Anti-obesity potential of rare sugar d-psicose by regulating lipid metabolism in rats.
d-Psicose is a new-generation sugar substitute with a low calorie count and can still offer the desirable sweetness. The objective of this study was to investigate the antiobesity potential of d-psicose and the possible mechanism using Wistar rats as the animal model. The animals were divided into five groups and supplemented with diets containing 5% of different carbohydrates, such as glucose, fructose, cellulose, d-psicose, and a control diet, for 4 weeks. After sacrifice, blood lipid profile, tissue morphology, and related genes participating in lipid metabolism were analyzed. The results indicated that the supplementation by d-psicose leads to minimum fat accumulation in rats when compared with the other carbohydrates. The blood lipid profile and antioxidative activity of the rat were also improved. d-Psicose can regulate lipid metabolism by increasing the lipid-metabolism-related enzymes such as SDH in serum and liver and HL in the liver. d-Psicose can prevent fat accumulation by suppressing the expression of lipogenesis-related gene ACCα and hepatic fatty acid uptake gene (FAS and SREBP-1c), while stimulating the expression for fatty-acid-oxidation-related gene including AMPK2α, HSL, and PPARα. In conclusion, d-psicose can be considered to be a healthy alternative to traditional sweeteners.


Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial.
Nevirapine given once-daily for the first 6, 14, or 28 weeks of life to infants exposed to HIV-1 via breastfeeding reduces transmission through this route compared with single-dose nevirapine at birth or neonatally. We aimed to assess incremental safety and efficacy of extension of such prophylaxis to 6 months. In our phase 3, randomised, double-blind, placebo-controlled HPTN 046 trial, we assessed the incremental benefit of extension of once-daily infant nevirapine from age 6 weeks to 6 months. We enrolled breastfeeding infants born to mothers with HIV-1 in four African countries within 7 days of birth. Following receipt of nevirapine from birth to 6 weeks, infants without HIV infection were randomly allocated (by use of a computer-generated permuted block algorithm with random block sizes and stratified by site and maternal antiretroviral treatment status) to receive extended nevirapine prophylaxis or placebo until 6 months or until breastfeeding cessation, whichever came first. The primary efficacy endpoint was HIV-1 infection in infants at 6 months and safety endpoints were adverse reactions in both groups. We used Kaplan-Meier analyses to compare differences in the primary outcome between groups. This study is registered with ClinicalTrials.gov, number NCT00074412. Between June 19, 2008, and March 12, 2010, we randomly allocated 1527 infants (762 nevirapine and 765 placebo); five of whom had HIV-1 infection at randomisation and were excluded from the primary analyses. In Kaplan-Meier analysis, 1·1% (95% CI 0·3-1·8) of infants who received extended nevirapine developed HIV-1 between 6 weeks and 6 months compared with 2·4% (1·3-3·6) of controls (difference 1·3%, 95% CI 0-2·6), equating to a 54% reduction in transmission (p=0·049). However, mortality (1·2% for nevirapine vs 1·1% for placebo; p=0·81) and combined HIV infection and mortality rates (2·3%vs 3·2%; p=0·27) did not differ between groups at 6 months. 125 (16%) of 758 infants given extended nevirapine and 116 (15%) of 761 controls had serious adverse events, but frequency of adverse events, serious adverse events, and deaths did not differ significantly between treatment groups. Nevirapine prophylaxis can safely be used to provide protection from mother-to-child transmission of HIV-1 via breastfeeding for infants up to 6 months of age. US National Institutes of Health.


Phase-resolved optical frequency domain imaging.
Phase-resolved Doppler optical coherence tomography has been used to image blood flow dynamics in various tissues using both time-domain and spectral-domain optical coherence tomography techniques. In this manuscript, we present phase-resolved Doppler imaging with a high-speed optical frequency domain imaging system. We demonstrate that by correcting for spurious timing-induced phase errors, excellent flow sensitivity can be achieved, limited only by the imaging signal-to-noise ratio. Conventional and Doppler images showing flow in an Intralipid phantom and in human skin are presented. Additionally, we demonstrate the ability of phase-resolved OFDI to measure high flow rates without the deleterious effects of fringe washout.


Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity.
The immune system has evolved specialized cellular and molecular mechanisms for targeting and regulating immune responses at epithelial surfaces. Here we show that small intestinal intraepithelial lymphocytes and lamina propria lymphocytes migrate to thymus-expressed chemokine (TECK). This attraction is mediated by CC chemokine receptor (CCR)9, a chemoattractant receptor expressed at high levels by essentially all CD4(+) and CD8(+) T lymphocytes in the small intestine. Only a small subset of lymphocytes in the colon are CCR9(+), and lymphocytes from other tissues including tonsils, lung, inflamed liver, normal or inflamed skin, inflamed synovium and synovial fluid, breast milk, and seminal fluid are universally CCR9(-). TECK expression is also restricted to the small intestine: immunohistochemistry reveals that intense anti-TECK reactivity characterizes crypt epithelium in the jejunum and ileum, but not in other epithelia of the digestive tract (including stomach and colon), skin, lung, or salivary gland. These results imply a restricted role for lymphocyte CCR9 and its ligand TECK in the small intestine, and provide the first evidence for distinctive mechanisms of lymphocyte recruitment that may permit functional specialization of immune responses in different segments of the gastrointestinal tract. Selective expression of chemokines by differentiated epithelium may represent an important mechanism for targeting and specialization of immune responses.


Proceedings of the 2021 American Burn Association State and Future of Burn Science Meeting.
Periodically, the American Burn Association (ABA) has convened a State of the Science meeting on various topics representing multiple disciplines within burn care and research. In 2021 at the request of the ABA President, meeting development was guided by the ABA's Burn Science Advisory Panel (BSAP) and a subgroup of meeting chairs. The goal of the meeting was to produce both an evaluation of the current literature and ongoing studies, and to produce a research agenda and/or define subject matter-relevant next steps to advance the field(s). Members of the BSAP defined the topics to be addressed and subsequently solicited for nominations of expert speakers and topic leaders from the ABA's Research Committee. Current background literature for each topic was compiled by the meeting chairs and the library then enhanced by the invited topic and breakout discussion leaders. The meeting was held in New Orleans, LA on November 2nd and 3rd and was formatted to allow for 12 different topics, each with two subtopics, to be addressed. Topic leaders provided a brief overview of each topic to approximately 100 attendees, followed by expert-lead breakout sessions for each topic that allowed for focused discussion among subject matter experts and interested participants. The breakout and topic group leaders worked with the participants to determine research needs and associated next steps including white papers, reviews and in some cases collaborative grant proposals. Here, summaries from each topic area will be presented to highlight the main foci of discussion and associated conclusions.


In situ quantification of protein binding to the plasma membrane.
This study presents a fluorescence-based assay that allows for direct measurement of protein binding to the plasma membrane inside living cells. An axial scan through the cell generates a fluorescence intensity profile that is analyzed to determine the membrane-bound and cytoplasmic concentrations of a peripheral membrane protein labeled by the enhanced green fluorescent protein (EGFP). The membrane binding curve is constructed by mapping those concentrations for a population of cells with a wide range of protein expression levels, and a fit of the binding curve determines the number of binding sites and the dissociation coefficient. We experimentally verified the technique, using myosin-1C-EGFP as a model system and fit its binding curve. Furthermore, we studied the protein-lipid interactions of the membrane binding domains from lactadherin and phospholipase C-δ1 to evaluate the feasibility of using competition binding experiments to identify specific lipid-protein interactions in living cells. Finally, we applied the technique to determine the lipid specificity, the number of binding sites, and the dissociation coefficient of membrane binding for the Gag matrix domain of human T-lymphotropic virus type 1, which provides insight into early assembly steps of the retrovirus.


Long-term in-vivo effect of various restorative materials on enamel and dentin of primary molars.
To explore the long-term in-vivo effect of different dental restorative materials on the surrounding enamel and dentin, in primary molars. Sixteen naturally exfoliated primary molars restored with amalgam, compomer, and glass-ionomer cement were collected after 2 to 5 years of function in the mouth. Four intact molars served as control. The teeth were sliced buccolingually and the ion content in the restorative material, the enamel, and the dentin surrounding the restoration was determined using a scanning electron microscopy-energy dispersive x-ray spectroscopy (SEM-EDS) program. Amalgam released copper to the enamel and dentin causing a bluish discoloration. No traces of mercury or other ions were detected in the enamel or dentin. The enamel and dentin surrounding the restoration showed reduced inorganic components and increased organic components. The enamel and dentin surrounding the compomer restoration showed similar to amalgam reduction in inorganic components and increased organic components. Traces of fluoride, aluminum, and silicon were found. The enamel and dentin of teeth restored with glass-ionomer cement showed the least reduction in inorganic components, with higher fluoride content and traces of aluminum, silicon, and strontium. This long-term in-vivo study showed release of copper ions from amalgam material to the enamel and dentin, but no traces of mercury. Amalgam and compomers showed no remineralization effect on the dentin surrounding the restoration. Glass-ionomer restorations showed remineralization effect on the tooth components and migration of inorganic ions from the enamel and dentin to the material.


ASPP1 deficiency promotes epithelial-mesenchymal transition, invasion and metastasis in colorectal cancer.
The apoptosis-stimulating protein of p53 (ASPP) family of proteins can regulate apoptosis by interacting with the p53 family and have been identified to play an important role in cancer progression. Previously, we have demonstrated that ASPP2 downregulation can promote invasion and migration by controlling β-catenin-dependent regulation of ZEB1, however, the role of ASPP1 in colorectal cancer (CRC) remains unclear. We analyzed data from The Cancer Genome Atlas (TCGA) and coupled this to in vitro experiments in CRC cell lines as well as to experimental pulmonary metastasis in vivo. Tissue microarrays of CRC patients with information of clinical-pathological parameters were also used to investigate the expression and function of ASPP1 in CRC. Here, we report that loss of ASPP1 is capable of enhancing migration and invasion in CRC, both in vivo and in vitro. We demonstrate that depletion of ASPP1 could activate expression of Snail2 via the NF-κB pathway and in turn, induce EMT; and this process is further exacerbated in RAS-mutated CRC. ASPP1 could be a prognostic factor in CRC, and the use of NF-κB inhibitors may provide new strategies for therapy against metastasis in ASPP1-depleted CRC patients.


