Leg Power As an Indicator of Risk of Injury or Illness in Police Recruits.
Tactical trainees, like those entering the police force, are required to undergo vigorous training as part of their occupational preparation. This training has the potential to cause injuries. In addition, the physical training, communal living and pressures of tactical training are known to induce immune suppression and have the potential to increase the risk of illness. The aim of this study was to investigate the relationship between leg power, as measured by a vertical jump (VJ), and rates of reported injuries and illnesses during police recruit training. Retrospective data from recruits (n = 1021) undergoing basic police recruit training at an Australian Police Force College was collected. Recruits completed a VJ assessment at the commencement of their second state of training. Formally reported illness and injuries were collected 12 weeks later, following completion of training. Correlations between VJ height and rates of reported illness and injury were low (r = -0.16 and -0.09, respectively) but significant (p < 0.005), with VJ height accounting for 2.6% and 0.8% of the variance in illness and injury rates, respectively. In terms of relative risks, recruits with the lowest recorded VJ heights were more than three times as likely as those with highest VJ heights to suffer injury and/or illness. Police recruits with lower VJ height are at a significantly greater risk of suffering an injury or illness during police basic recruit training.


Mechanotransduction in neutrophil activation and deactivation.
Mechanotransduction refers to the processes through which cells sense mechanical stimuli by converting them to biochemical signals and, thus, eliciting specific cellular responses. Cells sense mechanical stimuli from their 3D environment, including the extracellular matrix, neighboring cells and other mechanical forces. Incidentally, the emerging concept of mechanical homeostasis,long term or chronic regulation of mechanical properties, seems to apply to neutrophils in a peculiar manner, owing to neutrophils' ability to dynamically switch between the activated/primed and deactivated/deprimed states. While neutrophil activation has been known for over a century, its deactivation is a relatively recent discovery. Even more intriguing is the reversibility of neutrophil activation and deactivation. We review and critically evaluate recent findings that suggest physiological roles for neutrophil activation and deactivation and discuss possible mechanisms by which mechanical stimuli can drive the oscillation of neutrophils between the activated and resting states. We highlight several molecules that have been identified in neutrophil mechanotransduction, including cell adhesion and transmembrane receptors, cytoskeletal and ion channel molecules. The physiological and pathophysiological implications of such mechanically induced signal transduction in neutrophils are highlighted as a basis for future work. This article is part of a Special Issue entitled: Mechanobiology.


Engagement of the monocyte surface antigen CD14 induces lymphocyte function-associated antigen-1/intercellular adhesion molecule-1-dependent homotypic adhesion.
Murine anti-CD14 mAb which recognize different CD14 epitopes induced marked homotypic adhesion of normal human monocytes. Induction of aggregation by anti-CD14 mAb required Mg2+, occurred at an optimal temperature of 37 degrees C, but not at 4 degrees C, and exhibited a kinetics which differed from adhesion triggered by IFN-gamma and anti-CD43 mAb. Monocyte adhesion induced by anti-CD14 mAb required neither Fcy gamma R engagement nor cross-linking of CD14, because adhesion was induced by F(ab)'2 fragments, as well as by monovalent F(ab) fragments of anti-CD14 mAb. mAb to CD11a, CD18, and intercellular adhesion molecule-1 (ICAM-1), but not antibodies to CD11b and CD11c, inhibited monocyte adhesion induced by CD14 engagement. These results indicate that CD14-dependent adhesion is mediated by lymphocyte function-associated Ag-1/ICAM-1 interactions. This was confirmed by the absence of aggregation in anti-CD14-stimulated cells from a patient with leukocyte adhesion deficiency. Monocyte adhesion upon CD14 engagement was blocked by an inhibitor of protein kinases, sphingosine. This suggests that protein kinases play a role in the intracellular signaling pathway(s) which couple CD14 to lymphocyte function-associated Ag-1/ICAM-1.


ApoE receptor 2 controls neuronal survival in the adult brain.
A central pathogenic feature of neurodegenerative diseases and neurotrauma is the death of neurons. A mechanistic understanding of the factors and conditions that induce the dysfunction and death of neurons is essential for devising effective treatment strategies against neuronal loss after trauma or during aging. Because Apolipoprotein E (ApoE) is a major risk factor for several neurodegenerative diseases, including Alzheimer's disease , a direct or indirect role of ApoE receptors in the disease process is likely. Here we have used gene targeting in mice to investigate possible roles of ApoE receptors in the regulation of neuronal survival. We demonstrate that a differentially spliced isoform of an ApoE receptor, ApoE receptor 2 (Apoer2), is essential for protection against neuronal cell loss during normal aging. Furthermore, the same splice form selectively promotes neuronal cell death after injury through mechanisms that may involve serine/threonine kinases of the Jun N-terminal kinase (JNK) family. These findings raise the possibility that ApoE and its receptors cooperatively regulate common mechanisms that are essential to neuronal survival in the adult brain.


Effects of In-Season Velocity- Versus Percentage-Based Training in Academy Rugby League Players.
To compare the effects of velocity-based training (VBT) vs percentage-based training (PBT) on strength, speed, and jump performance in academy rugby league players during a 7-wk in-season mesocycle. A total of 27 rugby league players competing in the Super League U19s Championship were randomized to VBT (n = 12) or PBT (n = 15). Both groups completed a 7-wk resistance-training intervention (2×/wk) that involved the back squat. The PBT group used a fixed load based on a percentage of 1-repetition maximum (1-RM), whereas the VBT group used a modifiable load based on individualized velocity thresholds. Biomechanical and perceptual data were collected during each training session. Back-squat 1-RM, countermovement jump, reactive strength index, sprint times, and back-squat velocity at 40-90% 1-RM were assessed pretraining and posttraining. The PBT group showed likely to most likely improvements in 1-RM strength and reactive strength index, whereas the VBT group showed likely to very likely improvements in 1-RM strength, countermovement jump height, and back-squat velocity at 40% and 60% 1-RM. Sessional velocity and power were most likely greater during VBT compared with PBT (standardized mean differences = 1.8-2.4), while time under tension and perceptual training stress were likely lower (standardized mean differences = 0.49-0.66). The improvement in back-squat velocity at 60% 1-RM was likely greater following VBT compared with PBT (standardized mean difference = 0.50). VBT can be implemented during the competitive season, instead of traditional PBT, to improve training stimuli, decrease training stress, and promote velocity-specific adaptations.


In situ approach for testing the enantiopurity of chiral amines and amino alcohols by 1H NMR.
An in situ approach involving a simple mix and shake method for testing the enantiopurity of primary, secondary and tertiary chiral amines and their derivatives, chiral amino alcohols, by (1)H-NMR spectroscopy is developed. The protocol involves the in situ formation of chiral ammonium borate salt from a mixture of C2 symmetric chiral BINOL, trialkoxyborane and chiral amines. The proposed concept was demonstrated convincingly on a large number of chiral and pro-chiral amines and amino alcohols, and also aids the precise measurement of enantiomeric excess. The protocol can be completed in a couple of minutes directly in the NMR sample tube, without the need for any physical separation.


Disruption of Calcium Signaling in Fibroblasts and Attenuation of Bleomycin-Induced Fibrosis by Nifedipine.
Fibrotic lung disease afflicts millions of people; the central problem is progressive lung destruction and remodeling. We have shown that external growth factors regulate fibroblast function not only through canonical signaling pathways but also through propagation of periodic oscillations in Ca(2+). In this study, we characterized the pharmacological sensitivity of the Ca(2+)oscillations and determined whether a blocker of those oscillations can prevent the progression of fibrosis in vivo. We found Ca(2+) oscillations evoked by exogenously applied transforming growth factor β in normal human fibroblasts were substantially reduced by 1 μM nifedipine or 1 μM verapamil (both L-type blockers), by 2.7 μM mibefradil (a mixed L-/T-type blocker), by 40 μM NiCl2 (selective at this concentration against T-type current), by 30 mM KCl (which partially depolarizes the membrane and thereby fully inactivates T-type current but leaves L-type current intact), or by 1 mM NiCl2 (blocks both L- and T-type currents). In our in vivo study in mice, nifedipine prevented bleomycin-induced fibrotic changes (increased lung stiffness, overexpression of smooth muscle actin, increased extracellular matrix deposition, and increased soluble collagen and hydroxyproline content). Nifedipine had little or no effect on lung inflammation, suggesting its protective effect on lung fibrosis was not due to an antiinflammatory effect but rather was due to altering the profibrotic response to bleomycin. Collectively, these data show that nifedipine disrupts Ca(2+) oscillations in fibroblasts and prevents the impairment of lung function in the bleomycin model of pulmonary fibrosis. Our results provide compelling proof-of-principle that interfering with Ca(2+) signaling may be beneficial against pulmonary fibrosis.


Direct-to-consumer genetic testing with third party interpretation: beware of spurious results.
Direct-to-consumer (DTC) genetic tests aim to provide insights into issues as varied as ancestry, nutrition, athletic ability and child talent, and some also report on disease risks. DTC companies tend to present their tests as uniformly beneficial, but the quality of the information they provide can be doubtful. Tests often invite people to step between territories, from the consumer in search of 'fun' information to potential patient, and the boundaries between these roles become even murkier when individuals explore the raw data from their DTC tests using third-party interpretation websites. We discuss two composite cases from U.K. genetics centres where patients used third party interpretation services to analyse raw data from DTC genetic tests. They then presented to NHS clinical services requesting interventions based on the disease-associated variants found, only to find that these variants were not actually present: their 'pathogenic results' were spurious. We highlight the risk of false positives (as well as false negatives) from DTC genetic tests, and discuss whether these cases represent the start of a worrying trend, where publicly funded clinicians and clinical scientists increasingly need to spend time and money investigating genetic results of dubious validity.


