100-GHz transistors from wafer-scale epitaxial graphene.
The high carrier mobility of graphene has been exploited in field-effect transistors that operate at high frequencies. Transistors were fabricated on epitaxial graphene synthesized on the silicon face of a silicon carbide wafer, achieving a cutoff frequency of 100 gigahertz for a gate length of 240 nanometers. The high-frequency performance of these epitaxial graphene transistors exceeds that of state-of-the-art silicon transistors of the same gate length.


Steroid metabolism gene polymorphisms and their implications on breast and ovarian cancer prognosis.
A role for estrogen in the etiology of breast and ovarian cancers has been suggested; therefore, genetic polymorphisms in steroid metabolism genes could be involved in the carcinogenesis of these tumors. We have aimed to investigate the role of GSTP1 and CYP17 polymorphisms and their correlation with MSI (microsatellite instability) and LOH (loss of heterozygosity) in AR, ERβ and CYP19 genes in women from Espírito Santo State, Brazil. The study population consisted of 107 female breast and 24 ovarian tumors. GSTP1 and CYP17 polymorphisms were detected by polymerase chain reaction (PCR) amplification followed by restriction fragment length polymorphism (RFLP) analysis while MSI and LOH were analyzed by PCR. GSTP1 and CYP17 polymorphisms alone were not associated with an increased risk for breast or ovarian tumors. However, when combined with MSI/LOH in AR, ERβ and CYP19 genes, we were able to detect significant associations with the GSTP1 wild-type genotype in PR (progesterone receptor) negative breast cancers or the CYP17 wild-type genotype in ER (estrogen receptor) and PR-negative breast tumors. No associations with ovarian tumors were detected. Our results suggest that wild-type GSTP1 or CYP17 genes when combined with LOH/MSI in steroid metabolism genes may play a role in ER and/or PR negative breast cancers. These data support the hypothesis that genes related to steroid metabolism are important in the characterization of breast cancer and that the analysis of single polymorphisms may not be sufficient.


Orthobiologic Supplementation Improves Clinical Outcomes Following Lumbar Decompression Surgery.
Endoscopic-assisted lumbar decompression is a minimally invasive spine surgery which has been touted to reduce collateral tissue damage, incisional pain, recovery time and complications. Residual back or leg pain and recurrent herniation are commonly reported post-operative outcomes. It has been suggested that injecting orthobiologics like cryopreserved amniotic-derived products (ADPs) and bone marrow aspiration (BMA) into the surgery site would have additional benefit on patient outcomes. This is a Western Institutional Review Board (WIRB)-approved level 1, randomized controlled trial of prospectively collected patient demographic and outcomes data for endoscopic-assisted lumbar decompression surgery. The primary goal of this study was to compare patient outcomes of orthobiologic supplementation during endoscopic-assisted lumbar decompression surgery. Following WIRB approval, 269 patients underwent lumbar endoscopic-assisted decompressive surgery between January 2011 and October 2017. Patients were randomized to receive ADP, BMA, both, or no supplementation (control group). Outcomes were measured by post-operative questionnaires (visual analog scale (VAS), Oswestry disability index (ODI), 36-item short-form health survey (SF-36)) over 12 months. Mean VAS-leg for either BMA or ADP group displayed statistically significant improvements at 2 weeks (3.55 vs. 4.77, P = 0.002), 6 months (2.34 vs. 3.37, P = 0.026), and 9 months (2.18 vs. 3.57, P = 0.01) compared to no supplementation group (control group). Similarly, improvements in mean VAS-back were significant at 2 weeks (3.98 vs. 5.01, P = 0.011), 2 months (3.22 vs. 3.93, P = 0.04), 9 months (2.38 vs. 4.11, P = 0.004), and 12 months (2.23 vs. 3.58, P = 0.011) compared to no supplementation group (control group). There were statistically significant differences in the ODI (2 weeks, 42.19 vs. 31.11, P = 0.014) and SF-36 (4 months, 85 vs. 63, P = 0.043 for ADP only), but these differences did not subsist over time. Two patients (one control, one ADP) re-herniated at the same level. Orthobiologic BMA and ADP resulted in improved pain control during early post-operative periods.


The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template.
Mutations in SOX9, a gene essential for chondrocyte differentiation cause the human disease campomelic dysplasia (CD). To understand how SOX9 activates transcription, we characterized the DNA binding and cell-free transcription ability of wild-type SOX9 and a dimerization domain SOX9 mutant. Whereas formation of monomeric mutant SOX9-DNA complex increased linearly with increasing SOX9 concentrations, formation of a wild-type SOX9-DNA dimeric complex increased more slowly suggesting a more sigmoidal-type progression. Stability of SOX9-DNA complexes, however, was unaffected by the dimerization mutation. Both wild-type and mutant SOX9 activated transcription of a naked Col2a1 DNA template. However, after nucleosomal assembly, only wild-type and not the mutant was able to remodel chromatin and activate transcription of this template. Using a cell line, in which the Col2a1 vector was stably integrated, no differences were seen in the interactions of wild-type and mutant SOX9 with the chromatin of the Col2a1 vector using ChIP. However, the mutant was unable to activate transcription in agreement with in vitro results. We hypothesize that the SOX9 dimerization domain is necessary to remodel the Col2a1 chromatin in order to allow transcription to take place. These results further clarify the mechanism that accounts for CD in patients harboring SOX9 dimerization domain mutations.


Outcome of psychotherapy among early adolescents after trauma.
The authors evaluated the effectiveness of brief trauma/grief-focused psychotherapy among early adolescents exposed to the 1988 earthquake in Armenia. Posttraumatic stress and depressive reactions among treated and not treated subjects were evaluated pre- and postintervention, at 1 1/2 and 3 years after the earthquake, respectively. Severity of posttraumatic stress symptoms significantly decreased among the subjects given psychotherapy, while severity of these symptoms increased significantly among the subjects not treated with psychotherapy. The improvement in posttraumatic stress symptoms was attributable to improvement in all three symptom categories (intrusion, avoidance, and arousal) of posttraumatic stress disorder (PTSD). There was no change in severity of depressive symptoms among subjects given psychotherapy. However, depressive symptoms among subjects not treated with psychotherapy significantly worsened over time. The changes in severity of posttraumatic stress and depressive symptoms were positively correlated within both groups. The findings demonstrate the efficacy of trauma/grief-focused brief psychotherapy in alleviating PTSD symptoms and preventing the worsening of comorbid depression among early adolescents after a catastrophic disaster. The results support the broad use of such school-based interventions after major disasters and demonstrate the cross-cultural applicability of Western psychotherapeutic approaches.


Differential adipose tissue gene expression profiles in abacavir treated patients that may contribute to the understanding of cardiovascular risk: a microarray study.
To compare changes in gene expression by microarray from subcutaneous adipose tissue from HIV treatment naïve patients treated with efavirenz based regimens containing abacavir (ABC), tenofovir (TDF) or zidovidine (AZT). Subcutaneous fat biopsies were obtained before, at 6- and 18-24-months after treatment, and from HIV negative controls. Groups were age, ethnicity, weight, biochemical profile, and pre-treatment CD4 count matched. Microarray data was generated using the Agilent Whole Human Genome Microarray. Identification of differentially expressed genes and genomic response pathways was performed using limma and gene set enrichment analysis. There were significant divergences between ABC and the other two groups 6 months after treatment in genes controlling cell adhesion and environmental information processing, with some convergence at 18-24 months. Compared to controls the ABC group, but not AZT or TDF showed enrichment of genes controlling adherence junction, at 6 months and 18-24 months (adjusted p<0.05) and focal adhesions and tight junction at 6 months (p<0.5). Genes controlling leukocyte transendothelial migration (p<0.05) and ECM-receptor interactions (p = 0.04) were over-expressed in ABC compared to TDF and AZT at 6 months but not at 18-24 months. Enrichment of pathways and individual genes controlling cell adhesion and environmental information processing were specifically dysregulated in the ABC group in comparison with other treatments. There was little difference between AZT and TDF. After initiating treatment, there is divergence in the expression of genes controlling cell adhesion and environmental information processing between ABC and both TDF and AZT in subcutaneous adipose tissue. If similar changes are also taking place in other tissues including the coronary vasculature they may contribute to the increased risk of cardiovascular events reported in patients recently started on abacavir-containing regimens.


Burn septicaemia in Kuwait: associated demographic and clinical factors.
To study the demographic and clinical factors associated with burn septicaemia patients in Kuwait. All burn in-patients, who developed septicaemia at the Burns Unit, Al-Babtain Centre for Burns and Plastic Surgery, Kuwait, during a 9-year period (June 1992 to May 2001) were included in the study. The data were recorded for age, sex, nationality, cause and percentage of burns, inhalation injury, resuscitation, number of episodes, septicaemia on post-burn day, the microorganisms responsible in each episode, treatment and outcome for statistical analysis. Using SPSS (PC version 11.0) software, a probability level of p < 0.05 was considered significant. Of the 2,082 patients treated in the Burns Unit, 166 [8%; 99 (60%) males and 67 (40%) females] with a mean age of 26 years (range 1-70) had septicaemia. Significantly higher (p < 0.001) cases were recorded among Kuwaiti children (< or =14 years) and non-Kuwaitis (25-59 years) than other corresponding age groups. The total body surface area burned ranged from 2 to 95% (mean 42%) and the main cause of burn was flame (77.1%). Inhalation injury was diagnosed in 39 (23.5%) patients. A total of 253 septicaemic episodes occurred in all patients. The majority, 123 (74.1%), had a single episode and the remaining 43 (25.6%) had multiple (2-10) episodes. One hundred and fifty-five (61.3%) episodes were due to gram-positive organisms, mainly methicillin-resistant Staphylococcus aureus, and 32 (12.7%) were polymicrobial. One hundred and twenty-four (74.7%) patients had wound excision and skin grafting procedures and their survival was significantly higher (OR = 4.3; 95% CI: 1.98-9.31) than non-surgically treated patients. Thirty-nine (23.5%) patients died mainly due to multi-organ failure. The findings indicate that the patients with extensive flame burns were prone to developing septicaemia due mainly to gram-positive bacteria. The surgical excision of eschar and wound covering improved the outcome of the patients while prophylactic antibiotic treatment had no role in the incidence and outcome of the burn patients.


