Simulation modeling of the impact of proposed new simultaneous liver and kidney transplantation policies.
Increasing use of kidney grafts for simultaneous liver and kidney (SLK) transplants is causing concern about the most effective utilization of scarce kidney graft resources. This study evaluated the impact of implementing the proposed United Network for Organ Sharing SLK transplant policy on outcomes for end-stage liver disease (ESLD) and end-stage renal disease (ESRD) patients awaiting transplant. A Markov model was constructed to simulate a hypothetical cohort of ESLD patients over a 30-year time horizon starting from age 50. The model applies the different criteria being considered in the United Network for Organ Sharing policy and tallies outcomes, including numbers of procedures and life years after liver transplant alone (LTA) or SLK transplant. When 1-week pretransplant dialysis duration is required, the numbers of SLK transplants and LTAs would be 648 and 9,065, respectively. If the pretransplant dialysis duration is extended to 12 weeks, there would be 240 SLK transplants and 9,426 LTAs. This change results in a decrease of 6,483 life years among SLK transplant recipients and an increase of 4,971 life years among LTA recipients. However, by increasing the dialysis duration to 12 weeks from 1 week, 408 kidney grafts would be released to the kidney waitlist because of the decline in SLK transplants; this yields 796 additional life years gained among ESRD patients. Implementation of the proposed SLK transplant policy could restore access to kidney transplants for patients with ESRD albeit at the detriment of patients with ESLD and renal impairment.


Effective temperature and jamming transition in dense, gently sheared granular assemblies.
We present extensive computational results for the effective temperature, defined by the fluctuation-dissipation relation between the mean square displacement and the average displacement of grains, under the action of a weak, external perturbation, of a sheared, bi-disperse granular packing of compressible spheres. We study the dependence of this parameter on the shear rate and volume fractions, the type of particle and the observable in the fluctuation-dissipation relation. We find the same temperature for different tracer particles in the system. The temperature becomes independent on the shear rate for slow enough shear suggesting that it is the effective temperature of the jammed packing. However, we also show that the agreement of the effective temperature for different observables is only approximate, for very long times, suggesting that this definition may not capture the full thermodynamics of the system. On the other hand, we find good agreement between the dynamical effective temperature and a compactivity calculated assuming that all jammed states are equiprobable. Therefore, this definition of temperature may capture an instance of the ergodic hypothesis for granular materials as proposed by theoretical formalisms for jamming. Finally, our simulations indicate that the average shear stress and apparent shear viscosity follow the usual relation with the shear rate for complex fluids. Our results show that the application of shear induces jamming in packings whose particles interact by tangential forces.


A Revised Computational Neuroanatomy for Motor Control.
We discuss a new framework for understanding the structure of motor control. Our approach integrates existing models of motor control with the reality of hierarchical cortical processing and the parallel segregated loops that characterize cortical-subcortical connections. We also incorporate the recent claim that cortex functions via predictive representation and optimal information utilization. Our framework assumes that each cortical area engaged in motor control generates a predictive model of a different aspect of motor behavior. In maintaining these predictive models, each area interacts with a different part of the cerebellum and BG. These subcortical areas are thus engaged in domain-appropriate system identification and optimization. This refocuses the question of division of function among different cortical areas. What are the different aspects of motor behavior that are predictively modeled? We suggest that one fundamental division is between modeling of task and body whereas another is the model of state and action. Thus, we propose that the posterior parietal cortex, somatosensory cortex, premotor cortex, and motor cortex represent task state, body state, task action, and body action, respectively. In the second part of this review, we demonstrate how this division of labor can better account for many recent findings of movement encoding, especially in the premotor and posterior parietal cortices.


The health perspectives of Australian adolescents from same-sex parent families: a mixed methods study.
Research involving adolescents from same-sex parent families provides an important contribution to the evidence base on their health, well-being and the impact of stigma. To date reports on the perspectives of adolescents with same-sex attracted parents have been limited. This study aimed to describe the multidimensional experiences of physical, mental and social well-being of adolescents living in this context. A mixed methods study of adolescents with same-sex attracted parents comprising of an adolescent-report survey of 10- to 17-year-olds and family interviews with adolescents and their parents. Data were collected in 2012 and 2013 as part of the Australian Study of Child Health in Same-Sex Families. The findings from qualitative interviews with seven adolescents and responses to an open-ended survey question (n = 16) suggest four themes: perceptions of normality, positive concepts of health, spheres of life (including family, friends and community) and avoiding negativity. The quantitative sample of adolescents with same-sex attracted parents (n = 35) reported higher scores than population normative data on the dimensions general health and family activities within the Child Health Questionnaire (CHQ) as well as higher on the peer problems scale on the Strengths and Difficulties Questionnaire (SDQ). Perceived stigma correlates with lower health and well-being overall. Positive health outcomes are informed by the ways adolescents conceptualize health and how they construct their spheres of life. Peer relationships, and community perspectives of same-sex families, inform perceived stigma and its correlation with poorer health and well-being. Although adolescents see their families as essentially normal they are negatively affected by external societal stigma.


Upregulated insulin secretion in insulin-resistant mice: evidence of increased islet GLP1 receptor levels and GPR119-activated GLP1 secretion.
We previously demonstrated that the overall incretin effect and the β-cell responsiveness to glucagon-like peptide-1 (GLP1) are increased in insulin-resistant mice and may contribute to the upregulated β-cell function. Now we examined whether this could, first, be explained by increased islet GLP1 receptor (GLP1R) protein levels and, secondly, be leveraged by G-protein-coupled receptor 119 (GPR119) activation, which stimulates GLP1 secretion. Female C57BL/6J mice, fed a control (CD, 10% fat) or high-fat (HFD, 60% fat) diet for 8 weeks, were anesthetized and orally given a GPR119 receptor agonist (GSK706A; 10 mg/kg) or vehicle, followed after 10 min with gavage with a liquid mixed meal (0.285 kcal). Blood was sampled for determination of glucose, insulin, intact GLP1, and glucagon, and islets were isolated for studies on insulin and glucagon secretion and GLP1R protein levels. In HFD vs CD mice, GPR119 activation augmented the meal-induced increase in the release of both GLP1 (AUCGLP1 81±9.6 vs 37±6.9 pM×min, P=0.002) and insulin (AUCINS 253±29 vs 112±19 nM×min, P<0.001). GPR119 activation also significantly increased glucagon levels in both groups (P<0.01) with, however, no difference between the groups. By contrast, GPR119 activation did not affect islet hormone secretion from isolated islets. Glucose elimination after meal ingestion was significantly increased by GPR119 activation in HFD mice (0.57±0.04 vs 0.43±0.03% per min, P=0.014) but not in control mice. Islet GLP1R protein levels was higher in HFD vs CD mice (0.8±0.1 vs 0.5±0.1, P=0.035). In conclusion, insulin-resistant mice display increased islet GLP1R protein levels and augmented meal-induced GLP1 and insulin responses to GPR119 activation, which results in increased glucose elimination. We suggest that the increased islet GLP1R protein levels together with the increased GLP1 release may contribute to the upregulated β-cell function in insulin resistance.


Differential dimerization of variants linked to enhanced S-cone sensitivity syndrome (ESCS) located in the NR2E3 ligand-binding domain.
NR2E3 encodes the photoreceptor-specific nuclear hormone receptor that acts as a repressor of cone-specific gene expression in rod photoreceptors, and as an activator of several rod-specific genes. Recessive variants located in the ligand-binding domain (LBD) of NR2E3 cause enhanced short wavelength sensitive- (S-) cone syndrome (ESCS), a retinal degeneration characterized by an excess of S-cones and non-functional rods. We analyzed the dimerization properties of NR2E3 and the effect of disease-causing LBD missense variants by bioluminescence resonance energy transfer (BRET(2) ) protein interaction assays. Homodimerization was not affected in presence of p.A256V, p.R039G, p.R311Q, and p.R334G variants, but abolished in presence of p.L263P, p.L336P, p.L353V, p.R385P, and p.M407K variants. Homology modeling predicted structural changes induced by NR2E3 LBD variants. NR2E3 LBD variants did not affect interaction with CRX, but with NRL and rev-erbα/NR1D1. CRX and NRL heterodimerized more efficiently together, than did either with NR2E3. NR2E3 did not heterodimerize with TLX/NR2E1 and RXRα/NR2C1. The identification of a new compound heterozygous patient with detectable rod function, who expressed solely the p.A256V variant protein, suggests a correlation between LBD variants able to form functional NR2E3 dimers and atypical mild forms of ESCS with residual rod function.


A silica-based magnetic platform decorated with mixed ligand gold nanoparticles: a recyclable catalyst for esterification reactions.
A novel and convenient synthetic strategy for the preparation of magnetically responsive silica nanospheres decorated with mixed ligand protected gold nanoparticles is described. Gold nanoparticles are attached to the silica surface via stable amide bond formation. The hierarchical nanospheres show promising results as reusable and efficient catalysts for esterification reactions and they can be recovered through a simple magnetic separation.


Predicting frequent COPD exacerbations using primary care data.
Acute COPD exacerbations account for much of the rising disability and costs associated with COPD, but data on predictive risk factors are limited. The goal of the current study was to develop a robust, clinically based model to predict frequent exacerbation risk. Patients identified from the Optimum Patient Care Research Database (OPCRD) with a diagnostic code for COPD and a forced expiratory volume in 1 second/forced vital capacity ratio <0.7 were included in this historical follow-up study if they were ≥40 years old and had data encompassing the year before (predictor year) and year after (outcome year) study index date. The data set contained potential risk factors including demographic, clinical, and comorbid variables. Following univariable analysis, predictors of two or more exacerbations were fed into a stepwise multivariable logistic regression. Sensitivity analyses were conducted for subpopulations of patients without any asthma diagnosis ever and those with questionnaire data on symptoms and smoking pack-years. The full predictive model was validated against 1 year of prospective OPCRD data. The full data set contained 16,565 patients (53% male, median age 70 years), including 9,393 patients without any recorded asthma and 3,713 patients with questionnaire data. The full model retained eleven variables that significantly predicted two or more exacerbations, of which the number of exacerbations in the preceding year had the strongest association; others included height, age, forced expiratory volume in 1 second, and several comorbid conditions. Significant predictors not previously identified included eosinophilia and COPD Assessment Test score. The predictive ability of the full model (C statistic 0.751) changed little when applied to the validation data set (n=2,713; C statistic 0.735). Results of the sensitivity analyses supported the main findings. Patients at risk of exacerbation can be identified from routinely available, computerized primary care data. Further study is needed to validate the model in other patient populations.


