The ColonView (CV) Quick Test for Fecal Occult Blood Shows Significantly Higher Diagnostic Accuracy in Detecting Distal than Proximal Colorectal Cancer.
The present study compared the accuracy of ColonView (CV) quick test in detecting proximal versus distal colorectal cancer (CRC). A traditional guaiac-based fecal occult blood test (gFOBT) (Hemoccult SENSA) was used as a reference. A cohort of 368 colonoscopy-referral patients were asked to collect 3 consecutive fecal samples, to be analyzed by both assays (CV, SENSA). Receiver operating characteristic (ROC) analysis was used to find the optimal cut-off values for both Hb and Hb/Hp of the CV test. Summary hierarchical ROC (HSROC) curves were used to visualize the pooled overall accuracy of visually analysed (VA) and automatically analyzed (AA) reading modes in proximal and distal CRC detection. The overall specificity (Sp) of the AA reading mode for the proximal CRC and distal CRC endpoint was 73% and 76%, respectively. For proximal CRC, the two most sensitive AA tests showed 90% sensitivity (Se), while for distal CRC, the two most sensitive AA tests showed 100% Se. In the HSROC analysis, the AUC values were as follows: i) VA in proximal CRC: 0.765, ii) AA in proximal CRC: 0.878, iii) VA in distal CRC: 0.955 and iv) AA in distal CRC: 0.961. In roccomp analysis, AUC values were significantly different in: VA vs. AA in proximal CRC p=0.009; VA in proximal vs. VA in distal CRC p<0.0001; VA in proximal vs. AA in distal CRC p<0.0001; AA in proximal vs. VA in distal CRC p=0.021; AA in proximal CRC vs. AA in distal CRC p=0.006. The applicability of the CV test (a new-generation FIT) in CRC screening was confirmed. The AA reading was superior to VA (or SENSA) in its diagnostic accuracy in detecting proximal CRC patients. Distal CRCs were more accurately detected than proximal CRCs by both reading modes.


Structure-activity relationships and dose responses of polychlorinated dibenzo-p-dioxins for short-term effects in 2,3,7,8-tetrachlorodibenzo-p-dioxin-resistant and -sensitive rat strains.
Dose responses of the characteristic short-term effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (HxCDD), and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) were compared in the resistant Han/Wistar (Kuopio) (H/W) rats and the sensitive Long-Evans (Turku/AB) (L-E) rats. The resistance of H/W rats is linked to the altered H/W-type aryl hydrocarbon receptor (AHR). Exceptionally, in terms of acute lethality, the most potent congener for H/W rats is HxCDD, followed by HpCDD, PeCDD, and TCDD. The study objectives were to find out if this exceptional sensitivity of H/W rats also holds for nonlethal toxic endpoints and to compare potency and efficacy (magnitude of effect) of PCDDs between L-E and H/W rats. Dose responses for several endpoints were determined, modeled, and used for ED50 and relative potency (REP) calculations. For all endpoints measured, TCDD was the most potent congener, followed by PeCDD, HxCDD, and HpCDD in both strains, and the REP estimates were consistent with the current toxic equivalency factors (TEFs). For most endpoints, H/W rats showed smaller responses to all congeners than L-E rats, and this difference was due to lower efficacy rather than lower potency. H/W rats showed lower efficacy to body weight loss, serum aspartate aminotransferase activity, and serum concentrations of total bilirubin, free fatty acids, and thyroxine. In contrast, effects on cytochrome P4501A1 induction, thymus atrophy, and dental defects were similar in both strains. In conclusion, the results are in agreement with the current WHO-TEFs and imply that relative potency values derived from mortality are not necessarily valid for other endpoints. The results support our previous observations about two different types of AHR-mediated mechanisms. Type I effects are similar in both strains, and type II effects show decreased efficacy of toxic response in relation with the altered H/W-type AHR.


Risk factors for radiation pneumonitis after stereotactic radiation therapy for lung tumours: clinical usefulness of the planning target volume to total lung volume ratio.
To identify risk factors for symptomatic radiation pneumonitis (RP) after stereotactic radiation therapy (SRT) for lung tumours. We retrospectively evaluated 68 lung tumours in 63 patients treated with SRT between 2011 and 2015. RP was graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.0. SRT was delivered at 7.0-12.0 Gy per each fraction, once daily, to a total of 48-64 Gy (median, 50 Gy). Univariate analysis was performed to assess patient- and treatment-related factors, including age, sex, smoking index (SI), pulmonary function, tumour location, serum Krebs von den Lungen-6 value (KL-6), dose-volume metrics (V5, V10, V20, V30, V40 and VS5), homogeneity index of the planning target volume (PTV), PTV dose, mean lung dose (MLD), contralateral MLD and V2, PTV volume, lung volume and the PTV/lung volume ratio (PTV/Lung). Performance of PTV/Lung in predicting symptomatic RP was also analysed using receiver operating characteristic (ROC) analysis. The median follow-up period was 21 months. 10 of 63 patients (15.9%) developed symptomatic RP after SRT. On univariate analysis, V10, V20, PTV volume and PTV/Lung were significantly associated with occurrence of RP ≥Grade 2. ROC curves indicated that symptomatic RP could be predicted using PTV/Lung [area under curve (AUC): 0.88, confidence interval (CI: 0.78-0.95), cut-off value: 1.09, sensitivity: 90.0% and specificity: 72.4%]. PTV/Lung is a good predictor of symptomatic RP after SRT. Advances in knowledge: The cases with high PTV/Lung should be carefully monitored with caution for the occurrence of RP after SRT.


Use of Thiopurines During Conception and Pregnancy Is Not Associated With Adverse Pregnancy Outcomes or Health of Infants at One Year in a Prospective Study.
Most data on the safety of thiopurine therapy for inflammatory bowel disease (IBD) during pregnancy come from retrospective studies, which makes it difficult to adjust for confounding factors. We performed a prospective cohort study to determine whether thiopurine use affects pregnancy outcomes or health outcomes of children. We performed a prospective study of all women who visited the IBD preconception outpatient clinic at our tertiary health center in The Netherlands from December 2008 through May 2016. Patients were counseled before pregnancy and seen bimonthly during pregnancy. We collected and analyzed data on medication use, as well as lifestyle and clinical factors, during conception and pregnancy. Pregnancy outcomes (live birth, spontaneous abortion, elective abortion, and stillbirth), birth outcomes (gestational age, birth weight, and congenital abnormalities), and health outcomes of infants 1 year after birth were compared between women who did and did not use a thiopurine during conception and pregnancy. In addition, health outcomes of infants 1 year after birth were compared with infants born to mothers without IBD from the same geographic region. Our study comprised 309 women with confirmed IBD (216 with Crohn's disease, 85 with ulcerative colitis, and 8 with IBD unclassified). During the study period, 311 pregnancies of 232 women resulted in a live birth; a thiopurine was used during 108 pregnancies (35%). After correction for diagnosis, fertility treatment, and disease activity, there was no association between thiopurine use and spontaneous abortions. Birth outcomes were similar between women who did and did not use a thiopurine. Among infants 1 year of age, there were no differences in median growth, number of infections, allergies, adverse reactions to vaccinations, or chronic diseases between those born to women who did and did not use a thiopurine or between women with and without IBD. In this prospective cohort study, we found no association between maternal thiopurine use during pregnancy and increased spontaneous abortions, adverse birth outcomes, or adverse health outcomes of infants 1 year after birth.


Butyrate and glucose metabolism in isolated colonocytes in the developing rat colon.
The newborn colon is devoid of microflora, in that bacterial colonization is established after birth. Short chain fatty acids, products of bacterial fermentation, are the major energy source for colonocytes. Because it is not known whether colonocytes in the newborn can metabolize butyrate, this was examined in newborn and infant rat colon. Isolated colonocytes from rats of different perinatal ages were incubated with 14C-labeled butyrate or glucose in vitro. Complete oxidation was estimated by the production of 14C-labeled carbon dioxide, whereas intermediate metabolites were measured enzymatically. Oxidation of butyrate (in micromoles per hour per milligram of protein) was highest in newborns (5.83+/-1.76), declining to 1.32+/-0.28 at day 10 and to 0.34+/-0.04 in adult rats. Glucose oxidation was also highest at birth (0.39+/-0.23), with a minor increase at approximately day 20 (weaning period) before decreasing to adult levels (0.05+/-0). Butyrate oxidation was substantially higher than was glucose oxidation in all age groups. Production of metabolic intermediates paralleled substrate oxidation. Acetoacetate production was 4.35+/-2.68, 2.07+/-1.29, and 0.27+/-0.09 nmol/hr per milligram of protein in newborns, at postnatal day 10, and in adults, respectively. The corresponding values for beta-hydroxybutyrate were 3.62+/-3.35, 0.2+/-0.07, and 0.09+/-0.03 nmol/hr per milligram of protein; and L-lactate production was 0.54+/-0.52, 0.06+/-0.04, and 0.02+/-0 micromol/hr per milligram of protein respectively. Neonatal rat colon epithelial cells resemble adult colonocytes in their preference for butyrate as a metabolic substrate, indicating a constitutive expression of this property.


High-Intensity Interval Training Performed by Young Athletes: A Systematic Review and Meta-Analysis.
Background: High-intensity interval training (HIIT) is as a time-efficient alternative to moderate- or low-intensity continuous exercise for improving variables related to endurance and anaerobic performance in young and adolescent athletes. Objectives: To assess original research about enhancement of endurance and anaerobic exercise performance in young and adolescent athletes performing HIIT. Method: Relevant articles published in peer-reviewed journals were retrieved from the electronic databases PubMed and SPORTDiscus in December 2017. Inclusion criteria were: (i) controlled trials (HIIT vs. alternative training protocol) with pre-post design; (ii) healthy young athletes (≤18 years); (iii) assessing variables related to endurance and exercise performance. Hedges' g effect size (ES), and associated 95% confidence intervals were calculated for comparison of any outcome between experimental (HIIT) and alternative training protocol. Results: Twenty four studies, involving 577 athletes (mean age: 15.5 ± 2.2 years), were included in this review. HIIT exerted no or small positive mean ES on peak oxygen uptake (VO2peak), running performance, repeated sprint ability, jumping performance and submaximal heart rate. Although the mean ES for changes in VO2peak with HIIT is small (mean g = 0.10±0.28), the average increase in VO2peak from pre to post HIIT-interventions were 7.2 ± 6.9% vs. 4.3 ± 6.9% with any other alternative intervention. HIIT largely and positively affected running speed and oxygen consumption at various lactate- or ventilatory-based thresholds, as well as for sprint running performance. Calculations showed negative mean ES for change-of-direction ability (large), and peak blood lactate concentrations (small). Mean duration per training session for HIIT was shorter than for control interventions (28 ± 15 min vs. 38 ± 24 min). Conclusion: The present findings suggest that young athletes performing HIIT may improve certain important variables related to aerobic, as well as anaerobic, performance. With HIIT, most variables related to endurance improved to a higher extent, compared to alternative training protocols. However, based on ES, HIIT did not show clear superiority to the alternative training protocols. Nevertheless, young athletes may benefit from HIIT as it requires less time per training session leaving more time for training sport specific skills.


