Electronic assessment of clinical reasoning in clerkships: A mixed-methods comparison of long-menu key-feature problems with context-rich single best answer questions.
It remains unclear which item format would best suit the assessment of clinical reasoning: context-rich single best answer questions (crSBAs) or key-feature problems (KFPs). This study compared KFPs and crSBAs with respect to students' acceptance, their educational impact, and psychometric characteristics when used in a summative end-of-clinical-clerkship pediatric exam. Fifth-year medical students (n = 377) took a computer-based exam that included 6-9 KFPs and 9-20 crSBAs which assessed their clinical reasoning skills, in addition to an objective structured clinical exam (OSCE) that assessed their clinical skills. Each KFP consisted of a case vignette and three key features using a "long-menu" question format. We explored students' perceptions of the KFPs and crSBAs in eight focus groups and analyzed statistical data of 11 exams. Compared to crSBAs, KFPs were perceived as more realistic and difficult, providing a greater stimulus for the intense study of clinical reasoning, and were generally well accepted. The statistical analysis revealed no difference in difficulty, but KFPs resulted more reliable and efficient than crSBAs. The correlation between the two formats was high, while KFPs correlated more closely with the OSCE score. KFPs with long-menu exams seem to bring about a positive educational effect without psychometric drawbacks.


[Changes in the outer plexiform layer of the rabbit retina after long-term application of vincristine].
Rabbits which had been intravenously injected with Vincristine for six weeks showed changes in the outer plexiform layer of the retina after one year, which suggests the destruction of receptor cells, bipolar ganglion cells, and horizontal cells. Compensated cell damage accompanied by loss of microtubuli in the cytoplasma, autolytic vacuoles, granular material deposits, and membrane changes of the ribbon complex were frequently observed. A comparison between axons and dendrites showed a predominance of damaged dendritis over axons. Because short-term studies have not produced the same results, different regeneration capacities, which might have their origin in the endoplasmatic reticulum, are discussed.


Effect of cholecystokinin-pancreozymin (CCK-PZ) on glycoprotein secretion from mouse gallbladder epithelium: an ultrastructural and cytochemical study.
Structural changes in the gallbladder epithelial cells of the mouse were studied following in vivo and in vitro stimulation of the gallbladder with the gastrointestinal hormone cholecystokinin-pancreozymin (CCK-PZ). Signs of increased secretory activity were observed within the first 2-3 min after hormone administration. At the ultrastructural level, best visualized with the PA-CrA-silver technique, granule discharge was observed, as was an overall increase in size of the granules. After prolonged in vitro incubation or repeated in vivo stimulation, there was an almost total depletion of secretory granules. This phenomenon is accompanied by an enhanced uptake of extracellular thorium dioxide by endocytotic vesicles at the apical cell surface. An exocytosis-endocytosis coupling mechanism may be important for membrane conservation in the gallbladder epithelial cells. The findings establish that the hormone CCK-PZ stimulates the secretion of glycoproteins from the mouse gallbladder epithelium.


Investigating Serum Uric Acid as a Risk Factor in the Development of Delayed Renal Recovery in Living Kidney Donors.
Hyperuricemia has been associated with kidney disease and remains controversial with regard to its gender-specific differences and impact in living kidney donation. Between 2006 and 2015, charts of live kidney donors who underwent nephrectomy and had a minimum follow-up of 1 year were reviewed. A total of 291 donors were included and divided based on gender-specific pre-donation serum uric acid (SUA) tertiles. Renal functional outcomes included were estimated glomerular filtration rate (eGFR) at 6-month and 1-year follow-up and percentage of donors with a 1-year eGFR <60 mL/min/1.72 m2. Logistic regression analysis was done. Mean SUA tertiles were 5.8 ± 1.1 mg/dL in males and 4.1 ± 1 mg/dL in females. Females in the highest tertile (SUA >4.5 mg/dL) had lower 6-month (59.9 ± 10.3 vs 66.9 ± 14.1 vs 67.3 ± 12.1; P = .018) and 1-year (60.8 ± 10.6 vs 67.6 ± 10.8 vs 67.8 ± 11.8; P = .021) eGFR and a higher percentage of donors with 1-year eGFR <60 mL/min/1.73 m2 (59.5% vs 31.6% vs 23%; P = .002) compared with donors in the lower SUA tertiles (≤4.5 mg/dL). In males, there were similar eGFRs among SUA tertiles at 6-month and 1-year follow-up. In multivariate analysis, SUA was shown to be a significant predictor of developing stage 3 CKD (eGFR <60 mL/min/1.72 m2), 1 year after donation in females but not in males. Predonation SUA level is associated with the development of delayed renal recovery (GFR <60 mL/min/1.72 m2) 1 year after donation in females but not in males.


Impact of a bacterial consortium on the soil bacterial community structure and maize (Zea mays L.) cultivation.
Microorganisms are often applied as biofertilizer to crops to stimulate plant growth, increase yields and reduce inorganic N application. The survival and proliferation of these allochthonous microorganisms in soil is a necessary requisite for them to promote plant growth. We applied a sterilized or unsterilized not commercialized bacterial consortium mixed with cow manure leachate used by a farmer as biofertilizer to maize (Zea mays L.) in a greenhouse experiment, while maize development and the bacterial community structure was determined just before the biofertilizer was applied a first time (day 44), after three applications (day 89) and after six application at the end of the experiment (day 130). Application of sterilized or unsterilized biofertilizer with pH 4.3 and 864 mg NH4+-N kg-1 had no significant effect on maize growth. The application of the biofertilizer dominated by Lactobacillus (relative abundance 11.90%) or the sterilized biofertilizer changed the relative abundance of a limited number of bacterial groups, i.e. Delftia, Halomonas, Lactobacillus and Stenotrophomonas, without altering significantly the bacterial community structure. Cultivation of maize, however, affected significantly the bacterial community structure, which showed large significant variations over time in the cultivated and uncultivated soil. It was concluded that the bacteria applied as a biofertilizer had only a limited effect on the relative abundance of these groups in uncultivated or soil cultivated with maize.


Prognostic and therapeutic stratification in CLL: focus on 17p deletion and p53 mutation.
Chronic lymphocytic leukemia (CLL), a disorder for which B cell heterogeneity and increased cellular proliferation play central pathogenic roles, displays several genetic abnormalities that are associated with poor prognosis and have therapeutic implications. In this review, we discuss the prognostic role and therapeutic implications of chromosome 17p deletions and TP53 mutations in CLL. Unlike other recurrent genetic abnormalities, the frequency of TP53 alterations is relatively low in newly diagnosed patients, but increases sharply with disease progression, which suggests that these alterations represent an evolutionary mechanism of resistance. In comparison with patients without such abnormalities, those with 17p deletions and TP53 mutations have lower response rates and more aggressive disease. One important consequence of the diverse molecular mechanisms that affect the TP53 pathway is the need to assess both the presence of 17p deletion and TP53 mutations before treatment initiation. Several authors have attempted to incorporate TP53 abnormalities in different prognostic models for CLL, and the recent International Prognostic Index for Chronic Lymphocytic Leukemia formally considers patients with TP53 abnormalities (deletion 17p or TP53 mutation or both) as high-risk. Several novel agents may improve results in patients with CLL, including in those with TP53 mutations. Ibrutinib, idelalisib, and venetoclax have been approved in various settings and countries for treatment of CLL. Further progress in targeted therapy and judicious use of chemotherapy, monoclonal antibodies, and reduced-intensity allogeneic transplantation will provide patients with CLL in general, and those with TP53 abnormalities in particular, with a better prognosis.


Percolation Behaviour in the Magnetic Permeability and Electrical Conductivity in Conducting Magnetic - Insulating Non Magnetic Binary Composites.
Experimental results of the complex magnetic permeability (μ) and the electrical conductivity (σ) of a granular paramagnetic Gadolinium Gallium Garnet (GGG: 0.3 to 26 Vol. %) and Teflon (PTFE) system are presented, and discussed in relation to previously published (conductivity) and unpublished (permeability) studies on granular Fe3O4 - talc and Ni - talc wax systems. In these systems, plots of the real conductivity ( σ m ' ) against the volume fraction (φ) lie on a characteristic sigmoid curves that when fitted to the Two Exponent Phenomenological Percolation Equation (TEPPE), confirm the existence of "percolation microstructures" with critical volume fractions (φ c). The plots of the real and imaginary permeability ( μ m ' ) and ( μ m ″ ), satisfactorily fit to the TEPPE using the φ c obtained in each case from the "conductivity" measurements. In all three cases, the conductivity results gave the exponent t > 2, and the permeability results gave t < 1.


Cultural efficacy predicts body satisfaction for Māori.
This paper examines the relationship between body mass index (BMI), self-esteem and self-reported confidence and capability in expressing oneself culturally as Māori (cultural efficacy) for 5,470 Māori who participated in Te Rangahau o Te Tuakiri Māori me Ngā Waiaro ā-Pūtea | The Māori Identity and Financial Attitudes Study (MIFAS) in 2017. Adjusting for demographics, self-reported health, education and socio-economic status, we found that a higher BMI was associated with lower body satisfaction and self-esteem. However, higher scores on cultural efficacy were associated with higher levels of body satisfaction and self-esteem for respondents. Furthermore, the negative association between BMI and both body satisfaction and self-esteem was weaker for those with higher cultural efficacy. This held for BMI scores of 25, 30, and 35+. While our data suggest higher cultural efficacy may directly or interactively shield Māori from developing lowered self-esteem typically associated with higher BMI in Western populations, further research, using more comprehensive measures of body satisfaction should explore the extent to which Māori may find the Western "thin ideal" personally desirable for their own bodies.


Phenylboronic acid modified nanoparticles simultaneously target pancreatic cancer and its metastasis and alleviate immunosuppression.
Pancreatic ductal adenocarcinoma is one of the most lethal malignant tumors, its drug resistance, immunosuppression and metastasis makes the traditional chemotherapy and immunotherapy inefficient. Here we confirmed a 3-aminophenylboronic acid-modified low molecular weight heparin-D-α-tocopheryl succinate micellar nanoparticle (PBA-LMWH-TOS NP, PLT NP) could inhibit orthotopic pancreatic tumor and its spontaneous metastases. The small particle size and high affinity of PBA to sialic acid residue (SA) made PLT/PTX NPs significantly targeted and accumulated in both pancreatic tumor tissues and metastases. The immunosuppressive microenvironment of pancreatic tumor was most caused by the infiltration of immunosuppressive cells, mainly myeloid-derived suppressor cells (MDSCs). We first reported that P-selectin glycoprotein ligand-1 (PSGL-1) was expressed on the surfaces of MDSCs in pancreatic tumor tissues. Meanwhile, we found that LMWH could inhibit the early stage of adhesion cascade between vascular endothelial cells (VECs) and MDSCs by interfering with P-selectin/PSGL-1 binding, thus inhibiting MDSC recruitment to pancreatic tumor tissues. The therapeutic results indicated that PLT/PTX NPs could significantly improve the immune microenvironment of pancreatic tumor and inhibit spontaneous metastases. This nanosystem provides a new immune microenvironment regulation mechanism based on carrier materials in pancreatic tumor, and has high clinical application potential.


