Child marriage in Ghana: evidence from a multi-method study.
Child marriage remains a challenge in Ghana. Over the years, government and development partners have made various commitments and efforts to curb the phenomenon of child marriage. However, there is little empirical evidence on the predictors, norms and practices surrounding the practice to support their efforts, a gap this study sought to fill. The study employed a multiple-method approach to achieve the set objectives. Data from the women's file of the 2014 Ghana Demographic and Health Survey (GDHS) was used to examine the predictors of child marriage using frequencies and logistic regression methods. Data from Key Informant Interviews (KIIs) and Focus Group Discussions (FGDs) collected in Central and Northern regions of Ghana were used to examine norms and practices surrounding child marriage using thematic analysis. Two in ten (20.68%) girls in the quantitative sample married as children. The results revealed that girls who had never attended school compared to those who had ever attended school were more likely to marry as children (OR, 3.01). Compared with girls in the lowest wealth quintile, girls in the middle (OR, 0.59), fourth (OR, 0.37) and highest (OR, 0.32) wealth quintiles were less likely to marry as children. From the qualitative data, the study identified poverty, teenage pregnancy, and cultural norms such as betrothal marriage, exchange of girls for marriage and pressure from significant others as the drivers of child marriage. The findings show that various socio-economic and cultural factors such as education, teenage pregnancy and poverty influence child marriage. Hence, efforts to curb child marriage should be geared towards retention of girls in school, curbing teenage pregnancy, empowering girls economically, enforcing laws on child marriage in Ghana, as well as designing tailored advocacy programs to educate key stakeholders and adolescent girls on the consequences of child marriage. Additionally, there is the need to address socio-cultural norms/practices to help end child marriage.


Longwave infrared (LWIR) coded aperture dispersive spectrometer.
We describe a static aperture-coded, dispersive longwave infrared (LWIR) spectrometer that uses a microbolometer array at the detector plane. The two-dimensional aperture code is based on a row-doubled Hadamard mask with transmissive and opaque openings. The independent column code nature of the matrix makes for a mathematically well-defined pattern that spatially and spectrally maps the source information to the detector plane. Post-processing techniques on the data provide spectral estimates of the source. Comparative experimental results between a slit and coded aperture for emission spectroscopy from a CO(2) laser are demonstrated.


The Influence of Verbal Suggestion on Post-Needling Soreness and Pain Processing after Dry Needling Treatment: An Experimental Study.
It remains unclear as to whether verbal suggestions and expectancies can influence the perception of post-needling soreness. The aim of this study was to analyze the effects of verbal suggestions on post-needling soreness after dry needling of the trapezius muscle. This study is a randomized controlled trial including healthy subjects randomly assigned to one of three groups receiving different verbal suggestions about the effects of dry needling and the occurrence of post needling soreness (positive, negative, or neutral). Then, dry needling on a latent trigger point of the upper trapezius muscle was performed and the following outcomes were measured immediately after, 24, 48, and 72 h, and one week after the intervention: post-needling soreness intensity, pressure pain threshold (PPT), temporal summation (TS) and conditioned pain modulation (CPM). Seventy-three consecutive participants were screened and 42 participants (12 men and 30 women, aged: 24 ± 8 years old) were eligible and finished the study protocol. The results showed that verbal suggestion did not influence the perception of post-needling soreness, since there were no differences between groups (p < 0.05) on the intensity of post-needling soreness or tenderness over a one-week follow-up. Moreover, verbal suggestion did not associate with changes in sensorimotor variables of TS and CPM. The induction of different types of expectations through verbal suggestion does not influence the perception of acute pain perceived during the performance of a deep dry needling technique and post-needling pain or soreness after deep dry needling on a latent upper trapezius myofascial trigger point (MTrP).


Neonatal oxytocin administration and supplemental milk ameliorate the weaning transition and alter hormonal expression in the gastrointestinal tract in pigs.
The aim of this study was to investigate the influences of milk supplementation during lactation, over 1 wk after weaning, and oxytocin administration for the first 14 d of life on the pigs' response to weaning. Pigs from 20 litters were allocated to each of these 3 treatments in a randomized factorial design. Oxytocin was administered subcutaneously daily from 0 to 14 d of age at a rate of 10 I.U. per kg. The milk supplement consisted of a mixture of 25% skim milk powder offered either during lactation between 10 and 20 d of age or for the first week after weaning as a transitional diet along with dry pellets. Pigs were weaned at 21 d of age. Growth rate was measured from birth to slaughter at 140 d of age and feed intake of supplemental milk or feed from 10 to 56 d of age. Organ weights (heart, liver, stomach, and kidneys) and the gene expression of ghrelin, leptin, and glucagon-like peptides (glucagon-like peptide-1 and glucagon-like peptide-2) were measured in the stomach, ileum, and duodenum at 10, 21, and 28 d of age. Milk supplementation after weaning resulted in immediate feed intake and partially alleviated the depression in growth rate over the first 7 d postweaning (P < 0.001), but milk supplementation during lactation had no effects (P > 0.1). However, effects were only transient and disappeared once the milk liquid diet was removed. Neonatal oxytocin administration reduced weight loss over the first 2 d after weaning (P = 0.03), without affecting feed intake (P > 0.1), hence possibly reducing weaning stress. Seven days after weaning, oxytocin-treated pigs had greater stomach ghrelin and leptin expression (both P = 0.02), and pigs supplemented with milk after weaning had greater stomach leptin and glucagon-like peptide-2 expression (P = 0.02 and P = 0.05, respectively). Hence, neonatal oxytocin administration or postweaning milk supplementation are both effective means of enhancing gastric leptin expression and reducing weight loss at weaning, likely improving gut health during this critical period.


Pregabalin for peripheral neuropathic pain: a multicenter, enriched enrollment randomized withdrawal placebo-controlled trial.
To date, published neuropathic pain randomized controlled trials of pregabalin have involved primarily diabetic peripheral neuropathy (DPN) and postherpetic neuralgia (PHN). This multicenter trial evaluated pregabalin in a broader range of neuropathic pain etiologies. In this enriched enrollment randomized withdrawal trial, 256 patients received single blind, flexible dose pregabalin for 4 weeks; stable concomitant analgesics were allowed. One hundred sixty-five (65%) had a ≥30% pain improvement and 157 were randomized and treated, double blind, to either continue pregabalin (n=80) or to receive placebo (n=77) for 5 weeks. Of the single blind responders randomized, 81% on placebo and 86% on pregabalin completed the double-blind phase. At the double-blind endpoint, mean (SD) pain scores were 2.9 (1.9) in the pregabalin group and 3.5 (1.7) in the placebo group (P=0.002). These modest yet significant pregabalin-placebo differences were observed within each of the subgroups of patients with a diagnosis of either DPN or PHN (P=0.03), and with other diagnoses (P=0.02). Significant differences were also observed in sleep interference, Hospital Anxiety and Depression Scale Anxiety and Depression subscales, and other secondary measures. In total, 28 out of 80 (35.0%) in the pregabalin group and 28 out of 77 (36.4%) in the placebo group had either a meaningful increase in pain or discontinued the double-blind phase. Adverse events were consistent with the known tolerability profile of pregabalin and led to discontinuation of 9 during the single-blind phase, and 5 and 2 patients from the placebo and pregabalin groups, respectively. These results support previous evidence of pregabalin efficacy but further demonstrate efficacy and tolerability in a broader range of peripheral neuropathic pain conditions beyond just DPN and PHN.


Anterograde transneuronal viral tracing of central viscerosensory pathways in rats.
Previous studies demonstrated that strain H129 of herpes simplex virus-1 undergoes anterograde transneuronal transport in mice and primates after peripheral or central injection. In this study, H129 was used in rats to identify CNS regions that receive relayed viscero-sensory inputs from the stomach wall. We also examined whether transneuronal viral transport in this model is exclusively anterograde. H129 or an established retrograde transneuronal viral tracer, pseudorabies virus (PRV), was injected into the ventral stomach wall in intact rats or in rats with previous subdiaphragmatic vagal sensory deafferentation. Rats were perfused with fixative 3-5 d later, and tissues were processed for immunocytochemical detection of transported virus. In intact rats, H129 was transported transneuronally via vagal and spinal viscerosensory neurons to postsynaptic target cells in the medullary dorsal vagal complex and thoracic dorsal horn, respectively, with subsequent transport to discrete regions of the medullary and pontine reticular formation, cerebellum, parabrachial nucleus, periaqueductal gray, thalamus, hypothalamus, amygdala, bed nucleus of the stria terminalis, and other central sites. Comparison of labeling patterns in intact and vagal deafferented rats indicated that H129 also produced first-order retrograde infection of autonomic neurons that project directly to virus injection sites, similar to PRV. Unlike PRV, however, H129 was not transported transneuronally in the retrograde direction from infected neurons to central sources of presynaptic input. We conclude that transneuronal transport of H129 occurs exclusively in the anterograde direction to reveal CNS regions that receive direct and relayed viscerosensory signals.


Impairment of Nrf2- and Nitrergic-Mediated Gastrointestinal Motility in an MPTP Mouse Model of Parkinson's Disease.
Gastrointestinal (GI) motility dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Studies have indicated that GI motility functions are impaired before the onset of PD. To investigate the underlying mechanism of PD-induced GI dysmotility in MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine)-induced animal model. C57BL/6 mice were administered with or without a selective dopamine neurotoxin, MPTP, to induce parkinsonian symptoms. In addition to in vivo studies, in vitro experiments were also conducted in colon specimens using l-methyl-4-phenylpyridinium (MPP+), a metabolic product of MPTP. Gastric emptying, colon motility, nitrergic relaxation, and western blot experiments were performed as reported. MPTP-induced PD mice showed decreased expression of nuclear factor erythroid 2-related factor (Nrf2) and its target phase II genes in gastric and colon neuromuscular tissues. Decreased levels of tetrahydrobiopterin (BH4, a critical cofactor for nNOS dimerization) associated with uncoupling of nNOS in gastric and colon tissues exposed to MPTP. Impaired enteric nitrergic system led to delayed gastric emptying and slower colonic motility compared to the control mice. In vitro results in colon specimens confirm that activation of Nrf2 restored MPP+-induced suppression of alpha-synuclein, tyrosine hydroxylase (TH), Nrf2, and heme oxygenase-1. In vitro exposure to L-NAME [N(w)-nitro-L-arginine methyl ester], a NOS synthase inhibitor, reduced protein expression of TH in colon tissue homogenates. Loss of Nrf2/BH4/nNOS expression in PD impairs antioxidant gene expression, which deregulates NO synthesis, thereby contributing to the development of GI dysmotility and constipation. Nitric oxide appears to be important to maintain dopamine synthesis in the colon.


