Olaparib maintenance therapy in patients with platinum-sensitive, relapsed serous ovarian cancer and a BRCA mutation: Overall survival adjusted for postprogression poly(adenosine diphosphate ribose) polymerase inhibitor therapy.
Maintenance treatment with the oral poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor olaparib (Lynparza) in Study 19 (study number, D0810C00019; ClinicalTrials.gov identifier, NCT00753545) significantly improved progression-free survival in comparison with a placebo for patients with platinum-sensitive, relapsed serous ovarian cancer with a BRCA1/2 mutation (BRCAm), but an interim analysis revealed no statistically significant overall survival (OS) benefit. However, 23% of the patients receiving the placebo switched to a PARP inhibitor after progression. To investigate whether this had a confounding effect on OS, this article reports an exploratory post hoc analysis that excluded all patients from sites where 1 or more placebo patients received postprogression PARP inhibitor treatment. In Study 19, 136 of the 265 patients receiving olaparib or a placebo had a BRCAm. Sixteen patients treated at 11 of the 82 investigational sites received a PARP inhibitor after progression; these sites were excluded from this analysis, and 97 BRCAm patients at 50 sites were included. OS was assessed with a Cox proportional hazards model analogous to the primary study analysis. A supporting rank-preserving structural failure time (RPSFT) model analysis was undertaken for all 136 BRCAm patients. The OS hazard ratio (HR) was 0.52 (95% confidence interval [CI], 0.28-0.97) for the 97 BRCAm patients, whereas for the interim OS analysis with all 136 BRCAm patients, it was 0.73 (95% CI, 0.45-1.17). The supportive RPSFT analysis HR was approximately 0.66. The numerical improvement in the OS HR suggests that in Study 19, postprogression PARP inhibitor treatment had a confounding influence on the interim OS analysis for BRCAm patients. There is a degree of uncertainty due to the small sample size and the lack of data maturity. Cancer 2016;122:1844-52. © 2016 American Cancer Society.


Guidelines for identification of, advocacy for, and intervention in neurocognitive problems in survivors of childhood cancer: a report from the Children's Oncology Group.
With modern therapies and supportive care, survival of childhood cancer has increased considerably. Patients who have survived cancers involving the central nervous system or who have received therapy toxic to the developing brain are at risk of long-term neurocognitive sequelae. Negative outcomes are observed most frequently in survivors of acute lymphoblastic leukemia and brain tumors. The Children's Oncology Group Long-term Follow-up Guidelines Task Force on Neurocognitive/Behavioral Complications After Childhood Cancer has generated risk-based, exposure-related guidelines designed to direct the follow-up care of survivors of pediatric malignancies based on a comprehensive literature review and expert opinion. This article expands on these guidelines by reviewing the risk factors for the development of neurocognitive sequelae and describing the expected pattern of these disabilities. We herein present recommendations for the screening and management of neurocognitive late effects and outline important areas of school and legal advocacy for survivors with disabilities. Finally, we list resources that can guide patients, their parents, and their medical caregivers as they face the long-term neurocognitive consequences of cancer therapy.


Glissades Are Altered by Lesions to the Oculomotor Vermis but Not by Saccadic Adaptation.
Saccadic eye movements enable fast and precise scanning of the visual field, which is partially controlled by the posterior cerebellar vermis. Textbook saccades have a straight trajectory and a unimodal velocity profile, and hence have well-defined epochs of start and end. However, in practice only a fraction of saccades matches this description. One way in which a saccade can deviate from its trajectory is the presence of an overshoot or undershoot at the end of a saccadic eye movement just before fixation. This additional movement, known as a glissade, is regarded as a motor command error and was characterized decades ago but was almost never studied. Using rhesus macaques, we investigated the properties of glissades and changes to glissade kinematics following cerebellar lesions. Additionally, in monkeys with an intact cerebellum, we investigated whether the glissade amplitude can be modulated using multiple adaptation paradigms. Our results show that saccade kinematics are altered by the presence of a glissade, and that glissades do not appear to have any adaptive function as they do not bring the eye closer to the target. Quantification of these results establishes a detailed description of glissades. Further, we show that lesions to the posterior cerebellum have a deleterious effect on both saccade and glissade properties, which recovers over time. Finally, the saccadic adaptation experiments reveal that glissades cannot be modulated by this training paradigm. Together our work offers a functional study of glissades and provides new insight into the cerebellar involvement in this type of motor error.


Free association and analytic neutrality: the basic structure of the psychoanalytic situation.
This paper re-examines within a contemporary context an essential foundation of classical technique, the psychoanalytic situation. Defined in terms of basic elements of psychoanalytic relatedness which make possible the most profound exploration of human motivation, its core structure is viewed as an extraordinary interpersonal arrangement anchored by two clearly differentiated yet complimentary ways of relating: free-association and analytic neutrality. The patient's role, organized by the prerequisites of expressive freedom, is counter posed with the psychoanalyst's, which is structured to empower listening and understanding. Elaborating the parameters of this unique relationship, the authors emphasize the synergic effects of each participants' activity in creating a vehicle for destabilizing neurotic equilibrium. An extensive discussion of analytic neutrality, conceived as guiding ideal that informs all the analyst's attitudes and actions in the exploration of psychic reality, is presented. Specifically, the authors distinguish three essential dimensions which bear upon the interactive process: neutrality with regard to conflict, neutrality with regard to sequence, and neutrality with regard to transference. In contrast to the rigid constraint on human responsiveness often caricatured in the literature, this vision of technical neutrality establishes its vital contribution to the integrity, depth, and tone of any analytic process that unfolds.


Sphagnum establishment in alkaline fens: Importance of weather and water chemistry.
Sphagnum expansion to alkaline fens has accelerated during the last decades in Europe, leading to changes in diversity, habitat distributions and carbon storage. The causes are still not clearly understood and involve an interplay between climate change, hydrology, nutrient supply and Sphagnum physiology. We conducted a 4-year field experiment in eight fens in Central European highlands and assessed survival and establishment of individual apical shoot fragments of S. flexuosum, S. warnstorfii and S. squarrosum transplanted along the microtopographical gradient. In a laboratory experiment, we tested combined effects of desiccation and high calcium bicarbonate concentration on Sphagnum survival. We found that in unflooded positions, living shoots of Sphagnum and brown mosses lowered [Ca2+] and pH in their capillary water, in contrast to dead fragments; yet without differences between species. Survival and expansion of Sphagnum fragments, which did not die of acute calcium toxicity during first weeks/months, was negatively affected by dry weather and alkaline water chemistry, reflecting Sphagnum intolerance to desiccation and to combined high [Ca2+] and pH. Shoot fragments expanded to patches only when precipitation was high. Interestingly, non-toxic concentration of calcium bicarbonate reduced desiccation damage in Sphagnum, probably through protection of membranes or other cell components. This mechanism would facilitate Sphagnum survival in elevated, frequently desiccated microhabitats of calcareous fens such as brown-moss hummocks. However, since water-retaining capacity of few Sphagnum shoots is insufficient to change water chemistry in its surroundings, surface acidification may occur only once the environment (e.g. sufficient humidity) enabled expansion to larger mats. Then, the retained rainwater together with hardly decomposable Sphagnum litter would separate mire surface from groundwater, speeding up successional shift towards poor fens. Sphagnum expansion to alkaline fens is therefore more likely in humid regions.


Current Understanding of Innate Immune Cell Dysfunction in Childhood Undernutrition.
Undernutrition affects millions of children in low- and middle-income countries (LMIC) and underlies almost half of all deaths among children under 5 years old. The growth deficits that characterize childhood undernutrition (stunting and wasting) result from simultaneous underlying defects in multiple physiological processes, and current treatment regimens do not completely normalize these pathways. Most deaths among undernourished children are due to infections, indicating that their anti-pathogen immune responses are impaired. Defects in the body's first-line-of-defense against pathogens, the innate immune system, is a plausible yet understudied pathway that could contribute to this increased infection risk. In this review, we discuss the evidence for innate immune cell dysfunction from cohort studies of childhood undernutrition in LMIC, highlighting knowledge gaps in almost all innate immune cell types. We supplement these gaps with insights from relevant experimental models and make recommendations for how human and animal studies could be improved. A better understanding of innate immune function could inform future tractable immune-targeted interventions for childhood undernutrition to reduce mortality and improve long-term health, growth and development.


Corra: Computational framework and tools for LC-MS discovery and targeted mass spectrometry-based proteomics.
Quantitative proteomics holds great promise for identifying proteins that are differentially abundant between populations representing different physiological or disease states. A range of computational tools is now available for both isotopically labeled and label-free liquid chromatography mass spectrometry (LC-MS) based quantitative proteomics. However, they are generally not comparable to each other in terms of functionality, user interfaces, information input/output, and do not readily facilitate appropriate statistical data analysis. These limitations, along with the array of choices, present a daunting prospect for biologists, and other researchers not trained in bioinformatics, who wish to use LC-MS-based quantitative proteomics. We have developed Corra, a computational framework and tools for discovery-based LC-MS proteomics. Corra extends and adapts existing algorithms used for LC-MS-based proteomics, and statistical algorithms, originally developed for microarray data analyses, appropriate for LC-MS data analysis. Corra also adapts software engineering technologies (e.g. Google Web Toolkit, distributed processing) so that computationally intense data processing and statistical analyses can run on a remote server, while the user controls and manages the process from their own computer via a simple web interface. Corra also allows the user to output significantly differentially abundant LC-MS-detected peptide features in a form compatible with subsequent sequence identification via tandem mass spectrometry (MS/MS). We present two case studies to illustrate the application of Corra to commonly performed LC-MS-based biological workflows: a pilot biomarker discovery study of glycoproteins isolated from human plasma samples relevant to type 2 diabetes, and a study in yeast to identify in vivo targets of the protein kinase Ark1 via phosphopeptide profiling. The Corra computational framework leverages computational innovation to enable biologists or other researchers to process, analyze and visualize LC-MS data with what would otherwise be a complex and not user-friendly suite of tools. Corra enables appropriate statistical analyses, with controlled false-discovery rates, ultimately to inform subsequent targeted identification of differentially abundant peptides by MS/MS. For the user not trained in bioinformatics, Corra represents a complete, customizable, free and open source computational platform enabling LC-MS-based proteomic workflows, and as such, addresses an unmet need in the LC-MS proteomics field.


