Psychosocial interventions for patients with head and neck cancer: past, present, and future.
A diagnosis of head and neck cancer, like any cancer diagnosis, is often accompanied by much fear and uncertainty. In addition, patients with head and neck cancer face difficulties in eating, chewing, drinking, breathing, speaking, as well as changes in appearance. Simultaneously, the burden of head and neck cancer is often manifested in psychosocial dysfunction, which can have a negative impact on quality of life. Although a phenomenon well recognized, little is known about many factors that influence or impact psychosocial dysfunction in individuals with head and neck cancer. Even less is known about the effective management of psychosocial dysfunction. To date, there is evidence to suggest that psychosocial interventions generally provide an overall positive effect. Moreover, some intervention studies, such as education alone, have failed to achieve the desired results. In addition, some studies suggest an advantage of cognitive- behavioral therapy over other forms of psychological treatment. With the growing impetus to investigate factors associated with psychosocial dysfunction, and considerable advancement in the development and validation of many global and disease-specific measures, there is an opportunity for further research to develop an appropriate clinical intervention program for such patients.


Neuronal ablation of p-Akt at Ser473 leads to altered 5-HT1A/2A receptor function.
The serotonergic system regulates a wide range of behavior, including mood and impulsivity, and its dysregulation has been associated with mood disorders, autism spectrum disorder, and addiction. Diabetes is a risk factor for these conditions. Insulin resistance in the brain is specifically associated with susceptibility to psychostimulant abuse. Here, we examined whether phosphorylation of Akt, a key regulator of the insulin signaling pathway, controls serotonin (5-HT) signaling. To explore how impairment in Akt function regulates 5-HT homeostasis, we used a brain-specific rictor knockout (KO) mouse model of impaired neuronal phosphorylation of Akt at Ser473. Cortical 5-HT1A and 5-HT2A receptor binding was significantly elevated in rictor KO mice. Concomitant with this elevated receptor expression, the 5-HT1A receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) led to an increased hypothermic response in rictor KO mice. The increased cortical 5-HT1A receptor density was associated with higher 5-HT1A receptor levels on the cortical cell surface. In contrast, rictor KO mice displayed significantly reduced head-twitch response (HTR) to the 5-HT2A/C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), with evidence of impaired 5-HT2A/C receptor signaling. In vitro, pharmacological inhibition of Akt significantly increased 5-HT1A receptor expression and attenuated DOI-induced 5-HT2A receptor signaling, thereby lending credence to the observed in vivo cross-talk between neuronal Akt signaling and 5-HT receptor regulation. These data reveal that defective central Akt function alters 5-HT signaling as well as 5-HT-associated behaviors, demonstrating a novel role for Akt in maintaining neuronal 5-HT receptor function.


Use of MALDI Biotyper plus ClinProTools mass spectra analysis for correct identification of Streptococcus pneumoniae and Streptococcus mitis/oralis.
Differentiation of Streptococcus pneumoniae from other viridans group streptococci is well known to be challenging in clinical laboratories. Matrix assisted laser desorption ionisation-time of flight mass spectrometry (MALDI-TOF MS) had been reported to be a good alternative for Streptococcus species level identification. However, differentiation of S. pneumoniae from other Streptococcus mitis group organisms was found to be problematic using the Bruker MALDI Biotyper system. This study used the Bruker MALDI Biotyper system in addition to a mass spectra model analysis generated by 10 reference strains of S. pneumoniae, 8 strains of S. mitis and 2 strains of S. oralis in the ClinProTools to identify 28 clinical isolates of S. pneumoniae and 47 isolates of S. mitis/oralis. The results were compared with those generated by the MALDI Biotyper system alone. The percentages of correct species level identification using the MALDI Biotyper system alone and the direct transfer and extraction method were 66.7% (50/75) and 70.7% (53/75), respectively. With the additional ClinProTools mass spectra analysis, the percentages of correct identification by the direct transfer and extraction method increased to 85.3% (64/75) and 100% (75/75), respectively. This new workflow significantly improved the accuracy of S. pneumoniae and S. mitis/oralis identification. The additional ClinProTools mass spectra analysis with extraction method after MALDI Biotyper identification significantly improved the accuracy of identification among S. pneumoniae, S. oralis and S. mitis. The extra 15 min processing time of spectra analysis should be affordable in most clinical laboratories. We suggest that the same approach could be further explored in handling other bacterial species with high similarities.


Particle emissions from microalgae biodiesel combustion and their relative oxidative potential.
Microalgae are considered to be one of the most viable biodiesel feedstocks for the future due to their potential for providing economical, sustainable and cleaner alternatives to petroleum diesel. This study investigated the particle emissions from a commercially cultured microalgae and higher plant biodiesels at different blending ratios. With a high amount of long carbon chain lengths fatty acid methyl esters (C20 to C22), the microalgal biodiesel used had a vastly different average carbon chain length and level of unsaturation to conventional biodiesel, which significantly influenced particle emissions. Smaller blend percentages showed a larger reduction in particle emission than blend percentages of over 20%. This was due to the formation of a significant nucleation mode for the higher blends. In addition measurements of reactive oxygen species (ROS), showed that the oxidative potential of particles emitted from the microalgal biodiesel combustion were lower than that of regular diesel. Biodiesel oxygen content was less effective in suppressing particle emissions for biodiesels containing a high amount of polyunsaturated C20-C22 fatty acid methyl esters and generated significantly increased nucleation mode particle emissions. The observed increase in nucleation mode particle emission is postulated to be caused by very low volatility, high boiling point and high density, viscosity and surface tension of the microalgal biodiesel tested here. Therefore, in order to achieve similar PM (particulate matter) emission benefits for microalgal biodiesel likewise to conventional biodiesel, fatty acid methyl esters (FAMEs) with high amounts of polyunsaturated long-chain fatty acids (≥C20) may not be desirable in microalgal biodiesel composition.


Delineation of Borrelia burgdorferi sensu lato species by multilocus sequence analysis and confirmation of the delineation of Borrelia spielmanii sp. nov.
To evaluate multilocus sequence analysis (MLSA) for taxonomic purposes in the delineation of species within Borrelia burgdorferi sensu lato, seven relevant loci of various strains for which extensive DNA-DNA reassociation data were available were sequenced. MLSA delineation proved to be fully concordant with conventional methods. Our analysis confirmed the delineation of a novel species, Borrelia spielmanii sp. nov., previously known as 'Borrelia spielmani' Richter et al. 2004, with strain PC-Eq17N5T (=DSM 16813T = CIP 108855T) as the type strain.


Diversification of monoterpene indole alkaloid analogs through cross-coupling.
Catharanthus roseus monoterpene indole alkaloid analogs have been produced via a combination of biosynthetic and chemical strategies. Specifically, introduction of a chemical handle-a chlorine or a bromine-into the target molecule by mutasynthesis, followed by postbiosynthetic chemical derivatization using Pd-catalyzed Suzuki-Miyaura cross-coupling reactions robustly afforded aryl and heteroaryl analogs of these alkaloids.


Occlusal variation related to soft diet in a nonhuman primate.
Among 43 squirrel monkeys (Saimiri sciureus) raised either on naturally tough or on artificially soft foods, there are significant differences in occlusal features. Animals raised on soft foods show more rotated and displaced teeth, crowded premolars, and absolutely and relatively narrower dental arches. Dietary consistency may be a determinant of occlusal health.


N-glycosylation characterization by liquid chromatography with mass spectrometry.
Three methods are introduced here to fully characterize glycosylation at protein, peptides, and glycan levels by LC-MS (ESI TOF MS). At protein level, glycosylation could be detected by comparing protein masses with and without glycan. At peptide level, glycosylation sites could be detected by removing glycan and site specific glycosylation could be examined with glycopeptides. At glycan level, glycan profiling and identification could be achieved by analyzing released glycans labeled with procainamide. All these methods are MS based and able to provide a whole picture of glycosylation of a glycoprotein. These methods are also simple to implement in industrial or academic laboratory with proper training and instruments.


Expected performance of Quebec-French older adults on the Batterie Rapide de Dénomination (BARD).
Difficulties retrieving words during conversations, called anomia, are frequent in the late preclinical stage of Alzheimer's disease, in mild cognitive impairment, and in major neurocognitive disorders. Picture-naming tests, used to assess anomia, are too lengthy and are unsuitable for medical or nursing practices. The main objective of this study was to confirm the usefulness of the Batterie Rapide de Dénomination (BARD - Battery of Rapid Denomination), an electronically-administered picture-naming test comprising 10 pictures for which perfect naming scores were obtained in French, English and Flemish participants. In this study, the BARD was applied on 207 healthy, French-speaking participants from Quebec, aged 50 years and more, wherein the results demonstrated the ease of naming the 10 pictures of the test. However, their performance was not always flawless. Seven out of the 207 participants of produced one error on one specific picture, which led us to excluding this item from the BARD. Thus, this study established the utility of the BARD for clinical settings of French-Quebec populations. This screening test is ideally suited for bedside assessment in acute care settings, stroke units and medical environments providing primary and secondary care. Its use has the potential for improving referrals to more specialized resources.


