A longitudinal study of the infant nasopharyngeal microbiota: The effects of age, illness and antibiotic use in a cohort of South East Asian children.
A longitudinal study was undertaken in infants living in the Maela refugee camp on the Thailand-Myanmar border between 2007 and 2010. Nasopharyngeal swabs were collected monthly, from birth to 24 months of age, with additional swabs taken if the infant was diagnosed with pneumonia according to WHO clinical criteria. At the time of collection, swabs were cultured for Streptococcus pneumoniae and multiple serotype carriage was assessed. The bacterial 16S rRNA gene profiles of 544 swabs from 21 infants were analysed to see how the microbiota changes with age, respiratory infection, antibiotic consumption and pneumococcal acquisition. The nasopharyngeal microbiota is a somewhat homogenous community compared to that of other body sites. In this cohort it is dominated by five taxa: Moraxella, Streptococcus, Haemophilus, Corynebacterium and an uncharacterized Flavobacteriaceae taxon of 93% nucleotide similarity to Ornithobacterium. Infant age correlates with certain changes in the microbiota across the cohort: Staphylococcus and Corynebacterium are associated with the first few months of life while Moraxella and the uncharacterised Flavobacteriaceae increase in proportional abundance with age. Respiratory illness and antibiotic use often coincide with an unpredictable perturbation of the microbiota that differs from infant to infant and in different illness episodes. The previously described interaction between Dolosigranulum and Streptococcus was observed in these data. Monthly sampling demonstrates that the nasopharyngeal microbiota is in flux throughout the first two years of life, and that in this refugee camp population the pool of potential bacterial colonisers may be limited.


Management strategies to effect change in intensive care units: lessons from the world of business. Part II. Quality-improvement strategies.
The success of quality-improvement projects relies heavily on both project design and the metrics chosen to assess change. In Part II of this three-part American Thoracic Society Seminars series, we begin by describing methods for determining which data to collect, tools for data presentation, and strategies for data dissemination. As Avedis Donabedian detailed a half century ago, defining metrics in healthcare can be challenging; algorithmic determination of the best type of metric (outcome, process, or structure) can help intensive care unit (ICU) managers begin this process. Choosing appropriate graphical data displays (e.g., run charts) can prompt discussions about and promote quality improvement. Similarly, dashboards/scorecards are useful in presenting performance improvement data either publicly or privately in a visually appealing manner. To have compelling data to show, ICU managers must plan quality-improvement projects well. The second portion of this review details four quality-improvement tools-checklists, Six Sigma methodology, lean thinking, and Kaizen. Checklists have become commonplace in many ICUs to improve care quality; thinking about how to maximize their effectiveness is now of prime importance. Six Sigma methodology, lean thinking, and Kaizen are techniques that use multidisciplinary teams to organize thinking about process improvement, formalize change strategies, actualize initiatives, and measure progress. None originated within healthcare, but each has been used in the hospital environment with success. To conclude this part of the series, we demonstrate how to use these tools through an example of improving the timely administration of antibiotics to patients with sepsis.


Conserved kappa B element located downstream of the tumor necrosis factor alpha gene: distinct NF-kappa B binding pattern and enhancer activity in LPS activated murine macrophages.
Transcriptional activation of various genes by lipopolysaccharide (LPS) is known to be mediated, at least in part, by the NF-kappa B/Rel family of transcription factors. We have identified a novel kappa B element located immediately downstream of the TNF-alpha gene that is conserved together with its flanking sequences across species lines and can act as an LPS-responsive enhancer for reporter gene constructs driven by the minimal TNF promoter. In extracts from activated murine macrophages and macrophage cell lines this element binds several non-canonical NF-kappa B/Rel complexes, in addition to p50 (NFKB1) homodimer and p50-p65 (NKFB1-RelA) heterodimer. Combination of high-resolution electrophoretic mobility shift assays (EMSA) with monospecific antibodies and u.v.-cross-linking indicates that the prominent slow migrating complex III contain p65 homodimer and c-Rel. The appearance of complex III in EMSA parallels the translocation of p65 and c-Rel into the nucleus and occurs shortly after LPS induction. Transfection experiments with reporter constructs driven by this kappa B element indicate strong inducibility by LPS and p65, moderate inducibility by c-Rel and repression by p50. Functional activity of sandwich TNF-CAT-TNF constructs further suggests that LPS-inducible transcriptional activation of the TNF gene in murine macrophages may be partly mediated by a downstream enhancer.


Effect of glucocorticosteroid injections in tennis elbow verified on colour Doppler ultrasonography: evidence of inflammation.
It has previously been reported that lateral epicondylitis may be diagnosed with colour Doppler ultrasonography (US) by detecting hyperaemia inside the common extensor origin (CEO).This study reports on the association between Doppler US findings and the short-term response of US-guided corticosteroid injection in patients with LE. Case-only, blinded intervention study. Secondary care at a government hospital. 62 patients with LE verified by colour Doppler US. One US-guided corticosteroid injection was given into the CEO. Patients were evaluated at baseline before the injection and at 2 weeks of follow-up. Outcome measures were changes in pain score and US parameters (resistive index (RI) and the amount of colour within the CEO). Prognosticators for outcome were: use of computer mouse, symptom duration, elbow strain, RI, colour fraction, Likert pain score, pain at rest, pain during activity, age, height, weight, disease in dominant versus nondominant arm. All but one patient experienced improvement of general elbow pain perception at follow-up at 2 weeks. In parallel, Doppler US showed significant reduction in colour fraction (mean (standard deviation) with 95% confidence limits: baseline 0.14 (0.10), at follow-up 0.02 (0.02), p<0.0001). All but five patients showed a decrease in colour fraction; 74% decreased to 0. No clinical or US parameter could distinguish responders from non-responders. Corticosteroid injection has a marked short-term effect on pain and Doppler parameters. The reduction in hyperaemia mediated by an anti-inflammatory drug can be interpreted as evidence of an inflammatory component in LE.


Towards a harmonized method for the global reconnaissance of multi-class antimicrobials and other pharmaceuticals in wastewater and receiving surface waters.
Antimicrobial resistance is a worldwide problem that is both pressing and challenging due to the rate at which it is spreading, and the lack of understanding of the mechanisms that link human, animal and environmental sources contributing to its proliferation. One knowledge gap that requires immediate attention is the significance of antimicrobial residues and other pharmaceuticals that are being discharged from wastewater treatment plants (WWTPs) on the dissemination of antimicrobial resistance in the environment. In this work we provide an approach to develop a harmonized analytical method for 8 classes of antimicrobials and other pharmaceuticals that can be used for global monitoring in wastewater and receiving waters. Analysis of these trace organic chemicals in the influent and effluent wastewater, and in the respective upstream and downstream receiving waters from different countries across the globe is not trivial. Here, we demonstrated that sample preparation using solid-phase extraction (SPE) not only provides a convenient and cost-effective shipping of samples, but also adds stability to the analytes during international shipping. It is important that SPE cartridges are maintained at cold temperature during shipment if the duration is longer than 7 days because a significant decrease in recoveries were observed after 7 days in the cartridges stored at room temperature, especially for sulfonamides and tetracyclines. To compensate for sample degradation during shipment, and matrix effects in liquid chromatography/mass spectrometry, the use of stable isotope labeled compounds should be employed when available and affordable. The importance of applying a defined tolerance for the ion ratios (Q/q) that have been optimized for wastewater and surface water is discussed. The tolerance range was set to be the mean Q/q of the analyte standard at various concentrations ±40% for the influent, and ±30% for the effluent, upstream, and downstream samples; for tetracyclines and quinolones, however, the tolerance range was ±80% in order to minimize false negative and false positive detection. The optimized procedures were employed to reveal differences in antimicrobial and pharmaceutical concentrations in influent, effluent, and surface water samples from Hong Kong, India, Philippines, Sweden, Switzerland, and United States. The antimicrobials with the highest concentrations in influent and effluent samples were ciprofloxacin (48,103 ng/L, Hong Kong WWTP 1) and clarithromycin (5178 ng/L, India WWTP 2), respectively. On the other hand, diclofenac (108,000 ng/L, Sweden WWTP 2), caffeine (67,000 ng/L, India WWTP 1), and acetaminophen (28,000 ng/L, India WWTP 1) were the highest detected pharmaceuticals in the receiving surface water samples. Hong Kong showed the highest total antimicrobial concentrations that included macrolides, quinolones, and sulfonamides with concentrations reaching 60,000 ng/L levels in the influent. Antidepressants were predominant in Sweden, Switzerland, and the United States.


Acculturation and socioeconomic position as predictors of coronary calcification in a multiethnic sample.
Coronary calcium has recently emerged as a marker of subclinical coronary heart disease. Although there has been much interest in race differences in calcification, heterogeneity within race or ethnic groups has not been investigated. Data from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based study of coronary calcification, were used to investigate acculturation and socioeconomic position as predictors of coronary calcification within 2553 non-Hispanic whites, 1734 non-Hispanic blacks, 1457 Hispanics, and 797 Chinese residing in the United States. Coronary calcium was assessed by chest CT. Relative risk regression and linear regression were used to estimate adjusted associations of sociodemographic variables with the presence and amount of calcium. Not being born in the United States was associated with a lower prevalence of calcification in blacks (relative prevalence [RP], 0.75; 95% confidence limit [CL], 0.61 to 0.94) and Hispanics (RP, 0.89; 95% CL, 0.81 to 0.98) after adjustment for age, sex, income, and education. Years in the United States was positively associated with prevalence of calcification in non-US-born Chinese (adjusted RP per 10 years in United States, 1.06; 95% CL, 1.01 to 1.11) and non-US-born blacks (RP, 1.59; 95% CL, 1.22 to 2.06). Low education was associated with a higher prevalence of calcification in whites (adjusted RP for no high school versus complete college, 1.17; 95% CL, 1.05 to 1.32) but with lower prevalence of calcification in Hispanics (RP, 0.91; 95% CL, 0.77 to 1.09) (P for interaction=0.02). US birth and time in the United States were also positively associated with the extent of calcification in persons with detectable calcium. These differences did not appear to be accounted for by smoking, body mass index, LDL and HDL cholesterol, hypertension, and diabetes. Acculturation and socioeconomic factors are associated with differences in the prevalence and amount of coronary calcification within whites, Chinese, blacks, and Hispanics. The presence of this heterogeneity needs to be acknowledged in the quantification and investigation of race/ethnic differences.