A longitudinal study of the efficacy of interferon therapy in children with chronic hepatitis B.
Interferon alpha (IFN) is the most effective drug in the treatment of chronic hepatitis B. This article presents the results of IFN therapy and 28-month follow-up. 193 Caucasian children (130 boys and 63 girls) aged 1.5-17 years were treated with IFN for 20 weeks (3.0 MIU 3 times a week). They were examined at baseline (period 0), after 6 weeks (period 1), 12 weeks (period 2), 20 weeks (period 3), 6 months (period 4), 12 months (period 5), 18 months (period 6), and 24 months (period 7). HBcAg elimination drom period 3 was: 29.6%, 35.2%, 45.4%, 58.3%, in period 7 63.9% (significantly higher in girls). Significant positive correlations were found in several periods between IFN/m2 and HBeAg, HBsAg elimination, HBeAb, HBsAb presence and negatie correlations between IFN/m2 and ALT activity. ALT activity significantly decreased in girls between periods 0-3, in boys between 0-3 and 4-6. Significant positive correlations between ALT-0 and HBeAg, HBsAg elimination, HBeAb, HBsAb presence was seen in several periods, more frequently in girls. IFN transiently decreased Hb, leukocytes, and thrombocytes, especially in boys. No relationship was found between IFN therapy and bilirubin, protein, albumin and gammaglobulin concentrations. The prothrombin index increased after 6 months of IFN therapy in girls. The efficacy of IFN therapy is clearer with longer observation, especially in girls. A relationship was found between IFN dose and HBeAg/HbeAb and HBsAg/HBsAb seroconversion. IFN had a transient negative effect on the peripheral blood picture.


Manganese: brain transport and emerging research needs.
Idiopathic Parkinson's disease (IPD) represents a common neurodegenerative disorder. An estimated 2% of the U.S. population, age 65 and older, develops IPD. The number of IPD patients will certainly increase over the next several decades as the baby-boomers gradually step into this high-risk age group, concomitant with the increase in the average life expectancy. While many studies have suggested that industrial chemicals and pesticides may underlie IPD, its etiology remains elusive. Among the toxic metals, the relationship between manganese intoxication and IPD has long been recognized. The neurological signs of manganism have received close attention because they resemble several clinical disorders collectively described as extrapyramidal motor system dysfunction, and in particular, IPD and dystonia. However, distinct dissimilarities between IPD and manganism are well established, and it remains to be determined whether Mn plays an etiologic role in IPD. It is particularly noteworthy that as a result of a recent court decision, methylcyclopentadienyl Mn tricarbonyl (MMT) is presently available in the United States and Canada for use in fuel, replacing lead as an antiknock additive. The impact of potential long-term exposure to low levels of MMT combustion products that may be present in emissions from automobiles has yet to be fully evaluated. Nevertheless, it should be pointed out that recent studies with various environmental modeling approaches in the Montreal metropolitan (where MMT has been used for more than 10 years) suggest that airborne Mn levels were quite similar to those in areas where MMT was not used. These studies also show that Mn is emitted from the tail pipe of motor vehicles primarily as a mixture of manganese phosphate and manganese sulfate. This brief review characterizes the Mn speciation in the blood and the transport kinetics of Mn into the central nervous system, a critical step in the accumulation of Mn within the brain, outlines the potential susceptibility of selected populations (e.g., iron-deficient) to Mn exposure, and addresses future research needs for Mn.


Index episode-of-care propensity-matched comparison of transforaminal lumbar interbody fusion (TLIF) techniques: open traditional TLIF versus midline lumbar interbody fusion (MIDLIF) versus robot-assisted MIDLIF.
Posterior fixation with interbody cage placement can be accomplished via numerous techniques. In an attempt to expedite recovery by limiting muscle dissection, midline lumbar interbody fusion (MIDLIF) has been described. More recently, the authors have developed a robot-assisted MIDLIF (RA-MIDLIF) technique. The purpose of this study was to compare the index episode-of-care (iEOC) parameters between patients undergoing traditional open transforaminal lumbar interbody fusion (tTLIF), MIDLIF, and RA-MIDLIF. A retrospective review of a prospective, multisurgeon surgical database was performed. Consecutive patients undergoing 1- or 2-level tTLIF, MIDLIF, or RA-MIDLIF for degenerative lumbar conditions were identified. Patients in each cohort were propensity matched based on age, sex, smoking status, BMI, diagnosis, American Society of Anesthesiologists (ASA) class, and number of levels fused. Index EOC parameters such as length of stay (LOS), estimated blood loss (EBL), operating room (OR) time, and actual, direct hospital costs for the index surgical visit were analyzed. Of 281 and 249 patients undergoing tTLIF and MIDLIF, respectively, 52 cases in each cohort were successfully propensity matched to the authors' first 55 RA-MIDLIF cases. Consistent with propensity matching, there was no significant difference in age, sex, BMI, diagnosis, ASA class, or levels fused. Spondylolisthesis was the most common indication for surgery in all cohorts. The mean total iEOC was similar across all cohorts. Patients undergoing RA-MIDLIF had a shorter average LOS (1.53 days) than those undergoing either MIDLIF (2.71 days) or tTLIF (3.58 days). Both MIDLIF and RA-MIDLIF were associated with lower EBL and less OR time compared with tTLIF. Despite concerns for additional cost and time while introducing navigation or robotic technology, a propensity-matched comparison of the authors' first 52 RA-MIDLIF surgeries with tTLIF and MIDLIF showed promising results for reducing OR time, EBL, and LOS without increasing cost.


Using the theory of planned behaviour as a process evaluation tool in randomised trials of knowledge translation strategies: A case study from UK primary care.
Randomised trials of knowledge translation strategies for professional behaviour change can provide robust estimates of effectiveness, but offer little insight into the causal mechanisms by which any change is produced. To illustrate the applicability of causal methods within randomised trials, we undertook a theory-based process evaluation study within an implementation trial to explore whether the cognitions of primary care doctors' predicted their test requesting behaviours and, secondly, whether the trial results were mediated by the theoretical constructs. The process evaluation comprised a cross-sectional questionnaire survey of a random 50% sample of the randomised groups of primary care practices in Grampian (NHS Grampian), UK, who took part in a trial of the effect of enhanced feedback and brief educational reminders on test requesting behaviour. The process evaluation was based upon the Theory of Planned Behaviour and focussed on three of the test requesting behaviours that were targeted in the trial -- ferritin, follicle stimulating hormone (FSH), and Helicobacter Pylori serology (HPS). The questionnaire was completed by 131 primary care doctors (56%) from 42 (98%) of the sampled practices. Behavioural intention, attitude, and subjective norm were highly correlated for all the tests. There was no evidence that perceived behavioural control was correlated with any of the other measures. Simple linear regression analysis of the rate of test requests on minimum behavioural intentions had R2 of 11.1%, 12.5%, and 0.1% for ferritin, FSH, and HPS requesting, respectively. Mediational analysis showed that the trial results for ferritin and FSH were partially mediated (between 23% and 78% mediation) through intentions. The HPS trial result was not mediated through intention. This study demonstrated that a theory-based process evaluation can provide useful information on causal mechanisms that aid not only interpretation of the trial but also inform future evaluations and intervention development.


Marginal integrity: is the clinical performance of bonded restorations predictable in vitro?
In vitro testing of dental materials is daily routine for the preclinical investigation of restoratives. Although clinical trials remain the ultimate instrument, preclinical screenings are still important. However, it is still not fully understood whether clinical performance is predictable in the lab. The aim of this paper is to combine known facts and recent results to answer the question concerning in vitro predictability of clinical marginal integrity and related outcome. (a) The literature in the field from 1990-2005 was analyzed regarding marginal integrity in vitro and in vivo, especially in frequently cited papers. (b) Five different adhesives, a 4-step etch-and-rinse adhesive (Syntac), a 3-step etch-and-rinse adhesive (OptiBond FL), a 2-step etch-and-rinse adhesive (Single Bond), a 2-step self-etching adhesive (Clearfil SE Bond), and a 1-step self-etching adhesive (Xeno III) were used for bonding of a resin composite (Tetric Ceram) in Class I cavities (n = 8 in vitro and n = 8 in vivo). In vitro, the restorations were thermomechanically loaded (TML; 100,000 with 50 N and 2500 cycles of 5 degrees C/55 degrees C) according to a previously published protocol. Replicas of restorations were analyzed initially and after TML (in vitro) and two years of clinical service (respectively). (a) Marginal integrity is reliably predictable in laboratory in vitro studies by simulating clinical circumstances. However, marginal analyses of direct restorations in vitro still suffer from not being able to determine a lower boderline, ie, actually worse in vitro results may still result in acceptable restorations in vivo. (b) The in vitro-in vivo comparison revealed significantly better marginal adaptation in (enamel) margins when etch-and-rinse adhesives were used for bonding. After 2 years of clinical service, restorations bonded with self-etching adhesives did not clinically fail but exhibited significantly more marginal gaps. Clinical behavior of restoration margins is predictable. However, marginal adaptation is only one among several important aspects in restorative dentistry, ie, clinical outcome is not predictable from marginal integrity alone.