Acute procedural and six-month clinical outcome in patients treated with a dedicated bifurcation stent for left main stem disease: the TRYTON LM multicentre registry.
Tryton side branch (SB) reverse culotte stenting has been employed for the treatment of left main (LM) stem bifurcations in patients at high risk for bypass surgery. The aim of this study was to assess acute angiographic results and six-month clinical outcome after implantation of the Tryton stent in the LM. We studied 52 consecutive patients with LM disease treated in nine European centres. Angiographic and clinical data analysis was performed centrally. Fifty-one of 52 patients (age 68±11 yrs, 75% male, 42% unstable angina, SYNTAX score 20±8) were successfully treated with the Tryton stent. Medina class was 1,1,1 in 33 (63%), 1,0,1 in 7 (13%), 1,1,0 in 3 (6%), 0,1,1 in 8 (4%) and 0,0,1 in 1 (2%). The Tryton stent on a stepped balloon (diameter 3.5-2.5 mm) was used in 41/51 (80%) of cases. The mean main vessel stent diameter was 3.4±0.4 mm with an everolimus-eluting stent employed in 30/51 (59%) of cases. Final kissing balloon dilatation was performed in 48/51 (94%). Acute gain was 1.52±0.86 mm in the LM and 0.92±0.47 mm in the SB. The angiographic success rate was 100%; the procedural success rate reached 94%. Periprocedural MI occurred in three patients. At six-month follow-up, the TLR rate was 12%, MI 10% and cardiac death 2%. The hierarchical MACE rate at six months was 22%. No cases of definite stent thrombosis occurred. The use of the Tryton stent for treatment of LM bifurcation disease in combination with a conventional drug-eluting stent is feasible and achieves an optimal angiographic result. Safety of the procedure and six-month outcome are acceptable in this high-risk lesion PCI. Further safety and efficacy studies with long-term outcome assessment of this strategy are warranted.


Brassinosteroids regulate dissociation of BKI1, a negative regulator of BRI1 signaling, from the plasma membrane.
Brassinosteroids, the steroid hormones of plants, are perceived at the plasma membrane by a leucine-rich repeat receptor serine/threonine kinase called BRI1. We report a BRI1-interacting protein, BKI1, which is a negative regulator of brassinosteroid signaling. Brassinosteroids cause the rapid dissociation of BKI1-yellow fluorescent protein from the plasma membrane in a process that is dependent on BRI1-kinase. BKI1 is a substrate of BRI1 kinase and limits the interaction of BRI1 with its proposed coreceptor, BAK1, suggesting that BKI1 prevents the activation of BRI1.


Neuronuclear assessment of patients with epilepsy.
Epilepsy is a common chronic neurological disorder that is controlled with medication in approximately 70% of cases. When partial seizures are recurrent despite the use of antiepileptic drugs, resection of the epileptogenic cortex may be considered. Nuclear medicine plays an important role in the presurgical assessment of patients with refractory epilepsy. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) techniques are used to determine the seizure onset zone, which needs to be resected to render a patient seizure free. Correct localization of the ictal onset zone with the use of SPECT or PET is associated with a better surgical outcome. Ictal perfusion SPECT imaging with (99m)Tc-ethyl cysteinate dimer (ECD) or (99m)Tc-hexamethylpropyleneamine oxime (HMPAO) enables one to detect the seizure onset zone in a majority of cases, especially in patients with temporal lobe epilepsy. Interictal SPECT imaging, which is more widely available, is unreliable to determine the ictal onset zone and is usually only used for comparison with ictal SPECT images. Assessment of the ictal onset zone using subtracted ictal and interictal studies, overlayed on structural imaging has proven to be more sensitive and more specific compared with visual assessment. Video-electroencephalography monitoring in combination with ictal SPECT imaging, however, is only available in specialized centers. It is important to inject the perfusion tracer as early as possible after the beginning of a seizure and to be aware of patterns of seizure propagation. Interictal (18)F-fluorodeoxyglucose (FDG)-PET is routinely used to detect brain areas of hypometabolism, which usually encompass, but tend to be larger than, the seizure onset zone. Also, for assessment of FDG-PET, it is advisable to use an automated technique comparing the patient's images to a normal database in addition to visual interpretation of the images, since automated techniques have proven to be more accurate. In view of the thickness of the cortical ribbon, which may be below the resolution of the PET camera, posthoc partial volume correction or PET reconstruction incorporating the anatomical information of magnetic resonance imaging (MRI), may be useful for optimal assessment of glucose metabolism. Perfusion SPECT and interictal FDG-PET are able to demonstrate areas of abnormal perfusion and metabolism at a distance from the ictal onset zone, which may be associated with cognitive and psychiatric comorbidities, and may represent the functional deficit zone in epilepsy. Part of the functional deficit zone is a dynamic seizure-related process, which may resolve with cessation of seizures. In recent years, novel PET tracers have been developed to visualize not only glucose metabolism but also a wide variety of specific receptor systems. In patients with epilepsy, changes in the gamma-amino-butyric acid(A) receptor, opioid receptor, 5-HT(1A) serotonin receptor, nicotinic acetylcholine receptor systems, and others have been described. Because these tracers are not widely available and the superiority of studying these receptor systems over glucose metabolism in the presurgical evaluation of patients with refractory epilepsy remains to be proven, their use in clinical practice is limited at the moment. Finally, advances in small animal PET scanning allow the in vivo study of the process of epileptogenesis, starting from an initial brain insult to the development of seizures, in animal models of epilepsy. Potential new therapeutic targets may be discovered using this translational approach.


'Weighing up and balancing out': a meta-synthesis of barriers to antenatal care for marginalised women in high-income countries.
In high-resource settings around 20% of maternal deaths are attributed to women who fail to receive adequate antenatal care. Epidemiological evidence suggests many of these women belong to marginalised groups often living in areas of relative deprivation. Reasons for inadequate antenatal attendance have yet to be fully evaluated. To identify the factors affecting access to antenatal care for marginalised pregnant women living in developed countries. We included qualitative studies from developed countries published in English language journals (1980-2007). Qualitative studies exploring the views of marginalised women living in developed countries who either failed to attend for any antenatal care or did so late or irregularly. Eight studies fulfilled the selection criteria and were synthesised in accord with the techniques derived from meta-ethnography. Initial access is influenced by late pregnancy recognition and subsequent denial or acceptance. Continuing access appears to depend on a strategy of weighing up and balancing out of the perceived gains and losses. Personal resources in terms of time, money and social support are considered alongside service provision issues including the perceived quality of care, the trustworthiness and cultural sensitivity of staff and feelings of mutual respect. A nonthreatening, nonjudgemental antenatal service run by culturally sensitive staff may increase access to antenatal care for marginalised women. Multiagency initiatives aimed at raising awareness of, and providing access to, antenatal care may also increase uptake.


Control charts for monitoring mood stability as a predictor of severe episodes in patients with bipolar disorder.
Recurrent mood episodes and subsyndromal mood instability cause substantial disability in patients with bipolar disorder. Early identification of mood episodes enabling timely mood stabilization is an important clinical goal. This study investigates the ability of control chart methodology to predict manic and/or depressive episodes by applying Shewhart's control rules to weekly self-reported scores from mania and depression questionnaires. Shewhart's control rules were applied to weekly self-reported scores from the Altman Self-Rating Mania Scale (ASRM) and the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS) collected from 2001 to 2012 as part of the OXTEXT programme. Manic and depressive episodes were defined as an ASRM score ≥ 10 or a QIDS score ≥ 15, respectively. An episode-free run-in period of eight consecutive weeks without an episode of either type was used to calibrate control charts. Shewhart's rules were then applied to follow-up data. Their sensitivity and positive predictive value for predicting manic or depressive episodes within the next 4 weeks were calculated focusing on the first episode. Secondary analyses varying control chart type, length of episode-free run-in period, time frames to evaluate diagnostic accuracy, thresholds defining either manic or depressive episodes, and missing data methods were performed. Data from 146 participants (37% men) were included. The mean age was 43.4 (SD = 13.3) years. The median follow-up was 10 (IQR 5-40) weeks for mania and 10 (IQR 5-23) weeks for depression. A total of 53 (36%) participants had a manic episode and 67 (46%) had a depressive episode. For manic episodes, the sensitivity and positive predictive value of Shewhart's control rules were 30% (95% CI 19-45%) and 7% (95% CI 5-9%), and for depressive episodes, 33% (95% CI 22-46%) and 9% (95% CI 6-12%), respectively. Results from secondary analyses were similar to these. Tele-monitoring with control rules has the potential to predict about one-third of manic or depressive episodes before they occur, at the cost of a high false positive rate. Given the severe consequences of manic and depressive episodes, this trade-off may be desirable.


An experimental and computational evolution-based method to study a mode of co-evolution of overlapping open reading frames in the AAV2 viral genome.
Overlapping open reading frames (ORFs) in viral genomes undergo co-evolution; however, how individual amino acids coded by overlapping ORFs are structurally, functionally, and co-evolutionarily constrained remains difficult to address by conventional homologous sequence alignment approaches. We report here a new experimental and computational evolution-based methodology to address this question and report its preliminary application to elucidating a mode of co-evolution of the frame-shifted overlapping ORFs in the adeno-associated virus (AAV) serotype 2 viral genome. These ORFs encode both capsid VP protein and non-structural assembly-activating protein (AAP). To show proof of principle of the new method, we focused on the evolutionarily conserved QVKEVTQ and KSKRSRR motifs, a pair of overlapping heptapeptides in VP and AAP, respectively. In the new method, we first identified a large number of capsid-forming VP3 mutants and functionally competent AAP mutants of these motifs from mutant libraries by experimental directed evolution under no co-evolutionary constraints. We used Illumina sequencing to obtain a large dataset and then statistically assessed the viability of VP and AAP heptapeptide mutants. The obtained heptapeptide information was then integrated into an evolutionary algorithm, with which VP and AAP were co-evolved from random or native nucleotide sequences in silico. As a result, we demonstrate that these two heptapeptide motifs could exhibit high degeneracy if coded by separate nucleotide sequences, and elucidate how overlap-evoked co-evolutionary constraints play a role in making the VP and AAP heptapeptide sequences into the present shape. Specifically, we demonstrate that two valine (V) residues and β-strand propensity in QVKEVTQ are structurally important, the strongly negative and hydrophilic nature of KSKRSRR is functionally important, and overlap-evoked co-evolution imposes strong constraints on serine (S) residues in KSKRSRR, despite high degeneracy of the motifs in the absence of co-evolutionary constraints.