Stringent specificity in the construction of a GABAergic presynaptic inhibitory circuit.
GABAergic interneurons are key elements in neural coding, but the mechanisms that assemble inhibitory circuits remain unclear. In the spinal cord, the transfer of sensory signals to motor neurons is filtered by GABAergic interneurons that act presynaptically to inhibit sensory transmitter release and postsynaptically to inhibit motor neuron excitability. We show here that the connectivity and synaptic differentiation of GABAergic interneurons that mediate presynaptic inhibition is directed by their sensory targets. In the absence of sensory terminals these GABAergic neurons shun other available targets, fail to undergo presynaptic differentiation, and withdraw axons from the ventral spinal cord. A sensory-specific source of brain derived neurotrophic factor induces synaptic expression of the GABA synthetic enzyme GAD65--a defining biochemical feature of this set of interneurons. The organization of a GABAergic circuit that mediates presynaptic inhibition in the mammalian CNS is therefore controlled by a stringent program of sensory recognition and signaling.


Evaluation of the performance of C. DIFF QUIK CHEK COMPLETE and its usefulness in a hospital setting with a high prevalence of Clostridium difficile infection.
Rapid and accurate diagnosis of Clostridium difficile infection (CDI) is crucial for patient care, infection control, and efficient surveillance. We evaluated C. DIFF QUIK CHEK COMPLETE (QCC; TechLab), which detects glutamate dehydrogenase (GDH) antigen (QCC-Ag) and toxin A/B (QCC-Tox) simultaneously, and compared it to the laboratory diagnostics for CDI currently in use in a tertiary hospital setting with a high prevalence of CDI. QCC, RIDASCREEN C. difficile toxin A/B assay (Toxin EIA; R-Biopharm AG), chromID C. difficile agar (bioMérieux) culture (ChromID culture), and Xpert C. difficile PCR assay (Xpert PCR; Cepheid) were performed according to the manufacturers' instructions. Performances of the assays were compared against that of Xpert PCR as a reference. Of the 231 loose stool specimens, 83 (35.9%) were positive by Xpert PCR. The sensitivity, specificity, and positive and negative predictive values were 97.6%, 93.9%, 90.0%, and 98.6%, respectively, for QCC-Ag and 55.4%, 100%, 100%, and 80.0%, respectively, for QCC-Tox. The median threshold cycle values of the QCC-Tox(+) specimens were lower than those of the QCC-Tox(-) specimens. Results of QCC as an initial screening test were confirmed in 81.0% (187/231) of samples; these specimens did not require further testing. QCC is a rapid, easy, and cost-effective method that would be a useful first-line screening assay for laboratory diagnosis of CDI in a tertiary hospital with a high prevalence of CDI. A two-step algorithm using QCC as an initial screening tool, followed by Xpert PCR as a confirmatory test, is a practical and cost-effective approach.


Association of electrocardiographic left ventricular hypertrophy with incident cardiovascular disease in Japanese older hypertensive patients.
Our aim was to assess whether electrocardiographic left ventricular hypertrophy (ECG-LVH) is associated with a higher risk of cardiovascular disease (CVD) events, independent of 24-hour blood pressure (BP) and circulating levels of norepinephrine and hemostatic factors. In 514 older hypertensive patients (mean age 72.3 years; 37% men), we assessed ambulatory BP values, circulating levels of norepinephrine and hemostatic factors (plasma fibrinogen, prothrombin fragment 1+2 (F1+2), von Willebrand factor (vWF), and plasminogen activator inhibitor-1 (PAI-1)), and the presence or absence of ECG-LVH (Sokolow-Lyon voltage ≥ 3.5 mV). The incidence of CVD events (i.e., myocardial infarction and stroke) was prospectively ascertained. During an average 41 months of follow-up (1,751 person-years), 43 stroke and 3 myocardial infarction events occurred. At baseline, patients with ECG-LVH had higher mean 24-hour BP (148.8/83.8mm Hg vs. 135.7/77.2mm Hg) and circulating norepinephrine levels (404.6 pg/ml vs. 336.3 pg/ml) compared to those without ECG-LVH; the differences remained unchanged after adjustment for age, gender, smoking status, presence of diabetes, and antihypertensive medication uses at follow-up time (all P < 0.01). Cox proportional hazards models suggested that the hazard ratio (HR; 95% confidence interval (CI)) of CVD events for those with ECG-LVH was 4.4 (2.3-8.2), and the association between ECG-LVH and incident CVD events remained significant after adjustment for high 24-hour BP (≥130/80mm Hg), nocturnal SBP, circulating norepinephrine and fibrinogen levels (HRs, 3.5-4.2, all P < 0.001). In older hypertensive patients, ECG-LVH was associated with a higher risk of CVD events, independent of ambulatory BP parameters and circulating norepinephrine and fibrinogen levels.


Online comprehension across different semantic categories in preschool children with autism spectrum disorder.
Word comprehension across semantic categories is a key area of language development. Using online automated eye-tracking technology to reduce response demands during a word comprehension test may be advantageous in children with autism spectrum disorder (ASD). To measure online accuracy of word recognition across eleven semantic categories in preschool children with ASD and in typically developing (TD) children matched for gender and developmental age. Using eye-tracker methodology we measured the relative number of fixations on a target image as compared to a foil of the same category shown simultaneously on screen. This online accuracy measure was considered a measure of word understanding. We tested the relationship between online accuracy and offline word recognition and the effects of clinical variables on online accuracy. Twenty-four children with ASD and 21 TD control children underwent the eye-tracking task. On average, children with ASD were significantly less accurate at fixating on the target image than the TD children. After multiple comparison correction, no significant differences were found across the eleven semantic categories of the experiment between preschool children with ASD and younger TD children matched for developmental age. The ASD group showed higher intragroup variability consistent with greater variation in vocabulary growth rates. Direct effects of non-verbal cognitive levels, vocabulary levels and gesture productions on online word recognition in both groups support a dimensional view of language abilities in ASD. Online measures of word comprehension across different semantic categories show higher interindividual variability in children with ASD and may be useful for objectively monitor gains on targeted language interventions.


The predictive value of early acute kidney injury for long-term survival and quality of life of critically ill patients.
Prognostic factors for the combination of long-term survival and health-related quality of life (HRQoL) after intensive care unit (ICU) stay have not yet been studied. Our aim was to assess whether early acute kidney injury (eAKI), AKI occurring on the first day of ICU admission, is an independent predictor of this combined one-year outcome. We included all patients admitted to the mixed ICU of the University Medical Centre Utrecht between July 2009 and April 2013, excluding patients with chronic dialysis, cardiac surgery, and length of stay shorter than 24 hours. eAKI was defined using the risk, injury, failure, loss, end-stage renal failure (RIFLE) classification, using a newly developed algorithm to classify AKI based on routinely collected patient data. In one-year survivors, HRQoL was measured using the EuroQoL 5D-3L™ (EQ-5D) questionnaire. The primary outcome measure was "poor outcome", defined as an EQ-5D index score <0.4 or death after one year follow up. A multivariable Poisson regression model was performed to adjust for age, comorbidities, admission type and severity of disease factors. We enrolled 2,420 patients, of whom 871 (36.0 %) died within one year. An additional 286 of 1549 one-year survivors (11.8 %) experienced low HRQoL. The respective incidence of the RIFLE classes, risk, injury and failure, were 456 (18.8 %), 253 (10.5 %) and 123 (5.1 %). After adjustment for other covariates, the RIFLE classes, injury and failure, were independently associated with poor outcome (adjusted relative risk 1.14, 95 % CI 1.01, 1.29; p = 0.03, and 1.25, 95 % CI 1.01, 1.55; p = 0.04), when compared to no eAKI patients . The constituents of this composite outcome were also analysed separately. In a Cox regression model the RIFLE classes, injury and failure, were significantly associated with mortality (adjusted hazard ratio 1.35, 95 % CI 1.11, 1.65; p <0.01, and 1.78, 95 % CI 1.38, 2.30; p <0.01). In one-year survivors specifically, none of the RIFLE classes were significantly associated with low HRQoL. ICU patients with moderate or severe AKI during the first 24 hours have a higher probability of mortality or low HRQoL (combined poor outcome), one year after ICU admission. Together with other available early prognostic factors, information on early acute kidney injury could improve informed decision-making on the continuation or withdrawal of treatment in ICU patients.


A strong CD8+ T cell-stimulating supramolecular hydrogel.
The development of molecules with immune stimulatory properties is crucial for cancer immunotherapy. In this work, we combined two peptide-based molecules, tuftsin (TKPR) and Nap-GDFDFDY, to develop a novel self-assembling molecule Nap-GDFDFDYTKPR (Comp.3), which has strong CD8+ T cell stimulatory properties. Comp.3 could self-assemble into nanofibers and hydrogels, which significantly improved the stability of tuftsin against enzyme digestion. The nanofibers of Comp.3 enhanced the phagocytic activity of macrophages, promoted the maturation of DCs, and stimulated the expression of cytokines. In addition, it demonstrated an excellent anti-tumor efficacy in vivo by eliciting a strong CD8+ T immune response. Taken together, our observations revealed a powerful immune stimulating nanomaterial that is a promising compound for cancer immunotherapy.


