Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington's disease.
Huntington's disease is characterized by a complex and heterogeneous pathogenic profile. Studies have shown that disturbance in lipid homeostasis may represent a critical determinant in the progression of several neurodegenerative disorders. The recognition of perturbed lipid metabolism is only recently becoming evident in HD. In order to provide more insight into the nature of such a perturbation and into the effect its modulation may have in HD pathology, we investigated the metabolism of Sphingosine-1-phosphate (S1P), one of the most important bioactive lipids, in both animal models and patient samples. Here, we demonstrated that S1P metabolism is significantly disrupted in HD even at early stage of the disease and importantly, we revealed that such a dysfunction represents a common denominator among multiple disease models ranging from cells to humans through mouse models. Interestingly, the in vitro anti-apoptotic and the pro-survival actions seen after modulation of S1P-metabolizing enzymes allows this axis to emerge as a new druggable target and unfolds its promising therapeutic potential for the development of more effective and targeted interventions against this incurable condition.


Influences on HPV vaccination across levels of the social ecological model: perspectives from state level stakeholders.
Nationally, human papillomavirus (HPV) vaccination rates fall short of the Healthy People 2020 goal of 80% completion. Although strategies to increase these rates exist, low rates persist. We used concept mapping with state-level stakeholders to better understand barriers and facilitators to HPV vaccination. Concept mapping is a participatory research process in which respondents brainstorm ideas to a prompt and then sort ideas into piles. We present results of the brainstorming phase. We recruited participants identified by researchers' professional connections (n = 134) via e-mail invitations from five states (Iowa, South Dakota, Minnesota, Oregon, and Washington) working in adolescent health, sexual health, cancer prevention and control, or immunization. Using Concept Systems' online software we solicited participants' beliefs about what factors have the greatest influence on HPV vaccination rates in their states. From the original sample 58.2% (n = 78) of participants completed the brainstorming activity and generated 372 statements, our team removed duplicates and edited statements for clarity, which resulted in 172 statements. We coded statements using the Social Ecological Model (SEM) to understand at what level factors affecting HPV vaccination are occurring. There were 53 statements at the individual level, 22 at the interpersonal level, 21 in community, 51 in organizational, and 25 in policy. Our results suggest that a tiered approach, utilizing multi-level interventions instead of focusing on only one level may have the most benefit. Moreover, the policy-level influences identified by participants may be difficult to modify, thus efforts should focus on implementing evidence-based interventions to have the most meaningful impact.


Genomically complex lymphomas undergo sustained tumor regression upon MYC inactivation unless they acquire novel chromosomal translocations.
The targeted inactivation of oncogenes may be a specific and effective treatment for cancer. However, because human cancers are the consequence of multiple genetic changes, the inactivation of one oncogene may not be sufficient to cause sustained tumor regression. Moreover, cancers are genomically unstable and may readily compensate for the inactivation of a single oncogene. Here we confirm by spectral karyotypic analysis that MYC-induced hematopoietic tumors are highly genetically complex and genomically unstable. Nevertheless, the inactivation of MYC alone was found to be sufficient to induce sustained tumor regression. After prolonged MYC inactivation, some tumors exhibited a distinct propensity to relapse. When tumors relapsed, they no longer required the overexpression of MYC but instead acquired novel chromosomal translocations. We conclude that even highly genetically complex cancers are reversible on the inactivation of MYC, unless they acquire novel genetic alterations that can sustain a neoplastic phenotype.


Histone modifications, stem cells and prostate cancer.
Prostate cancer (PCa) is a very common neoplasm, which is generally treated by chemo-, radio-, and/or hormonal-therapy. After a variable time, PCa becomes resistant to conventional treatment, leading to patient death. Prostate tumor-initiating cells (TICs) and cancer repopulating cells (CRCs) are stem-like populations, driving respectively cancer initiation and progression. Histone modifiers (HMs) control gene expression in normal and cancer cells, thereby orchestrating key physiological and pathological processes. In particular, Polycomb group genes (PcGs) are a set of HMs crucial for lineage-specific gene silencing and stem cell self renewal. PcG products are organized into two main Polycomb Repressive Complexes (PRCs). At specific loci, PRC2 catalyzes histone H3 Lys27 trimethylation, which triggers gene silencing by recruiting PRC1, histone deacetylases and DNA methyl transferases. PRC1 catalyzes addition of the repressive mark histone H2A ubiquitination. Recently, the catalytic component of PRC1 (BMI1) was shown to play critical roles in prostate CRC self-renewal and resistance to chemotherapy, resulting in poorer prognosis. Similarly, pharmacological disruption of PRC2 by a small molecule inhibitor reduced the tumorigenicity and metastatic potential of prostate CRCs. Along with PcGs, some histone lysine demethylases (KDMs) are emerging as critical regulators of TIC/CRC biology. KDMs may be inhibited by specific small molecules, some of which display antitumor activity in PCa cells at micromolar concentrations. Since epigenetic gene regulation is crucial for stem cell biology, exploring the role of HMs in prostate cancer is a promising path that may lead to novel treatments.


Progenitor cell line (hPheo1) derived from a human pheochromocytoma tumor.
Pheochromocytomas are rare tumors generally arising in the medullary region of the adrenal gland. These tumors release excessive epinephrine and norepinephrine resulting in hypertension and cardiovascular crises for which surgery is the only definitive treatment. Molecular mechanisms that control tumor development and hormone production are poorly understood, and progress has been hampered by the lack of human cellular model systems. To study pheochromocytomas, we developed a stable progenitor pheochromocytoma cell line derived from a primary human tumor. After IRB approval and written informed consent, human pheochromocytoma tissue was excised, minced, dispersed enzymatically, and cultured in vitro. Primary pheochromocytoma cells were infected with a lentivirus vector carrying the catalytic subunit of human telomerase reverse transcriptase (hTERT). The hTERT immortalized cells (hPheo1) have been passaged >300 population doublings. The resulting cell line was characterized morphologically, biochemically and for expression of neuroendocrine properties. The expression of marker enzymes and proteins was assessed by immunofluorescence staining and immunoblotting. Telomerase activity was determined by using the telomeric repeat amplification protocol (TRAP) assay. We have established a human pheochromocytoma precursor cell line that expresses the neuroendocrine marker, chromogranin A, when differentiated in the presence of bone morphogenic protein 4 (BMP4), nerve growth factor (NGF), and dexamethasone. Phenylethanolamine N-methyltransferase (PNMT) expression is also detected with this differentiation regimen. CD-56 (also known as NCAM, neural cell adhesion molecule) is expressed in these cells, but CD31 (also known as PECAM-1, a marker of endothelial cells) is negative. We have maintained hTERT-immortalized progenitor cells derived from a pheochromocytoma (hPheo1) in culture for over 300 population doublings. This progenitor human cell line is normal diploid except for a deletion in the p16 region and has inducible neuroendocrine biomarkers. These cells should be a valuable reagent for studying mechanisms of tumor development and for testing novel therapeutic approaches.


Prevalence of enteric hepatitis A and E viruses in the Mekong River delta region of Vietnam.
A study of antibody prevalence for hepatitis A virus (HAV) and hepatitis E virus (HEV) was carried out in southwestern Vietnam in an area adjacent to a known focus of epidemic HEV transmission. The purpose of this investigation was first to provide a prevalence measure of hepatitis infections, and second to determine the outbreak potential of HEV as a function of the susceptible population. Blood specimens collected from 646 persons in randomly selected village hamlets were examined by an ELISA for anti-HEV IgG and anti-HAV IgG. The prevalences of anti-HEV IgG and anti-HAV IgG were 9% and 97%, respectively. There was a significant increase (P < 0.01) in age-specific anti-HEV IgG. A notable increase in anti-HAV IgG prevalence (P < 0.0001) occurred between child populations 0-4 (64%) and 5-9 (95%) years of age. No evidence of familial clustering of anti-HEV IgG-positive individuals was detected, and household crowding was not associated with the spread of HEV. Boiling of water was found to be of protective value against HEV transmission. A relatively low prevalence of anti-HEV indicates considerable HEV outbreak potential, against a background of 1) poor, water-related hygiene/sanitation, 2) dependence on a (likely human/animal waste)-contaminated Mekong riverine system, and 3) periodic river flooding.


Ref2, a regulatory subunit of the yeast protein phosphatase 1, is a novel component of cation homoeostasis.
Maintenance of cation homoeostasis is a key process for any living organism. Specific mutations in Glc7, the essential catalytic subunit of yeast protein phosphatase 1, result in salt and alkaline pH sensitivity, suggesting a role for this protein in cation homoeostasis. We screened a collection of Glc7 regulatory subunit mutants for altered tolerance to diverse cations (sodium, lithium and calcium) and alkaline pH. Among 18 candidates, only deletion of REF2 (RNA end formation 2) yielded increased sensitivity to these conditions, as well as to diverse organic toxic cations. The Ref2F374A mutation, which renders it unable to bind Glc7, did not rescue the salt-related phenotypes of the ref2 strain, suggesting that Ref2 function in cation homoeostasis is mediated by Glc7. The ref2 deletion mutant displays a marked decrease in lithium efflux, which can be explained by the inability of these cells to fully induce the Na+-ATPase ENA1 gene. The effect of lack of Ref2 is additive to that of blockage of the calcineurin pathway and might disrupt multiple mechanisms controlling ENA1 expression. ref2 cells display a striking defect in vacuolar morphogenesis, which probably accounts for the increased calcium levels observed under standard growth conditions and the strong calcium sensitivity of this mutant. Remarkably, the evidence collected indicates that the role of Ref2 in cation homoeostasis may be unrelated to its previously identified function in the formation of mRNA via the APT (for associated with Pta1) complex.


Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: A cost-utility analysis.
Familial hypercholesterolaemia (FH) is widely underdiagnosed. Cascade testing (CT) of relatives has been shown to be feasible, acceptable and cost-effective in the UK, but requires a supply of index cases. Feasibility of universal screening (US) at age 1-2 years was recently demonstrated. We examined whether this would be a cost-effective adjunct to CT in the UK, given the current and plausible future undiagnosed FH prevalence. Seven cholesterol and/or mutation-based US ± reverse cascade testing (RCT) alternatives were compared with no US in an incremental analysis with a healthcare perspective. A decision model was used to estimate costs and outcomes for cohorts exposed to the US component of each strategy. RCT case ascertainment was modelled using recent UK CT data, and probabilistic Markov models estimated lifetime costs and health outcomes for the cohorts screened under each alternative. 1000 Monte Carlo simulations were run for each model, and average outcomes reported. Further uncertainty was explored deterministically. Threshold analysis investigated the association between undiagnosed FH prevalence and cost-effectiveness. A strategy involving cholesterol screening followed by diagnostic genetic testing and RCT was the most cost-effective modelled (incremental cost-effectiveness ratio (ICER) versus no US £12,480/quality adjusted life year (QALY); probability of cost-effectiveness 96·8% at £20,000/QALY threshold). Cost-effectiveness was robust to both deterministic sensitivity analyses and threshold analyses that modelled ongoing case ascertainment at theoretical maximum levels. These findings support implementation of universal cholesterol screening followed by diagnostic genetic testing and RCT for FH, under a UK conventional willingness-to-pay threshold.


Characterizing the distribution and rates of microbial sulfate reduction at Middle Valley hydrothermal vents.
Few studies have directly measured sulfate reduction at hydrothermal vents, and relatively little is known about how environmental or ecological factors influence rates of sulfate reduction in vent environments. A better understanding of microbially mediated sulfate reduction in hydrothermal vent ecosystems may be achieved by integrating ecological and geochemical data with metabolic rate measurements. Here we present rates of microbially mediated sulfate reduction from three distinct hydrothermal vents in the Middle Valley vent field along the Juan de Fuca Ridge, as well as assessments of bacterial and archaeal diversity, estimates of total biomass and the abundance of functional genes related to sulfate reduction, and in situ geochemistry. Maximum rates of sulfate reduction occurred at 90 °C in all three deposits. Pyrosequencing and functional gene abundance data revealed differences in both biomass and community composition among sites, including differences in the abundance of known sulfate-reducing bacteria. The abundance of sequences for Thermodesulfovibro-like organisms and higher sulfate reduction rates at elevated temperatures suggests that Thermodesulfovibro-like organisms may have a role in sulfate reduction in warmer environments. The rates of sulfate reduction presented here suggest that--within anaerobic niches of hydrothermal deposits--heterotrophic sulfate reduction may be quite common and might contribute substantially to secondary productivity, underscoring the potential role of this process in both sulfur and carbon cycling at vents.


Regulation of restrictocin production in Aspergillus restrictus.
The production of restrictocin (a cytotoxin that specifically cleaves ribosomal RNA) by cultures of Aspergillus restrictus grown in liquid medium was investigated. The function of restrictocin, the method of its accumulation and the mode of resistance to restrictocin in A. restrictus are unknown. Previous studies have indicated that restrictocin accumulates in the medium with culture age. These observations have been extended in this study by cloning the cDNA of the res gene and using this cDNA clone to probe the onset of messenger RNA synthesis in the cells. The results of the Northern analysis were compared to the production and accumulation of restrictocin and morphological differentiation of the cells in culture. Restrictocin was found in the medium at the same time that mRNA was detected in the cells. This suggests that the leader sequence encoded by the cDNA provides an efficient secretion system for the protein. Both the protein and the mRNA were detected coincident with the formation of differentiated cell structures. These structures develop into conidiophores with one layer of sterigmata and conidia forming from the sterigmata. These results suggest that restrictocin is either involved in the process of conidiation or is coordinately regulated with differentiation leading to conidiation.


The Metabolic Reprogramming Induced by Sub-Optimal Nutritional and Light Inputs in Soilless Cultivated Green and Red Butterhead Lettuce.
Sub-optimal growing conditions have a major effect on plants; therefore, large efforts are devoted to maximizing the availability of agricultural inputs to crops. To increase the sustainable use of non-renewable inputs, attention is currently given to the study of plants under non-optimal conditions. In this work, we investigated the impact of sub-optimal macrocations availability and light intensity in two lettuce varieties that differ for the accumulation of secondary metabolites (i.e., 'Red Salanova' and 'Green Salanova'). Photosynthesis-related measurements and untargeted metabolomics were used to identify responses and pathways involved in stress resilience. The pigmented ('Red') and the non-pigmented ('Green Salanova') lettuce exhibited distinctive responses to sub-optimal conditions. The cultivar specific metabolomic signatures comprised a broad modulation of metabolism, including secondary metabolites, phytohormones, and membrane lipids signaling cascade. Several stress-related metabolites were altered by either treatment, including polyamines (and other nitrogen-containing compounds), phenylpropanoids, and lipids. The metabolomics and physiological response to macrocations availability and light intensity also implies that the effects of low-input sustainable farming systems should be evaluated considering a range of cultivar-specific positive and disadvantageous metabolic effects in addition to yield and other socio-economic parameters.


Luteolin Exerts Neuroprotection via Modulation of the p62/Keap1/Nrf2 Pathway in Intracerebral Hemorrhage.
Upregulation of neuronal oxidative stress is involved in the progression of secondary brain injury (SBI) following intracerebral hemorrhage (ICH). In this study, we investigated the potential effects and underlying mechanisms of luteolin on ICH-induced SBI. Autologous blood and oxyhemoglobin (OxyHb) were used to establish in vivo and in vitro models of ICH, respectively. Luteolin treatment effectively alleviated brain edema and ameliorated neurobehavioral dysfunction and memory loss in vivo. Also, in vivo, we found that luteolin promoted the activation of the sequestosome 1 (p62)/kelch-like enoyl-coenzyme A hydratase (ECH)-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by enhancing autophagy and increasing the translocation of Nrf2 to the nucleus. Meanwhile, luteolin inhibited the ubiquitination of Nrf2 and increased the expression levels of downstream antioxidant proteins, such as heme oxygenase-1 (HO-1) and reduced nicotinamide adenine dinucleotide phosphate (NADPH): quinine oxidoreductase 1 (NQO1). This effect of luteolin was also confirmed in vitro, which was reversed by the autophagy inhibitor, chloroquine (CQ). Additionally, we found that luteolin inhibited the production of neuronal mitochondrial superoxides (MitoSOX) and alleviated neuronal mitochondrial injury in vitro, as indicated via tetrachloro-tetraethylbenzimidazol carbocyanine-iodide (JC-1) staining and MitoSOX staining. Taken together, our findings demonstrate that luteolin enhances autophagy and anti-oxidative processes in both in vivo and in vitro models of ICH, and that activation of the p62-Keap1-Nrf2 pathway, is involved in such luteolin-induced neuroprotection. Hence, luteolin may represent a promising candidate for the treatment of ICH-induced SBI.


Fibrocalculous pancreatic diabetes. Long-term survival analysis.
To determine the long-term survival and causes of death in fibrocalculous pancreatic diabetes, a form of diabetes secondary to tropical chronic pancreatitis. A cohort of 370 patients with fibrocalculous pancreatic diabetes were analyzed with respect to survival time from the date of occurrence of the first symptom of the disease as well as after the onset of diabetes. The cause of death was analyzed in the patients who died. Cumulative survival rates were calculated by the actuarial method, and life table graphs were plotted by mathematical calculations. Long-term survival of patients with fibrocalculous pancreatic diabetes is much better today than that described 30 years ago. About 80% of patients were alive 35 years after the first episode of abdominal pain. The median survival time after the diagnosis of diabetes was 25 years. These figures, however, are still considerably lower than the life expectancy of the age- and sex-matched general population. Diabetic nephropathy was the main cause of death. Pancreatic cancer and other chronic pancreatitis-related causes as well as malnutrition and infections were also important contributors to mortality. The overall prognosis for patients with fibrocalculous pancreatic diabetes appears to have improved possibly because of earlier diagnosis, better management of diabetes, and improved nutrition.


miR398 and miR408 are up-regulated in response to water deficit in Medicago truncatula.
Plant microRNAs have been implicated in various abiotic stress responses. We identified several conserved microRNAs that showed differential expression in Medicago truncatula plants subjected to water deficit: miR169 is down-regulated only in the roots and miR398a/b and miR408 are strongly up-regulated in both shoots and roots. Down-regulation of miR169 in the roots did not correlate with accumulation of its target MtHAP2-1 transcripts, suggesting that its regulation may not occur at the mRNA level or may depend on other regulatory mechanisms, which do not involve this miRNA, in water-deficit conditions. The up-regulation of miR398a/b and miR408 and the clear down-regulation of their respective target genes, which encode the copper proteins COX5b (subunit 5b of mitochondrial cytochrome c oxidase) and plantacyanin, highlight the involvement of these miRNAs in response to water deprivation in M. truncatula. Also, miR398 up-regulation is inversely correlated with the down-regulation of copper superoxide dismutase, CSD1, during water deficit. The regulation of genes encoding copper proteins by miR398a/b and miR408 suggests a link between copper homeostasis and M. truncatula adaptation to progressive water deficit.


Mobile Phone Base Station Tower Settings Adjacent to School Buildings: Impact on Students' Cognitive Health.
The use of mobile phones has remarkably increased and become a basic need of daily life. Increasing subscriptions of mobile phones boost the installation of mobile phone base station towers (MPBSTs) in crowded commercial and residential areas including near school buildings. This study investigated the impact of exposure to radiofrequency electromagnetic field (RF-EMF) radiation generated by MPBSTs on cognitive functions. Two hundred and seventeen volunteer male students aged between 13 and 16 registered from two different intermediate schools: 124 students were from School 1 and 93 students were from School 2. The MPBSTs were located within 200 m from the school buildings. In School 1, RF-EMF was 2.010 µW/cm2 with a frequency of 925 MHz and in School 2, RF-EMF was 10.021 µW/cm2 with a frequency of 925 MHz. Students were exposed to EMFR for 6 hr a day, 5 days a week for a total period of 2 years. The Narda Safety Test Solution device SRM-3006 was used to measure RF-EMF in both schools, and cognitive functions tasks were measured by the Cambridge Neuropsychological Test Automated Battery (CANTAB). Significant impairment in Motor Screening Task (MOT; p = .03) and Spatial Working Memory (SWM) task ( p = .04) was identified among the group of students who were exposed to high RF-EMF produced by MPBSTs. High exposure to RF-EMF produced by MPBSTs was associated with delayed fine and gross motor skills, spatial working memory, and attention in school adolescents compared to students who were exposed to low RF-EMF.