Guidelines for the management of inflammatory bowel disease in adults.
The management of inflammatory bowel disease represents a key component of clinical practice for members of the British Society of Gastroenterology (BSG). There has been considerable progress in management strategies affecting all aspects of clinical care since the publication of previous BSG guidelines in 2004, necessitating the present revision. Key components of the present document worthy of attention as having been subject to re-assessment, and revision, and having direct impact on practice include: The data generated by the nationwide audits of inflammatory bowel disease (IBD) management in the UK in 2006, and 2008. The publication of 'Quality Care: service standards for the healthcare of people with IBD' in 2009. The introduction of the Montreal classification for Crohn's disease and ulcerative colitis. The revision of recommendations for the use of immunosuppressive therapy. The detailed analysis, guidelines and recommendations for the safe and appropriate use of biological therapies in Crohn's disease and ulcerative colitis. The reassessment of the role of surgery in disease management, with emphasis on the importance of multi-disciplinary decision-making in complex cases. The availablity of new data on the role of reconstructive surgery in ulcerative colitis. The cross-referencing to revised guidelines for colonoscopic surveillance, for the management of metabolic bone disease, and for the care of children with inflammatory bowel disease. Use of the BSG discussion forum available on the BSG website to enable ongoing feedback on the published document http://www.bsg.org.uk/forum (accessed Oct 2010). The present document is intended primarily for the use of clinicians in the United Kingdom, and serves to replace the previous BSG guidelines in IBD, while complementing recent consensus statements published by the European Crohn's and Colitis Organisation (ECCO) https://www.ecco-ibd.eu/index.php (accessed Oct 2010).


Running and the development of disability with age.
To determine, by longitudinal study, whether regular vigorous running activity is associated with accelerated, unchanged, or postponed development of disability with increasing age. 8-year prospective, longitudinal study with yearly assessments. 451 members of a runners' club and 330 community controls who were initially 50 to 72 years old (also characterized as "ever-runners" [n = 534] and "never-runners" [n = 247], respectively). The dependent variable was disability as assessed by the Health Assessment Questionnaire and separately validated in these participant cohorts. Covariates included age, sex, body mass index, comorbid conditions, education level, smoking history, alcohol intake, mean blood pressure, initial disability level, family history of arthritis, and radiologic evidence of osteoarthritis of the knee in a subsample. Initially, the runners were leaner, reported joint symptoms less frequently, took fewer medications, had fewer medical problems, and had fewer instances of and less severe disability, suggesting either that the average previous 12 years of running had improved health or that self-selection bias was present. After 8 years of longitudinal study, the differences in initial disability levels (0.026 compared with 0.079; P < 0.001) had steadily increased to 0.071 for runners compared with 0.242 for controls (P < 0.001). The difference was consistent for men and women. The rate of development of disability was several times lower in the runners' club members than in community controls; this difference persisted after adjusting for age, sex, body mass, baseline disability, smoking history, history of arthritis, or other comorbid conditions (slopes of progression of disability for the years 1984 to 1992, after adjusting for covariates: men in the runners' club, 0.004 [SE, 0.002]; community controls, 0.012 [SE, 0.002]; women in the runners' club, 0.009 [SE, 0.005]; community controls, 0.027 [SE, 0.004]; P < 0.002 for both sets of comparisons). In addition to differences in disability, there were significant differences in mortality between the runners' club members (1.49%) and community controls (7.09%) (P < 0.001). These differences remained significant after adjusting for age, sex, body mass, comorbid conditions, education level, smoking history, alcohol intake, and mean blood pressure (P < 0.002, conditional risk ratio for community controls compared with the runners, 4.27; 95% CI, 1.78 to 10.26). Older persons who engage in vigorous running and other aerobic activities have lower mortality and slower development of disability than do members of the general population. This association is probably related to increased aerobic activity, strength, fitness, and increased organ reserve rather than to an effect of postponed osteoarthritis development.


Improving quality of cancer care at community hospitals: impact of the National Cancer Institute Community Cancer Centers Program pilot.
Patients with cancer treated at community hospitals may experience decreased quality of care compared with patients treated at higher-volume cancer hospitals. The National Cancer Institute Community Cancer Centers Program (NCCCP) pilot is designed to enhance research and improve cancer care at community hospitals. We assessed changes in quality of care among the 16 initial NCCCP sites versus 25 similar hospitals that did not participate in the NCCCP. We compared changes in concordance with five National Quality Forum-approved quality of care measures (three for breast cancer, two for colon cancer) for patients diagnosed from 2006 to 2007 (pre-NCCCP initiation) versus 2008 to 2010 (post-NCCCP initiation) at NCCCP and comparison-group hospitals. Data were collected using the Commission on Cancer Rapid Quality Reporting System. Analyses were performed using multivariate logistic regression. Analyses included 18,608 patients with breast cancer and 7,031 patients with colon cancer. After NCCCP initiation, patient-level concordance rates for all five quality-of-care measures increased significantly among NCCCP and comparison-group hospitals. Increased quality of care among NCCCP sites was significantly greater than that among comparison-group hospitals for radiation therapy after breast-conserving surgery and hormonal therapy for women with hormone receptor-positive breast cancer. In multivariate regressions, increases in hormonal therapy among NCCCP-site patients were significantly greater than those among comparison-group hospitals. Both NCCCP and comparison-group hospitals showed improved quality of care; however, NCCCP sites had significantly greater improvements for a subset of measures. This greater increase may reflect the multidisciplinary focus of the NCCCP. Because many individuals receive cancer treatment at community hospitals, facilitating high-quality care in these environments must be a priority.


Three-in-one parenteral nutrition in neonates and pediatric patients: risks and benefits.
Parenteral nutrition (PN) is a life-sustaining therapy designed to deliver essential nutrients to patients unable to meet nutrition needs via the enteral route. PN may be delivered via a 2-in-1 system (one solution containing amino acids, dextrose, electrolytes, vitamins, minerals, and fluids and one solution containing intravenous fat emulsions [IVFEs]) or via a 3-in-1 system (all nutrients mixed in one container). Although the use of 3-in-1 PN solutions is not necessarily therapeutically advantageous, certain benefits may exist such as the potential to reduce the risk of contamination due to decreased manipulations; ease of administration, particularly in the home care setting; possible cost savings; and reduced IVFE wastage. However, the incorporation of IVFE in 3-in-1 solutions also presents unique risks for the neonatal and pediatric population such as decreased stability, increased lipid globule size, decreased sterility and the potential for increased microbial growth/infectious complications, the need to use a larger filter size, precipitation and compatibility risks, and an increased chance of catheter occlusion. This review outlines the unique issues and challenges to be considered when formulating neonatal and pediatric 3-in-1 PN admixtures. While 3-in-1 PN solutions may be advantageous for certain pediatric populations, specifically those dependent on home PN, the risks do not outweigh the benefits in neonatal patients, and use should be avoided in this population.


Incisional hernia following colorectal cancer surgery according to suture technique: Hughes Abdominal Repair Randomized Trial (HART).
Incisional hernias cause morbidity and may require further surgery. HART (Hughes Abdominal Repair Trial) assessed the effect of an alternative suture method on the incidence of incisional hernia following colorectal cancer surgery. A pragmatic multicentre single-blind RCT allocated patients undergoing midline incision for colorectal cancer to either Hughes closure (double far-near-near-far sutures of 1 nylon suture at 2-cm intervals along the fascia combined with conventional mass closure) or the surgeon's standard closure. The primary outcome was the incidence of incisional hernia at 1 year assessed by clinical examination. An intention-to-treat analysis was performed. Between August 2014 and February 2018, 802 patients were randomized to either Hughes closure (401) or the standard mass closure group (401). At 1 year after surgery, 672 patients (83.7 per cent) were included in the primary outcome analysis; 50 of 339 patients (14.8 per cent) in the Hughes group and 57 of 333 (17.1 per cent) in the standard closure group had incisional hernia (OR 0.84, 95 per cent c.i. 0.55 to 1.27; P = 0.402). At 2 years, 78 patients (28.7 per cent) in the Hughes repair group and 84 (31.8 per cent) in the standard closure group had incisional hernia (OR 0.86, 0.59 to 1.25; P = 0.429). Adverse events were similar in the two groups, apart from the rate of surgical-site infection, which was higher in the Hughes group (13.2 versus 7.7 per cent; OR 1.82, 1.14 to 2.91; P = 0.011). The incidence of incisional hernia after colorectal cancer surgery is high. There was no statistical difference in incidence between Hughes closure and mass closure at 1 or 2 years. ISRCTN25616490 (http://www.controlled-trials.com).


Preventative practices and effects of the COVID-19 pandemic on caregivers of children with pediatric pulmonary hypertension.
Pulmonary hypertension (PH) is a serious and life-threatening disease characterized by elevated mean arterial pressure and pulmonary vascular resistance. COVID-19 may exacerbate PH, as evidenced by higher mortality rates among those with PH. The objective of this study was to understand the unique burdens that the COVID-19 pandemic has placed upon families of children living with PH. Participants were recruited online through the "Families of children with pulmonary hypertension" Facebook group and asked to complete a survey about their experiences during the COVID-19 pandemic. A total of 139 parents/caregivers of children living with PH completed the online survey. Almost all (85.6%) of parents/caregivers had received the COVID-19 vaccine, though only 59.7% reported a willingness to vaccinate their child with PH against COVID-19. Over 75% of parents/caregivers felt that they practiced preventative measures (e.g., wearing a facemask, social distancing, and avoiding gatherings) more than those in the community where they live. They also reported several hardships related to caring for their child with PH during the pandemic such as financial duress, loss of work, and affording treatment costs. These findings indicate that parents/caregivers of children at higher risk for COVID-19 complications may be more willing to act on clinical recommendations themselves as proxy for protecting those at high risk. The economic, emotional and social impacts of COVID-19 are significantly greater for high-risk individuals.


Effect of fibrous capsule formation on doxorubicin distribution in radiofrequency ablated rat livers.
In this study, we report the histological findings of a combined therapy using radiofrequency ablation and intratumoral drug delivery in rat livers, with special attention to wound-healing processes and their effects on drug transport in post-ablated tissue. Doxorubicin-loaded millirods were implanted in rat livers that had undergone medial lobe ablation. Millirods and liver samples were retrieved upon animal sacrifice at time points ranging from 1 h to 8 days. Results demonstrate a clearly defined area of coagulative necrosis within the ablation boundary. The wound-healing response, complete with the appearance of inflammatory cells, neovascularization, and the formation of a fibrous capsule, was also observed. At the 8-day time point, fluorescence imaging analysis showed a higher concentration of doxorubicin localized within the ablation region, with its distribution hampered primarily by fibrous capsule formation at the boundary. Given the variant nature of ablated liver, a mathematical model devised previously by our laboratory describes the data well up to 4 days, but loses reliability at 8 days. These results provide useful mechanistic insights into the wound-healing response after radiofrequency ablation and polymer millirod implantation, as well as the impact this natural corollary has on drug distribution.