The effect of obesity in adolescence on adult health status.
To test the hypothesis that adolescent obesity would be associated with greater risks of adverse health in severely obese adults. Before weight loss surgery, adult participants in the Longitudinal Assessment of Bariatric Surgery-2 underwent detailed anthropometric and comorbidity assessment. Weight status at age 18 was retrospectively determined. Participants who were ≥80% certain of recalled height and weight at age 18 (1502 of 2308) were included. Log binomial regression was used to evaluate whether weight status at age 18 was independently associated with risk of comorbid conditions at time of surgery controlling for potential confounders. Median age and adult body mass index (BMI) were 47 years and 46, respectively. At age 18, 42% of subjects were healthy weight, 29% overweight, 16% class 1 obese, and 13% class ≥2 obese. Compared with healthy weight at age 18, class ≥2 obesity at age 18 independently increased the risk of lower-extremity venous edema with skin manifestations by 435% (P < .0001), severe walking limitation by 321% (P < .0001), abnormal kidney function by 302% (P < .0001), polycystic ovary syndrome by 74% (P = .03), asthma by 48% (P = .01), diabetes by 42% (P < .01), obstructive sleep apnea by 25% (P < .01), and hypertension (by varying degrees based on age and gender). Conversely, the associated risk of hyperlipidemia was reduced by 61% (P < .01). Severe obesity at age 18 was independently associated with increased risk of several comorbid conditions in adults undergoing bariatric surgery.


Inter-limb strength asymmetry in adolescent distance runners: Test-retest reliability and relationships with performance and running economy.
The purpose of this investigation was, firstly, to quantify the test-retest reliability of strength measures in adolescent distance runners; and secondly, to explore the relationships between inter-limb strength asymmetry and performance and running economy (RE) in a similar cohort of young runners. For the reliability study, twelve (n = 6 female) post-pubertal adolescent distance runners performed an isometric quarter-squat on a dual force plate and unilateral isometric hip extension and hip abduction tests on two occasions. For the correlation study, participants (n = 31) performed the strength tests plus a submaximal incremental running assessment and a maximal running test. Running economy was expressed as the average energy cost of running for all speeds below lactate turnpoint and was scaled for body mass using a previously calculated power exponent. Allometrically scaled peak force during the quarter-squat and peak torque in the hip strength tasks showed acceptable levels of reproducibility (typical error ≤6.3%). Relationships between strength asymmetry and performance and RE were low or negligible (r < 0.47, p > 0.05), except for hip abduction strength asymmetry and RE in the female participants (r = 0.85, p < 0.001, n = 16). Practitioners should consider inter-limb hip abduction strength asymmetry on an individual level, and attempting to reduce this asymmetry in females may positively impact RE.


Chlorpropamide-alcohol flush reaction and isoenzyme profiles of alcohol dehydrogenase and aldehyde dehydrogenase.
To investigate the enzymatic basis of the chlorpropamide-alcohol flush reaction (CPAF) we compared the isoenzyme profiles of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) from liver biopsies, and of ALDH alone from erythrocytes and leucocytes, in CPAF-positive and CPAF-negative subjects. No differences were seen in ADH or ALDH phenotypes, or in the relative activities of the isoenzymes, between the two groups before chlorpropamide was given; in particular, no subjects showed the 'null' ALDH phenotype that is associated with the alcohol flush reaction in oriental subjects. There was a significant decrease in erythrocyte ALDH activity after 7 days' treatment with chlorpropamide in CPAF-positive individuals but no such difference was seen in CPAF-negative subjects. These results indicate that CPAF has a different enzymatic basis from the alcohol flush reaction of oriental subjects and suggest that in CPAF-positive subjects erythrocyte ALDH may be particularly susceptible to inhibition by chlorpropamide.


Twisted nose: a new simple classification and surgical algorithm in Asians.
The purpose of this study was to present our experiences with correction of twisted nose in Asian patients using a new and simple classification and a surgical algorithm. A classification and standard surgical algorithm was followed to determine treatment strategies for 384 patients with twisted nose between June 2001 and July 2009. A retrospective chart review from the Tri-Service General Hospital archives was performed to collect patients' data and surgical details. A follow-up self-evaluation survey regarding satisfaction with nasal function and esthetics was distributed to all participants. Preoperative and postoperative standardized photography of the face were evaluated to judge objectively the esthetic outcomes of the surgery. There were 147, 131, and 106 patients in Type I, Type II, and Type III patients, respectively. The percentages of functionally satisfied and very satisfied patients were 95.2, 93.9, and 93.4% in Type I, Type II, and Type III groups, respectively. The percentages of esthetically satisfied or very satisfied patients were 89.1, 88.5, and 87.7% in Type I, Type II, and Type III groups, respectively. There were only 2 patients with type III deviation with residual deviation of dorsum objectively who were satisfied with the results after undergoing a revision rhinoplasty. Aside from residual deviation, the postoperative periods were uneventful and without major complications. We propose a new and simple classification and surgical algorithm to optimally correct twisted nose deformities for Asian patients. The classification and surgical algorithm, which is simple and reproducible especially for beginner, guides surgical decisions that yield consistently satisfactory functional and esthetic results.


Spacing enhances the learning of natural concepts: an investigation of mechanisms, metacognition, and aging.
In two experiments, we examined spacing effects on the learning of bird families and metacognitive assessments of such learning. Results revealed that spacing enhanced learning beyond massed study. These effects were increased by presenting birds in pairs so as to highlight differences among families during study (Experiment 1). Self-allocated study time provided evidence that more attention was paid during spaced than during massed study and resulted in no age differences in learning (Experiment 2). Metacognitive measures revealed sensitivity to the processing advantage of spaced study and to differences in classification difficulty across categories. No difference occurred in monitoring accuracy for young versus older adults. These findings provide evidence for discrimination- and attention-based accounts of the spacing effect in natural concept learning.


Error detection and error memory in spatial navigation as reflected by electrodermal activity.
The study investigated spatial navigation by means of electrodermal activity (EDA). Two groups of healthy subjects (group 1, age <38; group 2, age ≥ 38) were recorded during navigation through two 3-D virtual mazes differing in difficulty, that is, Maze Simple (MazeS) and Maze Complex (MazeC). Our results show (1) an effect of difficulty, that is, larger skin conductance responses (SCRs) and slower velocity profiles while navigating through MazeC as compared to MazeS. (2) An effect of age, that is, larger SCRs and faster velocity profiles in younger subjects (group 1) compared to older subjects (group 2). (3) An effect of maze region, that is, SCRs increased when subjects entered dead ends with group 1 (young group) decreasing in velocity, whereas group 2 (old group) increased in velocity. (4) And an error memory effect, that is, subjects who remembered an error at a given decision point (crossroads preceding dead ends in MazeC) from previous trials, and then if they did not repeat that error, elicited decreased SCRs as compared to subjects who did not remember and subsequently repeated an error. The latter aspect is the most impactful as it shows that EDA is able to reflect error detection and memory during spatial navigation. Our data designate EDA as suitable monitoring tool for identification and differentiation of the affective correlates underlying spatial navigation, which has recently attracted researchers' attention due to its increased use in 3-D virtual environments.


Inducing autophagy: a comparative phosphoproteomic study of the cellular response to ammonia and rapamycin.
Autophagy is a lysosomal-mediated catabolic process, which through degradation of different cytoplasmic components aids in maintaining cellular homeostasis and survival during exposure to extra- or intracellular stresses. Ammonia is a potential toxic and stress-inducing byproduct of glutamine catabolism, which has recently been found to induce autophagy in an MTOR independent way and support cancer cell survival. In this study, quantitative phosphoproteomics was applied to investigate the initial signaling events linking ammonia to the induction of autophagy. The MTOR inhibitor rapamycin was used as a reference treatment to emphasize the differences between an MTOR-dependent and -independent autophagy-induction. By this means 5901 phosphosites were identified of which 626 were treatment-specific regulated and 175 were coregulated. Investigation of the ammonia-specific regulated sites supported that MTOR activity was not affected, but indicated increased MAPK3 activity, regulation of proteins involved in Rho signal transduction, and a novel phosphorylation motif, serine-proline-threonine (SPT), which could be linked to cytoskeleton-associated proteins. MAPK3 could not be identified as the primary driver of ammonia-induced autophagy but instead the data suggested an upregulation of AMPK and the unfolded protein response (UPR), which might link ammonia to autophagy induction. Support of UPR induction was further obtained from the finding of increased protein levels of the ER stress markers DDIT3/CHOP and HSPA5 during ammonia treatment. The large-scale data set presented here comprises extensive high-quality quantitative information on phosphoprotein regulation in response to 2 very different autophagy inducers and should therefore be considered a general resource for the community.


Paternal involvement in Multisystemic Therapy: effects on adolescent outcomes and maternal depression.
The association between paternal involvement in therapy, adolescent outcomes and maternal depression was examined within the context of Multisystemic Therapy (MST), an empirically supported, family- and community-based treatment for antisocial adolescents. Ninety-nine families were recruited from five mental health agencies providing MST. We compared families with paternal involvement in therapy (PIT) to families with no paternal involvement in therapy (NPIT) in pre-post change in adolescents' externalizing and internalizing behaviours and also in maternal depression. There was a significant reduction in both groups in externalizing and internalizing behaviours. However, the magnitude of improvement was significantly greater for the PIT families. Both groups saw a significant reduction in maternal depression but no significant group differences were found. Results suggest that if possible, paternal figures should be encouraged to actively participate in therapy, as adolescents outcomes are enhanced when mothers and paternal figures participate in MST together.