Enhancing image contrast of carbon nanotubes on cellular background using helium ion microscope by varying helium ion fluence.
Carbon nanotubes (CNTs) have become an important nano entity for biomedical applications. Conventional methods of their imaging, often cannot be applied in biological samples due to an inadequate spatial resolution or poor contrast between the CNTs and the biological sample. Here we report a unique and effective detection method, which uses differences in conductivities of carbon nanotubes and HeLa cells. The technique involves the use of a helium ion microscope to image the sample with the surface charging artefacts created by the He+ and neutralised by electron flood gun. This enables us to obtain a few nanometre resolution images of CNTs in HeLa Cells with high contrast, which was achieved by tailoring the He+ fluence. Charging artefacts can be efficiently removed for conductive CNTs by a low amount of electrons, the fluence of which is not adequate to discharge the cell surface, resulting in high image contrast. Thus, this technique enables rapid detection of any conducting nano structures on insulating cellular background even in large fields of view and fine spatial resolution. The technique demonstrated has wider applications for researchers seeking enhanced contrast and high-resolution imaging of any conducting entity in a biological matrix - a commonly encountered issue of importance in drug delivery, tissue engineering and toxicological studies.


Anti-Swelling, Robust, and Adhesive Extracellular Matrix-Mimicking Hydrogel Used as Intraoral Dressing.
Due to the wet and dynamic environment of the oral cavity, the healing of intraoral wounds, such as tooth extraction wounds, requires stable and firm wound dressings. In clinical practice, cotton balls and gauzes, sponge plugs, or sutures are used to treat extraction wounds, but none of these means can continuously isolate the wound from the intraoral environment and facilitate ideal healing conditions. Herein, inspired by the natural extracellular matrix, a family of wound dressings is developed for intraoral wound repair. Infiltrating a ductile long-chain hydrogel network into a prefabricated, sturdy macromolecular meshwork and in situ crosslinking endowed the composite hydrogel with controllable swelling behaviors and robust mechanical properties. The macromolecular meshwork functioned as the backbone to support the composite and restricts the swelling of the long-chain hydrogel network. In vitro tests verified that this wound dressing can provide durable protection for intraoral wounds against complex irritations. Furthermore, accelerated wound healing occurred when the wound dressing is applied in vivo on a canine tooth extraction model, due to the effective reduction of acute inflammation. These results suggest that this family of bioinspired hydrogels has great potential for application as intraoral wound dressing.


Effect of lipopolysaccharide on angiotensin II type 1 receptor expression and function in human pulmonary microvascular endothelial cells.
Lipopolysaccharides (LPSs) are an important initiation factor in acute respiratory distress syndrome. The aim of the present study was to investigate the effect of LPSs on the regulation of angiotensin II (Ang II) receptors in human pulmonary microvascular endothelial cells (HPMECs). HPMECs were treated with 0, 50, 100 or 200 ng/ml LPS and incubated for 4, 8, 12 or 16 h. The expression of Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R) was determined using reverse transcription‑polymerase chain reaction and western blot analysis. The affinity to Ang II was measured using a radioligand binding assay. No AT2R expression was detected with or without LPS administration in HPMECs, and LPS treatment increased the expression level of AT1R. A time‑dependent increase of AT1R transcription was observed in the 50 ng/ml group, while in the 100 and 200 ng/ml groups, the AT1R mRNA levels reached peak values at 4 h and remained unchanged. The protein level of AT1R increased significantly in a dose‑dependent manner for each incubation time period. A time‑dependent increase in the protein level was observed in the 50 and 100 ng/ml groups. As for the 200 ng/ml group, the level of AT1R reached a peak value at 8 h. Maximal binding (Bmax) significantly increased following LPS treatment and Bmax of the 50 ng/ml group exhibited a time‑dependent increase. The Bmax of the 100 and 200 ng/ml groups reached peak values at 12 and 8 h, respectively, and decreased thereafter. The dissociation constant remained unchanged following LPS treatment. Thus, treatment with LPS increased AT1R expression and its Bmax to Ang II in HPMECs, however, did not alter the affinity of AT1R to Ang II.


Contemporary avian influenza A virus subtype H1, H6, H7, H10, and H15 hemagglutinin genes encode a mammalian virulence factor similar to the 1918 pandemic virus H1 hemagglutinin.
Zoonotic avian influenza virus infections may lead to epidemics or pandemics. The 1918 pandemic influenza virus has an avian influenza virus-like genome, and its H1 hemagglutinin was identified as a key mammalian virulence factor. A chimeric 1918 virus expressing a contemporary avian H1 hemagglutinin, however, displayed murine pathogenicity indistinguishable from that of the 1918 virus. Here, isogenic chimeric avian influenza viruses were constructed on an avian influenza virus backbone, differing only by hemagglutinin subtype expressed. Viruses expressing the avian H1, H6, H7, H10, and H15 subtypes were pathogenic in mice and cytopathic in normal human bronchial epithelial cells, in contrast to H2-, H3-, H5-, H9-, H11-, H13-, H14-, and H16-expressing viruses. Mouse pathogenicity was associated with pulmonary macrophage and neutrophil recruitment. These data suggest that avian influenza virus hemagglutinins H1, H6, H7, H10, and H15 contain inherent mammalian virulence factors and likely share a key virulence property of the 1918 virus. Consequently, zoonotic infections with avian influenza viruses bearing one of these hemagglutinins may cause enhanced disease in mammals. Influenza viruses from birds can cause outbreaks in humans and may contribute to the development of pandemics. The 1918 pandemic influenza virus has an avian influenza virus-like genome, and its main surface protein, an H1 subtype hemagglutinin, was identified as a key mammalian virulence factor. In a previous study, a 1918 virus expressing an avian H1 gene was as virulent in mice as the reconstructed 1918 virus. Here, a set of avian influenza viruses was constructed, differing only by hemagglutinin subtype. Viruses with the avian H1, H6, H7, H10, and H15 subtypes caused severe disease in mice and damaged human lung cells. Consequently, infections with avian influenza viruses bearing one of these hemagglutinins may cause enhanced disease in mammals, and therefore surveillance for human infections with these subtypes may be important in controlling future outbreaks.


SPANNER: A Self-Repairing Spiking Neural Network Hardware Architecture.
Recent research has shown that a glial cell of astrocyte underpins a self-repair mechanism in the human brain, where spiking neurons provide direct and indirect feedbacks to presynaptic terminals. These feedbacks modulate the synaptic transmission probability of release (PR). When synaptic faults occur, the neuron becomes silent or near silent due to the low PR of synapses; whereby the PRs of remaining healthy synapses are then increased by the indirect feedback from the astrocyte cell. In this paper, a novel hardware architecture of Self-rePAiring spiking Neural NEtwoRk (SPANNER) is proposed, which mimics this self-repairing capability in the human brain. This paper demonstrates that the hardware can self-detect and self-repair synaptic faults without the conventional components for the fault detection and fault repairing. Experimental results show that SPANNER can maintain the system performance with fault densities of up to 40%, and more importantly SPANNER has only a 20% performance degradation when the self-repairing architecture is significantly damaged at a fault density of 80%.


Sensor-augmented pump therapy in very young children with type 1 diabetes: an efficacy and feasibility observational study.
Efficacy and feasibility of sensor-augmented pump (SAP) therapy were evaluated in very young children with type 1 diabetes (T1D). SAP (Dexcom [San Diego, CA] Seven Plus™ usage combined with insulin pump) therapy was retrospectively evaluated in 28 children (15 boys) younger than 7 years (mean age, 5.8 ± 1.2 years; range, 3-7 years), with T1D. Glycosylated hemoglobin (HbA1c) was evaluated at baseline and at the end of the study, as were efficacy and feasibility of the system, using a rating scale (with 3 being the most positive). SAP has been used for at least 6 months by 85% of patients, with an overall good satisfaction (92%). The greatest perceived benefit was the reduced fear of hypoglycemia (score of 3, 81%). HbA1c significantly improved only in patients with baseline HbA1c >7.5% (P = 0.026). SAP therapy is effective and feasible in preschool children with T1D. In patients with high HbA1c at baseline it provide a 0.9% decrease, sustained for at least 6 months.


Stereoselective formations of K-region and non-K-region epoxides in the metabolism of chrysene by rat liver microsomal cytochrome P-450 isozymes.
The K-region 5,6-epoxide and non-K-region 1,2- and 3,4-epoxides of chrysene were isolated by normal phase high performance liquid chromatography (HPLC) from a mixture of products formed in the metabolism of chrysene by liver microsomes from untreated (control), phenobarbital-treated, or 3-methylcholanthrene-treated rats in the presence of an epoxide hydrolase inhibitor, 3,3,3-trichloropropylene 1,2-oxide. Epoxides were characterized by ultraviolet, mass, and circular dichroism spectral and chiral stationary phase HPLC analyses. Each of the metabolically formed epoxides was hydrated by rat liver microsomal epoxide hydrolase to a trans-dihydrodiol. The metabolically formed chrysene 5,6-epoxides were determined by chiral stationary phase HPLC and were found to contain (5S,6R):(5R,6S) enantiomer ratios of 68:32 (control), 71:29 (phenobarbital), and 5:95 (3-methylcholanthrene), respectively. The enantiomers of chrysene 1,2-epoxide and 3,4-epoxide were also resolved by chiral stationary phase HPLC. However, the enantiomeric compositions of the metabolically formed chrysene 1,2- and 3,4-epoxides, which racemized rapidly at room temperature, could not be directly determined. By using molecular oxygen-18 in the in vitro incubation of chrysene and by mass spectral analyses of the resulting oxygen-18-containing dihydrodiol metabolites and their acid-catalyzed dehydration (phenolic) products, both 1,2-epoxide and 3,4-epoxide were found to be converted by microsomal epoxide hydrolase-catalyzed water attack at predominantly (greater than or equal to 97%) the allylic carbons.


