Improved cortical boundary registration for locally distorted fMRI scans.
With continuing advances in MRI techniques and the emergence of higher static field strengths, submillimetre spatial resolution is now possible in human functional imaging experiments. This has opened up the way for more specific types of analysis, for example investigation of the cortical layers of the brain. With this increased specificity, it is important to correct for the geometrical distortions that are inherent to echo planar imaging (EPI). Inconveniently, higher field strength also increases these distortions. The resulting displacements can easily amount to several millimetres and as such pose a serious problem for laminar analysis. We here present a method, Recursive Boundary Registration (RBR), that corrects distortions between an anatomical and an EPI volume. By recursively applying Boundary Based Registration (BBR) on progressively smaller subregions of the brain we generate an accurate whole-brain registration, based on the grey-white matter contrast. Explicit care is taken that the deformation does not break the topology of the cortical surface, which is an important requirement for several of the most common subsequent steps in laminar analysis. We show that RBR obtains submillimetre accuracy with respect to a manually distorted gold standard, and apply it to a set of human in vivo scans to show a clear increase in spacial specificity. RBR further automates the process of non-linear distortion correction. This is an important step towards routine human laminar fMRI for large field of view acquisitions. We provide the code for the RBR algorithm, as well as a variety of functions to better investigate registration performance in a public GitHub repository, https://github.com/TimVanMourik/OpenFmriAnalysis, under the GPL 3.0 license.


HbD Punjab/HbQ India Compound Heterozygosity: An Unusual Association.
Haemoglobinopathies are the commonest hereditary disorders in India and pose a major health problem. Both beta thalassaemia and structural haemoglobin variants are relatively common in northwestern India. Here we report a 29-year-old Sindhi female who was referred to us for a haemoglobinopathy work up and genetic counseling since her spouse was a classical beta thalassaemia carrier. A complete blood count was done on an automated cell counter. Haemoglobin analysis was carried out using HPLC Variant Haemoglobin Testing System. The cellulose acetate electrophoresis was carried out [pH 8.9]. Confirmation of mutations was done by automated DNA sequencing. HPLC analysis showed four major peaks, HbA0, a peak in the HbD window, an unknown peak [retention time 4.74 minutes] and a peak in the HbC window. The HbA2 level was 2.2%, and the HbF level was 0.7%. Cellulose acetate electrophoresis at alkaline pH, a slow moving band was seen at the HbS/D position along with a prominent band at the HbA2 position. DNA sequencing of the β and α genes showed presence of the two hemoglobin variants: Hb D [β 121GAA → CAA] and Hb Q [α 64 AAG → GAG]. The δ globin gene was normal. The additional peak in the HbC window was due to the formation of a heterodimer hybrid. Both HbD Punjab and HbQ India are relatively common in India, but their co-inheritance has not been described in the country. This case is the third report of compound heterozygosity for HbQ India/HbD Punjab haemoglobinopathy globally and the second one from India.


Dissociation between vasospasm and functional improvement in a murine model of subarachnoid hemorrhage.
The efficacy of nimodipine was examined in a murine model of subarachnoid hemorrhage (SAH). End points included the diameter of the lumen of the middle cerebral artery (MCA) and behavioral outcome. An apolipoprotein E (apoE)-mimetic peptide, acetyl-AS-Aib-LRKL-Aib-KRLL-amide, previously shown to have promise in this model was tested both alone and in combination with nimodipine. The effects of carboxyamidotriazole (CAI), a non-voltage-gated calcium channel blocker, were explored using the same animal paradigm. Experimental SAH was induced in male C57B1/6J mice. For 3 days postoperatively, behavioral analyses were performed. In the first experiment, the mice were treated with vehicle or with low- or high-dose CAI for 3 days. In the second experiment, the mice were treated with vehicle, high- and low-dose nimodipine, and/or the apoE-mimetic peptide. On postoperative Day 3 each mouse was killed and perfused. Following this, the right MCA was removed and its lumen measured. Mice that received nimodipine demonstrated significant behavioral improvements when compared with vehicle-treated mice, but there was no clear dose-dependent effect on MCA diameter. Administration of the apoE-mimetic peptide was associated with improved functional performance and a significant reduction in vasospasm. Mice that received high-dose CAI performed worse on functional tests, despite a significant increase in the diameters of their MCA lumina. These results demonstrate a dissociation between vasospasm and neurological outcomes that is consistent with findings of previous clinical trials.


Neural stem cell niches in health and diseases.
Presence of neural stem cells in adult mammalian brains, including human, has been clearly demonstrated by several studies. The functional significance of adult neurogenesis is slowly emerging as new data indicate the sensitivity of this event to several "every day" external stimuli such as physical activity, learning, enriched environment, aging, stress and drugs. In addition, neurogenesis appears to be instrumental for task performance involving complex cognitive functions. Despite the growing body of evidence on the functional significance of NSC and despite the bulk of data concerning the molecular and cellular properties of NSCs and their niches, several critical questions are still open. In this work we review the literature describing i) old and new sites where NSC niche have been found in the CNS; ii) the intrinsic factors regulating the NSC potential; iii) the extrinsic factors that form the niche microenvironment. Moreover, we analyse NSC niche activation in iv) physiological and v) pathological conditions. Given the not static nature of NSCs that continuously change phenotype in response to environmental clues, a unique "identity card" for NSC identification is still lacking. Moreover, the multiple location of NSC niches that increase in diseases, leaves open the question of whether and how these structures communicate throughout long distance. We propose a model where all the NSC niches in the CNS may be connected in a functional network using the threads of the meningeal net as tracks.


Population impact of SARS-CoV-2 variants with enhanced transmissibility and/or partial immune escape.
SARS-CoV-2 variants of concern exhibit varying degrees of transmissibility and, in some cases, escape from acquired immunity. Much effort has been devoted to measuring these phenotypes, but understanding their impact on the course of the pandemic-especially that of immune escape-has remained a challenge. Here, we use a mathematical model to simulate the dynamics of wild-type and variant strains of SARS-CoV-2 in the context of vaccine rollout and nonpharmaceutical interventions. We show that variants with enhanced transmissibility frequently increase epidemic severity, whereas those with partial immune escape either fail to spread widely or primarily cause reinfections and breakthrough infections. However, when these phenotypes are combined, a variant can continue spreading even as immunity builds up in the population, limiting the impact of vaccination and exacerbating the epidemic. These findings help explain the trajectories of past and present SARS-CoV-2 variants and may inform variant assessment and response in the future.


Preparation and characterization of Ca(II) cross-linking modified pectin microspheres for Pb(II) adsorption.
A novel adsorbent, composed of cross-linked de-esterified pectin microspheres, was prepared via cross-linking with Ca(II) and modification by de-esterified pectin, low-methoxyl pectin (LMP) and pectic acid (PA). Fourier transform infrared (FTIR), energy dispersive spectrometry (EDS), scanning electron microscopy (SEM) and atomic absorption spectroscopy (AAS) were applied too, exhibiting a successful fabrication, good adsorption ability, and well-defined surface microstructure beneficial to Pb(II) adsorption. The adsorption ability of pectin microspheres (PMs), low-methoxyl pectin microspheres (LMPMs) and pectic acid microspheres (PAMs) for Pb(II) in aqueous solution were explored. The maximum adsorption capacity of PMs, LMPMs and PAMs was 127 mg·g-1, 292 mg·g-1 and 325 mg·g-1 at pH 5.0 respectively, indicating a great improvement of LMPMs and PAMs in the adsorption ability for Pb(II) compared with PMs. Furthermore, the adsorption mechanism was proposed. The experimental data were well fitted with pseudo-second-order kinetic and Langmuir isotherm models. Five-cycle reusability tests demonstrated that microspheres could be used repeatedly. All the results confirmed that LMPMs and PAMs, which presented outstanding adsorption capability and reusability, could be a good candidate for wastewater purification.


Health services for women, children and adolescents in conflict affected settings: experience from North and South Kivu, Democratic Republic of Congo.
Insecurity has characterized the Eastern regions of the Democratic Republic of Congo for decades. Providing health services to sustain women's and children's health during protracted conflict is challenging. This mixed-methods case study aimed to describe how reproductive, maternal, newborn, child, adolescent health and nutrition (RMNCAH+N) services have been offered in North and South Kivu since 2000 and how successful they were. We conducted a case study using a desk review of publicly available literature, secondary analysis of survey and health information system data, and primary qualitative interviews. The qualitative component provides insights on factors shaping RMNCAH+N design and implementation. We conducted 49 interviews with government officials, humanitarian agency staff and facility-based healthcare providers, and focus group discussions with community health workers in four health zones (Minova, Walungu, Ruanguba, Mweso). We applied framework analysis to investigate key themes across informants.The quantitative component used secondary data from nationwide surveys and the national health facility information system to estimate coverage of RMNCAH+N interventions at provincial and sub-provincial level. The association between insecurity on service provision was examined with random effects generalized least square models using health facility data from South Kivu. Coverage of selected preventive RMNCAH+N interventions seems high in North and South Kivu, often higher than the national level. Health facility data show a small negative association of insecurity and preventive service coverage within provinces. However, health outcomes are poorer in conflict-affected territories than in stable ones. The main challenges to service provisions identified by study respondents are the availability and retention of skilled personnel, the lack of basic materials and equipment as well as the insufficient financial resources to ensure health workers' regular payment, medicaments' availability and facilities' running costs. Insecurity exacerbates pre-existing challenges, but do not seem to represent the main barrier to service provision in North and South Kivu. Provision of preventive schedulable RMNCAH+N services has continued during intermittent conflict in North and South Kivu. The prolonged effort by non-governmental organizations and UN agencies to respond to humanitarian needs was likely key in maintaining intervention coverage despite conflict. Health actors and communities appear to have adapted to changing levels and nature of insecurity and developed strategies to ensure preventive services are provided and accessed. However, emergency non-schedulable RMNCAH+N interventions do not appear to be readily accessible. Achieving the Sustainable Development Goals will require increased access to life-saving interventions, especially for newborn and pregnant women.