Pay For Success And Population Health: Early Results From Eleven Projects Reveal Challenges And Promise.
Pay for success (PFS) is a type of social impact investing that uses private capital to finance proven prevention programs that help a government reduce public expenditures or achieve greater value. We conducted an analysis of the first eleven PFS projects in the United States to investigate the potential of PFS as a strategy for financing and disseminating interventions aimed at improving population health and health equity. The PFS approach has significant potential for bringing private-sector resources to interventions regarding social determinants of health. Nonetheless, a number of challenges remain, including structuring PFS initiatives so that optimal prevention benefits can be achieved and ensuring that PFS interventions and evaluation designs are based on rigorous research principles. In addition, increased policy attention regarding key PFS payout issues is needed, including the "wrong pockets" problem and legal barriers to using federal Medicaid funds as an investor payout source.


Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium.
Genome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies. Genotype data for single-nucleotide polymorphisms at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case-control studies for 11 645 lung cancer case patients and 14 954 control subjects, of whom 85% were white and 15% were Asian, were pooled. Associations between the variants and the risk of lung cancer were estimated by logistic regression models. All statistical tests were two-sided. Associations between 15q25 and the risk of lung cancer were replicated in white ever-smokers (rs16969968: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.21 to 1.32, P(trend) = 2 x 10(-26)), and this association was stronger for those diagnosed at younger ages. There was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, we confirmed statistically significant associations in whites for both rs2736100 (OR = 1.15, 95% CI = 1.10 to 1.20, P(trend) = 1 x 10(-10)) and rs402710 (OR = 1.14, 95% CI = 1.09 to 1.19, P(trend) = 5 x 10(-8)) and identified similar associations in Asians (rs2736100: OR = 1.23, 95% CI = 1.12 to 1.35, P(trend) = 2 x 10(-5); rs402710: OR = 1.15, 95% CI = 1.04 to 1.27, P(trend) = .007). The associations between the 5p15 variants and lung cancer differed by histology; odds ratios for rs2736100 were highest in adenocarcinoma and for rs402710 were highest in adenocarcinoma and squamous cell carcinomas. This pattern was observed in both ethnic groups. Neither of the two variants on chromosome 6p21 was associated with the risk of lung cancer. In this international genetic association study of lung cancer, previous associations found in white populations were replicated and new associations were identified in Asian populations. Future genetic studies of lung cancer should include detailed stratification by histology.


Cofactors and metabolites as protein folding helpers in metabolic diseases.
In the past few decades, improved early diagnosis methods, technological developments and an increasing crosstalk between clinicians and researchers has led to the identification of an increasing number of inborn metabolic diseases. In these disorders, missense mutations are the most frequent type of genetic defects, frequently resulting in defective protein folding. A better understanding at the molecular level of protein misfolding and its role in disease has prompted the emergence of therapies based in the use of small molecules that have the ability to correct protein folding defects. Well-known cases are reported for phenylketonuria and Gaucher's disease. Most of these compounds have a specific mechanism of action interacting directly with a particular protein, the so called pharmacological chaperones. Among such small molecules are protein ligands, either natural substrates or synthetic derivatives, cofactors, competitive inhibitors, and agonist/antagonists. In this review we will start by briefly overviewing the mechanisms through which such ligands exert a stabilizing action, and then move on to an extended discussion on therapeutic approaches and use of vitamins and substrates to correct protein misfolding in metabolic disorders. Examples of vitamins that have been successfully prescribed to rescue some cases of inborn errors of metabolism will be presented. In particular, the role of riboflavin supplementation in the treatment of fatty acid β-oxidation disorders will be thoroughly analyzed, focusing on recent reports that shed light on the molecular basis of vitamin responsiveness. Moreover, we will highlight the latest studies that point to a synergistic effect of cofactors and metabolites in the rescue of defective fatty acid β-oxidation enzymes. The synergism of multiple small molecules may underlie a promising general pharmacological strategy for the treatment of metabolic diseases in general.


Design of an ultralight and compact projection lens.
Driven by the need for lightweight head-mounted displays, we present the design of an ultralight and compact projection lens for a head-mounted projective display (HMPD). An HMPD consists of a pair of miniature projection lenses, beam splitters, and miniature displays mounted on the helmet and retroreflective sheeting materials placed strategically in the environment. The HMPD has been proposed recently as an alternative modality for three-dimensional visualization. After demonstrating the concept, building a first-generation custom-designed prototype, and investigating perception issues and application potentials, we designed an ultralight and compact projective lens with a diffractive optical element (DOE), plastic components, and aspheric surfaces for the next-generation prototype. The key contribution here lies in the conception, optimization, and assessment of the projection optics. Thus a brief review of the HMPD technology and related research is followed by a detail discussion of the conception and optimization of the ultralight and high-performance projection optics. The design of the DOE will be particularly described in detail. Finally, the diffraction efficiency of the DOE will be evaluated, and the overall performance of the optics will be assessed in both object space for the optical designer and visual space for possible end-users of the technology.


The development and validation of a short measure of functioning and well being for individuals with Parkinson's disease.
Parkinson's disease is a common degenerative neurological condition. A number of general health status measures exist but these may not address areas salient to specific diseases. We report here the development and validation of a short 39 item health status questionnaire for use in Parkinson's disease. Questionnaire items, generated from in-depth interviews with people with Parkinson's disease, were developed into a 65 item questionnaire. Data from a postal survey using the 65 item questionnaire were statistically analysed to produce a shorter questionnaire with 39 items and eight scales addressing different dimensions of Parkinson's disease. A second postal survey was conducted in order to assess the reliability and validity of the new 39 item questionnaire. The final questionnaire, referred to here as the 39 item Parkinson's Disease Questionnaire (PDQ-39), proved to have satisfactory internal and test-retest reliability, and construct validity in relation to other measures, reported by respondents with Parkinson's disease.


First determination of the spin relaxation properties of a nitronyl nitroxide in solution by electron spin echoes at X-band: a comparison with Tempone.
We studied by electron spin echo pulse methods the spin relaxation properties of a phenyl nitronyl nitroxide radical (2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide, PTIO) at X-band in fluid toluene solution in a wide temperature range, and in a water/glycerol 1:1 mixture near room temperature. The relaxation properties of PTIO have been compared with that of Tempone, as a widely used nitroxide. By a new procedure, based on experimental results on the temperature dependences of the relaxation times T(1) and T(2), and on the approximation of an isotropic brownian rotational diffusion, we separated non-secular, spin rotational and residual terms from the transverse relaxation rate to isolate secular and pseudosecular contributions. By comparing the results for the two radicals we found the differences in the magnetic properties that give rise to slower transverse (T(2)) and longitudinal (T(1)) electron spin relaxation for PTIO in the whole temperature range explored in this work.


Insulin Regulates Glycogen Synthesis in Human Endometrial Glands Through Increased GYS2.
Glycogen synthesis is a critical metabolic function of the endometrium to prepare for successful implantation and sustain embryo development. Yet, regulation of endometrial carbohydrate metabolism is poorly characterized. Whereas glycogen synthesis is attributed to progesterone, we previously found that the metabolic B isoform of the insulin receptor is maximally expressed in secretory-phase endometrium, indicating a potential role of insulin in glucose metabolism. We sought to determine whether insulin or progesterone regulates glycogen synthesis in human endometrium. Endometrial epithelial cells were isolated from 28 healthy women and treated with insulin, medroxyprogesterone (MPA), or vehicle. Intracellular glycogen and the activation of key enzymes were quantified. In epithelia, insulin induced a 4.4-fold increase in glycogen, whereas MPA did not alter glycogen content. Insulin inactivated glycogen synthase (GS) kinase 3α/β (GSK3α/β), relieving inhibition of GS. In a regulatory mechanism, distinct from liver and muscle, insulin also increased GS by 3.7-fold through increased GS 2 (GYS2) gene expression. We demonstrate that insulin, not progesterone, directly regulates glycogen synthesis through canonical acute inactivation of GSK3α/β and noncanonical stimulation of GYS2 transcription. Persistently elevated GS enables endometrium to synthesize glycogen constitutively, independent of short-term nutrient flux, during implantation and early pregnancy. This suggests that insulin plays a key, physiological role in endometrial glucose metabolism and underlines the need to delineate the effect of maternal obesity and hyperinsulinemia on fertility and fetal development.


Further developments in the use of semipermeable membrane devices as passive air samplers: application to PCBs.
There are several incentives for developing passive air sampling techniques for persistent organic pollutants (POPs). This paper reports on studies to further calibrate and optimize semipermeable membrane devices (SPMDs) for use as "integrated" air samplers of gas-phase POPs. These samplers are deployed over weeks/months/years. Polychlorinated biphenyls (PCBs) were used as the test compounds in this study, with three specific objectives: (i) to determine whether ambient wind speed limits the rate of uptake during typical deployment conditions; (ii) to monitor uptake and SPMD-air equilibrium for a range of compounds; and (iii) to assess the application of performance reference compounds (PRCs) in air sampling, to "correct" for site-specific differences in uptake rates. When deployed in Stevensons screens under ambient conditions, wind speed did not significantly affect uptake rates. Rather, differences in summer/winter uptake rates reported previously, using the same deployment devices as here, are due to temperature affecting compound permeability through the membrane. Results from the use of PRCs indicate that SPMDs should be spiked prior to exposure with a range of compounds that are not present in the atmosphere, so that uptake rates can be estimated from depuration rates during a particular deployment. Short-term deployments (e.g. days; few weeks) would need to use compound(s) with a low octanol:air partition coefficient (K(OA)) (e.g. 13C12 labeled PCB-28); long-term deployments (of many months to years) would need to use intermediate K(OA) compounds (e.g. 13C12 PCB-101; 13C12 PCB-153).