Does PPARγ2 gene Pro12Ala polymorphism affect nonalcoholic fatty liver disease risk? Evidence from a meta-analysis.
Genetic factors can substantially contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A missense Pro12Ala substitution in the PPARγ2 gene (rs1801282) has been studied in relation with NAFLD risk in different ethnic groups, but findings have been inconclusive. The aim of this was to evaluate the association between rs1801282 and NAFLD through meta-analysis of all relevant published evidence. A systematic search to find eligible studies was performed in Medline, HuGE Navigator, and SCOPUS databases. The strength of association was evaluated using odds ratios with 95% confidence intervals obtained from a random effect approach and under additive, dominant, co-dominant, recessive, and allelic contrast models. Seven studies comprising 1474 cases and 2259 controls met the eligibility criteria and included in the meta-analysis. Combined results did not indicate any predisposing or protective effect for rs1801282 under any of the assessed modes of inheritance. The rate of heterogeneity was generally high due to the inter-study variations in terms of age, gender, and ethnicity. Evidence from the current meta-analysis indicated that rs1801282 variants are not associated with NAFLD risk. Future large-scale studies are required to substantiate the present findings.


The value of liver resection for focal nodular hyperplasia: resection yes or no?
Focal nodular hyperplasia (FNH) are benign lesions in the liver. Although liver resection is generally not indicated in these patients, rare indications for surgical approaches indeed exist. We here report on our single-center experience with patients undergoing liver resection for FNH, focussing on preoperative diagnostic algorithms and quality of life (QoL) after surgery. Medical records of 100 consecutive patients undergoing liver resection for FNH between 1992 and 2012 were retrospectively analyzed with regard to diagnostic pathways and indications for surgery. Quality of life (QoL) before and after surgery was evaluated using validated assessment tools. Student's t test, one-way ANOVA, χ (2), and binary logistic regression analyses such as Wilcoxon-Mann-Whitney test were used, as indicated. A combination of at least two preoperative diagnostic imaging approaches was applied in 99 cases, of which 70 patients were subjected to further imaging or tumor biopsy. In most patients, there was more than one indication for liver resection, including tumor-associated symptoms with abdominal discomfort (n = 46, 40.7 %), balance of risk for malignancy/history of cancer (n = 54, 47.8 %/n = 18; 33.3 %), tumor enlargement/jaundice of vascular and biliary structures (n = 13, 11.5 %), such as incidental findings during elective operation (n = 1, 0.9 %). Postoperative morbidity was 19 %, with serious complications (>grade 2, Clavien-Dindo classification) being evident in 8 %. Perioperative mortality was 0 %. Liver resection was associated with a significant overall improvement in general health (very good-excellent: preoperatively 47.4 % vs. postoperatively 68.1 %; p = 0.015). Liver resection remains a valuable therapeutic option in the treatment of either symptomatic FNH or if malignancy cannot finally be ruled out. If clinically indicated, liver resection for FNH represents a safe approach and may lead to significant improvements of QoL especially in symptomatic patients.


Importance of the Choice of a Recombinant System to Produce Large Amounts of Functional Membrane Protein hERG.
Human ether-a-gogo related gene (hERG) product is the membrane potassium channel Kv11.1, which is involved in the electrical activity of the heart. As such, it is a key player in the toxicity of many drug candidates. Therefore, having this protein at hand during earlier stages of drug discovery is important for preventing later toxicity. Furthermore, having a fair quantity of functional channels may help in the development of the necessary techniques for gaining insight in this channel structure. Thus, we performed a comparative study of methods for over-expressing a mutated but functional, hERG in different orthologous hosts, such as yeast, bacteria, insect and human cell lines. We also engineered the protein to test various constructs of a functional channel. We obtained a significant amount of a functional mutant channel from HEK cells that we thoroughly characterized. The present work paves the way for the expression of large amounts of this protein, with which protein crystallization or cryo-electronic microscopy will be attempted. This will be a way to gain information on the structure of the hERG active site and its modelization to obtain data on the pauses of various reference compounds from the pharmacopeia, as well as to gain information about the thermodynamics of the hERG/ligand relationship.


In vitro blood flow in a rectangular PDMS microchannel: experimental observations using a confocal micro-PIV system.
Progress in microfabricated technologies has attracted the attention of researchers in several areas, including microcirculation. Microfluidic devices are expected to provide powerful tools not only to better understand the biophysical behavior of blood flow in microvessels, but also for disease diagnosis. Such microfluidic devices for biomedical applications must be compatible with state-of-the-art flow measuring techniques, such as confocal microparticle image velocimetry (PIV). This confocal system has the ability to not only quantify flow patterns inside microchannels with high spatial and temporal resolution, but can also be used to obtain velocity measurements for several optically sectioned images along the depth of the microchannel. In this study, we investigated the ability to obtain velocity measurements using physiological saline (PS) and in vitro blood in a rectangular polydimethysiloxane (PDMS) microchannel (300 microm wide, 45 microm deep) using a confocal micro-PIV system. Applying this combination, measurements of trace particles seeded in the flow were performed for both fluids at a constant flow rate (Re = 0.02). Velocity profiles were acquired by successive measurements at different depth positions to obtain three-dimensional (3-D) information on the behavior of both fluid flows. Generally, the velocity profiles were found to be markedly blunt in the central region, mainly due to the low aspect ratio (h/w = 0.15) of the rectangular microchannel. Predictions using a theoretical model for the rectangular microchannel corresponded quite well with the experimental micro-PIV results for the PS fluid. However, for the in vitro blood with 20% hematocrit, small fluctuations were found in the velocity profiles. The present study clearly shows that confocal micro-PIV can be effectively integrated with a PDMS microchannel and used to obtain blood velocity profiles along the full depth of the microchannel because of its unique 3-D optical sectioning ability. Advantages and disadvantages of PDMS microchannels over glass capillaries are also discussed.


Comparison of Nostocean hormogonium induction and its motility on solid plates between agar and gellan gum at varying gel matrix concentrations.
To establish a sensitive bioassay for Nostocean hormogonium induction, we compared the effectiveness of the morpho-differentiation induction on two gelled plates, agar and gellan gum, for anacardic acid C15:1-Δ8 decyl ester (1) (100 nmol/disc). On BG-110 (nitrogen-free) medium-based 0.6 and 0.8% agar plates, Nostoc sp. strain Yaku-1 isolated from a coralloid root of Cycas revoluta in Yakushima Island showed clear morpho-differentiation from filamentous aggregates into hormogonia, and the induced hormogonia dispersed within 24 h; however, similar hormogonium formation was not observed at agar concentrations of 1.0% or higher. Conversely, hormogonium induction was considerably more pronounced on gellan gum plates than those on agar plates through concentrations ranging from 0.6 to 1.6% even after 12 h of incubation, particularly active on the 0.8-1.0% gellan gum plates. Thus, gellan gum plates can achieve clear results within 12 h and are thus highly useful for primary screening for hormogonium-inducing factors (HIFs).


Physiologically based pharmacokinetic modeling of human exposure to perfluorooctanoic acid suggests historical non drinking-water exposures are important for predicting current serum concentrations.
Manufacturing of perfluorooctanoic acid (PFOA), a synthetic chemical with a long half-life in humans, peaked between 1970 and 2002, and has since diminished. In the United States, PFOA is detected in the blood of >99% of people tested, but serum concentrations have decreased since 1999. Much is known about exposure to PFOA in drinking water; however, the impact of non-drinking water PFOA exposure on serum PFOA concentrations is not well characterized. The objective of this research is to apply physiologically based pharmacokinetic (PBPK) modeling and Monte Carlo analysis to evaluate the impact of historic non-drinking water PFOA exposure on serum PFOA concentrations. In vitro to in vivo extrapolation was utilized to inform descriptions of PFOA transport in the kidney. Monte Carlo simulations were incorporated to evaluate factors that account for the large inter-individual variability of serum PFOA concentrations measured in individuals from North Alabama in 2010 and 2016, and the Mid-Ohio River Valley between 2005 and 2008. Predicted serum PFOA concentrations were within two-fold of experimental data. With incorporation of Monte Carlo simulations, the model successfully tracked the large variability of serum PFOA concentrations measured in populations from the Mid-Ohio River Valley. Simulation of exposure in a population of 45 adults from North Alabama successfully predicted 98% of individual serum PFOA concentrations measured in 2010 and 2016, respectively, when non-drinking water ingestion of PFOA exposure was included. Variation in serum PFOA concentrations may be due to inter-individual variability in the disposition of PFOA and potentially elevated historical non-drinking water exposures.


A cost analysis of a broad-spectrum antibiotic therapy in the empirical treatment of health care-associated infections in cirrhotic patients.
Early diagnosis and appropriate treatment of infections in cirrhosis are crucial. As new guidelines in this context, particularly for health care-associated (HCA) infections, would be needed, we performed a trial documenting whether an empirical broad-spectrum antibiotic therapy is more effective than the standard one for these infections. Because of the higher daily cost of broad-spectrum than standard antibiotics, we performed a cost analysis to compare: 1) total drug costs, 2) profitability of hospital admissions. This retrospective observational analysis was performed on patients enrolled in the trial NCT01820026, in which consecutive cirrhotic patients with HCA infections were randomly assigned to a standard vs a broad-spectrum treatment. Antibiotic daily doses, days of treatment, length of hospital stay, and DRG (diagnosis-related group) were recorded from the clinical trial medical records. The profitability of hospitalizations was calculated considering DRG tariffs divided by length of hospital stay. We considered 84 patients (42 for each group). The standard therapy allowed to obtain a first-line treatment cost lower than in the broad-spectrum therapy. Anyway, the latter, being related to a lower failure rate (19% vs 57.1%), resulted in cost saving in terms of cumulative antibiotic costs (first- and second-line treatments). The mean cost saving per patient for the broad-spectrum arm was €44.18 (-37.6%), with a total cost saving of about €2,000. Compared to standard group, we observed a statistically significant reduction in hospital stay from 17.8 to 11.8 days (p<0.002) for patients treated with broad-spectrum antibiotics. The distribution of DRG tariffs was similar in the two groups. According to DRG, the shorter length of hospital stay of the broad-spectrum group involved a higher mean profitable daily cost than standard group (€345.61 vs €252.23; +37%). Our study supports the idea that the use of a broad-spectrum empirical treatment for HCA infections in cirrhosis would be cost-saving and that hospitals need to be aware of the clinical and economic consequences of a wrong antibiotic treatment in this setting.