A database of geopositioned Middle East Respiratory Syndrome Coronavirus occurrences.
As a World Health Organization Research and Development Blueprint priority pathogen, there is a need to better understand the geographic distribution of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and its potential to infect mammals and humans. This database documents cases of MERS-CoV globally, with specific attention paid to zoonotic transmission. An initial literature search was conducted in PubMed, Web of Science, and Scopus; after screening articles according to the inclusion/exclusion criteria, a total of 208 sources were selected for extraction and geo-positioning. Each MERS-CoV occurrence was assigned one of the following classifications based upon published contextual information: index, unspecified, secondary, mammal, environmental, or imported. In total, this database is comprised of 861 unique geo-positioned MERS-CoV occurrences. The purpose of this article is to share a collated MERS-CoV database and extraction protocol that can be utilized in future mapping efforts for both MERS-CoV and other infectious diseases. More broadly, it may also provide useful data for the development of targeted MERS-CoV surveillance, which would prove invaluable in preventing future zoonotic spillover.


Transition to an elastomeric infusion pump in home care: an evidence-based approach.
A fatal overdose of a chemotherapeutic agent delivered to a patient via an electronic infusion device served as a stark reminder of the risks that infusion therapy poses to patients and health care providers and as the impetus for a strategy to optimize safe and efficient delivery of home infusion therapy. The Academic Center for Evidence-Based Practice Star Model of Knowledge Transformation was used as the evidence-based framework for the implementation of a portable infusion pump that supports home infusion of high-risk medications, leading to increased patient and caregiver satisfaction. Evaluation of this implementation supports the use of an elastomeric infusion device for a high-risk therapy.


p300 interacts with the N- and C-terminal part of PPARgamma2 in a ligand-independent and -dependent manner, respectively.
The nuclear peroxisome proliferator-activated receptor gamma (PPARgamma) activates the transcription of multiple genes involved in intra- and extracellular lipid metabolism. Several cofactors are crucial for the stimulation or the silencing of nuclear receptor transcriptional activities. The two homologous cofactors p300 and CREB-binding protein (CBP) have been shown to co-activate the ligand-dependent transcriptional activities of several nuclear receptors as well as the ligand-independent transcriptional activity of the androgen receptor. We show here that the interaction between p300/CBP and PPARgamma is complex and involves multiple domains in each protein. p300/CBP not only bind in a ligand-dependent manner to the DEF region of PPARgamma but also bind directly in a ligand-independent manner to a region in the AB domain localized between residue 31 to 99. In transfection experiments, p300/CBP could thereby enhance the transcriptional activities of both the activating function (AF)-1 and AF-2 domains. p300/CBP displays itself at least two docking sites for PPARgamma located in its N terminus (between residues 1 and 113 for CBP) and in the middle of the protein (between residues 1099 and 1460).


Emergency nurses' knowledge and understanding of their role in recognising and responding to patients with sepsis: A qualitative study.
Sepsis is a significant and time-sensitive clinical concern for patients who present to Emergency Departments (EDs). Existing guidelines do not define nurses' roles in managing sepsis. This study explored ED nurses' experiences and perceptions around recognising and responding to patients with sepsis, and their awareness of sepsis screening and prognostic tools. The knowledge and insights gained from this study may be used to inform local and international ED policies, and enrich nursing educational packages that may be used to improve quality of patient care and patient outcomes. Qualitative design incorporating semi-structured interviews with 14 ED nurses was undertaken. Thematic and consensus-based content analyses were used to explore transcripts. Six key themes were identified; (1) contribution of the organisation, (2) appreciation of knowledge, (3) appreciation of clinical urgency, (4) appreciation of importance of staff supervision, (5) awareness of the importance of staff experience, and (6) awareness of the need to seek advice. ED nurses' identified deficits in their capacity to recognise and respond to patients with sepsis, despite their vital role within the multidisciplinary team that cares for patients with sepsis. The knowledge and insights gained from this study can be used to inform ED policies, to enrich context-specific educational packages that aim to improve quality of patient care and outcomes and identify areas for further research. Development and implementation of a nurse-inclusive sepsis pathway may address many deficits identified in this study.


Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study.
Patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL) have a rapid disease course and a poor prognosis. Dasatinib, a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, has previously induced responses in patients with imatinib-resistant or -intolerant Ph-positive ALL. We present the interim results of a phase 2 study designed to further assess the efficacy, safety, and tolerability of dasatinib 140 mg in this patient population (n = 36). With a minimum follow-up of 8 months, treatment with dasatinib resulted in substantial hematologic and cytogenetic response rates. Major hematologic responses were achieved in 42% (15/36) of patients, 67% of whom remained progression-free. Complete cytogenetic responses were attained by 58% (21/36) of patients. The presence of BCR-ABL mutations conferring imatinib resistance did not preclude a response to dasatinib. Dasatinib was also tolerable, with 6% (2/36) of patients discontinuing therapy as a result of study-drug toxicity. Most adverse events (AEs) were grade 1 or 2; febrile neutropenia was the most frequent severe AE, but this and other cytopenias were manageable with dose reduction. Dasatinib represents a safe and effective treatment option and an important therapeutic advance for patients with Ph-positive ALL. This trial was registered at www.clinicaltrials.gov as #CA180015.


Bilateral chylothorax as a complication of internal jugular vein cannulation.
Central venous catheterization is one of the most prevalent procedures in the Intensive Care Unit. Complications are reported in about 15% of the patients and usually comprise of infection, arterial puncture, malpositioning, pneumothorax, local hematoma, hemothorax, and so on. Chylothorax is a rare complication of this procedure. We present a 42-year-old lady, who developed bilateral massive chylothorax after cannulation of her left internal jugular vein (IJV), due to direct injury to the thoracic duct during the procedure. The patient was successfully managed with bilateral chest tube drainage and omission of oral feeds for four days. Development of bilateral chylothorax as a complication of IJV cannulation is rare, but merits reporting, in view of a large number of central venous cannulations being undertaken. Critical care professionals should be aware of this rare complication of a common procedure to facilitate early identification and institute appropriate therapy.


Inflammatory cytokine gene expression in THP-1 cells exposed to Stachybotrys chartarum and Aspergillus versicolor.
Very little is known about the mechanisms that occur in human cells upon exposure to fungi as well as their mycotoxins. A better understanding of toxin-regulated gene expression would be helpful to identify safe levels of exposure and could eventually be the basis for establishing guidelines for remediation scenarios following a water intrusion event. In this research, cytokine mRNA expression patterns were investigated in the human monocytic THP-1 cell line exposed to fungal extracts of various fragment sizes obtained from Stachybotrys chartarum RTI 5802 and/or Aspergillus versicolor RTI 3843, two common and well-studied mycotoxin producing fungi. Cytokine mRNA expression was generally upregulated 2-10 times following a 24 h exposure to fungal extracts. Expression of the proinflammatory interleukin-1β, interleukin-8, and tumor necrosis factor-α genes increased while the anti-inflammatory gene interleukin-10 also increased albeit at very low level, suggesting that negative feedback regulation mechanism of production of proinflammatory cytokines initiated upon 24 h of incubation. In addition, submicron size extracts of A. versicolor caused significant death of THP-1 cells, whereas extracts of S. chartarum caused no cell death while the mixture of the two fungi had an intermediate effect. There was no general correlation between gene expression and fragment sizes, which suggests that all submicron fragments may contribute to inflammatory response.


Recognition of multivalent histone states associated with heterochromatin by UHRF1 protein.
Histone modifications and DNA methylation represent two layers of heritable epigenetic information that regulate eukaryotic chromatin structure and gene activity. UHRF1 is a unique factor that bridges these two layers; it is required for maintenance DNA methylation at hemimethylated CpG sites, which are specifically recognized through its SRA domain and also interacts with histone H3 trimethylated on lysine 9 (H3K9me3) in an unspecified manner. Here we show that UHRF1 contains a tandem Tudor domain (TTD) that recognizes H3 tail peptides with the heterochromatin-associated modification state of trimethylated lysine 9 and unmodified lysine 4 (H3K4me0/K9me3). Solution NMR and crystallographic data reveal the TTD simultaneously recognizes H3K9me3 through a conserved aromatic cage in the first Tudor subdomain and unmodified H3K4 within a groove between the tandem subdomains. The subdomains undergo a conformational adjustment upon peptide binding, distinct from previously reported mechanisms for dual histone mark recognition. Mutant UHRF1 protein deficient for H3K4me0/K9me3 binding shows altered localization to heterochromatic chromocenters and fails to reduce expression of a target gene, p16(INK4A), when overexpressed. Our results demonstrate a novel recognition mechanism for the combinatorial readout of histone modification states associated with gene silencing and add to the growing evidence for coordination of, and cross-talk between, the modification states of H3K4 and H3K9 in regulation of gene expression.


Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders.
Evidence supporting that gut problems are linked to ASD symptoms has been accumulating both in humans and animal models of ASD. Gut microbes and their metabolites may be linked not only to GI problems but also to ASD behavior symptoms. Despite this high interest, most previous studies have looked mainly at microbial structure, and studies on fecal metabolites are rare in the context of ASD. Thus, we aimed to detect fecal metabolites that may be present at significantly different concentrations between 21 children with ASD and 23 neurotypical children and to investigate its possible link to human gut microbiome. Using 1H-NMR spectroscopy and 16S rRNA gene amplicon sequencing, we examined metabolite profiles and microbial compositions in fecal samples, respectively. Of the 59 metabolites detected, isopropanol concentrations were significantly higher in feces of children with ASD after multiple testing corrections. We also observed similar trends of fecal metabolites to previous studies; children with ASD have higher fecal p-cresol and possibly lower GABA concentrations. In addition, Fisher Discriminant Analysis (FDA) with leave-out-validation suggested that a group of metabolites-caprate, nicotinate, glutamine, thymine, and aspartate-may potentially function as a modest biomarker to separate ASD participants from the neurotypical group (78% sensitivity and 81% specificity). Consistent with our previous Arizona cohort study, we also confirmed lower gut microbial diversity and reduced relative abundances of phylotypes most closely related to Prevotella copri in children with ASD. After multiple testing corrections, we also learned that relative abundances of Feacalibacterium prausnitzii and Haemophilus parainfluenzae were lower in feces of children with ASD. Despite a relatively short list of fecal metabolites, the data in this study support that children with ASD have altered metabolite profiles in feces when compared with neurotypical children and warrant further investigation of metabolites in larger cohorts.