The History of Dogma and the Story of Modernity: The Modern Age as "Second Overcoming of Gnosticism".
This paper explores how Blumenberg narrates the history of modernity as a second overcoming of Gnosticism. This detour through late antiquity illuminates the full meaning of his idea of modernity. Blumenberg develops important methodological insights about historical change, the threshold between epochs, etc. that appear in The Legitimacy of the Modern Age. We see the central role of the interpretation of Gnosticism but also of New Testament eschatology. Both are conceived as historical catalysts that provoke modernity's emergence but remain alien to its result. Thus the references to Gnosticism and surrounding contemporary discourses are essential for Blumenbeg's account of modernity.


Mechanical heart valves and oral anticoagulation: a survey of the Italian Society of Cardiac Surgery.
In the latest European guidelines for the management of valvular heart disease, mechanical valve prostheses maintain a strategic role, particularly for certain patient subsets and age groups. Despite the high number of devices implanted in clinical practice, particularly in non-European and North American regions, current scientific literature and debate seem to suggest a limited use of mechanical heart valves. The cardiac surgery community seems to be highly interested in biological and transcatheter valve prostheses but less interested in mechanical heart valves, including possible strategies for self-management of anticoagulation therapy. In this respect, the Italian Society of Cardiac Surgery (SICCH), in particular the Italian Group of Research for Outcome in Cardiac Surgery (GIROC), has promoted a survey among its members to stimulate the interest in this topic and express their opinion on this issue that, due to the prevalence of the affected population and the new treatment options for improving patients' quality of life, should be more appraised and debated in the cardiac surgery community. The recorded results, obtained on the answers to 111 questionnaires, seem to divide the specialists into 'pros' and 'contras' on a useful tool for the entire cardiac surgery community. For this reason, SICCH proposes in conclusion to declare its unified and institutional opinion on this topic.


Gemelli-obturator complex in the deep gluteal space: an anatomic and dynamic study.
To investigate the behavior of the sciatic nerve during hip rotation at subgluteal space. Sonographic examination (high-resolution ultrasound machine at 5.0-14 MHZ) of the gemelli-obturator internus complex following two approaches: (1) a study on cadavers and (2) a study on healthy volunteers. The cadavers were examined in pronation, pelvis-fixed position by forcing internal and external rotations of the hip with the knee in 90° flexion. Healthy volunteers were examined during passive internal and external hip rotation (prone position; lumbar and pelvic regions fixed). Subjects with a history of major trauma, surgery or pathologies affecting the examined regions were excluded. The analysis included eight hemipelvis from six fresh cadavers and 31 healthy volunteers. The anatomical study revealed the presence of connective tissue attaching the sciatic nerve to the structures of the gemellus-obturator system at deep subgluteal space. The amplitude of the nerve curvature during rotating position was significantly greater than during resting position. During passive internal rotation, the sciatic nerve of both cadavers and healthy volunteers transformed from a straight structure to a curved structure tethered at two points as the tendon of the obturator internus contracted downwards. Conversely, external hip rotation caused the nerve to relax. Anatomically, the sciatic nerve is closely related to the gemelli-obturator internus complex. This relationship results in a reproducible dynamic behavior of the sciatic nerve during passive hip rotation, which may contribute to explain the pathological mechanisms of the obturator internal gemellus syndrome.


Primary lymphoma of the larynx: new diagnostic and therapeutic approaches.
Tumors primary in the larynx, when not of squamous cell origin, require special diagnostic and therapeutic attention. An unexpected case of non-Hodgkin's lymphoma localized in the larynx in a patient with a brief history of dysphagia and hoarseness is discussed. This supraglottic tumor was extensively characterized at our institution for morphologic features by microlaryngoscopy, histology, immunocytochemical profiles with flow cytometry, chromosomal aberrations using banded karyotyping and extent of disease via PET-CT imaging. Our detailed analysis distinguished this neoplasm as a new-onset diffuse large B cell laryngeal lymphoma rather than a mucosa-associated lymphoid tissue lymphoma. A rational diagnostic approach guided the combination chemotherapy/immunotherapy treatment strategy instead of traditional localized radiation therapy. These findings highlight the importance of a thorough phenotypic and cytogenetic characterization of head and neck neoplasms, which has implications for downstream diagnostic considerations, interventional strategies and the available therapeutic options. The presence of nonsquamous laryngeal tumors reinforces the dictum to obtain a reliable tissue diagnosis before initiating definitive therapy.


Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to β-blocker therapy in type 1 long-QT syndrome.
β-Adrenergic stimulation is the main trigger for cardiac events in type 1 long-QT syndrome (LQT1). We evaluated a possible association between ion channel response to β-adrenergic stimulation and clinical response to β-blocker therapy according to mutation location. The study sample comprised 860 patients with genetically confirmed mutations in the KCNQ1 channel. Patients were categorized into carriers of missense mutations located in the cytoplasmic loops (C loops), membrane-spanning domain, C/N terminus, and nonmissense mutations. There were 27 aborted cardiac arrest and 78 sudden cardiac death events from birth through 40 years of age. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for aborted cardiac arrest or sudden cardiac death (hazard ratio versus nonmissense mutations=2.75; 95% confidence interval, 1.29-5.86; P=0.009). β-Blocker therapy was associated with a significantly greater reduction in the risk of aborted cardiac arrest or sudden cardiac death among patients with C-loop mutations than among all other patients (hazard ratio=0.12; 95% confidence interval, 0.02-0.73; P=0.02; and hazard ratio=0.82; 95% confidence interval, 0.31-2.13; P=0.68, respectively; P for interaction=0.04). Cellular expression studies showed that membrane spanning and C-loop mutations produced a similar decrease in current, but only C-loop mutations showed a pronounced reduction in channel activation in response to β-adrenergic stimulation. Patients with C-loop missense mutations in the KCNQ1 channel exhibit a high risk for life-threatening events and derive a pronounced benefit from treatment with β-blockers. Reduced channel activation after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.


Antimicrobial susceptibility and body site distribution of community isolates of coagulase-negative staphylococci.
The primary aim of this study was to determine antimicrobial resistance in coagulase-negative staphylococci (CoNS) from healthy adults in the community. Healthy adults (n = 114) were swabbed on six body sites; both armpits, both knee pits and both sides of the groin. Species determination was performed using Matrix Assisted Laser Desorption Ionization - Time of Flight (MALDI-TOF) and susceptibility testing for 11 relevant antimicrobials was performed by the disc diffusion method and minimal inhibitory concentration gradient test. In total, 693 CoNS isolates were identified. Susceptibility testing was done on 386 isolates; one CoNS from each species found on each participant from the different body sites. The prevalence of antimicrobial resistance in the CoNS isolates were; erythromycin (24.6%), fusidic acid (19.9%), tetracycline (11.4%), clindamycin (7.8%), gentamicin (6.2%) and cefoxitin (4.1%). Multidrug resistance was observed in 5.2% of the isolates. Staphylococcus epidermidis and S. hominis were the first and second most prevalent species on all three body sites. We conclude that CoNS isolates from healthy adults in the community have a much lower prevalence of antimicrobial resistance than reported in nosocomial CoNS isolates. Still, we believe that levels of resistance in community CoNS should be monitored as the consumption of antimicrobials in primary care in Norway is increasing.


Structure-based design of 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines as inhibitors of myeloid cell leukemia-1 (Mcl-1).
Mcl-1 has recently emerged as an attractive target to expand the armamentarium in the war on cancer. Using structure-based design, 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines were developed as a new chemotype to inhibit the Mcl-1 oncoprotein. The most potent compound inhibited Mcl-1 with a Ki of 120 nM, as determined by a fluorescence polarization competition assay. Direct binding was confirmed by 2D (1)H-(15)N HSQC NMR spectroscopy with (15)N-Mcl-1, which indicated that interactions with R263 and T266, and occupation of the p2 pocket are likely responsible for the potent binding affinity. The short and facile synthetic chemistry to access target molecules is expected to mediate lead optimization.


Maternal grandmothers improve nutritional status and survival of children in rural Gambia.
Hypotheses for the evolution of human female life-history characteristics have often focused on the social nature of human societies, which allows women to share the burden of childcare and provisioning amongst other members of their kin group. We test the hypothesis that child health and survival probabilities will be improved by the presence of kin using a longitudinal database from rural Gambia. We find that the only kin to improve the nutritional status of children significantly (apart from mothers) are maternal grandmothers, and that this is reflected in higher survival probabilities for children with living maternal grandmothers. There is also evidence that the reproductive status of the maternal grandmother influences child nutrition, with young children being taller in the presence of non-reproductive grandmothers than grandmothers who are still reproductively active. Paternal grandmothers and male kin, including fathers, have negligible impacts on the nutritional status and survival of children.


Addressing end of life care issues in a tertiary treatment centre: lessons learned from surveying parents' experiences.
Much of the work in children's hospitals is rightly focused on treatments aimed towards cure but this means that death is often seen as a failure and, as such, it may not be discussed or acknowledged as a possibility until very late in a child's stay in hospital. However, this reluctance can deny the child and their family the opportunity to be informed, prepare and make choices. A survey of the care received by parents whose child had died in a children's tertiary treatment centre led to a greater understanding of the parents' experiences and the ways in which care could be enhanced. Parents talked of the way in which the geography of the hospital could be disruptive and dislocating and yet they often had no place to be alone or in private. Communication was identified as a core issue with many parents being positive about the quality and timing of communication. However, other parents expressed a preference for more preparation about the possibility that their child might die. Some parents had positive experiences of follow-up visits after their child's death, whilst others remained frustrated and some felt this visit had made them re-live the experiences. The importance of kind, supportive and consistent care was clearly evidenced by the parents when they spoke about their feelings and emotions. The findings helped to develop and implement an End of Life Care Pathway and a pathway tool which aimed to enhance parents' experiences and to improve care. A further survey was triggered by the concern that the pathway was not being fully utilized and it became apparent that, despite the tool, staff were still reluctant to provide anticipatory guidance, even though many practical aspects of care scored well. The need for good communication that prepares parents for the eventuality that their child might or will die is one of the clearest lessons from the second survey. This is important as anticipatory guidance opens up parents - and children's - choices, and their opportunities to be involved and make decisions. More work needs to be undertaken in relation to continuing education of clinical staff, raising awareness of the resources available and empowering families by providing information.


