Review article: quality of follow-up care for anaphylaxis in the emergency department.
The prevalence of allergic disorders is rising, with a corresponding increase in patients presenting to an ED with anaphylaxis. Appropriate follow up is required for patients with anaphylaxis. We reviewed two potential performance indicators for the quality of post-discharge care: (i) the rate of self-injectable adrenaline prescription; and (ii) the referral rate for follow-up care with allergy specialists. A search of Cochrane Library, PubMed and Google Scholar was performed using the following initial search string: anaphylaxis and 'emergency department'. We considered any (interventional or observational design) study assessing post-discharge care in anaphylaxis, measured by either adrenaline self-injection prescription or allergist referral. Subjects were patients with (suspected) anaphylaxis or severe allergic reaction, with no age limit. This review summarises findings from 16 relevant papers, all retrospective analyses of post-discharge care for anaphylaxis. Weighted arithmetic means were calculated for rates of prescription of adrenaline auto-injector and referral to an allergist following admission to an ED in patients with (suspected) anaphylaxis or severe allergic reaction. Prescription rates for self-injected adrenaline at the time of discharge following anaphylaxis varied from 0% to 68%, with a mean of 44%. Allergist referral rates ranged from 0% to 84%, with a mean of 33%. This review demonstrates that there is room for improvement in post-discharge care for patients who present to the ED with an anaphylactic reaction.


Evolution of the metabolic and regulatory networks associated with oxygen availability in two phytopathogenic enterobacteria.
Dickeya dadantii and Pectobacterium atrosepticum are phytopathogenic enterobacteria capable of facultative anaerobic growth in a wide range of O2 concentrations found in plant and natural environments. The transcriptional response to O2 remains under-explored for these and other phytopathogenic enterobacteria although it has been well characterized for animal-associated genera including Escherichia coli and Salmonella enterica. Knowledge of the extent of conservation of the transcriptional response across orthologous genes in more distantly related species is useful to identify rates and patterns of regulon evolution. Evolutionary events such as loss and acquisition of genes by lateral transfer events along each evolutionary branch results in lineage-specific genes, some of which may have been subsequently incorporated into the O2-responsive stimulon. Here we present a comparison of transcriptional profiles measured using densely tiled oligonucleotide arrays for two phytopathogens, Dickeya dadantii 3937 and Pectobacterium atrosepticum SCRI1043, grown to mid-log phase in MOPS minimal medium (0.1% glucose) with and without O2. More than 7% of the genes of each phytopathogen are differentially expressed with greater than 3-fold changes under anaerobic conditions. In addition to anaerobic metabolism genes, the O2 responsive stimulon includes a variety of virulence and pathogenicity-genes. Few of these genes overlap with orthologous genes in the anaerobic stimulon of E. coli. We define these as the conserved core, in which the transcriptional pattern as well as genetic architecture are well preserved. This conserved core includes previously described anaerobic metabolic pathways such as fermentation. Other components of the anaerobic stimulon show variation in genetic content, genome architecture and regulation. Notably formate metabolism, nitrate/nitrite metabolism, and fermentative butanediol production, differ between E. coli and the phytopathogens. Surprisingly, the overlap of the anaerobic stimulon between the phytopathogens is also relatively small considering that they are closely related, occupy similar niches and employ similar strategies to cause disease. There are cases of interesting divergences in the pattern of transcription of genes between Dickeya and Pectobacterium for virulence-associated subsystems including the type VI secretion system (T6SS), suggesting that fine-tuning of the stimulon impacts interaction with plants or competing microbes. The small number of genes (an even smaller number if we consider operons) comprising the conserved core transcriptional response to O2 limitation demonstrates the extent of regulatory divergence prevalent in the Enterobacteriaceae. Our orthology-driven comparative transcriptomics approach indicates that the adaptive response in the eneterobacteria is a result of interaction of core (regulators) and lineage-specific (structural and regulatory) genes. Our subsystems based approach reveals that similar phenotypic outcomes are sometimes achieved by each organism using different genes and regulatory strategies.


Constraining the preservation of organic compounds in Mars analog nontronites after exposure to acid and alkaline fluids.
The presence of organic matter in lacustrine mudstone sediments at Gale crater was revealed by the Mars Science Laboratory Curiosity rover, which also identified smectite clay minerals. Analogue experiments on phyllosilicates formed under low temperature aqueous conditons have illustrated that these are excellent reservoirs to host organic compounds against the harsh surface conditions of Mars. Here, we evaluate whether the capacity of smectites to preserve organic compounds can be influenced by a short exposure to different diagenetic fluids. We analyzed the stability of glycine embedded within nontronite samples previously exposed to either acidic or alkaline fluids (hereafter referred to as "treated nontronites") under Mars-like surface conditions. Analyses performed using multiple techniques showed higher photodegradation of glycine in the acid-treated nontronite, triggered by decarboxylation and deamination processes. In constrast, our experiments showed that glycine molecules were preferably incorporated by ion exchange in the interlayer region of the alkali-treated nontronite, conferring them a better protection against the external conditions. Our results demonstrate that smectite previously exposed to fluids with different pH values influences how glycine is adsorbed into their interlayer regions, affecting their potential for preservation of organic compounds under contemporary Mars surface conditions.


The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy.
Hereditary sensory and autonomic neuropathy 1 (HSAN1) is an autosomal dominant disorder that can be caused by variants in SPTLC1 or SPTLC2, encoding subunits of serine palmitoyl-CoA transferase. Disease variants alter the enzyme's substrate specificity and lead to accumulation of neurotoxic 1-deoxysphingolipids. We describe two families with autosomal dominant HSAN1C caused by a new variant in SPTLC2, c.547C>T, p.(Arg183Trp). The variant changed a conserved amino acid and was not found in public variant databases. All patients had a relatively mild progressive distal sensory impairment, with onset after age 50. Small fibers were affected early, leading to abnormalities on quantitative sensory testing. Sural biopsy revealed a severe chronic axonal neuropathy with subtotal loss of myelinated axons, relatively preserved number of non-myelinated fibers and no signs for regeneration. Skin biopsy with PGP9.5 labeling showed lack of intraepidermal nerve endings early in the disease. Motor manifestations developed later in the disease course, but there was no evidence of autonomic involvement. Patients had elevated serum 1-deoxysphingolipids, and the variant protein produced elevated amounts of 1-deoxysphingolipids in vitro, which proved the pathogenicity of the variant. Our results expand the genetic spectrum of HSAN1C and provide further detail about the clinical characteristics. Sequencing of SPTLC2 should be considered in all patients presenting with mild late-onset sensory-predominant small or large fiber neuropathy.


Within-team Patterns of Communication and Referral in Multimodal Treatment of Chronic Low Back Pain Patients by an Integrative Care Team.
Nonspecific chronic low back pain (CLBP) is a highly prevalent and costly public health problem with few treatment options that provide consistent and greater than modest benefits. Treatment of CLBP is shifting from unimodal to multimodal and multidisciplinary approaches, including biopsychosocially-based complementary and integrative care. Multidisciplinary approaches require unique levels of communication and coordination amongst clinicians; however, to date few studies have evaluated patterns of communication and decision making amongst clinicians collaborating in the care of challenging patients with CLBP. As part of an observational study evaluating the effectiveness and cost-effectiveness of an integrative, team-based care model for the treatment of CLBP, we used multiple qualitative research methods to characterize within-team cross-referral and communication amongst jointly-trained practitioners representing diverse biomedical and complementary disciplines. Patterns of communication and coordinated care are summarized for 3 cases of CLBP treated by multiple members (≥3) of an integrative medical team embedded within an academic hospital. Patients were aged from 36 to 88 years with varied comorbidities. Qualitative content analysis revealed 5 emergent themes regarding integrative patient care and treatment decision in this clinic: (1) the fundamental importance of the clinic's formal teamwork training; (2) the critical communicative and collaborative function of regular team meetings; (3) the importance to patient care goals of having the varied disciplines practicing "under one roof"; (4) a universal commitment to understanding and treating patients as whole persons; and (5) a shared philosophy of helping patients to help themselves. These key themes are all interconnected and form the foundation of the clinic's culture. Our qualitative findings provide context for current trends in enhancing patient-centered, coordinated, and team-based care; efforts towards better understanding interprofessional communication; overcoming barriers to successful collaboration; and identifying best practices for fostering clinical teamwork and a strong team identity. Our findings also support the need for further qualitative research, in combination with quantitative research, for evaluating the effectiveness and cost-effectiveness of resource-intensive integrative models for the treatment of chronic conditions.


Yunnan orbivirus, a new orbivirus species isolated from Culex tritaeniorhynchus mosquitoes in China.
An orbivirus designated Yunnan orbivirus (YUOV) was isolated from Culex tritaeniorhynchus mosquitoes collected in the Yunnan province of China. Electron microscopy showed particles with typical orbivirus morphology. The YUOV genome was sequenced completely and compared with previously characterized orbivirus genomes. Significant identity scores were detected between proteins encoded by the segments (Seg-1 to Seg-10) of YUOV and those encoded by their homologues in insect-borne and tick-borne orbiviruses. Analysis of VP1 (Pol) and VP2 (T2, which correlates with the virus serogroup) indicated that YUOV is a new species of the genus Orbivirus that is unrelated to the other insect-borne orbiviruses. The replication of YUOV in mosquito cell lines was restricted to Aedes albopictus cells and the virus failed to replicate in mammalian cell lines. However, intraperitoneal injection of virus into naïve mice resulted in productive, non-lethal virus replication and viraemia. Infected mice developed serum neutralizing antibodies and were protected against a new infection challenge. Sequence analysis of clones from the segments encoding outer coat proteins (Seg-3 and Seg-6) of YUOV recovered from mouse blood did not show significant changes in the sequences. The availability of the complete genome sequence will facilitate the development of sequence-specific PCR assays for the study of YUOV epidemiology in the field.