The small muscle-specific protein Csl modifies cell shape and promotes myocyte fusion in an insulin-like growth factor 1-dependent manner.
We have isolated a murine cDNA encoding a 9-kD protein, Chisel (Csl), in a screen for transcriptional targets of the cardiac homeodomain factor Nkx2-5. Csl transcripts were detected in atria and ventricles of the heart and in all skeletal muscles and smooth muscles of the stomach and pulmonary veins. Csl protein was distributed throughout the cytoplasm in fetal muscles, although costameric and M-line localization to the muscle cytoskeleton became obvious after further maturation. Targeted disruption of Csl showed no overt muscle phenotype. However, ectopic expression in C2C12 myoblasts induced formation of lamellipodia in which Csl protein became tethered to membrane ruffles. Migration of these cells was retarded in a monolayer wound repair assay. Csl-expressing myoblasts differentiated and fused normally, although in the presence of insulin-like growth factor (IGF)-1 they showed dramatically enhanced fusion, leading to formation of large dysmorphogenic "myosacs." The activities of transcription factors nuclear factor of activated T cells (NFAT) and myocyte enhancer-binding factor (MEF)2, were also enhanced in an IGF-1 signaling-dependent manner. The dynamic cytoskeletal localization of Csl and its dominant effects on cell shape and behavior and transcription factor activity suggest that Csl plays a role in the regulatory network through which muscle cells coordinate their structural and functional states during growth, adaptation, and repair.


Patients' preference in the treatment of erectile dysfunction: a critical review of the literature.
The increase in the number of safe and effective ED treatments highlights the importance of patients' preference when choosing a therapeutic option. Several studies assessing these preferences are now available in published literature. This article aims to review and discuss the studies on patients' preference and the data concerning the reasons for preference for one PDE-5 inhibitor over another. A PubMed search was conducted for manuscripts published within the last 10 years containing the search items ED, preference, sildenafil, tadalafil or vardenafil. Selected articles were discerningly reviewed and summarized (design, limitations and relevance). The articles selected were peer reviewed publications on patients' preference and ED published in medical literature since 2000. Preference studies that include either two (tadalafil and sildenafil) or three PDE-5 inhibitors (tadalafil, sildenafil and vardenafil), showed that the majority of the patients preferred tadalafil versus either vardenafil or sildenafil. As the treatment of ED has evolved, patients' preference has become an important aspect of ED therapy, 52-65% of patients prefer tadalafil versus 12-20% vardenafil or 8-30% sildenafil. All founded studies have serious limitations, particularly in terms of dosing differences. Preference for tadalafil was mainly because of the longer duration of action that increases patients' freedom in sexual life. There is a consistency in patients' preference for tadalafil over sildenafil or vardenafil across the studies reviewed.


Self-monitoring of Blood Pressure in Patients With Hypertension-Related Multi-morbidity: Systematic Review and Individual Patient Data Meta-analysis.
Studies have shown that self-monitoring of blood pressure (BP) is effective when combined with co-interventions, but its efficacy varies in the presence of some co-morbidities. This study examined whether self-monitoring can reduce clinic BP in patients with hypertension-related co-morbidity. A systematic review was conducted of articles published in Medline, Embase, and the Cochrane Library up to January 2018. Randomized controlled trials of self-monitoring of BP were selected and individual patient data (IPD) were requested. Contributing studies were prospectively categorized by whether they examined a low/high-intensity co-intervention. Change in BP and likelihood of uncontrolled BP at 12 months were examined according to number and type of hypertension-related co-morbidity in a one-stage IPD meta-analysis. A total of 22 trials were eligible, 16 of which were able to provide IPD for the primary outcome, including 6,522 (89%) participants with follow-up data. Self-monitoring was associated with reduced clinic systolic BP compared to usual care at 12-month follow-up, regardless of the number of hypertension-related co-morbidities (-3.12 mm Hg, [95% confidence intervals -4.78, -1.46 mm Hg]; P value for interaction with number of morbidities = 0.260). Intense interventions were more effective than low-intensity interventions in patients with obesity (P < 0.001 for all outcomes), and possibly stroke (P < 0.004 for BP control outcome only), but this effect was not observed in patients with coronary heart disease, diabetes, or chronic kidney disease. Self-monitoring lowers BP regardless of the number of hypertension-related co-morbidities, but may only be effective in conditions such obesity or stroke when combined with high-intensity co-interventions.


Higher agrobiodiversity is associated with improved dietary diversity, but not child anthropometric status, of Mayan Achí people of Guatemala.
Child undernutrition remains one of the greatest challenges for public health nutrition in rural areas in developing countries. Interventions aiming to increase and conserve agrobiodiversity seem to be promising alternatives to improve child nutrition. However, the existing literature on these interventions is not conclusive about their effectiveness in combating child undernutrition. We tested the hypothesis that 'higher agrobiodiversity is associated with greater dietary diversity and better anthropometric status' in rural Guatemala.Design/Setting/SubjectsIn the summer of 2016, we conducted a cross-sectional study with a sample of 154 children (6-60 months). We conducted dietary recalls and structured interviews, measured children's weight and height, and visited food production systems (Milpas, home gardens, coffee plantations). Crop species richness, nutritional functional diversity, dietary diversity scores and anthropometric status were calculated. Higher food self-sufficiency, nutritional functional diversity and dietary diversity scores were positively correlated with higher crop and animal species richness. Contrarily, remoteness to the local market was negatively correlated with dietary diversity scores. However, higher dietary diversity scores were not correlated with better child anthropometric status. Better child anthropometric status was positively correlated with improved sanitary conditions and maternal education; and negatively correlated with large household size and frequent child morbidity. Agricultural diversification could diversify diets, increase nutrient availability and improve child anthropometry. However, these interventions need to be accompanied by sanitation improvements, family planning, nutritional education and women's empowerment to strengthen their positive effect on diet and nutrition.


Glucose transporter 2 mediates the hypoglycemia-induced increase in cerebral blood flow.
Glucose transporter 2 (Glut2)-positive cells are sparsely distributed in brain and play an important role in the stimulation of glucagon secretion in response to hypoglycemia. We aimed to determine if Glut2-positive cells can influence another response to hypoglycemia, i.e. increased cerebral blood flow (CBF). CBF of adult male mice devoid of Glut2, either globally (ripglut1:glut2-/-) or in the nervous system only (NG2KO), and their respective controls were studied under basal glycemia and insulin-induced hypoglycemia using quantitative perfusion magnetic resonance imaging at 9.4 T. The effect on CBF of optogenetic activation of hypoglycemia responsive Glut2-positive neurons of the paraventricular thalamic area was measured in mice expressing channelrhodopsin2 under the control of the Glut2 promoter. We found that in both ripglut1:glut2-/- mice and NG2KO mice, CBF in basal conditions was higher than in their respective controls and not further activated by hypoglycemia, as measured in the hippocampus, hypothalamus and whole brain. Conversely, optogenetic activation of Glut2-positive cells in the paraventricular thalamic nucleus induced a local increase in CBF similar to that induced by hypoglycemia. Thus, Glut2 expression in the nervous system is required for the control of CBF in response to changes in blood glucose concentrations.


The EGFR ligands Spitz and Keren act cooperatively in the Drosophila eye.
The EGFR signalling cascade is responsible for coordinating a wide variety of events during Drosophila eye development. It remains something of a mystery how it is that cells are able to interpret the signal so as to choose the appropriate response from the battery of possibilities: division, differentiation, cell shape change and so on. Since the cascade is essentially linear below the receptor, different cellular responses cannot be regulated by alternative signal transduction pathways. The main diversity lies upstream, in the multiple activating ligands. Spitz, Gurken and Vein have been long studied, but little is known about the physiological functions of the fourth ligand, Keren, although various roles have been predicted based on the differences between mutants in the known ligands and those of the receptor. Here, we have isolated a mutant in the keren gene, and demonstrate that Keren does indeed participate in EGFR signalling in the eye, where it acts redundantly with Spitz to control R8 spacing, cell clustering and survival. Thus, specificity cannot be determined by ligand choice, and must instead be a consequence of cell-intrinsic factors, although we speculate that there may be some quantitative differences in signalling elicited by the two ligands.


High Capacity Garnet-Based All-Solid-State Lithium Batteries: Fabrication and 3D-Microstructure Resolved Modeling.
The development of high-capacity, high-performance all-solid-state batteries requires the specific design and optimization of its components, especially on the positive electrode side. For the first time, we were able to produce a completely inorganic mixed positive electrode consisting only of LiCoO2 and Ta-substituted Li7La3Zr2O12 (LLZ:Ta) without the use of additional sintering aids or conducting additives, which has a high theoretical capacity density of 1 mAh/cm2. A true all-solid-state cell composed of a Li metal negative electrode, a LLZ:Ta garnet electrolyte, and a 25 μm thick LLZ:Ta + LiCoO2 mixed positive electrode was manufactured and characterized. The cell shows 81% utilization of theoretical capacity upon discharging at elevated temperatures and rather high discharge rates of 0.1 mA (0.1 C). However, even though the room temperature performance is also among the highest reported so far for similar cells, it still falls far short of the theoretical values. Therefore, a 3D reconstruction of the manufactured mixed positive electrode was used for the first time as input for microstructure-resolved continuum simulations. The simulations are able to reproduce the electrochemical behavior at elevated temperature favorably, however fail completely to predict the performance loss at room temperature. Extensive parameter studies were performed to identify the limiting processes, and as a result, interface phenomena occurring at the cathode active material/solid-electrolyte interface were found to be the most probable cause for the low performance at room temperature. Furthermore, the simulations are used for a sound estimation of the optimization potential that can be realized with this type of cell, which provides important guidelines for future oxide based all-solid-state battery research and fabrication.