Sequencing of 6.7 Mb of the melon genome using a BAC pooling strategy.
Cucumis melo (melon) belongs to the Cucurbitaceae family, whose economic importance among horticulture crops is second only to Solanaceae. Melon has a high intra-specific genetic variation, morphologic diversity and a small genome size (454 Mb), which make it suitable for a great variety of molecular and genetic studies. A number of genetic and genomic resources have already been developed, such as several genetic maps, BAC genomic libraries, a BAC-based physical map and EST collections. Sequence information would be invaluable to complete the picture of the melon genomic landscape, furthering our understanding of this species' evolution from its relatives and providing an important genetic tool. However, to this day there is little sequence data available, only a few melon genes and genomic regions are deposited in public databases. The development of massively parallel sequencing methods allows envisaging new strategies to obtain long fragments of genomic sequence at higher speed and lower cost than previous Sanger-based methods. In order to gain insight into the structure of a significant portion of the melon genome we set out to perform massive sequencing of pools of BAC clones. For this, a set of 57 BAC clones from a double haploid line was sequenced in two pools with the 454 system using both shotgun and paired-end approaches. The final assembly consists of an estimated 95% of the actual size of the melon BAC clones, with most likely complete sequences for 50 of the BACs, and a total sequence coverage of 39x. The accuracy of the assembly was assessed by comparing the previously available Sanger sequence of one of the BACs against its 454 sequence, and the polymorphisms found involved only 1.7 differences every 10,000 bp that were localized in 15 homopolymeric regions and two dinucleotide tandem repeats. Overall, the study provides approximately 6.7 Mb or 1.5% of the melon genome. The analysis of this new data has allowed us to gain further insight into characteristics of the melon genome such as gene density, average protein length, or microsatellite and transposon content. The annotation of the BAC sequences revealed a high degree of collinearity and protein sequence identity between melon and its close relative Cucumis sativus (cucumber). Transposon content analysis of the syntenic regions suggests that transposition activity after the split of both cucurbit species has been low in cucumber but very high in melon. The results presented here show that the strategy followed, which combines shotgun and BAC-end sequencing together with anchored marker information, is an excellent method for sequencing specific genomic regions, especially from relatively compact genomes such as that of melon. However, in agreement with other results, this map-based, BAC approach is confirmed to be an expensive way of sequencing a whole plant genome. Our results also provide a partial description of the melon genome's structure. Namely, our analysis shows that the melon genome is highly collinear with the smaller one of cucumber, the size difference being mainly due to the expansion of intergenic regions and proliferation of transposable elements.


Insulin sensitivity at diagnosis of Type 2 diabetes is not associated with subsequent cardiovascular disease (UKPDS 67).
Insulin resistance is common in Type 2 diabetes which, in turn, is associated with a markedly increased risk of cardiovascular disease. Whether insulin sensitivity measured after diagnosis of diabetes is associated with incident cardiovascular disease was evaluated in this prospective study. Three thousand five hundred and eighty-two subjects with newly diagnosed diabetes, recruited to the UK Prospective Diabetes Study (UKPDS), free of cardiovascular disease, and with complete information on insulin sensitivity and potential confounders, were followed prospectively to the first occurrence of (i) fatal or non-fatal myocardial infarction, MI (ii) fatal or non-fatal stroke, and (iii) coronary heart disease, CHD (fatal or non-fatal MI, sudden death or ischaemic heart disease). Insulin sensitivity was measured by Homeostatic Model Assessment (HOMA). Insulin sensitivity as measured by HOMA was not associated with subsequent MI, stroke, or CHD in univariate or multivariate models controlling for age, sex, ethnicity, HbA(1c), body mass index, plasma triglycerides, cholesterol and smoking. The hazard ratio associated with a doubling of insulin sensitivity with fatal or non-fatal MI in a multivariate model was 0.92 (95% confidence interval, CI, 0.80-1.05). These results were not changed by the exclusion of overweight patients randomized to metformin. Estimation of insulin sensitivity provides no additional useful information with respect to the risk of the first occurrence of cardiovascular disease in patients with newly diagnosed Type 2 diabetes. Among patients with Type 2 diabetes, insulin resistance is not a risk factor for cardiovascular disease.


Dopamine receptors in a songbird brain.
Dopamine is a key neuromodulatory transmitter in the brain. It acts through dopamine receptors to affect changes in neural activity, gene expression, and behavior. In songbirds, dopamine is released into the striatal song nucleus Area X, and the levels depend on social contexts of undirected and directed singing. This differential release is associated with differential expression of activity-dependent genes, such as egr1 (avian zenk), which in mammalian brain are modulated by dopamine receptors. Here we cloned from zebra finch brain cDNAs of all avian dopamine receptors: the D1 (D1A, D1B, D1D) and D2 (D2, D3, D4) families. Comparative sequence analyses of predicted proteins revealed expected phylogenetic relationships, in which the D1 family exists as single exon and the D2 family exists as spliced exon genes. In both zebra finch and chicken, the D1A, D1B, and D2 receptors were highly expressed in the striatum, the D1D and D3 throughout the pallium and within the mesopallium, respectively, and the D4 mainly in the cerebellum. Furthermore, within the zebra finch, all receptors, except for D4, showed differential expression in song nuclei relative to the surrounding regions and developmentally regulated expression that decreased for most receptors during the sensory acquisition and sensorimotor phases of song learning. Within Area X, half of the cells expressed both D1A and D2 receptors, and a higher proportion of the D1A-only-containing neurons expressed egr1 during undirected but not during directed singing. Our findings are consistent with hypotheses that dopamine receptors may be involved in song development and social context-dependent behaviors.


[Early Detection of COVID-19 in Portugal: Use of Clinical Records].
Syndromic surveillance allows early detection of changes in the population's morbidity pattern. The aim of this study is to evaluate the usefulness of indicators related to access to healthcare services, in COVID-19 surveillance. A time series analysis was performed using the weekly incidence rate of COVID-19 in Mainland Portugal, between weeks 14/2020 (March 30 to April 5) and 25/2020 (June 15 to 21), and six indicators: 1) COVID-19 consultations in primary healthcare; 2) number of COVID-19 emergency department visits; 3) number of emergency department visits due to viral pneumonia; 4) number of hospitalizations due to viral pneumonia; 5) proportion of emergency department visits due to viral pneumonia; and 6) proportion of hospitalizations for viral pneumonia. Pearson correlation and cross-correlations were computed. A strong correlation was found between the weekly incidence rate of COVID-19 and all indicators. [(1) 0.76; (2) 0.82; (3) 0.77; (4) 0.84; (5) 0.86; e (6) 0.90]. Emergency department visits and hospitalizations for viral pneumonia detect variations in the frequency of the disease with a one week lag compared to the incidence rate of COVID-19, in one week. COVID-19 consultations in primary healthcare and emergency department visits trail behind the incidence rate of COVID-19, in one week. The proportion of viral pneumonias in emergency department visits, or hospitalizations, is temporally aligned with the weekly incidence rate of COVID-19. The delay found in the COVID-19 primary healthcare consultations and emergency department visits, may be related to changes in access to healthcare services and clinical coding. Emergency department visits and hospitalizations for viral pneumonia may be useful in the early detection of COVID-19. Viral pneumonia may have been coded as being of unknown origin. Future monitoring of these indicators is necessary to ascertain whether the incidence of COVID-19 is significantly influenced by changes in testing strategies. The indicators described in this study will be an asset for the optimization of testing strategies, allocation of healthcare resources to the communities that are most vulnerable to severe morbidity and assessing vaccination impact. As such, surveillance systems based on clinical data will be a valuable complementary tool to SINAVE. The indicators under analysis could be used regularly, with special attention to viral pneumonias, to detect outbreaks of COVID-19. Information on pneumonia of unknown etiology may be considered in the surveillance of COVID-19.


Side-view holographic endomicroscopy via a custom-terminated multimode fibre.
Microendoscopes based on optical fibres have recently come to the fore as promising candidates allowing in-vivo observations of otherwise inaccessible biological structures in animal models. Despite being still in its infancy, imaging can now be performed at the tip of a single multimode fibre, by relying on powerful holographic methods for light control. Fibre based endoscopy is commonly performed en face, resulting in possible damage of the specimen owing to the direct contact between the distal end of the probe and target. On this ground, we designed an all-fibre probe with an engineered termination that reduces compression and damage to the tissue under investigation upon probe insertion. The geometry of the termination brings the field of view to a plane parallel to the fibre's longitudinal direction, conveying the probe with off-axis imaging capabilities. We show that its focusing ability also benefits from a higher numerical aperture, resulting in imaging with increased spatial resolution. The effect of probe insertion was investigated inside a tissue phantom comprising fluorescent particles suspended in agarose gel, and a comparison was established between the novel side-view probe and the standard en face fibre probe. This new concept paves the way to significantly less invasive deep-tissue imaging.


Ultrafast all-optical switching in nanoplasmonic waveguide with Kerr nonlinear resonator.
A novel ultrafast all-optical switching based on metal-insulator-metal nanoplasmonic waveguide with a Kerr nonlinear resonator is proposed and investigated numerically. With the finite-difference time-domain simulations, it is demonstrated that an obvious optical bistability of the signal light appears by varying the control-light intensity, and an excellent switching effect is achieved. This bistability originates from the intensity-dependent change induced in the dielectric constant of Kerr nonlinear material filled in the nanodisk resonator. It is found that the proposed all-optical switching exhibits femtosecond-scale feedback time.


Biological analysis of flexor tendon repair-failure stump tissue: A potential recycling of tissue for tendon regeneration.
Re-rupture is common after primary flexor tendon repair. Characterization of the biological changes in the ruptured tendon stumps would be helpful, not only to understand the biological responses to the failed tendon repair, but also to investigate if the tendon stumps could be used as a recycling biomaterial for tendon regeneration in the secondary grafting surgery. A canine flexor tendon repair and failure model was used. Following six weeks of repair failure, the tendon stumps were analyzed and characterized as isolated tendon-derived stem cells (TDSCs). Failed-repair stump tissue showed cellular accumulation of crumpled and disoriented collagen fibres. Compared with normal tendon, stump tissue had significantly higher gene expression of collagens I and III, matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and insulin-like growth factor (IGF). The stump TDSCs presented both mesenchymal stem and haematopoietic cell markers with significantly increased expression of CD34, CD44, and CD90 markers. Stump TDSCs exhibited similar migration but a lower proliferation rate, as well as similar osteogenic differentiation but a lower chondrogenic/adipogenic differentiation capability, compared with normal TDSCs. Stump TDSCs also showed increasing levels of SRY-box 2 (Sox2), octamer-binding transcription factor 4 (Oct4), tenomodulin (TNMD), and scleraxis (Scx) protein and gene expression. We found that a failed repair stump had increased cellularity that preserved both mesenchymal and haematopoietic stem cell characteristics, with higher collagen synthesis, MMP, and growth factor gene expression. This study provides evidence that tendon stump tissue has regenerative potential.Cite this article: C-C. Lu, T. Zhang, R. L. Reisdorf, P. C. Amadio, K-N. An, S. L. Moran, A. Gingery, C. Zhao. Biological analysis of flexor tendon repair-failure stump tissue: A potential recycling of tissue for tendon regeneration. Bone Joint Res 2019;8:232-245. DOI: 10.1302/2046-3758.86.BJR-2018-0239.R1.