Establishment of cell line from embryonic tissue of Pipistrellus ceylonicus bat species from India & its susceptibility to different viruses.
Pipistrellus ceylonicus bat species is widely distributed in South Asia, with additional populations recorded in China and Southeast Asia. Bats are the natural reservoir hosts for a number of emerging zoonotic diseases. Attempts to isolate bat-borne viruses in various terrestrial mammalian cell lines have sometimes been unsuccessful. The bat cell lines are useful in isolation and propagation of many of the viruses harboured by bats. New stable bat cell lines are needed to help such investigations and to assist in the study of bat immunology and virus-host interactions. In this study we made an attempt to develop a cell line from P. ceylonicus bats. An effort was made to establish cell line from embryo of P. ceylonicus species of bat after seeding to Dulbecco's modified eagle medium (DMEM) supplemented with 10 per cent foetal bovine serum; a primary cell line was established and designated as NIV-BtEPC. Mitochondrial DNA profile analysis was done using cyt-b and ND-1 gene sequences from the cell line. Phylogenetic tree was constructed using neighbour-joining algorithm for cyt-b and ND-1 genes with 1000-bootstrap replicates. NIV-BtEPC cell line was susceptible to Chandipura (CHPV) and novel adenovirus (BtAdv-RLM) isolated from Rousettus leschenaulti from India but did not support multiplication of a number of Bunyaviruses, Alphaviruses and Flavivirus. This might be useful for isolation of a range of viruses and investigation of unknown aetiological agents. In this study, a new bat cell line was developed from P. ceylonicus. This cell line was successfully tested for the susceptibility to Chandipura and BtAdv-RLM virus isolated from bats. The approach developed and optimised in this study may be applicable to the other species of bats and this established cell line can be used to facilitate virus isolation and basic research into virus-host interaction.


Optical design of transparent metal grids for plasmonic absorption enhancement in ultrathin organic solar cells.
Transparent metal grid combining with plasmonic absorption enhancement is a promising replacement to indium tin oxide thin films. We numerically demonstrate metal grids in one or two dimension lead to plasmonic absorption enhancements in ultrathin organic solar cells. In this paper, we study optical design of metal grids for plasmonic light trapping and identify different plasmonic modes of the surface plasmon polaritons excited at the interfaces of glass/metal grids, metal grids/active layers, and the localized surface plasmon resonance of the metal grids using numerical calculations. One dimension metal grids with the optimal design of a width and a period lead to the absorption enhancement in the ultrathin active layers of 20 nm thickness by a factor of 2.6 under transverse electric polarized light compared to the case without the metal grids. Similarly, two dimensional metal grids provide the absorption enhancement by a factor of 1.8 under randomly polarized light.


Anisotropic intrinsic lattice thermal conductivity of phosphorene from first principles.
Phosphorene, the single layer counterpart of black phosphorus, is a novel two-dimensional semiconductor with high carrier mobility and a large fundamental direct band gap, which has attracted tremendous interest recently. Its potential applications in nano-electronics and thermoelectrics call for fundamental study of the phonon transport. Here, we calculate the intrinsic lattice thermal conductivity of phosphorene by solving the phonon Boltzmann transport equation (BTE) based on first-principles calculations. The thermal conductivity of phosphorene at 300 K is 30.15 W m(-1) K(-1) (zigzag) and 13.65 W m(-1) K(-1) (armchair), showing an obvious anisotropy along different directions. The calculated thermal conductivity fits perfectly to the inverse relationship with temperature when the temperature is higher than Debye temperature (ΘD = 278.66 K). In comparison to graphene, the minor contribution around 5% of the ZA mode is responsible for the low thermal conductivity of phosphorene. In addition, the representative mean free path (MFP), a critical size for phonon transport, is also obtained.


Regulation of sugar transport via the multiple sugar metabolism operon of Streptococcus mutans by the phosphoenolpyruvate phosphotransferase system.
In this report, we provide evidence that the transport of sugars in Streptococcus mutans via the multiple sugar metabolism system is regulated by the phosphoenolpyruvate phosphotransferase system. A ptsI-defective mutant (DC10), when grown on the multiple sugar metabolism system substrate raffinose, exhibited reduced growth, transport, and glycolytic activity with raffinose relative to the parent strain BM71. Inhibition of [3H]raffinose uptake was also observed in both BM71 and DC10 with increasing concentrations of glucose and the glucose analogs alpha-methyl glucoside and 2-deoxyglucose.


Occupational exposure level of pig facility workers to chemical and biological pollutants.
The aim of the study was to assess the impact of a fattening season on the level of airborne chemical and microbial pollutants in the pig fattening house. Evaluation of the air composition as well as the microbiological air quality were made during 2 series, i.e. in the summer and winter period of fattening. Airborne gaseous pollutants were analyzed by gas (organic compounds) and liquid (inorganic compounds) chromatography methods. Air microbial contamination was determined in compliance with the Polish Standard PN-EN 13098:2007. The air/gas composition in the pig unit showed that irrespective of the fattening season, the level of determined pollutants - especially ammonia, volatile organic compounds (VOCs), including methanethiol and total dust - could have an adverse effect on the health of swine facility workers. The investigated pig building was found to be a source of chemical pollutants as well as biological agents. The total bacterial count in 1 m3 of air was 3.6×106 and 4.6×106 cfu, during the winter and summer periods of fattening, respectively. Gram-positive cocci predominated in both seasons. In the winter, fungi of the Trichoderma genus were represented equally often. In the summer period, up to 90% of the isolated fungus was Aspergillus spp. Workers engaged in swine rearing and production are occupationally exposed not only to a high concentration of microbial contamination, but also to irritating and odorogenous volatile compounds. Thus, activities directed at the promotion of health prevention strategies, as well as effective guidelines for safe and hygienic animal housing, should be implemented.


Analysis of conformational changes in the DNA junction-resolving enzyme T7 endonuclease I on binding a four-way junction using EPR.
The four-way (Holliday) DNA junction is the central intermediate in homologous recombination. It is ultimately resolved into two nicked-duplex species by the action of a junction-resolving enzyme. These enzymes are highly selective for the structure of branched DNA, yet as a class these proteins impose significant distortion on their target junctions. Bacteriophage T7 endonuclease I selectively binds and cleaves DNA four-way junctions. The protein is an extremely stable dimer, comprising two globular domains joined by a β-strand bridge with each active site including amino acids from both polypeptides. The crystal structure of endonuclease I has been solved both as free protein and in complex with a DNA junction, showing that the protein, as well as the junction, becomes distorted on binding. We have therefore used site-specific spin-labeling in conjunction with EPR distance measurements to analyze induced fit in the binding of endonuclease I to a DNA four-way junction. The results support the change in protein structure as it binds to the junction. In addition, we have examined the structure of wild type and catalytically inactive mutants alone and in complex with DNA. We demonstrate the presence of hitherto undefined metastable conformational states within endonuclease I, showing how these states can be influenced by DNA-junction binding or mutations within the active sites. In addition, we demonstrate a previously unobserved instability in the N-terminal α1-helix upon active site mutation. These studies reveal that structural changes in both DNA and protein occur in the action of this junction-resolving enzyme.


The effects of microencapsulated Lactobacillus casei on tumour cell growth: In vitro and in vivo studies.
It has been known for some time that the micro-milieu of solid tumours provides an ideal environment for growth of facultative and strictly anaerobic bacteria, and it has been shown that certain species including Lactobacillus and Clostridium can colonise those environments leading to regression of tumour growth. Such observations have given rise to the concept of bacteriolytic therapy where live microorganisms might be employed to colonise the tumour and exert a tumorolytic effect. In choosing such an approach, it would be advantageous to exploit a relatively non-pathogenic strain and provide some form of containment that would enable site-specific injection and minimise dispersion of the microorganism throughout the host. In testing the feasibility of such an approach, we prepared microencapsulated formulations of Lactobacillus casei NCDO 161 and demonstrated that conditioned extra-capsular culture media were toxic to tumour cells in vitro. We further investigated the effects of the microencapsulated formulations on tumour growth in vivo following direct intra-tumoural injection. The study demonstrates significant inhibition of tumour growth in vivo by these formulations and suggests potential therapeutic benefit of this approach in the treatment of solid tumours.


Controllable membrane remodeling by a modified fragment of the apoptotic protein Bax.
Intrinsic apoptosis is orchestrated by a group of proteins that mediate the coordinated disruption of mitochondrial membranes. Bax is a multi-domain protein that, upon activation, disrupts the integrity of the mitochondrial outer membrane by forming pores. We strategically introduced glutamic acids into a short sequence of the Bax protein that constitutively creates membrane pores. The resulting BaxE5 peptide efficiently permeabilizes membranes at acidic pH, showing low permeabilization at neutral pH. Atomic force microscopy (AFM) imaging showed that at acidic pH BaxE5 established several membrane remodeling modalities that progressively disturbed the integrity of the lipid bilayer. The AFM data offers vistas on the membrane disruption process, which starts with pore formation and progresses through localized exposure of membrane monolayers leading to stable and small (height ∼ 16 Å) lipid-peptide complexes. The different types of membrane morphology observed in the presence of BaxE5 suggest that the peptide can establish different types of membrane interactions. BaxE5 adopts a rare unstructured conformation when bound to membranes, which might facilitate the dynamic transition between those different states, and then promote membrane digestion.


Model for non-Gaussian intraday stock returns.
Stock prices are known to exhibit non-Gaussian dynamics, and there is much interest in understanding the origin of this behavior. Here, we present a model that explains the shape and scaling of the distribution of intraday stock price fluctuations (called intraday returns) and verify the model using a large database for several stocks traded on the London Stock Exchange. We provide evidence that the return distribution for these stocks is non-Gaussian and similar in shape and that the distribution appears stable over intraday time scales. We explain these results by assuming the volatility of returns is constant intraday but varies over longer periods such that its inverse square follows a gamma distribution. This produces returns that are Student distributed for intraday time scales. The predicted results show excellent agreement with the data for all stocks in our study and over all regions of the return distribution.


