Algorithmic Stability and Generalization of an Unsupervised Feature Selection Algorithm.
Feature selection, as a vital dimension reduction technique, reduces data dimension by identifying an essential subset of input features, which can facilitate interpretable insights into learning and inference processes. Algorithmic stability is a key characteristic of an algorithm regarding its sensitivity to perturbations of input samples. In this paper, we propose an innovative unsupervised feature selection algorithm attaining this stability with provable guarantees. The architecture of our algorithm consists of a feature scorer and a feature selector. The scorer trains a neural network (NN) to globally score all the features, and the selector adopts a dependent sub-NN to locally evaluate the representation abilities for selecting features. Further, we present algorithmic stability analysis and show that our algorithm has a performance guarantee via a generalization error bound. Extensive experimental results on real-world datasets demonstrate superior generalization performance of our proposed algorithm to strong baseline methods. Also, the properties revealed by our theoretical analysis and the stability of our algorithm-selected features are empirically confirmed.


Holistic face training enhances face processing in developmental prosopagnosia.
Prosopagnosia has largely been regarded as an untreatable disorder. However, recent case studies using cognitive training have shown that it is possible to enhance face recognition abilities in individuals with developmental prosopagnosia. Our goal was to determine if this approach could be effective in a larger population of developmental prosopagnosics. We trained 24 developmental prosopagnosics using a 3-week online face-training program targeting holistic face processing. Twelve subjects with developmental prosopagnosia were assessed before and after training, and the other 12 were assessed before and after a waiting period, they then performed the training, and were then assessed again. The assessments included measures of front-view face discrimination, face discrimination with view-point changes, measures of holistic face processing, and a 5-day diary to quantify potential real-world improvements. Compared with the waiting period, developmental prosopagnosics showed moderate but significant overall training-related improvements on measures of front-view face discrimination. Those who reached the more difficult levels of training ('better' trainees) showed the strongest improvements in front-view face discrimination and showed significantly increased holistic face processing to the point of being similar to that of unimpaired control subjects. Despite challenges in characterizing developmental prosopagnosics' everyday face recognition and potential biases in self-report, results also showed modest but consistent self-reported diary improvements. In summary, we demonstrate that by using cognitive training that targets holistic processing, it is possible to enhance face perception across a group of developmental prosopagnosics and further suggest that those who improved the most on the training task received the greatest benefits.


Repair protein persistence at DNA lesions characterizes XPF defect with Cockayne syndrome features.
The structure-specific ERCC1-XPF endonuclease plays a key role in DNA damage excision by nucleotide excision repair (NER) and interstrand crosslink repair. Mutations in this complex can either cause xeroderma pigmentosum (XP) or XP combined with Cockayne syndrome (XPCS-complex) or Fanconi anemia. However, most patients carry compound heterozygous mutations, which confounds the dissection of the phenotypic consequences for each of the identified XPF alleles. Here, we analyzed the functional impact of individual pathogenic XPF alleles on NER. We show that XP-causing mutations diminish XPF recruitment to DNA damage and only mildly affect global genome NER. In contrast, an XPCS-complex-specific mutation causes persistent recruitment of XPF and the upstream core NER machinery to DNA damage and severely impairs both global genome and transcription-coupled NER. Remarkably, persistence of NER factors at DNA damage appears to be a common feature of XPCS-complex cells, suggesting that this could be a determining factor contributing to the development of additional developmental and/or neurodegenerative features in XP patients.


Elucidating the chemical structure of native 1-deoxysphingosine.
The 1-deoxysphingolipids (1-deoxySLs) are formed by an alternate substrate usage of the enzyme, serine-palmitoyltransferase, and are devoid of the C1-OH-group present in canonical sphingolipids. Pathologically elevated 1-deoxySL levels are associated with the rare inherited neuropathy, HSAN1, and diabetes type 2 and might contribute to β cell failure and the diabetic sensory neuropathy. In analogy to canonical sphingolipids, it was assumed that 1-deoxySLs also bear a (4E) double bond, which is normally introduced by sphingolipid delta(4)-desaturase 1. This, however, was never confirmed. We therefore supplemented HEK293 cells with isotope-labeled D3-1-deoxysphinganine and compared the downstream formed D3-1-deoxysphingosine (1-deoxySO) to a commercial synthetic SPH m18:1(4E)(3OH) standard. Both compounds showed the same m/z, but differed in their RPLC retention time and atmospheric pressure chemical ionization in-source fragmentation, suggesting that the two compounds are structural isomers. Using dimethyl disulfide derivatization followed by MS(2) as well as differential-mobility spectrometry combined with ozone-induced dissociation MS, we identified the carbon-carbon double bond in native 1-deoxySO to be located at the (Δ14) position. Comparing the chromatographic behavior of native 1-deoxySO to chemically synthesized SPH m18:1(14Z) and (14E) stereoisomers assigned the native compound to be SPH m18:1(14Z). This indicates that 1-deoxySLs are metabolized differently than canonical sphingolipids.


STRICT POSTURING WITH OR WITHOUT BILATERAL PATCHING FOR POSTERIOR VITREOUS DETACHMENT-RELATED VITREOUS HEMORRHAGE.
To determine whether bilateral patching with posturing is superior to posturing alone in visualizing the superior retina in suspected posterior vitreous detachment (PVD)-related vitreous hemorrhage (VH). Prospective randomized controlled trial: 80 patients with fundus-obscuring VH due to suspected retinal tear were randomized to strict posturing and bilateral patching overnight (Treatment A, 40 patients) or posturing (Treatment B, 40 patients). Visualization of ≥4 clock hours superior retina. laser treatment, vitrectomy rate, and retinal detachment within 12 months. Intention-to-treat analysis: In 38/40 (95%) with Treatment A and 32/40 (80%) with Treatment B, the confirmed diagnosis was PVD-related VH. Visibility of the superior retina for all patients: 29/40 (73%) after Treatment A and 21/40 (53%) after Treatment B (P = 0.07). Subgroup analysis for confirmed PVD-related VH; visibility of the superior retina: 29/38 (76%) after Treatment A and 15/32 (47%) after Treatment B (P = 0.01). In subgroup analysis, vitrectomy rate within 12 months was 61% (Treatment A) and 53% (Treatment B) (P = 0.63). Retinal detachment: eight patients after each treatment. In patients with suspected PVD-related VH, overnight bilateral patching was not superior to posturing alone in superior retina visualization, but in a post-hoc analysis of patients with confirmed PVD-related VH, bilateral patching was superior.


Associations between urinary soy isoflavonoids and two inflammatory markers in adults in the United States in 2005-2008.
The aim of this study was to determine the association between urinary isoflavonoid (genistein, daidzein, and the daidzein metabolites O-desmethylangolensin (O-DMA) and equol) excretion and markers of inflammation in adults in the United States in National Health and Nutrition Examination Survey (NHANES) 2005-2008. The NHANES is a cross-sectional study conducted by the National Center for Health Statistics to study the health and nutritional status of people living in the United States. The analysis included 1,683 participants from study years 2005-2008 for whom urinary isoflavonoids were measured and who met inclusion criteria. Urinary isoflavonoids were measured by HPLC-APPI-MS/MS. Serum C-reactive protein (CRP) was measured by latex-based nephelometry. White blood cell (WBC) count was measured by Coulter counting. Multivariable linear regression was used to calculate the geometric mean values of the markers, and multivariable logistic regression was used to estimate the odds of high CRP (≥3 mg/L) and of high WBC count (≥7,900/μL) by quartile of urinary isoflavonoid (nmol/mg creatinine). The highest quartile of genistein (OR = 0.62; 95 % CI 0.39-0.99) was associated with significantly decreased odds of high CRP compared with the lowest quartile. The sum of daidzein and its metabolites was significantly inversely associated with serum CRP concentration (p-trend = 0.017). Equol was inversely associated with WBC count (p-trend < 0.0001). O-DMA was the only isoflavonoid whose excretion was significantly associated with a decrease in both CRP (p-trend = 0.024) and WBC count (p-trend < 0.0001). Though no clear pattern emerged, higher excretion of certain soy isoflavonoids was associated with decreased CRP concentration and WBC counts, suggesting a possible inverse association between soy intake and inflammation.


Brain microRNAs among social and solitary bees.
Evolutionary transitions to a social lifestyle in insects are associated with lineage-specific changes in gene expression, but the key nodes that drive these regulatory changes are unknown. We examined the relationship between social organization and lineage-specific microRNAs (miRNAs). Genome scans across 12 bee species showed that miRNA copy-number is mostly conserved and not associated with sociality. However, deep sequencing of small RNAs in six bee species revealed a substantial proportion (20-35%) of detected miRNAs had lineage-specific expression in the brain, 24-72% of which did not have homologues in other species. Lineage-specific miRNAs disproportionately target lineage-specific genes, and have lower expression levels than shared miRNAs. The predicted targets of lineage-specific miRNAs are not enriched for genes with caste-biased expression or genes under positive selection in social species. Together, these results suggest that novel miRNAs may coevolve with novel genes, and thus contribute to lineage-specific patterns of evolution in bees, but do not appear to have significant influence on social evolution. Our analyses also support the hypothesis that many new miRNAs are purged by selection due to deleterious effects on mRNA targets, and suggest genome structure is not as influential in regulating bee miRNA evolution as has been shown for mammalian miRNAs.


The Impact of Foster Care and Temporary Assistance for Needy Families (TANF) on Women's Drug Treatment Outcomes.
This study assesses the impact of having a child in foster care and receiving cash benefits through Temporary Assistance for Needy Families (TANF) on women's completion of a residential drug treatment program. The study's hypothesis was that drug treatment completion rates for women who had children in foster care and/or who were receiving TANF would differ from women who did not receive these services. The sample included 117 women age 19 to 54, in a Midwestern state. Findings suggest that women with a child or children in foster care were less likely to complete treatment. Women receiving cash benefits were also somewhat less likely to complete treatment than women not receiving these services. Women with children in foster care had similar levels of psychological, employment, and drug and alcohol concerns as other women, as measured by the Addiction Severity Index. Future research should focus on identifying strategies that enhance retention rates of these vulnerable women. Implications for improving treatment retention are discussed in light of the Adoption and Safe Families Act of 1997 and the Personal Responsibility and Work Opportunity Reconciliation Act of 1996.