Longer ice-free seasons increase the risk of nest depredation by polar bears for colonial breeding birds in the Canadian Arctic.
Northern polar regions have warmed more than other parts of the globe potentially amplifying the effects of climate change on biological communities. Ice-free seasons are becoming longer in many areas, which has reduced the time available to polar bears (Ursus maritimus) to hunt for seals and hampered bears' ability to meet their energetic demands. In this study, we examined polar bears' use of an ancillary prey resource, eggs of colonial nesting birds, in relation to diminishing sea ice coverage in a low latitude region of the Canadian Arctic. Long-term monitoring reveals that bear incursions onto common eider (Somateria mollissima) and thick-billed murre (Uria lomvia) nesting colonies have increased greater than sevenfold since the 1980s and that there is an inverse correlation between ice season length and bear presence. In surveys encompassing more than 1000 km of coastline during years of record low ice coverage (2010-2012), we encountered bears or bear sign on 34% of eider colonies and estimated greater egg loss as a consequence of depredation by bears than by more customary nest predators, such as foxes and gulls. Our findings demonstrate how changes in abiotic conditions caused by climate change have altered predator-prey dynamics and are leading to cascading ecological impacts in Arctic ecosystems.


Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects.
Autism is a severe neurodevelopmental disorder, which has a complex genetic predisposition. The ratio of males to females affected by autism is approximately 4:1, suggesting that sex specific factors are involved in its development. We reported previously the results of a genomewide screen for autism susceptibility loci in 83 affected sibling pairs (ASP), and follow up analysis in 152 ASP. Here, we report analysis of an expanded sample of 219 ASP, using sex and parent of origin linkage modelling at loci on chromosomes 2, 7, 9, 15, and 16. The results suggest that linkage to chromosomes 7q and 16p is contributed largely by the male-male ASP (MLS = 2.55 v 0.12, and MLS = 2.48 v 0.00, for the 145 male-male and 74 male-female/female-female ASP on chromosomes 7 and 16 respectively). Conversely linkage to chromosome 15q appears to be attributable to the male-female/female-female ASP (MLS = 2.62 v 0.00, for non-male and male-male ASP respectively). On chromosomes 2 and 9, all ASP contribute to linkage. These data, supported by permutation, suggest a possible sex limited effect of susceptibility loci on chromosomes 7, 15, and 16. Parent of origin linkage modelling indicates two distinct regions of paternal and maternal identity by descent sharing on chromosome 7 (paternal MLS = 1.46 at approximately 112 cM, and maternal MLS = 1.83 at approximately 135 cM; corresponding maternal and paternal MLS = 0.53 and 0.28 respectively), and maternal specific sharing on chromosome 9 (maternal MLS = 1.99 at approximately 30 cM; paternal MLS = 0.02). These data support the possibility of two discrete loci underlying linkage of autism to chromosome 7, and implicate possible parent of origin specific effects in the aetiology of autism.


Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice.
Obesity is associated with an enhanced inflammatory response that exacerbates insulin resistance and contributes to diabetes, atherosclerosis, and cardiovascular disease. One mechanism accounting for the increased inflammation associated with obesity is activation of the innate immune signaling pathway triggered by TLR4 recognition of saturated fatty acids, an event that is essential for lipid-induced insulin resistance. Using in vitro and in vivo systems to model lipid induction of TLR4-dependent inflammatory events in rodents, we show here that TLR4 is an upstream signaling component required for saturated fatty acid-induced ceramide biosynthesis. This increase in ceramide production was associated with the upregulation of genes driving ceramide biosynthesis, an event dependent of the activity of the proinflammatory kinase IKKβ. Importantly, increased ceramide production was not required for TLR4-dependent induction of inflammatory cytokines, but it was essential for TLR4-dependent insulin resistance. These findings suggest that sphingolipids such as ceramide might be key components of the signaling networks that link lipid-induced inflammatory pathways to the antagonism of insulin action that contributes to diabetes.


Sensitivity and specificity of cognitive and functional screening instruments for dementia: the Indo-U.S. Dementia Epidemiology Study.
There is a shortage of adequate screening instruments for dementia in poorly educated populations and non-English-speaking groups. An epidemiological survey was conducted in a population-based, largely illiterate, sample of 5,126 individuals aged 55 and older in 28 villages in the rural community of Ballabgarh in northern India. All participants were administered a general mental status test, the Hindi Mental State Examination (HMSE), and a brief battery of neuropsychological tests. Their informants answered a questionnaire assessing functional ability, the Everyday Abilities Scale for India (EASI). Six hundred thirty-two participants underwent clinical diagnostic evaluation for dementia. We investigated whether the sensitivity, specificity, and predictive value for dementia of the mental status test could be improved by the addition of the brief neuropsychological test battery or the functional questionnaire, comparing the instruments alone and in combination. In participants who could be tested cognitively, the HMSE, the neuropsychological battery, and EASI had sensitivities of 81.3%, 81.3%, and 62.5%, respectively, with specificities of 60.2%, 74.5%, and 89.7%, respectively. The combination of all three was 93.8% sensitive and 41.8% specific. The sensitivity of the HMSE alone was nonsignificantly improved by the addition of either the EASI or the neuropsychological battery, whereas its specificity was significantly decreased by either addition. An advantage of the EASI was that it could also be administered to informants of subjects who were cognitively untestable. In this largely illiterate community, with a low prevalence of dementia, the combination of cognitive tests and a functional ability questionnaire had substantial value for population screening.


Expressive Single Scattering for Light Shaft Stylization.
Light scattering in participating media is a natural phenomenon that is increasingly featured in movies and games, as it is visually pleasing and lends realism to a scene. In art, it may further be used to express a certain mood or emphasize objects. Here, artists often rely on stylization when creating scattering effects, not only because of the complexity of physically correct scattering, but also to increase expressiveness. Little research, however, focuses on artistically influencing the simulation of the scattering process in a virtual 3D scene. We propose novel stylization techniques, enabling artists to change the appearance of single scattering effects such as light shafts. Users can add, remove, or enhance light shafts using occluder manipulation. The colors of the light shafts can be stylized and animated using easily modifiable transfer functions. Alternatively, our system can optimize a light map given a simple user input for a number of desired views in the 3D world. Finally, we enable artists to control the heterogeneity of the underlying medium. Our stylized scattering solution is easy to use and compatible with standard rendering pipelines. It works for animated scenes and can be executed in real time to provide the artist with quick feedback.


Self-rated health and long-term prognosis of depression.
Indicators of prognosis should be considered to fully inform clinical decision making in the treatment of depression. This study examines whether self-rated health predicts long-term depression outcomes in primary care. Our analysis was based on the first 5 years of a prospective 10-year cohort study underway since January 2005 conducted in 30 randomly selected Australian primary care practices. Participants were 789 adult patients with a history of depressive symptoms. Main outcome measures include risks, risk differences, and risk ratios of major depressive syndrome (MDS) on the Patient Health Questionnaire. Retention rates during the 5 years were 660 (84%), 586 (74%), 560 (71%), 533 (68%), and 517 (66%). At baseline, MDS was present in 27% (95% CI, 23%-30%). Cross-sectional analysis of baseline data showed participants reporting poor or fair self-rated health had greater odds of chronic illness, MDS, and lower socioeconomic status than those reporting good to excellent self-rated health. For participants rating their health as poor to fair compared with those rating it good to excellent, risk ratios of MDS were 2.10 (95% CI, 1.60-2.76), 2.38 (95% CI, 1.77-3.20), 2.22 (95% CI, 1.70-2.89), 1.73 (95% CI, 1.30-2.28), and 2.15 (95% CI, 1.59-2.90) at 1, 2, 3, 4, and 5 years, after accounting for missing data using multiple imputation. After adjusting for age, sex, multimorbidity, and depression status and severity, self-rated health remained a predictor of MDS up to 5 years. Self-rated health offers family physicians an efficient and simple way to identify patients at risk of poor long-term depression outcomes and to inform therapeutic decision making.


Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency.
The objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI). Randomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden. Sixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20-40 mg once daily and hydrocortisone 20-40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness). In stage 1, patients had a median 1.5 (range, 1-9) intercurrent illness events with DR-HC and 1.0 (1-8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1-3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure. This long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy.


Systematic Review of the Surgical Treatment of Extremity Lymphedema.
Background Although conservative management of lymphedema remains the first-line approach, surgery is effective in select patients. The purpose of this study was to review the literature and develop a treatment algorithm based on the highest quality lymphedema research. Methods A systematic literature review was performed to examine the surgical treatments for lymphedema. Studies were categorized into five groups describing excision, liposuction, lymphovenous anastomosis (LVA), vascularized lymph node transfer (VLNT), and combined/multiple approaches. Studies were scored for methodological quality using the methodological index for nonrandomized studies (MINORS) scoring system. Results A total of 69 articles met inclusion criteria and were assigned MINORS scores with a maximum score of 16 or 24 for noncomparative or comparative studies, respectively. The average MINORS scores using noncomparative criteria were 12.1 for excision, 13.2 for liposuction, 12.6 for LVA, 13.1 for VLNT, and 13.5 for combined/multiple approaches. Loss to follow-up was the most common cause of low scores. Thirty-nine studies scoring > 12/16 or > 19/24 were considered high quality. In studies measuring excess volume reduction, the mean reduction was 96.6% (95% confidence interval [CI]: 86.2-107%) for liposuction, 33.1% (95% CI: 14.4-51.9%) for LVA, and 26.4% (95% CI: - 7.98 to 60.8%) for VLNT. Included excision articles did not report excess volume reduction. Conclusion Although the overall quality of lymphedema literature is fair, the MINORS scoring system is an effective method to isolate high-quality studies. These studies were used to develop an evidence-based algorithm to guide clinical practice. Further studies with a particular focus on patient follow-up will improve the validity of lymphedema surgery research.


