Efficacy of Vemurafenib in Patients With Non-Small-Cell Lung Cancer With BRAF V600 Mutation: An Open-Label, Single-Arm Cohort of the Histology-Independent VE-BASKET Study.
To study whether BRAF V600 mutations in non-small-cell lung cancer (NSCLC) may indicate sensitivity to the BRAF inhibitor vemurafenib, we included a cohort of patients with NSCLC in the vemurafenib basket (VE-BASKET) study. On the basis of observed early clinical activity, we expanded the cohort of patients with NSCLC. We present results from this cohort. This open-label, histology-independent, phase II study included six prespecified cohorts, including patients with NSCLC, and a seventh all-comers cohort. Patients received vemurafenib (960 mg two times per day) until disease progression or unacceptable toxicity. The primary end point of the final analysis was objective response rate (Response Evaluation Criteria in Solid Tumors, version 1.1). Secondary end points included progression-free survival, overall survival, and safety. Because the prespecified clinical benefit endpoint was met in the initial NSCLC cohort, the cohort was expanded. Sixty-two patients with BRAF V600-mutant NSCLC were enrolled and treated: 13% (n = 8) had received no prior systemic therapy, and 87% (n = 54) had received prior therapies. The objective response rate was 37.1% (95% CI, 25.2% to 50.3%) overall, 37.5% (95% CI, 8.5% to 75.5%) in previously untreated patients, and 37.0% (24.3% to 51.3%) in previously treated patients. Median progression-free survival was 6.5 months (95% CI, 5.2 to 9.0 months), and median overall survival was 15.4 months (95% CI, 9.6 to 22.8 months). The most common all-grade adverse event was nausea (40%). The safety profile of vemurafenib was similar to that observed in melanoma studies. Vemurafenib showed promising activity in patients with NSCLC harboring BRAF V600 mutations. The safety profile of vemurafenib was similar to previous observations in patients with melanoma. Our results suggest a role for single-agent BRAF inhibition in patients with NSCLC and BRAF V600 mutations.


Effects of dry needling on post-stroke spasticity, motor function and stability limits: a randomised clinical trial.
To determine the effects of inclusion of deep dry needling into a treatment session following the Bobath concept on spasticity, motor function and postural control after a stroke. 26 patients who had suffered a stroke were randomly assigned to one of two treatment groups: Bobath only, or Bobath plus dry needling. Both groups received a session including strengthening, stretching and reconditioning exercises following the principles of the Bobath concept. Patients in the Bobath plus dry needling group also received a single session of ultrasound-guided dry needling of the tibialis posterior. Spasticity (Modified Modified Ashworth Scale), function (Fugl-Meyer Scale) and stability limits (computerised dynamic posturography using the SMART EquiTest System) were collected before and 10 min after treatment by a blinded assessor. The parameters of the stability limits included movement velocity (MVL), maximum excursion (MXE), end-point excursion (EPE) and directional control (DCL). A greater number of individuals receiving Bobath plus dry needling exhibited a decrease in spasticity after treatment (P<0.001). Analysis of covariance (ANCOVA) showed that patients receiving Bobath plus dry needling exhibited greater improvements in the balance (0.8, 95% CI 0.2 to 1.4), sensory (1.7, 95% CI 0.7 to 2.7) and range of motion (3.2, 95% CI 2.0 to 4.4) domains of the Fugl-Meyer Scale than those receiving Bobath only. ANCOVA also found that subjects receiving dry needling showed a greater increase in MVL non-affected forward direction, EPE non-affected direction, MXE backward and MXE affected/non-affected, DCL backward and DCL affected backward direction, than those who did not receive it. The inclusion of deep dry needling into a treatment session following the Bobath concept was effective at decreasing spasticity and improving balance, range of motion and the accuracy of maintaining stability in patients who had experienced a stroke. NCT02579291.


Population Genetic Structure and Demographic History of Primula fasciculata in Southwest China.
Understanding the factors that drive the genetic structure of a species and its responses to past climatic changes is an important first step in modern population management. The response to the last glacial maximum (LGM) has been well studied, however, the effect of previous glaciation periods on plant demographic history is still not well studied. Here we investigated the population structure and demographic history of Primula fasciculata that widely occurs in the Hengduan Mountains and Qinghai-Tibetan Plateau. We obtained genomic data for 234 samples of the species using restriction site-associated DNA (RAD) sequencing and combined approximate Bayesian computation (ABC) and species distribution modeling (SDM) to evaluate the effects of multiple glaciation periods by testing several population divergence models and demographic scenarios. The analyses of population structure showed that P. fasciculata displays a striking population structure with six groups that could be identified genetically. Our ABC modeling suggested that the current groups diverged from ancestral populations located in the eastern Hengduan Mountains after the largest glaciation occurred in the region (~ 0.8-0.5 million years ago), which is consistent with the result of SDMs. Each current group has survived in different glacial refugia during the LGM and experienced expansions and/or bottlenecks since their divergence during or across the following Quaternary glacial cycles. Our study demonstrates the usefulness of population genomics for evaluating the effects of past climatic changes in alpine plant species with shallow population structure.


Piketty in the long run.
I examine the idea of 'the long run' in Piketty (2014) and related works. In contrast to simplistic interpretations of long-run models of income- and wealth-distribution Piketty (2014) draws on a rich economic analysis that models the intra- and inter-generational processes that underly the development of the wealth distribution. These processes inevitably involve both market and non-market mechanisms. To understand this approach, and to isolate the impact of different social and economic factors on inequality in the long run, we use the concept of an equilibrium distribution. However the long-run analysis of policy should not presume that there is an inherent tendency for the wealth distribution to approach equilibrium.


Effective frequency technique for finite spectral bandwidth effects.
A technique that uses a single effective frequency to represent the effects of finite spectral bandwidth for active and passive measurements centered on an absorption line, a trough region, or a slowly varying spectral feature is described. For Gaussian and rectangular instrumental line shapes, the effective frequency is shown to have a simple form that depends only on the instrumental line shape and bandwidth and not on the absorption line profile. The technique is applicable to a large class of active and passive measurements and simulations in both the laboratory and the atmosphere. Simulations show that the technique yields accuracies better than 0.1% for bandwidths less than 0.2 times the atmospheric linewidth for a rectangular line shape or better than 0.2% for a Gaussian.


Vaccination Route as a Determinant of Protective Antibody Responses against Herpes Simplex Virus.
Herpes simplex viruses (HSV) are significant global health problems associated with mucosal and neurologic disease. Prior experimental vaccines primarily elicited neutralizing antibodies targeting glycoprotein D (gD), but those that advanced to clinical efficacy trials have failed. Preclinical studies with an HSV-2 strain deleted in gD (ΔgD-2) administered subcutaneously demonstrated that it elicited a high titer, weakly neutralizing antibodies that activated Fcg receptors to mediate antibody-dependent cellular cytotoxicity (ADCC), and completely protected mice against lethal disease and latency following vaginal or skin challenge with HSV-1 or HSV-2. Vaccine efficacy, however, may be impacted by dose and route of immunization. Thus, the current studies were designed to compare immunogenicity and efficacy following different routes of vaccination with escalating doses of ΔgD-2. We compared ΔgD-2 with two other candidates: recombinant gD protein combined with aluminum hydroxide and monophosphoryl lipid A adjuvants and a replication-defective virus deleted in two proteins involved in viral replication, dl5-29. Compared to the subcutaneous route, intramuscular and/or intradermal immunization resulted in increased total HSV antibody responses for all three vaccines and boosted the ADCC, but not the neutralizing response to ΔgD and dl5-29. The adjuvanted gD protein vaccine provided only partial protection and failed to elicit ADCC independent of route of administration. In contrast, the increased ADCC following intramuscular or intradermal administration of DgD-2 or dl5-29 translated into significantly increased protection. The DgD-2 vaccine provided 100% protection at doses as low as 5 × 104 pfu when administered intramuscularly or intradermally, but not subcutaneously. However, administration of a combination of low dose subcutaneous DgD-2 and adjuvanted gD protein resulted in greater protection than low dose DgD-2 alone indicating that gD neutralizing antibodies may contribute to protection. Taken together, these results demonstrate that ADCC provides a more predictive correlate of protection against HSV challenge in mice and support intramuscular or intradermal routes of vaccination.


The Warwick Hip Trauma Evaluation Two -an abridged protocol for the WHiTE Two Study: An embedded randomised trial comparing the Dual-Mobility withpolyethylene cups in hip arthroplasty for fracture.
Fractures of the proximal femur are one of the greatest challenges facing the medical community, constituting a heavy socioeconomic burden worldwide. Controversy exists regarding the optimal treatment for independent patients with displaced intracapsular fractures of the proximal femur. The recognised alternatives are hemiarthroplasty and total hip replacement. At present there is no established standard of care, with both types of arthroplasty being used in many centres. The principal advantages of total hip replacement are a functional benefit over hemiarthroplasty and a reduced risk of revision surgery. The principal criticism is the increased risk of dislocation. We believe that an alternative acetabular component may reduce the risk of dislocation but still provide the functional benefit of total hip replacement in these patients. We therefore propose to investigate the dislocation risk of a dual-mobility acetabular component compared with standard polyethylene component in total hip replacement for independent patients with displaced intracapsular fractures of the proximal femur within the framework of the larger WHiTE (Warwick Hip Trauma Evaluation) Comprehensive Cohort Study. Cite this article: Bone Joint Res 2013;2:210-13.


Sequential assembly of flagellar radial spokes.
The unicellular alga Chlamydomonas can assemble two 10 μm flagella in 1 h from proteins synthesized in the cell body. Targeting and transporting these proteins to the flagella are simplified by preassembly of macromolecular complexes in the cell body. Radial spokes are flagellar complexes that are partially assembled in the cell body before entering the flagella. On the axoneme, radial spokes are "T" shaped structures with a head of five proteins and a stalk of 18 proteins that sediment together at 20S. In the cell body, radial spokes are partially assembled; about half of the radial spoke proteins (RSPs) form a 12S complex. In mutants lacking a single RSP, smaller spoke subassemblies were identified. When extracts from two such mutants were mixed in vitro the 12S complex was assembled from several smaller complexes demonstrating that portions of the stepwise assembly of radial spoke assembly can be carried out in vitro to elucidate the order of spoke assembly in the cell body.