Allogeneic bone onlay grafts for alveolar ridge augmentation: a systematic review.
This systematic review examines the published findings on the clinical effectiveness and predictability of allogeneic bone blocks for the correction of alveolar ridge deformities to support dental implant placement in humans. A bibliographic search was conducted of the MEDLINE and EMBASE databases for studies in which allogeneic block grafts were used for alveolar bone augmentation. The search was limited to human studies in English-language publications between 1950 and September 2008. Data extraction included the following outcomes: (1) vertical and/or horizontal bone gain/loss, (2) graft failure rate and complications, and (3) implant survival rate. The initial search identified 35 papers from the electronic databases, with nine publications meeting inclusion criteria: two case reports, six case series, and one prospective, multicenter, consecutive case series. No randomized controlled clinical trials were identified in the search. Observational studies (110 total patients) generally reported high rates of clinical graft incorporation (90% or greater) and implant survival (99% to 100%); however, the majority of reports involved selected defects in anterior regions with short-term follow-up (less than 3 years). Clinical evidence remains limited to case series and reports that differ with respect to alveolar ridge defect selection, treatment, and endpoints of therapy over short-term follow-up periods. Although case-based reports document the potential for allogeneic block grafts to support alveolar ridge augmentation and implant placement, insufficient evidence is available to establish treatment efficacy relative to graft incorporation, alveolar ridge augmentation, and long-term dental implant survival.


Allospecific rejection of MHC class I-deficient bone marrow by CD8 T cells.
Avoidance of long-term immunosuppression is a desired goal in organ transplantation. Mixed chimerism offers a promising approach to tolerance induction, and we have aimed to develop low-toxicity, nonimmunodepleting approaches to achieve this outcome. In a mouse model achieving fully MHC-mismatched allogeneic bone marrow engraftment with minimal conditioning (3 Gy total body irradiation followed by anti-CD154 and T cell-depleted allogeneic bone marrow cells), CD4 T cells in the recipient are required to promote tolerance of preexisting alloreactive recipient CD8 T cells and thereby permit chimerism induction. We now demonstrate that mice devoid of CD4 T cells and NK cells reject MHC Class I-deficient and Class I/Class II-deficient marrow in a CD8 T cell-dependent manner. This rejection is specific for donor alloantigens, since recipient hematopoiesis is not affected by donor marrow rejection and MHC Class I-deficient bone marrow that is syngeneic to the recipient is not rejected. Recipient CD8 T cells are activated and develop cytotoxicity against MHC Class I-deficient donor cells in association with rejection. These data implicate a novel CD8 T cell-dependent bone marrow rejection pathway, wherein recipient CD8 T cells indirectly activated by donor alloantigens promote direct killing, in a T cell receptor-independent manner, of Class I-deficient donor cells.


Ambient fine particulate matter alters cerebral hemodynamics in the elderly.
Short-term elevations in fine particulate matter air pollution (PM2.5) are associated with increased risk of acute cerebrovascular events. Evidence from the peripheral circulation suggests that vascular dysfunction may be a central mechanism. However, the effects of PM2.5 on cerebrovascular function and hemodynamics are unknown. We used transcranial Doppler ultrasound to measure beat-to-beat blood flow velocity in the middle cerebral artery at rest and in response to changes in end-tidal CO2 (cerebral vasoreactivity) and arterial blood pressure (cerebral autoregulation) in 482 participants from the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) of Boston study. We used linear mixed effects models with random subject intercepts to evaluate the association between cerebrovascular hemodynamic parameters and mean PM2.5 levels 1 to 28 days earlier adjusting for age, race, medical history, meteorologic covariates, day of week, temporal trends, and season. An interquartile range increase (3.0 µg/m(3)) in mean PM2.5 levels during the previous 28 days was associated with an 8.6% (95% confidence interval, 3.7%-13.8%; P<0.001) higher cerebral vascular resistance and a 7.5% (95% confidence interval, 4.2%-10.6%; P<0.001) lower blood flow velocity at rest. Measures of cerebral vasoreactivity and autoregulation were not associated with PM2.5 levels. In this cohort of community-dwelling seniors, exposure to PM2.5 was associated with higher resting cerebrovascular resistance and lower cerebral blood flow velocity. If replicated, these findings suggest that alterations in cerebrovascular hemodynamics may underlie the increased risk of particle-related acute cerebrovascular events.


Transcranial direct current stimulation (tDCS) for improving aphasia after stroke: a systematic review with network meta-analysis of randomized controlled trials.
Transcranial Direct Current Stimulation (tDCS) is an emerging approach for improving aphasia after stroke. However, it remains unclear what type of tDCS stimulation is most effective. Our aim was to give an overview of the evidence network regarding the efficacy and safety of tDCS and to estimate the effectiveness of the different stimulation types. This is a systematic review of randomized controlled trials with network meta-analysis (NMA). We searched the following databases until 4 February 2020: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, Web of Science, and four other databases. We included studies with adult people with stroke. We compared any kind of active tDCS (anodal, cathodal, or dual, that is applying anodal and cathodal tDCS concurrently) regarding improvement of our primary outcome of functional communication, versus control, after stroke. CRD42019135696. We included 25 studies with 471 participants. Our NMA showed that tDCS did not improve our primary outcome, that of functional communication. There was evidence of an effect of anodal tDCS, particularly over the left inferior frontal gyrus, in improving our secondary outcome, that of performance in naming nouns (SMD = 0.51; 95% CI 0.11 to 0.90). There was no difference in safety between tDCS and its control interventions, measured by the number of dropouts and adverse events. Comparing different application/protocols of tDCS shows that the anodal application, particularly over the left inferior frontal gyrus, seems to be the most promising tDCS treatment option to improve performance in naming in people with stroke.


The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo.
The CBFbeta subunit is the non-DNA-binding subunit of the heterodimeric core-binding factor (CBF). CBFbeta associates with DNA-binding CBFalpha subunits and increases their affinity for DNA. Genes encoding the CBFbeta subunit (CBFB) and one of the CBFalpha subunits (CBFA2, otherwise known as AML1) are the most frequent targets of chromosomal translocations in acute leukemias in humans. We and others previously demonstrated that homozygous disruption of the mouse Cbfa2 (AML1) gene results in embryonic lethality at midgestation due to hemorrhaging in the central nervous system and blocks fetal liver hematopoiesis. Here we demonstrate that homozygous mutation of the Cbfb gene results in the same phenotype. Our results demonstrate that the CBFbeta subunit is required for CBFalpha2 function in vivo.


Special relativity corrections for space-based lidars.
The theory of special relativity is used to analyze some of the physical phenomena associated with space-based coherent Doppler lidars aimed at Earth and the atmosphere. Two important cases of diffuse scattering and retroreflection by lidar targets are treated. For the case of diffuse scattering, we show that for a coaligned transmitter and receiver on the moving satellite, there is no angle between transmitted and returned radiation. However, the ray that enters the receiver does not correspond to a retroreflected ray by the target. For the retroreflection case there is misalignment between the transmitted ray and the received ray. In addition, the Doppler shift in the frequency and the amount of tip for the receiver aperture when needed are calculated. The error in estimating wind because of the Doppler shift in the frequency due to special relativity effects is examined. The results are then applied to a proposed space-based pulsed coherent Doppler lidar at NASA's Marshall Space Flight Center for wind and aerosol backscatter measurements. The lidar uses an orbiting spacecraft with a pulsed laser source and measures the Doppler shift between the transmitted and the received frequencies to determine the atmospheric wind velocities. We show that the special relativity effects are small for the proposed system.


Project VIVA: a multilevel community-based intervention to increase influenza vaccination rates among hard-to-reach populations in New York City.
We sought to determine whether the work of a community-based participatory research partnership increased interest in influenza vaccination among hard-to-reach individuals in urban settings. A partnership of researchers and community members carried out interventions for increasing acceptance of influenza vaccination in disadvantaged urban neighborhoods, focusing on hard-to-reach populations (e.g., substance abusers, immigrants, elderly, sex workers, and homeless persons) in East Harlem and the Bronx in New York City. Activities targeted the individual, community organization, and neighborhood levels and included dissemination of information, presentations at meetings, and provision of street-based and door-to-door vaccination during 2 influenza vaccine seasons. Participants were recruited via multiple modalities. Multivariable analyses were performed to compare interest in receiving vaccination pre- and postintervention. There was increased interest in receiving the influenza vaccine postintervention (P<.01). Being a member of a hard-to-reach population (P=.03), having ever received an influenza vaccine (P<.01), and being in a priority group for vaccination (P<.01) were also associated with greater interest in receiving the vaccine. Targeting underserved neighborhoods through a multilevel community-based participatory research intervention significantly increased interest in influenza vaccination, particularly among hard-to-reach populations. Such interventions hold promise for increasing vaccination rates annually and in pandemic situations.


Performance of different gastric cancer screening methods in Korea: a population-based study.
There is a lack of agreement on which gastric cancer screening method is the most effective in the general population. The present study compared the relative performance of upper-gastrointestinal series (UGIS) and endoscopy screening for gastric cancer. A population-based study was conducted using the National Cancer Screening Program (NCSP) database. We analyzed data on 2,690,731 men and women in Korea who underwent either UGIS or endoscopy screening for gastric cancer between January 1, 2002 and December 31, 2005. Final gastric cancer diagnosis was ascertained through linkage with the Korean Central Cancer Registry. We calculated positivity rate, gastric cancer detection rate, interval cancer rate, sensitivity, specificity, and positive predictive value of UGIS and endoscopy screening. The positivity rates for UGIS and endoscopy screening were 39.7 and 42.1 per 1,000 screenings, respectively. Gastric cancer detection rates were 0.68 and 2.61 per 1,000 screenings, respectively. In total, 2,067 interval cancers occurred within 1 year of a negative UGIS screening result (rate, 1.17/1,000) and 1,083 after a negative endoscopy screening result (rate, 1.17/1,000). The sensitivity of UGIS and endoscopy screening to detect gastric cancer was 36.7 and 69.0%, respectively, and specificity was 96.1 and 96.0%. The sensitivity of endoscopy screening to detect localized gastric cancer was 65.7%, which was statistically significantly higher than that of UGIS screening. Overall, endoscopy performed better than UGIS in the NCSP for gastric cancer. Further evaluation of the impact of these screening methods should take into account the corresponding costs and reduction in mortality.


Environmental rocking ratchet: Environmental rectification by a harmonically driven avoided crossing.
We propose a rocking ratchet designed as a symmetric quantum two-state system driven by a single periodic harmonic force and influenced symmetrically by thermal fluctuations. We show that the necessary broken symmetry can dynamically be achieved by a thermal environment that couples to the energy difference between the two states and the tunnel coupling between them. The quantum two-state system is driven by the harmonic periodic drive through its avoided crossing. The correspondingly driven dissipative quantum dynamics results on average in a finite population difference between both states. This then causes directed particle transport.


