introduced quantitative frameworks to reveal the complex relationship of various biasing genetic factors in PD, a neurodegenerative disease. We examined gene expression microarray and RNA-Seq datasets from human brain and blood tissues from PD-affected and control individuals. Differentially expressed genes (DEG) were identified for both brain and blood cells to determine common DEG overlaps. Based on neighborhood-based benchmarking and multilayer network topology approaches we then developed genetic associations of factors with PD. Overlapping DEG sets underwent gene enrichment using pathway analysis and gene ontology methods, which identified candidate common genes and pathways. We identified 12 significantly dysregulated genes shared by brain and blood cells, which were validated using dbGaP (gene SNP-disease linkage) database for gold-standard benchmarking of their significance in disease processes. Ontological and pathway analyses identified significant gene ontology and molecular pathways that indicate PD progression. In sum, we found possible novel links between pathological processes in brain tissue and blood cells by examining cell pathway commonalities, corroborating these associations using well validated datasets. This demonstrates that for brain-related pathologies combining gene expression analysis and blood cell cis-eQTL is a potentially powerful analytical approach. Thus, our methodologies facilitate data-driven approaches that can advance knowledge of disease mechanisms and may, with clinical validation, enable prediction of neurological dysfunction using blood cell transcript profiling.


Candida bloodstream infections in intensive care units: analysis of the extended prevalence of infection in intensive care unit study.
To provide a global, up-to-date picture of the prevalence, treatment, and outcomes of Candida bloodstream infections in intensive care unit patients and compare Candida with bacterial bloodstream infection. A retrospective analysis of the Extended Prevalence of Infection in the ICU Study (EPIC II). Demographic, physiological, infection-related and therapeutic data were collected. Patients were grouped as having Candida, Gram-positive, Gram-negative, and combined Candida/bacterial bloodstream infection. Outcome data were assessed at intensive care unit and hospital discharge. EPIC II included 1265 intensive care units in 76 countries. Patients in participating intensive care units on study day. None. Of the 14,414 patients in EPIC II, 99 patients had Candida bloodstream infections for a prevalence of 6.9 per 1000 patients. Sixty-one patients had candidemia alone and 38 patients had combined bloodstream infections. Candida albicans (n = 70) was the predominant species. Primary therapy included monotherapy with fluconazole (n = 39), caspofungin (n = 16), and a polyene-based product (n = 12). Combination therapy was infrequently used (n = 10). Compared with patients with Gram-positive (n = 420) and Gram-negative (n = 264) bloodstream infections, patients with candidemia were more likely to have solid tumors (p < .05) and appeared to have been in an intensive care unit longer (14 days [range, 5-25 days], 8 days [range, 3-20 days], and 10 days [range, 2-23 days], respectively), but this difference was not statistically significant. Severity of illness and organ dysfunction scores were similar between groups. Patients with Candida bloodstream infections, compared with patients with Gram-positive and Gram-negative bloodstream infections, had the greatest crude intensive care unit mortality rates (42.6%, 25.3%, and 29.1%, respectively) and longer intensive care unit lengths of stay (median [interquartile range]) (33 days [18-44], 20 days [9-43], and 21 days [8-46], respectively); however, these differences were not statistically significant. Candidemia remains a significant problem in intensive care units patients. In the EPIC II population, Candida albicans was the most common organism and fluconazole remained the predominant antifungal agent used. Candida bloodstream infections are associated with high intensive care unit and hospital mortality rates and resource use.


Impact of enzymatic and alkaline hydrolysis on CBD concentration in urine.
A sensitive and specific analytical method for cannabidiol (CBD) in urine was needed to define urinary CBD pharmacokinetics after controlled CBD administration, and to confirm compliance with CBD medications including Sativex-a cannabis plant extract containing 1:1 ∆(9)-tetrahydrocannabinol (THC) and CBD. Non-psychoactive CBD has a wide range of therapeutic applications and may also influence psychotropic smoked cannabis effects. Few methods exist for the quantification of CBD excretion in urine, and no data are available for phase II metabolism of CBD to CBD-glucuronide or CBD-sulfate. We optimized the hydrolysis of CBD-glucuronide and/or -sulfate, and developed and validated a GC-MS method for urinary CBD quantification. Solid-phase extraction isolated and concentrated analytes prior to GC-MS. Method validation included overnight hydrolysis (16 h) at 37 °C with 2,500 units β-glucuronidase from Red Abalone. Calibration curves were fit by linear least squares regression with 1/x (2) weighting with linear ranges (r(2) > 0.990) of 2.5-100 ng/mL for non-hydrolyzed CBD and 2.5-500 ng/mL for enzyme-hydrolyzed CBD. Bias was 88.7-105.3 %, imprecision 1.4-6.4 % CV and extraction efficiency 82.5-92.7 % (no hydrolysis) and 34.3-47.0 % (enzyme hydrolysis). Enzyme-hydrolyzed urine specimens exhibited more than a 250-fold CBD concentration increase compared to alkaline and non-hydrolyzed specimens. This method can be applied for urinary CBD quantification and further pharmacokinetics characterization following controlled CBD administration.


Shared action spaces: a basis function framework for social re-calibration of sensorimotor representations supporting joint action.
The article explores the possibilities of formalizing and explaining the mechanisms that support spatial and social perspective alignment sustained over the duration of a social interaction. The basic proposed principle is that in social contexts the mechanisms for sensorimotor transformations and multisensory integration (learn to) incorporate information relative to the other actor(s), similar to the "re-calibration" of visual receptive fields in response to repeated tool use. This process aligns or merges the co-actors' spatial representations and creates a "Shared Action Space" (SAS) supporting key computations of social interactions and joint actions; for example, the remapping between the coordinate systems and frames of reference of the co-actors, including perspective taking, the sensorimotor transformations required for lifting jointly an object, and the predictions of the sensory effects of such joint action. The social re-calibration is proposed to be based on common basis function maps (BFMs) and could constitute an optimal solution to sensorimotor transformation and multisensory integration in joint action or more in general social interaction contexts. However, certain situations such as discrepant postural and viewpoint alignment and associated differences in perspectives between the co-actors could constrain the process quite differently. We discuss how alignment is achieved in the first place, and how it is maintained over time, providing a taxonomy of various forms and mechanisms of space alignment and overlap based, for instance, on automaticity vs. control of the transformations between the two agents. Finally, we discuss the link between low-level mechanisms for the sharing of space and high-level mechanisms for the sharing of cognitive representations.


Tibial acceleration profiles during the menstrual cycle in female athletes.
Fluctuating levels of endogenous estrogen are thought to have an adverse effect on lower limb biomechanics, given the observed higher rate of ACL injury at certain phases of the menstrual cycle. The purpose of this study was to investigate the effects of fluctuating endogenous estrogen levels during the menstrual cycle on acceleration transients at the proximal tibia in young physically active females. Eleven females aged 16-18 years participated in this study and were compared to a male control group. Female subjects were tested at each of the four phases of the menstrual cycle: menses, follicular, ovulation and luteal. On each test occasion, acceleration transients at the proximal tibia were measured while subjects performed an abrupt deceleration task (simulated netball landing). No significant differences were found between the different phases of the menstrual cycle for peak tibial acceleration (PTA; P = 0.57), and time to zero tibial acceleration (TZTA; P = 0.59). However, there was a significant difference for time to peak tibial acceleration (TPTA) between menstruation and follicular (P = 0.04), menstruation and ovulation (P = 0.001), menstruation and luteal phase (P = 0.002), and follicular phase and ovulation (P = 0.007). In the male control group, no significant between-test session differences were observed for PTA (P = 0.48), TZTA (P = 0.08) and TPTA (P = 0.29). While there were no significant between-group differences for PTA (P = 0.21) and TZTA (P = 0.48), significant between-group differences were observed for TPTA (P = 0.001). The results of this project strongly suggest that serum estrogen fluctuations have an effect on tibial acceleration profiles in young female athletes during different phases of the menstrual cycle.


Cluster randomized controlled trial protocol: addressing reproductive coercion in health settings (ARCHES).
Women ages 16-29 utilizing family planning clinics for medical services experience higher rates of intimate partner violence (IPV) and reproductive coercion (RC) than their same-age peers, increasing risk for unintended pregnancy and related poor reproductive health outcomes. Brief interventions integrated into routine family planning care have shown promise in reducing risk for RC, but longer-term intervention effects on partner violence victimization, RC, and unintended pregnancy have not been examined. The 'Addressing Reproductive Coercion in Health Settings (ARCHES)' Intervention Study is a cluster randomized controlled trial evaluating the effectiveness of a brief, clinician-delivered universal education and counseling intervention to reduce IPV, RC and unintended pregnancy compared to standard-of-care in family planning clinic settings. The ARCHES intervention was refined based on formative research. Twenty five family planning clinics were randomized (in 17 clusters) to either a three hour training for all family planning clinic staff on how to deliver the ARCHES intervention or to a standard-of-care control condition. All women ages 16-29 seeking care in these family planning clinics were eligible to participate. Consenting clients use laptop computers to answer survey questions immediately prior to their clinic visit, a brief exit survey immediately after the clinic visit, a first follow up survey 12-20 weeks after the baseline visit (T2), and a final survey 12 months after the baseline (T3). Medical record chart review provides additional data about IPV and RC assessment and disclosure, sexual and reproductive health diagnoses, and health care utilization. Of 4009 women approached and determined to be eligible based on age (16-29 years old), 3687 (92 % participation) completed the baseline survey and were included in the sample. The ARCHES Intervention Study is a community-partnered study designed to provide arigorous assessment of the short (3-4 months) and long-term (12 months) effects of a brief, clinician-delivered universal education and counseling intervention to reduce IPC, RC and unintended pregnancy in family planning clinic settings. The trial features a cluster randomized controlled trial design, a comprehensive data collection schedule and a large sample size with excellent retention. ClinicialTrials.gov NCT01459458. Registered 10 October 2011.


