Perioperative management and outcomes of esophageal atresia and tracheoesophageal fistula.
Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a rare congenital anomaly lacking contemporary data detailing patient demographics, medical/surgical management and outcomes. Substantial variation in the care of infants with EA/TEF may affect both short- and long-term outcomes. The purpose of this study was to characterize the demographics, management strategies and outcomes in a contemporary multi-institutional cohort of infants diagnosed with EA/TEF to identify potential areas for standardization of care. A multi-institutional retrospective cohort study of infants with EA/TEF treated at 11 children's hospitals between 2009 and 2014 was performed. Over the 5year period, 396 cases were identified in the 11 centers (7±5 per center per year). All infants with a diagnosis of EA/TEF made within 30days of life who had surgical repair of their defect defined as esophageal reconstruction with or without ligation of TEF within the first six months of life were included. Demographic, operative, and outcome data were collected and analyzed to detect associations between variables. Prenatal suspicion or diagnosis of EA/TEF was present in 53 (13%). The most common anatomy was proximal EA with distal TEF (n=335; 85%) followed by pure EA (n=27; 7%). Clinically significant congenital heart disease (CHD) was present in 137 (35%). Mortality was 7.5% and significantly associated with CHD (p<0.0001). Postoperative morbidity occurred in 62% of the population, including 165 (42%) cases with anastomotic stricture requiring intervention, anastomotic leak in 89 (23%), vocal cord paresis/paralysis in 26 (7%), recurrent fistula in 19 (5%), and anastomotic dehiscence in 9 (2%). Substantial variation in practice across our institutions existed: bronchoscopy prior to repair was performed in 64% of cases (range: 0%-100%); proximal pouch contrast study in 21% (0%-69%); use of interposing material between the esophageal and tracheal suture lines in 38% (0%-69%); perioperative antibiotics ≥24h in 69% (36%-97%); and transanastomotic tubes in 73% (21%-100%). Contemporary treatment of EA/TEF is characterized by substantial variation in perioperative management and considerable postoperative morbidity and mortality. Future studies are planned to establish best practices and clinical care guidelines for infants with EA/TEF. Type of study: Treatment study. Level IV.


What do I do? Developing a taxonomy of chaplaincy activities and interventions for spiritual care in intensive care unit palliative care.
Chaplains are increasingly seen as key members of interdisciplinary palliative care teams, yet the specific interventions and hoped for outcomes of their work are poorly understood. This project served to develop a standard terminology inventory for the chaplaincy field, to be called the chaplaincy taxonomy. The research team used a mixed methods approach to generate, evaluate and validate items for the taxonomy. We conducted a literature review, retrospective chart review, focus groups, self-observation, experience sampling, concept mapping, and reliability testing. Chaplaincy activities focused primarily on palliative care in an intensive care unit setting in order to capture a broad cross section of chaplaincy activities. Literature and chart review resulted in 438 taxonomy items for testing. Chaplain focus groups generated an additional 100 items and removed 421 items as duplications. Self-Observation, Experience Sampling and Concept Mapping provided validity that the taxonomy items were actual activities that chaplains perform in their spiritual care. Inter-rater reliability for chaplains to identify taxonomy items from vignettes was 0.903. The 100 item chaplaincy taxonomy provides a strong foundation for a normative inventory of chaplaincy activities and outcomes. A deliberative process is proposed to further expand and refine the taxonomy to create a standard terminological inventory for the field of chaplaincy. A standard terminology could improve the ways inter-disciplinary palliative care teams communicate about chaplaincy activities and outcomes.


Inclusion and functionalization of polymers with cyclodextrins: current applications and future prospects.
The numerous hydroxyl groups available in cyclodextrins are active sites that can form different types of linkages. They can be crosslinked with one another, or they can be derivatized to produce monomers that can form linear or branched networks. Moreover, they can form inclusion complexes with polymers and different substrates, modifying their physicochemical properties. This review shows the different applications using polymers with cyclodextrins, either by forming inclusion complexes, ternary complexes, networks, or molecularly imprinted polymers (MIPs). On one hand, the use of cyclodextrins enhances the properties of each polymer, and on the other the use of polymers decreases the amount of cyclodextrins required in different formulations. Both cyclodextrins and polymers contribute synergistically in several applications such as pharmacological, nutritional, environmental, and other industrial fields. The use of polymers based on cyclodextrins is a low cost easy to use potential tool with great future prospects.


[Association between famine exposure during early life and BMI in adulthood].
Objective: To examine the influence of famine exposure during early life on BMI in adulthood. Methods: A total of 94 052 participants recruited in the baseline survey of China Kadoorie Biobank were included in this study. The participants who were born between October 1956 and September 1958, between October 1959 and September 1961 and between October 1962 and September 1964 were classified as group born before famine, group born during famine and group born after famine (control group). The regression coefficients and 95% confidence intervals (CIs) for BMI of famine exposure groups were estimated by linear regression model. And P values for interaction between famine and smoking, alcohol use, physical activity were estimated by likelihood ratio tests. Results: Compared with the group born after famine, in females, the group born during famine had higher BMI (coefficient: 0.12, 95% CI: 0.03-0.22) after adjusting other impact factors. Except physical activity (interaction: P<0.077), both smoking and alcohol use had modification effects on the associations between famine exposure and BMI (interaction: all P<0.001). Conclusion: Famine exposure during early life, especially during fetal period, might increase risks of overweight and obesity in females. Therefore, it is important to ensure the adequacy of nutrition during early life to prevent overweight or obesity in adulthood.


Rumbling Orchids: How To Assess Divergent Evolution Between Chloroplast Endosymbionts and the Nuclear Host.
Phylogenetic relationships inferred from multilocus organellar and nuclear DNA data are often difficult to resolve because of evolutionary conflicts among gene trees. However, conflicting or "outlier" associations (i.e., linked pairs of "operational terminal units" in two phylogenies) among these data sets often provide valuable information on evolutionary processes such as chloroplast capture following hybridization, incomplete lineage sorting, and horizontal gene transfer. Statistical tools that to date have been used in cophylogenetic studies only also have the potential to test for the degree of topological congruence between organellar and nuclear data sets and reliably detect outlier associations. Two distance-based methods, namely ParaFit and Procrustean Approach to Cophylogeny (PACo), were used in conjunction to detect those outliers contributing to conflicting phylogenies independently derived from chloroplast and nuclear sequence data. We explored their efficiency of retrieving outlier associations, and the impact of input data (unit branch length and additive trees) between data sets, by using several simulation approaches. To test their performance using real data sets, we additionally inferred the phylogenetic relationships within Neotropical Catasetinae (Epidendroideae, Orchidaceae), which is a suitable group to investigate phylogenetic incongruence because of hybridization processes between some of its constituent species. A comparison between trees derived from chloroplast and nuclear sequence data reflected strong, well-supported incongruence within Catasetum, Cycnoches, and Mormodes. As a result, outliers among chloroplast and nuclear data sets, and in experimental simulations, were successfully detected by PACo when using patristic distance matrices obtained from phylograms, but not from unit branch length trees. The performance of ParaFit was overall inferior compared to PACo, using either phylograms or unit branch lengths as input data. Because workflows for applying cophylogenetic analyses are not standardized yet, we provide a pipeline for executing PACo and ParaFit as well as displaying outlier associations in plots and trees by using the software R. The pipeline renders a method to identify outliers with high reliability and to assess the combinability of the independently derived data sets by means of statistical analyses.


Preconditioning Therapy in ABO-Incompatible Living Kidney Transplantation: A Systematic Review and Meta-Analysis.
ABO-incompatible (ABOi) kidney transplantation is now an established form of renal replacement therapy, but the efficacy and safety of the different types of preconditioning therapies are unclear. We aimed to synthesize the totality of the published evidence about the effects of any form of preconditioning therapies in living donor ABOi kidney transplantation on graft and patient outcomes. We searched MEDLINE, Embase, and Clinicaltrial.gov databases (inception through June 2015) to identify all studies that described the outcomes of adult living donor ABOi kidney transplantations using any form of preconditioning therapies. Two independent reviewers identified studies, extracted data, and assessed the risk of bias. Data were summarized using the random effects model, and heterogeneity was explored using subgroup analyses. We assessed confidence in the evidence using the Grading of Recommendations Assessment, Development, and Evaluation framework. Eighty-three studies (54 case reports and case series, 25 cohort, 2 case-control, and 2 registry studies) involving 4810 ABOi transplant recipients were identified. Overall, confidence in the available evidence was low. During a mean follow-up time of 28 (standard deviation [SD], 26.6) months, the overall graft survival for recipients who received immunoadsorption or apheresis was 94.1% (95% confidence interval [95%CI], 88.2%-97.1%) and 88.0% (95% CI, 82.6%-91.8%), respectively. For those who received rituximab or underwent splenectomy, the overall graft survival was 94.5% (95% CI, 91.6%-96.5%) and 79.7% (95% CI, 72.9%-85.1%), respectively. Data on other longer-term outcomes, including malignancy, were sparse. Rituximab or immunoadsorption appeared to be promising preconditioning strategies before ABOi kidney transplantation. However, the overall quality of evidence and the confidence in the observed treatment effects are low. The increased use of ABOi kidney transplantation needs to be matched with randomized trials of different types, dosing, and frequency of preconditioning therapies so that this scarce resource can be used most effectively and efficiently.


ABCG1 gene variants in suicidal behavior and aggression-related traits.
The ABCG1 transporter seems to be involved in human cholesterol and sterol homeostasis. As alterations in cholesterol homeostasis have been widely linked to aggression, violence and suicidal behavior, we considered ABCG1 as a candidate gene for these traits. We studied 5 gene variants of ABCG1 in a sample of 571 suicide attempters, healthy controls and suicide completers. We also analyzed the relation to aggression-related traits, assessed by STAXI and FAF. Regarding the genotypes, there was no association with completed or attempted suicide with the tested SNPs. Regarding alleles, only one SNP (rs1044317) showed a slight association with suicide attempters in comparison to the controls. Interestingly, rs225374 G allele carriers had higher scores on the STAXI subscales "State Anger" and "Anger Out", as well as on the FAF subscales "Spontaneous Aggression", "Irritability" and "Aggression". Carriers of the rs914189 G allele scored higher on the FAF subscales "Spontaneous Aggression", "Reactive Aggression" and "Aggression". Carriers of the rs1044317 G allele had lower scores for STAXI "Trait Anger" and "Trait Temperament", and higher scores for STAXI "Anger Control". Our results provide evidence that the ABCG1 may influence aggression-related traits. Given that these represent intermediate phenotypes of suicidal behavior, ABCG1 might also act on suicidal behavior through these traits. The observed associations warrant further replications.


Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo.
Neutrophil recruitment from blood to extravascular sites of sterile or infectious tissue damage is a hallmark of early innate immune responses, and the molecular events leading to cell exit from the bloodstream have been well defined. Once outside the vessel, individual neutrophils often show extremely coordinated chemotaxis and cluster formation reminiscent of the swarming behaviour of insects. The molecular players that direct this response at the single-cell and population levels within the complexity of an inflamed tissue are unknown. Using two-photon intravital microscopy in mouse models of sterile injury and infection, we show a critical role for intercellular signal relay among neutrophils mediated by the lipid leukotriene B4, which acutely amplifies local cell death signals to enhance the radius of highly directed interstitial neutrophil recruitment. Integrin receptors are dispensable for long-distance migration, but have a previously unappreciated role in maintaining dense cellular clusters when congregating neutrophils rearrange the collagenous fibre network of the dermis to form a collagen-free zone at the wound centre. In this newly formed environment, integrins, in concert with neutrophil-derived leukotriene B4 and other chemoattractants, promote local neutrophil interaction while forming a tight wound seal. This wound seal has borders that cease to grow in kinetic concert with late recruitment of monocytes and macrophages at the edge of the displaced collagen fibres. Together, these data provide an initial molecular map of the factors that contribute to neutrophil swarming in the extravascular space of a damaged tissue. They reveal how local events are propagated over large-range distances, and how auto-signalling produces coordinated, self-organized neutrophil-swarming behaviour that isolates the wound or infectious site from surrounding viable tissue.


Urodynamic evaluation after abdominal hysterectomies for gynecological malignancies.
The aim of this study was to evaluate the effect of abdominal hysterectomy made for gynecological malign diseases on lower urinary tract functions in asymptomatic patients by preoperative and postoperative urodynamic measurements. Thirty four asymptomatic women, who were operated for gynecological malignancies by abdominal hysterectomy from September 2008 to June 2009, in Dicle University Hospital Department of Obstetrics and Gynecology, were included in this study. Urodynamic measurements were performed before the operation and in the sixth week of surgery. No statistically significant changes were detected in first urge, normal urge, and strong urge, bladder capacity before and after surgery. The evaluation of functional urethral length showed a significant difference by UPP between pre and postoperative values (p = 0.003). The decreases in values of the maximum urethral pressure and the maximum urethral closing pressure were significant (p = 0.004 and p = 0.048). The voiding time was found to be statistically increased (p = 0.002), voided volume and residual urine volume were remained unchanged. There were no significant differences in other measurements. Preoperative and postoperative urodynamic studies are necessary to determine and cure urinary dysfunctions caused by abdominal hysterectomy.


Epidemiologic and molecular prognostic review of glioblastoma.
Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system malignancy with a median survival of 15 months. The average incidence rate of GBM is 3.19/100,000 population, and the median age of diagnosis is 64 years. Incidence is higher in men and individuals of white race and non-Hispanic ethnicity. Many genetic and environmental factors have been studied in GBM, but the majority are sporadic, and no risk factor accounting for a large proportion of GBMs has been identified. However, several favorable clinical prognostic factors are identified, including younger age at diagnosis, cerebellar location, high performance status, and maximal tumor resection. GBMs comprise of primary and secondary subtypes, which evolve through different genetic pathways, affect patients at different ages, and have differences in outcomes. We report the current epidemiology of GBM with new data from the Central Brain Tumor Registry of the United States 2006 to 2010 as well as demonstrate and discuss trends in incidence and survival. We also provide a concise review on molecular markers in GBM that have helped distinguish biologically similar subtypes of GBM and have prognostic and predictive value.


Bryostatin 1, a novel antineoplastic agent and protein kinase C activator, induces human myalgia and muscle metabolic defects: a 31P magnetic resonance spectroscopic study.
Bryostatin 1, a novel antineoplastic agent and protein kinase C (PKC) activator, has been found to induce myalgia (muscle pain) 48 h after administration in clinical trials. This is the dose-limiting toxicity and has restricted the duration of therapy in phase I trials. To investigate the mechanisms and try to increase toleration of the drug, we studied calf muscle metabolism of 14 patients at rest and during exercise and subsequent recovery using 31P magnetic resonance spectroscopy (MRS) before and 4 h, 48-72 h and 1-2 weeks following bryostatin therapy. In resting muscle there was a significant (P < 0.001) increase in the phosphodiester/adenosine 5'-triphosphate (PDE/ATP) ratio 48 h post bryostatin and in patients with myalgia compared with pre-bryostatin control studies. Following exercise, patients with myalgia showed significantly slower phosphocreatine (PCr) and ADP recovery half-time (P < or = 0.05) suggesting impaired mitochondrial (oxidative) energy production, possibly due to a direct effect on the mitochondria or secondary to reduced blood flow. The apparent proton efflux rate following exercise was significantly reduced 4 h after bryostatin (P < or = 0.05), suggesting reduced blood flow. The rate of post-exercise reoxygenation was studied in four patients by near-infrared spectroscopy 4 h post bryostatin. In three of these the rate was reduced, consistent with reduced muscle blood flow. Bryostatin 1 appeared to cause a long-lasting impairment of oxidative metabolism and proton washout from muscle, consistent with a vasoconstrictive action. Thus these studies provide evidence for two mechanisms of the dose-limiting toxicity for bryostatin. Prospective studies on the use of vasodilators to improve the tolerance of the drug should be carried out.


Poor Self-Rated Health Influences Hospital Service Use in Hospitalized Inpatients With Chronic Conditions in Taiwan.
Our aim was to investigate the association between self-rated health (SRH) and use of hospital services (ie, medical outpatient department, emergency department, and general ward. admissions). Cross-sectional study data were collected from 230 consecutive patients admitted to medical departments of a 2000-bed academic medical center in Taiwan using standardized operating procedures for data collection of SRH (ie, a single-item question inquiring overall perceived health status), medical disorders, depressive symptoms, and combined service utilization over a 1-year period (ie, number of visits to outpatient department, number of visits to emergency department, and number of hospitalizations). Electronic medical records were retrieved, with self-reported external medical visits added to in-hospital frequencies of service use to provide better estimation of health service utilization. Fifty-two percent of study patients rated their health as poor or very poor. Poor SRH was associated with more visits to medical outpatient department, emergency department, and hospital admission. Multivariate logistic regression demonstrated an independent association between poor SRH and services utilization after adjustment for age, gender, hypertension, diabetes, metastatic cancer, number of chronic illness, life-threatening event, life-time suicidal ideation, and depression. SRH may be a useful research tool to model medical service use for inpatients with chronic conditions.


A centrosomal theory of the short term evolutionary maintenance of sexual reproduction.
A new mode of inheritance is postulated in which a sexual offspring receives a contribution from each parent and selects the better to pass on to its own offspring. This could provide a simple advantage to sex over a sex whose magnitude is shown to be of the order of a doubling of fitness in each generation, large enough to cancel the twofold cost of sex. This possible advantage to sex can be realized only if a cell component is in fact inherited in this selectively ambiguous way. No such component is known of, but the eukaryotic centrosome is a possible candidate. The possibility is discussed that the centrosome contains an obligatorily non-digital replicator which has an essential function in the initiation of microtubules. If this theory is true, it has the capacity to apply as widely as sex is found, and it would rescue theories of the long-term maintenance of sex from the necessity to provide a twofold advantage in each generation. If false, the theory will soon be disproved.


Alternative Functional rad21 Paralogs in Fusarium oxysporum.
Cohesin, the sister chromatid cohesion complex, is an essential complex that ensures faithful sister chromatid segregation in eukaryotes. It also participates in DNA repair, transcription and maintenance of chromosome structure. Mitotic cohesin is composed of Smc1, Smc3, Scc3, and Rad21/Mcd1. The meiotic cohesin complex contains Rec8, a Rad21 paralog and not Rad21 itself. Very little is known about sister chromatid cohesion in fungal plant pathogens. Fusarium oxysporum is an important fungal plant pathogen without known sexual life cycle. Here, we describe that F. oxysporum encodes for three Rad21 paralogs; Rad21, Rec8, and the first alternative Rad21 paralog in the phylum of ascomycete. This last paralog is found only in several fungal plant pathogens from the Fusarium family and thus termed rad21nc (non-conserved). Conserved rad21 (rad21c), rad21nc, and rec8 genes are expressed in F. oxysporum although the expression of rad21c is much higher than the other paralogs. F. oxysporum strains deleted for the rad21nc or rec8 genes were analyzed for their role in fungal life cycle. Δrad21nc and Δrec8 single mutants were proficient in sporulation, conidia germination, hyphal growth and pathogenicity under optimal growth conditions. Interestingly, Δrad21nc and Δrec8 single mutants germinate less effectively than wild type (WT) strains under DNA replication and mitosis stresses. We provide here the first genetic analysis of alternative rad21nc and rec8 paralogs in filamentous fungi. Our results suggest that rad21nc and rec8 may have a unique role in cell cycle related functions of F. oxysporum.


Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts.
CSF and PET biomarkers of amyloid β and tau accurately detect Alzheimer's disease pathology, but the invasiveness, high cost, and poor availability of these detection methods restrict their widespread use as clinical diagnostic tools. CSF tau phosphorylated at threonine 181 (p-tau181) is a highly specific biomarker for Alzheimer's disease pathology. We aimed to assess whether blood p-tau181 could be used as a biomarker for Alzheimer's disease and for prediction of cognitive decline and hippocampal atrophy. We developed and validated an ultrasensitive blood immunoassay for p-tau181. Assay performance was evaluated in four clinic-based prospective cohorts. The discovery cohort comprised patients with Alzheimer's disease and age-matched controls. Two validation cohorts (TRIAD and BioFINDER-2) included cognitively unimpaired older adults (mean age 63-69 years), participants with mild cognitive impairment (MCI), Alzheimer's disease, and frontotemporal dementia. In addition, TRIAD included healthy young adults (mean age 23 years) and BioFINDER-2 included patients with other neurodegenerative disorders. The primary care cohort, which recruited participants in Montreal, Canada, comprised control participants from the community without a diagnosis of a neurological condition and patients referred from primary care physicians of the Canadian National Health Service for specialist care. Concentrations of plasma p-tau181 were compared with established CSF and PET biomarkers and longitudinal measurements using Spearman correlation, area under the curve (AUC), and linear regression analyses. We studied 37 individuals in the discovery cohort, 226 in the first validation cohort (TRIAD), 763 in the second validation cohort (BioFINDER-2), and 105 in the primary care cohort (n=1131 individuals). In all cohorts, plasma p-tau181 showed gradual increases along the Alzheimer's disease continuum, from the lowest concentrations in amyloid β-negative young adults and cognitively unimpaired older adults, through higher concentrations in the amyloid β-positive cognitively unimpaired older adults and MCI groups, to the highest concentrations in the amyloid β-positive MCI and Alzheimer's disease groups (p<0·001, Alzheimer's disease vs all other groups). Plasma p-tau181 distinguished Alzheimer's disease dementia from amyloid β-negative young adults (AUC=99·40%) and cognitively unimpaired older adults (AUC=90·21-98·24% across cohorts), as well as other neurodegenerative disorders, including frontotemporal dementia (AUC=82·76-100% across cohorts), vascular dementia (AUC=92·13%), progressive supranuclear palsy or corticobasal syndrome (AUC=88·47%), and Parkinson's disease or multiple systems atrophy (AUC=81·90%). Plasma p-tau181 was associated with PET-measured cerebral tau (AUC=83·08-93·11% across cohorts) and amyloid β (AUC=76·14-88·09% across cohorts) pathologies, and 1-year cognitive decline (p=0·0015) and hippocampal atrophy (p=0·015). In the primary care cohort, plasma p-tau181 discriminated Alzheimer's disease from young adults (AUC=100%) and cognitively unimpaired older adults (AUC=84·44%), but not from MCI (AUC=55·00%). Blood p-tau181 can predict tau and amyloid β pathologies, differentiate Alzheimer's disease from other neurodegenerative disorders, and identify Alzheimer's disease across the clinical continuum. Blood p-tau181 could be used as a simple, accessible, and scalable test for screening and diagnosis of Alzheimer's disease. Alzheimer Drug Discovery Foundation, European Research Council, Swedish Research Council, Swedish Alzheimer Foundation, Swedish Dementia Foundation, Alzheimer Society Research Program.


Dextromethorphan- and pseudoephedrine-induced agitated psychosis and ataxia: case report.
Pseudoephedrine and dextromethorphan are therapeutic constituents of numerous commonly used, over-the-counter cough and cold preparations. Although this drug combination is generally considered quite safe if utilized in recommended doses, overmedication or overdose can result in serious neurologic and cardiovascular abnormalities that occasionally can be life-threatening. We present a case of a 2-year-old child who developed hyperirritability, psychosis, and ataxia after being overmedicated with a pseudoephedrine/dextromethorphan combination cough preparation, and discuss probable mechanisms of toxicity and risk factors for adverse events.


Cost effectiveness of early discharge after uncomplicated acute myocardial infarction.
Reducing the length of hospitalizations can reduce short-term costs, but there are few data on the long-term clinical and economic consequences of early discharge. Using data from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, we identified 22,361 patients with acute myocardial infarction who had an uncomplicated course for 72 hours after thrombolysis. Then, using a decision-analytic model, we examined the cost effectiveness of an additional day of hospitalization in this group. We defined incremental survival attributable to another day of monitored hospitalization, using Kaplan-Meier estimates to determine the rate of resuscitation after cardiac arrest between 72 and 96 hours. Lifetime survival curves for each group in the decision-analytic model were estimated from empirical one-year survival data from GUSTO-1. The costs of key hospital resources (e.g., room and monitoring) were derived from data in the GUSTO-1 cost-effectiveness analysis. Of the patients with an uncomplicated course within 72 hours after thrombolysis, 16 had ventricular arrhythmias during the next 24 hours; 13 of these patients (81 percent) survived for at least 24 hours. On average, another 0.006 year of life per patient could be saved by keeping patients with an uncomplicated course in the hospital another day. At a cost of $624 for hospital and physicians' services, extending the hospital stay by another day would cost $105,629 per year of life saved. In sensitivity analyses, it was found that a fourth day of hospitalization would be economically attractive only if its cost could be reduced by more than 50 percent or if a high-risk subgroup could be identified in which the estimated survival benefit would be doubled. Hospitalization of patients with uncomplicated myocardial infarction beyond three days after thrombolysis is economically unattractive by conventional standards.


Amino acid substitutions in the pore helix of GluR6 control inhibition by membrane fatty acids.
RNA editing at the Q/R site in the GluR5 and GluR6 subunits of neuronal kainate receptors regulates channel inhibition by lipid-derived modulators including the cis-unsaturated fatty acids arachidonic acid and docosahexaenoic acid. Kainate receptor channels in which all of the subunits are in the edited (R) form exhibit strong inhibition by these compounds, whereas wild-type receptors that include a glutamine (Q) at the Q/R site in one or more subunits are resistant to inhibition. In the present study, we have performed an arginine scan of residues in the pore loop of the GluR6(Q) subunit. Amino acids within the range from -19 to +7 of the Q/R site of GluR6(Q) were individually mutated to arginine and the mutant cDNAs were expressed as homomeric channels in HEK 293 cells. All but one of the single arginine substitution mutants yielded functional channels. Only weak inhibition, typical of wild-type GluR6(Q) channels, was observed for substitutions +1 to +6 downstream of the Q/R site. However, arginine substitution at several locations upstream of the Q/R site resulted in homomeric channels exhibiting strong inhibition by fatty acids, which is characteristic of homomeric GluR6(R) channels. Based on homology with the pore loop of potassium channels, locations at which R substitution induces susceptibility to fatty acid inhibition face away from the cytoplasm toward the M1 and M3 helices and surrounding lipids.


Emotional Prosody Measurement (EPM): a voice-based evaluation method for psychological therapy effectiveness.
The voice embodies three sources of information: speech, the identity, and the emotional state of the speaker (i.e., emotional prosody). The latter feature is resembled by the variability of the F0 (also named fundamental frequency of pitch) (SD F0). To extract this feature, Emotional Prosody Measurement (EPM) was developed, which consists of 1) speech recording, 2) removal of speckle noise, 3) a Fourier Transform to extract the F0-signal, and 4) the determination of SD F0. After a pilot study in which six participants mimicked emotions by their voice, the core experiment was conducted to see whether EPM is successful. Twenty-five patients suffering from a panic disorder with agoraphobia participated. Two methods (story-telling and reliving) were used to trigger anxiety and were compared with comparable but more relaxed conditions. This resulted in a unique database of speech samples that was used to compare the EPM with the Subjective Unit of Distress to validate it as measure for anxiety/stress. The experimental manipulation of anxiety proved to be successful and EPM proved to be a successful evaluation method for psychological therapy effectiveness.


Effect of diet in females (F1) from prenatally undernourished mothers on metabolism and liver function in the F2 progeny is sex-specific.
Poor maternal nutrition sensitises to the development of metabolic diseases and obesity in adulthood over several generations. The prevalence increases when offspring is fed with a high-fat (HF) diet after weaning. This study aims to determine whether such metabolic profiles can be transmitted to the second generation and even aggravated when the mothers were exposed to overnutrition, with attention to potential sex differences. Pregnant Wistar rats were subjected to ad libitum (control) or 70% food-restricted diet (FR) during gestation (F0). At weaning, F1 females were allocated to three food protocols: (1) standard diet prior to and throughout gestation and lactation, (2) HF diet prior to and standard diet throughout gestation and lactation, and (3) HF diet prior to and throughout gestation and lactation. F2 offspring was studied between 16 and 32 weeks of age. FR-F2 offspring on standard diet showed normal adiposity and had no significant metabolic alterations in adulthood. Maternal HF diet resulted in sex-specific effects with metabolic disturbances more apparent in control offspring exposed to HF diet during gestation and lactation. Control offspring displayed glucose intolerance associated with insulin resistance in females. Female livers overexpressed lipogenesis genes and those of males the genes involved in lipid oxidation. Gene expression was significantly attenuated in the FR livers. Increased physical activity associated with elevated corticosterone levels was observed in FR females on standard diet and in all females from overnourished mothers. Maternal undernutrition during gestation (F0) improves the metabolic health of second-generation offspring with more beneficial effects in females.


First-order loss-less differentiators using long period gratings made in Er-doped fibers.
An active-fiber-based all-optical first-order temporal differentiator with power efficiency surpassing 100% is demonstrated experimentally. It is based on a long-period fiber grating (LPFG) inscribed into a piece of highly-doped Erbium-doped fiber (EDF). The performed theoretical analysis considers effects like relative position of the LPFG with respect to the input end of the EDF and influence of the input signal power. In the design, parameters like noise characteristics and level of non-linear interaction are taken into account. The advantages of such an implementation over the setup using concatenation of a passive LPFG with an amplifier lies in reducing the unwanted nonlinearities and reducing the amplified spontaneous emission (ASE).


Ibuprofen arginine for pain control during scaling and root planing: a randomized, triple-blind trial.
The aim of this controlled clinical trial was to investigate the analgesic efficacy and tolerability of ibuprofen arginine in patients with mild-to-moderate periodontitis during and after non-surgical periodontal treatment. This randomized, triple-blind, placebo-controlled, parallel-group trial assessed the analgesic efficacy of ibuprofen arginine (Spedifen) in patients undergoing routine periodontal scaling and root planing. 64 patients with chronic periodontitis received either 800 mg ibuprofen arginine or placebo 30 min. before treatment. Numeric pain and electronic visual analogue scales ranging from 0 to 100 were used. The average pain levels during treatment were lower following ibuprofen arginine (quartiles: 0.5, 4.5, 11) compared with placebo (4, 16, 26), corresponding to a percentage reduction in median pain of 72% (p=0.023). The median maximum pain was 28 (inter-quartile range 10-50) following placebo and 10 (4-31) following ibuprofen arginine (p=0.065). In patients with mild-to-moderate chronic periodontitis, ibuprofen arginine was safe and superior to placebo for alleviating pain during non-surgical periodontal treatment. Its painless administration and rapid onset of action make it well suitable for pain management in a general dental office.