Psychotic-like experiences and correlation with childhood trauma and other socio-demographic factors: A cross-sectional survey in adolescence and early adulthood in China.
Psychotic-like experiences (PLEs) in adolescence are found to be risk factors for later mental disorders. Previous research has also found that childhood trauma has a positive correlation with mental health problems. However, few studies have focused on the relationship between them, especially in adolescence and early adulthood. A total of 9122 students (age between 10 and 23.3) were surveyed and assessed with the positive and depressive subscales of the Community Assessment of Psychic Experiences and the Trauma History Questionnaire. A total of 20.7% students experienced frequent PLEs, 17.5% had frequent delusional experiences, and 7.6% had frequent hallucinatory experiences. Only a small portion of this sample experienced frequent PLEs, associated with more types of PLEs, more distress, and more depressive experiences. Several socio-demographic factors were associated with frequent PLEs in this sample, which could be further examined in future prevention studies. Students with frequent PLEs experienced significantly higher impact from trauma events, both at the time of the events and in the present, indicating a possible reciprocal effect between childhood trauma and PLEs. The impact of childhood trauma played an important role in the relationship between childhood trauma and PLEs.


Prevalence, Patterns, and Clinical Predictors of Left Ventricular Late Gadolinium Enhancement in Patients Undergoing Cardiac Magnetic Resonance Prior to Pulmonary Vein Antral Isolation for Atrial Fibrillation: A Cross-Sectional Observational Study.
Cardiac magnetic resonance (CMR) imaging is increasingly used to evaluate patients with atrial fibrillation (AF) before pulmonary vein antral isolation (PVAI). The purpose of this study was to assess the incidence and pattern of left ventricular (LV) late gadolinium enhancement (LGE) in patients undergoing CMR before PVAI and compare the clinical and demographic differences of patients with and without LV LGE. Clinical and demographic data on 62 patients (mean age 61 ± 7.9, 69% male) undergoing CMR before PVAI for AF were collected. Two observers, masked to clinical histories, independently recorded the prevalence, extent (number of myocardial segments), and pattern (subendocardial, midmyocardial, or subepicardial) of LV LGE in each patient. Clinical and demographic predictors of LV LGE were determined using logistic regression. Twenty-three patients (37%) demonstrated LV LGE affecting a mean of 3.0 ± 2.1 myocardial segments. There was no difference in LV ejection fraction between patients with and without LGE, and most (65%) patients with LGE had normal wall motion. Only age (P = 0.04) and a history of congestive heart failure (P = .03) were statistically significant independent predictors of LGE. The most common LGE pattern was midmyocardial, seen in 17 of 23 (74%) patients. Only 4 of 23 (17%) patients had LGE in an "expected" pattern based on clinical history. Of the remaining 19 patients, 4 had known congestive heart failure, 5 nonischemic cardiomyopathy, 4 known coronary artery disease, and 2 prior aortic valve replacement. Six of 23 (26%) patients had no known coronary artery, valvular, or myocardial disease. There is a high prevalence of unexpected LV scar in patients undergoing CMR before PVAI for AF, with most patients demonstrating a nonischemic pattern of LV LGE and no wall motion abnormalities (ie, subclinical disease). The high prevalence of unexpected LGE in these patients may argue for CMR as the modality of choice for imaging integration before PVAI, especially given the demonstrated prognostic value of LGE in this and other patient populations.


L-theanine and caffeine improve task switching but not intersensory attention or subjective alertness.
Tea ingredients L-theanine and caffeine have repeatedly been shown to deliver unique cognitive benefits when consumed in combination. The current randomized, placebo-controlled, double-blind, cross-over study compared a combination of L-theanine (97 mg) and caffeine (40 mg) to a placebo on two attention tasks and a self-report questionnaire before, and 10 and 60 min after consumption. The combination of L-theanine and caffeine significantly improved attention on a switch task as compared to the placebo, while subjective alertness and intersensory attention were not improved significantly. The results support previous evidence that L-theanine and caffeine in combination can improve attention.


Voluntary consumption of beverage alcohol by vervet monkeys: population screening, descriptive behavior and biochemical measures.
Seventeen percent of 196 feral vervet monkeys (Cercopithecus aethiops) spontaneously drank appreciable quantities of beverage alcohol in 3% sucrose in preference to 3% sucrose alone. Ethanol consumption increased over time, as did the concentration of ethanol tolerated. Willingness to select ethanol was stable over a three-year period, as measured by periodic retesting. Individual patterns of drinking and behavioral responses to ethanol were quite variable. Upon occasion, some animals drank to ataxia and unconsciousness; signs of withdrawal, including tremulousness, pacing, irritability and increased aggression, followed the abrupt discontinuation of ethanol availability. A variety of changes in social interaction, including increased orientation to external stimulus, increased incidence of stereotyped aggression and of other stereotyped behaviors and decreased frequency of affiliative behaviors were observed during ethanol periods, as compared to baseline scoring periods. In a small number of alcohol-preferring animals, CSF amine metabolites (5-hydroxyindoleacetic acid and homovanillic acid) were raised by drinking alcohol. These studies suggest that the alcohol-selecting vervet monkey may be complementary to established primate models of alcoholism.


The agent of Human Granulocytic Ehrlichiosis resides in an endosomal compartment.
The composition of cytoplasmic vacuoles containing the agent of Human Granulocytic Ehrlichiosis (HGE) was studied to investigate how this pathogen exists within infected host cells. Electron microscopy demonstrated that the HGE organism resides in a membrane-bound compartment within HL-60 cells: early forms of the HGE agent have a round reticular appearance while later structures are small and dense. Vacuoles containing HGE bacteria incorporated endocytosed colloidal gold particles, suggesting that they are part of the endocytic pathway. Antibodies directed to the mannose-6-phosphate receptor labeled vacuole membranes. Antibodies to the transferrin receptor and to the lysosomal membrane glycoprotein LAMP 1 did not. Moreover, 3-(2,4-dinitroanilino)-3'-amino-N-methyldipropylamine, which normally accumulates in compartments with low pH, was not present inside these vacuoles. These results suggest that vacuoles containing the agent of HGE fail to mature into phagolysosomes. We conclude that the agent of HGE appears to enter and modify part of the endocytic pathway.


Molecular vibration as a novel explanatory mechanism for the expression of animal colouration.
Animal colouration is characterized by the concentration of pigments in integumentary structures and by the nanoscale arrangement of constitutive elements. However, the influence of molecular vibration on colour expression has been overlooked in biology. Molecular vibration occurs in the infrared spectral region, but vibrational and electronic properties can influence each other. Thus, the vibration of pigment molecules may also affect their absorption properties and the resulting colours. We calculated for the first time the relative contribution of molecular vibration (by means of Raman spectroscopy) and concentration (by means of HPLC) of melanin polymers, the most common animal pigments, to generate diversity in plumage colour in 47 species of birds. Vibrational characteristics explained >9 times more variance in colour expression than the concentration of melanins. Additionally, we modelled melanin Raman spectra on the basis of the chemical structure of their constituent monomers and calculated the Huang-Rhys factors for each vibrational mode, which indicate the contribution of these modes to the electronic spectra responsible for the resulting colours. High Huang-Rhys factors frequently coincided with the vibrational modes of melanin monomers. Our results can be explained by the influence of molecular vibration on the absorption properties of melanins. The colour of organisms may thus mainly result from the vibrational properties of their molecules and only residually from their concentration. As a given melanin concentration can give rise to different colours because different structural melanin conformations can present different vibrational characteristics, vibrational effects may favour phenotypic plasticity and thus constitute an important evolutionary force.


Evaluating the benefits of digital pathology implementation: time savings in laboratory logistics.
The benefits of digital pathology for workflow improvement and thereby cost savings in pathology, at least partly outweighing investment costs, are being increasingly recognised. Successful implementations in a variety of scenarios have started to demonstrate the cost benefits of digital pathology for both research and routine diagnosis, contributing to a sound business case encouraging further adoption. To further support new adopters, there is still a need for detailed assessment of the impact that this technology has on the relevant pathology workflows, with an emphasis on time-saving. To assess the impact of digital pathology adoption on logistic laboratory tasks (i.e. not including pathologists' time for diagnosis-making) in the Laboratorium Pathologie Oost Nederland, a large regional pathology laboratory in The Netherlands. To quantify the benefits of digitisation, we analysed the differences between the traditional analogue and new digital workflows, carried out detailed measurements of all relevant steps in key analogue and digital processes, and compared the time spent. We modelled and assessed the logistic savings in five workflows: (i) routine diagnosis; (ii) multidisciplinary meeting; (iii) external revision requests; (iv) extra stainings; and (v) external consultation. On average, >19 working hours were saved on a typical day by working digitally, with the highest savings in routine diagnosis and multidisciplinary meeting workflows. By working digitally, a significant amount of time could be saved in a large regional pathology laboratory with a typical case mix. We also present the data in each workflow per task and concrete logistic steps to allow extrapolation to the context and case mix of other laboratories.


Associations between street connectivity and active transportation.
Past studies of associations between measures of the built environment, particularly street connectivity, and active transportation (AT) or leisure walking/bicycling have largely failed to account for spatial autocorrelation of connectivity variables and have seldom examined both the propensity for AT and its duration in a coherent fashion. Such efforts could improve our understanding of the spatial and behavioral aspects of AT. We analyzed spatially identified data from Los Angeles and San Diego Counties collected as part of the 2001 California Health Interview Survey. Principal components analysis indicated that ~85% of the variance in nine measures of street connectivity are accounted for by two components representing buffers with short blocks and dense nodes (PRIN1) or buffers with longer blocks that still maintain a grid like structure (PRIN2). PRIN1 and PRIN2 were positively associated with active transportation (AT) after adjustment for diverse demographic and health related variables. Propensity and duration of AT were correlated in both Los Angeles (r = 0.14) and San Diego (r = 0.49) at the zip code level. Multivariate analysis could account for the correlation between the two outcomes.After controlling for demography, measures of the built environment and other factors, no spatial autocorrelation remained for propensity to report AT (i.e., report of AT appeared to be independent among neighborhood residents). However, very localized correlation was evident in duration of AT, particularly in San Diego, where the variance of duration, after accounting for spatial autocorrelation, was 5% smaller within small neighborhoods (approximately 0.01 square latitude/longitude degrees = 0.6 mile diameter) compared to within larger zip code areas. Thus a finer spatial scale of analysis seems to be more appropriate for explaining variation in connectivity and AT. Joint analysis of the propensity and duration of AT behavior and an explicitly geographic approach can strengthen studies of the built environment and physical activity (PA), specifically AT. More rigorous analytical work on cross-sectional data, such as in the present study, continues to support the need for experimental and longitudinal study designs including the analysis of natural experiments to evaluate the utility of environmental interventions aimed at increasing PA.