Intravital microscopy identifies selectins that regulate T cell traffic into allografts.
T cell homing to sites of injury and inflammation is a critical step for adaptive immune responses. While much has been learned regarding T cell homing to lymphoid tissues, few studies have directly observed trafficking events during an effector response. In this study, we developed a model that uses intravital fluorescence videomicroscopy to determine the molecules critical to T cell rolling within skin allograft microvasculature during the effector phase of the rejection response. Additional studies were performed to quantify T cell infiltrates as rejection progressed. We found that P-selectin and E-selectin expressed on postcapillary venules play overlapping roles in the recruitment of activated T cells in a SCID reconstitution model of skin graft rejection and are important in T cell accumulation at the graft site. Surprisingly, we also found that naive T cells are recruited and accumulate via constitutive T cell L-selectin and upregulated L-selectin ligands on rejecting allograft vasculature. These data indicated that a specific retinue of molecules is upregulated during the rejection response, and they suggest potential future therapeutic targets.


Associations between body mass index across adult life and hip shapes at age 60 to 64: Evidence from the 1946 British birth cohort.
To examine the associations of body mass index (BMI) across adulthood with hip shapes at age 60-64years. Up to 1633 men and women from the MRC National Survey of Health and Development with repeat measures of BMI across adulthood and posterior-anterior dual-energy X-ray absorptiometry bone mineral density images of the proximal femur recorded at age 60-64 were included in analyses. Statistical shape modelling was applied to quantify independent variations in hip mode (HM), of which the first 6 were examined in relation to: i) BMI at each age of assessment; ii) BMI gain during different phases of adulthood; iii) age first overweight. Higher BMI at all ages (i.e. 15 to 60-64) and greater gains in BMI were associated with higher HM2 scores in both sexes (with positive HM2 values representing a shorter femoral neck and a wider and flatter femoral head). Similarly, younger age first overweight was associated with higher HM2 scores but only in men once current BMI was accounted for. In men, higher BMI at all ages was also associated with lower HM4 scores (with negative HM4 values representing a flatter femoral head, a wider neck and smaller neck shaft angle) but no associations with BMI gain or prolonged exposure to high BMI were found. Less consistent evidence of associations was found between BMI and the other four HMs. These results suggest that BMI across adulthood may be associated with specific variations in hip shapes in early old age.


Neuregulin 1 gene and variations in perceptual aberration of schizotypal personality in adolescents.
We test the hypothesis that the neuregulin 1 (NRG1 ) gene at chromosome 8p22-p12, which has been implicated as a susceptibility gene to schizophrenia, is associated with variations in schizotypal personality in non-clinical populations. A randomly selected sample of 905 adolescents were assessed for their personality features using the Perceptual Aberration Scale (PAS) and the Schizotypal Personality Questionnaire (SPQ) and genotyped for three single nucleotide polymorphisms (SNP8NRG221533, rs3924999, and rs2954041) at the NRG1 gene. Relations between the three genetic variants and continuous schizotypal personality scores were evaluated using ANOVA for single-locus analyses and haplotype trend regression test for multi-locus analyses. Single locus analysis showed that the A allele of rs3924999, a functional polymorphism in exon 2, had the largest effect size and exhibited a prominent allele-dose trend effect for the PAS score. Haplotype analyses using the haplotype trend regression test indicated that the A allele of rs3924999 was mainly responsible for the association with the PAS but not with the SPQ or its three factors, and the magnitude of significance was not strengthened by the combination of this allele with adjacent locus. Our study provides the first evidence for the association of NRG1 with schizotypal personality and indicates a possible role of NRG1 in the genetic etiology of schizophrenia through perceptual aberrations.


A comparative study on Vamana Karma with Madanaphala and Krutavedhana in Ekakushtha (Psoriasis).
Vamana Karma (therapeutic emesis) is the best therapy for the elimination of vitiated Kapha Dosha. In the present clinical practice Madanaphala (Randia dumetorum) is mainly used for Vamana Karma. Apart from Madanaphala, five other drugs, and in total 355 formulations are described in Charaka Samhita; one of them is Krutavedhana (Luffa acutangula) kalpa (formulations). Krutavedhana is specially indicated in Gadha (compact) Dosha condition like Kushtha (skin diseases), Garavisha (slow poison), and so on, for Vamana Karma. The present study aimed to observe the effect on Vamana Karma and by that its effect on Ekakushtha (Psoriasis). Krutavedhana Beeja Churna (seed powder) was given with Madhu (honey) and Saindhava (rock salt) as Vamana Yoga (emetic formulation), to compare it with Madanaphala Pippali Churna (seed powder). After the Sansarjana Krama (special dietetic schedule), Panchatikta Ghrita (medicated ghee) was given as Shamana Sneha (pacifying oleation). An average dose of Krutavedhana was 5.9 g. Krutavedhana could produce a good number of Vega (bouts), Pittanta Lakshana (bile coming out at the end of Vamana), and Pravara Shuddhi (maximum cleansing) in a majority of patients. Madanaphala is the best among all Vamaka (emetic) drugs, but Krutavedhana showed a similar to higher effect on Vamana Karma in terms of Antiki, Maniki, Vaigiki, and LaingikiShuddhi (cleansing criteria). Vamana Karma by Krutavedhana showed better relief in Matsyashakalopamam (silvery scale), Kandu (itching), and Rukshataa (dryness), while Madanapahala showed better relief in Krishnaruna Varna (erythema). After completion of the Shamana (pacifying) treatment, both the groups showed nearly the same effect on Asvedanam (lack of perspiration), Matsyashakalopamam, Kandu, Rukshataa, Krishnaruna Varna, and Mahaavaastu (bigger lesion).


Contamination status of POPs and BFRs and relationship with parasitic infection in finless porpoises (Neophocaena phocaenoides) from Seto Inland Sea and Omura Bay, Japan.
Contamination status of brominated flame retardants (BFRs) and persistent organic pollutants (POPs) in blubber of finless porpoises (Neophocaena phocaenoides) stranded along the coasts of Seto Inland Sea and Omura Bay in Japan were investigated. Levels of PCBs, DDTs and CHLs were significantly higher than those of HCHs, HCB, PBDEs and HBCDs. Concentrations of PBDEs and HBCDs, as well as organochlorine compounds in males increased with body length (p<0.05). Among 14 PBDE congeners analyzed, BDE-47 was the predominant, which is similar to those generally reported in biota. PBDEs, HBCDs and PCBs showed no obvious temporal trend in concentrations during the study period, suggesting continuous environmental release of these chemicals. On the other hand, levels of DDT, CHLs and HCHs have decreased. Concentrations of PCBs in liver trematode infected individuals were significantly higher than those in not infected individuals, implying there could be a relationship between contaminant levels and parasitic infection.


Perceptions of racism in healthcare among patients with systemic lupus erythematosus: a cross-sectional study.
Racial disparities in the clinical outcomes of systemic lupus erythematosus (SLE) exist. Perceived racial discrimination may contribute to disparities in health. To determine if perceived racism in healthcare differs by race among patients with SLE and to evaluate its contribution to racial disparities in SLE-related outcomes. 163 African-American (AA) and 180 white (WH) patients with SLE were enrolled. Structured interviews and chart reviews were done to determine perceptions of racism, SLE-related outcomes (Systemic Lupus International Collaborating Clinics (SLICC) Damage Index, SLE Disease Activity, Center for Epidemiologic Studies-Depression (CES-D)), and other variables that may affect perceptions of racism. Serial hierarchical multivariable logistic regression models were conducted. Race-stratified analyses were also performed. 56.0% of AA patients compared with 32.8% of WH patients had high perceptions of discrimination in healthcare (p<0.001). This difference remained (OR 4.75 (95% CI 2.41 to 8.68)) after adjustment for background, identity and healthcare experiences. Female gender (p=0.012) and lower trust in physicians (p<0.001) were also associated with high perceived racism. The odds of having greater disease damage (SLICC damage index ≥2) were higher in AA patients than in WH patients (crude OR 1.55 (95% CI 1.01 to 2.38)). The odds of having moderate to severe depression (CES-D ≥17) were also higher in AA patients than in WH patients (crude OR 1.94 (95% CI 1.26 to 2.98)). When adjusted for sociodemographic and clinical characteristics, racial disparities in disease damage and depression were no longer significant. Among AA patients, higher perceived racism was associated with having moderate to severe depression (adjusted OR 1.23 (95% CI 1.05 to 1.43)) even after adjusting for sociodemographic and clinical variables. Perceptions of racism in healthcare were more common in AA patients than in WH patients with SLE and were associated with depression. Interventions aimed at modifiable factors (eg, trust in providers) may reduce higher perceptions of race-based discrimination in SLE.


Food protein-induced enterocolitis syndrome: guidelines summary and practice recommendations.
Food protein-induced enterocolitis syndrome (FPIES) is a poorly understood non-IgE gastrointestinal-mediated food allergy that predominantly affects infants and young children. Cells of the innate immune system appear to be activated during an FPIES reaction. Acute FPIES typically presents between one and 4 hours after ingestion of the trigger food, with the principal symptom being profuse vomiting, and is often accompanied by pallor and lethargy. Additional features can include hypotension, hypothermia, diarrhoea, neutrophilia and thrombocytosis. In Australia, the most commonly reported foods responsible for FPIES are (in descending order) rice, cow's milk, egg, oats and chicken. Most children with FPIES react to only one food trigger, and thus, avoidance of multiple foods is often not indicated. FPIES is often misdiagnosed as sepsis or gastroenteritis. However, a diagnosis of FPIES is favoured if there is rapid resolution of symptoms within hours of presentation, an absence of fever, and a lack of a significant rise in C-reactive protein at presentation. Diagnosis is often hampered by the lack of awareness of FPIES, absence of reliable biomarkers, the non-specific nature of the presenting symptoms, and the delay between allergen exposure and symptoms. Although some national peak allergy bodies have attempted to improve the diagnosis and management of FPIES, up until 2017 there were no internationally agreed guidelines for its diagnosis and management.


