Two-stage subgroup-specific time-to-event (2S-Sub-TITE): An adaptive two-stage time-to-toxicity design for subgroup-specific dose finding in phase I oncology trials.
For phase I trials, the subgroup-specific time-to-event (Sub-TITE) design identifies the maximum tolerated dose (MTD) separately in 2+ heterogeneous patient subgroups. Sub-TITE allows borrowing strength and dynamic clustering across subgroups from the trial's start, but delaying the initiation of borrowing and clustering may improve trial accuracy. We propose the 2-stage Sub-TITE (2S-Sub-TITE) design in which the trial starts by estimating separate models per subgroup, and then initiates the Sub-TITE design at some pre-specified point of patient accrual. We evaluate the operating characteristics of the 2S-Sub-TITE design using simulations. Nine configurations of the 2S-Sub-TITE design (varying in timing of initiation of borrowing/clustering and prior probability of subgroup heterogeneity, p_hetero) and three control methods were compared across 1000 randomly-generated true toxicity probability scenarios. Effects of priors, sample size, escalation rules, target toxicity probability, accrual rate, and number of subgroups were evaluated. Metrics included: proportion of correct selection (PCS) of the true MTD, and average number of toxicities incurred. Among the 5 2S-Sub-TITE configurations (out of 9 total) with the highest PCS (45%) when the subgroup heterogeneity assumption is correct (all of which out-perform the control methods by 2%-6%), the configuration which enables borrowing and clustering allowance with p_hetero = 0.7 starting at 75% patient accrual best minimizes toxicities as well as losses in accuracy if the heterogeneity assumption is incorrect. For trials with high confidence in subgroup heterogeneity, the 2S-Sub-TITE configuration enabling borrowing/clustering with p_hetero = 0.7 starting at 75% patient accrual exhibits superior dose-finding accuracy compared to existing methods.


Analysis of Yarrowia lipolytica growth, catabolism, and terpenoid biosynthesis during utilization of lipid-derived feedstock.
This study employs biomass growth analyses and 13C-isotope tracing to investigate lipid feedstock utilization by Yarrowia lipolytica. Compared to glucose, oil-feedstock in the minimal medium increases the yeast's biomass yields and cell sizes, but decreases its protein content (<20% of total biomass) and enzyme abundances for product synthesis. Labeling results indicate a segregated metabolic network (the glycolysis vs. the TCA cycle) during co-catabolism of sugars (glucose or glycerol) with fatty acid substrates, which facilitates resource allocations for biosynthesis without catabolite repressions. This study has also examined the performance of a β-carotene producing strain in different growth mediums. Canola oil-containing yeast-peptone (YP) has resulted in the best β-carotene titer (121 ± 13 mg/L), two-fold higher than the glucose based YP medium. These results highlight the potential of Y. lipolytica for the valorization of waste-derived lipid feedstock.


Image quality in myopic eyes corrected with laser in situ keratomileusis and phakic intraocular lens.
To compare image quality due to higher-order aberrations following laser in situ keratomileusis (LASIK) or implantation of phakic intraocular lens (PIOL) to correct high myopia. Postoperative wavefront examinations, normalized to a pupil size of 5.5 mm, were obtained for 19 LASIK and 20 PIOL eyes for the same surgeon over the same time period. Higher-order aberrations and simulated retinal images were compared. For this small sample, the LASIK eyes yielded an average three times more spherical aberration and two times more coma than PIOL eyes. The effects of these differences were visualized using the simulated retinal images. Spherical aberration and coma are the major differences between postoperative LASIK and PIOL higher-order aberrations, and simulated retinal images can be used to visualize these effects.


Comparison of two enzyme immunoassays for the detection of Haemonchus contortus infections in sheep.
Two enzyme-linked immunosorbent assays (ELISA) using either excretory/secretory (ES) products or crude somatic antigens (CSA) of adult Haemonchus contortus were compared for their ability to detect antibodies against H. contortus in sheep. Serum samples obtained from a group of 32 H. contortus mono-infected sheep were tested in the two ELISAs and the obtained data were compared with the results of the faecal examinations of these sheep. The first sheep became patent 3 weeks post infection (p.i.) and all sheep had positive egg counts at week 5 p.i. The first antibodies against H. contortus were detected 1 week p.i. and all sheep were found positive by both ELISAs at week 4 p.i. Using sera from a large number of H. contortus-infected sheep a difference in sensitivity between the ES ELISA (97.7%) and the CSA ELISA (89.2%) was found. The specificity of each assay was determined by testing sera obtained from sheep with mono-infections of H. contortus, Trichostrongylus colubriformis, Trichostrongylus vitrinus, Ostertagia circumcincta, Nematodirus battus, Cooperia curticei, Fasciola hepatica, Taenia ovis or Eimeria spp. The specificity of the ES ELISA was 87.2%, whereas the specificity of the CSA ELISA was 82.7%.


Number of attempts required by emergency physicians to achieve competency in diaphragmatic ultrasound imaging.
This research aimed to determine the number of attempts that emergency physicians need to become proficient in undertaking diaphragmatic ultrasound imaging. A prospective observational study was conducted at the emergency department (ED) of a tertiary-care university hospital. Sixteen emergency physicians were each required to obtain a set of images of the right hemidiaphragm of five dyspneic patients using both diaphragmatic excursion and thickness techniques. The images were subsequently reviewed by a specialist using American College of Emergency Physician guidelines. If the evaluations of a physician did not reach the expected standard, the physician was to be given feedback and requested to collect images from another five patients. The process was to be repeated until such time as the images obtained by the physician were deemed to be up to standard. Eighty patients, twelve emergency medicine residents, and four attending physicians were enrolled. Following a didactic session on diaphragmatic ultrasound imaging and its interpretation, practicing on five patients proved sufficient to achieve an adequate level of competency in conducting diaphragmatic ultrasound examinations. Practicing on five patients is sufficient for emergency physicians to achieve an adequate level of competency in conducting right-sided diaphragmatic ultrasound examinations.


Placebos and the UK Medical Research Council--and the consumer perspective.
The UK Medical Research Council, in order to further its mission of maintaining and improving human health, supports a substantial number of clinical trials on a wide variety of medical questions; some of these trials involve the use of placebos as controls or to maintain blinding. Before providing support, proposed trials are carefully reviewed to assess scientific quality, and to determine whether a placebo is required and is ethical in addition to ethics review by independent Research Ethics Committees. Some questions such as the choice of placebos in trials in developing countries, in surgical trials and those involving alternative medicine require consideration of additional, specific issues. Involvement of consumers in MRC work has been increasing and includes the establishment of a Consumer Liaison Group; members of this group comment on patient information leaflets for clinical trials, helping to improve patient understanding of trials and ensuring topics like placebo use are explained clearly. Views differ on the value of placebos in clinical care and on their mechanism of' action; continuing research is helping to clarify the issues.


Comparing surgical outcomes of approaches to adrenalectomy - a systematic review and network meta-analysis of randomised clinical trials.
No randomised clinical trials (RCTs) have simultaneously compared the safety of open (OA), transperitoneal laparoscopic (TLA), posterior retroperitoneal (PRA), and robotic adrenalectomy (RA) for resecting adrenal tumours. To evaluate outcomes for OA, TLA, PRA, and RA from RCTs. A NMA was performed according to PRISMA-NMA guidelines. Analysis was performed using R packages and Shiny. Eight RCTs with 488 patients were included (mean age: 48.9 years). Overall, 44.5% of patients underwent TLA (217/488), 37.3% underwent PRA (182/488), 16.4% underwent RA (80/488), and just 1.8% patients underwent OA (9/488). The mean tumour size was 35 mm in largest diameter with mean sizes of 44.3 mm for RA, 40.9 mm for OA, 35.5 mm for TLA, and 34.4 mm for PRA (P < 0.001). TLA had the lowest blood loss (mean: 50.6 ml), complication rates (12.4%, 14/113), and conversion to open rates (1.3%, 2/157), while PRA had the shortest intra-operative duration (mean: 94 min), length of hospital stay (mean: 3.7 days), lowest visual analogue scale pain scores post-operatively (mean: 3.7), and was most cost-effective (mean: 1728 euros per case). At NMA, there was a significant increase in blood loss for OA (mean difference (MD): 117.00 ml (95% confidence interval (CI): 1.41-230.00)) with similar blood loss observed for PRA (MD: - 10.50 (95% CI: - 83.40-65.90)) compared to TLA. LTA and PRA are important contemporary options in achieving favourable outcomes following adrenalectomy. The next generation of RCTs may be more insightful for comparison surgical outcomes following RA, as this approach is likely to play a future role in minimally invasive adrenalectomy. CRD42022301005.


DNA microarray analysis of gene expression in eutopic endometrium from patients with deep endometriosis using laser capture microdissection.
To investigate differentially expressed genes in epithelial and stromal cells of eutopic endometrium from patients with deep endometriosis and women with normal pelvic cavities using laser capture microdissection and complementary DNA microarrays. Prospective study. University hospital. Patients with deep endometriosis and fertile women who underwent laparoscopic tubal ligation or reversal of tubal sterilization. Endometrial tissue biopsies during the late proliferative phase and early, mid-, and late secretory phases. Genes that were regulated with a change greater than threefold were selected as differentially expressed genes. Validation was performed with real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Microarray analysis identified up-regulation during the late secretory phase (patients with endometriosis vs. controls) of several genes in two important signaling pathways: RAS/RAF/MAPK and PI3K. This included the genes RON, SOS, 14-3-3 protein eta, and uPAR in epithelial cells and KSR and PI3K p85 regulatory subunit alpha in stromal cells; real-time RT-PCR analysis validated up-regulation of all six genes. The RAS/RAF/MAPK and PI3K pathways may be involved in initial development of endometriosis.


An analysis of resources for indigenous women in NSW about cervical screening.
To examine resources about cervical screening made available to Indigenous women in NSW. An Aboriginal woman, on behalf of another Aboriginal woman, telephoned 47 NSW based organisations in May 1998 for information about cervical screening. Received materials were analysed for format, content and readability and then submitted to a panel of Indigenous women for their feedback. Of those 34 organisations agreeing to send resources, only 20 (59%) did so. After removing duplicates, 12 cervical screening resources were available for review of which six were designed and printed in NSW and the other six originated outside NSW. Of the six resources developed in NSW, two (33%) were for Aboriginal women. Of the six resources originating from outside of NSW, another two (33%) also were for Aboriginal women. The Flesch readability scores for resources ranged from 58.6 to 87.27. Those developed in NSW had a significantly lower readability score than those from outside of NSW (p = 0.025). Despite lower education levels among the target group, there was no difference in the readability scores of resources designed for Indigenous women (p = 1). Most resources obtained by us were not tailored for Indigenous women. This study has set a base line for resources available for Indigenous women. Our method could be replicated in the future to evaluate and monitor improvement.