Hormonal regulation of colour change in eyes of a cryptic fish.
Colour change of the skin in lower vertebrates such as fish has been a subject of great scientific and public interest. However, colour change also takes place in eyes of fish and while an increasing amount of data indicates its importance in behaviour, very little is known about its regulation. Here, we report that both eye and skin coloration change in response to white to black background adaptation in live sand goby Pomatoschistus minutes, a bentic marine fish. Through in vitro experiments, we show that noradrenaline and melanocyte concentrating hormone (MCH) treatments cause aggregation of pigment organelles in the eye chromatophores. Daylight had no aggregating effect. Combining forskolin to elevate intracellular cyclic adenosine monophosphate (cAMP) with MCH resulted in complete pigment dispersal and darkening of the eyes, whereas combining prolactin, adrenocorticotrophic hormone (ACTH) or melanocyte stimulating hormone (α-MSH) with MCH resulted in more yellow and red eyes. ACTH and MSH also induced dispersal in the melanophores, resulting in overall darker eyes. By comparing analysis of eyes, skin and peritoneum, we conclude that the regulation pattern is similar between these different tissues in this species which is relevant for the cryptic life strategy of this species. With the exception of ACTH which resulted in most prominent melanophore pigment dispersal in the eyes, all other treatments provided similar results between tissue types. To our knowledge, this is the first study that has directly analysed hormonal regulation of physiological colour change in eyes of fish.


Automated high-content live animal drug screening using C. elegans expressing the aggregation prone serpin α1-antitrypsin Z.
The development of preclinical models amenable to live animal bioactive compound screening is an attractive approach to discovering effective pharmacological therapies for disorders caused by misfolded and aggregation-prone proteins. In general, however, live animal drug screening is labor and resource intensive, and has been hampered by the lack of robust assay designs and high throughput work-flows. Based on their small size, tissue transparency and ease of cultivation, the use of C. elegans should obviate many of the technical impediments associated with live animal drug screening. Moreover, their genetic tractability and accomplished record for providing insights into the molecular and cellular basis of human disease, should make C. elegans an ideal model system for in vivo drug discovery campaigns. The goal of this study was to determine whether C. elegans could be adapted to high-throughput and high-content drug screening strategies analogous to those developed for cell-based systems. Using transgenic animals expressing fluorescently-tagged proteins, we first developed a high-quality, high-throughput work-flow utilizing an automated fluorescence microscopy platform with integrated image acquisition and data analysis modules to qualitatively assess different biological processes including, growth, tissue development, cell viability and autophagy. We next adapted this technology to conduct a small molecule screen and identified compounds that altered the intracellular accumulation of the human aggregation prone mutant that causes liver disease in α1-antitrypsin deficiency. This study provides powerful validation for advancement in preclinical drug discovery campaigns by screening live C. elegans modeling α1-antitrypsin deficiency and other complex disease phenotypes on high-content imaging platforms.


The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase C beta Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter randomized clinical trial.
The purpose of this study was to evaluate the Safety and efficacy of the orally administered protein kinase C (PKC) beta isoform-selective inhibitor ruboxistaurin (RBX) in subjects with moderately severe to very severe nonproliferative diabetic retinopathy (NPDR). In this multicenter, double-masked, randomized, placebo-controlled study, 252 subjects received placebo or RBX (8, 16, or 32 mg/day) for 36-46 months. Patients had an Early Treatment Diabetic Retinopathy Study (ETDRS) retinopathy severity level between 47B and 53E inclusive, an ETDRS visual acuity of 20/125 or better, and no history of scatter (panretinal) photocoagulation. Efficacy measures included progression of DR, moderate visual loss (MVL) (doubling of the visual angle), and sustained MVL (SMVL). RBX was well tolerated without significant adverse effects but had no significant effect on the progression of DR. Compared with placebo, 32 mg/day RBX was associated with a delayed occurrence of MVL (log rank, P = 0.038) and of SMVL (P = 0.226). RBX reduction of SMVL was evident only in eyes with definite diabetic macular edema at baseline (10% 32 mg/day RBX vs. 25% placebo, P = 0.017). In multivariable Cox proportional hazard analysis, 32 mg/day RBX significantly reduced the risk of MVL compared with placebo (hazard ratio 0.37 [95% CI 0.17-0.80], P = 0.012). In this clinical trial, RBX was well tolerated and reduced the risk of visual loss but did not prevent DR progression.


Nintedanib, a triple angiokinase inhibitor, enhances cytotoxic therapy response in pancreatic cancer.
Angiogenesis remains a sensible target for pancreatic ductal adenocarcinoma (PDAC) therapy. VEGF, PDGF, FGF and their receptors are expressed at high levels and correlate with poor prognosis in human PDAC. Nintedanib is a triple angiokinase inhibitor that targets VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β signaling. We investigated the antitumor activity of nintedanib alone or in combination with the cytotoxic agent gemcitabine in experimental PDAC. Nintedanib inhibited proliferation of cells from multiple lineages found in PDAC, with gemcitabine enhancing inhibitory effects. Nintedanib blocked PI3K/MAPK activity and induced apoptosis in vitro and in vivo. In a heterotopic model, net local tumor growth compared to controls (100%) was 60.8 ± 10.5% in the gemcitabine group, -2.1 ± 9.9% after nintedanib therapy and -12.4 ± 16% after gemcitabine plus nintedanib therapy. Effects of therapy on intratumoral proliferation, microvessel density and apoptosis corresponded with tumor growth inhibition data. In a PDAC survival model, median animal survival after gemcitabine, nintedanib and gemcitabine plus nintedanib was 25, 31 and 38 days, respectively, compared to 16 days in controls. The strong antitumor activity of nintedanib in experimental PDAC supports the potential of nintedanib-controlled mechanisms as targets for improved clinical PDAC therapy.


Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients.
Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 - X-linked acrogigantism (X-LAG) - occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.


Automation of ROI extraction in hyperspectral breast images.
The extraction of regions-of-interest (ROIs) in hyperspectral images of breast cancer specimens is currently carried out manually or by visual inspection. In order to address the labor-intensive and time-consuming process of the manual extraction of ROIs in hyperspectral images, an algorithm is developed in this paper to automate the extraction process. This is achieved by using a contrast module and a homogeneity module to duplicate the same manual or visual steps that an expert goes through in order to extract ROIs. The success of the automated process is determined by comparing the classification rates of the automated approach with the manual approach in terms of the ability to separate cancer cases from normal cases.


Sudden cardiac death screening in adolescent athletes: an evaluation of compliance with national guidelines.
In the USA, the preparticipation physical evaluation (PPE) is the standard of care for screening eight million high-school athletes for their risk of sudden cardiac death (SCD). Our aim was to evaluate both physician and school compliance with national guidelines for SCD screening. We conducted a confidential survey of the Washington Chapter of the American Academy of Pediatrics (AAP), the Washington Academy of Family Physicians (WAFP) and Washington State high-school athletic directors. Responses were evaluated for compliance with the American Heart Association (AHA) guidelines for SCD screening. We received a response rate of 72% (559/776) from the AAP, 56% (554/990) from the WAFP and 78% (317/409) from the athletic directors. Only 6% of all providers and 0% of schools were in compliance with AHA guidelines. In addition, 47% of the physicians and 6% of athletic directors reported awareness of the guidelines. There was no difference in compliance between physician specialties (p=0.20). Physician location, years of experience and exposure to SCD were not significantly associated with compliance. Provider knowledge of the guidelines, number of PPE/month and frequency of referrals to cardiology were all positively associated with improved overall compliance (p<0.05). Despite the unaltered presence of the AHA SCD screening guidelines for the past 15 years, compliance with the recommendations is poor. Lack of compliance does not reflect clinical experience, but rather lack of knowledge of the guidelines themselves. New directions for provider education and policy requirements are needed to improve this implementation gap.


The impact of health maintenance organizations and competition on hospitals in Minneapolis/St. Paul.
The Healthcare Educational and Research Foundation (HERF) in Minneapolis undertook a two-year research project to study the effects of health maintenance organizations (HMOs) and competition on the hospital industry in Minneapolis/St. Paul. This article summarizes HERF's major findings surrounding three key questions: (1) do the HMOs in Minneapolis/St. Paul use fewer hospital resources relative to conventional payers?; (2) do recent overall community trends in inpatient use suggest evidence of hospital utilization-reducing effects attributable to HMOs?; and (3) given the highly visible competitive process among Minneapolis/St. Paul providers, do hospital cost and revenue data suggest any evidence of cost-containment? The findings (based on data through 1982) indicate that for comparable patients, Twin Cities HMOs appear to use fewer medical care resources per hospitalized patient. There was, however, no clear evidence of community-wide, utilization-reducing effects directly attributable to the "competitive effect" of HMO introduction and development in the market. In addition, there was no empirical evidence that HMOs (which had enrolled 25 percent of the consumer market by 1982), or other large buyers of inpatient services, have selected hospitals on the basis of price as hypothesized by competition advocates.


Allogeneic Hematopoietic Cell Transplant for HIV Patients with Hematologic Malignancies: The BMT CTN-0903/AMC-080 Trial.
We set out to assess feasibility and safety of allogeneic hematopoietic cell transplant in 17 persons with HIV in a phase II prospective multicenter trial. The primary endpoint was 100-day nonrelapse mortality (NRM). Patients had an 8/8 HLA-matched related or at least a 7/8 HLA-matched unrelated donor. Indications for transplant were acute leukemia, myelodysplasia, and lymphoma. Conditioning was myeloablative or reduced intensity. There was no NRM at 100 days. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 41%. At 1 year, overall survival was 59%; deaths were from relapsed/progressive disease (n = 5), acute GVHD (n = 1), adult respiratory distress syndrome (n = 1), and liver failure (n = 1). In patients who achieved complete chimerism, cell-associated HIV DNA and inducible infectious virus in the blood were not detectable. Blood and Marrow Transplant Clinical Trials Network 0903/AIDS Malignancy Consortium 080 was registered at www.clinicaltrials.gov (no. NCT01410344).