Metagenomic comparison of tracheal aspirate and mini-bronchial alveolar lavage for assessment of respiratory microbiota.
Accurate and informative microbiological testing is essential for guiding diagnosis and management of pneumonia in patients who are critically ill. Sampling of tracheal aspirate (TA) is less invasive compared with mini-bronchoalveolar lavage (mBAL) and is now recommended as a frontline diagnostic approach in patients who are mechanically ventilated, despite the historical belief that TA was suboptimal due to contamination from oral microbes. Advancements in metagenomic next-generation sequencing (mNGS) now permit assessment of airway microbiota without a need for culture and, as such, provide an opportunity to examine differences between mBAL and TA at a resolution previously unachievable. Here, we engaged shotgun mNGS to assess quantitatively the airway microbiome in matched mBAL and TA specimens from a prospective cohort of critically ill adults. We observed moderate differences between sample types across all subjects; however, we found significant compositional similarity in subjects with bacterial pneumonia, whose microbial communities were characterized by dominant pathogens. In contrast, in patients with noninfectious acute respiratory illnesses, significant differences were observed between sample types. Our findings suggest that TA sampling provides a similar assessment of airway microbiota as more invasive testing by mBAL in patients with pneumonia.


Alveolar epithelial fluid clearance mechanisms are intact after moderate hyperoxic lung injury in rats.
The capacity of the alveolar epithelial barrier to remove excess alveolar fluid from the airspaces of the lung was studied in an experimental model of moderate hyperoxic lung injury. Rats were exposed to 100% oxygen for 40 h in an exposure chamber and compared with control animals exposed to room air. Extravascular lung water was calculated gravimetrically. Alveolar and lung liquid clearance were studied over 1 h by instillation of a 5% albumin solution with 1.5 microCi of 125I-labeled albumin (6 mL/kg into both lungs). The concentration of both the unlabeled and labeled albumin was used to calculate alveolar liquid clearance. Hyperoxic rats developed pulmonary edema, with a 33% increase in extravascular lung water to 5.3 +/- 0.1 g of water per gram of dry lung, compared with 4.0 +/- 0.2 g of water per gram of dry lung in control rats (p < 0.05). This degree of edema was associated with a significant increase in the alveolar-arterial oxygen difference (241 +/- 61 vs 124 +/- 14 mm Hg in control animals exposed to room air, p < 0.05). Despite this moderate degree of lung injury, alveolar fluid clearance was normal (30 +/- 3%) compared with control rats (33 +/- 6%). Furthermore, the hyperoxic injured rats responded normally to an exogenous beta-adrenergic agonist (terbutaline, 10(-4) mol/L) with a 67% increase in the rate of alveolar liquid clearance (50 +/- 5%). Thus, in the setting of moderate hyperoxic lung injury, the alveolar epithelial barrier is still capable of removing fluid at a normal rate and responding to beta-adrenergic agonist treatment. These experimental results have potential clinical implications for patients with acute lung injury.


Effects of Raman pump power distribution on output spectrum in a multi-wavelength BRFL.
This paper aims to investigate changes in multi-wavelength Brillouin-Raman fiber laser (MBRFL) spectra characteristics that are influenced by variation of Raman pump power distribution along the two fiber-entry points. This is carried out by incorporating a Raman pump source with a set of couplers with various ratios. In this arrangement, the optimization of pumping ratio is properly carried out to achieve high number of lasing lines with 20 GHz spacing which yield the highest peak power discrepancy between odd- and even-order lasing lines and an excellent Stokes optical signal-to-noise ratio (S-OSNR). Employment of 50/50 coupler offers 212 flat amplitude channels with an average 27.5 dB S-OSNR and -10 dBm Stokes peak power when the Brillouin pump wavelength is set at 1543 nm. Achievements such flat and wide bandwidth MBRFL spectrum with 20 GHz spacing and excellent S-OSNR utilizing just a single pump source is significant in terms of simplicity and flexibility.


A systematic review and meta-synthesis: evaluating the effectiveness of nurse, midwife/allied health professional consultants.
This paper presents the findings of a systematic review and meta-synthesis, which was undertaken to identify and assess studies that evaluated the nurse/midwife/allied health professional consultant role. As part of the modernization agenda in the National Health Service the United Kingdom government proposed 'Consultant' posts for nurses/midwives and allied health professionals as an opportunity for experienced practitioners to extend their roles. Four key functions were identified as being significant to this role development: expert practice, leadership, education and research. Explicit within the proposal was a requirement of these new roles to be evaluated. Inclusion criteria focussed on studies where an aspect of the role had been evaluated or where the consultant carried out the research. A total of 1931 citations was filtered to reveal 107 studies that possibly met the inclusion criteria. Of these 107, 14 studies were critically appraised and subjected to thematic analysis. Study methodology varied but of the 14 studies, 10 involved some form of measurement. The others adopted a literature review or descriptive approach. The extent to which consultants were involved in all aspects of the 'four pillars' was assessed in only a small number of studies. However, a number of studies implicitly implied active engagement in expert practice and leadership by focussing on specific service developments. To date, a number of studies evaluating service developments, education, expert practice and leadership have been carried out. However although a number of studies have assessed perceived impact of the consultant role, no measure of actual benefit has been published to date. Studies that evaluate the cost benefit/outcomes of these roles in relation to both activity and quality of service are required.


Diagnostic Accuracy of Ultrasound With Color Flow Doppler in Children With Thyroid Nodules.
Thyroid nodules are increasingly recognized in children and are associated with a greater risk for thyroid cancer compared with adults. Thyroid ultrasound is the favored tool for evaluation of thyroid nodules; however, there are limited data regarding the accuracy of thyroid ultrasound to confirm features associated with a low risk of thyroid cancer in children. We examined whether thyroid ultrasound is capable of accurately identifying thyroid nodules at a low risk of malignancy in children. Using a retrospective cohort study design, we identified children age ≤18 years with thyroid nodules and adequate follow-up. Ultrasound images were reviewed independently by two blinded expert radiologists, and ultrasound characteristics were analyzed to determine optimal predictive value and reliability. A total of 417 subjects were found to have thyroid nodules, and 152 subjects had adequate follow-up; 59 (38.8%) of these were diagnosed with thyroid cancer. We evaluated 236 individual nodules. Features most consistent with benign nodules included small size, isoechoic echogenicity, partially cystic structure, sharp or noninfiltrative margins, absent Doppler flow, and absent calcifications. Significant variability was found between expert interpretations of ultrasound features. Thyroid nodule composition appears to be the most sensitive and reliable feature for stratifying the risk of thyroid cancer. Ultrasound accurately identified benign thyroid nodules in 80.9% of subjects (95% confidence interval, 74-86.6). Ultrasonography is useful for the evaluation of thyroid nodules, but we found no combination of ultrasound features sufficient to exclude thyroid cancer without a biopsy.


[Surgical Treatment of Acute Infective Endocarditis after Transcatheter Aortic Valve Replacement].
Infective endocarditis (IE) after transcatheter aortic valve replacement (TAVR) is a rare complication, but has a high mortality. An 86-year-old female with symptomatic severe aortic stenosis underwent TAVR at our hospital and she was discharged without complication after 10 days. She was readmitted with high fever and acute heart failure 1 month later. Blood culture revealed Staphylococcus, and echocardiography showed vegetation on the septal cusp of the tricuspid valve and perforation at the membranous ventricular septum. We decided to perform emergency operation due to active infection and intracardiac complication despite appropriate antibiotic treatment. The infected valve was replaced with a bioprosthetic valve and the right ventricular (RV)-left ventricular (LV) communication was closed with a bovine pericardial patch. The patient received the antibiotics for 6 week and was transferred to the previous facility.


Effects of feedback delay and agency on feedback-locked beta and theta power during reinforcement learning.
Feedback-based learning initiated by dopamine (DA) cell firing is crucial for adaptive behavior. The nature and context of feedback can vary, however, affecting how feedback is processed. For example, the feedback-related negativity (FRN) in the ERP in humans, which has been linked to the DA system, is reduced for delayed feedback and for observational compared to active learning. Recent research suggested that oscillations in the theta and beta band over the medio-frontal cortex reflect distinct feedback processing mechanisms. In this study, we hypothesized that the power in both frequency bands is affected by feedback delay and agency. We thus investigated effects of feedback delay (1 s vs. 7 s) on induced theta and beta band power and the FRN in a probabilistic feedback learning task in two participant groups, one learning actively and one by observation. For theta and beta, a larger power difference between negative and positive feedback for immediate than delayed feedback was found, driven by positive feedback for beta and by negative feedback for theta, while no differential modulation by agency was seen for theta or beta power following positive and negative feedback. These results indicate that feedback-locked beta and theta both reflect neural processes that are specific for the integration of feedback and recently preceding events, possibly linked to cognitive control and memory. With respect to the FRN amplitude, we could replicate previous findings of both delay and agency modulations, suggesting that the neural processes underlying feedback-locked ERPs and theta and beta power modulations differ.


Protective effects of maternal administration of total saponins of Codonopsis pilosula in the mice offspring following diarrhea: role of immune function, antioxidant function, and intestinal inflammatory injury.
Total saponins of Codonopsis (TSC) are a kind of critical bioactive substances in Codonopsis, which have anti-inflammatory, antioxidant, anti-ulcer, immunomodulatory effects, and protective effects on ulcerative enteritis. In this study, TSC (3.75 mL/kg, gavage) was administered once a day to 13-day gestation Kunming mice for 5 days. On day 13 of birth, the offspring were given Escherichia coli solution (0.15 mL/mouse, intraperitoneal injection) and senna leaf decoction (0.15 mL/mouse, gavage) once a day for 6 days. The results showed that gestation maternal administration of TSC effectively reduced the diarrhea index, increased the content of sIgA, IgG, SOD, and GSH, inhibited the TLR4/MyD88/NF-κB pathway in the intestine, reduced the expression of inflammatory factors, and alleviated intestinal injury in the littermates. The results provided a critical reference for the clinical application of TSC to control diarrhea in animal offspring.


Understanding Magnetic Resonance Imaging of Knee Cartilage Repair: A Focus on Clinical Relevance.
The aims of this review article are (a) to describe the principles of morphologic and compositional magnetic resonance imaging (MRI) techniques relevant for the imaging of knee cartilage repair surgery and their application to longitudinal studies and (b) to illustrate the clinical relevance of pre- and postsurgical MRI with correlation to intraoperative images. First, MRI sequences that can be applied for imaging of cartilage repair tissue in the knee are described, focusing on comparison of 2D and 3D fast spin echo and gradient recalled echo sequences. Imaging features of cartilage repair tissue are then discussed, including conventional (morphologic) MRI and compositional MRI techniques. More specifically, imaging techniques for specific cartilage repair surgery techniques as described above, as well as MRI-based semiquantitative scoring systems for the knee cartilage repair tissue-MR Observation of Cartilage Repair Tissue and Cartilage Repair OA Knee Score-are explained. Then, currently available surgical techniques are reviewed, including marrow stimulation, osteochondral autograft, osteochondral allograft, particulate cartilage allograft, autologous chondrocyte implantation, and others. Finally, ongoing research efforts and future direction of cartilage repair tissue imaging are discussed.