The prevalence and characteristics of childhood overweight in a multiethnic, school-based health setting.
The prevalence and correlates of overweight and the risk of overweight in minority children attending urban school-based health centers remains poorly characterized. The purpose of our study was to examine the prevalence and characteristics of overweight and at risk for overweight in low socioeconomic status minority children enrolled in East Harlem school-based health centers in New York City. A retrospective cross-sectional study during the period of September 2002 to August 2003. Four Pediatric School-based Health Centers in East Harlem. Children and adolescents, aged 5 to 18 years. We examined presence of overweight or the risk of overweight based on body mass index (BMI) percentile and other clinical characteristics. Bivariate and multivariate analyses were performed to assess the relationship between demographics and clinical characteristics with overweight and the risk of overweight. Of the 491 children enrolled, 45.8% were either overweight or at risk for overweight, with the highest risk observed in Hispanic/Latino children. This latter relation remained significant after adjusting for age, sex, and birthweight status. In addition, high screening office blood pressure was related to overweight status and higher BMI percentile. A large proportion of minorities, especially Hispanic/Latino children, attending school-based health centers in an urban community sample, are overweight or at risk for overweight. Elevated screening blood pressure was also a common co-morbidity. Further research should determine the predictors and correlates of overweight, and effective targeted school-based interventions should be tested in this high-risk population.


Time course of left ventricular dilation after myocardial infarction: influence of infarct-related artery and success of coronary thrombolysis.
Dilation of the left ventricle after myocardial infarction is common, occurs rapidly (within 2 weeks of infarction) and may be self-limited. To evaluate the time course of postinfarction left ventricular dilation and to assess the impact of successful coronary thrombolysis, serial radionuclide left ventricular volume analyses were performed in 36 patients undergoing attempted thrombolysis for acute transmural myocardial infarction. All patients underwent cardiac catheterization, coronary angiography and attempted thrombolysis within 7 h of the onset of symptoms. The site of coronary occlusion was the left anterior descending coronary artery in 17 patients, the right coronary artery in 18 and, in 1 patient, occluded bypass grafts to the right and left circumflex coronary arteries. Attempted reperfusion using a thrombolytic agent was successful in 22 individuals, occurring 5 +/- 1 h after the onset of symptoms. Gated radionuclide ventriculography was performed early (mean time 1 day after admission, n = 36), subacutely (mean time 11 days postinfarction, n = 36) and late after infarction (mean time 10.5 months, n = 25), and a geometric technique was used to measure serial left ventricular end-diastolic volume. Left ventricular end-diastolic volume for the entire group increased significantly (p less than 0.01) from 153 +/- 30 ml at baseline to 172 +/- 45 ml (at 11 days) to 220 +/- 63 ml (at 10.5 months). Twenty of 36 patients showed greater than 20% increase in left ventricular end-diastolic volume (dilation) with time. This appeared early in seven patients, occurred remote from infarction in seven others and showed a progressive pattern in six.(ABSTRACT TRUNCATED AT 250 WORDS)


Research of combined adsorption-coagulation process in treating petroleum refinery effluent.
The petroleum refinery industry generates a significant amount of wastewater that contains a high level of organic matter, which calls for effective and costly treatments. In this research, the effectiveness of the petroleum refinery effluent (PRE) treatment with physicochemical process of combined adsorption and coagulation was evaluated. The effects of initial pH, hydraulic condition , and combined sequence of treatment process, different treating reagent types and dosages on the chemical oxygen demand (COD) removal were investigated. Additionally, the elimination efficiency of pollutant wastewater was monitored by gas chromatography-mass spectrometry (GC-MS), and Fourier transformed infrared (FT-IR) spectrophotometer was adopted to describe the structure of the wastewater. Wooden activated carbon was chosen as adsorbent at the dosage of 10 g/L as a primary treatment, and 1500 mg/L polymeric magnesium ferric sulfate was used in coagulation. Results showed that adsorption and subsequent coagulation displayed the best performance when initial pH was 9 at shear rates (G) of G1 = 65 s-1 and G2 = 20 s-1, which reached maximal removal rate of COD and total organic carbon GC-MS testing result revealed that adsorption was effective in phenols and iso-alkanes removal, whereas coagulation was good at removing esters and n-alkanes.


Antibiotic delivery from bone-targeted mesoporous silica nanoparticles for the treatment of osteomyelitis caused by methicillin-resistant Staphylococcus aureus.
Osteomyelitis is a hard-to-treat infection of the bone and bone marrow that is mainly caused by Staphylococcus aureus, with an increasing incidence of methicillin-resistant S. aureus (MRSA). Owing to the aggressiveness of these bacteria in colonizing and destroying the bone, systemic antibiotic treatments fail to eradicate the infection. Instead, it normally entails surgery to remove the dead or infected bone. In this work, we report bone-targeted mesoporous silica nanoparticles for the treatment of osteomyelitis. The nanoparticles have been engineered with a functional gelatine/colistin coating able to hamper premature release from the mesopores while effectively disaggregating the bacterial biofilm. Because antibiotic resistance is a global emergency, we have designed two sets of identical nanoparticles, carrying each of them a clinically relevant antibiotic, that have demonstrated to have synergistic effect. The bone-targeted nanoparticles have been thoroughly evaluated in vitro and in vivo, obtaining a notable reduction of the amount of bacteria in the bone in just 24 h after only one dose, and paving the way for localized, nanoparticle-mediated treatment of MRSA-caused osteomyelitis. STATEMENT OF SIGNIFICANCE: In this work, we propose the use of bone-targeted mesoporous silica nanoparticles to address S. aureus-caused osteomyelitis that render synergistic therapeutic effect via multidrug delivery. Because the bacterial biofilm is responsible for an aggressive surgical approach and prolonged antibiotic treatment, the nanoparticles have been functionalized with a functional coating able to both disaggregate the biofilm, hamper premature antibiotic release and protect the intact bone. These engineered nanoparticles are able to effectively target bone tissue both in vitro and in vivo, showing high biocompatibility and elevated antibacterial effect.


Pulmonary function in diabetic children with and without persistent microalbuminuria.
The principal spirometric and plethysmographic parameters were measured in 68 (38 female) diabetic children and adolescents, aged from 6.01 to 22.00 years; their duration of disease ranged from 1 to 247 months. Thirty-four patients had persistent microalbuminuria. The patients were studied basally and after the Bruce test. All the spirometric parameters were normal in all children, with and without microalbuminuria. The presence of microalbuminuria seems not to be a risk factor for the developing of abnormal pulmonary function.


[Changes in erythrocyte membrane permeability after freezing with polyethylene oxide and glycerol].
Membrane ion permeability to sodium cations and phosphate anions, acid resistance and phospholipid composition were studied in erythrocytes frozen and thawed with 15% glycerol and 10% solution of polyethylene oxide 1500. An increase in membrane permeability to 22Na and HPO4(2-) against a background of reduction in phospholipids and total acid resistance was observed after rapid freezing-thawing and removing of cryoprotectants.


Organochlorine pesticides (OCPs), dioxin-like polychlorinated biphenyls (dl-PCBs), polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo furans (PCDD/Fs) in edible fish from Lake Volta, Lake Bosumtwi and Weija Lake in Ghana.
Organochlorine pesticides (OCPs), dioxin-like polychlorinated biphenyls (dl-PCBs), polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo furans (PCDD/Fs) were measured by a high resolution gas chromatograph-high resolution mass spectrometer (HRGC/HRMS) in selected edible fish from three freshwater bodies, Lake Volta, Lake Bosumtwi and Weija Lake in Ghana. The levels of organochlorine pesticides measured in this study were generally low. The highest concentration of OCPs was measured for dichlorodiphenyltrichloroethane compounds (DDTs) (p,p'-DDT, o,p'-DDT, p,p'-DDE, o,p'-DDE, p,p'-DDD and o,p'-DDD), followed by chlordane compounds (CHLs) (trans-chlordane, cis-chlordane, trans-nonachlor and cis-nonachlor), hexachlorobenzene (HCB) and gamma-hexachlorocyclohexane (γ-HCH). The relatively high ratio of p,p'-DDT/p,p'-DDE in tilapia and catfish with an extremely high value in catfish purchased from a local market at Madina, a suburb of Accra, however, suggests the fresh contamination of technical DDT in Ghana. Although PCDD/Fs and dl-PCBs showed relatively low levels, the concentrations are, however, comparable with recent data of some developed countries. There is a potential health risk from DDTs, PCDD/Fs and dl-PCBs for the general population of Ghana because fish is one of their important protein sources. It is therefore necessary to estimate the total intake of DDTs, PCDD/Fs and dl-PCBs, and to assess the health risks for the general population of Ghana.


ASCL1 is activated downstream of the ROR2/CREB signaling pathway to support lineage plasticity in prostate cancer.
Lineage plasticity is a form of therapy-induced drug resistance. In prostate cancer, androgen receptor (AR) pathway inhibitors potentially lead to the accretion of tumor relapse with loss of AR signaling and a shift from a luminal state to an alternate program. However, the molecular and signaling mechanisms orchestrating the development of lineage plasticity under the pressure of AR-targeted therapies are not fully understood. Here, a survey of receptor tyrosine kinases (RTKs) identifies ROR2 as the top upregulated RTK following AR pathway inhibition, which feeds into lineage plasticity by promoting stem-cell-like and neuronal networks. Mechanistically, ROR2 activates the ERK/CREB signaling pathway to modulate the expression of the lineage commitment transcription factor ASCL1. Collectively, our findings nominate ROR2 as a potential therapeutic target to reverse the ENZ-induced plastic phenotype and potentially re-sensitize tumors to AR pathway inhibitors.


Neuropsychological evaluation and parental assessment of behavioral and motor difficulties in children with neurofibromatosis type 1.
Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem disorder, with large inter and intrafamilial clinical variability and uncertain prognosis. In children with NF1 cognitive disorders, learning difficulties and behavioral problems are common. The present study aims to establish the neuropsychological and behavioral profiles of 78 patients with NF1, aged between 5 and 18 years, and to examine the relationship between these profiles and the transmission of NF1 (sporadic vs. familial), clinical manifestations, and environmental factors. We used several questionnaires completed by parents and neuropsychological tests. The results confirmed specific neuropsychological disabilities in children with NF1, especially involving visuospatial and fine motor skills, learning difficulties and behavioral problems. Cognitive difficulties were significantly more frequent in patients with familial than in those with sporadic NF1. All parental questionnaires were correlated with each other, but parental reports were not associated with FSIQ, SES, school status, and clinical manifestations of the disease. Neuropsychological tests were poorly related to parental reports of cognitive and behavioral difficulties.


