Wastewater quality and the risk of intestinal nematode infection in sewage farming families in hyderabad, India.
Use of sewage or wastewater in agriculture is becoming increasingly common as a result of a global water scarcity. Intestinal nematode infections have been identified as the main health risk associated with this practice. To protect consumer and farmer health, the World Health Organization (WHO) has established an intestinal nematode water quality standard. However, because of a lack of well-designed studies, the validity of this guideline is questioned. This report presents the findings of a study on the risk of intestinal nematode infections in farming families occupationally exposed to untreated and partially treated wastewater in Hyderabad, India. The study found an increased risk of hookworm (odds ratio [OR] 3.5, 95% confidence interval [CI] = 2.2-5.5), Ascaris lumbricoides (OR = 5.3, 95% CI = 2.0-14), and Trichuris trichiura (OR = 5.6, 95% CI = 1.8-18) infection when untreated wastewater (150 intestinal nematode ova/liter) was used for crop production. Use of partially treated wastewater (28 intestinal nematode ova/liter) was only associated with an increased risk (OR = 3.2, 95% CI = 1.2-8.6) of A. lumbricoides infection. The findings of the study suggest that the current WHO intestinal nematode guideline of 1 ova/liter is sufficient to protect farmer health.


Refining nursing assessment and management with a new postanaesthetic care discharge tool to minimize surgical patient risk.
To evaluate use of an evidence-based discharge tool, the Post-Anaesthetic Care Tool and its impact on nursing assessment, communication, and management of patients in the postanaesthetic care unit. Postanaesthetic care unit nurses manage patients immediately after surgery and make clinical decisions on discharge readiness. There is a lack of evidence-based guidance on assessing, documenting, and communicating the patient's postoperative experience. The Post-Anaesthetic Care Tool, which includes instructions for assessing discharge readiness and incorporates the ISOBAR acronym, was developed following a comprehensive systematic review and expert consultation. This quasiexperimental, multicentre, nonrandomized study was conducted in three postanaesthetic care units in Australia. Participants were nurses providing care to adults postgeneral anaesthesia. Episodes of care were observed before (N = 723) and after (N = 694) introduction of the evidence-based tool. Statistical methods (Chi-Square and Mann-Whitney U-Tests) were undertaken to analyse nursing assessment, communication, and management outcomes before and after implementation of the Post-Anaesthetic Care Tool. The Post-Anaesthetic Care Tool was associated with statistically significant improvements in the frequency of nursing assessment and responsiveness to complications including pain, nausea/vomiting and hypothermia. After the tool's introduction, nurses requested more medical reviews. This was associated with increased recognition of clinical deterioration and significant improvements in clarity of handover from the postanaesthetic care unit to the ward. The structured discharge tool, Post-Anaesthetic Care Tool, was associated with improved nursing management of patients in the postanaesthetic care unit and enabled early identification and response to clinical concerns.


Current practice for diagnosis and management of silent atrial fibrillation: results of the European Heart Rhythm Association survey.
Although it is well known that silent atrial fibrillation (AF) is associated with morbidity and mortality rates similar to those of symptomatic AF, no specific strategy for screening and management of this form of AF has been advocated. The purpose of this survey was to identify current practices for the diagnosis and management of silent AF. This survey is based on an electronic questionnaire sent to the European Heart Rhythm Association Research Network partners. Responses were received from 33 centres in 16 countries. The preferred screening methods for silent AF in patients with rhythm control by pharmacological therapy was 12-lead electrocardiogram (ECG) at outpatient visits (31.3%) and periodical 24 h Holter ECG recordings (34.4%), while after pulmonary vein isolation the corresponding figures were 6.3 and 65.6%, respectively. No consensus has been reached concerning the therapeutic approach for such patients. Most responders preferred rate control over rhythm control in patients with silent AF, although some favoured pulmonary vein isolation in young patients. However, oral anticoagulant therapy in patients at high thromboembolic risk was considered mandatory by most, provided that at least one episode of silent AF was documented, without recommending further investigations. The results of this survey have confirmed that there is currently no consensus regarding the screening and management of patients with silent AF and that clinical practice is not always consistent with the few existing evidence-based recommendations.


Herbal Medicine Offered as an Initiative Therapeutic Option for the Management of Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is a common malignant cancer and is the third leading cause of death worldwide. Effective treatment of this disease is limited by the complicated molecular mechanism underlying HCC pathogenesis. Thus, therapeutic options for HCC management are urgently needed. Targeting the Wnt/β-catenin, Hedgehog, Notch, and Hippo-YAP signaling pathways in cancer stem cell development has been extensively investigated as an alternative treatment. Herbal medicine has emerged as an initiative therapeutic option for HCC management because of its multi-level, multi-target, and coordinated intervention effects. In this article, we summarized the recent progress and clinical benefits of targeting the above mentioned signaling pathways and using natural products such as herbal medicine formulas to treat HCC. Proving the clinical success of herbal medicine is expected to deepen the knowledge on herbal medicine efficiency and hasten the adoption of new therapies. Copyright © 2016 John Wiley & Sons, Ltd.


A new fossil from the mid-Paleocene of New Zealand reveals an unexpected diversity of world's oldest penguins.
We describe leg bones of a giant penguin from the mid-Paleocene Waipara Greensand of New Zealand. The specimens were found at the type locality of Waimanu manneringi and together with this species they constitute the oldest penguin fossils known to date. Tarsometatarsus dimensions indicate a species that reached the size of Anthropornis nordenskjoeldi, one of the largest known penguin species. Stem group penguins therefore attained a giant size very early in their evolution, with this gigantism existing for more than 30 million years. The new fossils are from a species that is phylogenetically more derived than Waimanu, and the unexpected coexistence of Waimanu with more derived stem group Sphenisciformes documents a previously unknown diversity amongst the world's oldest penguins. The characteristic tarsometatarsus shape of penguins evolved early on, and the significant morphological disparity between Waimanu and the new fossil conflicts with recent Paleocene divergence estimates for penguins, suggesting an older, Late Cretaceous, origin.


Multidrug-resistant Plasmodium vivax associated with severe and fatal malaria: a prospective study in Papua, Indonesia.
Multidrug-resistant Plasmodium vivax (Pv) is widespread in eastern Indonesia, and emerging elsewhere in Asia-Pacific and South America, but is generally regarded as a benign disease. The aim of the study was to review the spectrum of disease associated with malaria due to Pv and P. falciparum (Pf) in patients presenting to a hospital in Timika, southern Papua, Indonesia. Data were prospectively collected from all patients attending the outpatient and inpatient departments of the only hospital in the region using systematic data forms and hospital computerised records. Between January 2004 and December 2007, clinical malaria was present in 16% (60,226/373,450) of hospital outpatients and 32% (12,171/37,800) of inpatients. Among patients admitted with slide-confirmed malaria, 64% of patients had Pf, 24% Pv, and 10.5% mixed infections. The proportion of malarial admissions attributable to Pv rose to 47% (415/887) in children under 1 y of age. Severe disease was present in 2,634 (22%) inpatients with malaria, with the risk greater among Pv (23% [675/2,937]) infections compared to Pf (20% [1,570/7,817]; odds ratio [OR] = 1.19 [95% confidence interval (CI) 1.08-1.32], p = 0.001), and greatest in patients with mixed infections (31% [389/1,273]); overall p < 0.0001. Severe anaemia (haemoglobin < 5 g/dl) was the major complication associated with Pv, accounting for 87% (589/675) of severe disease compared to 73% (1,144/1,570) of severe manifestations with Pf (p < 0.001). Pure Pv infection was also present in 78 patients with respiratory distress and 42 patients with coma. In total 242 (2.0%) patients with malaria died during admission: 2.2% (167/7,722) with Pf, 1.6% (46/2,916) with Pv, and 2.3% (29/1260) with mixed infections (p = 0.126). In this region with established high-grade chloroquine resistance to both Pv and Pf, Pv is associated with severe and fatal malaria particularly in young children. The epidemiology of P. vivax needs to be re-examined elsewhere where chloroquine resistance is increasing.


Nondiffusive transport regimes for suprathermal ions in turbulent plasmas.
The understanding of the transport of suprathermal ions in the presence of turbulence is important for fusion plasmas in the burning regime that will characterize reactors, and for space plasmas to understand the physics of particle acceleration. Here, three-dimensional measurements of a suprathermal ion beam in the toroidal plasma device TORPEX are presented. These measurements demonstrate, in a turbulent plasma, the existence of subdiffusive and superdiffusive transport of suprathermal ions, depending on their energy. This result stems from the unprecedented combination of uniquely resolved measurements and first-principles numerical simulations that reveal the mechanisms responsible for the nondiffusive transport. The transport regime is determined by the interaction of the suprathermal ion orbits with the turbulent plasma dynamics, and is strongly affected by the ratio of the suprathermal ion energy to the background plasma temperature.


Ferritin heavy chain protects the developing wing from reactive oxygen species and ferroptosis.
The interplay between signalling pathways and metabolism is crucial for tissue growth. Yet, it remains poorly understood. Here, we studied the consequences of modulating iron metabolism on the growth of Drosophila imaginal discs. We find that reducing the levels of the ferritin heavy chain in the larval wing discs leads to drastic growth defects, whereas light chain depletion causes only minor defects. Mutant cell clones for the heavy chain lack the ability to compete against Minute mutant cells. Reactive oxygen species (ROS) accumulate in wing discs with reduced heavy chain levels, causing severe mitochondrial defects and ferroptosis. Preventing ROS accumulation alleviates some of the growth defects. We propose that the increased expression of ferritin in hippo mutant cells may protect against ROS accumulation.


Identification of genes that interact with glp-1, a gene required for inductive cell interactions in Caenorhabditis elegans.
The glp-1 gene functions in two inductive cellular interactions and in development of the embryonic hypodermis of C. elegans. We have isolated six mutations as recessive suppressors of temperature-sensitive (ts) mutations of glp-1. By mapping and complementation tests, we found that these suppressors are mutations of known dumpy (dpy) genes; dpy genes are required for development of normal body shape. Based on this result, we asked whether mutations previously isolated in screens for mutants defective in body shape could also suppress glp-1(ts). From these tests, we learned that unselected mutations of eight genes required for normal C. elegans morphogenesis, including the four already identified, suppress glp-1(ts). All of these suppressors rescue all three mutant phenotypes of glp-1(ts) (defects in embryonic induction of pharyngeal tissue, in embryonic hypodermis development, and in induction of germline proliferation). However, they do not rescue putative glp-1 null mutants and therefore do not bypass the requirement for glp-1 in development. In the light of current ideas about the molecular nature of the glp-1 and suppressor gene products, we propose an interaction between the glp-1 protein and components of the extracellular matrix and speculate that this interaction may impose spatial constraints on the decision between mitosis and meiosis in the germline.


