What school-level and area-level factors influenced HPV and MenACWY vaccine coverage in England in 2016/2017? An ecological study.
To describe school-level and area-level factors that influence coverage of the school-delivered human papillomavirus (HPV) and meningococcal A, C, W and Y (MenACWY) programmes among adolescents. Ecological study. Aggregated 2016/2017 data from year 9 pupils were received from 1407 schools for HPV and 1432 schools for MenACWY. The unit of analysis was the school. Outcome measures were percentage point (pp) difference in vaccine coverage by schools' religious affiliation, school type, urban/rural, single sex/mixed and region. A subanalysis of mixed-sex, state-funded secondary schools also included deprivation, proportion of population from black and ethnic minorities, and school size. Muslim and Jewish schools had significantly lower coverage than schools of no religious character for HPV (24.0 (95% CI -38.2 to -9.8) and 20.5 (95% CI -30.7 to -10.4) pp lower, respectively) but not for MenACWY. Independent, special schools and pupil referral units had increasingly lower vaccine coverage compared with state-funded secondary schools for both HPV and MenACWY. For both vaccines, coverage was 2 pp higher in rural schools than in urban schools and lowest in London. Compared with mixed schools, HPV coverage was higher in male-only (3.7 pp, 95% CI 0.2 to 7.2) and female-only (4.8 pp, 95% CI 2 to 7.6) schools. In the subanalysis, schools located in least deprived areas had the highest coverage for both vaccines (3.8 (95% CI 0.9 to 6.8) and 10.4 (95% CI 7.0 to 13.8) pp for HPV and MenACWY, respectively), and the smallest schools had the lowest coverage (-10.4 (95% CI -14.1 to -6.8) and -7.9 (95% CI -12 to -3.8) for HPV and MenACWY, respectively). Tailored approaches are required to improve HPV vaccine coverage in Muslim and Jewish schools. In addition, better ways of reaching pupils in smaller specialist schools are needed.


Evaluating the social determinants of teenage pregnancy: a temporal analysis using a UK obstetric database from 1950 to 2010.
Teenage pregnancy is a known social problem which has been previously described using a number of deprivation measures. This study aimed to explore the temporal patterns of teenage pregnancy in Aberdeen, Scotland and to assess the discriminating ability of three measures of socioeconomic status. This was a population-based study from 1950 to 2010, using data from the Aberdeen Maternity Neonatal Databank (AMND). The main outcome variable was conceptions occurring in women aged less than 20 years. This study used two area-based measures, the Scottish Index of Multiple Deprivation (SIMD) and the Carstairs index, and one individual-based measure the Social Class based on Occupation (SCO). These measures were compared for their association with teenage conceptions using logistic regression models. The models were used to determine receiver operating characteristic (ROC) curves showing the discriminating ability of the measures. There was an overall decline in teenage conceptions over the 60-year period, but an increase in the rate ratio for deprived areas. All the measures of socioeconomic status were highly associated with teenage pregnancy. The adjusted OR of SIMD and teenage conception was 5.72 (95% CI 4.62 to 7.09), which compared the most deprived decile with the least deprived decile. The use of ROC curves showed that socioeconomic measures performed better than chance at determining teenage conceptions (χ(2)=21.67, p≤0.0001). They further showed that the SIMD had the largest area under the curve (AUC) with a value of 0.81 (95% CI 0.80 to 0.82), followed by the Carstairs index with an AUC of 0.80 (95% CI 0.78 to 0.80), then by SCO with an AUC of 0.79 (95% CI 0.78 to 0.80). Despite a slight decline in teenage pregnancies over the past decades, there is still an evident association between deprivation and teenage pregnancy. This study shows that all the measures of socioeconomic status were highly associated with teenage pregnancy, with the SIMD having the greatest discriminatory effect.


The effect of race and ethnicity on outcomes among patients in the intensive care unit: a comprehensive study involving socioeconomic status and resuscitation preferences.
We sought to determine whether race or ethnicity is independently associated with mortality or intensive care unit length of stay among critically ill patients after accounting for patients' clinical and demographic characteristics including socioeconomic status and resuscitation preferences. Historical cohort study of patients hospitalized in intensive care units. Adult intensive care units in 35 California hospitals during the years 2001-2004. A total of 9,518 intensive care unit patients (6,334 white, 655 black, 1,917 Hispanic, and 612 Asian/Pacific Islander patients). The primary outcome was risk-adjusted mortality and a secondary outcome was risk-adjusted intensive care unit length of stay. Crude hospital mortality was 15.9% among the entire cohort. Asian patients had the highest crude hospital mortality at 18.6% and black patients had the lowest at 15.0%. After adjusting for age and gender, Hispanic and Asian patients had a higher risk of death compared to white patients, but these differences were not significant after additional adjustment for severity of illness. Black patients had more acute physiologic derangements at intensive care unit admission and longer unadjusted intensive care unit lengths of stay. Intensive care unit length of stay was not significantly different among racial/ethnic groups after adjustment for demographic, clinical, and socioeconomic factors and do-not-resuscitate status. In an analysis restricted only to those who died, decedent black patients averaged 1.1 additional days in the intensive care unit (95% confidence interval, 0.26-2.6) compared to white patients who died, although this was not statistically significant. Hospital mortality and intensive care unit length of stay did not differ by race or ethnicity among this diverse cohort of critically ill patients after adjustment for severity of illness, resuscitation status, socioeconomic status, insurance status, and admission type. Black patients had more acute physiologic derangements at intensive care unit admission and were less likely to have a do-not-resuscitate order. These results suggest that among intensive care unit patients, there are no racial or ethnic differences in mortality within individual hospitals. If disparities in intensive care unit care exist, they may be explained by differences in the quality of care provided by hospitals that serve high proportions of minority patients.


Preliminary evidence of the association between monochlorinated bisphenol A exposure and type II diabetes mellitus: A pilot study.
Evidence for the association of bisphenol A (BPA) with type II diabetes mellitus (T2DM) has been inconsistent in human studies. In-vitro and animal studies indicate that chlorinated BPA derivatives aggravate BPA health effects via higher estrogenic activity and alteration of membrane-initiating signaling pathways. We evaluated the association between urinary monochlorinated BPA (mono-ClBPA) concentrations and the incidence of T2DM. In our cross-sectional study, we identified 20 adult participants (≥18 yr) who reported having T2DM (doctor-diagnosed) and 131 adults with normal health. First morning void urine samples were analyzed for total BPA and mono-ClBPA. Detection limits of the analytical method were 95 ng L(-1) for BPA and 32 ng L(-1) for mono-ClBPA. Multivariable logistic regression analyses and additive Bayesian network modeling were performed. After adjusting for age, gender, BMI, urinary total BPA and other confounders, the odds of having T2DM was 3.29 times higher (95% confidence interval, CI: 1.10, 11.4; P < 0.05) per unit increase in log-transformed and creatinine-adjusted urinary mono-ClBPA levels (n = 151); this relation did not hold for total BPA. The globally optimum Bayesian model corroborated the results of the logistic regression by expressing mono-ClBPA in the pathway of T2DM, and not for total BPA. An age-matched sensitivity analysis confirmed the increase in OR of T2DM by 3.04 times (95% CI: 1.10, 11.0; P < 0.05) per unit increase in log-transformed and creatinine-adjusted urinary mono-ClBPA concentration (n = 68). The urinary monochlorinated BPA derivative was significantly associated with T2DM, whereas the parent compound (total BPA) was not. Caution should be applied in interpreting these findings, as this is the first study to report this association and the sample size of participants with T2DM is small. Additional research with a larger sample size coupled with relevant toxicological studies is warranted.


A functional analysis of dopaminergic innervation of the neurohypophysis.
Dopaminergic neurons arising from cell bodies in the rostral arcuate nucleus of the hypothalamus have been shown to make axoaxonic contact with neurohypophyseal neurosecretory axons. In this study, electrical stimulation of the rostral arcuate nucleus depresses multiunit electrical activity recorded from neurosecretory axons within the neurohypophysis. After a single 5-s stimulus train, neurohypophyseal electrical activity is reduced to 6% of control. The superfusion of dopamine (5 micrograms/microliters) onto the neurohypophysis also has an inhibitory effect. Superfusion directly onto the neurohypophysis of the dopamine-receptor antagonist, pimozide (1 micrograms/microliters), abolishes the inhibitory effect of arcuate nucleus stimulation. These findings suggest that the dopaminergic innervation of the neurohypophysis may have an inhibitory influence on the release of neurohypophyseal hormones.


Layer-by-Layer Deposition: A Promising Environmentally Benign Flame-Retardant Treatment for Cotton, Polyester, Polyamide and Blended Textiles.
A detailed review of recent developments of layer-by-layer (LbL) deposition as a promising approach to reduce flammability of the most widely used fibers (cotton, polyester, polyamide and their blends) is presented. LbL deposition is an emerging green technology, showing numerous advantages over current commercially available finishing processes due to the use of water as a solvent for a variety of active substances. For flame-retardant (FR) purposes, different ingredients are able to build oppositely charged layers at very low concentrations in water (e.g., small organic molecules and macromolecules from renewable sources, inorganic compounds, metallic or oxide colloids, etc.). Since the layers on a textile substrate are bonded with pH and ion-sensitive electrostatic forces, the greatest technological drawback of LbL deposition for FR finishing is its non-resistance to washing cycles. Several possibilities of laundering durability improvements by different pre-treatments, as well as post-treatments to form covalent bonds between the layers, are presented in this review.


Effect of low-level Er:YAG laser irradiation on cultured human gingival fibroblasts.
Low-level laser irradiation has been reported to enhance wound healing. Activation of gingival fibroblasts (GF) has a potential for early wound healing in periodontal treatment. The present study aimed to investigate the direct effect of low-level Er:YAG laser irradiation on gingival fibroblasts proliferation in order to clarify the laser effect on healing. Cultured human gingival fibroblasts (hGF) were exposed to low-power, pulsed Er:YAG laser irradiation with different energy densities ranging from 1.68 to 5.0 J/cm(2). The cultures were analyzed by means of trypan blue staining and counted under a light microscope. The effect of Er:YAG laser on hGF was also evaluated using a transmission electron microscope (TEM). Cultures irradiated with Er:YAG laser presented faster cell growth when compared with untreated controls. This difference was statistically significant. Transmission electron microscopy revealed rough endoplasmic reticulum, prominent Golgi complexes, and mitochondria after laser irradiation. Our results showed that the low-level Er:YAG laser irradiation stimulates the proliferation of cultured gingival fibroblasts. The optimal stimulative energy density was found to be 3.37 J/cm(2). This result suggests that Er:YAG laser irradiation may be of therapeutic benefit for wound healing.