Cyclosporin A and the humoral response to blood transfusion in the rat: definition of antigens which suppress alloantibody formation.
1. Blood transfusions improve renal allograft survival rates, but may induce antibodies which are directed to class I major histocompatibility complex antigens and mediate hyperacute transplant rejection. A model to study the development of such antibodies was developed in inbred strains of rats. 2. The influence of transplantation antigens shared between an initial course of blood transfusions, given with cyclosporin A, and a subsequent antigenic challenge (blood transfusion), given without cyclosporin A, on alloantibody responses to class I major histocompatibility complex antigens was then investigated. 3. Cyclosporin A administration prevented the development of alloantibodies to class I major histocompatibility complex antigens during the initial transfusion period. 4. After the challenge transfusions, alloantibody responses to class I major histocompatibility complex antigens were suppressed when class I major histocompatibility complex or minor histocompatibility antigens were shared between the initial and final transfusions. 5. This suppression only extended to third party class I antigens when minor histocompatibility complex antigens were shared between the initial and final transfusions. Sharing of class I or class II antigens had no effect on alloantibody responses to third party class I antigens coexpressed on the same cell. 6. These studies suggest that cyclosporin A given with blood transfusions may prevent clinical sensitization while permitting the development of suppressor activity, mediated by shared minor histocompatibility complex determinants, to a broad range of potential donor antigens.


Immunization with SV40-transformed cells yields mainly MHC-restricted monoclonal antibodies.
Recognition of antigens on cell surfaces only in the context of the MHC-encoded alloantigens of the presenting cell (self + X) has classically been considered the province of T cells. However, evidence from several sources has indicated that B cells and antibodies can exhibit self + X-restricted recognition as well. This report concerns the mAb response to SV40-transformed H-2b fibroblast cell lines. The specificities of the antibodies obtained have been analyzed for binding to a panel of SV40-transformed H-2-syngeneic, H-2-allogeneic, and H-2b mutant fibroblast cell lines, as well as cell lines not bearing cell surface SV40 transformation-associated antigens. A large proportion of primary C57BL/6 (71%) and BALB/c (68%) splenic B cells responding to in vitro stimulation with SV40-transformed H-2b cells recognize cell surface antigens associated with SV40 transformation only when coexpressed with MHC antigens of the immunizing cell, particularly the Kb molecule, on transformed cells. To extensively define the nature of antigen recognition by these antibodies, we have generated and characterized nine hybridoma antibodies specific for SV40-transformed H-2-syngeneic cell lines. Seven of these hybridoma antibodies recognize SV40-associated transformation antigens in the context of H-2b molecules. Six of these are restricted by the Kb molecule and discriminate among a panel of SV40-transformed Kb mutant cell lines, thus confirming the participation of class I MHC-encoded molecules in the recognition by B cells of cell surface antigens.


Age, sex, and finish time as determinants of pacing in the marathon.
Previous researchers have suggested that faster marathoners tend to run at a more consistent pace compared with slower runners. None has examined the influence of sex and age on pacing. Therefore, the purpose of this study was to determine the simultaneous influences of age, sex, and run time on marathon pacing. Pacing was defined as the mean velocity of the last 9.7 km divided by that of the first 32.5 km (closer to 1.0 indicates better pacing). Subjects were 186 men and 133 women marathoners from the 2005, 2006, and 2007 races of a midwestern U.S. marathon. The course was a 1.6 km (1 mile) loop with pace markers throughout, thus facilitating pacing strategy. Each 1.6-km split time was measured electronically by way of shoe chip. The ambient temperature (never above 5°C) ensured that hyperthermia, a condition known to substantially slow marathon times and affect pacing, was not likely a factor. Multiple regression analysis indicated that age, sex, and run time (p < 0.01 for each) were simultaneously independent determinants of pacing. The lack of any 2- or 3-way interactions (p > 0.05 for each) suggests that the effects of 1 independent variable is not dependent upon the levels of others. We conclude that older, women, and faster are better pacers than younger, men, and slower marathoners, respectively. Coaches can use these findings to overcome such tendencies and increase the odds of more optimal pacing.


Leukocyte Esterase as a Biomarker in the Diagnosis of Periprosthetic Joint Infection.
BACKGROUND Total joint arthroplasty (TJA) has been one of the most rewarding interventions for treating patients suffering from joint disorders. However, periprosthetic joint infection (PJI) is a serious complication that frequently accompanies TJA. Our study aimed to investigate the application of the leukocyte esterase (LE) strip in the diagnosis of PJI. MATERIAL AND METHODS From October 2014 to July 2015, 72 patients who had undergone joint puncture after arthroplasty in our hospital were enrolled in this trial. One drop of synovial fluid from each available patient was applied to the LE strip, and the results were observed after 1-3 min. If the color turned to dark purple, we recognized this as a positive result, while other colors were regarded as negative results. Centrifugation was used when the synovial fluid was mixed with blood. The Musculoskeletal Infection Society (MSIS) definition was used as the standard reference to identify whether PJI was found in patients or not. The results of diagnosis and LE strips test were compared, and indicators reflecting diagnostic value were calculated. Correlation of the LE data with erythrocyte sedimentation rate (ESR), elevated C-reactive protein (CRP), synovial white blood cell (WBC) counts, and polymorphonuclear neutrophil (PMN) percentage was calculated. RESULTS By MSIS criteria, 38 patients were diagnosed with PJI and 34 patients were not infected. Two types of LE strip presented the same results with sensitivity of 84.21% (95% confidence interval [CI]: 68.75~93.98%), specificity of 97.06% (95% CI: 84.67~99.93%), positive predictive value (PPV) of 96.97% (95% CI: 84.24~99.92%), and negative predictive value (NPV) of 84.62% (95% CI: 69.47~94.14%). There were one false-positive case and six false-negative cases in this trial. There is a strong correlation between LE strip and synovial fluid PMN percentage. CONCLUSIONS The sensitivity and specificity of the LE strip in the diagnosis of PJI are quite high, which means the LE strip might be used as an alternative to diagnose PJI in clinical practice.


Prognostic significance of DNA ploidy, S-phase fraction, and tissue levels of aspartic, cysteine, and serine proteases in operable gastric carcinoma.
A consecutive series of 63 untreated patients undergoing surgical resection for stage I-IV gastric adenocarcinomas (GCs) has been prospectively studied. Our purpose was to analyze the predictive relevance of DNA ploidy, S-phase fraction (SPF), and tissue levels of lysosomal proteinases cathepsin D (CD), cathepsin B (CB), cathepsin L (CL), and urokinase-type plasminogen activator (uPA) and that of the intracellular cysteine proteinase inhibitor stefin A on clinical outcome. All of the patients taking part in this study were followed up for a median of 73 months. DNA aneuploidy was present in 71% of the cases (45/63), whereas 9% of these (4/45) showed multiclonality. Both DNA ploidy and SPF were associated with tumor-node-metastasis (TNM) stage and node status, whereas only DNA ploidy was related to depth of invasion. CB, CL, uPA, but not CD, levels were significantly higher in GC as compared to paired normal mucosa, whereas stefin A levels were lower in tumor tissues. CB levels were significantly associated with TNM stage, nodal status, histological grade, and DNA ploidy. At univariate analysis, only node involvement, advanced TNM stage, DNA aneuploidy, and high SPF proved to be significantly related to quicker relapse and to shorter overall survival, whereas depth of invasion was related only to survival. With multivariate analysis, only high SPF (>15.2%) was related to risk of relapse (RR = 8.50), whereas high SPF and DNA aneuploidy were independently related to risk of death (RR = 1.88 and 2.09, respectively). Our preliminary prospective study has identified SPF and DNA ploidy as important biological indicators for predicting the outcome of patients with GC.


Significant association between perceived HIV related stigma and late presentation for HIV/AIDS care in low and middle-income countries: A systematic review and meta-analysis.
Late presentation for human immunodeficiency virus (HIV) care is a major impediment for the success of antiretroviral therapy (ART) outcomes. The role that stigma plays as a potential barrier to timely diagnosis and treatment of HIV among people living with HIV/AIDS (acquired immunodeficiency syndrome) is ambivalent. This review aimed to assess the best available evidence regarding the association between perceived HIV related stigma and time to present for HIV/AIDS care. Quantitative studies conducted in English language between 2002 and 2016 that evaluated the association between HIV related stigma and late presentation for HIV care were sought across four major databases. This review considered studies that included the following outcome: 'late HIV testing', 'late HIV diagnosis' and 'late presentation for HIV care after testing'. Data were extracted using a standardized Joanna Briggs Institute (JBI) data extraction tool. Meta- analysis was undertaken using Revman-5 software. I2 and chi-square test were used to assess heterogeneity. Summary statistics were expressed as pooled odds ratio with 95% confidence intervals and corresponding p-value. Ten studies from low- and middle- income countries met the search criteria, including six (6) and four (4) case control studies and cross-sectional studies respectively. The total sample size in the included studies was 3,788 participants. Half (5) of the studies reported a significant association between stigma and late presentation for HIV care. The meta-analytical association showed that people who perceived high HIV related stigma had two times more probability of late presentation for HIV care than who perceived low stigma (pooled odds ratio = 2.4; 95%CI: 1.6-3.6, I2 = 79%). High perceptions of HIV related stigma influenced timely presentation for HIV care. In order to avoid late HIV care presentation due the fear of stigma among patients, health professionals should play a key role in informing and counselling patients on the benefits of early HIV testing or early entry to HIV care. Additionally, linking the systems and positive case tracing after HIV testing should be strengthened.


The COMET Initiative database: progress and activities from 2011 to 2013.
The Core Outcome Measures in Effectiveness Trials (COMET) Initiative database is an international repository of studies relevant to the development of core outcome sets. By the end of 2013, it included a unique collection of 306 studies. The website is increasingly being used, with more than 12,000 visits in 2013 (a 55% increase over 2012), 8,369 unique visitors (a 53% increase) and 6,844 new visitors (a 48% increase). There has been a rise in visits from outside the United Kingdom, with 2,405 such visits in 2013 (30% of all visits). By December 2013, a total of 4,205 searches had been completed, with 2,139 in 2013 alone.