Enteral nutritional supplementation prevents mesenteric lymph node T-cell suppression in burn injury.
To determine the effects of an immune-enhancing diet supplemented with glutamine, arginine, fish oil, and dietary nucleotides on mesenteric lymph node T-cell functional disturbances encountered after burn injury in rats. A prospective animal study. University medical center research laboratory. Adult male Sprague-Dawley rats. Rats received a 30%, total body surface, full-thickness burn. Burn-injury rats received the IMPACT diet supplemented with glutamine, arginine, fish oil, and nucleotides or arginine, fish oil, and nucleotides, or an isocaloric/isonitrogenous diet without supplementation with glutamine, arginine, fish oil, or nucleotides. Two days after injury, we found a significant decrease in the proliferation and interleukin-2 production by mesenteric lymph node T cells derived from rats fed on conventional chow compared with sham rats. The burn-related suppression of mesenteric lymph node T-cell proliferation and interleukin-2 production was prevented when the rats were fed on a high-protein diet rich in glutamine, arginine, fish oil, and nucleotides. We found that the immunostimulatory effects of the enriched diet are dependent on the presence of glutamine, arginine, fish oil, and nucleotides as feeding of rats on the isocaloric/isonitrogenous diet deficient in glutamine, arginine, fish oil, and nucleotides did not prevent the burn-related suppression of mesenteric lymph node T-cell dysfunction. Finally, our studies suggested that immunostimulatory effects of the diet are mediated by prostaglandin E(2) regulation of T-cell activation signaling molecule P59fyn. These results suggest that a diet rich in arginine, fish oil, and nucleotides, with and without glutamine, can effectively prevent T-cell dysfunction encountered after burn injury.


Influence of ambient temperature changes on intraoral scanning accuracy.
Different variables that decrease the accuracy of intraoral scanners (IOSs) have been identified. Ambient temperature changes can occur in the dental environment, but the impact of ambient temperature changes on intraoral scanning accuracy is unknown. The purpose of this in vitro study was to assess the impact of ambient temperature changes on the accuracy (trueness and precision) of an IOS. A complete arch maxillary dentate Type IV stone cast was obtained. Four 6-mm-diameter gauge balls were added to the maxillary cast to aid future evaluation measurements. The maxillary cast was digitized by using an industrial scanner (GOM Atos Q 3D 12M). The manufacturer's recommendations were followed in obtaining a reference scan. Then, the maxillary cast was digitized by using an IOS (TRIOS 4) according to the scanning protocol recommended by the manufacturer. Four groups were created depending on the ambient temperature change assessed: 24 °C or room temperature (24-D or control group), 19 °C or a 5-degree temperature drop (19-D group), 15 °C or a 9-degree temperature drop (15-D group), and 29 °C or a 5-degree temperature rise (29-D group). The Shapiro-Wilk and Kolmogorov-Smirnov tests revealed that the data were not normally distributed (P<.05). For trueness, the nonparametric Kruskal-Wallis followed by the Dwass-Steel-Critchlow-Fligner pairwise comparison tests were used. Precision analysis was obtained by using the Levene test based on the comparison of the standard deviations of the 4 groups with 95% Bonferroni confidence intervals for standard deviations (α=.05). The Kruskal-Wallis test revealed significant differences in the trueness values among all 4 groups (P<.001). Furthermore, significant differences between the linear discrepancy medians between the control and 19-D groups (P<.001), control and 15-D groups (P=.002), control and 29-D groups (P<.001), 19-D and 29-D groups (P=.003), and 15-D and 29-D groups (P<.001) were found. The Levene test for the comparison of the variances among the 4 groups did not detect a significant difference (P>.999), indicating that precision wise the 4 groups were not significantly different from each other. Ambient temperature changes had a detrimental effect on the accuracy (trueness and precision) of the IOS tested. Ambient temperature changes significantly decreased the scanning accuracy of the IOS system tested. Increasing the ambient temperature has a greater influence on the intraoral scanning accuracy of the IOS selected when compared with decreasing the ambient temperature.


Response of spontaneously hypertensive rats to 1,25(OH)2D3 in vivo.
Calcium absorption in spontaneously hypertensive rats (SHR) has been reported to be increased, decreased or not different from their normotensive Wistar Kyoto (WKy) control. One postulated reason for these conflicting results is an abnormal sensitivity to the intestinal effects of 1,25(OH)2D3 (1,25D3). Previous studies in everted duodenal sacs and perfused duodenum examined the acute response to 1,25D3 only in 12-week-old SHR, which however already had higher basal rates of calcium absorption. Inability to stimulate Ca absorption further was an unexcluded possibility. To test this hypothesis more vigorously, balance and in situ duodenal 45Ca uptake studies were performed in SHR and WKy using four separate protocols yielding the following results. First, in response to pharmacological doses of 1,25D3 (25 ng/100 g body wt/day X 3), four-week-old normotensive female SHR had higher net calcium absorption (41.4 vs. 31.1 mg/day; 61.6 vs. 48.1%), similar to the increases seen in the untreated state. These results suggest intrinsic epithelial differences independent of 1,25D3. Ca absorption was similarly higher in 1,25D3 treated male SHR (42.9 vs. 36.7 mg/day; 60.1 vs. 53.7%). Second, at 12 to 14 weeks of age, low doses of 1,25D3 (8 ng/100 g body wt/day X 6) stimulated net Ca absorption in the female SHR (33.0 to 39.1 mg/day), but not in WKy (26.8 to 29.3 mg/day). In the male, positive effects were again seen only in the SHR (25 to 45 mg/day). Third, in response to three weeks of dietary Ca deprivation, in situ duodenal 45Ca uptake, measured in the conscious awake state, was higher in 35-week-old SHR (70.9 vs. 53.0%).(ABSTRACT TRUNCATED AT 250 WORDS)


Pain syndrome induced by calcineurin inhibitor and resolved by conversion to sirolimus in a child after kidney transplantation: a case report.
Pain induced by calcineurin inhibitors is a rare complication of unknown pathogenesis. We have reported herein a 7-year-old child who presented with abdominal pain, vomiting, and weight loss showing no significant findings after an extensive laboratory and imaging workup. After conversion from tacrolimus to sirolimus, there was complete resolution of the gastrointestinal symptoms and pain; the patient displays excellent renal function. Calcineurin inhibitor-induced pain syndrome is diagnosis of exclusion but must be considered because the withdrawal of this immunosuppressive agent is associated with improvement in symptoms and quality of life.


Randomised clinical trial: the effects of perioperative probiotic treatment on barrier function and post-operative infectious complications in colorectal cancer surgery - a double-blind study.
Infection following abdominal operation remains a major factor affecting the morbidity of patients after surgery. To determine the effects of perioperative administration of probiotics on the gut barrier function and the surgical outcome in patients undergoing elective colorectal surgery. One hundred patients with colorectal carcinoma were randomly divided into the control group (n = 50) and the probiotics group (n = 50). The probiotics were given orally for 6 days preoperatively and 10 days post-operatively. Outcomes were measured by bacterial translocation, gut permeability, the effect on the faecal microbiota, and the clinical outcomes such as infectious-related complications and gut defecation function. Compared with the control group, probiotics group had increased transepithelial resistance (P < 0.05), reduced transmucosal permeation of horseradish peroxidase and lactulose/mannitol ratio, reduced bacterial translocation (P < 0.05), decreased ileal-bile acid binding protein (P < 0.05) and positive rate of blood bacterial DNA (P < 0.05) and an enhanced mucosal tight junction protein expression. They had decreased blood enteropathogenic bacteria and increased faecal bacterial variety. The post-operative recovery of peristalsis, incidence of diarrhoea, and infectious-related complications were also improved. Probiotics can improve the integrity of gut mucosal barrier by benefiting the faecal microbiota, and decreasing infectious complications in patients with colorectal cancer undergoing colorectomy.


Investigations on myelinogenesis in vitro: regulation of 5'-nucleotidase activity by thyroid hormone in cultures of dissociated cells from embryonic mouse brain.
The developmental pattern of the myelin-associated 5'-nucleotidase and its regulation by L-3,3',5,-triiodothyronine (T3) have been demonstrated in a culture system of cells dissociated from embryonic mouse brain. Hypothyroid calf serum containing low levels of T3 (31 ng/100 ml), and thyroxine, T4 (less than 1 microgram/ml), was used in the culture medium in place of normal calf serum (T3, 103 ng/100ml; T4, 5.7 micrograms/ml) to render the cultures responsive to exogenously added T3. By means of T3 supplementation, the lower levels of enzyme activity observed in the cultures grown in the presence of hypothyroid calf-serum containing medium could be restored to a considerable extent although not completely to normal values. Half-maximal stimulatory effect was obtained at 3.9 X 10(-8)M T3 concentration. Among the various substrates tested, 5'-AMP, 5'-UMP and 5'-CMP were equally good, while 5'-GMP yielded approximately half the activity.


The nationwide investigation of endocrine disruptors in sediment of harbours.
Various types of endocrine disruptors or environmental hormones flow from their sources down into harbours through rivers and other watercourses, and are accumulated in sediment on the sea bottom. Tributyltin, which has been used as paint for ship bottoms, is considered one of the endocrine disruptors. In close cooperation with the other ministries and agencies, the Ports and Harbours Bureau of the Ministry of Land, Infrastructure and Transport carried out an investigation in 1999 to determine the actual condition of 12 endocrine disruptors in the sediment of 39 harbours, in order to gather fundamental data to be used in future examinations of policy. Furthermore, in 2000 the bureau chose seven harbours out of the above 39 harbours as subjects of an additional investigation regarding the surface distribution of endocrine disruptors in the harbour areas and the synchronistic change of accumulation of dioxin and other substances. As the result of the investigation regarding the surface distribution of endocrine disruptors accumulated in seven harbours, relatively high concentrations were measured in the innermost parts of harbours and the mouths of rivers. Synchronistic changes in the amount of dioxin and other substances accumulated in sediments of five harbours were determined. Small amounts of dioxin and other substances, including an especially small amount of coplanar-PCBs, were found in the layers formed before or around 1950. Relatively large amounts of these substances were measured in the upper layers formed during roughly 1960-1990, though no significant yearly differences in concentration could be identified. This result coincides with the facts that, during roughly 1960-1980, PCP and CNP were used as agricultural chemicals and full-scale production of PCBs started in 1960.