In utero Zika virus exposure and neurodevelopment at 24 months in toddlers normocephalic at birth: a cohort study.
In utero exposure to Zika virus (ZIKV) is known to be associated with birth defects. The impact of in utero ZIKV exposure on neurodevelopmental outcomes in early childhood remains unclear. The objective of this study was to determine the impact of in utero ZIKV exposure on neurodevelopment at 24 months of age among toddlers who were born normocephalic to women who were pregnant during the 2016 ZIKV outbreak in French territories in the Americas. We conducted a population-based mother-child cohort study of women whose pregnancies overlapped with the 2016 ZIKV epidemic in Guadeloupe, Martinique, and French Guiana. Infants were included in this analysis if maternal ZIKV infection during pregnancy could be determined, the newborn had a gestational age ≥ 35 weeks, there were no abnormal transfontanelle cerebral ultrasound findings after delivery or no abnormal ultrasound findings on the last ultrasound performed during the third trimester of the mother's pregnancy, there was an absence of microcephaly at birth, and the parent completed the 24-month neurodevelopment assessment of the infant at 24 months (± 1 month) of age. ZIKV exposure of the toddler was determined by evidence of maternal ZIKV infection during pregnancy. Neurodevelopment assessments included the Ages and Stages Questionnaire (ASQ) for five dimensions of general development-communication, gross motor, fine motor, problem solving, and personal-social skills; the Modified Checklist for Autism on Toddlers (M-CHAT) for behavior; and the French MacArthur Inventory Scales (IFDC) for French language acquisition. Between June 2018 and August 2019, 156 toddlers with and 79 toddlers without in utero ZIKV exposure completed neurodevelopment assessments. Twenty-four (15.4%) ZIKV-exposed toddlers and 20 (25.3%) ZIKV-unexposed toddlers had an ASQ result below the reference - 2SD cut-off (P = 0.10) for at least one of the five ASQ dimensions. In one of the largest population-based cohorts of in utero ZIKV-exposed, normocephalic newborns to date, there were minimal differences apparent in neurodevelopment outcomes at 24 months of age compared to ZIKV-unexposed toddlers at 24 months of age. ClinicalTrials.gov, NCT02810210 . Registered 20 June 2016.


Critical Illness and Cardiac Dysfunction in Anthracycline-Exposed Pediatric Oncology Patients.
To determine if the presence of cardiac dysfunction in anthracycline-exposed pediatric oncology patients is associated with an increased frequency of PICU admission or mortality. Retrospective parallel cohort study. PICU at an academic freestanding children's hospital. Children with oncologic diagnoses who received anthracyclines between January 2006 and December 2014 and were admitted to the hospital within 1 year of completion of therapy. None. Charts of 734 patients were reviewed and 545 were included in analysis. Anthracycline-exposed pediatric oncology patients with cardiac dysfunction were more likely to be admitted to the PICU than those without cardiac dysfunction (87% vs 37% rate of PICU admission). PICU admission was also associated with identified infection and higher cumulative anthracycline dose. Once admitted to the PICU, those anthracycline-exposed patients with cardiac dysfunction had significantly higher mortality (26% vs 6%) and longer length of stay (7 vs 2 d) than children without cardiac dysfunction. Patients with cardiac dysfunction were more likely to require mechanical ventilation (59% vs 18%), required more vasoactive medications for longer, and were more likely to develop fluid overload. Death within 1 year of ICU admission was associated with higher cumulative anthracycline dose. Children with cancer who received anthracyclines, especially at higher doses, and who develop cardiac dysfunction are at higher risk of critical illness, have higher rates of multiple organ dysfunction and higher rates of mortality than anthracycline-exposed patients without cardiac dysfunction.


Involving the headteacher in the development of school-based health interventions: A mixed-methods outcome and process evaluation using the RE-AIM framework.
Although interventions delivered in school settings have the potential to improve children's health and well-being, the implementation of effective interventions in schools presents challenges. Previous research suggests facilitating greater autonomy for schools to select interventions aligned to their needs could improve implementation and maintenance. The aim of this mixed-methods outcome and process evaluation was to explore whether involving headteachers in the developmental stages of health interventions influenced adoption, effectiveness (e.g. pupil fitness and physical activity, assessed quantitatively), implementation and maintenance (assessed quantitatively and qualitatively). Three UK primary schools were provided with a choice of five evidence-based physical activity interventions: Playground scrapstore, daily classroom refreshers, alternative afterschool clubs, parent and child afterschool activities and an 'In the Zone' playground intervention. To evaluate the impact of this autonomous approach, semi-structured interviews with headteachers (n = 3), teachers (n = 3), and a private coach, and focus groups with pupils aged 9-11 (n = 6, 31 pupils, 15 boys), were undertaken. This was alongside an outcome and process evaluation, guided by the RE-AIM framework. This study assessed the impacts on adoption, implementation and maintenance of the autonomous approach and the effect on physical activity (seven day accelerometry-GENEActiv) and aerobic fitness (20m shuttle run). All three schools adopted different intervention components; alternative afterschool clubs, parent and child afterschool activities and daily classroom refreshers. Headteachers welcomed greater autonomy in developing school-based interventions and appreciated the more collaborative approach. Mixed results were reported for the effectiveness, implementation and maintenance of the interventions adopted. Allowing pupils choice and promoting a positive school environment were key factors for enhancing engagement. Moreover, promoting inclusive physical activity projects with a consideration of existing curriculum pressures aided implementation. This mixed-methods study provides valuable insights about autonomous approaches to inform further development, implementation and maintenance for future interventions.


Urinary concentrations of parabens and serum hormone levels, semen quality parameters, and sperm DNA damage.
Parabens are commonly used as antimicrobial preservatives in cosmetics, pharmaceuticals, and food and beverage processing. Widespread human exposure to parabens has been recently documented, and some parabens have demonstrated adverse effects on male reproduction in animal studies. However, human epidemiologic studies are lacking. We investigated relationships between urinary concentrations of parabens and markers of male reproductive health in an ongoing reproductive epidemiology study. Urine samples collected from male partners attending an infertility clinic were analyzed for methyl paraben (MP), propyl paraben (PP), butyl paraben (BP), and bisphenol A (BPA). Associations with serum hormone levels (n = 167), semen quality parameters (n = 190), and sperm DNA damage measures (n = 132) were assessed using multivariable linear regression. Detection rates in urine were 100% for MP, 92% for PP, and 32% for BP. We observed no statistically significant associations between MP or PP and the outcome measures. Categories of urinary BP concentration were not associated with hormone levels or conventional semen quality parameters, but they were positively associated with sperm DNA damage (p for trend = 0.03). When urinary BPA quartiles were added to the model, BP and BPA were both positively associated with sperm DNA damage (p for trend = 0.03). Assessment of paraben concentrations measured on repeated urine samples from a subset of the men (n = 78) revealed substantial temporal variability. We found no evidence for a relationship between urinary parabens and hormone levels or semen quality, although intraindividual variability in exposure and a modest sample size could have limited our ability to detect subtle relationships. Our observation of a relationship between BP and sperm DNA damage warrants further investigation.


Comparison of the value of the two- and one-hour glucose levels of the oral GTT in the diagnosis of diabetes in Pima Indians.
In many population and screening studies of diabetes, the one-hour glucose level of the GTT has been used to define the diabetic status of subjects. The one-hour postglucose load determination has been preferred over the two-hour value by many investigators primarily because of convenience and justified on the basis of the high correlation between the two values. Venous plasma glucose levels, one and two hours after 75-gm. carbohydrate load, were determined on over 1600 Pima Indians. In most sex and age groups, the frequency distributions of both the one-hour and two-hour glucose levels were clearly bimodal. By the logarithms of the glucose values these distributions were consistent with a model of two overlapping Gaussian distributions. The data indicate that for the Pima the amount of overlap of the distributions was greater for the one-hour than for the two-hour values. For each sex and decade the probabilities of misclassification of a normal as "hyperglycemic" and vice versa were smaller for the two-hour than for the one-hour values. Such misclassifications for the two-hour levels averaged 6.6 per cent and 11.6 per cent for the one-hour levels. The reproducivility of the GTT taken one to three weeks apart in a sample of ninety-nine Pima Indians showed that the two-hour level was superior to the one-hour level as measured by the mean values of the absolute difference between log GTT levels for test and retest values. The one-hour measurements also gave more disagreements between the classifications of diabetic status than the two-hour test values. If a single measure of glucose tolerance is to be selected for the diagnosis of diabetes among Pima Indians, these data provide a mathematical rationale for preferring the two-hour level to the one-hour determination.


Development and initial testing of the Person-centered Care Assessment Tool (P-CAT).
Person-centered care is increasingly regarded as being synonymous with best quality care. However, the concept and its precise meaning is a subject of debate and reliable and valid measurement tools are lacking. This article describes the development and initial testing of a new self-report assessment scale, the Person-centered Care Assessment Tool (P-CAT), which measures the extent to which long-term aged care staff rate their settings to be person-centered. A preliminary 39-item tool generated from research literature, expert consultations and research interviews with aged care staff (n = 37), people with early onset dementia (n = 11), and family members (n = 19) was distributed to a sample of Australian aged care staff (n = 220) and subjected to item analysis and reduction. Psychometric evaluation of the final 13-item tool was conducted using statistical estimates of validity and reliability. The results showed that the P-CAT was shown to be valid and homogeneous by factor, item and content analyses. Cronbach's alpha was satisfactory for the total scale (0.84), and the three subscales had values of 0.81, 0.77, and 0.31 respectively. Test-retest reliability were evaluated (n = 26) and all analyses indicated satisfactory estimates. This study provides preliminary evidence in support of the psychometric properties of the P-CAT when used in an Australian sample of long-term aged care staff. The tool contributes to the literature by making it possible to study person-centered care in relation to health outcomes, organizational models, characteristics and levels of staffing, degrees of care needs among residents, and impact of interventions.