Regional frequency analysis of drought severity and duration in Karkheh River Basin, Iran using univariate L-moments method.
Drought is one of the natural disasters that causes a great damage to human life and natural ecosystems. The main differences are in the gradual effect of drought over a relatively long period, impossibility of accurately determining time of the beginning and end of drought, and geographical extent of the associated effects. On the other hand, lack of a universally accepted definition of drought has added to the complexity of this phenomenon. In the last decade, due to increasing frequency of drought in Iran and reduction of water resources, its consequences have become apparent and have caused problems for planners and managers. So in this research, regional frequency analysis using L-moments methods was performed to investigate severity and duration of Standardized Precipitation Index (SPI), Standardized Evapotranspiration Index (SEI), Standardized Runoff Index (SRI), and Standardized Soil Moisture Index (SSI) and to study of meteorological, agricultural, and hydrological droughts in Karkheh River Basin in Iran. Using K-means clustering method, basin was divided into four homogeneous areas. Uncoordinated stations in each cluster were removed. The best regional distribution function was selected for each homogeneous region, and it was found that Pearson type (3) has the highest fit on the data set in the basin. Based on Hosking and Wallis heterogeneity test, Karkheh Basin with H1 < 1 was identified as acceptable homogeneous in all clusters. The results showed that hydrological drought occurs with a very short time delay in Karkheh River Basin after the meteorological drought, and two indicators show meteorological and hydrological drought conditions well. Agricultural drought occurs after meteorological and hydrological drought, respectively, and its severity and duration are less than the other indicators. Meteorological, hydrological, and agricultural droughts do not occur at the same time in all of the years. In general, the SPI drought index shows the most severe droughts compared with the other three indices. By this way, in 5- to 20-year return period with severity of 3SPI and in 20- to 100-year return period with severity of 7SPI, region IV or the western and northwestern areas of the basin has been affected by severe meteorological drought. By using the regional standardized quantities, it is possible to estimate the probability of drought in any part of the catchment that does not have sufficient data for hydrological studies.


Evaluation of a magnetic polysulfone microcapsule containing organic modified montmorillonite as a novel solid-phase extraction sorbent with chlorophenols as model compounds.
A porous polysulfone microcapsule containing organic modified montmorillonite and magnetic nanoparticles (OMMT-Fe(3)O(4)@PSF) has been successfully prepared by a phase-inversion method and evaluated as a magnetic solid-phase extraction (MSPE) sorbent for clean-up and enrichment of 4-chlorophenol (4-CP) and 2-chlorophenol (2-CP) in aqueous samples. Compared with a microcapsule containing the conventional extraction sorbent C18 (C18-Fe(3)O(4)@PSF), OMMT-Fe(3)O(4)@PSF had much lower cost, a faster adsorption rate, and superior uptake amounts for the investigated analytes. The proposed microcapsule has been developed for the extraction of 4-CP and 2-CP from environmental water samples and their analysis by high-performance liquid chromatography with UV detection (HPLC-UV). Various parameters, such as pH, extraction time, the mass of sorbent, and the desorption conditions, have been evaluated and the calibration curves of the chlorophenols were linear (R(2) ≥ 0.9985) in the range from 1.01 to 104.5 ng mL(-1). The limits of detection at a signal-to-noise (S/N) ratio of 3 were 0.22 and 0.17 ng mL(-1) and the limits of quantification calculated at S/N=10 were 1.52 and 1.07 ng mL(-1) for 2-CP and 4-CP, respectively. The recoveries of 2-CP and 4-CP from natural water and the treated wastewater samples were in the range of 84.4-115% with relative standard deviations (RSDs) lower than 7.0%. The results have demonstrated the suitability of the MSPE approach for the analysis of trace chlorophenols in aqueous samples.


MicroRNA-195 and microRNA-378 mediate tumor growth suppression by epigenetical regulation in gastric cancer.
The epigenetic regulation of microRNAs is one of several mechanisms underlying carcinogenesis. We found that microRNA-195 (miR-195) and microRNA-378 (miR-378) were significantly down-regulated in gastric cancer tissues and gastric cancer cell lines. The expression of miR-195 and miR-378 in gastric cancer cells was significantly restored by 5-aza-dC, a demethylation reagent. The low expression of miR-195 and miR-378 was closely related to the presence of promoter CpG island methylation. Treatment with miR-195/miR-378 mimics strikingly suppressed the growth of gastric cancer cells whereas promoted the growth of normal gastric epithelial cells. In contrast, administration of miR-195/miR-378 inhibitors significantly prevented the growth of normal gastric epithelial cells. Expression of cyclin-dependent kinase 6 and vascular endothelial growth factor was down-regulated by exogenous miR-195 and miR-378, respectively. In conclusion, miR-195 and miR-378 are abnormally expressed and epigenetically regulated in gastric cancer cell lines and tissues via the suppression of CDK6 and VEGF signaling, suggesting that miR-195 and miR-378 have tumor suppressor properties in gastric cancer.


Transitory population of cells in the temporal cortex of kittens.
A correlated study, using conventional electron microscopy and the Golgi method in the subplate layer and lower part of layer VI, in the developing temporal cortex of kittens has been made. Neuronal death was identified in semithin sections and with the electron microscope. The existence of presumptive degenerating cells in Golgi preparations has been suggested. This transitory population of early-generated subplate cells might be involved in the organization of cortical afferents before the final targets have completed their migrations.


Cystic echinococcosis in Poland: genetic variability and the first record of Echinococcus granulosus sensu stricto (G1 genotype) in the country.
Cystic echinococcosis is one of the most important zoonotic diseases affecting humans and livestock worldwide, and is endemic in Poland. A set of six isolates on larval stages of Echinococcus granulosus sensu lato tapeworms collected from three humans, two pigs and one sheep from Polish foci of CE was examined by DNA sequencing of two mitochondrial genes (cox1, rrnS). The results demonstrated the presence of E. canadensis and E. granulosus sensu stricto in the investigated hydatid cysts. The former species was found in all five isolates from pigs and humans derived from central Poland. In a sheep hydatid cyst originating from Lesser Poland Voivodeship in southern Poland, E. granulosus s. s. (G1 genotype) was identified. This is the first report of an unambiguously autochthonous infection with E. granulosus s. s. in Poland. The global distribution and host affiliations of the commonly occurring G1 microvariant with nucleotide change 56C/T in cox1, detected here in Polish sheep, are discussed. The finding that sheep harboured E. granulosus s. s. may have important consequences for developing effective hydatid control programmes in Poland due to its longer maturation rate in dogs compared with E. canadensis G7. This may lead to greater expenditures for purchasing anthelmintics to provide an appropriate dosing regime in sheep-raising areas of the country.


Carnosic acid protects neuronal HT22 Cells through activation of the antioxidant-responsive element in free carboxylic acid- and catechol hydroxyl moieties-dependent manners.
In a previous study, we found that carnosic acid (CA) protected cortical neurons by activating the Keap1/Nrf2 pathway, which activation was initiated by S-alkylation of the critical cysteine thiol of the Keap1 protein by the "electrophilic"quinone-type of CA [T. Satoh, K. Kosaka, K. Itoh, A. Kobayashi, M. Yamamoto, Y. Shimojo, C. Kitajima, J. Cui, J. Kamins, S. Okamoto, T. Shirasawa, S.A. Lipton, Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1. J Neurochem., in press]. In the present study, we used HT22 cells, a neuronal cell line, to test CA derivatives that might be more suitable for in vivo use, as an electrophile like CA might react with other molecules prior to reaching its intended target. CA and carnosol protected the HT22 cells against oxidative glutamate toxicity. CA activated the transcriptional antioxidant-responsive element of phase-2 genes including hemeoxygenase-1, NADPH-dependent quinone oxidoreductase, and gamma-glutamyl cysteine ligase, all of which provide neuroprotection by regulating cellular redox. This finding was confirmed by the result that CA significantly increased the level of glutathione. We synthesized a series of its analogues in which CA was esterified at its catechol hydroxyl moieties to prevent the oxidation from the catechol to quinone form or esterified at those moieties and its carbonic acid to stop the conversion from CA to carnosol. In both cases, the conversion and oxidation cannot occur until the alkyl groups are removed by an intracellular esterase. Thus, the most potent active form as the activator of the Keap1/Nrf2 pathway, the quinone-type CA, will be produced inside the cells. However, neither chemical modulation potentiated the neuroprotective effects, possibly because of increased lipophilicity. These results suggest that the neuroprotective effects of CA critically require both free carboxylic acid and catechol hydroxyl moieties. Thus, the hydrophilicity of CA might be a critical feature for its neuroprotective effects.


Bridging medical education goals and health system outcomes: An instrumental case study of pre-clerkship students' improvement projects.
Many medical schools engage students in health system improvement (HSI) efforts. Evaluation of these efforts often focuses on students' learning outcomes and rarely considers the impact on health systems, despite the significant commitment health systems make to these efforts. Our study identified and evaluated system-level outcomes of pre-clerkship medical students' engagement in HSI efforts. We used an instrumental case study approach to examine the effects of pre-clerkship medical students' engagement in HSI projects as part of a 15-month experiential curriculum. We extracted data from 53 project summaries and posters completed during the 2017-18 academic year and follow-up survey data collected in May 2019 from physician coaches and health system professionals who mentored students, contributed to these projects, and worked in the clinical microsystems where the projects occurred. We identified three categories and ten indicators of health system outcomes relevant to medical student engagement in HSI. Using these indicators, our evaluation found multiple benefits to the microsystems in which projects occurred. These included achievement of project aims, perceived immediate and sustained project impact on the health system, and development and implementation of projects with aims that aligned with national and health system priorities. Evaluation of HSI curricula needs to include effects on health systems so that program design can optimize the experience for all involved. Our study offers a framework others can use to evaluate system-level effects of project-based HSI curricula and shows several ways in which students' engagement can add value to health systems.