Ileocecal vascularized lymph node transfer for the treatment of extremity lymphedema: A case report.
Vascularized lymph node (VLN) transfer has been of high interest in the past decade for the treatment of lymphedema, since it has been shown to be effective in reducing limb volumes, decreasing infectious episodes and improving quality of life. Multiple donor sites have been described in the quest for the optimal one. Herein, we describe a novel lymph node flap option based on the ileocolic artery and vein. The ileocecal vascularized lymph node (IC-VLN) flap was used in the management of a 33-year-old male patient with lower extremity lymphedema secondary to left inguinal trauma. The patient had previously underwent a pedicled omentum flap transposition with minimal improvement in limb size and persistent episodes of infection. At 15 month follow-up, the IC-VLN flap improved the lymphatic drainage in the affected limb with a mean limb circumference reduction rate of 26.3%. No donor site complications or further episodes of infection were noted. According to our findings, the IC-VLN flap may be another option for VLN transfer in very selected cases. Nevertheless, larger series with a longer follow-up are required to analyze the efficacy and long-term results of this flap.


The multicopy sRNA LhrC controls expression of the oligopeptide-binding protein OppA in Listeria monocytogenes.
Listeria monocytogenes is the causative agent of the foodborne disease listeriosis. During infection, L. monocytogenes produces an array of non-coding RNAs, including the multicopy sRNA LhrC. These five, nearly identical sRNAs are highly induced in response to cell envelope stress and target the virulence adhesin lapB at the post-transcriptional level. Here, we demonstrate that LhrC controls expression of additional genes encoding cell envelope-associated proteins with virulence function. Using transcriptomics and proteomics, we identified a set of genes affected by LhrC in response to cell envelope stress. Three targets were significantly down-regulated by LhrC at both the RNA and protein level: lmo2349, tcsA and oppA. All three genes encode membrane-associated proteins: A putative substrate binding protein of an amino acid ABC transporter (Lmo2349); the CD4+ T cell-stimulating antigen TcsA, and the oligopeptide binding protein OppA, of which the latter 2 are required for full virulence of L. monocytogenes. For OppA, we show that LhrC acts by direct base paring to the ribosome binding site of the oppA mRNA, leading to an impediment of its translation and a decreased mRNA level. The sRNA-mRNA interaction depends on 2 of 3 CU-rich regions in LhrC allowing binding of 2 oppA mRNAs to a single LhrC molecule. Finally, we found that LhrC contributes to infection in macrophage-like cells. These findings demonstrate a central role for LhrC in controlling the level of OppA and other virulence-associated cell envelope proteins in response to cell envelope stress.


Whole transcriptome data analysis of mouse embryonic hematopoietic stem and progenitor cells that lack Geminin expression.
We performed cDNA microarrays (Affymetrix Mouse Gene 1.0 ST Chip) to analyze the transcriptome of hematopoietic stem and progenitor cells (HSPCs) from E15.5dpc wild type and Geminin (Gmnn) knockout embryos. Lineage negative cells from embryonic livers were isolated using fluorescence activated cell sorting. RNA samples were used to examine the transcriptional programs regulated by Geminin during embryonic hematopoiesis. The data sets were analyzed using the GeneSpring v12.5 platform (Agilent). The list of differentially expressed genes was filtered in meta-analyses to investigate the molecular basis of the phenotype observed in the knockout embryos, which exhibited defective hematopoiesis and death. The data from this study are related to the research article "Geminin deletion increases the number of fetal hematopoietic stem cells by affecting the expression of key transcription factors" (Karamitros et al., 2015) [1]. The microarray dataset has been deposited at the Gene Expression Omnibus (GEO) under accession GEO: GSE53056.


Clinical training experience in district general hospitals.
To estimate the nature and quantity of clinical experience available for trainees in paediatrics or general practice in acute general hospitals of differing sizes in the UK. To discuss implications for training and service configuration taking account of current Royal College recommendations (a minimum of 1,800 acute contacts each year and ideally covering a population of 450,000 to 500,000 people). Observed frequencies of diagnoses in Pinderfields Hospital, Wakefield were compared with those in five other hospitals in Yorkshire and four in the South of England, and with expected frequencies from a review of selected marker conditions using national routine and epidemiological data. Based on the Pinderfields data, we modelled expected frequencies of a wider range of diagnoses for different sized hospitals. Small units (1,800 or less acute referrals a year) provide adequate exposure to common conditions such as gastroenteritis (157 per annum) and asthma (171 per annum) but encounter serious or unusual disease rarely. When modelled for units serving larger populations, numbers of such disorders remain small. For example, about 0.5% of admissions require intensive care to the level of ventilatory support. Medium size units offer a wide range of experience but differ little from those serving the population of 500,000 proposed as being optimal for training. This standard is not justified by the evidence in this review. Closing or amalgamating units on the scale necessary to achieve this ideal would be impractical as only five hospitals in England have a paediatric workload equivalent to this population; it would also raise issues of access and equity.


IgY: clues to the origins of modern antibodies.
IgY is the functional equivalent of IgG in birds, reptiles and amphibia, but many aspects of its biology are poorly understood. Recent studies have increased awareness of the genetics and functions of this molecule, and have revealed its position as the ancestor of the uniquely mammalian antibodies IgG and IgE. Here, Greg Warr, Kathy Magor and David Higgins review current knowledge of IgY structure, function and expression in the context of the evolutionary role of this primitive immunoglobulin.


Reference intervals of spinal mobility measures in normal individuals: the MOBILITY study.
To establish reference intervals (RIs) for spinal mobility measures as recommended for patients with axial spondyloarthritis, and to determine the effect of age, height and gender on spinal mobility, in normal individuals. A cross-sectional study (MOBILITY) was conducted among normal individuals aged 20-69 years. Recruitment was stratified by gender, age (10-year categories) and height (10 cm categories). Eleven spinal mobility measures were assessed. Age specific RIs and percentiles were derived for each measure. 393 volunteers were included. All spinal mobility measures decreased with increasing age. Therefore, age specific RIs were developed. The 95% RIs (2.5th and 97.5th percentiles), as well as the 5th, 10th, 25th, 50th, 75th and 90th percentiles for each spinal mobility measure and different ages are presented. Mobility percentile curves were also plotted for each of the measures. For instance, the 95% RI for lateral spinal flexion was 16.2-28.0 cm for a 25-year-old subject, 13.2-25.0 cm for a 45-year-old subject and 10.1-21.9 cm for a 65-year-old subject. After adjustment for age, there was no need for gender specific RIs, while RIs of some measures are height-adjusted. Age specific RIs and percentiles were derived for each of the spinal mobility measures for normal individuals. These may guide clinicians when assessing the mobility of patients with axial spondyloarthritis. The RIs may serve as cut-off levels for 'normal' versus 'abnormal', whereas the mobility percentile curves may be used to assess the level of mobility of patients with axial spondyloarthritis.


A multi-aspect comparison study of supervised word sense disambiguation.
The aim of this study was to investigate relations among different aspects in supervised word sense disambiguation (WSD; supervised machine learning for disambiguating the sense of a term in a context) and compare supervised WSD in the biomedical domain with that in the general English domain. The study involves three data sets (a biomedical abbreviation data set, a general biomedical term data set, and a general English data set). The authors implemented three machine-learning algorithms, including (1) naïve Bayes (NBL) and decision lists (TDLL), (2) their adaptation of decision lists (ODLL), and (3) their mixed supervised learning (MSL). There were six feature representations (various combinations of collocations, bag of words, oriented bag of words, etc.) and five window sizes (2, 4, 6, 8, and 10). Supervised WSD is suitable only when there are enough sense-tagged instances with at least a few dozens of instances for each sense. Collocations combined with neighboring words are appropriate selections for the context. For terms with unrelated biomedical senses, a large window size such as the whole paragraph should be used, while for general English words a moderate window size between 4 and 10 should be used. The performance of the authors' implementation of decision list classifiers for abbreviations was better than that of traditional decision list classifiers. However, the opposite held for the other two sets. Also, the authors' mixed supervised learning was stable and generally better than others for all sets. From this study, it was found that different aspects of supervised WSD depend on each other. The experiment method presented in the study can be used to select the best supervised WSD classifier for each ambiguous term.


Retarded nuclear migration in Drosophila embryos with aberrant F-actin reorganization caused by maternal mutations and by cytochalasin treatment.
Three X-linked mutations of Drosophila melanogaster, gs(1)N26, gs(1)N441 and paralog, had a common maternal-effect phenotype. Mutant embryos show reduced egg contraction that normally occurs at an early cleavage stage in wild-type embryos. In addition, the mutants exhibited retarded nuclear migration while synchronous nuclear divisions were unaffected. The retarded migration causes nuclei to remain in the anterior part of the embryo retaining their spherical distribution even in a late cleavage stage. This consequently results in an extreme delay in nuclear arrival in the posterior periplasm. A mutant phenocopy was induced in wild-type embryos that were treated with cytochalasin B or D at a very early cleavage stage. Remarkable differences were noticed in the organization of cortical F-actin between the mutants and the wild type throughout the cleavage stage: obvious F-actin aggregates were dispersed in the cortex of mutant embryos, in contrast to the wild type where the cortical F-actin layer was smooth and underlying F-actin aggregates were smaller than those in the mutants; the transition of the distribution pattern of F-actin in the yolk mass, from the centralized to the fragmented type, occurred later in the mutants than in wild type. The results suggest that these mutations affect the mechanism underlying establishment and transition of F-actin organization required for normal egg contraction and nuclear migration in the cleavage embryos.


Apigenin inhibits cell migration through MAPK pathways in human bladder smooth muscle cells.
Apigenin, a nonmutagenic flavonoid, has been shown to possess free radical scavenging activities, anticarcinogenic properties, antioxidant and anti-inflammatory effects. Recently, apigenin was reported to cause gastric relaxation in murine. To assess possible effects of apigenin on migration of bladder smooth muscle (SM) cell, we isolated SM cells from peri-cancer tissue of human bladder and established a cell model that was capable to overexpress transiently MEKK1 (MEK kinase 1). Results showed that overexpression of active human MEKK1 by adenoviruses infection induced migration of human bladder smooth muscle (hBSM) cells and phosphorylation of MAPKs, ERK, JNK and p38, which are the downstream molecules of MEKK1. Then, hBSM cell overexpressing MEKK1 were exposed to apigenin (50 microM). Our data indicated that apigenin inhibited significantly activation/phosphorylation of MAPKs and migration of hBSM cells induced by MEKK1 overexpression. Besides, apigenin inhibited actin polymerization, which underlines muscle contraction and cell migration. The results suggest that apigenin inhibits activation of MAPKs and thereby the cell migration. The mechanism might be that apigenin blocks signal transmission from MEKK1 to MAPKs.