Accessing the mental space-Spatial working memory processes for language and vision overlap in precuneus.
The "overlapping systems" theory of language function argues that linguistic meaning construction crucially relies on contextual information provided by "nonlinguistic" cognitive systems, such as perception and memory. This study examines whether linguistic processing of spatial relations established by reading sentences call on the same posterior parietal neural system involved in processing spatial relations set up through visual input. Subjects read simple sentences, which presented two agents in relation to each other, and were subsequently asked to evaluate spatial (e.g., "Was he turned towards her?") and equally concrete nonspatial content (e.g., "Was he older than her?"). We found that recall of the spatial content relative to the nonspatial content resulted in higher BOLD response in a dorsoposterior network of brain regions, most significantly in precuneus, strikingly overlapping a network previously shown to be involved in recall of spatial aspects of images depicting similar scenarios. This supports a neurocognitive model of language function, where sentences establish meaning by interacting with the perceptual and working memory networks of the brain.


Restraint-stress-induced changes in exploratory behavior appear to be mediated by norepinephrine-stimulated release of CRF.
Exploratory behavior, measured by the time an animal spends investigating objects in a novel environment, has been shown to be sensitive to prior exposure of the animal to stressors. Using this paradigm, it was demonstrated previously that both corticotropin-releasing factor (CRF) and the alpha 2-adrenoreceptor antagonist, idazoxan, elicited stress-like decreases in exploratory behavior. Because an activation of cerebral noradrenergic systems is observed during stress, following intracerebroventricular (i.c.v.) administration of CRF, or following peripheral administration of idazoxan, the involvement of noradrenergic systems in the behavioral effect of restraint and CRF was examined. Inhibition of norepinephrine (NE) release using the alpha 2-agonist clonidine (25 micrograms/kg, i.p.) or the noradrenergic-selective neurotoxin DSP-4 antagonized the restraint-induced decrease in exploratory behavior. The combination of these 2 treatments completely prevented this effect of restraint. The alpha 1-receptor antagonist prazosin (200 micrograms/kg) also prevented the behavioral effect of restraint, whereas the alpha 1-agonist phenylephrine (50 or 100 ng, i.c.v.) decreased exploratory behavior. None of these treatments consistently altered locomotor activity as measured by the number of entries into the different compartments or the number of rears. These results implicate noradrenergic systems in the stress-related changes in this behavior, consistent with our parallel measures on the production of NE catabolites. Thus, both CRF and noradrenergic systems appear to be involved in the effect of restraint on exploratory behavior in this task. Neither DSP-4 nor prazosin had any effect on the CRF-induced decrease in exploratory behavior. However, the CRF antagonist alpha-helical CRF (20 micrograms, i.c.v.) reversed the decrease in exploratory behavior induced by phenylephrine. The most likely explanation is that the 2 systems act in tandem such that noradrenergic systems regulate the release of brain CRF via an alpha 1-adrenoreceptor. This arrangement parallels that involved in the release of hypothalamic CRF to activate the pituitary-adrenal axis. The implications of these results for research on stress-related behaviors and for the etiology of depression are discussed.


Time dependent expression of cytokines in Mycobacterium bovis infected cattle lymph nodes.
Advancements in the current diagnostic and vaccination protocols employed against bovine tuberculosis rely heavily upon a sound knowledge of the bovine immunological response. Central to this is the importance of timing in the cellular immune profile and how this dynamic process evolves post-Mycobacterium bovis challenge. In the present study, we quantitatively analysed mRNA expression of interferon gamma (IFN-γ), tumour necrosis factor alpha (TNF-α) and interleukins (IL) 4 and 10 within select thoracic lymph nodes of cattle infected with M. bovis for 5, 12 and 19 weeks as compared to non-infected bovine tissues. The M. bovis infected lymph nodes displayed significantly higher expression levels of IFN-γ and TNF-α as compared to the non-infected lymph node tissues. This, in conjunction with undetectable levels of IL4, suggests a pro-inflammatory cytokine response. However a significant increase was also detected in IL10 mRNA which is consistent with a described aspect of T(H)1 type T cells in Leishmania infection, a 'self-limiting' process in which cells produced both IFN-γ and IL10 with the aim of controlling the heightened immunopathological responses. This was further reflected when comparing the cytokine profiles of the individual lymph node types, as those displaying a higher IFN-γ/IL10 ratio also had a greater level of gross pathology. This data highlights the important role of IL10 in the bovine response to M. bovis infection and supports its involvement as an immunological marker of disease progression.


Oligonucleotide therapeutic approaches for Huntington disease.
Huntington disease is an autosomal dominant neurodegenerative disorder caused by a toxic expansion in the CAG repeat region of the huntingtin gene. Oligonucleotide approaches based on RNAi and antisense oligonucleotides provide promising new therapeutic strategies for direct intervention through reduced production of the causative mutant protein. Allele-specific and simultaneous mutant and wild-type allele-lowering strategies are being pursued with local delivery to the brain, each with relative merits. Delivery remains a key challenge for translational success, especially with chronic therapy. The potential of disease-modifying oligonucleotide approaches for Huntington disease will be revealed as they progress into clinical trials.


Postoperative analgesia for the surgical correction of congenital clubfoot: comparison between peripheral nerve block and caudal epidural block.
Correction of congenital clubfoot (CCF) is associated with severe postoperative pain. Caudal epidural block associated with general anesthesia is the anesthetic technique used more often in children, but it is limited by the short duration of the postoperative analgesia. Peripheral nerve blocks are associated with a low incidence of complications and prolonged analgesia. The objective of this study was to compare the duration of analgesia in peripheral nerve blocks and caudal block, as well as morphine consumption in the first 24 hours after correction of CCF in children. This is a randomized, double-blind study with children undergoing surgeries for posteromedial release of CCF, who were divided in four groups according to the anesthetic technique: caudal (ACa), sciatic and femoral block (IF), sciatic and saphenous block (IS), and sciatic block and local anesthesia (IL), associated with general anesthesia. In the first 24 hours, patients received oral dypirone and acetaminophen, and they were evaluated by anesthesiologists who were unaware of the technique used. Oral morphine (0.19 mg x kg(1) per day) was administered according to the scores of the CHIPPS (Children's and infants' postoperative pain scale) scale. One hundred and eighteen children separated into four groups: ACa (30), IF (32), IS (28), and IL (28) participated in this study. The mean time between the blockade and the first dose of morphine was 6.16 hours in group ACa, 7.05 hours in group IF, 7.58 in IS, and 8.18 hours in IL. Morphine consumption was 0.3 mg.kg-1 per day in all four groups. Significant differences were not observed among the groups. peripheral nerve blocks did not promote longer lasting analgesia or a decrease in morphine consumption in the first 24 hours in children undergoing CCF correction when compared to caudal epidural block.


Aromatase inhibitors and bipolar mood disorder: a case report.
To report a case in which the aromatase inhibitor letrozole produced irritable mood elevation followed by depression in a woman with a history of postpartum depression. A 60-year-old Caucasian woman who had a severe depressive episode after the birth of her only child, 32 years earlier, was treated successively with anastrozole and letrozole following a mastectomy, radiotherapy and chemotherapy. Mrs X was prescribed anastrozole for about 6 weeks. During this time she experienced labile mood, increased activity, tremulousness and difficulty sleeping. These symptoms disappeared after stopping the anastrozole. On letrozole, she developed an acute irritable activated mood elevation, which then subsided into a prolonged major depression after withdrawal of letrozole. These effects occurred during co-prescription of amitriptyline at a low dose for urinary frequency. The present case suggests caution may be warranted when employing aromatase inhibitors, especially in women with a past history of postpartum affective disorder or bipolar disorder. As with postpartum mania, the primary mechanism of the effect may be acute reduction in circulating oestrogen levels.


Cementless metaphyseal reverse shoulder arthroplasty: our preliminary experience.
Reverse shoulder arthroplasty (rTSA) is a largely used procedure with a wide variety of indications. The incidence of this surgery is increased in recent years and the literature expects similar trend for them future. Metaphyseal stem rTSA seems to be a promising solution considering major objectives the preservation of humeral bone stock and ease of revision. In our study we analyzed 19 patients treated with cementless metaphyseal stem rTSA for osteoarthritis (group A) and acute fractures (group B). In group A (7 patients) the average Constant score improved from 21,57 (16-29) to 56,85 (38-72), the average SST improved from 2,29 (1-4) to 9,43 (8-12) and the mean VAS score improved from 14,29 to 4,86. In group B (12 patients) the mean Constant-Murlay score at last follow up was 42,17; the average SST was 7 and average pain score was 8,92. Overall active range-of-motion (ROM) improved significantly. Surgical considerations, clinical (analyzing Constant score and Simple Shoulder Test) and radiological short-term outcomes are encouraging, with low rate of complications. Long term follow-up studies are necessary to confirm our findings and the potential benefits related to these implants.


Challenges of plastic waste generation and management in sub-Saharan Africa: A review.
Recently, the issues of land-based plastics and their associated challenges in the marine world have been widely publicised in the media and scientific literature. Thus far, despite these communications, there have been few reports that have focused on the issues that acute plastic waste generation and its poor management pose to human health and the global environment. Also, articles on ways to mitigate these issues particularly in sub-Saharan Africa have not been documented. Indeed, there is significant scope for improvements in plastic waste management in developing countries, which offer a wide range of economic and environmental benefits. Plastic waste generation in sub-Saharan Africa is dependent on many factors like urbanization, etc. Currently, the population of sub-Saharan Africa is around 1 billion as of the year 2019, the amount of generated waste is 180 million tonnes at the rate of 0.5% per capita per day, the amount that is openly dumped is 70% and the plastic waste generated annually is 17 million tonnes. Therefore, this study aims to provide an overview of the plastic lifecycle and problems associated with plastic waste management in sub-Saharan Africa, including current practices, public participation and opinion, and government regulations. In addition, this highlight aims to outline the impact of plastic waste proliferation on man and the environment; and the economic and environmental benefits of proper plastic waste management. Critical discussion of current processes and the suitability of potential solutions provide the basis for proposition on mitigation measures to avert the negative impact of plastic waste.