Second-Generation Antipsychotic Drugs in Anorexia Nervosa: A Meta-Analysis of Randomized Controlled Trials.
Background: Second-generation antipsychotic drugs (SGAs) are increasingly administered to achieve weight gain in anorexia nervosa. In this meta-analysis, we aimed to determine if any evidence for this treatment option can be derived from randomized controlled trials (RCTs). Methods: Based on the 'World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Eating Disorders', a systematic update literature search was applied to identify all RCTs investigating the efficacy, acceptability, and tolerability of SGAs in anorexia nervosa in comparison to placebo/no treatment. The primary outcome was weight gain measured by mean change in body mass index (BMI). Secondary outcomes were mean changes in Yale-Brown-Cornell Eating Disorders Scale (YBC-EDS) total score and Eating Disorders Inventory (EDI) total score and premature discontinuation of treatment. Employing a random-effects model standardized mean differences based on Hedges's g and Mantel-Haenszel risk ratios were calculated. Results: Seven RCTs (n = 201) investigating olanzapine (N = 4), quetiapine (N = 2), and risperidone (N = 1) were included. We found no statistically significant between-group differences for mean BMI change when pooling the SGAs (N = 7, n = 161; Hedges's g = 0.13, 95% CI: -0.17 to 0.43; p = 0.4) and when examining the individual drugs. Furthermore, the SGAs failed to differentiate statistically significantly from placebo/no treatment for all secondary outcomes. Conclusions: Based on the current evidence, pharmacological treatment of anorexia nervosa with SGAs cannot be generally recommended although some individuals or subgroups of patients might benefit from an antipsychotic medication. Further research is required to identify which patients will likely benefit from such a treatment option. © 2015 S. Karger AG, Basel.


Association of household cleaning agents and disinfectants with asthma in young German adults.
We scrutinised the association of private use of household sprays and disinfectants with asthma incidence in young adults in the transition from school to working life. Between 2007 and 2009,2051 young adults aged 19-24 years living in two major German cities took part in the Study on Occupational Allergy Risks II. Self-reported exposure to household sprays and disinfectants was characterised according to a composite score for frequency of use as no use (score=0), low use (score between 1 and the median), medium use (score between the median and the 90th percentile) and high use (score above the 90th percentile). Two outcome variables (current asthma and current wheezing) with four mutually exclusive categories (never, incident, persistent and remittent) were used for the risk analyses. Multinomial logistic regression models examined the association between the frequency of using household sprays and disinfectants with asthma and wheezing adjusting for potential confounders. Compared with no use, high use of disinfectants was associated with a more than twofold increased odds of incident asthma (OR 2.79, 95% CI 1.14 to 6.83). In addition, low/medium use of disinfectants was associated with remittent asthma (OR 2.39, 95% CI 1.29 to 4.47). The evidence for an association between high usage of household sprays and asthma incidence was weak (OR 2.79, 95% CI 0.84 to 9.20). Our results support the hypothesis of an association between the use of cleaning products and elevated risks for asthma and wheezing in young adults at the start of working life.


Role of Inducible Co-Stimulator (ICOS) in cancer immunotherapy.
Introduction: The promotion of antitumor response by targeting co-stimulatory B7 superfamily members has become evident to create a new wave of cancer immunotherapy. Inducible Co-Stimulator (ICOS), which is expressed on activated T cells, gained interest in the translational medicine community.Areas covered: We performed an extensive literature review using the keywords 'ICOS' and 'cancer', and the Clinicaltrials.gov database for early phase clinical trials targeting ICOS. In this review, we highlight the dual role of ICOS in oncogenesis in different malignancies. We summarize the current state of knowledge about ICOS/ICOSL pathway targeting by immunotherapies.Expert opinion: Due to its multifaceted link with anti-tumor immunity, both antagonist and agonist antibodies might be of interest to target the ICOS/ICOSL pathway for tumor treatment. Indeed, ICOS activation might potentiate the effect of an inhibitory checkpoint blockade, while its neutralization could decrease the function of immunosuppressive Tregs and inhibit lymphoid tumor cells expressing Tfh markers.


Corticosterone-Mediated Body Weight Loss Is an Important Catabolic Process for Poststroke Immunity and Survival.
Background and Purpose- Stroke-induced acute severe body weight (BW) loss is associated with a high rate of mortality during a critical poststroke period. Several interventions to reduce weight loss, however, have not been successful. Currently, the biological significance of this extraordinary catabolic process is not well understood. Spleen-derived monocytes/macrophages (MMs) are the major immune cells recruited to the injured brain. The trafficking of MMs has been shown to be important for tissue repair and recovery. The purpose of the study is to investigate whether the BW reduction is essential for MM-mediated immune response for mice to survive and whether a corticosterone-mediated catabolic event underlies the processes. Methods- C57BL/6 male mice (12-week-old) were subjected to transient middle cerebral artery occlusion. BW, total MMs, and their Ly-6Chigh and Ly-6Clow subsets were determined in the spleen, blood, and the brain in poststroke mice. Poststroke survival rate and MM subsets were determined in mice with adrenalectomy, sham-adrenalectomy, and adrenalectomy mice supplemented with corticosterone. Results- Stroke reduced BW with a maximum reduction at day 3 poststroke (17.2±5.2%). The reduction at day 3 was positively linked to injury severity and selective depletion of MMs, but no other types of immune cells, in the spleen. Notably, the splenic MM depletion was significantly greater in mice with severe BW reduction (≥18% at day 3). In the blood, stroke depleted circulating MMs to a similar degree in animals with moderate and severe BW loss. Ly-6C+ monocyte infiltration in the poststroke brain was greater in mice with severe BW loss. Blocking the catabolic process by adrenalectomy significantly increased poststroke mortality, but the mortality was partially rescued by corticosterone supplement in adrenalectomy mice. Conclusions- Stroke-induced BW loss facilitates MM-mediated immune response, and the adrenal corticosterone-mediated catabolic process is necessary for poststroke survival. Visual Overview- An online visual overview is available for this article.


Informative phenotypes for genetic studies of psychiatric disorders.
Despite its initial promise, there has been both progress and some set backs in genetic studies of the major psychiatric disorders of childhood and adulthood. Finding true susceptibility genes may be delayed because the most genetically informative phenotypes are not being used on a regular basis in linkage analysis and association studies. It is highly likely that using alternative phenotypes instead of DSM diagnostic categories will lead more rapid success in the search for these susceptibility genes. The objective of this paper is to describe the different types of informative phenotypes that can be employed in psychiatric genetic studies, to clarify their uses, to identify several methodologic issues the design and conduct of linkage and association studies that use alternative phenotypes and finally to suggest possible solutions to those difficulties. This is a conceptual review with a focus on methodological issues that may arise in psychiatric genetics and examples are taken from the literature on autism, schizophrenia, bipolar disorder, and alcoholism.


Discovery of Novel Latency-Associated Nuclear Antigen Inhibitors as Antiviral Agents Against Kaposi's Sarcoma-Associated Herpesvirus.
With the aim to develop novel antiviral agents against Kaposi's Sarcoma Herpesvirus (KSHV), we are targeting the latency-associated nuclear antigen (LANA). This protein plays an important role in viral genome maintenance during latent infection. LANA has the ability to tether the viral genome to the host nucleosomes and, thus, ensures latent persistence of the viral genome in the host cells. By inhibition of the LANA-DNA interaction, we seek to eliminate or reduce the load of the viral DNA in the host. To achieve this goal, we screened our in-house library using a dedicated fluorescence polarization (FP)-based competition assay, which allows for the quantification of LANA-DNA-interaction inhibition by small organic molecules. We successfully identified three different compound classes capable of disrupting this protein-nucleic acid interaction. We characterized these compounds by IC50 dose-response evaluation and confirmed the compound-LANA interaction using surface plasmon resonance (SPR) spectroscopy. Furthermore, two of the three hit scaffolds showed only marginal cytotoxicity in two human cell lines. Finally, we conducted STD-NMR competition experiments with our new hit compounds and a previously described fragment-sized inhibitor. Based on these results, future compound linking approaches could serve as a promising strategy for further optimization studies in order to generate highly potent KSHV inhibitors.


Hepatitis C Virus Infection and Risk of Venous Thromboembolism: A Systematic Review and Meta-Analysis.
Hepatitis C virus (HCV) infection is one of the leading causes of cirrhosis. As a result of chronic inflammatory response to the virus, HCV-infected patients may be at a higher risk of venous thromboembolism (VTE). However, the data on this association is unclear. This systematic review and meta-analysis was conducted with the aims to summarize all available evidence. A literature search was performed using MEDLINE and EMBASE from inception to April 2016. Studies that reported relative risks, odd ratios, or hazard ratios comparing the risk of VTE among HCV-infected patients vs. subjects without HCV infection were included. Pooled risk ratios (RR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. Three studies met our eligibility criteria and were included in analysis. The pooled RR of VTE in HCV-infected patients vs. subjects without HCV infection was 1.38 (95% CI, 1.08-1.77, I2 = 40%). Subgroup analysis showed that risk was increased for both pulmonary embolism (PE) and deep venous thrombosis (DVT) even though without adequate power to demonstrate statistical significance (Pooled RR of 1.34, 95% CI, 0.67-2.66 for PE and pooled RR 1.45, 95% CI, 0.93-2.77 for DVT). Our study demonstrated a significantly increased risk of VTE among HCV-infected patients. Further studies are required to clarify how this risk should be addressed in clinical practice.