Effect of partial hepatectomy on removal of O6-methylguanine from alkylated DNA by rat liver extracts.
1. The activity of an enzyme catalysing the loss of O6-methylguanine from methylated DNA was increasing during liver regeneration after partial hepatectomy. Activity was increased 3-fold by 24h and was maximal (6-fold increase) over the period 48-72h after operation. 2. This activity could also be induced by chronic treatment with dimethylnitrosamine, but the maximal response amounted to a 2-3-fold change (with the greater effect in male rats) after 4-6 weeks of exposure to daily doses of 2 mg of dimethylnitrosamine/kg. 3. Neither partial hepatectomy nor treatment with dimethylnitrosamine increased the activities of two other enzymes repairing alkylated DNA, DNA (7-methylguanine-)glycosylase and DNA (3-methyladenine-)glycosylase. 4. These results therefore indicate that there is a selective induction of the O6-methylguanine removal system during hepatocyte proliferation. Since this product is known to lead to mutations and its persistence in DNA throughout cell replication has been implicated in tumour initiation, this induction may play a role in resistance to carcinogenesis by alkylating agents.


Children's probability intuitions: understanding the expected value of complex gambles.
Two experiments used Information Integration Theory to study how children judge expected value of complex gambles in which alternative outcomes have different prizes. Six-year-olds, 9-year-olds and adults (N = 73 in Study 1, N = 28 in Study 2) saw chance games that involved shaking a marble in a bicolored tube. One prize was won if the marble stopped on blue, another if it stopped on yellow. Children judged how happy a puppet playing the game would be, with the prizes and probability of the blue and yellow outcomes varied factorially. Three main results appeared in both studies: First, participants in all age groups used the normatively prescribed multiplication rule for integrating probability and value of each individual outcome--a striking finding because multiplicative reasoning does not usually appear before 8 years of age in other domains. Second, all age groups based judgment of overall expected value meaningfully on both alternative outcomes, but there were individual differences--many participants deviated from the normative addition rule, showing risk seeking and risk averse patterns of judgment similar to the risk attitudes often found with adults. Third, even the youngest children took probability to be an abstract rather than physical property of the game. Overall, in contrast to the traditional view, the present results demonstrate functional understanding of probability and expected value in children as young as 5 or 6. These results contribute to the growing evidence on children's intuitive reasoning competence. This intuition can, on the one hand, support surprisingly precocious performance in young children, but it may also contribute to the biases evident in adults' judgment and decision.


Wash durability and optimal drying regimen of four brands of long-lasting insecticide-treated nets after repeated washing under tropical conditions.
The current study was undertaken to determine the optimal wash-drying regimen and the effects of different washing procedures on the efficacy, and durability of four brands of newly introduced long-lasting insecticide-treated nets (LLINs) under tropical conditions. In the current study, the following four LLINs were tested: Olyset, PermaNet 2.0, BASF and TNT. Nets were divided into three sets; one set was washed by hand rubbing and air-dried either hanging or spread on the ground in direct sunlight or hanging or spread on the ground under the shade. A second set was washed using the WHO protocol (machine) and the third set was washed by beating the nets on rocks. The biological activities of the nets were assessed by a three-minute bioassay cone test and the residual insecticide contents were determined using high performance liquid chromatography (HPLC) procedure. Nets that were dried hanging under the shade retained more insecticide, 62.5% and recorded higher mortality compared to nets which were dried lying on the ground in direct sunlight 58.8%, nets dried under the shade spread on the ground 56.3%, and 57.8% for nets dried hanging in direct sunlight. It was also observed that nets washed by the standard WHO protocol, retained more insecticide and were more effective in killing mosquitoes compared to nets washed by local methods of hand rubbing and beating on rocks. There were significant differences between drying regimens (p < 0.0001) and between washing procedures (p < 0.001) respectively. However, the effect of net type was statistically insignificant. The statistical differences on individual nets were also compared, for PermaNet and TNT there were no significant differences observed between the four drying regimens (p = 0.7944 and 0.4703) respectively). For BASF and Olyset, the differences were significant (p < 0.001 and p > 0.0001). The results of this study suggest that washing and drying regimen influence the insecticidal activity of LLINs. The standard WHOPES washing protocol underestimates the amount of insecticide washed from LLINs compared to the abrasive washing procedures that are used in the field. This suggests that there is need to educate net users to adopt a more gentle washing procedure while handling LLINs. The education should accompany net distribution campaigns.


Parent's information seeking in acute childhood illness: what helps and what hinders decision making?
Acute illness is a universal experience in early childhood. Parents find it difficult to determine whether or not their child requires medical care and seek information to inform their decision making. Little is known about parents' information seeking behaviour and what helps or hinders their decision making. This study aimed to explore parents' use of information resources during decision making in acute childhood illness at home. This exploratory qualitative study used focus groups and interviews to collect data from parents of children under 5 years of age. Twenty-seven parents were recruited in the East Midlands, UK, in South Asian and Gypsy/Travelling communities, a Children's Centre and a private sector day nursery. Parents' pre-consultation information seeking was dominated by the internet, albeit with limited success. Parents liked easy to access, professionally validated and simple messages with access to more detailed information. Some parents always sought information through personal contact, whilst others did so when independent information seeking failed. When consulting a healthcare professional, parents liked to be given information to refer to later, although the information received varied. Importantly, neither hard copy nor the internet was accessible for parents with low levels of literacy. Although there is a wealth of information parents can access independently, our findings indicate a need for easy access to clearly signposted, professionally validated resources and available in a range of formats provided through different delivery systems. One size does not fit all.


Molecular characteristics of Human Endogenous Retrovirus type-W in schizophrenia and bipolar disorder.
Epidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type 'W' family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10-4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders.


Autoassembly protein arrays for analyzing antibody cross-reactivity.
We report an autoassembly protein array capable of rapidly screening for aberrant antibody-antigen binding events. Our technique combines magnetic nanoparticle technology with proximity-based, magnetically responsive nanosensors for rapid (under 15 min) and high-density screening of antibody cross-reactivity at sensitivities down to 50 fM in a homogeneous assay. This method will enable the identification of the precise cause of aberrant or cross-reactive binding events in an easy-to-use, rapid, and high-throughput manner.


The role of informal networks in providing effective work opportunities for people with an intellectual disability.
Being in paid employment is socially valued, and is linked to health, financial security and time use. Issues arising from a lack of occupational choice and control, and from diminished role partnerships are particularly problematic in the lives of people with an intellectual disability. Informal support networks are shown to influence work opportunities for people without disabilities, but their impact on the work experiences of people with disability has not been thoroughly explored. The experience of 'work' and preparation for work was explored with a group of four people with an intellectual disability (the participants) and the key members of their informal support networks (network members) in New South Wales, Australia. Network members and participants were interviewed and participant observations of work and other activities were undertaken. Data analysis included open, conceptual and thematic coding. Data analysis software assisted in managing the large datasets across multiple team members. The insight and actions of network members created and sustained the employment and support opportunities that effectively matched the needs and interests of the participants. Recommendations for future research are outlined.


Protective effects of hydrogen-rich saline in preeclampsia rat model.
Hydrogen has been reported as a novel antioxidant to selectively reduce levels of toxic reactive-oxygen species (ROS). We investigated the effects of hydrogen-rich saline on the prevention of oxidative injuries in N(omega)-nitro-L-arginine methyl ester (L-NAME) induced rat model of preeclampsia (PE). Sprague-Dawley rats (n = 50) were randomized into five groups: non-pregnant; normal pregnancy; pregnancy + hydrogen saline, 5 ml/kg, intraperitoneal (i.p.); pregnancy + L-NAME, 60 mg/kg (i.p.); pregnancy + L-NAME + hydrogen saline rats. Terminations of pregnancy were performed on day 22 of gestation, when the placentas and kidneys were microscopically inspected; tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and malonyldialdehyde (MDA) were assessed; and the mean systolic BP, level of proteinuria, resorptions, and pups birth weights were recorded. It was found that the pups of hypertensive gravid rats treated with hydrogen-rich saline presented fewer number of resorptions than those of the group of pregnancy + L-NAME, 60 mg/kg i.p. (P < 0.05). Additionally, hydrogen-rich saline treatment decreased the blood and placental MDA, proteinuria and the pro-inflammatory cytokine TNF-α, IL-1β in the placental tissues compared with those in L-NAME-treated rats (all P < 0.05). The mean systolic BP showed no significant difference except on day 22 of gestation (P < 0.05). The preventive administration of hydrogen significantly attenuated the severity of PE, which might be ascribed to a reduction in inflammation response and oxidative stress. It could be concluded that hydrogen can be an effective antioxidant in the management of PE.


Positive effects of organic farming on below-ground mutualists: large-scale comparison of mycorrhizal fungal communities in agricultural soils.
*The impact of various agricultural practices on soil biodiversity and, in particular, on arbuscular mycorrhizal fungi (AMF), is still poorly understood, although AMF can provide benefit to plants and ecosystems. Here, we tested whether organic farming enhances AMF diversity and whether AMF communities from organically managed fields are more similar to those of species-rich grasslands or conventionally managed fields. *To address this issue, the AMF community composition was assessed in 26 arable fields (13 pairs of organically and conventionally managed fields) and five semi-natural grasslands, all on sandy soil. Terminal restriction fragment length polymorphism community fingerprinting was used to characterize AMF community composition. *The average number of AMF taxa was highest in grasslands (8.8), intermediate in organically managed fields (6.4) and significantly lower in conventionally managed fields (3.9). Moreover, AMF richness increased significantly with the time since conversion to organic agriculture. AMF communities of organically managed fields were also more similar to those of natural grasslands when compared with those under conventional management, and were less uniform than their conventional counterparts, as expressed by higher beta-diversity (between-site diversity). *We suggest that organic management in agro-ecosystems contributes to the restoration and maintenance of these important below-ground mutualists.