Acute effects of winter air pollution on respiratory function in schoolchildren in southern England.
To investigate the acute health effects of winter outdoor air pollution (nitrogen dioxide (NO(2)), ozone (O(3)), sulphur dioxide (SO(2)), sulphate (SO(4)(2-)),and particles (PM(10))) on schoolchildren in an area of southern England where levels of SO(2) had been reported to be high. A total of 179 children, aged 7-13, from three schools (two urban and one rural location), were included. Peak expiratory flow rate (PEFR) and presence or absence of upper respiratory infections were recorded on 63 school days from 1 November 1996 to 14 February 1997. Air pollution and meteorological data were taken from monitors at each school site. The analysis regressed daily PEFR on pollutant level adjusting for confounders and serial correlation and calculated a weighted pooled estimate of effect overall for each pollutant. In addition, large decrements in PEFR were analysed as a binary outcome. Same day, lag 1, lag 2, and a five day average of pollutant levels were used. There were no clear effects of any pollutant on mean PEFR. In addition, we analysed large PEFR decrements (a binary outcome), observing consistent negative associations with NO(2), SO(4)(2-), and PM(10), although few lag/pollutant combinations were significant: odds ratios (95% CI) for five day average effect: NO(2) 24 h average 1.043 (1.000 to 1.089), SO(4)(2-) 1.090 (0.898 to 1.322), PM(10) 1.037 (0.992 to 1.084). The observed effects of PM(10) (only) were stronger in wheezy children (1.114 (1.057 to 1.174)). There were no consistent negative associations between large decrements and ozone or SO(2). There is no strong evidence for acute effects of winter outdoor air pollution on mean PEFR overall in this area, but there is evidence for negative effects on large PEFR decrements.


A pilot study of pain-related anxiety and smoking-dependence motives among persons with chronic pain.
Complex interactions between pain and tobacco smoking have been of increasing interest to researchers and clinicians from a variety of disciplines. There is also recent evidence to suggest that pain-related anxiety may play an important role in the maintenance of tobacco dependence among persons with comorbid pain disorders. The goal of the current study was to evaluate the explanatory relevance of pain-related anxiety in relation to tobacco dependence among a sample of daily smokers with current chronic pain. Participants were recruited from the general population to complete an online survey that was developed to examine interrelations between chronic pain and tobacco smoking. Fifty-six of 129 (43%) daily smoking respondents met criteria for current chronic pain. Results indicated that pain-related anxiety accounted for a significant portion of the unique variance in total smoking dependence scores, and both primary and secondary dependence composite scores (as measured by the Wisconsin Inventory of Smoking Dependence Motives; Piper et al., 2004). It is noteworthy that these effects were observed above and beyond the variance accounted for by relevant sociodemographic factors, generalized anxiety, and pain severity. Pain-related anxiety was observed to be strongly associated with secondary dependence motives, which is consistent with a conceptualization of pain-related anxiety as an instrumental or situational motivator of smoking. These results suggest that tobacco smokers with comorbid pain disorders may be at risk for maintaining or exacerbating their dependence on tobacco, possibly due to individual differences in pain-related anxiety. These findings may help inform the development of tailored interventions for smokers with comorbid chronic pain.


Definition of a fundamental repeating unit in streptococcal glucosyltransferase glucan-binding regions and related sequences.
The C-termini of the glucosyltransferases (Gtfs) of oral streptococci are responsible for glucan binding. These glucan-binding domains (GBDs) are composed of a series of repeated sequences that have been classified into four different classes (A-D) by virtue of sequence similarity and which, by inference, have been suggested to be of functional importance. In contrast, we propose that repeat sequences evolve in response to selection for an increase in the number of copies of a particular domain through multiple duplication events occurring at different times. According to this hypothesis, repeats should possess various degrees of similarity, especially if only key residues are of functional importance. Analysis of the GBDs of the Gtfs indicated that a common fundamental repeat, designated the "YG" repeat, could be discerned within the "A", "B", "C", and "D" repeats. Similar elements were also conserved in the ligand-binding repeats of the Clostridium difficile toxins and the lysins and the PspA protein of Streptococcus pneumoniae, suggesting that similar selective pressures had also been imposed on these sequences. Analysis of the "YG" repeats present in the GtfJ and GtfK of Streptococcus salivarius indicated that some of the "YG" repeats in the GBDs of these proteins had arisen as a result of duplication events involving a series of three sequential "YG" repeats.


16S-rRNA-based analysis of bacterial diversity in the gut of fungus-cultivating termites (Microtermes and Odontotermes species).
The interaction between termites and their gut symbionts has continued to attract the curiosity of researchers over time. The aim of this study was to characterize and compare the bacterial diversity and community structure in the guts of three termites (Odontotermes somaliensis, Odontotermes sp. and Microtermes sp.) using 16S rRNA gene sequencing of clone libraries. Clone libraries were screened by restriction fragment length polymorphism and representative clones from O. somaliensis (100 out of 330 clones), Odontotermes sp. (100 out of 359 clones) and Microtermes sp. (96 out 336 clones) were sequenced. Phylogenetic analysis indicated seven bacterial phyla were represented: Bacteroidetes, Spirochaetes, Firmicutes, Proteobacteria, Synergistetes, Planctomycetes and Actinobacteria. Sequences representing the phylum Bacteroidetes (>60 %) were the most abundant group in Odontotermes while those of Spirochaetes (29 %) and Firmicutes (23 %) were the abundant groups in Microtermes. The gut bacterial community structure within the two Odontotermes species investigated here was almost identical at the phylum level, but the Microtermes sp. had a unique bacterial community structure. Bacterial diversity was higher in Odontotermes than in Microtermes. The affiliation and clustering of the sequences, often with those from other termites' guts, indicate a majority of the gut bacteria are autochthonous having mutualistic relationships with their hosts. The findings underscore the presence of termite-specific bacterial lineages, the majority of which are still uncultured.


Evolution of carbapenem resistance in Acinetobacter baumannii during a prolonged infection.
Acinetobacter baumannii is a common causative agent of hospital-acquired infections and a leading cause of infection in burns patients. Carbapenem-resistant A. baumannii is considered a major public-health threat and has been identified by the World Health Organization as the top priority organism requiring new antimicrobials. The most common mechanism for carbapenem resistance in A. baumannii is via horizontal acquisition of carbapenemase genes. In this study, we sampled 20 A. baumannii isolates from a patient with extensive burns, and characterized the evolution of carbapenem resistance over a 45 day period via Illumina and Oxford Nanopore sequencing. All isolates were multidrug resistant, carrying two genomic islands that harboured several antibiotic-resistance genes. Most isolates were genetically identical and represented a single founder genotype. We identified three novel non-synonymous substitutions associated with meropenem resistance: F136L and G288S in AdeB (part of the AdeABC efflux pump) associated with an increase in meropenem MIC to ≥8 µg ml-1; and A515V in FtsI (PBP3, a penicillin-binding protein) associated with a further increase in MIC to 32 µg ml-1. Structural modelling of AdeB and FtsI showed that these mutations affected their drug-binding sites and revealed mechanisms for meropenem resistance. Notably, one of the adeB mutations arose prior to meropenem therapy but following ciprofloxacin therapy, suggesting exposure to one drug whose resistance is mediated by the efflux pump can induce collateral resistance to other drugs to which the bacterium has not yet been exposed.


Rational non-interventional paternalism: why doctors ought to make judgments of what is best for their patients.
This paper argues that doctors ought to make all things considered value judgments about what is best for their patients. It illustrates some of the shortcomings of the model of doctor as 'fact-provider'. The 'fact-provider' model fails to take account of the fact that practising medicine necessarily involves making value judgments; that medical practice is a moral practice and requires that doctors reflect on what ought to be done, and that patients can make choices which fail to express their autonomy and which are based on mistaken judgments of value. If doctors are properly to respect patient autonomy and to function as moral agents, they must make evaluations of what their patients ought to do, all things considered. This paper argues for 'rational, non-interventional paternalism'. This is a practice in which doctors form conceptions of what is best for their patients and argue rationally with them. It differs from old-style paternalism in that it is not committed to doing what is best.


Influence of Setback Distance on Antibiotics and Antibiotic Resistance Genes in Runoff and Soil Following the Land Application of Swine Manure Slurry.
The environmental spread of antibiotics and antibiotic resistance genes (ARGs) from the land application of livestock wastes can be a potential public health threat. The objective of this study was to assess the effects of setback distance, which determines how close manure may be applied in relation to surface water, on the transport of antibiotics and ARGs in runoff and soil following land application of swine manure slurry. Rainfall simulation tests were conducted on field plots covered with wheat residues, each of which contained an upslope manure region where slurry was applied and an adjacent downslope setback region that did not receive slurry. Results show that all three antibiotics (chlortetracycline, lincomycin, and tiamulin) and seven out of the ten genes tested (erm(B), erm(C), intI1, tet(O), tet(Q), tet(X), and the 16S rRNA gene) decreased significantly in runoff with increased setback distance. Only blaTEM, chlortetracycline, and tiamulin decreased significantly in surface soil with increased setback distance, while the other analytes did not exhibit statistically significant trends. By using linear regression models with field data, we estimate that a setback distance between 34-67 m may allow manure-borne antibiotics and ARGs in runoff to reach background levels under the experimental conditions tested.


High complexity chronic heart failure management programmes: programme characteristics and 12 month patient outcomes.
Chronic heart failure management programmes (CHF-MPs) have been developed to improve, clinical outcomes in response to the high burden of disease from chronic heart failure (CHF). Programmes vary in model, duration, complexity of interventions and incorporation of evidence-based guidelines for programme delivery. Few studies have explored patient outcomes at 12 months from enrolment in a CHF. The aim of the current study was to explore the characteristics and clinical outcomes of patients enrolled in four high complexity CHF-MPs at 12 months after initial enrolment. A secondary aim was to explore the adoption of key evidence-based CHF management strategies in these programmes. After ethics approval, a multisite mixed methods design was implemented incorporating survey and chart audit. Programme characteristics and interventions used in four CHF-MPs were surveyed in Stage 1. Stage 2 involved a chart audit of patients enrolled in the programmes (N = 135) on or after the 1/1/07. Primary endpoints were all-cause hospitalisation and/or mortality at 12 months. Data were analysed using descriptive and inferential statistics. All programmes implemented a high complexity of evidence-based interventions consistent with national guidelines. However, documentation of New York Heart Association functional class was rare; limiting quantifiable evaluation of response to therapy throughout programme enrolment. The majority of patients (73%) had severe systolic heart failure with high co-morbidities reflected in a mean Charlson's total co-morbidity score of 3 (± 2.1). The high rate of baseline evidence-based, pharmacothe- rapy (beta-blocker: 86%, n = 112 and ACE inhibitor: 76%, n = 103) was maintained at 12 months (71% and 84% respectively). At 12 months all cause hospitalisation and/or mortality was 57% (n = 77). The CHF-MPs in this study implemented complex evidence-based interventions resulting in high rates of key medication prescription. However, despite the implementation of several evidence-based interventions, over a period of 12 months, more than half of the patients were rehospitalised or died.