Over-expression of human lipoprotein lipase in mouse mammary glands leads to reduction of milk triglyceride and delayed growth of suckling pups.
The mammary gland is a conserved site of lipoprotein lipase expression across species and lipoprotein lipase attachment to the luminal surface of mammary gland vascular endothelial cells has been implicated in the direction of circulating triglycerides into milk synthesis during lactation. Here we report generation of transgenic mice harboring a human lipoprotein lipase gene driven by a mammary gland-specific promoter. Lipoprotein lipase levels in transgenic milk was raised to 0.16 mg/ml, corresponding to an activity of 8772.95 mU/ml. High lipoprotein lipase activity led to a significant reduction of triglyceride concentration in milk, but other components were largely unchanged. Normal pups fed with transgenic milk showed inferior growth performances compared to those fed with normal milk. Our study suggests a possibility to reduce the triglyceride content of cow milk using transgenic technology.


Description of calls from private well owners to a national well water hotline, 2013.
Water Systems Council (WSC) is a national, non-profit organization providing education and resources to private household well owners. Since 2003, WSC has provided wellcare®, a toll-free telephone hotline to answer questions from the public regarding well stewardship. In order to identify knowledge gaps regarding well stewardship among private well owners, we obtained data from WSC and reviewed calls made during 2013 to wellcare®. WSC records data from each wellcare® call-including caller information, primary reason for call, main use of well water, and if they were calling about a cistern, private well, shared well, or spring. We searched for calls with key words indicating specific contaminants of interest and reviewed primary reasons for calls. Calls classified as primarily testing-related were further categorized depending on whether the caller asked about how to test well water or how to interpret testing results. During 2013, wellcare® received 1100 calls from private well owners who were residents of 48 states. Among these calls, 87 (8%) mentioned radon, 83 (8%) coliforms, 51 (5%) chemicals related to fracking, 34 (3%) arsenic, and 32 (3%) nitrates key words. Only 38% of private well owners reported conducting any well maintenance activities, such as inspecting, cleaning, repairing the well, or testing well water, during the previous 12 months. The primary reason for calls were related to well water testing (n=403), general information relating to wells (n=249), contaminants (n=229), and well water treatment (n=97). Among calls related to testing, 319 had questions about how to test their well water, and 33 had questions about how to interpret testing results. Calls from private well owners to the wellcare® Hotline during 2013 identified key knowledge gaps regarding well stewardship; well owners are generally not testing or maintaining their wells, have questions about well water testing treatment, and concerns about well water contaminants.


A rapid review investigating the potential impact of a pandemic on the mental health of young people aged 12-25 years.
In March 2020, the World Health Organization (WHO) officially declared the spread of coronavirus disease 2019 (COVID-19) as a pandemic. Adolescence and early adulthood are peak times for the onset of mental health difficulties. Exposure to a pandemic during this vulnerable developmental period places young people at significant risk of negative psychological experiences. The objective of this research was to summarise existing evidence on the potential impact of a pandemic on the mental health of 12-25 year olds. A rapid review of the published peer-reviewed literature, published between 1985 and 2020, using PsycINFO (Proquest) and Medline (Proquest) was conducted. Narrative synthesis was used across studies to identify key themes and concepts. This review found 3,359 papers, which was reduced to 12 papers for data extraction. Results regarding the prevalence of psychological difficulties in youth were mixed, with some studies finding this group experience heightened distress during an infectious disease outbreak, and others finding no age differences or higher distress among adults. Gender, coping, self-reported physical health and adoption of precautionary measures appear to play a role in moderating the psychological impact of an infectious disease outbreak. Most studies were conducted after the peak of an epidemic/pandemic or in the recovery period. More longitudinal research with young people, particularly adolescents in the general population, before and during the early stages of an infectious disease outbreak is needed to obtain a clear understanding of how best to support young people during these events.


Do airway inflammation and airway responsiveness markers at the start of apprenticeship predict their evolution during initial training? A longitudinal study among apprentice bakers, pastry makers and hairdressers.
The natural history of airway inflammation and symptoms in occupations at risk of asthma is still not fully understood. We aimed to study the evolution during apprenticeship of inflammation markers, bronchial hyperresponsiveness (BHR) and symptoms in at-risk subgroups as defined from measurements of markers made shortly after the start of training. Respiratory symptoms, FEV1 and airway resistance post-bronchial challenge (MBC) test results, fractional exhaled nitric oxide (FeNO) measurements, and eosinophils in nasal lavage fluid were investigated in apprentice bakers, pastry-makers and hairdressers. Four visits were conducted: at the start of the training and every six months thereafter. Four baseline risk groups were defined, based on, (i) a high level of FeNO (NO), (ii) eosinophils > 1% (Eosino), (iii) a ≥ 15% decrease in FEV1 during the MBC test (HR), and (iv) a ≥ 50% increase in the resistance (Resist). The statistical analysis relied on mixed models. At baseline, the inflammation markers were related to the MBC markers. There was no evidence to suggest that the baseline risk groups predict a differential evolution of the airway inflammation and bronchial responsiveness markers, or the asthma-like symptoms considered. The baseline risk groups defined from MBC test predicted the levels of MBC markers. Similarly, the baseline risk groups based on eosinophilic inflammation predicted the levels of markers for eosinophilia. These results were similar in the three training tracks, with the exception of the FeNO levels which were not different according to the Eosino risk group. Twelve possible new asthma cases were identified, only the HR risk group predicted their occurrence. Among this young population, at-risk groups based on initial high levels of inflammation markers did not experience any worsening during the follow-up. However, initial BHR predicted consistently high levels of all markers considered and occurrence of possible asthma.


Spectral domain-optical coherence tomography to detect localized retinal nerve fiber layer defects in glaucomatous eyes.
This study examines the ability of RTVue, Cirrus and Spectralis OCT Spectral domain-optical coherence tomographs (SD-OCT) to detect localized retinal nerve fiber layer defects in glaucomatous eyes. In this observational case series, four glaucoma patients (8 eyes) were selected from the University of California, San Diego Shiley Eye Center and the Diagnostic Innovations in Glaucoma Study (DIGS) based on the presence of documented localized RNFL defects in at least one eye confirmed by masked stereophotograph assessment. One RTVue 3D Disc scan, one RTVue NHM4 scan, one Cirrus Optic Disk Cube 200x200 scan and one Spectralis scan centered on the optic disc (15x15 scan angle, 768 A-scans x 73 B-scans) were obtained on all undilated eyes within a single session. Results were compared with those obtained from stereophotographs. In 6 eyes the presence of localized RNFL defects was detected by stereophotography. In general, by qualitatively evaluating the retinal thickness maps generated, all SD-OCT instruments examined were able to confirm the presence of localized glaucomatous structural damage seen on stereophotographs. This study confirms SD-OCT is a promising technology for glaucoma detection as it may assist clinicians identify the presence of localized glaucomatous structural damage.


Pre-/post-functionalization in dipyrrin metal complexes - antitumor and antibacterial activity of their glycosylated derivatives.
A post-functionalization route to tris(dipyrrinato) metal complexes is presented giving access to a range of new complexes relevant in the context of medicinal inorganic chemistry. A pentafluorophenyl group in the meso-position of the dipyrrin ligand serves as an anchor for the connection with alcohols and thiocarbohydrates. The photochemotherapeutic activity of the complexes has been assessed in cellular assays with tumor cell lines and against the Gram-positive bacterium S. aureus. Finally, it is shown that this post-functionalization is also applicable to other dipyrrinato metal complexes.


Naturopathic treatment for ear pain in children.
Otitis media is 1 of the most frequent diseases of early infancy and childhood and 1 of the most common reasons for children to visit a physician. In the past 2 decades, there has been a substantial increase in the diagnosis of otitis media worldwide. In the United States, 93% of all children have had at least 1 episode of acute otitis media (AOM) by 7 years of age. Otalgia is the hallmark of AOM. Most affected children either complain of earache or manifest behavior that the parents interpret as indicating ear pain. Treatment of the ear pain early in the course of AOM decreases both parental anxiety and the child's discomfort and accelerates the healing process. The objective of this study was to determine the efficacy and tolerability of naturopathic versus traditional treatment for the management of otalgia commonly associated with AOM in children. The study was designed as a double-blind trial in an outpatient community clinic. A total of 171 children who were aged 5 to 18 years and had otalgia and clinical findings associated with middle-ear infection were studied. The children were randomly assigned to receive treatment with Naturopathic Herbal Extract Ear Drops (NHED) or anesthetic ear drops, with or without amoxicillin. On enrollment, the children were assigned by computer-numbered randomization to receive NHED (contents: allium sativum, verbascum thapsus, calendula flores, hypericum perfoliatum, lavender, and vitamin E in olive oil) 5 drops 3 times daily, alone (group A) or together with a topical anesthetic (amethocaine and phenazone in glycerin) 5 drops 3 times daily (group B), or oral amoxicillin 80 mg/kg/d (maximum 500 mg/dose) divided into 3 doses with either NHED 5 drops 3 times daily (group C) or topical anesthetic 5 drops 3 times daily (group D). A double-blind design was used, and all ear drops were placed in identical bottles. Treatment was initiated by the nurse in all cases. A single physician (M.S.) evaluated and treated all of the patients included in the study and recorded all of the data. The presence or absence of ear pain was assessed over 3 days with a visual analog scale. Ear pain was assessed by a specially devised observational instrument based on previous reports. One side of the instrument consisted of a linear numbered scale, from 1 (no pain) to 10 (worst possible pain), and a corresponding color scale, ranging from blue to dark red. The reverse side contained a scale of 5 facial expressions, ranging from broad smile (no pain) to a sad and crying face (worst possible pain), and a corresponding color scale, ranging from blue to dark red. There were no significant between-group differences in patient age or gender, degree of fever, main symptoms, associated symptoms, and severity or laterality of acute otitis media. Each group had a statistically significant improvement in ear pain over the course of the 3 days. Patients who were given ear drops alone had a better response than patients who were given ear drops together with amoxicillin. Results were better in the NHED group than in the controls. Nevertheless, the findings indicated that the pain was mostly (80%) self-limited and could be explained simply by the time elapsed. The American Academy of Otolaryngology-Head and Neck Surgery guidelines recommend topical medications as the first line of treatment for ear pain in the absence of systemic infection or serious underlying disease. Because no evidence was found that systemic antibiotics alone improved treatment outcome, if antibiotics do not change the natural course of otitis media, then the main goal of treatment, as in the present study, should be to alleviate the ear pain. The alternative, naturopathic herbal extract medications, may offer many new possibilities in the management of ear pain associated with AOM. Primary care physicians should be aware that at least 10% of their patients may have tried 1 or more forms of alternative/complementary medicine before presenting for consultation. As it was widely reported in the medical literature, these herb, these herbal extracts have the potential to meet all of the requirements of appropriate medication that could be routinely used in the pediatric patient, namely in vitro bacteriostatic and bacteriocidal activity against common pathogens, immunostimulation ability, antioxidant activity, and anti-inflammatory effects. They are also well-absorbed with good penetration into the tissue surrounding the tympanic membrane. They have been found to enhance local immunologic activity. Finally, herbal extracts are well-tolerated (owing to their long elimination time), easy to administer, and less expensive than the new antibiotics. There are no documented side effects. On the basis of our findings that the group with the most significant treatment effects (NHED with topical anesthetic) explained only 7.3% of the total pain reduction, we propose that sometimes the general practitioner or pediatrician needs to give the human body a chance to repair itself. Nevertheless, if the physician believes that there is an indication for some treatment, especially if the parents are anxious, then a local treatment such as one used in our study might be adequate. This study suggests that in cases of ear pain caused by AOM in children in which active treatment, besides a simple 2- to 3-day waiting period, is needed, an herbal extract solution may be beneficial. Concomitant antibiotic treatment is apparently not contributory.