Role of metabolic syndrome components in HIV-associated sensory neuropathy.
Sensory neuropathy is a common peripheral nerve complication of HIV infection and highly active antiretroviral therapy. Metabolic syndrome (MetS), a cluster of risk factors for atherosclerosis and microvascular disease, is associated with sensory neuropathy in HIV-uninfected (HIV-negative) persons. We examined whether MetS or its components predispose individuals to HIV-associated sensory neuropathy (HIV-SN). From a prospective multicenter cohort of 1556 HIV-positive patients, a subgroup (n = 130) with fasting laboratory tests and sensory neuropathy assessment was selected. Sensory neuropathy was defined by symmetrically decreased reflexes or sensation loss in the legs. MetS was defined by presence of at least three risk factors: mean arterial pressure of at least 100 mmHg; triglycerides (TRGs) of at least 150 mg/dl and high-density lipoprotein cholesterol of less than 40 mg/dl for male patients, less than 50 mg/dl for female patients; body mass index of more than 25 kg/m; plasma glucose (GLU) of at least 100 mg/dl and self-reported diabetes mellitus type 2. Multivariate logistic regression examined the association between HIV-SN and MetS. After controlling for HIV-SN risk factors such as age, CD4 current, length of HIV infection, use of dideoxynucleoside reverse transcriptase inhibitors and protease inhibitors, MetS was not associated with HIV-SN (P = 0.72). However, when each MetS component was assessed, elevated TRG was a significant risk factor for HIV-SN. From the larger cohort, both diabetes mellitus type 2 (odds ratio = 1.4, P < 0.01) and elevated TRG (odds ratio = 1.4, P = 0.01) were risk factors for HIV-SN. The risk of HIV-SN was increased for diabetes mellitus type 2 and elevated TRG but not for other MetS components. Both increase the risk of sensory neuropathy in HIV-populations, but the mechanism(s) remains unclear.


TNIK inhibition abrogates colorectal cancer stemness.
Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik(-/-)/Apc(min/+) mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apc(min/+) mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach.


Avian ultraviolet/violet cones identified as probable magnetoreceptors.
The Radical-Pair-Model postulates that the reception of magnetic compass directions in birds is based on spin-chemical reactions in specialized photopigments in the eye, with cryptochromes discussed as candidate molecules. But so far, the exact subcellular characterization of these molecules in the retina remained unknown. We here describe the localization of cryptochrome 1a (Cry1a) in the retina of European robins, Erithacus rubecula, and domestic chickens, Gallus gallus, two species that have been shown to use the magnetic field for compass orientation. In both species, Cry1a is present exclusively in the ultraviolet/violet (UV/V) cones that are distributed across the entire retina. Electron microscopy shows Cry1a in ordered bands along the membrane discs of the outer segment, and cell fractionation reveals Cry1a in the membrane fraction, suggesting the possibility that Cry1a is anchored along membranes. We provide first structural evidence that Cry1a occurs within a sensory structure arranged in a way that fulfils essential requirements of the Radical-Pair-Model. Our findings, identifying the UV/V-cones as probable magnetoreceptors, support the assumption that Cry1a is indeed the receptor molecule mediating information on magnetic directions, and thus provide the Radical-Pair-Model with a profound histological background.


A hierarchical task analysis of cricothyroidotomy procedure for a virtual airway skills trainer simulator.
Despite the critical importance of cricothyroidotomy (CCT) for patient in extremis, clinical experience with CCT is infrequent, and current training tools are inadequate. The long-term goal is to develop a virtual airway skills trainer that requires a thorough task analysis to determine the critical procedural steps, learning metrics, and parameters for assessment. Hierarchical task analysis is performed to describe major tasks and subtasks for CCT. A rubric for performance scoring for each task was derived, and possible operative errors were identified. Time series analyses for 7 CCT videos were performed with 3 different observers. According to Pearson's correlation tests, 3 of the 7 major tasks had a strong correlation between their task times and performance scores. The task analysis forms the core of a proposed virtual CCT simulator, and highlights links between performance time and accuracy when teaching individual surgical steps of the procedure.


Male behaviour drives assortative reproduction during the initial stage of secondary contact.
Phenotypic divergence in allopatry can facilitate speciation by reducing the likelihood that individuals of different lineages hybridize during secondary contact. However, few studies have established the causes of reproductive isolation in the crucial early stages of secondary contact. Here, we establish behavioural causes of assortative reproduction between two phenotypically divergent lineages of the European wall lizard (Podarcis muralis), which have recently come into secondary contact. Parentage was highly assortative in experimental contact zones. However, despite pronounced divergence in male phenotypes, including chemical and visual sexual signals, there was no evidence that females discriminated between males of the two lineages in staged interactions or under naturalistic free-ranging conditions. Instead, assortative reproduction was driven by male mate preferences and, to a lesser extent, male-male competition. The effects were more pronounced when the habitat structure promoted high lizard densities. These results emphasize that assortative reproduction can occur in the absence of female choice and that male behaviour may play an important role in limiting hybridization during the initial stages of secondary contact.


Blood pressure and volume management in dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.
Blood pressure (BP) and volume control are critical components of dialysis care and have substantial impacts on patient symptoms, quality of life, and cardiovascular complications. Yet, developing consensus best practices for BP and volume control have been challenging, given the absence of objective measures of extracellular volume status and the lack of high-quality evidence for many therapeutic interventions. In February of 2019, Kidney Disease: Improving Global Outcomes (KDIGO) held a Controversies Conference titled Blood Pressure and Volume Management in Dialysis to assess the current state of knowledge related to BP and volume management and identify opportunities to improve clinical and patient-reported outcomes among individuals receiving maintenance dialysis. Four major topics were addressed: BP measurement, BP targets, and pharmacologic management of suboptimal BP; dialysis prescriptions as they relate to BP and volume; extracellular volume assessment and management with a focus on technology-based solutions; and volume-related patient symptoms and experiences. The overarching theme resulting from presentations and discussions was that managing BP and volume in dialysis involves weighing multiple clinical factors and risk considerations as well as patient lifestyle and preferences, all within a narrow therapeutic window for avoiding acute or chronic volume-related complications. Striking this challenging balance requires individualizing the dialysis prescription by incorporating comorbid health conditions, treatment hemodynamic patterns, clinical judgment, and patient preferences into decision-making, all within local resource constraints.


Sampling random directions within an elliptical cone.
This work extends the spherical surface sampling algorithm in order to uniformly generate random directions within an elliptical cone. This has applications in Monte Carlo particle transport simulations, for example modeling asymmetric beam divergence or scattering interactions. Two methods are presented. The first obeys the strict boundary of the elliptical cone. The second relaxes this requirement, increasing the range of generated directions by up to 10% for elliptical cones of extreme eccentricity. However, the second method is able to generate directions beyond the equator.


Hydrophilic and lipophilic radiopharmaceuticals as tracers in pharmaceutical development: in vitro--in vivo studies.
Scintigraphic studies have been performed to assess the release, both in vitro and in vivo, of radiotracers from tablet formulations. Four different tracers with differing physicochemical characteristics have been evaluated to assess their suitability as models for drug delivery. In-vitro disintegration and dissolution studies have been performed at pH 1, 4 and 7. In-vivo studies have been performed by scintigraphic imaging in healthy volunteers. Two hydrophilic tracers, (99mTc-DTPA) and (99mTc-MDP), and two lipophilic tracers, (99mTc-ECD) and (99mTc-MIBI), were used as drug models. Dissolution and disintegration profiles, differed depending on the drug model chosen. In vitro dissolution velocity constants indicated a probable retention of the radiotracer in the formulation. In vivo disintegration velocity constants showed important variability for each radiopharmaceutical. Pearson statistical test showed no correlation between in vitro drug release, and in vivo behaviour, for 99mTc-DTPA, 99mTc-ECD and 99mTc-MIBI. High correlation coefficients were found for 99mTc-MDP not only for in vitro dissolution and disintegration studies but also for in vivo scintigraphic studies. Scintigraphic studies have made a significant contribution to the development of drug delivery systems. It is essential, however, to choose the appropriate radiotracers as models of drug behaviour. This study has demonstrated significant differences in release patterns, depending on the model chosen. It is likely that each formulation would require the development of a specific model, rather than being able to use a generic drug model on the basis of its physicochemical characteristics.


Sodium Selenite Acts as an Otoprotectant against Neomycin-Induced Hair Cell Damage in a Zebrafish Model.
Sodium selenite is a trace element essential for many physiological functions in the body. It is involved in various biological processes; it acts as a cofactor for antioxidant enzymes that protect against free radicals and is reported to limit metal-mediated oxidative DNA damage. In the present study, we investigated the effect of sodium selenite on neomycin ototoxicity in wild-type and transgenic zebrafish (Brn3C: EGFP). Five or six days post-fertilization, zebrafish larvae were co-exposed to 125 μM neomycin and various concentrations (10 μM, 100 μM, 250 μM, and 500 μM) of sodium selenite for 1 h. Hair cells within neuromasts of the supraorbital (SO1 and SO2), otic (O1), and occipital (OC1) lateral lines were analyzed by fluorescence microscopy (n = 10 fish per treatment). Hair cell survival was estimated as the ratio of the hair cell numbers in each group compared to those of the control group that were not exposed to neomycin. Apoptosis and hair cell damage of neuromasts were evaluated using the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) assay and 2-[4-(dimethylamino) styryl]-N-ethylpyridinium iodide (DASPEI) assay, respectively. Ultrastructural changes were evaluated using scanning electron microscopy and transmission electron microscopy. Neuromast hair cells were preserved in zebrafish exposed to 125 μM neomycin and 500 μM sodium selenite for 1 h. Sodium selenite protected against neomycin-induced hair cell loss of neuromasts, reduced apoptosis, and prevented zebrafish ultrastructural changes. We propose that sodium selenite protects against neomycin-induced hair cell damage by inhibiting apoptosis, decreasing the disarray of stereocilia, and preventing ultrastructural changes in the neuromast hair cells of the zebrafish.