Inhibition of protein geranylgeranylation and RhoA/RhoA kinase pathway induces apoptosis in human endothelial cells.
Geranylgeranylation of RhoA small G-protein is essential for its localization to cell membranes and for its biological functions. Many RhoA effects are mediated by its downstream effector RhoA kinase. The role of protein geranylgeranylation and the RhoA pathway in the regulation of endothelial cell survival has not been elucidated. The hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor lovastatin depletes cellular pools of geranylgeranyl pyrophosphate and farnesol pyrophosphate and thereby inhibits both geranylgeranylation and farnesylation. Human umbilical vein endothelial cells (HUVECs) were exposed to lovastatin (3 microm-30 microm) for 48 h, and cell death was quantitatively determined by cytoplasmic histone-associated DNA fragments as well as caspase-3 activity. The assays showed that lovastatin caused a dose-dependent endothelial cell death. The addition of geranylgeraniol, which restores geranylgeranylation, rescued HUVEC from apoptosis. The geranylgeranyltransferase inhibitor GGTI-298, but not the farnesyltransferase inhibitor FTI-277, induced apoptosis in HUVEC. Cell death was also induced by a blockade of RhoA function by exoenzyme C3. In addition, treatment of HUVEC with the RhoA kinase inhibitors Y-27632 and HA-1077 caused dose-dependent cell death. Y-27632 did not inhibit other well known survival pathways, such as NF-kappa B, ERK, and phosphatidylinositol 3-kinase/Akt. However, there was an increase in p53 protein level concomitant with Y-27632-induced cell death. Unlike the apoptosis induced by TNF-alpha, which occurs only with inhibition of new protein synthesis, apoptosis induced by inhibitors of HMG-CoA reductase, geranylgeranyltransferase, or RhoA kinase was blocked by cycloheximide. Our data indicate that inhibition of protein geranylgeranylation and RhoA pathways induce apoptosis in HUVEC and that induction of p53 or other proapoptotic proteins is required for this process.


A systematic review and meta-analysis on primary percutaneous coronary intervention of an unprotected left main coronary artery culprit lesion in the setting of acute myocardial infarction.
This study sought to evaluate 30-day all-cause mortality of patients treated with primary percutaneous coronary intervention (PCI) presenting with an acute myocardial infarction (AMI) due to an unprotected left main coronary artery (ULMCA) culprit lesion. In addition, an average estimated mortality rate was extrapolated from the available data. There are limited data available on clinical outcome after primary PCI in patients presenting with AMI with unprotected left main as the infarct-related coronary artery. Medical literature databases were searched to identify cohort studies reporting on primary PCI for unprotected left main-related AMI. A total of 13 retrospective studies meeting all pre-specified criteria were included in the meta-analysis. No randomized trials were available. The primary endpoint for the meta-analysis was 30-day all-cause mortality. This meta-analysis comprises a total of 977 patients, of which 252 (26%) presented in cardiogenic shock. Thirty-day all-cause mortality was evaluated using a forest plot analysis and showed higher event rates in patients presenting with cardiogenic shock among all subgroups. The average estimated 30-day all-cause mortality was 15% in patients presenting without signs of cardiogenic shock and 55% in patients presenting with cardiogenic shock (relative risk: 3.74, 95% confidence interval [CI]: 2.95 to 4.76, p < 0.001). In this large meta-analysis of patients treated with primary PCI for AMI due to an ULMCA culprit lesion, the 30-day all-cause mortality in patients presenting with shock is much higher than in patients not presenting with shock. The estimated all-cause mortality data may serve as a benchmark for future reference.


Effects of Ca2+ and Zn2+ on trifluoperazine-S100 proteins interactions: induced circular dichroism and fluorescence spectra.
Interactions of trifluoperazine (TFP) with S100 proteins, EF-hand type Ca2+-binding proteins, in the presence of Ca2+ and Zn2+ were studied with induced circular dichroism (CD) and fluorescence spectra. The positive CD bands of TFP were induced at around 265 nm by adding either S100a or S100a0 protein in the presence of Ca2+. No CD band of TFP was, however, induced by adding S100b protein in the presence of Ca2+. Addition of Zn2+ to the TFP/S100 protein solutions did not induce any CD band at all. The fluorescence intensity of 2-p-toluidinylnaphthalene 6-sulfonate (TNS) bound to S100a or S100a0 protein decreased by adding TFP in the presence of Ca2+, while that bound to S100b protein decreased by adding TFP in the presence of Zn2+, indicating that TFP binds to S100a protein and S100a0 protein in a Ca2+-dependent manner and to S100b protein in a Zn2+-dependent manner. From these results together with other experimental findings it was suggested that (1) TFP binds to S100a protein and S100a0 protein in the presence of Ca2+, with half-saturation points of 18 and 3 microM, respectively, (2) TFP binds to S100b protein only in the presence of Zn2+, (3) alpha-subunit of S100 protein binds to TFP specifically in a Ca2+-dependent manner and beta-subunit in a Zn2+-dependent manner.


MCM2 expression levels predict diagnosis and prognosis in gastric cardiac cancer.
Gastric Cardiac Cancer (GCC) has high incidence and poor prognosis requiring early screening of high-risk populations. Minichromosome maintenance (MCM) proteins are used as diagnostic-biomarkers in many cancers but not validated for GCC. We evaluate MCM protein 2 (MCM2), comparing it with the validated markers Ki67 and PCNA. GCC and corresponding cardiac precancerous samples were immunostained with Ki67, MCM2 and PCNA antibodies. 90% of dysplasia samples expressed MCM2, whereas Ki67 and PCNA were expressed in 67% and 80% respectively. The sensitivity and negative predictive values of MCM2 were also superior at 90% and 87%, respectively. Ki67 and PCNA expression was correlated with MCM2, but their expressions seldom reached surface layers, whereas MCM2 manifested mostly in easily accessible superficial layers. Labeling indices (LI) of Ki67 and PCNA were also lower. Significant associations between LI (MCM2), LI (PCNA), and TNM-stages, lymph node metastases and GCC grade were found (P<0.05). Increased protein expressions were associated with reduced overall and disease-free survival (P<0.05). Although Ki67 and PCNA were significant prognostic factors, there was no significant improvement in multivariate statistical analyses, in contrast to LI (MCM2) findings. MCM2 is a sensitive, specific and efficient biomarker of GCC having potential use in clinic.


Aging-related changes of triose phosphate isomerase in hippocampus of senescence accelerated mouse and the intervention of acupuncture.
Glycometabolism disorder induced by triose phosphate isomerase (TPI) is closely related to Alzheimer's disease (AD). Senescence accelerated mouse (SAM) is often employed as an AD model characteristic of early cognitive impairment. In order to investigate the variation of TPI with aging, SAM prone 8 (SAMP8) and SAM resistant 1 (SAMR1) were divided into 2-month, 6-month, 8-month and 12-month group. For the analysis of acupuncture intervention, SAMP8 were divided into SAMP8 control group (Pc), SAMP8 acupoint group (Pa), SAMP8 non-acupoint group (Pn) and SAMR1 control group (Rc). Grading score of senescence and Morris water maze results showed that SAMP8 presented aging-related deterioration of learning and memory, and that acupuncture could improve the learning and memory ability of SAMP8. TPI activity and expression were detected by colorimetric method and Western blot analysis, respectively. When compared to SAMR1, TPI activity in 6-, 8- and 12-month SAMP8 decreased significantly. However, acupuncture intervention markedly up-regulated TPI activity in hippocampus of Pa. These findings suggested that the learning and memory deterioration of SAMP8 with aging might be associated with the lower TPI activity and that acupuncture could improve the cognitive impairment by increasing TPI activity, thus correcting the abnormal glycolysis metabolism and maintaining the brain homeostasis and internal environment.


Incorporation of tetracycline into impeded and unimpeded mandibular incisors of the mouse.
Twenty-four hours after a tetracycline injection, the unimpeded, and more rapidly erupting, mouse mandibular incisor contained 20% to 44% more tetracycline than the contralateral, uncut incisor. It was concluded that the increased tetracycline incorporation reflected a higher rate of mineralization associated with faster tooth formation in the unimpeded tooth. By measuring the amount of tetracycline which became incorporated at different times after an incisor was shortened, it was possible to investigate an early stage of the response of the incisor to cutting. A significant increase in the capacity of the tooth to incorporate tetracycline was detectable 4 h after shortening the tooth, and this was maximal after another 4 h.


A novel oriented immunosensor based on AuNPs-thionine-CMWCNTs and staphylococcal protein A for interleukin-6 analysis in complicated biological samples.
Interleukin-6 (IL-6) is of high importance for disease diagnosis and prognosis in human health since it's a crucial component in immune homeostasis, hematopoiesis, and metabolism. Herein, an immunosensor has been developed for monitoring IL-6, which is fabricated by Au nanoparticles (Au NPs)-thionine (THI)-carboxylated multi walled carbon nanotubes (CMWCNTs) as the substrate with high conductivity. Staphylococcal protein A (SPA) could directionally capture antibody to reduce steric hindrance caused by random immobilization. Built upon the high efficiency of IL-6 antibody immobilization by the SPA on the sensing surface, the immunosensor exhibited a favorable activity for IL-6 detection. Under optimal conditions, the biosensor presented a LOD of 2.87 pg mL-1 and a wide linear range from 0.01 ng mL-1 to 800 ng mL-1 in serum samples. Furthermore, the assembled sensor successfully quantified the IL-6 concentration in serum and different tissue lapping liquids (lung, heart, liver) from rats with myocardial infarction. The satisfactory performance of the proposed sensor not only broadens its application in clinical monitoring of IL-6 but also provides a novel approach to study inflammation in rats.


Effects of Glucagon-like Peptide-1 Receptor Agonists and Sodium-glucose Cotransporter 2 Inhibitors on Cardiorenal and Metabolic Outcomes in People Without Diabetes.
During the last decade, the results of large-scale, randomized, clinical trials on newer antidiabetic agents, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium glucose cotransporter type 2 (SGLT2) inhibitor, have been published showing promising findings on cardiovascular and renal outcomes. Besides improving glycemic control, GLP-1 receptor agonists have been shown to modify cardiovascular risk factors, such as insulin resistance, body weight, blood pressure (BP), and lipid profile. Additionally, SGLT2 inhibitors except for glycemic control have been shown to induce weight loss and decrease BP. However, there are limited data regarding their effect on patients without diabetes. Therefore, the aim of the present review is to summarize the existing literature data regarding the effects of newer antidiabetic therapies on patients without diabetes.