Differences in quality of antenatal care provided by midwives to low-risk pregnant dutch women in different ethnic groups.
The objective of this study was to evaluate whether differences existed in the adherence to the Dutch national guidelines regarding basic antenatal care by Dutch midwives for low-risk women of different ethnic groups. This was an observational study using data from electronic antenatal charts of 7 midwife practices (23 midwives), participating in the Generation R Study. The Generation R Study is a multiethnic, population-based, prospective, cohort study that is investigating the growth, development, and health of urban children from fetal life until young adulthood. The study is conducted in Rotterdam, The Netherlands. The antenatal charts of 2093 low-risk pregnant women with an expected birthing date in 2002 through 2004 were used to determine the mean quality of antenatal care scores for 7 ethnic groups. These scores reflected the degree of adherence to the guidelines regarding 10 tests and examinations. Few differences between ethnic groups were found in adherence to the guidelines that addressed the obstetric-technical quality of antenatal care. This finding applied more to nulliparous than to multiparous women. Adherence to guidelines was not always better in the antenatal care provided to native Dutch multiparous women when compared to other ethnic groups. Midwives adhered well to the guidelines regarding most tests. For all women, irrespective of ethnic background, hemoglobin was not measured as often as recommended, and this was especially the case for Moroccan, Surinamese-Creole, and Dutch-Antillean multiparous women. The poorer adherence regarding screening for hemoglobin needs further investigation, as women with African or Mediterranean heritage are more at risk for hemoglobinopathies. However, in general, midwives adhered well to the clinical guidelines regarding most tests irrespective of the ethnic background of the pregnant women. When differences were present, these were not systematically less favorable for non-Dutch pregnant women.


High Representation of Archaea Across All Depths in Oxic and Low-pH Sediment Layers Underlying an Acidic Stream.
Parys Mountain or Mynydd Parys (Isle of Anglesey, United Kingdom) is a mine-impacted environment, which accommodates a variety of acidophilic organisms. Our previous research of water and sediments from one of the surface acidic streams showed a high proportion of archaea in the total microbial community. To understand the spatial distribution of archaea, we sampled cores (0-20 cm) of sediment and conducted chemical analyses and taxonomic profiling of microbiomes using 16S rRNA gene amplicon sequencing in different core layers. The taxonomic affiliation of sequencing reads indicated that archaea represented between 6.2 and 54% of the microbial community at all sediment depths. Majority of archaea were associated with the order Thermoplasmatales, with the most abundant group of sequences being clustered closely with the phylotype B_DKE, followed by "E-plasma," "A-plasma," other yet uncultured Thermoplasmatales with Ferroplasma and Cuniculiplasma spp. represented in minor proportions. Thermoplasmatales were found at all depths and in the whole range of chemical conditions with their abundance correlating with sediment Fe, As, Cr, and Mn contents. The bacterial microbiome component was largely composed in all layers of sediment by members of the phyla Proteobacteria, Actinobacteria, Nitrospirae, Firmicutes, uncultured Chloroflexi (AD3 group), and Acidobacteria. This study has revealed a high abundance of Thermoplasmatales in acid mine drainage-affected sediment layers and pointed at these organisms being the main contributors to carbon, and probably to iron and sulfur cycles in this ecosystem.


A derivatization method for the simultaneous detection of glucosinolates and isothiocyanates in biological samples.
Various analytical methods have been established to quantify isothiocyanates (ITCs) that derive from glucosinolate hydrolysis. However, to date there is no valid method applicable to pharmacokinetic studies that detects both glucosinolates and ITCs. A specific derivatization procedure was developed for the determination of ITCs based on the formation of a stable N-(tert-butoxycarbonyl)-L-cysteine methyl ester derivative, which can be measured by high-performance liquid chromatography with ultraviolet detection after extraction with ethylacetate. The novel method, which is also applicable to the indirect determination of glucosinolates after their hydrolysis by myrosinase, was established for the simultaneous determination of glucoraphanin and sulforaphane. By derivatization, the sensitivity of ITC detection was increased 2.5-fold. Analytical recoveries from urine and plasma were greater than 75% and from feces were approximately 50%. The method showed intra- and interday variations of less than 11 and 13%, respectively. Applicability of the method was demonstrated in mice that received various doses of glucoraphanin or that were fed a glucoraphanin-rich diet. Besides glucoraphanin and sulforaphane, glucoerucin and erucin were detected in urine and feces of mice. The novel method provides an essential tool for the analysis of bioactive glucosinolates and their hydrolysis products and, thus, will contribute to the elucidation of their bioavailability.


Is attention deficit hyperactivity disorder over-represented among HIV-seronegative boys with haemophilia? Preliminary results from our centre.
Haemophilia care providers report anecdotally that many boys under their care bear the diagnosis of attention deficit hyperactivity disorder (ADHD). This study investigated the hypothesis that ADHD is over-represented among boys with haemophilia. All the boys with haemophilia, aged 5-14 years, who receive their comprehensive care at our centre were solicited to participate in this study. Of the 78 eligible boys, 34 (44%) were successfully contacted and agreed to participate. All participants were HIV-negative on both serological and PCR-based assays. The presence of ADHD symptoms was established via a parent- and teacher-completed standardized rating instrument. On the parent-rating scale, 26% of the participants exceeded the cut-off for inattentive ADHD, 18% for hyperactive/impulsive ADHD, and 18% for combined. On the teacher rating scale, 4% of the participants exceeded the cut-off for inattentive ADHD, but no participants were rated as having extreme hyperactive/impulsive or combined ADHD symptoms. Retrospectively, 29% of the participants had previously been diagnosed with ADHD, all treated with stimulant medications. Of note, 38% of our participants were enrolled in special education programmes. All of the above were more common in boys with haemophilia compared with national controls. A chart review of non-participating patients from the same clinic suggested that sampling bias is unlikely to account for these differences. These results provide the first empirical evidence that ADHD may be over-represented among boys with haemophilia.


Involving service users in delivering alcohol addiction therapy.
Involving and empowering people who use health services, and taking their experiences into account, has evolved from being considered good practice to being duties of the NHS. However, evidence suggests that the rate of progress and change has been slow, despite the constant emphasis on the merits of involving and engaging the public and patients. This article, written in collaboration with two service users, reports on efforts by nursing staff working in alcohol addiction to involve service users in setting up and managing the self-management and recovery training initiative at the Brian Hore Unit, part of the Manchester Mental Health and Social Care Trust. The article aims to encourage healthcare professionals to appreciate the benefits of proactive patient and public involvement for their organisations and for those who get involved.


Fibropapillomatosis in green turtles Chelonia mydas in Brazil: characteristics of tumors and virus.
Fibropapillomatosis (FP) is a benign neoplasia that affects physiological functions of sea turtles and may lead to death. High prevalence of FP in sea turtle populations has prompted several research groups to study the disease and the associated herpesvirus, chelonid herpesvirus 5 (ChHV5). The present study detected and quantified ChHV5 in 153 fibropapilloma samples collected from green turtles Chelonia mydas on the Brazilian coast between 2009 and 2010 to characterize the relationship between viral load and tumor characteristics. Of the tumor samples collected, 73 and 87% were positive for ChHV5 in conventional PCR and real-time PCR, respectively, and viral loads ranged between 1 and 118.62 copies cell⁻¹. Thirty-three percent of turtles were mildly, 28% were moderately and 39% were severely affected with FP. Skin samples were used as negative control. High viral loads correlated positively with increasing FP severity in turtles sampled on the Brazilian coast and with samples from turtles found dead in the states of São Paulo and Bahia. Six viral variants were detected in tumor samples, 4 of which were similar to the Atlantic phylogenetic group. Two variants were similar to the western Atlantic/eastern Caribbean phylogenetic group. Co-infection in turtles with more than one variant was observed in the states of São Paulo and Bahia.


Combined meta-analysis of systemic effects of allogeneic stem cell transplantation and systemic sclerosis.
Chronic graft-versus-host disease (cGVHD) is a major factor of morbidity and mortality for allogeneic stem cell transplantation (aSCT). The skin and internal organ involvement is the most common systemic complication of cGVHD and closely resembles systemic sclerosis (SSc). Circulating lymphocytes characterize the autoimmune nature of both conditions. Therefore we hypothesized that the common clinical manifestation (systemic organ and skin injury) and the common underlying players (lymphocytes) justify the combined meta-analysis of these diseases. The aSCT and SSc datasets were uploaded from Gene Expression Omnibus (GEO), a public functional genomics data repository. The available microarray studies of peripheral blood mononuclear cells (PBMCs) and isolated lymphocytes were limited to well established microarray platforms (Affymetrix, Agilent, Canvac, and Illumina) and experimental settings with ≥10 patients per group. The resulting pools of data were merged by unique gene identifier and analyzed by the expression genome-wide association studies (eGWAS) coupled with the subtraction of the cGVHD+ and cGVHD- molecular signatures. The eGWAS was applied to 47 and 50 lymphocyte profiles from aSCT and SSc patients, respectively. The identified 35 candidates were represented by 8 known cGVHD genes (including CXCR4, LTBR and PML) and 28 new candidate genes (including SEPX1 and DNJGB1). The further mutual subtraction of cGVHD+ and cGVHD- candidates and pathway analysis identified a list of 25 genes. Seven of these genes belong to the fibroblast development and function pathway, consisting of the well known cGVHD genes CCND1, JUN, and FOS, and the new molecular targets MMP2, FOSB, TNFAIP8, and DUSP1. These genes become primary candidates for a potential link of systemic effects of cGVHD and SSc. We designed a new approach for meta-analysis by combining data from different diseases using common clinical manifestation as a linker. This allowed us to power up the insufficient standalone meta-analysis of aSCT microarray studies, by adding SSc samples to the data pool. This new method has successfully identified novel molecular targets for systemic effects of both aSCT and SSc. We believe that this approach is generalizable and can be applied to an array of diseases with common clinical manifestations.