Ginkgo biloba responds to herbivory by activating early signaling and direct defenses.
Ginkgo biloba (Ginkgoaceae) is one of the most ancient living seed plants and is regarded as a living fossil. G. biloba has a broad spectrum of resistance or tolerance to many pathogens and herbivores because of the presence of toxic leaf compounds. Little is known about early and late events occurring in G. biloba upon herbivory. The aim of this study was to assess whether herbivory by the generalist Spodoptera littoralis was able to induce early signaling and direct defense in G. biloba by evaluating early and late responses. Early and late responses in mechanically wounded leaves and in leaves damaged by S. littoralis included plasma transmembrane potential (Vm) variations, time-course changes in both cytosolic calcium concentration ([Ca(2+)](cyt)) and H(2)O(2) production, the regulation of genes correlated to terpenoid and flavonoid biosynthesis, the induction of direct defense compounds, and the release of volatile organic compounds (VOCs). The results show that G. biloba responded to hebivory with a significant Vm depolarization which was associated to significant increases in both [Ca(2+)](cyt) and H(2)O(2). Several defense genes were regulated by herbivory, including those coding for ROS scavenging enzymes and the synthesis of terpenoids and flavonoids. Metabolomic analyses revealed the herbivore-induced production of several flavonoids and VOCs. Surprisingly, no significant induction by herbivory was found for two of the most characteristic G. biloba classes of bioactive compounds; ginkgolides and bilobalides. By studying early and late responses of G. biloba to herbivory, we provided the first evidence that this "living fossil" plant responds to herbivory with the same defense mechanisms adopted by the most recent angiosperms.


Screening of differentially expressed transcripts in infectious bursal disease virus-induced apoptotic chicken embryonic fibroblasts by using cDNA microarrays.
Infectious bursal disease virus (IBDV) induces apoptosis and immunosuppression. To understand the molecular mechanisms involved in the pathogenesis of infectious bursal disease (IBD) and the host-directed antiviral responses, cDNA microarrays were used to identify the differentially expressed transcripts in IBDV-infected chicken embryonic fibroblasts. The results suggest a general suppression of surface receptors, including CD40 ligand and SEMA4D. These are related to T- and B-cell activation and differentiation, which may contribute to the immunosuppression of IBD. In addition, activation of genes involved in Toll-like receptor- and interferon (IFN)-mediated antiviral responses was detected. In particular, upregulation of Toll-like receptor 3, a double-stranded (ds) RNA receptor, and MX1, an IFN-inducible antiviral GTPase, may represent the possible host-directed defence responses against the virus and its dsRNA genome. Interestingly, several lines of evidence suggest the modulation of G protein-coupled receptors and receptor tyrosine kinase signalling pathways, especially the possible transactivation of epidermal growth factor receptor by lysophosphatidic acid. Alteration of these may contribute to the previously reported activation of mitogen-activated protein kinases upon IBDV infection, resulting in macrophage activation and inflammatory responses. Additionally, numerous target genes and inducers of nuclear factor kappa B (NF-kappaB) were upregulated profoundly, implying that IBDV may modulate host-cell survival and apoptosis to support its replication and facilitate viral spread through NF-kappaB activation. In summary, this investigation of host-gene expression unravelled the candidate physiological pathways involved in host-virus interaction on a molecular level, providing a foundation for researchers to design experiments based on testable hypotheses targeting individual genes.


Antimicrobial resistance trends in fecal Salmonella isolates from northern California dairy cattle admitted to a veterinary teaching hospital, 2002-2016.
Nontyphoidal Salmonella infections contribute to approximately 1.2 million annual illnesses in the United States. Historical and recent outbreaks have been associated with dairy products, ground beef, and direct contact with cattle. Salmonella antimicrobial resistance (AMR) is a serious concern that can reduce successful treatment of infections, increasing recovery time, medical costs, and mortality rates in humans and animals. This highlights the need to track AMR in Salmonella isolated from cattle to improve treatment plans, manage trends in AMR, and prevent future AMR development. A total of 242 Salmonella isolates were retrieved from 9,162 cattle fecal samples submitted to the University of California, Davis Veterinary Medical Teaching Hospital from 2002 to 2016. These isolates were tested for antimicrobial susceptibility using a standardized broth dilution panel. Multidrug resistance (MDR) to three or more classes of antimicrobials was observed in 50.8% of isolates, and the most common MDR pattern was amoxicillin-ampicillin-cefoxitin-ceftiofur-ceftriaxone-chloramphenicol-streptomycin-tetracycline (23.2%). There were significantly greater odds for antimicrobial resistance to aminoglycosides (OR: 2.03, 95% CI: 1.1-3.7), penicillins (OR: 1.87, 95% CI: 1.007-3.5), and tetracyclines (OR: 1.87, 95% CI: 1.017-3.4) for the 2002-2009 period when compared to the 2010-2016 period. The most prevalent MDR serotypes were Newport (100% MDR, n = 52), Typhimurium (100%, n = 20), and Dublin (71% MDR, n = 46). Risk factors associated with higher odds for isolating MDR Salmonella included isolates from calves when compared to adult cattle (OR: 22.0; 95% C.I.: 3.9-125.7), and isolates obtained from cattle suspect of having salmonellosis versus from the infectious disease control surveillance program (OR:13.7; 95%C.I.: 2.8-66.8). Despite a temporal trend for reduced AMR to most antimicrobial drug classes, a lack of this observed in the 2002-2009 period when compared to the 2010-2016 period for important drug classes such as cephalosporins (OR: 1.6, 95% CI: 0.87-3.1), and a trend for temporal increase in resistant to quinolones drugs (P value 0.004) highlight the relevance of AMR surveillance in cattle with Salmonella infections with the aim of targeting future prophylactic interventions.


Subperiosteal release of the floor of the mouth in airway management in Pierre Robin sequence.
Procedures to relieve airway obstruction in Pierre Robin sequence (PRS) include glossopexy, mandibular distraction, and tracheostomy. Previously, it has been suggested that the imbalance of the genioglossus insertion on the mandible could be responsible for the micrognathia, tongue elevation, and glossoptosis seen in PRS. We performed a retrospective study to determine the usefulness of subperiosteal release of the floor of the mouth in PRS with airway problems. Between 1991 and 2005, 14 consecutive patients with PRS were treated with subperiosteal release of the floor of the mouth performed at the British Columbia's Children's Hospital. There were 8 boys and 6 girls. Mean age at surgery was 15 weeks (range, 1-68 weeks). Postoperative follow-up ranged from 8 months to 13 years. Seven patients (4 boys and 3 girls) were successfully treated, and a tracheostomy was prevented. Fifty-five percent of the syndromic patients needed a tracheostomy, whereas 1 patient (33%) with isolated PRS needed a tracheostomy. The most common syndrome associated with PRS was Stickler syndrome. Five (72%) of the 7 patients who required a tracheostomy were boys. If conservative measures fail to relieve supraglottic airway obstruction seen in patients with PRS, a subperiosteal release of the floor of the mouth can be an effective intervention in certain patients. It is a simple intervention with few complications and little morbidity. More investigations are mandatory to precisely define patient characteristics ideal for this intervention.


Brontides: natural explosive noises.
Episodes of explosive noises of natural origin, or brontides, have been well documented, often in association with seismic activity and in a few cases as precursors to major earthquakes. Ground-to-air acoustic transmission from shallow earthquakes can account for many of these episodes, but not for all, and other causes, such as the sudden eruption of gas from high-pressure sources in the ground may at times have been responsible. Confusion with distant thunder or artillery at times of anomalous sound propagation complicates the analysis, and more recently the greatly increased frequency of artificial explosive noises and sonic booms has tended to mask the recognition of natural brontides.