Interferon alfa subtypes and levels of type I interferons in the liver and peripheral mononuclear cells in patients with chronic hepatitis C and controls.
Viral infections stimulate the transcription of interferon type I, which includes IFN-alfa (IFN-alpha) (13 subtypes) and IFN-beta (a single substance). Hepatitis C virus (HCV) infection is remarkable by its ability to evade host antiviral defenses; however, there is little information as to whether endogenous IFN is activated or not in this disease. Additionally, despite the fact that the various IFN-alpha subtypes may differ in biological activity, there are no data concerning the IFN-alpha subtypes specifically expressed in normal and diseased liver tissue. Thus, we have analyzed the IFN-alpha subtypes and the mRNA levels of type I IFNs in samples of normal liver tissue and in liver from patients with chronic hepatitis C. Similar studies were performed in peripheral blood mononuclear cells (PBMC) from patients and controls. After amplification and cloning of IFN-alpha cDNA, we observed that 98 of the 100 clones from normal liver tissue corresponded to the IFN-alpha5 subtype. However, in livers with chronic hepatitis C and in PBMC from controls and patients, a variety of subtypes, in addition to IFN-alpha5, were detected, suggesting a participation of infiltrating leukocytes in the production of IFN-alpha in livers with chronic hepatitis C. As compared with controls, patients with chronic hepatitis C showed a significant increase in IFN-beta mRNA in both the liver and PBMC, while IFN-alpha mRNA was significantly increased in PBMC but markedly reduced in liver tissue. In conclusion, IFN-alpha5 is the sole IFN-alpha subtype expressed in normal liver tissue. The hepatic levels of IFN-alpha are reduced in chronic hepatitis C, an event that may favor viral persistence.


Juggling reveals a decisional component to tactile suppression.
Goal-directed movements are characterized by sensory suppression, that is, by decreased sensitivity to tactile stimuli. In the present study, we investigated tactile suppression during movement using a complex motor task: basic 3-ball juggling. It was hypothesized that a decrease in tactile sensitivity would be observed, together with a shift in participants' response bias while juggling. In a first experiment, participants had to detect a short gap in an otherwise continuous vibratory stimulus, which was delivered to their wrist under conditions of rest or else while juggling. In a second experiment, participants detected a short time gap in a continuous auditory signal, under the same conditions. In a final control experiment performed at rest, participants detected a short time gap in an auditory or tactile signal. In an additional condition, the detection of a gap in tactile stimulation was required under conditions of intramodal tactile interference. Participants were significantly less sensitive to detect a gap in tactile stimulation whilst juggling. Most importantly, these results were paired with a significant shift toward participants adopting a more conservative criterion when responding to the presence of the gap (i.e. they were more likely to say that a gap was not present). Taken together, these results demonstrate movement-related tactile sensory suppression and point to a decisional component in tactile suppression, thus suggesting that tactile suppression could already be triggered in the brain ahead of the motor command.


Parental socioeconomic status and risk of cerebral palsy in the child: evidence from two Nordic population-based cohorts.
We investigated whether the risk of cerebral palsy (CP) in the child varies by parents' socioeconomic status, in Denmark and Norway. We included almost 1.3 million children born in Demark during 1981-2007 and 2.4 million children born in Norway during 1967-2007, registered in the Medical Birth registries. Data on births were linked to Statistics Denmark and Norway to retrieve information on parents' education and relationship status and, in Denmark, also income. CP diagnoses were obtained from linkage with national registries. We used multivariate log-binominal regression models to estimate relative risk (RR) of CP according to parental socioeconomic status. There was a strong trend of decreasing risk of CP with additional education of both the mother and the father. These trends were nearly identical for the two parents, with a one-third reduction in risk for those with the highest education compared with parents with the lowest education. When both parents had high education, risk of CP was further reduced (RR 0.58, 0.53-0.63). Women with partners had a reduction in risk (RR 0.79, 0.74-0.85) compared with single mothers overall. Risk patterns were stable over time, across countries and within spastic bilateral and unilateral CP. Household income was not associated with risk of CP. Risk of CP in two Scandinavian countries was lower among educated parents and mothers with a partner, but unrelated to income. Factors underlying this stable association with education are unknown, but could include differences in potentially modifiable lifestyle factors and health behaviours.


Auto-antibody production and glomerulonephritis in congenic Slamf1-/- and Slamf2-/- [B6.129] but not in Slamf1-/- and Slamf2-/- [BALB/c.129] mice.
Several genes in an interval of human and mouse chromosome 1 are associated with a predisposition for systemic lupus erythematosus. Congenic mouse strains that contain a 129-derived genomic segment, which is embedded in the B6 genome, develop lupus because of epistatic interactions between the 129-derived and B6 genes, e.g. in B6.129chr1b mice. If a gene that is located on chromosome 1 is altered through homologous recombination in 129-derived embryonic stem cells (ES cells) and if the resultant knockout mouse is backcrossed with B6, interpretation of the phenotype of the mutant mouse may be affected by epistatic interactions between the 129 and B6 genomes. Here, we report that knockout mice of two adjacent chromosome 1 genes, Slamf1(-/-) and Slamf2(-/-), which were generated with the same 129-derived ES cell line, develop features of lupus, if backcrossed on to the B6 genetic background. By contrast, Slamf1(-/-) [BALB/c.129] and Slamf2(-/-) [BALB/c.129] do not develop disease. Surprisingly, Slamf1(-/-) [B6.129] mice develop both auto-antibodies and glomerulonephritis between 3 and 6 months of age, while disease fully develops in Slamf1(-/-) [B6.129] mice after 9-14 months. Functional analyses of CD4(+) T cells reveals that Slamf2(-/-) T cells are resistant to tolerance induction in vivo. We conclude that the Slamf2(-/-) mutation may have a unique influence on T-cell tolerance and lupus.


Monocyte TREM-1 membrane expression in non-infectious inflammation.
Sterile or non-infectious inflammation and severe infection are accompanied by very similar events. Damage (or danger)-associated molecular patterns and pathogen-associated molecular patterns trigger the release of inflammatory mediators and modulate the expression of cell surface receptors. The increased expression on monocytes and neutrophils of triggering receptor expressed on myeloid cells 1 is a hallmark of both infectious and non-infectious inflammation.


The effects of PTH, loading and surgical insult on cancellous bone at the bone-implant interface in the rabbit.
Enhancing the quantity and quality of cancellous bone with anabolic pharmacologic agents may lead to more successful outcomes of non-cemented joint replacements. Using a novel rabbit model of cancellous bone loading, we examined two specific questions regarding bone formation at the bone-implant interface: (1) does the administration of intermittent PTH, a potent anabolic agent, and mechanical loading individually and combined enhance the peri-implant cancellous bone volume fraction; and, (2) does surgical trauma enhance the anabolic effect of PTH on peri-implant bone volume fraction. In this model, PTH enhanced peri-implant bone volume fraction by 30% in loaded bone, while mechanical loading alone increased bone volume fraction modestly (+10%). Combined mechanical loading and PTH treatment had no synergistic effect on any cancellous parameters. However, a strong combined effect was found in bone volume fraction with combined surgery and PTH treatment (+34%) compared to intact control limbs. Adaptive changes in the cancellous bone tissue included increased ultimate stress and enhanced remodeling activity. The number of proliferative osteoblasts increased as did their expression of pro-collagen 1 and PTH receptor 1, and the number of TRAP positive osteoclasts also increased. In summary, both loading and intermittent PTH treatment enhanced peri-implant bone volume, and surgery and PTH treatment had a strong combined effect. This finding is of clinical importance since enhancing early osseointegration in the post-surgical period has numerous potential benefits.


Maximizing the efficacy of interoceptive exposure by optimizing inhibitory learning: a randomized controlled trial.
Cognitive-behavioral treatments for panic disorder (PD) emphasize interoceptive exposure (IE) to target anxiety sensitivity (AS) but vary considerably in its manner of delivery. This randomized controlled trial was conducted to compare the efficacy of the low-dose delivery of IE exercises often prescribed in treatment protocols to an intensive form of IE hypothesized to optimize inhibitory learning. Participants (N = 120) with elevated AS were randomly assigned to one of four single-session interventions: (a) low-dose IE as prescribed in Barlow and Craske's Panic Control Treatment, (b) low-dose IE without controlled breathing or a lengthy between-trial rest period, (c) intensive IE, or (d) expressive writing control. Compared to the other conditions, intensive IE produced significantly greater reductions in AS and fearful responding to a straw breathing task from pretreatment to posttreatment. Maintenance of gains during the follow-up period did not differ between conditions. Changes in fear toleration and negative outcome expectancies fully mediated the superior efficacy of intensive IE over low-dose IE. The two low intensity IE conditions produced particularly high rates of fear sensitization on between-trial and outcome variables. The findings suggest that the intensive delivery of IE exercises has the potential to improve the efficacy of exposure-based treatments for PD.