Aerobic and anaerobic metabolism for the zebrafish, Danio rerio, reared under normoxic and hypoxic conditions and exposed to acute hypoxia during development.
In order to verify the influence of chronic and acute ambient oxygen levels from egg to adult stage of the zebrafish, in vivo oxygen consumption (MO2), critical tensions of oxygen (Pcrit), heart rate (fH) and total body lactate concentration (Lc) were determined for Danio rerio (Hamilton, 1822) raised at 28 degrees C under normoxic (7.5 mgO2.L-1 or 80 mm.Hg-1) and hypoxic conditions (4.3 mgO2.L-1) and exposed to acute hypoxia during different developmental stages. Our findings confirmed that very early stages do not respond effectively to ambient acute hypoxia. However, after the stage corresponding to the age of 30 days, D. rerio was able to respond to acute hypoxia through effective physiological mechanisms involving aerobic and anaerobic metabolism. Such responses were more efficient for the fishes reared under hypoxia which showed that D. rerio survival capability increased during acclimation to mild hypoxia. Measurements of body mass and length showed that moderate hypoxia did not affect growth significantly until the fish reached the stage of 60 days. Moreover, a growth delay was verified for the hypoxic-reared animals. Also, the D. rerio eggs-to-larvae survival varied from 87.7 to 62.4% in animals reared under normoxia and mild hypoxia, respectively. However, the surviving animals raised under moderated hypoxia showed a better aptitude to regulate aerobic and anaerobic capacities when exposed to acute hypoxia.


Label-free detection of microarrays of biomolecules by oblique-incidence reflectivity difference microscopy.
We developed an oblique-incidence reflectivity difference (OI-RD) scanning microscope for label-free imaging of microarrays of biomolecules upon solid substrates. We demonstrate that hybridization reactions in an oligonucleotide microarray fabricated upon a glass slide can be detected by such an OI-RD microscope.


Thyroidectomy and parathyroidectomy in the dog and cat.
Thyroidectomy has become a fairly common surgical procedure in small animals because of the increasing incidence of thyroid tumors. Surgical removal of the thyroid gland can be routine or quite challenging, depending on the species (cat vs. dog) and the size and aggressiveness of the tumor. Many problems may be encountered with these patients, associated both with the disease and with the surgical treatment. Both thyroid and parathyroid tumors result in many alterations in the animal's homeostasis. These alterations must be recognized by the surgeon to maximize the chance of a successful outcome. This chapter deals with thyroidectomy and parathyroidectomy in dogs and cats. Indications for surgery, pathophysiology of thyroid and parathyroid neoplasia, preoperative care, surgical procedures, and postoperative care and complications will be discussed.


Adverse Pregnancy Outcomes Associated With Gestational Exposure to Antiepileptic Drugs.
Major congenital malformation risks in association with gestational exposure to antiepileptic drugs (AEDs) have been extensively studied. Less information is available on other adverse outcomes associated with the use of these drugs during pregnancy. This article critically examines the risk of fetal loss, intrauterine growth retardation (IUGR), and preterm birth following gestational exposure to 14 AEDs, based on information obtained from a recent network meta-analysis of mostly nonrandomized, observational studies. The AEDs studied were carbamazepine, clobazam, clonazepam, ethosuximide, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbitone, phenytoin, primidone, topiramate, valproate, and vigabatrin. The results show that very few AEDs are significantly associated with each adverse outcome and that the implicated AEDs are different for different outcomes. Furthermore, when one discounts findings obtained in small sample analyses, almost no significant associations remain. Next, even these associations become questionable when one considers that they could have been due to confounding by indication. Finally, the few significant associations may have been false-positive findings because they were identified after performing a very large number of statistical tests. These caveats notwithstanding, guidance should err on the side of caution. Therefore, a conservative conclusion is that whereas analyses based on exposures in 2,000-4,000 pregnancies suggest that lamotrigine and carbamazepine are not associated with an increased risk of fetal loss, IUGR, and preterm birth, there is insufficient evidence to either firmly indict or firmly exonerate the other AEDs with regard to these outcomes.


Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: A prospective cohort study.
In high-burden settings, case fatality rates are reported to be between 11% and 32% in hospitalized patients with HIV-associated tuberculosis, yet the underlying causes of mortality remain poorly characterized. Understanding causes of mortality could inform the development of novel management strategies to improve survival. We aimed to assess clinical and microbiologic determinants of mortality and to characterize the pathophysiological processes underlying death by evaluating host soluble inflammatory mediators and determined the relationship between these mediators and death as well as biomarkers of disseminated tuberculosis. Adult patients with HIV hospitalized with a new diagnosis of HIV-associated tuberculosis were enrolled in Cape Town between 2014 and 2016. Detailed tuberculosis diagnostic testing was performed. Biomarkers of tuberculosis dissemination and host soluble inflammatory mediators at baseline were assessed. Of 682 enrolled participants, 576 with tuberculosis (487/576, 84.5% microbiologically confirmed) were included in analyses. The median age was 37 years (IQR = 31-43), 51.2% were female, and the patients had advanced HIV with a median cluster of differentiation 4 (CD4) count of 58 cells/L (IQR = 21-120) and a median HIV viral load of 5.1 log10 copies/mL (IQR = 3.3-5.7). Antituberculosis therapy was initiated in 566/576 (98.3%) and 487/576 (84.5%) started therapy within 48 hours of enrolment. Twelve-week mortality was 124/576 (21.5%), with 46/124 (37.1%) deaths occurring within 7 days of enrolment. Clinical and microbiologic determinants of mortality included disseminated tuberculosis (positive urine lipoarabinomannan [LAM], urine Xpert MTB/RIF, or tuberculosis blood culture in 79.6% of deaths versus 60.7% of survivors, p = 0.001), sepsis syndrome (high lactate in 50.8% of deaths versus 28.9% of survivors, p < 0.001), and rifampicin-resistant tuberculosis (16.9% of deaths versus 7.2% of survivors, p = 0.002). Using non-supervised two-way hierarchical cluster and principal components analyses, we describe an immune profile dominated by mediators of the innate immune system and chemotactic signaling (interleukin-1 receptor antagonist [IL-1Ra], IL-6, IL-8, macrophage inflammatory protein-1 beta [MIP-1β]/C-C motif chemokine ligand 4 [CCL4], interferon gamma-induced protein-10 [IP-10]/C-X-C motif chemokine ligand 10 [CXCL10], MIP-1 alpha [MIP-1α]/CCL3), which segregated participants who died from those who survived. This immune profile was associated with mortality in a Cox proportional hazards model (adjusted hazard ratio [aHR] = 2.2, 95%CI = 1.9-2.7, p < 0.001) and with detection of biomarkers of disseminated tuberculosis. Clinicians attributing causes of death identified tuberculosis as a cause or one of the major causes of death in 89.5% of cases. We did not perform longitudinal sampling and did not have autopsy-confirmed causes of death. In this study, we did not identify a major contribution from coinfections to these deaths. Disseminated tuberculosis, sepsis syndrome, and rifampicin resistance were associated with mortality. An immune profile dominated by mediators of the innate immune system and chemotactic signaling was associated with both tuberculosis dissemination and mortality. These findings provide pathophysiologic insights into underlying causes of mortality and could be used to inform the development of novel treatment strategies and to develop methods to risk stratify patients to appropriately target novel interventions. Causal relationships cannot be established from this study.


Pressure tuning the Fermi level through the Dirac point of giant Rashba semiconductor BiTeI.
We report measurements of Shubnikov-de Haas oscillations in the giant Rashba semiconductor BiTeI under applied pressures up to ∼2 GPa. We observe one high frequency oscillation at all pressures and one low frequency oscillation that emerges between ∼0.3-0.7 GPa indicating the appearance of a second small Fermi surface. BiTeI has a conduction band bottom that is split into two sub-bands due to the strong Rashba coupling, resulting in a 'Dirac point'. Our results suggest that the chemical potential starts below the Dirac point in the conduction band at ambient pressure and moves upward, crossing it as pressure is increased. The presence of the chemical potential above this Dirac point results in two Fermi surfaces. We present a simple model that captures this effect and can be used to understand the pressure dependence of our sample parameters. These extracted parameters are in quantitative agreement with first-principles calculations and other experiments. The parameters extracted via our model support the notion that pressure brings the system closer to the predicted topological quantum phase transition.


An evaluation of the RapidHIT(®) system for reliably genotyping reference samples.
Short tandem repeat (STR) typing is used routinely for associating or excluding individuals with biological evidence left at a crime scene. Improvements have been made to reduce the turnaround time and labor involved with profile generation, but there is still some lag time between sample collection and interpretation of results. The RapidHIT(®) (IntegenX; Pleasanton, CA, USA) system is an automated instrument that is configured to perform DNA extraction, bead-based DNA normalization, amplification, electrophoresis of PCR amplicons, and data analysis of five reference swabs simultaneously. The RapidHIT system provided reliable STR profiles from reference buccal swabs in approximately 90min with nominal "hands-on" sample loading time with no evidence of contamination between samples. The overall success rate of typing buccal swabs was comparable to standard typing systems. In the event of a failed run due to instrument failure, the swab can be removed from the cartridge and reanalyzed in the RapidHIT system or with standard STR genotyping workflows.


Bicycle helmets.
Bicycling remains one of the most popular recreational sports among children in America and is the leading cause of recreational sports injuries treated in emergency departments. An estimated 23 000 children younger than 21 years sustained head injuries (excluding the face) while bicycling in 1998. The bicycle helmet is a very effective device that can prevent the occurrence of up to 88% of serious brain injuries. Despite this, most children do not wear a helmet each time they ride a bicycle, and adolescents are particularly resistant to helmet use. Recently, a group of national experts and government agencies renewed the call for all bicyclists to wear helmets. This policy statement describes the role of the pediatrician in helping attain universal helmet use among children and teens for each bicycle ride.