On the role of attention in generating explicit awareness of contingent relations: evidence from spatial priming.
In a series of four experiments, we examine the hypothesis that selective attention is crucial for the generation of conscious knowledge of contingency information. We investigated this question using a spatial priming task in which participants were required to localize a target letter in a probe display. In Experiment 1, participants kept track of the frequency with which the predictive letter in the prime appeared in various locations. This manipulation had a negligible impact on contingency awareness. Subsequent experiments requiring participants to attend to features (color, location) of the predictive letter increased contingency awareness somewhat, but there remained a large proportion of individuals who remained unaware of the strong contingency. Together the results of our experiments suggest that the construct of attention does not fully capture the processes that lead to contingency awareness, and suggest a critical role for bottom-up feature integration in explicit contingency learning.


Do statins reduce the risk of aneurysm development? A case-control study.
Recent studies in rats have demonstrated that statins may have an inhibitory effect on intracranial aneurysm (IA) development. The purpose of this study was to assess whether long-term statin use is associated with a reduced risk of IA formation in humans. This was a single-center case-control study that included consecutive patients admitted to the authors' institution between January 1, 2005, and December 31, 2008. A case was defined as a patient with a cerebral angiography-confirmed diagnosis of IA. Three controls were matched to each case based on age, sex, and index year of hospital admission. The primary exposure of interest was cumulative statin use. Conditional logistic regression was used to assess the relationship between statin intake and incidence of IA. In total, 1200 patients were included in the study. No overall association was found between statin use and incidence of IA formation (OR 1.08, 95% CI 0.69-1.69), nor when dichotomized into hydrophilic and lipophilic user, or between short (≤ 12-month) and long (≥ 36-month) duration of intake. Hypertension and smoking significantly increased the risk of IA development (OR 4.02, 95% CI 2.49-6.45, and OR 1.67, 95% CI 1.02-2.72, respectively). In contrast to recent experimental reports of the association between statins and a reduction of IA formation, the authors' findings suggest that in humans statins may have no significant beneficial effect on IA suppression.


Favorable Effects of a Ketogenic Diet on Physical Function, Perceived Energy, and Food Cravings in Women with Ovarian or Endometrial Cancer: A Randomized, Controlled Trial.
Ketogenic diets (KDs) are gaining attention as a potential adjuvant therapy for cancer, but data are limited for KDs' effects on quality of life. We hypothesized that the KD would (1) improve mental and physical function, including energy levels, (2) reduce hunger, and (3) diminish sweet and starchy food cravings in women with ovarian or endometrial cancer. Participants were randomized to a KD (70:25:5 energy from fat, protein, and carbohydrate) or the American Cancer Society diet (ACS: high-fiber, lower-fat). Questionnaires were administered at baseline and after 12 weeks on the assigned diet to assess changes in mental and physical health, perceived energy, appetite, and food cravings. We assessed both between-group differences and within-group changes using ANCOVA and paired t-tests, respectively. After 12 weeks, there was a significant between-group difference in adjusted physical function scores (p < 0.05), and KD participants not receiving chemotherapy reported a significant within-group reduction in fatigue (p < 0.05). There were no significant between-group differences in mental function, hunger, or appetite. There was a significant between-group difference in adjusted cravings for starchy foods and fast food fats at 12 weeks (p < 0.05 for both), with the KD group demonstrating less frequent cravings than the ACS. In conclusion, in women with ovarian or endometrial cancer, a KD does not negatively affect quality of life and in fact may improve physical function, increase energy, and diminish specific food cravings. This trial was registered at ClinicalTrials.gov as NCT03171506.


Multiple anthropogenic stressors influence the taxonomic and functional homogenization of macroinvertebrate communities on the mainstream of an urban-agricultural river in China.
Biodiversity loss is caused by intensive human activities and threatens human well-being. However, less is known about how the combined effects of multiple stressors on the diversity of internal (alpha diversity) and multidimensional (beta diversity) communities. Here, we conducted a long-term experiment to quantify the contribution of environmental stressors (including water quality, land use, climate factors, and hydrological regimes) to macroinvertebrate communities alpha and beta diversity in the mainstream of the Songhua River, the third largest river in China, from 2012 to 2019. Our results demonstrated that the alpha and beta diversity indices showed a decline during the study period, with the dissimilarity in community composition between sites decreasing significantly, especially in the impacted river sections (upper and midstream). Despite overall improvement in water quality after management intervention, multiple human-caused stressors still have led to biotic homogenization of macroinvertebrate communities in terms of both taxonomic and functional diversities in the past decade. Our study revealed the increased human land use explained an important portion of the variation of diversities, further indirectly promoting biotic homogenization by changing the physical and chemical factors of water quality, ultimately altering assemblage ecological processes. Furthermore, the facets of diversity have distinct response mechanisms to stressors, providing complementary information from the perspective of taxonomy and function to better reflect the ecological changes of communities. Environmental filtering determined taxonomic beta diversity, and functional beta diversity was driven by the joint efforts of stressors and spatial processes. Finally, we proposed that traditional water quality monitoring alone cannot fully reveal the status of river ecological environment protection, and more importantly, we should explore the continuous changes in biodiversity over the long term. Meanwhile, our results also highlight timely control of nutrient input and unreasonable expansion of land use can better curb the ecological degradation of rivers and promote the healthy and sustainable development of floodplain ecosystems.


Energy transfer between Eu3+ and Nd3+ in near-infrared emitting β-triketonate coordination polymers.
Isomorphous β-triketonate-based lanthanoid polymers containing tris(4-methylbenzoyl)methanide (mtbm) and Rb+ with formula {[Ln(Rb)(mtbm)4]2}n (Ln = Eu3+ and Nd3+) have been synthesised and structurally characterised. The photophysical properties for the Nd3+ complex presented relatively long lifetimes and high quantum yields in comparison with analogous β-diketonate complexes. Mixed lanthanoid complexes were also formed and their luminescence properties studied, with effective sensitisation of the 4F3/2 of Nd3+via the 5D0 of Eu3+, which is to the best of our knowledge the first example of Eu3+ to Nd3+ sensitisation in a structurally defined coordination complex or polymer.


PubTator: a web-based text mining tool for assisting biocuration.
Manually curating knowledge from biomedical literature into structured databases is highly expensive and time-consuming, making it difficult to keep pace with the rapid growth of the literature. There is therefore a pressing need to assist biocuration with automated text mining tools. Here, we describe PubTator, a web-based system for assisting biocuration. PubTator is different from the few existing tools by featuring a PubMed-like interface, which many biocurators find familiar, and being equipped with multiple challenge-winning text mining algorithms to ensure the quality of its automatic results. Through a formal evaluation with two external user groups, PubTator was shown to be capable of improving both the efficiency and accuracy of manual curation. PubTator is publicly available at http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/Demo/PubTator/.


Lipid raft redistribution and morphological cell polarization are separable processes providing a basis for hematopoietic stem and progenitor cell migration.
Freshly isolated human hematopoietic stem and progenitor cells (HSPCs) are small and round cells which upon cultivation adopt a polarized morphology and redistribute certain cell surface antigens. To functionally dissect this polarization process, we addressed impacts of protein synthesis, HSPC trafficking, cytoskeleton organization or lipid raft integrity on the establishment and maintenance of the cell polarity of human HSPCs. Effects on the morphology, sub-cellular distribution of lipid raft-associated molecular polarization markers (Flotillin-1, Flotillin-2, ICAM-3) and in vitro migration capabilities of treated cells were studied. We could distinguish two levels of cellular polarization, a molecular and a morphological level. Our data suggest that protein synthesis, lipid raft integrity and enzymatic activities of PI3K and aPKC are required to organize the molecular cell polarity. The morphological cell polarization process, however, also depends on actin polymerization and rho-GTPase activities. In summary, our data qualify HSPC polarization processes as new pharmaceutical target to interfere with migratory and with homing capabilities of HSPCs.


Inactive Lifestyles Among Young Children With Innocent Murmurs or Congenital Heart Disease, Regardless of Disease Severity or Treatment.
Sedentary lifestyle morbidities are common among children with congenital heart disease (CHD). Understanding the physical activity trajectory from early childhood could enhance timing and effectiveness of interventions. We recruited 154 children (56% male) at 12 to 47 months of age for this prospective, longitudinal, observational study. Physical activity and sedentary behaviour (7-day accelerometry) and motor skill (Peabody Developmental Motor Scales-2) were assessed every 8 months until 5 years of age and then annually. Mixed-effect repeated measures regression models described outcome trajectories across study assessments. Children had innocent heart murmurs (n = 28), CHD with insignificant hemodynamics not requiring treatment (n = 47), CHD treated by catheterization or surgery without cardiopulmonary bypass (n = 31), or CHD treated surgically with bypass (n = 48). Motor skill was age appropriate (Peabody 49.0 ± 8.4), but participants had lower physical activity (143 ± 41 minutes per day) and higher sedentary time (598 ± 89 minutes per day) than healthy peers, starting at 18 months of age. Movement behaviours were not related to treatment group (P > 0.10), and physical activity was below the recommended 180 minutes per day. Over time, physical activity, sedentary time, and motor skills were primarily related to the baseline measure of each outcome (P < 0.001). Children with simple or complex CHD or innocent heart murmurs have increased risk for sedentary lifestyles. Their physical activity and sedentary behaviours are established before 2 years of age, persist until school age, and are unrelated to motor skills. These results emphasize the need for interventions targeting the youngest children seen in cardiac clinics, regardless of diagnoses of CHD or innocent murmur.