The microcephalin ancestral allele in a Neanderthal individual.
The high frequency (around 0.70 worldwide) and the relatively young age (between 14,000 and 62,000 years) of a derived group of haplotypes, haplogroup D, at the microcephalin (MCPH1) locus led to the proposal that haplogroup D originated in a human lineage that separated from modern humans >1 million years ago, evolved under strong positive selection, and passed into the human gene pool by an episode of admixture circa 37,000 years ago. The geographic distribution of haplogroup D, with marked differences between Africa and Eurasia, suggested that the archaic human form admixing with anatomically modern humans might have been Neanderthal. Here we report the first PCR amplification and high-throughput sequencing of nuclear DNA at the microcephalin (MCPH1) locus from Neanderthal individual from Mezzena Rockshelter (Monti Lessini, Italy). We show that a well-preserved Neanderthal fossil dated at approximately 50,000 years B.P., was homozygous for the ancestral, non-D, allele. The high yield of Neanderthal mtDNA sequences of the studied specimen, the pattern of nucleotide misincorporation among sequences consistent with post-mortem DNA damage and an accurate control of the MCPH1 alleles in all personnel that manipulated the sample, make it extremely unlikely that this result might reflect modern DNA contamination. The MCPH1 genotype of the Monti Lessini (MLS) Neanderthal does not prove that there was no interbreeding between anatomically archaic and modern humans in Europe, but certainly shows that speculations on a possible Neanderthal origin of what is now the most common MCPH1 haplogroup are not supported by empirical evidence from ancient DNA.


High-dimensional prediction of binary outcomes in the presence of between-study heterogeneity.
Many prediction methods have been proposed in the literature, but most of them ignore heterogeneity between populations. Either only data from a single study or population is available for model building and evaluation, or when data from multiple studies make up the training dataset, studies are pooled before model building. As a result, prediction models might perform less than expected when applied to new subjects from new study populations. We propose a linear method for building prediction models with high-dimensional data from multiple studies. Our method explicitly addresses between-population variability and tends to select predictors that are predictive in most of the study populations. We employ empirical Bayes estimators and hence avoid selection bias during the variable selection process. Simulation results demonstrate that the new method works better than other linear prediction methods that ignore the between-study variability. Our method is developed for classification into two groups.


Historical, cultural, and contemporary influences on the status of women in nursing in Saudi Arabia.
Global nursing shortages have necessitated closer scrutiny of recruitment and retention initiatives of nurses both locally and internationally. For many decades the nursing workforce of Saudi Arabia has relied on international expatriates to be the backbone of the industry. In recent years however, Saudi women have been recruited into nursing preparation courses conducted at degree level. The many twists and turns of providing a local Saudi Arabian nursing workforce has paralleled Saudi's own history and this paper follows that journey. Our research has enabled us to provide some insights into nursing pre and post the enlightenment that accompanied the Prophet Mohammed's influence. We emphasize the influences of women leaders who emerged in Mohammed's time and bring lasting authority to the development of nursing in Saudi Arabia. The cultural issues that bind women in this society are explicated and related to recruitment and retention issues in nursing. Education matters, both past and present, are highlighted emphasizing the gains that nursing as a distinct occupation has made. Finally the paper concludes with a summation of contemporary achievements in Saudi Arabia moving nursing towards the much needed professional status and parity with other careers in health care.


Finishers and nonfinishers in the 'Swiss Cycling Marathon ' to qualify for the 'Race Across America '.
Knechtle, B, Knechtle, P, Rüst, CA, Rosemann, T, and Lepers, R. Finishers and nonfinishers in the 'Swiss Cycling Marathon' to qualify for the 'Race across America.' J Strength Cond Res 25(12): 3257-3263, 2011-We compared the characteristics of prerace anthropometry, previous experience, and training and support during the race in 39 finishers and 37 nonfinishers in the 'Swiss Cycling Marathon,' over 720 km. In this race, the cyclists intended to qualify for the 'Race across America,' the longest nonstop cycling race in the World from the West to the East of the USA. Finishers in the 'Swiss Cycling Marathon' had a lower body mass, a lower body mass index, lower circumferences of upper arm and thigh, a lower percent body fat, completed more weekly training units, covered more kilometers in the longest training ride, rode at a faster speed during training, rode more kilometers per week and for more hours, had more previous finishes in the 'Swiss Cycling Marathon' and a lighter race bike compared to the nonfinishers. In the bivariate analysis, the cycling distance per training unit (r = 0.37), the duration per training unit (r = 0.44), the speed per training unit (r = -0.59), using nutrition provided by the organizer (r = 0.50), and using own nutrition (r = 0.49) during the race were significantly and positively associated with race time. For practical applications, anthropometric characteristics such as a low body mass or low body fat were not related to race time, whereas training characteristics and nutrition during the race were associated with race time. The key to a successful finish in an ultraendurance cycling race such as the 'Swiss Cycling Marathon' seems a high speed in training and an appropriate nutrition during the race.


Nonsteroidal anti-inflammatory drugs for low back pain: an updated Cochrane review.
A systematic review of randomized controlled trials. To assess the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors in the treatment of nonspecific low back pain and to assess which type of NSAID is most effective. NSAIDs are the most frequently prescribed medications worldwide and are widely used for patients with low back pain. Selective COX-2 inhibitors are currently available and used for patients with low back pain. We searched the MEDLINE and EMBASE databases and the Cochrane Central Register of Controlled Trials up to and including June 2007 if reported in English, Dutch, or German. We also screened references given in relevant reviews and identified trials. Randomized trials and double-blind controlled trials of NSAIDs in nonspecific low back pain with or without sciatica were included. In total, 65 trials (total number of patients = 11,237) were included in this review. Twenty-eight trials (42%) were considered high quality. Statistically significant effects were found in favor of NSAIDs compared with placebo, but at the cost of statistically significant more side effects. There is moderate evidence that NSAIDs are not more effective than paracetamol for acute low back pain, but paracetamol had fewer side effects. There is moderate evidence that NSAIDs are not more effective than other drugs for acute low back pain. There is strong evidence that various types of NSAIDs, including COX-2 NSAIDs, are equally effective for acute low back pain. COX-2 NSAIDs had statistically significantly fewer side effects than traditional NSAIDs. The evidence from the 65 trials included in this review suggests that NSAIDs are effective for short-term symptomatic relief in patients with acute and chronic low back pain without sciatica. However, effect sizes are small. Furthermore, there does not seem to be a specific type of NSAID, which is clearly more effective than others. The selective COX-2 inhibitors showed fewer side effects compared with traditional NSAIDs in the randomized controlled trials included in this review. However, recent studies have shown that COX-2 inhibitors are associated with increased cardiovascular risks in specific patient populations.


Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers.
Quetiapine is an atypical antipsychotic drug used to treat schizophrenia and acute episodes of mania. Quetiapine is metabolized by CYP3A enzymes including CYP3A5 and is a substrate of P-glycoprotein, an efflux drug transporter encoded by the ABCB1 gene. We assessed the effects of ABCB1 [c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), c.3435C>T (rs1045642)] and CYP3A5*3 (6986A>G) (rs776746) polymorphisms on the pharmacokinetics of quetiapine in humans. Forty healthy male individuals were enrolled, and their ABCB1 and CYP3A5 polymorphisms were assessed. After a single dose of 100 mg quetiapine was administered, plasma concentrations of quetiapine were measured for 24 h and pharmacokinetic analysis was carried out. The ABCB1 polymorphisms including c.1236C>T, c.2677G>T/A, and c.3435C>>T did not affect plasma levels of quetiapine, and its pharmacokinetic parameters did not differ among ABCB1 genotype groups. However, the CYP3A5*3 polymorphism significantly affected the plasma level of quetiapine and its pharmacokinetics. The peak plasma concentration of quetiapine was 208.39 ng/ml for CYP3A5*1/*1, 243.46 ng/ml for CYP3A5*1/*3, and 332.94 ng/ml for CYP3A5*3/*3 (P=0.0118). The mean AUC(inf) (area under the time vs. concentration curve from 0 to infinity) value was 627.3, 712.77, and 1045.29 ng h/ml, respectively (P=0.0017). The results indicated that the genetic polymorphism of CYP3A5*3 but not ABCB1 significantly influences the plasma level of quetiapine and its pharmacokinetics. These findings suggest that the CYP3A5 genetic polymorphism affects the disposition of quetiapine and provide a plausible explanation for interindividual variation in the disposition of this drug.


Has protest increased since the 1970s? How a survey question can construct a spurious trend.
The literature on political participation asserts that protest has increased over the last four decades, all over the world. This trend is derived from surveys asking questions about participation in various forms of protest, including demonstrations, boycotts, and unofficial strikes. The latter question made sense in the context in which it was formulated, Britain in the early 1970s, and with regard to the original methodological aim, measuring 'protest potential'. The absence of a generic question on strikes, however, distorts our understanding of protest. Two sources of data on Britain in the 1980s and 1990 s - a population survey and an event catalogue - comprehensively measure strikes. They show that strikes greatly outnumbered demonstrations and other forms of protest. Another claim in the literature, that protesters are highly educated, no longer holds once strikes are properly counted. Strikes in Britain, as in many countries, have dramatically declined since the 1980s. This decline more than offsets any increase in demonstrations and boycotts, meaning that the total volume of protest has decreased. The episode illustrates how survey questions, when replicated without scrutiny, can misconstrue social trends.


A comparison between oculomotor rehabilitation and vestibular electrical stimulation in unilateral peripheral vestibular deficit.
Rehabilitation therapy is proved to be effective in reducing disability in patients with persistent symptoms of disequilibrium after acute unilateral peripheral vestibular deficit. The aim of this study was to evaluate the effects of oculomotor rehabilitation (group 2) on static balance and a dizziness handicap and to compare those with the effects to vestibular electrical stimulation (group 1). Before and after therapy, we tested 28 patients, using static posturography and.the dizziness handicap inventory short form. After therapy, all subjects reported a reduction of symptoms (p = .00019). In group 1, the reductions seen in eyes-opened length of the oscillations and eyes-opened and eyes-closed surface of the body sway were statistically significant, respectively (p = .04; p = .02; p = .02). Group 2 patients revealed better stability on all parameters, and the reductions of eyes-opened length and of eyes-opened correlation function between length and surface were statistically significant (p = .01 and p = .01, respectively). Analysis of the equilibrium system subcomponents did not show any variation. Oculomotor exercises,employed in most rehabilitative protocols and including head movements to improve vestibular adaptation, have proved to reduce the perceived overall impairment and postural sway in patients with recent unilateral vestibular disorders, even though the disorders are not associated with head movements. Comparison of our two study groups did not show any significant difference, revealing that both forms of therapy are effective.