[Congenital malformations in children born after IVF].
Major congenital malformations are a leading cause of perinatal morbidity and mortality. Congenital malformations are caused by three factors: genetic, environmental or multifactorial, all of which are present in the context of artificial reproductive techniques. In 1999 Bergh et al. conducted a retrospective study, which included all the children born following IVF treatment in Sweden. The relative risk found was RR = 1.39 [95% CI 1.25-1.54] and there was no stratification for maternal age and parity. In 2002 Hansen et al. conducted a well-established retrospective study in Western Australia. When only term singletons were included in the study, the OR found was OR = 2.1 [1.4-3.2] in the IVF group and OR = 2.2 [1.2-4] in the ICSI group. Results were stratified for maternal age, parity and offspring sex. A meta-analysis of 19 studies found a relative risk of 1.29 for major malformations among IVF pregnancies. Explanations for the increased risk of fetal malformations could be divided into three categories: first, the characteristics of the infertile population which include many risk factors: older age, lower parity, chronic diseases and infertility itself. Second, the techniques used to treat infertility are not physiologic. Third, the characteristics of the pregnancy achieved: the incidence of high-order pregnancies is much greater and this fact exposes the offspring to other risk factors such as preterm birth and low birth weight. Major advances in reproductive techniques offered hope for many couples, but they were also the reason for much concern regarding the outcome of the awaited offspring. The recent studies seem to justify some of those doubts.


Limited Evidence for Risk Factors for Proarrhythmia and Sudden Cardiac Death in Patients Using Antidepressants: Dutch Consensus on ECG Monitoring.
Currently, there is a lack of international and national guidelines or consensus documents with specific recommendations for electrocardiogram (ECG) screening and monitoring during antidepressant treatment. To make a proper estimation of the risk of cardiac arrhythmias and sudden (cardiac) death during antidepressant use, both the drug and patient-specific factors should be taken into account; however, solid evidence on how this should be done in clinical practice is lacking. Available recommendations on the management of QT(c) prolongation (with antidepressant treatment) emphasize that special attention should be given to high-risk patients; however, clinicians are in need of more concrete suggestions about how to select patients for ECG screening and monitoring. Based on a review of the literature, a Dutch multidisciplinary expert panel aimed to formulate specific guidelines to identify patients at risk for cardiac arrhythmias and sudden death by developing a consensus statement regarding ECG screening before, and monitoring during, antidepressant use. We first reviewed the literature to identify the relative risks of various risk factors on cardiac arrhythmia and sudden (cardiac) death during antidepressant use. These relative contributions of risk factors could not be determined since no systematic reviews or meta-analyses quantitatively addressed this topic. Because evidence was insufficient, additional expert opinion was used to formulate recommendations. This resulted in readily applicable recommendations for clinical practice for selection of high-risk patients for ECG screening and monitoring. ECG screening and monitoring is recommended before and following the start of QTc-prolonging antidepressants in the presence of vulnerability to QTc prolongation or two or more risk factors (age > 65 years, female sex, concomitant use of a QTc-prolonging drug or concomitant use of a drug that influences the metabolism of a QTc-prolonging drug, cardiac disease, excessive dosing and specific electrolyte disturbances).


Electric Stimulation of Neurogenesis Improves Behavioral Recovery After Focal Ischemia in Aged Rats.
The major aim of stroke therapies is to stimulate brain repair and to improve behavioral recuperation after cerebral ischemia. Despite remarkable advances in cell therapy for stroke, stem cell-based tissue replacement has not been achieved yet stimulating the search for alternative strategies for brain self-repair using the neurogenic zones of the brain, the dentate gyrus and the subventricular zone (SVZ). However, during aging, the potential of the hippocampus and the SVZ to generate new neuronal precursors, declines. We hypothesized that electrically stimulation of endogenous neurogenesis in aged rats could increase the odds of brain self-repair and improve behavioral recuperation after focal ischemia. Following stroke in aged animals, the rats were subjected to two sessions of electrical non-convulsive stimulation using ear-clip electrodes, at 7- and 24 days after MCAO. Animal were sacrificed after 48 days. We report that electrical stimulation (ES) stimulation of post-stroke aged rats led to an improved functional recovery of spatial long-term memory (T-maze) but not on the rotating pole or the inclined plane, both tests requiring complex sensorimotor skills. Surprisingly, ES had a detrimental effect on the asymmetric sensorimotor deficit. Histologically, there was a robust increase in the number of doublecortin-positive cells in the dentate gyrus and SVZ of the infarcted hemisphere and the presence of a considerable number of neurons expressing tubulin beta III in the infarcted area. Among the gene that were unique to ES, we noted increases in the expression of seizure related 6 homolog like which is one of the physiological substrate of the β-secretase BACE1 involved in the pathophysiology of the Alzheimer's disease and Igfbp3 and BDNF receptor mRNAs which has been shown to have a neuroprotective effect after cerebral ischemia. However, ES was associated with a long-term down regulation of cortical gene expression after stroke in aged rats suggesting that gene expression in the peri-infarcted cortical area may not be related to electrical stimulation induced-neurogenesis in the subventricular zone and hippocampus.


B cell lymphoma with different metabolic characteristics show distinct sensitivities to metabolic inhibitors.
Purpose: Cancer cells exhibit profound alterations in their metabolism (abnormal glucose and glutamine metabolism). Targeting cancer metabolism is a promising therapeutic strategy. Lymphoma can be classified into many different types and it is very complicated. Therefore, in this paper, we want to know whether the B cell lymphoma cells with different metabolic characteristics have distinct sensitivities to metabolic inhibitors. Methods: We classified 9 B cell lymphoma cell lines into different metabolic subtypes according to the dependency on glutamine and glucose. Then we detected the OCR, ECAR, glucose consumption and lactate production, mitochondrial content and growth rate. And we also determined the IC50 of these 9 cell lines to metabolic inhibitors. Results: According to the dependency on glutamine and glucose, we successfully classified three distinct metabolic subtypes in B cell lymphoma cell lines, one subtype was defined glutamine and glucose equally utilized subtype (GLN=Glu), whereas the other two subtypes were GLN-addicted and Glu-dependent. And these three subtypes showed striking differences in glucose and glutamine utilization, glycolysis and mitochondrial function, and proliferation rate. GLN-addicted and Glu-dependence subtypes also showed differences in cell sensitivity to inhibitors of glutamine and glycolysis metabolism, respectively. However, GLN=Glu subtype seems minimal sensitive to glycolytic and glutaminolytic inhibitors, and with high proliferation rate. Conclusions: The cells rely more on glucose/gltamine have a stronger sensitivity to glucose/glutamine depletion or glycolysis/ glutaminolysis inhibition and a lessened sensitivity to glutaminolysis/glycolysis inhibitors. To target tumor metabolism based on metabolic characteristics may provide a new therapeutic strategy for the treatment of B cell lymphoma.


Limb stiffness and postural tremor in the arm.
The relation between limb stiffness and postural tremor in the upper arm was investigated during a pointing task. The task goal was to minimize the amount of motion (tremor) at the index finger under levels of increasing limb stiffness. This study investigated the influence of increasing limb stiffness on the pattern of intra- and interlimb dynamics. The frequency profile of the tremor for all limb segments across all conditions displayed two peaks, one between 2-4 Hz and another between 8-12 Hz. A third, higher frequency component (20-22 Hz) was present in the index finger. Increasing limb stiffness through voluntary co-contraction of antagonistic muscle pairs effectively constrained the segments of the upper limb to increasingly operate as a single biomechanical degree of freedom. Higher levels of limb stiffness typically led to an increase in the frequency and power of the 2-4 and 8-12 Hz peaks. There was also a decrease in the frequency of the 20-22 Hz component of finger tremor. The act of reducing the effective degrees of freedom in joint space through voluntarily stiffening of the upper limbs also resulted in decreased performance as determined by an increase in finger tremor. In the preferred, natural level of limb stiffness, specific intralimb segment relations were observed but there was no significant interlimb coupling. The intralimb segment correlations were characterized by compensatory (out of phase) coupling between the upper arm/forearm and hand/index finger segment pairs of each limb that were organized about the action of the wrist joint. Increasing the degree of limb stiffness led to a decrease in the level of intralimb coupling. The findings suggest that the most efficient mechanism for reducing tremor at the periphery is that of compensatory coupling between relevant intralimb segments with a low level of limb stiffness.


Identification of amino acid residues in CD81 critical for interaction with hepatitis C virus envelope glycoprotein E2.
Human CD81 has been previously identified as the putative receptor for the hepatitis C virus envelope glycoprotein E2. The large extracellular loop (LEL) of human CD81 differs in four amino acid residues from that of the African green monkey (AGM), which does not bind E2. We mutated each of the four positions in human CD81 to the corresponding AGM residues and expressed them as soluble fusion LEL proteins in bacteria or as complete membrane proteins in mammalian cells. We found human amino acid 186 to be critical for the interaction with the viral envelope glycoprotein. This residue was also important for binding of certain anti-CD81 monoclonal antibodies. Mutating residues 188 and 196 did not affect E2 or antibody binding. Interestingly, mutation of residue 163 increased both E2 and antibody binding, suggesting that this amino acid contributes to the tertiary structure of CD81 and its ligand-binding ability. These observations have implications for the design of soluble high-affinity molecules that could target the CD81-E2 interaction site(s).


An evolutionary shift in the regulation of the Hippo pathway between mice and flies.
The Hippo pathway plays a key role in controlling organ growth in many animal species and its deregulation is associated with different types of cancer. Understanding the regulation of the Hippo pathway and discovering upstream regulators is thus a major quest. Interestingly, while the core of the Hippo pathway contains a highly conserved kinase cascade, different components have been identified as upstream regulators in Drosophila and vertebrates. However, whether the regulation of the Hippo pathway is indeed different between Drosophila and vertebrates or whether these differences are due to our limited analysis of these components in different organisms is not known. Here we show that the mouse Fat4 cadherin, the ortholog of the Hippo pathway regulator Fat in Drosophila, does not apparently regulate the Hippo pathway in the murine liver. In fact, we uncovered an evolutionary shift in many of the known upstream regulators at the base of the arthropod lineage. In this evolutionary transition, Fat and the adaptor protein Expanded gained novel domains that connected them to the Hippo pathway, whereas the cell-adhesion receptor Echinoid evolved as a new protein. Subsequently, the junctional adaptor protein Angiomotin (Amot) was lost and the downstream effector Yap lost its PDZ-binding motif that interacts with cell junction proteins. We conclude that fundamental differences exist in the upstream regulatory mechanisms of Hippo signaling between Drosophila and vertebrates.


