Exploring the Doctor of Nursing Practice project facilitator/mentor role.
The Doctor of Nursing Practice (DNP) facilitator/mentor is a collaborative member of the project team, yet little has been reported about this role. This qualitative study explored the experiences of DNP project facilitators. Focus groups were conducted using a purposeful sample of project facilitators. Focus group questions were developed using Gitlin, Lyons, and Kolodner's five-stage model of collaboration. Data were transcribed and content analyzed using Kruger and Casey methods. Three focus groups included 21 facilitators who were affiliated with an academic health system. Six themes emerged: (a) exploring student interest, (b) establishing a collaborative fit, (c) connecting with key stakeholders, (d) overcoming barriers, (e) role clarity, and (f) interaction. DNP project facilitators have an important role not only in students' formation, but also in contributing to the academic-practice partnership. The importance of the facilitator role as the student progresses through their DNP project cannot be overstated.


Effect of Molybdenum Nanoparticles on Blood Cells, Liver Enzymes, and Sexual Hormones in Male Rats.
Despite an increasing surge in application of nanoparticles in industries, there is a serious lack of information concerning their impact on human health and the environment. The present study investigated effects of molybdenum nanoparticles (Mo NPs) injected intraperitoneally into Sprague-Dawley rats at different doses of Mo NPs (5, 10, and 15 mg/kg BW per day) during a period of 28 days. Hematological and biochemical parameters as well as sexual hormones and histopathological examinations of the liver and testis were assessed and compared with control group. The results showed that the serum levels of testosterone decreased significantly in both groups of 10 and 15 mg (Mo NPs)/kg BW in comparison with the control group (p < 0.05). However, there were insignificant differences observed in luteinizing hormone (LH) levels and hematological parameters when compared with the control group (p > 0.05). The results of liver enzymes showed that serum levels of aspartate aminotransferase (AST) decreased significantly in both dosage groups of 5 and 10 mg/kg BW (Mo NPs) when compared with the control group (p < 0.05), and significant decrease obtained in lactate dehydrogenase (LDH) levels at dose of 5 mg/kg BW in comparison with the control group (p < 0.05). The histopathological examination of testis showed a decrease in number of Leydig cells. Also, the number of chronic inflammatory cells increased in portal triad and parenchyma in liver tissue of rats exposed to Mo NPs.


Apparent diffusion coefficient values and dynamic contrast enhancement patterns in differentiating seminomas from nonseminomatous testicular neoplasms.
The aim of this study is to investigate the role of apparent diffusion coefficient (ADC) values and dynamic contrast enhancement (DCE) patterns in differentiating seminomas from nonseminomatous germ cell tumors (NSGCTs). The MRI examinations of the scrotum of 26 men with histologically proven testicular GCTs were reviewed. DWI was performed in all patients, using a single shot, multi-slice spin-echo planar diffusion pulse sequence and b-values of 0 and 900 s/mm(2). Subtraction DCE-MRI was performed in 20 cases using a 3D fast-field echo sequence after gadolinium administration. Time-signal intensity curves were created and semi-quantitative parameters (peak enhancement, time to peak, wash-in and wash-out rate) were calculated. The Student's t-test was used to compare the mean values of ADC, peak enhancement, time to peak, wash-in and wash-out rate between seminomas and NSGCTs. ROC analysis was also performed. Histopathology disclosed the presence of 15 seminomas and 11 NSGCTs. The mean ± s.d. of ADC values (×10(-3)mm(2)/s) of seminomas (0.59 ± 0.009) were significantly lower than those of NSGCTs (0.90 ± 0.33) (P=0.01). The optimal ADC cut-off value was 0.68 × 10(-3)mm(2)/s. No differences between the two groups were observed for peak enhancement (P=0.18), time to peak (P=0.63) wash-in rate (P=0.32) and wash-out rate (P=0.18). ADC values may be used to preoperatively differentiate seminomas from NSGCTs.