Newly established ELISA for N-ERC/mesothelin improves diagnostic accuracy in patients with suspected pleural mesothelioma.
Pleural mesothelioma is an aggressive tumor, commonly caused by exposure to asbestos. The prognosis of mesothelioma remains disappointing despite multimodal treatment. We reported previously that N-ERC/mesothelin could be a useful biomarker for the early diagnosis of pleural mesothelioma and developed an enzyme-linked immunosorbent assay (ELISA) system for its detection. However, the reproducibility of our previous 7-16 ELISA system has been revealed to be unsatisfactory. To measure N-ERC/mesothelin more precisely, we developed a new 7-20 ELISA system. The subjects of this study were patients who were referred to our department with suspected pleural mesothelioma. The current study demonstrated that the newly established 7-20 ELISA system improved the sensitivity and specificity for diagnosing pleural mesothelioma compared with the previous system. Moreover, the 7-20 ELISA system showed better reproducibility and displayed the tendency of both higher sensitivity and higher specificity in plasma than in serum. Particularly for the epithelioid type, the area under the curve (AUC) and the diagnostic accuracy of N-ERC/mesothelin were excellent; the AUC was 0.91, the sensitivity was 0.95, and the specificity was 0.76 in plasma. In conclusion, assessment of N-ERC/mesothelin with our newly established 7-20 ELISA system is clinically useful for the precise diagnosis of pleural mesothelioma.


The lesson of supplementary treatment with Chinese medicine on severe laboratory-confirmed SARS patients.
Chinese medicine (CM) has been used to control infectious diseases for thousands of years. In 2003 outbreaks of severe acute respiratory syndrome (SARS) occurred in China, Hong Kong and Taiwan. In view of the possible beneficial effect of CM on SARS, we conducted this study to examine whether CM is of any benefit as a supplementary treatment of SARS. Four severe laboratory-confirmed SARS patients received routine western-medicine treatment plus different supplementary treatment: CM A, CM B and CM C (placebo control). We reported the course of the cases in terms of changes in chest radiographic scores. Case 1 treated as a placebo control passed away on the 9th day after onset of disease. The other three cases treated with CM A or CM B survived. The initial findings seemed to indicate a favorable effect of CM on management of SARS. The findings need to be verified with a larger sample. Using CM as a supplementary treatment of severe SARS seems to indicate that natural herbal medicine can be used against avian influenza. Hence, such related experience or clinical trials should be taken into consideration when facing the possible outbreak of avian influenza in the future.


The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients.
To estimate the mortality and length of stay in the intensive care unit (ICU) attributable to clinically important gastrointestinal bleeding in mechanically ventilated critically ill patients. Three strategies were used to estimate the mortality attributable to bleeding in two multicentre databases. The first method matched patients who bled with those who did not (matched cohort), using duration of ICU stay prior to the bleed, each of six domains of the Multiple Organ Dysfunction Score (MODS) measured 3 days prior to the bleed, APACHE II score, age, admitting diagnosis, and duration of mechanical ventilation. The second approach employed Cox proportional hazards regression to match bleeding and non-bleeding patients (model-based matched cohort). The third method, instead of matching, derived estimates based on regression modelling using the entire population (regression method). Three parallel analyses were conducted for the length of ICU stay attributable to clinically important bleeding. Sixteen Canadian university-affiliated ICUs. A total of 1666 critically ill patients receiving mechanical ventilation for at least 48 hours. We prospectively collected data on patient demographics, APACHE II score, admitting diagnosis, daily MODS, clinically important bleeding, length of ICU stay, and mortality. Independent adjudicators determined the occurrence of clinically important gastrointestinal bleeding, defined as overt bleeding in association with haemodynamic compromise or blood transfusion. Of 1666 patients, 59 developed clinically important gastrointestinal bleeding. The mean APACHE II score was 22.9 +/- 8.6 among bleeding patients and 23.3 +/- 7.7 among non-bleeding patients. The risk of death was increased in patients with bleeding using all three analytic approaches (matched cohort method: relative risk [RR]= 2.9, 95% confidence interval (CI)= 1.6-5.5; model-based matched cohort method: RR = 1.8, 95% CI = 1.1-2.9; and the regression method: RR = 4.1, 95% CI = 2.6-6.5). However, this was not significant for the adjusted regression method (RR = 1.0, 95% CI = 0.6-1.7). The median length of ICU stay attributable to clinically important bleeding for these three methods, respectively, was 3.8 days (95% CI = -0.01 to 7.6 days), 6.7 days (95% CI = 2.7-10.7 days), and 7.9 days (95% CI = 1.4-14.4 days). Clinically important upper gastrointestinal bleeding has an important attributable morbidity and mortality, associated with a RR of death of 1-4 and an excess length of ICU stay of approximately 4-8 days.


United States cancer reporting laws: structure and utility.
Authorities in 52 United States jurisdictions were contacted to determine the existence and structure of cancer reporting laws and registration systems. Of the 52 US reporting areas examined; 30 (58 per cent) had a law requiring cancer reporting; 36 (69 per cent) of the reporting areas had at least one centralized cancer registry covering a geographically defined population. Among the 30 areas with cancer reporting laws, 26 had population-based registries; of the 22 areas with no cancer reporting law, 10 had a population-based registry. Among the 30 areas with cancer reporting laws, 12 required one reporting source (hospital, physician, laboratory), 11 required two reporting sources, four required three reporting sources, two areas gave the health department the authority to designate reporting sources, and one did not specify any reporting source. While 11 of the laws provided legal protection for both the data provider and the cancer patient, eight did not specify any such legal protection. While 13 laws made provisions for research uses of cancer reporting data, 17 did not do so. None of the laws had ever been legally tested at or beyond the State Appellate Court level.


Management of infections caused by respiratory syncytial virus.
This is a consensus document compiled by the Medical Products Agency in Sweden and the Swedish Reference Group for Antiviral Therapy on management of respiratory syncytial virus (RSV) infections. Prophylaxis against RSV infections using palivizumab, a commercially available humanized monoclonal IgG1 antibody preparation, is recommended for children <2 y of age with chronic respiratory diseases requiring continuous treatment (oxygen and/or inhalations and/or steroids) during the previous 6 months and children <6 months old who were born before gestational week 26. Ribavirin inhalation treatment may be considered in high-risk infants with clinical symptoms indicating a serious course of an RSV infection. Treatment with ribavirin in combination with intravenous polyclonal immunoglobulin should be considered in patients who have received an allogenic stem cell transplantation or organ transplantation with >1 episode of rejection treatment and who have mild or moderate RSV pneumonia. Evidence-based documentation for treatment of other groups of patients is lacking.


EAU Guidelines on benign prostatic hyperplasia (BPH).
To establish guidelines for the diagnosis, treatment, and follow-up of BPH. A search of published work was conducted using Medline. In combination with expert opinions recommendations were made on the usefulness of tests for assessment and follow-up: mandatory, recommended, or optional. In addition, indications and outcomes for the different therapeutic options were reviewed. A digital rectal examination is mandatory in the assessment for the diagnosis of BPH. Recommended tests are the International Prostate Symptom Score, creatinine measurement (or renal ultrasound), uroflowmetry, and postvoid residual urine volume. All other tests are optional. The aim of treatment is to improve patients' quality of life, and it depends on the severity of the symptoms of BPH. The watchful waiting policy is recommended for patients with mild symptoms, medical treatment for patients with mild-moderate symptoms, and surgery for patients who failed medication or conservative management and who have moderate-severe symptoms, and/or complications of BPH which require surgery. Regarding non-surgical treatments, transurethral microwave thermotherapy is the most attractive option. These treatments should be reserved for patients who prefer to avoid surgery or who no longer respond favourably to medication. Finally, recommendations for follow-up tests and a recommended follow-up time schedule after BPH treatment are provided. Recommendations for assessment, possible therapeutic options, and follow-up of patients with BPH are made.


Extracellular access to the Na,K pump: pathway similar to ion channel.
In each normal Na,K pump cycle, first three sodium and then two potassium ions are transported; in both cases, the ions become temporarily occluded in pump conformations that isolate them from internal and external solutions. A major charge movement occurs during sodium translocation and accompanies the deocclusion of sodium ions or their release to the cell exterior, or both. The nature of the charge movement was examined by measurement of the undirectional sodium-22 efflux mediated by Nai-Nao exchange (Nai and Nao are internal and external sodium ions) in voltage-clamped, internally dialyzed squid giant axons in the absence of potassium; in this way the pump activity was restricted to the sodium-translocation pathway. Although electroneutral, the Nai-Nao exchange was nevertheless voltage-sensitive: increasingly negative potentials enhanced its rate along a saturating sigmoid curve. Such voltage dependence demonstrates that the release and rebinding of external sodium is the predominant charge-moving (hence, voltage-sensitive) step, suggesting that extracellular sodium ions must reach their binding sites deep in the pump molecule through a high-field access channel. This implies that part of the pump molecule is functionally analogous to an ion channel.


Men's preferences and trade-offs for prostate cancer screening: a discrete choice experiment.
Prostate cancer screening using prostate-specific antigen (PSA) remains controversial. In deciding about screening, men must weigh the benefits and harms: little is known about benefit: harm trade-offs men are willing to accept. The objective of this study was to assess men's preferences for PSA screening, and the trade-offs between benefits and harms men are willing to accept when deciding about screening. Preferences of 662 men aged 40-69 were assessed using a discrete choice experiment. PSA screening was described by six attributes: prostate cancer deaths, prostate cancer diagnoses, unnecessary biopsies from false-positive PSA tests, impotence, urinary incontinence/bowel problems and cost. A mixed logit model was used to examine the influence of attributes on men's preferences for PSA testing; benefit: harm trade-offs were also calculated. Men's preferences were significantly influenced by test characteristics, particularly potential mortality benefit, unnecessary biopsies and likelihood of urinary incontinence or bowel problems; preferences were also influenced by age, prior PSA testing experience and perceived risk of prostate cancer. Men were willing to accept between 65 and 233 of 10 000 extra men with unnecessary biopsies, and between 31 and 72 of 10 000 extra men with incontinence/bowel problems to avoid one prostate cancer death. Differences in valuations of attributes and trade-offs acceptable to men of different ages suggest a one size fits all approach to PSA testing, regardless of age, may not reflect men's preferences. Our results can be used by policymakers to ensure screening programmes are in line with men's preferences and by clinicians and patients to facilitate informed discussions of the most relevant benefits and downsides of PSA screening for an individual man.