Daily Rhythms in Mobile Telephone Communication.
Circadian rhythms are known to be important drivers of human activity and the recent availability of electronic records of human behaviour has provided fine-grained data of temporal patterns of activity on a large scale. Further, questionnaire studies have identified important individual differences in circadian rhythms, with people broadly categorised into morning-like or evening-like individuals. However, little is known about the social aspects of these circadian rhythms, or how they vary across individuals. In this study we use a unique 18-month dataset that combines mobile phone calls and questionnaire data to examine individual differences in the daily rhythms of mobile phone activity. We demonstrate clear individual differences in daily patterns of phone calls, and show that these individual differences are persistent despite a high degree of turnover in the individuals' social networks. Further, women's calls were longer than men's calls, especially during the evening and at night, and these calls were typically focused on a small number of emotionally intense relationships. These results demonstrate that individual differences in circadian rhythms are not just related to broad patterns of morningness and eveningness, but have a strong social component, in directing phone calls to specific individuals at specific times of day.


A conserved deubiquitinating enzyme controls cell growth by regulating RNA polymerase I stability.
Eukaryotic ribosome biogenesis requires hundreds of trans-acting factors and dozens of RNAs. Although most factors required for ribosome biogenesis have been identified, little is known about their regulation. Here, we reveal that the yeast deubiquitinating enzyme Ubp10 is localized to the nucleolus and that ubp10Δ cells have reduced pre-rRNAs, mature rRNAs, and translating ribosomes. Through proteomic analyses, we found that Ubp10 interacts with proteins that function in rRNA production and ribosome biogenesis. In particular, we discovered that the largest subunit of RNA polymerase I (RNAPI) is stabilized via Ubp10-mediated deubiquitination and that this is required in order to achieve optimal levels of ribosomes and cell growth. USP36, the human ortholog of Ubp10, complements the ubp10Δ allele for RNAPI stability, pre-rRNA processing, and cell growth in yeast, suggesting that deubiquitination of RNAPI may be conserved in eukaryotes. Our work implicates Ubp10/USP36 as a key regulator of rRNA production through control of RNAPI stability.


Individual patient factors associated with effective tinnitus treatment.
Little is known about patient factors that might influence outcomes of tinnitus interventions. Determining such factors would offer insights into why some individuals benefit from tinnitus intervention whereas others do not. The purpose of this study was to evaluate selected patient factors that may be associated with outcomes of tinnitus intervention. Factors studied include demographics, tinnitus characteristics, psychoacoustic tinnitus measures, audiometric data, and overall physical/emotional health status. A retrospective analysis was performed on data obtained from a controlled clinical study that compared factors associated with tinnitus relief after tinnitus masking and tinnitus retraining therapy. A total of 126 military veterans participated in this controlled clinical study. Of these, 89 completed outcome measures at both baseline and 12 mo and were included in the present analysis. A "responder" to intervention was identified as having a decrease (improvement) of 20 or more points on the Tinnitus Handicap Inventory between baseline and 12 mo. A "nonresponder" did not achieve a 20-point improvement on the Tinnitus Handicap Inventory. Individual patient factors were examined using independent t-tests or χ² analysis. A logistic regression model was used to determine how well each factor predicted treatment outcome (responder or nonresponder) while controlling for each of the other factors. Five patient factors were significantly different (p ≤ 0.05) between responders and nonresponders. Responders tended to (1) be younger in age; (2) have better low-frequency hearing sensitivity; (3) have greater problems with overall hearing; (4) be more likely to have tinnitus for shorter durations; and (5) perceive their tinnitus to be located "in the head" versus "in the ears." A logistic regression was then performed to determine how well each factor predicted the treatment outcome (responder versus nonresponder) while controlling for each of the other factors. RESULTS from the logistic regression revealed two of the five factors, localization of tinnitus and self-report of hearing problems, to be statistically significant. Examining the association of individual patient factors to a specific tinnitus intervention yielded several significant findings. Although these findings are not definitive, they reveal the capability that exists to perform these kinds of analyses to investigate relationships between individual patient characteristics and outcomes of intervention for tinnitus. Prospective research using systematic approaches is needed to identify these relationships that would contribute toward the ability to differentially predict outcomes of various tinnitus interventions. Obtaining this information would lead to more targeted therapy and ultimately more effective intervention.


Association of Coffee, Decaffeinated Coffee and Caffeine Intake from Coffee with Cognitive Performance in Older Adults: National Health and Nutrition Examination Survey (NHANES) 2011-2014.
The aim of this study was to examine the association of coffee, caffeinated coffee, decaffeinated coffee and caffeine intake from coffee with cognitive performance in older adults. we used data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Coffee and caffeine intake were obtained through two 24-hour dietary recalls. Cognitive performance was evaluated by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test, Animal Fluency test and Digit Symbol Substitution Test (DSST). Binary logistic regression and restricted cubic spline models were applied to evaluate the association of coffee and caffeine intake with cognitive performance. A total of 2513 participants aged 60 years or older were included. In the fully adjusted model, compared to those reporting no coffee consumption, those who reported 266.4-495 (g/day) had a multivariate adjusted odd ratio (OR) with 95% confidence interval (CI) of 0.56(0.35-0.89) for DSST test score, compared to those reporting no caffeinated coffee consumption, those who reported ≥384.8 (g/day) had a multivariate-adjusted OR (95% CI) of 0.68(0.48-0.97) for DSST test score, compared to the lowest quartile of caffeine intake from coffee, the multivariate adjusted OR (95% CI) of the quartile (Q) three was 0.62(0.38-0.98) for the CERAD test score. L-shaped associations were apparent for coffee, caffeinated coffee and caffeine from coffee with the DSST test score and CERAD test score. No significant association was observed between decaffeinated coffee and different dimensions of cognitive performance. Our study suggests that coffee, caffeinated coffee and caffeine from coffee were associated with cognitive performance, while decaffeinated coffee was not associated with cognitive performance.


Comparison of methods for predicting COVID-19-related death in the general population using the OpenSAFELY platform.
Obtaining accurate estimates of the risk of COVID-19-related death in the general population is challenging in the context of changing levels of circulating infection. We propose a modelling approach to predict 28-day COVID-19-related death which explicitly accounts for COVID-19 infection prevalence using a series of sub-studies from new landmark times incorporating time-updating proxy measures of COVID-19 infection prevalence. This was compared with an approach ignoring infection prevalence. The target population was adults registered at a general practice in England in March 2020. The outcome was 28-day COVID-19-related death. Predictors included demographic characteristics and comorbidities. Three proxies of local infection prevalence were used: model-based estimates, rate of COVID-19-related attendances in emergency care, and rate of suspected COVID-19 cases in primary care. We used data within the TPP SystmOne electronic health record system linked to Office for National Statistics mortality data, using the OpenSAFELY platform, working on behalf of NHS England. Prediction models were developed in case-cohort samples with a 100-day follow-up. Validation was undertaken in 28-day cohorts from the target population. We considered predictive performance (discrimination and calibration) in geographical and temporal subsets of data not used in developing the risk prediction models. Simple models were contrasted to models including a full range of predictors. Prediction models were developed on 11,972,947 individuals, of whom 7999 experienced COVID-19-related death. All models discriminated well between individuals who did and did not experience the outcome, including simple models adjusting only for basic demographics and number of comorbidities: C-statistics 0.92-0.94. However, absolute risk estimates were substantially miscalibrated when infection prevalence was not explicitly modelled. Our proposed models allow absolute risk estimation in the context of changing infection prevalence but predictive performance is sensitive to the proxy for infection prevalence. Simple models can provide excellent discrimination and may simplify implementation of risk prediction tools.


Amide proton transfer imaging of adult diffuse gliomas: correlation with histopathological grades.
Amide proton transfer (APT) imaging is a novel molecular MRI technique to detect endogenous mobile proteins and peptides through chemical exchange saturation transfer. We prospectively assessed the usefulness of APT imaging in predicting the histological grade of adult diffuse gliomas. Thirty-six consecutive patients with histopathologically proven diffuse glioma (48.1 ± 14.7 y old, 16 males and 20 females) were included in the study. APT MRI was conducted on a 3T clinical scanner and was obtained with 2 s saturation at 25 saturation frequency offsets ω = -6 to +6 ppm (step 0.5 ppm). δB0 maps were acquired separately for a point-by-point δB0 correction. APT signal intensity (SI) was defined as magnetization transfer asymmetry at 3.5 ppm: magnetization transfer ratio (MTR)asym = (S[-3.5 ppm] - S[+3.5 ppm])/S0. Regions of interest were carefully placed by 2 neuroradiologists in solid parts within brain tumors. The APT SI was compared with World Health Organization grade, Ki-67 labeling index (LI), and cell density. The mean APT SI values were 2.1 ± 0.4% in grade II gliomas (n = 8), 3.2 ± 0.9% in grade III gliomas (n = 10), and 4.1 ± 1.0% in grade IV gliomas (n = 18). Significant differences in APT intensity were observed between grades II and III (P < .05) and grades III and IV (P < .05), as well as between grades II and IV (P < .001). There were positive correlations between APT SI and Ki-67 LI (P = .01, R = 0.43) and between APT SI and cell density (P < .05, R = 0.38). The gliomas with microscopic necrosis showed higher APT SI than those without necrosis (P < .001). APT imaging can predict the histopathological grades of adult diffuse gliomas.


The effect of crystalloid versus medium molecular weight colloid solution on post-operative nausea and vomiting after ambulatory gynecological surgery - a prospective randomized trial.
Intravenous fluid is recommended in international guidelines to improve patient post-operative symptoms, particularly nausea and vomiting. The optimum fluid regimen has not been established. This prospective, randomized, blinded study was designed to determine if administration of equivolumes of a colloid (hydroxyethyl starch 130/0.4) reduced post operative nausea and vomiting in healthy volunteers undergoing ambulatory gynecologic laparoscopy surgery compared to a crystalloid solution (Hartmann's Solution). 120 patients were randomized to receive intravenous colloid (N = 60) or crystalloid (N = 60) intra-operatively. The volume of fluid administered was calculated at 1.5 ml.kg-1 per hour of fasting. Patients were interviewed to assess nausea, vomiting, anti-emetic use, dizziness, sore throat, headache and subjective general well being at 30 minutes and 2, 24 and 48 hours post operatively. Pulmonary function testing was performed on a subgroup. At 2 hours the proportion of patients experiencing nausea (38.2 % vs 17.9%, P = 0.03) and the mean nausea score were increased in the colloid compared to crystalloid group respectively (1.49 ± 0.3 vs 0.68 ± 0.2, P = 0.028). The incidence of vomiting and anti-emetic usage was low and did not differ between the groups. Sore throat, dizziness, headache and general well being were not different between the groups. A comparable reduction on post-operative FVC and FEV-1 and PEFR was observed in both groups. Intra-operative administration of colloid increased the incidence of early postoperative nausea and has no advantage over crystalloid for symptom control after gynaecological laparoscopic surgery.