A modified fluctuation assay reveals a natural mutator phenotype that drives mutation spectrum variation within Saccharomyces cerevisiae.
Although studies of Saccharomyces cerevisiae have provided many insights into mutagenesis and DNA repair, most of this work has focused on a few laboratory strains. Much less is known about the phenotypic effects of natural variation within S. cerevisiae's DNA repair pathways. Here, we use natural polymorphisms to detect historical mutation spectrum differences among several wild and domesticated S. cerevisiae strains. To determine whether these differences are likely caused by genetic mutation rate modifiers, we use a modified fluctuation assay with a CAN1 reporter to measure de novo mutation rates and spectra in 16 of the analyzed strains. We measure a 10-fold range of mutation rates and identify two strains with distinctive mutation spectra. These strains, known as AEQ and AAR, come from the panel's 'Mosaic beer' clade and share an enrichment for C > A mutations that is also observed in rare variation segregating throughout the genomes of several Mosaic beer and Mixed origin strains. Both AEQ and AAR are haploid derivatives of the diploid natural isolate CBS 1782, whose rare polymorphisms are enriched for C > A as well, suggesting that the underlying mutator allele is likely active in nature. We use a plasmid complementation test to show that AAR and AEQ share a mutator allele in the DNA repair gene OGG1, which excises 8-oxoguanine lesions that can cause C > A mutations if left unrepaired.


The potential mechanism of the diabetogenic action of streptozotocin: inhibition of pancreatic beta-cell O-GlcNAc-selective N-acetyl-beta-D-glucosaminidase.
Streptozotocin (STZ), an analogue of GlcNAc, inhibits purified rat spleen O-GlcNAc-selective N-acetyl-beta-D-glucosaminidase (O-GlcNAcase), the enzyme that removes O-GlcNAc from protein. We have shown previously that STZ increases pancreatic islet O-linked protein glycosylation. In light of these data, we investigated the possibility further that STZ causes beta-cell death by inhibiting O-GlcNAcase. In isolated islets, the time course and dose curve of STZ-induced O-glycosylation correlated with beta-cell toxicity. STZ inhibition of rat islet O-GlcNAcase activity also paralleled that of its beta-cell toxicity, with significant inhibition occurring at a concentration of 1 mM. In contrast, STZ inhibition of rat brain O-GlcNAcase and beta-TC3 insulinoma cell O-GlcNAcase was significantly right-shifted compared with islets, with STZ only significantly inhibiting activity at a concentration of 5 mM, the same concentration required for beta-TC3 cell toxicity. In comparison, N-methyl-N-nitrosourea, the nitric oxide-donating portion of STZ, did not cause increased islet O-glycosylation, beta-cell toxicity or inhibition of beta-cell O-GlcNAcase. Enhanced STZ sensitivity of islet O-GlcNAcase compared with O-GlcNAcase from other tissues or an insulinoma cell line suggests why actual islet beta-cells are particularly sensitive to STZ. Confirming this idea, STZ-induced islet beta-cell toxicity was completely blocked by GlcNAc, which also prevented STZ-induced O-GlcNAcase inhibition, but was not even partially blocked by glucose, glucosamine or GalNAc. Together, these data demonstrate that STZ's inhibition of beta-cell O-GlcNAcase is the mechanism that accounts for its diabetogenic toxicity.


Placental monocyte infiltrates in response to Plasmodium falciparum malaria infection and their association with adverse pregnancy outcomes.
Maternal anemia and low birth weight (LBW) may complicate malaria in pregnancy, and placental monocyte infiltrates have been associated with LBW, and anecdotally with anemia. We examined placental pathology from 357 Malawian women. Intervillous monocyte infiltrates were frequent in placental malaria and were not seen in uninfected placentas. Histology was grouped according to a 5-point scale. Dense monocyte infiltrates and presence of intramonocytic malaria pigment were associated with anemia and LBW. Of factors associated with LBW and/or anemia in univariate analysis, gravidity (P = 0.002), number of antenatal clinic (ANC) visits (P < 0.001), malaria pigment in fibrin (P = 0.03), and monocyte malaria pigment (P = 0.0001) remained associated with lower birth weight by multivariate analysis. Associated with maternal anemia were HIV infection (P < 0.0001), intervillous monocyte numbers (P < 0.0001), number of ANC visits (P = 0.002), and recent febrile symptoms (P = 0.0001). Pigment-containing placental monocytes are associated with anemia and LBW due to malaria, and may have a causative role in their development.


Early diagnosis of pancreatic cancer: challenges and new developments.
Pancreatic cancer is a lethal malignancy with its incidence almost equivalent to mortality. The complex pathophysiology, absence of early diagnostic and prognostic markers and unresponsiveness to radiation and chemotherapies are major barriers against successful therapy. Poor performance of therapeutic agents, even in the initial stage of invasive cases, emphasizes the importance of early detection for improved survival. The present review discusses the challenges and advances in biomarkers including serological signatures, circulating tumor cells, autoantibodies, epigenetic markers and miRNAs that are being explored to detect this cancer at early stages. Considering the long time gap between the development of malignant lesions and full-blown primary and metastatic pancreatic cancer, unique opportunities are being contemplated for the development of potential diagnostic and prognostic markers.


Systematic review of the potential role of cannabinoids as antiproliferative agents for urological cancers.
The palliative effects of cannabis sativa (marijuana), which include appetite stimulation, attenuation of nausea and emesis, and pain relief, are well known. The active components of cannabis sativa (cannabinoids) and their derivatives have received growing interest due to their diverse pharmacological activities, such as cell growth inhibition and tumour regression. The aim of this review is to look at the current evidence on the antiproliferative effects of cannabinoids in urological malignancies, including renal, prostate, bladder, and testicular cancers. We conducted a systematic review of studies exploring the effect of cannabinoids on tumour activity, including all study types except expert opinions. A formal search was run on Medline database from 1946 to September 2016, along with a hand-search on PubMed for relevant studies. The search yielded a total of 93 studies from Medline and PubMed, of which 23 studies were included in the final analysis. To date, there are various in vitro studies elucidating the potential mechanism of action of cannabinoids for urological cancers, along with population-based studies specifically for testicular malignancies. To date, no clinical trials have been conducted for urological cancer patients. These results demonstrate that the role of endocannabinoids for urological malignancies is an area of active research. Further research is required not only to evaluate the crosstalk between cancer signaling pathways and cannabinoids, but also large randomized clinical studies with urological patients need to be conducted before cannabinoids can be introduced as potential therapeutic options for urological neoplasms.


Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation.
The three-dimensional genome organization is critical for gene regulation and can malfunction in diseases like cancer. As a key regulator of genome organization, CCCTC-binding factor (CTCF) has been characterized as a DNA-binding protein with important functions in maintaining the topological structure of chromatin and inducing DNA looping. Among the prolific binding sites in the genome, several events with altered CTCF occupancy have been reported as associated with effects in physiology or disease. However, hitherto there is no comprehensive survey of genome-wide CTCF binding patterns across different human cancers. To dissect functions of CTCF binding, we systematically analyze over 700 CTCF ChIP-seq profiles across human tissues and cancers and identify cancer-specific CTCF binding patterns in six cancer types. We show that cancer-specific lost and gained CTCF binding events are associated with altered chromatin interactions, partially with DNA methylation changes, and rarely with sequence mutations. While lost bindings primarily occur near gene promoters, most gained CTCF binding events exhibit enhancer activities and are induced by oncogenic transcription factors. We validate these findings in T cell acute lymphoblastic leukemia cell lines and patient samples and show that oncogenic NOTCH1 induces specific CTCF binding and they cooperatively activate expression of target genes, indicating transcriptional condensation phenomena. Specific CTCF binding events occur in human cancers. Cancer-specific CTCF binding can be induced by other transcription factors to regulate oncogenic gene expression. Our results substantiate CTCF binding alteration as a functional epigenomic signature of cancer.


Direct Observation of Structural Heterogeneity and Tautomerization of Single Hypericin Molecules.
Tautomerization is a fundamental chemical reaction which involves the relocation of a proton in the reactants. Studying the optical properties of tautomeric species is challenging because of ensemble averaging. Many molecules, such as porphines, porphycenes, or phenanthroperylene quinones, exhibit a reorientation of the transition dipole moment (TDM) during tautomerization, which can be directly observed in single-molecule experiments. Here, we study single hypericin molecules, which is a prominent phenanthroperylene quinone showing antiviral, antidepressive, and photodynamical properties. Observing abrupt flipping of the image pattern combined with time-dependent density functional theory calculations allows drawing conclusions about the coexistence of four tautomers and their conversion path. This approach allows the unambiguous assignment of a TDM orientation to a specific tautomer and enables the determination of the chemical structure in situ. Our approach can be applied to other molecules showing TDM reorientation during tautomerization, helping to gain a deeper understanding of this important process.


Event-related functional magnetic resonance imaging changes during relational retrieval in normal aging and amnestic mild cognitive impairment.
The earliest cognitive deficits observed in amnestic mild cognitive impairment (aMCI) appear to center on memory tasks that require relational memory (RM), the ability to link or integrate unrelated pieces of information. RM impairments in aMCI likely reflect neural changes in the medial temporal lobe (MTL) and posterior parietal cortex (PPC). We tested the hypothesis that individuals with aMCI, as compared to cognitively normal (CN) controls, would recruit neural regions outside of the MTL and PPC to support relational memory. To this end, we directly compared the neural underpinnings of successful relational retrieval in aMCI and CN groups, using event-related functional magnetic resonance imaging (fMRI), holding constant the stimuli and encoding task. The fMRI data showed that the CN, compared to the aMCI, group activated left precuneus, left angular gyrus, right posterior cingulate, and right parahippocampal cortex during relational retrieval, while the aMCI group, relative to the CN group, activated superior temporal gyrus and supramarginal gyrus for this comparison. Such findings indicate an early shift in the functional neural architecture of relational retrieval in aMCI, and may prove useful in future studies aimed at capitalizing on functionally intact neural regions as targets for treatment and slowing of the disease course. (JINS, 2012, 18, 1-12).