Copying without perceiving: motor imagery in visual form agnosia.
Patient DF has severely impaired visual contour perception, despite being able to use that same visual information to guide her motor actions. We report that DF has developed a strategy to overcome some of her perceptual deficits. DF was first asked to copy single lines set at different orientations. She performed surprisingly accurately, although her responses were slow. When questioned, DF reported imagining tracing the line with her finger before copying the line on paper, although she was still unable to discriminate perceptually between different line orientations. We found that time restraints, or the requirement to perform secondary concurrent tasks, severely disrupted DF's orientation copying ability. We conclude that DF can use pure motor imagery to compensate for some of her perceptual difficulties.


Hand-mouth coordination, congenital absence of limb, and evidence for innate body schemas.
Studies of phantom limb in cases of congenital (aplasic) absence of limb have provided inadequate evidence concerning the innate neurological substrate responsible for the phantom. In this study we review evidence from ultrasonic and behavioral studies of hand-mouth coordination in utero and in early infancy, neurobiological studies in primates, and studies of neural reorganization following amputation. We suggest two complementary hypotheses to explain aplasic phantoms. First, aplasic phantoms are based on the existence of specific neural circuitry associated with innate motor schemas, such as the neural matrix responsible for early hand-mouth coordination. Second, aplasic phantoms are modified by mechanisms that involve a reorganization of neural representations of the missing limb within a complex network involving both cortical and subcortical structures.


Pharmacologic P2X purinergic receptor antagonism in the treatment of collagen-induced arthritis.
To assess the therapeutic potential of a P2X purinergic receptor antagonist, namely, periodate oxidized ATP, in collagen-induced arthritis (CIA). Arthritis was induced in male DBA/1J mice by immunization with type II collagen (CII). Animals showing digit inflammation and paw swelling were treated intraperitoneally with 100 μl of 3 mM oxidized ATP daily for 10 days. At the end of the treatment period, animals were killed and paws were removed for histologic analysis and evaluation of T cell infiltration. Humoral response to CII was analyzed, and specific serum autoantibody levels were correlated with the clinical scores observed in the different treatment groups. Treatment with oxidized ATP resulted in a sustained reduction in disease activity, which was associated with a significant decrease in CD3+ T cell infiltration in arthritic lesions and a significant amelioration of cartilage erosion. Peripheral Treg cells were significantly increased upon P2X blockade in mouse lymph nodes. Moreover, a marked reduction in circulating autoantibodies directed against mouse CII was detected. There was a significant correlation between serum autoantibody levels and the clinical efficacy of oxidized ATP. Our findings indicate that P2X receptor antagonism has important therapeutic potential in chronic inflammatory rheumatic disorders. Taken together, our results underscore the value of the P2X receptor signaling pathway as a potential pharmacologic target for the modulation of adaptive immunity in CIA.


Uncoupling of a nerve cell membrane junction by calcium-ion removal.
Calcium ion participates in maintaining electrical connections between the nerve cells of Retzius (Hirudo medicinalis). The conductance across the junction between these cells decreases with decreasing concentration of free, extracellular Ca(++) At a certain level of Ca(++) withdrawal from the cell system, junctional conductance reaches a critical low point at which the cells become functionally disconnected: the nerve impulses which are normally discharged in synchrony by the cells become asynchronous. These effects of Ca(++) on junctional connection are irreversible, in contrast to those on nonjunctional surface membrane permeability.


Field estimates of polyurethane foam - air partition coefficients for hexachlorobenzene, alpha-hexachlorocyclohexane and bromoanisoles.
Partition coefficients of gaseous semivolatile organic compounds (SVOCs) between polyurethane foam (PUF) and air (KPA) are needed in the estimation of sampling rates for PUF disk passive air samplers. We determined KPA in field experiments by conducting long-term (24-48 h) air sampling to saturate PUF traps and shorter runs (2-4 h) to measure air concentrations. Sampling events were done at daily mean temperatures ranging from 1.9 to 17.5 °C. Target compounds were hexachlorobenzene (HCB), alpha-hexachlorocyclohexane (α-HCH), 2,4-dibromoanisole (2,4-DiBA) and 2,4,6-tribromoanisole (2,4,6-TriBA). KPA (mL g(-1)) was calculated from quantities on the PUF traps at saturation (ng g(-1)) divided by air concentrations (ng mL(-1)). Enthalpies of PUF-to-air transfer (ΔHPA, kJ mol(-1)) were determined from the slopes of log KPA/mL g(-1) versus 1/T(K) for HCB and the bromoanisoles, KPA of α-HCH was measured only at 14.3 to 17.5 °C and ΔHPA was not determined. Experimental log KPA/mL g(-1) at 15 °C were HCB = 7.37; α-HCH = 8.08; 2,4-DiBA = 7.26 and 2,4,6-TriBA = 7.26. Experimental log KPA/mL g(-1) were compared with predictions based on an octanol-air partition coefficient (log KOA) model (Shoeib and Harner, 2002a) and a polyparameter linear free relationship (pp-LFER) model (Kamprad and Goss, 2007) using different sets of solute parameters. Predicted KP values varied by factors of 3 to over 30, depending on the compound and the model. Such discrepancies provide incentive for experimental measurements of KPA for other SVOCs.


A survey on orthodontic-restorative dental services in a NHS hospital.
The provision of a joint orthodontic-restorative hospital service is important in providing a quality service for some dental malocclusions. A prospective survey was carried out of the joint orthodontic-restorative clinic at Mayday University Hospital, during the months of January to August 2005. Data was collected using a data collection form. In total 61 patient's attended 4 joint clinics. Fifty per cent of referrals were by general dental practitioners. The commonest referral reasons were spacing and dental trauma. Over one third of patients were seen within 12 weeks of their referral, whilst two thirds start their treatment within 12 weeks of consultation. The commonest restorative treatment was periodontal therapy, crown and bridgework. Over one third of patients required joint orthodontic and restorative treatment. More than 12% of patients require oral surgery in the form of removal of impacted teeth, exposure of unerupted teeth, placement of bone anchors or orthognathic surgery. Consultation and treatment waiting times could be reduced by the introduction of more clinics and employment of more staff A representative in oral surgery maybe useful with the increase use of bone anchors and mini implants to aid joint orthodontic-restorative treatment. Access to an orthodontic and restorative consultant clinic is useful in providing patients with a high quality of multidisciplinary treatment planning in an efficient manner.


Abdominopelvic FLASH Irradiation Improves PD-1 Immune Checkpoint Inhibition in Preclinical Models of Ovarian Cancer.
Treatment of advanced ovarian cancer using PD-1/PD-L1 immune checkpoint blockade shows promise; however, current clinical trials are limited by modest response rates. Radiotherapy has been shown to synergize with PD-1/PD-L1 blockade in some cancers but has not been utilized in advanced ovarian cancer due to toxicity associated with conventional abdominopelvic irradiation. Ultrahigh-dose rate (FLASH) irradiation has emerged as a strategy to reduce radiation-induced toxicity, however, the immunomodulatory properties of FLASH irradiation remain unknown. Here, we demonstrate that single high-dose abdominopelvic FLASH irradiation promoted intestinal regeneration and maintained tumor control in a preclinical mouse model of ovarian cancer. Reduced tumor burden in conventional and FLASH-treated mice was associated with an early decrease in intratumoral regulatory T cells and a late increase in cytolytic CD8+ T cells. Compared with conventional irradiation, FLASH irradiation increased intratumoral T-cell infiltration at early timepoints. Moreover, FLASH irradiation maintained the ability to increase intratumoral CD8+ T-cell infiltration and enhance the efficacy of αPD-1 therapy in preclinical models of ovarian cancer. These data highlight the potential for FLASH irradiation to improve the therapeutic efficacy of checkpoint inhibition in the treatment of ovarian cancer.


Extrinsic factors, endocrine mechanisms, and behavioral indicators of migratory restlessness in wintering whooper swans (Cygnus cygnus).
Extrinsic factors, endocrine mechanisms, and behavioral indicators of migratory restlessness were studied in wintering whooper swans (Cygnus cygnus) in the Sanmenxia Swan National Wetland Park in western Henan Province, central China. First, the fecal glucocorticoid metabolite (FGM) concentration was established and related to mean air temperature or photo period (day length) using simple linear or non-linear regression models. After a model selection procedure, the best fitted model revealed that an increase of FGM concentration was associated with an increase in the squared mean air temperature (R2 = 0.88). Other models showed an increasing FGM concentration to correspond with increasing values of day length, squared day length, and mean air temperature-however without statistical support. In a second step, behavioral frequencies of seven behaviors were condensed into three behavioral principal components (PCs) using principal components analysis. Behavioral PCs largely corresponded to three activity phases described for wintering whooper swans in central China and were correlated with the FGM concentration using Spearman's rank-order correlations. Results revealed a significant correlation between FGM and behavioral PC2 (positive factor loadings from vigilance and preening, negative loading from foraging). Finally, we tested for an effect of behavioral PCs on changes in winter home range size using a set of multiple linear regression models. Results of averaged model parameter estimates showed only the behavioral PC3 (positive factor loadings from fighting and calling, negative loading from locomotion) had a marginal significant effect on home range size. Results confirmed findings of previous studies on migratory restlessness in whooper swans. However, due to the small sample size (N = 15 weeks) the effect of PC3 on home range size was weak and should be viewed with caution.


Fast Convolutional Neural Network Training Using Selective Data Sampling: Application to Hemorrhage Detection in Color Fundus Images.
Convolutional neural networks (CNNs) are deep learning network architectures that have pushed forward the state-of-the-art in a range of computer vision applications and are increasingly popular in medical image analysis. However, training of CNNs is time-consuming and challenging. In medical image analysis tasks, the majority of training examples are easy to classify and therefore contribute little to the CNN learning process. In this paper, we propose a method to improve and speed-up the CNN training for medical image analysis tasks by dynamically selecting misclassified negative samples during training. Training samples are heuristically sampled based on classification by the current status of the CNN. Weights are assigned to the training samples and informative samples are more likely to be included in the next CNN training iteration. We evaluated and compared our proposed method by training a CNN with (SeS) and without (NSeS) the selective sampling method. We focus on the detection of hemorrhages in color fundus images. A decreased training time from 170 epochs to 60 epochs with an increased performance-on par with two human experts-was achieved with areas under the receiver operating characteristics curve of 0.894 and 0.972 on two data sets. The SeS CNN statistically outperformed the NSeS CNN on an independent test set.