All-optical stabilization of a soliton frequency comb in a crystalline microresonator.
We demonstrate the all-optical stabilization of a low-noise temporal soliton based microresonator based optical frequency comb in a crystalline resonator via a new technique to control the repetition rate. This is accomplished by thermally heating the microresonator with an additional probe laser coupled to an auxiliary optical resonator mode. The carrier-envelope offset frequency is controlled by stabilizing the pump laser frequency to a reference optical frequency comb. We analyze the stabilization by performing an out-of-loop comparison and measure the overlapping Allan deviation. This all-optical stabilization technique can prove useful as an actuator for self-referenced microresonator frequency combs.


High-Tidal-Volume Mechanical Ventilation and Lung Inflammation in Intensive Care Patients With Normal Lungs.
This study was conducted to investigate whether high-tidal-volume mechanical ventilation is associated with increased lung inflammation compared with low-tidal-volume mechanical ventilation in critically ill patients with no evidence of lung injury. In this prospective, single-blind, randomized (1:1), parallel-group study, 18 critically ill patients with normal lungs were randomly assigned to receive mechanical ventilation with a tidal volume of either 6 mL/kg (low tidal volume) or 12 mL/kg (high tidal volume) during the first 4 days in the intensive care unit. At baseline and at 24, 48, and 96 hours, exhaled breath condensate was collected to measure interleukin 1β, interleukin 10, tumor necrosis factor α, and total nitric oxide metabolites. Interleukin 1β levels in exhaled breath condensate were significantly increased at 24 hours compared with baseline in the high-tidal-volume group but not in the low-tidal-volume group. The interleukin 1β increase in the high-tidal-volume group was transient. Exhaled breath condensate levels of interleukin 1β, interleukin 10, tumor necrosis factor α, and total nitric oxide metabolites did not differ significantly between the high-tidal-volume and low-tidal-volume groups at any time point. Short-term mechanical ventilation with a tidal volume of 12 mL/kg may trigger inflammatory responses in the lungs of intensive care unit patients without preexisting lung injury.


The Mazankowski Report: can we fix medicare with more private financing.
The Mazankowski Report is a very important contribution to the debate washing over Canada with regard to the future of its most cherished social program, medicare. While a complete analysis of the report is not possible in this brief comment, several observations and arguments should be made. First, the report's recommendations for a greater role for private financing undermines the other excellent recommendations made with regard to greater accountability, the rigorous pursuit of quality and greater flexibility regarding the role of the private sector in delivery (as opposed to financing). Second, the report's specific recommendation to establish a permanent, independent panel to determine what services should and should not be publicly funded is a worthwhile reform, but not for the reasons envisaged by the report's authors - that is, because it will result in a reduction in the range of services funded and save public dollars. Rather, it is a worthwhile initiative because engaging in a transparent and explicit determination of what is in and out of the publicly funded basket is likely to result in more political support for publicly funding a wide range of care rather than less.


Impact of the COVID-19 virus outbreak on movement and play behaviours of Canadian children and youth: a national survey.
Healthy childhood development is fostered through sufficient physical activity (PA; including time outdoors), limiting sedentary behaviours (SB), and adequate sleep; collectively known as movement behaviours. Though the COVID-19 virus outbreak has changed the daily lives of children and youth, it is unknown to what extent related restrictions may compromise the ability to play and meet movement behaviour recommendations. This secondary data analysis examined the immediate impacts of COVID-19 restrictions on movement and play behaviours in children and youth. A national sample of Canadian parents (n = 1472) of children (5-11 years) or youth (12-17 years) (54% girls) completed an online survey that assessed immediate changes in child movement and play behaviours during the COVID-19 outbreak. Behaviours included PA and play, SB, and sleep. Family demographics and parental factors that may influence movement behaviours were assessed. Correlations between behaviours and demographic and parental factors were determined. For open-ended questions, word frequency distributions were reported. Only 4.8% (2.8% girls, 6.5% boys) of children and 0.6% (0.8% girls, 0.5% boys) of youth were meeting combined movement behaviour guidelines during COVID-19 restrictions. Children and youth had lower PA levels, less outside time, higher SB (including leisure screen time), and more sleep during the outbreak. Parental encouragement and support, parental engagement in PA, and family dog ownership were positively associated with healthy movement behaviours. Although families spent less time in PA and more time in SB, several parents reported adopting new hobbies or accessing new resources. This study provides evidence of immediate collateral consequences of the COVID-19 outbreak, demonstrating an adverse impact on the movement and play behaviours of Canadian children and youth. These findings can guide efforts to preserve and promote child health during the COVID-19 outbreak and crisis recovery period, and to inform strategies to mitigate potential harm during future pandemics.


Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis.
The effects of pharmacological blood pressure lowering at normal or high-normal blood pressure ranges in people with or without pre-existing cardiovascular disease remains uncertain. We analysed individual participant data from randomised trials to investigate the effects of blood pressure lowering treatment on the risk of major cardiovascular events by baseline levels of systolic blood pressure. We did a meta-analysis of individual participant-level data from 48 randomised trials of pharmacological blood pressure lowering medications versus placebo or other classes of blood pressure-lowering medications, or between more versus less intensive treatment regimens, which had at least 1000 persons-years of follow-up in each group. Trials exclusively done with participants with heart failure or short-term interventions in participants with acute myocardial infarction or other acute settings were excluded. Data from 51 studies published between 1972 and 2013 were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We pooled the data to investigate the stratified effects of blood pressure-lowering treatment in participants with and without prevalent cardiovascular disease (ie, any reports of stroke, myocardial infarction, or ischaemic heart disease before randomisation), overall and across seven systolic blood pressure categories (ranging from <120 to ≥170 mm Hg). The primary outcome was a major cardiovascular event (defined as a composite of fatal and non-fatal stroke, fatal or non-fatal myocardial infarction or ischaemic heart disease, or heart failure causing death or requiring admission to hospital), analysed as per intention to treat. Data for 344 716 participants from 48 randomised clinical trials were available for this analysis. Pre-randomisation mean systolic/diastolic blood pressures were 146/84 mm Hg in participants with previous cardiovascular disease (n=157 728) and 157/89 mm Hg in participants without previous cardiovascular disease (n=186 988). There was substantial spread in participants' blood pressure at baseline, with 31 239 (19·8%) of participants with previous cardiovascular disease and 14 928 (8·0%) of individuals without previous cardiovascular disease having a systolic blood pressure of less than 130 mm Hg. The relative effects of blood pressure-lowering treatment were proportional to the intensity of systolic blood pressure reduction. After a median 4·15 years' follow-up (Q1-Q3 2·97-4·96), 42 324 participants (12·3%) had at least one major cardiovascular event. In participants without previous cardiovascular disease at baseline, the incidence rate for developing a major cardiovascular event per 1000 person-years was 31·9 (95% CI 31·3-32·5) in the comparator group and 25·9 (25·4-26·4) in the intervention group. In participants with previous cardiovascular disease at baseline, the corresponding rates were 39·7 (95% CI 39·0-40·5) and 36·0 (95% CI 35·3-36·7), in the comparator and intervention groups, respectively. Hazard ratios (HR) associated with a reduction of systolic blood pressure by 5 mm Hg for a major cardiovascular event were 0·91, 95% CI 0·89-0·94 for partipants without previous cardiovascular disease and 0·89, 0·86-0·92, for those with previous cardiovascular disease. In stratified analyses, there was no reliable evidence of heterogeneity of treatment effects on major cardiovascular events by baseline cardiovascular disease status or systolic blood pressure categories. In this large-scale analysis of randomised trials, a 5 mm Hg reduction of systolic blood pressure reduced the risk of major cardiovascular events by about 10%, irrespective of previous diagnoses of cardiovascular disease, and even at normal or high-normal blood pressure values. These findings suggest that a fixed degree of pharmacological blood pressure lowering is similarly effective for primary and secondary prevention of major cardiovascular disease, even at blood pressure levels currently not considered for treatment. Physicians communicating the indication for blood pressure lowering treatment to their patients should emphasise its importance on reducing cardiovascular risk rather than focusing on blood pressure reduction itself. British Heart Foundation, UK National Institute for Health Research, and Oxford Martin School.


Some neurobiological aspects of psychotherapy. A review.
Ever since the idea was accepted that memory is associated with alterations in synaptic strength, studies on the cellular and molecular mechanisms responsible for the plastic changes in neurons have attracted wide interest in the scientific community. This article explores the process of memory consolidation leading to persistent modifications in synaptic plasticity as a mechanism by which psychotherapy facilitates changes in the permanent storage of information acquired throughout the individual's life. The psychobiological interrelationships of affect, attachment, and memory offer a perspective regarding the etiology and treatment of clinical disturbances of affect. Analogies between brain physiology and modes of psychotherapy provide the foundation for a review of psychiatric disorders involving the inability to control fear, obsessions, compulsions, and delusions, all of which respond to psychotherapeutic interventions.