Aetiology of stillbirths and neonatal deaths in rural Ghana: implications for health programming in developing countries.
In developing countries many stillbirths and neonatal deaths occur at home and cause of death is not recorded by national health information systems. A community-level verbal autopsy tool was used to obtain data on the aetiology of stillbirths and neonatal deaths in rural Ghana. Objectives were to describe the timing and distribution of causes of stillbirths and neonatal deaths according to site of death (health facility or home). Data were collected from 1 January 2003 to 30 June 2004; 20,317 deliveries, 696 stillbirths and 623 neonatal deaths occurred over that time. Most deaths occurred in the antepartum period (28 weeks gestation to the onset of labour) (33.0%). However, the highest risk periods were during labour and delivery (intrapartum period) and the first day of life. Infections were a major cause of death in the antepartum (10.1%) and neonatal (40.3%) periods. The most important cause of intrapartum death was obstetric complications (59.3%). There were significantly fewer neonatal deaths resulting from birth asphyxia in the home than in the health facilities and more deaths from infection. Only 59 (20.7%) mothers of neonates who died at home reported that they sought care from an appropriate health care provider (doctor, nurse or health facility) during their baby's illness. The results from this study highlight the importance of studying community-level data in developing countries and the high risk of intrapartum stillbirths and infectious diseases in the rural African mother and neonate. Community-level interventions are urgently needed, especially interventions that reduce intrapartum deaths and infection rates in the mother and infant.


Pointers and Pitfalls in Interpreting Nutrition and Dietetics Research: The Importance of Statistical and Clinical Significance.
This monograph focuses on understanding statistical and clinical significance and is one in a research and statistics series published by the statistical team of the Journal of the Academy of Nutrition and Dietetics. The content covers the research questions, definition of clinical significance, hypothesis testing, P values, effect sizes, sample sizes, CIs, power analyses, minimal clinically important differences, and validity. This monograph concludes with a summary of the importance of clinical and statistical results for credentialed nutrition and dietetics practitioners to consider when assessing statistical and clinical significance. The assessment will help readers make subjective clinical judgments in the application of research findings based on their experience.


Do quantitative cultures of protected brush specimens modify the initial empirical therapy in ventilated patients with suspected pneumonia?
The real contribution of the protected specimen brush (PSB) to guide the choice of antimicrobial therapy in ventilated patients with severe pneumonia is not well established. This study aimed to assess how data obtained by PSB changed the initial empirical therapy. One hundred and ten ventilated patients with suspected pneumonia were entered into a prospective study. All patients underwent fibreoptic bronchoscopy within the first 24 h after clinical suspicion of pneumonia. Specimens were obtained by PSB and were processed for quantitative cultures using standard methods. When patients were started on empirical antibiotics, a standard therapeutic regimen was followed. The decision to introduce, withdraw, maintain, or modify antibiotic therapy, according to the PSB culture results, was left to the attending physician. Pneumonia was the final diagnosis in 45 (41%) of the 110 patients. Pneumonia was excluded in 47 (43%) patients and in the remaining 18 (16%) the diagnosis was uncertain. The initial therapeutic plans were considered to be adequate in 40 patients (36%) and inadequate in 37 cases (34%). In 17 patients (15%), therapeutic changes were made based on the results of PSB cultures. In one case appropriate antibiotics were introduced; in nine cases the therapeutic regimen was reduced to select a narrower and rational therapy; and in seven patients therapy was changed because the prescribed antimicrobial agents were ineffective against the organisms recovered. This study shows that therapeutic changes were made based on the results of PSB cultures in 38% of the patients with pneumonia. In contrast, the PSB technique has no impact on antimicrobial therapy of patients without pneumonia.


Understanding the Role of the Diagnostic 'Reflex' in the Elimination of Human African Trypanosomiasis.
To successfully eliminate human African trypanosomiasis (HAT), healthcare workers (HCWs) must maintain their diagnostic acuity to identify cases as the disease becomes rarer. HAT experts refer to this concept as a 'reflex' which incorporates the idea that diagnostic expertise, particularly skills involved in recognising which patients should be tested, comes from embodied knowledge, accrued through practice. We investigated diagnostic pathways in the detection of 32 symptomatic HAT patients in South Sudan and found that this 'reflex' was not confined to HCWs. Indeed, lay people suggested patients test for HAT in more than half of cases using similar practices to HCWs, highlighting the importance of the expertise present in disease-affected communities. Three typologies of diagnostic practice characterised patients' detection: 'syndromic suspicion', which closely resembled the idea of an expert diagnostic reflex, as well as 'pragmatic testing' and 'serendipitous detection', which depended on diagnostic expertise embedded in hospital and lay social structures when HAT-specific suspicion was ambivalent or even absent. As we approach elimination, health systems should embrace both expert and non-expert forms of diagnostic practice that can lead to detection. Supporting multidimensional access to HAT tests will be vital for HCWs and lay people to practice diagnosis and develop their expertise.


Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor.
Endothelial-derived epoxyeicosatrienoic acids may regulate vascular tone and are metabolized by soluble epoxide hydrolase enzymes (sEH). GSK2256294 is a potent and selective sEH inhibitor that was tested in two phase I studies. Single escalating doses of GSK2256294 2-20 mg or placebo were administered in a randomized crossover design to healthy male subjects or obese smokers. Once daily doses of 6 or 18 mg or placebo were administered for 14 days to obese smokers. Data were collected on safety, pharmacokinetics, sEH enzyme inhibition and blood biomarkers. Single doses of GSK2256294 10 mg were also administered to healthy younger males or healthy elderly males and females with and without food. Data on safety, pharmacokinetics and biliary metabolites were collected. GSK2256294 was well-tolerated with no serious adverse events (AEs) attributable to the drug. The most frequent AEs were headache and contact dermatitis. Plasma concentrations of GSK2256294 increased with single doses, with a half-life averaging 25-43 h. There was no significant effect of age, food or gender on pharmacokinetic parameters. Inhibition of sEH enzyme activity was dose-dependent, from an average of 41.9% on 2 mg (95% confidence interval [CI] -51.8, 77.7) to 99.8% on 20 mg (95% CI 99.3, 100.0) and sustained for up to 24 h. There were no significant changes in serum VEGF or plasma fibrinogen. GSK2256294 was well-tolerated and demonstrated sustained inhibition of sEH enzyme activity. These data support further investigation in patients with endothelial dysfunction or abnormal tissue repair, such as diabetes, wound healing or COPD.


Tensile strength and fracture of cemented granular aggregates.
Cemented granular aggregates include a broad class of geomaterials such as sedimentary rocks and some biomaterials such as the wheat endosperm. We present a 3D lattice element method for the simulation of such materials, modeled as a jammed assembly of particles bound together by a matrix partially filling the interstitial space. From extensive simulation data, we analyze the mechanical properties of aggregates subjected to tensile loading as a function of matrix volume fraction and particle-matrix adhesion. We observe a linear elastic behavior followed by a brutal failure along a fracture surface. The effective stiffness before failure increases almost linearly with the matrix volume fraction. We show that the tensile strength of the aggregates increases with both the increasing tensile strength at the particle-matrix interface and decreasing stress concentration as a function of matrix volume fraction. The proportion of broken bonds in the particle phase reveals a range of values of the particle-matrix adhesion and matrix volume fraction for which the cracks bypass the particles and hence no particle damage occurs. This limit is shown to depend on the relative toughness of the particle-matrix interface with respect to the particles.


Prevalence and incidence of symmetrical symptomatic peripheral neuropathy in patients with multidrug-resistant TB.
Symptomatic symmetrical peripheral neuropathy (SSPN) is common in patients with HIV infection. It is also a common adverse event associated with both tuberculosis (TB) treatment and antiretroviral therapy (ART), particularly stavudine. While tenofovir is the one of recommended first-line nucleotide reverse transcriptase inhibitors (NRTIs), there is a risk of nephrotoxicity when using tenofovir together with the aminoglycosides needed to treat multidrug-resistant (MDR) TB. Thus, stavudine is often chosen as a treatment option for the HIV-infected MDR TB patient. To assess whether use of stavudine both before and during treatment for MDR TB increased the prevalence and incidence of SSPN. MDR TB patients at Sizwe Tropical Disease Hospital were examined for signs of prevalent SSPN. Age, gender, HIV status, alcohol use, TB and HIV treatment regimens both prior to admission and current, and concomitant medications were recorded. In this cohort of 246 patients, we found that 24.4% of patients with MDR TB had SSPN at time of admission for treatment of MDR TB. They were more likely to be HIV-infected (odds ratio (OR) 3.21; 95% CI 1.25 - 8.21) and tended to have longer (>7 months) exposure to stavudine (OR 1.81; 95% CI 0.90 - 3.63). Incident SSPN occurred in 17% of patients and was associated with older age (hazard ratio (HR) 3.00; 95% CI 1.30 - 6.89) and exposure to terizidone (HR 2.98; 95% CI 0.94 to 4.61) or, to a lesser extent, with stavudine (crude HR 1.62; 95% CI 0.65 - 4.01) in the first 6 months of MDR TB treatment. This common adverse event emphasises the need for the development of less toxic drugs for the treatment of MDR TB.


Intrinsic and synaptic homeostatic plasticity in motoneurons from mice with glycine receptor mutations.
Inhibitory synaptic inputs to hypoglossal motoneurons (HMs) are important for modulating excitability in brainstem circuits. Here we ask whether reduced inhibition, as occurs in three murine mutants with distinct naturally occurring mutations in the glycine receptor (GlyR), leads to intrinsic and/or synaptic homeostatic plasticity. Whole cell recordings were obtained from HMs in transverse brainstem slices from wild-type (wt), spasmodic (spd), spastic (spa), and oscillator (ot) mice (C57Bl/6, approximately postnatal day 21). Passive and action potential (AP) properties in spd and ot HMs were similar to wt. In contrast, spa HMs had lower input resistances, more depolarized resting membrane potentials, higher rheobase currents, smaller AP amplitudes, and slower afterhyperpolarization current decay times. The excitability of HMs, assessed by "gain" in injected current/firing-frequency plots, was similar in all strains whereas the incidence of rebound spiking was increased in spd. The difference between recruitment and derecruitment current (i.e., ΔI) for AP discharge during ramp current injection was more negative in spa and ot. GABAA miniature inhibitory postsynaptic current (mIPSC) amplitude was increased in spa and ot but not spd, suggesting diminished glycinergic drive leads to compensatory adjustments in the other major fast inhibitory synaptic transmitter system in these mutants. Overall, our data suggest long-term reduction in glycinergic drive to HMs results in changes in intrinsic and synaptic properties that are consistent with homeostatic plasticity in spa and ot but not in spd. We propose such plasticity is an attempt to stabilize HM output, which succeeds in spa but fails in ot.