Comparison of nosocomial candidemia of pediatric and adult cases in 2-years period at a Turkish university hospital.
Although there are limited numerous reports of candidemia in adults, data on paediatrics are stil limeted. The aim of the present study was to compare the aetiology and risk factors of nosocomial candidemia among the paediatric and adults in our hospital. This study includes the patients hospitalised and diagnosed as fungemia at Ondokuz Mayis University Hospital between June 30, 2007 and June 30, 2009 whose blood cultures sent to our microbiology laboratory. After fungal growth was observed in blood cultures, the yeast cells were inoculated onto Saboraud glucose agar. The colonies were identified by conventional yeast identification methods and ID 32C yeast identification system according to the manifacturer's instructions. During this period 51 paediatric and 69 adults were studied. The most common yeast form was Candida albicans (43.3%) followed by C. parapsilosis (25.0%) and C. tropicalis (17.5%). Although the non-albicans Candida species represent more than half (56.7%) of all candidemic cases C. albicans was the most common frequent etiologic agent. There was no statistically significant difference between patient age (paediatric and adult) and distribution of Candida species (p>0.05) Neoplasia (in adults) and prematurity (in paediatrics) were the main underlying diseases. Predisposing factors and mortality rates were not different among paediatrics and adults. We reinforce the necessity of continous epidomiologic surveillance to follow the dynamics of candidemia.


Towards a European health research and innovation cloud (HRIC).
The European Union (EU) initiative on the Digital Transformation of Health and Care (Digicare) aims to provide the conditions necessary for building a secure, flexible, and decentralized digital health infrastructure. Creating a European Health Research and Innovation Cloud (HRIC) within this environment should enable data sharing and analysis for health research across the EU, in compliance with data protection legislation while preserving the full trust of the participants. Such a HRIC should learn from and build on existing data infrastructures, integrate best practices, and focus on the concrete needs of the community in terms of technologies, governance, management, regulation, and ethics requirements. Here, we describe the vision and expected benefits of digital data sharing in health research activities and present a roadmap that fosters the opportunities while answering the challenges of implementing a HRIC. For this, we put forward five specific recommendations and action points to ensure that a European HRIC: i) is built on established standards and guidelines, providing cloud technologies through an open and decentralized infrastructure; ii) is developed and certified to the highest standards of interoperability and data security that can be trusted by all stakeholders; iii) is supported by a robust ethical and legal framework that is compliant with the EU General Data Protection Regulation (GDPR); iv) establishes a proper environment for the training of new generations of data and medical scientists; and v) stimulates research and innovation in transnational collaborations through public and private initiatives and partnerships funded by the EU through Horizon 2020 and Horizon Europe.


Long-term home oxygen therapy in children and adolescents: analysis of clinical use and costs of a home care program.
To describe the clinical and laboratory characteristics of patients on long-term home oxygen therapy followed up by the home care program of Hospital das Clínicas, School of Medicine, Universidade de São Paulo, during a period of 8 years; to compare groups with and without secondary pulmonary hypertension; and to estimate the cost of the program using oxygen concentrators vs. oxygen cylinders provided by the hospital. A descriptive, retrospective cohort study of patients on long-term home oxygen therapy followed up from 2002 to 2009 at the Unit of Pulmonology, Children's Institute, Hospital das Clínicas, School of Medicine, Universidade de São Paulo. We studied 165 patients, of whom 53% were male, with the following medians: age at the beginning of oxygen therapy--3.6 years; duration of oxygen therapy--7 years; and survival time after beginning of oxygen therapy--3.4 years. The main diagnoses were: cystic fibrosis (22%), bronchopulmonary dysplasia (19%), and bronchiolitis obliterans (15%). Of the 33 patients who underwent spirometry, 70% had severe obstructive lung disease. Echocardiogram was performed in 134 patients; 51% of them had secondary pulmonary hypertension. There was a statistically significant association between pulmonary hypertension and need of higher oxygen flows (chi-square, p = 0.011), and between pulmonary hypertension and longer duration of oxygen therapy (Logrank, p = 0.0001). There was no statistically significant difference between survival time after the beginning of oxygen therapy and pulmonary hypertension. The average monthly costs of the program were US$ 7,392.93 for concentrators and US$ 16,630.92 for cylinders. Long-term home oxygen therapy was used to treat different chronic diseases, predominantly in infants and preschool children. There was a high frequency of pulmonary hypertension associated with longer periods of oxygen use and greater oxygen flow, without association with survival rate. The use of concentrators instead of cylinders may reduce costs significantly.


Linear-in-wavenumber actively-mode-locked wavelength-swept laser.
We report on an akinetic actively-mode-locked wavelength-swept laser (ASL) with a sweep that is highly linear in wavenumber. By tailoring the drive waveform of the intracavity modulator, the wavenumber sweep was further linearized to enable high fidelity frequency-domain interferometric ranging without resampling of the acquired data. Used for catheter-based optical coherence tomography, the ASL showed comparable imaging performance to a state-of-the-art polygon-based wavelength-swept source at a matching sweep rate of 103.6 kHz, a duty cycle of 95%, and a bandwidth of 100 nm, centered at 1330 nm.


An Early Cretaceous tribosphenic mammal and metatherian evolution.
Derived features of a new boreosphenidan mammal from the Lower Cretaceous Yixian Formation of China suggest that it has a closer relationship to metatherians (including extant marsupials) than to eutherians (including extant placentals). This fossil dates to 125 million years ago and extends the record of marsupial relatives with skeletal remains by 50 million years. It also has many foot structures known only from climbing and tree-living extant mammals, suggesting that early crown therians exploited diverse niches. New data from this fossil support the view that Asia was likely the center for the diversification of the earliest metatherians and eutherians during the Early Cretaceous.


Expanding the scope of chemiluminescence in bioanalysis with functional nanomaterials.
Nanomaterial-enabled chemiluminescence (CL) detection has become a growing area of interest in recent years. We review the development of nanomaterial-based CL detection strategies and their applications in bioanalysis. Much progress has been achieved in the past decade, but most attempts still remain in the proof-of-concept stage. This review highlights recent advances in nanomaterials in CL detection and organizes them into three groups based on their role in detection: as a sensing platform, as a signal probe, and applications in homogeneous systems. Furthermore, we have discussed the critical challenges we are facing and future prospects of this field.


Underestimated ecosystem carbon turnover time and sequestration under the steady state assumption: A perspective from long-term data assimilation.
It is critical to accurately estimate carbon (C) turnover time as it dominates the uncertainty in ecosystem C sinks and their response to future climate change. In the absence of direct observations of ecosystem C losses, C turnover times are commonly estimated under the steady state assumption (SSA), which has been applied across a large range of temporal and spatial scales including many at which the validity of the assumption is likely to be violated. However, the errors associated with improperly applying SSA to estimate C turnover time and its covariance with climate as well as ecosystem C sequestrations have yet to be fully quantified. Here, we developed a novel model-data fusion framework and systematically analyzed the SSA-induced biases using time-series data collected from 10 permanent forest plots in the eastern China monsoon region. The results showed that (a) the SSA significantly underestimated mean turnover times (MTTs) by 29%, thereby leading to a 4.83-fold underestimation of the net ecosystem productivity (NEP) in these forest ecosystems, a major C sink globally; (b) the SSA-induced bias in MTT and NEP correlates negatively with forest age, which provides a significant caveat for applying the SSA to young-aged ecosystems; and (c) the sensitivity of MTT to temperature and precipitation was 22% and 42% lower, respectively, under the SSA. Thus, under the expected climate change, spatiotemporal changes in MTT are likely to be underestimated, thereby resulting in large errors in the variability of predicted global NEP. With the development of observation technology and the accumulation of spatiotemporal data, we suggest estimating MTTs at the disequilibrium state via long-term data assimilation, thereby effectively reducing the uncertainty in ecosystem C sequestration estimations and providing a better understanding of regional or global C cycle dynamics and C-climate feedback.


Preferential expression of a mutant allele of the amplified MDR1 (ABCB1) gene in drug-resistant variants of a human sarcoma.
Activation of the MDR1 (ABCB1) gene is a common event conferring multidrug resistance (MDR) in human cancers. We investigated MDR1 activation in MDR variants of a human sarcoma line, some of which express a mutant MDR1, which facilitated the study of allelic gene expression. Structural alterations of MDR1, gene copy numbers, and allelic expression were analyzed by cytogenetic karyotyping, oligonucleotide hybridization, Southern blotting, polymerase chain reaction, and DNA heteroduplex assays. Both chromosome 7 alterations and several cytogenetic changes involving the 7q21 locus are associated with the development of MDR in these sarcoma cells. Multistep-selected cells and their revertants contain three- to six-fold MDR1 gene amplification compared with that of the drug-sensitive parental cell line MES-SA and single-step doxorubicin-selected mutants. MDR1 gene amplification precedes the emergence of a mutant allele in cells that were coselected with doxorubicin and a cyclosporin inhibitor of P-glycoprotein (P-gp). Allele-specific oligonucleotide hybridization showed that the endogenous mutant allele was present as a single copy, with multiple copies of the normal allele. Reselection of revertant cells with doxorubicin in either the presence or the absence of the P-gp inhibitor resulted in exclusive reexpression of the mutant MDR1 allele, regardless of the presence of multiple wild-type MDR1 alleles. These data provide new insights into how multiple alleles are regulated in the amplicon of drug-resistant cancer cells and indicate that increased expression of an amplified gene can result from selective transcription of a single mutant allele of the gene.