The Impact of Dry-Land Sprint Start Training on the Short Track Speed Skating Start.
Haug, WB, Drinkwater, EJ, Cicero, NJ, Barthell, JA, and Chapman, DW. The impact of dry-land sprint start training on the short track speed skating start. J Strength Cond Res 33(2): 544-548, 2019-This investigation sought to determine the effects of dry-land sprint start training on short track speed skating (STSS) start performance. Nine highly trained short track athletes completed a control period of normal STSS training followed by a 4-week training intervention. Before and after the control and intervention periods, athletes performed 3 electronically timed dry-land and on-ice 14.43 m maximal sprint start efforts. The intervention consisted of 2 sprint sessions per week consisting of 9 electronically timed 14.43 m dry-land sprint starts in addition to normal STSS training. The control period resulted in no substantial change in on-ice start performance (mean Δ: -0.01 seconds, 95% confidence limit [CL]: -0.08 to 0.05 seconds; effect size [ES]: -0.05; trivial); however, a small change was observed in dry-land start performance (mean Δ: -0.07 seconds, 95% CL: -0.13 to -0.02 seconds; ES: -0.49). After brief specific dry-land sprint start training, a small improvement was observed in both on-ice (Mean Δ: -0.07 seconds, 95% CL: -0.13 to -0.01 seconds; ES: -0.33) and dry-land (Mean Δ: -0.04 seconds, 95% CL: -0.09 to 0.00 seconds; ES: -0.29) start performance. This investigation suggests that STSS start performance can be improved through a brief dry-land sprint start training program.


Application of a congener-specific debromination model to study photodebromination, anaerobic microbial debromination, and FE0 reduction of polybrominated diphenyl ethers.
A model was used to predict the photodebromination of the BDE-203, 197, 196, and 153, the major components of the octa-polybrominated diphenyl ether (PBDE) technical mixture, as well as BDE-47, and the predicted results were compared to the experimental results. The predicted reaction time profiles of the photodebromination products correlate well with the experimental results. In addition, the slope of the linear regression between the measured product concentrations of the first step of the photodebromination products and their enthalpies of formation was found to be close to their theoretical value. The photodebromination results of the octa-BDE technical mixture were compared with anaerobic microbial debromination results and were found to be the same in both experiments. The debromination pathways of technical octa-BDE mixture were identified and BDE-154, 99, 47, and 31 were found to be the most abundant hexa-, penta-, tetra-, and tri-BDE debromination products, respectively. In addition to photodebromination and anaerobic biodebromination, the model prediction was also compared to the zero-valent iron reduction of BDE-209, 100, and 47 and the same debromination products were observed. Good correlation was observed between the photodebromination rate constants of fifteen PBDE congeners and their calculated lowest unoccupied molecular orbital (LUMO) energies, indicating that PBDE photodebromination is caused by electron transfer. Furthermore, the rate constants for the three different PBDE debromination processes are controlled by C-Br bond dissociation energy. With the model from the present study, the major debromination products for any PBDE congener released into the environment can be predicted.


Recent trends in adolescent substance use, primary care screening, and updates in treatment options.
To provide a brief overview on trends in common substances of abuse in adolescents, a summary of tools to evaluate adolescent substance abuse in an outpatient setting, and an update of outpatient and inpatient treatment options. Recent national data suggest an overall slight decline in the use of tobacco, crystal methamphetamine, heroin, and club drugs. No significant change was noted in the use of alcohol, marijuana, and cocaine. Yearly screening of all adolescents for substance use is recommended. This can be accomplished in an office setting using mnemonics, structured interview techniques, and brief screens for substance abuse. If a problem is identified, various outpatient and inpatient treatments are available. Individual, family, and group therapy methods are available. Other options include acute detoxification programs, partial hospitalization, acute residential treatment, residential treatment centers and wilderness programs. Pharmacological treatments are available for nicotine, alcohol, and opioid addiction. Tobacco, alcohol, marijuana, and other drugs remain a significant problem among adolescents in the United States. Pediatricians should screen and assess all adolescents on a yearly basis. If a problem is identified, there are many options for treatment, including pharmacologic treatment as well as individual, family, or group therapy in an inpatient or outpatient setting.


Production and functional characterization of human recombinant FGF-6 protein.
The fibroblast growth factor (FGF) gene family to date comprises seven members and has been implicated in a wide range of physiological and biological processes, including angiogenesis, morphogenesis, and tumorigenesis. The FGFs are mitogens for a broad range of cells of various embryological origins and can act as differentiation factors. The FGFs can bind to tyrosine kinase and non-tyrosine kinase transmembrane receptors; the physiological basis for this is still unknown. In order to study more thoroughly the activities of FGF-6, we have constructed a bacterial expression vector by inserting FGF-6 complementary DNA sequences into the T7 RNA polymerase-based pET3a vector. The resulting construct is able to drive the expression of a high amount of FGF-6 protein in Escherichia coli, which can be solubilized and purified through heparin-Sepharose chromatography and high salt elution. The purified FGF-6 protein displays a strong mitogenic activity on BALB/c 3T3 cells and is able to morphologically transform these cells. By contrast, adult bovine aortic endothelial cells, which normally require the presence of FGF-2 for their growth, show only a limited mitogenic response that is highly dependent on heparin concentration.


The early development of medial coronoid disease in growing Labrador retrievers: radiographic, computed tomographic, necropsy and micro-computed tomographic findings.
Medial coronoid disease (MCD) encompasses lesions of the entire medial coronoid process (MCP), both of the articular cartilage and the subchondral bone. To detect the earliest signs of MCD, radiography and computed tomography were used to monitor the development of MCD in 14 Labrador retrievers, from 6 to 7 weeks of age until euthanasia. The definitive diagnosis of MCD was based on necropsy and micro-computed tomography findings. The frequency of MCD in the dogs studied was 50%. Radiographic findings did not provide evidence of MCD, ulnar subtrochlear sclerosis or blunting of the cranial edge of the MCP. Computed tomography was more sensitive (30.8%) than radiography (0%) in detecting early MCD, with the earliest signs detectable at 14 weeks of age. A combination of the necropsy and micro-computed tomography findings of the MCP showed that MCD was manifested as a lesion of only the subchondral bone in dogs <18 weeks of age. In all dogs (affected and unaffected), there was close contact between the base of the MCP and the proximal radial head in the congruent joints. Computed tomography and micro-computed tomography findings indicated that the lesions of MCD probably originated at the base of the MCP.


Water-in-oil-in-water double emulsion for the delivery of starter cultures in reduced-salt moromi fermentation of soy sauce.
This study investigated the application of water-oil-water (W1/O/W2) double emulsions (DE) for yeast encapsulation and sequential inoculation of Zygosaccharomyces rouxii and Tetragenococcus halophilus in moromi stage of soy sauce fermentation with reduced NaCl and/or substitution with KCl. Z. rouxii and T. halophilus were incorporated in the internal W1 and external W2 phase of DE, respectively. NaCl reduction and substitution promoted T. halophilus growth to 8.88 log CFU/mL, accompanied with faster sugar depletion and enhanced lactic acid production. Reducing NaCl without substitution increased the final pH (5.49) and decreased alcohols, acids, esters, furan and phenol content. However, the application of DE resulted in moromi with similar microbiological and physicochemical characteristics to that of high-salt. Principal component analysis of GC-MS data demonstrated that the reduced-salt moromi had identical aroma profile to that obtained in the standard one, indicating the feasibility of producing low-salt soy sauce without compromising its quality.


American College of Sports Medicine roundtable on exercise guidelines for cancer survivors.
Early detection and improved treatments for cancer have resulted in roughly 12 million survivors alive in the United States today. This growing population faces unique challenges from their disease and treatments, including risk for recurrent cancer, other chronic diseases, and persistent adverse effects on physical functioning and quality of life. Historically, clinicians advised cancer patients to rest and to avoid activity; however, emerging research on exercise has challenged this recommendation. To this end, a roundtable was convened by American College of Sports Medicine to distill the literature on the safety and efficacy of exercise training during and after adjuvant cancer therapy and to provide guidelines. The roundtable concluded that exercise training is safe during and after cancer treatments and results in improvements in physical functioning, quality of life, and cancer-related fatigue in several cancer survivor groups. Implications for disease outcomes and survival are still unknown. Nevertheless, the benefits to physical functioning and quality of life are sufficient for the recommendation that cancer survivors follow the 2008 Physical Activity Guidelines for Americans, with specific exercise programming adaptations based on disease and treatment-related adverse effects. The advice to "avoid inactivity," even in cancer patients with existing disease or undergoing difficult treatments, is likely helpful.


Tonically discharging genioglossus motor units show no evidence of rate coding with hypercapnia.
The genioglossus (GG) is considered the principle protrudor muscle of the human tongue. Unlike most skeletal muscles, GG electromyographic (EMG) activities are robustly preserved in sleep and thus may fulfill a critical role in preserving airway patency. Previous studies in human subjects also confirm that the GG EMG increases in response to chemoreceptor and mechanoreceptor stimulation. This increase occurs secondary to the recruitment of previously inactive motor units (MUs) and/or an increase in firing rate of already active MUs. Which strategy the nervous system uses when the synaptic drive onto GG motoneurons increases is not known. Here we report on GG whole muscle and tonic MU activities under conditions that mimic sleep, i.e., mild-moderate elevations in CO(2) (3% inspired CO(2) or the addition of a 1.0 l dead space) and elevated airway resistance. Based on previous work in rat, we hypothesized that mild hypercapnia would increase the firing rates of tonic MUs and that these effects would be further potentiated by a modest increase in airway resistance. Fine wire and tungsten microelectrodes were inserted into the GG to record whole muscle and single MU activities in 21 subjects (13 women, 8 men; 20-55 yr). Either 3% inspired CO(2) or added dead space resulted in a 200-300% increase in the amplitude of both tonic and phasic components of the whole muscle GG EMG and a doubling of minute ventilation. Despite these changes, recordings obtained from a total of 84 tonically discharging GG single MUs provide no evidence of a change in firing rate under any of the conditions. On this basis we conclude that in healthy adults, the increase in the tonic component of the whole muscle GG EMG secondary to mild hypercapnia is due almost exclusively to the recruitment of previously inactive MUs.