Tube feeding in patients with advanced dementia: a review of the evidence.
Patients with advanced dementia frequently develop eating difficulties and weight loss. Enteral feeding tubes are often used in this situation, yet benefits and risks of this therapy are unclear. We searched MEDLINE, 1966 through March 1999, to identify data about whether tube feeding in patients with advanced dementia can prevent aspiration pneumonia, prolong survival, reduce the risk of pressure sores or infections, improve function, or provide palliation. We found no published randomized trials that compare tube feeding with oral feeding. We found no data to suggest that tube feeding improves any of these clinically important outcomes and some data to suggest that it does not. Further, risks are substantial. The widespread practice of tube feeding should be carefully reconsidered, and we believe that for severely demented patients the practice should be discouraged on clinical grounds.


Low Complication Rate of Anterior Lumbar Spine Surgery in an Ambulatory Surgery Center.
As healthcare costs rise, attempts are being made to perform an increasing proportion of spine surgery in ambulatory surgery centers (ASCs). ASCs are more efficient, both economically and functionally. There remains uncertainty regarding the safety of performing anterior lumbar procedures requiring vascular access, as little has been published on this subset of patients. This is a consecutive case series analysis of anterior lumbar spine surgeries that were performed in a free-standing ASC in a private-practice setting over a 1-year period, including anterior lumbar interbody fusion, artificial disc replacement, and hybrid procedures. The preoperative, intraoperative, and postoperative data recorded included age, gender, body mass index, tobacco use, and the presence of diabetes; level and procedure, operating room time, estimated blood loss, complications; discharge site, occurrence of reoperation, hospital admission, or any medical complication or infection over a 90-day period. Fifty-one patients underwent 63 treated levels (34 artificial disc replacement, 29 anterior lumbar interbody fusion): 40 single-level, 10 two-level, one three-level. Average age was 45 years; 27 female, 24 males. None of the patients were diabetics, three were current smokers, seven were former smokers. Average body mass index was 27 ± 4 (range 16-36). Average total anesthesia time was 100 minutes (range 57-187 minutes). Average estimated blood loss was 23 mL (range 5-250 mL). Seventy-one percent of patients were discharged directly home, 29% to an aftercare facility. In the 30-day postoperative period there were no deaths, one hospital admission for pain, and no significant medical complications or surgical site infections. In this consecutive case series artificial disc replacement or anterior lumbar interbody fusion was performed at 63 levels in 51 patients in the ASC setting with an observed major complication rate of zero and hospital unplanned admission rate of 2% (1/51). This provides some evidence that these procedures are safe to perform in the ASC setting. However, a highly experienced vascular surgeon and efficient surgical team, and strict patient selection criteria are all critical in making this possible.


The utilization of appropriate osteoporosis medications improves following a multifaceted educational intervention: the Canadian quality circle project (CQC).
Osteoporosis is a serious but treatable condition. However, appropriate therapy utilization of the disease remains suboptimal. Thus, the objective of the study was to change physicians' therapy administration behavior in accordance with the Osteoporosis Canada 2002 guidelines. The Project was a two year cohort study that consisted of five Quality Circle (QC) phases that included: 1) Training & Baseline Data Collection, 2) First Educational Intervention & First Follow-Up Data Collection 3) First Strategy Implementation Session, 4) Final Educational Intervention & Final Follow-up Data Collection, and 5) Final Strategy Implementation Session. A total of 340 family physicians formed 34 QCs and participated in the study. Physicians evaluated a total of 8376, 7354 and 3673 randomly selected patient charts at baseline, follow-up #1 and the final follow-up, respectively. Patients were divided into three groups; the high-risk, low-risk, and low-risk without fracture groups. The generalized estimating equations technique was utilized to model the change over time of whether physicians The odds of appropriate therapy was 1.29 (95% CI: 1.13, 1.46), and 1.41 (95% CI: 1.20, 1.66) in the high risk group, 1.15 (95% CI: 0.97, 1.36), and 1.16 (95% CI: 0.93, 1.44) in the low risk group, and 1.20 (95% CI: 1.01, 1.43), and 1.23 (95% CI: 0.97, 1.55) in the low risk group without fractures at follow-up #1 and the final follow-up, respectively. QCs methodology was successful in increasing physicians' appropriate use of osteoporosis medications in accordance with Osteoporosis Canada guidelines.


Role of histology in providing prognostic information in mycosis fungoides.
Many patients who present with patch and early plaque stage mycosis fungoides follow an indolent course and survive for many years following diagnosis. A certain subset of patients, however, have rapidly progressive disease leading to accelerated demise. We examined 21 histologic sections from initial biopsies taken from patients with stable disease and 26 from patients with rapidly progressive disease in order to evaluate the role of histology in predicting the disease course. Two or three authors examined each case and scored each of 24 histologic parameters using a previously described four-point scale with no knowledge of the patients' clinical courses. Interobserver agreement was quite high. The only histologic parameter that demonstrated statistical differences between the two groups of patients was degree of acanthosis. The degree of spongiosis, number of eosinophils, amount of hyperconvolution of dermal lymphocytes and density of the dermal infiltrate approached statistical significance but did not attain this level. All of these differences were quite small. No differences were seen for the other 19 parameters. Patients with rapidly progressive disease tended to have more acanthosis, a few more hyperconvoluted dermal lymphocytes, a slightly greater number of eosinophils and perhaps a slightly more dense dermal infiltrate than patients who had stable disease. However, as all of these changes were very slight, it appears unlikely that evaluation of any single biopsy specimen for the histologic parameters we studied is helpful in predicting the prognosis for a specific patient.


Transferring the entatic-state principle to copper photochemistry.
The entatic state denotes a distorted coordination geometry of a complex from its typical arrangement that generates an improvement to its function. The entatic-state principle has been observed to apply to copper electron-transfer proteins and it results in a lowering of the reorganization energy of the electron-transfer process. It is thus crucial for a multitude of biochemical processes, but its importance to photoactive complexes is unexplored. Here we study a copper complex-with a specifically designed constraining ligand geometry-that exhibits metal-to-ligand charge-transfer state lifetimes that are very short. The guanidine-quinoline ligand used here acts on the bis(chelated) copper(I) centre, allowing only small structural changes after photoexcitation that result in very fast structural dynamics. The data were collected using a multimethod approach that featured time-resolved ultraviolet-visible, infrared and X-ray absorption and optical emission spectroscopy. Through supporting density functional calculations, we deliver a detailed picture of the structural dynamics in the picosecond-to-nanosecond time range.


A physiologically based pharmacokinetic model for fluoride uptake by bone.
A sex-specific, physiologically based pharmacokinetic (pbpk) model has been developed to describe the absorption, distribution, and elimination of fluorides in rats and humans. Growth curves generated by plotting mean body weights (kg) against age (weeks or years) are included in the simulation model to allow the integration of chronic fluoride exposure from birth to old age. The model incorporates age and body weight dependence of the physiological processes that control the uptake of fluoride by bone and the elimination of fluoride by the kidneys. Six compartments make up the model. These are lung, liver, kidney, bone, and slowly and rapidly perfused compartments. The model also includes two bone subcompartments: a small, flow-limited, rapidly exchangeable surface bone compartment and a bulk virtually nonexchangeable inner bone compartment. The inner bone compartment contains nearly all of the whole body content of fluoride, which, in the longer time frame, may be mobilized through the process of bone modeling and remodeling. The model has been validated by comparing the model predictions with experimental data gathered in rats and humans after drinking water and dietary ingestion of fluoride. This physiological model description of absorption, distribution, and elimination of fluoride from the body permits the analysis of the combined effect of ingesting and inhaling fluorides on the target organ, bone. Estimates of fluoride concentrations in bone are calculated and related to chronic fluoride toxicity. The model is thus useful for predicting some of the long-term metabolic features and tissue concentrations of fluoride that may be of value in understanding positive or negative effects of fluoride on human health. In addition, the pbpk model provides a basis for across-species extrapolation of the effective fluoride dose at the target tissue, bone, in the assessment of risk from different exposure conditions.


Negative Transpulmonary Pressure Disrupts Airway Morphogenesis by Suppressing Fgf10.
Mechanical forces are increasingly recognized as important determinants of cell and tissue phenotype and also appear to play a critical role in organ development. During the fetal stages of lung morphogenesis, the pressure of the fluid within the lumen of the airways is higher than that within the chest cavity, resulting in a positive transpulmonary pressure. Several congenital defects decrease or reverse transpulmonary pressure across the developing airways and are associated with a reduced number of branches and a correspondingly underdeveloped lung that is insufficient for gas exchange after birth. The small size of the early pseudoglandular stage lung and its relative inaccessibility in utero have precluded experimental investigation of the effects of transpulmonary pressure on early branching morphogenesis. Here, we present a simple culture model to explore the effects of negative transpulmonary pressure on development of the embryonic airways. We found that negative transpulmonary pressure decreases branching, and that it does so in part by altering the expression of fibroblast growth factor 10 (Fgf10). The morphogenesis of lungs maintained under negative transpulmonary pressure can be rescued by supplementing the culture medium with exogenous FGF10. These data suggest that Fgf10 expression is regulated by mechanical stress in the developing airways. Understanding the mechanical signaling pathways that connect transpulmonary pressure to FGF10 can lead to the establishment of novel non-surgical approaches for ameliorating congenital lung defects.