A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation.
Leukotriene A(4) hydrolase (LTA(4)H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene B(4) (LTB(4)). LTA(4)H also possesses aminopeptidase activity with unknown substrate and physiological importance; we identified the neutrophil chemoattractant proline-glycine-proline (PGP) as this physiological substrate. PGP is a biomarker for chronic obstructive pulmonary disease (COPD) and is implicated in neutrophil persistence in the lung. In acute neutrophil-driven inflammation, PGP was degraded by LTA(4)H, which facilitated the resolution of inflammation. In contrast, cigarette smoke, a major risk factor for the development of COPD, selectively inhibited LTA(4)H aminopeptidase activity, which led to the accumulation of PGP and neutrophils. These studies imply that therapeutic strategies inhibiting LTA(4)H to prevent LTB(4) generation may not reduce neutrophil recruitment because of elevated levels of PGP.


Low-intensity light-induced drug release from a dual delivery system comprising of a drug loaded liposome and a photosensitive conjugate.
This study reports the development of a binary drug delivery system consisting of charged liposomes and an oppositely charged peptide-photosensitiser conjugate. Liposomes were prepared with phosphatidyl-l-serine as a negatively charged lipid. Calcein, a fluorophore marker, and doxorubicin, an anticancer drug, were used as model hydrophilic loads. The conjugate consisted of a positively charged arginine-rich peptide synthesised by solid-phase peptide synthesis, and a phthalocyanine derivative with characteristic absorption around 685 nm. Illumination of the binary system with far-red light of 12-15 mW/cm2 intensity resulted in 5- to 15-fold increase in release of payloads from the liposomes. The mechanism of drug release was based on photosensitised oxidation of lipids destabilising the liposomal membrane. The cytotoxicity of the liposomes loaded with doxorubicin was tested on B16-F10 melanoma and Y79 retinoblastoma cells. The cytotoxicity of the illuminated binary system in melanoma cell line was significantly higher as compared to the system without illumination. The components of the binary system can be individually prepared and stored with greater storage stability. However, their combination will allow for substantial release of hydrophilic payload from the liposomes under externally applied light.


Sensing global changes in local patterns of energy consumption in cities during the early stages of the COVID-19 pandemic.
COVID-19, and the wider social and economic impacts that a global pandemic entails, led to unprecedented reductions in energy consumption globally. Whilst estimates of changes in energy consumption have emerged at the national scale, detailed sub-regional estimates to allow for global comparisons are less developed. Using night-time light satellite imagery from December 2019-June 2020 across 50 of the world's largest urban conurbations, we provide high resolution estimates (450 m2) of spatio-temporal changes in urban energy consumption in response to COVID-19. Contextualising this imagery with modelling based on indicators of mobility, stringency of government response, and COVID-19 rates, we provide novel insights into the potential drivers of changes in urban energy consumption during a global pandemic. Our results highlight the diversity of changes in energy consumption between and within cities in response to COVID-19, moderating dominant narratives of a shift in energy demand away from dense urban areas. Further modelling highlights how the stringency of the government's response to COVID-19 is likely a defining factor in shaping resultant reductions in urban energy consumption.


Enantiospecificity in achiral zeolites for asymmetric catalysis.
This article highlights the recent fundamental study in using achiral and chiral porous materials for the potential applications in asymmetric catalysis. Thanks to the new-generation synchrotron X-ray powder diffraction (SXRD) facilities, we reveal the presence of the unique 'chiral region' in achiral zeolites with the MFI topology. Both the inherent site-isolation effect of the active sites and internal confinement restraints in zeolites are critical for creating 'chiral regions' that can aid the design of more enantioselective catalytic reactions. We also offer an outlook on the challenges and opportunities of this research area.


Flash illusions induced by visual, auditory, and audiovisual stimuli.
When two objects are flashed at one location in close temporal proximity in the visual periphery, an intriguing illusion occurs whereby a single flash presented concurrently at another location appears to flash twice (the visual double-flash illusion: Chatterjee et al., 2011, Wilson & Singer, 1981). Here, for the first time, we investigate the time course of the effect, and directly compare it to the time course of the auditory (sound-induced flash illusion) effect, for both fission (single test flash, double inducer) and fusion (double test flash, single inducer) conditions, across stimulus onset asynchronies (SOAs) of 30 to 250 ms. In addition, using a novel audiovisual stimulus, we directly compare the cue strength of the two modalities, and whether they are additive in effect. The results show that the time course of fission and fusion is different for visual inducers, but not for auditory inducers. In audiovisual conditions, in situations of uncertainty, observers tended to follow the more reliable (auditory) cue. There was little evidence for a superadditive effect of auditory and visual cues; rather, observers tended to follow one or the other modality. The results suggest that the visually induced flash illusion and the auditory-induced effect may both stem from perceptual uncertainty, with the difference in time courses attributable to the lower temporal resolution of vision compared to audition.


Probing ultrafast excitation energy transfer of the chlorosome with exciton-phonon variational dynamics.
The chlorosome antenna complex is a fascinating structure which due to its immense scale, accurate simulation of excitation energy transfer (EET) dynamics supposes a genuine computational challenge. Resonant vibronic modes have been recently identified in 2D spectra of the chlorosome which motivates our present endeavour of modelling electronic and vibrational degrees of freedom on an equal footing. Following the Dirac-Frenkel time-dependent variational principle, we exploit a general theory of polaron dynamics in two-dimensional lattices based on the Holstein molecular crystal model and investigate a single rod model of pigment aggregates. Unlike reduced formalisms, explicit integration of the degrees of freedom of both the system and the bath requires extensive computational resources. We exploit the architecture of graphic processor units (GPUs) by implementing our simulations on this platform. The simulation of dynamic properties of hundreds or even thousands of pigments is thus achievable in just a few hours. The potential investigation and design of natural or engineered two-dimensional pigment networks can thus be accommodated. Due to the lack of consensus regarding the precise arrangement of chromophores in the chlorosome, helicity and dimerization are investigated independently, extracting their contributions to both optical and EET properties. The presence of dimerization is found to slow down the delocalization process. Exciton delocalization is completed in 100 fs in a single rod aggregate whose dimensions (20 nm) fairly exceed the estimated extent of a coherent domain. Ultrafast energy relaxation in the exciton manifold occurs in 50 fs and the duration of super-diffusive transport is found to last for about 80 fs.


Demonstration of the transmembrane nature of the acetylcholine receptor by labeling with anti-receptor antibodies.
Antibodies raised in rabbits to Triton-solubilized, purified acetylcholine receptor from Torpedo californica were used to immunospecifically label intact T. californica electroplaque membrane vesicles attached to cover slips and oriented with the extracellular face of the synaptic membrane facing outward. Hemocyanin conjugated to Protein A was then used as a marker, making the antibody binding visible at the electron microscope level. Parallel labeling experiments were performed on vesicles attached to cover slips and sheared by sonication, leaving their cytoplasmic faces fully exposed to the labeling solution. While differences in antibody populations among different rabbits were observed, antigenic determinants of the receptor were present on both faces of the membrane, with those on the extracellular side more numerous than those on the cytoplasmic side, demonstrating the transmembrane nature of the receptor molecule.


Body part identification in 1- to 2-year-old children.
The purpose of this study was to examine the developmental sequence of body part identification in very young children, 11 to 25 months of age. In the first part of the study, 113 children, divided into five age groups (12-month-olds, 15-month-olds, 18-month-olds, 21-month-olds, and 24-month-olds), were asked to point to 20 body parts on a doll. The results indicated a positive correlation between number of parts correctly identified and increasing age. No sex differences or Sex X Age interactions were found. In the second part of the study, the difference between pointing to body parts on the self and pointing to body parts on a doll was examined in two groups of 2-year-olds. The results indicated no significant difference between the ability to point to body parts on a doll and the ability to point to body parts on the self. Factors that may contribute to the development of body part identification in 1- to 2-year-olds and the sequence in which body parts are learned are discussed. The results help provide diagnostic criteria for children with suspected delays in cognitive, language, or body scheme development.


Antimicrobial resistance and the standards of the World Organisation for Animal Health.
Antimicrobial resistance and the use of antimicrobial agents in veterinary medicine are complex issues that are currently a source of major international concern. It is therefore essential for the World Organisation for Animal Health (OIE) to consider this issue, while at the same time continuing to address the problem of zoonotic diseases. That is why the OIE has included objectives for veterinary drugs, especially antimicrobials, in its Strategic Plan. The OIE plays an active part in discussions on this subject in conjunction with other international organisations working in this field, such as the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO). Furthermore, the OIE has adopted guidelines both for defining harmonised methodologies for antimicrobial resistance surveillance and monitoring and for helping countries to conduct a risk analysis tailored to their situation and to take appropriate management measures. The OIE has included this issue in its programme of assistance to countries by offering them structural enhancement tools: the Tool for the Evaluation of Performance of Veterinary Services (O1E PVS Tool), PVS Gap Analysis, veterinary legislation support, and training for veterinary national focal points, with the aid of its Collaborating Centres for veterinary medicinal products. Only by mobilising all countries to improve the quality of antimicrobials, to introduce antimicrobial resistance surveillance and to implement measures for the responsible and prudent use of antimicrobials, will it be possible to halt the spread of antimicrobial resistance.


Patient perspective of systemic lupus erythematosus in relation to health-related quality of life concepts: a qualitative study.
We sought to understand the patients' 'lived experiences of systemic lupus erythematosus (SLE)' by exploring, describing and clarifying the patients' perspective of how they felt about having SLE and how the disease impacted on their lives, both positively and/or negatively. An interpretative phenomenological approach was employed. Semi-structured interviews were undertaken with 30 females with SLE across a wide range of age (21 to 75 years), disease characteristics, disease duration (1 to 28 years) and ethnicity (Whites, South Asians). Eleven themes emerged as important to the patients: prognosis and course of disease; body image; effects of treatment; emotional difficulties; inability to plan due to disease unpredictability; fatigue; pain; career prospects and loss of income; memory loss/concentration; reliance on others to assist with everyday tasks; and pregnancy issues. Most patients reported a negative impact of SLE on their lives although a few patients found positive aspects to having SLE. The findings of this study identified themes important to patients with SLE and these themes will inform clinicians on the patients' perspective of having SLE.