Burosumab treatment in adults with X-linked hypophosphataemia: 96-week patient-reported outcomes and ambulatory function from a randomised phase 3 trial and open-label extension.
To report the impact of burosumab on patient-reported outcomes (PROs) and ambulatory function in adults with X-linked hypophosphataemia (XLH) through 96 weeks. Adults diagnosed with XLH were randomised 1:1 in a double-blinded trial to receive subcutaneous burosumab 1 mg/kg or placebo every 4 weeks for 24 weeks (NCT02526160). Thereafter, all subjects received burosumab every 4 weeks until week 96. PROs were measured using the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC), Brief Pain Inventory-Short Form (BPI-SF) and Brief Fatigue Inventory (BFI), and ambulatory function was measured with the 6 min walk test (6MWT). Subjects (N=134) were randomised to burosumab (n=68) or placebo (n=66) for 24 weeks. At baseline, subjects experienced pain, stiffness, and impaired physical and ambulatory function. At week 24, subjects receiving burosumab achieved statistically significant improvement in some BPI-SF scores, BFI worst fatigue (average and greatest) and WOMAC stiffness. At week 48, all WOMAC and BPI-SF scores achieved statistically significant improvement, with some WOMAC and BFI scores achieving meaningful and significant change from baseline. At week 96, all WOMAC, BPI-SF and BFI achieved statistically significant improvement, with selected scores in all measures also achieving meaningful change. Improvement in 6MWT distance and percent predicted were statistically significant at all time points from 24 weeks. Adults with XLH have substantial burden of disease as assessed by PROs and 6MWT. Burosumab treatment improved phosphate homoeostasis and was associated with a steady and consistent improvement in PROs and ambulatory function. NCT02526160.


Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors.
Rapid generation of drug-resistant mutations in HIV-1 reverse transcriptase (RT), a prime target for anti-HIV therapy, poses a major impediment to effective anti-HIV treatment. Our previous efforts have led to the development of two novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with piperidine-substituted thiophene[3,2-d]pyrimidine scaffolds, compounds K-5a2 and 25a, which demonstrate highly potent anti-HIV-1 activities and improved resistance profiles compared with etravirine and rilpivirine, respectively. Here, we have determined the crystal structures of HIV-1 wild-type (WT) RT and seven RT variants bearing prevalent drug-resistant mutations in complex with K-5a2 or 25a at ~2 Å resolution. These high-resolution structures illustrate the molecular details of the extensive hydrophobic interactions and the network of main chain hydrogen bonds formed between the NNRTIs and the RT inhibitor-binding pocket, and provide valuable insights into the favorable structural features that can be employed for designing NNRTIs that are broadly active against drug-resistant HIV-1 variants.


Tactile and proprioceptive dysfunction differentiates cervical dystonia with and without tremor.
To determine whether different phenotypes of cervical dystonia (CD) express different types and levels of somatosensory impairment. We assessed somatosensory function in patients with CD with and without tremor (n = 12 each) and in healthy age-matched controls (n = 22) by measuring tactile temporal discrimination thresholds of the nondystonic forearm and proprioceptive acuity in both the dystonic (head/neck) and nondystonic body segments (forearm/hand) using a joint position-matching task. The head or the wrist was passively displaced along different axes to distinct joint positions by the experimenter or through a robotic exoskeleton. Participants actively reproduced the experienced joint position, and the absolute joint position-matching error between the target and the reproduced positions served as a marker of proprioceptive acuity. Tactile temporal discrimination thresholds were significantly elevated in both CD subgroups compared to controls. Proprioceptive acuity of both the dystonic and nondystonic body segments was elevated in patients with CD and tremor with respect to both healthy controls and patients with CD without tremor. That is, tactile abnormalities were a shared dysfunction of both CD phenotypes, while proprioceptive dysfunction was observed in patients with CD with tremor. Our findings suggest that the pathophysiology in CD can be characterized by 2 abnormal neural processes: a dysfunctional somatosensory gating mechanism involving the basal ganglia that triggers involuntary muscle spasms and abnormal processing of proprioceptive information within a defective corticocerebellar loop, likely affecting the feedback and feedforward control of head positioning. This dysfunction is expressed mainly in CD with tremor.


Control of mitochondrial pH by uncoupling protein 4 in astrocytes promotes neuronal survival.
Brain activity is energetically costly and requires a steady and highly regulated flow of energy equivalents between neural cells. It is believed that a substantial share of cerebral glucose, the major source of energy of the brain, will preferentially be metabolized in astrocytes via aerobic glycolysis. The aim of this study was to evaluate whether uncoupling proteins (UCPs), located in the inner membrane of mitochondria, play a role in setting up the metabolic response pattern of astrocytes. UCPs are believed to mediate the transmembrane transfer of protons, resulting in the uncoupling of oxidative phosphorylation from ATP production. UCPs are therefore potentially important regulators of energy fluxes. The main UCP isoforms expressed in the brain are UCP2, UCP4, and UCP5. We examined in particular the role of UCP4 in neuron-astrocyte metabolic coupling and measured a range of functional metabolic parameters including mitochondrial electrical potential and pH, reactive oxygen species production, NAD/NADH ratio, ATP/ADP ratio, CO2 and lactate production, and oxygen consumption rate. In brief, we found that UCP4 regulates the intramitochondrial pH of astrocytes, which acidifies as a consequence of glutamate uptake, with the main consequence of reducing efficiency of mitochondrial ATP production. The diminished ATP production is effectively compensated by enhancement of glycolysis. This nonoxidative production of energy is not associated with deleterious H2O2 production. We show that astrocytes expressing more UCP4 produced more lactate, which is used as an energy source by neurons, and had the ability to enhance neuronal survival.


A novel method for studying the temporal relationship between type 2 diabetes mellitus and cancer using the electronic medical record.
We developed an algorithm for the identification of patients with type 2 diabetes and ascertainment of the date of diabetes onset for examination of the temporal relationship between diabetes and cancer using data in the electronic medical record (EMR). The Marshfield Clinic EMR was searched for patients who developed type 2 diabetes between January 1, 1995 and December 31, 2009 using a combination of diagnostic codes and laboratory data. Subjects without diabetes were also identified and matched to subjects with diabetes by age, gender, smoking history, residence, and date of diabetes onset/reference date. The final cohort consisted of 11,236 subjects with and 54,365 subjects without diabetes. Stringent requirements for laboratory values resulted in a decrease in the number of potential subjects by nearly 70%. Mean observation time in the EMR was similar for both groups with 13-14 years before and 5-7 years after the reference date. The two cohorts were largely similar except that BMI and frequency of healthcare encounters were greater in subjects with diabetes. The cohort described here will be useful for the examination of the temporal relationship between diabetes and cancer and is unique in that it allows for determination of the date of diabetes onset with reasonable accuracy.


Pulmonary Epithelial TLR4 Activation Leads to Lung Injury in Neonatal Necrotizing Enterocolitis.
We seek to define the mechanisms leading to the development of lung disease in the setting of neonatal necrotizing enterocolitis (NEC), a life-threatening gastrointestinal disease of premature infants characterized by the sudden onset of intestinal necrosis. NEC development in mice requires activation of the LPS receptor TLR4 on the intestinal epithelium, through its effects on modulating epithelial injury and repair. Although NEC-associated lung injury is more severe than the lung injury that occurs in premature infants without NEC, the mechanisms leading to its development remain unknown. In this study, we now show that TLR4 expression in the lung gradually increases during postnatal development, and that mice and humans with NEC-associated lung inflammation express higher levels of pulmonary TLR4 than do age-matched controls. NEC in wild-type newborn mice resulted in significant pulmonary injury that was prevented by deletion of TLR4 from the pulmonary epithelium, indicating a role for pulmonary TLR4 in lung injury development. Mechanistically, intestinal epithelial TLR4 activation induced high-mobility group box 1 release from the intestine, which activated pulmonary epithelial TLR4, leading to the induction of the neutrophil recruiting CXCL5 and the influx of proinflammatory neutrophils to the lung. Strikingly, the aerosolized administration of a novel carbohydrate TLR4 inhibitor prevented CXCL5 upregulation and blocked NEC-induced lung injury in mice. These findings illustrate the critical role of pulmonary TLR4 in the development of NEC-associated lung injury, and they suggest that inhibition of this innate immune receptor in the neonatal lung may prevent this devastating complication of NEC.


Traffic exhaust to wildfires: PM2.5 measurements with fixed and portable, low-cost LoRaWAN-connected sensors.
Air pollution with PM2.5 (particulate matter smaller than 2.5 micro-metres in diameter) is a major health hazard in many cities worldwide, but since measuring instruments have traditionally been expensive, monitoring sites are rare and generally show only background concentrations. With the advent of low-cost, wirelessly connected sensors, air quality measurements are increasingly being made in places where many people spend time and pollution is much worse: on streets near traffic. In the interests of enabling members of the public to measure the air that they breathe, we took an open-source approach to designing a device for measuring PM2.5. Parts are relatively cheap, but of good quality and can be easily found in electronics or hardware stores, or on-line. Software is open source and the free LoRaWAN-based "The Things Network" the platform. A number of low-cost sensors we tested had problems, but those selected performed well when co-located with reference-quality instruments. A network of the devices was deployed in an urban centre, yielding valuable data for an extended time. Concentrations of PM2.5 at street level were often ten times worse than at air quality stations. The devices and network offer the opportunity for measurements in locations that concern the public.