The γ-secretase inhibitor 2-[(1R)-1-[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl) amino]ethyl-5-fluorobenzenebutanoic acid (BMS-299897) alleviates Aβ1-42 seeding and short-term memory deficits in the Aβ25-35 mouse model of Alzheimer's disease.
Alzheimer's disease pathomimetic toxicity could be induced in mice within one week after the intracerebroventricular (i.c.v.) injection of an aggregated preparation of the highly toxic and endogenous amyloid-β fragment Aβ(25-35). It was recently reported that Aβ(25-35) also provokes a modification of APP processing with accumulation of endogenous Aβ(1-42). We here analyzed whether a γ-secretase inhibitor, BMS-299897, attenuated this Aβ(25-35)-induced Aβ(1-42) seeding and toxicity. The compound was administered at 0.1-1 nmol/mouse, concomittantly with Aβ(25-35) (9 nmol) in male Swiss mice. After one week, the contents in Aβ(1-42) and Aβ(1-40), and the levels in lipid peroxidation were analyzed in the mouse hippocampus. Mice were submitted to spontaneous alternation, passive avoidance and object recognition to analyze their short- and long-term memory abilities. Aβ(25-35) increased Aβ(1-42) content (+240%) but failed to affect Aβ(1-40). BMS-299897 blocked the increase in Aβ(1-42) content and decreased Aβ(1-40) levels significantly. The compound did not affect Aβ(25-35)-induced increase in hippocampal lipid peroxidation. Behaviorally, BMS-299897 blocked the Aβ(25-35)-induced deficits in spontaneous alternation or novel object recognition, using a 1h intertrial time interval. BMS-299896 failed to affect the passive avoidance impairments or novel object recognition, using a 24h intertrial time interval. These results confirmed that Aβ(25-35) injection provoked an accumulation in endogenous Aβ(1-42), an effect blocked by γ-secretase inhibition. This Aβ(1-42) accumulation marginally contributed to the toxicity or long-term memory deficits. However, since the seeded Aβ(1-42) affected short-term memory, the rapid Aβ(25-35) injection Alzheimer's disease model could be used to screen the activity of new secretase inhibitors.


Image logic algebra and its optical implementations.
A generic language for optical parallel processing image logic algebra (ILA), is proposed. In ILA a neighborhood configuration pattern (NCP) is introduced, and image transformations are defined by the use of NCP operations. The comprehensive relationship of ILA to symbolic substitution, optical array logic, mathematical morphology, and binary image algebra are clarified. Furthermore, an architecture that is suited for ILA and its optical implementations is proposed.


Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature.
Recently developed potent and selective CDK4/6 inhibitors fall into two classes based on structure and toxicity profiles in clinical studies. One class, exemplified by palbociclib and ribociclib, exhibits neutropenia as a dose-limiting toxicity and requires discontinuous dosing. In contrast, the structurally distinct CDK4/6 inhibitor abemaciclib is dosed continuously, and has diarrhea and fatigue as dose-limiting toxicities. In preclinical models, palbociclib has been extensively studied and induces cell cycle inhibition in an RB-dependent manner. Thus far, abemaciclib has been less extensively evaluated. We found that abemaciclib cell cycle inhibitory activity is RB-dependent at clinically achievable concentrations. Abemaciclib elicited potent suppression of RB/E2F regulated genes associated with prognosis in ER-positive breast cancer. However, unlike palbociclib, at 250nM-1 µM doses abemaciclib induced cell death in RB-deficient cell lines. This response was associated with a rapidly-induced multi-vacuolar phenotype indicative of lysosomal membrane permeabilization that could be ameliorated with chloroquine. This event was not a reflection of inhibition of other CDK family members, but could be recapitulated with CBX4945 that inhibits casein and DYRK/HIPK kinases. To determine if these "off-target" features of abemaciclib were observed in vivo, mice harboring matched RB-positive and negative xenografts were treated with palbociclib and abemaciclib. In vivo, all of the apparent activity of abemaciclib was RB-dependent and strongly elicited suppression of cell cycle regulatory genes in a fashion markedly similar to palbociclib. Using gene expression data from cell lines and tumors treated with abemaciclib and palbociclib a composite signature of response to CDK4/6 inhibition was developed that included many genes that are individually required for tumor cell proliferation or viability. These data indicate that while abemaciclib and palbociclib can exert distinct biological and molecular effects, there are common gene expression features that could be broadly utilized in measuring the response to CDK4/6 inhibition.


Embodying emotion.
Recent theories of embodied cognition suggest new ways to look at how we process emotional information. The theories suggest that perceiving and thinking about emotion involve perceptual, somatovisceral, and motoric reexperiencing (collectively referred to as "embodiment") of the relevant emotion in one's self. The embodiment of emotion, when induced in human participants by manipulations of facial expression and posture in the laboratory, causally affects how emotional information is processed. Congruence between the recipient's bodily expression of emotion and the sender's emotional tone of language, for instance, facilitates comprehension of the communication, whereas incongruence can impair comprehension. Taken all together, recent findings provide a scientific account of the familiar contention that "when you're smiling, the whole world smiles with you."


How much alcohol should we infuse in the coronary artery of hypertrophic cardiomyopathy patients?
Although alcohol septal ablation (ASA) is increasingly used in hypertrophic cardiomyopathy (HC) patients who are refractory to medical therapy, the amount of alcohol that is required has not been well studied. This study sought to determine the amount of alcohol that is necessary to achieve clinical benefits of ASA. Myocardial perfusion imaging was used to determine the size of the myocardial infarction produced by ASA in 54 HC patients. Left ventricular outflow gradients (LVOTg) were determined invasively before and after ASA and by Doppler echocardiography before and at a median of 3 months after ASA. LVOTg decreased at rest and after provocation in response to ASA and this was maintained on follow-up at 3 months. There was no relationship between the amount of alcohol infused and the infarct mass as determined by myocardial perfusion imaging. While the infarct mass was not correlated with the drop in the LVOTg at rest or with provocation, the quantity of alcohol infused was correlated with the drop in LVOTg at rest (r = 0.27, p = 0.05) and with provocation (r = 0.34, p = 0.02). Furthermore, infusing more than 2ml of absolute alcohol was associated with a drop in the LVOTg by more than 60 mmHg at rest (p = 0.02) and by more than 130 mmHg with provocation (p = 0.05). Although lower amounts of alcohol infusion are desirable to avoid side-effects, it might be prudent to infuse around 2 ml of absolute alcohol in order to achieve the desirable degree of LVOTg reduction in ASA.


Decomposition of a sensory prediction error signal for visuomotor adaptation.
To accomplish effective motor control, the brain contains an internal forward model that predicts the expected sensory consequence of a motor command. When this prediction is inaccurate, a sensory prediction error is produced which adapts the forward model to make more accurate predictions of future movements. Other types of errors, such as task performance errors or reward, play less of a role in adapting a forward model. This raises the following question: What unique information is conveyed by the sensory prediction error that results in forward model adaptation? sensory prediction errors typically contain both the magnitude and direction of the error, but it is unclear if both components are necessary for adaptation or a single component is sufficient. In this article, we address this by having participants learn to counter a visuomotor rotation, which induces an angular mismatch between movements of the hand and visual feedback. We manipulated the information content of the visual feedback, in the form of a line, which accurately represented only the magnitude (distance), direction, or both magnitude and direction, of the virtual cursor relative to the target. We demonstrate that sensorimotor adaptation does not occur, or is minimal, when feedback is limited to information about the magnitude of an error. In contrast, sensorimotor adaptation is present when feedback is limited only to the direction of an error or when it contains combined direction and magnitude information. This result stands in contrast to current computational models of cerebellar-based sensorimotor adaptation that use error magnitude to drive adaptation. (PsycINFO Database Record


WITHDRAWN: Anticonvulsants for fibromyalgia.
Fibromyalgia (FM) is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue. People often report high disability levels and poor health-related quality of life (HRQoL). Drug therapy focuses on reducing key symptoms and disability, and improving HRQoL. Anticonvulsants (antiepileptic drugs) are drugs frequently used for the treatment of chronic pain syndromes. To assess the benefits and harms of anticonvulsants for treating FM symptoms. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 8, 2013), MEDLINE (1966 to August 2013), PsycINFO (1966 to August 2013), SCOPUS (1980 to August 2013) and the reference lists of reviewed articles for published studies and www.clinicaltrials.gov (to August 2013) for unpublished trials. We selected randomised controlled trials of any formulation of anticonvulsants used for the treatment of people with FM of any age. Two review authors independently extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion. We included eight studies: five with pregabalin and one study each with gabapentin, lacosamide and levetiracetam. A total of 2480 people were included into anticonvulsants groups and 1099 people in placebo groups. The median therapy phase of the studies was 13 weeks. The amount and quality of evidence were insufficient to draw definite conclusions on the efficacy and safety of gabapentin, lacosamide and levetiracetam in FM. The amount and quality of evidence was sufficient to draw definite conclusions on the efficacy and safety of pregabalin in FM. Therefore, we focused on our interpretation of the evidence for pregabalin due to our greater certainty about its effects and its greater relevance to clinical practice. All pregabalin studies had a low risk of bias. Reporting a 50% or greater reduction in pain was more frequent with pregabalin use than with a placebo (risk ratio (RR) 1.59; 95% confidence interval (CI) 1.33 to 1.90; number needed to treat for an additional beneficial outcome (NNTB) 12; 95% CI 9 to 21). The number of people who reported being 'much' or 'very much' improved was higher with pregabalin than with placebo (RR 1.38; 95% CI 1.23 to 1.55; NNTB 9; 95% CI 7 to 15). Pregabalin did not substantially reduce fatigue (SMD -0.17; 95% CI -0.25 to -0.09; 2.7% absolute improvement on a 1 to 50 scale) compared with placebo. Pregabalin had a small benefit over placebo in reducing sleep problems by 6.2% fewer points on a scale of 0 to 100 (standardised mean difference (SMD) -0.35; 95% CI -0.43 to -0.27). The dropout rate due to adverse events was higher with pregabalin use than with placebo use (RR 1.68; 95% CI 1.36 to 2.07; number needed to treat for an additional harmful outcome (NNTH) 13; 95% CI 9 to 23). There was no significant difference in serious adverse events between pregabalin and placebo use (RR 1.03; 95% CI 0.71 to 1.49). Dizziness was reported as an adverse event more frequently with pregabalin use than with placebo use (RR 3.77; 95% CI 3.06 to 4.63; NNTH 4; 95% CI 3 to 5). The anticonvulsant, pregabalin, demonstrated a small benefit over placebo in reducing pain and sleep problems. Pregabalin use was shown not to substantially reduce fatigue compared with placebo. Study dropout rates due to adverse events were higher with pregabalin use compared with placebo. Dizziness was a particularly frequent adverse event seen with pregabalin use. At the time of writing this review, pregabalin is the only anticonvulsant drug approved for treating FM in the US and in 25 other non-European countries. However, pregabalin has not been approved for treating FM in Europe. The amount and quality of evidence were insufficient to draw definite conclusions on the efficacy and safety of gabapentin, lacosamide and levetiracetam in FM.