Seizures in supratentorial meningioma: a systematic review and meta-analysis.
OBJECT Meningioma is the most common benign intracranial tumor, and patients with supratentorial meningioma frequently suffer from seizures. The rates and predictors of seizures in patients with meningioma have been significantly under-studied, even in comparison with other brain tumor types. Improved strategies for the prediction, treatment, and prevention of seizures in patients with meningioma is an important goal, because tumor-related epilepsy significantly impacts patient quality of life. METHODS The authors performed a systematic review of PubMed for manuscripts published between January 1980 and September 2014, examining rates of pre- and postoperative seizures in supratentorial meningioma, and evaluating potential predictors of seizures with separate meta-analyses. RESULTS The authors identified 39 observational case series for inclusion in the study, but no controlled trials. Preoperative seizures were observed in 29.2% of 4709 patients with supratentorial meningioma, and were significantly predicted by male sex (OR 1.74, 95% CI 1.30-2.34); an absence of headache (OR 1.77, 95% CI 1.04-3.25); peritumoral edema (OR 7.48, 95% CI 6.13-9.47); and non-skull base location (OR 1.77, 95% CI 1.04-3.25). After surgery, seizure freedom was achieved in 69.3% of 703 patients with preoperative epilepsy, and was more than twice as likely in those without peritumoral edema, although an insufficient number of studies were available for formal meta-analysis of this association. Of 1085 individuals without preoperative epilepsy who underwent resection, new postoperative seizures were seen in 12.3% of patients. No difference in the rate of new postoperative seizures was observed with or without perioperative prophylactic anticonvulsants. CONCLUSIONS Seizures are common in supratentorial meningioma, particularly in tumors associated with brain edema, and seizure freedom is a critical treatment goal. Favorable seizure control can be achieved with resection, but evidence does not support routine use of prophylactic anticonvulsants in patients without seizures. Limitations associated with systematic review and meta-analysis should be considered when interpreting these results.


Interventions to Decrease Carotid-Intima Media Thickness in Children and Adolescents With Type 1 Diabetes: A Systematic Review and Meta-Analysis.
Hyperglycemia is associated with a higher cardiovascular risk, as evidenced by increased carotid-intima media thickness (CIMT) in youth with diabetes. We conducted a systematic review and meta-analysis to assess the effect of pharmacological or non-pharmacological interventions on CIMT in children and adolescents with prediabetes or diabetes. We conducted systematic searches of MEDLINE, EMBASE, and CENTRAL, together with supplementary searches in trial registers and other sources for studies completed up to September 2019. Interventional studies assessing ultrasound CIMT in children and adolescents with prediabetes or diabetes were considered for inclusion. Where appropriate, data were pooled across studies using random-effect meta-analysis. Quality was assessed using The Cochrane Collaboration's risk-of-bias tool and a CIMT reliability tool. Six studies involving 644 children with type 1 diabetes mellitus were included. No study involved children with prediabetes or type 2 diabetes. Three randomized controlled trials (RCTs) evaluated the effects of metformin, quinapril, and atorvastatin. Three non-randomized studies, with a before-and-after design, evaluated the effects of physical exercise and continuous subcutaneous insulin infusion (CSII). The mean CIMT at baseline ranged from 0.40 to 0.51 mm. The pooled difference in CIMT was -0.01 mm (95% CI: -0.04 to 0.01) for metformin compared to placebo (2 studies; 135 participants; I2: 0%). The difference in CIMT was -0.01 mm (95% CI: -0.03 to 0.01) for quinapril compared to placebo (1 study; 406 participants). The mean change from baseline in CIMT was -0.03 mm (95% CI: -0.14 to 0.08) after physical exercise (1 study; 7 participants). Inconsistent results were reported for CSII or for atorvastatin. CIMT measurement was rated at a higher quality on all reliability domains in 3 (50%) studies. The confidence in results is limited by the low number of RCTs and their small sample sizes, as well as the high risk of bias in before-and-after studies. Some pharmacological interventions may decrease CIMT in children with type 1 diabetes. However, there is great uncertainty with respect to their effects and no strong conclusions can be drawn. Further evidence from larger RCTs is required. PROSPERO, CRD42017075169.


Relationship Between Non-invasive Brain Stimulation-induced Plasticity and Capacity for Motor Learning.
Cortical plasticity plays a key role in motor learning (ML). Non-invasive brain stimulation (NIBS) paradigms have been used to modulate plasticity in the human motor cortex in order to facilitate ML. However, little is known about the relationship between NIBS-induced plasticity over M1 and ML capacity. NIBS-induced MEP changes are related to ML capacity. 56 subjects participated in three NIBS (paired associative stimulation, anodal transcranial direct current stimulation and intermittent theta-burst stimulation), and in three lab-based ML task (serial reaction time, visuomotor adaptation and sequential visual isometric pinch task) sessions. After clustering the patterns of response to the different NIBS protocols, we compared the ML variables between the different patterns found. We used regression analysis to explore further the relationship between ML capacity and summary measures of the MEPs change. We ran correlations with the "responders" group only. We found no differences in ML variables between clusters. Greater response to NIBS protocols may be predictive of poor performance within certain blocks of the VAT. "Responders" to AtDCS and to iTBS showed significantly faster reaction times than "non-responders." However, the physiological significance of these results is uncertain. MEP changes induced in M1 by PAS, AtDCS and iTBS appear to have little, if any, association with the ML capacity tested with the SRTT, the VAT and the SVIPT. However, cortical excitability changes induced in M1 by AtDCS and iTBS may be related to reaction time and retention of newly acquired skills in certain motor learning tasks.


Overcome of Carbon Catabolite Repression of Bioinsecticides Production by Sporeless Bacillus thuringiensis through Adequate Fermentation Technology.
The overcoming of catabolite repression, in bioinsecticides production by sporeless Bacillus thuringiensis strain S22 was investigated into fully controlled 3 L fermenter, using glucose based medium. When applying adequate oxygen profile throughout the fermentation period (75% oxygen saturation), it was possible to partially overcome the catabolite repression, normally occurring at high initial glucose concentrations (30 and 40 g/L glucose). Moreover, toxin production yield by sporeless strain S22 was markedly improved by the adoption of the fed-batch intermittent cultures technology. With 22.5 g/L glucose used into culture medium, toxin production was improved by about 36% when applying fed-batch culture compared to one batch. Consequently, the proposed fed-batch strategy was efficient for the overcome of the carbon catabolite repression. So, it was possible to overproduce insecticidal crystal proteins into highly concentrated medium.


Feasibility and promise of a couple-based HIV/STI preventive intervention for methamphetamine-using, black men who have sex with men.
Accumulating evidence supports couple-based approaches for HIV/STI preventive interventions. Yet, to date, no studies have examined couple-based sexual risk reductions intervention specifically for men who have sex with men (MSM) from populations with elevated rates of HIV/STI transmission, such as black MSM and methamphetamine-involved MSM. We pilot tested-using a pre-/post-test design-a seven-session couple-based intervention for black, methamphetamine-using, black MSM couples engaging in sexual risk. Feasibility was assessed via recruitment and retention rates; potential efficacy relied on self-reported sexual risk and drug use prior to and two months following intervention delivery. We enrolled 34 couples (N = 68 men). Over 80% attended all seven intervention sessions, and retention exceeded 95% at two-month follow-up. At follow-up, participants reported significantly fewer sexual partners, fewer episodes of unprotected anal sex, and greater condom use with their main partner; participants also reported significantly less methamphetamine use, any illicit drug use, and number of illicit drugs used. These findings indicate that couple-based HIV/STI intervention is feasible and promising for at-risk black MSM couples.


Dose selective dissociation of water and solute excretion after renal alpha-2 adrenoceptor stimulation.
In vitro studies have demonstrated an antagonism of the renal effects of vasopressin after alpha-2 adrenoceptor stimulation. Whether the effect of alpha-2 adrenoceptor stimulation in relation to sodium and water excretion in vivo is mediated through independent mechanisms is unclear. The dose-response relationship between renal alpha-2 adrenoceptor stimulation (clonidine) and water and electrolyte excretion was evaluated in anesthetized rats. Rats were nephrectomized unilaterally 7 to 10 days before the experimental day to allow isolation of renal function. A base-line level of sodium and water excretion was established by the infusion of saline (0.097 ml/min i.v.). In separate groups of rats, clonidine was infused directly into the renal artery at 0 (vehicle), 0.1, 0.3, 1 or 3 micrograms/kg/min at 0.0034 ml/min. The lower doses (0.1, 0.3 and 1 microgram/kg/min) produced a dose-related increase in urine volume and free water clearance and a decrease in urine osmolality. Electrolyte or solute excretion was not altered at these infusion rates even though urine volume increased 4-fold. The highest dose investigated (3 micrograms/kg/min) increased urine volume (9-fold) and sodium excretion (4-fold). Free water clearance and osmolar clearance were also increased. The effects of clonidine were attenuated by yohimbine but not prazosin indicating these effects were mediated by alpha-2 adrenoceptor stimulation. These results demonstrate a dose-related selectivity of alpha-2 adrenoceptor stimulation for water and sodium excretion. The increase in water excretion at the lower infusion rates would be consistent with the antagonism of the renal effects of vasopressin. The potent natriuresis observed only at higher doses indicates another mechanism may be involved.


Moyamoya: Indiana University Medical Center experience.
Moyamoya usually presents with cerebral ischemia in children and intracranial hemorrhage in adults. Treatment remains controversial. We reviewed our experience from June 1995 to August 1999 of 20 adult and pediatric angiographically diagnosed patients with moyamoya to report their clinical presentation, radiological findings, management, and clinical outcomes. The mean age of patients at symptom onset was 17 years (range, 2-54 years). Patients were divided into 2 age groups (group 1, <18 years; group 2, > or =18 years). There were 13 patients in group 1 and 7 patients in group 2. Ischemic strokes or transient ischemic attacks were the predominant initial presentations in both groups. One patient in group 2 had an intraparenchymal brain hemorrhage. Five patients received medical treatment, and 15 had surgical revascularization. The mean time from symptom onset to surgical procedure was significantly longer for patients in group 1 than for those in group 2 (P =.03). The mean follow-up time was 36 months. One patient in group 1 had an ischemic stroke. There was no difference in stroke recurrence, mortality, or modified Rankin scale score among medically or surgically treated patients. Moyamoya disease may have a different presentation and more benign natural history in our population than in Asian populations. Our findings emphasize the need to better understand the natural history of patients with moyamoya as well as the clinical benefit of different treatment modalities. Structured multicenter randomized clinical trials are needed to further assess the best treatment modalities for patients with moyamoya in the United States.