Carotid Intima-Media Thickness Is Associated With White Matter Hyperintensities: The Northern Manhattan Study.
Brain white matter hyperintensities (WMH) have been associated with increased risk of stroke, cognitive decline, and dementia. WMH can be a manifestation of small vessel disease, although the total microvascular contribution to multifactorial WMH pathophysiology remains unknown. We hypothesized a possible relationship between carotid intima-media thickness (cIMT), an ultrasound imaging marker of subclinical vascular disease, and brain WMH in a multiethnic, elderly stroke-free community-based cohort. We evaluated the relationship between cIMT and WMH in the population-based Northern Manhattan Study, among individuals free of stroke. We used linear regression to examine the association of continuous measures of cIMT with quantitatively derived WMH volume, as a proportion of cranial volume, measured from fluid-attenuaded inversion recovery magnetic resonance imaging while adjusting for sociodemographics, lifestyle, and vascular risk factors. In a cohort of 1229 participants (mean age, 71±9 years; 60% women, 15% White; 18% Black; 65% Hispanics), the mean cIMT was 0.71±0.08 mm and the median log-transformed WMH volume was 0.36 (interquartile range, 0.21-0.76). In a multivariable model, larger cIMT was significantly associated with greater WMH volume (β=0.046 per SD cIMT; P=0.04). Age and race/ethnicity were significant modifiers (P for age, 0.02; and P for race/ethnicity, 0.04). cIMT was associated with WMH volume in participants 70 years or older (β=0.088 per SD cIMT; P=0.01) and among Hispanics (β=0.084 per SD cIMT; P=0.003). Larger cIMT was associated with greater burden of cerebral WM lesions independently of demographics and traditional vascular risk factors, particularly among elderly and Hispanic participants, who are at high risk for stroke and cognitive decline.


A Longitudinal Cohort Study Investigating Inadequate Preparation and Death and Dying in Nursing Students: Implications for the Aftermath of the COVID-19 Pandemic.
To investigate how changes in the levels of preparedness and experiences of death and dying influence nursing students' mental health. The COVID-19 pandemic is likely to cause significant trauma in the nursing population. The lack of preparation, in combination with a substantial loss of life, may have implications for the longer-term mental health of the nursing workforce. Nursing students have, in many cases, been an important part of the emergency response. A longitudinal cohort study was conducted in the academic year 2014/15 with data collected at two time points. There was a 7-month time period between data collection. Participants completed paper-based questionnaires measuring demographics, academic stressors, clinical stressors, and mental health. 358 nursing students at time point one and 347 at time point two (97% retention) completed the survey. Inadequate preparation (OR: 1.783) and the inadequate preparation x death and dying interaction term (OR: 4.115) significantly increased risk of mental health problems over time. Increased death and dying alone did not increase mental health risk. The results of this study suggest that it is not the increase in death and dying per se that causes mental health difficulties, but that it is instead the experience of high levels of death and dying in combination with inadequate preparation. The data are considered within the context of the COVID-19 pandemic, with both inadequate preparation and the scale of death and dying being two significant stressors during the emergency period.


Post-liquefaction reconsolidation of sand.
Loosely packed sand that is saturated with water can liquefy during an earthquake, potentially causing significant damage. Once the shaking is over, the excess pore water pressures that developed during the earthquake gradually dissipate, while the surface of the soil settles, in a process called post-liquefaction reconsolidation. When examining reconsolidation, the soil is typically divided in liquefied and solidified parts, which are modelled separately. The aim of this paper is to show that this fragmentation is not necessary. By assuming that the hydraulic conductivity and the one-dimensional stiffness of liquefied sand have real, positive values, the equation of consolidation can be numerically solved throughout a reconsolidating layer. Predictions made in this manner show good agreement with geotechnical centrifuge experiments. It is shown that the variation of one-dimensional stiffness with effective stress and void ratio is the most crucial parameter in accurately capturing reconsolidation.


Factors controlling the reactivity of hydrogen sulfide with hemeproteins.
Hemoglobin I (HbI) from the clam Lucina pectinata is an intriguing hemeprotein that binds and transports H(2)S to sulfide-oxidizing chemoautotrophic bacteria to maintain a symbiotic relationship and to protect the mollusk from H(2)S toxicity. Single point mutations at E7, B10, and E11 were introduced into the HbI heme pocket to define the reactivity of sulfide with hemeproteins. The functional and structural properties of mutant and wild-type recombinant proteins were first evaluated using the well-known ferrous CO and O(2) derivatives. The effects of these mutations on the ferric environment were then studied in the metaquo and hydrogen sulfide derivatives. The results obtained with the ferrous HbI mutants show that all the E7 substitutions and the PheB10Tyr mutation influence directly CO and O(2) binding and stability while the B10 and E11 substitutions induce distal structural rearrangements that affect ligand entry and escape indirectly. For the metaquo-GlnE7His, -PheB10Val, -PheB10Leu, and -E11 variants, two individual distal structures are suggested, one of which is associated with H-bonding interactions between the E7 residues and the bound water. Similar H-bonding interactions are invoked for these HbI-H(2)S mutant derivatives and the rHbI, altering in turn sulfide reactivity within these protein samples. This is evident in the resonance Raman spectra of these HbI-H(2)S complexes, which show reduction of heme iron as judged by the appearance of the nu(4) oxidation state marker at 1356 cm(-1), indicative of heme-Fe(II) species. This reduction process depends strongly on distal mutations showing faster reduction for those HbI mutants exhibiting the strongest H-bonding interactions. Overall, the results presented here show that (a) H(2)S association is regulated by external kinetic barriers, (b) H(2)S release is controlled by two competing reactions involving simple sulfide dissociation and heme reduction, (c) at high H(2)S concentrations, reduction of the ferric center dominates, and (d) reduction of the heme is also enhanced in those HbI mutants having polar distal environments.


Molecular findings among patients referred for clinical whole-exome sequencing.
Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders. To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome. Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient's physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay. Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings. A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%-31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%-27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%-47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%-25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics. Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.


Aflatoxicosis alters avian renal function, calcium, and vitamin D metabolism.
Experiments were designed to determine the effects of aflatoxicosis on avian renal function, calcium (CA), inorganic phosphorous (Pi), and vitamin D metabolism, and to determine if the effects of aflatoxin are reversible upon discontinuation of toxin administration. Three-week-old male broiler chickens (n = 12 per treatment) received aflatoxin (AF; 2 mg/kg po) or an equal volume of corn oil, the AF carrier vehicle, for 10 consecutive days. After 10 d of treatment, half of the birds from each treatment group were anesthetized and prepared for renal function analysis, which included a 2-h phosphate loading period. Ten days after discontinuation of AF treatment, the remaining birds in each treatment group were anesthetized and prepared for renal function analysis. AF decreased plasma 25-hydroxy vitamin D [25(OH)D] and 1,25-dihydroxy vitamin D [1,25(OH)2D] levels after 5 d of treatment. After 10 d of treatment, urine flow rate (V), fractional sodium excretion (FENa), and fractional potassium excretion (FEK) were lower in AF-treated birds. In addition, total plasma Ca tended to be lower (p = .10) and fractional Ca excretion (FECa) tended to be higher (p = .10) in the AF-treated birds. Intravenous phosphate loading produced a sharp increase in urine hydrogen ion concentration ([H+]) in the AF-treated birds. Glomerular filtration rate (GFR) was reduced and plasma osmolality was increased in AF-treated birds 10 d after discontinuation of toxin administration. The results indicate that AF directly or indirectly affects Ca and Pi metabolism in avians. At the present time, the effects may be related to altered vitamin D and parathyroid hormone (PTH) metabolism. Aflatoxicosis may decrease endogenous PTH synthesis and the renal sensitivity to PTH. The AF-related increase in urine [H+] during phosphate loading is probably due to increased Na+/H+ counterport, suggesting that AF stimulates sodium reabsorption. Also, the decrease in GFR exhibited 10 d after toxin removal indicates that AF may cause prolonged alteration in renal function.


Correlates of Marijuana Drugged Driving and Openness to Driving While High: Evidence from Colorado and Washington.
A potential unintended consequence of legalizing recreational marijuana is increased marijuana-related driving impairment. Some states where recreational marijuana is legal have begun implementing interventions to mitigate driving under the influence (DUI) of marijuana, including media campaigns to increase knowledge about DUI laws. However, little is known about the associations between knowledge of DUI laws and marijuana DUI behavior. In this study, we provide new data from a survey of marijuana users in Colorado and Washington to examine associations between marijuana drugged driving and two potential behavioral precursors of marijuana DUI. We also explore other factors that may influence marijuana DUI. Data are from an online survey of marijuana users in Colorado and Washington. Respondents who reported any marijuana use in the past 30 days (n = 865) served as the analytic sample. We examined prevalence of two behavioral outcomes: (1) any driving of a motor vehicle while high in the past year and (2) driving a motor vehicle within 1 hour of using marijuana 5 or more times in the past month. Additional outcomes measuring willingness to drive while high were also assessed. Logistic regressions were used to estimate each outcome as a function of two multi-item scales measuring knowledge of the legal consequences of driving high and perceptions that driving while high is not safe. Additional covariates for potential confounders were included in each model. Prevalence of past-year driving while under the influence of marijuana was 43.6% among respondents. The prevalence of driving within 1 hour of using marijuana at least 5 times in the past month was 23.9%. Increased perception that driving high is unsafe was associated with lower odds of past-year marijuana DUI (OR = 0.31, P < 0.01) and lower past-month odds of driving 5 or more times within 1 hour of using marijuana (OR = 0.26, P < 0.01). Increased knowledge of marijuana DUI laws was also associated with lower odds of each of these outcomes (OR = 0.63, P < 0.01, OR = 0.69, P = 0.02, respectively). Post-estimation Wald tests confirmed the negative associations with marijuana DUI were greater in magnitude for safety perceptions than knowledge of DUI laws. Increased perceptions that driving while high is unsafe was associated with significantly lower willingness to drive after using marijuana while increased knowledge of marijuana DUI laws was not associated with these outcomes. Despite recent interventions targeting public awareness of the legal consequences of marijuana DUI, our results suggest that knowledge of these laws is a weaker predictor of DUI behavior than perceptions that driving high is unsafe. In addition, safety perceptions predict decreased openness to driving high while knowledge of DUI laws was not associated with openness. These findings suggest that interventions for reducing the incidence of marijuana DUI are likely to be more successful by targeting safety perceptions related to marijuana DUI rather than knowledge of DUI laws. We caution that because these data are limited to an online convenience sample, results may not be generalizable beyond our sample.