A carbohydrate-binding family 48 module enables feruloyl esterase action on polymeric arabinoxylan.
Feruloyl esterases (EC 22.214.171.124), belonging to carbohydrate esterase family 1 (CE1), hydrolyze ester bonds between ferulic acid (FA) and arabinose moieties in arabinoxylans. Recently, some CE1 enzymes identified in metagenomics studies have been predicted to contain a family 48 carbohydrate-binding module (CBM48), a CBM family associated with starch binding. Two of these CE1s, wastewater treatment sludge (wts) Fae1A and wtsFae1B isolated from wastewater treatment surplus sludge, have a cognate CBM48 domain and are feruloyl esterases, and wtsFae1A binds arabinoxylan. Here, we show that wtsFae1B also binds to arabinoxylan and that neither binds starch. Surface plasmon resonance analysis revealed that wtsFae1B's Kd for xylohexaose is 14.8 μm and that it does not bind to starch mimics, β-cyclodextrin, or maltohexaose. Interestingly, in the absence of CBM48 domains, the CE1 regions from wtsFae1A and wtsFae1B did not bind arabinoxylan and were also unable to catalyze FA release from arabinoxylan. Pretreatment with a β-d-1,4-xylanase did enable CE1 domain-mediated FA release from arabinoxylan in the absence of CBM48, indicating that CBM48 is essential for the CE1 activity on the polysaccharide. Crystal structures of wtsFae1A (at 1.63 Å resolution) and wtsFae1B (1.98 Å) revealed that both are folded proteins comprising structurally-conserved hydrogen bonds that lock the CBM48 position relative to that of the CE1 domain. wtsFae1A docking indicated that both enzymes accommodate the arabinoxylan backbone in a cleft at the CE1-CBM48 domain interface. Binding at this cleft appears to enable CE1 activities on polymeric arabinoxylan, illustrating an unexpected and crucial role of CBM48 domains for accommodating arabinoxylan.


"Step by Step". A feasibility study of a lunchtime walking intervention designed to increase walking, improve mental well-being and work performance in sedentary employees: Rationale and study design.
Following an extensive recruitment campaign, a 16-week lunchtime intervention to increase walking was implemented with insufficiently physically active University employees to examine programme feasibility and the effects of the programme in increasing walking behaviour, and in improving well-being and work performance. A feasibility study in which participants were randomised to an immediate treatment or a delayed treatment control (to start at 10 weeks) group. For the first ten weeks of the intervention, participants took part in three facilitator-led group walks per week each of thirty minutes duration and were challenged to accumulate another sixty minutes of walking during the weekends. In the second phase of the intervention, the organised group walks ceased to be offered and participants were encouraged to self-organise their walks. Motivational principles were employed using contemporary motivational theory. Outcome measures (including self-reported walking, step counts, cardiovascular fitness, general and work-related well-being and work performance) were assessed at baseline, at the end of the 16-week intervention and (for some) four months after the end of the intervention. Process and outcome assessments were also taken throughout, and following, the intervention. The results of the intervention will determine the feasibility of implementing a lunchtime walking programme to increase walking behaviour, well-being and performance in sedentary employees. If successful, there is scope to implement definitive trials across a range of worksites with the aim of improving both employee and organisational health. Current Controlled Trials ISRCTN81504663.


Structures of neutral Au7, Au19, and Au20 clusters in the gas phase.
The catalytic properties of gold nanoparticles are determined by their electronic and geometric structures. We revealed the geometries of several small neutral gold clusters in the gas phase by using vibrational spectroscopy between 47 and 220 wavenumbers. A two-dimensional structure for neutral Au7 and a pyramidal structure for neutral Au20 can be unambiguously assigned. The reduction of the symmetry when a corner atom is cut from the tetrahedral Au20 cluster is directly reflected in the vibrational spectrum of Au19.


Relationship between the chronic pain grade and measures of physical, social and psychological well-being.
Chronic pain is an important cause of suffering, disability and loss of productivity within the community. Chronic pain can also be viewed as a multidimensional phenomenon, and may be associated with increased suffering of a social and psychological nature, as well as physical suffering. In this paper, the severity of the chronic pain gradings (CPG) is defined in terms of physical, social and psychological well-being, as measured by the SF36 and Glasgow Pain Questionnaire. Although previous work has shown the chronic pain grade to be a valid measure of chronic pain severity, little is known of the relationship between this and other health measures. A random sample of 5036 individuals, representative of the general population, stratified for age and sex, was drawn. A further sample of 4175 patients was drawn from a list of patients enrolled for repeat prescriptions for analgesic medication. A questionnaire survey was carried out, and response rates of 82 and 87% were achieved, respectively. The comparisons described confirm the widespread impact of chronic pain on all aspects of health, supporting the multidimensional view. These findings are important in addressing the management of chronic pain patients, and in particular, the social and psychological well-being of a patient needs to be addressed in parallel with the physical well-being in order to successfully reduce the suffering associated with chronic pain.


C. elegans screen identifies autophagy genes specific to multicellular organisms.
The molecular understanding of autophagy has originated almost exclusively from yeast genetic studies. Little is known about essential autophagy components specific to higher eukaryotes. Here we perform genetic screens in C. elegans and identify four metazoan-specific autophagy genes, named epg-2, -3, -4, and -5. Genetic analysis reveals that epg-2, -3, -4, and -5 define discrete genetic steps of the autophagy pathway. epg-2 encodes a coiled-coil protein that functions in specific autophagic cargo recognition. Mammalian homologs of EPG-3/VMP1, EPG-4/EI24, and EPG-5/mEPG5 are essential for starvation-induced autophagy. VMP1 regulates autophagosome formation by controlling the duration of omegasomes. EI24 and mEPG5 are required for formation of degradative autolysosomes. This study establishes C. elegans as a multicellular genetic model to delineate the autophagy pathway and provides mechanistic insights into the metazoan-specific autophagic process.


The unc-8 and sup-40 genes regulate ion channel function in Caenorhabditis elegans motorneurons.
Two Caenorhabditis elegans genes, unc-8 and sup-40, have been newly identified, by genetic criteria, as regulating ion channel function in motorneurons. Two dominant unc-8 alleles cause motorneuron swelling similar to that of other neuronal types in dominant mutants of the deg-1 gene family, which is homologous to a mammalian gene family encoding amiloride-sensitive sodium channel subunits. As for previously identified deg-1 family members, unc-8 dominant mutations are recessively suppressed by mutations in the mec-6 gene, which probably encodes a second type of channel component. An unusual dominant mutation, sup-41 (lb125), also co-suppresses unc-8 and deg-1, suggesting the existence of yet another common component of ion channels containing unc-8 or deg-1 subunits. Dominant, transacting, intragenic suppressor mutations have been isolated for both unc-8 and deg-1, consistent with the idea that, like their mammalian homologues, the two gene products function as multimers. The sup-40 (lb130) mutation dominantly suppresses unc-8 motorneuron swelling and produces a novel swelling phenotype in hypodermal nuclei. sup-40 may encode an ion channel component or regulator that can correct the osmotic defect caused by abnormal unc-8 channels.


Analyzing the Variation of Building Density Using High Spatial Resolution Satellite Images: the Example of Shanghai City.
Building density is an important issue in urban planning and land management. In the article, building coverage ratio (BCR) and floor area ratio (FAR) values extracted from high resolution satellite images were used to indicate buildings' stretching on the surface and growth along the third dimension within areas of interest in Shanghai City, P.R. China. The results show that the variation of FAR is higher than that of BCR in the inner circle, and that the newer commercial centers have higher FAR and lower BCR values, while the traditional commercial areas have higher FAR and BCR ratios. By comparing different residential areas, it was found that the historical "Shikumen" areas and the old residential areas built before 1980s have higher BCR and lower FAR, while the new residential areas have higher FAR and lower BCR, except for the villa areas. These results suggest that both older building areas and villa areas use land resources in an inefficient way, and therefore better planning and management of urban land are needed for those fast economic growing regions.


Relationship of hepatocellular carcinoma to soya food consumption: a cohort-based, case-control study in Japan.
To determine if the risk of hepatocellular carcinoma (HCC) is reduced by consumption of soya foods, we conducted a case-control study within a cohort of Japanese A-bomb survivors. We compared the prediagnosis consumption of isoflavone-rich miso soup and tofu to HCC risk, adjusting for hepatitis B (HBV) and C (HCV) viral infections, the major HCC risk factors in this population. The study included 176 pathologist-confirmed cases of HCC diagnosed in 1964-1988 and 560 controls who died of diseases other than liver cancer. We examined dietary information collected at least 2 years before diagnosis or death and tissue-based measures of viral hepatitis. Using logistic regression, crude ORs were 0.5 (95% CI 0.29-0.95) and 0.5 (95% CI 0.20-0.99) for high vs. low miso soup and tofu intake, respectively. Adjusting for year of birth, sex, HBV, HCV and other factors, the OR for miso soup was unchanged at 0.5 (95% CI 0.14-1.55), and miso results were similar when ORs were recalculated separately for earlier and later birth cohorts to assess consistency of results. The adjusted OR for tofu was 0.9 (95% CI 0.20-3.51). We also found a statistically significant (p < 0.0001) interaction between sex and HCV, with risk of HCC being substantially higher for women. We conclude that consumption of miso soup and other soya foods may reduce HCC risk.