Microbial deracemization of alpha-substituted carboxylic acids.
An enzyme system of Nocardia diaphanozonaria JCM 3208 catalyzes the inversion of the chirality of various alpha-substituted carboxylic acids, such as 2-phenylpropanoic acid and 2-phenoxypropanoic acid derivatives, via a novel deracemization reaction.


l-Carnitine ameliorates the oxidative stress response to angiotensin II by modulating NADPH oxidase through a reduction in protein kinase c activity and NF-κB translocation to the nucleus.
l-Carnitine (LC) exerts beneficial effects in arterial hypertension due, in part, to its antioxidant capacity. We investigated the signalling pathways involved in the effect of LC on angiotensin II (Ang II)-induced NADPH oxidase activation in NRK-52E cells. Ang II increased the generation of superoxide anion from NADPH oxidase, as well as the amount of hydrogen peroxide and nitrotyrosine. Co-incubation with LC managed to prevent these alterations and also reverted the changes in NADPH oxidase expression triggered by Ang II. Cell signalling studies evidenced that LC did not modify Ang II-induced phosphorylation of Akt, p38 MAPK or ERK1/2. On the other hand, a significant decrease in PKC activity, and inhibition of nuclear factor kappa B (NF-kB) translocation, were attributable to LC incubation. In conclusion, LC counteracts the pro-oxidative response to Ang II by modulating NADPH oxidase enzyme via reducing the activity of PKC and the translocation of NF-kB to the nucleus.


Supply and demand - a health economic perspective on the Australian hospital and elective surgery crisis.
The COVID-19 pandemic has contributed to longstanding structural shortfalls in the supply of healthcare services in high-income countries, including Australia. These impacts are reflected in Australian public hospital key performance indicators for acute care, elective surgery and hospital exit block. The challenges occur in the context of increased demand following the suspension of a range of healthcare services during the pandemic. The main supply challenge is suitable numbers of skilled healthcare workers. Rebalancing of supply and demand in healthcare is challenging, but needs to be achieved.


Potentiation of chlorinated hydrocarbon toxicity by 2,5-hexanedione in primary cultures of adult rat hepatocytes.
Primary cultures of adult rat hepatocytes were used to investigate potentiation of halocarbon-induced hepatotoxicity by aliphatic ketones. Male Sprague-Dawley rats were pretreated with corn oil or 2,5-hexanedione (HD; 15 mmol/kg, po) in corn oil. Eighteen hours later the hepatocytes were isolated and cultured in Williams' Medium E and exposed to several concentrations of the hepatotoxicants carbon tetrachloride, chloroform, deutero-chloroform, or 1,1,2-trichloroethane. The cytotoxicity of these halocarbons as measured by release of the cytosolic enzyme lactate dehydrogenase into the culture medium was both time- and concentration-dependent. Halocarbon-induced cytotoxicity was exacerbated in cells isolated from HD-pretreated rats with significant increases in LDH release over cells isolated from corn oil-pretreated rats. In addition, chloroform was significantly more toxic than deutero-chloroform in hepatocytes from either corn oil- or HD-pretreated rats. Primary monolayer cultures were useful for studying ketone-induced potentiation, halocarbon-induced hepatocellular toxicity, and the mechanisms by which these effects occur.


Untiring Pursuit for Glucarate-Based Molecular Imaging Probes.
Glucarate, a physiologic end-product of the D-glucuronic acid pathway in mammals, is a six-carbon dicarboxylic acid with a wide range of uses. Glucarate-based molecular imaging probes including [99mTc]glucarate and [18F]glucarate have been developed and demonstrated to have infarct/necrosis-avid and/or tumor-seeking properties, showing potential applications in early detection of myocardial infarction, evaluation of tissue viability, monitoring of therapeutic effectiveness, and noninvasive imaging of certain tumors including drug-resistant ones. The mechanism by which [99mTc]glucarate localizes in acute necrotic tissues has been demonstrated to be largely attributable to its binding to the positively charged histones, which become accessible after the disruption of the cell and nuclear membranes as a result of irreversible damage, while the tumor-seeking mechanism of [99mTc]glucarate has been found to be closely related to glucose transporter 5 expression. Moreover, the recently developed [18F]glucarate provides a new alternative probe for positron emission tomography imaging and may have potential advantages over [99mTc]glucarate. In this review, we present the untiring pursuit for glucarate-based molecular imaging probes as infarct/necrosis-avid agent and/or tumor-seeking agent. Moreover, the limitations and the prospects for future research of glucarate-based molecular probes are also discussed.