Treat decision making in catastrophic illness.
Through conceptual discussion and consideration of a case study, this paper examines how physicians respond to the availability of an innovative treatment of a serious illness. It is argued that the unusual economic environment of the delivery of catastrophic illness care works with the "social contract" in medicine to encourage the use of innovative therapies, even before their efficacy has been demonstrated and often irrespective of their costs, in striking contrast with the conventional innovation adoption process. The primary constraint on catastrophic illness treatment may well be the technology or the state of knowledge. In the case of the management of leukemias in Connecticut, decisions to use drug therapies appear to have been based on a treatment trend rather than on the inherent merits of the therapies. The trend seems to have spread from the treatment of one leukemia, which responded significantly, to the management of three other leukemias. The influence on treatment decisions of a few indiviudal varibles differed across the leukemia. For example, treatment decisions in the acute leukemias were unrelated to the patient's economic status, whereas receipt of chemotherapy for one of the chronic leukemias was significantly positively correlated with economic status.


Effects of Substance Use and Sex Practices on the Intestinal Microbiome During HIV-1 Infection.
Human immunodeficiency virus type 1 (HIV-1) infection alters the human intestinal microbiome; however, behavioral factors driving these changes remain poorly defined. Here we examine the effects of substance use and sex behavior on the microbiome during HIV-1 infection. Archival rectal swab specimens, urine drug test results, and responses to substance use and sex behavior questionnaires were obtained from 37 HIV-positive participants at 2 time points, separated by 6 months, in a cohort examining the effects of substance use in men who have sex with men (MSM). Microbiome profiling was performed using 16S ribosomal RNA gene sequencing, and associations with behavioral factors were examined using 0-inflated negative binomial regression. Further analysis of selected variables of interest was performed using propensity scores to account for multiple confounders. Using permutational multivariate analysis of variance, we found that receptive anal intercourse, methamphetamine use, and marijuana use were among the most important drivers of microbiome variation. Propensity score-adjusted analyses revealed that methamphetamine use and marijuana use displayed unique associations; methamphetamine use was associated with an increased abundance of Porphyromonas and Granulicatella organisms and a decreased abundance of Ruminococcus, Collinsella, and Parabacteroides organisms, whereas marijuana use was associated with an increased abundance of Ruminococcus, Clostridium cluster IV, Solobacterium, and Fusobacterium organisms and a decreased abundance of Acidaminococcus, Prevotella, Dialister, Anaerostipes, and Dorea organisms. Drug use and sex behavior are important factors associated with intestinal dysbiosis during chronic HIV-1 infection among young MSM.


Economic evaluation for the US of nab-paclitaxel plus gemcitabine versus FOLFIRINOX versus gemcitabine in the treatment of metastatic pancreas cancer.
Nab-paclitaxel plus gemcitabine (NAB-P + GEM) and FOLFIRINOX have shown superior efficacy over gemcitabine (GEM) in the treatment of metastatic pancreatic ductal adenocarcinoma (mPDA). Although the incremental clinical benefits are modest, both treatments represent significant advances in the treatment of a high-mortality cancer. In this independent economic evaluation for the US, the aim was to estimate the comparative cost-utility and cost-effectiveness of these three regimens from the payer perspective. In the absence of a direct treatment comparison in a single clinical trial, the Bucher indirect comparison method was used to estimate the comparative efficacy of each regimen. A Markov model evaluated life years (LY) and quality-adjusted life years (QALY) gained with NAB-P + GEM and FOLFIRINOX over GEM, expressed as incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR). All costs and outcomes were discounted at 3%/year. The impact of parameter uncertainty on the model was assessed by probabilistic sensitivity analyses. NAB-P + GEM was associated with differentials of +0.180 LY and +0.127 QALY gained over GEM at an incremental total cost of $25,965; yielding an ICER of $144,096/LY and ICUR of $204,369/QALY gained. FOLFIRINOX was associated with differentials of +0.368 LY and +0.249 QALY gained over GEM at an incremental total cost of $93,045; yielding an ICER of $253,162/LY and ICUR of $372,813/QALY gained. In indirect comparison, the overall survival hazard ratio (OS HR) for NAB-P + GEM vs FOLFIRINOX was 0.79 (95%CI = 0.59-1.05), indicating no superiority in OS of either regimen. FOLFIRINOX had an ICER of $358,067/LY and an ICUR of $547,480/QALY gained over NAB-P + GEM. Tornado diagrams identified variation in the OS HR, but no other parameters, to impact the NAB-P + GEM and FOLFIRINOX ICURs. In the absence of a statistically significant difference in OS between NAB-P + GEM and FOLFIRINOX, this US analysis indicates that the greater economic benefit in terms of cost-savings and incremental cost-effectiveness and cost-utility ratios favors NAB-P + GEM over FOLFIRINOX.


Effects of genetic variants of ST8SIA2 and NCAM1 genes on seasonal mood changes and circadian preference in the general population.
ST8SIA2 and NCAM1 are functionally related genes forming polysialic acid (PSA) - neural cell adhesion molecule (NCAM) complex in suprachiasmatic nucleus (SCN), the regulating site of circadian biological rhythm. In this study, the relationship of ST8SIA2 and NCAM1 with circadian and seasonal rhythms of human behavior was explored. Subjects were 261 healthy Korean adults who were free of any history of clinically significant psychiatric symptoms. The phenotypes were circadian preference and seasonal change of mood and behavior (seasonality) measured by the Composite Scale of Morningness and the Seasonal Pattern Assessment Questionnaire, respectively. Thirty-four single nucleotide polymorphisms (SNPs) across the ST8SIA2 region and 15 SNPs of NCAM1 were analyzed. A nominally significant association with seasonality and circadian preference was observed in 21 variants of both genes. After corrections for multiple testing, associations of 8 SNPs of ST8SIA2 and 2 SNPs of NCAM1 with seasonality remained significant. Some of these SNPs were also associated with psychiatric disorders in previous studies. This study demonstrated a meaningful and/or suggestive evidence of association between behavioral phenotypes reflecting human biological rhythm and two interplaying genes involved in the plasticity of SCN's neuronal network.


Role of duplex ultrasound in the diagnosis and assessment of carotid body tumour: A literature review.
Carotid body tumour is a rare disease, a slow growing highly vascular tumour of the carotid body tissue and the most common type of the paraganglioma. This article reviews the pathological, clinical and ultrasound features of carotid body tumours and discusses the role of duplex ultrasound in the diagnosis and assessment of this condition. The initial presentation of carotid body tumour is usually a painless palpable neck mass. Some patients may experience local pressure symptoms as well as symptoms from vagal, hypoglossal and cervical sympathetic nerve impingement. Percutaneous needle aspiration or incisional biopsy is contraindicated for the diagnosis of carotid body tumours. Duplex ultrasound, computed tomography scan, magnetic resonance scan and angiography are commonly used diagnostic tools for this condition. Complete surgical excision of carotid body tumour is the treatment of choice as radiation therapy and chemotherapy are unsatisfactory. Based on vascularity and location, duplex ultrasound scan is able to diagnose carotid body tumour and differentiate it from many other masses in the neck. This non-invasive, inexpensive and readily available diagnostic tool can be used as a first-line imaging modality for the diagnosis and assessment of carotid body tumours.


Hydrophilic modification of polystyrene with hydrophobin for time-resolved immunofluorometric assay.
Herein we reported that a hydrophobin film was used as a solid support on the polystyrene surface for immobilizing antibodies in the time-resolved immunofluorometric assay (TR-IFMA). Quartz crystal microbalance with dissipative monitoring (QCM-D), X-ray photoelectron spectroscopy (XPS) and water contact angle (WCA) measurements, as well as atomic force microscope (AFM) were used to characterize the hydrophilic modification of polystyrene surface with Class I hydrophobin isolated from Grifola frondosa (HGFI). The performance of HGFI-modified polystyrene was evaluated by TR-IFMA of carcinoembryonic antigen (CEA). QCM-D revealed that HGFI formed an intact monolayer on the polystyrene at pH 5. XPS and WCA measurements showed that self-assembling HGFI could render polystyrene surface hydrophilic for three months. AFM indicated that an end-on antibody monolayer was adsorbed on the HGFI film rather than multilayers on the polystyrene in a side-on orientation. Furthermore, a linear calibration curve (from 5 to 600 ng/mL) of CEA showed HGFI-modified polystyrene had higher detection sensitivity than unmodified ones in TR-IFMA. This present method for modifying polystyrene is simple without severe chemical treatment and may have wide applicability to functionalize other supports for immobilizing biomolecules.


Integrated safety summary for trifluridine/tipiracil (TAS-102).
Trifluridine/tipiracil, an oral treatment combining trifluridine (an antineoplastic thymidine-based nucleoside analog) and tipiracil hydrochloride (a thymidine phosphorylase inhibitor), led to significant improvement in overall survival in metastatic colorectal cancer (mCRC) patients refractory to standard therapy in the phase III RECOURSE trial. Here, we report an integrated summary of the safety of trifluridine/tipiracil. The main safety analysis includes integrated data from the RECOURSE and J003 studies (safety data group 2) of patients with refractory mCRC receiving trifluridine/tipiracil at the recommended starting dose: 35 mg/m twice daily for 5 days with 2 days' rest for 2 weeks, followed by a 14-day rest (one cycle). Integrated data from a larger group of mCRC patients receiving trifluridine/tipiracil at the recommended starting dose (group 1) and nonintegrated data on serious adverse events (SAEs) representing all clinical experience with trifluridine/tipiracil as of the data cutoff date (group 3) are also summarized. In group 2, myelosuppressive and all-grade gastrointestinal adverse events (AEs) were more frequent in trifluridine/tipiracil patients than in placebo patients. The trifluridine/tipiracil and placebo patients had similar frequencies of AEs leading to discontinuation (9.0 vs. 11.5%) and SAEs (27.7 vs. 29.2%); fatal AEs were more frequent in placebo patients than in trifluridine/tipiracil patients (9.3 vs. 2.8%). AEs leading to interruptions/delays/reductions were more frequent in trifluridine/tipiracil patients (56.3 vs. 12.7%). Trifluridine/tipiracil was generally well tolerated, but over 50% of patients required interruptions/delays/reductions. There was a low rate of discontinuations, SAEs, and fatal AEs. This analysis confirms the safety profile observed in RECOURSE.