'Should I Buy Her a Doll'? Motherhood and Turner Syndrome in Poland.
Turner syndrome (TS) is a genetic condition that affects only girls and women, leading to health issues including infertility. Patients usually require recombinant growth hormone, and sex hormone therapy. Based on our anthropological research in Poland, we posit questions regarding the management of societal expectations by female parents regarding the femininity of their daughters, especially within the context of infertility. We query: Is it possible to understand TS and its consequences as not only being an obstacle to future plans, but also having emancipatory potential? To answer this question, we refer to the concept of hope and analyze the interpretative work of mothers of girls with TS.


Somatic selection of poorly differentiating variant stem cell clones could be a key to human ageing.
Any replicating system in which heritable variants with differing replicative potentials can arise is subject to a Darwinian evolutionary process. The continually replicating adult tissue stem cells that control the integrity of many tissues of long-lived, multicellular, complex vertebrate organisms, including humans, constitute such a replicating system. Our suggestion is that somatic selection for mutations (or stable epigenetic changes) that cause an increased rate of adult tissue stem cell proliferation, and their long-term persistence, at the expense of normal differentiation, is a major key to the ageing process. Once an organism has passed the reproductive age, there is no longer any significant counterselection at the organismal level to this inevitable cellular level Darwinian process.


Cannabidiol inhibitory effect on marble-burying behaviour: involvement of CB1 receptors.
Cannabidiol (CBD) is a major non-psychotomimetic component of Cannabis sativa that has been shown to have an anxiolytic effect in human and animal models. Earlier studies suggest that these effects involve facilitation of serotonin, a neurotransmitter that has also been related to obsessive-compulsive disorder. On the basis of this evidence, this study investigated the effects of CBD in C57BL/6J mice submitted to the marble-burying test (MBT), an animal model proposed to reflect compulsive behaviour. CBD (15, 30 and 60 mg/kg) induced a significant decrease in the number of buried marbles compared with controls (34, 41 and 48%, respectively). A similar, although larger, decrease was also found after the serotonin selective reuptake inhibitor paroxetine (10 mg/kg, 77% decrease) and the benzodiazepine diazepam (2.5 mg/kg, 84% decrease). The effect of CBD (30 mg/kg) was still significant after 7 days of daily repeated administration, whereas the effect of diazepam disappeared. Pretreatment with WAY100635 (3 mg/kg), a 5HT1A receptor antagonist, prevented the effects of paroxetine but failed to alter those of CBD. These latter effects, however, were prevented by pretreatment with the CB1 receptor antagonist AM251 (1 mg/kg). These results indicated that CBD and paroxetine decrease the number of buried marbles in the MBT through distinct pharmacological mechanisms. They also suggest a potential role of drugs acting on the cannabinoid system in modulating compulsive behaviour.


Methanogenesis, sulfate reduction and crude oil biodegradation in hot Alaskan oilfields.
Petrochemical and geological evidence suggest that petroleum in most reservoirs is anaerobically biodegraded to some extent. However, the conditions for this metabolism and the cultivation of the requisite microorganisms are rarely established. Here, we report on microbial hydrocarbon metabolism in two distinct oilfields on the North Slope of Alaska (designated Fields A and B). Signature anaerobic hydrocarbon metabolites were detected in produced water from the two oilfields offering evidence of in situ biodegradation activity. Rate measurements revealed that sulfate reduction was an important electron accepting process in Field A (6-807 µmol S l(-1) day(-1)), but of lesser consequence in Field B (0.1-10 µmol S l(-1) day(-1)). Correspondingly, enrichments established at 55°C with a variety of hydrocarbon mixtures showed relatively high sulfate consumption but low methane production in Field A incubations, whereas the opposite was true of the Field B enrichments. Repeated transfer of a Field B enrichment showed ongoing methane production in the presence of crude oil that correlated with ≥ 50% depletion of several component hydrocarbons. Molecular-based microbial community analysis of the methanogenic oil-utilizing consortium revealed five bacterial taxa affiliating with the orders Thermotogales, Synergistales, Deferribacterales (two taxa) and Thermoanaerobacterales that have known fermentative or syntrophic capability and one methanogen that is most closely affiliated with uncultured clones in the H(2)-using family Methanobacteriaceae. The findings demonstrate that oilfield-associated microbial assemblages can metabolize crude oil under the thermophilic and anaerobic conditions prevalent in many petroleum reservoirs.


Modelling the effects of condom use and antiretroviral therapy in controlling HIV/AIDS among heterosexuals, homosexuals and bisexuals.
A deterministic compartmental sex-structured HIV/AIDS model for assessing the effects of homosexuals and bisexuals in heterosexual settings in which homosexuality and bisexuality issues have remained taboo is presented. We extend the model to focus on the effects of condom use as a single strategy approach in HIV prevention in the absence of any other intervention strategies. Initially, we model the use of male condoms, followed by incorporating the use of both the female and male condoms. The model includes two primary factors in condom use to control HIV which are condom efficacy and compliance. Reproductive numbers for these models are computed and compared to assess the effectiveness of male and female condom use in a community. We also extend the basic model to consider the effects of antiretroviral therapy as a single strategy. The results from the study show that condoms can reduce the number of secondary infectives and thus can slow the development of the HIV/AIDS epidemic. Further, we note from the study that treatment of AIDS patients may enlarge the epidemic when the treatment drugs are not 100% effective and when treated AIDS patients indulge in risky sexual behaviour. Thus, the treatment with amelioration of AIDS patients should be accompanied with intense public health educational programs, which are capable of changing the attitude of treated AIDS patients towards safe sex. It is also shown from the study that the use of condoms in settings with the treatment may help in reducing the number of secondary infections thus slowing the epidemic.


Aldosterone stimulates vacuolar H(+)-ATPase activity in renal acid-secretory intercalated cells mainly via a protein kinase C-dependent pathway.
Urinary acidification in the collecting duct is mediated by the activity of H(+)-ATPases and is stimulated by various factors including angiotensin II and aldosterone. Classically, aldosterone effects are mediated via the mineralocorticoid receptor. Recently, we demonstrated a nongenomic stimulatory effect of aldosterone on H(+)-ATPase activity in acid-secretory intercalated cells of isolated mouse outer medullary collecting ducts (OMCD). Here we investigated the intracellular signaling cascade mediating this stimulatory effect. Aldosterone stimulated H(+)-ATPase activity in isolated mouse and human OMCDs. This effect was blocked by suramin, a general G protein inhibitor, and GP-2A, a specific G(αq) inhibitor, whereas pertussis toxin was without effect. Inhibition of phospholipase C with U-73122, chelation of intracellular Ca(2+) with BAPTA, and blockade of protein kinase C prevented the stimulation of H(+)-ATPases. Stimulation of PKC by DOG mimicked the effect of aldosterone on H(+)-ATPase activity. Similarly, aldosterone and DOG induced a rapid translocation of H(+)-ATPases to the luminal side of OMCD cells in vivo. In addition, PD098059, an inhibitor of ERK1/2 activation, blocked the aldosterone and DOG effects. Inhibition of PKA with H89 or KT2750 prevented and incubation with 8-bromoadenosine-cAMP mildly increased H(+)-ATPase activity. Thus, the nongenomic modulation of H(+)-ATPase activity in OMCD-intercalated cells by aldosterone involves several intracellular pathways and may be mediated by a G(αq) protein-coupled receptor and PKC. PKA and cAMP appear to have a modulatory effect. The rapid nongenomic action of aldosterone may participate in the regulation of H(+)-ATPase activity and contribute to final urinary acidification.


Does obesity predict knee pain over fourteen years in women, independently of radiographic changes?
To examine longitudinal patterns in body mass index (BMI) over 14 years and its association with knee pain in the Chingford Study. We studied a total of 594 women with BMI data from clinic visits at years (Y) 1, 5, 10, and 15. Knee pain at Y15 was assessed by questionnaire. Associations between BMI over 14 years and knee pain at Y15 were examined using logistic regression. BMI significantly increased from Y1 to Y15 (P < 0.0005) with medians (interquartile ranges) of 24.5 kg/m(2) (22.5-27.2 kg/m(2) ) and 26.5 kg/m(2) (23.9-30.1 kg/m(2) ), respectively. At Y15, 45.1% of subjects had knee pain. A greater BMI at Y1 (odds ratio [OR] 1.34, 95% confidence interval [95% CI] 1.05-1.69), at Y15 (OR 1.34, 95% CI 1.10-1.61), and change in BMI over 15 years (OR 1.40, 95% CI 1.00-1.93) were significant predictors of knee pain at Y15 (P < 0.05). BMI change was associated with bilateral (OR 1.61, 95% CI 1.05-1.76, P = 0.024) but not unilateral knee pain (OR 1.22, 95% CI 0.73-1.76, P = 0.298). The association between BMI change and knee pain was independent of radiographic knee osteoarthritis (OA). The strength of association between BMI and knee pain at Y15 was similar during followup measurements. Over 14 years, a higher BMI predicts knee pain at Y15 in women, independently of radiographic knee OA. When adjusted, the association was significant in bilateral, not unilateral, knee pain, suggesting alternative pathologic mechanisms may exist. The longitudinal effect of BMI on knee pain at Y15 is equally important at any time point, which may assist reducing the population burden of knee pain.


The AMPA receptor biophysical gating properties and binding site: Focus on novel curcumin-based diazepines as non-competitive antagonists.
Investigating the binding site of six novel curcumin-based diazepine compounds as a non-competitive antagonist on ionotropic, AMPA-type glutamate receptors, including homomeric and heteromeric subunits. These receptors play a pivotal role in neurodegenerative diseases such as Alzheimer's and epilepsy due to excitotoxicity. Furthermore, it appears that AMPAR signaling plays a significant role in disease development outside the nervous system, as a potential relationship between AMPAR activation and cancer development may exist. Study the biophysical gating effects of the curcumin-based diazepine on AMPAR variants and identify CBD binding sites on AMPARs with the hopes of discovering more potent drug candidates with less undesirable side effects. Our current study uses patch-clamp electrophysiology technology to estimate whole-cell amplitudes changes when exposing HEK293T cells expressing AMPAR subunits to different curcumin-based diazepines. The non-competitive antagonist curcumin-based compounds successfully reduced AMPAR activation currents and increased the rate of desensitization and deactivation. CBD-4 and CBD-5 show the most significant impact on AMPARs, reducing the current by 7-fold. The results contrast with those obtained by the halogenated benzodiazepine-fused curcumins reported previously and lake pyrimidine and pyrazine moieties. This indicates that the N's presence in the effused rings plays a significant role in binding to receptors. CBD-4 showed the highest effect on GluA2 subunits in receptors, while CBD-5 most dramatically impacting GluA1 homomeric receptors, demonstrating that the compounds are more selective towards AMPA-type glutamate receptors. The compounds also showed significant cytotoxic activities against breast cancer cell line (MCF-7), with CBD-4 having the most significant impact. Curcumin-based compounds (i.e., CBD-4 and CBD-5) yield significant neurodegenerative drug potential, and it creates a novel structure with significant activities in reducing AMPAR excitation compared to traditional benzodiazepine analogs, yet their binding mechanisms are still not fully understood. Moreover, AMPARs appear to have a potential influence on cancer development, and the curcumin-based compounds might provide insight into the nature of this relationship.