Phylogenomic Insights into the Evolution of Stinging Wasps and the Origins of Ants and Bees.
The stinging wasps (Hymenoptera: Aculeata) are an extremely diverse lineage of hymenopteran insects, encompassing over 70,000 described species and a diversity of life history traits, including ectoparasitism, cleptoparasitism, predation, pollen feeding (bees [Anthophila] and Masarinae), and eusociality (social vespid wasps, ants, and some bees) [1]. The most well-studied lineages of Aculeata are the ants, which are ecologically dominant in most terrestrial ecosystems [2], and the bees, the most important lineage of angiosperm-pollinating insects [3]. Establishing the phylogenetic affinities of ants and bees helps us understand and reconstruct patterns of social evolution as well as fully appreciate the biological implications of the switch from carnivory to pollen feeding (pollenivory). Despite recent advancements in aculeate phylogeny [4-11], considerable uncertainty remains regarding higher-level relationships within Aculeata, including the phylogenetic affinities of ants and bees [5-7]. We used ultraconserved element (UCE) phylogenomics [7, 12] to resolve relationships among stinging-wasp families, gathering sequence data from >800 UCE loci and 187 samples, including 30 out of 31 aculeate families. We analyzed the 187-taxon dataset using multiple analytical approaches, and we evaluated several alternative taxon sets. We also tested alternative hypotheses for the phylogenetic positions of ants and bees. Our results present a highly supported phylogeny of the stinging wasps. Most importantly, we find unequivocal evidence that ants are the sister group to bees+apoid wasps (Apoidea) and that bees are nested within a paraphyletic Crabronidae. We also demonstrate that taxon choice can fundamentally impact tree topology and clade support in phylogenomic inference.


A Log-Rectilinear Transformation for Foveated 360-degree Video Streaming.
With the rapidly increasing resolutions of 360° cameras, head-mounted displays, and live-streaming services, streaming high-resolution panoramic videos over limited-bandwidth networks is becoming a critical challenge. Foveated video streaming can address this rising challenge in the context of eye-tracking-equipped virtual reality head-mounted displays. However, conventional log-polar foveated rendering suffers from a number of visual artifacts such as aliasing and flickering. In this paper, we introduce a new log-rectilinear transformation that incorporates summed-area table filtering and off-the-shelf video codecs to enable foveated streaming of 360° videos suitable for VR headsets with built-in eye-tracking. To validate our approach, we build a client-server system prototype for streaming 360° videos which leverages parallel algorithms over real-time video transcoding. We conduct quantitative experiments on an existing 360° video dataset and observe that the log-rectilinear transformation paired with summed-area table filtering heavily reduces flickering compared to log-polar subsampling while also yielding an additional 10% reduction in bandwidth usage.


Positive selection differs between protein secondary structure elements in Drosophila.
Different protein secondary structure elements have different physicochemical properties and roles in the protein, which may determine their evolutionary flexibility. However, it is not clear to what extent protein structure affects the way Darwinian selection acts at the amino acid level. Using phylogeny-based likelihood tests for positive selection, we have examined the relationship between protein secondary structure and selection across six species of Drosophila. We find that amino acids that form disordered regions, such as random coils, are far more likely to be under positive selection than expected from their proportion in the proteins, and residues in helices and beta-structures are subject to less positive selection than predicted. In addition, it appears that sites undergoing positive selection are more likely than expected to occur close to one another in the protein sequence. Finally, on a genome-wide scale, we have determined that positively selected sites are found more frequently toward the gene ends. Our results demonstrate that protein structures with a greater degree of organization and strong hydrophobicity, represented here as helices and beta-structures, are less tolerant to molecular adaptation than disordered, hydrophilic regions, across a diverse set of proteins.


Sclerosing cholangitis.
Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown etiology. Immunogenetic factors are considered important in its pathogenesis. The genetic susceptibility to primary sclerosing cholangitis is associated, in part, with the HLA HLA-DRB1, DQA1, DQB1 haplotype. Liver histology in primary sclerosing cholangitis is characterized by a portal inflammatory infiltrate mostly composed of memory T cells. Many patients eventually will develop cholangiocarcinoma, and inactivation of the p16 tumor-suppressor gene might be involved in neoplastic transformation. Alcohol consumption might be a risk factor for cholangiocarcinoma, and, in some patients, elevation of serum CA19-9 marks the neoplastic transformation. To date, no medical treatment has been proven effective. Endoscopic therapy might be useful in some patients, but controlled studies are lacking. Liver transplantation remains the only effective treatment. Posttransplant survival and quality of life are continuously improving despite the fact that the disease may recur in some patients after transplantation. Nevertheless, patient selection and timing of indication for liver transplantation remain uncertain.


Seeing the same words differently: the time course of automaticity and top-down intention in reading.
We investigated how linguistic intention affects the time course of visual word recognition by comparing the brain's electrophysiological response to a word's lexical frequency, a well-established psycholinguistic marker of lexical access, when participants actively retrieve the meaning of the written input (semantic categorization) versus a situation where no language processing is necessary (ink color categorization). In the semantic task, the ERPs elicited by high-frequency words started to diverge from those elicited by low-frequency words as early as 120 msec after stimulus onset. On the other hand, when categorizing the colored font of the very same words in the color task, word frequency did not modulate ERPs until some 100 msec later (220 msec poststimulus onset) and did so for a shorter period and with a smaller scalp distribution. The results demonstrate that, although written words indeed elicit automatic recognition processes in the brain, the speed and quality of lexical processing critically depends on the top-down intention to engage in a linguistic task.


Protecting the geyser basins of Yellowstone National Park: toward a new national policy for a vulnerable environmental resource.
Geyser basins provide high value recreation, scientific, economic and national heritage benefits. Geysers are globally rare, in part, because development activities have quenched about 260 of the natural endowment. Today, more than half of the world's remaining geysers are located in Yellowstone National Park, northwest Wyoming, USA. However, the hydrothermal reservoirs that supply Yellowstone's geysers extend well beyond the Park borders, and onto two "Known Geothermal Resource Areas"-Island Park to the west and Corwin Springs on the north. Geysers are sensitive geologic features that are easily quenched by nearby geothermal wells. Therefore, the potential for geothermal energy development adjacent to Yellowstone poses a threat to the sustainability of about 500 geysers and 10,000 hydrothermal features. The purpose here is to propose that Yellowstone be protected by a "Geyser Protection Area" (GPA) extending in a 120-km radius from Old Faithful Geyser. The GPA concept would prohibit geothermal and large-scale groundwater wells, and thereby protect the water and heat supply of the hydrothermal reservoirs that support Yellowstone's geyser basins and important hot springs. Proactive federal leadership, including buyouts of private groundwater development rights, can assist in navigating the GPA through the greater Yellowstone area's "wicked" public policy environment. Moreover, the potential impacts on geyser basins from intrusive research sampling techniques are considered in order to facilitate the updating of national park research regulations to a precautionary standard. The GPA model can provide the basis for protecting the world's few remaining geyser basins.


Functional recovery among elderly people one year after hip fracture surgery.
The purposes of the present study were to follow up on the recovery of activities of daily living (ADL) and instrumental activities of daily living (IADL) one year after hip fracture in elderly people and to understand the factors that affect functional recovery. Information for this one-year study was obtained through structured interviews during the first week after admission, at discharge, three months and one year after fracture. One hundred and three elderly people over 65 years old, with femoral neck fractures and intertrochanteric fractures due to falling down were recruited from a medical center in Taipei. The results were as follows: In most cases, ADL and IADL in elderly people could not be recovered to the status before fracture in the one-year period of follow-up; the most rapid recovery period was within three months after discharge. In terms of ADL before fracture, 93.2 %, 74.8 %, and about 90 % of patients could walk, climb stairs, and take care of themselves (feeding, toileting, dressing), respectively; however, only 70.9 %, 49.1 % and about 75 % of patients respectively could walk, climb stairs and take care of themselves one year after hip fracture. As for IADL, 73.8 % of patients could walk outdoors before fracture, but only 58.2 % could walk outdoors one year after fracture. The factor on which ADL recovery within one year after hip fracture depended was the ability to walk outdoors before fracture. It explained 39.7 % of total variance in ADL. As for IADL, significant predictors included doing housework, marital status and use of walking aids before fracture. These items explained 56.1% of total variance in IADL. The findings point to the functional decline of elderly people after hip fracture and suggest the importance of focusing on hospital-based multidisciplinary interventions and discharge


Weighted parsimony phylogeny of the family Characidae (Teleostei: Characiformes).
The family Characidae, including more than 1000 species, lacks a phylogenetic diagnosis, with many of its genera currently considered as incertae sedis. The aims of the present study are to propose a phylogenetic diagnosis and to assess higher-level relationships of and within Characidae. In this regard, 360 morphological characters are studied for 160 species of Characidae and related families. Phylogenetic analyses under implied weighting and self-weighted optimization are presented, exploring a broad range of parameters. The analysis under self-weighted optimization is innovative for this size of matrices. Familial status of Serrasalmidae is supported, and Acestrorhynchidae and Cynodontidae are included in a monophyletic Characidae. Engraulisoma taeniatum is transferred from Characidae to Gasteropelecidae. Thus constituted, the monophyly of Characidae is supported by seven synapomorphies. A new subfamily, Heterocharacinae, is proposed, and the subfamilies Aphyocharacinae, Aphyoditeinae, Characinae, Gymnocharacinae, and Stevardiinae are redefined. The Glandulocaudinae are included in Stevardiinae together with remaining members of "clade A" (sensuMalabarba and Weitzman, 2003. Comun. Mus. Ciênc. Tecnol. PUCRS, Sér. Zool. 16, 67-151.) and the genera Aulixidens and Nantis. Most incertae sedis genera are assigned, at least tentatively, to a phylogenetically diagnosed clade.


Observation of accelerating parabolic beams.
We report the first observation of accelerating parabolic beams. These accelerating parabolic beams are similar to the Airy beams because they exhibit the unusual ability to remain diffraction-free while having a quadratic transverse shift during propagation. The amplitude and phase masks required to generate these beams are encoded onto a single liquid crystal display. Experimental results agree well with theory.


Long-term prognosis after acute anterior infarction with atrioventricular block.
The purpose of this study was to evaluate the need for permanent pacing in patients who have survived the effects of anterior myocardial infarction with complete heart block and have returned to sinus rhythm but who are left with impairment of intraventricular conduction. We have reviewed 52 patients with complete heart block complicating recent anterior myocardial infarction. Temporary pacing was instituted in all patients. There were 25 hospital survivors who were followed for an average of 49 months. Long-term pacing was established in 4 patients. Of the 21 patients in sinus rhythm, 14 had partial bilateral bundle-branch block with either right bundle-branch block and left anterior hemiblock or right bundle-branch block and left posterior hemiblock; at the end of the follow-up period, 10 of these 14 were alive and well. Furthermore, permanent pacing failed to prevent sudden death in 2 patients. At the present time, therefore, we conclude that long-term pacing is not justified in patients, otherwise asymptomatic, with partial bilateral bundle-branch block persisting after transient complete heart block in anterior myocardial infarction.