[Functional esophageal exploration in the assessment of gastroesophageal reflux].
During the past decade technologic progress has led to the increase use of oesophageal function testing, which is now available in clinical current practice. Ambulatory oesophageal pH monitoring is advocated as one of the best means for assessing the reflux of acid into the oesophagus. This technique can document abnormal gastro-oesophageal reflux (GOR) in patients with atypical symptoms or no endoscopic oesophagitis. The event marker allows to establish the correlation between occurrence of reflux and symptoms. This relationship can be quantified in the form of a symptom index; 24-hours pH monitoring can indicate objective criteria to define success of medical or surgical treatment. Oesophageal manometry analyses the lower oesophageal sphincter pressure and the oesophageal peristaltic function. This technique has a high prognostic value. The lower oesophageal sphincter pressure is not significantly different in patient with GOR but a severe hypotensive value is correlated with the severity of peptic oesophagitis. Peristaltic dysfunction is not specific but also increases with the severity of reflux disease. Pre-operative oesophageal manometry is recommended for identifying patients with oesophageal motility disorders and achalasia in whom anti-reflux surgery may precipitate postoperative dysphagia. The control of postoperative manometric data may be useful in the evaluation of surgery failure or recurrence of reflux symptoms.


Evaluation of toxic effects of metformin hydrochloride and glibenclamide on some organs of male rats.
Metformin hydrochloride (MET) and glibenclamide (GB) are used in the management of Type 2 Diabetes (T2D). This study was designed to investigate the toxic effect of MET and GB in the Liver, kidney and testis of rats. Twenty one rats were divided into three groups of seven rats each; group 1 served as control, groups 2 and 3 received GB and MET at doses of 5 and 30 mg/kg, respectively, for 21 days by oral gavage. Results indicate that MET and GB treatment did not affect body weight-gain in the rats. Also, there were no treatment-related changes in the absolute and relative weights of liver, kidney, and testis in MET and GB-treated rats relative to controls. However, significant increase (p<0.05) in testicular lipid peroxidation levels were accompanied by reduction in epididymal sperm count and motility in MET and GB-treated rats, whereas sperm live/dead ratio was unaffected. Specifically, MET and GB decreased sperm count and motility by 34%, 31% and 25%, 28%, respectively. Activities of hepatic and renal superoxide dismutase (SOD) and catalase (CAT), serum alkaline phosphatase, lactate dehydrogenase and alanine aminotransferase were not significantly (p>0.05) affected in MET and GB-treated rats, whereas testicular SOD, CAT, glutathione, serum aspartate aminotransferase and conjugated bilirubin were markedly affected by MET treatment. Histopathological results showed marked necrosis, degeneration of seminiferous tubules and defoliation of spermatocytes in testis of MET-treated rats. Taken together, MET and GB induced lipid peroxidation, affected seminal qualities and decreased antioxidant status. These drugs may interfere with normal biochemical processes in testis and liver of the rats.


Neighborhood effects on the efficacy of a program to prevent youth alcohol use.
This study examines how neighborhood characteristics affect program efficacy. Data come from a randomized trial of a substance use prevention program called keepin' it REAL, which was administered to a predominantly Mexican American sample of 4,622 middle school students in Phoenix, Arizona, beginning in 1998. Multilevel models and multiple imputation techniques address clustered data and attrition. Among less linguistically acculturated Latinos, living in poorer neighborhoods and those with many single-mother families decreased program effectiveness in combating alcohol use. High neighborhood immigrant composition increased program effectiveness. Unexpectedly, the program was also more effective in neighborhoods with higher rates of crime. There were no significant effects on program efficacy for the more linguistically acculturated Latinos and non-Hispanic White students. Findings are discussed in light of theories of neighborhood social disorganization, immigrant adaptation, and social isolation.


Extending admixture mapping to nuclear pedigrees: application to sarcoidosis.
We describe statistical methods that extend the application of admixture mapping from unrelated individuals to nuclear pedigrees, allowing existing pedigree-based collections to be fully exploited. Computational challenges have been overcome by developing a fast algorithm that exploits the factorial structure of the underlying model of ancestry transitions. This has been implemented as an extension of the program ADMIXMAP. We demonstrate the application of the method to a study of sarcoidosis in African Americans that has previously been analyzed only as an admixture mapping study restricted to unrelated individuals. Although the ancestry signals detected in this pedigree analysis are generally similar to those detected in the earlier analysis of unrelated cases, we are able to extract more information and this yields a much sharper exclusion map; using the classical criterion of an LOD score of minus 2, the pedigree analysis is able to exclude a risk ratio of 2 or more associated with African ancestry over 96% of the genome, compared with only 83% in the earlier analysis of unrelated individuals only. Although the pedigree extension of ADMIXMAP can use ancestry-informative markers only at relatively low density, it can use imputed ancestry states from programs such as WINPOP or HAPMIX that use dense SNP marker genotypes for admixture mapping. This extends both the efficiency and the range of application of this powerful gene mapping method.


Coherent synthesis using carrier-envelope phase-controlled pulses from a dual-color femtosecond optical parametric oscillator.
By using a dual-color femtosecond optical parametric oscillator (OPO), a coherent waveform was synthesized from two coresonant near-infrared signal pulses whose center wavelengths had a separation of 100 nm. Immediately after the OPO cavity the pulses had independent carrier-envelope phase-slip frequencies, and synthesis was achieved by shifting these frequencies using an acousto-optic modulator driven by an internally generated difference frequency. Soliton self-frequency shifted pulses from a photonic crystal fiber and a cross-correlation frequency-resolved optical gating (XFROG) measurement were used to analyze the result of the synthesis experiment and revealed that the synthesized waveform was a train of high-contrast 30 fs pulses.


Psychosocial outcome in adult men born with hypospadias.
Hypospadias, which is a surgically treated congenital malformation of the male urethra, may have a negative impact on quality of life. This aspect has previously been subject to limited research. This study examined the long-term psychosocial outcome of a large cohort of adult males born with hypospadias. The purpose of this case-control study was to assess a possible negative influence on the psychosocial outcome in adult males with hypospadias. Males with hypospadias treated in Sweden and aged ≥18 years old participated in this follow-up study. Age-matched men and university students were recruited as controls. The participants answered a questionnaire designed to reflect the subjective quality of life, social factors, need of support and follow-up, and the perceived impact of the disease upon upbringing. It also looked at the validated Psychological General Well-Being (PGWB) questionnaire and Relationship Questionnaire (RQ). A total of 167 patients (median age 34 years, 63% distal, 24% mid, and 13% proximal hypospadias) and 169 controls (median age 33 years) participated in the study. Patients had their first operation at 4 years of age (median) and the median follow-up time was 29 years following the first surgery. Men with hypospadias had a comparable total quality of life level with a mean total PGWB score of 82 (normal range 78-83) compared with 85.6 in controls. Scores on wellbeing and vitality were lower, even if the differences were small. Hypospadias did not affect marital status, presence of children in the family, frequency of employment or experience of bullying. These men more often lived at home with their parents (P=0.001) and had a lower level of education (P=0.004), even if the educational level in both patients and controls was high compared with the general Swedish population. Patients with proximal hypospadias were shorter compared with controls (P=0.003), which was consistent with the prenatal growth restriction associated with hypospadias. The group with proximal hypospadias expressed a greater need for medical (45.5%) follow-up compared with mid (28.2%) and distal (18.1%) cases (P=0.001). Patients with proximal hypospadias tended to avoid close relationships because of fear of being hurt. The findings suggested that patients treated for hypospadias have a good HRQoL, can be expected to have a normal psychosocial life, and marry and have children. Repeated follow-up and psychological support during childhood/adolescence is however of great importance for patients with more proximal hypospadias.


Physician versus paramedic in the setting of ground forces operations: are they interchangeable?
The setting of military ground force operations can be demanding and requires a matched medical assistance plan. A major consideration is the type of medical caregiver that is assigned to the mission. We studied the similarities, differences, advantages, and disadvantages of physicians versus paramedics in this scenario. We interviewed 20 ground force physicians, highly experienced in this setting. We summarized their responses and formulated quantitative decision-making tables regarding two sorts of missions: a long-duration mission, far from friendly definitive care, and a short-duration mission, close to friendly hospitals. The major areas in which physicians and paramedics differ, pertinent to a ground force operation are: formal education, on-job training, knowledge base, ability to treat a wide variety of medical conditions, ability to perform manual lifesaving procedures, social and moral impact, availability, physical fitness, combat skills, and cost. Of a maximum score of 100 points, for a long-term mission a physician scores 77.7 points while a paramedic scores 63.6 points. The scores for a short-term mission are 72.7 and 67.9, respectively. Physicians and paramedics are distinct groups of medical caregivers and this is also true for the setting of ground force operations. They are not interchangeable. Our data show that a physician has a relative advantage over a paramedic, especially in long-term missions, far from friendly facilities. A physician is the first choice for all kinds of military ground force missions while a paramedic can be a reasonable substitute for missions of short duration, close to definitive care.


Contribution of sulfate and sulfoesters to total sulfur intake in infants fed human milk.
Colostrum (d 2-4) and mature human milk samples (d 23-30) collected from eight mothers giving birth at 31 +/- 7 wk of gestation were analyzed for total sulfur, free inorganic sulfate and acid labile sulfoesters. The data presented are representative of complete 24-h expressions. Total sulfur was measured using a wet digestion procedure in which all forms of sulfur were converted to inorganic sulfate. The sulfate was quantified by a radiometric barium precipitation assay. Total sulfur showed no marked diurnal variation, but the mean concentration in 19 colostrum samples (10.2 +/- 4.2 mmol/L) was significantly higher than in 14 mature milk samples (4.3 +/- 0.8 mmol/L) (P less than 0.001). The range of predicted 24-h intakes of sulfur by infants fed colostrum (0.78-3.22 mmol/kg body weight) was slightly higher than those fed mature milk (0.54-1.06 mmol/kg), but it was not significantly different. The combined fractions of free inorganic sulfate and acid-labile sulfoester fractions contribute less than 5% to the total sulfur content of either colostrum or mature milk. However, the physiological significance of these milk components remains to be determined.