Enabling the hypothesis-driven prioritization of ligand candidates in big databases: Screenlamp and its application to GPCR inhibitor discovery for invasive species control.
While the advantage of screening vast databases of molecules to cover greater molecular diversity is often mentioned, in reality, only a few studies have been published demonstrating inhibitor discovery by screening more than a million compounds for features that mimic a known three-dimensional (3D) ligand. Two factors contribute: the general difficulty of discovering potent inhibitors, and the lack of free, user-friendly software to incorporate project-specific knowledge and user hypotheses into 3D ligand-based screening. The Screenlamp modular toolkit presented here was developed with these needs in mind. We show Screenlamp's ability to screen more than 12 million commercially available molecules and identify potent in vivo inhibitors of a G protein-coupled bile acid receptor within the first year of a discovery project. This pheromone receptor governs sea lamprey reproductive behavior, and to our knowledge, this project is the first to establish the efficacy of computational screening in discovering lead compounds for aquatic invasive species control. Significant enhancement in activity came from selecting compounds based on one of the hypotheses: that matching two distal oxygen groups in the 3D structure of the pheromone is crucial for activity. Six of the 15 most active compounds met these criteria. A second hypothesis-that presence of an alkyl sulfate side chain results in high activity-identified another 6 compounds in the top 10, demonstrating the significant benefits of hypothesis-driven screening.


Rabies Elimination in Rural Kenya: Need for Improved Availability of Human Vaccines, Awareness and Knowledge on Rabies and Its Management Among Healthcare Workers.
In Africa, rabies causes an estimated 24,000 human deaths annually. Mass dog vaccinations coupled with timely post-exposure prophylaxis (PEP) for dog-bite patients are the main interventions to eliminate human rabies deaths. A well-informed healthcare workforce and the availability and accessibility of rabies biologicals at health facilities are critical in reducing rabies deaths. We assessed awareness and knowledge regarding rabies and the management of rabies among healthcare workers, and PEP availability in rural eastern Kenya. We interviewed 73 healthcare workers from 42 healthcare units in 13 wards in Makueni and Kibwezi West sub-counties, Makueni County, Kenya in November 2018. Data on demographics, years of work experience, knowledge of rabies, management of bite and rabies patients, and availability of rabies biologicals were collected and analyzed. Rabies PEP vaccines were available in only 5 (12%) of 42 health facilities. None of the health facilities had rabies immunoglobulins in stock at the time of the study. PEP was primarily administered intramuscularly, with only 11% (n = 8) of the healthcare workers and 17% (7/42) healthcare facilities aware of the dose-sparing intradermal route. Less than a quarter of the healthcare workers were aware of the World Health Organization categorization of bite wounds that guides the use of PEP. Eighteen percent (n = 13) of healthcare workers reported they would administer PEP for category I exposures even though PEP is not recommended for this category of exposure. Only one of six respondents with acute encephalitis consultation considered rabies as a differential diagnosis highlighting the low index of suspicion for rabies. The availability and use of PEP for rabies was sub-optimal. We identified two urgent needs to support rabies elimination programmes: improving availability and access to PEP; and targeted training of the healthcare workers to improve awareness on bite wound management, judicious use of PEP including appropriate risk assessment following bites and the use of the dose-sparing intradermal route in facilities seeing multiple bite patients. Global and domestic funding plan that address these gaps in the human health sector is needed for efficient rabies elimination in Africa.


[Diabetes mellitus and the female reproductive system tumors].
The article discusses various pathophysiological conditions and processes that lead to the development of tumors in diabetes mellitus. These include obesity, hyperglycemia, hyperinsulinemia, inflammation, and oxidative stress. The data of epidemiological studies are given, in which it was found that diabetes mellitus (both type 1 and type 2) increases the risk of developing the female reproductive system tumors, such as ovarian cancer, endometrial cancer, while for cervical cancer, vaginal cancer and vulvar cancer, such a relationship has not been clearly identified.


S100B Protein as a Post-traumatic Biomarker for Prediction of Brain Death in Association With Patient Outcomes.
S100B is a calcium-binding protein, belonging to the S100 family proteins which are characterized by their high solubility and, currently, comprises 21 members which are expressed in a cell-specific manner. If we can predict the possibility of definite brain death after brain injury, we will rescue some organs of body to transplant proposes. In this regard our study focused on the S100B protein value in predicting brain death after head trauma. In this study, the use of serum level of protein S100, 24 hours after trauma has been considered as a reliable index for predicting brain death. 72 patients (50 male and 22 female) aged 5 - 80 years old (median 40 ± 17.72 years) with severe head traumas (GCS≤8) were recruited in this cross-sectional study. Glasgow Coma Scale (GCS) and computed tomography (CT) scan findings were recorded for all patients, and then a single 5mL blood sample was obtained from each patient on admission, after 48 hours and a week later or after brain death to determine the level of S100B protein. Primary and the last GCS of patients had a predictive value in determining brain death (P < 0.0005), also there was a significant correlation between GCS and level of S100B protein. There was a significant correlation between CT scan findings and S100B protein only after 48 hours of trauma. Changes in S100B protein, especially the levels of this dimer 48 hours after trauma can be used as marker to predict brain death. Alongside other known prognostic factors such as age, GCS and diameters of the pupils, however, this factor individually can not conclusive predict the patient's clinical course and incidence of brain death. However, it is suitable to use GCS, CT scan, clinical symptoms and biomarkers together for a perfect prediction of brain death.


Identification and Expression Analysis of Genes Induced in Response to Tomato chlorosis virus Infection in Tomato.
Tomato (Solanum lycopersicum) is one of the most widely grown and economically important vegetable crops in the world. Tomato chlorosis virus (ToCV) is one of the recently emerged viruses of tomato distributed worldwide. ToCV-tomato interaction was investigated at the molecular level for determining changes in the expression of tomato genes in response to ToCV infection in this study. A cDNA library enriched with genes induced in response to ToCV infection were constructed and 240 cDNAs were sequenced from this library. The macroarray analysis of 108 cDNAs revealed that the expression of 92 non-redundant tomato genes was induced by 1.5-fold or greater in response to ToCV infection. The majority of ToCV-induced genes identified in this study were associated with a variety of cellular functions including transcription, defense and defense signaling, metabolism, energy, transport facilitation, protein synthesis and fate and cellular biogenesis. Twenty ToCV-induced genes from different functional groups were selected and induction of 19 of these genes in response to ToCV infection was validated by RT-qPCR assay. Finally, the expression of 6 selected genes was analyzed in different stages of ToCV infection from 0 to 45 dpi. While the expression of three of these genes was only induced by ToCV infection, others were induced both by ToCV infection and wounding. The result showed that ToCV induced the basic defense response and activated the defense signaling in tomato plants at different stages of the infection. Functions of these defense related genes and their potential roles in disease development and resistance to ToCV are also discussed.


Report from the First Latin American Urological Oncology Symposium (SLAURO) 19-21 June 2014, Viña del Mar, Chile.
Cancer is one of the most important diseases in Chile, with alarming incidence and mortality rates that are among the highest in Latin America. Economic growth in South America has led to demographic change, with an aging population typical of developed countries, but also a growing population with cancer. The incidence and mortality of urological cancers in Chile is significant, and has led to the formulation of health laws and policies promoting the early treatment of urological cancers. It is also well known that there are regions of Chile with extremely high incidence and mortality of bladder cancer caused by arsenic exposure. SLAURO (Simposio Latinoamericano de Urología Oncológica [Latin American Oncological Urology Symposium]) is a new Latin American forum for discussing and promoting knowledge of urological cancers across the region.


Serum IgA preferentially binds to cationic polypeptides in IgA nephropathy.
The observation of negatively charged IgA in the mesangium of patients with primary IgA nephropathy (IgA-GN) prompted us to study the charge of serum IgA in IgA-GN, Henoch Schönlein purpura (HSP), alcoholic liver cirrhosis (ALC), membranous nephropathy (MGN) and systemic lupus erythematosus (SLE). Since no abnormal distribution of IgA isoelectric points was detected by isoelectric focusing studies, we developed a sensitive charge-dependent assay using plates coated with either cationized BSA (cBSA) or poly-L-lysine. In 15 IgA-GN sera, the amount of IgA reacting specifically with cBSA (cBSA-IgA) was almost linearly correlated with the poly-L-lysine-binding IgA (r = 0.97, P = 0.0006), suggesting that both assays detect charge-dependent interactions and thus probably measure anionic IgA. Significantly high serum levels of cBSA-IgA were observed in 56% of IgA-GN patients and in 40% of ALC patients. In contrast, normal serum levels of cBSA-IgA were detected in HSP, MGN and SLE. Both, the mono- or polymeric IgA bound to cBSA in a patient's serum studied. Contrasting with the presence of anionic IgA, no increase of cBSA-IgG was observed in IgA-GN. IgA rheumatoid factor (IgA-RF) assay showed high levels in IgA-GN (39%) and in ALC (25%). IgA-RF levels did not correlate with the amount of cBSA-IgA. When 18 patients with IgA-GN were tested after kidney transplantation, increased levels of cBSA-IgA and/or IgA-RF were found to be associated with the recurrence of mesangial IgA deposits in the graft. This suggests that both negatively charged IgA and IgA-RF may play a role in the recurrence of mesangial IgA deposits.