Management of Intrauterine Contraception in Early Pregnancy.
Women with rare intrauterine contraception (IUC) failures are advised to have their IUC removed because of the risk of poor obstetric outcomes with a retained IUC. Specifics regarding IUC removal in early pregnancy including techniques for removal, rates of success, and immediate pregnancy outcomes following removal are not well described, however. The objective of this study was to identify women with an IUC in early pregnancy examined at a tertiary care center with the primary objective of describing IUC removal attempts, IUC removal successes, and pregnancy outcomes at 20 weeks following IUC removal. Case series of women with concurrent IUC and early pregnancy who presented to a tertiary care ultrasound center by 12 weeks' gestation. A total of 3116 women had an early pregnancy ultrasound during the study period. Nineteen (19/3116, 0.61%) women underwent ultrasounds that identified a pregnancy before 12 weeks and an IUC in the uterus. A copper IUC was identified in 11 women (11/19, 58%) on their first ultrasound, and a levonogestrel IUC was identified in 5 women (5/19, 26%). Seventeen (17/19, 88%) women attempted to remove their IUC; 11 of 69 (69%) were successfully removed on the first attempt. Fourteen (14/19; 74%) women with an IUC examined by 12 weeks' gestation had an ongoing pregnancy at 20 weeks compared with 1782 (1782/2678, 67%; P = 0.209) women without an IUC. Pregnancy with IUC is rare. Among the 19 women who were found to have an in situ IUC and early pregnancy, most had a successful IUC removal and had an ongoing pregnancy at 20 weeks' gestation. In our case series, IUC removal in the first trimester was a straightforward procedure and likely successful.


The Role of Combination Therapy in Pediatric Inflammatory Bowel Disease: A Clinical Report from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.
The treatment goal for children suffering from inflammatory bowel disease has been evolving with biologic therapies like anti-tumor necrosis factor agents assuming a more central role in treatment of more aggressive and extensive phenotype. Earlier introduction of anti-tumor necrosis factor agents have shown to be more effective and may even alter the natural history of inflammatory bowel disease. Development of anti-drug antibodies, however, limits long-term usage and leads to dose adjustment in almost half of patients treated with these medications. One of the strategies to minimize the development of anti-drug antibodies has been concomitant use of immunomodulator medications, resulting in fewer infusion reactions and sustained trough levels, potentially lowering the need for dose adjustments. Balanced with these benefits of optimized dosing and likely more sustained response, however, is the concern about increased risk of complications, such as infections and malignancies. The current manuscript reviews the available pediatric literature regarding efficacy, safety, and side effect profile of combination (immunomodulator and biologics) therapy in pediatric Crohn disease and ulcerative colitis, with particular emphasis on cost constraints, and recommendations for selection of patients who would benefit most from combination therapy.


Polarization eigenstates for twisted-nematic liquid-crystal displays.
We derive theoretical expressions for the eigenvalues and the eigenvectors for a twisted-nematic liquid-crystal display (LCD) as a function of the twist angle and the birefringence by use of the Jones-matrix formalism. These polarization eigenvectors are of particular interest for phase-only transmission because they propagate unchanged through the display. We find that the eigenvectors are elliptically polarized and that the ellipticity changes as a function of the birefringence of the LCD (which is proportional to the external voltage applied to the display). We can define an average eigenvector over a desired range for the applied voltage. We show, using Jones matrices, how this average eigenvector can be generated using a quarter-wave plate and a linear polarizer having appropriate orientation angles. Using this average eigenvector, we show that superior phase-only operation can be obtained over a given operating range for the LCD compared with other approaches.


Bioassay of p-cresidine for possible carcinogenicity.
A bioassay of p-cresidine for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. p-Cresidine was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. The dietary concentrations used in the chronic bioassay for low and high dose rats were 0.5 and 1.0 percent, respectively. The time-weighted average concentrations fed to low dose male, low dose female, high dose male and high dose female mice were 0.22, 0.22. 0.46, and 0.44 percent, respectively. All dosed animals, except for high dose male mice, were administered p-cresidine in the diet for 104 weeks and observed for an additional period of up to 2 weeks. All high dose male mice were dead by the end of week 92. For each species, 50 animals of each sex were placed on test as controls and fed only the basal laboratory diet. Mortality rates were dose-related for both sexes of both species. That incidences of certain tumors were higher in low dose than in high dose groups was probably due to accelerated mortality in the high dose group. In dosed rats of both sexes, statistically significant incidences of bladder carcinomas (combined incidences of papillary carcinomas, squamous-cell carcinomas, transitional-cell papillomas, transitional-cell carcinomas, and undifferentiated carcinomas) and olfactory neuroblastomas were observed. The combined incidence of neoplastic nodules of the liver, hepatocelular carcinomas, or mixed hepato/cholangio carcinomas was also significant in low dose male rats. In both male and female dosed mice, the incidence of bladder carcinomas (combined incidence of carcinomas NOS, squamous-cell carcinomas, and transitional carcinomas) was significant. The incidence of hepatocellular carcinomas was also significant in dosed female mice. Under the conditions of this bioassay, p-cresidine was carcinogenic to Fischer 344 rats, causing increased incidences of carcinomas and of papillomas of the urinary bladder in both sexes, increased incidences of olfactory neuroblastomas in both sexes, and of liver tumors in males. p-Cresidine was also carcinogenic in B6C3F1 mice, causing carcinomas of the urinary bladders in both sexes and hepatocellular carcinomas in females.


Numb and Numblike regulate sarcomere assembly and maintenance.
A sarcomere is the contractile unit of the myofibril in striated muscles such as cardiac and skeletal muscles. The assembly of sarcomeres depends on multiple molecules that serve as raw materials and participate in the assembly process. However, the mechanism of this critical assembly process remains largely unknown. Here, we found that the cell fate determinant Numb and its homolog Numblike regulated sarcomere assembly and maintenance in striated muscles. We discovered that Numb and Numblike are sarcomeric molecules that were gradually confined to the Z-disc during striated muscle development. Conditional knockout of Numb and Numblike severely compromised sarcomere assembly and its integrity and thus caused organelle dysfunction. Notably, we identified that Numb and Numblike served as sarcomeric α-Actin-binding proteins (ABPs) and shared a conserved domain that can bind to the barbed end of sarcomeric α-Actin. In vitro fluorometric α-Actin polymerization assay showed that Numb and Numblike also played a role in the sarcomeric α-Actin polymerization process. Last, we demonstrate that Numb and Numblike regulate sarcomeric α-Actinin-dependent (ACTN-dependent) Z-disc consolidation in the sarcomere assembly and maintenance. In summary, our studies show that Numb and its homolog Numblike regulate sarcomere assembly and maintenance in striated muscles, and demonstrate a molecular mechanism by which Numb/Numblike, sarcomeric α-Actin, and ACTN cooperate to control thin filament formation and Z-disc consolidation.


Routine endoscopy for esophageal cancer is suggestive for patients with oral, oropharyngeal and hypopharyngeal cancer.
This study attempted to reveal the incidence and risk of synchronous and metachronous esophageal cancer in subjects with oral, oropharyngeal and hypopharyngeal cancer based on a population-wide database in Taiwan. We retrieved data for this cross-sectional study from the Taiwanese Longitudinal Health Insurance Database 2000. The study group included 2,965 subjects who had received their first-time diagnosis of oral/oropharyngeal/hypopharyngeal cancer in 2002∼2009. We assigned the date of their first diagnosis of oral/oropharyngeal/hypopharyngeal cancer as the index date. We also randomly retrieved 29,650 comparison subjects matched with the study subjects in terms of gender and age group. We assigned their first medical utilization that occurred in the index year as the index date for the comparison group. We further performed a conditional logistic regression to investigate the association between esophageal cancer and oral cancer. Results showed that prevalences of esophageal cancer within 3 months before and after the index date were respectively 2.19% and 0.04% for the study and comparison groups. A conditional logistic regression revealed that the odds ratio (OR) of esophageal cancer for subjects with oral/oropharyngeal/hypopharyngeal cancer was 55.33 (95% confidence interval (CI): 29.86∼102.52) compared to comparison subjects. Furthermore, compared to comparison subjects, ORs for esophageal cancer were respectively 18.41 (95% CI: 8.50-39.85), 40.49 (95% CI: 15.11∼108.64), and 240.96 (95% CI: 125.49-462.69) for study subjects with a malignancy of the oral cavity, oropharynx, and hypopharynx. We concluded that there were relatively high chances for synchronous and metachronous esophageal cancers being detected through panendoscopy in patients with oral, oropharyngeal, and hypopharyngeal cancers. The routine use of panendoscopy in such patients should be encouraged with a higher priority.