Structure and interaction roles in the release profile of chalcone-loaded liposomes.
The structures and molecular interactions of established synthetic chalcones were correlated with their release profiles from asolectin liposomes. The effects of chalcones on the properties of liposomes were evaluated by dynamic light scattering (DLS), ultraviolet-visible spectroscopy (UV-VIS), horizontal attenuated total reflection Fourier transform infrared (HATR-FTIR), 31P nuclear magnetic resonance (31P NMR), zeta (ζ) potential and differential scanning calorimetry (DSC). The profiles and mechanisms of release were accessed according to the Korsmeyer-Peppas model. Results obtained allowed the establishment of a relationship between the chalcone release profile and 1) the ordering effects of chalcones in different membrane regions, 2) their polar or interfacial location in the lipid layer, 3) the influence of hydroxy and methoxy substituents, 4) their effect on reorientation of lipid choline-phosphate regions. The obtained data may improve the development of chalcone-based systems to be used in the therapy of chronic and acute diseases.


Preparation and antigenic property of methyl 3 beta-hydroxy-19-oxo-5-cholen-24-oate 19-(O-carboxymethyl) oxime-bovine serum albumin conjugate.
The preparation and antigenic property of 3 beta-hydroxy-5-cholen-24-oic acid-bovine serum albumin (BSA) conjugate in which the hapten is linked to the carrier protein through an (O-carboxymethyl) oxime bridge at the C-19 position on the steroid nucleus is described. Antibody raised against antigen in the rabbit possessed high titer and specificity to 3 beta-hydroxy-5-cholen-24-oic acid, exhibiting no significant cross-reactions with various bile acids.


Regulation of the chitin degradation and utilization system by the ChiX small RNA in Serratia marcescens 2170.
Serratia marcescens 2170 produces three different types of chitinases and chitin-binding protein CBP21. We found that transposon insertion into the 5' untranslated region (5' UTR) of chiPQ-ctb led to defective chitinase and CBP21 production. ChiX small RNA possessed the complementary sequence of the 5' UTRs of the chiPQ-ctb and chiR and repressed the expression of chiP and chiR. ChiX was detected in a medium containing glucose, glycerol, GlcNAc, and (GlcNAc)2, but the expression of both chiP and chiR was only observed in a medium containing (GlcNAc)2. ∆chiX mutant produced chitinases, CBP21, and chitobiase without induction. chiP transcripts were more abundant than those of chiR or chiX in a medium containing (GlcNAc)2. These results suggest that the constitutively expressed ChiX binds to the highly abundant chiP 5' UTR, thereby leading to the induction of chiR mRNA translation and the subsequent expression of chitinases and CBP21.


Pulmonary atresia with intact ventricular septum and hypoplastic right ventricle in an Arabian foal.
Pulmonary atresia with intact ventricular septum, rudimentary tricuspid valve, hypoplastic right ventricle, and right-to-left atrial shunting were identified in a four-day-old, male Arabian foal with clinical signs of cyanotic heart disease. Pulmonary blood flow was apparently derived from a ductus arteriosus. Echocardiographic evaluation revealed the majority of cardiac abnormalities and also findings compatible with right-sided congestive heart failure. Congenital cardiac defects have a high incidence in this breed, and this is the first description of this combination of congenital cardiac defects.