Nucleotide excision repair syndromes: molecular basis and clinical symptoms.
The phenotypic consequences of a nucleotide excision repair (NER) defect in man are apparent from three distinct inborn diseases characterized by hypersensitivity of the skin to ultraviolet light and a remarkable clinical and genetic heterogeneity. These are the prototype repair syndrome, xeroderma pigmentosum (XP) (seven genetic complementation groups, designated XP-A to XP-G), Cockayne's syndrome (two groups: CS-A and CS-B) and PIBIDS, a peculiar photosensitive form of the brittle hair disease trichothiodystrophy (TTD, at least two groups of which one equivalent to XP-D). To investigate the mechanism of NER and to resolve the molecular defect in these NER deficiency diseases we have focused on the cloning and characterization of human DNA repair genes. One of the genes that we cloned is ERCC3. It specifies a chromatin binding helicase. Transfection and microinjection experiments demonstrated that mutations in ERCC3 are responsible for XP complementation group B, a very rare form of XP that is simultaneously associated with Cockayne's syndrome (CS). The ERCC3 protein was found to be part of a multiprotein complex (TFIIH) required for transcription initiation of most structural genes and for NER. This defines the additional, hitherto unknown vital function of the gene. This ERCC3 gene and several other NER genes involved in transcription initiation will be discussed.


Human Serum Modifies Aggregation Properties of Commonly Used Epidural Steroids.
Case reports of catastrophic neurological sequelae during ESIs have questioned the safety of this procedure. A proposed mechanism is particulate steroid embolization resulting in neuralischemia. Previous reports have described steroid clumping in common epidural injection mixtures. We demonstrate that physiologic medium can also modify aggregation. To inspect and compare aggregative properties of steroid preparations with and without human serum. Academic tertiary care center. Particulate steroids display different aggregation characteristics in serum compared to non-physiologic solutions. Solutions were inspected under light microscopy: betamethasone sodium phosphate/betamethasone acetate, methylprednisolone, and dexamethasone were each mixed in lidocaine 1%, bupivacaine 0.5%, or sterile water in a 1:1 ratio. All preparations were inspected under light microscopy with 100x and 400x magnifications by a pathologist blinded to our expectations and hypothesis. Five random viewing fields were selected within each slide and the number of aggregates per field and the number of particles per aggregate was evaluated. The addition of serum had a significant effect on steroid particle aggregation and number of particles per aggregate. This study was limited by sample size as only 2 sets of human serum samples were tested with each preparation against one non-serum control. Additionally, as steroid preparations were evaluated under light microscopy, the ex vivo setting must be considered in the interpretation of results. Finally, mixing preparations with human serum as opposed to whole blood was necessary to allow for improved visibility on light microscopy despite the fact that whole blood may be necessary to more closely emulate in vivo coagulation setting. Overall, the presence of serum resulted in fewer large steroid particle aggregates when compared to non-serum control samples. Amongst particulate steroids, betamethasone with bupivacaine 0.5% demonstrated the fewest and smallest particle aggregates, suggesting that preparation may reduce the risk of embolic infarction. Methylprednisolone formed significantly larger particles in bupivicaine 0.5% with serum compared to non-serum controls.


Single-layer MoS2 formation by sulfidation of molybdenum oxides in different oxidation states on Au(111).
The sulfidation of a MoO3 precursor into MoS2 is an important step in the preparation of catalysts for the hydrodesulfurization process that is widely utilized in oil refineries. Molybdenum oxides are also the most commonly used precursors for MoS2 growth in, e.g., the synthesis of novel two-dimensional materials. In the present study, we investigate the transformation of MoOx into MoS2 on a model Au(111) surface through sulfidation in H2S gas atmosphere using in situ scanning tunneling microscopy and X-ray photoemission spectroscopy. We find that progressive annealing steps of physical vapor deposited MoO3 powder allow us to control the stoichiometry and oxidation state of the precursor oxide. Subsequently, we investigate the sulfidation of the compounds ranging from pure low-oxygen Mo to fully oxidized MoO3 oxide sulfidation using two different methods. We find that the prerequisite for the efficient formation of MoS2 is that Mo stays in the highest Mo6+ state before sulfidation, whereas the presence of the reduced MoOx phase impedes the MoS2 growth. We also find that it is more efficient to form MoS2 by post-sulfidation of MoOx rather than its reactive deposition in H2S gas, which leads to rather stable amorphous oxysulfide phases.


Assessing the potential risk of Zika virus epidemics in temperate areas with established Aedes albopictus populations.
Based on 2015 abundance of Aedes albopictus in nine northern Italian municipalities with temperate continental/oceanic climate, we estimated the basic reproductive number R0 for Zika virus (ZIKV) to be systematically below the epidemic threshold in most scenarios. Results were sensitive to the value of the probability of mosquito infection after biting a viraemic host. Therefore, further studies are required to improve models and predictions, namely evaluating vector competence and potential non-vector transmissions.


Experiencing External Workplace Violence: Differences in Indicators Between Three Types of Emergency Responders.
Police officers, firefighters, and emergency medical workers are at a relatively high risk of experiencing external workplace violence (EWPV), that is, violence initiated by people outside the organization. Based on criminal opportunities theories, the aim of this research was to study to what extent socio-demographic and work characteristics are related to experiencing EWPV. In addition, the aim was to explore how these relations differ between the three types of emergency responders. Data from a workplace violence survey of the Ministry of the Interior and Kingdom Relations of the Netherlands was used, from which emergency medical workers ( n = 264), firefighters ( n = 255), and police officers ( n = 296) were selected. Results indicated that police officers experienced most and firefighters experienced least EWPV. Younger professionals and professionals who have more frequent and risky contact experienced more EWPV. The expectations that males and those with less skills or experience to avoid EWPV experience more EWPV were not convincingly supported. The relationships between characteristics and EWPV, and the explanatory power of the models, differed between types of emergency responders. The studied characteristics best explained variations in EWPV of police officers, and therefore prevention of EWPV by addressing these characteristics will be most successful for police officers. The prediction of EWPV should be improved, for example, by studying the relationship with "attractiveness" or "vulnerability" of the possible victim, such as psychological characteristics of professionals. The study showed that research about indicators and prevention of EWPV should be aimed at separate professions.


What if Minkowski had been ageusic? An alternative angle on diabetes.
Despite decades of intensive investigation, the basic pathophysiological mechanisms responsible for the metabolic derangements associated with diabetes mellitus have remained elusive. Explored here is the possibility that traditional concepts in this area might have carried the wrong emphasis. It is suggested that the phenomena of insulin resistance and hyperglycemia might be more readily understood if viewed in the context of underlying abnormalities of lipid metabolism.


Quantifying the electron donating capacities of sulfide and dissolved organic matter in sediment pore waters of wetlands.
Electron donating capacity (EDC) values were determined for a set of pore water samples collected from the sediments of four separate wetlands in the Cottonwood Lakes Study Area in Jamestown, ND by mediated electrochemical analysis, reaction with substituted nitro(so)benzenes, and calculation based on measured organic carbon and sulfide concentrations. The samples were taken from four hydrologically connected and increasingly sulfidic wetlands within the study site. Parallel trends in EDC values related to hydrologic conditions and to in situ reduced sulfur content were observed by all three methodologies. In particular, it was found that sulfide and dissolved organic matter (DOM) are the primary and secondary reductants, respectively, in these systems. The efficacy of these reductants in transforming organic contaminants, however, is largely driven by native pore water reduced sulfur content. Manipulation of the systems demonstrate that while DOM is capable of reducing highly oxidized contaminants or reactive intermediates, this likely only occurs once the reducing capacity of the sulfide is exhausted. Sulfide therefore was the dominant electron donor in the pore water samples.


A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus.
Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.


Antiadhesive properties of Abelmoschus esculentus (Okra) immature fruit extract against Helicobacter pylori adhesion.
Traditional Asian and African medicine use immature okra fruits (Abelmoschus esculentus) as mucilaginous food to combat gastritis. Its effectiveness is due to polysaccharides that inhibit the adhesion of Helicobacter pylori to stomach tissue. The present study investigates the antiadhesive effect in mechanistic detail. A standardized aqueous fresh extract (Okra FE) from immature okra fruits was used for a quantitative in vitro adhesion assay with FITC-labled H. pylori J99, 2 clinical isolates, AGS cells, and fluorescence-activated cell sorting. Bacterial adhesins affected by FE were pinpointed using a dot-blot overlay assay with immobilized Lewis(b), sialyl-Lewis(a), H-1, laminin, and fibronectin. (125)I-radiolabeled Okra FE polymer served for binding studies to different H. pylori strains and interaction experiments with BabA and SabA. Iron nanoparticles with different coatings were used to investigate the influence of the charge-dependence of an interaction on the H. pylori surface. Okra FE dose-dependently (0.2 to 2 mg/mL) inhibited H. pylori binding to AGS cells. FE inhibited the adhesive binding of membrane proteins BabA, SabA, and HpA to its specific ligands. Radiolabeled compounds from FE bound non-specifically to different strains of H. pylori, as well as to BabA/SabA deficient mutants, indicating an interaction with a still-unknown membrane structure in the vicinity of the adhesins. The binding depended on the charge of the inhibitors. Okra FE did not lead to subsequent feedback regulation or increased expression of adhesins or virulence factors. Non-specific interactions between high molecular compounds from okra fruits and the H. pylori surface lead to strong antiadhesive effects.


The dynamics of alkaline phosphatase activity during operculum regeneration in the polychaete Pomatoceros lamarckii.
Alkaline phosphatase enzymes are found throughout the living world and fulfil a variety of functions. They have been linked to regeneration, stem cells and biomineralisation in a range of animals. Here we describe the pattern of alkaline phosphatase activity in a spiralian appendage, the operculum of the serpulid polychaete Pomatoceros lamarckii. The P. lamarckii operculum is reinforced by a calcified opercular plate and is capable of rapid regeneration, making it an ideal model system to study these key processes in annelids. Alkaline phosphatase activity is present in mesodermal tissues of both intact and regenerating opercular filaments, in a strongly regionalised pattern correlated with major morphological features. Based on the lack of epidermal activity and the broad distribution of staining in mesodermal tissues, calcification- or stem cell-specific roles are unlikely. Transcriptomic data reveal that at least four distinct genes contribute to the detected activity. Opercular alkaline phosphatase activity is sensitive to levamisole. Phylogenetic analysis of metazoan alkaline phosphatases indicates homology of the P. lamarckii sequences to other annelid alkaline phosphatases, and shows that metazoan alkaline phosphatase evolution was characterised by extensive lineage-specific duplications.