The epidemiology of emerging infectious diseases and pandemics.
The spectrum of human pathogens and the infectious diseases they cause is continuously changing through evolution, selection and changes in the way human populations interact with their environment and each other. New human pathogens often emerge or re-emerge from an animal reservoir, emphasizing the central role that non-human reservoirs play in human infectious diseases. The 1918 pandemic of influenza virus A/H1N1 and the 2020 pandemic of coronavirus disease 2019 (COVID-19) are the most dramatic examples of this in recent human history. Pathogens can also re-emerge with new characteristics, such as multidrug resistance, or in different places, such as Ebola virus in West Africa in 2013 and Zika virus in Brazil in 2015, to cause new epidemics. Most human pathogens have a history of evolution in which they first emerge and cause epidemics, become unstably adapted, re-emerge periodically and then - without intervention - eventually become endemic, with the potential for future outbreaks.


Post-place care: disrupting place-care ontologies.
With the advent of telecare and the logic of information technologies in health care, the idea of placeless care has taken root, capturing imaginations and promising placeless caring futures. This 'de-territorialisation of care' has been challenged by studies of care practices 'on the ground', showing that care is always (materially) placed. Yet, while sociological scholarship has taken the role of place seriously, there is little conceptual attention for how we may think through immateriality and the changing nature of place in health care. Based on a case study of the introduction of a sensory reality technology into a care organisation, this paper argues that we need (1) to push the definition of placed care into new (digitally produced) landscapes and (2) a new vocabulary, with which to address and conceptualise this changing nature of care places. The paper introduces the term post-place, as a first step in developing such a vocabulary. Post-place care, unlike the idea of placeless care or emplaced care, is an inclusive, open and generative concept. Its strength lies in its disruptive potential for challenging existing place-care ontologies and opening up productive space for thinking through the changing landscapes of health care.


Adherence influences monocyte responsiveness to interleukin-10.
We studied the effects of adherence on the properties of interleukin (IL)-10 on monocyte-enriched peripheral blood mononuclear cells. We found that the decrease of CD11b expression induced by IL-10 was enhanced by adherence. Toll-like receptor (TLR)2 and TLR4 mRNA, as well as TLR4 surface expression, were significantly up-regulated by IL-10 in adherent cells. The absence of adherence prevented the inhibitory effects of IL-10 on lipopolysaccharide-induced tumor necrosis factor (TNF) and granulocyte-colony stimulating factor production and increased IL-1beta production and soluble TNF receptor II release in IL-10-pretreated cells. Similarly, the absence of adherence amplified the enhancement of phagocytosis induced by IL-10. Tyk2 and signal transducer and activator of transcription 3 (STAT3) phosphorylation and suppressor of cytokine signaling 3 (SOCS3) expression were induced by IL-10 in both conditions, but a longer activation and/or expression were observed in adherent monocytes. Finally, heme oxygenase-1, an anti-inflammatory molecule, was induced by IL-10 in adherent monocytes, whereas its expression remained low in nonadherent cells. Altogether, these data illustrate that adherence modulates the properties and the anti-inflammatory effects of IL-10.


Twin-beam generation in a triply resonant dual-cavity optical parametric oscillator.
We demonstrate a low-threshold twin-beam generator using a cw triply resonant optical parametric oscillator consisting of two coupled cavities: one that resonates the signal and idler waves and the other the pump field. An intensity correlation of 5.5 dB was observed at 3 MHz for a type-II phase-matched KTP optical parametric oscillator.


Chemical intervention in plant sugar signalling increases yield and resilience.
The pressing global issue of food insecurity due to population growth, diminishing land and variable climate can only be addressed in agriculture by improving both maximum crop yield potential and resilience. Genetic modification is one potential solution, but has yet to achieve worldwide acceptance, particularly for crops such as wheat. Trehalose-6-phosphate (T6P), a central sugar signal in plants, regulates sucrose use and allocation, underpinning crop growth and development. Here we show that application of a chemical intervention strategy directly modulates T6P levels in planta. Plant-permeable analogues of T6P were designed and constructed based on a 'signalling-precursor' concept for permeability, ready uptake and sunlight-triggered release of T6P in planta. We show that chemical intervention in a potent sugar signal increases grain yield, whereas application to vegetative tissue improves recovery and resurrection from drought. This technology offers a means to combine increases in yield with crop stress resilience. Given the generality of the T6P pathway in plants and other small-molecule signals in biology, these studies suggest that suitable synthetic exogenous small-molecule signal precursors can be used to directly enhance plant performance and perhaps other organism function.


In vitro drug susceptibility of two strains of the wildlife trypanosome, Trypanosoma copemani: A comparison with Trypanosoma cruzi.
Trypanosomes are blood protozoan parasites that are capable of producing illness in the vertebrate host. Within Australia, several native Trypanosoma species have been described infecting wildlife. However, only Trypanosoma copemani has been associated with pathological lesions in wildlife hosts and more recently has been associated with the drastic decline of the critically endangered woylie (Bettongia penicillata). The impact that some trypanosomes have on the health of the vertebrate host has led to the development of numerous drug compounds that could inhibit the growth or kill the parasite. This study investigated and compared the in vitro susceptibility of two strains of T. copemani (G1 and G2) and one strain of Trypanosoma cruzi (10R26) against drugs that are known to show trypanocidal activity (benznidazole, posaconazole, miltefosine and melarsoprol) and against four lead compounds, two fenarimols and two pyridine derivatives (EPL-BS1937, EPL-BS2391, EPL-BS0967, and EPL-BS1246), that have been developed primarily against T.cruzi. The in vitro cytotoxicity of all drugs against L6 rat myoblast cells was also assessed. Results showed that both strains of T. copemani were more susceptible to all drugs and lead compounds than T. cruzi, with all IC50 values in the low and sub-μM range for both species. Melarsoprol and miltefosine exhibited the highest drug activity against both T. copemani and T. cruzi, but they also showed the highest toxicity in L6 cells. Interestingly, both fenarimol and pyridine derivative compounds were more active against T. copemani and T. cruzi than the reference drugs benznidazole and posaconazole. T. copemani strains exhibited differences in susceptibility to all drugs demonstrating once again considerable differences in their biological behaviour.


Age-related changes in the fracture resistance of male Fischer F344 rat bone.
In addition to the loss in bone volume that occurs with age, there is a decline in material properties. To test new therapies or diagnostic tools that target such properties as material strength and toughness, a pre-clinical model of aging would be useful in which changes in bone are similar to those that occur with aging in humans. Toward that end, we hypothesized that similar to human bone, the estimated toughness and material strength of cortical bone at the apparent-level decreases with age in the male Fischer F344 rat. In addition, we tested whether the known decline in trabecular architecture in rats translated to an age-related decrease in vertebra (VB) strength and whether non-X-ray techniques could quantify tissue changes at micron and sub-micron length scales. Bones were harvested from 6-, 12-, and 24-month (mo.) old rats (n=12 per age). Despite a loss in trabecular bone with age, VB compressive strength was similar among the age groups. Similarly, whole-bone strength (peak force) in bending was maintained (femur) or increased (radius) with aging. There was though an age-related decrease in post-yield toughness (radius) and bending strength (femur). The ability to resist crack initiation was actually higher for the 12-mo. and 24-mo. than for 6-mo. rats (notch femur), but the estimated work to propagate the crack was less for the aged bone. For the femur diaphysis region, porosity increased while bound water decreased with age. For the radius diaphysis, there was an age-related increase in non-enzymatic and mature enzymatic collagen crosslinks. Raman spectroscopy analysis of embedded cross-sections of the tibia mid-shaft detected an increase in carbonate subsitution with advanced aging for both inner and outer tissue.


Graphene-stabilized lipid monolayer heterostructures: a novel biomembrane superstructure.
Chemically defined and electronically benign interfaces are attractive substrates for graphene and other two-dimensional materials. Here, we introduce lipid monolayers as an alternative, structurally ordered, and chemically versatile support for graphene. Deposition of graphene on the lipids resulted in a more ordered monolayer than regions without graphene. The lipids also offered graphene a more uniform and smoother support, reducing graphene hysteresis loop and the average value of the charge neutrality point under applied voltages. Our approach promises to be effective towards measuring experimentally biochemical phenomena within lipid monolayers and bilayers.


Stimulated effects in N(2) and CH(4) gases.
Stimulated Brillouin scattering from N(2) and CH(4) using a giant-pulse laser has been observed in an arrangement whereby the laser cannot relase and amplify the back-scattered radiation. This allows a quantitative study of the parameters affecting stimulated Brillouin scattering. The back-scattered beam converges at the same angle at which the laser beam diverges. The Brillouin component can have a narrow spectral width, one-third that of the laser itself, and in some cases can have a duration of only a few nanoseconds. N(2) at high pressure can back-scatter as much as 45% of the incident power. The speeds of sound in CH(4) and N(2) have been measured at lower pressures than were previously reported.


Cyberbullying: The Discriminant Factors Among Cyberbullies, Cybervictims, and Cyberbully-Victims in a Czech Adolescent Sample.
Although the research on cyberbullying has increased dramatically in recent years, still little is known about how cyberbullying participant groups (i.e., cyberbullies, cybervictims, and cyberbully-victims) differ from one another. This study aims to discriminate between these groups at an individual and relational level by controlling for age and gender. Self-control, offline aggression, and self-esteem are analyzed as individual-level variables. Parental attachment and peer rejection are involved as relational-level variables. A total of 2,092 Czech adolescents aged 12 to 18 were enrolled from a random sample of 34 primary and secondary schools located in the South Moravian region of the Czech Republic. Discriminant function analyses indicated that the participant groups are discriminated by two functions. The first function increases the separation between cyberbullies and cyberbully-victims from cybervictims, indicating that cyberbullies and cyberbully-victims are similar to each other in terms of low self-control, offline aggression, and gender, and have higher scores on measures of low self-esteem and offline aggression. However, cyberbully-victims had the highest scores on these measures. The second function discriminates between all three groups, which indicates that those variables included in the second function (i.e., parental attachment, peer rejection, self-esteem, and age) distinguish all three involved groups.