Base-Resolution Sequencing Methods for Whole-Transcriptome Quantification of mRNA Modifications.
ConspectusRNA molecules are not merely a combination of four bases of A, C, G, and U. Chemical modifications occur in almost all RNA species and play diverse roles in gene expression regulation. The abundant cellular RNAs, such as ribosomal RNA (rRNA) and transfer RNA (tRNA), are known to have the highest density of RNA modifications, which exert critical functions in rRNA and tRNA biogenesis, stability, and subsequent translation. In recent years, modifications on low-abundance RNA species in mammalian cells, such as messenger RNA (mRNA), regulatory noncoding RNA (ncRNA), and chromatin-associated RNA (caRNA), have been shown to contain multiple different chemical modifications with functional significance.As the most abundant mRNA modification in mammals, N6-methyladenosine (m6A) affects nearly every stage of mRNA processing and metabolism, with the antibody-based m6A-MeRIP-seq (methylated RNA immunoprecipitation sequencing) followed by high-throughput sequencing widely employed in mapping m6A distribution transcriptome-wide in diverse biological systems. In addition to m6A, other chemical modifications such as pseudouridine (Ψ), 2'-O-methylation (Nm), 5-methylcytidine (m5C), internal N7-methylguanosine (m7G), N1-methyladenosine (m1A), N4-acetylcytidine (ac4C), etc. also exist in polyA-tailed RNA in mammalian cells, requiring effective mapping approaches for whole-transcriptome profiling of these non-m6A mRNA modifications. Like m6A, the antibody-based enrichment followed by sequencing has been the primary method to study distributions of these modifications. Methods to more quantitatively map these modifications would dramatically improve our understanding of distributions and modification density of these chemical marks on RNA, thereby bettering informing functional implications. In this Account, aimed at both single-base resolution and modification fraction quantification, we summarize our recent advances in developing a series of chemistry- or biochemistry-based methods to quantitatively map RNA modifications, including m6A, Ψ, m5C, m1A, 2'-O-methylation (Nm), and internal m7G, in mammalian mRNA at base resolution. These new methods, including m6A-SAC-seq, eTAM-seq, BID-seq, UBS-seq, DAMM-seq, m1A-quant-seq, Nm-Mut-seq, and m7G-quant-seq, promise to conduct base-resolution mapping of most major mRNA modifications with low RNA input and uncover dynamic changes in modification stoichiometry during biological and physiological processes, facilitating future investigations on these RNA modifications in regulating cellular gene expression and as potential biomarkers for clinical diagnosis and prognosis. These quantitative sequencing methods allow the mapping of most mRNA modifications with limited input sample requirements. The same modifications on diverse RNA species, such as caRNA, ncRNA, nuclear nascent RNA, mitochondrial RNA, cell-free RNA (cfRNA), etc., could be sequenced using the same methods.


Isolation of cDNA clones encoding the 80-kd subunit protein of the human autoantigen Ku (p70/p80) by antisera raised against ciliary processes of human eye donors.
To isolate and characterize human nonpigmented ocular ciliary epithelial cDNA clones by screening a cDNA library constructed from the established human nonpigmented ciliary epithelial cell line (ODM-2) with sera raised against ciliary processes of human eye donors (cadavers). An ODM-2 cDNA expression library in lambda Uni-ZAP-XR vector was screened with sera of mouse anti-human ciliary processes. The cDNA inserts from plaque-purified clones were sequenced by the dideoxy-chain termination method with T3 and T7 polymerase. Sera were assayed by Western blot analysis and indirect immunofluorescence and were then compared with sera, enriched in anti-Ku antibodies, collected from patients with scleroderma polymyositis overlap syndrome. Immunoscreening of 2.5 x 10(5) independent clones with sera induced experimentally in total tissue homogenates of human ciliary processes led to the isolation of four cDNA-positive clones. Three clones, designated A1, D1, and D3 and containing inserts measuring 1.4 kb to 1.8 kb, were found to be identical in DNA sequence analysis to that of the 80-kd subunit protein of the human autoantigen Ku (p70/p80). The fourth clone, designated D2, failed to show any significantly similarity with previously known genes. Cell extracts from human ciliary processes and ODM-2 cells were analyzed by immunoblotting with anti-human ciliary process sera. The pattern of proteins immunodetected was compared with the profile of proteins immunodetected with human anti-Ku sera from a patient with scleroderma polymyositis overlap syndrome. These results demonstrated that sera from anti-human ciliary processes recognize a variety of antigens in ODM-2 cells and are strikingly rich in antibodies to the 80-kd subunit protein of Ku (p70/p80). Furthermore, indirect immunofluorescence analysis supported the observation that anti-human ciliary processes sera labeled nuclear antigens in a human ciliary epithelium cell line and cross species in bovine ciliary epithelial cell, thus demonstrating the nuclear localization of Ku antigen. The mRNA in the human eye was found to be widely expressed in all tested ocular tissues and in ODM-2 cells. The ocular ciliary epithelium induces a species-specific immune response in xenogenic animals. In particular, the human ciliary epithelium elicits a strong immune recognition of the 80-kd subunit protein of the human autoantigen Ku (p70/p80) in ODM-2 cells.


Parental binge alcohol abuse alters F1 generation hypothalamic gene expression in the absence of direct fetal alcohol exposure.
Adolescent binge alcohol exposure has long-lasting effects on the expression of hypothalamic genes that regulate the stress response, even in the absence of subsequent adult alcohol exposure. This suggests that alcohol can induce permanent gene expression changes, potentially through epigenetic modifications to specific genes. Epigenetic modifications can be transmitted to future generations therefore, and in these studies we investigated the effects of adolescent binge alcohol exposure on hypothalamic gene expression patterns in the F1 generation offspring. It has been well documented that maternal alcohol exposure during fetal development can have devastating neurological consequences. However, less is known about the consequences of maternal and/or paternal alcohol exposure outside of the gestational time frame. Here, we exposed adolescent male and female rats to a repeated binge EtOH exposure paradigm and then mated them in adulthood. Hypothalamic samples were taken from the offspring of these animals at postnatal day (PND) 7 and subjected to a genome-wide microarray analysis followed by qRT-PCR for selected genes. Importantly, the parents were not intoxicated at the time of mating and were not exposed to EtOH at any time during gestation therefore the offspring were never directly exposed to EtOH. Our results showed that the offspring of alcohol-exposed parents had significant differences compared to offspring from alcohol-naïve parents. Specifically, major differences were observed in the expression of genes that mediate neurogenesis and synaptic plasticity during neurodevelopment, genes important for directing chromatin remodeling, posttranslational modifications or transcription regulation, as well as genes involved in regulation of obesity and reproductive function. These data demonstrate that repeated binge alcohol exposure during pubertal development can potentially have detrimental effects on future offspring even in the absence of direct fetal alcohol exposure.


How plastic is spatial hearing?
The location of a sound source is derived by the auditory system from spatial cues present in the signals at the two ears. These cues include interaural timing and level differences, as well as monaural spectral cues generated by the external ear. The values of these cues vary with individual differences in the shape and dimensions of the head and external ears. We have examined the neurophysiological consequences of these intersubject variations by recording the responses of neurons in ferret primary auditory cortex to virtual sound sources mimicking the animal's own ears or those of other ferrets. For most neurons, the structure of the spatial response fields changed significantly when acoustic cues measured from another animal were presented. This is consistent with the finding that humans localize less accurately when listening to virtual sounds from other subjects. To examine the role of experience in shaping the ability to localize sound, we have studied the behavioural consequences of altering binaural cues by chronically plugging one ear. Ferrets raised and tested with one ear plugged learned to localize as accurately as control animals, which is consistent with previous findings that the representation of auditory space in the midbrain can accommodate abnormal sensory cues during development. Adaptive changes in behaviour were also observed in adults, particularly if they were provided with regular practice in the localization task. Together, these findings suggest that the neural circuits responsible for sound localization can be recalibrated throughout life.


Factors associated with parents' attitudes to the HPV vaccination of their adolescent sons : A systematic review.
The objective of the study was to identify factors associated with human papilloma virus (HPV) vaccine acceptability in parents of adolescent boys. This information is critical to the development of approaches to optimise HPV vaccine uptake among this population group. We performed a systematic search of the literature in addressing factors influencing parental attitudes to and beliefs about HPV vaccine and its acceptability for use. The findings were organised within the framework of the Health Belief Model (HBM) and summarised using a semi quantitative method. Eighteen studies met the inclusion criteria. Parental decisions were predominantly shaped by the perceived benefits of the vaccine; perceived risk of sons contracting the HPV infection, and having recommendations from health care providers. Fear of side effects and uncertainty about vaccine effectiveness, as well as cost and lack of healthcare, were barriers to HPV vaccination. Other factors such as knowledge, family characteristics, parent-child dialogue and egalitarian values appeared to be important when deciding whether to vaccinate boys. HPV vaccine uptake among male adolescents is suboptimal. Future programs need to address the predictors of uptake by educating parents about the boys' high susceptibility to infection, the benefits of vaccination, and reduce concerns regarding perceived barriers. Additionally, uptake may be facilitated by encouraging health care provider endorsement, particularly in countries without government-funded immunisation programs.


The Paediatric Admission Quality of Care (PAQC) score: designing a tool to measure the quality of early inpatient paediatric care in a low-income setting.
Evaluating clinician compliance with recommended steps in clinical guidelines provides one measure of quality of process of care but can result in a multiplicity of indicators across illnesses, making it problematic to produce any summative picture of process quality, information that may be most useful to policy-makers and managers. We set out to develop a clinically logical summative measure of the quality of care provided to children admitted to hospital in Kenya spanning the three diagnoses present in 60% or more of admissions that would provide a patient-level measure of quality of care in the face of comorbidity. We developed a conceptual model of care based on three domains: assessment, diagnosis and treatment of illnesses. Individual items within domains correspond to recommended processes of care within national clinical practice guidelines. Summative scores were created to reduce redundancy and enable aggregation across illnesses while maintaining a clear link to clinical domains and our conceptual model. The potential application of the score was explored using data from more than 12 000 children from eight hospitals included in a prior intervention study in Kenya. Summative scores obtained from items representing discrete clinical decision points reduced redundancy, aided balance of score contribution across domains and enabled direct comparison of disease-specific scores and the calculation of scores for children with comorbidity. This work describes the development of a summative Paediatric Admission Quality of Care score measured at the patient level that spans three common diseases. The score may be an efficient tool for assessing quality with an ability to adjust for case mix or other patient-level factors if needed. The score principles may have applicability to multiple illnesses and settings. Future analysis will be needed to validate the score.