Effects on cardiopulmonary function and oxygen delivery of doses of romifidine and xylazine followed by constant rate infusions in standing horses.
The objective of this study was to compare the cardiopulmonary effects of a xylazine or romifidine loading-dose, followed by a constant rate infusion (CRI) of the same α(2)-agonist. Nine research horses were treated in a randomized, blinded, crossover design with xylazine or romifidine. After instrumentation, a loading dose of intravenous xylazine (1mg/kg) or romifidine (80μg/kg) was administered, immediately followed by a CRI of xylazine (0.69mg/kg/h) or romifidine (30μg/kg/h) for a duration of 2h. Cardiopulmonary variables were recorded before bolus administration, during CRI, and for 1h after discontinuing drug administration. A significant decrease in haemoglobin concentration (tHb), arterial oxygen content (CaO(2)), oxygen delivery (D˙O(2)), mixed venous partial pressure of oxygen, heart rate, and cardiac output (Q˙t) followed the loading dose with both treatments. Carotid arterial blood pressure (ABP), systemic vascular resistance, and right atrial pressure (RAP) increased significantly. The increased ABP was followed by a significant decrease compared to baseline. Mean pulmonary arterial pressure increased significantly with romifidine only. No significant changes in stroke volume, arterial partial pressure of oxygen, and oxygen consumption were observed. Changes in Q˙t and RAP were more pronounced with romifidine. During CRI, tHb, and CaO(2) were significantly higher with romifidine, whereas D˙O(2) did not differ between treatments. Overall, cardiopulmonary effects were more pronounced and lasted longer with romifidine compared to xylazine. However, during CRI, there was no difference in D˙O(2) between drugs. With both α(2)-agonists, cardiovascular effects were most pronounced after loading dose administration and tended to stabilize during CRI.


An implementation method based on ERS imaging mode for sun sensor with 1 kHz update rate and 1″ precision level.
Stringent attitude determination accuracy through a high bandwidth is required for the development of the advanced space technologies, such as earth observation and laser communication. In this work, we presented a novel proposal for a digital sun sensor with high accuracy, large Field of View (FOV) and ultra-high data update rate. The Electronic Rolling Shutter (ERS) imaging mode of an APS CMOS detector was employed and an "amplifier factor" was introduced to improve the data update rate significantly. Based on the idea of the multiplexing detector, a novel mask integrated with two kinds of aperture patterns was also introduced to implement its distinctive performance of high precision and large FOV. Test results show that the ERS based sun sensor is capable of achieving the data update rate of 1 kHz and precision of 1.1″ (1σ) within a 105° × 105° FOV. The digital sun sensor can play an important role in precise attitude determination and provide a broader application for high accuracy satellites.


Diazepam sorption to PVC- and non-PVC-based tubes in administration sets with quantitative determination using a high-performance liquid chromatographic method.
Diazepam is highly sorbed to the plastic materials of administration sets for intravenous infusion. This can be detrimental as it should be delivered to the patient at the administered amount for efficacy and safety. We report here the sorption levels of diazepam onto various types of tubes in administration sets. The tube materials of the administration sets included polyvinylchloride (PVC) and the non-PVC materials such as polyurethane (PU) and polyolefin (PO) were used. Two conditions of diazepam administered in preclinical and clinical settings were tested using an infusion pump. Injections were prepared by diluting diazepam to 20mg/500mL and 10mg/100mL in 5% dextrose. Diluted diazepam solutions at the concentrations of 10mg/100mL and 20mg/500mL were separately delivered through 1m of tubing at 1mL/min for 1.05 and 4.05h. Samples were analyzed using a high-performance liquid chromatography with UV detection. PVC- and PU-based tubes showed higher sorption of diazepam than did PO-based tubes. PO-based tubes delivered more than 90% of the administered diazepam. The results showed that PO-based tubes of administration sets have a promising potential to deliver hydrophobic drugs like diazepam with minimal sorption levels. In addition, the tube materials in administration sets may be one of the critical factors to ensure drug efficacy and safety.


Contribution of gender to pathophysiology and clinical presentation of IBS: should management be different in women?
The irritable bowel syndrome (IBS) is found more commonly in women than men. It is more prevalent in patients with chronic fatigue syndrome, fibromyalgia, and chronic pelvic pain, all syndromes characterized by pain and found predominantly in women. This article reviews evidence for a role of biological sex factors and gender on the pathways mediating visceral pain. The effect of gonadal hormones on gastrointestinal motility and the sensory afferent pathway and central processing of visceral stimuli and the contribution of gender role to the clinical presentation are discussed. Although differences in responses to treatment modalities between genders exist, the approach to IBS patients in both genders is quite similar. Nevertheless, a special attention to gender role and stress-related factors should be addressed. New developments in research, outlined in the paper, might bring more gender-specific treatments in the future.


Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer.
The orphan G protein-coupled receptor GPR55 has been directly or indirectly related to basic alterations that drive malignant growth: uncontrolled cancer cell proliferation, sustained angiogenesis, and cancer cell adhesion and migration. However, little is known about the involvement of this receptor in metastasis. Here, we show that elevated GPR55 expression in human tumors is associated with the aggressive basal/triple-negative breast cancer population, higher probability to develop metastases, and therefore poor patient prognosis. Activation of GPR55 by its proposed endogenous ligand lysophosphatidylinositol confers pro-invasive features on breast cancer cells both in vitro and in vivo. Specifically, this effect is elicited by coupling to Gq/11 heterotrimeric proteins and the subsequent activation, through ERK, of the transcription factor ETV4/PEA3. Together, these data show that GPR55 promotes breast cancer metastasis, and supports the notion that this orphan receptor may constitute a new therapeutic target and potential biomarker in the highly aggressive triple-negative subtype.


Antibiotic-nanomedicines: facing the challenge of effective treatment of antibiotic-resistant respiratory tract infections.
Respiratory tract infections are one of the most frequent infections worldwide, with an increasing number being associated with (multiple) antibiotic-resistant pathogens. Improved treatment requires the development of new therapeutic strategies, including the possible development of antibiotic-nanomedicines. Antibiotic-nanomedicines comprise antibiotic molecules coupled to nanocarriers via surface adsorption, surface attachment, entrapment or conjugation and can be administered via aerosolization. The efficacy and tolerability of this approach has been shown in clinical studies, with amikacin liposome inhalation suspension being the first inhalatory antibiotic-nanomedicine approved by the US FDA. In this special report, we summarize and discuss the potential value and the clinical status of antibiotic-nanomedicines for the treatment of (antibiotic-resistant) respiratory tract infections.


The Effect of the Intercondylar Notch Shape and Notch Width Index on Anterior Cruciate Ligament Injuries.
Anterior cruciate ligament is one of the commonly injured ligaments in knee. The shape and dimension of the femoral notch has been linked with the risk of anterior cruciate ligament injury. The aim of this study was to study the risk of Anterior cruciate ligament injury with notch morphology in the Nepalese population. This study is a case control study. Cases undergoing arthroscopic surgery at 2 tertiary level centers were enrolled. Patients with arthroscopic confirmation of Anterior cruciate ligament tear were taken as case and those without tear were taken as control. Axial Magnetic resonance Imaging sequence was used to study notch. Sections at the level of popliteal groove was taken for study and shapes were identified as A, U and W type, and notch width index was calculated. These variables were correlated with presence or absence of Anterior cruciate ligament tear. Out of 118 cases, 59 had tear, and 59 had no tear. Tear was found in 74% of Type A notch compared to 30.15% in Type U notch. The femoral notch width index was low in 42.59% of A type notch patients compared to 20.63% with U type notch. Analysis of notch width index among patients with Anterior cruciate ligament tears, showed that 40.67% of Anterior cruciate ligament torn knee had narrow notch compared to 22% in non- injured group, which was statistically significant. Type A notch and narrow notch both are risk factors for Anterior cruciate ligament tear.


Effects of acebutolol and other structurally related beta adrenergic blockers on transmembrane action potential in guinea-pig papillary muscles.
The effects of acebutolol (13-134 microM), pindolol (10-50 microM), oxprenolol (16-66 microM) and (+) and (-)-Kö592 (39-193 microM) on action potentials were investigated in isolated guinea-pig papillary muscles. All the drugs reduced Vmax at 1 Hz, dose-dependently. The reduction was less prominent with prolongation of the interstimulus interval until there was virtually no reduction. The time course of recovery of Vmax during diastole was studied by assessing Vmax in premature responses at 0.1 Hz or in responses after interrupting driving stimuli at 1 Hz. Time constants of recovery thus estimated were 12 to 14 sec for acebutolol and pindolol, 3 to 6 sec for oxprenolol and 0.7 to 1 sec for (-)-Kö592. The reduction of Vmax was rate dependent for all the drugs, and at 5 Hz, the order of potency was oxprenolol > pindolol > acebutolol congruent to (-)- and (+)-Kö592. The most potent was alprenolol (3.5-17.5 microM), which we have already studied in detail. At 1 Hz or lower, the action potential duration was shortened by application of all the compounds mentioned except acebutolol, but tended to be longer than in control, at higher rates for all the drugs. We conclude that molecular bulkiness and dimension may be associated with the time constant of recovery, whereas the potency at high driving rates may be correlated roughly linearly with the lipid solubility of the agents.