Surgical management of renal cell carcinoma with associated tumor thrombus extending into the inferior vena cava: A 10-year single-center experience.
Renal cell carcinoma (RCC) is a tumor that has a tendency of vascular invasion by extending to the inferior vena cava (IVC) after the renal vein. The total resection of the renal tumor and tumor thrombus is considered the optimal treatment. In our study, we aimed to present the results related to 34 consecutive cases of RCC with tumor thrombus. Of the 442 patients diagnosed with renal tumors between January 2008 and January 2018, 34 (7.6%) had tumor thrombus over the renal vein extending to the IVC. The data of the 34 patients with tumor thrombus were retrospectively reviewed and included in the study. All the 34 patients underwent radical nephrectomy with tumor thrombectomy. The presence of thrombus was evaluated using contrast-enhanced abdominal tomography, magnetic resonance imaging, or color Doppler ultrasonography. The level of thrombus was classified using the Mayo Clinic tumor thrombus classification. Surgery was performed transperitoneally through a modified Chevron incision and mostly in collaboration with other clinics. Complications were classified according to the Clavien system. Of the 34 patients, 22 were males and 12 were females. The mean follow-up period was 36±27.2 months in patients who had a mean age of 61±10.9 years. The mean tumor size was 10.5±3.3 cm. The number of patients according to the thrombus levels I, II, and III were 20, 9, and 5, respectively. The average blood loss was 744±285.4 mL. Radical surgery for all patients who had direct invasion to the vena cava wall and/or level II and III was performed by gastrointestinal and cardiothoracic surgeons. Cardiopulmonary bypass was not performed in any patient. Minor complications (Clavien grades 1-2) were seen in 8 (23.5%) patients, while 2 (5.8%) patients had major complications (Clavien grades 3-5). The mean follow-up period was 36 months (range, 6-72 months). The overall 5-year survival rate was 85.2%. We think that radical nephrectomy and caval thrombectomy is a safe and effective method in patients with RCC without tumor exceeding the diaphragmatic level. We believe that the surgical success rate can be increased using a multidisciplinary approach in selected cases.


Is being malnourished according to the ESPEN definition for malnutrition associated with clinically relevant outcome measures in geriatric outpatients?
A body of evidence is supporting the association between (the risk of) malnutrition in relation to physical performance, muscle strength, risk for depression and cognitive status in geriatric outpatients. Associations between being malnourished according to the newly proposed ESPEN definition for malnutrition and clinically relevant outcome measures of the aforementioned variables have not been confirmed yet. Therefore, the aim of this study was to examine the association between being malnourished according to the ESPEN definition and clinically relevant outcome measures in geriatric outpatients. Associations between malnutrition and handgrip strength (HGS, kg), short physical performance battery (SPPB-score, points), timed up and go test (TUG, seconds), and hospital anxiety and depression scale (HADS depression score, points), were analysed using linear regression. History of falls (falls, yes/no) and a low score on the Mini Mental-State Examination (MMSE-score ≤ 24 points) were analysed using logistic regression. All analyses were adjusted for age and gender. A total of 185 geriatric outpatients (60% women) were included. The mean age was 82 (± 7.3) years. Being malnourished (8.2%) according to the ESPEN definition was significantly associated with a lower HGS (- 3.38 kg, p = 0.031), lower SPPB score (- 1.8 point, p = 0.025), higher TUG time (1.35 times higher time, p = 0.020) and higher HADS depression score (2.03 times higher score, p = 0.007). Being malnourished tended towards an association with falls (OR 3.84, p = 0.087). No significant association was found with low MMSE score (OR 2.61, p = 0.110). This study is the first to confirm the association between being malnourished, defined by the ESPEN definition and clinically relevant outcome measures in geriatric outpatients.


CHRNA3 rs1051730 genotype and short-term smoking cessation.
The rs1051730 genetic variant within the CHRNA5-A3-B4 gene cluster is associated with heaviness of smoking and has recently been reported to be associated with likelihood of stopping smoking. We investigated the potential association of rs1051730 genotype with reduced likelihood of smoking cessation in 2 cohorts of treatment-seeking smokers in primary care in the United Kingdom. Data were drawn from 2 clinical trials on which DNA was available. One sample was a randomized placebo-controlled trial of nicotine transdermal patch and the other sample an open-label trial where all participants received nicotine transdermal patch. Smoking status was biochemically verified. Logistic regression was used to assess evidence for association in each sample, and data were combined within a meta-analysis. There was evidence of association of rs1051730 genotype with short-term (4-week) cessation in our open-label trial sample but not our placebo-controlled trial sample. When combined in a meta-analysis, this effect remained. There was no evidence of association at later follow-up intervals. Adjustment for cigarette consumption and tobacco dependence did not alter these results substantially. Our data, taken together with previous recent studies, provide some support for a weak association between this variant and short-term smoking cessation in treatment-seeking smokers, which does not seem to operate only among those receiving nicotine replacement therapy. Moreover, the rs1051730 variant may not merely operate as a marker for dependence or heaviness of smoking.


Back to basics: HIV/AIDS belongs with sexual and reproductive health.
The Programme of Action of the International Conference on Population and Development (ICPD) held in Cairo in 1994 offers a comprehensive framework for achieving sexual and reproductive health and rights, including the prevention and treatment of HIV/AIDS, and for advancing other development goals. The United Nations Millennium Development Goals now incorporate a target of universal access to sexual and reproductive health within the goal of improving maternal health, but combating HIV remains a separate project with malaria and tuberculosis. We present a brief history of key decisions made by WHO, other United Nations' agencies, the United Nations Millennium Project and major donors that have led to the separation of HIV/AIDS from its logical programmatic base in sexual and reproductive health and rights. This fragmentation does a disservice to the achievement of both sets of goals and objectives. In urging a return to the original ICPD construct as a framework for action, we call for renewed leadership commitment, investment in health systems to deliver comprehensive sexual and reproductive health services, including HIV/AIDS prevention and treatment, comprehensive youth programmes, streamlined country strategies and donor support. All investments in research, policies and programmes should build systematically on the natural synergies inherent in the ICPD model to maximize their effectiveness and efficiency and to strengthen the capacity of health systems to deliver universally accessible sexual and reproductive health information and services.


Siderophore-independent acquisition of transferrin-bound iron by Haemophilus influenzae type b.
The specificity by which Haemophilus species acquired iron from transferrin (TF) was investigated. In a plate bioassay H. influenzae used iron bound to human, bovine and rabbit TFs but not mouse, rat, dog, horse, guinea-pig, pig or ovo- TFs or human and bovine lactoferrins. In contrast, H. pleuropneumoniae used iron only from pig TF whilst H. parainfluenzae was unable to utilize iron bound to any of the human or animal TFs tested. The inhibition of growth imposed on H. influenzae type b strain Eagan by the addition of the synthetic iron chelator EDDA to the culture medium was reversed by 30% iron-saturated human TF added directly to the medium but not when the TF was contained inside a dialysis bag. Dot-blotting of whole cells revealed that human TF bound to the surface of bacteria cultured in iron-restricted but not in iron-plentiful media. Incubation of whole bacterial cells in the presence of the proteolytic enzyme trypsin also abolished TF-binding activity, suggesting that the TF receptor was a protein. In competition dot blotting experiments, human and bovine but not rabbit, dog, mouse or guinea-pig TFs blocked the binding of a horseradish peroxidase--human TF conjugate. SDS-PAGE and Western blotting of outer membranes revealed the presence of a TF-binding protein of approximately 72 kDa. These results suggest that the acquisition of TF-bound iron by H. influenzae type b probably involves a direct interaction with an outer-membrane protein which shows some TF-species specificity.


PLD1 rather than PLD2 regulates phorbol-ester-, adhesion-dependent and Fc{gamma}-receptor-stimulated ROS production in neutrophils.
The signalling lipid phosphatidic acid (PA) is generated by the hydrolysis of phosphatidylcholine (PC), which is catalysed by phospholipase D (PLD) enzymes. Neutrophils, important cells of the innate immune system, maintain the body's defence against infection. Previous studies have implicated PLD-generated PA in neutrophil function; these have relied heavily on the use of primary alcohols to act as inhibitors of PA production. The recent development of isoform-selective small molecule inhibitors and the generation of a knockout mouse model provide us with accurate tools to study the role of PLDs in neutrophil responses. We show that PLD1 is a regulator of phorbol-ester-, chemoattractant, adhesion-dependent and Fcγ-receptor-stimulated production of reactive oxygen species (ROS) in neutrophils. Significantly we found that this role of PLD is isoform specific: the absence of PLD2 does not negatively affect these processes. Contrary to expectation, other functions required for an efficient immune response operate effectively in Pld2-deficient neutrophils or when both isoforms are inhibited pharmacologically. We conclude that although PLD1 does have important regulatory roles in neutrophils, the field has been confused by the use of primary alcohols; now that gold standard Pld-knockout mouse models are available, previous work might need to be reassessed.