Characteristic electron microscopic findings in the skin of patients with fibromyalgia: preliminary study.
This blinded study was done to determine if there are any abnormal electron microscopic (EM) findings in the skin of fibromyalgia syndrome (FMS) patients, which might contribute to or be due to the increased pain sensitivity seen in this condition. Skin biopsy samples were obtained from 13 FMS patients and 5 control subjects. All tissues were prepared for EM examination by immediate prefixation in 2.5% glutaraldehyde for 2 h and postfixation in 1% osmium acid for 24 h. Ultrathin sections on grids were stained by uranyl acetate and lead citrate. Biopsies were read by an individual without knowledge of participant status. Five skin biopsies from healthy controls showed relatively even distribution of variegated sized unmyelinated axons sheathed well by complicatedly folded Schwann cell membranes. In tissues from 9/13 FMS patients, unmyelinated Schwann cells were noted to be ballooned, whereas this finding was not noted in any controls (p = 0.029). Axons in most patients trended towards being localized in the periphery of the unmyelinated Schwann cell sheaths (p = 0.002). Particularly, peripheral localization of axon in the unmyelinated Schwann cell sheath had a strong relationship with ballooning of Schwann cell (p = 0.042), simplified folding of Schwann cell sheath (p = 0.039) and smaller axon (p = 0.034). Myelinated nerve fibers were unremarkable. The EM findings seen in the skin of FMS patients show unusual patterns of unmyelinated nerve fibers as well as associated Schwann cells. If these findings are replicated in a larger study, these abnormalities may contribute to, or be due to, the lower pain threshold seen in FMS patients.


Diffusion tensor imaging of the cortical plate and subplate in very-low-birth-weight infants.
Many intervention studies in preterm infants aim to improve neurodevelopmental outcome, but short-term proxy outcome measurements are lacking. Cortical plate and subplate development could be such a marker. Our aim was to provide normal DTI reference values for the cortical plate and subplate of preterm infants. As part of an ongoing study we analysed diffusion tensor imaging (DTI) images of 19 preterm infants without evidence of injury on conventional MRI, with normal outcome (Bayley-II assessed at age 2), and scanned in the first 4 days of life. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values in the frontal and temporal subplate and cortical plate were measured in single and multiple voxel regions of interest (ROI) placed on predefined regions. Using single-voxel ROIs, statistically significant inverse correlation was found between gestational age (GA) and FA of the frontal (r = -0.5938, P = 0.0058) and temporal (r = -0.4912, P = 0.0327) cortical plate. ADC values had a significant positive correlation with GA in the frontal (r = 0.5427, P = 0.0164) and temporal (r = 0.5540, P = 0.0138) subplate. Diffusion tensor imaging allows in vivo exploration of the evolving cortical plate and subplate. We provide FA and ADC values of the subplate and cortical plate in very-low-birth-weight (VLBW) infants with normal developmental outcome that can be used as reference values.


Implication of DNA polymerase lambda in alignment-based gap filling for nonhomologous DNA end joining in human nuclear extracts.
Accurate repair of free radical-mediated DNA double-strand breaks by the nonhomologous end joining pathway requires replacement of fragmented nucleotides in the aligned ends by a gap-filling DNA polymerase. Nuclear extracts of human HeLa cells, supplemented with recombinant XRCC4-DNA ligase IV complex (XRCC4/ligase IV), were capable of accurately rejoining model double-strand break substrates with a 1- or 2-base gap, and the gap-filling step was dependent on XRCC4/ligase IV. To determine what polymerase was responsible for gap filling, end joining was examined in the presence of polyclonal antibodies against each of two prime candidate enzymes, DNA polymerases mu and lambda, both of which were present in the extracts. For a DNA substrate with partially complementary 3' overhangs and a 2-base gap, antibodies to polymerase lambda completely eliminated both gap filling and accurate end joining, whereas antibodies to polymerase mu had little effect. Immunodepletion of polymerase lambda, but not polymerase mu, likewise blocked both gap filling and end joining, and both functions could be restored by addition of recombinant polymerase lambda. Recombinant polymerase mu, and a truncated polymerase lambda lacking the Brca1 C-terminal domain, were at least 10-fold less active in restoring gap filling to the immunodepleted extracts, and polymerase beta was completely inactive. The results suggest that polymerase lambda is the primary gap-filling polymerase for accurate nonhomologous end joining, and that the Brca1 C-terminal domain is required for this activity.


Is being small for gestational age a risk factor for strabismus and refractive errors at 3 years of age?
Visual problems, cerebral visual impairment, refractive errors and strabismus are commonly found in preterm infants in long-term follow-ups. The aim of this study was to determine the factors that lead to the development of amblyogenic risk factors, such as high refractive errors, anisometropia and strabismus, in the long-term evaluation of preterm infants. We retrospectively evaluated children who were screened for retinopathy of prematurity (ROP) and who had a 3rd year ophthalmologic examination. The impacts of sex, gestational age (GA), birth weight (BW), BW for GA, being small for gestational age (SGA), being appropriate for gestational age (AGA), multiple pregnancies and the results of ROP screening on refractive errors and the development of strabismus were evaluated by logistic regression analysis. The SGA and AGA groups were compared in terms of refractive errors and presence of strabismus. Six hundred and eight children, including 317 (52.1%) males and 291 (47.9%) females, were included in the study. The mean GA was 31 ± 3 weeks (24-36), and the mean BW was 1505 ± 435 g (600-2460). The number of SGA-born children was 101 (16.6%). Manifest deviation was detected in 42 (5.6%) children, and optical correction was required in 101 (16.6%) children. Being an SGA infant and multiple pregnancies were risk factors for refractive errors requiring optical correction, and hyperopia (≥3.00 D) was found to be a risk factor for the development of strabismus in the multivariate regression analysis. Additionally, the SGA group was at high risk for strabismus, hyperopia, high astigmatism and the need for optical correction. We concluded that SGA seems to be associated with an increased risk of strabismus and a high refractive error. It should be taken into consideration during follow-up examinations of SGA infants.


Photodegradation using TiO2-activated borosilicate tubes.
This study examines the photocatalytic activity of titanium dioxide (TiO2) semiconductor supported on borosilicate tubes (cut-off 290 nm) towards removal of a mix of persistent organic pollutants (POPs) from water. For this purpose, two widely used analgesic and anti-inflammatory drugs (NSAIDs), ibuprofen (IBU) and mefenamic acid, along with MCPA sodium monohydrate, which is a common herbicide frequently used in the agricultural activities, were selected as a case study. Borosilicate tubes were coated with titanium oxide through two different approaches: sol-gel dip-coating and a hybrid nanoparticle dip-coating and plasma-enhanced chemical vapour deposition (PECVD) process. The photochemical reactor that hosts the titania-coated tubes was designed to permit continuous throughput of liquid feed stream. The photodegradation experiments were performed in laboratory conditions under artificial irradiation simulating solar light. The efficiency of direct photolysis and heterogeneous photocatalysis (TiO2) was investigated, and the performance of each coating method was evaluated. Kinetic studies for each experiment were accomplished, the overall results showed poor efficiency and insufficient removal for NSAIDs through direct photolysis, whereas applying heterogeneous photacatalysis with TiO2 coated on borosilicate tubes was found to accelerate their degradation rate with complete decomposition. Concomitantly, kinetic experimental results showed a critical difference of performance for the two coating methods used; in particular, the degradation rates of pollutants by the sol-gel-coated tubes were much faster than the degradation by the nanoparticle/PECVD-coated tubes. Using TiO2 supported on borosilicate tubes appears to be a promising alternative to conventional TiO2 suspension and avoid post-separation stages. The results achieved in this study can be used to optimise large-scale applications, and expanding the study to cover a wide range of pollutants will lead to achieve more representative results.


Cognitive therapy as an early treatment for post-traumatic stress disorder in children and adolescents: a randomized controlled trial addressing preliminary efficacy and mechanisms of action.
Few efficacious early treatments for post-traumatic stress disorder (PTSD) in children and adolescents exist. Previous trials have intervened within the first month post-trauma and focused on secondary prevention of later post-traumatic stress; however, considerable natural recovery may still occur up to 6-months post-trauma. No trials have addressed the early treatment of established PTSD (i.e. 2- to 6-months post-trauma). Twenty-nine youth (8-17 years) with PTSD (according to age-appropriate DSM-IV or ICD-10 diagnostic criteria) after a single-event trauma in the previous 2-6 months were randomly allocated to Cognitive Therapy for PTSD (CT-PTSD; n = 14) or waiting list (WL; n = 15) for 10 weeks. Significantly more participants were free of PTSD after CT-PTSD (71%) than WL (27%) at posttreatment (intent-to-treat, 95% CI for difference .04-.71). CT-PTSD yielded greater improvement on child-report questionnaire measures of PTSD, depression and anxiety; clinician-rated functioning; and parent-reported outcomes. Recovery after CT-PTSD was maintained at 6- and 12-month posttreatment. Beneficial effects of CT-PTSD were mediated through changes in appraisals and safety-seeking behaviours, as predicted by cognitive models of PTSD. CT-PTSD was considered acceptable on the basis of low dropout and high treatment credibility and therapist alliance ratings. This trial provides preliminary support for the efficacy and acceptability of CT-PTSD as an early treatment for PTSD in youth. Moreover, the trial did not support the extension of 'watchful waiting' into the 2- to 6-month post-trauma window, as significant improvements in the WL arm (particularly in terms of functioning and depression) were not observed. Replication in larger samples is needed, but attention to recruitment issues will be required.