Computational methods to detect conserved non-genic elements in phylogenetically isolated genomes: application to zebrafish.
Many important model organisms for biomedical and evolutionary research have sequenced genomes, but occupy a phylogenetically isolated position, evolutionarily distant from other sequenced genomes. This phylogenetic isolation is exemplified for zebrafish, a vertebrate model for cis-regulation, development and human disease, whose evolutionary distance to all other currently sequenced fish exceeds the distance between human and chicken. Such large distances make it difficult to align genomes and use them for comparative analysis beyond gene-focused questions. In particular, detecting conserved non-genic elements (CNEs) as promising cis-regulatory elements with biological importance is challenging. Here, we develop a general comparative genomics framework to align isolated genomes and to comprehensively detect CNEs. Our approach integrates highly sensitive and quality-controlled local alignments and uses alignment transitivity and ancestral reconstruction to bridge large evolutionary distances. We apply our framework to zebrafish and demonstrate substantially improved CNE detection and quality compared with previous sets. Our zebrafish CNE set comprises 54 533 CNEs, of which 11 792 (22%) are conserved to human or mouse. Our zebrafish CNEs (http://zebrafish.stanford.edu) are highly enriched in known enhancers and extend existing experimental (ChIP-Seq) sets. The same framework can now be applied to the isolated genomes of frog, amphioxus, Caenorhabditis elegans and many others.


Kinetically Selective Inhibitors of Human Carbonic Anhydrase Isozymes I, II, VII, IX, XII, and XIII.
To get a better understanding of the possibility of developing selective carbonic anhydrase (CA) inhibitors, interactions between 17 benzenesulphonamide ligands and 6 human CAs (full-length CA I, II, VII, and XIII and catalytic domains of CA IX and XII) were characterized using surface plasmon resonance and fluorescent-based thermal shift assays. Kinetics revealed that the strongest binders had subnanomolar affinities with low dissociation rates (i.e., kd values around 1 × 10(-3) s(-1)) or were essentially irreversible. Chemodynamic analysis of the interactions highlighted an intrinsic mechanism of the CA-sulphonamide interaction kinetics and showed that slow dissociation rates were mediated by large hydrophobic contacts. The studied inhibitors demonstrated a high cross-reactivity within the protein family. However, according to chemical phylogenetic analysis developed for kinetic data, several ligands were found to be selective against certain CA isozymes, indicating that it should be possible to develop selective CA inhibitors suitable for clinical use.


Identifying who has long COVID in the USA: a machine learning approach using N3C data.
Post-acute sequelae of SARS-CoV-2 infection, known as long COVID, have severely affected recovery from the COVID-19 pandemic for patients and society alike. Long COVID is characterised by evolving, heterogeneous symptoms, making it challenging to derive an unambiguous definition. Studies of electronic health records are a crucial element of the US National Institutes of Health's RECOVER Initiative, which is addressing the urgent need to understand long COVID, identify treatments, and accurately identify who has it-the latter is the aim of this study. Using the National COVID Cohort Collaborative's (N3C) electronic health record repository, we developed XGBoost machine learning models to identify potential patients with long COVID. We defined our base population (n=1 793 604) as any non-deceased adult patient (age ≥18 years) with either an International Classification of Diseases-10-Clinical Modification COVID-19 diagnosis code (U07.1) from an inpatient or emergency visit, or a positive SARS-CoV-2 PCR or antigen test, and for whom at least 90 days have passed since COVID-19 index date. We examined demographics, health-care utilisation, diagnoses, and medications for 97 995 adults with COVID-19. We used data on these features and 597 patients from a long COVID clinic to train three machine learning models to identify potential long COVID among all patients with COVID-19, patients hospitalised with COVID-19, and patients who had COVID-19 but were not hospitalised. Feature importance was determined via Shapley values. We further validated the models on data from a fourth site. Our models identified, with high accuracy, patients who potentially have long COVID, achieving areas under the receiver operator characteristic curve of 0·92 (all patients), 0·90 (hospitalised), and 0·85 (non-hospitalised). Important features, as defined by Shapley values, include rate of health-care utilisation, patient age, dyspnoea, and other diagnosis and medication information available within the electronic health record. Patients identified by our models as potentially having long COVID can be interpreted as patients warranting care at a specialty clinic for long COVID, which is an essential proxy for long COVID diagnosis as its definition continues to evolve. We also achieve the urgent goal of identifying potential long COVID in patients for clinical trials. As more data sources are identified, our models can be retrained and tuned based on the needs of individual studies. US National Institutes of Health and National Center for Advancing Translational Sciences through the RECOVER Initiative.


Reactions to Testing HIV Negative: An Assessment of Measurement Invariance and Associations with Condomless Anal Sex among English and Spanish-speaking Latinx Sexual Minority Men in the United States.
Among the many effective prevention strategies, frequent HIV testing continues to be promoted to reduce the risk of HIV transmission among sexual minority men (SMM). Testing negative for HIV can result in varied reactions that influence subsequent HIV transmission behaviors, yet the extant research has primarily been conducted in English. The current study examined measurement invariance of a Spanish-translated Inventory of Reactions to Testing HIV Negative (IRTHN). The study also examined whether the IRTHN was associated with subsequent condomless anal sex. Data were drawn from 2,170 Latinx SMM subsample of the UNITE Cohort Study. We conducted a multigroup confirmatory factor analysis to test for measurement invariance between participants who opted to take the survey in English (n = 2,024) and those who opted to take it in Spanish (n = 128). We also examined if the IRTHN is associated with subsequent CAS. The results were suggestive of partial invariance. The subscales of Luck and Invulernability were associated with CAS at the 12-month follow-up. Practice and research-based implications are discussed.


Infantile Malignant Osteopetrosis: Delay in Diagnosis Eliminates Chance of Cure.
A 4.5 year-old girl presented with abdominal distention, failure to thrive, visual and hearing loss. In her medical history there was meningitis in the neonatal period, convulsions, enlargement of her head, nistagmus and exophtalmus at the tenth month. When she was 15 month-old, she had ventriculoperitoneal shunt and surgical transection of the filum terminale due to tethered cord. When she was 3 yearold she had headaches and swallowing difficulties and she underwent suboccipital craniectomi and C1 laminectomi. On admission to our Center she had normal mental and motor development, high arched palate, only three teeth, hepatosplenomegaly, weight and height below 3 percentile, leukoerythroblastic anemia and thrombocytopenia. Roentgenograms of bones showed sclerosis and no medullary tissue could be obtained in bone marrow biopsy. Diagnosis was infantile malignant osteopetrosis but the patient can not be referred to bone marrow transplantation due to delay in diagnosis and irreversible visual and hearing loss and lack of medullary space for marrow engraftment.


Impacts of Drought on Maize and Soybean Production in Northeast China During the Past Five Decades.
Climate change has a distinct impact on agriculture in China, particularly in the northeast, a key agriculture area sensitive to extreme hydroclimate events. Using monthly climate and agriculture data, the influence of drought on maize and soybean yields-two of the main crops in the region-in northeast China since 1961 to 2017 were investigated. The results showed that the temperature in the growing season increased by 1.0 °C from the period 1998-2017 to the period 1961-1980, while the annual precipitation decreased slightly. However, precipitation trends varied throughout the growing season (May-September), increasing slightly in May and June, but decreasing in July, August and September, associated with the weakening of the East Asian summer monsoon. Consequently, the annual and growing season drought frequency increased by 15%, and 25%, respectively, in the period 1998-2017 relative to the period 1961-1980. The highest drought frequency (55%) was observed in September. At the same time, the drought intensity during the growing season increased by 7.8%. The increasing frequency and intensity of drought had negative influences on the two crops. During moderate drought years in the period 1961-2017, 3.2% and 10.4% of the provincial maize and soybean yields were lost, respectively. However, during more severe drought years, losses doubled for soybean (21.8%), but increased more than four-fold for maize (14.0%). Moreover, in comparison to the period 1961-1980, a higher proportion of the yields were lost in the period 1998-2017, particularly for maize, which increased by 15% (increase for soybean was 2.4%). This change largely depends on increasing droughts in August and September, when both crops are in their filling stages. The impact of drought on maize and soybean production was different during different growth stages, where a strong relationship was noted between drought and yield loss of soybean in its filling stage. Given the sensitivity of maize and soybean yields in northeast China to drought, and the observed production trends, climate change will likely have significant negative impacts on productivity in the future.


RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors.
Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors. We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed. Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L-mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)-pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L-mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor. Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann-La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.).


Dimensions of patient-provider communication and diabetes self-care in an ethnically diverse population.
Patient-provider communication is essential for effective care of diabetes and other chronic illnesses. However, the relative impact of general versus disease-specific communication on self-management is poorly understood, as are the determinants of these 2 communication dimensions. Cross-sectional survey. Three VA heath care systems, 1 county health care system, and 1 university-based health care system. Seven hundred fifty-two diabetes patients were enrolled. Fifty-two percent were nonwhite, 18% had less than a high-school education, and 8% were primarily Spanish-speaking. Patients' assessments of providers' general and diabetes-specific communication were measured using validated scales. Self-reported foot care; and adherence to hypoglycemic medications, dietary recommendations, and exercise were measured using standard items. General and diabetes-specific communication reports were only moderately correlated (r =.35) and had differing predictors. In multivariate probit analyses, both dimensions of communication were independently associated with self-care in each of the 4 areas examined. Sociodemographically vulnerable patients (racial and language minorities and those with less education) reported communication that was as good or better than that reported by other patients. Patients receiving most of their diabetes care from their primary provider and patients with a longer primary care relationship reported better general communication. VA and county clinic patients reported better diabetes-specific communication than did university clinic patients. General and diabetes-specific communication are related but unique facets of patient-provider interactions, and improving either one may improve self-management. Providers in these sites are communicating successfully with vulnerable patients. These findings reinforce the potential importance of continuity and differences among VA, county, and university health care systems as determinants of patient-provider communication.