The Risk of Second Primary Malignancies in Patients With Lung Neuroendocrine Tumors: A Population-Based Study on SEER Database.
We investigated the at-risk sites of second primary malignancies (SPMs) and evaluate the risk factors of SPMs among lung neuroendocrine tumors (LNETs) survivors by using the surveillance, epidemiology, and end results (SEER) database. Propensity-score matching was performed to conduct a case-control study from the surveillance, epidemiology, and end results (SEER) database. Cox regression analysis and multiple primary standardized incidence ratios were performed to investigate the risk factors of occurrence of SPMs among patients with LNETs. Of 3,206 patients with LNETs after matching, 539 developed SPMs. The risk of developing SPMs was higher in older patients (55-74 vs ≦54: hazard ratios [HR] 1.875; age ≧75 vs ≦54: HR 2.713), higher-stage of LNETs (regional vs localized: HR 1.387; distant vs localized: HR 2.732) and recent periods of diagnosis (2004-2014 vs 1984-1993: HR 1.735). Patients with SCLC, TC and LENEC had a higher risk for SPMs compared to general population. Lung and bronchus, larynx and some digestive organs had higher risk for SPMs while some sex hormone related organs like prostate, breast, and female reproductive system had a lower incidence of SPMs. Patients with LNETs had overall higher risks of SPMs than general population. Different types of second primary malignancies occurred in different periods after LNETs were diagnosed. Further investigations are required to screen different second primary malignancies for those with primary LNETs.


Energy expenditure and caloric and protein intake in infants following the Norwood procedure.
Cardiopulmonary bypass in infants results in a hypermetabolic response. Energy requirements of these patients have not been well studied. We assessed energy expenditure and caloric and protein intake during the first 3 days following the Norwood procedure. Clinical investigation. Children's hospital. Seventeen infants (15 boys, age 4-92 days, median 7 days). VO2 and VCO2 were continuously measured using respiratory mass spectrometry in 17 infants for the first 72 hrs following the Norwood procedure. The respiratory quotient was determined as VCO2/VO2. Energy expenditure was calculated using the modified Weir equation. Measurements were collected at 2- to 4-hr intervals. The mean values in the first 8 hrs, hours 8-32, hours 32-56, and the last 16 hrs were used as representative values for postoperative days 0, 1, 2, and 3. Total caloric and protein intakes were recorded for each day. Energy expenditure, VO2, and VCO2 were initially high; declined rapidly during the first 8 hrs; and were maintained relatively stable in the following hours (p < .0001). Respiratory quotient showed a significant linear increase over the 72 hrs (p = .002). Energy expenditure on days 0, 1, 2, and 3 was 43 +/- 11, 39 +/- 8, 39 +/- 8, and 41 +/- 6 kcal/kg/day, respectively. Total caloric intake was 3 +/- 1, 14 +/- 5, 31 +/- 16, and 51 +/- 16 kcal/kg/day. Protein intake was 0, 0.2 +/- 0.2, 0.6 +/- 0.5, and 0.9 +/- 0.5 g/kg/day on days 0, 1, 2, and 3, respectively. Infants exhibit a hypermetabolic response immediately following the Norwood procedure. Caloric and protein intake was inadequate to meet energy expenditure during the first 2 days after surgery. Further studies are warranted to examine the effects of caloric and protein supplementation on postoperative outcomes in infants after cardiopulmonary bypass.


Author Correction: Multicellular 3D Neurovascular Unit Model for Assessing Hypoxia and Neuroinflammation Induced Blood-Brain Barrier Dysfunction.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Pulmonary ventilation and micro-structural findings in congenital diaphragmatic hernia.
With increasing survival of patients with more severe forms of congenital diaphragmatic hernia (CDH) and risk of long-term respiratory morbidity, studies on lung morphology are needed. We used hyperpolarised (3) He MRI and anatomical (1) H MRI in a cohort of young adult CDH patients to image regional lung ventilation and microstructure, focusing on morphological and micro-structural (alveolar) abnormalities. Nine patients with left-sided CDH, born 1975-1993, were studied. Regional ventilation was imaged with hyperpolarised (3) He MRI, and the (3) He apparent diffusion coefficient (ADC) was computed separately for the ipsilateral and contralateral lungs. (1) H MRI was used to image lung anatomy, total lung volume and motion during free-breathing. (3) He MRI showed ventilation abnormalities in six patients, ranging from a single ipsilateral ventilation defect (3 patients) to multiple ventilation defects in both lungs (one patient treated with extra corporeal membrane oxygenation). In eight patients, (3) He ADC values for the ipsilateral lung were significantly higher than those for the contralateral lung. Functional and micro-structural changes persist into adulthood in most CDH patients. Ipsilateral elevated (3) He ADC values are consistent with enlargement of mean dimensions of the confining lung micro-structure at the alveolar level.


Recognition and capture of metastatic hepatocellular carcinoma cells using aptamer-conjugated quantum dots and magnetic particles.
Metastatic recurrence is the most important biological behavior of hepatocellular carcinoma (HCC) and the main cause of treatment failure. Early prediction of metastasis is currently impossible due to the lack of specific molecular probes to recognize metastatic HCC cells. Aptamers have recently emerged as promising potential molecular probes for biomedical applications. Two well-matched HCC cell lines including HCCLM9 with high metastatic potential and MHCC97-L with low metastatic potential, were used to select aptamers for HCC metastasis. With a whole-cell-SELEX strategy, in which HCCLM9 cells were used as target cells and MHCC97-L cells as subtractive cell, 6 potential aptamers had been generated. Detailed study on selected aptamer LY-1 revealed that it could bind metastatic HCC cells with high affinity and specificity, not only in cells culture and animal models of HCC metastasis, but also in clinical HCC specimens. Moreover, the aptamer LY-1 and magnetic particles conjugates could efficiently capture the HCC cells from complex mixture whole blood. These studies demonstrated that this HCC specific aptamer LY-1 could be a promising molecular probe to recognize metastatic HCC cells.


Methods to measure the binding of therapeutic monoclonal antibodies to the human Fc receptor FcγRIII (CD16) using real time kinetic analysis and flow cytometry.
Two different methods have been developed to measure the binding of therapeutic antibodies to the low affinity human Fc receptor FcγRIII (CD16). The first measures binding of antibody to recombinant soluble receptor by surface plasmon resonance and the second uses flow cytometry to measure antibody binding to cells which express the receptor. Both methods have been formatted as parallel line assays and show high levels of accuracy, precision and linearity, making them suitable for comparability, potency and stability assays. They are both readily able to detect structural differences such as glycosylation, which affect Fc receptor binding. The same approaches can be used to measure the binding of any antibody to any Fc receptor. These assays show greater internal precision and long-term reproducibility than traditional cell-based assays such as antibody-dependent cell-mediated cytotoxicity. A combinational approach with a target binding might be appropriate for routine drug batch release as these assays are likely to be significantly more sensitive to small changes in drug structure or activity.


Comparison of Seven Healthy Lifestyle Scores Cardiometabolic Health: Age, Sex, and Lifestyle Interactions in the NutrIMDEA Web-Based Study.
Global health status concerns both the assessment of wellbeing as well as the associated individualized determinants including quality of life and lifestyle factors. This study aimed to evaluate seven cardiometabolic health related scores and the influence, as well as interactions of lifestyle, heart-related and health-related quality of life (HRQoL) factors in order to inform the future implementation of precision public health (PPH). Data collected from 17,333 participants who were enrolled of the NutrIMDEA study. The data collection period was between May 2020 and November 2020 through an online survey. The baseline questionnaire collected information on socio-demographic data, cardiometabolic history, anthropometric variables and lifestyle aspects. Also, physical and mental component scores of SF12 Health Survey (PCS12/MCS12) were assessed as HRQoL features, which were applied to estimated seven scores (LS7, HLS, 20-years DRS %, FBS, CLI, WAI derived, LWB-I). Most indices (except FBS, CLI, 20-years DRS % and WAI derived) showed that cardiometabolic outcomes and HRQoL measures were dependent on interactions by age and sex. The largest ponderal effect was found in PA total and Mediterranean Diet Score (MEDAS-14) interaction using LS7 as reference. However, using LWB-I as standard, the greatest effect was found in the quality-of-life feature MCS12. Noteworthy, LS7 showed good discrimination against PCS12, while LWB-I demonstrated excellent discrimination to MCS12. A major finding was the interplay between MEDAS-14 and PA on the LS7 scale as well as major effects of lifestyle factors and MCS12/PCS12 among scores, which need to be accounted with precision when implementing cardiometabolic screenings with PPH purposes.


"It Hurts as If…": Pain-Associated Language, Visual Characterization, and Storytelling in Hmong Adults.
Pain is challenging to diagnose and manage in primary care, especially when patients have limited English proficiency (LEP). Little is known about whether LEP patients can provide pain information that is consistent with the process and the content that providers expect in a clinical interaction. We explore how LEP Hmong patients communicate their pain to providers in primary care settings. A qualitative study with 67 Hmong participants (63% female and x̄ age = 53.7 years) were recruited from a Midwestern state. Semistructured interviews on pain communication were conducted, audio-recorded, transcribed, and analyzed using directed content analysis. The Hmong participants described pain using stories that generally had the same dimensions of information that providers require for pain assessment. These included references to time, causality, associated symptoms or related experiences, intensity, and consequences of pain. However, the participants expressed some pain dimensions in language that was not shared by providers: visual metaphors that were generally in reference to pain quality and fewer words for pain location, intensity, and some qualities. Participants used two strategies to decide whether they should tell their pain story: assessing the provider and determining whether their story was appreciated. The perception that providers underappreciated their stories resulted in dissatisfaction and undertreatment of pain. Ultimately, this resulted in having less frequent contact with providers or changing providers. Findings demonstrate a discordance in the expected process and content of the clinical interaction between LEP Hmong patients and providers, suggesting the need for culturally appropriate pain assessments in this population.


A comparative study of some more important experimental animal peroxide metabolism enzymes.
1. We have studied and compared the peroxide metabolism enzymes (SOD, P and C) of the main organs of fresh-water mollusc, chicken, mouse, guinea-pig, rabbit, cat and dog. 2. The liver exhibited the highest SOD activity. The enzymatic activities of the organ homogenates of the guinea-pig stand out in comparison with the values for the other homogenates examined. 3. The liver, kidney and total brain homogenates of the chicken and the vertebrates display no, or only a very low P activity. The highest P activities were measured in the haemolysates. 4. The C and SOD values exhibit a certain parallelism. 5. The peroxide metabolism enzyme activities calculated by utilizing the protein measurements permit the establishment of a more realistic enzymatic activity.