Polymerase specific error rates and profiles identified by single molecule sequencing.
DNA polymerases have an innate error rate which is polymerase and DNA context specific. Historically the mutational rate and profiles have been measured using a variety of methods, each with their own technical limitations. Here we used the unique properties of single molecule sequencing to evaluate the mutational rate and profiles of six DNA polymerases at the sequence level. In addition to accurately determining mutations in double strands, single molecule sequencing also captures direction specific transversions and transitions through the analysis of heteroduplexes. Not only did the error rates vary, but also the direction specific transitions differed among polymerases.


Response of Bell Pepper Cultivars to Bacterial Spot Pathogen Races that Individually Overcome Major Resistance Genes.
The effect of major resistance genes (Bs1, Bs2, and Bs3) or gene combinations for resistance to bacterial spot of bell peppers (Xanthomonas campestris pv. vesicatoria) in 15 commercial cultivars on disease reduction and yield were studied during 1995 and 1996. Reaction of cultivars to specific races (races 1, 2, or 3) of the pathogen corresponded with seed company claims for resistance against these races. Races 1 to 4 were used as initial inoculum in 1995, and races 1 to 6 in 1996 field experiments. Cultivars with no known resistance genes to bacterial spot (e.g., Camelot, Jupiter, and Valiant), a single resistance gene (X3R Camelot, King Arthur), or a combination of Bs1 and Bs3 genes (Guardian, Sentinel, and Admiral) were severely diseased. Yields were reduced in all inoculated cultivars compared to non-inoculated cultivars used as controls. Although races 4 and 6 caused significant disease in cultivars with only Bs1 (King Arthur) or Bs2 (X3R Camelot) genes, cultivars with a combination of Bs1 and Bs2 (Boynton Bell, PR9300-8) had much lower levels of bacterial spot. Roger 4178, a hybrid with a combination of Bs1, Bs2, and Bs3 genes, had the lowest disease ratings. Overall, race 3 was predominant during 1995, while races 3 and 6 were recovered most frequently in 1996.


Toward universal protein post-translational modification detection in high throughput format.
Post-translational modification (PTM) of proteins plays essential regulatory roles in a variety of pathological conditions. Reliable and practical assays are required to accelerate the discovery of inhibitors and activators for PTM related diseases. Today, methodologies are based on specific or group-specific PTM recognition of e.g. phosphate for kinase activity without extending to other type of PTMs. Here we have established a universal time-resolved luminescence assay on a peptide-break platform for the direct detection of wide variety of PTMs. The developed assay is based on the leucine zipper concept wherein a europium-chelate labeled detection peptide and a non-labeled peptide substrate form a highly luminescent dimer. As an active PTM enzyme at sub or low nanomolar concentration modifies the substrate peptide, the luminescent signal of the detached detection peptide is quenched in the presence of soluble quenchers. The functionality of this universal assay technique has been demonstrated for the monitoring of phosphorylation, dephosphorylation, deacetylation, and citrullination with high applicability also to other PTMs in a high throughput format.


Problems related to the use of animals for therapeutic and care purposes. The Document of the National Committee for Bioethics.
The Italian Ministry of Health, in 2002, instructed the National Committee for Bioethics to carefully review and ultimately provide evidence for future legislative bills in various aspects. One such matter was that of the subject of "Pet Therapy", generically viewed as a "man-animal" relationship, with the purpose of proving beneficiary to both human health and welfare. The necessity of a bioethical approach was deemed important in establishing the concrete benefits for mankind (and the research required to demonstrate this) whilst also considering any possible malaise inflicted on those animals participating. The final recommendations decided upon, took into consideration effectiveness, cost, suitable alternatives, discussion of the intervention with the patient.


Autophagy in herpesvirus immune control and immune escape.
Autophagy delivers cytoplasmic constituents for lysosomal degradation, and thereby facilitates pathogen degradation and pathogen fragment loading onto MHC molecules for antigen presentation to T cells. Herpesviruses have been used to demonstrate these novel functions of autophagy, which previously has been primarily appreciated for its pro-survival role during starvation. In this review, we summarize recent findings how macroautophagy restricts herpesvirus infections directly, how macroautophagy and chaperone mediated autophagy contribute to herpesviral antigen presentation on MHC molecules, and which mechanisms herpesviruses have developed to interfere with these pathways. These studies suggest that herpesviruses significantly modulate autophagy to escape from its functions in innate and adaptive immunity.


Anthracnose Disease of Carpetgrass (Axonopus compressus) Caused by Colletotrichum hainanense sp. nov.
Carpetgrass (Axonopus compressus) is a creeping, stoloniferous, perennial warm-season grass that is adapted to humid tropical and subtropical climates. Recently, outbreaks of anthracnose disease of A. compressus caused by an unidentified Colletotrichum sp. were observed in the Hainan and Guangdong provinces in southern China. In late winter and early spring, the disease incidence reached 100% in some badly infected lawns. Under high-moisture conditions, the crowns and oldest leaf sheaths of the majority of the plants became necrotic, which led to whole lawns turning reddish brown. Pathogenicity was confirmed by inoculating uninfected A. compressus plants with a conidial suspension of the Colletotrichum sp. isolated from diseased Axonopus plants. Phylogenetic analyses of the combined internal transcribed spacer, Sod2, Apn2, and Apn2/Mat1 sequences revealed the pathogen to be a novel species of the Colletotrichum graminicola species complex. Microscopic examination showed that the species was also morphologically distinct from related Colletotrichum species. As a result of the phylogenetic, morphological, and pathogenicity analyses, we propose the name Colletotrichum hainanense for this pathogen of A. compressus in southern China.


Discovery and Preclinical Pharmacology of INE963, a Potent and Fast-Acting Blood-Stage Antimalarial with a High Barrier to Resistance and Potential for Single-Dose Cures in Uncomplicated Malaria.
A series of 5-aryl-2-amino-imidazothiadiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage Plasmodium falciparum (Pf) growth inhibition assay. A lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, and toxicity properties and extended pharmacological profiles culminated in the identification of INE963 (1), which demonstrates potent cellular activity against Pf 3D7 (EC50 = 0.006 μM) and achieves "artemisinin-like" kill kinetics in vitro with a parasite clearance time of <24 h. A single dose of 30 mg/kg is fully curative in the Pf-humanized severe combined immunodeficient mouse model. INE963 (1) also exhibits a high barrier to resistance in drug selection studies and a long half-life (T1/2) across species. These properties suggest the significant potential for INE963 (1) to provide a curative therapy for uncomplicated malaria with short dosing regimens. For these reasons, INE963 (1) was progressed through GLP toxicology studies and is now undergoing Ph1 clinical trials.


[Innovative care and self-care strategies for people with chronic diseases in Latin America].
To identify innovative strategies for improved care and self-care of patients with chronic diseases (CD) in Latin America and to explore interest in creating a Latin American network of professionals in this field. A descriptive study based on a survey of key experts with recognized national or regional leadership in CD patient care. The 25-question questionnaire sought information on their experiences with care and self-care initiatives for CD patients, descriptions of successful initiatives, the perceived ability of countries to innovate in this area, their interest in participating in a network of Latin American professionals in this field, and more. Content analysis was performed to develop recommendations for the Region. Responses were obtained from 17 (37.8%) of the 45 experts approached; 82.4% confirmed their knowledge of of involvement with an innovative initiative related to the subject. Initial development does exist in each of the three innovative strategy types: peer care, informal caregivers, and telenursing, the latter being the least explored. There is real interest in forming a Latin American network that focuses on development of innovative self-care strategies for CD patients. Support for a joint network is promising. Priorities are building skills in this area and developing innovative proposals for improved CD patient care in the Region. Innovative measures should be complementary and adapted to the specific context of each scenario.


Pulmonary embolism after insertion of a Greenfield filter.
This report describes a case in which a patient had a Greenfield filter placed at the time of diagnosis of deep vein thrombosis (DVT) when he was asymptomatic for pulmonary embolism. Later in the patient's hospital course, a typical clincal picture of pulmonary embolism developed. The issues examined in this report include: (1) the incidence of asymptomatic pulmonary embolism; (2) the value of the baseline ventilation perfusion (VQ) lung scan for the diagnosis of DVT; and (3) the value of an echocardiogram in diagnosing pulmonary embolism. It appears reasonable that patients in whom DVT is diagnosed undergo baseline VQ scanning. This procedure would prevent the misdiagnosis of a new pulmonary embolism while the patient is on anticoagulation therapy and possibly avoid unnecessary invasive diagnostic procedures. The case described demonstrates the usefulness of the echocardiogram and a transthoracic echo in the diagnosis of pulmonary embolism. It also points out the surprisingly high incidence of silent pulmonary embolism in patients in whom DVT is diagnosed.