KLHDC7B-DT aggravates pancreatic ductal adenocarcinoma development via inducing cross-talk between cancer cells and macrophages.
Tumor microenvironment (TME) exerts key roles in pancreatic ductal adenocarcinoma (PDAC) development. However, the factors regulating the cross-talk between PDAC cells and TME are largely unknown. In the present study, we identified a long noncoding RNA (lncRNA) KLHDC7B divergent transcript (KLHDC7B-DT), which was up-regulated in PDAC and correlated with poor survival of PDAC patients. Functional assays demonstrated that KLHDC7B-DT enhanced PDAC cell proliferation, migration, and invasion. Mechanistically, KLHDC7B-DT was found to directly bind IL-6 promoter, induce open chromatin structure at IL-6 promoter region, activate IL-6 transcription, and up-regulate IL-6 expression and secretion. The expression of KLHDC7B-DT was positively correlated with IL-6 in PDAC tissues. Via inducing IL-6 secretion, KLHDC7B-DT activated STAT3 signaling in PDAC cells in an autocrine manner. Furthermore, KLHDC7B-DT also activated STAT3 signaling in macrophages in a paracrine manner, which induced macrophage M2 polarization. KLHDC7B-DT overexpressed PDAC cells-primed macrophages promoted PDAC cell proliferation, migration, and invasion. Blocking IL-6/STAT3 signaling reversed the effects of KLHDC7B-DT on macrophage M2 polarization and PDAC cell proliferation, migration, and invasion. In conclusion, KLHDC7B-DT enhanced malignant behaviors of PDAC cells via IL-6-induced macrophage M2 polarization and IL-6-activated STAT3 signaling in PDAC cells. The cross-talk between PDAC cells and macrophages induced by KLHDC7B-DT represents potential therapeutic target for PDAC.


Genotype/phenotype correlation in autosomal recessive lamellar ichthyosis.
Autosomal recessive lamellar ichthyosis is a severe congenital disorder of keratinization, characterized by variable erythema of the whole body surface and by different scaling patterns. Recently, mutations have been identified in patients with lamellar ichthyosis in the TGM1 gene coding for keratinocyte transglutaminase, and a second locus has been mapped to chromosome 2. We have now analyzed the genotype/phenotype correlation in a total of 14 families with lamellar ichthyosis. Linkage analyses using microsatellites in the region of the TGM1 gene confirmed genetic heterogeneity. In patients not linked to the TGM1 gene, the second region identified on chromosome 2 and a further candidate region on chromosome 20 were excluded, confirming as well the existence of at least three loci for lamellar ichthyosis. Sequence analyses of the TGM1 gene in families compatible with linkage to this locus revealed seven different missense mutations, five of these unpublished so far, and one splice mutation. No genotype/phenotype correlation for mutations in the TGM1 gene was found in this group of patients, which included two unrelated patients homozygous for the same mutation. Similarly, no clear difference in the clinical picture was seen between patients with TGM1 mutations and those unlinked to the TGM1 locus. Comparison of genetic and clinical classifications for patients with lamellar ichthyosis shows no consistency and thus indicates that clinical criteria currently in use cannot discriminate between the molecularly different forms of the disease.


Cellular resolution models for even skipped regulation in the entire Drosophila embryo.
Transcriptional control ensures genes are expressed in the right amounts at the correct times and locations. Understanding quantitatively how regulatory systems convert input signals to appropriate outputs remains a challenge. For the first time, we successfully model even skipped (eve) stripes 2 and 3+7 across the entire fly embryo at cellular resolution. A straightforward statistical relationship explains how transcription factor (TF) concentrations define eve's complex spatial expression, without the need for pairwise interactions or cross-regulatory dynamics. Simulating thousands of TF combinations, we recover known regulators and suggest new candidates. Finally, we accurately predict the intricate effects of perturbations including TF mutations and misexpression. Our approach imposes minimal assumptions about regulatory function; instead we infer underlying mechanisms from models that best fit the data, like the lack of TF-specific thresholds and the positional value of homotypic interactions. Our study provides a general and quantitative method for elucidating the regulation of diverse biological systems. DOI:http://dx.doi.org/10.7554/eLife.00522.001.


Layer-specific properties of the persistent sodium current in sensorimotor cortex.
We evaluated the characteristics of the persistent sodium current (I(NaP)) in pyramidal neurons of layers II/III and V in slices of rat sensorimotor cortex using whole cell patch-clamp recordings. In both layers, I(NaP) began activating around -60 mV and was half-activated at -43 mV. The I(NaP) peak amplitude and density were significantly higher in layer V. The voltage-dependent I(NaP) steady-state inactivation occurred at potentials that were significantly more positive in layer V (V(1/2): -42.3 +/- 1.1 mV) than in layer II/III (V(1/2): -46.8 +/- 1.6 mV). In both layers, a current fraction corresponding to about 25% of the maximal peak amplitude did not inactivate. The time course of I(NaP) inactivation and recovery from inactivation could be fitted with a biexponential function. In layer V pyramidal neurons the faster time constant of development of inactivation had variable values, ranging from 158.0 to 1,133.8 ms, but it was on average significantly slower than that in layer II/III (425.9 +/- 80.5 vs. 145.8 +/- 18.2 ms). In both layers, I(NaP) did not completely inactivate even with very long conditioning depolarizations (40 s at -10 mV). Recovery from inactivation was similar in the two layers. Layer V intrinsically bursting and regular spiking nonadapting neurons showed particularly prolonged depolarized plateau potentials when Ca2+ and K+ currents were blocked and slower early phase of I(NaP) development of inactivation. The biexponential kinetics characterizing the time-dependent inactivation of I(NaP) in layers II/III and V indicates a complex inactivating process that is incomplete, allowing a residual "persistent" current fraction that does not inactivate. Moreover, our data indicate that I(NaP) has uneven inactivation properties in pyramidal neurons of different layers of rat sensorimotor cortex. The higher current density, the rightward shifted voltage dependency of inactivation as well the slower kinetics of inactivation characterizing I(NaP) in layer V with respect to layer II/III pyramidal neurons may play a significant role in their ability to fire recurrent action potential bursts, as well in the high susceptibility to generate epileptic events.


Motivational interviewing to improve self-care in heart failure patients (MOTIVATE-HF): a randomized controlled trial.
Self-care, an essential component of heart failure (HF) treatment, is inadequate in most patients. We evaluated if motivational interviewing (MI) (i) improves patient self-care maintenance (primary endpoint; e.g. taking medications), self-care management (e.g. responding to symptoms) and self-care confidence (or self-efficacy) 3 months after enrolment; (ii) changes self-care over 1 year, and (iii) augments patient self-care if informal caregivers are involved. Parallel randomized controlled trial (1:1:1). A sample of 510 patients (median 74 years, 58% male) and caregivers (median 55 years, 75% female) was randomized to Arm 1 (MI only for patients), Arm 2 (MI for patients and caregivers), or Arm 3 (usual care). The intervention in Arms 1 and 2 consisted of one face-to-face MI session with three telephone contacts. Self-care was evaluated with the Self-Care of HF Index measuring self-care maintenance, management, and confidence. Scores on each scale range from 0 to 100 with higher scores indicating better self-care; ≥70 is considered adequate. At 3 months, self-care maintenance improved 6.99, 7.42 and 2.58 points in Arms 1, 2, and 3, respectively (P = 0.028). Self-care maintenance was adequate in 18.4%, 19.4%, and 9.2% of patients in Arms 1, 2 and 3, respectively (P = 0.016). Over 1 year, self-care maintenance, management, and confidence scores in Arms 1 and 2 were significantly higher than in Arm 3 in several follow-ups. Over 1 year, Arm 2 had the best scores in self-care management. MI significantly improved self-care in HF patients. Including caregivers may potentiate the effect, especially in self-care management. ClinicalTrial.gov, identifier: NCT02894502.


Consequences of combining siRNA-mediated DNA methyltransferase 1 depletion with 5-aza-2'-deoxycytidine in human leukemic KG1 cells.
5-azacytidine and 5-aza-2'-deoxycytidine are clinically used to treat patients with blood neoplasia. Their antileukemic property is mediated by the trapping and the subsequent degradation of a family of proteins, the DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) leading to DNA demethylation, tumor suppressor gene re-expression and DNA damage. Here we studied the respective role of each DNMT in the human leukemia KG1 cell line using a RNA interference approach. In addition we addressed the role of DNA damage formation in DNA demethylation by 5-aza-2'-deoxycytidine. Our data show that DNMT1 is the main DNMT involved in DNA methylation maintenance in KG1 cells and in mediating DNA damage formation upon exposure to 5-aza-2'-deoxycytidine. Moreover, KG1 cells express the DNMT1 protein at a level above the one required to ensure DNA methylation maintenance, and we identified a threshold for DNMT1 depletion that needs to be exceeded to achieve DNA demethylation. Most interestingly, by combining DNMT1 siRNA and treatment with low dose of 5-aza-2'-deoxycytidine, it is possible to uncouple DNA damage formation from DNA demethylation. This work strongly suggests that a direct pharmacological inhibition of DNMT1, unlike the use of 5-aza-2'-deoxycytidine, should lead to tumor suppressor gene hypomethylation and re-expression without inducing major DNA damage in leukemia.