Evaluation of sentinel lymph node metastasis alone guided by three-dimensional computed tomographic lymphography in video-assisted breast surgery.
Detailed relations between lymph nodes and lymph flow can be clarified by three-dimensional computed tomographic (3D-CT) lymphangiography. Systematic collection of lymph nodes based on 3D-CT lymphangiography can decrease unnecessary lymph node dissection and attendant complications. To mark the sentinel lymph node (SLN) on the skin, 3D-CT lymphangiography was performed the day before the surgery. Iopamiron 300 (2 ml) was injected subcutaneously. A 16-channel multidetector-row helical CT scan image was reconstructed to produce a 3D image of lymph ducts and lymph nodes. Biopsy of SLN was performed by a dye-staining method using Visiport-aided endoscopy. Stained lymph nodes were located by following the dye in the lymph ducts on a video monitor. For SLN-metastasis-positive patients, standard axillary lymph node dissection (levels 1 and 2) was performed with video assistance. Since December 2001, video-assisted breast surgery has been performed for 180 patients, SLN biopsy for 150 patients, and 3D-CT lymphangiography for 110 patients. Findings show that SLN-positive metastasis (n = 31) was accompanied by SLN metastasis alone in 14 patients. One-node metastasis, except for SLN, was observed in seven patients, two-node metastasis in three patients, and metastasis involving more than three nodes in seven patients. Review of the lymphoid path using 3D-CT lymphangiography confirmed that metastasis occurred in order of lymph flow. Absence of metastasis in the second and third SLNs, even in patients with SLN metastasis, obviates the need for dissection of more nodes.


Plant growth promoting traits of phosphate-solubilizing rhizobacteria isolated from apple trees in trans Himalayan region of Himachal Pradesh.
Two hundred and six phosphate-solubilizing rhizobacteria (PSB) were isolated from rhizosphere soil (RS) and root endosphere (ER) of apple trees from different sites of four locations viz., Chamba, Shimla, Kinnaur and Kullu of Himachal Pradesh, Northern India, and were screened for plant growth promoting traits (PGPTs) by using culture dependent procedures. Indole acetic acid (IAA) production was detected in 50 isolates (24.2 %), siderophore synthesis in 53 isolates (25.7 %), hydrocyanic acid (HCN) in 40 isolates (19.4 %) and percentage growth inhibition against Dematophora necatrix in 61 isolates (29.6 %). Overall, 54.3 % of PSB isolates from RS and 64.4 % from ER showed none of the PGPTs tested. Among the PSB showing PGPTs, 10.6 % had single trait and 30.6 % had multiple traits showing two (10.7 %), three (14.1 %) and four (5.8 %) types of PGPTs. The Shannon-Weaver diversity index (H') revealed that PGPT-possessing PSBs in RS were more abundant than ER. Clustering analysis by principal component analysis showed that ER was most important factor influencing the ecological distribution and physiological characterization of PGPT-possessing PSB. There was a positive correlation (0.94, p < 0.05) between HCN and antifungal activity producers, and IAA and antifungal activity producers (0.99, p < 0.05). Significant positive correlation (0.42, p < 0.05) between HCN producers and altitude was also noted.


Organizational-level predictors of adoption across time: naltrexone in private substance-use disorders treatment centers.
Prominent on the nation's research agenda on substance-use disorders treatment is the dissemination of effective pharmacotherapies. Thus, the purpose of this article is to use a "diffusion of innovations" theoretical framework to examine the organizationallevel predictors of the adoption of a pharmacotherapy, naltrexone (Revia), in private substance use-disorders treatment centers (N = 165). Data for these analyses were derived from the National Treatment Center Study, which contains four waves of data collected between 1994 and 2003. An event history model examined the impact of culture, leadership characteristics, internal structure, and external characteristics on the likelihood of adopting naltrexone between 1994 and 2003. The results suggest that organizations embracing a 12-step model and those employing more experienced administrators were significantly less likely to adopt naltrexone. Moreover, treatment centers that used prescription drugs, possessed an employee handbook, were accredited, and operated on a for-profit basis were significantly more likely to adopt naltrexone over time. Structural characteristics do affect the innovation adoption behaviors of private substanceuse disorders treatment centers. Organizational-level "research to practice" implications to further the adoption of innovative evidence-based treatments are discussed.


Temporal variation of SOC storage and crop yield and its relationship - A fourteen year field trial about tillage practices in a double paddy cropping system, China.
Carbon (C) sequestration in agricultural systems is recommended as a beneficial measure for climate change mitigation and food security. Despite much research, the relationship between soil organic carbon (SOC) storage and sustainable crop productivity has not been identified for various agricultural ecosystems, especially in the paddy ecosystem where conservation tillage has been adopted. Thus, a long-term experiment was conducted to evaluate the effects of tillage practices on SOC storage, yield, and their relationship in a double-cropped rice (Oryza sativa L.) paddy in Southern China from 2005 to 2018. Four tillage systems were investigated: no-till with residue retained on the soil surface (NTS), rotary tillage with residue retention (RTS), plow tillage with residue retention (CTS), and plow tillage with residue removed (CT). The SOC accumulation in the 0-20 cm layer in tillage systems included two stages: the rapid accumulation stage (2005-2007) and the slow fluctuation stage (2007-2018), with a tendency for C saturation. After reaching C saturation, the increase in SOC storage was not obvious, even with continued C input, and the SOC storage under different tillage systems was inconsistent. In general, SOC storage under NTS was the greatest. Interannual changes were not significant, while cumulative yield (2005-2018) was highest under CTS (162.13 t ha-1), followed by RTS (158.46 t ha-1), NTS (153.99 t ha-1), and CT (149.70 t ha-1). Tillage practices had no effect on the yield stability of late rice, but a significant difference in early rice was noticed between CTS and RTS. A non-linear relationship between rice yield and SOC storage was significant (P < 0.0001). With increasing SOC, yields tended to increase first and then decrease. Thus, innovative tillage strategies (such as NTS) could increase SOC storage before it reaches C saturation, but maintaining SOC storage within a reasonable range and optimizing SOC distribution might be more beneficial for crop productivity than a higher SOC storage, especially in C-rich paddy fields.


A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinases.
The p21-activated kinases (PAKs) are serine/threonine kinases that are involved in a wide variety of cellular functions including cytoskeletal motility, apoptosis, and cell cycle regulation. PAKs are inactivated by blockage of the active site of the kinase domain by an N-terminal regulatory domain. GTP-bound forms of Cdc42 and Rac bind to the regulatory domain and displace it, thereby allowing phosphorylation of the kinase domain and maximal activation. A key step in the activation process is the phosphorylation of the activation loop of one PAK kinase domain by another, but little is known about the underlying recognition events that make this phosphorylation specific. We show that the phosphorylated kinase domain of PAK2 dimerizes in solution and that this association is prevented by addition of a substrate peptide. We have identified a crystallographic dimer in a previously determined crystal structure of activated PAK1 in which two kinase domains are arranged face to face and interact through a surface on the large lobe of the kinase domain that is exposed upon release of the auto-inhibitory domain. The crystallographic dimer is suggestive of an engagement that mediates trans-autophosphorylation. Mutations at the predicted dimerization interface block dimerization and reduce the rate of autophosphorylation, supporting the role of this interface in PAK activation.


Network-based multi-task learning models for biomarker selection and cancer outcome prediction.
Detecting cancer gene expression and transcriptome changes with mRNA-sequencing or array-based data are important for understanding the molecular mechanisms underlying carcinogenesis and cellular events during cancer progression. In previous studies, the differentially expressed genes were detected across patients in one cancer type. These studies ignored the role of mRNA expression changes in driving tumorigenic mechanisms that are either universal or specific in different tumor types. To address the problem, we introduce two network-based multi-task learning frameworks, NetML and NetSML, to discover common differentially expressed genes shared across different cancer types as well as differentially expressed genes specific to each cancer type. The proposed frameworks consider the common latent gene co-expression modules and gene-sample biclusters underlying the multiple cancer datasets to learn the knowledge crossing different tumor types. Large-scale experiments on simulations and real cancer high-throughput datasets validate that the proposed network-based multi-task learning frameworks perform better sample classification compared with the models without the knowledge sharing across different cancer types. The common and cancer-specific molecular signatures detected by multi-task learning frameworks on The Cancer Genome Atlas ovarian, breast and prostate cancer datasets are correlated with the known marker genes and enriched in cancer-relevant Kyoto Encyclopedia of Genes and Genome pathways and gene ontology terms. Source code is available at: https://github.com/compbiolabucf/NetML. Supplementary data are available at Bioinformatics online.


Toxic epidermal necrolysis.
Although Ms Weeks was supported throughout this period, we were concerned that she would require further psychological help. At the end of her stay she decided that she did not require help. However, she knew that if at a later date she changed her mind, it would be arranged. Ms Weeks was offered an appointment with the Red Cross camouflage service, which was on hand to offer advice about appropriate techniques to hide the hyperpigmentation on her face and other exposed areas, but this again was declined. Ms Weeks was in ICU for three-and-a-half weeks and her skin healed well. She was left with multihyperpigmented skin, which over time may resolve itself.


Determination of pulmonary to systemic blood flow ratio in children by a simplified Doppler echocardiographic method.
Doppler echocardiographic determination of the pulmonary to systemic blood flow (Qp/Qs) ratio requires calculation of pulmonary artery and aortic luminal areas and integrals of the Doppler systolic velocity curves. To simplify the Doppler calculation of the Qp/Qs ratio, the square of the ratio of pulmonary to aortic luminal diameters, substituted for the ratio of vessel areas, was multiplied by the ratio of pulmonary to aortic peak flow velocities, substituted for the ratio of velocity time integrals. The Qp/Qs ratios were calculated by both the conventional and the simplified Doppler method in 42 children, 1 month to 16 years of age. Fifteen children had no evidence of shunt and 27 had an intracardiac left to right shunt at the atrial or ventricular level, or both. In children with a shunt, the Qp/Qs ratio obtained at cardiac catheterization by oximetry ranged from 1.4:1 to 4.3:1. Both the conventional and the simplified Doppler Qp/Qs ratios correlated well with the oximetric Qp/Qs ratios (r = 0.94 and 0.93, respectively). Since the pulmonary to aortic luminal area ratio and velocity time integral ratio varied in each patient, neither measurement alone correlated well with the oximetric Qp/Qs ratio and, therefore, neither alone could be used as an estimate of the Qp/Qs ratio. The simplified Doppler calculation of the Qp/Qs ratio, which requires less time and no computer facilities, provides an excellent estimate of the Qp/Qs ratio in children.


Preservation of evoked potentials in a case of anterior spinal artery syndrome.
A case of anterior spinal artery syndrome is presented for which there are neurologic, electrophysiologic, and pathologic correlations. Ten days prior to her death, a 52-year-old hypertensive female developed severe chest pain and lower extremity weakness. A diagnosis of aortic dissection resulting in an anterior spinal artery syndrome was made. Intraoperative posterior tibial somatosensory evoked potentials demonstrated normal morphology and latencies. Autopsy revealed an infarction of the anterior portion of the thoraco-lumbar spinal cord with preservation of the posterior columns. This case demonstrates that severe spinal cord injury can exist in the presence of preserved somatosensory evoked potentials.