Effect of zinc fertilization on cadmium toxicity in durum and bread wheat grown in zinc-deficient soil.
The effect of increasing application of zinc (Zn) and cadmium (Cd) on shoot dry weight and shoot concentrations of Zn and Cd was studied in bread and durum wheat cultivars. Plants were grown in severely Zn-deficient calcareous soil treated with increasing Zn (0 and 10 mg kg(-1) soil) and Cd (0, 10 and 25 mg kg(-1) soil) and harvested after 35 and 65 days of growth under greenhouse conditions. Growing plants without Zn fertilization caused severe depression in shoot growth, especially in durum wheat and at high Cd treatment. Cadmium treatments resulted in rapid development of necrotic patches on the base and sheath parts of the oldest leaves of both wheat cultivars, but symptoms were more severe in durum wheat and under Zn deficiency. Decreases in shoot dry weight from increasing Cd application were more severe in Zn-deficient plants. Severity of Cd toxicity symptoms in durum and bread wheat at different Zn treatments did not show any relation to the Cd concentrations in shoot. Increasing Cd application to Zn-deficient plants tended to decrease Zn concentrations in Zn-deficient plants, whereas in plants with adequate Zn, concentrations of Zn were either not affected or increased by Cd. The results show that durum wheat was more sensitive to both Zn deficiency and Cd toxicity as compared to bread wheat. Cadmium toxicity in the shoot was alleviated by Zn treatment, but this was not accompanied by a corresponding decrease in shoot concentrations of Cd. Our results are compatible with the hypothesis that Zn protects plants from Cd toxicity by improving plant defense against Cd-induced oxidative stress and by competing with Cd for binding to critical cell constituents such as enzymes and membrane protein and lipids.


Service user preferences for diabetes education in remote and rural areas of the Highlands and Islands of Scotland.
Diabetes prevalence in Scotland is 5.3%, with type 2 diabetes accounting for 86.7% of all cases in the National Health Service Highlands health board area and 85.7% in the Western Isles. Structured education is a key component in the management of this chronic disease. However, current group session models are less feasible in lower-population non-urban environments due to distance, participant numbers and access to appropriately trained healthcare professionals. Group sessions may also be a less attractive option in small communities, where people tend to have close day-to-day personal contact. This study assesses the access and delivery preferences of remote and rural service users in the Highlands and Western Isles to structured diabetes education programs. The study used a mixed methods approach of focus groups and questionnaires with people with type 2 diabetes in the Highlands and Islands of Scotland. Both modes of participation were designed to explore perception of diabetes knowledge, diabetes education and use of technology. One-to-one delivery was the delivery method of choice; however, there was a preference for a digital approach over group education sessions. Service users expressed a strong desire to be able to learn at their own pace, when and where they wanted to, and with no requirement to travel. To address these requirements an online resource, providing access to both learning sessions and trusted sources of information, was the preferred mode of delivery. People with type 2 diabetes living in remote and rural areas of the Scottish Highlands and Islands who already use the internet are receptive to the use of digital technology for delivery of diabetes education and are interested in learning more about management of their condition through this medium. They believe that a technology approach will provide them with more control over the pace of learning, and where and when this learning can take place.


The Tough Guy prehospital experience: patterns of injury at a major UK endurance event.
Data from mass gathering events help when planning allocation of resources and in setting standards of care. There is currently a lack of data from the UK. To determine the frequency of injuries and hospital transfer rates at a large outdoor endurance event. 251 patient attendances from four consecutive events over 2 years (two summers two winters; 2006-2007) were analysed. 1%-2% of contenders required medical help. Hypothermia (n = 84), soft tissue problems (n = 71) and musculoskeletal problems (n = 51) were the most common conditions encountered. 4% of patients required immediate transfer to the hospital. The medical team was able to prevent 31 hospital transfers, which represents a reduction of 78%. 13% of cases specifically required a doctor who was able to prevent more immediate hospital transfers than other care givers. The majority of injuries were classified as minor (n = 228), with the remaining as intermediate (n = 23); there were no life-threatening injuries or deaths. No patient required intravenous fluid. Overall, in winter, more patients were treated when compared with summer (157 vs 94). There were significantly more retirements in winter (69 vs 22, p<0.001), although hospital transfer rates were similar. Medical teams should plan for casualty rates of 1%-2% of competitors and hospital transfer rates of approximately 5% of patients treated. Outdoor events in winter create more casualties than in summer and require greater resources. Trauma and exposure injuries are common; critical illness is uncommon. An adequately equipped and skilled medical team reduces hospital admissions.


The Impact of Erythropoietin on Short- and Long-Term Kidney-Related Outcomes in Neonates of Extremely Low Gestational Age. Results of a Multicenter, Double-Blind, Placebo-Controlled Randomized Clinical Trial.
To evaluate whether extremely low gestational age neonates (ELGANs) randomized to erythropoietin have better or worse kidney-related outcomes during hospitalization and at 22-26 months of corrected gestational age (cGA) compared with those randomized to placebo. We performed an ancillary study to a multicenter double-blind, placebo-controlled randomized clinical trial of erythropoietin in ELGANs. The prevalence of severe (stage 2 or 3) acute kidney injury (AKI) was 18.2%. We did not find a statistically significant difference between those randomized to erythropoietin vs placebo for in-hospital primary (severe AKI) or secondary outcomes (any AKI and serum creatinine/cystatin C values at days 0, 7, 9, and 14). At 22-26 months of cGA, 16% of the cohort had an estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m2, 35.8% had urine albumin/creatinine ratio >30 mg/g, 23% had a systolic blood pressure (SBP) >95th percentile for age, and 40% had a diastolic blood pressure (DBP) >95th percentile for age. SBP >90th percentile occurred less often among recipients of erythropoietin (P < .04). This association remained even after controlling for gestational age, site, and sibship (aOR 0.6; 95% CI 0.39-0.92). We did not find statistically significant differences between treatment groups in eGFR, albumin/creatinine ratio, rates of SBP >95th percentile, or DBP >90th or >95th percentiles at the 2 year follow-up visit. ELGANs have high rates of in-hospital AKI and kidney-related problems at 22-26 months of cGA. Recombinant erythropoietin may protect ELGANs against long-term elevated SBP but does not appear to protect from AKI, low eGFR, albuminuria, or elevated DBP at 22-26 months of cGA.


Bioelectrical impedance and zoometry for body composition analysis in domestic cats.
Zoometric measurements and bioelectrical impedance analysis were evaluated as methods of body composition determination in healthy cats. Zoometric and impedance measurements were taken on 22 anesthetized adult cats of various ages, genders, breeds, and body weights. The cats were then euthanatized. The bodies were processed through a tissue homogenizer and free-catch specimens were taken, freeze-dried, and analyzed for total body water, protein, fat, potassium, and ash content. Stepwise regression analysis was implemented to identify statistically significant relationships between the chemically determined dependent variables (total body water, protein, potassium, fat-free mass, fat mass, and percent body fat) and the zoometric measurements, with or without bioelectrical impedance analysis. Statistical analysis revealed high correlations between the dependent variables and the corresponding predicted values of those variables. Body weight alone was a poor predictor of body composition in these cats. On the basis of these findings, we suggest that zoometric and bioelectrical impedance measurements may serve as practical, noninvasive, simple, and accurate methods for estimating body composition in domestic cats.


Enhanced three-dimensional integral imaging system by use of double display devices.
We propose an enhanced three-dimensional (3D) integral imaging system using multiple display devices. Experimental results with double devices prove the improvement in the image depth for a given image quality. We present experiments on an enhanced 3D integral imaging system using double display devices, in which two 3D subimages that cover different depth ranges are separately generated in each device, and then they are combined with a beam splitter to reconstruct the whole 3D image with an enhanced depth of view. In a similar manner, the double-device system can also be used to obtain a wider viewing angle by combining two images with different viewing angle ranges. We discuss the possibility of 3D integral imaging systems using multiple display devices as extensions of the system with double display devices.


Early Insights from Statistical and Mathematical Modeling of Key Epidemiologic Parameters of COVID-19.
We report key epidemiologic parameter estimates for coronavirus disease identified in peer-reviewed publications, preprint articles, and online reports. Range estimates for incubation period were 1.8-6.9 days, serial interval 4.0-7.5 days, and doubling time 2.3-7.4 days. The effective reproductive number varied widely, with reductions attributable to interventions. Case burden and infection fatality ratios increased with patient age. Implementation of combined interventions could reduce cases and delay epidemic peak up to 1 month. These parameters for transmission, disease severity, and intervention effectiveness are critical for guiding policy decisions. Estimates will likely change as new information becomes available.