New insights into human immunity from ancient genomics.
Population genetic studies have clearly indicated that immunity and host defense are among the functions most frequently subject to natural selection, and increased our understanding of the biological relevance of the corresponding genes and their contribution to variable immune traits and diseases. Herein, we will focus on some recently studied forms of human adaptation to infectious agents, including hybridization with now-extinct hominins, such as Neanderthals and Denisovans, and admixture between modern human populations. These studies, which are partly enabled by the technological advances in the sequencing of DNA from ancient remains, provide new insight into the sources of immune response variation in contemporary humans, such as the recently reported link between Neanderthal heritage and susceptibility to severe COVID-19 disease. Furthermore, ancient DNA analyses, in both humans and pathogens, allow to measure the action of natural selection on immune genes across time and to reconstruct the impact of past epidemics on the evolution of human immunity.


Stress-induced cocaine seeking requires a beta-2 adrenergic receptor-regulated pathway from the ventral bed nucleus of the stria terminalis that regulates CRF actions in the ventral tegmental area.
The ventral bed nucleus of the stria terminalis (vBNST) has been implicated in stress-induced cocaine use. Here we demonstrate that, in the vBNST, corticotropin releasing factor (CRF) is expressed in neurons that innervate the ventral tegmental area (VTA), a site where the CRF receptor antagonist antalarmin prevents the reinstatement of cocaine seeking by a stressor, intermittent footshock, following intravenous self-administration in rats. The vBNST receives dense noradrenergic innervation and expresses β adrenergic receptors (ARs). Footshock-induced reinstatement was prevented by bilateral intra-vBNST injection of the β-2 AR antagonist, ICI-118,551, but not the β-1 AR antagonist, betaxolol. Moreover, bilateral intra-vBNST injection of the β-2 AR agonist, clenbuterol, but not the β-1 agonist, dobutamine, reinstated cocaine seeking, suggesting that activation of vBNST β-2 AR is both necessary for stress-induced reinstatement and sufficient to induce cocaine seeking. The contribution of a β-2 AR-regulated vBNST-to-VTA pathway that releases CRF was investigated using a disconnection approach. Injection of ICI-118,551 into the vBNST in one hemisphere and antalarmin into the VTA of the contralateral hemisphere prevented footshock-induced reinstatement, whereas ipsilateral manipulations failed to attenuate stress-induced cocaine seeking, suggesting that β-2 AR regulate vBNST efferents that release CRF into the VTA, activating CRF receptors, and promoting cocaine use. Last, reinstatement by clenbuterol delivered bilaterally into the vBNST was prevented by bilateral vBNST pretreatment with antalarmin, indicating that β-2 AR-mediated actions in the vBNST also require local CRF receptor activation. Understanding the processes through which stress induces cocaine seeking should guide the development of new treatments for addiction.


Reduced dietary salt for the prevention of cardiovascular disease.
This is an update of a Cochrane review that was first published in 2011 of the effects of reducing dietary salt intake, through advice to reduce salt intake or low-sodium salt substitution, on mortality and cardiovascular events. 1. To assess the long-term effects of advice and salt substitution, aimed at reducing dietary salt, on mortality and cardiovascular morbidity.2. To investigate whether a reduction in blood pressure is an explanatory factor in the effect of such dietary interventions on mortality and cardiovascular outcomes. We updated the searches of CENTRAL (2013, Issue 4), MEDLINE (OVID, 1946 to April week 3 2013), EMBASE (OVID, 1947 to 30 April 2013) and CINAHL (EBSCO, inception to 1 April 2013) and last ran these on 1 May 2013. We also checked the references of included studies and reviews. We applied no language restrictions. Trials fulfilled the following criteria: (1) randomised, with follow-up of at least six months, (2) the intervention was reduced dietary salt (through advice to reduce salt intake or low-sodium salt substitution), (3) participants were adults and (4) mortality or cardiovascular morbidity data were available. Two review authors independently assessed whether studies met these criteria. A single author extracted data and assessed study validity, and a second author checked this. We contacted trial authors where possible to obtain missing information. We extracted events and calculated risk ratios (RRs) and 95% confidence intervals (CIs). Eight studies met the inclusion criteria: three in normotensives (n = 3518) and five in hypertensives or mixed populations of normo- and hypertensives (n = 3766). End of trial follow-up ranged from six to 36 months and the longest observational follow-up (after trial end) was 12.7 years.The risk ratios (RR) for all-cause mortality in normotensives were imprecise and showed no evidence of reduction (end of trial RR 0.67, 95% confidence interval (CI) 0.40 to 1.12, 60 deaths; longest follow-up RR 0.90, 95% CI 0.58 to 1.40, 79 deaths n=3518) or in hypertensives (end of trial RR 1.00, 95% CI 0.86 to 1.15, 565 deaths; longest follow-up RR 0.99, 95% CI 0.87 to 1.14, 674 deaths n=3085). There was weak evidence of benefit for cardiovascular mortality (hypertensives: end of trial RR 0.67, 95% CI 0.45 to 1.01, 106 events n=2656) and for cardiovascular events (hypertensives: end of trial RR 0.76, 95% CI 0.57 to 1.01, 194 events, four studies, n = 3397; normotensives: at longest follow-up RR 0.71, 95% CI 0.42 to 1.20, 200 events; hypertensives: RR 0.77, 95% CI 0.57 to 1.02, 192 events; pooled analysis of six trials RR 0.77, 95% CI 0.63 to 0.95, n = 5912). These findings were driven by one trial among retirement home residents that reduced salt intake in the kitchens of the homes, thereby not requiring individual behaviour change.Advice to reduce salt showed small reductions in systolic blood pressure (mean difference (MD) -1.15 mmHg, 95% CI -2.32 to 0.02 n=2079) and diastolic blood pressure (MD -0.80 mmHg, 95% CI -1.37 to -0.23 n=2079) in normotensives and greater reductions in systolic blood pressure in hypertensives (MD -4.14 mmHg, 95% CI -5.84 to -2.43 n=675), but no difference in diastolic blood pressure (MD -3.74 mmHg, 95% CI -8.41 to 0.93 n=675).Overall many of the trials failed to report sufficient detail to assess their potential risk of bias. Health-related quality of life was assessed in one trial in normotensives, which reported significant improvements in well-being but no data were presented. Despite collating more event data than previous systematic reviews of randomised controlled trials, there is insufficient power to confirm clinically important effects of dietary advice and salt substitution on cardiovascular mortality in normotensive or hypertensive populations. Our estimates of the clinical benefits from advice to reduce dietary salt are imprecise, but are larger than would be predicted from the small blood pressure reductions achieved. Further well-powered studies would be needed to obtain more precise estimates. Our findings do not support individual dietary advice as a means of restricting salt intake. It is possible that alternative strategies that do not require individual behaviour change may be effective and merit further trials.


The dorsal cochlear nucleus of the mouse: a light microscopic analysis of neurons that project to the inferior colliculus.
In the mouse dorsal cochlear nucleus (DCN), all members of a distinct class of large multipolar neurons were shown to project to the contralateral inferior colliculus by using retrograde horseradish peroxidase techniques. Typically, these multipolar neurons have the largest cell bodies in the nucleus and are distributed in layers II, III, and IV. Each contains a round, pale nucleus with a prominent nucleolus and conspicuous Nissl bodies. In Golgi preparations, however, two types of large cells could be distinguished on the basis of dendritic characteristics. Pyramidal cells form relatively flattened, slablike dendritic fields whose alignment contributes to the laminar organization of the DCN. They represent 75-80% of the large cell population and are found in layer II and the superficial region of layer III. Giant cells represent the other type of large multipolar neuron and are distributed in the deeper regions of layer III and in layer IV. Their ellipsoidal dendritic fields are formed by long and relatively unbranched dendrites that project across the laminae. The differences in dendritic morphology imply that each cell class segregates its afferent input in distinct ways and subserves different auditory functions.


The small intestine shields the liver from fructose-induced steatosis.
Per capita fructose consumption has increased 100-fold over the last century1. Epidemiological studies suggest that excessive fructose consumption, and especially consumption of sweet drinks, is associated with hyperlipidaemia, non-alcoholic fatty liver disease, obesity and diabetes2-7. Fructose metabolism begins with its phosphorylation by the enzyme ketohexokinase (KHK), which exists in two alternatively spliced forms8. The more active isozyme, KHK-C, is expressed most strongly in the liver, but also substantially in the small intestine9,10 where it drives dietary fructose absorption and conversion into other metabolites before fructose reaches the liver11-13. It is unclear whether intestinal fructose metabolism prevents or contributes to fructose-induced lipogenesis and liver pathology. Here we show that intestinal fructose catabolism mitigates fructose-induced hepatic lipogenesis. In mice, intestine-specific KHK-C deletion increases dietary fructose transit to the liver and gut microbiota and sensitizes mice to fructose's hyperlipidaemic effects and hepatic steatosis. In contrast, intestine-specific KHK-C overexpression promotes intestinal fructose clearance and decreases fructose-induced lipogenesis. Thus, intestinal fructose clearance capacity controls the rate at which fructose can be safely ingested. Consistent with this, we show that the same amount of fructose is more strongly lipogenic when drunk than eaten, or when administered as a single gavage, as opposed to multiple doses spread over 45 min. Collectively, these data demonstrate that fructose induces lipogenesis when its dietary intake rate exceeds the intestinal clearance capacity. In the modern context of ready food availability, the resulting fructose spillover drives metabolic syndrome. Slower fructose intake, tailored to intestinal capacity, can mitigate these consequences.