Reanalysis of the German PISA Data: A Comparison of Different Approaches for Trend Estimation With a Particular Emphasis on Mode Effects.
International large-scale assessments, such as the Program for International Student Assessment (PISA), are conducted to provide information on the effectiveness of education systems. In PISA, the target population of 15-year-old students is assessed every 3 years. Trends show whether competencies have changed in the countries between PISA cycles. In order to provide valid trend estimates, it is desirable to retain the same test conditions and statistical methods in all PISA cycles. In PISA 2015, however, the test mode changed from paper-based to computer-based tests, and the scaling method was changed. In this paper, we investigate the effects of these changes on trend estimation in PISA using German data from all PISA cycles (2000-2015). Our findings suggest that the change from paper-based to computer-based tests could have a severe impact on trend estimation but that the change of the scaling model did not substantially change the trend estimates.


Winter lupus flares are associated with low vitamin D levels in a retrospective longitudinal study of Italian adult patients.
Patients with systemic lupus erythematosus (SLE) are prone to hypo-vitaminosis D because of their photosensitivity. Vitamin D (vit.D) has beneficial effects not only on bone metabolism but also on the function of the immune system. The relationship between SLE disease activity and vit.D status is controversial and little is known on the effects of current supplementation strategies given for osteoporosis in raising vit.D levels. Vit.D levels were measured longitudinally in 50 SLE patients from Northern Italy at two time-points (winter and summer) during disease remission. Thirty patients were also evaluated during a flare. As controls, 170 healthy donors were enrolled. All the samples were analysed for 25-OH vit.D levels by a chemiluminescence assay (DiaSorin SpA, Italy). SLE patients had lower vit.D levels than controls in the summer (median 29.4 vs. 39.2 ng/ml, p=0.005) but not in the winter (26.4 vs. 21.6 ng/ml). During wintertime, 36 SLE patients were supplemented with vit.D drops (n=24; 48%), vit.D+calcium tablets (n=12; 24%), while 14 (28%) received no supplementation. Patients on oral drops had significantly higher vit.D levels than patients on tablets. The median weekly dosage was higher for oral drops than for tablets (6250 vs. 4560 UI, p=0.009). Winter flares were associated with lower vit.D levels in comparison with remission during the same season for each patient (21.1 vs. 30 ng/ml). Current strategies of vit.D supplementation seem to be not sufficient for reaching an optimal vit.D status in Italian SLE patients. Vit.D and calcium tablets were less effective, probably because of lower vit.D content and poorer compliance. Vit.D insufficiency detected in the wintertime can be either a predisposing factor for flare or the consequence of the flare itself in SLE patients.


Differential Stoichiometry among Core Ribosomal Proteins.
Understanding the regulation and structure of ribosomes is essential to understanding protein synthesis and its dysregulation in disease. While ribosomes are believed to have a fixed stoichiometry among their core ribosomal proteins (RPs), some experiments suggest a more variable composition. Testing such variability requires direct and precise quantification of RPs. We used mass spectrometry to directly quantify RPs across monosomes and polysomes of mouse embryonic stem cells (ESC) and budding yeast. Our data show that the stoichiometry among core RPs in wild-type yeast cells and ESC depends both on the growth conditions and on the number of ribosomes bound per mRNA. Furthermore, we find that the fitness of cells with a deleted RP-gene is inversely proportional to the enrichment of the corresponding RP in polysomes. Together, our findings support the existence of ribosomes with distinct protein composition and physiological function.


Dual regression physiological modeling of resting-state EPI power spectra: Effects of healthy aging.
Aging and disease-related changes in the arteriovasculature have been linked to elevated levels of cardiac cycle-induced pulsatility in the cerebral microcirculation. Functional magnetic resonance imaging (fMRI), acquired fast enough to unalias the cardiac frequency contributions, can be used to study these physiological signals in the brain. Here, we propose an iterative dual regression analysis in the frequency domain to model single voxel power spectra of echo planar imaging (EPI) data using external recordings of the cardiac and respiratory cycles as input. We further show that a data-driven variant, without external physiological traces, produces comparable results. We use this framework to map and quantify cardiac and respiratory contributions in healthy aging. We found a significant increase in the spatial extent of cardiac modulated white matter voxels with age, whereas the overall strength of cardiac-related EPI power did not show an age effect.


Effects of irrigation on debris and smear layer on canal walls prepared by two rotary techniques: a scanning electron microscopic study.
Debris and smear layer were evaluated in canals prepared with either Lightspeed (LS) or ProFile (PF) rotary instruments. Irrigants used were tap water (group A) or alternating 5.25% NaOCl and 17% EDTA (group B). Apical stops were prepared to size 52.5 in the LS and to size 6 (approximately ISO size 36) in the PF techniques. The roots were split longitudinally and examined at apical, middle and coronal levels for debris and the smear layer using a 5-step scale. Using only water, mean debris scores were similar for LS and PF. In contrast, with EDTA/NaOCl, LS- and PF-prepared canals had similar debris scores at the apical and coronal levels, but there was a significant difference at the middle level. Mean smear layer scores were similar in LS- and PF-shaped canals when water was the sole irrigant. In contrast, with NaOCl and EDTA, mean smear layer scores were significantly different at the apical and middle levels, but not at the coronal level. Neither technique was superior in removing debris, but larger canal preparations obtained in this study with LS instruments enabled a more effective removal of the smear layer in the EDTA-NaOCl group.


Blood flow to contracting human muscles: influence of increased sympathetic activity.
The purpose of this study was to examine the effects of the increased sympathetic activity elicited by the upright posture on blood flow to exercising human forearm muscles. Six subjects performed light and heavy rhythmic forearm exercise. Trials were conducted with the subjects supine and standing. Forearm blood flow (FBF, plethysmography) and skin blood flow (laser Doppler) were measured during brief pauses in the contractions. Arterial blood pressure and heart rate were also measured. During the first 6 min of light exercise, blood flow was similar in the supine and standing positions (approximately 15 ml.min-1.100 ml-1); from minutes 7 to 20 FBF was approximately 3-7 ml.min-1.100 ml-1 less in the standing position (P less than 0.05). When 5 min of heavy exercise immediately followed the light exercise, FBF was approximately 30-35 ml.min-1.100 ml-1 in the supine position. These values were approximately 8-12 ml.min-1.100 ml-1 greater than those observed in the upright position (P less than 0.05). When light exercise did not precede 8 min of heavy exercise, the blood flow at the end of minute 1 was similar in the supine and standing positions but was approximately 6-9 ml.min-1.100 ml-1 lower in the standing position during minutes 2-8. Heart rate was always approximately 10-20 beats higher in the upright position (P less than 0.05). Forearm skin blood flow and mean arterial pressure were similar in the two positions, indicating that the changes in FBF resulted from differences in the caliber of the resistance vessels in the forearm muscles.(ABSTRACT TRUNCATED AT 250 WORDS)


Alveolar macrophages are critical for broadly-reactive antibody-mediated protection against influenza A virus in mice.
The aim of candidate universal influenza vaccines is to provide broad protection against influenza A and B viruses. Studies have demonstrated that broadly reactive antibodies require Fc-Fc gamma receptor interactions for optimal protection; however, the innate effector cells responsible for mediating this protection remain largely unknown. Here, we examine the roles of alveolar macrophages, natural killer cells, and neutrophils in antibody-mediated protection. We demonstrate that alveolar macrophages play a dominant role in conferring protection provided by both broadly neutralizing and non-neutralizing antibodies in mice. Our data also reveal the potential mechanisms by which alveolar macrophages mediate protection in vivo, namely antibody-induced inflammation and antibody-dependent cellular phagocytosis. This study highlights the importance of innate effector cells in establishing a broad-spectrum antiviral state, as well as providing a better understanding of how multiple arms of the immune system cooperate to achieve an optimal antiviral response following influenza virus infection or immunization.Broadly reactive antibodies that recognize influenza A virus HA can be protective, but the mechanism is not completely understood. Here, He et al. show that the inflammatory response and phagocytosis mediated by the interaction between protective antibodies and macrophages are essential for protection.


First-exposure adaptive resistance to aminoglycoside antibiotics in vivo with meaning for optimal clinical use.
The first exposure of gram-negative bacilli to an aminoglycoside antibiotic in vitro induces a biphasic bactericidal response and adaptive drug resistance (G. L. Daikos, G. G. Jackson, V. T. Lolans, and D. M. Livermore, J. Infect. Dis. 162:414-420, 1990; G. G. Jackson, G. L. Daikos, and V. T. Lolans, J. Infect. Dis. 162:408-413, 1990). The therapeutic implications were examined in netilmicin treatment of a Pseudomonas aeruginosa infection of normal and neutropenic mice. For 2 h after the first dose, the bactericidal rates were rapid, 0.75, 1.0, and 1.5 log10 CFU/h with doses of 10, 30, and 60 mg/kg, respectively. Each twofold increase in dosage reduced the number of surviving bacteria fivefold. Between 2 and 6 h, the second-phase bactericidal rate was slow, less than or equal to 0.3 log10 CFU/h, regardless of the dose. In a multiple-dose regimen, the same amount of netilmicin given in one dose was 70 and 90% more effective than two or three doses, respectively. Doses calculated to keep the drug level in plasma above the MIC were less effective than regimens giving first exposure to a high drug concentration. Adaptive resistance occurred when doses were given more than 2 h after the start of treatment. Temporary survival of bacteremic neutropenic mice was 60 to 70% greater with a second dose at 2 h than after a longer interval. In a thigh infection of neutropenic mice treated every 2 h, doses 4, 6, and 8 h after the first one showed no bactericidal effect. A drug-free interval of 8 h (20 times the drug half-life) renewed bacterial susceptibility to drug action. The results in vivo confirm the biphasic bactericidal action and induction of adaptive resistance that characterized first exposure of gram-negative bacilli to aminoglycoside antibiotics. The phenomena have meaning for the optimum clinical use of aminoglycosides.


Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HIV Replication and PD-1 Expression on CD4+ T Cells.
The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the human immunodeficiency virus (HIV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the local tissues to suppress HIV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs elicit the antiviral response remain to be fully elucidated. In this study, we generated the functional HIV-1 Gag epitope SL9-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the suppression of SL9-specific iPSC-CTLs on viral replication and the protection of CD4+ T cells. A chimeric HIV-1, i.e., EcoHIV, was used to produce HIV replication in mice. We show that adoptive transfer of SL9-specific iPSC-CTLs greatly suppressed EcoHIV replication in the peritoneal macrophages and spleen in the animal model. Furthermore, we demonstrate that the adoptive transfer significantly reduced expression of PD-1 on CD4+ T cells in the spleen and generated persistent anti-HIV memory T cells. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the local tissues to suppress HIV replication and prevent CD4+ T cell exhaustion through reduction of PD-1 expression.


Discharge Age and Weight for Very Preterm Infants: 2005-2018.
A complex set of medical, social, and financial factors underlie decisions to discharge very preterm infants. As care practices change, whether postmenstrual age and weight at discharge have changed is unknown. Between 2005 and 2018, 824 US Vermont Oxford Network member hospitals reported 314 811 infants 24 to 29 weeks' gestational age at birth without major congenital abnormalities who survived to discharge from the hospital. Using quantile regression, adjusting for infant characteristics and complexity of hospital course, we estimated differences in median age, weight, and discharge weight z score at discharge stratified by gestational age at birth and by NICU type. From 2005 to 2018, postmenstrual age at discharge increased an estimated 8 (compatibility interval [CI]: 8 to 9) days for all infants. For infants initially discharged from the hospital, discharge weight increased an estimated 316 (CI: 308 to 324) grams, and median discharge weight z score increased an estimated 0.19 (CI: 0.18 to 0.20) standard units. Increases occurred within all birth gestational ages and across all NICU types. The proportion of infants discharged home from the hospital on human milk increased, and the proportions of infants discharged home from the hospital on oxygen or a cardiorespiratory monitor decreased. Gestational age and weight at discharge increased steadily from 2005 to 2018 for survivors 24 to 29 weeks' gestation with undetermined causes, benefits, and costs.


A descriptive study of commonly used postoperative approaches to pediatric stoma care in a developing country.
Construction of an enterostomy is a common procedure in pediatric surgery. However, caring for the child with a stoma is challenging for parents in developing countries. Modern devices such as colostomy bags and accessories are expensive and not readily available. The purpose of this study was to describe methods of effluent collection and peristomal skin protection used by the mothers of colostomy patients. A prospective, descriptive study was conducted between January and December 2011 during the first three postoperative outpatient clinic visits among mothers of children who had a colostomy constructed in the authors' hospital. The mothers of 44 children (27 males, 17 females, median age 3.3 months, range 2 days to 11 years) consented to participate. Demographic and clinical data were obtained from the records, and mothers were interviewed and asked to describe their preferred methods of colostomy effluent collection and peristomal skin protection. The stomas also were inspected at each clinic visit. Anorectal malformations were the most common indication for a colostomy (32, 72.73%), followed by Hirschsprung's disease (11, 25%). Forty-two (42) patients had a divided sigmoid colostomy (95.45%); two patients had a right loop transverse colostomy (4.55%). Nine mothers alternated between two different collection methods. The diaper collection method was described most frequently (22 out of 53; 41.51%), followed by wraparound waistbands (19; 35.85%) and improvised colostomy bags (12; 22.64%). Peristomal skin excoriations were commonly seen within the first 3 weeks postsurgery and had mostly disappeared by the week 6 postoperative visit. Petrolatum jelly was the most commonly used barrier ointment. These locally available, acceptable, and affordable collection methods may be useful for children in other developing countries.


Interleukin-1beta -induced changes in blood-brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: a magnetic resonance study.
The cytokine interleukin-1beta (IL-1beta) is implicated in a broad spectrum of CNS pathologies, in which it is thought to exacerbate neuronal loss. Here, the effects of injecting recombinant rat IL-1beta into the striatum of 3-week-old rats were followed noninvasively from 2 to 123 hr using magnetic resonance imaging and spectroscopy. Four hours after injection of IL-1beta (1 ng in 1 microliter), cerebral blood volume was significantly increased, the blood-brain barrier (BBB) became permeable to intravenously administered contrast agent between 4.5 and 5 hr, and the apparent diffusion coefficient (ADC) of brain water fell by 6 hr (5.42 +/- 0. 35 x 10(-4) mm(2)/sec treated, 7.35 +/- 0.77 x 10(-)(4) mm(2)/sec control; p < 0.001). At 24 hr the BBB was again intact, but the ADC, although partially recovered, remained depressed at both 24 and 123 hr (p < 0.03). Depleting the animals of neutrophils before IL-1beta injection prevented the BBB permeability at all time points, but the ADC was still depressed at 6 hr (6.64 +/- 0.34 x 10(-4) mm(2)/sec treated, 7.49 +/- 0.38 x 10(-4) mm(2)/sec control; p < 0.005). No changes were seen in brain metabolites using proton spectroscopy at 6 hr after IL-1beta. Intraparenchymal injection of IL-1beta caused a neutrophil-dependent transient increase in BBB permeability. The presence of neutrophils within the brain parenchyma significantly contributed to the IL-1beta-induced changes in cerebral blood volume and the ADC of brain water. However, IL-1beta apparently had a direct effect on the resident cell populations, which persisted well after all recruited leukocytes had disappeared. Thus the action of IL-1beta alone can give rise to magnetic resonance imaging-visible changes that are normally attributed to alterations to cellular homeostasis.


Antigens in culture supernatant of Mycobacterium tuberculosis: epitopes defined by monoclonal and human antibodies.
Antigens of Mycobacterium tuberculosis found in the supernatant of heat-treated cultures were characterized in order to explore whether antigens from this source could be used for the development of a serological test. Culture supernatants and sonicates of 12, 25 and 39 d cultures were analysed by SDS-PAGE. In culture supernatant, major protein bands of 65, 24, and 12 kDa were visible after Coomassie brilliant blue staining. Using murine monoclonal antibodies in Western blots, a pattern of protein bands distinct from that of the corresponding M. tuberculosis sonicates was found in all the culture supernatants. Gel permeation chromatography, in the presence of SDS, was used to separate the major protein bands in the culture supernatant. In ELISA, sera from 20 of 26 patients with tuberculosis reacted with fractions containing mainly 24 kDa or 12 kDa proteins, whereas none of the control sera reacted. In Western blots, each patient serum had its own characteristic banding pattern with culture supernatant, but all the sera from tuberculosis patients and control subjects reacted with protein bands of 65, 61, 58, 30 and 24 kDa. The 12 kDa protein was recognized only by sera from patients with tuberculosis in both Western blots and ELISA. This suggests that different kinds of epitopes on proteins of M. tuberculosis are detected by human antibodies in Western blots and ELISA. We assume that epitopes recognized in Western blots by patients with tuberculosis and control subjects are ubiquitous and are also present on normal commensal bacteria. Epitopes recognized by only some patients with tuberculosis in Western blots may be linear and M. tuberculosis specific. Epitopes recognized by tuberculosis patients but by none of the control subjects in ELISA may be conformation related and M. tuberculosis specific. The major protein bands found in supernatants of heat-treated cultures, 24 and 12 kDa, possess epitopes that may be M. tuberculosis specific and are potentially valuable for the development of a serological test.


Buckling without Bending: A New Paradigm in Morphogenesis.
A curious feature of organ and organoid morphogenesis is that in certain cases, spatial oscillations in the thickness of the growing "film" are out of phase with the deformation of the slower-growing "substrate," while in other cases, the oscillations are in phase. The former cannot be explained by elastic bilayer instability, and contradict the notion that there is a universal mechanism by which brains, intestines, teeth, and other organs develop surface wrinkles and folds. Inspired by the microstructure of the embryonic cerebellum, we develop a new model of 2D morphogenesis in which system-spanning elastic fibers endow the organ with a preferred radius, while a separate fiber network resides in the otherwise fluidlike film at the outer edge of the organ and resists thickness gradients thereof. The tendency of the film to uniformly thicken or thin is described via a "growth potential." Several features of cerebellum, +blebbistatin organoid, and retinal fovea morphogenesis, including out-of-phase behavior and a film thickness amplitude that is comparable to the radius amplitude, are readily explained by our simple analytical model, as may be an observed scale invariance in the number of folds in the cerebellum. We also study a nonlinear variant of the model, propose further biological and bioinspired applications, and address how our model is and is not unique to the developing nervous system.


The bacterial parasite Pasteuria ramosa is not killed if it fails to infect: implications for coevolution.
Strong selection on parasites, as well as on hosts, is crucial for fueling coevolutionary dynamics. Selection will be especially strong if parasites that encounter resistant hosts are destroyed and diluted from the local environment. We tested whether spores of the bacterial parasite Pasteuria ramosa were passed through the gut (the route of infection) of their host, Daphnia magna, and whether passaged spores remained viable for a "second chance" at infecting a new host. In particular, we tested if this viability (estimated via infectivity) depended on host genotype, whether or not the genotype was susceptible, and on initial parasite dose. Our results show that Pasteuria spores generally remain viable after passage through both susceptible and resistant Daphnia. Furthermore, these spores remained infectious even after being frozen for several weeks. If parasites can get a second chance at infecting hosts in the wild, selection for infection success in the first instance will be reduced. This could also weaken reciprocal selection on hosts and slow the coevolutionary process.


Effects of pharmacologic treatment based on airflow limitation and breathlessness on daily physical activity in patients with chronic obstructive pulmonary disease.
Improvement in the daily physical activity (PA) is important for the management of chronic obstructive pulmonary disease (COPD). However, the effects of pharmacologic treatment on PA are not well understood. We evaluated the effects of additional medications, including bronchodilator with or without inhaled corticosteroid, based on airflow limitation and breathlessness on the PA in COPD patients and the factors that could predict or affect the improvement in PA. A prospective non-randomized observational study was employed. Twenty-one COPD subjects without any other diseases that might reduce PA were recruited. The PA was measured with a triaxial accelerometer for 2 weeks, and pulmonary function tests and incremental shuttle walking tests were administered before and after 4-week treatment with an additional medication. Bronchodilation was obtained by additional medication. The mean values of PA evaluated by metabolic equivalents (METs) at ≥3.0 METs and the duration of PA at ≥3.0 METs and ≥3.5 METs were improved by medication. The % change in the duration of PA at ≥3.5 METs was significantly correlated with the baseline functional residual capacity (FRC), residual volume, and inspiratory capacity/total lung capacity. However, the % change in the duration of PA at any intensity was not correlated with the % changes of any values of the pulmonary function tests or incremental shuttle walking test except the PA at ≥2.5 METs with FRC. Medication could improve the PA in patients with COPD, especially at a relatively high intensity of activity when medication was administered based on airflow limitation and breathlessness. The improvement was seen in the patients with better baseline lung volume, but was not correlated with the improvements in the pulmonary function tests or exercise capacity.