Crossed beam polyatomic reaction dynamics: recent advances and new insights.
Over the past ten years or so, great advances in our understanding of the dynamics of elementary (bimolecular) polyatomic reactions in the gas-phase have occurred. This has been made possible by critical improvements (a) in crossed molecular beam (CMB) instruments with rotating mass spectrometric detection and time-of-flight analysis, especially following the implementation of soft ionization (by tunable low energy electrons or vacuum-ultraviolet synchrotron radiation) for product detection with increased sensitivity and universal detection power, and (b) in REMPI-slice velocity map ion imaging (VMI) detection techniques in pulsed CMB experiments for obtaining product pair-correlated information through high-resolution measurements directly in the center of mass system. The improved universal CMB method is permitting us to identify all primary reaction products, characterize their formation dynamics, and determine the branching ratios (BRs) for multichannel non-adiabatic reactions, such as those of ground state oxygen atoms, O(3P), with unsaturated hydrocarbons (alkynes, alkenes, dienes). The improved slice VMI CMB technique is permitting us to explore at an unprecedented level of detail, through pair-correlated measurements, the reaction dynamics of a prototype polyatomic molecule such as CH4 (and isotopologues) in its ground state with a variety of important X radicals such as F, Cl, O, and OH. In this review, we highlight this recent progress in the field of CMB reaction dynamics, with an emphasis on the experimental side, but with the related theoretical work, at the level of state-of-the-art calculations of both the underlying potential energy surfaces and the reaction dynamics, noted throughout. In particular, the focus is (a) on the effect of molecular complexity and structure on product distributions, branching ratios and role of intersystem crossing for the multichannel, addition-elimination reactions of unsaturated hydrocarbons with O atoms, and (b) on the very detailed dynamics of the abstraction reactions of ground-state methane (and isotopologues) with atoms (F, Cl, O) and diatoms (OH), with inclusion of also rotational mode specificity in the vibrationally excited methane reactions.


Psychological targeting as an effective approach to digital mass persuasion.
People are exposed to persuasive communication across many different contexts: Governments, companies, and political parties use persuasive appeals to encourage people to eat healthier, purchase a particular product, or vote for a specific candidate. Laboratory studies show that such persuasive appeals are more effective in influencing behavior when they are tailored to individuals' unique psychological characteristics. However, the investigation of large-scale psychological persuasion in the real world has been hindered by the questionnaire-based nature of psychological assessment. Recent research, however, shows that people's psychological characteristics can be accurately predicted from their digital footprints, such as their Facebook Likes or Tweets. Capitalizing on this form of psychological assessment from digital footprints, we test the effects of psychological persuasion on people's actual behavior in an ecologically valid setting. In three field experiments that reached over 3.5 million individuals with psychologically tailored advertising, we find that matching the content of persuasive appeals to individuals' psychological characteristics significantly altered their behavior as measured by clicks and purchases. Persuasive appeals that were matched to people's extraversion or openness-to-experience level resulted in up to 40% more clicks and up to 50% more purchases than their mismatching or unpersonalized counterparts. Our findings suggest that the application of psychological targeting makes it possible to influence the behavior of large groups of people by tailoring persuasive appeals to the psychological needs of the target audiences. We discuss both the potential benefits of this method for helping individuals make better decisions and the potential pitfalls related to manipulation and privacy.


[Measurement and performance analysis of functional neural network].
The measurement of network is one of the important researches in resolving neuronal population information processing mechanism using complex network theory. For the quantitative measurement problem of functional neural network, the relation between the measure indexes, i.e. the clustering coefficient, the global efficiency, the characteristic path length and the transitivity, and the network topology was analyzed. Then, the spike-based functional neural network was established and the simulation results showed that the measured network could represent the original neural connections among neurons. On the basis of the former work, the coding of functional neural network in nidopallium caudolaterale (NCL) about pigeon's motion behaviors was studied. We found that the NCL functional neural network effectively encoded the motion behaviors of the pigeon, and there were significant differences in four indexes among the left-turning, the forward and the right-turning. Overall, the establishment method of spike-based functional neural network is available and it is an effective tool to parse the brain information processing mechanism.


Characterization of a Multipeptide Lantibiotic Locus in Streptococcus pneumoniae.
Bacterial communities are established through a combination of cooperative and antagonistic interactions between the inhabitants. Competitive interactions often involve the production of antimicrobial substances, including bacteriocins, which are small antimicrobial peptides that target other community members. Despite the nearly ubiquitous presence of bacteriocin-encoding loci, inhibitory activity has been attributed to only a small fraction of gene clusters. In this study, we characterized a novel locus (the pld locus) in the pathogen Streptococcus pneumoniae that drives the production of a bacteriocin called pneumolancidin, which has broad antimicrobial activity. The locus encodes an unusual tandem array of four inhibitory peptides, three of which are absolutely required for antibacterial activity. The three peptide sequences are similar but appear to play distinct roles in regulation and inhibition. A modification enzyme typically found in loci encoding a class of highly modified bacteriocins called lantibiotics was required for inhibitory activity. The production of pneumolancidin is controlled by a two-component regulatory system that is activated by the accumulation of modified peptides. The locus is located on a mobile element that has been found in many pneumococcal lineages, although not all elements carry the pld genes. Intriguingly, a minimal region containing only the genes required for pneumolancidin immunity was found in several Streptococcus mitis strains. The pneumolancidin-producing strain can inhibit nearly all pneumococci tested to date and provided a competitive advantage in vivo. These peptides not only represent a unique strategy for bacterial competition but also are an important resource to guide the development of new antimicrobials. Successful colonization of a polymicrobial host surface is a prerequisite for the subsequent development of disease for many bacterial pathogens. Bacterial factors that directly inhibit the growth of neighbors may provide an advantage during colonization if the inhibition of competitors outweighs the energy for production. In this work, we found that production of a potent antimicrobial called pneumolancidin conferred a competitive advantage to the pathogen Streptococcus pneumoniae. S. pneumoniae secreting pneumolancidin inhibits a wide array of Gram-positive organisms, including all but one tested pneumococcal strain. The pneumolancidin genetic locus is of particular interest because it encodes three similar modified peptides (lantibiotics), each of which has a distinct role in the function of the locus. Lantibiotics represent a relatively untapped resource for the development of clinically useful antibiotics which are desperately needed. The broad inhibitory activity of pneumolancidin makes it an ideal candidate for further characterization and development.


Immunocytochemical study of retinal diode laser photocoagulation in the rat.
To determine the nature of the cellular infiltrate, alterations in cell adhesion molecules, and MHC II antigen expression in the rat retina following diode laser retinal photocoagulation. 20 normal Lister rats underwent diode laser photocoagulation of the retina. Frozen sections from eyes enucleated at 0, 1, 5, 13, and 33 days post laser were examined for T cells (R7.3), CD4 T cells (W3/25), activated CD4 T cells (OX-40), CD8 T cells (OX-8), B cells (OX-33), and macrophages (OX-42), MHC II antigen (OX-6), and E-Selectin-1, VCAM-1, and ICAM-1. Retinal diode laser photocoagulation stimulated a wound healing response in the outer retina and choroid. The cellular infiltrate included macrophages and activated CD4 T cells at 13 and 33 days post laser. Glial cells in the inner plexiform and inner nuclear layers expressed MHC II antigen at 24 hours only. ICAM-1 antigen was induced in RPE cells and in Muller cells in the inner retina at all time intervals post laser and intense staining for ICAM-1 was present around intraretinal migrated cells at 13 and 33 days post laser. VCAM-1 antigen expression was induced in the choroidal vascular endothelium and RPE at 13 and 33 days after laser as was E-Selectin-1 antigen expression which was also evident focally at the external limiting membrane in association with migrated cells adjacent to the burn. These results suggest that alterations in cell adhesion molecules may regulate the migration and activation of retinal pigment epithelium, macrophages and CD4 T cells at the outer blood-retinal barrier and choroid following diode laser photocoagulation of the normal Lister rat retina.


Systems analysis of metabolic phenotypes: what have we learnt?
Flux is one of the most informative measures of metabolic behavior. Its estimation requires integration of experimental and modeling approaches and, thus, is at the heart of metabolic systems biology. In this review, we argue that flux analysis and modeling of a range of plant systems points to the importance of the supply of metabolic inputs and demand for metabolic end-products as key drivers of metabolic behavior. This has implications for metabolic engineering, and the use of in silico models will be important to help design more effective engineering strategies. We also consider the importance of cell type-specific metabolism and the challenges of characterizing metabolism at this resolution. A combination of new measurement technologies and modeling approaches is bringing us closer to integrating metabolic behavior with whole-plant physiology and growth.


Genetic basis of functional variability in adhesion G protein-coupled receptors.
The enormous sizes of adhesion G protein-coupled receptors (aGPCRs) go along with complex genomic exon-intron architectures giving rise to multiple mRNA variants. There is a need for a comprehensive catalog of aGPCR variants for proper evaluation of the complex functions of aGPCRs found in structural, in vitro and animal model studies. We used an established bioinformatics pipeline to extract, quantify and visualize mRNA variants of aGPCRs from deeply sequenced transcriptomes. Data analysis showed that aGPCRs have multiple transcription start sites even within introns and that tissue-specific splicing is frequent. On average, 19 significantly expressed transcript variants are derived from a given aGPCR gene. The domain architecture of the N terminus encoded by transcript variants often differs and N termini without or with an incomplete seven-helix transmembrane anchor as well as separate seven-helix transmembrane domains are frequently derived from aGPCR genes. Experimental analyses of selected aGPCR transcript variants revealed marked functional differences. Our analysis has an impact on a rational design of aGPCR constructs for structural analyses and gene-deficient mouse lines and provides new support for independent functions of both, the large N terminus and the transmembrane domain of aGPCRs.