Material Stock Demographics: Cars in Great Britain.
Recent literature on material flow analysis has been focused on quantitative characterization of past material flows. Fewer analyses exist on past and prospective quantification of stocks of materials in-use. Some of these analyses explore the composition of products' stocks, but a focus on the characterization of material stocks and its relation with service delivery is often neglected. We propose the use of the methods of human demography to characterize material stocks, defined herein as stock demographics, exploring the insights that this approach could provide for the sustainable management of materials. We exemplify an application of stock demographics by characterizing the composition and service delivery of iron, steel, and aluminum stocks of cars in Great Britain, 2002-2012. The results show that in this period the stock has become heavier, it is traveling less, and it is idle for more time. The visualization of material stocks' dynamics demonstrates the pace of product replacement as a function of its usefulness and enables the formulation of policy interventions and the exploration of future trends.


The solution structure of the r(gcg)d(TATACCC):d(GGGTATACGC) Okazaki fragment contains two distinct duplex morphologies connected by a junction.
Okazaki fragments are important intermediates in DNA replication. Chimeric duplexes that are structurally equivalent to Okazaki fragments also occur during reverse transcription of RNA retroviruses. Such duplexes consist of an RNA-DNA chimeric strand base-paired to a pure DNA strand; hence they have a hybrid duplex "left half" covalently linked to a "right half" that is pure DNA. We have determined the solution structure of the synthetic Okazaki fragment r(gcg)d(TATACCC):d(GGGTATACGC) by means of two-dimensional NMR, restrained molecular dynamics and full relaxation matrix simulation of the two-dimensional nuclear Overhauser effect spectra at various mixing times. The large negative x-displacement and large positive inclination in the hybrid section of the duplex are structural characteristics similar to those found in pure hybrid duplexes. However, the DNA sugar puckers and the width and depth of the minor groove in the pure DNA section are more like B-form DNA, especially beyond the junction. Thus, this Okazaki fragment duplex assumes a conformation in solution that is a chimeric mixture of hybrid-form (H-form) and B-form structures and the overall molecule cannot be classified as either an A-form or a B-form duplex. The co-existence of these two different conformations in a single duplex gives rise to a structural discontinuity with a bend of approximately 18.1 (+/- 0.4) degrees at the junction between the hybrid and DNA segments that may be important for reverse transcriptase binding and RNase H cleavage of such molecules. Despite the fact that the solution structure is quite different from the all A-form structure reported recently for the exact same molecule in the crystalline state, a surprising number of local helical parameters were found to be quite similar to those reported for the crystal structure.


Excess mortality in the United States in the 21st century.
We use three indexes to identify how age-specific mortality rates in the United States compare to those in a composite of five large European countries since 2000. First, we examine the ratio of age-specific death rates in the United States to those in Europe. These show a sharp deterioration in the US position since 2000. Applying European age-specific death rates in 2017 to the US population, we then show that adverse mortality conditions in the United States resulted in 400,700 excess deaths that year. Finally, we show that these excess deaths entailed a loss of 13.0 My of life. In 2017, excess deaths and years of life lost in the United States represent a larger annual loss of life than that associated with the COVID-19 epidemic in 2020.


Continuous arteriovenous rewarming: experimental results and thermodynamic model simulation of treatment for hypothermia.
We evaluated a technique for treating hypothermia that uses extracorporeal circulation but does not require heparin or pump assistance. Hypothermia to 29.5 degrees C was induced in eight anesthetized dogs, and thermistors placed in the pulmonary artery, liver, bladder, esophagus, rectum, muscle, and skin. Four experimental animals were rewarmed by creating a fistula which connected arterial and venous femoral lines to an interposed counter-current heat exchanger. External rewarming was used in four controls. Bleeding time (BT), coagulation profile (PT, PTT, TT), and cardiac output (CO) were measured during rewarming. Core temperature (T) rose significantly faster with CAVR (0.00001). Average time to rewarming was 45 min, vs. 4 hrs in controls. Haptoglobin, platelet, fibrinogen, and fibrin split product levels were unaffected. Continuous arteriovenous rewarming (CAVR) improved T, CO, BT, and coagulation profile faster than any method yet reported not requiring heparin or cardiac bypass. The application of CAVR in post-traumatic hypothermia warrants further investigation.


Procedure-specific surgical site infection rates and postdischarge surveillance in Scotland.
To investigate the impact of postdischarge surveillance (PDS) on surgical-site infection (SSI) rates for selected surgical procedures in acute care hospitals in Scotland. Prospective surveillance of SSI after selected surgical procedures. The Scottish Surveillance of Healthcare Associated Infection Programme (SSHAIP), which is based on the methodology of the Centers for Disease Control and Prevention (CDC) National Nosocomial Infections Surveillance system (NNIS). Thirty-two of 46 acute care hospitals throughout Scotland contributed data to SSHAIP for this study. Data were from 21,710 operations that took place between April 1, 2002, and June 30, 2004; nine categories of surgical procedures were analyzed. CDC NNIS system definitions and methods were used for SSI PDS. PDS is a voluntary component of the mandatory SSI surveillance program in Scotland. PDS was categorized as none, passive, active without direct observation, and active with direct observation. From our study information, PDS data were available for 12,885 operations (59%). A total of 2,793 procedures (13%) were associated with passive PDS and 10,092 (46%) with active PDS. The SSI rate among the 8,825 operations with no PDS was 2.61% (95% confidence interval [CI], 2.3%-3.0%), which was significantly lower than the SSI rate found among the 12,885 operations for which PDS was performed (6.34% [95% CI, 5.9%-6.8%]). For breast surgery, cesarean section, hip replacement, and abdominal hysterectomy, the rate of SSI when PDS was performed was significantly higher than that when PDS was not performed (P<.01 for each procedure). No differences in SSI rates were found for surgery to repair fractured neck of the femur or for knee replacement. SSI rates were examined according to procedure type, performance of PDS, and NNIS risk index; rates of SSI increased with NNIS risk index within procedure group and PDS group. Logistic regression analyses confirmed that procedure type, performance of PDS, and NNIS risk index were all statistically independent predictors of report of an SSI (P<.05). This Scottish national data set incorporates a substantial amount of PDS data. We recommend a procedure-specific approach to PDS, with direct observation of patients after breast surgery, cesarean section, and hysterectomy, for which the length of stay is typically short. Readmission surveillance may be adequate to detect most SSIs after orthopedic surgery or vascular surgery, for which the length of stay is typically longer.


SMAP-HydroBlocks, a 30-m satellite-based soil moisture dataset for the conterminous US.
Soil moisture plays a key role in controlling land-atmosphere interactions, with implications for water resources, agriculture, climate, and ecosystem dynamics. Although soil moisture varies strongly across the landscape, current monitoring capabilities are limited to coarse-scale satellite retrievals and a few regional in-situ networks. Here, we introduce SMAP-HydroBlocks (SMAP-HB), a high-resolution satellite-based surface soil moisture dataset at an unprecedented 30-m resolution (2015-2019) across the conterminous United States. SMAP-HB was produced by using a scalable cluster-based merging scheme that combines high-resolution land surface modeling, radiative transfer modeling, machine learning, SMAP satellite microwave data, and in-situ observations. We evaluated the resulting dataset over 1,192 observational sites. SMAP-HB performed substantially better than the current state-of-the-art SMAP products, showing a median temporal correlation of 0.73 ± 0.13 and a median Kling-Gupta Efficiency of 0.52 ± 0.20. The largest benefit of SMAP-HB is, however, the high spatial detail and improved representation of the soil moisture spatial variability and spatial accuracy with respect to SMAP products. The SMAP-HB dataset is available via zenodo and at https://waterai.earth/smaphb .


Social precursors to onset and recovery from episodes of common mental illness.
Social disadvantage and lack of social support have been identified as important risk factors for the onset and continuance of episodes of common mental illness. This study aimed to identify the social precursors to episodes of and recovery from common mental illness in a large, general population sample over eight yearly intervals. The analytical samples were drawn from those aged > or = 16 in the British Household Panel Survey from 1991 to 1998. The samples were: (1) onset--over 42,000 paired years from 10,204 persons; (2) recovery--over 10,000 paired years from 4878 persons; and (3) 1812 spells with observed onset and recovery. Markov and discrete-time complementary log-log models were used. Common mental illness was measured using the 12-item General Health Questionnaire. Sex, age, changes in marital and employment status, physical health, family care and social support were all associated with differential rates of onset and recovery. Severity of disorder was associated with less likelihood of recovery and longer time to recovery. The study confirms many previous findings concerning social factors associated with onset and recovery. Low social support acted as expected by increasing chances of onset and decreasing chances of recovery. Other social factors such as separation or divorce, becoming and remaining unemployed, health limiting daily activities, caring for a sick relative all decreased chances of recovery. The chances of observing a change in state (either onset or recovery) decreased with the number of prior observations in that state. Reduced rates of recovery with increasing degrees of severity of distress was expected, but not previously demonstrated.


Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus.
Recently, a novel coronavirus (2019-nCoV) has emerged from Wuhan, China, causing symptoms in humans similar to those caused by severe acute respiratory syndrome coronavirus (SARS-CoV). Since the SARS-CoV outbreak in 2002, extensive structural analyses have revealed key atomic-level interactions between the SARS-CoV spike protein receptor-binding domain (RBD) and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. Here, we analyzed the potential receptor usage by 2019-nCoV, based on the rich knowledge about SARS-CoV and the newly released sequence of 2019-nCoV. First, the sequence of 2019-nCoV RBD, including its receptor-binding motif (RBM) that directly contacts ACE2, is similar to that of SARS-CoV, strongly suggesting that 2019-nCoV uses ACE2 as its receptor. Second, several critical residues in 2019-nCoV RBM (particularly Gln493) provide favorable interactions with human ACE2, consistent with 2019-nCoV's capacity for human cell infection. Third, several other critical residues in 2019-nCoV RBM (particularly Asn501) are compatible with, but not ideal for, binding human ACE2, suggesting that 2019-nCoV has acquired some capacity for human-to-human transmission. Last, while phylogenetic analysis indicates a bat origin of 2019-nCoV, 2019-nCoV also potentially recognizes ACE2 from a diversity of animal species (except mice and rats), implicating these animal species as possible intermediate hosts or animal models for 2019-nCoV infections. These analyses provide insights into the receptor usage, cell entry, host cell infectivity and animal origin of 2019-nCoV and may help epidemic surveillance and preventive measures against 2019-nCoV.IMPORTANCE The recent emergence of Wuhan coronavirus (2019-nCoV) puts the world on alert. 2019-nCoV is reminiscent of the SARS-CoV outbreak in 2002 to 2003. Our decade-long structural studies on the receptor recognition by SARS-CoV have identified key interactions between SARS-CoV spike protein and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. One of the goals of SARS-CoV research was to build an atomic-level iterative framework of virus-receptor interactions to facilitate epidemic surveillance, predict species-specific receptor usage, and identify potential animal hosts and animal models of viruses. Based on the sequence of 2019-nCoV spike protein, we apply this predictive framework to provide novel insights into the receptor usage and likely host range of 2019-nCoV. This study provides a robust test of this reiterative framework, providing the basic, translational, and public health research communities with predictive insights that may help study and battle this novel 2019-nCoV.