Critical review of the impacts of grazing intensity on soil organic carbon storage and other soil quality indicators in extensively managed grasslands.
Livestock grazing intensity (GI) is thought to have a major impact on soil organic carbon (SOC) storage and soil quality indicators in grassland agroecosystems. To critically investigate this, we conducted a global review and meta-analysis of 83 studies of extensive grazing, covering 164 sites across different countries and climatic zones. Unlike previous published reviews we normalized the SOC and total nitrogen (TN) data to a 30 cm depth to be compatible with IPCC guidelines. We also calculated a normalized GI and divided the data into four main groups depending on the regional climate (dry warm, DW; dry cool, DC; moist warm, MW; moist cool, MC). Our results show that taken across all climatic zones and GIs, grazing (below the carrying capacity of the systems) results in a decrease in SOC storage, although its impact on SOC is climate-dependent. When assessed for different regional climates, all GI levels increased SOC stocks under the MW climate (+7.6%) whilst there were reductions under the MC climate (-19%). Under the DW and DC climates, only the low (+5.8%) and low to medium (+16.1%) grazing intensities, respectively, were associated with increased SOC stocks. High GI significantly increased SOC for C4-dominated grassland compared to C3-dominated grassland and C3-C4 mixed grasslands. It was also associated with significant increases in TN and bulk density but had no effect on soil pH. To protect grassland soils from degradation, we recommend that GI and management practices should be optimized according to climate region and grassland type (C3, C4 or C3-C4 mixed).


Post-treatment with plant extracts used in Brazilian folk medicine caused a partial reversal of the antiproliferative effect of glyphosate in the Allium cepa test.
Species of the genus Psychotria are used for multiple purposes in Brazilian folk medicine, either as water infusions, baths or poultices. This study was aimed to evaluate the genotoxic and antiproliferative effects of infusions of Psychotria brachypoda and P. birotula on the Allium cepa test. Exposure to distilled water was used as a negative control, while exposure to glyphosate was used as a positive control. The interaction of extracts (as a post-treatment) with the effects of glyphosate was also studied. Results showed that glyphosate and the extracts of both P. brachypoda and P. birotula reduced the mitotic index as compared with the negative control (distilled water). Surprisingly, however, both extracts from P. brachypoda and P. birotula caused a partial reversal of the antiproliferative effect of glyphosate when used as a post-treatment. Glyphosate also induced the highest number of cells with chromosomal alterations, which was followed by that of P. birotula extracts. However, the extracts from P. brachypoda did not show any significant genotoxic effect. Post-treatment of glyphosate-treated samples with distilled water allowed a partial recovery of the genotoxic effect of glyphosate, and some of the Psychotria extracts also did so. Notably, post-treatment of glyphosate-treated samples with P. brachypoda extracts induced a statistically significant apoptotic effect. It is concluded that P. brachypoda extracts show antiproliferative effects and are not genotoxic, while extracts of P. birotula show a less potent antiproliferative effect and may induce chromosomal abnormalities. The finding of a partial reversion of the effects of glyphosate by a post-treatment with extracts from both plants should be followed up.


Carvacrol: from ancient flavoring to neuromodulatory agent.
Oregano and thyme essential oils are used for therapeutic, aromatic and gastronomic purposes due to their richness in active substances, like carvacrol; however, the effects of the latter on the central nervous system have been poorly investigated. The aim of our study was to define the effects of carvacrol on brain neurochemistry and behavioural outcome in rats. Biogenic amine content in the prefrontal cortex and hippocampus after chronic or acute oral carvacrol administration was measured. Animals were assessed by a forced swimming test. Carvacrol, administered for seven consecutive days (12.5 mg/kg p.o.), was able to increase dopamine and serotonin levels in the prefrontal cortex and hippocampus. When single doses were used (150 and 450 mg/kg p.o.), dopamine content was increased in the prefrontal cortex at both dose levels. On the contrary, a significant dopamine reduction in hippocampus of animals treated with 450 mg/kg of carvacrol was found. Acute carvacrol administration only significantly reduced serotonin content in either the prefrontal cortex or in the hippocampus at the highest dose. Moreover, acute carvacrol was ineffective in producing changes in the forced swimming test. Our data suggest that carvacrol is a brain-active molecule that clearly influences neuronal activity through modulation of neurotransmitters. If regularly ingested in low concentrations, it might determine feelings of well-being and could possibly have positive reinforcer effects.


Mammary Stem Cell Self-Renewal Is Regulated by Slit2/Robo1 Signaling through SNAI1 and mINSC.
Tissue homeostasis requires somatic stem cell maintenance; however, mechanisms regulating this process during organogenesis are not well understood. Here, we identify asymmetrically renewing basal and luminal stem cells in the mammary end bud. We demonstrate that SLIT2/ROBO1 signaling regulates the choice between self-renewing asymmetric cell divisions (ACDs) and expansive symmetric cell divisions (SCDs) by governing Inscuteable (mInsc), a key member of the spindle orientation machinery, through the transcription factor Snail (SNAI1). Loss of SLIT2/ROBO1 signaling increases SNAI1 in the nucleus. Overexpression of SNAI1 increases mInsc expression, an effect that is inhibited by SLIT2 treatment. Increased mInsc does not change cell proliferation in the mammary gland (MG) but instead causes more basal cap cells to divide via SCD, at the expense of ACD, leading to more stem cells and larger outgrowths. Together, our studies provide insight into how the number of mammary stem cells is regulated by the extracellular cue SLIT2.


Improved perfusion with rt-PA and hirulog in a rabbit model of embolic stroke.
We conducted a study using diffusion-weighted (DWI) and perfusion-weighted (PWI) magnetic resonance imaging (MRI) to evaluate the efficacy of thrombolysis in an embolic stroke model with recombinant tissue plasminogen activator (rt-PA) and hirulog, a novel direct-acting antithrombin. DWI can identify areas of ischemia minutes from stroke onset, while PWI identifies regions of impaired blood flow. Right internal carotid arteries of 36 rabbits were embolized using aged heterologous thrombi. Baseline DWI and PWI scans were obtained to confirm successful embolization. Four animals with no observable DWI lesion on the initial scan were excluded; therefore, a total of 32 animals were randomized to one of three treatment groups: rt-PA (n = 11), rt-PA plus hirulog (n = 11), or placebo (n = 10). Treatment was begun 1 h after stroke induction. Intravenous doses were as follows: rt-PA, 5 mg/kg over 0.5 h with 20% of the total dose given as a bolus; hirulog, 1 mg/kg bolus followed by 5 mg/kg over 1 h. MRI was performed at 2, 3, and 5 h following embolization. Six hours after embolization, brains were harvested, examined for hemorrhage, then prepared for histologic analysis. The rt-PA decreased fibrinogen levels by 73%, and hirulog prolonged the aPTT to four times the control value. Posttreatment areas of diffusion abnormality and perfusion delay were expressed as a ratio of baseline values. Significantly improved perfusion was seen in the rt-PA plus hirulog group compared with placebo (normalized ratios of the perfusion delay areas were as follows: placebo, 1.58, 0.47-3.59; rt-PA, 1.12, 0.04-3.95; rt-PA and hirulog, 0.40, 0.02-1.08; p < 0.05). Comparison of diffusion abnormality ratios measured at 5 h showed trends favoring reduced lesion size in both groups given rt-PA (normalized ratios of diffusion abnormality areas were as follows: placebo, 3.69, 0.39-15.71; rt-PA, 2.57, 0.74-5.00; rt-PA and hirulog, 1.95, 0.33-6.80; p = 0.32). Significant cerebral hemorrhage was observed in one placebo, two rt-PA, and three rt-PA plus hirulog treated animals. One fatal systemic hemorrhage was observed in each of the rt-PA groups. We conclude that rt-PA plus hirulog improves cerebral perfusion but does not necessarily reduce cerebral injury. DWI and PWI are useful methods for monitoring thrombolysis.


The relative value of conventional staging procedures for developing prognostic models in extensive-stage small-cell lung cancer.
Published prognostic models for small-cell lung cancer (SCLC) have either combined limited- and extensive-stage patients or have not included standard anatomic staging information to assess the relative value of the knowledge of specific sites and number of sites of metastases in predicting survival in extensive-stage disease. We studied 136 extensive-stage patients in whom traditional staging procedures were performed and in whom other previously demonstrated significant pretreatment variables were determined. Using the Cox proportional hazards model, when all data were included, three variables were significant: performance status (PS) (P = .0001), number of sites of metastases (P = .0010), and age (P = .0029). A prognostic algorithm was developed using these variables, which divided the patients into three distinct groups. When the anatomic staging data were omitted, the serum albumin (P = .0313) was the only variable in addition to PS (P = .0001) and age (P = .0064) that was significant. An alternative algorithm using these three variables was nearly as predictive as the original. Therefore, in extensive-stage patients, reasonable pretreatment prognostic information can be obtained without using the number or specific sites of metastases as variables once the presence of distant metastases has been demonstrated.