Effect of coffee on the compositional shift of oral indigenous microbiota cultured in vitro.
Coffee is a widely consumed beverage containing organic compounds with antibacterial activity. To investigate its possible effect on the growth of oral indigenous microbiota, saliva samples collected from nine young adults were inoculated into brain heart infusion (BHI) medium with or without addition of coffee compounds and cultured at 37°C in 5% CO2 for 12 h. The total bacterial density and composition after cultivation for 0, 6, and 12 h were determined by quantitative PCR analysis and 16S rRNA gene sequencing, respectively. The increase in total bacterial load was significantly inhibited by addition of the coffee compounds. The microbiota was mostly composed of Streptococcus species after culture in BHI medium regardless of the addition of coffee compounds. The proportion of Streptococcus salivarius was significantly reduced after addition of coffee relative to that in untreated medium alone, whereas the proportions of Streptococcus mitis and Streptococcus infantis were increased. These results suggest that exposure to coffee affects the composition of the oral Streptococcus population, in addition to inhibiting the overall growth of salivary bacteria. Considered in the light of data from earlier epidemiological studies, it is possible to conclude that coffee consumption contributes to better health.


Engineering and manufacturing of pharmaceutical co-crystals: a review of solvent-free manufacturing technologies.
Design and synthesis of pharmaceutical cocrystals have received great interest in recent years. Cocrystallization of drug substances offers a tremendous opportunity for the development of new drug products with superior physical and pharmacological properties such as solubility, stability, hydroscopicity, dissolution rates and bioavailability. It is now possible to engineer and develop cocrystals via 'green chemistry' and environmentally friendly approaches such as solid-state synthesis in the absence of organic solvents. In addition, significant efforts have been directed towards computational screening, cocrystal manufacturing in a continuous manner and real-time monitoring for quality purposes by using various analytical tools. Pharmaceutical cocrystals are not fully exploited yet and there is a lot of ground to cover before they can be successfully utilized as medical products.


Review. Reflections on amyloidosis in Papua New Guinea.
The amyloidoses comprise a heterogeneous group of diseases in which 1 out of more than 25 human proteins aggregates into characteristic beta-sheet fibrils with some unique properties. Aggregation is nucleation dependent. Among the known amyloid-forming constituents is the prion protein, well known for its ability to transmit misfolding and disease from one individual to another. There is increasing evidence that other amyloid forms also may be transmissible but only if certain prerequisites are fulfilled. One of these forms is systemic AA-amyloidosis in which an acute-phase reactant, serum AA, is over-expressed and, possibly after cleavage, aggregates into amyloid fibrils, causing disease. In a mouse model, this disorder can easily be transmitted from one animal to another both by intravenous and oral routes. Also, synthetic amyloid-like fibrils made from defined small peptides have this property, indicating a prion-like transmission mechanism. Even some fibrils occurring in the environment can transmit AA-amyloidosis in the murine model. AA-amyloidosis is particularly common in certain areas of Papua New Guinea, probably due to the endemicity of malaria and perhaps genetic predisposition. Now, when kuru is disappearing, more interest should be focused on the potentially lethal systemic AA-amyloidosis.


Role of estimation of arterial blood gases in the management of stridor.
We studied the epidemiology and etiology of stridor in our patients along with the role of arterial blood gas (ABG) analysis in their management. We also reviewed their prognostic indices and the clinical outcomes. It was a prospective study in a tertiary referral hospital in which 72 patients presenting with stridor, were independently evaluated by 3 different clinicians and clinically classified into mild, moderate and severe. Based on ABG values (pH, PO2, PCO2), we defined 3 groups of patients viz, those in respiratory failure, impending respiratory failure and those with no evidence of failure. Treatment was directed at the cause of stridor. Clinical outcomes were assessed and results classified as resolved, improved, stable and death. Out of 72 patients, kappa coefficient of agreement between the 3 observers were found to be 0.014, indicating poor interobserver reliability for the working clinical classification. However, ABG analysis indicated otherwise, with 6 patients in respiratory failure, 19 progressing to impending failure. Hence we complied by the more objective ABG analysis in planning management. Laryngomalacia in children and hypopharyngeal malignancies in adults were found to be the most common causes of stridor in our study. As compared to other conditions, laryngomalacia in children had a poorer outcome (p = 0.001). Early detection of impending respiratory failure was instrumental in achieving better clinical outcomes in our patients presenting with stridor. Thus we inferred that ABG analysis is a valuable tool in the effective management of stridor.


Genome-wide association mapping in a diverse spring barley collection reveals the presence of QTL hotspots and candidate genes for root and shoot architecture traits at seedling stage.
Adaptation to drought-prone environments requires robust root architecture. Genotypes with a more vigorous root system have the potential to better adapt to soils with limited moisture content. However, root architecture is complex at both, phenotypic and genetic level. Customized mapping panels in combination with efficient screenings methods can resolve the underlying genetic factors of root traits. A mapping panel of 233 spring barley genotypes was evaluated for root and shoot architecture traits under non-stress and osmotic stress. A genome-wide association study elucidated 65 involved genomic regions. Among them were 34 root-specific loci, eleven hotspots with associations to up to eight traits and twelve stress-specific loci. A list of candidate genes was established based on educated guess. Selected genes were tested for associated polymorphisms. By this, 14 genes were identified as promising candidates, ten remained suggestive and 15 were rejected. The data support the important role of flowering time genes, including HvPpd-H1, HvCry2, HvCO4 and HvPRR73. Moreover, seven root-related genes, HERK2, HvARF04, HvEXPB1, PIN5, PIN7, PME5 and WOX5 are confirmed as promising candidates. For the QTL with the highest allelic effect for root thickness and plant biomass a homologue of the Arabidopsis Trx-m3 was revealed as the most promising candidate. This study provides a catalogue of hotspots for seedling growth, root and stress-specific genomic regions along with candidate genes for future potential incorporation in breeding attempts for enhanced yield potential, particularly in drought-prone environments. Root architecture is under polygenic control. The co-localization of well-known major genes for barley development and flowering time with QTL hotspots highlights their importance for seedling growth. Association analysis revealed the involvement of HvPpd-H1 in the development of the root system. The co-localization of root QTL with HERK2, HvARF04, HvEXPB1, PIN5, PIN7, PME5 and WOX5 represents a starting point to explore the roles of these genes in barley. Accordingly, the genes HvHOX2, HsfA2b, HvHAK2, and Dhn9, known to be involved in abiotic stress response, were located within stress-specific QTL regions and await future validation.


Esthesioneuroblastoma in pediatric and adolescent age. A report from the TREP project in cooperation with the Italian Neuroblastoma and Soft Tissue Sarcoma Committees.
Esthesioneuroblastoma (ENB) is a rare, aggressive tumor with no established treatment in children. We analyzed a series of pediatric ENB patients with the aim of improving our knowledge of this disease. 9 patients (6 males; age 0.9-18 years, median 9.9) were identified by searching the AIEOP (Italian Association of Pediatric Hematology and Oncology) registry and the national databases of rare tumors, soft tissue sarcomas (STS) and neuroblastomas. The data on the cases included in STS treatment protocols were collected prospectively and histology was centrally reviewed; the data and histology concerning the other children were reviewed for the purpose of this analysis. All tumors occurred in the sinonasal region with bone erosion (7 patients) and intracranial (4) or intraorbital (4) extension. Three patients were in Kadish stage B, and 6 in stage C. Complete tumor resection was very difficult to achieve, but adding chemotherapy and radiotherapy enabled tumor control in 8 patients. Response to chemotherapy was evident in 5/7 evaluable cases. Radiotherapy (48.5-60 Gy) was delivered in all children but one, due to early disease progression. With a median follow-up of 13.4 years (range 9.2-22.9), 7 patients are alive in 1st and one in 2nd complete remission. All surviving patients developed treatment-related sequelae, the most frequent being endocrine dysfunctions (4 patients) and craniofacial growth impairments (4 patients). Our findings confirm that ENB in children has an aggressive presentation, but multimodal therapy can cure most patients. Our results are encouraging but future strategies must optimize treatment in terms of survival and related morbidities.


Assessing the Preferences for Criteria in Multi-Criteria Decision Analysis in Treatments for Rare Diseases.
Background: Increasingly, multi-criteria decision analysis has gained importance as a method by which to assess the value of orphan drugs. However, very little attention has been given to the weight (relative preferences) of the individual criteria used in a framework. Aims: This study sought to gain an understanding of the preferential weights that should be allocated in a multi-criteria decision analysis framework for orphan drugs, from a multi-stakeholder perspective. Method: Using key MCDA criteria for orphan drugs reported in the literature, we developed an interactive web-based survey tool to capture preferences for different criteria from a general stakeholder sample who were requested to assign weights from a reimbursement perspective. Each criterion could be assigned a weight on a sliding scale from 0 to 100% as long as the sum of all the criteria was 100%. We subsequently used the interactive tool with an expert focus group, followed up with a group discussion regarding each criterion and their perspectives on the weight that each criterion should be allocated when assessing an orphan drug. The expert focus group participants were then able to adjust their weights, if the group discussion had changed their perspectives. Results: The interactive tool was completed by 120 general stakeholder sample from a wide range of countries and professional backgrounds and an expert focus group of ten members. The results showed the differences in perspectives on the importance of criteria. Both groups considered Treatment efficacy to be the most important criterion. The general stakeholder sample weighted Treatment safety at 12.03% compared to the expert focus group's average of 20%. The results also demonstrated the value of the group discussion, which provided additional insights into the perspectives on the importance of criteria in assessing orphan drugs. Conclusion: This study aimed to contribute to the important aspect of preferences for different criteria in MCDA. This study sheds light on the important aspect of the preferences of the different criteria. All respondents agreed on the relative importance of Treatment efficacy and Treatment safety, criteria that are captured in conventional cost-effectiveness studies, but they also expressed the view that in addition to those, several disease-related and drug-related criteria should be included in MCDA frameworks for assessing orphan drugs.