Update on endovenous laser ablation: 2011.
In 2001, the use of endovenous laser ablation (EVLA) was introduced to the United States to treat superficial venous insufficiency. EVLA has subsequently undergone a rapid rise in popularity and usage with a concomitant decrease in traditional operative saphenectomy. Since its inception, the use of EVLA to treat superficial venous insufficiency has advanced significantly. The efficacy of treatment has been validated using both hemoglobin-specific laser wavelength and water-specific laser wavelength lasers. Currently, laser optimization is focusing on reducing postprocedural sequelae. The clinical parameters that correlate best with improved postoperative recovery use lower power/energy settings, water-specific laser wavelength lasers, and jacket or radial-emitting tips. Future study is still required to assess the durability of treatment at lower power and energy settings coupled with jacket or radial-emitting tip fibers. Long-term follow-up using duplex imaging is recommended to ensure persistent treatment success.


Transvenous high energy shock for ablating atrioventricular conduction in man. Observations on the histological effects.
Transvenous ablation of atrioventricular conduction by high energy shock through a pacing wire has been used as a method of controlling the ventricular response to rapid atrial arrhythmias. A patient in whom this technique successfully controlled refractory tachycardia was admitted with severe left ventricular impairment five months after the procedure and died. The heart was examined at necropsy. There was no sign of endocardial damage in the region of the atrioventricular node-His bundle. Histological sections failed to show any scarring, inflammation, or infiltration in the region of the atrioventricular node. On the contrary, there was no evidence of any surviving atrioventricular nodal tissue. The mechanism of this effect is not known. The lack of endocardial or myocardial damage further confirms the safety of this new method of controlling tachycardia.


Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP.
RNA transcripts are subject to posttranscriptional gene regulation involving hundreds of RNA-binding proteins (RBPs) and microRNA-containing ribonucleoprotein complexes (miRNPs) expressed in a cell-type dependent fashion. We developed a cell-based crosslinking approach to determine at high resolution and transcriptome-wide the binding sites of cellular RBPs and miRNPs. The crosslinked sites are revealed by thymidine to cytidine transitions in the cDNAs prepared from immunopurified RNPs of 4-thiouridine-treated cells. We determined the binding sites and regulatory consequences for several intensely studied RBPs and miRNPs, including PUM2, QKI, IGF2BP1-3, AGO/EIF2C1-4 and TNRC6A-C. Our study revealed that these factors bind thousands of sites containing defined sequence motifs and have distinct preferences for exonic versus intronic or coding versus untranslated transcript regions. The precise mapping of binding sites across the transcriptome will be critical to the interpretation of the rapidly emerging data on genetic variation between individuals and how these variations contribute to complex genetic diseases.


Sodium butyrate inhibits pathogenic yeast growth and enhances the functions of macrophages.
Butyrate is a short-chain fatty acid that is produced by several human commensal bacteria, such as Clostridium and Lactobacillus species. Butyrate is also known to inhibit histone deacetylase. In this study we assessed the antifungal activity of sodium butyrate (SB) against the human pathogenic yeasts Candida albicans, Candida parapsilosis and Cryptococcus neoformans. The growth and virulence traits of the yeasts were assayed in vitro and during interaction with macrophages in the presence of SB. SB strongly inhibited yeast growth in a concentration-dependent manner, inhibited virulence traits such as filamentation in C. albicans and melanization and capsule formation in C. neoformans and, importantly, significantly decreased yeast biofilm formation. SB also enhanced the antifungal activity of azole drugs. Notably, SB augmented the antifungal activity of macrophages by enhancing the production of reactive oxygen species. The phagocytic rate and killing activity of macrophages significantly increased in the presence of SB, which coincided with an increase in nitric oxide production. These results demonstrate that SB exerts significant antifungal activity on pathogenic yeasts and enhances the antimicrobial actions of macrophages in response to these microbes.


Quantitative trait loci modulate renal cystic disease severity in the mouse bpk model.
Numerous mouse models of polycystic kidney disease (PKD) have been described in which the mutant phenotypes closely resemble human PKD with regard to morphology, cyst localization, and disease progression. As in human PKD, genetic background affects the disease phenotype in mouse PKD models. Using experimental crosses, these modifying effects can be dissected into discrete genetic factors referred to as quantitative trait loci. The locus for the mouse bpk model was recently mapped to chromosome (Chr) 10. In the course of these studies, marked variability was observed in the renal cystic disease expressed in F2 bpk/bpk homozygotes of a (BALB/c-+/bpk x CAST/Ei)F1 intercross. The current study was undertaken to further characterize the renal cystic disease as quantitative trait in this F2 cohort and to map the genetic modifiers that modulate this phenotype. Whole-genome scans revealed a CAST-derived locus on distal Chr 6, near D6Mit14, that affects renal cystic disease severity. Additional analyses identified loci on Chr 1, Chr 2, and Chr 4, as well as a possible interaction between the Chr 6 locus and a locus on distal Chr 1, near D1Mit17. Interestingly, the gene encoding RGS7, a regulator of G protein signaling that binds to polycystin-1, was mapped to the same Chr 1 interval. It is concluded that the severity of the bpk renal cystic disease phenotype is modulated by multiple loci and possibly by epistatic interaction among them. It is hypothesized that the gene encoding the polycystin-binding partner RGS7 is a candidate for the Chr 1 genetic modifier.


Δ9-tetrahydrocannabinol exposure during rat pregnancy leads to symmetrical fetal growth restriction and labyrinth-specific vascular defects in the placenta.
1 in 5 women report cannabis use during pregnancy, with nausea cited as their primary motivation. Studies show that (-)-△9-tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient in cannabis, causes fetal growth restriction, though the mechanisms are not well understood. Given the critical role of the placenta to transfer oxygen and nutrients from mother, to the fetus, any compromise in the development of fetal-placental circulation significantly affects maternal-fetal exchange and thereby, fetal growth. The goal of this study was to examine, in rats, the impact of maternal Δ9-THC exposure on fetal development, neonatal outcomes, and placental development. Dams received a daily intraperitoneal injection (i.p.) of vehicle control or Δ9-THC (3 mg/kg) from embryonic (E)6.5 through 22. Dams were allowed to deliver normally to measure pregnancy and neonatal outcomes, with a subset sacrificed at E19.5 for placenta assessment via immunohistochemistry and qPCR. Gestational Δ9-THC exposure resulted in pups born with symmetrical fetal growth restriction, with catch up growth by post-natal day (PND)21. During pregnancy there were no changes to maternal food intake, maternal weight gain, litter size, or gestational length. E19.5 placentas from Δ9-THC-exposed pregnancies exhibited a phenotype characterized by increased labyrinth area, reduced Epcam expression (marker of labyrinth trophoblast progenitors), altered maternal blood space, decreased fetal capillary area and an increased recruitment of pericytes with greater collagen deposition, when compared to vehicle controls. Further, at E19.5 labyrinth trophoblast had reduced glucose transporter 1 (GLUT1) and glucocorticoid receptor (GR) expression in response to Δ9-THC exposure. In conclusion, maternal exposure to Δ9-THC effectively compromised fetal growth, which may be a result of the adversely affected labyrinth zone development. These findings implicate GLUT1 as a Δ9-THC target and provide a potential mechanism for the fetal growth restriction observed in women who use cannabis during pregnancy.


Inhibition of hydrocarbon autoxidation by nitroxide-catalyzed cross-dismutation of hydroperoxyl and alkylperoxyl radicals.
Nitroxides are putative intermediates in the accepted reaction mechanisms of the diarylamine and hindered amine antioxidants that are universally added to preserve synthetic and natural hydrocarbon-based materials. New methodology which enables monitoring of hydrocarbon autoxidations at low rates of radical generation has revealed that diarylnitroxides and hindered nitroxides are far better inhibitors of unsaturated hydrocarbon autoxidation than their precursor amines, implying intervention of a different mechanism. Experimental and computational investigations suggest that the nitroxides catalyze the cross-dismutation of hydroperoxyl and alkylperoxyl radicals to yield O2 and a hydroperoxide, thereby halting the autoxidation chain reaction. The hydroperoxyl radicals - key players in hydrocarbon combustion, but essentially unknown in autoxidation - are proposed to derive from a tunneling-enhanced intramolecular (1,4-) hydrogen-atom transfer/elimination sequence from oxygenated radical addition intermediates. These insights suggest that nitroxides are preferred additives for the protection of hydrocarbon-based materials from autoxidation since they exhibit catalytic activity under conditions where their precursor amines are less effective and/or inefficiently converted to nitroxides in situ.


Cardiovascular mortality in a Western Asian country: results from the Iran Cohort Consortium.
Cardiovascular mortality in Western Asia is high and still rising. However, most data documented on risk prediction has been derived from Western countries and few population-based cohort studies have been conducted in this region. The current study aimed to present the process of pooling data and cardiovascular disease (CVD) mortality incidences for four Iranian cohorts. From the Iran Cohort Consortium, the Golestan Cohort Study (GCS), Tehran Lipid and Glucose Study, Isfahan Cohort Study (ICS) and the Shahroud Eye Cohort Study (ShECS) were eligible for the current study since they had appropriate data and follow-up visits. Age-standardised CVD mortality rates were estimated for ages 40-80 and 40-65 years. Cox regression was used to compare mortalities among cohorts. Adjusted marginal rates were calculated using Poisson regression. Overall, 61 291 participants (34 880 women) aged 40-80 years, free of CVD at baseline, were included. During 504 606 person-years of follow-up, 1981 CVD deaths (885 women) occurred. Age-standardised/sex-standardised premature CVD mortality rates were estimated from 133 per 100 000 person-years (95% CI 81 to 184) in ShECS to 366 (95% CI 342 to 389) in the GCS. Compared with urban women, rural women had higher CVD mortality in the GCS but not in the ICS. The GCS population had a higher risk of CVD mortality, compared with the others, adjusted for conventional CVD risk factors. The incidence of CVD mortality is high with some differences between urban and rural cohorts in Iran as a Western Asian country. Pooling data facilitates the opportunity to globally evaluate risk prediction models.