A cascade of biological invasions and parasite spillback in man-made Lake Kariba.
Parasite spillback, the infection of a non-indigenous organism by a native parasite, is a highly important although understudied component of ecological invasion dynamics. Here, through the first analysis of the parasite fauna of lymnaeid gastropods of Lake Kariba (Zimbabwe). We illustrate how the creation of an artificial lake may lead to a cascade of biological invasions in which an invasive aquatic plant promotes the proliferation of invasive gastropods, which in turn alters the epidemiology of trematodiases of potential medical and veterinary importance. Using a new multiplex Rapid Diagnostic PCR assay, we assessed the prevalence of Fasciola sp. infections in the gastropod populations. Both gastropod hosts and trematode parasites were identified using DNA barcoding. We provide the first record of the invasive North-American gastropod Pseudosuccinea columella in Lake Kariba. This species was found at 14 out of 16 sampled sites and its abundance was strongly positively correlated with the abundance of the invasive South-American water hyacinth (Eichhornia crassipes). About 65% of the P. columella specimens analysed were infected with a hitherto unknown Fasciola species. Phylogenetic analyses indicate close affinity to Fasciola hepatica and F. gigantica, which cause fasciolosis, an important liver disease affecting both ruminants and humans. In addition, another non-native Lymnaeid species was found: a Radix sp. that clustered closely with a Vietnamese Radix species. Radix sp. hosted both amphistome and Fasciola trematodes. By linking an invasion cascade and parasite spillback, this study shows how both processes can act in combination to lead to potentially important epidemiological changes.


Role for IL-10 in inducing functional impairment of monocytes upon TLR4 ligation in patients with chronic HCV infections.
The consequences of chronic infection with the HCV on immunity to distinct pathogens are not fully appreciated, despite the potent modulatory effects of HCV on the immune system. We observed that upon TLR4 ligation, monocytes from chronic HCV patients demonstrated three to five times lower TNF and IL-12p40 production as compared with healthy individuals. However, augmented production of TNF, IL-12p40, and IL-12p70 by monocytes was observed upon stimulation with R848. Importantly, we observed that the levels of IL-10 in chronic HCV patients are higher in serum and that more IL-10 is produced by monocytes as compared with healthy individuals. The inhibitory effect of IL-10 on the production of proinflammatory cytokines by monocytes was only observed upon LPS stimulation but not upon R848 stimulation, showing that only the TLR4 pathway in monocytes is sensitive to the suppressive effects of IL-10. Interestingly, monocytes stimulated with the TLR4 agonist, but not TLR8 agonist, produced higher levels of IL-10 when exposed to patient serum as compared with serum from healthy individuals. Our results indicate that by differentially affecting TLR4 and TLR8 pathways, IL-10 may mediate highly selective modulation of the function of monocytes observed in chronic HCV patients. This suggests that there is no overall increased susceptibility to pathogens but a specific suppression of the functionality of TLR4 signaling pathway in monocytes, which is, at least partly, mediated via IL-10.


The defined-contribution plan: the next generation of healthcare financing.
In response to rising health insurance premiums, many purchasers of coverage are evaluating the possibility of implementing defined-contribution health insurance plans. Under a defined-contribution plan, employers or the government pay a specified portion of the premium, and the consumer chooses a plan from a menu of options, paying the balance of the premium based on their plan selection. A shift to a defined-contribution model will have far-reaching implications for consumers, employer and government purchasers, payers, and providers. Providers will face changes in consumption patterns and the need to develop a brand image, market their strengths directly to consumers, educate consumers about their services and pricing, and reconfigure infrastructures to be able to respond efficiently to consumer demands.


Middle East respiratory syndrome coronavirus not detected in children hospitalized with acute respiratory illness in Amman, Jordan, March 2010 to September 2012.
Hospitalized children < 2 years of age in Amman, Jordan, admitted for fever and/or respiratory symptoms, were tested for Middle East respiratory syndrome coronavirus (MERS-CoV): MERS-CoV by real-time RT-PCR (rRT-PCR). This was a prospective year-round viral surveillance study in children <2 years of age admitted with acute respiratory symptoms and/or fever from March 2010 to September 2012 and enrolled from a government-run hospital, Al-Bashir in Amman, Jordan. Clinical and demographic data, including antibiotic use, were collected. Combined nasal/throat swabs were collected, aliquoted, and frozen at -80°C. Specimen aliquots were shipped to Vanderbilt University and the Centers for Disease Control and Prevention (CDC), and tested by rRT-PCR for MERS-CoV. Of the 2433 subjects enrolled from 16 March 2010 to 10 September 2012, 2427 subjects had viral testing and clinical data. Of 1898 specimens prospectively tested for other viruses between 16 March 2010 and 18 March 2012, 474 samples did not have other common respiratory viruses detected. These samples were tested at CDC for MERS-CoV and all were negative by rRT-PCR for MERS-CoV. Of the remaining 531 samples, collected from 19 March 2012 to 10 September 2012 and tested at Vanderbilt, none were positive for MERS-CoV. Our negative findings from a large sample of young Jordanian children hospitalized with fever and/or respiratory symptoms suggest that MERS-CoV was not widely circulating in Amman, Jordan, during the 30-month period of prospective, active surveillance occurring before and after the first documented MERS-CoV outbreak in the Middle East region.


[Pulmonary complications from pandemic AH1N1 influenza: clinical-radiological features].
We describe the epidemiology, clinical features, radiological findings, therapy and course for 15 patients hospitalized at the Infectious Diseases UOC of Gravina Hospital Caltagirone for a serious respiratory condition with verified infection A (H1N1) from 9 November to 22 December 2009. We retrospectively reviewed medical records, laboratory and instrumental tests performed on hospitalized patients. All patients had significant respiratory impairment: nine had co-morbidities and risk factors such as obesity, pregnancy, immunosuppressant conditions and muscular dystrophy. Symptoms were similar to those of seasonal influenza; radiological investigation of the chest (RX and CT) presents lung involvement in 80% of patients and changes in the bio-humoral indices. Development into acute respiratory distress syndrome (ARDS) was observed in six patients: three were ventilated with a Venturi mask, three were treated in intensive care and two patients used extracorporeal membrane oxygenation (ECMO). Two died. All patients received antiviral and symptomatic therapy for 5-21 days. A(H1N1) virus infection led to a mild to moderate flu syndrome, which was often cured by symptomatic treatment; some patients required hospitalization for viral pneumonia, mixed pneumonia or ARDS. In previous flu epidemics there was no development into ARDS (40% in our series).


Protein metabolism and growth of term infants in response to a reduced-protein, 40:60 whey: casein formula with added tryptophan.
The effects of an experimental reduced-protein (13 g/L), milk-based formula with a whey-casein ratio of 40:60 and added tryptophan (Trp) (490 mumol/L, or 100 mg/L; EF) were measured by growth and protein biochemistry in term infants from 0 to 12 wk postnatally. Newborn infants (n = 95) were randomly assigned to receive EF or conventional formula (15 g protein/L, whey-casein ratio of 60:40; CF) and compared with 58 breast-fed infants (BF). Growth velocity for weight, length, and head circumference was similar between groups. In 79 infants, blood was sampled preprandially at 4, 8, and 12 wk. For all times, plasma Trp was similar in BF and EF infants (58.4 +/- 10.4 vs 59.5 +/- 14.7 mumol/L, mean +/- SD) but lower in CF infants (53.4 +/- 8.4, P < 0.05). The plasma Trp-large neutral amino acid (AA) ratio was higher with EF than with CF, as was prealbumin (P < 0.05). Formula-fed infants had higher (P < 0.05) plasma urea, prealbumin, total essential AA, branched-chain AA, and threonine than did BF infants. A reduced-protein formula with added Trp resulted in Trp status similar to that in BF infants, without compromising growth or protein biochemistry compared with CF infants.


Mapping and correcting the influence of gaze position on pupil size measurements.
Pupil size is correlated with a wide variety of important cognitive variables and is increasingly being used by cognitive scientists. Pupil data can be recorded inexpensively and non-invasively by many commonly used video-based eye-tracking cameras. Despite the relative ease of data collection and increasing prevalence of pupil data in the cognitive literature, researchers often underestimate the methodological challenges associated with controlling for confounds that can result in misinterpretation of their data. One serious confound that is often not properly controlled is pupil foreshortening error (PFE)-the foreshortening of the pupil image as the eye rotates away from the camera. Here we systematically map PFE using an artificial eye model and then apply a geometric model correction. Three artificial eyes with different fixed pupil sizes were used to systematically measure changes in pupil size as a function of gaze position with a desktop EyeLink 1000 tracker. A grid-based map of pupil measurements was recorded with each artificial eye across three experimental layouts of the eye-tracking camera and display. Large, systematic deviations in pupil size were observed across all nine maps. The measured PFE was corrected by a geometric model that expressed the foreshortening of the pupil area as a function of the cosine of the angle between the eye-to-camera axis and the eye-to-stimulus axis. The model reduced the root mean squared error of pupil measurements by 82.5 % when the model parameters were pre-set to the physical layout dimensions, and by 97.5 % when they were optimized to fit the empirical error surface.


Design constraints for wavelength-division-multiplexed filters with minimal side-channel impairment.
The design of wavelength-division-multiplexed (WDM) filters requires control of both the attributes of the filter within the reflection band and the filter's effects on adjacent bands. Causality arguments are used to give the minimum dispersion that can be achieved in the transmission of an adjacent channel in terms of the bandwidth, sidelobe suppression, and channel spacing of WDM filters. The ripple in the side-channel dispersion is also related to the sidelobe properties. Results for a synthesized grating design and its calculated spectrum are compared with the theoretical limits on dispersion.


Safeguarding patient privacy in electronic healthcare in the USA: the legal view.
The conflict between the sweeping power of technology to access and assemble personal information and the ongoing concern about our privacy and security is ever increasing. While we gradually need higher electronic access to medical information, issues relating to patient privacy and reducing vulnerability to security breaches surmount. In this paper, we take a legal perspective and examine the existing patchwork of laws and obligations governing health information in the USA. The study finds that as Electronic Medical Records (EMRs) increase in scope and dissemination, privacy protections gradually decrease due to the shortcomings in the legal system. The contributions of this paper are (1) an overview of the legal EMR issues in the USA, and (2) the identification of the unresolved legal issues and how these will escalate when health information is transmitted over wireless networks. More specifically, the paper discusses federal and state government regulations such as the Electronic Communications Privacy Act, the Health Insurance Portability and Accountability Act (HIPAA) and judicial intervention. Based on the legal overview, the unresolved challenges are identified and suggestions for future research are included.