Endostatin binds to the catalytic domain of matrix metalloproteinase-2.
We previously reported that endostatin inhibits endothelial and tumor cellular invasion by blocking activation and catalytic activity of matrix metalloproteinase (MMP)-2. Here we have examined the domain of proMMP-2 responsible for the binding of endostatin using surface plasmon resonance. ProMMP-2 and proMMP-2deltaHP lacking the hinge and hemopexin-like (HP) domains bound little to the immobilized endostatin. The active MMP-2 and MMP-2deltaHP, but not the HP domain of MMP-2, bound to endostatin at similar levels. In addition, preincubation of MMP-2 and MMP-2deltaHP with the MMP inhibitor actinonin, which binds to the active site of MMP-2, abolished their bindings to endostatin. These results indicate that endostatin binds to neither the latent proMMP-2 nor the HP domain but to the catalytic domain of MMP-2.


Effect of insulin on the lytic action of lysophosphatidylcholine in lipid bilayers.
The effect of insulin on the bilayer properties of dimyristoylphosphatidylcholine liposomes at the gel and the liquid crystalline state was measured by differential scanning calorimetry and absorbance at 450 nm. It is found that insulin promotes a decrease in the enthalpy of the gel-liquid crystalline transition without displacing the transition temperature. Under these conditions the lytic action of monomyristoylphospatidylcholine is enhanced, decreasing the critical lytic concentrations to values comparable to the bilayer at the gel state. The effect of the lysoderivate on liposomes in contact with increasing concentrations of insulin promotes a reorganization of the lipids into smaller particles as inferred from fluorescence dequenching, turbidity and exclusion chromatography assay. It is concluded that the action of lysoderivates can be enhanced, at temperatures above the transition temperature, by proteins that without spanning the lipid bilayers can perturb the bilayer interface.


[The duality of the qualitative determinacy of the epidemic process in anthroponoses as the main trait distinguishing them from the epidemic manifestations of zoonotic diseases in man].
The present article substantiates the necessity of defining more accurately the notion "epidemic process" and using this term only in reference to anthroponotic diseases. Proceeding from the philosophical concept of the qualitative definiteness of material objects and phenomena, the author proposes to distinguish the epidemic process in anthroponoses from mass spread of zoonotic diseases among humans on the basis of using the systemic qualities of the epidemic process, and in particular the principle of the dual character of the qualitative definiteness of objects and phenomena as the distinctive feature of the epidemic process of anthroponoses. Distinction, based on this principle, between anthroponotic diseases and zoonotic diseases in groups of humans must be reflected in the definitions of these phenomena. The application of the term "epidemic process" only in reference to anthroponotic diseases is proposed, while zoonotic diseases in groups of humans should be considered as epidemic manifestations of zoonotic infections.


The role of financial incentives in shaping clinical practice patterns and practice efficiency.
The US healthcare system is evolving from one in which most providers have been paid on some variation of a fee-for-service basis to one in which many or most providers will be paid on a capitated basis. Will this change in financial incentives make a difference in how coronary artery disease and heart failure are treated and managed? Although the evidence is equivocal and limited, two recent studies suggest that capitation and other global payment incentives may dramatically alter clinical practice patterns in treating cardiovascular disease and substantially reduce cardiac-care costs. Clinical cost-effectiveness research efforts must be intensified. Thought leaders in the field of cardiology must move forcefully in developing, disseminating, and encouraging cardiac-care providers to accept and implement evidence-based clinical practice guidelines. The alternative may be ill-advised tradeoffs decided in a decentralized, competitive marketplace, with algorithms being developed de facto by individual practitioners or groups in response to capitated reimbursement constraints. The resulting practice could reduce healthcare use and spending without being cost-effective. Unexpected and undesirable health outcomes could ensue.


Dynamic Supramolecular Template: Multiple Stimuli-Controlled Size Adjustment of Porous Networks.
Dynamically switchable porous networks offer exciting potential in functionalizing surfaces. The structure and morphology of the networks can be controlled by applying external stimuli. Here, a dynamic supramolecular template assembled by 1,3,5-tris(4-carboxyphenyl)benzene (BTB) is successfully achieved at the liquid-solid interface by applying two external stimuli simultaneously. Upon varying the concentration of BTB solution together with switching the polarity of the sample bias, self-assembled monolayers (SAMs) undergo phase transitions twice: an immediate transition from a compact structure to a macroporous (honeycomb) structure as a response to the change in the electric field and a fast-changing transition from the macroporous to a microporous (oblique) structure. With saturated BTB solution, however, the initial compact structure can only transform into the oblique structure after switching the polarity of the sample bias without the appearance of a honeycomb structure. The different phase transitions suggest that the dynamic supramolecular template can only survive at a specific concentration range and is obtainable by performing multiple stimuli simultaneously. Interestingly, introducing a guest molecule to the system can adjust the phase transition process and effectively stabilize the honeycomb structure of BTB. The flexibility associated with the porous networks renders it a dynamic supramolecular template for guest binding.


Effect of tebuconazole and trifloxystrobin on Ceratocystis fimbriata to control black rot of sweet potato: processes of reactive oxygen species generation and antioxidant defense responses.
Black rot, caused by Ceratocystis fimbriata, is one of the most destructive disease of sweet potato worldwide, resulting in significant yield losses. However, a proper management system can increase resistance to this disease. Therefore, this study investigated the potential of using tebuconazole (TEB) and trifloxystrobin (TRI) to improve the antioxidant defense systems in sweet potato as well as the inhibitory effects on the growth of and antioxidant activity in C. fimbriata. Four days after inoculating cut surfaces of sweet potato disks with C. fimbriata, disease development was reduced by different concentrations of TEB + TRI. Infection by C. fimbriata increased the levels of hydrogen peroxide (H2O2), malondialdehyde (MDA), and electrolyte leakage (EL), and the activity of lipoxygenase (LOX) by 138, 152, 73, and 282%, respectively, in sweet potato disks, relative to control. In the sweet potato disks, C. fimbriata reduced the antioxidant enzyme activities as well as the contents of ascorbate (AsA) and reduced glutathione (GSH) by 82 and 91%, respectively, compared with control. However, TEB + TRI reduced the oxidative damage in the C. fimbriata-inoculated sweet potato disks by enhancing the antioxidant defense systems. On the other hand, applying TEB + TRI increased the levels of H2O2, MDA, and EL, and increased the activity of LOX in C. fimbriata, in which the contents of AsA and GSH decreased, and therefore, inhibited the growth of C. fimbriata. These results suggest that TEB + TRI can significantly control black rot disease in sweet potato by inhibiting the growth of C. fimbriata.


Effects of coordination training on the technical development in 10-/13-year-old football players.
The aim of this study was to determine the effects of coordination training carried out by 10- and 13-year-old male football players on the performance of dribbling, passing, shooting, ball bouncing and wall-volley skills. A total of 45 male football players were divided into three 15 participants groups. The experimental group performed 30 min coordination training three days a week for ten weeks while the control group one continued their routine training and control group two performed unstructured football training. Measurements included Mor and Christian, Yeagley and Johnson football skill tests. Pre- and post-test measurements were compared by an ANOVA 2×3. A significant level of P<0.05 was established. All the skills, dribbling (P<0.001), passing (P<0.001), shooting (P<0.001), ball bouncing (P=0.047) and wall-volley (P<0.001), improved after ten weeks in the experimental group, while only passing (P=0.006), shooting (P=0.007) and wall-volley (P<0.001) improved in the control group one and none of the skills improved in the control group two (P>0.05). The improvement was significant in the experimental group in comparison with the control groups (P<0.001). The implementation of coordination exercises in combination with structured football training has been shown to be effective in improving general football ability among 10-13 male players.


The impact of deontological and teleological variables on the intention to visit green hotel: The moderating role of trust.
Green hotels have grown in popularity due to customers' increased awareness of environmental issues. This study aims to construct and evaluate a model that combines the theory of Planned Behavior (TPB) and the theory of ethics to explain green hotel visitors' intentions and behavior. The study also considers the role of trust & subjective norms as a moderator. The framework of the study was evaluated using a quantitative method. Most of the respondents to the study, which was carried out in Noakhali, Bangladesh, were students at Noakhali Science and Technology University and their family members. The data was collected from 414 respondents and analyzed using the structural equation modeling (SEM) technique. The data collection took around two weeks, starting from December 3, 2021. According to the study's findings, the deontological (Moral obligation and justice) and teleological variables (perceived benefit and perceived risk) significantly influence green hotel visitors' intentions and actual behavior. Moreover, trust noticeably influences the relationship between subjective norm (SN) and Intention, and subjective norm affects the connection between attitude and intention. Therefore, hotel management can utilize this research to examine and understand visitors' intention and actual behavior to visit green hotels, which will assist them in attracting guests by portraying their services as eco-friendly. Furthermore, the findings may help hotel management formulate competitive marketing strategies, design effective promotional tools, and help generate an eco-conscious customer base.


Serum interleukin-8 as a serologic marker of activity in Behçet's disease.
Immune dysregulation has been shown to be one of the major aspects of the yet unknown pathogenesis of Behçet's disease. Interleukin-8 (IL-8), a major chemokine with pivotal effects concerning leukocytes and endothelial cells, has been found to be elevated in patients with Behçet's disease. To evaluate the significance of elevated levels of IL-8 with respect to the activity of Behçet's disease. Sixty-seven consecutive patients with Behçet's disease (37 males, 30 females; 32.5 +/- 9.3 years) were enrolled in our study. The number of active clinical manifestations at the time of serum sampling was recorded. The degree of association between disease activity and IL-8, C-reactive protein, and erythrocyte sedimentation rate was assessed. Serum levels of IL-8 increased as the number of clinically involved organs increased (P < 0.05). C-reactive protein and the erythrocyte sedimentation rate showed no correlation with disease activity. Our study confirms that the IL-8 level is a more sensitive marker of disease activity than the erythrocyte sedimentation rate and C-reactive protein. It may be assumed that IL-8 plays an important role in the pathophysiology of Behçet's disease.