Scan without evidence of dopaminergic deficit: A 10-year retrospective study.
123I-ioflupane SPECT is a powerful method to assess nigrostriatal dopamine system integrity. Several independent studies have shown that 1-15% of patients with suspected degenerative parkinsonism, mainly PD, have scans without evidence of dopaminergic deficit (SWEDD). It has been proposed that most SWEDD patients either present with a non-degenerative condition mimicking PD, such as atypical tremor or dystonia, or demonstrate an abnormal scan when repeated later. We here hypothesized that scan interpretation methods may also play a crucial yet underestimated role in this issue. We previously established age-dependent reference values of striatal uptake by analyzing scans from a cohort of patients with non-degenerative conditions. We then studied a large population with well-established degenerative parkinsonism (N = 410, 80% with PD), using identical imaging protocol, to evaluate the prevalence of patients with normal scans based on routine visual assessment. Each scan was eventually reassessed using the same automated method as for controls and a detailed 3D analysis. Ten potential SWEDD cases (2.4%) were identified. However, both reassessment methods independently showed that these scans were all outside reference limits and/or visually abnormal when reexamined carefully, except for one case (0.2%) with corticobasal syndrome. SPECT misinterpretation emerges as an important contributor to the SWEDD population, suggesting that suspected SWEDD cases should prompt not only a serious diagnosis challenge but, equally important, a detailed scan reassessment. True SWEDD cases seem extremely rare in degenerative parkinsonism. We propose that the very concept of SWEDD is more confusing than helpful and should be definitely abandoned.


Achieving Long Distance Sensing Using Semiconductor Laser with Optical Feedback by Operating at Switching Status.
In this study, a novel distance sensing method is presented by using a semiconductor laser (SL) with optical feedback (OF) and operating the SL at a switching status happened between two nonlinear dynamic states (stable state and period-one state). In this case, without the need for any electronic or optical modulation devices, the laser intensity can be modulated in a square wave form due to the switching via utilizing the inherent SL dynamics. The periodicity in the switching enables us to develop a new approach for long-distance sensing compared to other SL with OF-based distance measurement systems and lift the relevant restrictions that existed in the systems. Moreover, the impact of system controllable parameters on the duty cycle of the square wave signals generated was investigated on how to maintain the proposed system robustly operating at the switching status. Both simulation and experiment verified the proposed sensing approach.


Physical activity, spirometry and quality-of-life in chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) has a high level of morbidity. There is limited information about levels of physical activity among community dwelling subjects with the disease and its association with lung function and quality of life. In this study, 176 subjects with COPD were recruited from general practices. Physical activity was measured over 7 days using pedometers, quality-of-life using the St. George's Respiratory Questionnaire, and lung function using spirometry, 124 subjects, 60% male, aged 70 +/- 8 years were included in the analysis. Physical activity levels were low, median steps/day for males = 3621, IQR = 4247 and for females = 4287, IQR = 3063. Overall physical activity (median steps/day = 3716, IQR = 3682) was significantly associated with the forced expiratory volume in one second (r = 0.39, p < 0.001) and with St. George's Respiratory Questionnaire score (r = -0.28, p < 0.01). In conclusion, we have demonstrated that in a community-based sample of people with COPD, daily physical activity levels were low compared with usual levels reported for the general population. Physical activity was significantly associated with disease severity, measured by lung function, and quality-of-life.


Racial and Ethnic Variations in Preventive Dental Care Utilization among Middle-Aged and Older Americans, 1999-2008.
This study examined recent trends of preventive dental care utilization among Americans aged 50 and above, focusing on variations across racial and ethnic groups including Whites, Blacks, Hispanics, American Indians/Alaska Natives, and Asians. Self-reported information on oral health behaviors was collected from 644,635 participants in the Behavioral Risk Factor Surveillance System between 1999 and 2008. Despite a significant upward trend of frequency of dental cleaning from 1999 to 2008 (OR = 1.02), in 2008 still only 56-77% of any ethnic or racial group reported having had a dental cleaning in the previous 12 months. Relative to Whites, Blacks (OR = 0.65) were less likely to have a dental cleaning in the previous 12 months. These variations persisted even when SES, health conditions, health behaviors, and number of permanent teeth were controlled. In contrast, Hispanics, Asians, and American Indians/Alaskan Natives did not differ from Whites in dental cleanings. This is the first study to provide national estimates of the frequency of dental cleaning and associated trends over time for five major ethnic groups aged 50 and above in the U.S. simultaneously. Our findings suggest that public health programs with an emphasis on educating middle-aged and older minority populations on the benefits of oral health could have a large impact, as there is much room for improvement. Given the importance of oral health and a population that is rapidly becoming older and more diverse, the need for improved dental care utilization is significant.


Corrective osteotomy for volarly malunited distal radius fracture.
To retrospectively analyze consecutive cases with opening wedge corrective osteotomy of the volarly malunited distal radius with iliac bone graft, including preoperative and postoperative comparison of symptoms, visual analog scale (VAS), Japanese Society for Surgery of the Hand version of the Disabilities of the Arm, Shoulder, and Hand (DASH-JSSH) questionnaires, radiographic indices, clinical results as evaluated by modified Mayo wrist score, and complications. Subjects were 28 patients with volarly malunited distal radius fracture treated by transverse opening wedge osteotomy with oblique iliac bone graft. Preoperative symptoms included wrist deformity, weakness of grip strength, and marked restriction of supination range. Postoperative symptoms, radiographic parameters, clinical results, and complications were analyzed at an average of 25 months of follow-up. We also analyzed the union period of the radius in younger patients (< or =45 years old) and older patients (>45 years old). Mean preoperative visual analog scale was 45, improving significantly to 3 postoperatively. Range of wrist motion improved in all 28 patients, with supination range improving from 16 degrees preoperatively to 80 degrees postoperatively. Mean preoperative DASH-JSSH score was 55, improving to 9 postoperatively. Radiography revealed that volar tilt improved from 32 degrees preoperatively to 10 degrees postoperatively, and radial inclination increased from 17 degrees to 21 degrees . Preoperative ulnar variance of +5.9 mm was corrected to -0.1 mm postoperatively. All 28 wrists demonstrated bony union at the osteotomy site after an average of 52 days (younger patients, 51 days; older patients, 54 days). No complications, significant radiographic correction loss, or nonunion were seen after at least 2 years of follow-up. Modified Mayo wrist score was excellent in 16 patients, good in 10 patients, and fair in 2 patients. Opening wedge osteotomy for volarly malunited distal radius fracture restored bony configuration of the distal radius, decreased pain, and improved grip strength and range of wrist motion, particularly for forearm supination. No complications or noteworthy correction loss were noted after surgery, even in older patients. Therapeutic IV.


Do Facebook Status Updates Reflect Subjective Well-Being?
Nowadays, millions of people around the world use social networking sites to express everyday thoughts and feelings. Many researchers have tried to make use of social media to study users' online behaviors and psychological states. However, previous studies show mixed results about whether self-generated contents on Facebook reflect users' subjective well-being (SWB). This study analyzed Facebook status updates to determine the extent to which users' emotional expression predicted their SWB-specifically their self-reported satisfaction with life. It was found that positive emotional expressions on Facebook did not correlate with life satisfaction, whereas negative emotional expressions within the past 9-10 months (but not beyond) were significantly related to life satisfaction. These findings suggest that both the type of emotional expressions and the time frame of status updates determine whether emotional expressions in Facebook status updates can effectively reflect users' SWB. The findings shed light on the characteristics of online social media and improve the understanding of how user-generated contents reflect users' psychological states.


Dietary options and behavior suggested by plant biomarker evidence in an early human habitat.
The availability of plants and freshwater shapes the diets and social behavior of chimpanzees, our closest living relative. However, limited evidence about the spatial relationships shared between ancestral human (hominin) remains, edible resources, refuge, and freshwater leaves the influence of local resources on our species' evolution open to debate. Exceptionally well-preserved organic geochemical fossils--biomarkers--preserved in a soil horizon resolve different plant communities at meter scales across a contiguous 25,000 m(2) archaeological land surface at Olduvai Gorge from about 2 Ma. Biomarkers reveal hominins had access to aquatic plants and protective woods in a patchwork landscape, which included a spring-fed wetland near a woodland that both were surrounded by open grassland. Numerous cut-marked animal bones are located within the wooded area, and within meters of wetland vegetation delineated by biomarkers for ferns and sedges. Taken together, plant biomarkers, clustered bone debris, and hominin remains define a clear spatial pattern that places animal butchery amid the refuge of an isolated forest patch and near freshwater with diverse edible resources.


Sexually active older Australian's knowledge of sexually transmitted infections and safer sexual practices.
Rates of sexually transmitted infections (STIs) are rising among older Australians. We conducted a large survey of older people's knowledge of STIs and safer sexual practices. A total of 2,137 Australians aged 60 years and older completed the survey, which included 15 questions assessing knowledge of STIs and safer sexual practices. We examined both levels of knowledge and factors associated with an overall knowledge score. In total, 1,652 respondents reported having sex in the past five years and answered all knowledge questions. This group had good general knowledge but poorer knowledge in areas such as the protection offered by condoms and potential transmission modes for specific STIs. Women had better knowledge than men. Men in their 60s, men with higher education levels, and men who thought they were at risk of STIs reported better knowledge than other men. Knowledge was also better among men and women who had been tested for STIs or reported 'other' sources of knowledge on STIs. Many older Australians lack knowledge of STIs and safer sexual practices. Implications for public health: To reverse current trends toward increasing STI diagnoses in this population, policies and education campaigns aimed at improving knowledge levels may need to be considered.