Prediction of two month modified Rankin Scale with an ordinal prediction model in patients with aneurysmal subarachnoid haemorrhage.
Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with a frequently disabling outcome. Our aim was to develop a prognostic model to predict an ordinal clinical outcome at two months in patients with aSAH. We studied patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomized multicentre trial to compare coiling and clipping in aSAH patients.Several models were explored to estimate a patient's outcome according to the modified Rankin Scale (mRS) at two months after aSAH. Our final model was validated internally with bootstrapping techniques. The study population comprised of 2,128 patients of whom 159 patients died within 2 months (8%). Multivariable proportional odds analysis identified World Federation of Neurosurgical Societies (WFNS) grade as the most important predictor, followed by age, sex, lumen size of the aneurysm, Fisher grade, vasospasm on angiography, and treatment modality. The model discriminated moderately between those with poor and good mRS scores (c statistic = 0.65), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.64). We presented a calibrated and internally validated ordinal prognostic model to predict two month mRS in aSAH patients who survived the early stage up till a treatment decision. Although generalizability of the model is limited due to the selected population in which it was developed, this model could eventually be used to support clinical decision making after external validation. International Standard Randomised Controlled Trial, Number ISRCTN49866681.


Structure modification of a milk protein-based model food affects postprandial intestinal peptide release and fullness in healthy young men.
Physico-chemical and textural properties of foods in addition to their chemical composition modify postprandial metabolism and signals from the gastrointestinal tract. Enzymatic cross-linking of protein is a tool to modify food texture and structure without changing nutritional composition. We investigated the effects of structure modification of a milk protein-based model food and the type of milk protein used on postprandial hormonal, metabolic and appetitive responses. Healthy males (n 8) consumed an isoenergetic and isovolumic test product containing either whey protein (Wh, low-viscous liquid), casein (Cas, high-viscous liquid) or Cas protein cross-linked with transglutaminase (Cas-TG, rigid gel) in a randomised order. Blood samples were drawn for plasma glucose, insulin, cholecystokinin (CCK), glucagon-like peptide 1 and peptide YY analysis for 4 h. Appetite was assessed at concomitant time points. Cas and Wh were more potent in lowering postprandial glucose than Cas-TG during the first hour. Insulin concentrations peaked at 30 min, but the peaks were more pronounced for Cas and Wh than for Cas-TG. The increase in CCK was similar for Cas and Wh in the first 15 min, whereas for Cas-TG, the CCK release was significantly lower, but more sustained. The feeling of fullness was stronger after the consumption of Cas-TG than after the consumption of Cas and Wh. The present results suggest that food structure is more effective in modulating the postprandial responses than the type of dairy protein used. Modification of protein-based food structure could thus offer a possible tool for lowering postprandial glucose and insulin concentrations and enhancing postprandial fullness.


A Basic Phase Diagram of Neuronal Dynamics.
The extreme complexity of the brain has attracted the attention of neuroscientists and other researchers for a long time. More recently, the neuromorphic hardware has matured to provide a new powerful tool to study neuronal dynamics. Here, we study neuronal dynamics using different settings on a neuromorphic chip built with flexible parameters of neuron models. Our unique setting in the network of leaky integrate-and-fire (LIF) neurons is to introduce a weak noise environment. We observed three different types of collective neuronal activities, or phases, separated by sharp boundaries, or phase transitions. From this, we construct a rudimentary phase diagram of neuronal dynamics and demonstrate that a noise-induced chaotic phase (N-phase), which is dominated by neuronal avalanche activity (intermittent aperiodic neuron firing), emerges in the presence of noise and its width grows with the noise intensity. The dynamics can be manipulated in this N-phase. Our results and comparison with clinical data is consistent with the literature and our previous work showing that healthy brain must reside in the N-phase. We argue that the brain phase diagram with further refinement may be used for the diagnosis and treatment of mental disease and also suggest that the dynamics may be manipulated to serve as a means of new information processing (e.g., for optimization). Neuromorphic chips, similar to the one we used but with a variety of neuron models, may be used to further enhance the understanding of human brain function and accelerate the development of neuroscience research.


CDK6 is an essential direct target of NUP98 fusion proteins in acute myeloid leukemia.
Fusion proteins involving Nucleoporin 98 (NUP98) are recurrently found in acute myeloid leukemia (AML) and are associated with poor prognosis. Lack of mechanistic insight into NUP98-fusion-dependent oncogenic transformation has so far precluded the development of rational targeted therapies. We reasoned that different NUP98-fusion proteins deregulate a common set of transcriptional targets that might be exploitable for therapy. To decipher transcriptional programs controlled by diverse NUP98-fusion proteins, we developed mouse models for regulatable expression of NUP98/NSD1, NUP98/JARID1A, and NUP98/DDX10. By integrating chromatin occupancy profiles of NUP98-fusion proteins with transcriptome profiling upon acute fusion protein inactivation in vivo, we defined the core set of direct transcriptional targets of NUP98-fusion proteins. Among those, CDK6 was highly expressed in murine and human AML samples. Loss of CDK6 severely attenuated NUP98-fusion-driven leukemogenesis, and NUP98-fusion AML was sensitive to pharmacologic CDK6 inhibition in vitro and in vivo. These findings identify CDK6 as a conserved, critical direct target of NUP98-fusion proteins, proposing CDK4/CDK6 inhibitors as a new rational treatment option for AML patients with NUP98-fusions.


Regime Shift in an Exploited Fish Community Related to Natural Climate Oscillations.
Identifying the various drivers of marine ecosystem regime shifts and disentangling their respective influence are critical tasks for understanding biodiversity dynamics and properly managing exploited living resources such as marine fish communities. Unfortunately, the mechanisms and forcing factors underlying regime shifts in marine fish communities are still largely unknown although climate forcing and anthropogenic pressures such as fishing have been suggested as key determinants. Based on a 24-year-long time-series of scientific surveys monitoring 55 fish and cephalopods species, we report here a rapid and persistent structural change in the exploited fish community of the eastern English Channel from strong to moderate dominance of small-bodied forage fish species with low temperature preferendum that occurred in the mid-1990s. This shift was related to a concomitant warming of the North Atlantic Ocean as attested by a switch of the Atlantic Multidecadal Oscillation from a cold to a warm phase. Interestingly, observed changes in the fish community structure were opposite to those classically induced by exploitation as larger fish species of higher trophic level increased in abundance. Despite not playing a direct role in the regime shift, fishing still appeared as a forcing factor affecting community structure. Moreover, although related to climate, the regime shift may have been facilitated by strong historic exploitation that certainly primed the system by favoring the large dominance of small-bodied fish species that are particularly sensitive to climatic variations. These results emphasize that particular attention should be paid to multidecadal natural climate variability and its interactions with both fishing and climate warming when aiming at sustainable exploitation and ecosystem conservation.


Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma.
Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-development targets. NUPR1 is a multifunctional IDP, over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. By screening 1120 FDA-approved compounds, fifteen candidates were selected, and their interactions with NUPR1 were characterized by experimental and simulation techniques. The protein remained disordered upon binding to all fifteen candidates. These compounds were tested in PDAC-derived cell-based assays, and all induced cell-growth arrest and senescence, reduced cell migration, and decreased chemoresistance, mimicking NUPR1-deficiency. The most effective compound completely arrested tumor development in vivo on xenografted PDAC-derived cells in mice. Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC, our study proves the possibility to target the 'fuzzy' interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs.


Surface biopassivation of replicated poly(dimethylsiloxane) microfluidic channels and application to heterogeneous immunoreaction with on-chip fluorescence detection.
Poly(dimethylsiloxane) (PDMS) appeared recently as a material of choice for rapid and accurate replication of polymer-based microfluidic networks. However, due to its hydrophobicity, the surface strongly interacts with apolar analytes or species containing apolar domains, resulting in significant uncontrolled adsorption on channel walls. This contribution describes the application and characterization of a PDMS surface treatment that considerably decreases adsorption of low and high molecular mass substances to channel walls while maintaining a modest cathodic electroosmotic flow. Channels are modified with a three-layer biotin-neutravidin sandwich coating, made of biotinylated IgG, neutravidin, and biotinylated dextran. By replacing biotinylated dextran with any biotinylated reagent, the modified surface can be readily patterned with biochemical probes, such as antibodies. Combination of probe immobilization chemistry with low nonspecific binding enables affinity binding assays within channel networks. The example of an electrokinetic driven, heterogeneous immunoreaction for human IgG is described.


Extensive Mobilome-Driven Genome Diversification in Mouse Gut-Associated Bacteroides vulgatus mpk.
Like many other Bacteroides species, Bacteroides vulgatus strain mpk, a mouse fecal isolate which was shown to promote intestinal homeostasis, utilizes a variety of mobile elements for genome evolution. Based on sequences collected by Pacific Biosciences SMRT sequencing technology, we discuss the challenges of assembling and studying a bacterial genome of high plasticity. Additionally, we conducted comparative genomics comparing this commensal strain with the B. vulgatus type strain ATCC 8482 as well as multiple other Bacteroides and Parabacteroides strains to reveal the most important differences and identify the unique features of B. vulgatus mpk. The genome of B. vulgatus mpk harbors a large and diverse set of mobile element proteins compared with other sequenced Bacteroides strains. We found evidence of a number of different horizontal gene transfer events and a genome landscape that has been extensively altered by different mobilization events. A CRISPR/Cas system could be identified that provides a possible mechanism for preventing the integration of invading external DNA. We propose that the high genome plasticity and the introduced genome instabilities of B. vulgatus mpk arising from the various mobilization events might play an important role not only in its adaptation to the challenging intestinal environment in general, but also in its ability to interact with the gut microbiota.


A universal algorithm for genome-wide in silicio identification of biologically significant gene promoter putative cis-regulatory-elements; identification of new elements for reactive oxygen species and sucrose signaling in Arabidopsis.
Short motifs of many cis-regulatory elements (CREs) can be found in the promoters of most Arabidopsis genes, and this raises the question of how their presence can confer specific regulation. We developed a universal algorithm to test the biological significance of CREs by first identifying every Arabidopsis gene with a CRE and then statistically correlating the presence or absence of the element with the gene expression profile on multiple DNA microarrays. This algorithm was successfully verified for previously characterized abscisic acid, ethylene, sucrose and drought responsive CREs in Arabidopsis, showing that the presence of these elements indeed correlates with treatment-specific gene induction. Later, we used standard motif sampling methods to identify 128 putative motifs induced by excess light, reactive oxygen species and sucrose. Our algorithm was able to filter 20 out of 128 novel CREs which significantly correlated with gene induction by either heat, reactive oxygen species and/or sucrose. The position, orientation and sequence specificity of CREs was tested in silicio by analyzing the expression of genes with naturally occurring sequence variations. In three novel CREs the forward orientation correlated with sucrose induction and the reverse orientation with sucrose suppression. The functionality of the predicted novel CREs was experimentally confirmed using Arabidopsis cell-suspension cultures transformed with short promoter fragments or artificial promoters fused with the GUS reporter gene. Our genome-wide analysis opens up new possibilities for in silicio verification of the biological significance of newly discovered CREs, and allows for subsequent selection of such CREs for experimental studies.