In Silico Analysis of the Small Molecule Content of Outer Membrane Vesicles Produced by Bacteroides thetaiotaomicron Indicates an Extensive Metabolic Link between Microbe and Host.
The interactions between the gut microbiota and its host are of central importance to the health of the host. Outer membrane vesicles (OMVs) are produced ubiquitously by Gram-negative bacteria including the gut commensal Bacteroides thetaiotaomicron. These vesicles can interact with the host in various ways but until now their complement of small molecules has not been investigated in this context. Using an untargeted high-coverage metabolomic approach we have measured the small molecule content of these vesicles in contrasting in vitro conditions to establish what role these metabolites could perform when packed into these vesicles. B. thetaiotaomicron packs OMVs with a highly conserved core set of small molecules which are strikingly enriched with mouse-digestible metabolites and with metabolites previously shown to be associated with colonization of the murine GIT. By use of an expanded genome-scale metabolic model of B. thetaiotaomicron and a potential host (the mouse) we have established many possible metabolic pathways between the two organisms that were previously unknown, and have found several putative novel metabolic functions for mouse that are supported by gene annotations, but that do not currently appear in existing mouse metabolic networks. The lipidome of these OMVs bears no relation to the mouse lipidome, so the purpose of this particular composition of lipids remains unclear. We conclude from this analysis that through intimate symbiotic evolution OMVs produced by B. thetaiotaomicron are likely to have been adopted as a conduit for small molecules bound for the mammalian host in vivo.


Binocular motor coordination during saccades and fixations while reading: a magnitude and time analysis.
Reading involves saccades and fixations. Misalignment of the eyes should be small enough to allow sensory fusion. Recent studies reported disparity of the eyes during fixations. This study examines disconjugacy, i.e. change in disparity over time, both during saccades and fixations. Text reading saccades and saccades to single targets of similar sizes (2.5 degrees ) are compared. Young subjects were screened to avoid problems of binocular vision and oculomotor vergence. The results show high quality of motor binocular coordination in both tasks: the amplitude difference between the saccade of the eyes was approximately 0.16 degrees ; during the fixation period, the drift difference was only 0.13 degrees . The disconjugate drift occurred mainly during the first 48 ms of fixation, was equally distributed to the eyes and was often reducing the saccade disconjugacy. Quality of coordination regardless of the task is indicative of robust physiological mechanisms. We suggest the existence of active binocular control mechanisms in which vergence signals may have a central role. Even computation of saccades may be based on continuous interaction between saccade and vergence.


Antibiotic regimens for treatment of infections due to multidrug-resistant Gram-negative pathogens: An evidence-based literature review.
Evidences regarding the efficacy of different antibiotic regimens proposed for treatment of multidrug-resistant (MDR) Gram-negative pathogens have been reviewed. Available data in Scopus, Medline, EMBASE, the Cochrane central register of controlled trials, and Cochrane database of systematic reviews have been collected. Several antibiotic regimens are proposed for treatment of MDR Gram-negative infections (defined as nonsusceptibility to at least one agent in three or more antimicrobial categories). The most challenging issue is the treatment of carbapenem-resistant (CR) Gram-negative pathogens. A carbapenem plus either colistin or tigecycline was the most effective regimen for treatment of CR Gram-negative pathogens with low-level resistance (minimal inhibitory concentration [MIC] ≤ 8 mg/L). However, in high-level resistance (MIC > 8 mg/L), combination of colistin and tigecycline showed promising effect.


Preoperative biliary drainage in patients with hilar cholangiocarcinoma undergoing major hepatectomy.
To investigate the effect of preoperative biliary drainage (PBD) in jaundiced patients with hilar cholangiocarcinoma (HCCA) undergoing major liver resections. An observational study was carried out by reviewing a prospectively maintained database of HCCA patients who underwent major liver resection for curative therapy from January 2002 to December 2012. Patients were divided into two groups based on whether PBD was performed: a drained group and an undrained group. Patient baseline characteristics, preoperative factors, perioperative and short-term postoperative outcomes were compared between the two groups. Risk factors for postoperative complications were also analyzed by logistic regression test with calculating OR and 95%CI. In total, 78 jaundiced patients with HCCA underwent major liver resection: 32 had PBD prior to operation while 46 did not have PBD. The two groups were comparable with respect to age, sex, body mass index and co-morbidities. Furthermore, there was no significant difference in the total bilirubin (TBIL) levels between the drained group and the undrained group at admission (294.2 ± 135.7 vs 254.0 ± 63.5, P = 0.126). PBD significantly improved liver function, reducing not only the bilirubin levels but also other liver enzymes. The preoperative TBIL level was significantly lower in the drained group as compared to the undrained group (108.1 ± 60.6 vs 265.7 ± 69.1, P = 0.000). The rate of overall postoperative complications (53.1% vs 58.7%, P = 0.626), reoperation rate (6.3% vs 6.5%, P = 1.000), postoperative hospital stay (16.5 vs 15.0, P = 0.221) and mortality (9.4% vs 4.3%, P = 0.673) were similar between the two groups. In addition, there was no significant difference in infectious complications (40.6% vs 23.9%, P = 0.116) and noninfectious complications (31.3% vs 47.8%, P = 0.143) between the two groups. Univariate and multivariate analyses revealed that preoperative TBIL > 170 μmol/L (OR = 13.690, 95%CI: 1.275-147.028, P = 0.031), Bismuth-Corlette classification (OR = 0.013, 95%CI: 0.001-0.166, P = 0.001) and extended liver resection (OR = 14.010, 95%CI: 1.130-173.646, P = 0.040) were independent risk factors for postoperative complications. Overall postoperative morbidity and mortality rates after major liver resection are not improved by PBD in HCCA patients with jaundice. Preoperative TBIL > 170 μmol/L, Bismuth-Corlette classification and extended liver resection are independent risk factors linked to postoperative complications.


Volatilization and recovery of mercury from mercury-polluted soils and wastewaters using mercury-resistant Acidithiobacillus ferrooxidans strains SUG 2-2 and MON-1.
Iron-oxidizing bacterium, Acidithiobacillus ferrooxidans, is one of the most important bacteria for the bioleaching of copper and gold ores. In order to use the mercury reducing activity of A. ferrooxidans for the bioremediation of mercury, mercury-resistant A. ferrooxidans strains SUG 2-2 and MON-1 were screened among 150 strains of iron-oxidizing bacteria isolated from natural environments. It was found that strains SUG 2-2 and MON-1 have a novel ferrous iron-dependent mercury volatilization activity as well as an NADPH-dependent mercury reductase activity. Strain MON-1 has an organomercurial lyase-like activity and grew most rapidly in an iron medium with 0.1 microM p-chloromercuribenzoic acid among 11 A. ferrooxidans strains tested. Nearly 100% of the total mercury in mercury-polluted soil or mercury wastewater was volatilized and recovered by incubating SUG 2-2 or MON-1 cells in 20 ml of an acidified water (pH 2.5) with ferrous iron, suggesting that these mercury-resistant strains can be used for the bioremediation of inorganic and organic mercurial compounds. We show for the first time that MON-1 cells immobilized in polyvinyl alcohol (PVA) resins could efficiently volatilize mercury from 2 L of a synthetic mercury-polluted wastewater (pH 2.5) containing 40 microM Hg(2+) and ferrous iron. The MON-1-immobilized PVA resins were used repeatedly.


Prospects for biodiversity.
Assuming no radical transformation in human behavior, we can expect important changes in biodiversity and ecosystem services by 2050. A considerable number of species extinctions will have taken place. Existing large blocks of tropical forest will be much reduced and fragmented, but temperate forests and some tropical forests will be stable or increasing in area, although the latter will be biotically impoverished. Marine ecosystems will be very different from today's, with few large marine predators, and freshwater biodiversity will be severely reduced almost everywhere. These changes will not, in themselves, threaten the survival of humans as a species.


Fast oxygen exchange and diffusion kinetics of grain boundaries in Sr-doped LaMnO3 thin films.
In this study, the contribution of grain boundaries to the oxygen reduction and diffusion kinetics of La0.8Sr0.2MnO3 (LSM) thin films is investigated. Polycrystalline LSM thin films with columnar grains of different grain sizes as well as epitaxial thin films were prepared by pulsed laser deposition. (18)O tracer exchange experiments were performed at temperatures from 570 °C to 810 °C and subsequently analyzed by secondary ion mass spectrometry (SIMS). The isotope concentration depth profiles of polycrystalline films clearly indicate contributions from diffusion and surface exchange in grains as well as in grain boundaries. Measured depth profiles were analyzed by finite element modeling and revealed the diffusion coefficients D and oxygen exchange coefficients k of both the grain bulk and grain boundaries. Values obtained for grain boundaries (Dgb and kgb) are almost three orders of magnitude higher than those of the grains (Dg and kg). Hence, grain boundaries may not only facilitate fast oxygen diffusion but also fast oxygen exchange kinetics. Variation of the A-site stoichiometry ((La0.8Sr0.2)0.95MnO3) did not lead to large changes of the kinetic parameters. Properties found for epitaxial layers without grain boundaries (Db and kb) are close to those of the grains in polycrystalline layers.


Selection and biased gene conversion in a multigene family: consequences of interallelic bias and threshold selection.
In a previous paper, I investigated the interactions in a gene family of additive selection and biased gene conversion in a finite population when conversion events are rare. Here I extend my "weak-conversion limit" model by allowing biased interallelic conversion (conversion between alleles at the same locus) of arbitrary frequency and various threshold selection schemes for rare interlocus conversion events. I suggest that it is not unreasonable for gene families to experience threshold fitness functions, and show that certain types of thresholds can greatly constrain the rate at which advantageous alleles are fixed as compared to other fitness schemes, such as additive selection. It is also shown that the double sampling process operating on a gene family in a finite population (sampling over the number of genes in the gene family and over the number of individuals in the population) can have interesting consequences. For selectively neutral alleles that experience interallelic bias, the probability of fixation at each single locus may be essentially neutral, but the cumulative effects on the entire gene family of small departures from neutrality can be significant, especially if the gene family is large. Thus, in some situations, gene families can respond to directional forces that are weak in comparison to drift at single loci.


The SIT4 protein phosphatase functions in late G1 for progression into S phase.
Saccharomyces cerevisiae strains containing temperature-sensitive mutations in the SIT4 protein phosphatase arrest in late G1 at the nonpermissive temperature. Order-of-function analysis shows that SIT4 is required in late G1 for progression into S phase. While the levels of SIT4 do not change in the cell cycle, SIT4 associates with two high-molecular-weight phosphoproteins in a cell-cycle-dependent fashion. In addition, we have identified a polymorphic gene, SSD1, that in some versions can suppress the lethality due to a deletion of SIT4 and can also partially suppress the phenotypic defects due to a null mutation in BCY1. The SSD1 protein is implicated in G1 control and has a region of similarity to the dis3 protein of Schizosaccharomyces pombe. We have also identified a gene, PPH2alpha, that in high copy number can partially suppress the growth defect of sit4 strains. The PPH2 alpha gene encodes a predicted protein that is 80% identical to the catalytic domain of mammalian type 2A protein phosphatases but also has an acidic amino-terminal extension not present in other phosphatases.