An Electronic Pre-Exposure Prophylaxis Initiation and Maintenance Home Care System for Nonurban Young Men Who Have Sex With Men: Protocol for a Randomized Controlled Trial.
Pre-exposure prophylaxis (PrEP) is highly efficacious for preventing HIV but has not yet been brought to scale among at-risk persons. In several clinical trials in urban areas, technology-based interventions have shown a positive impact on PrEP adherence. In rural and small-town areas in the United States, which often do not have geographically proximal access to PrEP providers, additional support may be needed. This may be particularly true for younger persons who are more likely to face multiple barriers to accessing PrEP services. Home-based care, accomplished through a tailored mobile phone app, specimen self-collection (SSC), and interactive video consultations, could increase both PrEP initiation and persistence in care. The goal of this study is to assess the initiation and persistence in PrEP care for those randomized to a home-care intervention (electronic PrEP, ePrEP) relative to those assigned to the standard of care (control) condition. We will conduct additional assessments, including quantitative and qualitative analyses, to contextualize trial results and facilitate scale-up. This 2-arm, randomized controlled trial will enroll young men who have sex with men (YMSM) aged between 18 and 24 years from rural areas of Georgia, Mississippi, and North Carolina. The trial will seek to recruit a diverse sample, targeting 50% participation among highly impacted groups of black or Latino men who have sex with men. Intervention participants will receive a study app that incorporates a messaging platform, a scheduling and milestone-based tracking system for PrEP care progress, electronic behavioral surveys, and interactive video consultations with a clinician. Complemented by SSC kits mailed to laboratories for standard PrEP-related monitoring, the ePrEP system will allow participants to access PrEP care without leaving their homes. YMSM randomized to the control condition will receive a listing of nearest local PrEP providers to receive standard PrEP care. Both groups will complete quarterly electronic surveys. The primary outcome, assessed at 6 and 12 months after randomization, will be the difference in the proportion of intervention versus control participants that achieve protective levels of the active metabolite of oral PrEP (tenofovir diphosphate in dried blood spots). Enrollment will begin in May 2019, with study completion in 2022. This trial will determine whether home PrEP care provided through an app-based platform is an efficacious means of expanding access to PrEP care for a diverse group of YMSM in rural and small-town areas of the United States. ClinicalTrials.gov NCT03729570; https://clinicaltrials.gov/ct2/show/NCT03729570 (Archived by WebCite at http://www.webcitation.org/78RE2Qizf). PRR1-10.2196/13982.


Human health risk assessment of air emissions from development of unconventional natural gas resources.
Technological advances (e.g. directional drilling, hydraulic fracturing), have led to increases in unconventional natural gas development (NGD), raising questions about health impacts. We estimated health risks for exposures to air emissions from a NGD project in Garfield County, Colorado with the objective of supporting risk prevention recommendations in a health impact assessment (HIA). We used EPA guidance to estimate chronic and subchronic non-cancer hazard indices and cancer risks from exposure to hydrocarbons for two populations: (1) residents living >½ mile from wells and (2) residents living ≤ ½ mile from wells. Residents living ≤ ½ mile from wells are at greater risk for health effects from NGD than are residents living >½ mile from wells. Subchronic exposures to air pollutants during well completion activities present the greatest potential for health effects. The subchronic non-cancer hazard index (HI) of 5 for residents ≤ ½ mile from wells was driven primarily by exposure to trimethylbenzenes, xylenes, and aliphatic hydrocarbons. Chronic HIs were 1 and 0.4. for residents ≤ ½ mile from wells and >½ mile from wells, respectively. Cumulative cancer risks were 10 in a million and 6 in a million for residents living ≤ ½ mile and >½ mile from wells, respectively, with benzene as the major contributor to the risk. Risk assessment can be used in HIAs to direct health risk prevention strategies. Risk management approaches should focus on reducing exposures to emissions during well completions. These preliminary results indicate that health effects resulting from air emissions during unconventional NGD warrant further study. Prospective studies should focus on health effects associated with air pollution.


The Beneficial Effects of Taurine to Counteract Sarcopenia.
Aging is a multifactorial process characterized by several features including low-grade inflammation, increased oxidative stress and reduced regenerative capacity, which ultimately lead to alteration in morpho-functional properties of skeletal muscle, thus promoting sarcopenia. This condition is characterized by a gradual loss of muscle mass due to an unbalance between protein synthesis and degradation, finally conveying in functional decline and disability. The development of specific therapeutic approaches able to block or reverse this condition may represent an invaluable tool for the promotion of a healthy aging among elderly people. It is well established that changes in the quantity and the quality of dietary proteins, as well as the intake of specific amino acids, are able to counteract some of the physiopathological processes related to the progression of the loss of muscle mass and may have beneficial effects in improving the anabolic response of muscle in the elderly. Taurine is a non-essential amino acid expressed in high concentration in several mammalian tissues and particularly in skeletal muscle where it is involved in the modulation of intracellular calcium concentration and ion channel regulation and where it also acts as an antioxidant and anti-inflammatory factor. The aim of this review is to summarize the pleiotropic effects of taurine on specific muscle targets and to discuss its role in regulating signaling pathways involved in the maintenance of muscle homeostasis. We also highlight the potential use of taurine as a therapeutic molecule for the amelioration of skeletal muscle function and performance severely compromised during aging.


The enduring role of the Emergency Medical Treatment and Active Labor Act.
The Emergency Medical Treatment and Active Labor Act (EMTALA) is a seminal law that imposes screening, stabilization, and transfer duties on all Medicare-participating hospitals that have emergency departments. More than twenty-five years after its enactment, EMTALA continues to generate controversy over the scope and depth of its obligations on issues ranging from the nature of the screening obligation and rules regarding on-call specialists to whether EMTALA's stabilization protections exclude emergency inpatients. Despite ongoing questions that flow from its detailed provisions, EMTALA is an enduring testament to society's evolving views that hospitals must provide emergency care not only to their established patients but to the broader communities they serve.


Comparison of biopsy-proven giant cell arteritis in North America and Southern Europe: a population-based study.
To compare clinical characteristics, treatment and prognosis of two population-based cohorts of patients with biopsy-proven giant cell arteritis (GCA) from Olmsted County, Minnesota, USA (Olmsted cohort) and the Reggio Emilia area, Northern Italy (Reggio cohort). All patients residing in Olmsted County and the Reggio Emilia area with a new diagnosis of biopsy-proven GCA in 1986-2007 were retrospectively identified. Patients were followed from GCA diagnosis to death, migration or September 2011. The study included 110 patients in the Olmsted and 144 in the Reggio cohort. Compared with the Olmsted cohort, patients from the Reggio cohort had longer duration of symptoms prior to diagnosis (median 1.4 months vs. 0.7, p<0.001) and were younger (mean 74.6 years vs. 77.8, p=0.002), more likely to have cranial symptoms (93% vs. 86%, p=0.048), permanent vision loss (21% vs. 6%, p=0.001) and systemic symptoms (67% vs. 46%, p=0.001). ESR and CRP were higher (mean 88 mm/h vs. 73, and 89.0 mg/L vs. 35.2, both p<0.001) in the Reggio cohort. Patients from the Olmsted cohort received a higher initial prednisone dose (mean 53.6 mg/day vs. 49.5, p=0.001). There were no differences in relapse rates, cumulative glucocorticoid (GC) dosages at 1, 2 and 5 years, and time to first GC discontinuation. Geographical, genetic and/or environmental factors may contribute to the different clinical features at onset of GCA observed in this study.


New insights in protein phosphorylation: a signature for protein phosphatase 1 interacting proteins.
Protein phosphatase 1 is regulated by the interaction between a catalytic subunit (PP1c) and multiple interacting proteins that allow the specific dephosphorylation of diverse cellular targets. This communication proposes to use the simultaneous presence of distinct consensus PP1c docking motifs R/K-x(0,1)-V-x-F and F-x-x-R/K-x-R/K as a signature to identify proteins putatively interacting with the PP1c. To develop this concept, we propose a new website, http://pp1 signature.pasteur.fr, which allows the identification of putative PP1-interacting proteins containing the two distinct PP1c docking consensus motifs represented in the Swissprot library. To validate the new concept of signature, we were able to characterise, by co-immunoprecipitation, four new PP1c interacting proteins randomly selected from the database in our website.


The oesophageal string test: a novel, minimally invasive method measures mucosal inflammation in eosinophilic oesophagitis.
Eosinophil predominant inflammation characterises histological features of eosinophilic oesophagitis (EoE). Endoscopy with biopsy is currently the only method to assess oesophageal mucosal inflammation in EoE. We hypothesised that measurements of luminal eosinophil-derived proteins would correlate with oesophageal mucosal inflammation in children with EoE. The Enterotest diagnostic device was used to develop an oesophageal string test (EST) as a minimally invasive clinical device. EST samples and oesophageal mucosal biopsies were obtained from children undergoing upper endoscopy for clinically defined indications. Eosinophil-derived proteins including eosinophil secondary granule proteins (major basic protein-1, eosinophil-derived neurotoxin, eosinophil cationic protein, eosinophil peroxidase) and Charcot-Leyden crystal protein/galectin-10 were measured by ELISA in luminal effluents eluted from ESTs and extracts of mucosal biopsies. ESTs were performed in 41 children with active EoE (n=14), EoE in remission (n=8), gastro-oesophageal reflux disease (n=4) and controls with normal oesophagus (n=15). EST measurement of eosinophil-derived protein biomarkers significantly distinguished between children with active EoE, treated EoE in remission, gastro-oesophageal reflux disease and normal oesophagus. Levels of luminal eosinophil-derived proteins in EST samples significantly correlated with peak and mean oesophageal eosinophils/high power field (HPF), eosinophil peroxidase indices and levels of the same eosinophil-derived proteins in extracts of oesophageal biopsies. The presence of eosinophil-derived proteins in luminal secretions is reflective of mucosal inflammation in children with EoE. The EST is a novel, minimally invasive device for measuring oesophageal eosinophilic inflammation in children with EoE.