Role of C-terminal direct repeating units of the Streptococcus mutans glucosyltransferase-S in glucan binding.
The C-terminal glucan-binding domain of the glucosyltransferase-S of Streptococcus mutans GS-5 contains five 65-amino-acid direct repeating units. A series of deletion derivatives of both the glucosyltransferase-S and its glucan-binding domain were constructed and analyzed. The results demonstrated that the four C-terminal direct repeating units constituted part of the minimum domain required for glucan binding.


Magnetic resonance imaging anatomy of the normal equine larynx and pharynx.
The purpose of the present study was to describe normal magnetic resonance (MR) imaging anatomy of the equine larynx and pharynx and to present the optimal protocol, sequences, and possible limitations of this examination technique. Using a 0.3 T unit, the laryngeal and pharyngeal regions was imaged in two horses. The protocol consisted of sagittal and transverse T2-weighted (T2w) fast spin echo, transverse T1-weighted (T1w) spin echo, and dorsal high-resolution T1w gradient echo (both pre- and postcontrast enhancement) sequences. Euthanasia was performed at the end of the imaging procedure. Macroscopic anatomy of the cadaver sections were compared with the MR images in transverse, midsagittal, and parasagittal planes. There was good differentiation of anatomic structures, including soft tissues. The laryngeal cartilages, hyoid apparatus, and upper airway muscle groups with their attachments could be clearly identified. However, it was not always possible to delineate individual muscles in each plane. Most useful were both T2w and T1w transverse sequences. Intravenous application of contrast medium was helpful to identify blood vessels. The MR images corresponded with the macroscopic anatomy of cadaver sections.


Associations of udder-health indicators with cow factors and with intramammary infection in dairy cows.
The objective of this study was to investigate if and how cow factors and intramammary infection (IMI) are associated with 4 different udder-health indicators in dairy cows as a first step in investigating whether the diagnostic performance of these indicators can be improved. The investigated indicators were somatic cell count (SCC), lactate dehydrogenase (LDH), N-acetyl-β-d-glucosaminidase (NAGase), and alkaline phosphatase (AP) measured in milk. In this cross-sectional study, approximately 1,000 cows from 25 dairy herds were sampled for bacteriology (quarter milk samples) during 3 consecutive days: the day before test milking, at the day of test milking, and at the day after test milking. The whole-udder test milking sample was analyzed for milk composition, SCC, LDH, NAGase, and AP. Cow data (parity, breed, milk yield, percentage of milk fat and protein, milk urea concentration, and days in milk from the sampled test milking) were collected from the Swedish milk-recording scheme. Of the sampled cows 485 were considered IMI negative and were used in multivariable mixed-effect linear regression models to investigate associations between cow factors and the udder-health indicators. A second modeling including all cows, both IMI negative and IMI positive (256 cows), was also performed. The results showed that all udder-health indicators were affected by cow factors but that different cow factors were associated with different indicators. Intramammary-infection status was significantly associated with all udder-health indicators except AP. Parity and milk urea concentration were the only cow factors associated with all indicators in all models. The significant cow factors explained 23% of the variation in SCC and >30% of the variation in LDH, NAGase, and AP in IMI-negative cows, showing that LDH, NAGase, and AP are more affected than SCC by cow factors. The IMI status explained 23% of the variation in SCC in the model with all cows but only 7% of the variation in LDH and 2% of the variation in NAGase, indicating that SCC has the best potential as a diagnostic tool in finding cows with IMI. However, further studies are needed to investigate whether the diagnostic properties of these udder-health indicators will improve with adjustment according to their associations with different cow factors when used as a diagnostic tool for finding cows with IMI.


Circadian and noncircadian modulation of autophagy in photoreceptors and retinal pigment epithelium.
Autophagy in photoreceptors and the RPE promotes homeostasis and survival. The purpose of this study is to determine the daily pattern of changes in autophagy and factors contributing to its regulation in the outer retina. Levels of autophagy markers in the retina and RPE were evaluated over a 24-hour period. To assess the role of phagocytosis in stimulating autophagy in the RPE, cultured RPE-J cells were incubated with isolated photoreceptor outer segments and levels of autophagy markers were measured. Electron microscopy was performed on retina sections and RPE-J cells to assess formation of double-membraned vesicles consistent with autophagosomes. In wild-type C57BL/6 mice maintained under normal cycling light conditions, autophagy in photoreceptor cells and the RPE exhibited a bimodal pattern of activation. In photoreceptors, shifts between light and dark evoked a sharp decrease in autophagy that was followed by a time-dependent increase. In photoreceptors, translocation of transducin and arrestin from the outer to inner segment appeared to contribute to the light-dependent upregulation of autophagy. In contrast, the cyclic variations in RPE autophagy were independent of lighting conditions, and are triggered, at least in part, by ingestion of outer segments. Activation of autophagy in the outer retina exhibits a bimodal pattern that correlates with shifts in transduction proteins within the photoreceptor and by circadian ingestion of outer segments in the RPE. These dynamic shifts suggest a critical role for this pathway in maintaining homeostasis, with further study needed to define the mechanisms underlying the regulation of this phenomenon.


Expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue is not increased in human obesity.
Central obesity is associated with increased morbidity and mortality. Preadipocyte proliferation and differentiation contribute to increases in adipose tissue mass, yet the mechanisms that underlie these processes remain unclear. Patients with glucocorticoid excess develop a reversible form of central obesity, but circulating cortisol levels in idiopathic obesity are invariably normal. We have hypothesized that the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), by converting inactive cortisone to active cortisol in adipose tissue, might be an important autocrine regulator of fat mass. Paired omental and sc fat biopsies were obtained from 32 women (median age, 43 yr; range, 28-65; median body mass index, 27.5 kg/m(2); range, 19.7-39.2) undergoing elective abdominal surgery. 11beta-HSD1 activity and mRNA levels were assessed in whole tissue and in isolated preadipocytes and adipocytes using specific enzyme assays and real-time PCR. Preadipocyte proliferation was measured using tritiated thymidine incorporation. Whole adipose tissue 11beta-HSD1 mRNA levels did not differ between omental and sc samples (P = 0.73). In addition, mRNA levels did not correlate with body mass index (omental: r = 0.1; P = 0.6; sc: r = 0.15; P = 0.4). In keeping with earlier studies, 11beta-HSD1 mRNA levels were higher in omental compared with sc preadipocytes. However, in cultured omental preadipocytes, 11beta-HSD1 activity inversely correlated with body mass index (r = -0.47; P = 0.03). In omental preadipocytes, both cortisol and cortisone decreased proliferation (P < 0.05). Inhibition of 11beta-HSD1 with glycyrrhetinic acid partially reversed the cortisone-induced decrease in preadipocyte proliferation (P < 0.05). Enhanced preadipocyte proliferation within omental adipose tissue as a consequence of decreased 11beta-HSD1 mRNA levels and activity may contribute to increases in visceral adipose tissue mass in obese patients.


Quantitative cerebral blood flow using xenon-enhanced CT after decompressive craniectomy in traumatic brain injury.
OBJECTIVE Few studies have reported on changes in quantitative cerebral blood flow (CBF) after decompressive craniectomy and the impact of these measures on clinical outcome. The aim of the present study was to evaluate global and regional CBF patterns in relation to cerebral hemodynamic parameters in patients after decompressive craniectomy for traumatic brain injury (TBI). METHODS The authors studied clinical and imaging data of patients who underwent xenon-enhanced CT (XeCT) CBF studies after decompressive craniectomy for evacuation of a mass lesion and/or to relieve intractable intracranial hypertension. Cerebral hemodynamic parameters prior to decompressive craniectomy and at the time of the XeCT CBF study were recorded. Global and regional CBF after decompressive craniectomy was measured using XeCT. Regional cortical CBF was measured under the craniectomy defect as well as for each cerebral hemisphere. Associations between CBF, cerebral hemodynamics, and early clinical outcome were assessed. RESULTS Twenty-seven patients were included in this study. The majority of patients (88.9%) had an initial Glasgow Coma Scale score ≤ 8. The median time between injury and decompressive surgery was 9 hours. Primary decompressive surgery (within 24 hours) was performed in the majority of patients (n = 18, 66.7%). Six patients had died by the time of discharge. XeCT CBF studies were performed a median of 51 hours after decompressive surgery. The mean global CBF after decompressive craniectomy was 49.9 ± 21.3 ml/100 g/min. The mean cortical CBF under the craniectomy defect was 46.0 ± 21.7 ml/100 g/min. Patients who were dead at discharge had significantly lower postcraniectomy CBF under the craniectomy defect (30.1 ± 22.9 vs 50.6 ± 19.6 ml/100 g/min; p = 0.039). These patients also had lower global CBF (36.7 ± 23.4 vs 53.7 ± 19.7 ml/100 g/min; p = 0.09), as well as lower CBF for the ipsilateral (33.3 ± 27.2 vs 51.8 ± 19.7 ml/100 g/min; p = 0.07) and contralateral (36.7 ± 19.2 vs 55.2 ± 21.9 ml/100 g/min; p = 0.08) hemispheres, but these differences were not statistically significant. The patients who died also had significantly lower cerebral perfusion pressure (52 ± 17.4 vs 75.3 ± 10.9 mm Hg; p = 0.001). CONCLUSIONS In the presence of global hypoperfusion, regional cerebral hypoperfusion under the craniectomy defect is associated with early mortality in patients with TBI. Further study is needed to determine the value of incorporating CBF studies into clinical decision making for severe traumatic brain injury.