Barrett's adenocarcinomas resemble adenocarcinomas of the gastric cardia in terms of chromosomal copy number changes, but relate to squamous cell carcinomas of the distal oesophagus with respect to the presence of high-level amplifications.
Three different cancers predominantly occur at the gastro-oesophageal junction: squamous cell carcinomas of the distal oesophagus, adenocarcinomas of the distal oesophagus (Barrett's carcinomas), and adenocarcinomas of the gastric cardia. The aim of the present study was to investigate how, and to what extent, Barrett's carcinoma differs from adenocarcinoma of the gastric cardia on the one hand and squamous cell carcinoma of the distal oesophagus on the other, with respect to chromosomal aberrations and related gene expression. The present study analysed 14 squamous cell carcinomas, 24 Barrett's carcinomas, and 16 carcinomas of the gastric cardia. Comparative genomic hybridization revealed chromosomal abnormalities in all cases. Typical chromosomal aberrations for the squamous cell carcinoma type were gains at 3q and 11q13, and losses at 3p, 4q, 9p, 11q, and 13q. In contrast, typical copy number changes for both cardiac and Barrett's adenocarcinomas were gains at 2q, 7p, and 13q, and losses at 17p. High-level amplification occurred in all three groups, but its frequency in the cardiac carcinomas was lower than in the other two groups. In conclusion, squamous cell carcinomas are characterized by chromosomal aberrations which are distinct from those seen in carcinomas of the gastric cardia and in Barrett's adenocarcinomas. With respect to Barrett's cancer, the chromosomal aberrations more closely reflect the adenocarcinoma phenotype than the squamous origin of the epithelium.


Trigonal scaffolds for multivalent targeting of melanocortin receptors.
Melanocortin receptors can be used as biomarkers to detect and possibly treat melanoma. To these ends, molecules bearing one, two, or three copies of the weakly binding ligand MSH(4) were attached to scaffolds based on phloroglucinol, tripropargylamine, and 1,4,7-triazacyclononane by means of the copper-assisted azide-alkyne cyclization. This synthetic design allows rapid assembly of multivalent molecules. The bioactivities of these compounds were evaluated using a competitive binding assay that employed human embryonic kidney cells engineered to overexpress the melanocortin 4 receptor. The divalent molecules exhibited 10- to 30-fold higher levels of inhibition when compared to the corresponding monovalent molecules, consistent with divalent binding. The trivalent molecules were only statistically (∼2-fold) better than the divalent molecules, still consistent with divalent binding but inconsistent with trivalent binding. Possible reasons for these behaviors and planned refinements of the multivalent constructs targeting melanocortin receptors based on these scaffolds are discussed.


Comparative evaluation of agroindustrial byproducts for the production of alkaline protease by wild and mutant strains of Bacillus subtilis in submerged and solid state fermentation.
The present study describes the screening of different agroindustrial byproducts for enhanced production of alkaline protease by a wild and EMS induced mutant strain of Bacillus subtilis IH-72(EMS8). During submerged fermentation, different agro-industrial byproducts were tested which include defatted seed meals of rape, guar, sunflower, gluten, cotton, soybean, and gram. In addition to these meals, rice bran, wheat bran, and wheat flour were also evaluated for protease production. Of all the byproducts tested, soybean meal at a concentration of 20 g/L gave maximum production of the enzyme, that is, 5.74 ± 0.26 U/mL from wild and 11.28 ± 0.45 U/mL from mutant strain, during submerged fermentation. Different mesh sizes (coarse, medium, and fine) of the soybean meal were also evaluated, and a finely ground soybean meal (fine mesh) was found to be the best. In addition to the defatted seed meals, their alkali extracts were also tested for the production of alkaline protease by Bacillus subtilis, but these were proved nonsignificant for enhanced production of the enzyme. The production of the enzyme was also studied in solid state fermentation, and different agro-industrial byproducts were also evaluated for enzyme production. Wheat bran partially replaced with guar meal was found as the best substrate for maximum enzyme production under solid state fermentation conditions.


Is arterial stiffening associated with adiposity, severity of obesity and other contemporary cardiometabolic markers in a community sample of adolescents with obesity in the UK?
Cardiovascular disease (CVD) prediction is problematic within groups of obese adolescents as measures such as adiposity and metabolic markers lack validation. Pulse wave velocity (PWV), a proxy for arterial stiffening, is a potential way to contemporaneously capture adolescents at greater risk of CVD. To investigate associations between PWV and 1) adiposity and 2) other conventional metabolic factors in a community sample of (>95th centile body mass index (BMI)). Cross-sectional measurement and analysis in a hospital-based research centre drawn from a community sample of adolescents recruited to an obesity intervention at baseline. 174 adolescents (12-19 years) with obesity (>95th centile BMI). 37% were male, while 66 (38%) were white, 53 (30%) black, 36 (21%) South Asian, 19 (11%) mixed/other. Participants with endocrine, genetic causes of obesity and chronic medical conditions (excluding asthma) were excluded. BMI z-score (zBMI), waist z-score, fat mass index (FMI: measured using bioimpedance), sagittal abdominal dimension (SAD), cardiometabolic blood tests and resting blood pressure (BP) were collected. Carotid-radial PWV was measured by a single operator. PWV was associated with age but not pubertal stage. PWV was positively associated with adiposity (zBMI: coefficient 0.44 (95% CI 0.08 to 0.79); FMI: coefficient 0.05 (95% CI 0.00 to 0.10); waist z-score: coefficient 0.27 (95% CI 0.00 to 0.53); SAD: coefficient 0.06 (95% CI: 0.00 to 0.12)). There was no association between PWV and BP, and few associations with cardiometabolic bloods. Associations between PWV and adiposity measures were robust to adjustment in multivariable models except for SAD. Participants with zBMI >2.5 SD and >3.5 SD had greater average PWV but overlap between groups was large. In our sample, increasing adiposity was positively associated with arterial stiffness, however partitioning by severity was not reliable. Lack of associations between BP, cardiometabolic bloods and arterial stiffness questions the reliability of these factors for predicting CVD risk in adolescents with obesity.


Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers in Patients Without Heart Failure? Insights From 254,301 Patients From Randomized Trials.
To compare the efficacy and safety of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) in patients without heart failure. Meta-analysis of randomized trials identified using PubMed, Embase, and Cochrane Central Register of Controlled Trials searches from January 1, 1980, through April 13, 2015, of ACEis and ARBs compared with placebo or active controls and corroborated with head-to-head trials of ARBs vs ACEis. Outcomes were all-cause mortality, cardiovascular death, myocardial infarction (MI), angina, stroke, heart failure, revascularization, and new-onset diabetes. Our search yielded 106 randomized trials that enrolled 254,301 patients. Compared with placebo, ACEis but not ARBs reduced the outcomes of all-cause mortality (ACEis vs placebo: relative risk [RR], 0.89; 95% CI, 0.80-1.00; ARBs vs placebo: RR, 1.01; 95% CI, 0.96-1.06; Pinteraction=.04), cardiovascular death (RR, 0.83; 95% CI, 0.70-0.99 and RR, 1.02; 95% CI, 0.92-1.14; Pinteraction=.05), and MI (RR, 0.83; 95% CI, 0.78-0.90 and RR, 0.93; 95% CI, 0.85-1.03; Pinteraction=.06). The meta-regression analysis revealed that the difference between ACEis and ARBs compared with placebo was due to a higher placebo event rate in the ACEis trials (most of these trials were conducted a decade earlier than the ARB trials) for the outcome of all-cause mortality (P=.001), cardiovascular death (P<.001), and MI (P=.02). Sensitivity analyses restricted to trials published after 2000 revealed similar outcomes with ACEis vs placebo and ARBs vs placebo (Pinteraction>.05). Head-to-head comparison trials of ARBs vs ACEis exhibited no difference in outcomes except for a lower risk of drug withdrawal due to adverse effects with ARBs (RR, 0.72; 95% CI, 0.65-0.81). In patients without heart failure, evidence from placebo-controlled trials (restricted to trials after 2000), active controlled trials, and head-to-head randomized trials all suggest ARBs to be as efficacious and safe as ACEis, with the added advantage of better tolerability.


EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma.
This guideline provides recommendations for diagnostic and therapeutic procedures for patients with malignant gliomas. We differentiate evidence-based standards from reasonable options or non-evidence-based measures that should no longer be considered. The recommendations herein should provide a framework and assurance for the choice of diagnostic procedures and therapeutic measures and aim to reduce complications from unnecessary treatment and cost. The guideline contributes to a critical appreciation of concurrent drugs with a focus on the controlled use of anticonvulsants and steroids. It should serve as a guideline for all professionals involved in the diagnostics and care of glioma patients and also as a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in Europe. Implementation of the recommendations summarised here will need interdisciplinary structures of care for patients with brain tumours and structured processes of diagnostic and therapeutic procedures.


Biomechanical properties and microstructure of neonatal porcine ventricles.
Neonatal heart disorders represent a major clinical challenge, with congenital heart disease alone affecting 36,000 new-borns annually within the European Union. Surgical intervention to restore normal function includes the implantation of synthetic and biological materials; however, a lack of experimental data describing the mechanical behaviour of neonatal cardiac tissue is likely to contribute to the relatively poor short- and long-term outcome of these implants. This study focused on characterising the mechanical behaviour of neonatal cardiac tissue using a porcine model, to enhance the understanding of how this differs to the equivalent mature tissue. The biomechanical properties of neonatal porcine cardiac tissue were characterised by uniaxial tensile, biaxial tensile, and simple shear loading modes, using samples collected from the anterior and posterior walls of the right and left ventricles. Histological images were prepared using Masson's trichrome staining, to enable assessment of the microstructure and correlation with tissue behaviour. The mechanical tests demonstrated that the neonatal cardiac tissue is non-linear, anisotropic, viscoelastic and heterogeneous. Our data provide a baseline describing the biomechanical behaviour of immature porcine cardiac tissue. Comparison with published data also indicated that the neonatal porcine cardiac tissue exhibits one-half the stiffness of mature porcine tissue in uniaxial extension testing, one-third in biaxial extension testing, and one-fourth stiffness in simple shear testing; hence, it provides an indication as to the relative change in characteristics associated with tissue maturation. These data may prove valuable to researchers investigating neonatal cardiac mechanics.