Spatial and orientational dependence of electron transfer parameters in aggregates of iridium-containing host materials for OLEDs: coupling constrained density functional theory with molecular dynamics.
The efficient transport of charge within the bulk of active molecular materials is one of the main factors affecting the efficiency and performance of organic electronic devices. In amorphous molecular aggregates, the observed effective mobility of charge carriers is usually considered as resulting from the convolution of the manifold of intermolecular configurations. In this picture, individual molecules are considered as spherically-symmetric scattering points for charge hopping. Yet, the details of the molecular structure and the topology of the electronic states involved in the charge transport mechanism affect dramatically the intermolecular electronic coupling even in amorphous materials. In this work, we link the morphology of aggregates, in terms of intermolecular configurations, as obtained from atomistic molecular dynamics, to the distribution of diabatic electronic couplings and charge transfer energies, computed by constrained density functional theory simulations. In particular, we focus on aggregates of an organometallic system with multidentate ligands, the iridium complex fac-tris(1,3-diphenyl-benzimidazolin-2-ylidene-C,C2')iridium(iii) (DPBIC), commonly used in OLEDs as host transporter and emitter. Despite the quasi-spherical symmetry of the molecule, our simulations suggest a strong correlation between intermolecular orientation and electronic coupling, indicating a strong impact of the mutual orientation of molecules on charge transport in bulk molecular materials.


Topical application of alpha-tocopherol modulates the antioxidant network and diminishes ultraviolet-induced oxidative damage in murine skin.
The aim of this study was to investigate the effects of topical alpha-tocopherol application on epidermal and dermal antioxidants and its ability to prevent ultraviolet (UV)-induced oxidative damage. Hairless mice received topical applications of alpha-tocopherol 24 h before a single, acute UV irradiation (10 x minimal erythemal dose). The four major antioxidant enzymes (catalase, superoxide dismutase, glutathione reductase and glutathione peroxidase), hydrophilic and lipophilic antioxidants, and lipid hydroperoxides, markers of oxidative damage, were assayed in both epidermis and dermis of hairless mice. Topical alpha-tocopherol treatment increased dermal superoxide dismutase activity by 30% (P < 0.01) and protected epidermal glutathione peroxidase and superoxide dismutase from depletion after UV irradiation. Total and reduced glutathione levels in the epidermis increased by 50% after the topical treatment (P < 0.05), as did dermal ascorbate levels (by 40%: P < 0.01). The topical treatment increased alpha-tocopherol levels both in the epidermis (62-fold) and the dermis (22-fold: P < 0.001 in each layer). Furthermore, alpha-tocopherol treatment significantly reduced the formation of epidermal lipid hydroperoxides after UV irradiation (P < 0.05). These results demonstrate that topical administration of alpha-tocopherol protects cutaneous tissues against oxidative damage induced by UV irradiation in vivo, and suggest that the underlying mechanism of this effect involves the up-regulation of a network of enzymatic and non-enzymatic antioxidants.


Effects of pruritogens and algogens on rostral ventromedial medullary ON and OFF cells.
Rostroventromedial medulla (RVM) ON and OFF cells are thought to facilitate and inhibit spinal nociceptive transmission, respectively. However, it is unknown how ON and OFF cells respond to pruritic stimuli or how they contribute to descending modulation of spinal itch signaling. In pentobarbital sodium-anesthetized mice, single-unit recordings were made in RVM from ON and OFF cells identified by their respective increase or decrease in firing that occurred just before nocifensive hindlimb withdrawal elicited by paw pinch. Of RVM ON cells, 75% (21/28) were excited by intradermal histamine, 50% (10/20) by intradermal chloroquine, and 75% (27/36) by intradermal capsaicin. Most chemically responsive units also responded to a scratch stimulus applied to the injected hindpaw. Few ON cells responded to intradermal injection of vehicle (saline: 5/32; Tween 2/17) but still responded to scratching. For OFF cells, intradermal histamine and scratching inhibited 32% (6/19) with no effect of histamine in the remainder. Intradermal chloroquine inhibited 44% (4/9) and intradermal capsaicin inhibited 61% (11/18) of OFF cells. Few OFF cells were affected by vehicles (Tween: 1 inhibited, 7 unaffected; saline: 3 excited, 1 inhibited, 8 unaffected). Both ON and OFF cells that responded to one chemical usually also responded to others, whereas units unresponsive to the first-tested chemical tended not to respond to others. These results indicate that ascending pruriceptive signals activate RVM ON cells and inhibit RVM OFF cells. These effects are considered to facilitate and disinhibit spinal pain transmission, respectively. It is currently not clear if spinal itch transmission is similarly modulated. NEW & NOTEWORTHY The rostroventromedial medulla (RVM) contains ON and OFF cells that are, respectively, excited and inhibited by noxious stimuli and have descending projections that facilitate and inhibit spinal nociceptive transmission. Most RVM ON cells were excited, and OFF cells inhibited, by intradermal injection of the pruritogens histamine and chloroquine, as well as the algogen capsaicin. These results indicate that itchy stimuli activate RVM neurons that presumably give rise to descending modulation of spinal itch transmission.


Chromatin protein L3MBTL1 is dispensable for development and tumor suppression in mice.
L3MBTL1, a paralogue of Drosophila tumor suppressor lethal(3)malignant brain tumor (l(3)mbt), binds histones in a methylation state-dependent manner and contributes to higher order chromatin structure and transcriptional repression. It is the founding member of a family of MBT domain-containing proteins that has three members in Drosophila and nine in mice and humans. Knockdown experiments in cell lines suggested that L3MBTL1 has non-redundant roles in the suppression of oncogene expression. We generated a mutant mouse strain that lacks exons 13-20 of L3mbtl1. Markedly reduced levels of a mutant mRNA with an out-of-frame fusion of exons 12 and 21 were expressed, but a mutant protein was undetectable by Western blot analysis. L3MBTL1(-/-) mice developed and reproduced normally. The highest expression of L3MBTL1 was detected in the brain, but its disruption did not affect brain development, spontaneous movement, and motor coordination. Despite previous implications of L3mbtl1 in the biology of hematopoietic transcriptional regulators, lack of L3MBTL1 did not result in deficiencies in lymphopoiesis or hematopoiesis. In contrast with its demonstrated biochemical activities, embryonic stem (ES) cells lacking L3MBTL1 displayed no abnormalities in H4 lysine 20 (H4K20) mono-, di-, or trimethylation; had normal global chromatin density as assessed by micrococcal nuclease digests; and expressed normal levels of c-myc. Embryonic fibroblasts lacking L3MBTL1 displayed unaltered cell cycle arrest and down-regulation of cyclin E expression after irradiation. In cohorts of mice followed for more than 2 years, lack of L3MBTL1 did not alter normal lifespan or survival with or without sublethal irradiation.


Robust alginate/hyaluronic acid thiol-yne click-hydrogel scaffolds with superior mechanical performance and stability for load-bearing soft tissue engineering.
Hydrogels based on hyaluronic acid (HA) exhibit great potential as tissue engineering (TE) scaffolds as a consequence of their unique biological features. Herein, we examine how the advantages of two natural polymers (i.e. HA and alginate) are combined with the efficiency and rapid nature of the thiol-yne click chemistry reaction to obtain biocompatible matrices with tailored properties. Our injectable click-hydrogels revealed excellent mechanical performance, long-term stability, high cytocompatibility and adequate stiffness for the targeted application. This simple approach yielded HA hydrogels with characteristics that make them suitable for applications as 3D scaffolds to support and promote soft tissue regeneration.


A systematic review on the anxiolytic effects of aromatherapy on rodents under experimentally induced anxiety models.
We reviewed studies from 1999 to 2009 on anxiolytic effects of different essential oils toward rodents in anxiety-related behavioral models. Journal papers that evaluated the anxiolytic effects of essential oils for rodents were extracted from available electronic data bases. The results based on 14 studies showed that different rodent species were recruited including ICR mice and Swiss mice. Most of studies applied the Elevated Plus Maze (EPM) as the animal behavioral model. Lavender oil was the most popular within the 14 studies. Lavender and rose oils were found to be effective in some of the studies. Only one study reported the underlying neurophysiological mechanism in terms of concentrations of emotionally related neuro-transmitters such as dopamine, serotonin, and their derivatives, in various brain regions. Some essential oils are found to be effective to induce anxiolytic effect in rodents under different animal anxiety models. However, more standardized experimental procedures and outcome measures are needed in future studies. Translational research to human subjects is also recommended.


[Autotransfusion of ultraviolet-irradiated blood in destructive pneumonia of young children].
Analysis of the results of clinicoimmunological study of the use of autotransfusion of blood treated by ultraviolet irradiation (ABUVI) in infants with acute purulent destructive pneumonia (APDP) revealed that imbalance of cellular and humoral immunity factors was the main factor determining the severity of the disease. ABUVI is an effective measure for correcting the immune response of the child's organism to the bacterial aggression through adequate production of monocytic phagocytes and plasma cells of the blood. It also influences the completeness of humoral immunity and reduction of T-lymphocyte deficiency in the acute phase of the disease. ABUVI raises the efficacy of complex treatment of toxicoseptic forms of APDR, reduces 1.7-fold the terms of treatment, and reduces considerably the mortality rate of this disease in young children.


Staged demodulation and decoding.
Coding for the phase noise channel is investigated in the paper. Specifically, Wiener's phase noise, which induces memory in the channel, is considered. A general coding principle for channels with memory is the interleaving of two or more codes. The interleaved codes are decoded in sequence, using past decisions to help future decoding. The paper proposes a method based on this principle, and shows its benefits through numerical results obtained by computer simulation. Analysis of the channel capacity given by the proposed method is also worked out in the paper.


Common genetic variants influence human subcortical brain structures.
The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.


Genetic diversity and association analysis for salinity tolerance, heading date and plant height of barley germplasm using simple sequence repeat markers.
The objective of this study was to investigate the genetic diversity of barley accessions. Additionally, association trait analysis was conducted for grain yield under salinity, heading date and plant height. For this purpose, 48 barley genotypes were analyzed with 22 microsatellite simple sequence repeat (SSR) markers. Four of the 22 markers (Bmac316, scssr03907, HVM67 and Bmag770) were able to differentiate all barley genotypes. Cluster and principal coordinate analysis allowed a clear grouping between countries from the same region. The genotypes used in this study have been evaluated for agronomic performance in different environments. Conducting association analysis for grain yield under salinity conditions using TASSEL software revealed a close association of the marker Bmag749 (2H, bin 13) in two different environments with common significant alleles (175, 177), whereas the HVHOTR1 marker (2H, bin 3) was only significant in Sakhar_Egypt with alleles size being 158 and 161. Heading date also showed an association with scssr03907 through the common significant specific allele 111 and EBmac0415 markers in three different agro climatic locations, whereas HVCMA, scssr00103 and HVM67 were linked to heading date in the Egyptian environment only. The plant height association analysis revealed significant markers Bmag770 via the significant allele 152 and scssr09398.