Optimization of a reversible hood for protecting a pedestrian's head during car collisions.
This study evaluated and optimized the performance of a reversible hood (RH) for the prevention of the head injuries of an adult pedestrian from car collisions. The FE model of a production car front was introduced and validated. The baseline RH was developed from the original hood in the validated car front model. In order to evaluate the protective performance of the baseline RH, the FE models of an adult headform and a 50th percentile human head were used in parallel to impact the baseline RH. Based on the evaluation, the response surface method was applied to optimize the RH in terms of the material stiffness, lifting speed, and lifted height. Finally, the headform model and the human head model were again used to evaluate the protective performance of the optimized RH. It was found that the lifted baseline RH can obviously reduce the impact responses of the headform model and the human head model by comparing with the retracted and lifting baseline RH. When the optimized RH was lifted, the HIC values of the headform model and the human head model were further reduced to much lower than 1000. The risk of pedestrian head injuries can be prevented as required by EEVC WG17.


How Many Patients Achieve an Acceptable Symptom State After Hip Arthroscopy for Femoroacetabular Impingement Syndrome? A Cross-sectional Study Including PASS Cutoff Values for the HAGOS and iHOT-33.
Hip arthroscopy is a viable treatment for femoroacetabular impingement syndrome (FAIS). Clinically relevant improvements in hip function and pain after surgery are often reported, but it is less clear how many patients achieve an acceptable symptom state (Patient Acceptable Symptom State [PASS]). To investigate the proportion of patients who achieved a PASS 12 to 24 months after hip arthroscopy and to determine the cutoff scores of the 2 recommended and valid patient-reported outcome measures (the subscales of the Copenhagen Hip and Groin Outcome Score [HAGOS] and the International Hip Outcome Tool-33 [iHOT-33]) for which patients are most likely to achieve PASS. Cohort study; Level of evidence, 3. Eligible study patients were identified in the Danish Hip Arthroscopy Registry. An electronic questionnaire was used to collect data on PASS, HAGOS, and iHOT-33 12 to 24 months after surgery. PASS was measured using an anchor question. Receiver operating characteristic curve analyses were applied to identify the PASS cutoff values of HAGOS and iHOT-33 scores. A total of 137 individuals (mean age at surgery, 35.4 ± 9.4 years) were included in the study at a mean follow-up of 18.5 ± 3.2 months after surgery. At follow-up, 64 individuals (46.7%; 95% CI, 38.6-55.1) reported PASS. Higher HAGOS and iHOT-33 values were observed for participants who reported PASS compared with those who did not report PASS (Cohen d ≥ 1.06; P < .001). Cutoff scores for HAGOS subscales (42.5-82.5) and iHOT-33 (67.00) showed excellent to outstanding discriminative ability in predicting PASS (area under the curve, 0.82-0.92). In total, 46% of individuals having hip arthroscopy for FAIS achieved PASS at 12 to 24 months of follow-up. Patients who achieved PASS had statistically significant and substantially better self-reported hip function compared with those who did not achieve PASS. Cutoff values at HAGOS subscales and iHOT-33 showed excellent to outstanding discriminative ability in predicting patients with PASS.


Obesity-related plasma hemodilution and PSA concentration among men with prostate cancer.
Recent studies have suggested that obese men have lower serum prostate-specific antigen (PSA) concentrations than nonobese men. Because men with higher body mass index (BMI) have greater circulating plasma volumes, lower PSA concentrations among obese men may be due to hemodilution. To determine the association between hemodilution and PSA concentration in obese men with prostate cancer. Retrospective study of men who underwent radical prostatectomy for prostate adenocarcinoma from 1988 to 2006, using data from the databases of the Shared Equal Access Regional Cancer Hospital (n = 1373), Duke Prostate Center (n = 1974), and Johns Hopkins Hospital (n = 10 287). Multivariate linear regression models adjusting for clinicopathological characteristics were used to analyze the main outcome measures. Associations between BMI and mean adjusted PSA concentrations, mean plasma volume, and mean adjusted PSA mass (total circulating PSA protein, calculated as PSA concentration multiplied by plasma volume), assessed by determining P values for trend. After controlling for clinicopathological characteristics, higher BMI was significantly associated with higher plasma volume (P < .001 for trend) and lower PSA concentrations (P < or = .02 for trend) in all cohorts. In 2 of the 3 cohorts, PSA mass did not change significantly with increasing BMI. In the third cohort, higher BMI was associated with increased PSA mass (P < .001 for trend), but only between BMI category less than 25 and the other categories. In men undergoing radical prostatectomy, higher BMI was associated with higher plasma volume; hemodilution may therefore be responsible for the lower serum PSA concentrations among obese men with prostate cancer. Prospective studies are needed to evaluate this association in screened populations.


High-sensitivity troponin as an outcome predictor in acute medical admissions.
Troponin estimation is increasingly performed on emergency medical admissions. We report on a high-sensitivity troponin (hscTn) assay, introduced in January 2011, and its relevance to in-hospital mortality in such patients. To evaluate the impact of hscTn results on in-hospital mortality and the value of incorporating troponin into a predictive score of in-hospital mortality. All patients admitted as general medical emergencies between January 2011 and October 2012 were studied. Patients admitted under other admitting services including cardiology were excluded. We examined outcomes using generalised estimating equations, an extension of generalised linear models that permitted adjustment for correlated observations (readmissions). Margins statistics used adjusted predictions to test for interactions of key predictors while controlling for other variables using computations of the average marginal effect. A total of 11 132 admission episodes were recorded. The in-hospital mortality for patients with predefined cut-offs was 1.9% when no troponin assay was requested, 5.1% when the troponin result was below the 25 ng/L 'normal' cut-off, 9.7% for a troponin result ≥25 and <50 ng/L, 14.5% for a troponin result ≥50 and <100 ng/L, 34.4% for a troponin result ≥100 and <1000 ng/L, and 58.3% for a troponin result >1000 ng/L. The OR for an in-hospital death for troponin-positive patients was 2.02 (95% CI 1.84 to 2.21); when adjusted for other mortality predictors including illness severity, the OR remained significant at 2.83 (95% CI 2.20 to 3.64). The incorporation of troponin into a multivariate logistic predictive algorithm resulted in an area under the receiver operating characteristic curve to predict an in-hospital death of 0.87 (95% CI 0.85 to 0.88). An increase in troponin carries prognostic information in acutely ill medical patients; the extent of the risk conferred justifies incorporation of this information into predictive algorithms for hospital mortality.


Measure of processes of care: a review of 20 years of research.
This article reviews literature on findings from the Measure of Processes of Care (MPOC) to assess family-centred services. Systematic searches for papers citing MPOC in both PubMed and Web of Science identified 107 articles. Fifty-five met the criterion for inclusion in this review in that they reported MPOC data. Over the past 20 years MPOC has been used in settings additional to the children's treatment centres for which it was designed; used in 11 countries and translated into 14 languages; and used to measure change in respondents' perceptions over time. MPOC findings have also informed our understanding of the provision of family-centred services. Overall, parents report that service providers do a good job of providing respectful, comprehensive services in partnership with families, but that there remain limitations in the provision of general information, an area for improvement. Finally, MPOC has been shown to correlate with various other measures related to the provision of family-centred services. The MPOC 'family' of measures can be used to assess both families' and service providers' experiences and perceptions of the family-centredness of services received/provided. Opportunities abound for further research enquiries.


Tousled-like kinase-dependent phosphorylation of Rad9 plays a role in cell cycle progression and G2/M checkpoint exit.
Genomic integrity is preserved by checkpoints, which act to delay cell cycle progression in the presence of DNA damage or replication stress. The heterotrimeric Rad9-Rad1-Hus1 (9-1-1) complex is a PCNA-like clamp that is loaded onto DNA at structures resulting from damage and is important for initiating and maintaining the checkpoint response. Rad9 possesses a C-terminal tail that is phosphorylated constitutively and in response to cell cycle position and DNA damage. Previous studies have identified tousled-like kinase 1 (TLK1) as a kinase that may modify Rad9. Here we show that Rad9 is phosphorylated in a TLK-dependent manner in vitro and in vivo, and that T355 within the C-terminal tail is the primary targeted residue. Phosphorylation of Rad9 at T355 is quickly reduced upon exposure to ionizing radiation before returning to baseline later in the damage response. We also show that TLK1 and Rad9 interact constitutively, and that this interaction is enhanced in chromatin-bound Rad9 at later stages of the damage response. Furthermore, we demonstrate via siRNA-mediated depletion that TLK1 is required for progression through S-phase in normally cycling cells, and that cells lacking TLK1 display a prolonged G2/M arrest upon exposure to ionizing radiation, a phenotype that is mimicked by over-expression of a Rad9-T355A mutant. Given that TLK1 has previously been shown to be transiently inactivated upon phosphorylation by Chk1 in response to DNA damage, we propose that TLK1 and Chk1 act in concert to modulate the phosphorylation status of Rad9, which in turn serves to regulate the DNA damage response.


Projected land ice contributions to twenty-first-century sea level rise.
The land ice contribution to global mean sea level rise has not yet been predicted1 using ice sheet and glacier models for the latest set of socio-economic scenarios, nor using coordinated exploration of uncertainties arising from the various computer models involved. Two recent international projects generated a large suite of projections using multiple models2-8, but primarily used previous-generation scenarios9 and climate models10, and could not fully explore known uncertainties. Here we estimate probability distributions for these projections under the new scenarios11,12 using statistical emulation of the ice sheet and glacier models. We find that limiting global warming to 1.5 degrees Celsius would halve the land ice contribution to twenty-first-century sea level rise, relative to current emissions pledges. The median decreases from 25 to 13 centimetres sea level equivalent (SLE) by 2100, with glaciers responsible for half the sea level contribution. The projected Antarctic contribution does not show a clear response to the emissions scenario, owing to uncertainties in the competing processes of increasing ice loss and snowfall accumulation in a warming climate. However, under risk-averse (pessimistic) assumptions, Antarctic ice loss could be five times higher, increasing the median land ice contribution to 42 centimetres SLE under current policies and pledges, with the 95th percentile projection exceeding half a metre even under 1.5 degrees Celsius warming. This would severely limit the possibility of mitigating future coastal flooding. Given this large range (between 13 centimetres SLE using the main projections under 1.5 degrees Celsius warming and 42 centimetres SLE using risk-averse projections under current pledges), adaptation planning for twenty-first-century sea level rise must account for a factor-of-three uncertainty in the land ice contribution until climate policies and the Antarctic response are further constrained.