The carotid intima media thickness: a predictor of the clincal coronary events.
The Carotid Intima-Media Thickness (CIMT) is a simple and an inexpensive tool which can be used to assess the cumulative effect of atherosclerotic risk factors and it is also an independent predictor of the future cardiovascular risk. Nevertheless, criticism has been raised throughout the scientific community, based on the observations which indicated a weak correlation between CIMT and coronary atherosclerosis. It has been suggested by the International Atherosclerosis Project, that the atherosclerotic process occurs at the same time in the carotid, cerebral and the coronary arteries. Measurement of the Carotid Intima-Media Thickness (CIMT) of the Common Carotid Artery (CCA) by B-mode ultrasound was found to be a suitable non-invasive method, to visualize the arterial walls and to monitor the early stages of the atherosclerotic process. This study sought to determine the usefulness of B-mode ultrasound as a non-invasive marker to examine the association between CIMT and the extent and the severity of coronary artery disease and its association with the cardiovascular risk factors, if any. A cross-sectional study was done among hundred cases and hundred age and sex matched controls who were in the age group of 30-65 years. The cases included those who had undergone coronary angiography. The controls included non-diabetic non-hypertensives with no cardiovascular risk factors. The CIMT was assessed by using a 7MHz linear array transducer. Fasting blood samples were collected for measuring the blood sugar and the lipid profiles. The statistical analysis was done by using the Student's t test and ANOVA and a p value of <0.001 was considered to be significant. The Average Carotid Intima Media Thickness (AVCIMT) was higher in the cases (0.90 vs 0.47 in controls, p<0.001, very highly significant). The AVCIMT was found to be higher in those with triple vessel disease (1.00mm) <double vessel disease (0.91mm) <single vessel disease (0.82mm) <normal coronaries (0.65mm). The easy applicability and the non invasive nature of B-mode ultrasonography make it suitable for use as a surrogate endpoint for measuring the atherosclerotic burden in people with cardiovascular risk factors. Even in this present study, we found a significant association between the extent of carotid atherosclerosis which was measured by B-mode ultrasound, and the presence, its extent, or the lack of coronary atherosclerosis which was documented by coronary angiography.


Zingiber officinale Roscoe ameliorates anticancer antibiotic doxorubicin-induced acute cardiotoxicity in rat.
Oxidative stress (OS) has been suggested in the cardiotoxicity induced by anticancer antibiotic doxorubicin (DXN). The cardioprotective effects of aqueous ethanol extract of Zingiber officinale was evaluated against DXN-induced acute cardiac damage in rat. The results of the study demonstrated that Z. officinale significantly and dose dependently protected the cardiotoxicity induced by DXN. The activities of serum glutamate oxaloacetate transaminase and serum lactate dehydrogenase activity in the DXN alone treated group of animals were significantly (p<0.01) elevated when compared to normal animals. The activities were reduced in the Z. officinale (200 and 400 mg/kg, p.o) plus DXN treated groups. The cardiac malondialdehyde was elevated in the DXN alone treated group and declined significantly in the Z. officinale (400 mg/kg) plus DXN treated group. The results concluded that aqueous ethanol extract of Z. officinale ameliorated DXN-induced cardiotoxicity. The protection can be ascribed to the free radical scavenging activity of Z. officinale. This protective effect may suggest the adjuvant role of Z. officinale against OS induced by cancer chemotherapeutants, which warrant further research.


Intraspecific phylogenetic congruence among multiple symbiont genomes.
Eukaryotes often form intimate endosymbioses with prokaryotic organisms. Cases in which these symbionts are transmitted cytoplasmically to host progeny create the potential for co-speciation or congruent evolution among the distinct genomes of these partners. If symbionts do not move horizontally between different eukaryotic hosts, strict phylogenetic congruence of their genomes is predicted and should extend to relationships within a single host species. Conversely, even rare 'host shifts' among closely related lineages should yield conflicting tree topologies at the intraspecific level. Here, we investigate the historical associations among four symbiotic genomes residing within an aphid host: the mitochondrial DNA of Uroleucon ambrosiae aphids, the bacterial chromosome of their Buchnera bacterial endosymbionts, and two plasmids associated with Buchnera. DNA sequence polymorphisms provided a significant phylogenetic signal and no homoplasy for each data set, yielding completely and significantly congruent phylogenies for these four genomes and no evidence of horizontal transmission. This study thus provides the first evidence for strictly vertical transmission and 'co-speciation' of symbiotic organisms at the intraspecific level, and represents the lowest phylogenetic level at which such coevolution has been demonstrated. These results may reflect the obligate nature of this intimate mutualism and indicate opportunities for adaptive coevolution among linked symbiont genomes.


Especial skill effect across age and performance level: the nature and degree of generalization.
It has been claimed that an especial skill emerges after massive amounts of basketball practice. Despite this no direct evidence is available to support this claim. The authors aimed to shed light on this question. Thirty-seven male basketball players took part representing four groups: 2 groups of senior players, a cadet group, and a group of juniors. Players performed free throw shots from 7 distances including shots from the free throw line (15 ft). It was shown that an especial skill was present in senior players, but not in junior players who had only 3 years of playing experience. The authors present a descriptive model of especial skill and express it using the formalism of a hierarchical Bayesian model to fit the data and estimate the parameters. This model can account not only for the results, which indicate the presence and a substantial degree of generalizability of especial skill to nearby distances, but also for results of the original study on especial skill where it was proposed that specificity in practice leads to the emergence of the especial skill.


Phylogeography of the green turtle, Chelonia mydas, in the Southwest Indian Ocean.
Patterns of mitochondrial DNA (mtDNA) variation were used to analyse the population genetic structure of southwestern Indian Ocean green turtle (Chelonia mydas) populations. Analysis of sequence variation over 396 bp of the mtDNA control region revealed seven haplotypes among 288 individuals from 10 nesting sites in the Southwest Indian Ocean. This is the first time that Atlantic Ocean haplotypes have been recorded among any Indo-Pacific nesting populations. Previous studies indicated that the Cape of Good Hope was a major biogeographical barrier between the Atlantic and Indian Oceans because evidence for gene flow in the last 1.5 million years has yet to emerge. This study, by sampling localities adjacent to this barrier, demonstrates that recent gene flow has occurred from the Atlantic Ocean into the Indian Ocean via the Cape of Good Hope. We also found compelling genetic evidence that green turtles nesting at the rookeries of the South Mozambique Channel (SMC) and those nesting in the North Mozambique Channel (NMC) belong to separate genetic stocks. Furthermore, the SMC could be subdivided in two different genetic stocks, one in Europa and the other one in Juan de Nova. We suggest that this particular genetic pattern along the Mozambique Channel is attributable to a recent colonization from the Atlantic Ocean and is maintained by oceanic conditions in the northern and southern Mozambique Channel that influence early stages in the green turtle life cycle.


TopoMap: A 0-dimensional Homology Preserving Projection of High-Dimensional Data.
Multidimensional Projection is a fundamental tool for high-dimensional data analytics and visualization. With very few exceptions, projection techniques are designed to map data from a high-dimensional space to a visual space so as to preserve some dissimilarity (similarity) measure, such as the Euclidean distance for example. In fact, although adopting distinct mathematical formulations designed to favor different aspects of the data, most multidimensional projection methods strive to preserve dissimilarity measures that encapsulate geometric properties such as distances or the proximity relation between data objects. However, geometric relations are not the only interesting property to be preserved in a projection. For instance, the analysis of particular structures such as clusters and outliers could be more reliably performed if the mapping process gives some guarantee as to topological invariants such as connected components and loops. This paper introduces TopoMap, a novel projection technique which provides topological guarantees during the mapping process. In particular, the proposed method performs the mapping from a high-dimensional space to a visual space, while preserving the 0-dimensional persistence diagram of the Rips filtration of the high-dimensional data, ensuring that the filtrations generate the same connected components when applied to the original as well as projected data. The presented case studies show that the topological guarantee provided by TopoMap not only brings confidence to the visual analytic process but also can be used to assist in the assessment of other projection methods.


Activation of downstream epidermal growth factor receptor (EGFR) signaling provides gefitinib-resistance in cells carrying EGFR mutation.
Patients with pulmonary adenocarcinoma carrying the epidermal growth factor receptor (EGFR) mutation tend to display dramatic clinical response to treatment with the EGFR tyrosine kinase inhibitor gefitinib. Unfortunately, in many cases the cancer cells eventually acquire resistance, and this limits the duration of efficacy. To gain insight into these acquired resistance mechanisms, we first prepared HEK293T cell line stably transfected with either wild-type (WT) or mutant (L858R) EGFR, and then expressed oncogenic K-Ras12V mutant in the latter transfectant. Although 293T cells expressing wild-type EGFR did not show any growth inhibition by gefitinib treatment similarly to the non-transfected cells, the cells expressing the EGFR-L858R were exquisitely sensitive. Consistently, phospho-Akt levels were decreased in response to gefitinib in cells expressing EGFR-L858R but not in cells with EGFR-WT. In contrast, 293T cells expressing both EGFR-L858R and oncogenic K-Ras were able to proliferate even in the presence of high concentration of gefitinib probably by inducing Erk1/2 activation. We also expressed K-Ras12V in the gefitinib-sensitive pulmonary adenocarcinoma cell line PC-9, which harbors an in-frame deletion in the EGFR gene. The activated K-Ras inhibited the effects of gefitinib treatment on cell growth, cell death induction and levels of phospho-Akt, as well as phospho-Erk. These data indicate that activated Ras could substitute most of the upstream EGFR signal, and are consistent with the hypothesis that mutational activation of targets immediately downstream from the EGFR could induce the secondary resistance to gefitinib in patients with lung cancer carrying EGFR mutation.


Polatuzumab Vedotin for the Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Transplant-Ineligible Patients.
Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma. Although 5-year survival rates in the first-line setting can range from 60% to 70%, up to 50% of patients become refractory or relapse after treatment (Crump et al., 2017). The standard treatment for relapsed/refractory diffuse large B-cell lymphoma is salvage chemotherapy followed by autologous stem cell transplant. Nonetheless, over 60% of patients are transplant ineligible, and there is currently no standard treatment option for these patients (Sarkozy & Sehn, 2018). Age, comorbidities, performance status, and disease deemed not responsive to chemotherapy conditioning are various factors potentially disqualifying patients for transplant. There is a strong demand for novel therapies. Polatuzumab vedotin, a targeted immunotherapy, was approved in 2019 by the U.S. Food & Drug Administration for the treatment of relapsed/refractory diffuse large B-cell lymphoma and is recommended by the National Comprehensive Cancer Network for patients who are transplant ineligible. This article reviews the pharmacology of polatuzumab vedotin, along with its performance in clinical trials, financial considerations, and management of adverse effects.