Effervescence-induced amorphous solid dispersions with improved drug solubility and dissolution.
The current study aimed to investigate drug carrier miscibility in pharmaceutical solid dispersions (SD) and include the effervescent system, i.e. Effervescence-induced amorphous solid dispersions (ESD), to enhance the solubility of a poorly water-soluble Glibenclamide (GLB). Kollidon VA 64, PEG-3350, and Gelucire-50/13 were selected as the water-soluble carriers. The miscibility of the drug-carrier was predicted by molecular dynamics simulation, Hansen solubility parameters, Flory-Huggins theory, and Gibb's free energy. Solid dispersions were prepared by microwave, solvent evaporation, lyophilization, and Hot Melt Extrusion (HME) methods. The prepared solid dispersions were subjected to solubility, in-vitro dissolution, and other characterization studies. The in-silico and theoretical approach suggested that the selected polymers exhibited better miscibility with GLB. Solid-state characterizations like FTIR and 1H NMR proved the formation of intermolecular hydrogen bonding between the drug and carriers, which was comparatively higher in ESDs than SDs. DSC, PXRD, and microscopic examination of GLB and SDs confirmed the amorphization of GLB, which was higher in ESDs than SDs. Gibb's free energy concept suggested that the prepared solid dispersions will be stable at room temperature. Ex-vivo intestinal absorption study on optimized ESDs prepared with Kollidon VA64 using the HME technique exhibited a higher flux and permeability coefficient than the pure drug suggesting a better drug delivery. The drug-carrier miscibility was successfully studied in SDs of GLB. The addition of the effervescent agent further enhanced the solubility and dissolution of GLB. Additionally, this might exhibit a better bioavailability, confirmed by ex-vivo intestinal absorption study.


[Chiasmata distribution in the normal karyotype of mice].
The number of chiasmata per cell and variance of chiasmata numbers were studied, as well as the recombinational interaction between different bivalents in CBA/Lac mice male line. No competition of bivalents for chiasmata was discovered in mice; at the same time, the chiasmata within one arm of the chromosome interfere with each other. The number of chiasmata per bivalent is estimated for each chromosome independently. The number of chiasmata per chromosome is limited both from below (minimum one chiasma independently of its size) and from above (positive interference of chiasmata).


Risk Factors for Suffocation and Unexplained Causes of Infant Deaths.
Observational studies have improved our understanding of the risk factors for sudden infant death syndrome, but separate examination of risk for sleep-related suffocation and unexplained infant deaths has been limited. We examined the association between unsafe infant sleep practices and sudden infant deaths (sleep-related suffocation and unexplained causes including sudden infant death syndrome). We conducted a population-based case-control study using 2016 to 2017 Centers for Disease Control and Prevention data. Controls were liveborn infants from the Pregnancy Risk Assessment Monitoring System; cases were from the Sudden Unexpected Infant Death Case Registry. We calculated risk factor prevalence among cases and controls and crude and adjusted odds ratios. We included 112 sleep-related suffocation cases with 448 age-matched controls and 300 unexplained infant death cases with 1200 age-matched controls. Adjusted odds for sleep-related suffocation ranged from 18.7 (95% confidence interval [CI]: 6.8-51.3) among infants not sharing a room with their mother or caregiver to 1.9 (95% CI: 0.9-4.1) among infants with nonsupine sleep positioning. Adjusted odds for unexplained death ranged from 7.6 (95% CI: 4.7-12.2) among infants not sharing a room with their mother or caregiver to 1.6 (95% CI: 1.1-2.4) among nonsupine positioned infants. We confirmed previously identified risk factors for unexplained infant death and independently estimated risk factors for sleep-related suffocation. Significance of associations for suffocation followed similar patterns but was of larger magnitude. This information can be used to improve messaging about safe infant sleep.


NKG2D ligands mediate immunosurveillance of senescent cells.
Cellular senescence is a stress response mechanism that limits tumorigenesis and tissue damage. Induction of cellular senescence commonly coincides with an immunogenic phenotype that promotes self-elimination by components of the immune system, thereby facilitating tumor suppression and limiting excess fibrosis during wound repair. The mechanisms by which senescent cells regulate their immune surveillance are not completely understood. Here we show that ligands of an activating Natural Killer (NK) cell receptor (NKG2D), MICA and ULBP2 are consistently up-regulated following induction of replicative senescence, oncogene-induced senescence and DNA damage - induced senescence. MICA and ULBP2 proteins are necessary for efficient NK-mediated cytotoxicity towards senescent fibroblasts. The mechanisms regulating the initial expression of NKG2D ligands in senescent cells are dependent on a DNA damage response, whilst continuous expression of these ligands is regulated by the ERK signaling pathway. In liver fibrosis, the accumulation of senescent activated stellate cells is increased in mice lacking NKG2D receptor leading to increased fibrosis. Overall, our results provide new insights into the mechanisms regulating the expression of immune ligands in senescent cells and reveal the importance of NKG2D receptor-ligand interaction in protecting against liver fibrosis.


Transition metal(II) complexes of a novel symmetrical benzothiazole-based ligand: synthesis, spectral/structural characterization and fluorescence properties.
2,6-bis (benzothiazol-2-yl)-4-(tert-butyl) phenol ligand (HL) derived from o-aminothiophenol and 4-tert-butyl-2,6-diformylphenol was synthesized and characterized by using elemental analysis, FTIR, X-ray crystallographic analysis, (1)H and (13)C-NMR and UV-vis spectra. Its complexes with Cu (II), Ni (II) and Co (II) were prepared and isolated as solid products and characterized by elemental analysis, spectral techniques as well as magnetic susceptibility. The FTIR spectra showed that the benzothiazole-based ligand under investigation behaves as a bidentate ligand. The UV-vis spectra and magnetic moment data suggested an octahedral geometry around Ni (II) and Co (II) complexes, and tetragonal geometry for Cu (II) complex. Moreover, the evaluation of absorption and emission properties of the ligand and its complexes were carried out in different solvents. The ligand and its complexes showed absorption maxima in the range of 275 - 432 nm, and emission maxima from 367 to 581 nm in toluene, tetrahydrofuran and ethyl acetate.


Changes in in vitro gas and methane production from rumen fluid from dairy cows during adaptation to feed additives in vivo.
The adaptation of dairy cows to methane (CH4)-mitigating feed additives was evaluated using the in vitro gas production (GP) technique. Nine rumen-fistulated lactating Holstein cows were grouped into three blocks and within blocks randomly assigned to one of three experimental diets: Control (CON; no feed additive), Agolin Ruminant® (AR; 0.05 g/kg dry matter (DM)) or lauric acid (LA; 30 g/kg DM). Total mixed rations composed of maize silage, grass silage and concentrate were fed in a 40 : 30 : 30 ratio on DM basis. Rumen fluid was collected from each cow at days -4, 1, 4, 8, 15 and 22 relative to the introduction of the additives in the diets. On each of these days, a 48-h GP experiment was performed in which rumen fluid from each individual donor cow was incubated with each of the three substrates that reflected the treatment diets offered to the cows. DM intake was on average 19.8, 20.1 and 16.2 kg/day with an average fat- and protein-corrected milk production of 30.7, 31.7 and 26.2 kg/day with diet CON, AR and LA, respectively. In general, feed additives in the donor cow diet had a larger effect on gas and CH4 production than the same additives in the incubation substrate. Incubation substrate affected asymptotic GP, half-time of asymptotic CH4 production, total volatile fatty acid (VFA) concentration, molar proportions of propionate and butyrate and degradation of organic matter (OMD), but did not affect CH4 production. No substrate×day interactions were observed. A significant diet×day interaction was observed for in vitro gas and CH4 production, total VFA concentration, molar proportions of VFA and OMD. From day 4 onwards, the LA diet persistently reduced gas and CH4 production, total VFA concentration, acetate molar proportion and OMD, and increased propionate molar proportion. In vitro CH4 production was reduced by the AR diet on day 8, but not on days 15 and 22. In line with these findings, the molar proportion of propionate in fermentation fluid was greater, and that of acetate smaller, for the AR diet than for the CON diet on day 8, but not on days 15 and 22. Overall, the data indicate a short-term effect of AR on CH4 production, whereas the CH4-mitigating effect of LA persisted.


Specific functions for Mediator complex subunits from different modules in the transcriptional response of Arabidopsis thaliana to abiotic stress.
Adverse environmental conditions are detrimental to plant growth and development. Acclimation to abiotic stress conditions involves activation of signaling pathways which often results in changes in gene expression via networks of transcription factors (TFs). Mediator is a highly conserved co-regulator complex and an essential component of the transcriptional machinery in eukaryotes. Some Mediator subunits have been implicated in stress-responsive signaling pathways; however, much remains unknown regarding the role of plant Mediator in abiotic stress responses. Here, we use RNA-seq to analyze the transcriptional response of Arabidopsis thaliana to heat, cold and salt stress conditions. We identify a set of common abiotic stress regulons and describe the sequential and combinatorial nature of TFs involved in their transcriptional regulation. Furthermore, we identify stress-specific roles for the Mediator subunits MED9, MED16, MED18 and CDK8, and putative TFs connecting them to different stress signaling pathways. Our data also indicate different modes of action for subunits or modules of Mediator at the same gene loci, including a co-repressor function for MED16 prior to stress. These results illuminate a poorly understood but important player in the transcriptional response of plants to abiotic stress and identify target genes and mechanisms as a prelude to further biochemical characterization.


Rank-One Matrix Completion With Automatic Rank Estimation via L1-Norm Regularization.
Completing a matrix from a small subset of its entries, i.e., matrix completion is a challenging problem arising from many real-world applications, such as machine learning and computer vision. One popular approach to solve the matrix completion problem is based on low-rank decomposition/factorization. Low-rank matrix decomposition-based methods often require a prespecified rank, which is difficult to determine in practice. In this paper, we propose a novel low-rank decomposition-based matrix completion method with automatic rank estimation. Our method is based on rank-one approximation, where a matrix is represented as a weighted summation of a set of rank-one matrices. To automatically determine the rank of an incomplete matrix, we impose L1-norm regularization on the weight vector and simultaneously minimize the reconstruction error. After obtaining the rank, we further remove the L1-norm regularizer and refine recovery results. With a correctly estimated rank, we can obtain the optimal solution under certain conditions. Experimental results on both synthetic and real-world data demonstrate that the proposed method not only has good performance in rank estimation, but also achieves better recovery accuracy than competing methods.