Sex differences in auditory verbal hallucinations in early, middle and late adolescence: results from a survey of 17 451 Japanese students aged 12-18 years.
Women have higher rates of auditory verbal hallucinations (AVH) than men; however, less is known about sex differences in the prevalence of AVH in early, middle and late adolescence. We sought to elucidate the differences in the prevalence of AVH and to examine the degree to which these differences could be explained by differences in levels of depressive symptoms. We used a cross-sectional design and a self-reported questionnaire. Participants were recruited from public junior and senior high schools in Tsu, Mie Prefecture and Kochi Prefecture, Japan. In total, 19 436 students were contacted and 18 250 participated. Responses from 17 451 students with no missing data were analysed (aged 12-18 years, Mage=15.2 years (SD=1.7), 50.6% girls). AVH were assessed through one of four items adopted from the schizophrenia section of the Japanese version of the Diagnostic Interview Schedule for Children. Depressive symptoms were assessed using the 12-item General Health Questionnaire. The prevalence of AVH was 7.0% among early adolescents (aged 12-13 years), 6.2% among middle adolescents (aged 14-15 years) and 4.8% among late adolescents (aged 16-18 years). Being female was significantly associated with a higher prevalence of AVH through adolescence (OR=1.71, 95% CI 1.31 to 2.23 in early adolescence; OR=1.42, 95% CI 1.14 to 1.76 in middle adolescence; OR=1.52, 95% CI 1.23 to 1.87 in late adolescence); however, these differences became non-significant after adjusting for depressive symptoms (OR=1.21, 95% CI 0.92 to 1.60; OR=1.00, 95% CI 0.80 to 1.25; OR=1.16, 95% CI 0.93 to 1.44, respectively). Sex differences in auditory hallucinations are seen in both adult and youth populations. The higher rates of auditory verbal hallucinations seen in girls may be secondary to the differences in the rate of depressive symptoms.


[Development of methods for measuring the emptying time of solid and liquid test meals in rat stomachs].
Different methods for experimental measuring the gastric emptying time in the rat have been developed. For the invasive method of measuring the stomach emptying time of a solid test meal containing Amberlite pellets too many animals are necessary. On the other hand, for the non-invasive examination of the emptying of a radioactively marked liquid test meal by scintigraphy the resolution of the gamma-camera is too low. However we were able to develop a non-invasive fluoroscopic method for the simultaneous measurement of the gastric emptying of a solid (10 radiodense markers) and a liquid (0.5 ml diluted contrast medium) test meal. Using this method it was possible to examine the influence of stomach motility stimulating drugs, such as the parasympathomimeticum carbachol and the dopamine antagonist metoclopramide.


Diagnosis and Assessment of Apathy in Elderly Chinese Patients With Cerebral Small Vessel Disease.
Objective: The study aimed to estimate the frequency of apathy in Chinese patients with cerebral small vessel disease (CSVD) and investigate the relationship between apathy and neuroimaging markers of CSVD. Methods: A total of 150 CSVD aged patients were recruited for a cross-sectional observational study. Following the new revised version of diagnostic criteria for apathy (DCA), each patient was evaluated successively by the neuropsychiatric inventory (NPI-apathy), geriatric depression scale (GDS), and caregiver burden scale (CBS). The MRI presence of lacunes, white matter hyperintensities, cerebral microbleeds, and perivascular spaces were rated independently. Furthermore, presence of all these MRI markers were summed in a score of 0-4 representing all CSVD features combined. Results: According to the DCA, we found that the frequency of apathy in Chinese Alzheimer's disease patients reached 37.33%, with lack of and diminished goal-directed activities in the dimension of behavior/cognition. We did not find a close relationship between apathy and depression. Caregiver burden was positively correlated with apathy severity. Apathy, but not depression, was positively associated with total CSVD burden, rather than a separate MRI marker of CSVD. Conclusion: As a key component of neuropsychiatric symptoms, apathy was common in Chinese elderly with CSVD, more attention should be paid to apathy in clinical practice of CSVD.


Direct Catalytic Asymmetric Mannich-Type Reaction of α-N3 Amide.
An α-N3 7-azaindoline amide serves as a latent enolate to directly engage in an asymmetric Mannich-type reaction with N-thiophosphinoyl imines by the action of a cooperative catalyst. The thus-obtained highly enantioenriched anti-adduct was transformed into β-amino-α-azido acid in high yield by simple acidic treatment.


Corticosteroids in Crohn's disease.
Crohn's disease is a lifelong illness characterized by chronic recurrent flares. The precise etiology of Crohn's disease is unknown. However, it appears to involve an enhanced systemic immune response and intensified local intestinal mucosal inflammatory activity, mediated through various inflammatory cells and an array of proinflammatory cytokines. Corticosteroids have been the mainstay of treatment of Crohn's disease. The controlled trials of the National Cooperative Crohn's Disease Study and the European Cooperative Crohn's Disease Study established that corticosteroids were effective for the induction of remission in Crohn's disease for the duration of the studies (6-17 wk). However, corticosteroids have not been shown to have an impact on the maintenance of long term remission in patients with Crohn's disease. In addition, they are associated with a high potential for dependence and serious toxic side effects. Alternative classes of medical therapy for Crohn's disease, including modified corticosteroids and a group of new biological therapies, have proven to be efficacious in the management of active and/or quiescent Crohn's disease.


Reconstructive urology and tissue engineering: Converging developmental paths.
Reconstructive urology is a complex and demanding branch of modern urology. Complicated cases, necessity of microsurgical approach, and constant exposure to urine make urinary reconstruction especially difficult. With impaired healing, excessive scarring, and recurring fibrosis, functional results are still not satisfying. For better, more successful outcomes, a novel tissue engineering technology-based solutions are being gradually investigated. The use of tissue engineering is the most promising strategy to improve results of reconstructive urology procedures due to possibility of designing organ-specific grafts. Moreover, targeted modification of healing environment by stem cells and growth factors is a unique opportunity that might bring reconstructive urology on molecular level. This review defined limitations and problems encountered in reconstructive urology and discussed relevant tissue engineering-based achievements in the field of urethra, urinary bladder, and ureter regeneration. The background justifying tissue engineering approach to urethra, urinary bladder, and ureter reconstruction was discussed. Then, the wide range of experimental methods utilising biomaterials and cell seeding was deliberated to show readers the current tools offered by tissue engineering. At the end, we characterised major challenges that are needed to be addressed before tissue entering would become standard technology in urological departments.


Sleep disturbances and mental strain in university students: results from an online survey in Luxembourg and Germany.
This study examined the prevalence of sleep disturbances and mental strain in students from two European countries, Luxembourg and Germany. A total of 2831 students took part in an online survey, with 2777 students from Germany and 184 students from Luxembourg. Sleep disturbances were assessed with the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale, and aspects of mental strain using the Patient Health Questionnaire, the Social-Interactive-Anxiety Scale, the self-efficacy questionnaire and the test anxiety questionnaire. In addition, we also assessed students' chronotypes. Across the whole sample mean scores on the sleep questionnaires were above the cut-off for clinically relevant sleep problems, indicating an increased prevalence of sleep disturbances in students from both countries. Sleep quality was impaired in 42.8%, and 17.9% showed clinically relevant scores. Overall 25.5% reported elevated depression and 13.3% social phobia symptoms, while 45% indicated elevated stress levels. Sleep quality, daytime sleepiness, chronotype, depression scores, stress levels, test anxiety, and self-efficacy differed significantly between men and women, but there were no differences between countries. Sleep disturbances and mental strain in students are common, with the current results replicating previous findings. Students from Luxembourg and Germany are affected equally.


Secondary gait changes in patients with medial compartment knee osteoarthritis: increased load at the ankle, knee, and hip during walking.
This study tested the hypothesis that gait changes related to knee osteoarthritis (OA) of varied severity are associated with increased loads at the ankle, knee, and hip. Forty-two patients with bilateral medial compartment knee OA and 42 control subjects matched for sex, age, height, and mass were studied. Nineteen patients had Kellgren/Lawrence (K/L) radiographic severity grades of 1 or 2, and 23 patients had K/L grades of 3 or 4. Three-dimensional kinematics and kinetics were measured in the hip, knee, and ankle while the subjects walked at a self-selected speed. Patients with more severe knee OA had greater first peak knee adduction moments than their matched control subjects (P = 0.039) and than patients with less severe knee OA (P < 0.001). All patients with knee OA made initial contact with the ground with the knee in a more extended position than that exhibited by control subjects. An increased axial loading rate was present in all joints of the lower extremity. Patients with more severe knee OA had lower hip adduction moments compared with their matched control subjects. The secondary gait changes observed among patients with knee OA reflect a potential strategy to shift the body's weight more rapidly from the contralateral limb to the support limb, which appears to be successful in reducing the load at the knee in only patients with less severe knee OA. The increased loading rate in the lower extremity joints may lead to a faster progression of existing OA and to the onset of OA at joints adjacent to the knee. Interventions for knee OA should therefore be assessed for their effects on the mechanics of all joints of the lower extremity.


Overview: translating Hsp90 biology into Hsp90 drugs.
The Hsp90 molecular chaperone has emerged as one of the most exciting targets for cancer drug development. Hsp90 is overexpressed in many malignancies, very likely as a result of the stress that is induced both by the hostile cancer microenvironment and also by the mutation and abberant expression of oncoproteins. A particularly attractive feature of Hsp90 as a cancer drug target is that it is required for the conformational stability and function of a wide range of oncogenic 'client' proteins, including c-Raf-1, Cdk4, ErbB2, mutant p53, c-Met, Polo-1 and telomerase hTERT. Inhibition of Hsp90 should therefore block multiple mission critical oncogenic pathways in the cancer cell, leading to inhibition of all the hallmark traits of malignancy. This combinatorial blockade of oncogenic targets should give rise to board spectrum antitumour activity across multiple cancer types. The 'druggability' of Hsp90 was confirmed by the discovery that the natural products geldanamycin and radicicol, which have anticancer activity, exert their biological effects by inhibiting the essential ATPase activity associated with the N-terminal domain of the protein. The first-in-class Hsp90 inhibitor has entered clinical trial and provided proof of concept that Hsp90 can be inhibited and clinical benefit seen at non-toxic doses. Further development is underway and a related analogue 17DMAG also shows promise in preclinical models. In addition, novel Hsp90 inhibitors have been identified using methods such as high throughput screening and x-ray crystallography. The opportunities and challenges involved in translating the fast moving biology of Hsp90 into patient benefit is discussed.