Alpha-lipoic acid decreases thiol reactivity of the insulin receptor and protein tyrosine phosphatase 1B in 3T3-L1 adipocytes.
Alpha-lipoic acid is known to increase insulin sensitivity in vivo and to stimulate glucose uptake into adipose and muscle cells in vitro. In this study, alpha-lipoic acid was demonstrated to stimulate the autophosphorylation of insulin receptor and glucose uptake into 3T3-L1 adipocytes by reducing the thiol reactivity of intracellular proteins. To elucidate mechanism of this effect, role of protein thiol groups and H(2)O(2) in insulin receptor autophosphorylation and glucose uptake was investigated in 3T3-L1 adipocytes following stimulation with alpha-lipoic acid. Alpha-lipoic acid or insulin treatment of adipocytes increased intracellular level of oxidants, decreased thiol reactivity of the insulin receptor beta-subunit, increased tyrosine phosphorylation of the insulin receptor, and enhanced glucose uptake. Alpha-lipoic acid or insulin-stimulated glucose uptake was inhibited (i) by alkylation of intracellular, but not extracellular, thiol groups downstream of insulin receptor activation, and (ii) by diphenylene iodonium at the level of the insulin receptor autophosphorylation. alpha-Lipoic acid also inhibited protein tyrosine phosphatase activity and decreased thiol reactivity of protein tyrosine phosphatase 1B. These findings indicate that oxidants produced by alpha-lipoic acid or insulin are involved in activation of insulin receptor and in inactivation of protein tyrosine phosphatases, which eventually result in elevated glucose uptake into 3T3-L1 adipocytes.


Immunohistochemical analysis of collagen types I, III, IV and alpha-actin in the urethra of sexually intact and ovariectomized beagles.
Urinary incontinence is a widespread problem in both postmenopausal women and ovariectomized dogs. The objective of this study was to investigate the influence of ovariectomy on the immunoreactivity and the distribution pattern of collagens I, III, IV and alpha-actin in the canine urethra. The immunohistochemical results were evaluated in five sexually intact and five ovariectomized beagles. The immunostaining of both collagens I and III delineated urethral connective tissue fibres and co-localized within in the fibres of both groups. The basement membranes of smooth muscle cells and sinusoids showed marked type IV collagen expression, whereas only faint immunoreactivity was present at the urothelial-stromal interface. No differences could be detected in the expression or distribution of the assessed collagen types and actin between ovariectomized and control animals. In conclusion, ovariectomy does not appear to have an effect on urethral collagens I, III, IV and smooth muscle actin in the dog, as ascertained by immunohistochemistry.


Conditional gene expression in the mouse using a Sleeping Beauty gene-trap transposon.
Insertional mutagenesis techniques with transposable elements have been popular among geneticists studying model organisms from E. coli to Drosophila and, more recently, the mouse. One such element is the Sleeping Beauty (SB) transposon that has been shown in several studies to be an effective insertional mutagen in the mouse germline. SB transposon vector studies have employed different functional elements and reporter molecules to disrupt and report the expression of endogenous mouse genes. We sought to generate a transposon system that would be capable of reporting the expression pattern of a mouse gene while allowing for conditional expression of a gene of interest in a tissue- or temporal-specific pattern. Here we report the systematic development and testing of a transposon-based gene-trap system incorporating the doxycycline-repressible Tet-Off (tTA) system that is capable of activating the expression of genes under control of a Tet response element (TRE) promoter. We demonstrate that the gene trap system is fully functional in vitro by introducing the "gene-trap tTA" vector into human cells by transposition and identifying clones that activate expression of a TRE-luciferase transgene in a doxycycline-dependent manner. In transgenic mice, we mobilize gene-trap tTA vectors, discover parameters that can affect germline mobilization rates, and identify candidate gene insertions to demonstrate the in vivo functionality of the vector system. We further demonstrate that the gene-trap can act as a reporter of endogenous gene expression and it can be coupled with bioluminescent imaging to identify genes with tissue-specific expression patterns. Akin to the GAL4/UAS system used in the fly, we have made progress developing a tool for mutating and revealing the expression of mouse genes by generating the tTA transactivator in the presence of a secondary TRE-regulated reporter molecule. A vector like the gene-trap tTA could provide a means for both annotating mouse genes and creating a resource of mice that express a regulable transcription factor in temporally- and tissue-specific patterns for conditional gene expression studies. These mice would be a valuable resource to the mouse genetics community for purpose of dissecting mammalian gene function.


Performance analysis of incoherent multi-wavelength OCDMA systems under the impact of four-wave mixing.
In this paper, we comprehensively analyze the impact of four wave mixing (FWM) on the performance of incoherent multi-wavelength optical code-division multiple-access (MW-OCDMA) systems. We also consider many other interferences and noises, including multiple access interference, optical beating interference, and receiver noise, in the analysis. From the numerical results, we can find the power ranges of different MW-OCDMA systems, in which the impact of FWM is dominant and consequently results in an increase in the bit-error rate of the systems. We also find that the impact of FWM becomes more severe when the frequency spacing is small and/or dispersion-shifted fiber is used. In addition, we quantitatively discuss the impact of FWM on the number of supportable users and power penalty in the MW-OCDMA systems.


Accuracy of a remote quantitative image analysis in the whole slide images.
The rationale for choosing a remote quantitative method supporting a diagnostic decision requires some empirical studies and knowledge on scenarios including valid telepathology standards. The tumours of the central nervous system [CNS] are graded on the base of the morphological features and the Ki-67 labelling Index [Ki-67 LI]. Various methods have been applied for Ki-67 LI estimation. Recently we have introduced the Computerized Analysis of Medical Images [CAMI] software for an automated Ki-67 LI counting in the digital images. Aims of our study was to explore the accuracy and reliability of a remote assessment of Ki-67 LI with CAMI software applied to the whole slide images [WSI]. The WSI representing CNS tumours: 18 meningiomas and 10 oligodendrogliomas were stored on the server of the Warsaw University of Technology. The digital copies of entire glass slides were created automatically by the Aperio ScanScope CS with objective 20x or 40x. Aperio's Image Scope software provided functionality for a remote viewing of WSI. The Ki-67 LI assessment was carried on within 2 out of 20 selected fields of view (objective 40x) representing the highest labelling areas in each WSI. The Ki-67 LI counting was performed by 3 various methods: 1) the manual reading in the light microscope - LM, 2) the automated counting with CAMI software on the digital images - DI , and 3) the remote quantitation on the WSIs - as WSI method. The quality of WSIs and technical efficiency of the on-line system were analysed. The comparative statistical analysis was performed for the results obtained by 3 methods of Ki-67 LI counting. The preliminary analysis showed that in 18% of WSI the results of Ki-67 LI differed from those obtained in other 2 methods of counting when the quality of the glass slides was below the standard range. The results of our investigations indicate that the remote automated Ki-67 LI analysis performed with the CAMI algorithm on the whole slide images of meningiomas and oligodendrogliomas could be successfully used as an alternative method to the manual reading as well as to the digital images quantitation with CAMI software. According to our observation a need of a remote supervision/consultation and training for the effective use of remote quantitative analysis of WSI is necessary.


Efficacy and Safety of Topical Clascoterone Cream, 1%, for Treatment in Patients With Facial Acne: Two Phase 3 Randomized Clinical Trials.
Acne is a common, multifactorial skin condition, and treatments with novel mechanisms have been elusive. To assess the safety and efficacy of clascoterone cream, 1%, a novel topical androgen receptor inhibitor, in 2 phase 3 randomized clinical trials (CB-03-01/25 and CB-03-01/26). Two identical, multicenter, randomized, vehicle-controlled, double-blind, phase 3 studies conducted from November 2015 to April 2018 evaluated the efficacy and safety of use of clascoterone cream, 1%, in males and nonpregnant females 9 years and older with moderate or severe facial acne as scored on the Investigator's Global Assessment scale. Participants were enrolled if they had 30 to 75 inflammatory lesions and 30 to 100 noninflammatory lesions. Patients were randomized to treatment with clascoterone cream, 1%, or vehicle cream and applied approximately 1 g to the whole face twice daily for 12 weeks. Treatment success was defined as an Investigator's Global Assessment score of 0 (clear) or 1 (almost clear), and a 2-grade or greater improvement from baseline and absolute change from baseline in noninflammatory and inflammatory lesion counts at week 12. Safety measures included adverse event frequency and severity. A total of 1440 patients were randomzied in 2 studies. In CB-03-01/25, 353 participants were randomized to treatment with clascoterone cream, 1% (median [range] age, 18.0 [10-58] years; 221 [62.6%] female), and 355 participants were randomized to treatment with vehicle cream (median [range] age, 18.0 [9-50] years; 215 (60.6%) female); in CB-03-01/26, 369 participants were randomized to treatment with clascoterone cream, 1% (median [range] age, 18.0 [10-50] years; 243 [65.9%] female), and 363 participants were randomized to treatment with vehicle cream (median [range] age, 18.0 [range, 11-42] years; 221 [60.9%] female). At week 12, treatment success rates in CB-03-01/25 and CB-03-01/26 with clascoterone cream, 1%, were 18.4% (point estimate, 2.3; 95% CI, 1.4-3.8; P < .001) and 20.3% (point estimate, 3.7; 95% CI, 2.2-6.3; P < .001) vs 9.0% and 6.5% with vehicle, respectively. At week 12, in both CB-03-01/25 and CB-03-01/26, treatment with clascoterone cream, 1%, resulted in a significant reduction in absolute noninflammatory lesions from baseline to -19.4 (point estimate difference, -6.4; 95% CI, -10.3 to -2.6; P < .001) and -19.4 (point estimate difference, -8.6; 95% CI, -12.3 to -4.9; P < .001) vs -13.0 and -10.8 with vehicle, respectively, as well as a reduction in inflammatory lesions from baseline to -19.3 (point estimate difference, -3.8; 95% CI, -6.4 to -1.3; P < .001) and -20.0 (point estimate difference, -7.4; 95% CI, -9.8 to -5.1; P < .001) vs -15.5 and -12.6 with vehicle, respectively. Adverse events rates were low and mostly mild; the predominant local skin reaction was trace or mild erythema. Use of clascoterone cream, 1%, for acne treatment appears to demonstrate favorable efficacy and safety with low adverse event rates. ClinicalTrials.gov Identifiers: NCT02608450 and NCT02608476.