Thymic precursors of TCRαβ(+)CD8αα(+) intraepithelial lymphocytes are negative for CD103.
CD5(+)TCRαβ(+) cells in CD4(-)CD8(-) double negative (DN) thymocytes are generally regarded as the thymic precursors of TCRαβ(+)CD8αα(+) intestinal intraepithelial lymphocytes (IELs). However, this population is not homogenous and can be subdivided based on the expression of cell surface markers such as CD103. In this study, we aimed to define a cell population that is enriched in thymic IEL precursors. Here we report that only CD103(-) but not CD103(+)cells in the CD5(+)TCRαβ(+) DN thymocyte population can give rise to TCRαβ(+)CD8αα(+) IELs or IEL-like cells in in vivo injections and in vitro cultures, respectively. In addition, we demonstrate that IL-15 stimulation alone is sufficient for upregulation of CD8αα in CD103(-)CD5(+)TCRαβ(+) DN thymocytes. We also found that the CD103(-)CD5(+)TCRαβ(+) DN population can be further separated into two fractions: CD69(-/lo) and CD69(+). Of these two fractions, only CD69(-/lo) cells can give rise to CD8αα IEL-like cells in the presence of IL-15 in in vitro cultures. Based on these results, we conclude that a CD69(-/lo)CD103(-)CD5(+)TCRαβ(+) DN population is highly enriched in thymic IEL precursors.


Income shock and food insecurity prediction Vietnam under the pandemic.
As COVID-19 threatens the food security of vulnerable populations across the globe, there is an increasing need to identify places that are affected most in order to target aid. We propose a two-step approach to predict changes in food insecurity risk caused by income shocks at a granular level using existing household-level data and external information on aggregate income shocks. We apply this approach to assess changes in food insecurity risk during the pandemic in Vietnam. Using national household survey data between 2010 and 2018, we first estimate that a 10% decrease in income leads to a 3.5% increase in food insecurity. We then use the 2019 national Labor Force Survey to predict changes in the share of food-insecure households caused by the income shocks during the pandemic for 702 districts. We find that the small, predicted change in food insecurity risk at the national level masks substantial variation at the district level, and changes in food insecurity risk are larger among young children. Food relief policies, therefore, should prioritize a small number of districts predicted to be severely affected.


Treatment Outcome with Fosravuconazole for Onychomycosis.
Fosravuconazole L-lysine ethanolate (F-RVCZ), a ravuconazole prodrug, is a newly available agent with high expectations for efficacy in the treatment of onychomycosis. However, clinical data regarding the efficacy of F-RVCZ are limited because the drug was launched only in Japan in 2018. Therefore, we analyzed the outcome of F-RVCZ therapy in the treatment of onychomycosis at outpatient dermatology clinics in Japan. We examined data for 109 patients (68 male, 41 female) with varying clinical type, including total dystrophic onychomycosis and dermatophytoma, and a wide range of age groups, including the elderly. The complete cure rate at 12 weeks was 6.4% (7/109) and 67.9% (74/109) at the last visit (mean time to last visit: 32 ± 14.2 weeks). Mean rate of improvement in the affected nail area was 49.1 ± 23.3% at 12 weeks and 86.8 ± 22.4% at the last visit. Efficacy at 12 weeks and the last visit, respectively, was as follows: none, 4 cases and 1 case; slight, 35 cases and 4 cases; moderate, 51 cases and 21 cases; significant, 12 cases and 9 cases; complete cure, 7 cases and 74 cases. There were no serious adverse events. This retrospective survey was the first large-scale analysis of actual clinical practice outcomes and had minimal exclusions. Compared to previous reports, our results demonstrated excellent efficacy of F-RVCZ therapy in a variety of patients. Considering our results and the ease of oral administration (1 capsule/day for 12 weeks) and few adverse events, F-RVCZ therapy appears to be a useful option for the treatment of onychomycosis.


Tongue Nodule as Primary Manifestation of American Cutaneous Leishmaniasis in an Immunocompetent Patient.
Leishmaniasis is a parasitic disease considered an endemic public health problem in developing countries, where it is a reportable disease. Isolated oral manifestation is rare, and its clinical manifestations are variable. In this paper we describe an unusual case of an immunocompetent patient, 57-year-old man with a painless reddish submucosal nodule located on the tongue dorsum. Microscopical analysis showed chronic inflammatory infiltrate with macrophages containing leishmania in cytoplasmic vacuoles. PCR assays confirmed the diagnosis and patient was treated with meglumine antimoniate for 30 days. Absence of the parasite was confirmed by PCR. Thirteen years after treatment, a scar fibrosis persisted on the tongue dorsum. The case reported reveals that leishmaniasis should be considered in the diagnosis of tongue nodules in immunocompetent patients.


PARASITE PRESSURE AND THE EVOLUTION OF AMANITIN TOLERANCE IN DROSOPHILA.
Approximately one-half of the members of the Drosophila quinaria species-group are mycophagous. The mushroom-breeding species D. falleni, D. recens, and D. phalerata are far more tolerant of the mushroom toxin α-amanitin than are D. guinaria, D. palustris, and D. subpalustris, which breed in decaying water plants. The non-mycophagous species, however, are physiologically capable of larval development in mushrooms, showing that high levels of amanitin tolerance are not necessary for mycophagy. A primary selective advantage of amanitin tolerance among the mycophagous species is that it allows them to breed in mushrooms that are toxic to nematodes that infest Drosophila in other fungi and render them infertile. Parasitism, then, may be an important factor governing evolutionary patterns of resource utilization in these species.


Allergen-specific immunotherapy for local allergic rhinitis: a systematic review and meta-analysis.
Local allergic rhinitis (LAR) is a phenotype of chronic rhinitis exhibiting a local Th2-driven inflammation without positive clinical markers of atopy. Immunomodulatory effects of allergen-specific immunotherapy (AIT) induce allergen-specific tolerance. However, AIT is not well-recognized as a treatment for LAR. Systematic search on six electronic databases and registries was performed. Experimental and observational studies of AIT for LAR patients were retrieved. The primary outcomes were symptom score, medication score, combined symptom medication score, and disease-specific quality of life. Secondary outcomes were serum specific(s) IgG4, sIgE, and adverse events. Four double-blind randomized controlled trials (156 patients) from two research units assessed the effects of subcutaneous immunotherapy (SCIT). Compared with placebo, SCIT showed significant reductions in symptom score, medication score, combined symptom medication score, disease-specific quality of life, and an increase in serum sIgG4. There was no significant change in serum sIgE. Likewise, two observational studies (one using SCIT and one using sublingual immunotherapy) improved post-therapeutic symptom score. No studies assessed the effects after discontinuation of treatment. AIT was safe without serious adverse events. AIT has beneficial effects and safe for LAR. Its effects are restricted to studies with short-term follow-up. AIT may be considered in LAR patients.


DNA encoding for an efficient 'Omics processing.
The exponential growth of available DNA sequences and the increased interoperability of biological information is triggering intergovernmental efforts aimed at increasing the access, dissemination, and analysis of sequence data. Achieving the efficient storage and processing of DNA material is an important goal that parallels well with the foreseen coding standardization on the horizon. This paper proposes novel coding approaches, for both the dissemination and processing of sequences, where the speed of the DNA processing is shown to be boosted by exploring more than the normally utilized eight bits for encoding a single nucleotide. Further gains are achieved by encoding the nucleotides together with their trailing alignment information as a single 64-bit data structure. The paper also proposes a slight modification to the established FASTA scheme in order to improve on its representation of alignment information. The significance of the propositions is confirmed by the encouraging results from empirical tests.


Comparisons of Schlemm's canal and trabecular meshwork morphologies between juvenile and primary open angle glaucoma.
The histologic differences in Schlemm's canal (SC) and trabecular meshwork (TM), obtained from the trabeculectomy specimens of different age-group glaucoma patients, were compared. This study involved 44 trabeculectomy specimens of 37 juvenile-onset open-angle glaucoma (JOAG) patients (Group A) and 24 trabeculectomy specimens of 24 elderly-onset primary OAG (POAG) patients (age range: 70-79 years, Group B) with no familial history of POAG. Clinical parameters of gender, maximum intraocular pressure (IOP), and the number of glaucoma medications used prior to trabeculectomy were investigated and compared between the two groups. From light microscopy photographs of hematoxylin-eosin, and immunohistochemical staining of markers for SC endothelium (SCE), the total SC length (TSC), comprised of the opened-SC length (OSC) and the closed-SC length (CSC), the percentage of CSC in TSC (%CSC), the percentage of positive SCE marker in CSC (%PinCSC), and the percentage of negative SCE marker in OSC (%NinOSC) were analyzed. Moreover, podoplanin staining patterns in the TM were investigated and compared between the two groups. Among the clinical parameters, the mean maximum IOP in Group A (33.41 ± 9.24 mmHg) was the only significant parameter when compared to that in Group B (22.96 ± 7.17 mmHg, P = 0.000003). TSC in Group A was significantly shorter than that in Group B (P = 0.00092), and %CSC (P = 0.00004) and %PinCSC (P = 0.00342) in Group B were significantly higher than those in Group A. No statistically significant difference in %NinOSC was found between Group A and Group B (P = 0.76060). Juxtacanalicular tissue (JCT) in Group A showed compact and weak staining with podoplanin, while the JCT and closed-SC area in Group B showed intense staining. In the Group A subjects, TSC (P = 0.04819) and OSC (P = 0.02867) were significantly shorter in the non-familial cases than in the familial cases. Platelet coagulations 10-37 μm in size at the defect of the SCE in the inner wall of the SC were observed in 8 eyes (18%) and 4 eyes (17%) in Group A and Group B, respectively. The platelets appeared to repair the SCE damage for maintaining the blood aqueous barrier in both groups of POAG eyes. Smaller SC diameters and accompanying TM abnormality were features observed in the young-onset JOAG patients, thus suggesting developmental abnormalities in the outflow routes. The collapse of SC lumen, presumably due to aging, was the feature observed in the elderly-onset POAG patients. In Group A, the significantly higher IOP, despite of no significant number of topical medications used prior to trabeculectomy, also suggested that JOAG eyes can be categorized as a distinct type of POAG from the eyes of elder-aged POAG patients. The SCE drop out observed in the glaucomatous eyes of the different age groups suggested that worsening of IOP control may possibly occur equally in both groups.