Educational paper: neonatal skin lesions.
Although most skin lesions in neonates are transient or benign, they may also be the presenting symptom of a life-threatening disease such as herpes neonatorum. In the present review, we present a short overview of neonatal skin lesions and a practical table to guide the general paediatrician in the diagnosis and management of neonatal skin lesions. Recent reviews are cited for further reading.


Development of an intergeneric hybrid between Oryza sativa L. and Leersia perrieri (A. Camus) Launert.
An intergeneric hybrid was successfully developed between Oryza sativa L. (IRRI 154) and Leersia perrieri (A. Camus) Launert using embryo rescue technique in this study. A low crossability value (0.07%) implied that there was high incompatibility between the two species of the hybrid. The F1 hybrid showed intermediate phenotypic characteristics between the parents but the plant height was very short. The erect plant type resembled the female parent IRRI 154 but the leaves were similar to L. perrieri. Cytological analysis revealed highly non-homology between chromosomes of the two species as the F1 plants showed 24 univalents without any chromosome pairing. The F1 hybrid plant was further confirmed by PCR analysis using the newly designed 11 indel markers showing polymorphism between O. sativa and L. perrieri. This intergeneric hybrid will open up opportunities to transfer novel valuable traits from L. perrieri into cultivated rice.


Production of gluconic acid using Micrococcus sp.: optimisation of carbon and nitrogen sources.
A process for production of gluconic acid from glucose by a Micrococcus sp. is described. More than 400 bacterial cultures isolated from local soil were tested for gluconic acid production. Three isolates, were selected on basis of their ability to produce gluconic acid and high titrable acidity. These were identified as Micrococcus sp. and were named M 27, M 54 and M 81. Nutritional and other parameters for maximum production of gluconic acid by the selected isolates were optimised. It was found that Micrococcus sp. isolate M 27 gave highest yield of 8.19 g gluconic acid from 9 g glucose utilised giving 91% conversion effeciency.


Cathinone stability in authentic urine specimens.
Synthetic cathinones are encountered in a variety of antemortem and postmortem forensic toxicology investigations. Earlier experimental studies using fortified urine have evaluated analyte, temperature and pH-dependent variables associated with their stability. The purpose of this study was to compare experimental findings with those obtained using authentic urine from cathinone users. In this report we compare cathinone concentrations in 180 authentic unpreserved urine specimens, following known periods of refrigerated storage. These findings are compared with previously published experimental data using fortified drug-free urine. Liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q/TOF-MS) was used to target 22 cathinones. Quantitative results were compared in urine specimens (pH 4.5-10) following 5-17 months of storage. The 180 specimens resulted in 164 quantitative findings involving α-PVP, ethylone, methylone, MDPV and pentylone. Initial drug concentrations ranged from 25ng/mL to over 100,000ng/mL. Upon reanalysis, the percentage of drug remaining (0-119%) was correlated with storage time and specimen pH. The ability to reconfirm original results was not correlated with storage time. Instead, specimen pH was far more predictive. The relationship between initial and final drug concentration was highly pH-dependent, yielding significant correlations for α-PVP, ethylone and methylone, particularly under acidic conditions. These results are in good agreement with experimental findings and highlight the critical importance of specimen pH, rather than conventional time dependent variables, when considering cathinone stability in biological samples. The potential for pre-analytical changes in cathinone concentrations must be carefully considered when interpreting their results.


Effect of a high dose of glucosamine on systemic and tissue inflammation in an experimental model of atherosclerosis aggravated by chronic arthritis.
Glucosamine sulfate (GS) is a glycosaminoglycan with anti-inflammatory and immunoregulatory properties. Here we set out to explore the effect of GS administration on markers of systemic and local inflammation in rabbits with atherosclerosis aggravated by chronic arthritis. Atherosclerosis was induced in rabbits by maintaining them on a hyperlipidemic diet after producing an endothelial lesion in the femoral arteries. Simultaneously, chronic arthritis was induced in these animals by repeated intra-articular injections of ovalbumin in previously immunized rabbits. A group of these rabbits was treated prophylactically with oral GS (500 mg.kg(-1).day(-1)), and, when the animals were killed, serum was extracted and peripheral blood mononuclear cells (PBMC) were isolated. Furthermore, the femoral arteries, thoracic aorta, and synovial membranes were examined in gene expression studies and histologically. GS administration reduced circulating levels of the C-reactive protein and of interleukin-6. GS also lowered nuclear factor-kappaB activation in PBMC, and it downregulated the expression of both the CCL2 (monocyte chemoattractant protein) and cyclooxygenase-2 genes in these cells. Lesions at the femoral wall were milder after GS treatment, as reflected by the intimal-to-media thickened ratio and the absence of aortic lesions. Indeed, GS also attenuated the histological lesions in synovial tissue. In a combined rabbit model of chronic arthritis and atherosclerosis, orally administered GS reduced the markers of inflammation in peripheral blood, as well as the femoral and synovial membrane lesions. GS also prevented the development of inflammation-associated aortic lesions. These results suggest an atheroprotective effect of GS.


CGGBP1 phosphorylation constitutes a telomere-protection signal.
The shelterin proteins are required for telomere integrity. Shelterin dysfunction can lead to initiation of unwarranted DNA damage and repair pathways at chromosomal termini. Interestingly, many shelterin accessory proteins are involved in DNA damage signaling and repair. We demonstrate here that in normal human fibroblasts, telomeric ends are protected by phosphorylation of CGG triplet repeat-binding protein 1 (CGGBP1) at serine 164 (S164). We show that serine 164 is a major phosphorylation site on CGGBP1 with important functions. We provide evidence that one of the kinases that can phosphorylate S164 CGGBP1 is ATR. Overexpression of S164A phospho-deficient CGGBP1 exerted a dominant-negative effect, causing telomeric dysfunction, accelerated telomere shortening, enhanced fusion of telomeres, and crisis. However, overexpression of wild-type or phospho-mimicking S164E CGGBP1 did not cause these effects. This telomere damage was associated with reduced binding of the shelterin protein POT1 to telomeric DNA. Our results suggest that CGGBP1 phosphorylation at S164 is a novel telomere protection signal, which can affect telomere-protective function of the shelterin complex.


Risk factors leading to trabeculectomy surgery of glaucoma patient using Japanese nationwide administrative claims data: a retrospective non-interventional cohort study.
Early recognition and management of baseline risk factors may play an important role in reducing glaucoma surgery burdens. However, no studies have investigated them using real-world data in Japan or other countries. This study aimed to clarify the risk factors leading to trabeculectomy surgery, which is the most common procedure of glaucoma surgery, of glaucoma patient using the Japanese nationwide administrative claims data associated with the diagnosis procedure combination (DPC) system. It was a retrospective, non-interventional cohort study. Data were collected from patients who were admitted to DPC participating hospitals, nationwide acute care hospitals and were diagnosed with glaucoma between 2012 to 2018. The primary outcome was the risk factors associated with trabeculectomy surgery. The association between baseline characteristics and trabeculectomy surgery was identified using multivariable logistic regression analysis by comparing patients with and without trabeculectomy surgery. Meanwhile, the secondary outcomes included the rate of comorbidities, the rate of concomitant drug use and the treatment patterns of glaucoma eye drops at the index admission. Among patients with trabeculectomy surgery, the risk factors leading to cataract surgery were also evaluated as subgroup analysis. A total of 29,599 patients included in the analysis, 12,038 and 17,561 patients were in the glaucoma surgery and non-glaucoma surgery cohorts, respectively. The factors associated with the increase in trabeculectomy surgery were having allergies, taking concomitant drugs including cancer, depression, ischemic heart disease and peptic ulcer, being diagnosed with primary open-angle glaucoma and longer length of stay in hospital. In contrast, the factors associated with the decrease in trabeculectomy surgery were having hypertension, taking hypertension drug, age ≥ 80 and female. Special focus on Japanese patients with glaucoma who have allergy-related comorbidities or take immune, nervous, circulatory or gastrointestinal system-related concomitant drugs seems to be desirable.


Tapping into Plant-Microbiome Interactions through the Lens of Multi-Omics Techniques.
This review highlights the pivotal role of root exudates in the rhizosphere, especially the interactions between plants and microbes and between plants and plants. Root exudates determine soil nutrient mobilization, plant nutritional status, and the communication of plant roots with microbes. Root exudates contain diverse specialized signaling metabolites (primary and secondary). The spatial behavior of these metabolites around the root zone strongly influences rhizosphere microorganisms through an intimate compatible interaction, thereby regulating complex biological and ecological mechanisms. In this context, we reviewed the current understanding of the biological phenomenon of allelopathy, which is mediated by phytotoxic compounds (called allelochemicals) released by plants into the soil that affect the growth, survival, development, ecological infestation, and intensification of other plant species and microbes in natural communities or agricultural systems. Advances in next-generation sequencing (NGS), such as metagenomics and metatranscriptomics, have opened the possibility of better understanding the effects of secreted metabolites on the composition and activity of root-associated microbial communities. Nevertheless, understanding the role of secretory metabolites in microbiome manipulation can assist in designing next-generation microbial inoculants for targeted disease mitigation and improved plant growth using the synthetic microbial communities (SynComs) tool. Besides a discussion on different approaches, we highlighted the advantages of conjugation of metabolomic approaches with genetic design (metabolite-based genome-wide association studies) in dissecting metabolome diversity and understanding the genetic components of metabolite accumulation. Recent advances in the field of metabolomics have expedited comprehensive and rapid profiling and discovery of novel bioactive compounds in root exudates. In this context, we discussed the expanding array of metabolomics platforms for metabolome profiling and their integration with multivariate data analysis, which is crucial to explore the biosynthesis pathway, as well as the regulation of associated pathways at the gene, transcript, and protein levels, and finally their role in determining and shaping the rhizomicrobiome.


Linear viscoelastic properties of the vertex model for epithelial tissues.
Epithelial tissues act as barriers and, therefore, must repair themselves, respond to environmental changes and grow without compromising their integrity. Consequently, they exhibit complex viscoelastic rheological behavior where constituent cells actively tune their mechanical properties to change the overall response of the tissue, e.g., from solid-like to fluid-like. Mesoscopic mechanical properties of epithelia are commonly modeled with the vertex model. While previous studies have predominantly focused on the rheological properties of the vertex model at long time scales, we systematically studied the full dynamic range by applying small oscillatory shear and bulk deformations in both solid-like and fluid-like phases for regular hexagonal and disordered cell configurations. We found that the shear and bulk responses in the fluid and solid phases can be described by standard spring-dashpot viscoelastic models. Furthermore, the solid-fluid transition can be tuned by applying pre-deformation to the system. Our study provides insights into the mechanisms by which epithelia can regulate their rich rheological behavior.