Bending and puncturing the influenza lipid envelope.
Lysosomes, enveloped viruses, as well as synaptic and secretory vesicles are all examples of natural nanocontainers (diameter ≈ 100 nm) which specifically rely on their lipid bilayer to protect and exchange their contents with the cell. We have applied methods primarily based on atomic force microscopy and finite element modeling that allow precise investigation of the mechanical properties of the influenza virus lipid envelope. The mechanical properties of small, spherical vesicles made from PR8 influenza lipids were probed by an atomic force microscopy tip applying forces up to 0.2 nN, which led to an elastic deformation up to 20%, on average. The liposome deformation was modeled using finite element methods to extract the lipid bilayer elastic properties. We found that influenza liposomes were softer than what would be expected for a gel phase bilayer and highly deformable: Consistent with previous suggestion that influenza lipids do not undergo a major phase transition, we observe that the stiffness of influenza liposomes increases gradually and weakly (within one order of magnitude) with temperature. Surprisingly, influenza liposomes were, in most cases, able to withstand wall-to-wall deformation, and forces >1 nN were generally required to puncture the influenza envelope, which is similar to viral protein shells. Hence, the choice of a highly flexible lipid envelope may provide as efficient a protection for a viral genome as a stiff protein shell.


Treatment of higher risk myelodysplastic syndrome patients unresponsive to hypomethylating agents with ON 01910.Na.
In a Phase I/II clinical trial, 13 higher risk red blood cell-dependent myelodysplastic syndrome (MDS) patients unresponsive to hypomethylating therapy were treated with the multikinase inhibitor ON 01910.Na. Responses occurred in all morphologic, prognostic risk and cytogenetic subgroups, including four patients with marrow complete responses among eight with stable disease, associated with good drug tolerance. In a subset of patients, a novel nanoscale immunoassay showed substantially decreased AKT2 phosphorylation in CD34+ marrow cells from patients responding to therapy but not those who progressed on therapy. These data demonstrate encouraging efficacy and drug tolerance with ON 01910.Na treatment of higher risk MDS patients.


Microstructural and compositional analysis of strontium-doped lead zirconate titanate thin films on gold-coated silicon substrates.
This article discusses the results of transmission electron microscopy (TEM)-based characterization of strontium-doped lead zirconate titanate (PSZT) thin films. The thin films were deposited by radio frequency magnetron sputtering at 300 degrees C on gold-coated silicon substrates, which used a 15 nm titanium adhesion layer between the 150 nm thick gold film and (100) silicon. The TEM analysis was carried out using a combination of high-resolution imaging, energy filtered imaging, energy dispersive X-ray (EDX) analysis, and hollow cone illumination. At the interface between the PSZT films and gold, an amorphous silicon-rich layer (about 4 nm thick) was observed, with the film composition remaining uniform otherwise. The films were found to be polycrystalline with a columnar structure perpendicular to the substrate. Interdiffusion between the bottom metal layers and silicon was observed and was confirmed using secondary ion mass spectrometry. This occurs due to the temperature of deposition (300 degrees C) being close to the eutectic point of gold and silicon (363 degrees C). The diffused regions in silicon were composed primarily of gold (analyzed by EDX) and were bounded by (111) silicon planes, highlighted by the triangular diffused regions observed in the two-dimensional TEM image.


Ecosystem Interactions Underlie the Spread of Avian Influenza A Viruses with Pandemic Potential.
Despite evidence for avian influenza A virus (AIV) transmission between wild and domestic ecosystems, the roles of bird migration and poultry trade in the spread of viruses remain enigmatic. In this study, we integrate ecosystem interactions into a phylogeographic model to assess the contribution of wild and domestic hosts to AIV distribution and persistence. Analysis of globally sampled AIV datasets shows frequent two-way transmission between wild and domestic ecosystems. In general, viral flow from domestic to wild bird populations was restricted to within a geographic region. In contrast, spillover from wild to domestic populations occurred both within and between regions. Wild birds mediated long-distance dispersal at intercontinental scales whereas viral spread among poultry populations was a major driver of regional spread. Viral spread between poultry flocks frequently originated from persistent lineages circulating in regions of intensive poultry production. Our analysis of long-term surveillance data demonstrates that meaningful insights can be inferred from integrating ecosystem into phylogeographic reconstructions that may be consequential for pandemic preparedness and livestock protection.


Patients with multiple sclerosis show increased oxidative stress markers and somatic telomere length shortening.
Lipid peroxidation due to oxidative stress (OS) may play an important role in the pathogenesis of chronic systemic inflammatory diseases such as multiple sclerosis (MS). Telomeres, repeated sequences that cap chromosome ends, undergo shortening with each cycle of cell division, resulting in cellular senescence. Research regarding telomere shortening has provided novel insight into the pathogenesis of various diseases. We hypothesized that OS damage leads to inflammatory reactions, which subsequently shortens the telomere length in MS. We enrolled 59 patients with MS, and age- and gender-matched 60 healthy controls. We divided MS subjects into three groups matched for age and gender according to the severity of disability: relatively benign course (BMS), secondary progressive MS, and primary progressive MS (PPMS). We analyzed the telomere length in peripheral blood mononuclear cells and the 8-iso-PGF2α concentration in urine, a reliable and stable marker of lipid peroxidation in vivo. The data showed significant higher levels of urinary 8-iso-PGF2α in MS subjects than in the controls. The lag-time, which represents the direct measurement of the resistance of low-density lipoprotein to oxidation, was shorter in the PPMS subjects than in the groups. Compared to that observed in the controls, the mean telomere length was significantly shorter in the PPMS group, whereas no significant telomere shortening was found between the controls and other subjects. Our data suggest that a decreased telomere length and enhanced lipid peroxidation reflects the severest stage of MS.


Stereo and motion parallax cues in human 3D vision: can they vanish without a trace?
In an immersive virtual reality environment, subjects fail to notice when a scene expands or contracts around them, despite correct and consistent information from binocular stereopsis and motion parallax, resulting in gross failures of size constancy (A. Glennerster, L. Tcheang, S. J. Gilson, A. W. Fitzgibbon, & A. J. Parker, 2006). We determined whether the integration of stereopsis/motion parallax cues with texture-based cues could be modified through feedback. Subjects compared the size of two objects, each visible when the room was of a different size. As the subject walked, the room expanded or contracted, although subjects failed to notice any change. Subjects were given feedback about the accuracy of their size judgments, where the "correct" size setting was defined either by texture-based cues or (in a separate experiment) by stereo/motion parallax cues. Because of feedback, observers were able to adjust responses such that fewer errors were made. For texture-based feedback, the pattern of responses was consistent with observers weighting texture cues more heavily. However, for stereo/motion parallax feedback, performance in many conditions became worse such that, paradoxically, biases moved away from the point reinforced by the feedback. This can be explained by assuming that subjects remap the relationship between stereo/motion parallax cues and perceived size or that they develop strategies to change their criterion for a size match on different trials. In either case, subjects appear not to have direct access to stereo/motion parallax cues.


Staphylococcus aureus toxin suppresses antigen-specific T cell responses.
Staphylococcus aureus remains a leading cause of human infection. These infections frequently recur when the skin is a primary site of infection, especially in infants and children. In contrast, invasive staphylococcal disease is less commonly associated with reinfection, suggesting that tissue-specific mechanisms govern the development of immunity. Knowledge of how S. aureus manipulates protective immunity has been hampered by a lack of antigen-specific models to interrogate the T cell response. Using a chicken egg OVA-expressing S. aureus strain to analyze OVA-specific T cell responses, we demonstrated that primary skin infection was associated with impaired development of T cell memory. Conversely, invasive infection induced antigen-specific memory and protected against reinfection. This defect in adaptive immunity following skin infection was associated with a loss of DCs, attributable to S. aureus α-toxin (Hla) expression. Gene- and immunization-based approaches to protect against Hla during skin infection restored the T cell response. Within the human population, exposure to α-toxin through skin infection may modulate the establishment of T cell-mediated immunity, adversely affecting long-term protection. These studies prompt consideration that vaccination targeting S. aureus may be most effective if delivered prior to initial contact with the organism.


Unreported cases in the 2014-2016 Ebola epidemic: Spatiotemporal variation, and implications for estimating transmission.
In the recent 2014-2016 Ebola epidemic in West Africa, non-hospitalized cases were an important component of the chain of transmission. However, non-hospitalized cases are at increased risk of going unreported because of barriers to access to healthcare. Furthermore, underreporting rates may fluctuate over space and time, biasing estimates of disease transmission rates, which are important for understanding spread and planning control measures. We performed a retrospective analysis on community deaths during the recent Ebola epidemic in Sierra Leone to estimate the number of unreported non-hospitalized cases, and to quantify how Ebola reporting rates varied across locations and over time. We then tested if variation in reporting rates affected the estimates of disease transmission rates that were used in surveillance and response. We found significant variation in reporting rates among districts, and district-specific rates of increase in reporting over time. Correcting time series of numbers of cases for variable reporting rates led, in some instances, to different estimates of the time-varying reproduction number of the epidemic, particularly outside the capital. Future analyses that compare Ebola transmission rates over time and across locations may be improved by considering the impacts of differential reporting rates.