Bayesian evaluation of effect size after replicating an original study.
The vast majority of published results in the literature is statistically significant, which raises concerns about their reliability. The Reproducibility Project Psychology (RPP) and Experimental Economics Replication Project (EE-RP) both replicated a large number of published studies in psychology and economics. The original study and replication were statistically significant in 36.1% in RPP and 68.8% in EE-RP suggesting many null effects among the replicated studies. However, evidence in favor of the null hypothesis cannot be examined with null hypothesis significance testing. We developed a Bayesian meta-analysis method called snapshot hybrid that is easy to use and understand and quantifies the amount of evidence in favor of a zero, small, medium and large effect. The method computes posterior model probabilities for a zero, small, medium, and large effect and adjusts for publication bias by taking into account that the original study is statistically significant. We first analytically approximate the methods performance, and demonstrate the necessity to control for the original study's significance to enable the accumulation of evidence for a true zero effect. Then we applied the method to the data of RPP and EE-RP, showing that the underlying effect sizes of the included studies in EE-RP are generally larger than in RPP, but that the sample sizes of especially the included studies in RPP are often too small to draw definite conclusions about the true effect size. We also illustrate how snapshot hybrid can be used to determine the required sample size of the replication akin to power analysis in null hypothesis significance testing and present an easy to use web application (https://rvanaert.shinyapps.io/snapshot/) and R code for applying the method.


Coherent amygdalocortical theta promotes fear memory consolidation during paradoxical sleep.
Brain activity in sleep plays a crucial role in memory consolidation, an offline process that determines the long-term strength of memory traces. Consolidation efficacy differs across individuals, but the brain activity dynamics underlying these differences remain unknown. Here, we studied how interindividual variability in fear memory consolidation relates to neural activity in brain structures that participate in Pavlovian fear learning. From the end of training to testing 24 h later, some rats showed increased and others decreased conditioned fear responses. We found that overnight bidirectional changes in fear memory were selectively correlated with modifications in theta coherence between the amygdala, medial prefrontal cortex, and hippocampus during paradoxical sleep. Thus, our results suggest that theta coordination in the limbic system may influence interindividual differences in memory consolidation of aversive experiences.


Behavior analysts in the war on poverty: Developing an operant antipoverty program.
Poverty is associated with poor health and affects many United States residents. The therapeutic workplace, an operant intervention designed to treat unemployed adults with histories of drug addiction, could form the basis for an effective antipoverty program. Under the therapeutic workplace, participants receive pay for work. To promote drug abstinence or medication adherence, participants must provide drug-free urine samples or take scheduled doses of medication, respectively, to maintain maximum pay. Therapeutic workplace participants receive job-skills training in Phase 1 and perform income-producing jobs in Phase 2. Many unemployed, drug-addicted adults lack skills they would need to obtain high-skilled and high-paying jobs. Many of these individuals attend therapeutic workplace training reliably, but only when offered stipends for attendance. They also work on training programs reliably, but only when they earn stipends for performance on training programs. A therapeutic workplace social business can promote employment, although special contingencies may be needed to ensure that participants are punctual and work entire work shifts, and social businesses do not reliably promote community employment. Therapeutic workplace participants work with an employment specialist to seek community employment, but primarily when they earn financial incentives. Reducing poverty is more challenging than promoting employment, because it requires promoting employment in higher paying, full-time and steady jobs. Although a daunting challenge, promoting the type of employment needed to reduce poverty is an important goal, both because of the obvious benefit in reducing poverty itself and in the potential secondary benefit of reducing poverty-related health disparities. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Whole-cell microtiter plate screening assay for terminal hydroxylation of fatty acids by P450s.
A readily available galactose oxidase (GOase) variant was used to develop a whole cell screening assay. This endpoint detection system was applied in a proof-of-concept approach by screening a focussed mutant library. This led to the discovery of the thus far most active P450 Marinobacter aquaeolei mutant catalysing the terminal hydroxylation of fatty acids.


Pelvic anatomy on preoperative magnetic resonance imaging can predict early continence after robot-assisted radical prostatectomy.
Postoperative incontinence is multifactorial after radical prostatectomy. Using endorectal coil MRI, we examined features of the male urethra and accompanying muscular sphincter to predict continence after robot-assisted radical prostatectomy (RARP). 80 patients underwent preoperative 1.5 Tesla endorectal coil MRI. Urethral length was measured in the coronal plane. All patients underwent RARP. Questionnaires were completed by patients at monthly intervals. The primary end point was time to continence defined as necessitating 0 to 1 pad per day (PPD). Statistical analysis was performed using Cox regression models to create both univariate and multivariate survival models. Mean age was 59.7 (standard deviation [SD] 7.1); 98% had bilateral nerve sparing. Mean urethral length was 17.1 mm (SD 4.5 mm). Mean prostate size was 34.7 g (SD 17.8). By 3 months, 60 patients achieved 1 PPD (mean 8.1 weeks, SD 9.4) and 34 patients achieved 0 PPD (mean 10.5 weeks, SD 8.0). Time to social continence was significantly related to prostate size both as a continuous variable (P=0.01), and as a dichotomized variable of ≥ 50 vs<50 g (P=0.02). Increased urethral length was related to decreased time to continence both as a continuous variable (P=0.06), and when dichotomized to ≥ 20 vs<20 mm (P=0.08). In addition to larger prostate size (hazard ratio [HR] 0.97, P<0.04), older age (0.95 P<0.025) was also associated with a longer time to achieve 0 PPD. Multivariate analysis revealed that longer urethral length was associated with a faster recovery of continence (HR 1.11, P<0.01). After controlling for age and urethral length, patients with a prostate size ≥ 50 g had 75% lower likelihood of achieving continence at all time points when compared with patients with prostate size <50 g (HR 0.25; 95% confidence interval: 0.06, 1.06; P=0.06). Longer urethral length increased the likelihood of achieving continence at all time points postoperatively. Advanced age and larger prostate size were negatively associated with continence outcomes.


Shifting care from community hospitals to intensive community support: a mixed method study.
Aim To examine how the introduction of intensive community support (ICS) affected admissions to community hospital (CH) and to explore the views of patients, carers and health professionals on this transition. ICS was introduced to provide an alternative to CH provision for patients (mostly very elderly) requiring general rehabilitation. Routine data from both services were analysed to identify the number of admissions and length of stay between September 2012 and September 2014. In total, 10 patients took part in qualitative interviews. Qualitative interviews and focus groups were undertaken with 19 staff members, including managers and clinicians. Findings There were 5653 admissions to CH and 1710 to ICS between September 2012 and September 2014. In the five months before the introduction of ICS, admission rates to CH were on average 217/month; in the final five months of the study, when both services were fully operational, average numbers of patients admitted were: CH 162 (a 25% reduction), ICS 97, total 259 (a 19% increase). Patients and carers rated both ICS and CH favourably compared with acute hospital care. Those who had experienced both services felt each to be appropriate at the time; they appreciated the 24 h availability of staff in CH when they were more dependent, and the convenience of being at home after they had improved. In general, staff welcomed the introduction of ICS and appreciated the advantages of home-based rehabilitation. Managers had a clearer vision of ICS than staff on the ground, some of whom felt underprepared to work in the community. There was a consensus that ICS was managing less complex and dependent patients than had been envisaged. ICS can provide a feasible adjunct to CH that is acceptable to patients. More work is needed to promote the vision of ICS amongst staff in both community and acute sectors.


Gain-of-function Lyn induces anemia: appropriate Lyn activity is essential for normal erythropoiesis and Epo receptor signaling.
Lyn is involved in erythropoietin (Epo)-receptor signaling and erythroid homeostasis. Downstream pathways influenced following Lyn activation and their significance to erythropoiesis remain unclear. To address this, we assessed a gain-of-function Lyn mutation (Lyn(up/up)) on erythropoiesis and Epo receptor signaling. Adult Lyn(up/up) mice were anemic, with dysmorphic red cells (spherocyte-like, acanthocytes) in their circulation, indicative of hemolytic anemia and resembling the human disorder chorea acanthocytosis. Heterozygous Lyn(+/up) mice became increasingly anemic with age, indicating that the mutation was dominant. In an attempt to overcome this anemia, extramedullary erythropoiesis was activated. As the mice aged, the levels of different immature erythroid populations changed, indicating compensatory mechanisms to produce more erythrocytes were dynamic. Changes in Epo signaling were observed in Lyn(+/up) erythroid cell lines and primary CD71(+) Lyn(up/up) erythroblasts, including significant alterations to the phosphorylation of Lyn, the Epo receptor, Janus kinase 2, Signal Transducer and Action of Transcription-5, GRB2-associated-binding protein-2, Akt, and Forkhead box O3. As a consequence of altered Lyn signaling, Lyn(+/up) cells remained viable in the absence of Epo but displayed delayed Epo-induced differentiation. These data demonstrate that Lyn gene dosage and activity are critical for normal erythropoiesis; constitutively active Lyn alters Epo signaling, which in turn produces erythroid defects.


CXCL12/CXCR4 axis triggers the activation of EGF receptor and ERK signaling pathway in CsA-induced proliferation of human trophoblast cells.
Our previous study has demonstrated Cyclosporin A (CsA) promotes the proliferation of human trophoblast cells. Therefore, we further investigate the intracellular signaling pathway involved in the CsA-induced proliferation of human trophoblast cells. Enzyme-linked immunosorbent assay (ELISA) was performed to evaluate the regulation of CsA on CXCL12 secretion in human trophoblast cells. Immunofluorescence analysis and western blotting analysis were used to investigate the role of CXCL12/CXCR4 axis in the CsA-induced epidermal growth factor receptor (EGFR) phosphorylation in human trophoblast cells. 5-Bromo-2'-deoxyuridine (BrdU) cell proliferation assay was performed to analyze the involvement of EGFR and its downstream extracellular signal-regulated protein kinase (ERK) signaling pathway in the CsA-induced proliferation of human trophoblast cells. Low concentration of CsA promoted the secretion of CXCL12, and recombinant human CXCL12 promoted the phosphorylation of EGFR in primary human trophoblast cells and choriocarcinoma cell line JEG-3. The inhibition of CXCL12 or CXCR4 by either neutralizing antibodies or small interfering RNA (siRNA) could completely block the CsA-induced EGFR phosphorylation. The CsA-induced proliferation of human trophoblast cells was effectively abrogated by the EGFR inhibitor AG1478 as well as the ERK inhibitor U0126, but not by the PI3K/PKB inhibitor LY294002. CsA promoted the activation of ERK in JEG-3 cells, which was markedly abrogated in the presence of CXCL12 siRNA, or CXCR4 siRNA, or AG1478. CsA may promote EGFR activation via CXCL12/CXCR4 axis, and EGFR downstream ERK signaling pathway may be involved in the CsA-induced proliferation of human trophoblast cells.