In-line sample concentration in capillary electrophoresis by cyclodextrin to admicelle microextraction.
Cyclodextrins (CDs) as a pseudophase in pseudophase-to-pseudophase microextraction (P2ME) in capillary zone electrophoresis (CZE) are proposed. In this P2ME mode called CD to admicelle ME, a long plug of dilute analyte solution prepared in cetyltrimethylammonium bromide (CTAB) at the critical micellar concentration was injected into the capillary. This formed CTAB admicelles at the interface between the solution and the negatively charged capillary surface, where the analytes were trapped. The injection of CD solution released the admicelles and the analytes from the capillary surface due to the formation of stable CD/CTAB inclusion complexes. The analytes are concentrated at the CD front during injection and voltage separation. Various neutral CDs were found to be effective for CD to admicelle ME. To implement this in-line sample concentration technique in CZE, CD concentration, sample injection time, and sample:CD solution injection ratio were optimized. The optimized conditions for five model anionic analytes, namely, 4-bromophenol, sulindac, sulfamethizole, 4-vinylbenzoic acid, and succinylsulfathiazole, were 20 mM α-CD in 20 mM sodium tetraborate (pH 9.2) solution, sample injection time of 370 s, and CD:sample injection ratio of 1:2. The sensitivity enhancement factors (SEFs) were between 112 and 168. The SEFs of sulindac and sulfamethizole in particular were similar to previously published off-line microextraction techniques, which are typically time-consuming. The calculated values of LOQ, intra-/inter-day (n = 6/n = 10, 3 days) repeatability, and linearity (R2) of CD to admicelle ME were 0.0125-0.05 µg/mL, 1.5-4.6%, 1.8-4.8%, and ≥0.999, respectively. Finally, the potential of CD to admicelle ME to the analysis of artificial urine samples was demonstrated.


Time to antibiotics is unrelated to outcome in pediatric patients with fever in neutropenia presenting without severe disease during chemotherapy for cancer.
Fever in neutropenia (FN) remains an unavoidable, potentially lethal complication of chemotherapy. Timely administration of empirical broad-spectrum intravenous antibiotics has become standard of care. But the impact of time to antibiotics (TTA), the lag period between recognition of fever or arrival at the hospital to start of antibiotics, remains unclear. Here we aimed to analyze the association between TTA and safety relevant events (SRE) in data from a prospective multicenter study. We analyzed the association between time from recognition of fever to start of antibiotics (TTA) and SRE (death, admission to intensive care unit, severe sepsis and bacteremia) with three-level mixed logistic regression. We adjusted for possible triage bias using a propensity score and stratified the analysis by severity of disease at presentation with FN. We analyzed 266 FN episodes, including 53 (20%) with SRE, reported in 140 of 269 patients recruited from April 2016 to August 2018. TTA (median, 120 min; interquartile range, 49-180 min) was not associated with SRE, with a trend for less SREs in episodes with longer TTA. Analyses applying the propensity score suggested a relevant triage bias. Only in patients with severe disease at presentation there was a trend for an association of longer TTA with more SRE. In conclusion, TTA was unrelated to poor clinical outcome in pediatric patients with FN presenting without severe disease. We saw strong evidence for triage bias which could only be partially adjusted.


Increased tolerance to salt stress in the phosphate-accumulating Arabidopsis mutants siz1 and pho2.
High salinity is an environmental factor that inhibits plant growth and development, leading to large losses in crop yields. We report here that mutations in SIZ1 or PHO2, which cause more accumulation of phosphate compared with the wild type, enhance tolerance to salt stress. The siz1 and pho2 mutations reduce the uptake and accumulation of Na(+). These mutations are also able to suppress the Na(+) hypersensitivity of the sos3-1 mutant, and genetic analyses suggest that SIZ1 and SOS3 or PHO2 and SOS3 have an additive effect on the response to salt stress. Furthermore, the siz1 mutation cannot suppress the Li(+) hypersensitivity of the sos3-1 mutant. These results indicate that the phosphate-accumulating mutants siz1 and pho2 reduce the uptake and accumulation of Na(+), leading to enhanced salt tolerance, and that, genetically, SIZ1 and PHO2 are likely independent of SOS3-dependent salt signaling.


Tight linkage between a splicing mutation and a specific DNA haplotype in phenylketonuria.
The first phenylketonuria mutation identified in the human phenylalanine hydroxylase gene is a single base substitution (GT----AT) in the canonical 5'-splice donor site of intron 12. Direct hybridization analysis using specific oligonucleotide probes demonstrates that the mutation is tightly associated with a specific restriction fragment-length polymorphism haplotype among mutant alleles. The splicing mutation is the most prevalent phenylketonuria allele among Caucasians, and the results suggest the possibility of detecting carriers of the genetic trait who have no family history of phenylketonuria.


Fast exact leave-one-out cross-validation of sparse least-squares support vector machines.
Leave-one-out cross-validation has been shown to give an almost unbiased estimator of the generalisation properties of statistical models, and therefore provides a sensible criterion for model selection and comparison. In this paper we show that exact leave-one-out cross-validation of sparse Least-Squares Support Vector Machines (LS-SVMs) can be implemented with a computational complexity of only O(ln2) floating point operations, rather than the O(l2n2) operations of a naïve implementation, where l is the number of training patterns and n is the number of basis vectors. As a result, leave-one-out cross-validation becomes a practical proposition for model selection in large scale applications. For clarity the exposition concentrates on sparse least-squares support vector machines in the context of non-linear regression, but is equally applicable in a pattern recognition setting.


Health impact assessment of the 2012 London Olympic transport plans.
Transport is a structural determinant of health. We have assessed the potential of transport plans for the 2012 London Olympic Games to achieve the sustainability commitment of 'encouraging healthy living'. We compared national and London-wide policies against developments described in the Transport Assessment, a public planning document, for the period of the Games and the aftermath legacy. National and London policies recommend modal shift in travel-more walking and cycling for health benefits, and fewer motor vehicles journeys to reduce harm and risks. For the Games, most spectators will use public transport, with low pollution and injury impacts and some are predicted to attend by cycling or walking. Redevelopment of the Olympics site after the Games will provide green areas for cycling and walking and better public transport, but road traffic is predicted to increase and noise and air pollution will persist above recommended levels. Transport planning for the London Olympic Games is contributing to sustainability. The impact on population health should be measured prospectively.


Communication and collaboration skills training in Radiation Oncology in Australia and New Zealand: A qualitative study.
Effective communication and collaboration with patients, carers and between healthcare professionals improves patient management. This study aimed to explore essential communication and collaboration skills training (CCST) for a radiation oncologist (RO) to inform competencies, learning outcomes and enhance curriculum training methods. Eight focus group discussions with 10 fellows and 14 trainees of the Faculty of Radiation Oncology, Royal Australian and New Zealand College of Radiologists (FRO RANZCR) were conducted face to face between October 2018 and March 2019. Participants included doctors from culturally and linguistically diverse backgrounds, working in public and private, metropolitan, and rural sectors. Data were recorded, transcribed verbatim, managed in Excel, and coded using a qualitative content analysis framework. The study was approved by South Eastern Sydney Local Health District HREC (18/186). Participants provided informed written consent. After achieving thematic saturation, four predominant themes emerged. These were as follows: (1) Enablers and barriers to effective communication and collaboration; (2) written communication; (3) communicating bad news; and (4) multidisciplinary team meeting collaboration. Managing uncertainty and workplace culture emerged as interconnected sub-themes. There is a current lack of CCST in radiation oncology in Australia and New Zealand. The most common theme that emerged to improve CCST focused on increasing the exposure to a variety of communication and collaboration clinical scenarios, which are observed and upon which immediate structured feedback is given. Consultants and trainees offered tangible suggestions on how to improve the curriculum. These findings underscore the importance of using a combination of structured teaching methods and work-based assessments. CCST templates are recommended.


The impact of the physician on the accrual to randomized clinical trials in patients with primary operable breast cancer.
Randomized clinical trials (RCT) are the best way to define optimal treatment, but the accrual rates for hardly any trials have been reported. We analyzed retrospectively the participation of patients in eight phase III multicenter RTCs. Out of a total of 738 patients treated in a single institution for operable breast cancer over a 3-year period, 455 patients (62%) were eligible for at least one of the ongoing trials. Overall, 81% of the patients were informed and 47% of the eligible patients consented to participate. The accrual was 100% to a study with an aggressive combined modality treatment arm for patients with a poor prognosis. A low accrual rate was seen in two trials: 6% in the "elderly" trial comparing tamoxifen only with mastectomy and 10% to the "axilla" trial comparing surgery with radiotherapy to the axilla. The clinicians failed to inform most of these patients about the two trials. In the literature seven of the eight trials were reported; two of them (29%) failed to accrue enough patients.


Sofosbuvir-velpatasvir in adults with hepatitis C virus infection and compensated cirrhosis in Japan.
Protease-free regimens for chronic hepatitis C virus (HCV) infection are safe and effective for persons with either compensated or decompensated cirrhosis. We examined the efficacy and safety of sofosbuvir-velpatasvir in participants with HCV and compensated cirrhosis in Japan. This was a Phase 3, multi-center, open-label study. At 20 sites, 37 individuals with chronic HCV infection of any genotype and compensated cirrhosis received sofosbuvir-velpatasvir (400 mg/100 mg) daily for 12 weeks. Participants were treatment-naïve or treatment-experienced with interferon-based treatments with or without HCV NS3/4A protease inhibitors. Prior exposure with HCV NS5A or NS5B inhibitors was prohibited. The primary study endpoint was sustained virologic response 12 weeks after treatment (SVR12). Among participants, 62% had HCV genotype 1 infection, and 38% had HCV genotype 2. More than three quarters (29/37, 78%) were HCV treatment naïve. All participants (37/37, 100%) achieved SVR12. Seventeen participants (46%) and three participants (8%) had pretreatment resistance-associated substitutions to HCV NS5A and NS5B nucleoside inhibitors respectively, yet no on-treatment breakthrough or relapse occurred. Sofosbuvir-velpatasvir for 12 weeks treatment was safe and well tolerated. The most commonly reported adverse events were headache (8%, 3/37) and diarrhea (5%, 2/37). One serious adverse event, patella fracture, occurred and was considered not treatment related. No participants discontinued study treatment due to an adverse event. Three participants (8%) had a Grade 3 laboratory abnormality; all were hyperglycemia. Sofosbuvir-velpatasvir resulted in high SVR rates and was well tolerated among Japanese patients with HCV and compensated cirrhosis. This single-tablet regimen offers a highly effective, protease-inhibitor free regimen for treating HCV. gov Identifier: NCT04112303.