Interventions for restoring patency of occluded central venous catheter lumens.
Central venous catheters (CVCs) facilitate the administration of intravenous drugs, fluids, blood products and parenteral nutrition to patients with either chronic disease or critical illness. Despite a pivotal role within medical management, a common complication associated with CVC use is occlusion of the CVC lumen(s). CVC occlusion can interrupt and cause serious delays in administration of treatment interventions. The primary objective of this review was to assess the efficacy and safety of different interventions used to restore patency of occluded CVC lumens, in adults and children. We identified trials by searching the Cochrane Central Register of Clinical Trials (CENTRAL) (The Cochrane Library 2011, Issue 9); OvidSP MEDLINE (1950 to September 2011); OvidSP EMBASE (1980 to September 2011) and NHS Evidence CINAHL (1982 to September 2011). We also searched clinical trial registers, handsearched reference lists, contacted pharmaceutical companies and authors of publications that met the inclusion criteria to identify trials. We selected randomized controlled trials which investigated the efficacy of an intervention (chemical, surgical or drug) used to restore patency to an occluded CVC lumen, in either adults or children. Three authors independently assessed those studies that met the inclusion criteria for quality and extracted the relevant data using a standardized form. No studies were found that investigated the efficacy and safety of either chemical or surgical interventions.Seven studies (eight papers) with a total of 632 participants were identified from the search. They investigated different comparisons, strengths of thrombolytic or anticoagulant drug interventions for treating CVC lumen occlusion thought to be caused by a thrombus.There was low quality evidence from a meta-analysis of two studies suggesting that urokinase (various strengths) was more effective than placebo for restoring patency to occluded CVC lumens in adults and children with underlying medical conditions (relative risk (RR) 2.09, 95% confidence interval (CI) 1.47 to 2.95), with a number needed to treat of 4 (95% CI 2 to 8). There was insufficient evidence to draw conclusions on the safety of urokinase.The overall quality of the evidence provided by these studies was low to very low due to one or more domains being assessed as either at 'unclear risk of bias' or 'high risk of bias'. Furthermore, the total number of participants in these studies was small and consequently may lead to spurious results. There is inadequate evidence to draw strong conclusions on the efficacy or safety of the drug interventions included in this review. There is some low quality evidence from a meta-analysis of two studies investigating urokinase (various strengths) and some very low evidence from two single studies investigating alteplase 2 mg/2 mL that suggest that these two drug interventions may be effective in treating withdrawal or total occlusion of CVC lumens caused by thrombosis. Further high quality, sufficiently powered research is still required to look at the efficacy and safety of urokinase, alteplase and other chemical, surgical and drug interventions for treating CVC lumen occlusion. Research studies which exclusively include child participants are especially warranted.


Physiologic and molecular bases of muscle hypertrophy and atrophy: impact of resistance exercise on human skeletal muscle (protein and exercise dose effects).
Normally, skeletal muscle mass is unchanged, beyond periods of growth, but it begins to decline in the fourth or fifth decade of life. The mass of skeletal muscle is maintained by ingestion of protein-containing meals. With feeding, muscle protein synthesis (MPS) is stimulated and a small suppression of muscle protein breakdown (MPB) occurs, such that protein balance becomes positive (MPS>MPB). As the postprandial period subsides and a transition toward fasting occurs, the balance of muscle protein turnover becomes negative again (MPB>MPS). Thus, during maintenance of skeletal muscle mass, the long-term net result is that MPS is balanced by MPB. Acutely, however, it is of interest to determine what regulates feeding-induced increases in MPS, since it appears that, in a number of scenarios (for example aging, disuse, and wasting diseases), a suppression of MPS in response to feeding is a common finding. In fact, recent findings point to the fact that loss of skeletal muscle mass with disuse and aging is due not chronic changes in MPS or MPB, but to a blunted feeding-induced rise in MPS. Resistance exercise is a potent stimulator of MPS and appears to synergistically enhance the gains stimulated by feeding. As such, resistance exercise is an important countermeasure to disuse atrophy and to age-related declines in skeletal muscle mass. What is less well understood is how the intensity and volume of the resistance exercise stimulus is sufficient to result in rises in MPS. Recent advances in this area are discussed here, with a focus on human in vivo data.


Clinician views of referring people with negative symptoms to outcome research: a questionnaire survey.
This paper reports on a survey of mental health clinician views of including people with psychosis and negative symptoms in outcome research. A questionnaire was forwarded to clinicians (the majority of whom were mental health nurses) completing post-registration undergraduate and postgraduate degree courses in psychosocial interventions for psychosis. Fifty questionnaires were returned (a response rate of 84.7%). A total of 47% of respondents indicated that they might refrain from offering this group as potential participants to clinical trials. Thematic analysis suggests views that negative symptoms are not amenable to treatment inform such decisions. The results highlight the potential difficulties faced by researchers investigating new treatments for people with negative symptoms, and suggest further exploration of clinician views of referring this group to research and psychosocial treatments is warranted.


Viewpoint: Availability of oestrogen receptor and HER2 status for the breast multidisciplinary meeting discussion; time to get it right.
The efficacy and pivotal role of the multidisciplinary meeting (MDM) in informed decision making is well established. It aims to provide a forum in which clinical evidence combines with individual patient data to create a personalized treatment plan. It does not fulfil this role adequately when undertaken without the full results of the patient's investigations being available. Neither doctor nor patient can make an informed decision about treatment options without knowledge of the tumour receptor status. Both targeted therapies and the aim to treat a majority of patients within clinical trials must now drive MDM decision making to be based on accuracy and best available treatment choices. A fully informed decision on treatment delayed by 1-2 weeks is clearly preferable to rushed time target-driven decisions made without the patient being offered a fully informed choice as ratified by a multidisciplinary team. Whilst the early anxiety of waiting for all relevant information to be available may be stressful for patients, not being sure that they have been offered fully informed treatment choices is also stressful and could cause longer lasting anxiety both during and after treatment. MDMs need to develop (along with targeted therapies) to retain their role as a forum whereby patients receive a correct, but specifically a full diagnosis and allow a fully informed discussion of all treatment options, including pre-operative clinical trials.


Restitution in mapping models with an arbitrary amount of memory.
Restitution, the characteristic shortening of action potential duration (APD) with increased heart rate, has been studied extensively because of its purported link to the onset of fibrillation. Restitution is often represented in the form of mapping models where APD is a function of previous diastolic intervals (DIs) and/or APDs, A(n+1)=F(D(n),A(n),D(n-1),A(n-1),...), where A(n+1) is the APD following a DI given by D(n). The number of variables previous to D(n) determines the degree of memory in the mapping model. Recent experiments have shown that mapping models should contain at least three variables (D(n),A(n),D(n-1)) to reproduce a restitution portrait (RP) that is qualitatively similar to that seen experimentally, where the RP shows three different types of restitution curves (RCs) [dynamic, S1-S2, and constant-basic cycle length (BCL)] simultaneously. However, an interpretation of the different RCs has only been presented in detail for mapping models of one and two variables. Here we present an analysis of the different RCs in the RP for mapping models with an arbitrary amount of memory. We determine the number of variables necessary to represent the different RCs in the RP. We also present a graphical visualization of these RCs. Our analysis reveals that the dynamic and S1-S2 RCs reside on two-dimensional surfaces, and therefore provide limited information for mapping models with more than two variables. However, constant-BCL restitution is a feature of the RP that depends on higher dimensions and can possibly be used to determine a lower bound on the dimensionality of cardiac dynamics.


Identification of 5-hydroxycytidine at position 2501 concludes characterization of modified nucleotides in E. coli 23S rRNA.
Complete characterization of a biomolecule's chemical structure is crucial in the full understanding of the relations between their structure and function. The dominating components in ribosomes are ribosomal RNAs (rRNAs), and the entire rRNA-but a single modified nucleoside at position 2501 in 23S rRNA-has previously been characterized in the bacterium Escherichia coli. Despite a first report nearly 20 years ago, the chemical nature of the modification at position 2501 has remained elusive, and attempts to isolate it have so far been unsuccessful. We unambiguously identify this last unknown modification as 5-hydroxycytidine-a novel modification in RNA. Identification of 5-hydroxycytidine was completed by liquid chromatography under nonoxidizing conditions using a graphitized carbon stationary phase in combination with ion trap tandem mass spectrometry and by comparing the fragmentation behavior of the natural nucleoside with that of a chemically synthesized ditto. Furthermore, we show that 5-hydroxycytidine is also present in the equivalent position of 23S rRNA from the bacterium Deinococcus radiodurans. Given the unstable nature of 5-hydroxycytidine, this modification might be found in other RNAs when applying the proper analytical conditions as described here.


Knowledge of and attitudes to HIV/AIDS of senior secondary school pupils and trainee teachers in Udupi District, Karnataka, India.
A cross-sectional descriptive study using a questionnaire with mostly closed-ended questions was carried out on 990 pupils and 46 trainee teachers to investigate their knowledge of and attitudes to HIV/AIDS. Pupils in one school were reassessed after a health talk and distribution of a handout. Despite having had no formal sex education, most respondents were reasonably well informed about the transmission of HIV. However, there were many misconceptions about transmission and prevention and 16.9% of pupils were found to possess very little knowledge of HIV/AIDS. Mass media, teachers and health workers were quoted as the main sources of knowledge. It was found that 24.3% pupils and 6.3% of trainee teachers thought there was a cure, and 27.4% of pupils and 14% of trainee teachers thought there was a vaccine to prevent HIV infection. Schools that were rural, private and English-speaking scored better, as did male students and schools teaching science. The necessity of formal sex education was expressed by 98.5% of pupils and all the trainee teachers. The pupils who were reassessed after receiving a talk and handout showed significant improvement in their knowledge and a change in attitude (p < 0.01). The mass media are important in disseminating knowledge on HIV/AIDS in India but due to the lack of inter-personal approaches to the education system, knowledge is inadequate and misconceptions exist.


In vitro assessment of the prebiotic potential of Aloe vera mucilage and its impact on the human microbiota.
Aloe vera mucilage is reported to be rich in acemannan that is a polysaccharide with a backbone of β-(1→4)-D-mannose residues acetylated at the C-2 and C-3 positions and contains some side chains of galactose and arabinose attached to the C-6 carbon. The evaluation of the prebiotic potential of Aloe vera mucilage was carried out by in vitro fermentation using intestinal microbiota from six healthy donors as the inoculum. The prebiotic activity was assessed through the quantification of short chain fatty acids (SCFA) and the evaluation of dynamic bacterial population in mixed faecal cultures by fluorescence in situ hybridization (FISH). Our findings support the possible incorporation of the Aloe vera mucilage in the development of a variety of food products known as prebiotics aimed at improving gastrointestinal health.