Human iPSC-derived endothelial cell sprouting assay in synthetic hydrogel arrays.
Activation of vascular endothelial cells (ECs) by growth factors initiates a cascade of events during angiogenesis in vivo consisting of EC tip cell selection, sprout formation, EC stalk cell proliferation, and ultimately vascular stabilization by support cells. Although EC functional assays can recapitulate one or more aspects of angiogenesis in vitro, they are often limited by undefined substrates and lack of dependence on key angiogenic signaling axes. Here, we designed and characterized a chemically-defined model of endothelial sprouting behavior in vitro using human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs). We rapidly encapsulated iPSC-ECs at high density in poly(ethylene glycol) (PEG) hydrogel spheres using thiol-ene chemistry and subsequently encapsulated cell-dense hydrogel spheres in a cell-free hydrogel layer. The hydrogel sprouting array supported pro-angiogenic phenotype of iPSC-ECs and supported growth factor-dependent proliferation and sprouting behavior. iPSC-ECs in the sprouting model responded appropriately to several reference pharmacological angiogenesis inhibitors of vascular endothelial growth factor, NF-κB, matrix metalloproteinase-2/9, protein kinase activity, and β-tubulin, which confirms their functional role in endothelial sprouting. A blinded screen of 38 putative vascular disrupting compounds from the US Environmental Protection Agency's ToxCast library identified six compounds that inhibited iPSC-EC sprouting and five compounds that were overtly cytotoxic to iPSC-ECs at a single concentration. The chemically-defined iPSC-EC sprouting model (iSM) is thus amenable to enhanced-throughput screening of small molecular libraries for effects on angiogenic sprouting and iPSC-EC toxicity assessment. Angiogenesis assays that are commonly used for drug screening and toxicity assessment applications typically utilize natural substrates like Matrigel(TM) that are difficult to spatially pattern, costly, ill-defined, and may exhibit lot-to-lot variability. Herein, we describe a novel angiogenic sprouting assay using chemically-defined, bioinert poly(ethylene glycol) hydrogels functionalized with biomimetic peptides to promote cell attachment and degradation in a reproducible format that may mitigate the need for natural substrates. The quantitative assay of angiogenic sprouting here enables precise control over the initial conditions and can be formulated into arrays for screening. The sprouting assay here was dependent on key angiogenic signaling axes in a screen of angiogenesis inhibitors and a blinded screen of putative vascular disrupting compounds from the US-EPA.


Increased immunoendocrine cells in intestinal mucosa of postinfectious irritable bowel syndrome patients 3 years after acute Shigella infection--an observation in a small case control study.
Postinfectiously irritable bowel syndrome (PI-IBS) develops in 3-30% of individuals with bacterial gastroenteritis. Recent studies demonstrated increases in inflammatory components in gut mucosa of PI-IBS patients even after complete resolution of infection. We aimed to investigate histological changes in colon and rectum of PI-IBS subjects after long term period of infection. We recruited PI-IBS subjects who had been diagnosed IBS after complete resolution of enteritis caused by shigellosis outbreak 3 years earlier. We compared unmatched four groups, PI-IBS (n = 4), non PI-IBS (n = 7), D-IBS (n = 7, diarrhea predominant type) and healthy controls (n = 10). All of them underwent colonoscopic biopsy at three areas, including descending colon (DC), sigmoid colon (SC) and rectum, which were assessed for 5-hydroxytryptamine (5-HT)/peptide YY (PYY)-containing enterochromaffin (EC) cell, intraepithelial (IEL) and lamina propria T lymphocyte (CD3), CD8 lymphocytes, mast cells and CD68/calprotectin+ macrophages. All subjects had no structural or gross abnormalities at colonoscopy. In PI-IBS, 5-HT containing EC cells, PYY containing EC cells, IELs, CD3 lymphocytes, CD8 lymphocytes, mast cells, and CD68 + macrophages were increased compared to control (p < 0.05). In D-IBS, PYY containing EC cells, IELs, and CD3 lymphocytes were increased compared to control (p < 0.05). In PI-IBS, 5-HT containing EC cells tended to increase and PYY containing EC cells, CD8 lymphocytes, mast cells, and CD68+ macrophages were increased compared to non PI-IBS (p < 0.05). Calprotectin + marcrophages were decreased in PI-IBS, non PI-IBS and IBS compared to control. The immunoendocrine cells were sporadically increased in PI-IBS, non PI-IBS and D-IBS compared with control. Our findings in a very small number of patients suggest that mucosal inflammation may play a role in long-term PI-IBS, and that other sub-groups of IBS and larger scale studies are needed to confirm this observation.


Natural product modulators of transient receptor potential (TRP) channels as potential anti-cancer agents.
Treatment of cancer is a significant challenge in clinical medicine, and its research is a top priority in chemical biology and drug discovery. Consequently, there is an urgent need for identifying innovative chemotypes capable of modulating unexploited drug targets. The transient receptor potential (TRPs) channels persist scarcely explored as targets, despite intervening in a plethora of pathophysiological events in numerous diseases, including cancer. Both agonists and antagonists have proven capable of evoking phenotype changes leading to either cell death or reduced cell migration. Among these, natural products entail biologically pre-validated and privileged architectures for TRP recognition. Furthermore, several natural products have significantly contributed to our current knowledge on TRP biology. In this Tutorial Review we focus on selected natural products, e.g. capsaicinoids, cannabinoids and terpenes, by highlighting challenges and opportunities in their use as starting points for designing natural product-inspired TRP channel modulators. Importantly, the de-orphanization of natural products as TRP channel ligands may leverage their exploration as viable strategy for developing anticancer therapies. Finally, we foresee that TRP channels may be explored for the selective pharmacodelivery of cytotoxic payloads to diseased tissues, providing an innovative platform in chemical biology and molecular medicine.


Development and Feasibility of a Regulated, Supramaximal High-Intensity Training Program Adapted for Older Individuals.
Background: High-intensity training (HIT) with extremely short intervals (designated here as supramaximal HIT) is a time-efficient training method for health and performance. However, a protocol for regulation and control of intensity is missing, impeding implementation in various groups, such as older individuals. Methods: This study presents the development and characteristics of a novel training protocol with regulated and controlled supramaximal intervals adapted for older people. Using both quantitative and qualitative analyses, we explored the feasibility of the program, performed in a group training setting, with physically active older individuals (aged 65-75, n = 7; five women). The developed supramaximal HIT program consisted of 10 × 6 s cycle sprint intervals with ∼1 min of active recovery with the following key characteristics: (1) an individual target power output was reached and maintained during all intervals and regulated and expressed as the percentage of the estimated maximum mean power output for the duration of the interval (i.e., 6 s); (2) pedaling cadence was standardized for all participants, while resistance was individualized; and (3) the protocol enabled controlled and systematic adjustments of training intensity following standardized escalation criteria. Aim: Our aim was to test the feasibility of a novel training regimen with regulated and controlled supramaximal HIT, adapted for older people. The feasibility criteria for the program were to support participants in reaching a supramaximal intensity (i.e., power output > 100% of estimated VO2 max), avoid inducing a negative affective response, and have participants perceive it as feasible and acceptable. Results: All feasibility criteria were met. The standardized escalation procedure provided safe escalation of training load up to a supramaximal intensity (around three times the power output at estimated VO2 max). The participants never reported negative affective responses, and they perceived the program as fun and feasible. Conclusion: This novel program offers a usable methodology for further studies on supramaximal HIT among older individuals with different levels of physical capacity. Future research should explore the effects of the program in various populations of older people and their experiences and long-term adherence compared with other forms of training.


Optimal design for the quasi-phase- matching three-wave mixing.
Expressions for the quasi-phase-matching (QPM) three-wave mixing (TWM) with arbitrary grating structure and phase shift are obtained in this paper, for the first time, under the small-signal approximation. The expressions can be extensively applied to the all-optical signal processing for TWM, in which the signal and pump bandwidth of the wavelength conversion in DFM and the all-optical gate (AOG) bandwidth in SFM are all optimized. The optimal results from our expressions are compared with the results from the coupled-mode equations of QPM-TWM. Compared with loss free, the propagation loss in waveguides can decrease the conversion efficiency, but only a little change for the bandwidth.


Using human error theory to explore the supply of non-prescription medicines from community pharmacies.
The importance of theory in underpinning interventions to promote effective professional practice is gaining recognition. The Medical Research Council framework for complex interventions has assisted in promoting awareness and adoption of theory into study design. Human error theory has previously been used by high risk industries but its relevance to healthcare settings and patient safety requires further investigation. This study used this theory as a framework to explore non-prescription medicine supply from community pharmacies. The relevance to other healthcare settings and behaviours is discussed. A 25% random sample was made of 364 observed consultations for non-prescription medicines. Each of the 91 consultations was assessed by two groups: a consensus group (stage 1) to identify common problems with the consultation process, and an expert group (stages 2 and 3) to apply human error theory to these consultations. Paired assessors (most of whom were pharmacists) categorised the perceived problems occurring in each consultation (stage 1). During stage 2 paired assessors from an expert group (comprising patient safety experts, community pharmacists and psychologists) considered whether each consultation was compliant with professional guidelines for the supply of pharmacy medicines. Each non-compliant consultation identified during stage 2 was then categorised as a slip/lapse, mistake, or violation using human error theory (stage 3). During stage 1 most consultations (n = 75, 83%) were deemed deficient in information exchange. At stage 2, paired assessors varied in attributing non-compliance to specific error types. Where agreement was achieved, the error type most often selected was "violation" (n = 27, 51.9%, stage 3). Consultations involving product requests were less likely to be guideline compliant than symptom presentations (OR 0.30, 95% CI 0.10 to 0.95, p = 0.05). The large proportion of consultations classified as violations suggests that either pharmacy staff are unaware of professional guidelines and thus do not follow them (therefore these acts would not be violations), or that they knowingly violate the guidelines due to reasons that need further research. The methods presented here could be used in other healthcare settings to explore healthcare professional behaviour and to develop strategies to promote patient safety and effective professional practice.