Intraperitoneal supplementation of iron alleviates dextran sodium sulfate-induced colitis by enhancing intestinal barrier function.
Iron supplementation is necessary for the treatment of anemia, one of the most frequent complications in inflammatory bowel disease (IBD). However, oral iron supplementation leads to an exacerbation of intestinal inflammation. Gut barrier plays a key role in the pathogenesis of IBD. The aim of this study was to characterize the interrelationship between systemic iron, intestinal barrier and the development of intestinal inflammation in a dextran sulfate sodium (DSS) induced experimental colitis mice model. We found that DSS-treated mice developed severe inflammation of colon, but became much healthy when intraperitoneal injection with iron. Iron supplementation alleviated colonic and systemic inflammation by lower histological scores, restorative morphology of colonic villi, and reduced expression of pro-inflammatory cytokines. Moreover, intraperitoneal supplementation of iron enhanced intestinal barrier function by upregulating the colonic expressions of tight junction proteins, restoring intestinal immune homeostasis by regulating immune cell infiltration and T lymphocyte subsets, and increasing mucous secretion of goblet cells in the colon. High-throughput sequencing of fecal 16 S rRNA showed that iron injection significantly increased the relative abundance of Bacteroidetes, which was suppressed in the gut microbiota of DSS-induced colitis mice. These results provided evidences supporting the protective effects of systemic iron repletion by intraperitoneal injection of iron on intestinal barrier functions. The finding highlights a novel approach for the treatment of IBD with iron injection therapy.


Socio-economic and environmental effects influencing the development of leprosy in Bahia, north-eastern Brazil.
To investigate spatial clusters and possible associations between relative risks of leprosy with socio-economic and environmental factors, taking into account diagnosed cases in children under 15 years old. An ecological study was conceived using data aggregated by municipality to identify possible spatial clusters of leprosy from 2005 to 2011. Relative risks were calculated accounting for the respective covariate gender. The second stage of the analysis consisted of verifying possible associations between the relative risks of leprosy as a dependent variable, and socio-economic and environmental variables as independent. This was performed using a multivariate regression analysis according to a previously defined conceptual framework. Overall rates have decreased from 0.88/10 000 in 2005 to 0.52 in 2011. Spatial scan statistics identified 4 high-risk and 6 low-risk clusters. In the regression model, after allowing for spatial dependence, relative risks were associated with higher percentage of water bodies, higher Gini index, higher percentage of urban population, larger average number of dwellers by permanent residence and smaller percentage of residents born in Bahia. Although relative risks of leprosy in Bahia have been decreasing, they remain very high. The association between relative risks of leprosy and water bodies in the proposed geographic scale indicates that hypothesis linking M. leprae and humid environments cannot be discarded. Socio-economic conditions such as inequality, a greater number of dwellers by residence and migration are derived from the urbanisation process carried out in this State. Precarious settlements and poor living conditions in the cities would favour the continuity of leprosy transmission.


Serum platelet factor 4 is a reliable activity parameter in adult patients with inflammatory bowel disease: A pilot study.
To investigate the diagnostic utility of serum platelet factor 4 (PF4) levels and to assess its accuracy in detecting inflammatory bowel disease activity.This study included 45 patients with ulcerative colitis (UC), 45 patients with Crohn disease (CD), and 30 control subjects at Jinling Hospital between May 2014 and July 2015. Laboratory tests measured white blood count, C-reactive protein, erythrocyte sedimentation rate, and platelet count. PF4 was examined by enzyme-linked immunosorbent assays. Patients were divided into 2 groups according to disease activity: active and inactive.Median PF4 values dramatically increased in UC and CD patients compared with the healthy group (UC: 26.64 [20.00-36.22] mg/mL vs 20.02 [14.63-26.83] mg/mL, P = 0.002; CD: 25.56 [18.57-36.36] mg/mL vs 20.02 [14.63-26.83] mg/mL, P = 0.014); however, the serum PF4 levels between UC and CD failed to show a significant difference (26.64 [20.00-36.22] mg/mL vs 25.56 [18.57-36.36] mg/mL, P = 0.521). Furthermore, serum PF4 levels were elevated in both UC and CD patients with active disease (UC: 20.19 [14.89-23.53] mg/mL vs 28.86 [22.57-37.29] mg/mL, P < 0.001; CD: 18.33 [16.72-25.77] mg/mL vs 34.38 [22.58-39.92] mg/mL, P < 0.001). Multivariate analysis revealed higher PF4 level as an independent predictor of disease activity in UC and CD patients (UC: odds ratio 30.375, P = 0.002; CD: odds ratio 54.167, P < 0.001). The cut-off level of PF4 for distinguishing active from inactive UC patients was 24.1 mg/mL. While in CD patients, the cut-off level of PF4 was 19.24 mg/mL.Serum PF4 levels could be a potential biomarker for monitoring the disease activity of inflammatory bowel disease.


Abdominal apoplexy: A rare case of spontaneous middle colic artery rupture with transverse colectomy.
Idiopathic spontaneous intraperitoneal hemorrhage (ISIH) is a rare but potentially fatal entity. The majority of the reported cases of ISIH due to middle colic artery rupture are associated with pseudoaneurysm. Our case is unique in that no pathology could be identified. To our knowledge, this is the third case report in the literature of a spontaneous middle colic artery rupture with no underlying pathology. In our report, we present the case of a 27-years old male presenting with a hemoperitoneum due to ruptured middle colic artery with no evidence of pseudoaneurysm or any other pathology. The patient's hemodynamic status deteriorated abruptly requiring a damage control exploratory laparotomy for evacuation of the hemoperitoneum, ligation of the middle colic artery and transverse colectomy. The post-operative course was uneventful afterwards and the patient was discharged a week after presentation with full recovery. Patients with ISIH might exhibit the "double rupture" phenomenon, compromising their hemodynamic stability and necessitating urgent surgical interventions. CTA can be of paramount importance to guide such interventions if the patient's clinical status permits. Angiographic embolization is an acceptable alternative approach in specific situations. ISIH should be on the differential diagnosis of any young patient presenting to the ED with an acute abdomen, regardless of the identifiable risk factors.


Recent progress in online, comprehensive two-dimensional high-performance liquid chromatography for non-proteomic applications.
Comprehensive two-dimensional HPLC (2DLC) has been used very successfully in proteomics applications for over a decade. Increasingly we are seeing online, comprehensive 2DLC used for non-proteomic applications. This article gives an overview of the state of the art of this technique, with emphasis on current trends in theory and practice that are exciting and hold the most promise for advancing the performance of 2DLC. Specifically, the recently commercialized small, superficially porous packing materials are very well suited to use in the second dimension of online 2DLC where analysis speed is critical and largely dictates the performance of the 2DLC system. Further, the recent development of optimization schemes and associated software that support the use of different second-dimension elution modes in a single 2DLC analysis will improve the flexibility and effectiveness of 2DLC separations. Excluding separations of peptides, proteins, and polymers, 2DLC systems utilizing reversed-phase separation in one dimension, and either normal phase or reversed-phase in the other dimension continue to be the most popular. Although these systems have been applied mostly to complex biological materials, we are beginning to see applications in the analysis of pharmaceutical materials for ingredient purity and degradation profiling. The general lack of robust, easy-to-use commercially available software is arguably the greatest impediment to wider application of 2DLC methods. This situation is improving slowly, however, and at least two commercially available software packages have been described in the peer-reviewed literature. This is an exciting time in the development of online 2DLC.


Vital capacity versus maximal inspiratory pressure in patients with Guillain-Barré syndrome and myasthenia gravis.
The objective is to determine whether maximal inspiratory pressure (P(imax)) measurement is more sensitive than vital capacity (VC) measurement to detect acute respiratory muscle failure considering a theoretical curvilinear relationship between volume and pressure. Review of VC and P(imax) of all patients hospitalized in ICU for Guillain-Barré syndrome (GBS) and myasthenia gravis (MG) exacerbation. 84 consecutive caucasian patients between 19- and 70-years-old hospitalized in intensive care unit from April 2008 to December 2010, for MG exacerbation (44 patients) and GBS (40 patients). The regression curve between VC and P(imax) was linear rather than exponential (r = 0.599, P > 0.0001). The contingency table demonstrated agreement between VC and P(imax) (χ(2)= 26.7, P = 0.0001), with similar number of patients having abnormal P(imax) associated to normal VC and normal P(imax) associated to abnormal VC (9 (10.7%) vs. 8 (9.5%) respectively). Six of the patients developed an important decrease of VC from normal value to less than 60% of the predicted value and did not present evident curvilinear relationship between VC and P(imax) during this follow-up. Because the regression between VC and P(imax) was linear rather than curvilinear, P(imax) was not more sensitive than VC for early detection of respiratory muscle failure in patients hospitalized in ICU for GBS and MG exacerbation. Therefore, VC remains well suited to assess acute respiratory muscle failure and P(imax) gives poor additional information.


Pre-training inactivation of basolateral amygdala and mediodorsal thalamus, but not orbitofrontal cortex or prelimbic cortex, impairs devaluation in a multiple-response/multiple-reinforcer cued operant task.
Reinforcer devaluation is a task often used to model flexible goal-directed behavior. Here, we inactivated basolateral amygdala (BLA), orbitofrontal cortex (OFC), mediodorsal thalamus (MD) (Exp. 1) and prelimbic cortex (PL) (Exp. 3) in rats during multiple-response/multiple-reinforcer operant training with levers available to earn reinforcers during cued trials. After two training days with each lever-food relationship, a reinforcer was devalued through selective satiety and devaluation was assessed in a choice test with the brain areas non-inactivated. The control and OFC and PL inactivation groups exhibited a devaluation effect, but the BLA or MD groups did not. Since the OFC is proposed to be required in devaluation tasks when a discrete cue signals an outcome and PL is proposed to be required when responses based on lever spatial-location guide behavior, we ran new rats through a cue-switching experiment (Exp. 2) to determine the strategy rats use to complete our task (attending to the discrete light cue or spatial lever location). Both groups (cue switched and cue normal) showed a devaluation effect based on the lever spatial location, suggesting that rats rely on the spatial lever location to guide behavior. Future studies will determine whether OFC and PL can compensate for each other to show intact devaluation when the functioning of one of them is impaired.


Pepper yellow mosaic virus, a new potyvirus in sweetpepper, Capsicum annuum.
A potyvirus was found causing yellow mosaic and veinal banding in sweetpepper in Central and Southeast Brazil. The sequence analysis of the 3' terminal region of the viral RNA revealed a coat protein of 278 amino acids, followed by 275 nucleotides in the 3'-untranslated region preceding a polyadenylated tail. The virus shared 77.4% coat protein amino acid identity with Pepper severe mosaic virus, the closest Potyvirus species. The 3'-untranslated region was highly divergent from other potyviruses. Based on these results, the virus found in sweetpepper plants could be considered as a new potyvirus. The name Pepper yellow mosaic virus (PepYMV) is suggested.