Increase in resting tension of tracheal muscle due to rigor during metabolic inhibition.
Resting tension of canine tracheal smooth muscle increased when glucose and oxygen were withdrawn from the bathing medium. Similar treatment of muscle stimulated with carbachol caused first a relaxation and then a secondary increase in tension. The increase in tension due t0 metabolic inhibition, unlike normal tracheal contractions, was insensitive to calcium depletion, was not associated with an active state, and was accompanied by marked reduction of tissue adenosine triphosphate, creatine phosphate, and glycogen content. Because muscle stiffness was also increased we concluded that hypoxic glucose-free contracture is due to rigor and not to an increased tissue calcium level as has been previously suggested. Rigor shortening during lightly loaded isotonic conditions is better maintained than rigor tension during isometric conditions. Our results also indicate that rigor tension is reduced irreversibly on imposition of a load and, therefore, the load-extension relationship during rigor in smooth muscle should be studied by making only small load changes.


Using Audience Response Technology to provide formative feedback on pharmacology performance for non-medical prescribing students--a preliminary evaluation.
The use of anonymous audience response technology (ART) to actively engage students in classroom learning has been evaluated positively across multiple settings. To date, however, there has been no empirical evaluation of the use of individualised ART handsets and formative feedback of ART scores. The present study investigates student perceptions of such a system and the relationship between formative feedback results and exam performance. Four successive cohorts of Non-Medical Prescribing students (n=107) had access to the individualised ART system and three of these groups (n=72) completed a questionnaire about their perceptions of using ART. Semi-structured interviews were carried out with a purposive sample of seven students who achieved a range of scores on the formative feedback. Using data from all four cohorts of students, the relationship between mean ART scores and summative pharmacology exam score was examined using a non-parametric correlation. Questionnaire and interview data suggested that the use of ART enhanced the classroom environment, motivated students and promoted learning. Questionnaire data demonstrated that students found the formative feedback helpful for identifying their learning needs (95.6%), guiding their independent study (86.8%), and as a revision tool (88.3%). Interviewees particularly valued the objectivity of the individualised feedback which helped them to self-manage their learning. Interviewees' initial anxiety about revealing their level of pharmacology knowledge to the lecturer and to themselves reduced over time as students focused on the learning benefits associated with the feedback.A significant positive correlation was found between students' formative feedback scores and their summative pharmacology exam scores (Spearman's rho = 0.71, N=107, p<.01). Despite initial anxiety about the use of individualised ART units, students rated the helpfulness of the individualised handsets and personalised formative feedback highly. The significant correlation between ART response scores and student exam scores suggests that formative feedback can provide students with a useful reference point in terms of their level of exam-readiness.


Bloating and distention in irritable bowel syndrome: the role of gas production and visceral sensation after lactose ingestion in a population with lactase deficiency.
Bloating and distention are often attributed to dietary factors by patients with irritable bowel syndrome (IBS). This study examined the effects of gas production and visceral hypersensitivity on digestive symptoms after lactose ingestion in a population with lactase deficiency. IBS patients (n=277) and healthy controls (HCs, n=64) underwent a 20-g lactose hydrogen breath test (LHBT) with evaluation of hydrogen gas production and lactose intolerance (LI) symptoms. Abdominal distention (199 IBS, 40 HCs) was measured during LHBT. Rectal sensitivity (74 IBS, 64 HCs) was assessed by barostat studies. Hydrogen production and distention were similar in IBS patients and HCs during LHBT; however, LI was more frequent in IBS (53.8 vs. 28.1%, P<0.001), especially bloating (39.0% vs. 14.1%, P<0.001) and borborygmi (39.0 vs. 21.9%, P=0.010). Only 59.0% of patients with bloating had distention. No correlation was observed between girth increment and bloating (P=0.585). IBS patients had lower rectal sensory thresholds (P=0.001). Multivariate analysis indicated that hydrogen production increased bloating (odds ratio (OR) 2.19, 95% confidence interval (CI) 1.09-4.39, P=0.028) and borborygmi (OR 12.37, 95% CI 3.34-45.83, P<0.001) but not distention (P=0.673). Visceral hypersensitivity was associated with bloating (OR 6.61, 95% CI 1.75-25.00, P=0.005) and total symptom score (OR 3.78, 95% CI 1.30-10.99, P=0.014). Gas production and visceral hypersensitivity both contribute to digestive symptoms, especially bloating and borborygmi, in IBS patients after lactose ingestion. Objective abdominal distention is not correlated with subjective bloating.


Incidence of cardiac interventions and associated cardiac arrest outcomes in patients with nonshockable initial rhythms and no ST elevation post resuscitation.
Out of Hospital Cardiac arrest (OHCA) survivors with ST elevation (STE) with or without shockable rhythms often benefit from coronary angiography (CAG) and, if indicated, percutaneous coronary intervention (PCI). However, the benefits of CAG and PCI in OHCA survivors with nonshockable rhythms (PEA/asystole) and no STE are debated. Using the International Cardiac Arrest Registry (INTCAR 2.0), representing 44 centers in the US and Europe, comatose OHCA survivors with known presenting rhythms and post resuscitation ECGs were identified. Survival to hospital discharge, neurological recovery on discharge, and impact of CAG with or without PCI on such outcome were assessed and compared with other groups (shockable rhythms with or without STE). Total of 2113 OHCA survivors were identified and described as; nonshockable/no STE (Nsh-NST) (n = 940, 44.5%), shockable/no STE (Sh-NST) (n = 716, 33.9%), nonshockable/STE (Nsh-ST) (n = 110, 5.2%), and shockable/STE (Sh-ST) (n = 347, 16.4%). Of Nsh-NST, 13.7% (129) were previously healthy before CA and only 17.3% (161) underwent CAG; of those, 30.4% (52) underwent PCI. A total of 18.6% (174) Nsh-NST patients survived to hospital discharge, with 57.5% (100) of such survivors having good neurological recovery (cerebral performance category 1 or 2) on discharge. Coronary angiography was associated with improved odds for survival and neurological recovery among all groups, including those with NSh-NST. Nonshockable initial rhythms with no ST elevation post resuscitation was the most common presentation after OHCA. Although most of these patients did not undergo coronary angiography, among those who did, 1 in 4 patients had a culprit lesion and underwent revascularization. Invasive CAG should be at least considered for all OHCA survivors, including those with nonshockable rhythms and no ST elevation post resuscitation. Out of hospital cardiac arrest (OHCA) survivors with ST elevation and/or shockable rhythms benefit from coronary angiography and revascularization. Nonshockable cardiac arrest survivors with no ST elevation have the worst prognosis and rarely undergo coronary angiography. Nonshockable rhythms with no ST elevation was the most common presentation after OHCA and among a small subgroup underwent coronary angiography, 1 in 4 patients with had culprit lesion and underwent revascularization. Coronary angiography was associated with high prevalence of acute culprit coronary lesions and should be considered for those with a probably cardiac cause for their arres.


Molecular phylogeny of the family Vorticellidae (Ciliophora, Peritrichia) using combined datasets with a special emphasis on the three morphologically similar genera Carchesium, Epicarchesium and Apocarchesium.
Little is known about the phylogeny of the family Vorticellidae at the generic level because few comprehensive analyses of molecular phylogenetic relationships between members of this group have, so far, been done. As a result, the phylogenetic positions of some genera that were based originally on morphological analyses remain controversial. In the present study, we performed phylogenetic analyses of vorticellids based on the sequence of the small-subunit (SSU) rRNA gene, including one species of the genus Apocarchesium, for which no sequence has previously been reported. Phylogenetic trees were reconstructed with SSU rRNA gene sequences by using four different methods (Bayesian analysis, maximum-likelihood, neighbour-joining and maximum-parsimony) and had a consistent branching pattern. Members of the genera Vorticella (except V. microstoma) and Carchesium formed a clearly defined, well supported clade that was divergent from the clade comprising members of the genera Pseudovorticella and Epicarchesium, suggesting that the differences in the silverline system (transverse vs reticulate) among vorticellids may be the result of genuine evolutionary divergence. Members of the newly established genus Apocarchesium clustered within the family Vorticellidae basal to the clade containing members of the genera Pseudovorticella and Epicarchesium and were distinct from members of the genus Carchesium, supporting the validity of Apocarchesium as a novel genus. Additional phylogenetic analyses of 21 strains representing seven genera from the families Vorticellidae and Zoothamniidae were performed with single datasets (ITS1-5.8S-ITS2, ITS2 alone) and combined datasets (SSU rRNA+ITS1-5.8S-ITS2, SSU rRNA+ITS2) to explore further the phylogenetic relationship between the three morphologically similar genera Carchesium, Epicarchesium and Apocarchesium, using characteristics not included in previous analyses. The phylogenetic trees reconstructed with combined datasets were more robust and therefore more reliable than those based on single datasets and supported the results of trees based on SSU rRNA sequences.


Network growth for enhanced natural selection.
Natural selection and random drift are competing phenomena for explaining the evolution of populations. Combining a highly fit mutant with a population structure that improves the odds that the mutation spreads through the whole population tips the balance in favor of natural selection. The probability that the spread occurs, known as the fixation probability, depends heavily on how the population is structured. Certain topologies, albeit highly artificially contrived, have been shown to exist that favor fixation. We present a randomized mechanism for network growth that is loosely inspired in some of these topologies' key properties and demonstrate, through simulations, that it is capable of giving rise to structured populations for which the fixation probability significantly surpasses that of an unstructured population. This discovery provides important support to the notion that natural selection can be enhanced over random drift in naturally occurring population structures.