Role of anti-angiogenesis agents in treating NSCLC: focus on bevacizumab and VEGFR tyrosine kinase inhibitors.
Successful inhibition of angiogenesis with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has improved the efficacy seen with standard cytotoxic therapy in NSCLC. The addition of bevacizumab to first-line chemotherapy improved response rate and progression free survival and added 2 months to median overall survival for those patients with advanced stage NSCLC on the treatment arm of E4599. Bevacizumab is now a standard agent to add to frontline carboplatin and paclitaxel for patients with newly diagnosed NSCLC who meet the eligibility criteria from the landmark E4599 trial. Unfortunately about half of all patients are not eligible either because they have squamous histology, brain metastases, or are on anti-coagulation. Ongoing trials are further exploring the safety of bevacizumab in these patient populations, as well as in combination with other cytotoxic regimens. Exploration of other applications of bevacizumab in the second-line and adjuvant setting are ongoing as well. The largest class of drugs that block angiogenesis are the multi-targeted tyrosine kinase inhibitors (TKIs) that target the VEGF receptor (VEGFR). These drugs are still in development, and though two are now on the market for treating other malignancies, their role in NSCLC is under investigation. These agents have the advantages of hitting multiple targets, convenient oral administration, and potential for lower cost. Their lack of target specificity leads to unexpected toxicity, but also promising efficacy. For example, the overall objective response rate of 9.5% with single agent sunitinib compares similarly to that of pemetrexed or docetaxel in previously treated NSCLC patients, but toxicity, notably fatigue, lead to discontinuation in 38% of patients. Hypertension, hemorrhage and cavitation are common toxicities amongst this class of agents. Rash, fatigue, myalgia, and hand-foot syndrome are more specifically seen with TKIs. These compounds may also be synergistic or additive with traditional cytotoxic chemotherapy drugs and other novel compounds. In early trials sorafenib as a single agent has shown no clinical response in previously treated NSCLC patients, whereas clinical benefit in combination with erlotinib or chemotherapy has been seen in early studies. Vandetanib has demonstrated objective responses as a single agent and in combination with chemotherapy in previously treated NSCLC patients. A phase I trial of AZD2171 with carboplatin and paclitaxel in newly diagnosed advanced stage NSCLC also demonstrated promising results with 6 of 15 patients achieving partial responses. NSCLC specific trials are also underway, or in development for pazopanib, axitinib, AMG 706, XL647, enzastaurin, and other TKIs. Other anti-angiogenesis agents with different mechanisms of action include thalidomide and its derivatives, monoclonal antibodies to the VEGFRs, and VEGF Trap, a chimeric molecule which combines extracellular portions of VEGFR1 and VEGFR2 with the Fc portion of immunoglobulin G1 to form a molecule that binds and "traps" VEGF. Despite modest improvements, prognosis continues to be poor for patients with advanced NSCLC. Bevacizumab is a first step into the world of angiogenesis inhibitors for NSCLC and though it only offers a modest survival benefit in a limited patient population, it paves the way for the development of the next generation of anti-angiogenesis inhibitors. We can hope that further improvements in survival will follow.


Metagenomic analysis identifies human adenovirus 31 in children with acute flaccid paralysis in Tunisia.
A variety of viruses can cause acute flaccid paralysis (AFP). However, the causative agent, sometimes, remains undetermined. Metagenomics helps in identifying viruses not diagnosed by conventional methods. Stool samples from AFP (n = 104) and non-AFP (n = 114) cases that tested enterovirus-negative by WHO standard methods were investigated. A metagenomics approach, first used on five pools of four samples each, revealed the presence of adenovirus sequences. Amplification in A549 cells and full-genome sequencing were used for complete virus identification and for designing a PCR assay to screen individual related samples. Metagenomic analysis showed that adenovirus sequences that were closely to the A31 and A61 genotypes were the most abundant. Two out of the corresponding 20 individual samples were found positive by PCR, and isolates were obtained in cell culture. Phylogenetic analysis based on complete genome sequences showed that the viruses belong to HAdV-A31 genotype (98-100% nucleotide sequence identity). PCR analysis of stool samples from all AFP and non-AFP cases revealed that a larger proportion of the positive samples were from AFP cases (17.3%) than from non-AFP cases (2.4%). These results open the way to studies aiming to test a possible role of HAdV-A31 in the pathogenesis of AFP.


Parenting by anxious mothers: effects of disorder subtype, context and child characteristics.
There has been increasing research interest in parenting by anxious adults; however, little is known about anxiety-subtype effects, or effects of the context in which parenting is assessed. Two groups of anxious mothers, social phobia (N = 50), generalised anxiety disorder (N = 38), and nonanxious controls (N = 62) were assessed with their 4.9-year-old children in three tasks: two presented threat specifically relevant to each maternal disorder, namely, a social threat task where the child had to give a speech, and a nonsocial threat task where the child had to explore potentially scary objects; the third was a nonthreat task (playing with play dough). Seven parenting dimensions were scored. Effects on parenting of maternal anxiety subgroup and task, and their interactions, were examined, as were effects of earlier child behavioural inhibition and currently manifest anxiety. There were no parenting differences between maternal groups in the nonthreat play-dough task; parenting difficulties in the two anxious groups were principally evident in the disorder-specific challenge. Parenting differences between nonanxious and anxious mothers occurred independently of child characteristics. There was little evidence for particular forms of parenting difficulty being unique to maternal disorder. Anxious mothers' parenting difficulties emerge when occurring under challenge, especially when this is disorder-specific. These effects should be considered in research and clinical practice.


Risk of spontaneous bacterial peritonitis associated with gastric Acid suppression.
The primary objective of this study was to determine the association between the use of gastric acid suppressants (GAS) and the risk of developing spontaneous bacterial peritonitis (SBP) in patients with advanced liver cirrhosis (LC). A case-control study nested within a cohort of 480,000 representatives of Taiwan National Health Insurance beneficiaries was carried out. A case was matched with 100 controls on age, gender, and index date of SBP diagnosis. GAS use was identified from the 1-year period before the index date. Conditional logistic regression analysis was used to adjust for various unbalanced covariates between users and nonusers of GAS. A total of 947 cases of SBP were identified among the 86,418 patients with advanced LC. A significant increased risk of developing SBP was found to be associated with current (within 30 days), and recent (within 30-90 day) use of 2 different classes of GAS: proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs). The confounder adjusted rate ratio (aRR) for the current use of PPIs was 2.77 (95% CI: 1.90-4.04) and H2RAs was 2.62 (95% CI: 2.00-3.42). The risk of SBP attenuated for the recent use of PPIs (aRR: 2.20, 95%CI: 1.60-3.02) or H2RAs (aRR: 1.72, 95% CI: 1.25-2.37). In addition, sensitivity analysis using hospitalized SBP as the primary outcome showed a similar risk for the current use of PPIs (aRR, 3.24; 95% CI: 2.08-5.05) and H2RAs (aRR 2.43; 95% CI 1.71-3.46). Furthermore, higher cumulative days of gastric acid suppression were associated with a higher risk of SBP (trend P < 0.0001). To conclude, exposure to GAS was associated with an increased risk of SBP in patients with advanced LC. The association was more pronounced in current PPI users compared with nonusers.


Disturbance in hitting accuracy by professional and collegiate baseball players due to intentional change of target position.
The present study investigated bat control of skilled baseball batters during tee batting, faced with an intentional change in target position. Twelve, skilled, male baseball players (M age = 24 yr., SD = 4) participated in the study. Participants were instructed to hit a baseball off a tee 0.8 m from the ground (Hitting condition), and also to deliberately swing just above the ball (Air Swing condition). The task for the participants was to perform, in alternate order, 15 swings at a real baseball on a stationary tee and 15 swings at an imaginary ball that was said to be on top of the real baseball. The participants were instructed to hit the ball toward center field just as they would hit in a game. While most participants could hit the real ball in the sweet area of the bat, only one participant did so in the Air Swing condition. Average distances from the center of the sweet area to ball center at the moment of ball-bat contact in the Air Swing condition (85 mm) were significantly greater than the distance in the Hitting condition (38 mm). The larger error in hitting an imaginary ball in the sweet area could be due to perceptual changes following the batter's altered focus, expectation of a lack of contact, and/or lack of feedback from the swing. It was suggested that baseball batters should be aware of the possible error in hitting accurately when they intentionally shifted the target.


Polysilicon-chromium-gold intracellular chips for multi-functional biomedical applications.
The development of micro- and nanosystems for their use in biomedicine is a continuously growing field. One of the major goals of such platforms is to combine multiple functions in a single entity. However, achieving the design of an efficient and safe micro- or nanoplatform has shown to be strongly influenced by its interaction with the biological systems, where particle features or cell types play a critical role. In this work, the feasibility of using multi-material pSi-Cr-Au intracellular chips (MMICCs) for multifunctional applications by characterizing their interactions with two different cell lines, one tumorigenic and one non-tumorigenic, in terms of biocompatibility, internalization and intracellular fate, has been explored. Moreover, the impact of MMICCs on the induction of an inflammatory response has been assessed by evaluating TNFα, IL1b, IL6, and IL10 human inflammatory cytokines secretion by macrophages. Results show that MMICCs are biocompatible and their internalization efficiency is strongly dependent on the cell type. Finally as a proof-of-concept, MMICCs have been dually functionalized with transferrin and pHrodo™ Red, SE to target cancer cells and detect intracellular pH, respectively. In conclusion, MMICCs can be used as multi-functional devices due to their high biocompatibility, non-inflammatory properties and the ability of developing multiple functions.


Radiation therapy in the management of brain metastases from renal cell carcinoma.
Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain radiotherapy has been used for palliation. With advances in radiation oncology, stereotactic radiosurgery and hypofractionated stereotactic radiotherapy have been utilized for RCC brain metastases, producing excellent outcomes. This review details the role of radiotherapy in various subgroups of patients with RCC brain metastases as well as the associated toxicities and outcomes. Newer radiosensitizers (eg, motexafin gadolinium [Xcytrin]) and chemotherapeutic agents (eg, temozolomide [Temodar]) used in combination with radiotherapy will also be discussed.


[Recommendations for the use of diagnostic testing in low respiratory infections in children older than three months].
Recommendations for the use of diagnostic testing in low respiratory infection in children older than 3 months were produced by the Groupe de Recherche sur les Avancées en Pneumo-Pédiatrie (GRAPP) under the auspices of the French Paediatric Pulmonology and Allergology Society (SP(2)A). The Haute Autorité de santé (HAS) methodology, based on formalized consensus, was used. A first panel of experts analyzed the English and French literature to provide a second panel of experts with recommendations to validate. Only the recommendations are presented here, but the full text is available on the SP(2)A website.