Prophylactic Palmitoylethanolamide Prolongs Survival and Decreases Detrimental Inflammation in Aged Mice With Bacterial Meningitis.
Easy-to-achieve interventions to promote healthy longevity are desired to diminish the incidence and severity of infections, as well as associated disability upon recovery. The dietary supplement palmitoylethanolamide (PEA) exerts anti-inflammatory and neuroprotective properties. Here, we investigated the effect of prophylactic PEA on the early immune response, clinical course, and survival of old mice after intracerebral E. coli K1 infection. Nineteen-month-old wild type mice were treated intraperitoneally with two doses of either 0.1 mg PEA/kg in 250 μl vehicle solution (n = 19) or with 250 μl vehicle solution only as controls (n = 19), 12 h and 30 min prior to intracerebral E. coli K1 infection. The intraperitoneal route was chosen to reduce distress in mice and to ensure exact dosing. Survival time, bacterial loads in cerebellum, blood, spleen, liver, and microglia counts and activation scores in the brain were evaluated. We measured the levels of IL-1β, IL-6, MIP-1α, and CXCL1 in cerebellum and spleen, as well as of bioactive lipids in serum in PEA- and vehicle-treated animals 24 h after infection. In the absence of antibiotic therapy, the median survival time of PEA-pre-treated infected mice was prolonged by 18 h compared to mice of the vehicle-pre-treated infected group (P = 0.031). PEA prophylaxis delayed the onset of clinical symptoms (P = 0.037). This protective effect was associated with lower bacterial loads in the spleen, liver, and blood compared to those of vehicle-injected animals (P ≤ 0.037). PEA-pre-treated animals showed diminished levels of pro-inflammatory cytokines and chemokines in spleen 24 h after infection, as well as reduced serum concentrations of arachidonic acid and of one of its metabolites, 20-hydroxyeicosatetraenoic acid. In the brain, prophylactic PEA tended to reduce bacterial titers and attenuated microglial activation in aged infected animals (P = 0.042). Our findings suggest that prophylactic PEA can counteract infection associated detrimental responses in old animals. Accordingly, PEA treatment slowed the onset of infection symptoms and prolonged the survival of old infected mice. In a clinical setting, prophylactic administration of PEA might extend the potential therapeutic window where antibiotic therapy can be initiated to rescue elderly patients.


Pathological findings in reduction mammoplasty specimens: A South African perspective.
Preoperative, intraoperative and follow-up guidelines for managing occult carcinoma in reduction mammoplasty specimens are scant We retrospectively analysed the records and pathology reports of 200 patients who had undergone reduction mammoplasty at two major public hospitals in Johannesburg, South Africa, during 2009-2014. Demographic data, their history of breast cancer and preoperative screening, the surgical techniques used and pathological reports were included. In all cases preoperative screening for breast cancer had been negative. All the patients were female, mean age 37.1 years, range 20-84 (standard deviation 11.9). All reductions were performed using standard techniques. Benign pathology was observed in 98 patients (49%) and malignant pathology in four (2%). The most common benign pathology observed was fibrocystic disease, and the most common malignant pathology ductal carcinoma in situ. Patient age correlated significantly with benign or malignant disease. Reduction mammoplasty produces tissue that should always be sent for pathological assessment. Patients should be stratified by risk, as doing so helps in selecting both the surgical setting and the approach to pathological analysis of the specimen. While the incidence of occult carcinoma in reduction mammoplasty specimens is low, all patients undergoing the procedure should be informed that tissue will be sent for pathological examination, allowing them to prepare to receive possible news of breast cancer and be adequately equipped for subsequent decision-making.


Outcomes of liver transplantation for hepatitis B: a single-center study of 35 patients.
Results of liver transplantation (LT) for hepatitis B (HBV) have improved in the past decade but recently drug resistance has been described, the clinical significance of which is unclear. The aims of this study were to evaluate outcomes of LT for HBV and describe the prevalence of drug resistance. A retrospective chart analysis and review of the organ transplant database was performed to identify all patients transplanted for HBV between December 1982 and April 2004 who survived more than 3 months. Thirty-five patients were transplanted for HBV during this period: 27 men and 8 women. Median age at LT was 48.8 years (range 18.9 to 74.3). Four patients were transplanted for fulminant liver failure and 31 for decompensated cirrhosis. Intramuscular HBIG was administered to 8 patients and intravenous HBIG to 32 patients, data were unavailable for three patients. Lamivudine was prescribed for 18 patients (58%) pre-OLT and for 31 patients (88.6%) post-LT. Drug-resistant HBV developed in two patients (5.71%) receiving lamivudine and HBIG. Adefovir substitution resulted in improvement in liver function tests, in HBV DNA and in histology in both patients. Twenty-five patients are currently alive with and 1-year survival of 95% and a 5-year survival of 75%. Causes of death were respiratory failure (n = 3), metastatic cancer of unknown primary (n = 2), renal failure (n = 2), sepsis (n = 1), cerebrovascular accident (n = 1), and cerebral edema (n = 1). LT for HBV shows survival rates comparable to other liver transplant recipients. Lamivudine resistance was rare in this series but responded to adefovir substitution.


Predicting poor outcomes in children aged 1-12 with respiratory tract infections: A systematic review.
Demand for NHS services is high and rising. In children respiratory tract infections (RTI) are the most common reason for consultation with primary care. Understanding which features are associated with good and poor prognosis with RTI will help develop interventions to support parents manage illness. To identify symptoms, signs, and investigation results associated with good and poor prognosis, and clinical decision making in children aged 1-12 years with RTI symptoms, at home and presenting to ambulatory care. Systematic literature review. We searched MEDLINE, EMBASE, Cinahl, Web of Science and the Cochrane database of systematic reviews for studies of children aged 1 to 12 years with a RTI or related condition reporting symptoms, signs and investigation results associated with prognostic outcomes. Quality was assessed using the QUIPS tool. We included 27 studies which included 34802 children and measured 192 factors. Nine studies explored future outcomes and the remainder explored clinical management from the initial consultation with the health services. None were conducted in a home setting. Respiratory signs, vomiting, fever, dehydration and tachycardia at the initial contact were associated with future hospitalisation. Little evidence was available for other outcomes. Some evidence is available to clinicians to stratify risk of, future hospitalisation, but not of other prognostic outcomes. There is little evidence available to parents to identify children at risk of poor prognosis. Research is needed into whether poor prognosis can be predicted by parents in the home.


Contribution of Mitophagy to Cell-Mediated Mineralization: Revisiting a 50-Year-Old Conundrum.
Biomineralization in vertebrates is initiated via amorphous calcium phosphate (ACP) precursors. These precursors infiltrate the extracellular collagen matrix where they undergo phase transformation into intrafibrillar carbonated apatite. Although it is well established that ACP precursors are released from intracellular vesicles through exocytosis, an unsolved enigma in this cell-mediated mineralization process is how ACP precursors, initially produced in the mitochondria, are translocated to the intracellular vesicles. The present study proposes that mitophagy provides the mechanism for transfer of ACP precursors from the dysfunctioned mitochondria to autophagosomes, which, upon fusion with lysosomes, become autolysosomes where the mitochondrial ACP precursors coalesce to form larger intravesicular granules, prior to their release into the extracellular matrix. Apart from endowing the mitochondria with the function of ACP delivery through mitophagy, the present results indicate that mitophagy, triggered upon intramitochondrial ACP accumulation in osteogenic lineage-committed mesenchymal stem cells, participates in the biomineralization process through the BMP/Smad signaling pathway.


Diagnosis and treatment of pancreatic exocrine insufficiency.
Pancreatic exocrine insufficiency (PEI), defined as a secretion of pancreatic enzymes and bicarbonate insufficient to maintain a normal digestion, is a frequent but frequently underdiagnosed and undertreated condition. PEI may be secondary to different pancreatic diseases and extrapancreatic conditions. Recent data support the high clinical relevance of PEI and its treatment. Together with symptoms of maldigestion, PEI is associated with nutritional deficiencies leading to osteoporosis, low-trauma fractures, sarcopenia and increased mortality. No single widely available test allows to diagnose PEI accurately. Diagnosis of PEI requires the evaluation of symptoms, nutritional markers and a noninvasive pancreatic function test in the appropriate clinical context. Pancreatic enzyme replacement therapy (PERT) improves digestion, symptoms, nutritional status and quality of life of patients with PEI. In addition, PERT is associated with a longer survival in patients with unresectable pancreatic cancer and after surgery for pancreatic cancer or chronic pancreatitis. Awareness of PEI in different clinical conditions is required. Nutritional advice and appropriate PERT are mandatory to reduce the morbidity and mortality associated with PEI. Further studies on the clinical impact of PEI and its treatment are needed, especially in diseases other than chronic pancreatitis and cystic fibrosis.


Interpreting and reporting fracture classification and operation type in hip fracture: implications for research studies and routine national audits.
This study explores data quality in operation type and fracture classification recorded as part of a large research study and a national audit with an independent review. At 17 centres, an expert surgeon reviewed a randomly selected subset of cases from their centre with regard to fracture classification using the AO system and type of operation performed. Agreement for these variables was then compared with the data collected during conduct of the World Hip Trauma Evaluation (WHiTE) cohort study. Both types of surgery and fracture classification were collapsed to identify the level of detail of reporting that achieved meaningful agreement. In the National Hip Fracture Database (NHFD), the types of operation and fracture classification were explored to identify the proportion of "highly improbable" combinations. The records were reviewed for 903 cases. Agreement for the subtypes of extracapsular fracture was poor; most centres achieved no better than "fair" agreement. When the classification was collapsed to a single option for "extracapsular" fracture, only four centres failed to have at least "moderate" agreement. There was only "moderate" agreement for the subtypes of intracapsular fracture, which improved to "substantial" when collapsed to "intracapsular". Subtrochanteric fracture types were well reported with "substantial" agreement. There was near "perfect" agreement for internal fixation procedures. "Perfect" or "substantial" agreement was achieved when the type of arthroplasty surgery was reported at the level of "hemiarthroplasty" and "total hip replacement". When reviewing data submitted to the NHFD, a minimum of 5.2% of cases contained "highly improbable" procedures for the stated fracture classification. The complexity of collecting fracture classification data at a national scale compromises the accuracy with which detailed classification systems can be reported. Data around type of surgery performed show similar tendencies. Data capture, reporting, and interpretation in future studies must take this into account. Cite this article: Bone Joint J 2019;101-B:1292-1299.