Genotype/age interactions on aggressive behavior in gonadally intact estrogen receptor beta knockout (betaERKO) male mice.
Estrogen, as an aromatized metabolite of testosterone, has a facilitatory effect on male aggressive behavior in mice. Two subtypes of estrogen receptors, alpha (ER-alpha) and beta (ER-beta), in the brain are known to bind estrogen. Previous studies revealed that the lack of ER-alpha gene severely reduced the induction of male aggressive behavior. In contrast, mice that lacked the ER-beta gene tended to be more aggressive than wild type (WT) control mice, although the behavioral effects of ER-beta gene disruption were dependent on their social experience. These findings lead us to hypothesize that estrogen may facilitate aggression via ER-alpha whereas it may inhibit aggression via ER-beta. In the present study, we further investigated the role of ER-beta in the regulation of aggressive behavior by examining developmental changes starting at the time of first onset, around the age of puberty. Aggressive behaviors of ER-beta gene knockout (betaERKO) mice were examined in three different age groups, puberty, young-adult, and adult. Each mouse was tested every other day for three times in a resident-intruder paradigm against olfactory bulbectomized intruder mice and their trunk blood was collected for measurements of serum testosterone after the completion of the study. Overall, betaERKO mice were significantly more aggressive than WT. These genotype differences were more pronounced in puberty and young adult age groups, but not apparent in the adult age group, in which betaERKO mice were less aggressive than those in two younger age groups. Serum testosterone levels of betaERKO mice were significantly higher than those of WT mice only in the pubertal age group, but not in young adult (when betaERKO mice were still significantly more aggressive than WT mice) and adult (when no genotype differences in aggression were found) age groups. These results suggest that ER-beta mediated actions of gonadal steroids may more profoundly be involved in the inhibitory regulation of aggressive behavior in pubertal and young adult mice.


Serum and Urine Leptin Concentrations in Children Before and After Treatment of Urinary Tract Infection.
Urinary tract infection (UTI) among children is sometimes associated with anorexia and sometimes failure to thrive. Appetite-regulating hormones may be a causative factor. Leptin regulates appetite, food intake, and body weight via hypothalamic melanocortin-4 receptor. Leptin is also a potential cytokine for inflammation. The aim of this study was to evaluate serum and urine leptin before and after treatment of children with UTI. In this before-after study, serum and urine leptin were measured in 40 patients with UTI at admission and 5 days after treatment. Pyelonephritis was suggested by signs and symptoms and confirmed with positive urine culture and dimercaptosuccinic acid renal scintigraphy. Other measurements included urinalysis, urine culture, urine creatinine level, complete blood count, erythrocyte sedimentation rate, C-reactive protein level and serum levels of urea, creatinine, glucose, cholesterol, and triglyceride. The mean serum leptin level was 6.85 ± 18.90 ng/mL before the treatment and 8.29 ± 18.30 ng/mL after the treatment, the difference of which was not significant (P = .64). There were significant correlations between serum leptin and age, weight, and C-reactive protein. Urine leptin levels were reduced significantly from 0.75 ± 0.82 ng/mL to 0.46 ± 0.27 ng/mL after the treatment (P = .03). A significant correlation was observed between urine leptin level with age and weight. Serum leptin level did not change significantly after treatment of UTI, but urine leptin significantly decreased. Serum leptin level was higher in patients with anorexia in comparison with children with normal appetite; however, the difference was not significant.


Inactivation of SSM4, a new Saccharomyces cerevisiae gene, suppresses mRNA instability due to rna14 mutations.
Decay rates of mRNAs depend on many elements and among these, the role of the poly(A) tail is now well established. In the yeast Saccharomyces cerevisiae, thermosensitive mutations in two genes, RNA14 and RNA15, result in mRNAs having shorter poly(A) tails and reduced half-life. To identify other components interacting in the same process, we have used a genetic approach to isolate mutations that suppress the thermosensitivity of an rna14 mutant strain. Mutations in a single locus, named SSM4, not only suppress the cell growth phenotype but also the mRNA instability and extend the short mRNA poly(A) tails. The frequency of appearance and the recessive nature of these mutations suggested that the suppressor effect was probably due to a loss of function. We failed to clone the SSM4 gene directly by complementation, owing to its absence from gene banks; it later emerged that the gene is toxic to Escherichia coli, but we have nevertheless been able to clone the SSM4 sequence by Ty element transposition tagging. Disruption of the SSM4 gene does not affect cell viability and suppresses the rna14 mutant phenotypes. The protein encoded by the SSM4 gene has a calculated molecular mass of 151 kDa and does not contain any known motif or show homology with known proteins. The toxicity of the SSM4 gene in E. coli suggests that a direct biochemical activity is associated with the corresponding protein.


Incidence of cardiac arrests and unexpected deaths in surgical patients before and after implementation of a rapid response system.
Rapid response systems (RRSs) are considered an important tool for improving patient safety. We studied the effect of an RRS on the incidence of cardiac arrests and unexpected deaths. Retrospective before- after study in a university medical centre. We included 1376 surgical patients before (period 1) and 2410 patients after introduction of the RRS (period 2). Outcome measures were corrected for the baseline covariates age, gender and ASA. The number of patients who experienced a cardiac arrest and/or who died unexpectedly decreased non significantly from 0.50% (7/1376) in period 1 to 0.25% (6/2410) in period 2 (odds ratio (OR) 0.43, CI 0.14-1.30). The individual number of cardiac arrests decreased non-significantly from 0.29% (4/1367) to 0.12% (3/2410) (OR 0.38, CI 0.09-1.73) and the number of unexpected deaths decreased non-significantly from 0.36% (5/1376) to 0.17% (4/2410) (OR 0.42, CI 0.11-1.59). In contrast, the number of unplanned ICU admissions increased from 2.47% (34/1376) in period 1 to 4.15% (100/2400) in period 2 (OR 1.66, CI 1.07-2.55). Median APACHE ll score at unplanned ICU admissions was 16 in period 1 versus 16 in period 2 (NS). Adherence to RRS procedures. Observed abnormal early warning scores ≤72 h preceding a cardiac arrest, unexpected death or an unplanned ICU admission increased from 65% (24/37 events) in period 1 to 91% (91/101 events) in period 2 (p < 0.001). Related ward physician interventions increased from 38% (9/24 events) to 89% (81/91 events) (p < 0.001). In period 2, ward physicians activated the medical emergency team in 65% of the events (59/91), although in 16% (15/91 events) activation was delayed for one or two days. The overall medical emergency team dose was 56/1000 admissions. Introduction of an RRS resulted in a 50% reduction in cardiac arrest rates and/or unexpected death. However, this decrease was not statistically significant partly due to the low base-line incidence. Moreover, delayed activation due to the two-tiered medical emergency team activation procedure and suboptimal adherence of the ward staff to the RRS procedures may have further abated the positive results.


The effect of genetic and environmental variation on metabolic gene expression.
What is the relationship between genetic or environmental variation and the variation in messenger RNA (mRNA) expression? To address this, microarrays were used to examine the effect of genetic and environmental variation on cardiac mRNA expression for metabolic genes in three groups of Fundulus heteroclitus: (i) individuals sampled in the field (field), (ii) field individuals acclimated for 6 months to laboratory conditions (acclimated), or (iii) individuals bred for 10 successive generations in a laboratory environment (G10). The G10 individuals have significantly less genetic variation than individuals obtained in the field and had a significantly lower variation in mRNA expression across all genes in comparison to the other two groups (P = 0.001). When examining the gene specific variation, 22 genes had variation in expression that was significantly different among groups with lower variation in G10 individuals than in acclimated individuals. Additionally, there were fewer genes with significant differences in expression among G10 individuals vs. either acclimated or field individuals: 66 genes have statistically different levels of expression vs. 107 or 97 for acclimated or field groups. Based on the permutation of the data, these differences in the number of genes with significant differences among individuals within a group are unlikely to occur by chance (P < 0.01). Surprisingly, variation in mRNA expression in field individuals is lower than in acclimated individuals. Relative to the variation among individual within a group, few genes have significant differences in expression among groups (seven, 2.3%) and none of these are different between acclimated and field individuals. The results support the concept that genetic variation affects variation in mRNA expression and also suggests that temporal environmental variation associated with estuarine environments does not increase the variation among individuals or add to the differences among groups.


Increased serum levels of lipopolysaccharide and antiflagellin antibodies in patients with diarrhea-predominant irritable bowel syndrome.
Innate immune responses to conserved microbial products such as lipopolysaccharide (LPS) and flagellin are likely important in microbial-host interactions and intestinal homeostasis. We hypothesized that bacterial translocation and activation of mucosal immunity against common microbial antigens might be involved in the development of irritable bowel syndrome (IBS). We therefore compared serum levels of LPS, soluble CD14 (sCD14), and flagellin antibodies between patients with different subtypes of IBS and healthy controls. We analyzed serum obtained from 88 patients (74 females) aged 19(43)-73 years and 106 healthy volunteers (77 females) aged 19(38)-62 years. Diarrhea-predominant IBS (D-IBS) was present in 32 patients (36%), 23 patients (26%) had constipation-predominant IBS (C-IBS), and 33 patients (38%) had A-IBS. We used ELISA for sCD14 and antiflagellin immunoglobulin G and limulus amebocyte assay for LPS. Abdominal symptoms and psychiatric comorbidities were assessed using validated questionnaires. We found a significantly higher serum level of LPS in patients with D-IBS compared to controls (p = 0.0155). The level of antibodies to flagellin was higher in patients with IBS than in controls (mainly driven by higher levels in D-IBS, p = 0.0018). The levels of sCD14 were lower in D-IBS patients compared to controls (p = 0.0498). We found a weak, but significant correlation between the levels of antiflagellin antibodies and anxiety among IBS patients (ρ = 0.38; p = 0.0045). Our results support the concept that immune reactivity to luminal antigens may have a role in the development of D-IBS. The serum level of antiflagellin antibodies was found to correlate with patients' self-reported anxiety score.