Characterization of two complete Isospora mitochondrial genomes from passerine birds: Isospora serinuse in a domestic canary and Isospora manorinae in a yellow-throated miner.
The genus term Isospora is now applied specifically to parasites of birds, with the term Cystoisospora preferred for parasites which infect mammals. Isospora is a common parasitic coccidian in birds worldwide, especially in passerine birds, in which it can cause systemic coccidiosis. The complete mitochondrial genome sequences from two recently identified Isospora species; Isospora serinuse in a domestic canary and Isospora manorinae in a yellow-throated miner, were sequenced and compared with those of other closely related coccidian species. The complete mitochondrial genome sequence for Isospora serinuse is 6260bp in size and 6223bp for Isospora manorinae. The mitochondrial genomes of Isospora serinuse and Isospora manorinae include three protein-coding genes (COI, COIII and CytB), 19 LSU and 14 SSU rDNA fragments, including one newly identified putative LSU fragment in Isospora sp. The arrangement of coding regions in these two Isospora species were identical to that of available Isospora sp. and Eimeria spp. mitochondrial genomes and the start codon usage for protein coding genes was conservative. Phylogenetic analysis of the mt genome of the two Isospora species based on the three coding regions further support that the monophyletic nature of avian Isospora.


Removal of ibuprofen from synthetic wastewater using photocatalytic method in the presence of FeO photocatalyst supported on modified Iranian clinoptilolite.
This study investigated the removal of an organic drug called ibuprofen from the wastewater containing this drug. Iron oxide supported on modified Iranian clinoptilolite was used as the photocatalyst in the presence of the light of a solar lamp. XRD, SEM, EDAX, and FT-IR analyses were performed to detect the prepared photocatalyst. The results of photocatalytic identification analyses proved the suitable loading of iron oxide supported on modified Iranian clinoptilolite. This study investigated the effect of initial concentration of ibuprofen (5-25 mg/L), photocatalyst concentration (100-300 mg/L), and process time (10-240 min) on the removal from ibuprofen from wastewater containing this drug. The experiments were performed in a setup in the presence of a solar lamp with a flux of 300 W/m2. The results indicated that with the initial ibuprofen concentration of 25 mg/L, photocatalyst concentration of 300 mg/L, and time of 210 min, the highest percentage of ibuprofen removal and ibuprofen adsorbed on the catalyst were 99.80% and 83.17 mg/g, respectively. Kinetic modeling was then performed using the Langmuir-Hinshelwood model, and a quasi-first-order kinetic model showed a good agreement with the results obtained. Finally, the recovery of the photocatalyst was investigated, and the results showed that under optimal conditions about 91% of ibuprofen was removed after five re-uses of the photocatalyst.


Increased Medial Elbow Torque Is Associated With Ball Velocity Rather Than a History of Medial Elbow Injuries in Youth Baseball Pitchers.
This study compared medial elbow torque in youth baseball pitchers with and without a history of medial elbow injuries to determine the relationship between medial elbow torque during pitching and having a history of medial elbow injuries. We recruited 171 youth baseball pitchers aged 9 to 12 years old. The exclusion criteria included current pain with pitching, history of surgery on the tested extremity, or osteochondritis dissecans of the humeral capitellum. The participants were grouped into 3 groups: injury <1-year, injury >1-year, and control, based on ultrasonographic abnormalities of the elbow and the presence of elbow pain. Pitchers pitched 3 fastballs while wearing a sensor sleeve that recorded the medial elbow torque, arm speed, and shoulder rotation. Ball velocity was measured using a radar gun. The final analysis included 164 pitchers. Thirty were assigned to the injury <1-year group, 34 to the injury >1-year group, and 100 to the control group. The medial elbow torque was significantly greater in the injury <1-year group compared with the control group (18.6 ± 3.6 Nm vs 16.2 ± 4.8 Nm, P = .023). A multiple regression analysis revealed that ball velocity (B = 0.282, P < .001) and body weight (B = -0.224, P < .001) were significantly associated with medial elbow torque, but not with the history of medial elbow injuries. Increased medial elbow torque was associated with greater ball velocity regardless of the history of medial elbow injuries. Youth baseball pitchers with a history of medial elbow injuries within one year had greater medial elbow torque during pitching; however, having a history of medial elbow injuries was not an independent factor in increasing medial elbow torque. Limiting the ball velocity can reduce medial elbow torque and may prevent elbow injuries in youth baseball pitchers. Level II, prospective comparative prognostic investigation with the patients enrolled at different time point.


Contribution of GADD45 family members to cell death suppression by cellular Bcl-xL and cytomegalovirus vMIA.
Mammalian cells and viruses encode inhibitors of programmed cell death that localize to mitochondria and suppress apoptosis initiated by a wide variety of inducers. Mutagenesis was used to probe the role of a predicted alpha-helical region within the hydrophobic antiapoptotic domain (AAD) of cytomegalovirus vMIA, the UL37x1 gene product. This region was found to be essential for cell death suppression activity. A screen for proteins that interacted with the AAD of functional vMIA but that failed to interact with mutants identified growth arrest and DNA damage 45 (GADD45alpha), a cell cycle regulatory protein activated by genotoxic stress, as a candidate cellular binding partner. GADD45alpha interaction required the AAD alpha-helical character that also dictated GADD45alpha-mediated enhancement of death suppression. vMIA mutants that failed to interact with GADD45alpha were completely nonfunctional in cell death suppression, and any of the three GADD45 family members (GADD45alpha, GADD45beta/MyD118, or GADD45gamma/OIG37/CR6/GRP17) was able to cooperate with vMIA; however, none influenced cell death when introduced into cells alone. GADD45alpha was found to increase vMIA protein levels comparably to treatment with protease inhibitors MG132 and ALLN. Targeted short interfering RNA knockdown of all three GADD45 family members maximally reduced vMIA activity, and this reduction was abrogated by additional GADD45alpha. Interestingly, GADD45 family members were also able to bind and enhance cell death suppression by Bcl-xL, a member of the Bcl-2 family of cell death suppressors, suggesting a direct cooperative link between apoptosis and the proteins that regulate the DNA damage response.


Patients with multiple hepatocellular carcinomas within the UCSF criteria have outcomes after curative resection similar to patients within the BCLC early-stage criteria.
Surgical strategies for the treatment of multiple hepatocellular carcinomas (HCC) remain controversial. This study compared the prognostic power of the University of California, San Francisco (UCSF) criteria with the Barcelona Clinic Liver Cancer (BCLC) early-stage criteria. Clinical and survival data of 162 multiple-HCC patients in Child-Pugh class A who underwent curative resection were retrospectively reviewed. Prognostic risk factors were analyzed using univariate and multivariate analyses. UCSF criteria were shown to independently predict overall and disease-free survival. In patients within the UCSF criteria, 3-year overall and disease-free survivals were significantly better than in those exceeding the UCSF criteria (68 vs. 34 % and 54 vs. 26 %, respectively; both p < 0.001). There were no significant differences in 3-year overall and disease-free survival between patients within the UCSF criteria but exceeding the BCLC early stage and patients with BCLC early-stage disease (71 vs. 66 %, p = 0.506 and 57 vs. 50 %, p = 0.666, respectively). Tumors within the UCSF criteria were associated with a lower incidence of high-grade tumor (p = 0.009), microvascular invasion (p = 0.005), 3-month death (p = 0.046), prolonged Pringle's maneuver (p = 0.005), and surgical margin <0.5 cm (p < 0.001) than those exceeding the UCSF criteria. Tumors within the UCSF criteria but exceeding the BCLC early stage had invasiveness and surgical difficulty similar to those within the BCLC early-stage criteria. Multiple HCC patients within the UCSF criteria benefit from curative resection. Expansion of curative treatment is justified.


[What do we know about the prevalence of pain caused by malignancy?].
Since there is no epidemiologic assessment of the frequency of pain caused by tumor in Germany, tumor-pain-prevalence is estimated indirectly on the basis of mortality and median survival. Knowing that about 50% of all patients having metastases or incurable locoregional recurrence suffer from pain every day, the product of median survival times mortality was calculated to achieve the number of patients' days with tumor-caused pain per year (82,710,690 days in Germany 1995). By division with 365 (days), it is calculated that 226,605 patients require tumor pain related treatment at one day in Germany. Another calculation based on Bonica's publications that 60-90% of patients suffering from advanced cancer are having pain and based on an estimated tumor prevalence 1989/90 revealed a tumor pain prevalence of 221,826. Thus both methods result in the estimation, that about 220,000 patients require tumor-pain-related treatment at one day in Germany.


Noninvasive analysis of aldose reductase activities in rat testis: 3-FDG NMR spectroscopy and imaging.
Noninvasive investigation of aldose reductase activities in rat testis was performed using 3-fluoro-3-deoxy-D-glucose (3-FDG) and nuclear magnetic resonance (NMR) spectroscopy/imaging. Quantitative determination of testis aldose reductase activities, expressed as the sorbitol index, showed a value similar to that of brain. Sorbitol imaging demonstrated aldose reductase activities in testis to be confined primarily to the central region of this organ. The 3-FDG 19F NMR method appears to have clinical potential in the evaluation of testicular function, especially that of spermatogenesis, noninvasively.


Intrarachidial Misplacement of a Venous Stent for Iliofemoral Deep Vein Thrombosis.
Complications due to venous thrombectomy and iliofemoral stenting in a patient with May-Thurner syndrome are reported. The patient presented with a third episode of deep vein thrombosis (DVT). A computed tomography (CT) scan confirmed the clinical suspicion of left iliofemoral vein thrombosis. After thrombectomy and stenting, the patient complained of left foot paralysis. CT showed the misplaced stent to be in the intrarachidial space. Surgical removal of the stent and new endovascular stenting resulted in complete recovery. This is the first description of this kind of complication after stenting of the left iliofemoral vein. Peri-operative Xray appeared to confirm correct placement of the stent via bilateral femoral venous access. Is a profile control image necessary in patients with an important collateral venous network including large veins?


Psychometric Properties of 2 Participation Measures in Veterans With Mild Traumatic Brain Injury.
To compare the psychometric properties of 2 commonly used participation measures: the Community Reintegration of Service Members (CRIS) and the Participation Assessment with Recombined Tools-Objective (PART-O) in veterans with mild traumatic brain injury (mTBI). Data were collected from 2 cross-sectional observation studies conducted in 2 Veterans Affairs medical centers. Questionnaires were completed in-person or by mail. Veterans with mTBI (N=201) were recruited from the Michael E. DeBakey Veterans Affairs Medical Center in Houston (n=94) and the Malcom Randall North Florida/South Georgia Veterans Health System (n=107). Not applicable. CRIS and PART-O. We conducted Rasch analysis on the PART-O and on 3 subscales of the CRIS (extent of participation, perceived limitation, and satisfaction). For PART-O, results showed PART-O has questionable unidimensionality. For both instruments, some rating categories were underused, and rating scales did not advance accordingly. Compared with PART-O, the CRIS was able to distinguish more categories of person's ability (>5 vs 2 for PART-O) and had better internal consistency as indicated by higher Cronbach α (.96-.98 vs .65 for PART-O). To capture participation unique to veterans with mTBI, CRIS has greater potential to detect a change in participation and is therefore recommended over PART-O. Rating scales of both instruments, however, need further refinement. We suggest future studies examine collapsed rating categories and use qualitative methods to redefine categories.