The interplay between structure and function in redox-based resistance switching.
We report a study of the relationship between oxide microstructure at the scale of tens of nanometres and resistance switching behaviour in silicon oxide. In the case of sputtered amorphous oxides, the presence of columnar structure enables efficient resistance switching by providing an initial structured distribution of defects that can act as precursors for the formation of chains of conductive oxygen vacancies under the application of appropriate electrical bias. Increasing electrode interface roughness decreases electroforming voltages and reduces the distribution of switching voltages. Any contribution to these effects from field enhancement at rough interfaces is secondary to changes in oxide microstructure templated by interface structure.


Proteolytic processing of the Cryptosporidium glycoprotein gp40/15 by human furin and by a parasite-derived furin-like protease activity.
The apicomplexan parasite Cryptosporidium causes diarrheal disease worldwide. Proteolytic processing of proteins plays a significant role in host cell invasion by apicomplexan parasites. In previous studies, we described gp40/15, a Cryptosporidium sp. glycoprotein that is proteolytically cleaved to yield two surface glycopeptides (gp40 and gp15), which are implicated in mediating infection of host cells. In the present study, we showed that biosynthetically labeled gp40/15 is processed in Cryptosporidium parvum-infected HCT-8 cells. We identified a putative furin cleavage site RSRR downward arrow in the deduced amino acid sequence of gp40/15 from C. parvum and from all Cryptosporidium hominis subtypes except subtype 1e. Both human furin and a protease activity present in a C. parvum lysate cleaved recombinant C. parvum gp40/15 protein into 2 peptides, identified as gp40 and gp15 by size and by immunoreactivity with specific antibodies. C. hominis gp40/15 subtype 1e, in which the RSRR sequence is replaced by ISKR, has an alternative furin cleavage site (KSISKR downward arrow) and was also cleaved by both furin and the C. parvum lysate. Site-directed mutagenesis of the C. parvum RSRR sequence to ASRR resulted in inhibition of cleavage by furin and the C. parvum lysate. Cleavage of recombinant gp40/15 and a synthetic furin substrate by the C. parvum lysate was inhibited by serine protease inhibitors, by the specific furin inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone (Dec-RVKR-cmk), and by calcium chelators, suggesting that the parasite expresses a Ca2+ dependent, furin-like protease activity. The furin inhibitor Dec-RVKR-cmk decreased C. parvum infection of HCT-8 cells, suggesting that a furin-like protease activity may be involved in mediating host-parasite interactions.


Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy.
We describe the generation and characterization of the first inducible 'fatless' model system, the FAT-ATTAC mouse (fat apoptosis through targeted activation of caspase 8). This transgenic mouse develops identically to wild-type littermates. Apoptosis of adipocytes can be induced at any developmental stage by administration of a FK1012 analog leading to the dimerization of a membrane-bound, adipocyte-specific caspase 8-FKBP fusion protein. Within 2 weeks of dimerizer administration, FAT-ATTAC mice show near-knockout levels of circulating adipokines and markedly reduced levels of adipose tissue. FAT-ATTAC mice are glucose intolerant, have diminished basal and endotoxin-stimulated systemic inflammation, are less responsive to glucose-stimulated insulin secretion and show increased food intake independent of the effects of leptin. Most importantly, we show that functional adipocytes can be recovered upon cessation of treatment, allowing the study of adipogenesis in vivo, as well as a detailed examination of the importance of the adipocyte in the regulation of multiple physiological functions and pathological states.


Molecular phylogenetic analysis supports a Gondwanan origin of the Hyriidae (Mollusca: Bivalvia: Unionida) and the paraphyly of Australasian taxa.
The freshwater mussel family Hyriidae (Mollusca: Bivalvia: Unionida) has a disjunct trans-Pacific distribution in Australasia and South America. Previous phylogenetic analyses have estimated the evolutionary relationships of the family and the major infra-familial taxa (Velesunioninae and Hyriinae: Hyridellini in Australia; Hyriinae: Hyriini, Castaliini, and Rhipidodontini in South America), but taxon and character sampling have been too incomplete to support a predictive classification or allow testing of biogeographical hypotheses. We sampled 30 freshwater mussel individuals representing the aforementioned hyriid taxa, as well as outgroup species representing the five other freshwater mussel families and their marine sister group (order Trigoniida). Our ingroup included representatives of all Australian genera. Phylogenetic relationships were estimated from three gene fragments (nuclear 28S, COI and 16S mtDNA) using maximum parsimony, maximum likelihood, and Bayesian inference, and we applied a Bayesian relaxed clock model calibrated with fossil dates to estimate node ages. Our analyses found good support for monophyly of the Hyriidae and the subfamilies and tribes, as well as the paraphyly of the Australasian taxa (Velesunioninae, (Hyridellini, (Rhipidodontini, (Castaliini, Hyriini)))). The Hyriidae was recovered as sister to a clade comprised of all other Recent freshwater mussel families. Our molecular date estimation supported Cretaceous origins of the major hyriid clades, pre-dating the Tertiary isolation of South America from Antarctica/Australia. We hypothesize that early diversification of the Hyriidae was driven by terrestrial barriers on Gondwana rather than marine barriers following disintegration of the super-continent.


Activation of AKT by O-linked N-acetylglucosamine induces vascular calcification in diabetes mellitus.
Vascular calcification is a serious cardiovascular complication that contributes to the increased morbidity and mortality of patients with diabetes mellitus. Hyperglycemia, a hallmark of diabetes mellitus, is associated with increased vascular calcification and increased modification of proteins by O-linked N-acetylglucosamine (O-GlcNAcylation). We sought to determine the role of protein O-GlcNAcylation in regulating vascular calcification and the underlying mechanisms. Low-dose streptozotocin-induced diabetic mice exhibited increased aortic O-GlcNAcylation and vascular calcification, which was also associated with impaired aortic compliance in mice. Elevation of O-GlcNAcylation by administration of Thiamet-G, a potent inhibitor for O-GlcNAcase that removes O-GlcNAcylation, further accelerated vascular calcification and worsened aortic compliance of diabetic mice in vivo. Increased O-GlcNAcylation, either by Thiamet-G or O-GlcNAcase knockdown, promoted calcification of primary mouse vascular smooth muscle cells. Increased O-GlcNAcylation in diabetic arteries or in the O-GlcNAcase knockdown vascular smooth muscle cell upregulated expression of the osteogenic transcription factor Runx2 and enhanced activation of AKT. O-GlcNAcylation of AKT at two new sites, T430 and T479, promoted AKT phosphorylation, which in turn enhanced vascular smooth muscle cell calcification. Site-directed mutation of AKT at T430 and T479 decreased O-GlcNAcylation, inhibited phosphorylation of AKT at S473 and binding of mammalian target of rapamycin complex 2 to AKT, and subsequently blocked Runx2 transactivity and vascular smooth muscle cell calcification. O-GlcNAcylation of AKT at 2 new sites enhanced AKT phosphorylation and activation, thus promoting vascular calcification. Our studies have identified a novel causative effect of O-GlcNAcylation in regulating vascular calcification in diabetes mellitus and uncovered a key molecular mechanism underlying O-GlcNAcylation-mediated activation of AKT.


Validation of the Death and Dying Distress Scale (DADDS-Sp) in a population with advanced cancer in Chile.
Developing instruments to screen for relevant aspects of advanced illness is key to identifying palliative needs and evaluating the effectiveness of interventions in this population. The objective of this project is to validate the Death and Dying Distress Scale in Spanish (DADDS-Sp) for screening anxiety about death and evaluating psychometric properties for people with advanced cancer. DADDS is a 15-item self-administered questionnaire that assesses thoughts and feelings related to death and the process of dying. A cross-sectional, descriptive, psychometric validation study was conducted in two cancer centres in Santiago de Chile. Included were patients over 18 years of age with incurable and/or metastatic cancer, fluent in Spanish, and a life expectancy of more than 3 months. Reliability was analysed using Cronbach's alpha, and confirmatory factor analysis was performed following the model of the original scale. Seventy four patients participated in the study. The median age was 63 years. Of the sample, 59% identified themselves as women. On average, participants reported low anxiety about death (mean = 21, SD = 18). Women have more death anxiety. The reliability analysis yielded a value of α = 0.93 (IC = 0.91-0.95). Factor analysis with a one-factor structure yielded Comparative Fit Index (CFI) = 0. 0.972, Root Mean Square Error of Approximation (RMSEA) = 0.092, Standardized Root Mean Square Residual (SRMR) = 0.085 and Tucker-Lewis Index (TLI) = 0.968. The model with a two-factor structure yielded CFI = 0.989, RMSEA = 0.059, SRMR = 0.075 and TLI = 0.987, suggesting that the two-factor model has a better fit for the data studied. DADDS-Sp is psychometrically valid for use in a Spanish-speaking population, yielding high reliability and internal consistency. A majority of the Chilean patients reported a low level of anxiety about death although about 10% presented with severe anxiety, so their identification for adequate clinical management is fundamental.


Graph Spectral Characterization of Brain Cortical Morphology.
The human brain cortical layer has a convoluted morphology that is unique to each individual. Characterization of the cortical morphology is necessary in longitudinal studies of structural brain change, as well as in discriminating individuals in health and disease. A method for encoding the cortical morphology in the form of a graph is presented. The design of graphs that encode the global cerebral hemisphere cortices as well as localized cortical regions is proposed. Spectral metrics derived from these graphs are then studied and proposed as descriptors of cortical morphology. As proof-of-concept of their applicability in characterizing cortical morphology, the metrics are studied in the context of hemispheric asymmetry as well as gender dependent discrimination of cortical morphology.