T Cells on Engineered Substrates: The Impact of TCR Clustering Is Enhanced by LFA-1 Engagement.
We created APC-mimetic synthetic substrates to study the impact of ligand clustering on T cell activation and spreading. The substrates exhibit antibodies directed against the TCR-complex in the form of a patterned array of sub micrometric dots surrounded by a fluid supported lipid bilayer (SLB) which may itself be functionalized with another bio-molecule. We show that for T cell adhesion mediated by T cell receptor (TCR) alone, in the patterned, but not in the corresponding homogeneous controls, the TCR, ZAP-70 and actin are present in the form of clusters or patches that co-localize with the ligand-dots. However, global cell scale parameters like cell area and actin distribution are only weakly impacted by ligand clustering. In presence of ICAM-1 - the ligand of the T cell integrin LFA-1 - on the SLB, the TCR is still clustered due to the patterning of its ligands, but now global parameters are also impacted. The actin organization changes to a peripheral ring, resembling the classical actin distribution seen on homogeneous substrates, the patterned membrane topography disappears and the membrane is flat, whereas the cell area increases significantly. These observations taken together point to a possible pivotal role for LFA-1 in amplifying the effect of TCR-clustering. No such effect is evident for co-engagement of CD28, affected via its ligand B7.2. Unlike on ICAM-1, on B7.2 cell spreading and actin organization are similar for homogeneous and patterned substrates. However, TCR and ZAP-70 clusters are still formed in the patterned case. These results indicate complementary role for LFA-1 and CD28 in the regulation and putative coupling of TCR micro-clusters to actin. The engineered substrates presented here clearly have the potential to act as platform for fundamental research in immune cell biology, as well as translational analyses in immunotherapy, for example to screen molecules for their role in T cell adhesion/activation.


Registered report: investigating a preference for certainty in conversation among autistic adults compared to dyslexic adults and the general population.
Social communication difficulties are a diagnostic feature in autism. These difficulties are sometimes attributed, at least in part, to impaired ability in making inferences about what other people mean. In this registered report, we test a competing hypothesis that the communication profile of adults on the autism spectrum can be more strongly characterised by reduced confidence in making inferences in the face of uncertain information. We will test this hypothesis by comparing the performance of 100 autistic and 100 non-autistic adults on a test of implied meaning, using a test of grammaticality judgements as a control task. We hypothesise that autistic adults will report substantially lower confidence, allowing for differences in accuracy, than non-autistic adults on the test of implied meaning compared to the grammaticality test. In addition, we hypothesise that reduced confidence in drawing inferences will relate to the cognitive trait Intolerance of Uncertainty and self-reported social communication challenges. Finally, we will conduct exploratory analysis to assess the specificity of the communication profile of the autistic adults by comparing their performance to that of dyslexic adults, who might also be expected to experience challenges with language and communication.


Fluoride and arsenic exposure affects spatial memory and activates the ERK/CREB signaling pathway in offspring rats.
Fluoride and arsenic are inorganic contaminants that occur in the natural environment. Chronic fluoride and/or arsenic exposure can induce developmental neurotoxicity and negatively influence intelligence in children, although the underlying molecular mechanisms are poorly understood. This study explored the effects of fluoride and arsenic exposure in drinking water on spatial learning, memory and key protein expression in the ERK/CREB signaling pathway in hippocampal and cerebral cortex tissue in rat offspring. Pregnant rats were divided into four groups. Control rats drank tap water, while rats in the three exposure groups drank water with sodium fluoride (100mg/L), sodium arsenite (75mg/L), and a sodium fluoride (100mg/L) and sodium arsenite (75mg/L) combination during gestation and lactation. After weaning, rat pups drank the same solution as their mothers. Spatial learning and memory ability of pups at postnatal day 21 (PND21) and postnatal day 42 (PND42) were measured using a Morris water maze. ERK, phospho-ERK (p-ERK), CREB and phospho-CREB (p-CREB) protein expression in the hippocampus and cerebral cortex was detected using Western blot. Compared with the control pups, escape latencies increased in PND42 pups exposed to arsenic and co-exposed to fluoride and arsenic, and the short-term and long-term spatial memory ability declined in pups exposed to fluoride and arsenic, both alone and in combination. Compared with controls, ERK and p-ERK levels decreased in the hippocampus and cerebral cortex in pups exposed to combined fluoride and arsenic. CREB protein expression in the cerebral cortex decreased in pups exposed to fluoride, arsenic, and the fluoride and arsenic combination. p-CREB protein expression in both the hippocampus and cerebral cortex was decreased in pups exposed to fluoride and arsenic in combination compared to the control group. There were negative correlation between the proteins expression and escape latency periods in pups. These data indicate that exposure to fluoride and arsenic in early life stage changes ERK, p-ERK, CREB and p-CREB protein expression in the hippocampus and cerebral cortex of rat offspring at PND21 and PND 42, which may contribute to impaired neurodevelopment following exposure.


Fungal community structure in disease suppressive soils assessed by 28S LSU gene sequencing.
Natural biological suppression of soil-borne diseases is a function of the activity and composition of soil microbial communities. Soil microbe and phytopathogen interactions can occur prior to crop sowing and/or in the rhizosphere, subsequently influencing both plant growth and productivity. Research on suppressive microbial communities has concentrated on bacteria although fungi can also influence soil-borne disease. Fungi were analyzed in co-located soils 'suppressive' or 'non-suppressive' for disease caused by Rhizoctonia solani AG 8 at two sites in South Australia using 454 pyrosequencing targeting the fungal 28S LSU rRNA gene. DNA was extracted from a minimum of 125 g of soil per replicate to reduce the micro-scale community variability, and from soil samples taken at sowing and from the rhizosphere at 7 weeks to cover the peak Rhizoctonia infection period. A total of ∼ 994,000 reads were classified into 917 genera covering 54% of the RDP Fungal Classifier database, a high diversity for an alkaline, low organic matter soil. Statistical analyses and community ordinations revealed significant differences in fungal community composition between suppressive and non-suppressive soil and between soil type/location. The majority of differences associated with suppressive soils were attributed to less than 40 genera including a number of endophytic species with plant pathogen suppression potentials and mycoparasites such as Xylaria spp. Non-suppressive soils were dominated by Alternaria, Gibberella and Penicillum. Pyrosequencing generated a detailed description of fungal community structure and identified candidate taxa that may influence pathogen-plant interactions in stable disease suppression.


When Physicians Say No: Predictors of Request Denial and Subsequent Patient Satisfaction.
Physician denial of patient requests is associated with lower patient satisfaction. Our objective was to explore factors that influence physician request denial and patient satisfaction after request denial. Cross-sectional observational study of 1141 adult patients seen during 1319 outpatient visits with 56 primary care physicians. We measured patients' postvisit self-report of requests and request fulfillment, visit satisfaction, sociodemographics, health status, symptom burden, life satisfaction, medical skepticism, and whether patients saw their usual physician and a faculty or resident physician. We used mixed-effects regression analyses to identify predictors of request denial and visit satisfaction among patients who had a request denied. Patients made at least 1 request at 867 visits (65.7%) with at least 1 denied request reported at 182 visits (21.0%). Patients who saw their usual physician were less likely to report a request denial (adjusted Odds Ratio [aOR], 0.61; 95% CI, 0.42 to 0.88), and patients with the highest symptom burden (aOR, 2.21; 95% CI, 1.38 to 3.55) or greater medical skepticism (aOR, 1.35; 95% CI, 1.03 to 1.78) were more likely to report request denials. After request denials, patients seeing their usual physicians reported significantly greater visit satisfaction compared with not seeing their usual physician (adjusted percentile rank in visit satisfaction: 12.4%; 95% CI, 3.5% to 21.2%). Approximately one fifth of visits in primary care have a denied request. Having an office visit with one's usual physician is associated with reduced likelihood of request denial and may mitigate the adverse impacts of request denial on patient visit satisfaction.


Enteric-coated mycophenolate sodium delivers bioequivalent MPA exposure compared with mycophenolate mofetil.
Mycophenolic acid (MPA), the active moiety of mycophenolate mofetil (MMF), is routinely used as an adjunct immunosuppressant therapy in renal transplantation. Although highly effective, MMF therapy is associated with significant gastrointestinal adverse effects. Enteric-coated mycophenolate sodium (EC-MPS) is an advanced formulation delivering MPA. The enteric coat dissolves at pH > 5 allowing for MPA delivery in the small intestine. A single-center, open-label, randomized, three-way crossover study of 24 stable Caucasian renal transplant patients receiving cyclosporine-based immunosuppression, compared the relative bioavailability of two EC-MPS doses (640 and 720 mg) with MMF (1000 mg). Both EC-MPS doses delivered bioequivalent mean MPA exposure (AUC(0-infinity)) compared with 1000 mg MMF: 60.7 microg h/mL for 640 mg EC-MPS, 66.5 microg h/mL for 720 mg EC-MPS, and 63.7 microg h/mL for 1000 mg MMF. Median t(max) was significantly delayed for both EC-MPS doses compared with MMF (2.0 h vs. 0.75 h, respectively; p < 0.01), consistent with a functional enteric coating of EC-MPS. Furthermore, both EC-MPS doses were bioequivalent to 1000 mg MMF for AUC and C(max) for mycophenolic acid glucuronide. All three treatments were well tolerated. The EC-MPS 720 mg dose most closely approximated the MPA exposure of 1000 mg MMF and was selected for subsequent phase III studies.


Brain stimulation, mathematical, and numerical training: Contribution of core and noncore skills.
Mathematical abilities that are correlated with various life outcomes vary across individuals. One approach to improve mathematical abilities is by understanding the underlying cognitive functions. Theoretical and experimental evidence suggest that mathematical abilities are subserved by "core" and "noncore" skills. Core skills are commonly regarded as the "innate" capacity to attend to and process numerical information, while noncore skills are those that are important for mathematical cognition, but are not exclusive to the mathematical domain such as executive functions, spatial skills, and attention. In recent years, mathematical training has been combined with the application of noninvasive brain stimulation to further enhance training outcomes. However, the development of more strategic training paradigms is hindered by the lack of understanding on the contributory nature of core and noncore skills and their neural underpinnings. In the current review, we will examine the effects of brain stimulation with focus on transcranial electrical stimulation on core and noncore skills, and its impact on mathematical and numerical training. We will conclude with a discussion on the theoretical and experimental implications of these studies and directions for further research.