Proapoptotic kinase MST2 coordinates signaling crosstalk between RASSF1A, Raf-1, and Akt.
Mammalian MST kinases function in stress-induced apoptosis to limit tumor progression. However, there is limited understanding about MST2 control by key regulators of cell division and survival. Raf-1 binds and inhibits MST2 kinase, whereas dissociation from Raf-1 and binding to tumor suppressor protein RASSF1A activates MST2. Akt phosphorylates MST2 in response to mitogens, oncogenic Ras, or depletion of tumor suppressor phosphatase and tensin homologue deleted on chromosome 10. We identified T117 and T384 as Akt phosphorylation sites in MST2. Mutation of these sites inhibited MST2 binding to Raf-1 kinase but enhanced binding to tumor suppressor RASSF1A, accentuating downstream c-Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinase signaling and promoting apoptosis. We determined that MST2 phosphorylation by Akt limits MST2 activity in two ways: first, by blocking its binding to RASSF1A and by promoting its association into the Raf-1 inhibitory complex, and second, by preventing homodimerization of MST2, which is needed for its activation. Dissociation of the Raf-1-MST2 complex promoted mitogenic signaling and coordinately licensed apoptotic risk. Using Ras effector domain mutants, we found that Akt is essential to prevent MST2 activation after mitogenic stimulation. Our findings elucidate how MST2 serves as a hub to integrate biological outputs of the Raf-1 and Akt pathways.


Accurate variant detection across non-amplified and whole genome amplified DNA using targeted next generation sequencing.
Many hypothesis-driven genetic studies require the ability to comprehensively and efficiently target specific regions of the genome to detect sequence variations. Often, sample availability is limited requiring the use of whole genome amplification (WGA). We evaluated a high-throughput microdroplet-based PCR approach in combination with next generation sequencing (NGS) to target 384 discrete exons from 373 genes involved in cancer. In our evaluation, we compared the performance of six non-amplified gDNA samples from two HapMap family trios. Three of these samples were also preamplified by WGA and evaluated. We tested sample pooling or multiplexing strategies at different stages of the tested targeted NGS (T-NGS) workflow. The results demonstrated comparable sequence performance between non-amplified and preamplified samples and between different indexing strategies [sequence specificity of 66.0% ± 3.4%, uniformity (coverage at 0.2× of the mean) of 85.6% ± 0.6%]. The average genotype concordance maintained across all the samples was 99.5% ± 0.4%, regardless of sample type or pooling strategy. We did not detect any errors in the Mendelian patterns of inheritance of genotypes between the parents and offspring within each trio. We also demonstrated the ability to detect minor allele frequencies within the pooled samples that conform to predicted models. Our described PCR-based sample multiplex approach and the ability to use WGA material for NGS may enable researchers to perform deep resequencing studies and explore variants at very low frequencies and cost.


α-Satellite: An AI-Driven System and Benchmark Datasets for Dynamic COVID-19 Risk Assessment in the United States.
The fast evolving and deadly outbreak of coronavirus disease (COVID-19) has posed grand challenges to human society. To slow the spread of virus infections and better respond for community mitigation, by advancing capabilities of artificial intelligence (AI) and leveraging the large-scale and up-to-date data generated from heterogeneous sources (e.g., disease related data, demographic, mobility and social media data), in this work, we propose and develop an AI-driven system (named α-Satellite), as an initial offering, to provide dynamic COVID-19 risk assessment in the United States. More specifically, given a point of interest (POI), the system will automatically provide risk indices associated with it in a hierarchical manner (e.g., state, county, POI) to enable people to select appropriate actions for protection while minimizing disruptions to daily life. To comprehensively evaluate our system for dynamic COVID-19 risk assessment, we first conduct a set of empirical studies; and then we validate it based on a real-world dataset consisting of 5,060 annotated POIs, which achieves the area of under curve (AUC) of 0.9202. As of June 18, 2020, α-Satellite has had 56,980 users. Based on the feedback from its large-scale users, we perform further analysis and have three key findings: i) people from more severe regions (i.e., with larger numbers of COVID-19 cases) have stronger interests using our system to assist with actionable information; ii) users are more concerned about their nearby areas in terms of COVID-19 risks; iii) the user feedback about their perceptions towards COVID-19 risks of their query POIs indicate the challenge of public concerns about the safety versus its negative effects on society and the economy. Our system and generated datasets have been made publicly accessible via our website.


Replication competent HIV-1 viruses that express intragenomic microRNA reveal discrete RNA-interference mechanisms that affect viral replication.
It remains unclear whether retroviruses can encode and express an intragenomic microRNA (miRNA). Some have suggested that processing by the Drosha and Dicer enzymes might preclude the viability of a replicating retroviral RNA genome that contains a cis-embedded miRNA. To date, while many studies have shown that lentiviral vectors containing miRNAs can transduce mammalian cells and express the inserted miRNA efficiently, no study has examined the impact on the replication of a lentivirus such as HIV-1 after the deliberate intragenomic insertion of a bona fide miRNA. We have constructed several HIV-1 molecular clones, each containing a discrete cellular miRNA positioned in Nef. These retroviral genomes express the inserted miRNA and are generally replication competent in T-cells. The inserted intragenomic miRNA was observed to elicit two different consequences for HIV-1 replication. First, the expression of miRNAs with predicted target sequences in the HIV-1 genome was found to reduce viral replication. Second, in one case, where an inserted miRNA was unusually well-processed by Drosha, this processing event inhibited viral replication. This is the first study to examine in detail the replication competence of HIV-1 genomes that express cis-embedded miRNAs. The results indicate that a replication competent retroviral genome is not precluded from encoding and expressing a viral miRNA.


Comparison of a bioimpedance monitor with dual-energy x-ray absorptiometry for noninvasive estimation of percentage body fat in dogs.
To assess performance of a portable bioimpedance monitor for measurement of body composition in dogs. 24 client-owned dogs. Percentage body fat was measured via dual-energy x-ray absorptiometry (DEXA) and with a portable bioimpedance monitor, and body condition score (BCS) was measured by use of a 9-integer scale. Although the precision of the bioimpedance monitor was good, this varied among dogs. Body position (standing vs sternal) had no effect on bioimpedance results. There was a significant association between results determined via DEXA and bioimpedance, but this association was weaker than between DEXA and BCS. When agreement was assessed via Bland-Altman plot, the bioimpedance monitor under- and overestimated values at high and low body fat percentages, respectively. In 9 dogs, body fat measurements were taken before and after weight loss to determine the proportional loss of tissue mass during weight management. There was a significant difference in the estimated percentage of weight lost as fat between the DEXA and bioimpedance methods. Although percentage body fat measured by use of a portable bioimpedance monitor correlated well with values determined via DEXA, the imprecision and inaccuracy in dogs with high percentage body fat could make the monitor inappropriate for clinical practice.


Effective immobilization of glucose oxidase on chitosan submicron particles from gladius of Todarodes pacificus for glucose sensing.
An effective enzymatic glucose biosensor was developed by immobilizing glucose oxidase on chitosan submicron particles synthesized from the gladius of Todarodes pacificus (GCSP). The chemically synthesized chitosan from gladius was pulverized to submicron particles by ball milling technique, which was further characterized and compared with the standard chitosan (SCS). The degree of deacetylation of GCSP was determined using FTIR spectroscopy which was comparable to the value of standard chitosan. The glucose oxidase (GOx) was immobilized over GCSP on porous zinc oxide/platinum nanoparticle (ZnO/Pt) based electrode. The morphological and structural properties of the electrodes were analyzed using scanning electron microscopy and X-ray diffraction analysis. The glucose sensing behavior of electrode was estimated using electrochemical analysis and showed an excellent analytical performance. The electrode ZnO/Pt/GCSP conjugated with GOx displayed high sensitivity (88.76 μA mM(-1) cm(-2)) with low detection limit in short response time. In addition, the very low value of Michaelis-Menten constant for GCSP based electrode contributes a better affinity of the electrode surface towards glucose oxidase.


Hearts with concordant ventriculoarterial connections but parallel arterial trunks.
To determine the characteristic morphological features of hearts with concordant ventriculoarterial connections and parallel arterial trunks, and to provide unequivocally a method to describe their anatomy. DESIGN, METHODS AND PATIENTS: The entire cardiac database and cardiac pathological archive at the Hospital for Sick Children, Toronto, Ontario, Canada, was interrogated to identify all patients with concordant ventriculoarterial connections and parallel arterial trunks. The clinical records, autopsy reports and actual cardiac specimens of those who underwent autopsy, were reviewed. 8 cases meeting our criteria were identified. The infundibular anatomy was variable, including four hearts with bilateral infundibulums, three with subpulmonary infundibulums and one with bilaterally absent infundibulums. Considerable variability was also found in the type of atrial arrangement, along with the morphology of the atrioventricular junctions. The most common findings were the usual atrial arrangement (n = 5), left juxtaposition of the right atrial appendages (n = 3), an atrial septal defect (n = 6), univentricular atrioventricular connection (n = 5), ventricular septal defect (n = 8) and pulmonary obstruction (n = 4). In addition, five specimens had either a single coronary artery or two coronary arteries arising from the anticipated right coronary aortic sinus. Concordant ventriculoarterial connections with parallel arterial trunks can be found in a variety of segmental combinations. An accurate diagnosis of these rare hearts can be achieved by detailed analysis of not only the ventriculoarterial connections but also the infundibular anatomy and the spatial relationship of the arterial trunks. Particular attention to the coronary arteries is warranted.