Effects of defaunation on in situ dry matter and nitrogen disappearance in steers and growth of lambs.
Trials were conducted to determine effects of defaunation procedures on protozoal concentrations and in situ nutrient disappearance in steers and to determine effects of defaunation and supplemental protein source on performance of lambs. Four ruminally cannulated steers were isolated from other ruminants and fed a dehydrated alfalfa-cracked corn diet for three periods with four replicates (steers) per period. Treatments were as follows: 1) control (no defaunation), 2) dosing fasted steers for two consecutive days with 40 g dioctyl sulfosuccinate (DSS) and 3) daily feeding of 40 g DSS to defaunated, nonfasted steers. Ten days post-dosing with DSS (treatment 2), three steers were free of protozoa but one steer still had a ruminal concentration of .6 x 10(4) protozoa/ml. Compared to steers prior to defaunation, treating steers for 2 d with DSS decreased (P less than .05) both in situ soybean meal (SBM) N disappearance at 3, 6 and 9 h of incubation and in situ orchardgrass DM disappearance at 24 h of incubation. Feeding 40 g of DSS daily for 10 d was not successful in maintaining the rumen free of protozoa. Thirty crossbred Targhee lambs (avg wt, 25 kg) were defaunated with DSS and allotted by BW and sex to five treatments: 1) defaunated, fish meal supplemented at 9.5% dietary CP (FM-9.5% CP), 2) defaunated, SBM-9.5% CP, 3) refaunated, FM-9.5% CP, 4) refaunated, SBM-9.5% CP and 5) refaunated SBM-12% CP. Defaunated lambs remained free of protozoa during the 56-d performance trial that was initiated 24 d after the defaunation procedure.(ABSTRACT TRUNCATED AT 250 WORDS)


NI(ii) phosphine and phosphide complexes supported by a PNP-pyrrole pincer ligand.
The reaction between [(PNpyrP)NiCl] (1, PNpyrP = 2,5-bis((di-iso-propylphosphino)-methyl)-1H-pyrrolide) and TlPF6 in the presence of a monodentate phosphine ligand led to cationic nickel phosphine and phosphite complexes, [(PNpyrP)Ni(PHPh2)][PF6] (2), [(PNpyrP)Ni(PMe3)][PF6] (3), and [(PNpyrP)Ni{P(OMe)3}][PF6] (4). Compound 2 can be deprotonated resulting in the generation of a terminal phosphido complex, [(PNpyrP)Ni(PPh2)] (5). When 3 is subjected to a base, a methyl proton of PMe3 is abstracted to afford [(PNpyrP)Ni(CH2PMe2)] (6), containing a methylene bridge between Ni and the external phosphine. Compounds 2-6 were characterized by single crystal X-ray diffraction in addition to multi-nuclear NMR spectroscopy and elemental analysis.


Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity.
Alterations in the apoptosis of immune cells have been associated with autoimmunity. Here, we have identified a homozygous missense mutation in the gene encoding the base excision repair enzyme Nei endonuclease VIII-like 3 (NEIL3) that abolished enzymatic activity in 3 siblings from a consanguineous family. The NEIL3 mutation was associated with fatal recurrent infections, severe autoimmunity, hypogammaglobulinemia, and impaired B cell function in these individuals. The same homozygous NEIL3 mutation was also identified in an asymptomatic individual who exhibited elevated levels of serum autoantibodies and defective peripheral B cell tolerance, but normal B cell function. Further analysis of the patients revealed an absence of LPS-responsive beige-like anchor (LRBA) protein expression, a known cause of immunodeficiency. We next examined the contribution of NEIL3 to the maintenance of self-tolerance in Neil3-/- mice. Although Neil3-/- mice displayed normal B cell function, they exhibited elevated serum levels of autoantibodies and developed nephritis following treatment with poly(I:C) to mimic microbial stimulation. In Neil3-/- mice, splenic T and B cells as well as germinal center B cells from Peyer's patches showed marked increases in apoptosis and cell death, indicating the potential release of self-antigens that favor autoimmunity. These findings demonstrate that deficiency in NEIL3 is associated with increased lymphocyte apoptosis, autoantibodies, and predisposition to autoimmunity.


Past present: Relationship dynamics may differ among discordant gay male couples depending on HIV infection history.
Discordant couples are unique because neither partner shares the same serostatus. Yet research overlooks how they became discordant, mistakenly assuming that they have always been that way and, by extension, that being discordant impacts the relationship in a similar manner. This study examines HIV infection history and its impact on relationship dynamics using qualitative data from 35 discordant gay male couples. Most couples met discordant (69%); however, many did not (31%). Those couples that met discordant felt being discordant had a lesser impact on their sexual and relational satisfaction, while those that did not meet discordant felt it had a greater impact, reporting sexual frustration and anxiety over seroconverting. This suggests that relationship dynamics may differ for discordant couples depending on HIV infection history. HIV prevention and counseling services for discordant couples can be better tailored and more effective when differences in HIV infection history are recognized.


Forensic acarology: an introduction.
Mites can be found in all imaginable terrestrial habitats, in freshwater, and in salt water. Mites can be found in our houses and furnishings, on our clothes, and even in the pores of our skin-almost every single person carries mites. Most of the time, we are unaware of them because they are small and easily overlooked, and-most of the time-they do not cause trouble. In fact, they may even proof useful, for instance in forensics. The first arthropod scavengers colonising a dead body will be flies with phoretic mites. The flies will complete their life cycle in and around the corpse, while the mites may feed on the immature stages of the flies. The mites will reproduce much faster than their carriers, offering themselves as valuable timeline markers. There are environments where insects are absent or rare or the environmental conditions impede their access to the corpse. Here, mites that are already present and mites that arrive walking, through air currents or material transfer become important. At the end of the ninetieth century, the work of Jean Pierre Mégnin became the starting point of forensic acarology. Mégnin documented his observations in 'La Faune des Cadavres' [The Fauna of Carcasses]. He was the first to list eight distinct waves of arthropods colonising human carcasses. The first wave included flies and mites, the sixth wave was composed of mites exclusively. The scope of forensic acarology goes further than mites as indicators of time of death. Mites are micro-habitat specific and might provide evidential data on movement or relocation of bodies, or locating a suspect at the scene of a crime. Because of their high diversity, wide occurrence, and abundance, mites may be of great value in the analysis of trace evidence.


Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression.
Psilocybin shows efficacy to alleviate depression in human clinical trials for six or more months after only one or two treatments. Another hallucinogenic drug, esketamine, has recently been U.S. Food and Drug Administration (FDA)-approved as a rapid-acting antidepressant. The mechanistic basis for the antidepressant effects of psilocybin and ketamine appear to be conserved. The efficacy of these two medications has not, however, been directly compared either clinically or preclinically. Further, whether or not a profound subjective existential experience is necessary for psilocybin to have antidepressant effects is unknown. To address these questions, we tested psilocybin, lysergic acid diethylamide (LSD), and ketamine in a rat model for depression. As in humans, a single administration of psilocybin or LSD produced persistent antidepressant-like effects in our model. In contrast, ketamine produced only a transient antidepressant-like effect. Our results indicate that classic psychedelics may have therapeutic efficacy that is more persistent than that of ketamine, and also suggest that a subjective existential experience may not be necessary for therapeutic effects.


The role of out-of-school factors in the literacy problem.
When U.S. children enter school, their reading skills vary widely by their socioeconomic status, race and ethnicity, and immigrant status. Because these literacy gaps exist before children enter school, observes Jane Waldfogel, the disparities must arise from conditions outside of schools--from the children's families and communities. And the same out-of-school factors may continue to influence reading skills as children progress through school. Waldfogel examines how specific out-of-school factors may contribute to literacy gaps at school entry and to the widening of the gaps for some groups thereafter. Some factors are important across groups. For instance, differences in parenting help explain black-white literacy gaps as well as gaps associated with socioeconomic status. Other factors differ by group. For instance, key influences on early literacy for immigrant children are the language spoken at home, parental proficiency in English, and whether a child participates in preschool. What happens to early gaps in literacy during the school years also varies by group. Reading gaps for Hispanic children tend to close or stabilize after a few years, perhaps because of such out-of-school factors as strong families, less crime, or better peer group attitudes in Hispanic communities. But black-white gaps and gaps between children from socioeconomically disadvantaged and more advantaged families tend to widen during the school years. An important challenge for future research is to understand why that is the case. Waldfogel concludes that addressing early literacy gaps, and later gaps, requires tailoring policy responses depending on which group is being targeted. But across all groups, one important conclusion holds. Although out-of-school factors contribute--sometimes in major ways--to literacy disparities, says Waldfogel, schools have a responsibility to try to close such gaps. Research on the out-of-school sources of literacy problems can support schools in this effort by helping practitioners and policy makers better understand which children are likely to encounter problems in literacy and why, as well as what schools and others can do to address those problems.


Autism: towards an integration of clinical, genetic, neuropsychological, and neurobiological perspectives.
Autism constitutes one of the best validated child psychiatric disorders. Empirical research has succeeded in delineating the key clinical phenomena, in demonstrating strong genetic influences on the underlying liability, and in identifying basic cognitive deficits. A range of neurobiological abnormalities has also been found, although the replicability of specific findings has not been high. An understanding of the causal processes leading to autism, and accounting for the marked variability in its manifestations, requires an integration across these different levels of enquiry. Although this is not yet possible, a partial integration provides a useful strategy for identifying key research questions, the limitations of existing hypotheses, and future research directions that are likely to prove fruitful. The research findings for each research level are critically reviewed in order to consider how to move towards an integration across levels.