Acute Biventricular Mechanical Circulatory Support for Cardiogenic Shock.
Biventricular failure is associated with high in-hospital mortality. Limited data regarding the efficacy of biventricular Impella axial flow catheters (BiPella) support for biventricular failure exist. The aim of this study was to explore the clinical utility of percutaneously delivered BiPella as a novel acute mechanical support strategy for patients with cardiogenic shock complicated by biventricular failure. We retrospectively analyzed data from 20 patients receiving BiPella for biventricular failure from 5 tertiary-care hospitals in the United States. Left ventricular support was achieved with an Impella 5.0 (n=8), Impella CP (n=11), or Impella 2.5 (n=1). All patients received the Impella RP for right ventricular (RV) support. BiPella use was recorded in the setting of acute myocardial infarction (n=11), advanced heart failure (n=7), and myocarditis (n=2). Mean flows achieved were 3.4±1.2 and 3.5±0.5 for left ventricular and RV devices, respectively. Total in-hospital mortality was 50%. No intraprocedural mortality was observed. Major complications included limb ischemia (n=1), hemolysis (n=6), and Thrombolysis in Myocardial Infarction major bleeding (n=7). Compared with nonsurvivors, survivors were younger, had a lower number of inotropes or vasopressors used before BiPella, and were more likely to have both devices implanted simultaneously during the same procedure. Compared with nonsurvivors, survivors had lower pulmonary artery pressures and RV stroke work index before BiPella. Indices of RV afterload were quantified for 14 subjects. Among these patients, nonsurvivors had higher pulmonary vascular resistance (6.8; 95% confidence interval [95% CI], 5.5-8.1 versus 1.9; 95% CI, 0.8-3.0; P<0.01), effective pulmonary artery elastance (1129; 95% CI, 876-1383 versus 458; 95% CI, 263-653; P<0.01), and lower pulmonary artery compliance (1.5; 95% CI, 0.9-2.1 versus 2.7; 95% CI, 1.8-3.6; P<0.05). This is the largest, retrospective analysis of BiPella for cardiogenic shock. BiPella is feasible, reduces cardiac filling pressures and improves cardiac output across a range of causes for cardiogenic shock. Simultaneous left ventricular and RV device implantation and lower RV afterload may be associated with better outcomes with BiPella. Future prospective studies of BiPella for cardiogenic shock are required.


Diffraction by a subwavelength-sized aperture in a metal plane.
We present an experimental study on the diffraction of light by an aperture small compared with the wavelength. The aperture is illuminated by laser light guided in a metal-clad tapered optical fiber. We investigate different orientations of the aperture in the plane: normal to the cleaved plane, oblique to the cleaved plane, and off-center. We measure the far-field, two-dimensional intensity distributions of the diffracted light as functions of angle coordinates theta and phi in a full half-space for various polarization states and analyze the patterns by using low-order multipole fields. We also examine the near- and far-field effects of placing small periodic corrugations near the aperture, focusing on the role of surface-wave excitations. We measure the near-field intensity distributions near the aperture with a near-field scanning optical microscope and discuss their relation to the far-field diffracted fields.


A successful cognitive-behavioural intervention that failed: a case study of adolescent conduct disorder at a school for the disadvantaged.
Conduct Disorder (CD) is a widespread problem in southern Africa. The aim of the study was to design, implement and evaluate a multi-modal cognitive-behavioural intervention based on treatments developed overseas, in order to investigate whether this approach can be transported to a South African school for deprived children. The target adolescent had a history of severely disruptive behaviour and was facing expulsion from a shelter for homeless children and his school. A thorough assessment served as the basis for a case formulation and treatment plan. Intervention included 23 individual sessions focussing on bereavement and the learning of self-control skills and prosocial behaviours, as well as contingency management training for school and shelter staff. Progress was tracked with a behaviour checklist completed daily by the teacher and regular interviews with school and shelter staff. After four months, the disruptive behaviour was eliminated. However, he was involved in stealing with some other learners and expelled anyway. Nevertheless the case study provides evidence for the transportability of the cognitive-behavioural approach to this kind of setting and documents the way in which a comprehensive intervention can be tailored to the needs of a child with a severely deprived background and little social support.


A Randomized Pilot Study Assessing if SEDLine Monitoring During Induction of Surgical Patients is Associated With Reduced Dosage of Administered Induction Agents.
Background. Intubations, especially in emergent settings, carry a high risk of hemodynamic instability with potentially catastrophic outcomes. Weight-based dosing of induction drugs can be inappropriately high for elective or emergent intubations and lead to hemodynamic instability. We hypothesized that monitoring the patient state index of SEDLine monitors (Masimo, Irvine, CA) would decrease the dose of induction drugs in the operating room during elective intubations.Methods. In this randomized study, SEDLine monitoring was provided to the intervention group but not to the control group during the induction of anesthesia in the operating room. Anesthesia providers in the intervention group were advised to titrate induction drugs to a Patient State Index of <50 before proceeding with intubation. The primary outcome was the induction dose of propofol and etomidate per kilogram normalized to propofol dose equivalents. Secondary outcomes included supplemental doses of ketamine, midazolam, fentanyl, phenylephrine, and ephedrine per kg, time from induction to intubation, administration of additional propofol or vasopressors after induction, mean arterial pressure ≥ or <65 mmHg, and lowest mean arterial pressure post-induction.Results. We found no significant difference in propofol equivalents between groups (P = .41). Using a SEDLine decreased the odds that a patient would require vasopressors during induction (odds ratio of .39 [95% confidence interval, .15-.98]).Conclusion. SEDLine monitoring during induction did not decrease dosing of the induction drugs etomidate and propofol but decreased the odds of receiving vasopressors. Further studies are warranted to assess the utility of processed electroencephalography in emergent intubations outside of the operating room.


Random walk with priorities in communicationlike networks.
We study a model for a random walk of two classes of particles (A and B). Where both species are present in the same site, the motion of A's takes precedence over that of B's. The model was originally proposed and analyzed in Maragakis et al. [Phys. Rev. E 77, 020103(R) (2008)]; here we provide additional results. We solve analytically the diffusion coefficients of the two species in lattices for a number of protocols. In networks, we find that the probability of a B particle to be free decreases exponentially with the node degree. In scale-free networks, this leads to localization of the B's at the hubs and arrest of their motion. To remedy this, we investigate several strategies to avoid trapping of the B's, including moving an A instead of the hindered B, allowing a trapped B to hop with a small probability, biased walk toward non-hub nodes, and limiting the capacity of nodes. We obtain analytic results for lattices and networks, and we discuss the advantages and shortcomings of the possible strategies.


Complete Genome of Ignavibacterium album, a Metabolically Versatile, Flagellated, Facultative Anaerobe from the Phylum Chlorobi.
Prior to the recent discovery of Ignavibacterium album (I. album), anaerobic photoautotrophic green sulfur bacteria (GSB) were the only members of the bacterial phylum Chlorobi that had been grown axenically. In contrast to GSB, sequence analysis of the 3.7-Mbp genome of I. album shows that this recently described member of the phylum Chlorobi is a chemoheterotroph with a versatile metabolism. I. album lacks genes for photosynthesis and sulfur oxidation but has a full set of genes for flagella and chemotaxis. The occurrence of genes for multiple electron transfer complexes suggests that I. album is capable of organoheterotrophy under both oxic and anoxic conditions. The occurrence of genes encoding enzymes for CO(2) fixation as well as other enzymes of the reductive TCA cycle suggests that mixotrophy may be possible under certain growth conditions. However, known biosynthetic pathways for several amino acids are incomplete; this suggests that I. album is dependent upon on exogenous sources of these metabolites or employs novel biosynthetic pathways. Comparisons of I. album and other members of the phylum Chlorobi suggest that the physiology of the ancestors of this phylum might have been quite different from that of modern GSB.


The frequency-dependent AC photoresistance behavior of ZnO thin films grown on different sapphire substrates.
Zinc oxide (ZnO) thin films were grown by pulsed layer deposition under an N2 atmosphere at low pressures on a- and r-plane sapphire substrates. Structural studies using X-ray diffraction confirmed that all films had a wurtzite phase. ZnO thin films on a- and r-plane sapphire have grown with orientations along the [0002] and [112[combining macron]0] directions, respectively. Room temperature photoluminescence measurements indicate that the presence of native point defects (interstitial zinc, oxygen vacancies, oxygen antisites and zinc vacancies) is more preponderant for ZnO thin films grown on the r-plane sapphire substrate than the sample grown on the a-plane sapphire substrate. Room temperature impedance spectroscopy measurements were performed in an alternating current frequency range from 40 to 105 Hz in the dark and under normal light. An unusual positive photoresistance effect is observed at frequencies above 100 kHz, which we suggest to be due to intrinsic defects present in the ZnO thin films. Furthermore, an analysis of the optical time response revealed that the film grown on the r-plane sapphire substrate responds faster (characteristic relaxation times for τ1, τ2 and τ3 of 0.05, 0.26 and 6.00 min, respectively) than the film grown on the a-plane sapphire substrate (characteristic relaxation times for τ1, τ2 and τ3 of 0.10, 0.73 and 4.02 min, respectively).


COVID-19 IDD: A global survey exploring the impact of COVID-19 on individuals with intellectual and developmental disabilities and their caregivers.
Background: This protocol outlines research to explore the impact of coronavirus disease 2019 (COVID-19) on individuals who have intellectual and developmental disabilities and their caregivers. Evidence suggests that people with intellectual and developmental disabilities experience disparities in healthcare access and utilisation. This disparity was evident early in the pandemic when discussions arose regarding the potential exclusion of this population to critical care. Methods: An anonymous online survey will be conducted with caregivers, both family members and paid staff, to explore the impact of COVID-19 on this population in terms of demographics, living arrangements, access to services, the impact of social distancing, and also carer wellbeing. The survey will be developed by the research team, many of whom are experts in intellectual disability within their own jurisdictions. Using back-translation our team will translate the survey for distribution in 16 countries worldwide for international comparison. The survey team have extensive personal and professional networks in intellectual disability and will promote the survey widely on social media with the support of local disability and advocacy agencies. Statistical descriptive and comparative analyses will be conducted. Ethical approval has been obtained for this study from University College Dublin's Human Research Ethics Committee (HS-20-28-Linehan). Dissemination: Study findings will be prepared in a number of formats in order to meet the needs of different audiences. Outputs will include academic papers, lessons learned paper, practice guidelines, reports, infographics and video content. These outputs will be directed to families, frontline and management delivering disability services, national-level policy makers, healthcare quality and delivery authorities, national pandemic organisations and international bodies.