Pentachlorophenol distribution in a fresh water ecosystem.
The results of this investigation have shown that PCP persisted in leaf litter and sediments for at least seventeen months following contamination. This persistence provides a potential for continuous contamination of the water column and biological magnification via detritus- and benthic-feeding organisms. An investigation of these factors is presently underway.


Skip segment Hirschsprung's disease: a case report and novel management technique.
Skip segment Hirschsprung's disease is a condition where an area of normally ganglionated intestine is interspersed proximally and distally by aganglionic segments. The occurrence of skip segment has no clear embryological explanation, contrary to the present concept of failure of cranio-caudal migration of neural crest-derived cells in Hirschsprung's disease. Only 25 case reports have been published in literature so far and this is possibly the first to be reported from Asia. We report one such case with novel surgical management.


Importance of endothelial function in mediating the benefits of lipid-lowering therapy.
Trials of lipid lowering by various methods have clearly demonstrated the benefits, clinically and angiographically. Evidence of slowed arterial disease progression and even regression has been convincing but modest, at best. For example, among those treated intensively in the Familial Atherosclerosis Treatment Study (FATS), the mean improvement in proximal stenosis severity was <1% per patient, and only 12% of all lesions showed convincing regression. Despite these modest arterial benefits, the associated reductions in major cardiovascular events have been surprisingly great (24-35% in 3 recent large trials and > or =50% in angiographic trials using combination therapies). The process of plaque disruption helps explain this discrepancy. Disruption can be predicted by a large accumulation of core lipid in the plaque and a high density of lipid-laden macrophages in its thinned fibrous cap. Lesions with these characteristics comprise only 10-20% of the overall lesion population but account for 60-90% of the acute clinical events. Lipid-lowering therapy has beneficial effects on these "high-risk" features of plaque morphology. The composite of data presented here supports the hypothesis that lipid-lowering therapy selectively depletes lipids from this relatively small but dangerous subgroup of fatty lesions, effectively stabilizing them.


Usefulness of Nutraceuticals (Armolipid Plus) Versus Ezetimibe and Combination in Statin-Intolerant Patients With Dyslipidemia With Coronary Heart Disease.
Statins are extensively used to treat dyslipidemia, but, because of their low tolerability profile, they are discontinued in a significant proportion of patients. Ezetimibe and nutraceuticals have been introduced as alternative therapies and have proved to be effective and well tolerated. A single-blind, single-center, randomized, prospective, and parallel group trial comparing a combination of nutraceuticals (red yeast rice, policosanol, berberine, folic acid, coenzyme Q10 and astaxanthin), called Armolipid Plus, and ezetimibe for 3 months in terms of efficacy and tolerability. Patients who did not achieve their therapeutic target (low-density lipoprotein cholesterol <100 mg/dl) could add the alternative treatment on top of randomized treatment for another 12 months: 100 patients who are dyslipidemic with ischemic heart disease treated with percutaneous coronary intervention were enrolled (ezetimibe n = 50, nutraceutical n = 50). Efficacy (lipid profile) and tolerability (adverse events, transaminases, and creatine kinase) were assessed after 3 and 12 months. After 3 months, 14 patients in the nutraceutical group achieved their therapeutic target, whereas none of the patients in the ezetimibe group did. At 1-year follow-up, 58 patients (72.5%) of the combined therapy group (n = 86) and 14 (100%) of the nutraceutical group reached the therapeutic goal. No patients experienced important undesirable effects. In conclusion, nutraceuticals alone or in combination with ezetimibe are well tolerated and improve the lipid profile in statin-intolerant patients with coronary heart disease. Further studies are needed to assess long-term effects of nutraceuticals on mortality.


A rare case of Maffucci's syndrome combined with tuberculum sellae enchondroma, pituitary adenoma and thyroid adenoma.
Maffucci's syndrome is a rare, congenital mesodermal dysplasia combined with dyschondroplasia and haemangiomatosis, and there are only about 150 reported cases. This syndrome is often combined with other neoplasms. Our case was associated with goitre, enchondroma of the tuberculum sellae and pituitary adenoma; the latter brought about disturbance of vision. Including ours, four cases of Maffucci's syndrome associated with pituitary adenoma are found in the literature. In the case of Maffucci's syndrome, it is necessary to examine associated disease as well as associated pituitary adenoma and skull base enchondroma, similar to the correlation of von Recklinghausen's disease with acoustic neurinoma.


De-escalation of the cumulative central radiation dose according to the tumor response can reduce rectal toxicity without compromising the treatment outcome in patients with uterine cervical cancer.
To assess the treatment outcome and toxicity of a low cumulative central dose using a midline block (MLB) during external beam radiotherapy (EBRT). Between January 1988 and December 2010, 1559 patients with FIGO stage IB-IIB uterine cervical cancer that underwent EBRT and high-dose-rate intracavitary brachytherapy (HDR-ICBT) were retrospectively analyzed. During EBRT, MLB was performed (n=1195, MLB group) when a sufficient response was achieved to insert the tandem through the cervical canal and place ovoids in the vaginal cavity. MLB was not applied for patients with a slow tumor response (n=364, non-MLB group). The doses were estimated according to the International Commission on Radiation Units and Measurements (ICRU) points. The biologically equivalent dose in 2-Gy fractions (EQD2) was calculated to estimate the cumulative dose from EBRT and ICBT. EQD2pointA, EQD2rectum, and EQD2bladder were all significantly lower in the MLB group (all P<0.05). The 10-year grade≥2 late rectal toxicity rate was significantly lower in the MLB group (P=0.012), while there was no significant difference in late genitourinary and small bowel toxicity. ICRU rectal and bladder doses showed significant predictability on late rectal and bladder toxicities. After propensity score matching, all patient and tumor characteristics were well matched and the survival and recurrence rates between the two groups were similar (all P>0.05), despite the lower EQD2pointA in the MLB group (P<0.001). Applying MLB according to tumor response during EBRT lowered the cumulative central dose and reduced late rectal toxicity without compromising treatment outcome.


Presynaptic HCN channel activity is required for the expression of long-term potentiation at lateral amygdala to basal amygdala synapses.
Recently, we reported that auditory fear conditioning leads to the presynaptic potentiation at lateral amygdala to basal amygdala (LA-BA) synapses that shares the mechanism with high-frequency stimulation (HFS)-induced long-term potentiation (LTP) ex vivo. In the present study, we further examined the molecular mechanisms underlying the HFS-induced presynaptic LTP. We found that a presynaptic elevation of Ca2+ was required for the LTP induction. Interestingly, the blockade of presynaptic but not postsynaptic HCN channels with ZD7288 completely abolished LTP induction. While ZD7288 did not alter basal synaptic transmission, the blocker fully reversed previously established LTP, indicating that HCN channels are also required for the maintenance of LTP. Indeed, HCN3 and HCN4 channels were preferentially localized in the presynaptic boutons of LA afferents. Furthermore, an inhibition of either GABAB receptors or GIRK channels eliminated the inhibitory effect of HCN blockade on the LTP induction. Collectively, we suggest that activation of presynaptic HCN channels may counteract membrane hyperpolarization during tetanic stimulation, and thereby contributes to the presynaptic LTP at LA-BA synapses.


[ASA-intolerance syndrome and persistent rhinosinusitis : Differential diagnosis and treatment].
A differential diagnosis of persistent chronic rhinosinusitis is ASA-intolerance syndrome (AIS), also known as Aspirin®‑exacerbated respiratory disease (AERD), Samter-Trias (Samter's disease, Morbus Widal). Particularly in cases of frequent recurrency of nasal polyps in combination with bronchial asthma and hypersensitivity reactions to acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAR) can often be referred to an underlying AIS. The pathogenesis of this syndrome is attributed to a misallocation of the arachidonic acid metabolism, resulting in an increased leukotriene production. The diagnosis may be difficult in the early stages of the disease with incomplete triad of symptoms. Therapy may consist of paranasal sinuses surgery, drug therapy and adaptive deactivation as the only causal treatment option for patients with AIS. For adaptive desactivation, positive effects were actually shown even in patients with long-term recurrent or persistent complaints of chronic rhinosinusitis.


The glomerular lesions in endotheliotropic hemolytic nephroangiopathy (hemolytic uremic syndrome, malignant nephrosclerosis, post partum renal insufficiency).
The term "Endotheliotropic Hemolytic Nephroangiopathy" (EHN) comprises various clinically or pathomorphologically defined disease states with severe renal lesions (e.g. hemolytic uremic syndrome, malignant nephrosclerosis, post partum renal insufficiency) which, to date, have been considered as different entities. We attempted to assign accompanying glomerular changes based upon light and electron microscopy to the above mentioned clinical pictures and their various stages. The accordingly classified glomerular lesions (G1--G3 and Ga) are of critical importance in pathohistological differential diagnosis. Since it is assumed that fibrin is a causing event in the pathogenesis of the vascular lesions, quantitative evaluation of glomerular fibrin deposits was done. The results, when viewed with respect to time, lead to the conclusion that the microthrombotic component represents a secondary phenomenon. Thus, the primary and hence pathogenetically most important finding is a severe damage to the endothelium of the terminal renal vasculature. This endothelial damage although being expressed with variable intensity has to be regarded as the common denominator inherent to all types of glomerular lesions in EHN.


The impact of progressive overload on the proportion and frequency of positive cardio-respiratory fitness responders.
The proportion of individuals whose cardio-respiratory fitness change after endurance training does not exceed the test's measurement error can be 40 %. We determined if progressively increasing treadmill run intensity compared to maintaining the same run intensity, improved the responder proportion to a 6-week 20-minute treadmill training regimen. The intervention response standard deviation method estimated the proportion of responders attributable to progressively increasing run intensity. The mixed-effects model demonstrated V̇O2 peak improved significantly more in the progressive versus constant run intensity group. The proportion of V̇O2 peak responses above the smallest worthwhile change attributable to progressively increasing run intensity was 63.6 %.


Genetic changes following hybridization and genome doubling in synthetic Brassica napus.
Genetic changes were investigated in two sets of independently synthesized Brasscia napus allopolyploids by the AFLP approach in the present study. We found that 1.17 % of the loci showed genetic changes following both hybridization and genome doubling in the synthesized B. napus F04J2 relative to its diploid progenitors, B. rapa (AA genome) and B. oleracea (CC genome). No significant difference between the proportion of A-genome-specific genetic changes and that of C-genome-specific genetic changes was detected in B. napus F04J2. Approximately 0.6 % of the loci displayed genetic changes following somatic genome doubling in the amphidiploid B. napus DCE11 relative to the amphihaploid in the dimorphic plants. This study showed that rapid genetic changes occurred after hybridization and/or genome doubling in synthesized B. napus allopolyploids and indicated that both hybridization and genome doubling could affect the genomic architecture in newly formed allopolyploids.