A Combination of Divergence and Conservatism in the Niche Evolution of the Moorish Gecko, Tarentola mauritanica (Gekkota: Phyllodactylidae).
The quantification of realized niche overlap and the integration of species distribution models (SDMs) with calibrated phylogenies to study niche evolution are becoming not only powerful tools to understand speciation events, but can also be used as proxies regarding the delimitation of cryptic species. We applied these techniques in order to unravel how the fundamental niche evolved during cladogenesis within the Tarentola mauritanica species-complex. Our results suggest that diversification within this complex, during the Miocene and Pleistocene, is associated with both niche divergence and niche conservatism, with a pattern that varies depending on whether the variables involved are related to the mean or seasonality of temperature and humidity. Moreover, climatic variables related to humidity and temperature seasonality were involved in the niche shift and genetic diversification of the European/North African clade during the Pleistocene and in its maintenance in a fundamental niche distinct from that of the remaining members of the group. This study further highlights the need for a taxonomic revision of the T. mauritanica species-complex.


Exploration of advanced porous organic polymers as a platform for biomimetic catalysis and molecular recognition.
Nature has long been a dominant source of inspiration in the area of chemistry, serving as prototypes for the design of materials with proficient performance. In this Feature article, we present our efforts to explore porous organic polymers (POPs) as a platform for the construction of biomimetic materials to enable new technologies to achieve efficient conversions and molecular recognition. For each aspect, we first present the chemical basis of nature, followed by depicting the principles and design strategies involved for functionalizing POPs along with a summary of critical requirements for materials, culminating in a demonstration of unique features of POPs. Our endeavours in using POPs to address the fundamental scientific problems related to biomimetic catalysis and adsorption are then illustrated to show their enormous potential and capabilities for applications ranging from concerted catalysis to radionuclide sequestration. To conclude, we present a personal perspective on the challenges and opportunities in this emerging field.


Relationship between chemotherapy use and cognitive impairments in older women with breast cancer: findings from a large population-based cohort.
Several small scale clinical trials indicated a possible relationship between chemotherapy administration and the increased risk of cognitive impairments in patients with breast cancer, but little information was available from large population-based cohort studies. We studied 62,565 women who were diagnosed with stages I-IV breast cancer at age ≥65 years from 1991 through 2002 from 16 regions in the Surveillance, Epidemiology and End Results program who were free of cognitive impairments at diagnosis with up to 16 years of follow-up, and also studied 9752 matched cohort based on the propensity of receiving chemotherapy. The cumulative incidence of cognitive impairments was calculated and the time to event (cognitive impairments) analysis was conducted using Cox hazard regression model. Overall, patients who received chemotherapy were 8% more likely to have drug-induced dementia compared with those without chemotherapy, but that was not statistically significant after adjusting for patient and tumor characteristics (hazard ratio = 1.08, 95% confidence interval = 0.85-1.37). The risk of developing Alzheimer disease, vascular dementia, or other dementias was significantly lower in patients receiving chemotherapy except for cognitive disorder which was not significantly different between the 2 chemotherapy groups. The results were somewhat similar in the entire cohort and the matched cohort based on the probability of receiving chemotherapy. There was no significant association between chemotherapy and the risk of developing drug-induced dementia and unspecified cognitive disorders. The risk of developing Alzheimer disease, vascular dementia, or other dementias was significantly lower in patients receiving chemotherapy. This study with long-term follow-up did not support the findings that chemotherapy was associated with an increased risk of late stage cognitive impairments.


Establishment of efficacy and safety assessment of human adipose tissue-derived mesenchymal stem cells (hATMSCs) in a nude rat femoral segmental defect model.
Human adipose tissue-derived mesenchymal stem cell (hATMSC) have emerged as a potentially powerful tool for bone repair, but an appropriate evaluation system has not been established. The purpose of this study was to establish a preclinical assessment system to evaluate the efficacy and safety of cell therapies in a nude rat bone defect model. Segmental defects (5 mm) were created in the femoral diaphyses and transplanted with cell media (control), hydroxyapatite/tricalcium phosphate scaffolds (HA/TCP, Group I), hATMSCs (Group II), or three cell-loading density of hATMSC-loaded HA/TCP (Group III-V). Healing response was evaluated by serial radiography, micro-computed tomography and histology at 16 weeks. To address safety-concerns, we conducted a GLP-compliant toxicity study. Scanning electron microscopy studies showed that hATMSCs filled the pores/surfaces of scaffolds in a cell-loading density-dependent manner. We detected significant increases in bone formation in the hATMSC-loaded HA/TCP groups compared with other groups. The amount of new bone formation increased with increases in loaded cell number. In a toxicity study, no significant hATMSC-related changes were found in body weights, clinical signs, hematological/biochemical values, organ weights, or histopathological findings. In conclusion, hATMSCs loaded on HA/TCP enhance the repair of bone defects and was found to be safe under our preclinical efficacy/safety hybrid assessment system.


ERK1/2-EGR1-SRSF10 Axis Mediated Alternative Splicing Plays a Critical Role in Head and Neck Cancer.
Aberrant alternative splicing is recognized to promote cancer pathogenesis, but the underlying mechanism is yet to be clear. Here, in this study, we report the frequent upregulation of SRSF10 (serine and arginine-rich splicing factor 10), a member of an expanded family of SR splicing factors, in the head and neck cancer (HNC) patients sample in comparison to paired normal tissues. We observed that SRSF10 plays a crucial role in HNC tumorigenesis by affecting the pro-death, pro-survical splice variants of BCL2L1 (BCL2 Like 1: BCLx: Apoptosis Regulator) and the two splice variants of PKM (Pyruvate kinase M), PKM1 normal isoform to PKM2 cancer-specific isoform. SRSF10 is a unique splicing factor with a similar domain organization to that of SR proteins but functions differently as it acts as a sequence-specific splicing activator in its phosphorylated form. Although a body of research studied the role of SRSF10 in the splicing process, the regulatory mechanisms underlying SRSF10 upregulation in the tumor are not very clear. In this study, we aim to dissect the pathway that regulates the SRSF10 upregulation in HNC. Our results uncover the role of transcription factor EGR1 (Early Growth Response1) in elevating the SRSF10 expression; EGR1 binds to the promoter of SRSF10 and promotes TET1 binding leading to the CpG demethylation (hydroxymethylation) in the adjacent position of the EGR1 binding motif, which thereby instigate SRSF10 expression in HNC. Interestingly we also observed that the EGR1 level is in the sink with the ERK1/2 pathway, and therefore, inhibition of the ERK1/2 pathway leads to the decreased EGR1 and SRSF10 expression level. Together, this is the first report to the best of our knowledge where we characterize the ERK 1/2-EGR1-SRSF10 axis regulating the cancer-specific splicing, which plays a critical role in HNC and could be a therapeutic target for better management of HNC patients.


Clustering and optimal arrangement of enzymes in reaction-diffusion systems.
Enzymes within biochemical pathways are often colocalized, yet the consequences of specific spatial enzyme arrangements remain poorly understood. We study the impact of enzyme arrangement on reaction efficiency within a reaction-diffusion model. The optimal arrangement transitions from a cluster to a distributed profile as a single parameter, which controls the probability of reaction versus diffusive loss of pathway intermediates, is varied. We introduce the concept of enzyme exposure to explain how this transition arises from the stochastic nature of molecular reactions and diffusion.


Daphnia predation on the amphibian chytrid fungus and its impacts on disease risk in tadpoles.
Direct predation upon parasites has the potential to reduce infection in host populations. For example, the fungal parasite of amphibians, Batrachochytrium dendrobatidis (Bd), is commonly transmitted through a free-swimming zoospore stage that may be vulnerable to predation. Potential predators of Bd include freshwater zooplankton that graze on organisms in the water column. We tested the ability of two species of freshwater crustacean (Daphnia magna and D. dentifera) to consume Bd and to reduce Bd density in water and infection in tadpoles. In a series of laboratory experiments, we allowed Daphnia to graze in water containing Bd while manipulating Daphnia densities, Daphnia species identity, grazing periods and concentrations of suspended algae (Ankistrodesmus falcatus). We then exposed tadpoles to the grazed water. We found that high densities of D. magna reduced the amount of Bd detected in water, leading to a reduction in the proportion of tadpoles that became infected. Daphnia dentifera, a smaller species of Daphnia, also reduced Bd in water samples, but did not have an effect on tadpole infection. We also found that algae affected Bd in complex ways. When Daphnia were absent, less Bd was detected in water and tadpole samples when concentrations of algae were higher, indicating a direct negative effect of algae on Bd. When Daphnia were present, however, the amount of Bd detected in water samples showed the opposite trend, with less Bd when densities of algae were lower. Our results indicate that Daphnia can reduce Bd levels in water and infection in tadpoles, but these effects vary with species, algal concentration, and Daphnia density. Therefore, the ability of predators to consume parasites and reduce infection is likely to vary depending on ecological context.


Impact of seawater-quality and water treatment procedures on the active bacterial assemblages at two desalination sites.
Inorganic and organic compounds, particles and microorganisms in intake waters are mainly responsible for fouling of reverse osmosis membranes, which reduces the efficiency of the desalination process. The characterization of seawater quality to better predict its fouling potential remains a challenge for the desalination field and little is known about the seasonal variability of water quality parameters in the coastal waters used to supply desalination plants. In this study, standard water quality methods were combined with flow cytometry and molecular methods (16S rRNA sequencing and fingerprinting) to assess in parallel, the physicochemical properties, the microbial abundance and the active microbial community composition of the intake waters and their associated pretreated waters at two desalination sites from July 2007 to July 2008. The overall assessment of quality parameters revealed that microfiltration followed by slow sand filtration were the most efficient in removing microorganisms than the conventional dual media filtration routinely used in full-scale desalination plants, and that all treatments were inefficient for organic matter reduction. Temporal variation of the environmental parameters such as temperature, turbidity and silt density index only moderately affected the bacterial community structure in raw waters, but that interestingly, water treatment compartments changed the composition and diversity of the metabolically active bacterial populations and thus create distinct ecological post-treatment niches.