Appropriate expression of P57kip2 drives trophoblast fusion via cell cycle arrest.
The syncytiotrophoblast, derived from cytotrophoblast fusion, is responsible for maternal-fetal exchanges, secretion of pregnancy-related hormones, and fetal defense against pathogens. Inadequate cytotrophoblast fusion can lead to pregnancy disorders, such as preeclampsia and fetal growth restriction. However, little is known about the mechanism of cytotrophoblast fusion in both physiological and pathological pregnancy conditions. In this study, P57kip2 (P57), a cell cycle-dependent kinase inhibitor that negatively regulates the cell cycle, was found to be up-regulated during the process of syncytialization in both primary trophoblast cells and BeWo cells. Co-immunofluorescence with proliferation markers Ki67 and Cyclin-CDK factors further showed that P57 specifically localizes in the post-mitotic cytotrophoblast subtype of the early pregnancy villi. Overexpression of P57 promoted trophoblast syncytialization by arresting the cell cycle at the G1/G0 phase and inhibiting proliferation. Blocking of the cell cycle through a serum starvation culture resulted in an enhancement of cytotrophoblast fusion and the up-regulation of P57. In both spontaneous cytotrophoblast fusion and forskolin-induced BeWo cell fusion models, an initial up-regulation of P57 was observed followed by a subsequent down-regulation. These findings indicate that proper expression of P57 at cytotrophoblast differentiation nodes plays an important role in trophoblast syncytialization.


Shape variation of bilayer membrane daughter vesicles induced by anisotropic membrane inclusions.
A theoretical model of a two-component bilayer membrane was used in order to describe the influence of anisotropic membrane inclusions on shapes of membrane daughter micro and nano vesicles. It was shown that for weakly anisotropic inclusions the stable vesicle shapes are only slightly out-of-round. In contrast, for strongly anisotropic inclusions the stable vesicle shapes may significantly differ from spheres, i.e. they have a flattened oblate shape at small numbers of inclusions in the membrane, and an elongated cigar-like prolate shape at high numbers of inclusions in the vesicle membrane.


Importance of residual stresses in the Brillouin gain spectrum of single mode optical fibers.
Residual stresses inside optical fibers can impact significantly on Brillouin spectrum properties. We have analyzed the importance of internal stresses on the Brillouin Gain Spectrum (BGS) for a conventional G.652 fiber and compared modeling results to measurements. Then the residual internal stresses have been investigated for a set of trench-assisted fibers: fibers are coming from a single preform with different draw tensions. Numerical modeling based on measured internal stresses profiles are compared with corresponding BGS experimental results. Clearly, Brillouin spectrum is shifted linearly versus draw tension with a coefficient of -20MHz/100g and its linewidth increases.


Virus and CTL dynamics in the extrafollicular and follicular tissue compartments in SIV-infected macaques.
Data from SIV-infected macaques indicate that virus-specific cytotoxic T lymphocytes (CTL) are mostly present in the extrafollicular (EF) compartment of the lymphoid tissue, with reduced homing to the follicular (F) site. This contributes to the majority of the virus being present in the follicle and represents a barrier to virus control. Using mathematical models, we investigate these dynamics. Two models are analyzed. The first assumes that CTL can only become stimulated and expand in the extrafollicular compartment, with migration accounting for the presence of CTL in the follicle. In the second model, follicular CTL can also undergo antigen-induced expansion. Consistent with experimental data, both models predict increased virus compartmentalization in the presence of stronger CTL responses and lower virus loads, and a more pronounced rise of extrafollicular compared to follicular virus during CD8 cell depletion experiments. The models, however, differ in other aspects. The follicular expansion model results in dynamics that promote the clearance of productive infection in the extrafollicular site, with any productively infected cells found being the result of immigration from the follicle. This is not observed in the model without follicular CTL expansion. The models further predict different consequences of introducing engineered, follicular-homing CTL, which has been proposed as a therapeutic means to improve virus control. Without follicular CTL expansion, this is predicted to result in a reduction of virus load in both compartments. The follicular CTL expansion model, however, makes the counter-intuitive prediction that addition of F-homing CTL not only results in a reduction of follicular virus load, but also in an increase in extrafollicular virus replication. These predictions remain to be experimentally tested, which will be relevant for distinguishing between models and for understanding how therapeutic introduction of F-homing CTL might impact the overall dynamics of the infection.


Relatedness-based Multi-Entity Summarization.
Representing world knowledge in a machine processable format is important as entities and their descriptions have fueled tremendous growth in knowledge-rich information processing platforms, services, and systems. Prominent applications of knowledge graphs include search engines (e.g., Google Search and Microsoft Bing), email clients (e.g., Gmail), and intelligent personal assistants (e.g., Google Now, Amazon Echo, and Apple's Siri). In this paper, we present an approach that can summarize facts about a collection of entities by analyzing their relatedness in preference to summarizing each entity in isolation. Specifically, we generate informative entity summaries by selecting: (i) inter-entity facts that are similar and (ii) intra-entity facts that are important and diverse. We employ a constrained knapsack problem solving approach to efficiently compute entity summaries. We perform both qualitative and quantitative experiments and demonstrate that our approach yields promising results compared to two other stand-alone state-of-the-art entity summarization approaches.


Minding the gaps: health financing, universal health coverage and gender.
In a webinar in 2015 on health financing and gender, the question was raised why we need to focus on gender, given that a well-functioning system moving towards Universal Health Coverage (UHC) will automatically be equitable and gender balanced. This article provides a reflection on this question from a panel of health financing and gender experts.We trace the evidence of how health-financing reforms have impacted gender and health access through a general literature review and a more detailed case-study of India. We find that unless explicit attention is paid to gender and its intersectionality with other social stratifications, through explicit protection and careful linking of benefits to needs of target populations (e.g. poor women, unemployed men, female-headed households), movement towards UHC can fail to achieve gender balance or improve equity, and may even exacerbate gender inequity. Political trade-offs are made on the road to UHC and the needs of less powerful groups, which can include women and children, are not necessarily given priority.We identify the need for closer collaboration between health economists and gender experts, and highlight a number of research gaps in this field which should be addressed. While some aspects of cost sharing and some analysis of expenditure on maternal and child health have been analysed from a gender perspective, there is a much richer set of research questions to be explored to guide policy making. Given the political nature of UHC decisions, political economy as well as technical research should be prioritized.We conclude that countries should adopt an equitable approach towards achieving UHC and, therefore, prioritize high-need groups and those requiring additional financial protection, in particular women and children. This constitutes the 'progressive universalism' advocated for by the 2013 Lancet Commission on Investing in Health.


Modulation of osteogenic differentiation in human skeletal cells in Vitro by 5-azacytidine.
Cellular differentiation is controlled by a variety of factors including gene methylation, which represses particular genes as cell fate is determined. The incorporation of 5-azacytidine (5azaC) into DNA in vitro prevents methylation and thus can alter cellular differentiation pathways. Human bone marrow fibroblasts and MG63 cells treated with 5azaC were used as models of osteogenic progenitors and of a more mature osteoblast phenotype, respectively. The capacity for differentiation of these cells following treatment with glucocorticoids was investigated. 5azaC treatment led to significant expression of the osteoblastic marker alkaline phosphatase in MG63 osteosarcoma cells, which was further augmented by glucocorticoids; however, in human marrow fibroblasts alkaline phosphatase activity was only observed in glucocorticoid-treated cultures. MG63 cells represent a phenotype late in the osteogenic lineage in which demethylation is sufficient to induce alkaline phosphatase activity. Marrow fibroblasts are at an earlier stage of differentiation and require stimulation with glucocorticoids. In contrast, the expression of osteocalcin, an osteoblastic marker, was unaffected by 5azaC treatment, suggesting that regulation of expression of the osteocalcin gene does not involve methylation. These models provide novel approaches to the study of the control of differentiation in the marrow fibroblastic system.


A crosslinguistic PET study of tone perception.
In studies of pitch processing, a fundamental question is whether shared neural mechanisms at higher cortical levels are engaged for pitch perception of linguistic and nonlinguistic auditory stimuli. Positron emission tomography (PET) was used in a crosslinguistic study to compare pitch processing in native speakers of two tone languages (that is, languages in which variations in pitch patterns are used to distinguish lexical meaning), Chinese and Thai, with those of English, a nontone language. Five subjects from each language group were scanned under three active tasks (tone, pitch, and consonant) that required focused-attention, speeded-response, auditory discrimination judgments, and one passive baseline as silence. Subjects were instructed to judge pitch patterns of Thai lexical tones in the tone condition; pitch patterns of nonspeech stimuli in the pitch condition; syllable-initial consonants in the consonant condition. Analysis was carried out by paired-image subtraction. When comparing the tone to the pitch task, only the Thai group showed significant activation in the left frontal operculum. Activation of the left frontal operculum in the Thai group suggests that phonological processing of suprasegmental as well as segmental units occurs in the vicinity of Broca's area. Baseline subtractions showed significant activation in the anterior insular region for the English and Chinese groups, but not Thai, providing further support for the existence of possibly two parallel, separate pathways projecting from the temporo-parietal to the frontal language area. More generally, these differential patterns of brain activation across language groups and tasks support the view that pitch patterns are processed at higher cortical levels in a top-down manner according to their linguistic function in a particular language.