A cross-system comparison of bacterial and fungal biomass in detritus pools of headwater streams.
The absolute amount of microbial biomass and relative contribution of fungi and bacteria are expected to vary among types of organic matter (OM) within a stream and will vary among streams because of differences in organic matter quality and quantity. Common types of benthic detritus [leaves, small wood, and fine benthic organic matter (FBOM)] were sampled in 9 small (1st-3rd order) streams selected to represent a range of important controlling factors such as surrounding vegetation, detritus standing stocks, and water chemistry. Direct counts of bacteria and measurements of ergosterol (a fungal sterol) were used to describe variation in bacterial and fungal biomass. There were significant differences in bacterial abundance among types of organic matter with higher densities per unit mass of organic matter on fine particles relative to either leaves or wood surfaces. In contrast, ergosterol concentrations were significantly greater on leaves and wood, confirming the predominance of fungal biomass in these larger size classes. In general, bacterial abundance per unit organic matter was less variable than fungal biomass, suggesting bacteria will be a more predictable component of stream microbial communities. For 7 of the 9 streams, the standing stock of fine benthic organic matter was large enough that habitat-weighted reach-scale bacterial biomass was equal to or greater than fungal biomass. The quantities of leaves and small wood varied among streams such that the relative contribution of reach-scale fungal biomass ranged from 10% to as much as 90% of microbial biomass. Ergosterol concentrations were positively associated with substrate C:N ratio while bacterial abundance was negatively correlated with C:N. Both these relationships are confounded by particle size, i.e., leaves and wood had higher C:N than fine benthic organic matter. There was a weak positive relationship between bacterial abundance and streamwater soluble reactive phosphorus concentration, but no apparent pattern between either bacteria or fungi and streamwater dissolved inorganic nitrogen. The variation in microbial biomass per unit organic matter and the relative abundance of different types of organic matter contributed equally to driving differences in total microbial biomass at the reach scale.


Discharge antithrombotic strategies among patients with acute coronary syndrome previously on warfarin anticoagulation: physician practice in the CRUSADE registry.
Patients experiencing acute coronary syndromes (ACS) with high-risk features frequently undergo percutaneous coronary intervention (PCI) with stent placement, prompting the requisite administration of aspirin and clopidogrel. The current management of ACS patients with a concomitant indication for warfarin anticoagulant therapy is a question of growing interest and clinical relevance. We analyzed discharge antithrombotic medication use among all patients with non-ST-segment elevation (NSTE) ACS enrolled in the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines (CRUSADE) initiative who were receiving warfarin at the time of hospital admission. Multivariable logistic regression was used to determine factors associated with a decision to discontinue warfarin at discharge. Among 5673 patients with ACS previously on home warfarin, 1357 (24%) were not discharged on warfarin. In the subset of 1247 patients who underwent coronary stenting, 60% were prescribed triple anticoagulation therapy (aspirin, clopidogrel, and warfarin), 31% were given aspirin and clopidogrel without warfarin, and 3% received warfarin and aspirin without clopidogrel. Factors associated with a decision not to continue warfarin at the time of hospital discharge included in-hospital red blood cell transfusion, non-white race, prior stroke, and discharge clopidogrel use. The decision to continue warfarin at discharge correlated with perceived bleeding risk and was unaffected by patients' stroke risk. Physician practices vary with regard to the perceived optimal antithrombotic strategy at time of hospital discharge among patients with ACS with a concomitant indication for warfarin. Decisions are influenced primarily by other medication use and anticipated bleeding risk. Further research is needed to guide patient care based on the safety and efficacy of antiplatelet-anticoagulant combined pharmacotherapy.


Common genetic determinants of intraocular pressure and primary open-angle glaucoma.
Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p=1.4×10(-8)), and with rs7555523, located in TMCO1 at 1q24.1 (p=1.6×10(-8)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p=2.4×10(-2) for rs11656696 and p=9.1×10(-4) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.


Genetic variations in the sonic hedgehog pathway affect clinical outcomes in non-muscle-invasive bladder cancer.
Sonic hedgehog (Shh) pathway genetic variations may affect bladder cancer risk and clinical outcomes. Therefore, we genotyped 177 single-nucleotide polymorphisms (SNP) in 11 Shh pathway genes in a study including 803 bladder cancer cases and 803 controls. We assessed SNP associations with cancer risk and clinical outcomes in 419 cases of non-muscle-invasive bladder cancer (NMIBC) and 318 cases of muscle-invasive and metastatic bladder cancer (MiMBC). Only three SNPs (GLI3 rs3823720, rs3735361, and rs10951671) reached nominal significance in association with risk (P ≤ 0.05), which became nonsignificant after adjusting for multiple comparisons. Nine SNPs reached a nominally significant individual association with recurrence of NMIBC in patients who received transurethral resection (TUR) only (P ≤ 0.05), of which two (SHH rs1233560 and GLI2 rs11685068) were replicated independently in 356 TUR-only NMIBC patients, with P values of 1.0 × 10(-3) (SHH rs1233560) and 1.3 × 10(-3) (GLI2 rs11685068). Nine SNPs also reached a nominally significant individual association with clinical outcome of NMIBC patients who received Bacillus Calmette-Guérin (BCG; P ≤ 0.05), of which two, the independent GLI3 variants rs6463089 and rs3801192, remained significant after adjusting for multiple comparisons (P = 2 × 10(-4) and 9 × 10(-4), respectively). The wild-type genotype of either of these SNPs was associated with a lower recurrence rate and longer recurrence-free survival (versus the variants). Although three SNPs (GLI2 rs735557, GLI2 rs4848632, and SHH rs208684) showed nominal significance in association with overall survival in MiMBC patients (P ≤ 0.05), none remained significant after multiple-comparison adjustments. Germ-line genetic variations in the Shh pathway predicted clinical outcomes of TUR and BCG for NMIBC patients.


South Asian women with diabetes: Psychosocial challenges and management: Consensus statement.
Diabetes is the ninth leading cause of death in women globally. In South Asians mortality in women with diabetes stands second highest. There is a marked gender discrimination which is faced by women across South Asia esp in access to services and support for diabetes, resulting in high rates of morbidity and mortality in women with diabetes. The most important risk factor identified for the diabetes epidemic is obesity along with genetic susceptibility. Lack of health care, social and cultural disparity, discrimination at work, disparity in marriage, restricted medical facilities are prevalent. Diabetes and depression are common in women. Increasing age, low level of education, low socioeconomic conditions, difficulties posed in finding partners, frequent divorce and family history of psychiatric illness are significant risk factors for diabetes and depression. Such patients usually have poor metabolic control, higher complication rates, increased healthcare costs, lost productivity, lower quality of life as well as increased risk of death. Preconception counseling should be incorporated in the routine diabetes clinic visit for all women of childbearing potential. Women with diabetes should have information and access to contraception. Proper family planning counseling and psychological support can help stop practices such as female foeticide and multiple pregnancies. Psychological support to patients and their families are needed to break the barrier. There is emerging evidence that women with diabetes are more prone to untoward outcomes as compared to men. Central obesity, metabolic syndrome and the polycystic ovary syndrome show ethnic specific differences in South Asian women. Optimal sexuality is an integral part of holistic health. Shortage of trained female health care professionals, lack of privacy in over-crowded health care facilities, a social taboo attached to such matters, and lack of confidence in patients contribute to the neglect of sexual issues in women attending diabetes clinics across South Asia. Guidelines for counselling in female sexual dysfunction, written in culturally appropriate manner for South Asia, are needed. Diabetes affects women more severely because of their unique biological, cultural and socioeconomic circumstances. Women have limited access to health care facilities because of illiteracy, ignorance and negative social customs. Transcending the gender hierarchy and inequality is a formidable challenge. Sensitising men, empowering women on self care and providing peer support maybe the answer to this challenge. It is essential for health care providers to use appropriate coping mechanism such as building psychological contact with the patient, including family and friends as part of social support and empower patient with complete process of managing diabetes. Increasing awareness through the media, seminars, posters, group discussions and education, regular monitoring and consulting the doctor, support group for women and facilities for aerobic exercises are recommended. The health care systems should consider custom-designed prevention and control programs tailored for women based on local and regional attitudes on health care, cultural beliefs, and available social support systems. Policies that empower adolescent girls and young women to take control of their metabolic management must be encouraged. Provision of gender specific diabetes education with a holistic life-cycle approach is recommended.


Self-organized origami.
In origami, form follows the sequential spatial organization of folds. This requires continuous intervention and raises a natural question: Can origami arise through self-organization? We answer this affirmatively by examining the possible physical origin for the Miura-ori leaf-folding patterns that arise naturally in insect wings, leaves, and other laminae-like organelles. In particular, we point out examples where biaxial compression of an elastically supported thin film, such as that due to differential growth, shrinkage, desiccation, or thermal expansion, spontaneously generates these patterns, and we provide a simple theoretical explanation for their occurrence.


Physical cues of ovulatory status: a failure to replicate enhanced facial attractiveness and reduced waist-to-hip ratio at high fertility.
We investigated women's facial attractiveness and body shape as a function of menstrual cycle phase, with the expectation from previous research that both would be enhanced during the high fertile phase. To control for the effects of women's daily behaviors on their appearance and waistline, we visited 37 normally cycling women twice in their dorm, where we photographed and measured them at low and high fertile days of their cycle immediately upon their waking. Seventy-four judges from a separate institution chose, for each woman, the picture they thought was more attractive. We analyzed a subset of 20 women who, by forward counting, had a High Fertility visit between Days 10-13 and a Low Fertility visit between Days 20-23; and we also analyzed a subsample of 17 women who, by reverse counting, had a High Fertility visit on the days leading to ovulation and a Low Fertility visit one week after ovulation. In neither set of analyses were women's waist- to-hip ratios lower nearer ovulation, and in neither set were women's high fertile pictures chosen at an above-chance rate by either male or female judges. We did not find evidence that facial attractiveness and waist-to-hip ratio are reliable physical cues of ovulatory status.