Molecular mechanisms of limb regeneration: insights from regenerating legs of the cricket Gryllus bimaculatus.
This review summarizes recent advances in leg regeneration research, focusing on the cricket Gryllus bimaculatus. Recent studies have revealed molecular mechanisms on blastema formation, establishment of positional information, and epigenetic regulation during leg regeneration. Especially, these studies have provided molecular bases in classical conceptual models such as the polar coordinate model, the intercalation model, the boundary model, the steepness model, etc., which were proposed to interpret regeneration processes of the cockroach legs. When a leg is amputated, a blastema is formed through the activation of the Janus-kinase (Jak)/Signal-Transduction-and-Activator-of-Transcription (STAT) pathway. Subsequently, the Hedgehog/Wingless/Decapentaplegic/Epidermal-growth-factor pathways instruct distalization in the blastema, designated as the molecular boundary model. Downstream targets of this pathway are transcription factors Distal-less (Dll) and dachshund (dac), functioning as key regulators of proximodistal pattern formation. Dll and dac specify the distal and proximal regions in the blastema, respectively, through the regulation of tarsal patterning genes. The expression of leg patterning genes during regeneration may be epigenetically controlled by histone H3K27 methylation via Enhancer-of-zeste and Ubiquitously-transcribed-tetratricopeptide-repeat-gene-X-chromosome. For the molecular mechanism of intercalation of the missing structures between the amputated position and the most distal one, Dachsous/Fat (Ds/Ft) steepness model has been proposed, in which the Ds/Ft pathway maintains positional information and determines leg size through dac expression. This model was theoretically verified to interpret the experimental results obtained with cricket legs. Availability of whole-genome sequence information, regeneration-dependent RNA interference, and genome editing technique will have the cricket be an ideal model system to reveal gene functions in leg regeneration.


Genotypic and allelic frequencies of gene polymorphisms associated with meat tenderness in Nellore beef cattle.
The objectives of this study were to characterize the allelic and genotypic frequencies of polymorphisms in the µ-calpain and calpastatin genes, and to assess their association with meat tenderness and animal growth in Nellore cattle. We evaluated 605 Nellore animals at 24 months of age, on average, at slaughter. The polymorphisms were determined for the molecular markers CAPN316, CAPN530, CAPN4751, CAPN4753, and UOGACAST1. Analyses of meat tenderness at 7, 14, and 21 days of maturation were performed in samples of longissimus thoracis obtained between the 12th and 13th rib and sheared using a Warner Bratzler Shear Force. Significant effects were observed for meat tenderness at days 7, 14, and 21 of maturation for the marker CAPN4751, at day 21 for the marker CAPN4753, and at days 14 and 21 for the marker UOGCAST1. For genotypic combinations of markers, the results were significant for the combination CAPN4751/UOGCAST1 in the three maturation periods and CAPN4753/UOGCAST1 at days 14 and 21 of maturation.


"Children get sick all the time": A qualitative study of socio-cultural and health system factors contributing to recurrent child illnesses in rural Burkina Faso.
In Burkina Faso, the government has implemented various health sector reforms in order to overcome financial and geographical barriers to citizens' access to primary healthcare throughout the country. Despite these efforts, morbidity and mortality rates among children remain high and the utilization of public healthcare services low. This study explores the relationship between mothers' intentions to use public health services in cases of child sickness, their social strategies and cultural practices to act on these intentions and the actual services provided at the primary health care facilities. Focusing on mothers as the primary caregivers, we follow their pathways from the onset of symptoms through their various attempts of providing treatment for their sick children. The overall objective is to discuss the interconnectedness of various factors, inside and outside of the primary health care services that contribute to the continuing high child morbidity and mortality rates. The study is based on ethnographic fieldwork, including in-depth interviews and follow-up interviews with 27 mothers, informal observations of daily-life activities and structured observations of clinical encounters. Data analysis took the form of thematic analysis. Focusing on the mothers' social strategies and cultural practices, three forms of responses/actions have been identified: home-treatment, consultation with a traditional specialist, and consultation at the primary health care services. Due to their accumulated vulnerabilities, mothers shift pragmatically from one treatment to another. However, the sporadic nature of their treatment-seeking hinders them in obtaining long-term solutions and the result is recurrent child illnesses and relapses over long periods of time. The routinization of the clinical encounter at rural dispensaries furthermore fails to address these complexities of children's illnesses. The analysis of case studies, interviews and observations shows how mothers in a rural area struggle and often fail to receive care at public healthcare facilities. Health service delivery could be organized in a manner that responds better to the needs of these mothers in terms of both access and retention.


Permanent translocation heterozygosity and sex determination in East african mistletoes.
Viscum fischeri has 2n = 23 chromosomes in male plants. These fornm 7 bivalents and a translocation chain of 9 chromosomes during meiosis. Pollen with 11-and 12-chromosome genomes is thus produced. Female plants have 2n = 22 chromosomes and produce 11 bivalents during meiosis. Sex determination is technically a rare multiple X-multiple Y type, but more importantly it provides the mechanism whereby permanent translocation heterozygosity is maintained in the system. In a second species, Viscum engleri, male plants have 2n=28 chromosomes associating as 11 bivalents and a ring of 6 chomosomes at meiosis.


What constitutes prescription drug misuse? Problems and pitfalls of current conceptualizations.
Many medications with sedative, anxiolytic, analgesic, or stimulant properties have the potential to be inappropriately used. However, because these substances have beneficial effects, many issues pertinent to understanding prescription drug misuse may differ from those associated with other misused substances. There is currently a lack of consensus about what constitutes prescription misuse and a wide range of operational criteria have been proposed. Inappropriate medication use is frequently defined on the basis of user characteristics (i.e. any non-prescribed use), the reason for use (i.e. use for recreational purposes), the presence of clinically significant symptoms (i.e. meeting diagnostic criteria for abuse and dependence) or on the presence of any of these factors. In cases where multiple criteria are used to define misuse there is often a lack of differentiation among them, while studies that use more specific criteria tend to exclude certain types of misuse from consideration altogether. In addition, in some cases there are a number of potential ways that a single operational criterion can be met and many of these may be associated with substantially different risks, harms, and predictors. Due to considerable variability in the classification of medication misuse both within and between studies, it is currently difficult to interpret the clinical significance of existing findings or to determine the true magnitude of problems associated with any particular form of misuse. In the present review many of the problems and challenges for adequately defining prescription drug misuse will be overviewed and recommendations will be made on how to better characterize this phenomenon.


Angiotensin (1-7) receptor antagonism equalizes angiotensin II-induced hypertension in male and female spontaneously hypertensive rats.
Females are less sensitive to the hypertensive effects of angiotensin II compared with males, although the molecular mechanisms responsible are unknown. We hypothesize that differential activation of angiotensin II, angiotensin (1-7), angiotensin II type 1, angiotensin II type 2, and mas levels in the renal cortex of male and female spontaneously hypertensive rats contribute to sex differences in the blood pressure response to angiotensin II infusion. Males had a greater increase in blood pressure after angiotensin II infusion than females (males: 150±2 to 186±3 mm Hg; females: 137±3 to 160±4 mm Hg; P<0.05). Angiotensin II infusion resulted in comparable increases in plasma and renal cortical angiotensin II levels in both sexes. Renal cortical angiotensin (1-7) levels were higher in female rats under basal conditions (195±10 versus 67±11 ng/g of cortex; P<0.05) and after angiotensin II infusion (281±25 versus 205±47 ng/g of cortex; P<0.05) compared with male rats. In the renal cortex of male rats, angiotensin II infusion decreased angiotensin II type 1 protein expression and increased angiotensin II type 2 expression with no change in mas expression. In female rats there was an increase in mas receptor protein expression with angiotensin II infusion, although angiotensin II type 1 and angiotensin II type 2 expressions were unchanged. Male and female rats were then treated with the angiotensin (1-7) mas receptor antagonist A-779 in the absence and presence of angiotensin II. A-779 equalized the blood pressure response to angiotensin II in males and females (blood pressure at the end of treatment: males, 166±4 mm Hg; females, 164±5 mm Hg). In conclusion, angiotensin (1-7) contributes to the sex difference in angiotensin II-induced increases in blood pressure in spontaneously hypertensive rats.


Toward a simulation approach for alkene ring-closing metathesis: scope and limitations of a model for RCM.
A published model for revealing solvent effects on the ring-closing metathesis (RCM) reaction of diethyl diallylmalonate 7 has been evaluated over a wider range of conditions, to assess its suitability for new applications. Unfortunately, the model is too flexible and the published rate constants do not agree with experimental studies in the literature. However, by fixing the values of important rate constants and restricting the concentration ranges studied, useful conclusions can be drawn about the relative rates of RCM of different substrates, precatalyst concentration can be simulated accurately and the effect of precatalyst loading can be anticipated. Progress has also been made toward applying the model to precatalyst evaluation, but further modifications to the model are necessary to achieve much broader aims.


Epigenetic Heterogeneity of B-Cell Lymphoma: Chromatin Modifiers.
We systematically studied the expression of more than fifty histone and DNA (de)methylating enzymes in lymphoma and healthy controls. As a main result, we found that the expression levels of nearly all enzymes become markedly disturbed in lymphoma, suggesting deregulation of large parts of the epigenetic machinery. We discuss the effect of DNA promoter methylation and of transcriptional activity in the context of mutated epigenetic modifiers such as EZH2 and MLL2. As another mechanism, we studied the coupling between the energy metabolism and epigenetics via metabolites that act as cofactors of JmjC-type demethylases. Our study results suggest that Burkitt's lymphoma and diffuse large B-cell Lymphoma differ by an imbalance of repressive and poised promoters, which is governed predominantly by the activity of methyltransferases and the underrepresentation of demethylases in this regulation. The data further suggest that coupling of epigenetics with the energy metabolism can also be an important factor in lymphomagenesis in the absence of direct mutations of genes in metabolic pathways. Understanding of epigenetic deregulation in lymphoma and possibly in cancers in general must go beyond simple schemes using only a few modes of regulation.