Strategies to enhance chronic disease self-management: how can we apply this to stroke?
Social Cognition Theory and the cognitive construct of self-efficacy often form the theoretical basis for many chronic disease self-management programmes. Self-efficacy can be influenced through these programmes and has been shown to be predictive of greater levels of functioning and psychological well-being. Stroke is regarded as a complex chronic disability, and individuals may share many of the same concerns as those living with other chronic diseases such as arthritis and chronic pulmonary disease. However there has been minimal reported research on the utility of self-management programmes following stroke. To comprehend the composition of chronic disease self-management programmes which could be applied to stroke, this paper examined the theoretical basis of self-management and particularly the evidence relating to interventions which have utilized self-efficacy enhancing strategies. Selected papers were retrieved from an extensive search of literature using Medline, Cinahl, PsychInfo and Web of Science databases and the Cochrane Collaboration. The search request focused on literature that specifically related to chronic disease, self-management and self-efficacy that had been published since 1995. However, seminal literature on self-efficacy produced prior to this date was also included. There is strong evidence to support the use of self-management programmes and their effect on self-efficacy and associated health outcomes. While there are differences in the nature of each chronic condition, there are similarities in the core skills required for self-management. Many effective strategies could be incorporated into current stroke rehabilitation programmes or used to develop targeted self-management interventions. Future research which informs stroke rehabilitation should utilize the evidence relating to other chronic conditions. This could be used to develop the most effective methods of equipping individuals following stroke to cope confidently with the transition from being discharged from therapy towards effective self-management in the longer term.


Development and Validity Testing of an Arthritis Self-Management Assessment Tool.
Because of the chronic, progressive nature of arthritis and the substantial effects it has on quality of life, patients may benefit from self-management. However, no valid, reliable self-management assessment tool has been devised for patients with arthritis. This study was conducted to develop a comprehensive self-management assessment tool for patients with arthritis, that is, the Arthritis Self-Management Assessment Tool (ASMAT). To develop a list of qualified items corresponding to the conceptual definitions and attributes of arthritis self-management, a measurement model was established on the basis of theoretical and empirical foundations. Content validity testing was conducted to evaluate whether listed items were suitable for assessing arthritis self-management. Construct validity and reliability of the ASMAT were tested. Construct validity was examined using confirmatory factor analysis and nomological validity. The 32-item ASMAT was developed with a sample composed of patients in a clinic in South Korea. Content validity testing validated the 32 items, which comprised medical (10 items), behavioral (13 items), and psychoemotional (9 items) management subscales. Construct validity testing of the ASMAT showed that the 32 items properly corresponded with conceptual constructs of arthritis self-management, and were suitable for assessing self-management ability in patients with arthritis. Reliability was also well supported. The ASMAT devised in the present study may aid the evaluation of patient self-management ability and the effectiveness of self-management interventions. The authors believe the developed tool may also aid the identification of problems associated with the adoption of self-management practice, and thus improve symptom management, independence, and quality of life of patients with arthritis.


Linkage between Fitness of Yeast Cells and Adenylate Kinase Catalysis.
Enzymes have evolved with highly specific values of their catalytic parameters kcat and KM. This poses fundamental biological questions about the selection pressures responsible for evolutionary tuning of these parameters. Here we are address these questions for the enzyme adenylate kinase (Adk) in eukaryotic yeast cells. A plasmid shuffling system was developed to allow quantification of relative fitness (calculated from growth rates) of yeast in response to perturbations of Adk activity introduced through mutations. Biophysical characterization verified that all variants studied were properly folded and that the mutations did not cause any substantial differences to thermal stability. We found that cytosolic Adk is essential for yeast viability in our strain background and that viability could not be restored with a catalytically dead, although properly folded Adk variant. There exist a massive overcapacity of Adk catalytic activity and only 12% of the wild type kcat is required for optimal growth at the stress condition 20°C. In summary, the approach developed here has provided new insights into the evolutionary tuning of kcat for Adk in a eukaryotic organism. The developed methodology may also become useful for uncovering new aspects of active site dynamics and also in enzyme design since a large library of enzyme variants can be screened rapidly by identifying viable colonies.


Lipoprotein metabolism by rat hepatomas. Studies on the etiology of defective dietary feedback inhibition of cholesterol synthesis.
In contrast to normal liver, it is known that in vivo hepatomas fail to decrease their rate of cholesterol biosynthesis in response to increased dietary cholesterol. From a consideration of the available data it has been hypothesized that the defect might lie in the delivery of cholesterol to the hepatoma cell. To study this further, lipoprotein interactions with rat hepatoma cells in tissue culture (HTC 7288C) and with the same cell line in vivo were investigated. HTC cells grown in a medium containing 10% calf serum exhibited saturable, specific, calcium-dependent binding of rat 125I-chylomicron remnants at 4 degrees C with half maximal saturation at 4.8 micrograms protein/ml and maximum binding of 96 ng protein/10(6) cells. At 4 degrees C, HTC cells also bound human 125I-low density lipoprotein (LDL) specifically, but bound it with a much lower affinity. These cells also exhibited specific binding for rat LDL and rat hypercholesterolemic very low density lipoprotein (VLDL). All these lipoproteins were degraded by HTC cells. Thus, it was concluded that hepatoma cells possess lipoprotein receptors that recognize and process LDL, VLDL, and chylomicron remnants. Overnight incubation of HTC cells in lipid-depleted medium containing 0.5 microM compactin increased binding of rat chylomicron remnants and of hypercholesterolemic VLDL approximately 1.7-fold without a significant change in binding affinity. LDL binding also increased, by approximately 3.5-fold. These changes were also observed when binding and internalization were measured at 37 degrees C. After HTC cells were incubated in lipid-depleted medium, the rate at which [14C]acetate was incorporated into [14C]cholesterol increased 2.5-fold. Inclusion of rat chylomicron remnants at 5-10 micrograms protein/ml prevented this increase in acetate incorporation or, if added after culture in lipid-depleted medium, reduced the increased levels back to control values. However, the rate of acetate incorporation into cholesterol by cells grown in complete medium was not decreased to levels below base line by rat chylomicron remnants. Inclusion of human LDL only partially prevented the rise or only partially reduced the increased levels back to control and did not reduce control levels below base line. Hypercholesterolemic VLDL, which contain more cholesterol per particle than chylomicron remnants, did reduce [14C]acetate incorporation to below control levels. Therefore, the intracellular mechanism for down regulation of cholesterol synthesis by lipoproteins is intact in these cells. Based on these results we hypothesized that a relative lack of lipoprotein receptors expressed by hepatomas in vivo in comparison with those expressed by normal liver would explain the apparent absence of feedback inhibition of cholesterol synthesis. Consistent with this hypothesis, the binding of chylomicron remnants to liver cell membranes was 3-5 times greater than to membranes from tumors grown in vivo subcutaneously or intramuscularly. Membranes from tumor cells grown in vitro bound remnants least well. It is proposed that the relative lack of receptors places the hepatoma at a disadvantage in competing with the liver for lipoproteins of dietary origin and may account for the lack of feedback regulation of cholesterol synthesis in hepatomas.


Treatment with granulocyte-macrophage colony-stimulating factor is associated with reduced indoleamine 2,3-dioxygenase activity and kynurenine pathway catabolites in patients with severe sepsis and septic shock.
The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) controls tryptophan metabolism and is induced by pro-inflammatory stimuli. We investigated whether immunostimulatory treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) influences IDO activity and tryptophan metabolism in sepsis. Thirty-six patients with severe sepsis/septic shock and sepsis-associated immunosuppression (assessed using monocytic human leukocyte antigen-DR (mHLA-DR) expression) were assessed in a controlled trial of GM-CSF or placebo treatment for 8 days. Using tandem mass spectrometry, levels of tryptophan, kynurenine, kynurenic acid, quinolinic acid, 5-hydroxytryptophan, serotonin, and estimated IDO activity were determined in a blinded fashion over a 9-day interval. At baseline, tryptophan and metabolite levels did not differ between the study groups. Although tryptophan levels were unchanged in both groups over the treatment interval (all p>0.8), IDO activity was markedly reduced after GM-CSF treatment (35.4 +/- 21.0 vs 21.6 +/-9.9 (baseline vs day 9), p = 0.02). IDO activity differed significantly between the 2 groups after therapy (p = 0.03). Metabolites downstream of IDO (kynurenine, quinolinic acid, kynurenic acid) were all induced in sepsis and declined in the GM-CSF group, but not in controls. Serotonin pathway metabolites remained unchanged in both groups (all p>0.15). Moreover, IDO activity correlated with procalcitonin (p< 0.0001, r = 0.56) and mHLA-DR levels (p = 0.005, r = -0.28) in the overall samples group. Thus, GM-CSF therapy is associated with decreased IDO activity and reduced kynurenine pathway catabolites in sepsis. This may be due to an improved antibacterial defence.


Predictors of Ventriculoperitoneal Shunt Revision in Patients with Idiopathic Normal Pressure Hydrocephalus.
Few studies have focused on predictive factors of ventriculoperitoneal (VP) shunt revision in patients with idiopathic normal pressure hydrocephalus (iNPH). This study aims to determine whether comorbidities and baseline symptoms are associated with the need for shunt revision. A retrospective review of patients with iNPH treated with VP shunts by the senior author from 1993 to 2013 was conducted. Demographics and baseline symptoms were compared between patients with and without shunt revision. The need for revision, total number of revisions, and time to first revision were examined. Statistical analysis was performed using simple logistic, linear, and Poisson regression, and a multivariate analysis was performed. A total of 347 patients with iNPH who received VP shunts were included. One hundred patients (28.8%) required shunt revision, with an average of 1.38 ± 0.76 revisions per patient. Mean time to revision was 19.2 ± 31.7 months. Gait and cognitive symptoms were associated with fewer revisions (incidence rate ratio, 0.45 and 0.67; P = 0.03 and 0.004, respectively). Headaches and urinary incontinence showed a greater time to revision (32.0 and 12.0 months; P = 0.014 and <0.0005, respectively). Gait instability demonstrated decreased time to revision (P < 0.0005). Preoperative symptoms, such as headaches, gait instability, cognitive decline, and urinary incontinence, were significantly correlated with number of revisions and time to first revision. These factors should be considered during the initial counseling of prognosis for patients with iNPH receiving VP shunts.