Arthroscopically Assisted Cannulated Screw Fixation for Treating Type III Tibial Intercondylar Eminence Fractures: A Short-Term Retrospective Controlled Study.
Background: This study presents the clinical results from 22 children who underwent minimally invasive arthroscopically assisted screw fixation for the treatment of intercondylar eminence fractures. Methods: We retrospectively analyzed the clinical data of 22 children (aged 7.5 to 13.5 years) with type III tibial intercondylar eminence fractures who were treated in our department from March 2007 to September 2019. According to the type of operation, the patients were divided into two groups: group A (n = 12) received arthroscopically assisted cannulated screw fixation, and group B (n = 10) received open reduction and cannulated screw internal fixation. Radiography scans, Lysholm scores, International Knee Documentation Committee (IKDC) 2,000 subjective scores, Tegner scores, range of motion (ROM) of the knee, the anterior drawer test (ADT), the Lachman test, and the pivot-shift test were used to evaluate the clinical efficacy. Results: All 22 children were evaluated over a 12 to 58 month follow-up period (mean: 27.5 months). At the final exam, group A was significantly superior to group B in Lysholm scores (93.33 ± 3.55 vs. 86.20 ± 4.52), IKDC scores (92.06 ± 3.55 vs. 86.07 ± 5.81), and Tegner scores (7.75 ± 0.87 vs. 6.40 ± 0.52) and presented shorter operative times (25.42 ± 3.97 vs. 35.00 ± 5.27). The differences were statistically significant (P < 0.05). All the incisions healed primarily. No complications, such as fracture fragment displacement, delayed epiphyseal growth, or knee joint dysfunction, were observed. The drawer test, Lachman test, and pivot-shift test were negative for all patients. Conclusions: Arthroscopically assisted cannulated screw fixation is effective and safe for the treatment of tibial intercondylar eminence fractures, providing excellent stability and quick recovery of joint function.


Most common dermatologic problems identified by internists, 1990-1994.
Internists in all settings see many patients with skin conditions. Thus, their education in dermatology is important. Information on which areas of dermatology are most commonly seen in internal medicine practices is necessary for designing effective educational programs on skin disease. To determine what types of dermatologic problems internists most commonly diagnose. National Ambulatory Medical Care Survey data from 1990 to 1994 were analyzed for dermatologic diagnoses. Physicians specializing in internal medicine and all its subspecialties were compared with dermatologists and with other physicians. The most common skin disorders diagnosed by internists were dermatitis (15.8% of all diagnoses) and bacterial skin infections (14.0% of all diagnoses). Combined, bacterial, fungal, and viral infections included 28.3% of the most common dermatologic diagnoses made by internists. The top 10 most common diagnoses accounted for 57.9% of all skin-related diagnoses and the top 20 most common diagnoses accounted for 72.8%. Internists were more likely to see patients for bacterial skin infections, herpes infection, exanthem, urticaria, and insect bites while dermatologists more commonly saw patients for actinic and seborrheic keratoses, warts, benign and malignant skin tumors, and psoriasis. The most common dermatologic diseases diagnosed by internists differ considerably from those diagnosed by dermatologists. Because dermatologists do much of the dermatology teaching of internal medicine residents, it is important to recognize these differences to place emphasis on the proper areas of study. Some common or serious skin conditions not often diagnosed by internists such as psoriasis and melanoma also deserve attention in internal medicine training programs.


Identification by flagellum display of an epithelial cell- and fibronectin-binding function in the SlpA surface protein of Lactobacillus brevis.
Depletion of the SlpA protein from the bacterial surface greatly reduced the adhesion of Lactobacillus brevis ATCC 8287 to the human intestinal cell lines Caco-2 and Intestine 407, the endothelial cell line EA-hy926, and the urinary bladder cell line T24, as well as immobilized fibronectin. For functional analysis of the SlpA surface protein, different regions of the slpA gene were expressed as internal in-frame fusions in the variable region of the fliC(H7) gene of Escherichia coli. The resulting chimeric flagella carried inserts up to 275 amino acids long from the mature S-layer protein, which is 435 amino acids in size. The expression of the SlpA fragments on the chimeric flagella was assessed by immunoelectron microscopy and Western blotting using anti-SlpA antibodies, and their binding to human cells was assessed by indirect immunofluorescence. Chimeric flagella harboring inserts that represented the N-terminal part of the S-layer protein bound to the epithelial cell lines, whereas the C-terminal part of the S-layer protein did not confer binding on the flagella. The shortest S-layer peptide capable of detectable binding was 81 amino acid residues in size and represented residues 96 through 176 in the unprocessed S-layer protein. The bacteria and the chimeric flagella did not show detectable binding to erythrocytes, whereas the SlpA-expressing ATCC 8287 cells as well as the chimeric SlpA 96-245/FliC flagella bound to immobilized fibronectin. The N-terminal SlpA peptide 96-176 or 96-200 fused to FliC was not recognized in Western blotting or immunoelectron microscopy by a polyclonal serum raised against the S-layer protein; the antiserum, however, reacted in immunofluorescence with the ATCC 8287 cells. In contrast, an antiserum raised against the His-tagged peptide 96-245 of SlpA bound to the hybrid flagella with the N-terminal SlpA inserts but did not react with ATCC 8287 cells. The results identify the S-layer of L. brevis ATCC 8287 as an adhesin with affinity for human epithelial cells and fibronectin and locate the receptor-binding region within a fragment of 81 amino acids in the N-terminal part of the molecule, which in native S-layer seems inaccessible to antibodies.


Microwave-Hydrothermal Treated Grape Peel as an Efficient Biosorbent for Methylene Blue Removal.
Biosorption using agricultural wastes has been proven as a low cost and efficient way for wastewater treatment. Herein, grape peel treated by microwave- and conventional-hydrothermal processes was used as low cost biosorbent to remove methylene blue (MB) from aqueous solutions. The adsorption parameters including the initial pH value, dosage of biosorbents, contact time, and initial MB concentration were investigated to find the optimum adsorption conditions. The biosorbent obtained by microwave-hydrothermal treatment only for 3 min at 180 °C (microwave-hydrothermal treated grape peel, MGP) showed faster kinetics and higher adsorption capability than that produced by a conventional-hydrothermal process (hydrothermal treated grape peel, HGP) with a duration time of 16 h. The maximum adsorption capability of MGP under the optimum conditions (pH = 11, a dosage of 2.50 g/L) as determined with the Langmuir model reached 215.7 mg/g, which was among the best values achieved so far on biosorbents. These results demonstrated that the grape peel treated by a quick microwave-hydrothermal process can be a very promising low cost and efficient biosorbent for organic dye removal from aqueous solutions.


A new plating medium for the isolation of enteric pathogens. II. Comparison of hektoen enteric agar with SS and EMB agar.
During this study, 2,855 stool specimens from patients at Cook County Hospital were cultured for enteric pathogens. Hektoen Enteric Agar (HE) was compared with E M B and S S Agars by replicate samplings with both direct and indirect methods. Shigella species were recovered more than twice as often on HE Agar as on S S Agar by both methods. With the direct method only, out of 98 Shigella isolated, 97 were isolated from HE Agar, 74 were recovered from E M B Agar, and 40 were found on S S Agar. In addition, HE yielded better isolation of Salmonella strains than did S S or E M B by either direct or indirect methods. The greater efficiency of HE medium is discussed with respect to colonial recognition of enteric pathogens.


Phocoenamicins B and C, New Antibacterial Spirotetronates Isolated from a Marine Micromonospora sp.
Phocoenamicins B and C (1 and 2), together with the known spirotetronate phocoenamicin (3), were isolated from cultures of Micromonospora sp. The acetone extract from a culture of this strain, isolated from marine sediments collected in the Canary Islands, displayed activity against methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium tuberculosis H37Ra and Mycobacterium bovis. Bioassay-guided fractionation of this extract using SP207ss column chromatography and preparative reversed-phased HPLC led to the isolation of the new compounds 1 and 2 belonging to the spirotetronate class of polyketides. Their structures were determined using a combination of HRMS, 1D and 2D NMR experiments and comparison with the spectra reported for phocoenamicin. Antibacterial activity tests of the pure compounds against these pathogens revealed minimal inhibitory concentration (MIC) values ranging from 4 to 64 µg/mL for MRSA, and 16 to 32 µg/mL for M. tuberculosis H37Ra, with no significant activity found against M. bovis and vancomycin-resistant Enterococcus faecium (VRE) at concentrations below 128 µg/mL, and weak activity detected against Bacillus subtilis grown on agar plates.


Theoretical hydraulic consequences of vein graft taper.
Internal diameter is a strong predictor of patency of infrainguinal vein grafts. However, most vein grafts are tapered, with variable diameter along their length. It is unknown which diameter is most important in determining graft resistive properties, that is, its mean diameter, minimum diameter, or some geometric combination thereof. The purpose of this analysis was to examine the hydraulic consequences of vein graft tapering, with longitudinal impedance (Z(L)), a conduit-specific measure of pulsatile resistance along straight rigid tubes. Proximal and distal graft pressure, pressure gradient (DeltaP), and blood flow (Q) were measured intraoperatively in a 100 cm bypass graft and digitally recorded for 10 seconds at 200 Hz. With the Womersley solution for fully developed fluid flow in a rigid tube, a series of DeltaP waveforms were generated for graft diameters ranging from 1.2 to 8.2 mm. With an axisymmetric form of the Navier-Stokes equations, a second series of DeltaP waveforms were computed for grafts with long smooth symmetric tapers ranging from 0% to 90%, with geometric mean diameter of 3.2, 4.2, and 5.2 mm (%Taper = 100 x [proximal diameter - distal diameter]/proximal diameter). For each set of DeltaP and Q, Z(L) was calculated as DeltaP/Q, plotted over a range of 8 Hz, and integrated over 4 Hz to yield integral Z(L). The architecture of the calculated DeltaP and Z(L) waveforms closely approximated their measured counterparts, validating the method. As expected, Z(L) was highly diameter-dependent in a nonlinear fashion. With a clinically relevant boundary of less than 50 x 10(3) dyne/cm(5) as "acceptable," the minimum acceptable diameter of nontapered 100 cm bypass conduits was 4.3 mm. Analysis of graft taper revealed that small amounts of taper in large conduits were well-tolerated. For example, introduction of 32% taper in a 5.2 mm graft (6.2 mm --> 4.2 mm) caused only an 8% increase in integral Z(L) (from 32 to 35 x 10(3) dyne/cm(5)). More pronounced taper in smaller conduits rendered them unacceptable. For example, 53% taper of a 4.2 mm graft (5.7 mm --> 2.7 mm) created a conduit with integral Z(L) of 70 x 10(3) dyne/cm(5), well above the acceptable limit. The relationship between Z(L) and percent taper was nonlinear and strongly dependent on mean diameter. The relationship between Z(L) and diameter in vein grafts is nonlinear; thus Z(L) increases rapidly in conduits smaller than 4 mm. Tapered vein grafts behave hydraulically like nontapered grafts, provided their geometric mean is greater than 4 mm and their degree of taper is less than 40%. Tapered veins are satisfactory conduits for long-segment bypass grafts, provided their mean diameter is acceptable.