Genetic control of hematopoietic development in Xenopus and zebrafish.
Blood development has been highly conserved during evolution. Hematopoietic cells in amphibian and fish embryos, as in mammalian embryos, emerge and progressively differentiate in several locations. Hematopoiesis, including of the immune system, is similar in the amphibian, Xenopus, to mammals and the embryos are ideal for tissue transplantation and lineage labelling experiments, which have enabled the elucidation of the distinct origins of embryonic and adult hematopoietic cells, as well as their migration pathways and organ colonisation behaviours. The zebrafish hematopoietic system is less well understood, but these embryos have recently emerged as a powerful system for both genetic analysis and imaging. In this review, we summarise our current knowledge of the cellular and genetic basis of ontogeny of the hematopoietic system in Xenopus and zebrafish embryos.


Gene expression changes during retinal development and rod specification.
Retinitis pigmentosa (RP) typically results from individual mutations in any one of >70 genes that cause rod photoreceptor cells to degenerate prematurely, eventually resulting in blindness. Gene therapies targeting individual RP genes have shown efficacy at clinical trial; however, these therapies require the surviving photoreceptor cells to be viable and functional, and may be economically feasible for only the more commonly mutated genes. An alternative potential treatment strategy, particularly for late stage disease, may involve stem cell transplants into the photoreceptor layer of the retina. Rod progenitors from postnatal mouse retinas can be transplanted and can form photoreceptors in recipient adult retinas; optimal numbers of transplantable cells are obtained from postnatal day 3-5 (P3-5) retinas. These cells can also be expanded in culture; however, this results in the loss of photoreceptor potential. Gene expression differences between postnatal retinas, cultured retinal progenitor cells (RPCs), and rod photoreceptor precursors were investigated to identify gene expression patterns involved in the specification of rod photoreceptors. Microarrays were used to investigate differences in gene expression between cultured RPCs that have lost photoreceptor potential, P1 retinas, and fresh P5 retinas that contain significant numbers of transplantable photoreceptors. Additionally, fluorescence-activated cell sorting (FACS) sorted Rho-eGFP-expressing rod photoreceptor precursors were compared with Rho-eGFP-negative cells from the same P5 retinas. Differential expression was confirmed with quantitative polymerase chain reaction (q-PCR). Analysis of the microarray data sets, including the use of t-distributed stochastic neighbor embedding (t-SNE) to identify expression pattern neighbors of key photoreceptor specific genes, resulted in the identification of 636 genes differentially regulated during rod specification. Forty-four of these genes when mutated have previously been found to cause retinal disease. Although gene function in other tissues may be known, the retinal function of approximately 61% of the gene list is as yet undetermined. Many of these genes' promoters contain binding sites for the key photoreceptor transcription factors Crx and Nr2e3; moreover, the genomic clustering of differentially regulated genes appears to be non-random. This study aids in understanding gene expression differences between rod photoreceptor progenitors versus cultured RPCs that have lost photoreceptor potential. The results provide insights into rod photoreceptor development and should expedite the development of cell-based treatments for RP. Furthermore, the data set includes a large number of retinopathy genes; less-well-characterized genes within this data set are a resource for those seeking to identify novel retinopathy genes in patients with RP (GEO accession: GSE59201).


The Role of Rehabilitative Ultrasound Imaging Technique in the Lumbopelvic Region as a Diagnosis and Treatment Tool in Physiotherapy: Systematic Review, Meta-Analysis and Meta-Regression.
Rehabilitative ultrasound imaging (RUSI) technique seems to be a valid and reliable tool for diagnosis and treatment in physiotherapy and has been widely studied in the lumbopelvic region the last three decades. The aims for this utility in clinical settings must be review through a systematic review, meta-analysis and meta-regression. A systematic review was designed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines with PROSPERO registration and per review in all phases of the process using COVIDENCE, analysis of risk of bias and meta-analysis using REVMAN, and meta-regression calculation using STATA. Database screening provided 6544 references, out of which 321 reported narrative synthesis, and 21 reported quantitative synthesis, while only 7 of them provided comparable data to meta-analyze the variables pain and muscle thickness. In most cases, the forest plots showed considerable I2 heterogeneity indexes for multifidus muscle thickness (I2 = 95%), low back pain (I2 = 92%) and abdominal pain (I2 = 95%), not important for transversus abdominis muscle thickness (I2 = 22%), significant heterogenity (I2 = 69%) depending on the subgroup and not important internal oblique muscle thickness (I2 = 0%) and external oblique muscle thickness (I2 = 0%). Meta-regression did not provide significant data for the correlations between the variables analyzed and the intervention, age, and BMI (Body Mass Index). This review reveals that RUSI could contribute to a high reliability of the measurements in the lumbopelvic region with validity and reliability for the assessments, as well as showing promising results for diagnosis and intervention assessment in physiotherapy compared to the traditional model, allowing for future lines of research in this area.


Incidence of aplastic anemia in Turkey: a hospital-based prospective multicentre study.
The incidence of aplastic anemia among hospitalized adult patients was prospectively determined in this first study in Turkey. New cases of aplastic anemia among patients 14 years and older who were admitted to the study centers were included in a 3 year survey. Seventy-three patients fulfilled the diagnostic criteria, yielding a mean annual incidence rate of 1.14 cases in 10(3) admissions. The male-to-female ratio of the cases (1.6:1) differed from the almost equal ratio of the larger population of Turkey. The median age was 30 years and females were younger at diagnosis. The age distribution of the cases was different from that of the population; showing two incidence peaks in both sexes. The majority of the patients (89%) had severe disease.


Genome-wide analysis of cellular response to bacterial genotoxin CdtB in yeast.
The cytolethal distending toxins (CDTs) are secreted virulence proteins produced by several bacterial pathogens, and the subunit CdtB has the ability to create DNA lesions, primarily DNA single-strand breaks (SSBs) in vitro, and cause cell cycle arrest, cellular distension, and cell death in both mammalian and yeast cells. To elucidate the components of the mechanisms underlying the response to CdtB-induced DNA lesions, a CdtB expression plasmid was transformed into a series of diploid yeast strains harboring deletions in 4,708 nonessential genes. A total of 4,706 of these clones were successfully transformed, which we have now designated as a systematic transformation array (STA), and were subsequently screened. We identified 61 sensitive strains from the STA whose deleted genes can be categorized into a number of groups, including DNA metabolism, chromosome segregation, vesicular traffic, RNA catabolism, protein translation, morphogenesis, and nuclear transport, as well as one unknown open reading frame. However, only 28 of these strains were found to be sensitive to HO endonuclease, which is known to create a DNA double-strand break (DSB), suggesting that CdtB-induced DNA lesion is not similar to the direct DSB. Amazingly, CdtB expression elicits severe growth defects in haploid yeast cells, but only marginal defects in diploid yeast cells. The presence and absence of genes known to be involved in DNA repair in these genome-wide data reveal that CdtB-induced DNA damage is specifically repaired well in the diploid by homologous recombination but not by other repair mechanisms. Our present results provide insights into how CdtB pathogenesis is linked to eukaryotic cellular functions.


The complete genome sequence of Escherichia coli EC958: a high quality reference sequence for the globally disseminated multidrug resistant E. coli O25b:H4-ST131 clone.
Escherichia coli ST131 is now recognised as a leading contributor to urinary tract and bloodstream infections in both community and clinical settings. Here we present the complete, annotated genome of E. coli EC958, which was isolated from the urine of a patient presenting with a urinary tract infection in the Northwest region of England and represents the most well characterised ST131 strain. Sequencing was carried out using the Pacific Biosciences platform, which provided sufficient depth and read-length to produce a complete genome without the need for other technologies. The discovery of spurious contigs within the assembly that correspond to site-specific inversions in the tail fibre regions of prophages demonstrates the potential for this technology to reveal dynamic evolutionary mechanisms. E. coli EC958 belongs to the major subgroup of ST131 strains that produce the CTX-M-15 extended spectrum β-lactamase, are fluoroquinolone resistant and encode the fimH30 type 1 fimbrial adhesin. This subgroup includes the Indian strain NA114 and the North American strain JJ1886. A comparison of the genomes of EC958, JJ1886 and NA114 revealed that differences in the arrangement of genomic islands, prophages and other repetitive elements in the NA114 genome are not biologically relevant and are due to misassembly. The availability of a high quality uropathogenic E. coli ST131 genome provides a reference for understanding this multidrug resistant pathogen and will facilitate novel functional, comparative and clinical studies of the E. coli ST131 clonal lineage.


eIF4E threshold levels differ in governing normal and neoplastic expansion of mammary stem and luminal progenitor cells.
Translation initiation factor eIF4E mediates normal cell proliferation, yet induces tumorigenesis when overexpressed. The mechanisms by which eIF4E directs such distinct biologic outputs remain unknown. We found that mouse mammary morphogenesis during pregnancy and lactation is accompanied by increased cap-binding capability of eIF4E and activation of the eIF4E-dependent translational apparatus, but only subtle oscillations in eIF4E abundance. Using a transgenic mouse model engineered so that lactogenic hormones stimulate a sustained increase in eIF4E abundance in stem/progenitor cells of lactogenic mammary epithelium during successive pregnancy/lactation cycles, eIF4E overexpression increased self-renewal, triggered DNA replication stress, and induced formation of premalignant and malignant lesions. Using complementary in vivo and ex vivo approaches, we found that increasing eIF4E levels rescued cells harboring oncogenic c-Myc or H-RasV12 from DNA replication stress and oncogene-induced replication catastrophe. Our findings indicate that distinct threshold levels of eIF4E govern its biologic output in lactating mammary glands and that eIF4E overexpression in the context of stem/progenitor cell population expansion can initiate malignant transformation by enabling cells to evade DNA damage checkpoints activated by oncogenic stimuli. Maintaining eIF4E levels below its proneoplastic threshold is an important anticancer defense in normal cells, with important implications for understanding pregnancy-associated breast cancer.