[Official position of the Chilean Society of Climacteric on the management of climacteric women].
The health of many women is affected in the climacteric period, either by symptoms that deteriorate their life quality (QL) or by chronic diseases that affect their life expectancy. Therefore, it is mandatory to evaluate these two aspects, having as core objectives for any eventual therapeutic intervention, the improvement of QL and the reduction of cardiovascular risk and fractures. To evaluate QL it is mandatory to follow structured interviews that weigh systematically climacteric symptoms such as the Menopause Rating Scale (MRS). The paradigm of the metabolic syndrome constitutes a suitable frame to evaluate cardiovascular risk. Age, a low body weight, a history of fractures and steroid use are risk factors for fractures. A proper evaluation will allow the detection of patients with a low QL or a high risk for chronic disease, therefore identifying those women who require therapy. The clinical management should include recommendations to improve lifestyles, increase physical activity, avoidance of smoking and to follow a low calorie diet rich in vegetables and fruits. Hormonal therapy is the most efficient treatment to improve the QL and its risk is minimized when it is used in low doses or by the transdermal route. Tibolone is an alternative, especially useful in patients with mood disorders and sexual dysfunction. Vaginal estrogens are also a good option, when urogenital symptoms are the main complaint. Some antidepressants can be an effective therapy in patients with vasomotor symptoms who are not willing or cannot use estrogens. The effectiveness of any alternative therapy for menopausal symptoms has not been demonstrated. Dyslipidemia, hypertension, obesity and insulin resistance should be managed according to guidelines. Calcium and vitamin D have positive effects on bone density and certain tendency to reduce vertebral fractures. Bisphosphonates decrease the risk of vertebral fractures.


Serum markers of bone metastases in postmenopausal breast cancer patients treated with formestane.
Bone metabolism marker evaluation is expected to play an auxiliary role in the diagnosis and follow-up of bone metastases in patients affected by different types of neoplasms. In this study we have evaluated osteoblastic and osteoclastic markers in 18 patients with bone metastases from breast cancer at diagnosis and for 1 year of follow-up during treatment with the aromatase inhibitor formestane. Osteoblastic markers include the carboxy-terminal propeptide of type I procollagen, the bone-specific alkaline phosphatase and the bone GLA protein. The carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) was evaluated as a marker of osteoclastic activity. The patients were classified into three groups according to clinical response. A good correlation between marker level modifications and clinical evolution of skeletal metastases was observed for all the examined markers. Patients with progressive disease showed increasing levels of all markers, whereas patients in regression showed a reduction compared to the basal levels; patients with stable disease fell in between these two categories. We also found that basal ICTP values have prognostic significance: in the stable and progressive disease group they were higher than in the partial response group.


A phase II study of intraperitoneal cisplatin and thiotepa in residual ovarian carcinoma: a Gynecologic Oncology Group study.
Patients with advanced epithelial ovarian cancer treated with salvage therapy using new combinations of systemic chemotherapy, radiation therapy, and systemic immunotherapy have had limited success. Since the most common site of relapse or failure to conventional systemic chemotherapy has been the peritoneal cavity, intraperitoneal (IP) chemotherapy was selected to treat small-volume residual disease. Sixty-five patients were entered on a protocol using intraperitoneal cisplatin and thiotepa following a response to intravenous cisplatin-based chemotherapy. Patients had surgically documented residual disease (0.5 cm or less maximum tumor diameter) at completion of preprotocol surgery and had no clinical, radiologic, or histologic evidence of extraperitoneal disease. Cisplatin (100 mg/m2) and thiotepa 30 mg/m2 was delivered intraperitoneally every 4 weeks for a maximum of six cycles. The dose of thiotepa was reduced to 12 mg/m2 due to unexpected severe myelosuppression. Of the 52 evaluable patients, grade 4 neutropenia, thrombocytopenia, neurotoxicity, and nephrotoxicity were observed in 31, 19, 13, and 6% of patients, respectively. For all evaluable patients, the complete response rate was 19% and the partial response rate was 2% for a total response rate of 21%. Of 16 patients who had a reassessment laparotomy, 10 patients achieved a surgically documented complete response and 1 patient had a partial response. Four patients are still in response for 67+, 70+, 70+, and 73+ months after third-look surgery. Three patients who did not undergo third-look surgery after chemotherapy are alive and clinically free of disease at 49+, 69+, and 85+ months. Thiotepa, when used with cisplatin for IP salvage therapy in patients with advanced or recurrent ovarian cancer, may produce significant myelosuppression and doses must be adjusted accordingly. In cisplatin-sensitive patients with small-volume residual ovarian cancer, IP cisplatin and thiotepa appears to have activity. Determining the utility of this approach will require a randomized trial.


Low blood cell counts in wild Japanese monkeys after the Fukushima Daiichi nuclear disaster.
In April 2012 we carried out a 1-year hematological study on a population of wild Japanese monkeys inhabiting the forest area of Fukushima City. This area is located 70 km from the Fukushima Daiichi Nuclear Power Plant (NPP), which released a large amount of radioactive material into the environment following the Great East Japan Earthquake of 2011. For comparison, we examined monkeys inhabiting the Shimokita Peninsula in Aomori Prefecture, located approximately 400 km from the NPP. Total muscle cesium concentration in Fukushima monkeys was in the range of 78-1778 Bq/kg, whereas the level of cesium was below the detection limit in all Shimokita monkeys. Compared with Shimokita monkeys, Fukushima monkeys had significantly low white and red blood cell counts, hemoglobin, and hematocrit, and the white blood cell count in immature monkeys showed a significant negative correlation with muscle cesium concentration. These results suggest that the exposure to some form of radioactive material contributed to hematological changes in Fukushima monkeys.


Facile One-Step Route for the Development of in Situ Cocatalyst-Modified Ti3+ Self-Doped TiO2 for Improved Visible-Light Photocatalytic Activity.
Development of visible-light-driven photocatalysts by employing a relatively simple, efficient, and cost-effective one-step process is essential for commercial applications. Herein, we report for the first time the synthesis of in situ Cu-ion modified Ti3+ self-doped rutile TiO2 by such a facile one-step solution precursor plasma spray (SPPS) process using a water-soluble titanium precursor. In the SPPS process, Ti3+ self-doping on Ti4+ of rutile TiO2 is found to take place because of electron transfer from the created oxygen vacancies to Ti4+-ions. In situ Cu modification of the above Ti3+ self-doped rutile TiO2 by additionally introducing a Cu solution into plasma plume is also demonstrated. While the Ti3+ self-doping induces broad absorption in the visible-light region, the addition of Cu ion leads to even broader absorption in the visible region owing to resulting synergistic properties. The above materials were evaluated for various self-cleaning photocatalytic applications under visible-light illumination. Cu-ion modified Ti3+ self-doped rutile TiO2 is noted to exhibit a remarkably enhanced visible-light activity in comparison with Ti3+ self-doped rutile TiO2, with the latter itself outperforming commercial TiO2 photocatalysts, thereby suggesting the suitability of the material for indoor applications. The broad visible-light absorption by Ti3+ self-doping, the holes with strong oxidation power generated in the valence band, and electrons in Ti3+ isolated states that are effectively separated into the high reductive sites of Cu ions upon visible-light irradiation, accounts for improved photocatalytic activity. Moreover, the synthesis process (SPPS) provides a valuable alternative to orthodox multistep processes for the preparation of such visible-light-driven photocatalysts.


Genetic analysis of the Cronobacter sakazakii O4 to O7 O-antigen gene clusters and development of a PCR assay for identification of all C. sakazakii O serotypes.
The Gram-negative bacterium Cronobacter sakazakii is an emerging food-borne pathogen that causes severe invasive infections in neonates. Variation in the O-antigen lipopolysaccharide in the outer membrane provides the basis for Gram-negative bacteria serotyping. The O-antigen serotyping scheme for C. sakazakii, which includes seven serotypes (O1 to O7), has been recently established, and the O-antigen gene clusters and specific primers for three C. sakazakii serotypes (O1, O2, and O3) have been characterized. In this study, the C. sakazakii O4, O5, O6, and O7 O-antigen gene clusters were sequenced, and gene functions were predicted on the basis of homology. C. sakazakii O4 shared a similar O-antigen gene cluster with Escherichia coli O103. The general features and anomalies of all seven C. sakazakii O-antigen gene clusters were evaluated and the relationship between O-antigen structures and their gene clusters were investigated. Serotype-specific genes for O4 to O7 were identified, and a molecular serotyping method for all C. sakazakii O serotypes, a multiplex PCR assay, was developed by screening against 136 strains of C. sakazakii and closely related species. The sensitivity of PCR-based serotyping method was determined to be 0.01 ng of genomic DNA and 10(3) CFU of each strain/ml. This study completes the elucidation of C. sakazakii O-antigen genetics and provides a molecular method suitable for the identification of C. sakazakii O1 to O7 strains.


Molecular diffusion in tissue-engineered cartilage constructs: effects of scaffold material, time, and culture conditions.
Diffusion is likely to be the primary mechanism for macromolecular transport in tissue-engineered cartilage, and providing an adequate nutrient supply via diffusion may be necessary for cell proliferation and extracellular matrix production. The goal of this study was to measure the diffusivity of tissue-engineered cartilage constructs as a function of scaffold material, culture conditions, and time in culture. Diffusion coefficients of four different-sized fluorescent dextrans were measured by fluorescence recovery after photobleaching in tissue-engineered cartilage constructs seeded with human adipose-derived stem cells or acellular constructs on scaffolds of alginate, agarose, gelatin, or fibrin that were cultured for 1 or 28 days in either chondrogenic or control conditions. Diffusivities in the constructs were much greater than those of native cartilage. The diffusivity of acellular constructs increased 62% from Day 1 to Day 28, whereas diffusivity of cellular constructs decreased 42% and 27% in chondrogenic and control cultures, respectively. The decrease in diffusivity in cellular constructs is likely due to new matrix synthesis, which may be enhanced with chondrogenic media, and matrix contraction by the cells in the fibrin and gelatin scaffolds. The increase in diffusivity in the acellular constructs is probably due to scaffold degradation and swelling.