Effectiveness of public health messaging and communication channels during smoke events: A rapid systematic review.
Exposure to smoke emitted from wildfire and planned burns (i.e., smoke events) has been associated with numerous negative health outcomes, including respiratory symptoms and conditions. This rapid review investigates recent evidence (post-2009) regarding the effectiveness of public health messaging during smoke events. The objectives were to determine the effectiveness of various communication channels used and public health messages disseminated during smoke events, for general and at-risk populations. A search of 12 databases and grey literature yielded 1775 unique articles, of which 10 were included in this review. Principal results were: 1) Smoke-related public health messages are communicated via a variety of channels, but limited evidence is available regarding their effectiveness for the general public or at-risk groups. 2) Messages that use simple language are more commonly recalled, understood, and complied with. Compliance differs according to socio-demographic characteristics. 3) At-risk groups may be advised to stay indoors before the general population, in order to protect the most vulnerable people in a community. The research included in this review was observational and predominantly descriptive, and is therefore unable to sufficiently answer questions regarding effectiveness. Experimental research, as well as evaluations, are required to examine the effectiveness of modern communication channels, channels to reach at-risk groups, and the 'stay indoors' message.


Early and immediately restored and loaded dental implants for single-tooth and partial-arch applications.
The objective of this consensus committee report was to review the available literature published predominantly in refereed journals to summarize findings, data, and conclusions as they related to reduced healing times and protocols for single-tooth and partial-arch clinical situations. Early loading of dental implants has been defined as restoration of implants in or out of occlusion at least 48 hours after implant placement, but at a shorter time interval than conventional healing. Immediate loading or restoration has been defined as attachment of a restoration in or out of direct occlusal function within 48 hours of surgical placement. Six articles addressing early loading, with a mixture of single-tooth and partial-arch clinical conditions and including some controlled cohort studies, were reviewed. Immediate loading or restoration of dental implants in single-tooth and partial-arch applications, was extensively reviewed. An attempt was made to isolate and categorize similar case types to discern trends and relevant factors. Variables that were considered included single- or multiple-tooth conditions, immediate or delayed placement in extraction sockets, effect of implant surface and geometry, bone quality, implant stability, surgical technique, occlusal design, effect of cigarette smoking, and stability of results. Combined data from 6 early loading studies on single-tooth and partial-arch applications revealed 1,046 implants with a survival rate of 98.2%. Long-term data for most of the early loading studies were not yet available. Most of the publications on immediate loading or restoration of dental implants were written as case series rather than scientific studies. In general, most publications indicated that with attention to appropriate factors, implant survival with immediate restoration was comparable to the results with conventional and early loading protocols. It should be recognized that, with few exceptions, these conclusions may be misleading statistical phenomena of the authors, as most publications were written by exceptionally experienced, highly skilled practitioners working under tightly controlled clinical conditions on a relatively small, statistically inconclusive number of implants and patients.


The efficacy of sequential therapy in eradication of Helicobacter pylori in Turkey.
Most of the studies about sequential therapy that have been reported from Turkey were levofloxacin based. We aimed to compare the Helicobacter pylori (H. pylori) eradication rates of standard triple, sequential and quadruple therapies including claritromycin regimes in this study. A total of 160 patients with dyspeptic symptoms were enrolled to the study. The patients were randomized to four groups of treatment protocols. And 40 patients received standard triple therapy for 2 weeks, 40 patients received bismuth containing quadruple therapy for 2 weeks, 40 patients received 5 + 5 clarithromycin-based sequential therapy, and 40 patients received 7 + 7 clarithromycin-based sequential therapy. H. pylori eradication was assessed by C 14 urea breath test 4 weeks after therapy. Out of 160 patients with H. pylori infection, 131 (81.9%) were eradicated successfully and 29 (18.1%) failed to eradicate H. pylori infection. H. pylori eradication was achieved in 28 of 40 patients receiving standard triple therapy (70%), in 33 of 40 patients receiving quadruple therapy (82.5%), in 37 of 40 patients receiving 5 + 5 sequential therapy (92.5%), and in 33 of 40 patients receiving 7 + 7 sequential therapy (82. 5%). Statistics revealed that 5 + 5 sequential therapy led to significantly higher H. pylori eradication rates compared with that of standard triple therapy (P = 0.019). There was no statically difference between 5 + 5 sequential therapy and the other therapy groups' eradication rates, but it was higher than all of the protocols. H. pylori eradication rate with sequential therapy in our patients with nonulcer dyspepsia was higher than those of patients with standard therapy (93% versus 82%, respectively, P>0.05). 5 + 5 sequential therapy was associated with significantly higher eradication rate of H. pylori compared with standard triple therapy in our study cohort.


Predictors of neonatal mortality: development and validation of prognostic models using prospective data from rural Bangladesh.
To assess the extent to which maternal histories of newborn danger signs independently or combined with birth weight and/or gestational age (GA) can capture and/or predict postsecond day (age>48 hours) neonatal death. Data from a cluster-randomised trial conducted in rural Bangladesh were split into development and validation sets. The prompted recall of danger signs and birth weight measurements were collected within 48 hours postchildbirth. Maternally recalled danger signs included cyanosis (any part of the infant's body was blue at birth), non-cephalic presentation (part other than head came out first at birth), lethargy (weak or no arm/leg movement and/or cry at birth), trouble suckling (infant unable to suckle/feed normally in the 2 days after birth or before death, collected 1-month postpartum or from verbal autopsy). Last menstrual period was collected at maternal enrolment early in pregnancy. Singleton newborns surviving 2 days past childbirth were eligible for analysis. Prognostic multivariable models were developed and internally validated. Recalling ≥1 sign of lethargy, cyanosis, non-cephalic presentation or trouble suckling identified postsecond day neonatal death with 65.3% sensitivity, 60.8% specificity, 2.1% positive predictive value (PPV) and 99.3% negative predictive value (NPV) in the development set. Requiring either lethargy or weight <2.5 kg identified 89.1% of deaths (at 39.7% specificity, 1.9% PPV and 99.6% NPV) while lethargy or preterm birth (<37 weeks) captured 81.0% of deaths (at 53.6% specificity, 2.3% PPV and 99.5% NPV). A simplified model (birth weight, GA, lethargy, cyanosis, non-cephalic presentation and trouble suckling) predicted death with good discrimination (validation area under the receiver-operator characteristic curve (AUC) 0.80, 95% CI 0.73 to 0.87). A further simplified model (GA, non-cephalic presentation, lethargy, trouble suckling) predicted death with moderate discrimination (validation AUC 0.74, 95% CI 0.66 to 0.81). Maternally recalled danger signs, coupled to either birth weight or GA, can predict and capture postsecond day neonatal death with high discrimination and sensitivity.


Genes, molecules and patients--emerging topics to guide clinical pain research.
This review selectively explores some areas of pain research that, until recently, have been poorly understood. We have chosen four topics that relate to clinical pain and we discuss the underlying mechanisms and related pathophysiologies contributing to these pain states. A key issue in pain medicine involves crucial events and mediators that contribute to normal and abnormal pain signaling, but remain unseen without genetic, biomarker or imaging analysis. Here we consider how the altered genetic make-up of familial pains reveals the human importance of channels discovered by preclinical research, followed by the contribution of receptors as stimulus transducers in cold sensing and cold pain. Finally we review recent data on the neuro-immune interactions in chronic pain and the potential targets for treatment in cancer-induced bone pain.


Phenotypic Covariation and Morphological Diversification in the Ruminant Skull.
Differences among clades in their diversification patterns result from a combination of extrinsic and intrinsic factors. In this study, I examined the role of intrinsic factors in the morphological diversification of ruminants, in general, and in the differences between bovids and cervids, in particular. Using skull morphology, which embodies many of the adaptations that distinguish bovids and cervids, I examined 132 of the 200 extant ruminant species. As a proxy for intrinsic constraints, I quantified different aspects of the phenotypic covariation structure within species and compared them with the among-species divergence patterns, using phylogenetic comparative methods. My results show that for most species, divergence is well aligned with their phenotypic covariance matrix and that those that are better aligned have diverged further away from their ancestor. Bovids have dispersed into a wider range of directions in morphospace than cervids, and their overall disparity is higher. This difference is best explained by the lower eccentricity of bovids' within-species covariance matrices. These results are consistent with the role of intrinsic constraints in determining amount, range, and direction of dispersion and demonstrate that intrinsic constraints can influence macroevolutionary patterns even as the covariance structure evolves.


Behavioral interventions for pediatric insomnia: one treatment may not fit all.
Behavioral interventions for pediatric insomnia are cost-effective and benefit most families, but there is no evidence indicating which treatments are most suitable for specific patient populations. This randomized controlled trial evaluated the moderating role of infant separation anxiety in two brief interventions for infant sleep problems. Ninety-one infants aged 9-18 months (61% boys) with pediatric insomnia were randomized to either Checking-in, a Graduated extinction protocol which involves gradual separation from parents, or to the Camping-out intervention, in which parental presence is maintained. Sleep was measured using actigraphy and parent reports. Infant separation anxiety was observed in the laboratory. Assessments were completed at baseline, post-treatment and 6-month follow-up. Improvement in sleep was demonstrated following both interventions and maintained at follow-up. Separation anxiety did not change significantly following treatment. Infant separation anxiety moderated treatment efficacy, with greater benefit for infants with high separation anxiety in the Camping-out compared to the Checking-in intervention. This study provides support for considering infant separation anxiety in the effort to personalize treatment for pediatric insomnia. Pediatricians should incorporate evaluation of infant separation anxiety to assessment processes, and favor more gentle treatment approaches, such as Camping-out, over Graduated extinction for highly anxious infants. NCT01489215.