Evolutionary origin of the turtle skull.
Transitional fossils informing the origin of turtles are among the most sought-after discoveries in palaeontology. Despite strong genomic evidence indicating that turtles evolved from within the diapsid radiation (which includes all other living reptiles), evidence of the inferred transformation between an ancestral turtle with an open, diapsid skull to the closed, anapsid condition of modern turtles remains elusive. Here we use high-resolution computed tomography and a novel character/taxon matrix to study the skull of Eunotosaurus africanus, a 260-million-year-old fossil reptile from the Karoo Basin of South Africa, whose distinctive postcranial skeleton shares many unique features with the shelled body plan of turtles. Scepticism regarding the status of Eunotosaurus as the earliest stem turtle arises from the possibility that these shell-related features are the products of evolutionary convergence. Our phylogenetic analyses indicate strong cranial support for Eunotosaurus as a critical transitional form in turtle evolution, thus fortifying a 40-million-year extension to the turtle stem and moving the ecological context of its origin back onto land. Furthermore, we find unexpected evidence that Eunotosaurus is a diapsid reptile in the process of becoming secondarily anapsid. This is important because categorizing the skull based on the number of openings in the complex of dermal bone covering the adductor chamber has long held sway in amniote systematics, and still represents a common organizational scheme for teaching the evolutionary history of the group. These discoveries allow us to articulate a detailed and testable hypothesis of fenestral closure along the turtle stem. Our results suggest that Eunotosaurus represents a crucially important link in a chain that will eventually lead to consilience in reptile systematics, paving the way for synthetic studies of amniote evolution and development.


The use of optically stimulated luminescence from AL2O3:C in the dosimetry of high-energy heavy charged particle fields.
This paper presents two different approaches of quantifying the optically stimulated luminescence (OSL) response of Al(2)O(3):C to high-energy heavy charged particles (HCPs). The OSL efficiency of Al(2)O(3):C exposed to different HCPs is defined as the sensitivity of the material to HCPs normalised by the sensitivity to gamma. In this paper, we investigate the possibility of introducing a 'mean efficiency' eta(mean), which when used in conjunction with the total gamma dose D(gamma) measured for a mixed radiation exposure allows for the determination of the absorbed dose without the need to determine the individual contributions of different types of radiation to the OSL signal. We tested the hypothesis that information regarding the 'mean efficiency' eta(mean) is contained in the shape of the OSL decay curve, using several approaches in the analysis of the OSL data. This analysis was applied to various mixed field irradiations performed at the HIMAC facility, Chiba, Japan. The results of this analysis are discussed.


De novo mutations implicate novel genes in systemic lupus erythematosus.
The omnigenic model of complex disease stipulates that the majority of the heritability will be explained by the effects of common variation on genes in the periphery of core disease pathways. Rare variant associations, expected to explain far less of the heritability, may be enriched in core disease genes and thus will be instrumental in the understanding of complex disease pathogenesis and their potential therapeutic targets. Here, using complementary whole-exome sequencing, high-density imputation, and in vitro cellular assays, we identify candidate core genes in the pathogenesis of systemic lupus erythematosus (SLE). Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE parent-affected-offspring trios and identified 14 genes with missense de novo mutations (DNM), none of which are within the >80 SLE susceptibility loci implicated through genome-wide association studies. In a follow-up cohort of 10, 995 individuals of matched European ancestry, we imputed genotype data to the density of the combined UK10K-1000 genomes Phase III reference panel across the 14 candidate genes. Gene-level analyses indicate three functional candidates: DNMT3A, PRKCD, and C1QTNF4. We identify a burden of rare variants across PRKCD associated with SLE risk (P = 0.0028), and across DNMT3A associated with two severe disease prognosis sub-phenotypes (P = 0.0005 and P = 0.0033). We further characterise the TNF-dependent functions of the third candidate gene C1QTNF4 on NF-κB activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our results identify three novel genes in SLE susceptibility and support extreme-phenotype sampling and DNM gene discovery to aid the search for core disease genes implicated through rare variation.


Construction and application of a promoter-probe plasmid that allows chromogenic identification in Streptomyces lividans.
We cloned a Streptomyces coelicolor A3(2) DNA fragment which directed synthesis of a brown pigment, presumably a shunt product in the actinorhodin biosynthetic pathway, on the plasmid vector pIJ41 in Streptomyces lividans. The pigment production was observed only when the DNA fragment was inserted downstream from a functional promoter sequence. By subcloning the fragment together with in vitro manipulation, a promoter-probe plasmid vector (pARC1) with a unique BamHI cloning site was constructed that allows chromogenic identification of transcriptional control signals in Streptomyces lividans based on the expression of the cloned pigment gene(s). The Escherichia coli tac (trp-lac hybrid) promoter, consisting of 92 base pairs and a promoter region including the leader sequence of erythromycin resistance gene (ermC) on staphylococcal plasmid pE194, when ligated in the correct orientation in the BamHI site of pARC1, promoted expression of the cloned pigment gene(s) in Streptomyces lividans, whereas the Saccharomyces cerevisiae GAL7 promoter did not. In the case of the ermC, induction of the pigment production by the addition of either erythromycin or lincomycin, but not virginiamycin, was observed. The system was also shown to be useful and convenient in isolating transcriptional control signals of Streptomyces chromosomal DNA and estimating their activities.


The utility of placing sphenoidal electrodes under the foramen ovale with fluoroscopic guidance.
Although sphenoidal electrodes are widely used to detect epileptiform activity, there is no agreement on an optimal target to which electrodes should be aimed. The purpose of this study was to determine whether fluoroscopic guidance is a reliable method for placing electrodes directly below the foramen ovale and whether such positioning enhances their capacity to detect epileptiform activity when compared to similar electrodes placed blindly into the infratemporal fossa. We examined the surface/sphenoidal EEG recordings of 17 patients with intractable partial seizures of anterotemporal origin, after fluoroscopically placed sphenoidal electrodes (FPSE) had been inserted to lie just below the foramen ovale. A criterion for eligibility was a previous prolonged video/EEG monitoring with blindly placed sphenoidal electrodes (BPSE) that failed to detect seizures with a focal onset. No blindly placed electrode, for which there was radiographic documentation, reached the foramen ovale. Fluoroscopic guidance assured accurate targeting. FPSE detected a unilateral anterotemporal interictal focus in four patients in whom BPSE had failed to record any interictal spikes and detected bitemporal independent interictal foci in one patient in whom BPSE had identified only unilateral spikes. In nine other patients, the spike count obtained with FPSE recordings increased by > 100% when compared to that obtained with BPSE recordings. FPSE recorded seizures with an anterotemporal focal onset pattern in 10 patients in whom BPSE had recorded seizures with a regional, lateralized, or nonlocalized onset pattern. In nine of these 10 patients, this was adequate to recommend surgery and avoid invasive monitoring. Fluoroscopic guidance assures accurate targeting of the foramen ovale. When compared to BPSE, FPSE resulted in better detection of interictal and ictal epileptiform activity of mesial-basal-temporal origin.


Development and validation a nomogram for predicting the risk of severe COVID-19: A multi-center study in Sichuan, China.
Since December 2019, coronavirus disease 2019 (COVID-19) emerged in Wuhan and spread across the globe. The objective of this study is to build and validate a practical nomogram for estimating the risk of severe COVID-19. A cohort of 366 patients with laboratory-confirmed COVID-19 was used to develop a prediction model using data collected from 47 locations in Sichuan province from January 2020 to February 2020. The primary outcome was the development of severe COVID-19 during hospitalization. The least absolute shrinkage and selection operator (LASSO) regression model was used to reduce data size and select relevant features. Multivariable logistic regression analysis was applied to build a prediction model incorporating the selected features. The performance of the nomogram regarding the C-index, calibration, discrimination, and clinical usefulness was assessed. Internal validation was assessed by bootstrapping. The median age of the cohort was 43 years. Severe patients were older than mild patients by a median of 6 years. Fever, cough, and dyspnea were more common in severe patients. The individualized prediction nomogram included seven predictors: body temperature at admission, cough, dyspnea, hypertension, cardiovascular disease, chronic liver disease, and chronic kidney disease. The model had good discrimination with an area under the curve of 0.862, C-index of 0.863 (95% confidence interval, 0.801-0.925), and good calibration. A high C-index value of 0.839 was reached in the interval validation. Decision curve analysis showed that the prediction nomogram was clinically useful. We established an early warning model incorporating clinical characteristics that could be quickly obtained on admission. This model can be used to help predict severe COVID-19 and identify patients at risk of developing severe disease.


Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells.
We investigated the intracellular uptake of different sized and shaped colloidal gold nanoparticles. We showed that kinetics and saturation concentrations are highly dependent upon the physical dimensions of the nanoparticles (e.g., uptake half-life of 14, 50, and 74 nm nanoparticles is 2.10, 1.90, and 2.24 h, respectively). The findings from this study will have implications in the chemical design of nanostructures for biomedical applications (e.g., tuning intracellular delivery rates and amounts by nanoscale dimensions and engineering complex, multifunctional nanostructures for imaging and therapeutics).


Toward Improved Understanding of the Interactions between Poorly Soluble Drugs and Cellulose Nanofibers.
Cellulose nanofibers (CNFs) have interesting physicochemical and colloidal properties that have been recently exploited in novel drug-delivery systems for tailored release of poorly soluble drugs. The morphology and release kinetics of such drug-delivery systems heavily relied on the drug-CNF interactions; however, in-depth understanding of the interactions was lacking. Herein, the interactions between a poorly soluble model drug molecule, furosemide, and cationic cellulose nanofibers with two different degrees of substitution are studied by sorption experiments, Fourier transform infrared spectroscopy, and molecular dynamics (MD) simulation. Both MD simulations and experimental results confirmed the spontaneous sorption of drug onto CNF. Simulations further showed that adsorption occurred by the flat aryl ring of furosemide. The spontaneous sorption was commensurate with large entropy gains as a result of release of surface-bound water. Association between furosemide molecules furthermore enabled surface precipitation as indicated by both simulations and experiments. Finally, sorption was also found not to be driven by charge neutralization, between positive CNF surface charges and the furosemide negative charge, so that surface area is the single most important parameter determining the amount of sorbed drug. An optimized CNF-furosemide drug-delivery vehicle thus needs to have a maximized specific surface area irrespective of the surface charge with which it is achieved. The findings also provide important insights into the design principles of CNF-based filters suitable for removal of poorly soluble drugs from wastewater.