[Scurvy in intensive care despite vitamin supplementation].
Scurvy can occur in hospitalized patients despite vitamin supplementation. A 63 Year-old patient who had spent several weeks in intensive care developed an unexplained anemia and ecchymoses. Despite daily administration of 130 mg/day of vitamin C since his admission, his ascorbic acid blood levels had collapsed. Administration of 1g/day relieved the symptoms within four weeks. Whether a deficiency had existed prior to admission or not, scurvy developed during the week of intensive care despite parenteral nutrition supplying a daily dose of 130 mg of vitamin C. Such deficiencies decompensated in surgical situations remain a reality in developed countries. In certain pathological contexts and in all the growing number of cases in elderly patients and many surgical indications, the need for vitamin C supplementation has to be defined. The needs at that particular time must be taken into account and the prior nutritional status.


Can β2-agonists have an ergogenic effect on strength, sprint or power performance? Systematic review and meta-analysis of RCTs.
We aimed to examine the effect of β2-agonists on anaerobic performance in healthy non-asthmatic subjects. Systematic review and meta-analysis. We searched four databases (PubMed, Embase, SPORTDiscus and Web of Science) for randomised controlled trials, published until December 2019, examining the effect of β2-agonists on maximal physical performance lasting 1 min or shorter. Data are presented as standardised difference in mean (SDM) with 95% confidence intervals (95% CI). 34 studies were included in the present meta-analysis. The studies include 44 different randomised and placebo-controlled comparisons with β2-agonists comprising 323 participants in crossover trials, and 149 participants in parallel trials. In the overall analyses, β2-agonists improved anaerobic performance by 5% (SDM 0.29, 95% CI 0.16 to 0.42), but the effect was related to dose and administration route. In a stratified analysis, the SDM was 0.14 (95% CI 0.00 to 0.28) for approved β2-agonists and 0.46 (95% CI 0.24 to 0.68) for prohibited β2-agonists, respectively. Furthermore, SDM was 0.16 (95% CI 0.02 to 0.30) for inhaled administration and 0.51 (95% CI 0.25 to 0.77) for oral administration, respectively, and 0.20 (95% CI 0.07 to 0.33) for acute treatment and 0.50 (95% CI 0.20 to 0.80) for treatment for multiple weeks. Analyses stratified for the type of performance showed that strength (0.35, 95% CI 0.15 to 0.55) and sprint (0.17, 95% CI 0.06 to 0.29) performance were improved by β2-agonists. Our study shows that non-asthmatic subjects can improve sprint and strength performance by using β2-agonists. It is uncertain, however, whether World Anti-Doping Agency (WADA)-approved doses of β2-agonists improve performance. Our results support that the use of β2-agonists should be controlled and restricted to athletes with documented asthma. PROSPERO CRD42018109223.


Hypertension, diuretics and antihypertensives in relation to bladder cancer.
The aim of this study is to investigate the relationships between hypertension, hypertension medication and bladder cancer risk in a population-based case-control study conducted in Los Angeles. Non-Asians between the ages of 25 and 64 years with histologically confirmed bladder cancers diagnosed between 1987 and 1996 were identified through the Los Angeles County Cancer Surveillance Program. A total of 1585 cases and their age-, gender- and race-matched neighborhood controls were included in the analyses. Conditional logistic regression models were used to examine the relationship between history of hypertension, medication use and bladder cancer risk. A history of hypertension was not related to bladder cancer; however, among hypertensive individuals, there was a significant difference in bladder cancer risk related to the use of diuretics or antihypertensive drugs (P for heterogeneity = 0.004). Compared with individuals without hypertension, hypertensive individuals who regularly used diuretics/antihypertensives had a similar risk [odds ratio (OR) 1.06; 95% confidence interval (CI) 0.86-1.30], whereas untreated hypertensive subjects had a 35% reduction in risk (OR: 0.65; 95% CI: 0.48-0.88). A greater reduction in bladder cancer risk was observed among current-smokers (OR: 0.43; 95% CI: 0.27-0.71) and carriers of GSTM1-null (homozygous absence) genotypes (OR: 0.43; 95% CI: 0.22-0.85). Similarly, among smokers with GSTM1-null genotype, levels of 4-aminobiphenyl-hemoglobin adducts were significantly lower among untreated hypertensive individuals (45.7 pg/g Hb) compared with individuals without hypertension (79.8 pg/g Hb) (P = 0.009). In conclusion, untreated hypertension was associated with a reduced risk of bladder cancer.


Prestroke antiplatelet agents in first-ever ischemic stroke: clinical effects.
To investigate whether prestroke antiplatelet agent (PA) use was associated with initial stroke severity. This was a retrospective, case-control study based on data from a prospectively collected hospital-based stroke registry (Korea University Stroke Registry). A total of 3,025 patients who were admitted with a diagnosis of first-ever ischemic stroke within 5 days of symptom onset were included. Stroke severity was measured with the NIH Stroke Scale (NIHSS). NIHSS score ≤4 at admission was categorized as mild stroke. Patients from the PA group were matched with those from the non-PA group using estimated propensity scores at a 1:1 ratio. Stepwise multivariable logistic regression analyses were performed on patients in the matched datasets with initial mild stroke. Patients' mean age was 66.3 ± 13.0 years, and 1,850 were men (61.5%). A total of 748 patients had been taking antiplatelet agents prior to stroke onset; 644 patients (86.1%) were taking a single antiplatelet agent. Among these agents, aspirin (83.7%) was the most common. A total of 102 patients (13.6%) were taking 2 antiplatelet agents. Multivariable analysis after propensity score matching demonstrated that PA use was associated with initial mild stroke (odds ratio 1.344; 95% confidence interval 1.014-1.782). PA use was associated with decreased first-ever stroke severity, suggesting that it has a beneficial effect. This study provides Class II evidence that prestroke use of antiplatelet agents reduces stroke severity in patients with first-ever acute ischemic stroke.


Novel Gyrification Networks Reveal Links with Psychiatric Risk Factors in Early Illness.
Adult gyrification provides a window into coordinated early neurodevelopment when disruptions predispose individuals to psychiatric illness. We hypothesized that the echoes of such disruptions should be observed within structural gyrification networks in early psychiatric illness that would demonstrate associations with developmentally relevant variables rather than specific psychiatric symptoms. We employed a new data-driven method (Orthogonal Projective Non-Negative Matrix Factorization) to delineate novel gyrification-based networks of structural covariance in 308 healthy controls. Gyrification within the networks was then compared to 713 patients with recent onset psychosis or depression, and at clinical high-risk. Associations with diagnosis, symptoms, cognition, and functioning were investigated using linear models. Results demonstrated 18 novel gyrification networks in controls as verified by internal and external validation. Gyrification was reduced in patients in temporal-insular, lateral occipital, and lateral fronto-parietal networks (pFDR < 0.01) and was not moderated by illness group. Higher gyrification was associated with better cognitive performance and lifetime role functioning, but not with symptoms. The findings demonstrated that gyrification can be parsed into novel brain networks that highlight generalized illness effects linked to developmental vulnerability. When combined, our study widens the window into the etiology of psychiatric risk and its expression in adulthood.


ATRA therapy restores normal renal function and renal reserve and prevents renal failure.
This article presents clinical data which suggest that the current dosage of losartan 50 to 100 mg/day may not be the optimum in many cases, especially if used as monotherapy in the treatment of proteinuria and we may have to increase to 200 mg/day. However, about 30% of patients cannot take angiotensin-converting enzyme inhibitor (ACEI) because of the side effect of cough. To potentiate the anti-proteinuric effect of losartan, especially for patients who do not adhere to a low salt diet, a 12.5-mg dose of hydro-chlorothiazide may further decrease proteinuria. The main message of this article is that we would have to, in many instances, increase the dose of losartan to a minimum of 100 mg/day or 100 mg twice a day for some patients for optimal therapy. The second message is to monitor the creatinine clearance test (CCT) and to start therapy when CCT is reduced and not wait for serum creatinine to rise to abnormal levels (renal impairment) before starting therapy. The first group involves half a dozen patients with hypertension but no proteinuria. Therapy with losartan is shown to improve the renal function. This data suggest that losartan, apart from its use in reduction of proteinuria, can be used in patients with mild renal impairment without proteinuria to reverse the mild renal impairment and preserve renal function. The second group deals with 3 patients with low creatinine clearance. After a followup period of an average of 3 years, they all developed renal impairment. In another 6 patients, the data suggest that we should perhaps treat patients with low CCT as soon as possible and with dose ranging from 100 to 200 mg/day if necessary, to derive maximum beneficial effect. The third group highlights 5 patients with high CCT due to glomerular hyperfiltration. With time, the high CCT decreases and renal impairment sets in. The data suggest that patients with high CCT should be treated early to prevent renal impairment. The fourth group illustrates 6 patients where their proteinuria was markedly reduced with the increase of losartan from 100 mg/day to 200 mg/day, suggesting that losartan 200 mg/day is probably the optimum dose. In conclusion, apart from its traditional usage in reduction of proteinuria to retard progression to renal failure, the data suggest that losartan is also indicated in patients with renal impairment in the absence of proteinuria; patients with low CCT, patients with high CCT and patients who do not respond to a dosage of 100 mg/day should have the dosage increased to 100 mg twice daily to increase efficacy of losartan. It is hoped that with these new and earlier indications as well as increased dosage of losartan starting with 100 mg, whenever possible, and increasing to 200 mg/day, if there is no response, we can prevent more patients from developing renal failure. Based on these observations, further randomised controlled trials should be designed to address these issues.