Pooled analysis of 3 European case-control studies: I. Reproductive factors and risk of epithelial ovarian cancer.
The role of reproductive factors in the aetiology of epithelial ovarian cancer has been re-assessed in a meta-analysis of 3 hospital-based case-control studies conducted in Europe (i.e. Italy, the United Kingdom and Greece), providing a total dataset of 1,140 cases and 2,724 controls. Multiple logistic regression models were used to obtain relative risk (RR) estimates adjusted for study centre, age, socio-cultural indicators, age at menopause, and oral contraceptive use. The risk decreased with increasing number of births and the trend in risk was significant (chi 2(1) = 7.50, p less than 0.01). In comparison to nulliparous women, those who reported 4 or more births had a 40% reduction in risk of ovarian cancer (RR = 0.6, 95% confidence interval, CI: 0.4-0.8). An RR estimate of 1.4 (95% CI: 1.1-1.7) as found, overall, for age of 35 or more at first birth compared to age of 25 or less at first birth. In each stratum and overall, nulliparous women did not appear to be at increased risk compared to those who delayed birth of their first child until age 35 or more. In each study, as well as in the overall dataset, an inverse association between number of abortions and ovarian cancer risk emerged. Overall, the inverse relationship was highly significant, RR estimates for 1 and 2 or more abortions, as compared to none, being 0.9 (95% CI: 0.8 and 1.1) and 0.7 (95% CI: 0.6-0.9) respectively. The effects of parity, age at first birth and number of abortions emerged consistently in various strata of study centre and age.


ISMICS Consensus Conference and Statements of Randomized Controlled Trials of Off-Pump Versus Conventional Coronary Artery Bypass Surgery.
At this consensus conference, we developed evidence-informed consensus statements and recommendations on the practice of off-pump coronary artery bypass graft (OPCAB) by systematically reviewing and performing meta-analysis of the randomized controlled trials (RCTs) comparing OPCAB and conventional coronary artery bypass (CCAB). All RCTs of OPCAB versus CCAB through April 2013 were screened, and 102 relevant RCTs (19,101 patients) were included in a systematic review and meta-analysis (15 RCTs of 9551 high-risk patients; and 87 RCTs of 9550 low-risk patients) in accordance with the Cochrane Collaboration and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology. Consensus statements for the risks and benefits of OPCAB surgery in mortality, morbidity, and resource use were developed based on best available evidence. Compared to CCAB, it is reasonable to perform OPCAB to reduce risks of stroke [class IIa, level of evidence (LOE) A], renal dysfunction/failure (class IIa, LOE A), blood transfusion (class I, LOE A), respiratory failure (class I, LOE A), atrial fibrillation (class I, LOE A), wound infection (class I, LOE A), ventilation time, and ICU and hospital length of stay (class I, LOE A). However, OPCAB may be associated with a reduced number of grafts performed (class I, LOE A) and with diminished graft patency (class IIa, LOE A, with increased coronary reintervention at 1 year and beyond (class IIa, LOE A), as well as increased mortality at a median follow-up of 5 years (class IIb, LOE A). OPCAB compared with CCAB may improve outcomes in the short-term (stroke, renal dysfunction, blood transfusion, respiratory failure, atrial fibrillation, wound infection, ventilation time, and length of stay). However, over the longer-term, OPCAB may be associated with reduced graft patency, and increased risk of cardiac re-intervention and death.


A variant-centric perspective on geographic patterns of human allele frequency variation.
A key challenge in human genetics is to understand the geographic distribution of human genetic variation. Often genetic variation is described by showing relationships among populations or individuals, drawing inferences over many variants. Here, we introduce an alternative representation of genetic variation that reveals the relative abundance of different allele frequency patterns. This approach allows viewers to easily see several features of human genetic structure: (1) most variants are rare and geographically localized, (2) variants that are common in a single geographic region are more likely to be shared across the globe than to be private to that region, and (3) where two individuals differ, it is most often due to variants that are found globally, regardless of whether the individuals are from the same region or different regions. Our variant-centric visualization clarifies the geographic patterns of human variation and can help address misconceptions about genetic differentiation among populations.


SME-4-producing Serratia marcescens from Argentina belonging to clade 2 of the S. marcescens phylogeny.
SME carbapenemases are increasingly reported, especially from North and South America. Here, we describe an SME-4-producing Serratia marcescens (SME-Sm) clinical isolate from Argentina and compare its genome with other SME-Sm and Sm isolates recovered from public databases. Sm isolates were characterized by WGS using Illumina technology, susceptibility testing and MIC determination. Carbapenemase activity was revealed by biochemical tests based on imipenem hydrolysis. A whole-genome phylogeny was estimated for all the Sm isolates retrieved from public databases with kSNP3 and a whole-genome phylogenetic analysis based on non-recombinant core SNPs was inferred for Sm complete genomes and for those encoding any blaSME variants. Sm163 was resistant to amoxicillin, temocillin, aztreonam and carbapenems, remaining susceptible to extended-spectrum cephalosporins. WGS analysis of Sm163 revealed a genome of 5139329 bp and a chromosomally encoded blaSME-4 carbapenemase gene located on a genomic island closely related to SmarGI1-1 of Sm N11-02820. Comparison of the Sm genomes revealed that the 14 SME-Sm isolates possess this genomic island inserted at the same loci, that 13/14 belong to clade 1 and that 11/14 form a well-defined subcluster of cluster I of Sm clade 1, while Sm163 belongs to clade 2, suggesting that an SME-encoding genomic island may have been transferred between isolates from different clades. To the best of our knowledge this is the first report of an SME-4-encoding Sm from Argentina. The blaSME-4 gene is located on a SmarGI1-1-like genomic island. The genome of Sm163 belongs to clade 2, unlike all the other SME-Sm isolates, which belong to clade 1.


Western corn rootworm pyrethroid resistance confirmed by aerial application simulations of commercial insecticides.
The western corn rootworm (Diabrotica virgifera virgifera LeConte) (WCR) is a major insect pest of corn (Zea mays L.) in the United States (US) and is highly adaptable to multiple management tactics. A low level of WCR field-evolved resistance to pyrethroid insecticides has been confirmed in the US western Corn Belt by laboratory dose-response bioassays. Further investigation has identified detoxification enzymes as a potential part of the WCR resistance mechanism, which could affect the performance of insecticides that are structurally related to pyrethroids, such as organophosphates. Thus, the responses of pyrethroid-resistant and -susceptible WCR populations to the commonly used pyrethroid bifenthrin and organophosphate dimethoate were compared in active ingredient bioassays. Results revealed a relatively low level of WCR resistance to both active ingredients. Therefore, a simulated aerial application bioassay technique was developed to evaluate how the estimated resistance levels would affect performance of registered rates of formulated products. The simulated aerial application technique confirmed pyrethroid resistance to formulated rates of bifenthrin whereas formulated dimethoate provided optimal control. Results suggest that the relationship between levels of resistance observed in dose-response bioassays and actual efficacy of formulated product needs to be further explored to understand the practical implications of resistance.


Computational identification of protein S-sulfenylation sites by incorporating the multiple sequence features information.
Cysteine S-sulfenylation is a major type of posttranslational modification that contributes to protein structure and function regulation in many cellular processes. Experimental identification of S-sulfenylation sites is challenging, due to the low abundance of proteins and the inefficient experimental methods. Computational identification of S-sulfenylation sites is an alternative strategy to annotate the S-sulfenylated proteome. In this study, a novel computational predictor SulCysSite was developed for accurate prediction of S-sulfenylation sites based on multiple sequence features, including amino acid index properties, binary amino acid codes, position specific scoring matrix, and compositions of profile-based amino acids. To learn the prediction model of SulCysSite, a random forest classifier was applied. The final SulCysSite achieved an AUC value of 0.819 in a 10-fold cross-validation test. It also exhibited higher performance than other existing computational predictors. In addition, the hidden and complex mechanisms were extracted from the predictive model of SulCysSite to investigate the understandable rules (i.e. feature combination) of S-sulfenylation sites. The SulCysSite is a useful computational resource for prediction of S-sulfenylation sites. The online interface and datasets are publicly available at .


A case of Kallmann syndrome carrying a missense mutation in alternatively spliced exon 8A encoding the immunoglobulin-like domain IIIb of fibroblast growth factor receptor 1.
Fibroblast growth factor receptor 1 (FGFR1) is one of the causative genes for Kallmann syndrome (KS), which is characterized by isolated hypogonadotropic hypogonadism with anosmia/hyposmia. The third immunoglobulin-like domain (D3) of FGFR1 has the isoforms FGFR1-IIIb and FGFR1-IIIc, which are generated by alternative splicing of exons 8A and 8B, respectively. To date, the only mutations to have been identified in D3 of FGFR1 are in exon 8B. We performed mutation analysis of FGFR1 in a 23-year-old female patient with KS and found a missense mutation (c.1072C>T) in exon 8A of FGFR1. The c.1072C>T mutation was not detected in her family members or in 220 normal Japanese and 100 Caucasian female controls. No mutation in other KS genes, KS 1, prokineticin-2, prokineticin receptor-2 and FGF-8 was detected in the affected patient or in her family members. Therefore, this is the first case of KS carrying a de novo missense mutation in FGFR1 exon 8A, suggesting that isoform FGFR1-IIIb, as well as isoform FGFR1-IIIc, plays a crucial role in the pathogenesis of KS.


A Quantitative Analysis of the Role of Oxygen Tension in FLASH Radiation Therapy.
Recent demonstrations of normal tissue sparing by high-dose, high-dose-rate FLASH radiation therapy have driven considerable interest in its application to improve clinical outcomes. However, significant uncertainty remains about the underlying mechanisms of FLASH sparing and how deliveries can be optimized to maximize benefit from this effect. Rapid oxygen depletion has been suggested as a potential mechanism by which these effects occur, but this has yet to be quantitatively tested against experimental data. Models of oxygen kinetics during irradiation were used to develop a time-dependent model of the oxygen enhancement ratio in mammalian cells that incorporates oxygen depletion. The characteristics of this model were then explored in terms of the dose and dose-rate dependence of the oxygen enhancement ratio. This model was also fit to experimental data from both in vitro and in vivo data sets. In cases of FLASH radiation therapy, this model suggests that oxygen levels can be depleted by amounts that are sufficient to affect radiosensitivity only in conditions of intermediate oxygen tension, with no effect seen at high or very low initial oxygen levels. The model also effectively reproduced the dose, dose rate, and oxygen tension dependence of responses to FLASH radiation therapy in a range of systems, with model parameters compatible with published data. Oxygen depletion provides a credible quantitative model to understand the biological effects of FLASH radiation therapy and is compatible with a range of experimental observations of FLASH sparing. These results highlight the need for more detailed quantification of oxygen depletion under high-dose-rate radiation exposures in relevant systems and the importance of oxygen tension in target tissues for FLASH sparing to be observed.