Admission CT perfusion may overestimate initial infarct core: the ghost infarct core concept.
Identifying infarct core on admission is essential to establish the amount of salvageable tissue and indicate reperfusion therapies. Infarct core is established on CT perfusion (CTP) as the severely hypoperfused area, however the correlation between hypoperfusion and infarct core may be time-dependent as it is not a direct indicator of tissue damage. This study aims to characterize those cases in which the admission core lesion on CTP does not reflect an infarct on follow-up imaging. We studied patients with cerebral large vessel occlusion who underwent CTP on admission but received endovascular thrombectomy based on a non-contrast CT Alberta Stroke Program Early CT Score (ASPECTS) >6. Admission infarct core was measured on initial cerebral blood volume (CBV) CTP and final infarct on follow-up CT. We defined ghost infarct core (GIC) as initial core minus final infarct >10 mL. 79 patients were studied. Median National Institutes of Health Stroke Scale (NIHSS) score was 17 (11-20), median time from symptoms to CTP was 215 (87-327) min, and recanalization rate (TICI 2b-3) was 77%. Thirty patients (38%) presented with a GIC >10 mL. GIC >10 mL was associated with recanalization (TICI 2b-3: 90% vs 68%; p=0.026), admission glycemia (<185 mg/dL: 42% vs 0%; p=0.028), and time to CTP (<185 min: 51% vs >185 min: 26%; p=0.033). An adjusted logistic regression model identified time from symptom to CTP imaging <185 min as the only predictor of GIC >10 mL (OR 2.89, 95% CI 1.04 to 8.09). At 24 hours, clinical improvement was more frequent in patients with GIC >10 mL (66.6% vs 39%; p=0.017). CT perfusion may overestimate final infarct core, especially in the early time window. Selecting patients for reperfusion therapies based on the CTP mismatch concept may deny treatment to patients who might still benefit from reperfusion.


Role of focal adhesions and mechanical stresses in the formation and progression of the lamellipodium-lamellum interface [corrected].
Actin network in the front part of a moving cell is organized into a lamellipodium and a lamellum. A distinct lamellipodium-lamellum interface is associated with focal adhesions and consists of a series of arclike segments linking neighboring focal adhesions in the front row. The interface advances by leaping onto new rows of focal adhesions maturating underneath the lamellipodium. We propose a mechanism of the lamellipodium-lamellum boundary generation, shape formation, and progression based on the elastic stresses generated in the lamellipodial actin gel by its friction against the focal adhesions. The crucial assumption of the model is that stretching stresses trigger actin gel disintegration. We compute the stress distribution throughout the actin gel and show that the gel-disintegrating stresses drive formation of a gel boundary passing through the row of focal adhesions. Our computations recover the lamellipodium-lamellum boundary shapes detected in cells and predict the mode of the boundary transition to the row of the newly maturing focal adhesions in agreement with the experimental observations. The model fully accounts for the current phenomenology of the lamellipodium-lamellum interface formation and advancing, and makes experimentally testable predictions on the dependence of these phenomena on the sizes of the focal adhesions, the character of the focal adhesion distribution on the substrate, and the velocity of the actin retrograde flow with respect to the focal adhesions. The phase diagram resulting from the model provides a background for quantitative classification of different cell types with respect to their ability to form a lamellipodium-lamellum interface. In addition, the model suggests a mechanism of nucleation of the dorsal and arclike actin bundles found in the lamellum.


Difficult airway response team: a novel quality improvement program for managing hospital-wide airway emergencies.
Difficult airway cases can quickly become emergencies, increasing the risk of life-threatening complications or death. Emergency airway management outside the operating room is particularly challenging. We developed a quality improvement program-the Difficult Airway Response Team (DART)-to improve emergency airway management outside the operating room. DART was implemented by a team of anesthesiologists, otolaryngologists, trauma surgeons, emergency medicine physicians, and risk managers in 2005 at The Johns Hopkins Hospital in Baltimore, Maryland. The DART program had 3 core components: operations, safety, and education. The operations component focused on developing a multidisciplinary difficult airway response team, standardizing the emergency response process, and deploying difficult airway equipment carts throughout the hospital. The safety component focused on real-time monitoring of DART activations and learning from past DART events to continuously improve system-level performance. This objective entailed monitoring the paging system, reporting difficult airway events and DART activations to a Web-based registry, and using in situ simulations to identify and mitigate defects in the emergency airway management process. The educational component included development of a multispecialty difficult airway curriculum encompassing case-based lectures, simulation, and team building/communication to ensure consistency of care. Educational materials were also developed for non-DART staff and patients to inform them about the needs of patients with difficult airways and ensure continuity of care with other providers after discharge. Between July 2008 and June 2013, DART managed 360 adult difficult airway events comprising 8% of all code activations. Predisposing patient factors included body mass index >40, history of head and neck tumor, prior difficult intubation, cervical spine injury, airway edema, airway bleeding, and previous or current tracheostomy. Twenty-three patients (6%) required emergent surgical airways. Sixty-two patients (17%) were stabilized and transported to the operating room for definitive airway management. There were no airway management-related deaths, sentinel events, or malpractice claims in adult patients managed by DART. Five in situ simulations conducted in the first program year improved DART's teamwork, communication, and response times and increased the functionality of the difficult airway carts. Over the 5-year period, we conducted 18 airway courses, through which >200 providers were trained. DART is a comprehensive program for improving difficult airway management. Future studies will examine the comparative effectiveness of the DART program and evaluate how DART has impacted patient outcomes, operational efficiency, and costs of care.


APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction.
Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer's disease.


Preparation of superoxide dismutase loaded chitosan microspheres: characterization and release studies.
Superoxide dismutase (SOD) is the most potent antioxidant enzyme. In this study, SOD was encapsulated in chitosan microspheres to obtain suitable sustained protein delivery. Protein-loaded chitosan microspheres with various formulations were prepared based on complex coacervation process. Due to the inherent characteristic of SOD, high encapsulation efficiency could not be obtained with simple preparation method. The pH of chitosan solution is 3.0; when the chitosan microspheres were prepared with this solution, encapsulation was low. Therefore, several strategies have been tested to increase the encapsulation efficiency and good results have been obtained. 70-80% protein encapsulation efficiency was obtained. The addition of PEG to the protein solution enhanced the encapsulation efficiency also. Mean sizes of microspheres were between 1.38 and 1.94 microm. Factors affecting the release behaviour of SOD from microspheres have been studied. They included pH values of chitosan solution (the pH of chitosan solution is 3.0), addition of PEG to the protein solution and the use of adsorption technique. In general, biphasic release profiles were obtained with these formulations. The protein activity changed between 70 and 100% during the release. In general, the protein activity remained in acceptable limits. The SOD encapsulated chitosan microspheres can be prepared by changing the pH or addition of PEG, allowing the safe incorporation of protein for controlled release.


Arthrodesis of the ankle: a critical analysis.
Arthrodeses of 81 ankles performed by a single surgeon were reviewed after a 12- to 74-month follow up. Average time to union was 13.8 weeks, and 71 (88%) of 81 ankles healed without a second surgery. Ten (12%) of the 81 ankles failed to unite. Of the 10 nonunions, two developed a dense fibrous union without screw failure, and eight underwent revisional surgery. Seven of the revisions united and one has a persistent nonunion. The transfibular approach was utilized, and specific factors related to this approach were assessed. A greater resection of the medial malleolus correlated to a longer healing time and to an increased rate of nonunion. Sixty (96%) of the 63 patients who returned for follow up had no signs or symptoms attributable to malalignment. The average postoperative score for ankle-hindfoot on the AOFAS evaluation was 74 points, and rate of the patient satisfaction was 65 (89%) of the 73 patients. There was no correlation between outcomes and patients ages. Greater tarsal mobility correlated with a higher postoperative score and to higher level of satisfaction.


Quantitative method for specific nucleic acid sequences using competitive polymerase chain reaction with an alternately binding probe.
We have developed a simple, cost-effective, and accurate method for the quantification of specific nucleic acid sequences by the combined use of competitive PCR and a sequence-specific fluorescent probe that binds to either the gene of interest (target) or internal standard (competitor), referred to as alternately binding probe (ABProbe). In this method, the target and competitor were coamplified with the ABProbe, and then the fluorescence intensity was measured. The ratio of the target to the competitor can be calculated from the fluorescence intensity of the ABProbe using fluorescence quenching and fluorescence resonance energy transfer, that is, the starting quantity of the target is successfully calculated by end-point fluorescence measurement. Therefore, this method eliminates the complex post-PCR steps and expensive devices for real-time fluorescence measurement. We called this method alternately binding probe competitive PCR (ABC-PCR). We quantified amoA as a model target by ABC-PCR and real-time PCR. By comparison, the sensitivity, accuracy, and precision of ABC-PCR were similar to those of real-time PCR. Moreover, ABC-PCR was able to correctly quantify DNA even when PCR was inhibited by humic acid; therefore, this method will enable accurate DNA quantification for biological samples that contain PCR inhibitors.


Data processing for atomic resolution electron energy loss spectroscopy.
The high beam current and subangstrom resolution of aberration-corrected scanning transmission electron microscopes has enabled electron energy loss spectroscopy (EELS) mapping with atomic resolution. These spectral maps are often dose limited and spatially oversampled, leading to low counts/channel and are thus highly sensitive to errors in background estimation. However, by taking advantage of redundancy in the dataset map, one can improve background estimation and increase chemical sensitivity. We consider two such approaches--linear combination of power laws and local background averaging--that reduce background error and improve signal extraction. Principal component analysis (PCA) can also be used to analyze spectrum images, but the poor peak-to-background ratio in EELS can lead to serious artifacts if raw EELS data are PCA filtered. We identify common artifacts and discuss alternative approaches. These algorithms are implemented within the Cornell Spectrum Imager, an open source software package for spectroscopic analysis.