Body flexibility and incident hypertension: The Niigata wellness study.
A high level of physical fitness, especially cardiorespiratory fitness, is associated with lower incidence of hypertension. However, the relationship between flexibility, which is a component of physical fitness, and the incidence of hypertension is unknown. The purpose of this study was to investigate the relationship between flexibility and the incidence of hypertension in a cohort study. A total of 22,972 (14,805 men and 8167 women; median age 49 years) normotensive participants were included in this study. Between April 2001 and March 2002, flexibility (standing forward bending) was measured using a standing trunk flexion meter. The participants were divided into quartiles of flexibility by sex and age group. Hypertension was defined as systolic blood pressure ≥ 140 mm Hg, diastolic blood pressure ≥ 90 mm Hg, or a self-reported history of previously diagnosed hypertension or current medication for hypertension at a health examination between April 2002 and March 2008. Hazard ratios and 95% confidence intervals (95% CI) for the incidence of hypertension were estimated using Cox proportional hazards models after adjusting for age, sex, body mass index, exercise habits, smoking status, and drinking status. During 102,948 person years of follow-up (median 5.6 years), 4235 participants developed hypertension. Compared with the lowest flexibility (quartile 1), hazard ratios and 95% CI were 0.96 (0.88 - 1.04) for quartile 2, 0.94 (0.86 - 1.03) for quartile 3, and 0.83 (0.76 - 0.91) for quartile 4. A high level of flexibility was associated with lower incidence of hypertension, independent of other confounding factors.


Strange baryon resonance production in sqrt s NN=200 GeV p+p and Au+Au collisions.
We report the measurements of Sigma(1385) and Lambda(1520) production in p+p and Au+Au collisions at sqrt[s{NN}]=200 GeV from the STAR Collaboration. The yields and the p(T) spectra are presented and discussed in terms of chemical and thermal freeze-out conditions and compared to model predictions. Thermal and microscopic models do not adequately describe the yields of all the resonances produced in central Au+Au collisions. Our results indicate that there may be a time span between chemical and thermal freeze-out during which elastic hadronic interactions occur.


The Effect of Disease Activity on Birth Outcomes in a Nationwide Cohort of Women with Moderate to Severe Inflammatory Bowel Disease.
Active inflammatory bowel disease (IBD) during conception and pregnancy may increase the risk of adverse birth outcomes. Former studies have examined heterogeneous groups of women with varying degrees of IBD severity. We aimed to examine the effect of active IBD on birth outcomes in a more homogeneous group of women with a moderate to severe disease course. Since in Denmark, moderate to severe IBD is an indication for use of anti-tumor necrosis factor-α therapy, we examined all women who used anti-tumor necrosis factor therapy during pregnancy. We identified a nationwide cohort of 219 singleton pregnancies in women treated with anti-tumor necrosis factor-α therapy during pregnancy (2005-2014). Pregnancies with clinical disease activity (65.8%) constituted the exposed cohort and pregnancies without disease activity constituted the unexposed (34.2%). Disease activity scores were supported by levels of fecal calprotectin. Outcomes included low birth weight, preterm birth, and congenital anomalies. In women with IBD, disease activity was associated with adjusted odds ratio of low birth weight and preterm birth; 2.05 (95% confidence interval, 0.37-11.35) and 2.64 (95% confidence interval, 0.85-8.17), respectively. In those with clinical moderate to severe disease activity, the odds ratio for preterm birth was 3.60 (95% confidence interval, 1.14-11.36). In women with ulcerative colitis and disease activity, 19.5% had a child with low birth weight and 29.3% gave birth preterm. In women with moderate to severe IBD, 66% experienced disease activity during pregnancy. In those with the highest degree of disease activity, the risk of preterm birth was increased 3 to 4 folds. The proportion of adverse birth outcomes was high, particularly among women with ulcerative colitis and disease activity.


Characterization of viral, bacterial, and parasitic causes of disease in small-scale chicken flocks in the Mekong Delta of Vietnam.
In the Mekong Delta region of Vietnam, small-scale chicken farming is common. However, high levels of disease or mortality in such flocks impair economic development and challenge the livelihoods of many rural households. We investigated 61 diseased small-scale flocks (122 chickens) for evidence of infection with 5 bacteria, 4 viruses, and helminths. Serological profiles (ELISA) were also determined against 6 of these pathogens. The aims of this study were the following: (1) to investigate the prevalence of different pathogens and to compare the probability of detection of bacterial pathogens using PCR and culture; (2) to investigate the relationship between detection of organisms in birds' tissues and the observed morbidity and mortality, as well as their antibody profile; and (3) to characterize risk factors for infection with specific viral or bacterial pathogens. We used PCR to test for viral (viruses causing infectious bronchitis [IB], highly pathogenic avian influenza [HPAI], Newcastle disease, and infectious bursal disease [IBD]) and bacterial pathogens (Mycoplasma gallisepticum, Pasteurella multocida, Avibacterium paragallinarum, and Ornithobacterium rhinotracheale [ORT]). The latter two were also investigated in respiratory tissues by conventional culture. Colisepticemic Escherichia coli was investigated by liver or spleen culture. In 49 of 61 (80.3%) flocks, at least one bacterial or viral pathogen was detected, and in 29 (47.5%) flocks, more than one pathogen was detected. A. paragallinarum was detected in 62.3% flocks, followed by M. gallisepticum (26.2%), viruses causing IBD (24.6%) and IB (21.3%), septicemic E. coli (14.8%), ORT (13.1%), and HPAI viruses (4.9%). Of all flocks, 67.2% flocks were colonized by helminths. Mortality was highest among flocks infected with HPAI (100%, interquartile range [IQR]: 81.6-100%) and lowest with flocks infected with ORT (5.3%, IQR: 1.1-9.0%). The results indicated slight agreement (kappa ≤ 0.167) between detection by PCR and culture for both A. paragallinarum and ORT, as well as between the presence of cestodes and ORT infection (kappa = 0.317). Control of A. paragallinarum, viruses causing HPAI, IBD, and IB, M. gallisepticum, and gastrointestinal helminths should be a priority in small-scale flocks.


Currently available in vitro methods used in the regulatory toxicology.
About two decades ago in vitro mutagenicity tests were adopted as the first in vitro methods in regulatory toxicology. For reasons of animal welfare and better science, many validation studies of various in vitro methods were performed between 1985 and 1995 for their potential to replace the Draize eye irritation test. Albeit the fact that four in vitro methods (HET-CAM, BCOP, IRE, and ECE) have gained regulatory tolerance in Europe for the classification of severe eye irritants, the lessons learned mainly from these validation studies led to the definition of internationally harmonised OECD validation principles and acceptance criteria (Final Report of the OECD Workshop on Harmonization of Validation and Acceptance Criteria for Alternative Toxicological Tests Methods, 1996. OECD Publication Office, Paris, France). Application of these principles to prevalidation and validation studies, and additional special studies performed in Europe with the support of ECVAM, ended in the scientific validation of new in vitro methods for the prediction of skin corrosivity and phototoxicity. They were accepted for regulatory use in Europe and adopted on 8 June 2000 as test methods B. 40 and B. 41 of Annex V of Directive 67/548/EEC. In quite a different approach, European industry has submitted in-house validation data to support a Draft OECD Test Guideline for in vitro dermal absorption testing, which-after peer review and a long lasting international discussion-will now be adopted by the OECD. The increasing importance of regulatory measures derived from quantitative cytotoxicity tests, and some examples of regulatory accepted in vitro methods, where the specific purpose is restricted to a specific regulation (e.g. testing of medicinal products, or medical devices), are also addressed.


C-reactive protein point-of-care testing for safely reducing antibiotics for acute exacerbations of chronic obstructive pulmonary disease: the PACE RCT.
Most patients presenting with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in primary care are prescribed antibiotics, but these may not be beneficial, and they can cause side effects and increase the risk of subsequent resistant infections. Point-of-care tests (POCTs) could safely reduce inappropriate antibiotic prescribing and antimicrobial resistance. To determine whether or not the use of a C-reactive protein (CRP) POCT to guide prescribing decisions for AECOPD reduces antibiotic consumption without having a negative impact on chronic obstructive pulmonary disease (COPD) health status and is cost-effective. A multicentre, parallel-arm, randomised controlled open trial with an embedded process, and a health economic evaluation. General practices in Wales and England. A UK NHS perspective was used for the economic analysis. Adults (aged ≥ 40 years) with a primary care diagnosis of COPD, presenting with an AECOPD (with at least one of increased dyspnoea, increased sputum volume and increased sputum purulence) of between 24 hours' and 21 days' duration. CRP POCTs to guide antibiotic prescribing decisions for AECOPD, compared with usual care (no CRP POCT), using remote online randomisation. Patient-reported antibiotic consumption for AECOPD within 4 weeks post randomisation and COPD health status as measured with the Clinical COPD Questionnaire (CCQ) at 2 weeks. For the economic evaluation, patient-reported resource use and the EuroQol-5 Dimensions were included. In total, 653 participants were randomised from 86 general practices. Three withdrew consent and one was randomised in error, leaving 324 participants in the usual-care arm and 325 participants in the CRP POCT arm. Antibiotics were consumed for AECOPD by 212 out of 274 participants (77.4%) and 150 out of 263 participants (57.0%) in the usual-care and CRP POCT arm, respectively [adjusted odds ratio 0.31, 95% confidence interval (CI) 0.20 to 0.47]. The CCQ analysis comprised 282 and 281 participants in the usual-care and CRP POCT arms, respectively, and the adjusted mean CCQ score difference at 2 weeks was 0.19 points (two-sided 90% CI -0.33 to -0.05 points). The upper limit of the CI did not contain the prespecified non-inferiority margin of 0.3. The total cost from a NHS perspective at 4 weeks was £17.59 per patient higher in the CRP POCT arm (95% CI -£34.80 to £69.98; p = 0.408). The mean incremental cost-effectiveness ratios were £222 per 1% reduction in antibiotic consumption compared with usual care at 4 weeks and £15,251 per quality-adjusted life-year gained at 6 months with no significant changes in sensitivity analyses. Patients and clinicians were generally supportive of including CRP POCT in the assessment of AECOPD. A CRP POCT diagnostic strategy achieved meaningful reductions in patient-reported antibiotic consumption without impairing COPD health status or increasing costs. There were no associated harms and both patients and clinicians valued the diagnostic strategy. Implementation studies that also build on our qualitative findings could help determine the effect of this intervention over the longer term. Current Controlled Trials ISRCTN24346473. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 15. See the NIHR Journals Library website for further project information.