A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial.
Hypertension cannot always be adequately controlled with available drugs. We investigated the blood-pressure-lowering effects of the new vasodilatory, selective endothelin type A antagonist, darusentan, in patients with treatment-resistant hypertension. This randomised, double-blind study was undertaken in 117 sites in North and South America, Europe, New Zealand, and Australia. 379 patients with systolic blood pressure of 140 mm Hg or more (>/=130 mm Hg if patient had diabetes or chronic kidney disease) who were receiving at least three blood-pressure-lowering drugs, including a diuretic, at full or maximum tolerated doses were randomly assigned to 14 weeks' treatment with placebo (n=132) or darusentan 50 mg (n=81), 100 mg (n=81), or 300 mg (n=85) taken once daily. Randomisation was made centrally via an automated telephone system, and patients and all investigators were masked to treatment assignments. The primary endpoints were changes in sitting systolic and diastolic blood pressures. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00330369. All randomly assigned participants were analysed. The mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg (SD 14/8) with placebo, 17/10 mm Hg (15/9) with darusentan 50 mg, 18/10 mm Hg (16/9) with darusentan 100 mg, and 18/11 mm Hg (18/10) with darusentan 300 mg (p<0.0001 for all effects). The main adverse effects were related to fluid accumulation. Oedema or fluid retention occurred in 67 (27%) patients given darusentan compared with 19 (14%) given placebo. One patient in the placebo group died (sudden cardiac death), and five patients in the three darusentan dose groups combined had cardiac-related serious adverse events. Darusentan provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs. As with other vasodilatory drugs, fluid management with effective diuretic therapy might be needed. Gilead Sciences.


HSF1 phosphorylation by ERK/GSK3 suppresses RNF126 to sustain IGF-IIR expression for hypertension-induced cardiomyocyte hypertrophy.
Hypertension-induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure (HF). Inhibition of extracellular signal-regulated kinases (ERK) efficaciously suppressed angiotensin II (ANG II)-induced cardiomyocyte hypertrophy and apoptosis by blocking insulin-like growth factor II receptor (IGF-IIR) signaling. However, the detailed mechanism by which ANG II induces ERK-mediated IGF-IIR signaling remains elusive. Here, we found that ANG II activated ERK to upregulate IGF-IIR expression via the angiotensin II type I receptor (AT1 R). ERK activation subsequently phosphorylates HSF1 at serine 307, leading to a secondary phosphorylation by glycogen synthase kinase III (GSK3) at serine 303. Moreover, we found that ANG II mediated ERK/GSK3-induced IGF-IIR protein stability by downregulating the E3 ubiquitin ligase of IGF-IIR RING finger protein CXXVI (RNF126). The expression of RNF126 decreased following ANG II-induced HSF1S303 phosphorylation, resulting in IGF-IIR protein stability and increased cardiomyocyte injury. Inhibition of GSK3 significantly alleviated ANG II-induced cardiac hypertrophy in vivo and in vitro. Taken together, these results suggest that HSF1 phosphorylation stabilizes IGF-IIR protein stability by downregulating RNF126 during cardiac hypertrophy. ANG II activates ERK/GSK3 to phosphorylate HSF1, resulting in RNF126 degradation, which stabilizes IGF-IIR protein expression and eventually results in cardiac hypertrophy. HSF1 could be a valuable therapeutic target for cardiac diseases among hypertensive patients.


Dissection of ESAT-6 system 1 of Mycobacterium tuberculosis and impact on immunogenicity and virulence.
The dedicated secretion system ESX-1 of Mycobacterium tuberculosis encoded by the extended RD1 region (extRD1) assures export of the ESAT-6 protein and its partner, the 10-kDa culture filtrate protein CFP-10, and is missing from the vaccine strains M. bovis BCG and M. microti. Here, we systematically investigated the involvement of each individual ESX-1 gene in the secretion of both antigens, specific immunogenicity, and virulence. ESX-1-complemented BCG and M. microti strains were more efficiently engulfed by bone-marrow-derived macrophages than controls, and this may account for the enhanced in vivo growth of ESX-1-carrying strains. Inactivation of gene pe35 (Rv3872) impaired expression of CFP-10 and ESAT-6, suggesting a role in regulation. Genes Rv3868, Rv3869, Rv3870, Rv3871, and Rv3877 encoding an ATP-dependent chaperone and translocon were essential for secretion of ESAT-6 and CFP-10 in contrast to ppe68 Rv3873 and Rv3876, whose inactivation did not impair secretion of ESAT-6. A strict correlation was found between ESAT-6 export and the generation of ESAT-6 specific T-cell responses in mice. Furthermore, ESAT-6 secretion and specific immunogenicity were almost always correlated with enhanced virulence in the SCID mouse model. Only loss of Rv3865 and part of Rv3866 did not affect ESAT-6 secretion or immunogenicity but led to attenuation. This suggests that Rv3865/66 represent a new virulence factor that is independent from ESAT-6 secretion. The present study has allowed us to identify new aspects of the extRD1 region of M. tuberculosis and to explore its role in the pathogenesis of tuberculosis.


Cadherin-mediated cell adhesion is critical for the closing of the mouse optic fissure.
Coloboma is a congenital disease that contributes significantly to childhood blindness. It results from the failure in closing the optic fissure, a transient opening on the ventral side of the developing eye. Although human and mouse genetic studies have identified a number of genes associated with coloboma, the detailed cellular mechanisms underlying the optic fissure closure and coloboma formation remain largely undefined. N-cadherin-mediated cell adhesion has been shown to be important for the optic fissure closure in zebrafish, but it remains to be determined experimentally how cell-cell adhesions are involved in the mammalian optic fissure closing process. α-Catenin is required for cell adhesion mediated by all of the classic cadherin molecules, including N-cadherin. In this study, we used the Cre-mediated conditional knockout technique to specifically delete α-catenin from the developing mouse eye to show that it is required for the successful closing of the optic fissure. In α-catenin conditional mutant optic cups, the major cell fates, including the optic fissure margin, neural retina and retinal pigmented epithelium, are specified normally, and the retinal progenitor cells proliferate normally. However, adherens junctions components, including N-cadherin, β-catenin and filamentous actin, fail to accumulate on the apical side of α-catenin mutant retinal progenitor cells, where adherens junctions are normally abundant, and the organization of the neural retina and the optic fissure margin is disrupted. Finally, the α-catenin mutant retina gradually degenerates in the adult mouse eye. Therefore, our results show that α-catenin-mediated cell adhesion and cell organization are important for the fissure closure in mice, and further suggest that genes that regulate cell adhesion may underlie certain coloboma cases in humans.


Seasonal patterns of suicide, depression and electroconvulsive therapy.
This study examined the hypothesis that there are seasonal variations for suicide, hospital admissions for depressive illnesses and electroconvulsive therapy and that these are inter-related. It was found that the seasonal variations did coincide, with peaks occurring in the Ontario spring and autumn. The importance of depression as a cause of suicide and the effect of electroconvulsive therapy upon the suicide rate are discussed.


Rods Contribute to Visual Behavior in Larval Zebrafish.
Although zebrafish rods begin to develop as early as 2 days postfertilization (dpf), they are not deemed anatomically mature and functional until 15 to 21 dpf. A recent study detected a small electroretinogram (ERG) from rods in a cone mutant called no optokinetic response f (nof) at 5 dpf, suggesting that young rods are functional. Whether they can mediate behavioral responses in larvae is unknown. We first confirmed rod function by measuring nof ERGs under photopic and scotopic illumination at 6 dpf. We evaluated the role of rods in visual behaviors using two different assays: the visual-motor response (VMR) and optokinetic response (OKR). We measured responses from wild-type (WT) larvae and nof mutants under photopic and scotopic illuminations at 6 dpf. Nof mutants lacked a photopic ERG. However, after prolonged dark adaptation, they displayed scotopic ERGs. Compared with WT larvae, the nof mutants displayed reduced VMRs. The VMR difference during light onset gradually diminished with decreased illumination and became nearly identical at lower light intensities. Additionally, light-adapted nof mutants did not display an OKR, whereas dark-adapted nof mutants displayed scotopic OKRs. Because the nof mutants lacked a photopic ERG but displayed scotopic ERGs after dark adaptation, the mutants clearly had functional rods. WT larvae and the nof mutants displayed comparable scotopic light-On VMRs and scotopic OKRs after dark adaptation, suggesting that these responses were driven primarily by rods. Together, these observations indicate that rods contribute to zebrafish visual behaviors as early as 6 dpf.


#MeToo and Google Inquiries Into Sexual Violence: A Hashtag Campaign Can Sustain Information Seeking.
The #MeToo Movement has brought new attention to sexual harassment and assault. While the movement originates with activist Tarana Burke, actor Alyssa Milano used the phrase on Twitter in October 2017 in response to multiple sexual harassment allegations against Hollywood producer Harvey Weinstein. Within 24 hours, 53,000 people tweeted comments and/or shared personal experiences of sexual violence. The study objective was to measure how information seeking via Google searches for sexual harassment and assault changed following Milano's tweet and whether this change was sustained in spite of celebrity scandals. Weekly Google search inquiries in the United States were downloaded for the terms metoo, sexual assault, sexual harassment, sexual abuse, and rape for January 1, 2017 to July 15, 2018. Seven related news events about perpetrator accusations were considered. Results showed that searches for metoo increased dramatically after the Weinstein accusation and stayed high during subsequent accusations. A small decrease in searches followed, but the number remained very high relative to baseline (the period before the Weinstein accusation). Searches for sexual assault and sexual harassment increased substantially immediately following the Weinstein accusation, stayed high during subsequent accusations, and saw a decline after the accusation of Matt Lauer (talk show host; last event considered). We estimated a 40% to 70% reduction in searches 6 months after the Lauer accusation, though the increase in searches relative to baseline remained statistically significant. For sexual abuse and rape, the number of searches returned close to baseline by 6 months. It appears that the #MeToo movement sparked greater information seeking that was sustained beyond the associated events. Given its recent ubiquitous use in the media and public life, hashtag activism such as #MeToo can be used to draw further attention to the next steps in addressing sexual assault and harassment, moving public web inquiries from information seeking to action.