Analyzing variations in changes over time: development of the Pattern-Oriented Longitudinal Analysis approach.
Longitudinal qualitative research in nursing is rare but becoming more common. Data collection and analysis over time provide some intriguing possibilities to better understand processes, development, and change in illness experience, healthcare organizations, and self-management. This paper aims to present a process for analyzing qualitative longitudinal data material, namely the Pattern-Oriented Longitudinal Analysis approach (POLA). We developed this approach after synthesizing experiences from two longitudinal qualitative projects and comparing our procedures and reflections with the relevant literature. Using the POLA approach, researchers can describe complexity and variation in changes over time. During the analysis process, emphasis is put on visualizing and identifying change at both an individual and a group level. Ontological and epistemological assumptions for the approach are also described. The benefit of this approach is the possibility to describe complexity and diversity in processes over time, which is important for the development of nursing knowledge. The analysis approach can be further used and developed by researchers seeking to understand variance or contextual features in processes and changes over time.


A dopa decarboxylase modulating the immune response of scallop Chlamys farreri.
Dopa decarboxylase (DDC) is a pyridoxal 5-phosphate (PLP)-dependent enzyme that catalyzes the decarboxylation of L-Dopa to dopamine, and involved in complex neuroendocrine-immune regulatory network. The function for DDC in the immunomodulation remains unclear in invertebrate. The full-length cDNA encoding DDC (designated CfDDC) was cloned from mollusc scallop Chlamys farreri. It contained an open reading frame encoding a polypeptide of 560 amino acids. The CfDDC mRNA transcripts could be detected in all the tested tissues, including the immune tissues haemocytes and hepatopancreas. After scallops were treated with LPS stimulation, the mRNA expression level of CfDDC in haemocytes increased significantly (5.5-fold, P<0.05) at 3 h and reached the peak at 12 h (9.8-fold, P<0.05), and then recovered to the baseline level. The recombinant protein of CfDDC (rCfDDC) was expressed in Escherichia coli BL21 (DE3)-Transetta, and 1 mg rCfDDC could catalyze the production of 1.651±0.22 ng dopamine within 1 h in vitro. When the haemocytes were incubated with rCfDDC-coated agarose beads, the haemocyte encapsulation to the beads was increased significantly from 70% at 6 h to 93% at 24 h in vitro in comparison with that in the control (23% at 6 h to 25% at 24 h), and the increased haemocyte encapsulation was repressed by the addition of rCfDDC antibody (which is acquired via immunization 6-week old rats with rCfDDC). After the injection of DDC inhibitor methyldopa, the ROS level in haemocytes of scallops was decreased significantly to 0.41-fold (P<0.05) of blank group at 12 h and 0.47-fold (P<0.05) at 24 h, respectively. These results collectively suggested that CfDDC, as a homologue of DDC in scallop, modulated the immune responses such as haemocytes encapsulation as well as the ROS level through its catalytic activity, functioning as an indispensable immunomodulating enzyme in the neuroendocrine-immune regulatory network of mollusc.


Mechanism of action and value of N-acetylcysteine in the treatment of early and late acetaminophen poisoning: a critical review.
The mechanism of action of N-acetylcysteine in early acetaminophen poisoning is well understood, but much remains to be learned of the mechanism of its possible benefit in acetaminophen poisoning presenting beyond 15 hours. Selective review of medical literature. N-acetylcysteine should be used in all cases of early acetaminophen poisoning where the plasma acetaminophen concentration lies "above the line;" which line is chosen depends on individual preference and whether enzyme induction is suspected. Particular care should be taken with the use of the nomogram for patients with chronic excess ingestion of acetaminophen or for those who have taken slow-release formulations. While there is a trend suggesting a beneficial effect of N-acetylcysteine in some patients presenting beyond 15 hours, further research is necessary to establish just how effective N-acetylcysteine is, particularly in patients presenting with fulminant hepatic failure. Candidate mechanisms for a beneficial effect in-clude improvement of liver blood flow, glutathione replenishment, modification of cytokine production, and free radical or oxygen scavenging. Hemody-namic and oxygen delivery and utilization parameters must be monitored carefully during delayed N-acetylcysteine treatment of patients with fulminant hepatic failure, as unwanted vasodilation may be deleterious to the maintenance of mean arterial blood pressure.


Who should have surgery for spinal stenosis? Treatment effect predictors in SPORT.
Combined prospective randomized controlled trial and observational cohort study of spinal stenosis (SpS) with an as-treated analysis. To determine modifiers of the treatment effect (TE) of surgery (the difference between surgical and nonoperative outcomes) for SpS using subgroup analysis. The Spine Patient Outcomes Research Trial demonstrated a positive surgical TE for SpS at the group level. However, individual characteristics may affect TE. No previous studies have evaluated TE modifiers in SpS. SpS patients were treated with either surgery (n = 419) or nonoperative care (n = 235) and were analyzed according to treatment received. Fifty-three baseline variables were used to define subgroups for calculating the time-weighted average TE for the Oswestry Disability Index (ODI) over 4 years (TE = ΔODIsurgery - ΔODInonoperative). Variables with significant subgroup × treatment interactions (P < 0.05) were simultaneously entered into a multivariate model to select independent TE predictors. Other than smokers, all analyzed subgroups including at least 50 patients improved significantly more with surgery than with nonoperative treatment (P < 0.05). Multivariate analysis demonstrated: baseline ODI ≤ 56 (TE -15.0 vs. -4.4, ODI > 56, P < 0.001), not smoking (TE -11.7 vs. -1.6 smokers, P < 0.001), neuroforaminal stenosis (TE -14.2 vs. -8.7 no neuroforaminal stenosis, P = 0.002), predominant leg pain (TE -11.5 vs. -7.3 predominant back pain, P = 0.035), not lifting at work (TE -12.5 vs. -0.5 lifting at work, P = 0.017), and the presence of a neurological deficit (TE -13.3 vs. -7.2 no neurological deficit, P < 0.001) were associated with greater TE. With the exception of smokers, patients who met strict inclusion criteria improved more with surgery than with nonoperative treatment, regardless of other specific characteristics. However, TE varied significantly across certain subgroups, and these data can be used to individualize shared decision making discussions about likely outcomes. Smoking cessation should be considered before surgery for SpS.


Risk of Hypoxemia by Induction Technique Among Infants and Neonates Undergoing Pyloromyotomy.
In patients presenting for pyloromyotomy, most practitioners prioritize rapid securement of the airway due to concern for aspiration. However, there is a lack of consensus and limited evidence on the choice between rapid sequence induction (RSI) and modified RSI (mRSI). The medical records of all patients presenting for pyloromyotomy from May 2012 to December 2018 were reviewed. The risk of hypoxemia (peripheral oxygen saturation [Spo2], <90%) during induction was compared between RSI and mRSI cohorts for all patients identified as well as in the neonate subgroup by univariate and multivariable logistic regression analysis. Complications (aspiration, intensive care unit admission, bradycardia, postoperative stridor, and hypotension) and initial intubation success for both cohorts were also compared. A total of 296 patients were identified: 181 in the RSI and 115 in the mRSI cohorts. RSI was associated with significantly higher rates of hypoxemia than mRSI (RSI, 30% [23%-37%]; mRSI, 17% [10%-24%]; P = .016). In multivariable logistic regression analysis of all patients, the adjusted odds ratio (OR) of hypoxemia for RSI versus mRSI was 2.8 (95% confidence interval [CI], 1.5-5.3; P = .003) and the OR of hypoxemia for multiple versus a single intubation attempt was 11.4 (95% CI, 5.8-22.5; P < .001). In multivariable logistic regression analysis of neonatal subgroup, the OR of hypoxemia for RSI versus mRSI was 6.5 (95% CI, 2.0-22.2; P < .001) and the OR of hypoxemia for multiple intubation versus single intubation attempts was 18.1 (95% CI, 4.7-40; P < .001). There were no induction-related complications in either the RSI and mRSI cohorts, and the initial intubation success rate was identical for both cohorts (78%). In infants presenting for pyloromyotomy, anesthetic induction with mRSI compared with RSI was associated with significantly less hypoxemia without an observed increase in aspiration events. In addition, the need for multiple intubation attempts was a strong predictor of hypoxemia. The increased risk of hypoxemia associated with RSI and multiple intubation attempts was even more pronounced in neonatal patients.


Newer antiplatelet agents in acute coronary syndromes.
Aspirin is accepted as standard therapy in the management of acute coronary syndromes, but has significant limitations, including intolerance, allergy, resistance, peptic ulceration, and intracranial hemorrhage. Recent trials involving approximately 18,000 patients with unstable angina have investigated the efficacy and safety of glycoprotein IIb/IIIa receptor antagonists, which block the final common pathway of platelet aggregation. The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) trial compared tirofiban with heparin and found a 33% reduction in the composite end point of death, myocardial infarction, or refractory ischemia at 48 hours. In the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial, patients were randomly assigned to receive either heparin, tirofiban, or both. At 7 days, the patients who had received heparin and tirofiban had a 34% lower incidence of the composite end point of death, myocardial infarction, or refractory ischemia than those treated with heparin alone. The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial randomly assigned patients to receive either eptifibatide or placebo. At 30 days, the rate of death or myocardial infarction was reduced by 9.6% in the eptifibatide group compared with the placebo group. In the Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON) trial, patients were randomly assigned to receive either low- or high-dose lamifiban with or without heparin, or heparin alone. There were no differences between the treatment groups at 30 days, but at 6 months the patients randomly assigned to receive low-dose lamifiban had a 23% lower incidence of death or myocardial infarction, perhaps because of long-term passivation of the plaque. Overall, IIb/IIIa antagonists have been shown to be safe and beneficial in patients with unstable angina, particularly during the infusion period. However, there remain a number of unanswered questions concerning treatment with these agents, such as the appropriate dosing regimens and the safety and efficacy of combining intravenous antiplatelet therapy with other agents such as low-molecular-weight heparin, thrombolytic agents, and oral agents.