Serum transferrin receptor in children: usefulness for determinating the nature of anemia in infection.
To know the variations of serum transferrin receptor (sTfR) and its indices depending on the status of body iron and the presence of infection in children, to evaluate their usefulness for recognizing the nature of anemia in infection, and to know the role of erythropoietic activity in these conditions. Three hundred and sixty-eight children between 1 and 10 years were included: 206 healthy children; 60 iron deficient anemic children (IDA); 102 with anemia and infectious disease, 58 of them meeting criteria for IDA. We measured hemoglobin, red cell indices, reticulocytes, transferrin saturation, serum ferritin, erythrocyte protoporphyrin, serum erythropoietin, and sTfR. Statistic method: ANOVA test, multiple linear regression, and ROC curve. sTfR, sTfR/ferritin ratio, and sTfR-logferritin index values were found to increase significantly in IDA children. These values were significantly lower in infectious anemia than iron deficiency states. Serum erythropoietin only was elevated significantly in iron deficiency states. In children without infection, mean corpuscular hemoglobin, erythrocyte protoporphirin, erythropoietin logarithm, and total-iron-binding-capacity logarithm predicted 81% of sTfR variability. sTfR and its indices showed a very high sensitivity and specificity for recognizing iron deficiency states. In children with IDA and infection sensitivity for sTfR/ferritin ratio was low (area under the curve: 0.71; 95% confidence interval: 0.64-0.88). For discriminating the nature of anemia in infection the cut-off point obtained for sTfR, sTfR/ferritin ratio, and sTfR-F index were 3, 70, and 1.8, respectively, and their sensitivity and specificity were also very high. sTfR, sTfR/ferritin ratio, and sTfR-F index are useful parameters for recognizing iron deficiency and the nature of anemia in infection. In IDA+infection, sTfR/ferritin ratio should not be recommended in the diagnosis of iron deficiency. In iron deficiency, erythropoietic activity has a secondary role as predictor factor of sTfR levels.


The effect of attention bias modification on depressive symptoms in a comorbid sample: a randomized controlled trial.
Studies investigating the long-term effect of attention bias modification (ABM) in clinical samples are lacking. This study investigates the 6-months follow-up effect of ABM on depressive symptoms in participant with major depressive disorder with and without comorbid disorders. We conducted a double-blind randomized sham-controlled trial in 101 participants between 19 November 2019, and 17 August 2021. Follow-up ended 3 April 2022. Participants were allocated to ABM or sham condition twice daily for 14 consecutive days. Primary outcomes were the total score on the Beck Depression Inventory-II (BDI-II) at 6 months, mean Brief State Rumination Inventory (BSRI) score post-treatment and reduction in BSRI post-treatment. Secondary outcome was change in attentional bias (AB). The trial was preregistered in ClinicalTrials.gov (#NCT04137367). A total of 118 patients aged 18-65 years were assessed for eligibility, and 101 were randomized and subjected to intention-to-treat analyses. At 6 months, ABM had no effect on depression and anxiety compared to a sham condition. While rumination decreased during the intervention, there was no effect of condition on rumination and AB. Predictor analysis did not reveal differences between participants with ongoing major depressive episode or comorbid anxiety. Compared to sham training, there was no effect of ABM on depressive symptoms at 6-months follow-up. Since the intervention failed at modifying AB, it is unclear whether changes in AB are related to long-term outcomes.


L-Carnitine reduces the negative effects of formalin on sperm parameters, chromatin condensation and apoptosis in mice: An experimental study.
Formalin is commonly applied as an antiseptic and tissue fixative. It has reactive molecules that lead to its cytotoxic effects. According to recent studies, formalin causes a change in the testicular and sperm structure and L-carnitine (LC) acts as an antioxidant to counteract its effects. This study aimed to investigate the protective effects of LC on the parameters, chromatin condensation and apoptosis of mice sperm exposed to formalin. In this experimental study, 24 balb/c mice (25-40 gr,10-12 wk) were divided into three groups (n = 8/each): group I without any injections or gavage; group II, received 10 mg/ kg formalin intraperitoneally (I.P); and group III was exposed to formalin and LC, where a dose of 10 mg/kg formalin was injected I.P daily and LC the dose of 100 mg/kg was kept in a solvent solution. After 31 days, the sperm examination was performed as follows: to evaluate chromatin and DNA quality of the sperm, we applied aniline blue (AB), toluidine blue (TB), chromomycin A3 (CMA3), and terminal transferase-mediated deoxy uridine triphosphate biotin end labeling (TUNEL) tests. Sperm parameters such as count, motility, morphology, and viability displayed a significant decrease in the formalin group. While the data exhibited a considerable augment in sperm parameters in the formalin + LC than the formalin and control groups (p < 0.001), significant differences were detected between groups with respect to TB staining, TUNEL test, CMA3 test and AB staining in the formalin and formalin + LC groups. LC can reduce the negative effects of formalin on sperm parameters, chromatin stability, and percentage of apoptosis in an animal model.


Estimating the associations of apparent temperature and inflammatory, hemostatic, and lipid markers in a cohort of midlife women.
Associations between temperature and cardiovascular (CVD) mortality have been reported, but the underlying biological mechanisms remain uncertain. We explored the association between apparent temperature and serum biomarkers for CVD. Using linear mixed effects models, we examined the relationships between residence-proximate apparent temperature (same day and 1, 7, and 30 days prior) and several inflammatory, hemostatic, and lipid biomarkers for midlife women from 1999 through 2004. Our study population consisted of 2,306 women with mean age of 51 years (± 3 years) enrolled in Study of Women's Health Across the Nation (SWAN) in Chicago, Illinois; Detroit, Michigan; Los Angeles and Oakland, California; Newark, New Jersey; and Pittsburgh, Pennsylvania. Mean daily apparent temperature was calculated using temperature and relative humidity data provided by the National Climatic Data Center and the US Environmental Protection Agency, while daily data for fine particles, ozone, carbon monoxide, and nitrogen dioxide from the US Environmental Protection Agency Air Quality Data Mart were considered as confounders. All analyses were stratified by warm and cold seasons. More significant (p < 0.10) negative associations were found during the warm season for various lag times, including hs-CRP, fibrinogen, tissue plasminogen activator antigen (tPA-ag), tissue plasminogen activator antigen (PAI-1), Factor VIIc, high-density lipoprotein (HDL), and total cholesterol. During the cold season, significant negative associations for fibrinogen and HDL, but significant positive associations for tPA-ag, PAI-1, and triglycerides were observed for various lag times. With the exception of ozone, pollutants did not confound these associations. Apparent temperature was associated with several serum biomarkers of CVD risk in midlife women, shedding light on potential mechanisms.


Low pH modulation of recombinant vanilloid receptors and perivascular capsaicin-sensitive sensory neurotransmission.
The effect of low pH on capsaicin-sensitive sensory neurotransmission in the rat isolated mesenteric arterial bed and at recombinant (rVR1) vanilloid receptors was investigated. Mesenteric sensory neurogenic vasorelaxation elicited by electrical field stimulation was reversibly inhibited by lowering pH from 7.4 to 6.9 and 6.3. Capsaicin-induced vasorelaxation was not different at pH 6.9, but was attenuated at pH 6.3. Vasorelaxation to calcitonin gene-related peptide, the principal sensory motor neurotransmitter in rat mesenteric arteries, was not different at pH 6.9 or pH 6.3. In rVR1-transfected HEK293 cells, acidic conditions enhanced the affinities of capsaicin and capsazepine at rVR1, but did not affect the potency of carbachol at endogenous muscarinic receptors. Following inactivation of endogenous acid-sensitive ion channels, lowering pH (6.0-4.5) directly increased [Ca2+]i in rVR1-HEK293 cells (EC50 5.5). This response was abolished by 1 microM capsazepine. In conclusion, a decrease in pH (to 6.9 and 6.3) enhances the affinity of capsaicin at rVR1, but inhibits sensory neurotransmission in the rat mesenteric arterial bed. This likely explains why there is no evidence of an enhancement of sensitivity to capsaicin at endogenous vanilloid receptors, as observed with rVR1. When pH is reduced still further (6.0-5.5) there is direct activation of rVR1.


A pilot study exploring mental health consumers' experiences with the police.
Police encounters with people experiencing mental illness are both common and problematic. While there is an international body of literature on police officers' perceptions of mental-health-related incidents, few studies have sought to understand these encounters from the perspectives of people experiencing mental illness. This pilot study recruited 26 people through a state-wide Consumer Advisory Group who completed an online survey regarding their encounters with police. Results indicated that when people perceived procedurally just treatment from police they were more likely to co-operate with them and to evaluate the encounter positively. The nature of police involvement and levels of internalised stigma moderated the association between perceived procedural justice and their evaluation. Prior contacts were also important in shaping participants' overall attitudes towards police. Findings highlight the importance of officers treating people experiencing mental illness fairly and respectfully to facilitate peaceful encounters and help foster more positive perceptions of the police.


R factor tetracycline and chloramphenicol resistance in Escherichia coli K12 cmlB mutants.
The isolation of Escherichia coli chromosomal mutants that increased the level of resistance of a partially tetracycline-sensitive mutant of RI00-I is described. Plasmid-less derivatives of these moderately resistant mutants were phenotypically similar to the cmlB mutants described by Reeve (1966, 1968), and also mapped in the same region. The level of intrinsic resistance to both chloramphenicol and tetracycline was increased about twofold. Also, the levels of R factor-determined resistance to these drugs were increased by this host mutation and tetracycline resistance was expressed constitutively. A cmlB accumulated tetracycline at a threefold lower rate than the wild-type strain, and it is proposed that the mutants have an altered permeability to the drugs and that this acts synergistically with the products of the R factor chloramphenicol and tetracycline resistance genes.