Serum Neurofilament Light Chain Measurement in MS: Hurdles to Clinical Translation.
Measurement of serum neurofilament light chain concentration (sNfL) promises to become a convenient, cost effective and meaningful adjunct for multiple sclerosis (MS) prognostication as well as monitoring disease activity in response to treatment. Despite the remarkable progress and an ever-increasing literature supporting the potential role of sNfL in MS over the last 5 years, a number of hurdles remain before this test can be integrated into routine clinical practice. In this review we highlight these hurdles, broadly classified by concerns relating to clinical validity and analytical validity. After setting out an aspirational roadmap as to how many of these issues can be overcome, we conclude by sharing our vision of the current and future role of sNfL assays in MS clinical practice.


Intranasal diamorphine as an alternative to intramuscular morphine: pharmacokinetic and pharmacodynamic aspects.
Diamorphine is a semisynthetic derivative of morphine that is currently licensed for use in the treatment of moderate to severe acute pain, administered by the intramuscular, intravenous or subcutaneous routes. It is highly water-soluble and has a number of properties that render it suitable for administration via the nasal route. Administration via the intranasal route is well described for other drugs, but has only recently been evaluated in a clinical setting for diamorphine. A well-tolerated and rapidly effective analgesic agent has proven elusive in the paediatric setting. The pharmacokinetic profile of intranasal diamorphine in adults has been systematically studied. It is rapidly and dose-dependently absorbed as a dry powder, with peak plasma concentrations occurring within 5 minutes, and has a similar pharmacokinetic profile to that of intramuscular diamorphine. It is rapidly converted to 6-acetylmorphine (peak concentrations within 5-10 minutes) and thence to morphine (peak concentrations within 1 hour). The pharmacodynamic properties of intranasal diamorphine have also been studied in comparison with intramuscular diamorphine. Intranasal and intramuscular administration of diamorphine resulted in similar physiological responses (including pupil diameter, respiration rate and temperature). Changes in behavioural measures (including euphoria, sedation and dysphoria) were also similar. Intranasal administration of diamorphine, therefore, produces the expected drug effects on the same timescale and of the same magnitude as intramuscular injection. Intranasal diamorphine has been clinically evaluated in a randomised controlled trial versus intramuscular morphine in the setting of acute orthopaedic pain in children with fractures. Intranasal diamorphine provided the same overall degree of pain relief as intramuscular morphine, but with a quicker onset of action. It was found to be well tolerated with an acceptable safety profile. It has also been studied in the setting of patient-controlled analgesia for postoperative pain in adults, with encouraging results. The pharmacokinetic and pharmacodynamic properties of intranasal diamorphine, and particularly the ability to administer it without a needle (and therefore reduce the incidence of transmissible infection), have made this a popular route for abuse amongst opioid addicts. In this setting, however, the intranasal route is not free from adverse events, including deaths. The primary clinical need in the paediatric population is for a well tolerated, effective and expedient analgesic agent that is safe to use; intranasal diamorphine has pharmacokinetic properties that would make it suitable for such a clinical indication and, in clinical evaluations to date, appears to be promising.


Evolutionary stability of vigilance coordination among social foragers.
Coordination can greatly improve the efficiency of anti-predatory vigilance scans by increasing predator detection for a constant proportion of time spent vigilant. However, it has been rarely found in nature and most studies have detected or assumed independent scanning by group members. In this study, we analysed the functional consequences of the coordinated alternation of vigilance scanning by group foragers. We introduce coordination by assuming that interscan intervals (ISIs) follow a modified gamma distribution. Depending on the parameters of the distribution, successive scans can be evenly spaced (coordinated scanning) or may present a high overlap (uncoordinated scanning). Comparing evolutionarily stable strategies for animals that do not coordinate their scanning with animals that do coordinate their anti-predator behaviour shows that coordination has a marked effect on survival probability. Moreover, the coordinating strategy is quite robust against mutants that scan independently with exponential distributions of ISIs. However, coordination breaks down when animals can continuously adjust their level of coordination by deciding the proportion of time they spend monitoring the behaviour of other group members. In this case, coordination is only evolutionarily stable if it can be very easily achieved.


Response of dairy cows to high doses of a sustained-release bovine somatotropin administered during two lactations. 1. Production response.
This study evaluated the effect of sometribove (zinc methionyl bST) in a sustained-release formulation administered to lactating cows at concentrations up to 3.0 g every 14 d over two lactations. Eighty-two lactating Holstein cows in their first, second, or third lactation were assigned to the study. Cows received .6, 1.8, or 3.0 g of bST in one, three, or five intramuscular injections of a unit dose (.6 g) every 2 wk. Controls received five injections of the vehicle (equivalent volume to the 3.0-g treatment) every 2 wk. Injections were administered from 60 +/- 3 d postpartum until dry-off or necropsy. Thirty-eight animals were continued on treatment for a second consecutive lactation. During the 1st yr of treatment, bST increased mean 3.5% FCM by 7.2, 9.4, and 8.4 kg/d over control production (21.1 kg/d). During the 2nd yr, milk response to .6, 1.8, and 3.0 g of bST averaged 10.6, 3.6, and 4.9 kg/d over controls (24.8 kg/d). The incidence of clinical mastitis increased in the 3.0-g group relative to controls during the 2nd yr. Thus, salable FCM averaged 8.1, 9.1, and 6.2 kg/d above controls (yr 1) and 12.1, 4.7, and -2.8 kg/d (yr 2) for the .6-, 1.8-, and 3.0-g groups. Salable FCM was unaffected by mastitis at a proposed commercial dose (.6 g). Milk fat, protein, lactose, calcium, phosphorus, zinc, magnesium, and ash concentrations were unaffected by bST treatment. Calculated energy, calcium, phosphorus, and protein balances also were unaffected except for early decreases of up to 5 Mcal/d, and 40, 20, and 600 g/d, respectively, until feed intake increased. Milk serum bST concentrations greater than the assay limit of sensitivity (1 ng/ml) were routinely measurable only at doses of 1.8 and 3.0 g. Results confirmed that bST concentrations in milk serum are exceedingly small. Overall, supraphysiological doses of sometribove increased milk production with little effect on composition. No toxic effects of bST were observed.


Making psychiatry moral again: the role of psychiatry in patient moral development.
Psychiatric involvement in patient morality is controversial. If psychiatrists are tasked with shaping patient morality, the coercive potential of psychiatry is increased, treatment may be unfairly administered on the basis of patients' moral beliefs rather than medical need, moral disputes could damage the therapeutic relationship and, in any case, we are often uncertain or conflicted about what is morally right. Yet, there is also a strong case for the view that psychiatry often works through improving patient morality and, therefore, should aim to do so. Our goal is to offer a practical and ethical path through this conflict. We argue that the default psychiatric approach to patient morality should be procedural, whereby patients are helped to express their own moral beliefs. Such a procedural approach avoids the brunt of objections to psychiatric involvement in patient morality. However, in a small subset of cases where patients' moral beliefs are sufficiently distorted or underdeveloped, we claim that psychiatrists should move to a substantive approach and shape the content of those beliefs when they are relevant to psychiatric outcomes. The substantive approach is prone to the above objections but we argue it is nevertheless justified in this subset of cases.


Effects of Lactobacillus pentosus in Children with Allergen-Sensitized Atopic Dermatitis.
Recent studies have shown that oral administration of probiotics may improve the immune imbalance caused by dysbiosis of the gut microbiome in atopic dermatitis (AD). This study aimed to investigate the clinical and immunological effects of Lactobacillus pentosus in children with mild to moderate AD. Children aged 2-13 years with AD were randomized to receive either 1.0 × 1010 colony-forming units of L. pentosus or placebo, daily, for 12 weeks. The clinical severity of AD and transepidermal water loss were evaluated. Blood eosinophil counts, serum total immunoglobulin E (IgE), and cytokine levels were measured. The diversity and composition of the gut microbiota were also analyzed. Eighty-two children were recruited, and 41 were assigned to the probiotics intervention group. The mean scoring of atopic dermatitis (SCORAD) indices at baseline were 30.4 and 34.3 for the probiotics and placebo groups, respectively. At week 12, the mean indices were 23.6 and 23.1 for the probiotics and placebo groups, respectively. Clinical severity decreased significantly over time in both groups, with no significant difference between the two groups. In both groups, there were no significant differences in cytokine levels, microbial diversity, or the relative abundance of the gut microbiota at week 12 compared with the corresponding baseline values. The mean subjective scores of SCORAD indices after intervention for the probiotics group were significantly lower than those for the placebo group in IgE sensitized AD (P = 0.019). Our results show improved symptoms in the probiotics and placebo groups, and we could not find additional effects of L. pentosus in AD. However, the mean subjective scores of SCORAD indices for the probiotics group are significantly improved compared with those for the placebo group in allergen-sensitized AD.


Empirically derived guidance for social scientists to influence environmental policy.
Failure to stem trends of ecological disruption and associated loss of ecosystem services worldwide is partly due to the inadequate integration of the human dimension into environmental decision-making. Decision-makers need knowledge of the human dimension of resource systems and of the social consequences of decision-making if environmental management is to be effective and adaptive. Social scientists have a central role to play, but little guidance exists to help them influence decision-making processes. We distil 348 years of cumulative experience shared by 31 environmental experts across three continents into advice for social scientists seeking to increase their influence in the environmental policy arena. Results focus on the importance of process, engagement, empathy and acumen and reveal the importance of understanding and actively participating in policy processes through co-producing knowledge and building trust. The insights gained during this research might empower a science-driven cultural change in science-policy relations for the routine integration of the human dimension in environmental decision making; ultimately for an improved outlook for earth's ecosystems and the billions of people that depend on them.