N-myc downstream regulated gene 1/Cap43 suppresses tumor growth and angiogenesis of pancreatic cancer through attenuation of inhibitor of kappaB kinase beta expression.
N-myc downstream regulated gene 1 (NDRG1)/Cap43 expression is a predictive marker of good prognosis in patients with pancreatic cancer as we reported previously. In this study, NDRG1/Cap43 decreased the expression of various chemoattractants, including CXC chemokines for inflammatory cells, and the recruitment of macrophages and neutrophils with suppression of both angiogenesis and growth in mouse xenograft models. We further found that NDRG1/Cap43 induced nuclear factor-kappaB (NF-kappaB) signaling attenuation through marked decreases in inhibitor of kappaB kinase (IKK) beta expression and IkappaBalpha phosphorylation. Decreased IKKbeta expression in cells overexpressing NDRG1/Cap43 resulted in reduction of both nuclear translocation of p65 and p50 and their binding to the NF-kappaB motif. The introduction of an exogenous IKKbeta gene restored NDRG1/Cap43-suppressed expression of melanoma growth-stimulating activity alpha/CXCL1, epithelial-derived neutrophil activating protein-78/CXCL5, interleukin-8/CXCL8 and vascular endothelial growth factor-A, accompanied by increased phosphorylation of IkappaBalpha in NDRG1/Cap43-expressing cells. In patients with pancreatic cancer, NDRG1/Cap43 expression levels were also inversely correlated with the number of infiltrating macrophages in the tumor stroma. This study suggests a novel mechanism by which NDRG1/Cap43 modulates tumor angiogenesis/growth and infiltration of macrophages/neutrophils through attenuation of NF-kappaB signaling.


Protein-bound and free UV filters in cataract lenses. The concentration of UV filters is much lower than in normal lenses.
In human cataract lenses the UV filters, 3-hydroxykynurenine glucoside (3OHKG) and kynurenine (Kyn) were found to be covalently bound to proteins and the levels in the nucleus were much higher than in the cortex. The levels of the bound UV filters in cataract nuclei were much lower than those in age-matched normal lenses. 3-Hydroxykynurenine could not be detected in cataract lenses. As with normal lenses, protein-bound 3OHKG in cataract lenses was found at the highest levels followed by Kyn. Free UV filter concentrations were also markedly reduced in cataract lenses. This feature may well contribute to the lower protein-bound levels; however, there was no clear relationship between free and bound UV filter contents when individual lenses were examined. We propose that since cysteine is a major site for UV filter binding, the well-documented oxidation of protein sulfhydryl groups during the progression of nuclear cataract may account, in part, for the pronounced decrease in bound UV filters in cataract lenses.


The Ill-Fated Quest for Fame in Psychological Research.
The question "Am I famous yet?" directs our attention to the outcome of the journey of being a psychological scientist. There is nothing inherently wrong with wanting to achieve the highest possible outcomes when pursuing a goal. However, for a researcher, fame is an outcome that is very vague, abstract, distal, and unlikely to be attained. Focusing on this outcome might undermine motivation and persistence in the difficult endeavor of doing excellent research and contributing to psychological knowledge. To become an excellent psychological scientist might be a better outcome to which to aspire. However, focusing on the outcome seems generally less adaptive than focusing on the process of goal pursuit. A focus on the process of research is more likely to lead to higher motivation and persistence, and it might increase performance. In sum, the question "Am I famous yet?" might be ill conceived and might be better replaced by the question "How do I make a contribution to psychological science?"


Post-diagnosis social networks, and lifestyle and treatment factors in the After Breast Cancer Pooling Project.
Larger social networks have been associated with better breast cancer survival. To investigate potential mediators, we evaluated associations of social network size and diversity with lifestyle and treatment factors associated with prognosis. We included 9331 women from the After Breast Cancer Pooling Project who provided data on social networks within approximately two years following diagnosis. A social network index was derived from information about the presence of a spouse or intimate partner, religious ties, community participation, friendship ties, and numbers of living relatives. Diversity was assessed as variety of ties, independent of size. We used logistic regression to evaluate associations with outcomes and evaluated whether effect estimates differed using meta-analytic techniques. Associations were similar across cohorts though analyses of smoking and alcohol included US cohorts only because of low prevalence of these behaviors in the Shanghai cohort. Socially isolated women were more likely to be obese (OR = 1.21, 95% CI:1.03-1.42), have low physical activity (<10 MET-hours/week, OR = 1.55, 95% CI:1.36-1.78), be current smokers (OR = 2.77, 95% CI:2.09-3.68), and have high alcohol intake (≥15 g/d, OR = 1.23, 95% CI:1.00-1.51), compared with socially integrated women. Among node positive cases from three cohorts, socially isolated women were more likely not to receive chemotherapy (OR = 2.10, 95% CI:1.30-3.39); associations differed in a fourth cohort. Other associations (nonsignificant) were consistent with less intensive treatment in socially isolated women. Low social network diversity was independently associated with more adverse lifestyle, but not clinical, factors. Small, less diverse social networks measured post-diagnosis were associated with more adverse lifestyle factors and less intensive cancer treatment. Copyright © 2016 John Wiley & Sons, Ltd.


cDNA cloning, expression, and functional characterization of PI31, a proline-rich inhibitor of the proteasome.
The primary structure of PI31, a protein inhibitor of the 20 S proteasome, was deduced by cDNA cloning and sequencing. The human protein has a calculated molecular weight of 29,792, a value in excellent accord with 31,000, as estimated by SDS-polyacrylamide gel electrophoresis for purified bovine PI31, and is not similar to any other protein in current data bases. PI31 is a proline-rich protein, particularly within its carboxyl-terminal half where 26% of the amino acids are proline. Wild-type PI31 and various truncation mutants were expressed in Escherichia coli and purified to homogeneity. Recombinant wild-type PI31 displayed structural and functional properties similar to those of PI31 purified from bovine red blood cells and inhibited the hydrolysis of protein and peptide substrates by the 20 S proteasome. Analysis of truncation mutants demonstrated that proteasome inhibition was conferred by the carboxyl-terminal proline-rich domain of PI31, which appears to have an extended secondary structure. Inhibition of the 20 S proteasome by PI31 involved formation a proteasome-PI31 complex. In addition to its direct inhibition of the 20 S proteasome, PI31 inhibited the activation of the proteasome by each of two proteasome regulatory proteins, PA700 and PA28. These results suggest that PI31 plays an important role in control of proteasome function, including that in ubiquitin-dependent pathways of protein degradation.


Feasibility of Non-Invasive Vagus Nerve Stimulation (gammaCore VET™) for the Treatment of Refractory Seizure Activity in Dogs.
Idiopathic epilepsy is the most common chronic neurologic condition in dogs. Approximately 20-30% of those dogs are refractory to standard medical therapy and commonly experience side effects from antiepileptic drugs. Non-invasive vagus nerve stimulation (nVNS) has been frequently used in human medicine as an adjunct seizure therapy with low incidence of adverse events. Canine studies are limited to invasive surgical implants with no non-invasive evaluations currently published. We investigated the feasibility and efficacy of nVNS (gammaCore VET) as an adjunct treatment for refractory epilepsy in dogs. In total, 14 client-owned dogs completed the trial of either 8- or 16-week treatment periods during which they received 90-120 s stimulation three times per day in the region of the left cervical vagus nerve. Owners recorded seizure type (focal or generalized) and frequency as well as any adverse effects. Out of 14 dogs, nine achieved a reduction in seizure frequency and four were considered responders with a 50% or greater reduction in seizures from baseline to the final treatment period. However, there was no statistically significant difference in overall seizure frequency (p = 0.53) or percent change in seizure frequency between groups (p = 0.75). Adverse effects occurred in 25% of dogs originally enrolled, with reports of a hoarse bark and limb trembling, lethargy, behavioral changes, and an increase in seizure frequency. Non-invasive VNS was found to be safe and easy to administer with mild adverse events. It is considered a feasible treatment option as an adjunct therapy in refractory seizures and should be further investigated.


Serum concentrations of keratan sulfate, osteocalcin, and pyridinoline crosslinks after oral administration of glucosamine to standardbred horses during race training.
To determine the effects of orally administered glucosamine on concentrations of markers of bone and cartilage metabolism in Standardbred horses during race training. Twenty 16- to 20-month-old Standardbreds beginning race training. Horses were randomly assigned to 2 groups. One group received glucosamine hydrochloride (4 g, PO, q 12 h), and the second (control) group received glucose (4 g, PO, q 12 h). Serum samples were obtained prior to onset of the study (baseline) and at regular intervals for 48 weeks for determination of concentrations of keratan sulfate (KS), osteocalcin (OC), and pyridinoline crosslinks (PYD). Osteocalcin concentrations changed significantly with time; mean serum concentrations were significantly higher than baseline values for samples obtained at 24 to 48 weeks after onset of the study. Although a significant effect of time was observed for mean concentration of KS, concentrations did not differ significantly from baseline values at any time during the study when groups were analyzed separately. However, pooled analysis revealed significant increases of mean serum KS concentration at weeks 24 and 30. Significant changes in serum PYD concentrations were not detected. Oral administration of glucosamine did not significantly affect serum concentrations of any of the markers. Increased serum OC in clinically normal Standardbreds during race training may reflect bone formation that accompanies adaptive remodeling of the appendicular skeleton. For these experimental conditions, glucosamine did not appear to exert a detectable influence on serum concentrations of these 3 markers of connective tissue metabolism.


Pulsed electromagnetic fields promote collagen production in bone marrow fibroblasts via athermal mechanisms.
Primary and passaged cultures of fibroblasts (RBMFs) raised from the bone marrow stroma of young rabbits were treated with pulsed electromagnetic fields (PEMFs) from the start of each culture until 1 week after they became confluent. the PEMF treatment had no effect on cell proliferation, estimated by phase contrast microscopy, by 3H-thymidine incorporation into DNA, or by total DNA assay. Collagen production, estimated by conversion of 3H-proline to 3H-hydroxyproline in nondialyzable material was markedly elevated in postconfluent cultures, but not in cultures that had only just reached confluence. About 65 of 3H-hydroxyproline was in low molecular weight form, and a correlation between collagen breakdown and cyclic AMP (cAMP) levels in RBMFs was demonstrated by adding dibutyryl cAMP or prostaglandin E3 (PGE2) to the culture medium concurrently with 3H-proline. The PEMF apparatus caused an insufficient temperature rise (less than 0.1 degree C) to account for these results. We propose that the rise in collagen production is consistent with the hypothesis that PEMFs act by reducing cAMP levels in RBMFs, and that thermal effects are insignificant.