Intraoperative biometry for intraocular lens (IOL) power calculation at silicone oil removal.
Cataract development is common following retinal detachment surgery that necessitates silicone oil injection. Intraocular lens (IOL) power calculation in the presence of silicone oil is challenging for many reasons. The authors evaluated the accuracy of intraoperative biometry during cataract surgery in silicone-filled eyes. Twelve cases of cataract in eyes filled with silicone oil after retinal detachment surgery were included. Preoperatively, keratometric readings were documented. Intraoperative axial length was measured following removal of silicone oil using a sterile probe of the Nidek Echoscan US800 unit. IOL power calculation was computed using the SRK/T formula. This was followed by phacoemulsification and foldable lens implantation. Postoperative refraction allowed evaluation of the accuracy of intraoperative biometry. The predictability of three different formulas was also compared (Holladay, SRK/T, and SRK II). Seven men and five women with a mean age of 50.2 years were included in the study. The mean postoperative spherical equivalent using the described technique was 6.77 +/- 0.43 diopters. SRK/T and Holladay formula had the best predictability for high axial length eyes, whereas the three studied formulas showed no significant differences in predictability in eyes with normal axial length. Intraoperative biometry proved to have good predictability for the absolute postoperative refractive error in cataract surgery for eyes at the time of silicone oil removal. This predictability was accurate independent of axial length.


Cost-effectiveness analysis of trastuzumab deruxtecan in patients with HER2-low advanced breast cancer based on DESTINY-Breast04.
Breast cancer is a rapidly raising healthcare problem worldwide. DESTINY-Breast04 demonstrated that trastuzumab deruxtecan (T-Dxd) had a survival advantage comparing to the physician's choice of chemotherapy for patients with HER2-low metastatic breast cancer. But at the same time, this expensive novel treatment also brought an economic burden. This study assessed the cost-effectiveness of T-Dxd based on results of DESTINY-Breast04 from the perspective of Chinese healthcare system. A three-state partitioned-survival model [progression-free survival (PFS), progressive disease (PD) and death] based on data from DESTINY-Breast04 and Chinese healthcare system was used to estimate the incremental cost-effectiveness ratio (ICER) of T-Dxd vs. the physician's choice of chemotherapy for HER2-low metastatic breast cancer. Costs, quality-adjusted life-years (QALYs) and the ICER in terms of 2022 US$ per QALY gained were calculated for both hormone receptor-positive cohort and all patients. One-way and probabilistic sensitivity analyses were performed to assess the model robustness. Compared with the physician's choice of chemotherapy, T-Dxd increased costs by $104,168.30, while gaining 0.31 QALYs, resulting in an ICER of $336,026.77 per QALY in all patients. The costs of T-Dxd and the utility of PFS were the crucial factors in determining the ICER. In the hormone receptor-positive cohort, the ICER was lower than that in all patients, with the ICER of $274,905.72 per QALY. The ICER was much higher than the commonly accepted willingness-to-pay threshold ($357,96.83 per QALY). T-Dxd as second- or subsequent-line treatment is not a cost-effective treatment option for HER2-low metastatic breast cancer from the perspective of the Chinese healthcare system.


Scalable Production of Few-Layer Boron Sheets by Liquid-Phase Exfoliation and Their Superior Supercapacitive Performance.
Although two-dimensional boron (B) has attracted much attention in electronics and optoelectronics due to its unique physical and chemical properties, in-depth investigations and applications have been limited by the current synthesis techniques. Herein, we demonstrate that high-quality few-layer B sheets can be prepared in large quantities by sonication-assisted liquid-phase exfoliation. By simply varying the exfoliating solvent types and centrifugation speeds, the lateral size and thickness of the exfoliated B sheets can be controllably tuned. Additionally, the exfoliated few-layer B sheets exhibit excellent stability and outstanding dispersion in organic solvents without aggregates for more than 50 days under ambient conditions, owing to the presence of a solvent residue shell on the B sheet surface that provides excellent protection against air oxidation. Moreover, we also demonstrate the use of the exfoliated few-layer B sheets for high-performance supercapacitor electrode materials. This as-prepared device exhibits impressive electrochemical performance with a wide potential window of up to 3.0 V, excellent energy density as high as 46.1 Wh/kg at a power density of 478.5 W/kg, and excellent cycling stability with 88.7% retention of the initial specific capacitance after 6000 cycles. This current work not only demonstrates an effective strategy for the synthesis of the few-layer B sheets in a controlled manner but also makes the resulting materials promising for next-generation optoelectronics and energy storage applications.


Risk factors for undernutrition of young children in a rural area of South Africa.
To identify the factors associated with childhood undernutrition. Cross-sectional survey. Hlabisa health district in KwaZulu/Natal, South Africa. Eight hundred and sixty-eight children aged 3-59 months. Questionnaire survey and anthropometric survey of 516 random households with children in the health district. Multivariate analysis took into account the hierarchical relationships between the proposed risk factors. This conceptual model was built up during qualitative studies and with reference to international research in this area. The mean Z-scores for weight-for-age and height-for-age were -0.52 (95% confidence interval (CI) -0.44 to -0.60) and -1.25 (95% CI -1.15 to -1.35), respectively. Of the children, 26.3% (95% CI 23.3-29.3%) were stunted, 12.0% (95% CI 9.8-4.2%) were underweight-for-age (UWFA) and only 1.3% were wasted. Migrant father, mother's education, literate mother, whether the house was made of traditional materials, the presence of a toilet, whether the last child was breast-fed, duration of breast-feeding and birth weight were found to be significantly related to UWFA, the latter with an odds ratio of more than eight. While there are individual health and feeding behaviours that need to be addressed, this study has also uncovered the maternal and socio-economic factors which present an array of constraints in the social environment shaping the infant feeding and caring practices employed by women. For the full potential of nutrition promotion activities to be realised, there is a need to address some of these 'deeper' constraints.


[Detection, significance and control of paramyxoviruses in birds].
Infection, disease and mortality due to various paramyxoviruses currently occur fairly frequently in both domestic fowl and in captive and free-living birds. These viruses are therefore of economic and ecologic significance, and may also cause zoonoses. The current legal status of the detection and control of paramyxovirus-associated diseases or epidemics are described. Prophylactic vaccination against Newcastle disease using live and inactivated vaccines, as required by the fowl disease regulations, remains of great importance in maintaining health and productivity of the fowl. Correct immunisation also includes checking the effectiveness using serological methods.


A novel domain sequence of connectin localized at the I band of skeletal muscle sarcomeres: homology to neurofilament subunits.
A cDNA of 4.0 kb was cloned from a chicken embryo skeletal muscle cDNA library, using an antibody to muscle elastic protein connectin (titin), the molecular mass of which is estimated to be 3,000 kDa. Immunoelectron microscopy revealed that the antiserum raised against the product of the cDNA expressed in E. coli bound to the epitopes of the connectin filament near the N2 line of chicken breast muscle sarcomeres. The predicted amino acid sequence contains eight immunoglobulin C2 motifs and regions highly homologous with the high and medium molecular weight subunits of neurofilament. In addition, there are regions homologous with desmoplakin, calsequestrin, and calpastatin.


[Clinical workload at the outpatient neuropediatric clinic].
To obtain rapidly the basic clinical information from individual patients and about the total practice in a hospital based neuropediatric out patient clinic. A database file was designed, performed by the medical staff during or immediately after the patients visit. A descriptive study of data obtained through 1995 is reported. 1,226 patients visited the clinic during the whole year, generating 2,315 visits. The percentage of new patients is larger than that of other pediatric specialties, except for pediatric cardiology, but it is similar to that reported by adult neurological patients. Age distribution show a bimodal curve with a peak during the first year of age and a second one at 11 years. Geographic distribution is similar to that of other outpatient clinics of our center. The most frequent motive, annually, to consult was headache followed by suspected epilepsy. The most frequent diagnoses in new patients were epilepsy, migraine and tension type headaches. Prevalence of diagnosis in the total number of patients visited showed the highest frequency of epilepsy, followed by mental retardation and cerebral palsy. EEG was study most often performed, and 46% of total number of patients had neuroimaging studies. The pharmacological agent used in the largest number of patients was sodium valproate while phenobarbital was the product most often discontinued. Non antiepileptic drugs were used in a comparative small number of cases. The percentage of patients discharged for chronic and severe diseases was 20% annually, while it amounted to 40% in new patients. This type of information allows doctors to plan resources needed at the clinic and by the patients, but it is not appropriate for other tasks belonging to the management area, since it would require a larger infrastructure than the one usually provided at the outpatient clinic.


Respiratory and Musculoskeletal Long-Term Outcomes after Surgical Resection of Congenital Cystic Adenomatoid Malformation of the Lung in Newborns, Infants, and Toddlers.
The long-term outcomes of children who underwent surgery for congenital cystic adenomatoid malformation of the lung (CCAML) are not well documented, particularly regarding orthopaedic and respiratory follow-up (FU). The aim of this study was to assess the long-term pulmonary and orthopaedic outcomes of surgically treated CCAML in newborns, infants, and toddlers. Retrospective examination of prospectively recorded data of consecutive patients with CCAML who underwent surgery at our tertiary referral institution from January 2000 to December 2015 (newborns, infants, and toddlers). Clinical, radiological, and surgical data, as well as FU data were revised. A multidisciplinary team followed the patients after discharge at scheduled time points. Seventy-seven patients were included. After surgery, patients were followed for a median of 8 years (range: 1-19 years) until they reached a median age of 8 years (range: 2-19 years). Thirty patients (39%) developed wheezing and 21 (27%) had lower respiratory tract infections (LRTIs) within 4 years of age. However, more than 50% of patients with respiratory symptoms underwent complete remission in the following 4 years. Thirty-one patients (40%) developed at least one minimal musculoskeletal deformity. Eighteen (23%) had scoliosis, 17 (22%) thoracic asymmetry, 10 (12%) pectus excavatum, and 5 (6%) winged scapula. Patients operated for CCAML had good overall outcomes despite pulmonary symptoms and musculoskeletal sequelae. Even though these issues are frequently paucisymptomatic, trying to use less-invasive procedures (such as minimally axillary open "muscle-sparing" thoracotomy or thoracoscopy) may reduce this burden. A structured multidisciplinary FU is required.


Caring for patients with difficult-to-heal ulcers.
This article presents Coloplast's chronic wound care guide for community nurses, in which wound management is described in terms of assessment, treatment and reassessment. Choosing the optimal wound dressing is explained separately. Three case studies are used to demonstrate the use of the guide. Using the guide as a framework is straightforward and easily interpreted by health professionals with varying levels of wound care knowledge and experience, therefore enabling health care professionals to use evidence based practice to improve patient outcomes.