Are metal stents effective for palliation of malignant dysphagia and fistulas?
One of the available treatments for unresectable oesophagogastric malignancies is the insertion of metal stents. We evaluated prospectively 147 patients suffering from malignant dysphagia and/or fistula, after inserting a self-expandable metal stent. The study included 147 patients (87 males, mean age 73 years). Dysphagia before and after stent placement was scored. Patients were divided in two groups according to dysphagia grade: group A (grade 0, 1) and group B (grades 2, 3, 4). Three types of stents were used: the Ultraflex stent (covered and uncovered) and the Flamingo one (covered). The total number of self-expandable metal stents placed was 183. A total of 92 of them were inserted following the combined endoscopic and fluoroscopic approach (42 by injecting lipiodol), while 91 were placed under endoscopic control only. Early and late complications were evaluated. Mean dysphagia score in group A, 1 day and 1 month after the procedure, was slightly reduced from 0.8 to 0.5/0.6 (p=NS), respectively. However, there was a statistically significant improvement (p<0.001) of mean dysphagia score in group B, from 2.4 initially to 1.1/1.4. Early complications occurred in 37 cases, late ones in 51. According to severity, minor complications occurred in 24 patients, major in 42, while life-threatening ones in 22. Survival ranged from 1 to 611 days and 1-week mortality was 9%. Stent-related death occurred in six patients. All kinds of endoscopic methods used for stenting in the present study were easy to perform even on an out-patient basis. Insertion of self-expandable metal stents is effective in patients with dysphagia scores > or = 2. It might not clinically improve patients with dysphagia score <2, so selection of patients for stenting is essential to avoid unnecessary procedures. Moreover, their high cost, high complication rates and low overall survival may improve following better selection criteria.


Crystal structure of family 5 uracil-DNA glycosylase bound to DNA.
Uracil-DNA glycosylase (UDG) removes uracil generated by the deamination of cytosine or misincorporation of deoxyuridine monophosphate. Within the UDG superfamily, a fifth UDG family lacks a polar residue in the active-site motif, which mediates the hydrolysis of the glycosidic bond by activation of a water molecule in UDG families 1-4. We have determined the crystal structure of a novel family 5 UDG from Thermus thermophilus HB8 complexed with DNA containing an abasic site. The active-site structure suggests this enzyme uses both steric force and water activation for its excision reaction. A conserved asparagine residue acts as a ligand to the catalytic water molecule. The structure also implies that another water molecule acts as a barrier during substrate recognition. Based on no significant open-closed conformational change upon binding to DNA, we propose a "slide-in" mechanism for initial damage recognition.


Neurobiological responses to stereotactic focal irradiation of the adult rodent hippocampus.
Radiation effectively treats brain tumors and other pathologies but dose and treatment plans are limited by normal tissue injury, a major cause of morbidity in survivors. Clinically significant normal tissue injury can occur even with therapies that target pathological tissue and limit out-of-target irradiation. Elucidating the mechanisms underlying normal tissue injury is facilitated by studying the effects of focal irradiation and comparing irradiated and un-irradiated tissue in experimental animals. Young adult rats were irradiated using the Leksell Gamma Knife® with a 10 Gy maximum dose directed at the left hippocampus and shaped to minimize irradiation contralaterally. At least 95% of targeted hippocampus received ≥3 Gy, while all points in the contralateral hippocampus received <0.3 Gy. Neuronal and microglial markers of damage were assessed in the targeted and contralateral hemispheres of Gamma Knife®-treated rats and compared to non-irradiated controls. Acute cell death and sustained changes in neurogenesis and in microglia occurred in the dentate gyrus of the targeted, but not the contralateral, hippocampus, providing experimental evidence that focal irradiation at doses received by peri-target regions during targeted radiation therapy produces robust normal tissue responses. Additional studies using this approach will facilitate assessment of in vivo dose responses and the cellular and molecular mechanisms of radiation-induced brain injury.


An 125I radioimmunoassay for primary conjugated bile salts.
Cholylglycylhistamine, a derivative of cholic acid, has been synthesized and characterized. This derivative has been iodinated using Na125I and chloramine-T and purified free from unlabeled cholylglycylhistamine. Application of this iodinated bile salt derivative to radioimmunoassay of bile salts in human serum is reported. Antibody titers have uniformly increased over titers used in tritium-based assays; some antibodies are usable in dilutions of 1:80,000. The radioimmunoassay described here was found to measure predominantly the primary conjugated bile salts. Sensitivity has been maintained, with the least detectable amount being 0.5 pmoles per assay tube. Normal values in human serum are 3.47 +/- 2.16 (SD) nmoles per ml.


Climate change and oceanic barriers: genetic differentiation in Pomatomus saltatrix (Pisces: Pomatomidae) in the North Atlantic Ocean and the Mediterranean Sea.
Nucleotide variation of partial cytochrome b sequences was analysed in the bluefish Pomatomus saltatrix to investigate the population-structuring roles of climate change and oceanic barriers. Western and eastern North Atlantic Ocean populations appeared to be totally isolated, with the latter connected to the Mediterranean Sea within which further structuring occurred.


Phase I single center trial of ketogenic diet for adults with traumatic brain injury.
Traumatic Brain injury (TBI) is a major cause of mortality and morbidity in the United States. Ketogenic diet (KD) has been shown to have neuroprotective effects in acute brain injury, but limited data about its use in adult TBI patients is available. The objective of this study is to investigate the feasibility and safety of ketogenic diet (KD) for adult TBI patients in the Neuroscience Intensive Care Unit (NSICU). TBI patients admitted to NSICU between June 2019 to March 2021 were enrolled in this single-center, open label, single-arm prospective intervention study. The primary feasibility outcome was achievement of ketosis (detection and maintenance of serum beta-hydroxybutyrate (BOB) levels above normal); secondary outcomes included laboratory and clinical adverse effects related to KD. 10 adults with TBI with Abbreviated Injury Score (AIS)-Head ≥3 and ventriculostomy catheter to monitor intracranial pressure met inclusion/exclusion criteria and were placed on KD. Mean age was 47 years, and all patients were male. Eight out of 10 patients achieved ketosis within mean 2.2 days. KD was initiated within 8-33 h (average 23 h) of hospital admission. No clinical adverse effects were noted, 2 patients developed hypertriglyceridemia and 1 patient developed hypoglycemia. Serum glucose showed a decreasing trend in most patients. This pilot study shows that KD is feasible in the management of TBI patients. A randomized controlled trial (RCT) is justified to further understand the optimal serum BOB levels, dose and duration of KD in TBI and its effect on the outcome. CLINICALTRIALS. NCT03982602, Registered 06/11/2019, https://clinicaltrials.gov/ct2/show/NCT03982602?term=brain+injury&cond=ketogenic+diet&draw=2&rank=3.


On the timescale of stimulus-based action-effect learning.
When performing an action, people pick up associations between their actions and the resulting consequences of that action, a phenomenon that has been termed response (R)-effect (E) learning. In the present study, we investigated incidental R-E learning in a forced-choice-that is, a stimulus (S)-based-acquisition mode. Specifically, the study examined at which timescale R-E learning evolves-that is, how many encounters are actually needed to form stable R-E associations. The learning of R-E associations was assessed in a subsequent test phase via effect-based response priming. Experiment 1 tested 4 different numbers of S-R-E repetitions for a 2-2-2 S-R-E mapping. Experiment 2 disentangled the contributions of S-E and R-E associations to the facilitating impact of effect-based response priming by means of a 4-2-4 S-R-E mapping. Experiment 3 investigated whether R-E associations can be picked up even when a given E cannot be unequivocally predicted based on the antecedent S in case of inconsistent S-R-E couplings. Together, the results of the present study clearly show that R-E learning occurs in a stimulus-based action mode and that it evolves very rapidly after only 12 S-R-E repetitions. Moreover, the present findings suggest that at least in this initial phase of learning, complete S-R-E consistency seems to be relevant for R-E learning.


Multiscalar cellular automaton simulates in-vivo tumour-stroma patterns calibrated from in-vitro assay data.
The tumour stroma -or tumour microenvironment- is an important constituent of solid cancers and it is thought to be one of the main obstacles to quantitative translation of drug activity between the preclinical and clinical phases of drug development. The tumour-stroma relationship has been described as being both pro- and antitumour in multiple studies. However, the causality of this complex biological relationship between the tumour and stroma has not yet been explored in a quantitative manner in complex tumour morphologies. To understand how these stromal and microenvironmental factors contribute to tumour physiology and how oxygen distributes within them, we have developed a lattice-based multiscalar cellular automaton model. This model uses principles of cytokine and oxygen diffusion as well as cell motility and plasticity to describe tumour-stroma landscapes. Furthermore, to calibrate the model, we propose an innovative modelling platform to extract model parameters from multiple in-vitro assays. This platform provides a novel way to extract meta-data that can be used to complement in-vivo studies and can be further applied in other contexts. Here we show the necessity of the tumour-stroma opposing relationship for the model simulations to successfully describe the in-vivo stromal patterns of the human lung cancer cell lines Calu3 and Calu6, as models of clinical and preclinical tumour-stromal topologies. This is especially relevant to drugs that target the tumour microenvironment, such as antiangiogenics, compounds targeting the hedgehog pathway or immune checkpoint inhibitors, and is potentially a key platform to understand the mechanistic drivers for these drugs. The tumour-stroma automaton model presented here enables the interpretation of complex in-vitro data and uses it to parametrise a model for in-vivo tumour-stromal relationships.


Bézier curve parametrisation and echo state network methods for solving optimal control problems of SIR model.
In this work, we introduce an optimal control problem with two control variables of the SIR (susceptible-infected-recovered) epidemic model to minimise the infective and susceptible individuals. To solve the control problem, we use direct Bernstein-Bézier parametrisation of the control variables and metaheuristic optimisation methods of an objective function, and indirect methods, adaptive critic design (ACD) with echo state networks (ESNs) and Pontryagin's maximum principle. We propose Bernstein-Bézier parametrisation and ESNs based algorithms to solve optimal control problems for systems governed by differential equations. We use ACD with ESNs to approximate co-state equations. Our simulations have shown that the proposed two methods are able to solve optimal control problems.