C-Arm computed tomography (CACT)-guided balloon pulmonary angioplasty (BPA): Evaluation of patient safety and peri- and post-procedural complications.
To assess the frequency and severity of complications of balloon pulmonary angioplasty (BPA) using C-arm computed tomography (CACT) guidance. 266 consecutive interventions in 67 patients (42 females, mean age 66 ± 13 years) were included. Selective CACT was acquired prior to the intervention for three-dimensional (3D) guidance and to select appropriate balloon size based on the measured vessel diameter. Complications during and after the procedure, the need for further interventions and the impact on patient safety and outcome were assessed and categorised according to the SIR Classification System to Complications by Outcome (Grade A-F). Overall, 237 interventions were conducted without any complications (89.1%). Minor complications not requiring additional treatment occurred during or after 25 procedures (9.4%), including recurring dry cough in four patients during a total of 11 interventions (4.1%) (Grade A), three focal dissections of the targeted pulmonary artery (1.1%), four cases of pulmonary haemorrhage (1.5%), one case of reperfusion oedema (0.4%) and six cases of post-interventional short-term hemoptysis (2.3%) (Grade B). Four cases of major complications requiring additional treatment were observed (1.5%): one case of pulmonary haemorrhage (0.4%) and two cases of post-interventional haemoptysis (0.8%), all resolved after medical therapy without requiring further intervention, and one case of atrial tachycardia induced during catheterisation, subsequently requiring pharmacological cardioversion (0.4%) (Grade C). No fatal or life-threatening peri- or post-interventional complications or mortality were observed (Grade D-F). BPA performed under CACT guidance appears to be a safe procedure with a low risk of severe complications. • CACT guidance of BPA is safe and successful. • CACT-guided BPA procedures have a low complication profile. • CACT guidance is a valuable tool to navigate BPA.


Carboplatin and pemetrexed in the management of malignant pleural mesothelioma: a realistic treatment option?
Malignant pleural mesothelioma is an aggressive cancer. Chemotherapy with cisplatin and pemetrexed can improve overall survival but has a toxic profile. Substitution of cisplatin with carboplatin may avoid some potential side-effects. Therefore, we undertook a retrospective review to assess the effectiveness and tolerability of carboplatin and pemetrexed in patients with malignant pleural mesothelioma in clinical practice. Patients with malignant pleural mesothelioma who had been treated with carboplatin and pemetrexed were retrospectively identified from pharmacy databases. The endpoints were disease control rate, time to treatment failure, clinical improvement rate and overall survival. We also evaluated any significant haematological and non-haematological toxicities. A total of 49 patients were identified. Of 45 evaluable cases, the disease control rate was achieved in 34 patients (69%, 95% CI 55-82, intention to treat analysis). The clinical response rate was achieved in 34 out of 49 patients (69%, 95% CI 55-82). The median time to treatment failure was 4.6 months (95% CI 3.4-5.8) and median overall survival was 14 months (95% CI 9.5-18.5). Grade 3/4 haematological toxicities were observed in 7 patients (14.3%). Grade 3/4 non-haematological toxicities were seen in 12 patients (24.5%). No toxic deaths were recorded. The combination of carboplatin and pemetrexed may be a viable option in the treatment of malignant pleural mesothelioma.


Electrocatalytic oxidation behavior of NADH at Pt/Fe3O4/reduced-graphene oxide nanohybrids modified glassy carbon electrode and its determination.
We have developed Pt/Fe3O4/reduced-graphene oxide nanohybrids modified glassy carbon (Pt/Fe3O4/RGO/GC) electrode as a novel system for the preparation of electrochemical sensing platform. Characterization of as-made composite was determined using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), transmission electron microscopy (TEM), atomic force microscopy (AFM) and energy-dispersive analysis of X-ray (EDAX) where the Pt, Fe, Si, O and C elements were observed. The Pt/Fe3O4/RGO/GC electrode was characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Due to the synergistic effect between Pt, Fe3O4 and RGO, the nanohybrid exhibited excellent performance toward dihydronicotinamide adenine dinucleotide (NADH) oxidation in 0.1M phosphate buffer solution, pH7.0, with a low detection limit of 5nM.


Changes of serum midkine as a dynamic prognostic factor to monitor disease status in papillary thyroid cancer.
This study aimed to investigate the value of dynamic changes of midkine (MK) to monitor post-surgical patients with papillary thyroid cancer (PTC) who were managed with I therapies.MK concentration at initial I ablation therapy (MK1) as well as 10 to 12 months thereafter (MK2) was evaluated. And the dynamic changes of thyroglobulin (Tg) were compared (Tg1 and Tg2). Patients with MK influencing co-morbidities and with positive thyroglobulin antibodies were excluded. Concentrations of MK were measured by enzyme-linked immunosorbent assay.There were 241 PTC patients (36 males, 205 females) enrolled, 55 cases had metastases (8 males, 47 females) during their follow-up. Cox regression showed if Tg2 decreased (compared with Tg1), but not to less than 1.0ng/mL under TSH stimulation, the risk of metastases was 12.554 times more than if it could decrease to the optimal level. If Tg2 increased, the risk is 19.461 times higher. As for MK, if MK2 level decreased (compared with MK1), but not to a normal level, the risk of metastases is 3.006. If MK2 level increased, it would be 5.030 likely to had metastases.Our results indicated that MK could potentially be used as a disease monitoring biomarker for PTC, although inferior to Tg.


Maxillofacial education in the time of COVID-19: the West Midlands experience.
COVID-19 has accelerated a reliance on virtual technology for the delivery of postgraduate surgical education. We sought to develop a regional teaching programme with robust quality assurance. Webinars were delivered on a weekly basis by subspecialty experts using Zoom™ augmented with interactive polling software. Trainee feedback comprised Likert item rating on content and delivery, free text comments and self-assessed confidence levels using visual analogue scale (VAS) scores. A focus group was also convened and transcripts assessed with grounded theory analysis. Likert items revealed 442 (93.2%) positive responses regarding content and 642 (96.7%) positive responses regarding trainer delivery. There were statistically significant improvements in VAS scores across all programme content. Key themes from the focus group analysis were the pragmatics of delivering online education, issues surrounding trainer interactivity in the virtual world, the identification of the FRCS as a driving factor and a desire for case-based content and pre-learning of information (the 'flipped classroom'). We are continuing to be reactive to trainee feedback in developing our online learning programme which will also include a regional Moodle-based virtual learning environment (VLE), the subject of future educational research in our region.


Coronary artery spasm: involvement of small intramyocardial branches.
A study was conducted to determine if the small (resistance) vessels of the coronary circulation could undergo spasm comparable to that of the major conductance (epicardial) arteries which in the rat measure 275-300 micron in diameter. This information may be relevant to the growing evidence of ischemic myocardial disease without significant coronary atherosclerosis or even spasm of the larger vessels. Vascular corrosion casts of the coronary circulation were prepared in the rat 20 min after intravenous injection of arginine vasopressin, a powerful coronary constrictor substance, under continuous electrocardiographic monitoring. Electrocardiographic changes observed consisted of S-T segment elevation and conduction disturbances, implying ischemic effects on the myocardium. Corrosion casts revealed spasm of smaller arteries only (50-150 micron diameter). Controls (vehicle-injected or untreated) showed no abnormalities of the coronary vasculature. These results suggest that myocardial vessels of this size are comparable in their potential for spasm to the large conductance arteries. Similar findings in patients involving smaller vessels could explain ischemic myocardial events in the absence of significant spasm, or organic stenosing pathology of major coronary arteries. As a corollary, it is suggested that the term "coronary artery spasm" could be enlarged in its definition to include other levels of the coronary circulation rather than that of the large conductance arteries alone.


Hepatitis C virus infection and diabetes: A complex bidirectional relationship.
Chronic hepatitis C (CHC) and diabetes represent two severe chronic conditions responsible for a considerable number of deaths worldwide. They have a complex, bidirectional relationship. On the one hand, several cohort studies have shown that chronic HCV infection increases both the risk of developing diabetes in non-diabetic subjects (by inducing insulin resistance and promoting β-cell dysfunction) as well as the risk of developing macro and microvascular complications in patients with known diabetes; on the other hand, diabetes is an independent risk factor for liver-related events among patients with CHC, including a higher incidence of hepatocellular carcinoma, liver-related death and transplantation. Importantly, sustained virological response, which can be obtained in the vast majority of patients with the use of direct antiviral agents, does not only lead to a lower rate of liver-related outcomes, but also to improvements of glycemic control and reduction in the rate of complications among patients with diabetes. The aim of this review is to summarize available clinical evidence on the association among CHC, diabetes and related clinical outcomes. We will also briefly discuss the biological mechanisms underpinning the association between CHC and diabetes, as well as the implications this relationship should have on everyday clinical practice.


Comparative postoperative outcomes of GGN-dominant vs single lesion lung adenocarcinomas.
Multiple synchronous ground glass nodules (GGNs) are known to be malignant, however, they tend to progress slowly. Multiple synchronous lesions in the same patient which show different characteristics must be treated individually. This was a retrospective review of 34 lung adenocarcinoma patients with multiple synchronous GGNs in an Asian population. One hundred twenty-seven single lung adenocarcinoma patients were included for comparison purposes. The follow-up period was 5 years for all patients. The 5-year overall survival (OS) patients with multiple lesions did not differ from that of the patients with single lesions to a statistically significant extent (Single: 81.8% vs. Multiple: 88.2%, P = 0.3602). Dominant tumors (DTs) with a ground glass component and consolidation were divided into three categories based on the consolidation-to-tumor ratio on radiological imaging. No significant differences were observed among the three DT categories. Twenty-four patients had unresected GGNs, while a progression of the unresected GGN occurred in 10 of these cases. The OS and disease-free survival (DFS) curves of patients with and without GGN progression did not differ to a statistically significant extent (OS: 80% vs. 92.9%, P = 0.3870; DFS: 80% vs. 100%, P = 0.0977). The outcomes were best predicted by the stage of the DT. After surgery patients require a careful follow-up because unresected GGNs may show progression. At the same time, the increase in residual lesions and the appearance of new GGNs were not related to OS. The management of such patients should be determined according to the DT with the worst prognosis.