Nomogram for predicting level V lymph node metastases in papillary thyroid carcinoma with clinically lateral lymph node metastases: A large retrospective cohort study of 1037 patients from FDUSCC.
Objective: Extensive lateral neck dissection (LND), especially routine level V dissection, may potentially increase morbidity and have no significant benefit to survival in patients with papillary thyroid carcinoma (PTC). Our study aimed to determine the pattern and risk factors for level V lymph node metastasis (LNM) and to develop an assessment model based on a nomogram for predicting whether level V dissection is necessary. Methods: A total of 1037 PTC patients with clinically suspected LNM (N1b) who underwent total thyroidectomy (TT) with central LND and unilateral LND from 2011 to 2015 were retrospectively retrieved. Univariate and multivariate analyses were performed to examine risk factors associated with level V metastasis. A nomogram for predicting level V metastasis was established and internally validated. Results: The overall rate of level V metastasis was 21.3% (221/1037). Unilateral central LNM (CLNM), level II/III/IV metastasis, extra nodal extension (ENE) and lymph node (LN) size ≥2 cm were found to be independent predictive factors for level V metastasis (P<0.05). In the nomogram, ENE was confirmed as the largest contributor to scores, followed by LN size, unilateral CLNM and level IV/III/II metastasis. The discrimination of the prediction model was 0.738 (95% confidence interval (CI): 0.703-0.773, P<0.001). Conclusions: The rate of level V metastasis in N1b PTC patients was apparently lower than that of other levels. With the help of our nomogram, a modified lateral neck dissection encompassing levels II-V and a strictly postoperative evaluation may be indicated when the patient has a high score.


Role of minimal residual disease in the management of acute myeloid leukemia-a case-based discussion.
AML is stratified into risk-categories based on cytogenetic and molecular features that prognosticate survival and facilitate treatment algorithms, though there is still significant heterogeneity within risk groupings with regard to risk of relapse and prognosis. The ambiguity regarding prognosis is due in large part to the relatively outdated criteria used to determine response to therapy. Whereas risk assessment has evolved to adopt cytogenetic and molecular profiling, response criteria are still largely determined by bone marrow morphologic assessment and peripheral cell count recovery. Minimal residual disease refers to the detection of a persistent population of leukemic cells below the threshold for morphologic CR determination. MRD assessment represents standard of care for ALL and PML, but concerns over prognostic capability and standardization have limited its use in AML. However, recent advancements in MRD assessment and research supporting the use of MRD assessment in AML require the reconsideration and review of this clinical tool in this disease entity. This review article will first compare and contrast the major modalities used to assess MRD in AML, such as RQ-PCR and flow cytometry, as well as touching upon newer technologies such as next-generation sequencing and digital droplet PCR. The majority of the article will discuss the evidence supporting the use of MRD assessment to prognosticate disease at various time points during treatment, and review the limited number of studies that have incorporated MRD assessment into novel treatment algorithms for AML. The article concludes by discussing the current major limitations to the implementation of MRD assessment in this disease. The manuscript is bookended by a clinical vignette that highlights the need for further research and refinement of this clinical tool.


Vaccination and testing of the border workforce for COVID-19 and risk of community outbreaks: a modelling study.
Throughout 2020 and the first part of 2021, Australia and New Zealand have followed a COVID-19 elimination strategy. Both countries require overseas arrivals to quarantine in government-managed facilities at the border. In both countries, community outbreaks of COVID-19 have been started via infection of a border worker. This workforce is rightly being prioritized for vaccination. However, although vaccines are highly effective in preventing disease, their effectiveness in preventing infection with and transmission of SARS-CoV-2 is less certain. There is a danger that vaccination could prevent symptoms of COVID-19 but not prevent transmission. Here, we use a stochastic model of SARS-CoV-2 transmission and testing to investigate the effect that vaccination of border workers has on the risk of an outbreak in an unvaccinated community. We simulate the model starting with a single infected border worker and measure the number of people who are infected before the first case is detected by testing. We show that if a vaccine reduces transmission by 50%, vaccination of border workers increases the risk of a major outbreak from around 7% per seed case to around 9% per seed case. The lower the vaccine effectiveness against transmission, the higher the risk. The increase in risk as a result of vaccination can be mitigated by increasing the frequency of routine testing for high-exposure vaccinated groups.


Should health care come with a warranty?
How health care providers get paid has implications for the delivery of care and cost control; the topic is especially important during an economic downturn with persistent growth in health spending. Adding "warranties" to care is an innovation that transfers risk to providers, because payment includes allowances for defects. How do such warranties affect patient care and bottom lines? We examine a proposed payment model to illustrate the role of warranties in health care and their potential impact on providers' behavior and profitability. We conclude that warranties could motivate providers to improve quality and could increase their profit margins.


Minireview: Metabolism of female reproduction: regulatory mechanisms and clinical implications.
Female fertility is highly dependent on successful regulation of energy metabolism. Central processes in the hypothalamus monitor the metabolic state of the organism and, together with metabolic hormones, drive the peripheral availability of energy for cellular functions. In the ovary, the oocyte and neighboring somatic cells of the follicle work in unison to achieve successful metabolism of carbohydrates, amino acids, and lipids. Metabolic disturbances such as anorexia nervosa, obesity, and diabetes mellitus have clinically important consequences on human reproduction. In this article, we review the metabolic determinants of female reproduction and their role in infertility.


Identifying cases of heroin toxicity where 6-acetylmorphine (6-AM) is not detected by toxicological analyses.
Heroin has a half-life of 2-6 min and is metabolized too quickly to be detected in autopsy samples. The presence of 6-acetylmophine (6-AM) in urine, blood, or other samples is convincing evidence of heroin use by a decedent, but 6-AM itself has a half-life of 6-25 min before it is hydrolyzed to morphine, so 6-AM may not be present in sufficient concentration to detect in postmortem samples. Codeine is often present in heroin preparations as an impurity and is not a metabolite of heroin. Studies report that a ratio of morphine to codeine greater than one indicates heroin use. We hypothesize that the ratio of morphine to codeine in our decedents abusing drugs intravenously will be no different in individuals with 6-AM present than in individuals where no 6-AM is detected, and we report our study of this hypothesis. All accidental deaths investigated by the Jefferson County Coroner/Medical Examiner Office from 2010 to 2013 with morphine detected in blood samples collected at autopsy were reviewed. Five deaths where trauma caused or contributed to death were excluded from the review. The presence or absence of 6-AM and the concentrations of morphine and codeine were recorded for each case. The ratio of morphine to codeine was calculated for all decedents. Any individual in whom no morphine or codeine was detected in a postmortem sample was excluded from further study. Absence or presence of drug paraphernalia or evidence of intravascular (IV) drug use was documented in each case to identify IV drug users. The proportion of the IV drug users with and without 6-AM present in a postmortem sample was compared to the M/C ratio for the individuals. Of the 230 deaths included in the analysis, 103 IV drug users with quantifiable morphine and codeine in a postmortem sample were identified allowing for calculation of an M/C ratio. In these IV drug users, the M/C ratio was greater than 1 in 98 % of decedents. When controlling for the absence or presence of 6-AM there was no statistically significant difference in the proportion of IV drug users when compared to non IV drug users with an M/C ratio of greater than 1 (p = 1.000). The M/C ratio in IV drug users, if greater than 1, is seen in deaths due to heroin toxicity where 6-AM is detected in a postmortem sample. This study provides evidence that a M/C ratio greater than one in an IV drug user is evidence of a death due to heroin toxicity even if 6-AM is not detected in the blood. Using the M/C ratio, in addition to scene and autopsy findings, provides sufficient evidence to show heroin is the source of the morphine and codeine. Listing heroin as a cause or contributing factor in deaths with evidence of IV drug abuse and where the M/C ratio exceeds 1 will improve identification of heroin fatalities, which will allow better allocation of resources for public health initiatives.


Esterase-Sensitive and pH-Controlled Carbon Monoxide Prodrugs for Treating Systemic Inflammation.
A bottleneck for developing CO-based therapeutics is the lack of a safe and controllable delivery form. Herein, we describe efforts toward organic CO prodrugs with dual-responsive endogenous triggers. One representative CO prodrug showed significant anti-inflammatory effects both in vitro and in a LPS-simulated systemic inflammation model. These results firmly establish such CO prodrugs as either research tools or candidate compounds for the treatment of systemic inflammation or inflammation related organ injuries.


On the thermodynamics and kinetics of hydrophobic interactions at interfaces.
We have studied how primitive hydrophobic interactions between two or more small nonpolar solutes are affected by the presence of surfaces. We show that the desolvation barriers present in the potential of mean force between the solutes in bulk water are significantly reduced near an extended hydrophobic surface. Correspondingly, the kinetics of hydrophobic contact formation and breakage are faster near a hydrophobic surface than near a hydrophilic surface or in the bulk. We propose that the reduction in the desolvation barrier is a consequence of the fact that water near extended hydrophobic surfaces is akin to that at a liquid-vapor interface and is easily displaced. We support this proposal with three independent observations. First, when small hydrophobic solutes are brought near a hydrophobic surface, they induce local dewetting, thereby facilitating the reduction of desolvation barriers. Second, our results and those of Patel et al. (Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 17678-17683) show that, whereas the association of small solutes in bulk water is driven by entropy, that near hydrophobic surfaces is driven by enthalpy, suggesting that the physics of interface deformation is important. Third, moving water away from its vapor-liquid coexistence, by applying hydrostatic pressure, leads to recovery of bulklike signatures (e.g., the presence of a desolvation barrier and an entropic driving force) in the association of solutes. These observations for simple solutes also translate to end-to-end contact formation in a model peptide with hydrophobic end groups, for which lowering of the desolvation barrier and acceleration of contact formation are observed near a hydrophobic surface. Our results suggest that extended hydrophobic surfaces, such as air-water or hydrocarbon-water surfaces, could serve as excellent platforms for catalyzing hydrophobically driven assembly.


Race as an independent risk factor for breast cancer survival: breast cancer outcomes from the medical college of georgia tumor registry.
Causes of racial disparities in breast cancer survival remain unclear. This study assesses overall survival (OS) after diagnosis between black and white women and examines factors that might correlate with this disparity. Data were obtained from the Medical College of Georgia Tumor Registry. Cases included those diagnosed between 1990 and 2005. We analyzed race, stage, age of diagnosis, and treatment received: chemotherapy, radiation, surgery, and hormonal therapy. A Cox proportional hazards model was used to determine differences in OS. Compared with 670 white women, 489 black women were more likely to be younger, have later-stage disease at diagnosis, and were less likely to have received hormonal therapy. Both groups received similar rates of radiation, surgery, and chemotherapy. Black women had significantly poorer OS (adjusted hazard ratio, 1.35; 95% CI, 1.12-1.63). White women had a 5-year OS of 54% compared with 45% in black women (P = .0031). Having received radiation, surgery, or chemotherapy was not associated with OS. White women were more likely to have received hormonal therapy, which had a significant protective effect. However, a stratified analysis (between those who received hormonal therapy and those who did not) showed similar results, whereas black women experienced poorer OS in both strata. Black women with breast cancer had a significantly poorer OS compared with white women. White women received more hormonal therapy, which had a protective effect. There were no differences in treatment received regarding radiation, surgery, or chemotherapy, and these treatments were not associated with OS. The reasons for racial disparities in breast cancer OS remain complex.


Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function.
Toll-like receptors (TLRs) represent a class of transmembrane pattern recognition receptors essential for microbial recognition and control of innate immune responses. Commensal bacteria play an important role in maintaining tolerance and active stability of the intestinal epithelial barrier by suppressing intestinal inflammation, yet the mechanisms of action are unknown. The aim of this study was to determine the functional relevance of TLR2 to control tight junction (TJ)-associated intestinal epithelial barrier integrity to balance mucosal homeostasis against inflammatory stress-induced damage. TLR2 ligand (synthetic Pam(3)Cys-SK4 [PCSK])-induced activation of signaling cascades and TJ-associated distribution was assessed by using Western blotting and confocal microscopy combined with functional transfection and inhibitor studies in model intestinal epithelial cell (IEC) lines (IEC-6, Caco-2) or primary IEC cultured short-term ex vivo. DSS colitis was induced by standard protocol in wild-type, TLR2-/-, and MyD88-/- mice. Spontaneous apoptosis was assessed by terminal deoxinucleotidyl-transferase-mediated dUTP-biotin nick end-labeling. Data from in vitro and ex vivo models of intestinal epithelial cells revealed that TLR2 stimulation effectively preserves TJ-associated barrier assembly against stress-induced damage through promotion of PI3K/Akt-mediated cell survival via MyD88. Furthermore, in vivo studies underscored that TLR2-mediated TJ regulation critically determines susceptibility to intestinal injury and inflammation. Inflammatory stress in mice deficient of TLR2 or MyD88 induced early TJ-associated disruption interrelated with anti-apoptotic failure of the intestinal epithelial barrier. Oral treatment of colitis with the TLR2 ligand PCSK significantly suppressed mucosal inflammation and apoptosis by efficiently restoring TJ-associated integrity of the intestinal epithelium in vivo. TLR2 may provide a target to pharmacologically modulate mucosal injury and intestinal inflammation.


Inequities in neonatal survival interventions: evidence from national surveys.
Nearly four million children die during the first four weeks of life every year, yet known and effective interventions exist. Neonatal mortality has to be addressed to reach the millennium development goal for child survival. To determine the extent of within-country inequities in neonatal mortality and effective intervention coverage. Neonatal, infant and child (under 2 years) mortality rates were calculated from empirical data from Demographic and Health Surveys for eight countries using direct estimation techniques. Wealth groups were constructed using the World Bank wealth index; neonatal mortality inequities were evaluated by comparing low:high quintile ratios; concentration indices were calculated for intervention coverage rates. The proportion of under-2 deaths occurring in the neonatal period ranged from 24.3% (Malawi) to 49.4% (Bangladesh). In all countries (excluding Haiti) inequities in neonatal mortality and intervention coverage were evident across wealth groups with more deaths and less coverage in the poorest, compared with the richest, quintile; the largest mortality differential was 2.1 (Nicaragua) and the smallest was 1.2 (Eritrea). In Nicaragua 33% of the poorest women had a skilled delivery compared with 98% of the richest; in Cambodia for antenatal care this was 18% (poorest) and 71% (richest). Low coverage of interventions tended to show top inequity patterns whereas high coverage tended to show bottom inequity patterns. Reducing inequity is a necessary step in reducing neonatal deaths and also total child deaths. Intervention efforts need to begin to integrate approaches relevant to equity in programme design, implementation, monitoring and evaluation.


ICP-MS Assessment of Hair Essential Trace Elements and Minerals in Russian Preschool and Primary School Children with Attention-Deficit/Hyperactivity Disorder (ADHD).
The objective of the present study was to investigate the relationship between hair essential trace element and mineral content and ADHD in preschool (4-6 years old) and primary school children (6-10 years old) in relation to age and gender. Hair essential trace element and mineral content in 90 Russian children with ADHD and 90 age- and gender-matched neurotypical controls were assessed using inductively coupled plasma mass-spectrometry after microwave digestion. The obtained data demonstrate that hair Co, Cu, Mn, Si, and Zn contents in ADHD children was significantly reduced by 18%, 10%, 27%, 16%, and 19% as compared to the control values, respectively. The most significant decrease in children with ADHD was observed for hair Mg levels, being 29% lower than those in neurotypical children. After adjustment for age and gender, the observed difference in hair element content was more characteristic for preschool children and girls, respectively. Multiple linear regression analysis demonstrated that in a crude model (hair element levels as predictors), only hair Zn content was significantly inversely associated with ADHD (β = - 0.169; p = 0.025). Adjustment for anthropometric parameters (model 2) did not increase the predictive ability of the model, although it improved the association between hair Zn and ADHD in children (β = - 0.194; p = 0.014). Hypothetically, the observed alterations may at least partially contribute to neurobehavioral disturbances in children with ADHD. Moreover, the results of the present study raise the question about the potential benefits of Zn and Mg supplementation in children with ADHD. However, further detailed studies are required to investigate micronutrient deficiencies in ADHD.


The ambiguity of ethnicity as risk factor of vitamin D deficiency--a case study of Danish vitamin D policy documents.
To explore how ethnic minorities at risk of vitamin D deficiency are constructed in Danish policy documents (current as of April 2009), regarding vitamin D supplementation. Ten policy documents were analysed through content analysis, focusing on definitions and explanations of ethnic minorities being at risk of vitamin D deficiency. This formed the basis for an analysis of constructions of ethnic minorities at risk which was undertaken using the Social Construction of Technology (SCOT) theory as an organising framework. The analysis showed a high degree of interpretative flexibility regarding how ethnic minorities are constructed as a risk group for vitamin D deficiency. The ten documents analysed revealed eight different constructions of the ethnic minorities groups at risk. A low degree of interpretative flexibility was found regarding the importance of skin colour and skin covering. Major disagreements were found regarding the importance attributed to the Islamic religion, other traditions, immigration, gender and age, and use of an evolutionary explanation for the increased risk. Ethnic minorities at risk of vitamin D deficiency are constructed very differently in Danish policies current as of April 2009. A more precise definition of ethnic minorities in policies and research may be helpful in seeking to identify which ethnic minorities are and are not at risk of vitamin D deficiency.


Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus.
Celastrol is a natural pentacyclic triterpene used in traditional Chinese medicine with significant weight-lowering effects. Celastrol-administered mice at 100 μg/kg decrease food consumption and body weight via a leptin-dependent mechanism, yet its molecular targets in this pathway remain elusive. Here, we demonstrate in vivo that celastrol-induced weight loss is largely mediated by the inhibition of leptin negative regulators protein tyrosine phosphatase (PTP) 1B (PTP1B) and T-cell PTP (TCPTP) in the arcuate nucleus (ARC) of the hypothalamus. We show in vitro that celastrol binds reversibly and inhibits noncompetitively PTP1B and TCPTP. NMR data map the binding site to an allosteric site in the catalytic domain that is in proximity of the active site. By using a panel of PTPs implicated in hypothalamic leptin signaling, we show that celastrol additionally inhibited PTEN and SHP2 but had no activity toward other phosphatases of the PTP family. These results suggest that PTP1B and TCPTP in the ARC are essential for celastrol's weight lowering effects in adult obese mice.


Independent association of obstructive sleep apnea with Barrett's esophagus.
Current guidelines suggest screening at-risk groups of patients for Barrett's esophagus (BE), a precursor to esophageal cancer. Although BE and obstructive sleep apnea (OSA) have common risk factors, including elevated body mass index and gastroesophageal reflux disease (GERD), the relationship between these two conditions has not been well established. Retrospectively, all patients who had undergone a polysomnography and esophagogastroduodenoscopy at West Virginia University Hospital from 2013 to 2018 were identified and divided into groups on the basis of the presence or absence of OSA. Clinical course and procedure reports were reviewed to identify relevant variables. One thousand ninety-one patients met inclusion criteria; 60.9% were female, and mean age of participants was 53.5 years. Univariate analysis revealed that male gender, age, diagnosis of OSA, severity of OSA, and a clinical diagnosis of GERD were associated with BE (P values < 0.05). Multiple logistic regression incorporating age, sex, clinical diagnosis of GERD, smoking history, body mass index, Helicobacter pylori status, and presence of hiatal hernia was utilized. Patients with OSA had an increased risk of BE than had those without OSA (P < 0.001, odds ratio 3.26 [1.72-6.85]). The risk increased with increasing severity of OSA, categorized in apnea-hypopnea index increments of 10. Obstructive sleep apnea is associated with BE, a relationship that is independent of other known risk factors. Additionally, this risk increases with increasing severity of OSA. Future efforts should determine if patients with severe OSA need to be screened for BE due to its potential for causing esophageal cancer.


Morbidity and mortality associated with obesity.
Obesity and its repercussions constitute an important source of morbidity, impaired quality of life and its complications can have a major bearing on life expectancy. The present article summarizes the most important co-morbidities of obesity and their prevalence. Furthermore, it describes classification and grading systems that can be used to assess the individual and combined impact of co-morbid conditions on mortality risk. The literature was screened for assessment tools that can be deployed in the quantification of morbidity and mortality risk in individual patients. Thirteen specific domains have been identified that account for morbidity and mortality in obesity. Cardiovascular disease (CVD) and cancer account for the greatest mortality risk associated with obesity. The King's Criteria and Edmonton Obesity Staging System (EOSS) were identified as useful tools for the detection and monitoring of individual patient mortality risk in obesity care. The stark facts on the complications of obesity should be capitalized on to improve patient management and knowledge and referred to in the wider dissemination of public health messages aimed at improving primary prevention.