Relationships between appetite and quality of life in hemodialysis patients.
The aim of this paper was to investigate the association between appetite and kidney-disease specific quality of life in maintenance hemodialysis patients. Quality of life (QoL) was measured using the kidney disease quality of life survey. Appetite was measured using self-reported categories and a visual analog scale. Other nutritional parameters included Patient-Generated Subjective Global Assessment (PGSGA), dietary intake, body mass index and biochemical markers C-reactive protein and albumin. Even in this well nourished sample (n=62) of hemodialysis patients, PGSGA score (r=-0.629), subjective hunger sensations (r=0.420) and body mass index (r=-0.409) were all significantly associated with the physical health domain of QoL. As self-reported appetite declined, QoL was significantly lower in nine domains which were mostly in the SF36 component and covered social functioning and physical domains. Appetite and other nutritional parameters were not as strongly associated with the Mental Health domain and Kidney Disease Component Summary Domains. Nutritional parameters, especially PGSGA score and appetite, appear to be important components of the physical health domain of QoL. As even small reductions in nutritional status were associated with significantly lower QoL scores, monitoring appetite and nutritional status is an important component of care for hemodialysis patients.


Free fatty acid production in Escherichia coli under phosphate-limited conditions.
Microbially synthesized fatty acids are an attractive platform for producing renewable alternatives to petrochemically derived transportation fuels and oleochemicals. Free fatty acids (FFA) are a direct precursor to many high-value compounds that can be made via biochemical and ex vivo catalytic pathways. To be competitive with current petrochemicals, flux through these pathways must be optimized to approach theoretical yields. Using a plasmid-free, FFA-producing strain of Escherichia coli, a set of chemostat experiments were conducted to gather data for FFA production under phosphate limitation. A prior study focused on carbon-limited conditions strongly implicated non-carbon limitations as a preferred media formulation for maximizing FFA yield. Here, additional data were collected to expand an established kinetic model of FFA production and identify targets for further metabolic engineering. The updated model was able to successfully predict the strain's behavior and FFA production in a batch culture. The highest yield observed under phosphate-limiting conditions (0.1 g FFA/g glucose) was obtained at a dilution rate of 0.1 h(-1), and the highest biomass-specific productivity (0.068 g FFA/gDCW/h) was observed at a dilution rate of 0.25 h(-1). Phosphate limitation increased yield (∼45 %) and biomass-specific productivity (∼300 %) relative to carbon-limited cultivations using the same strain. FFA production under phosphate limitation also led to a cellular maintenance energy ∼400 % higher (0.28 g/gDCW/h) than that seen under carbon limitation.


Immunotherapy of systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a remarkably heterogeneous multisystem autoimmune disease. Improved understanding of the immunopathogenesis of this disorder over the past two decades is now being applied to therapy, with treatment being directed at specific immunological targets. This review will focus on both new uses for established therapies as well as on the introduction of novel agents. It is premature to claim that any one agent has superior efficacy to current therapies. However, the willingness of investigators supported by the pharmaceutical and biotechnology industries to evaluate the efficacy and safety of new products in controlled clinical trials may provide answers.


A randomized double blind comparison of atosiban in patients with recurrent implantation failure undergoing IVF treatment.
Patients with recurrent implantation failure (RIF) may have more uterine contractions. Several observational studies suggested that atosiban administration around embryo transfer resulted in higher pregnancy rates in RIF patients. This study aimed to evaluate the effect of atosiban given before fresh embryo transfer on pregnancy outcomes of women with RIF. A prospective, randomized, double-blind controlled clinical trial was performed in IVF center of Shanghai First Maternity and Infant Hospital. According to a computer-generated randomization list, 194 infertile women with RIF received fresh embryo transfer between July 2017 and December 2019 were randomly allocated into the atosiban (n = 97) and the placebo (n = 97) groups. Women in the treatment group received atosiban intravenously about 30 min before embryo transfer with a bolus dose of 6.75 mg over one minute. Those in the placebo group received only normal saline infusion for the same duration. There was no significant difference in the live birth rate between the atosiban and placebo groups (42.3% vs 35.1%, P = 0.302, RR = 1.206 (0.844-1.723)). No significant differences were found between the two groups in the positive pregnancy test, clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy and implantation rates. Similar results were found when stratified by the number of embryos previously transferred, number of previous failed embryo transfers, frequency of endometrial peristalsis on embryo transfer day (≥ 3 waves/min) or serum estradiol (E2) on the day of hCG above the median level. And, there was no correlation between the serum E2 level on the day of hCG and the frequency of endometrial peristalsis on embryo transfer day. The frequency of endometrial peristalsis on embryo transfer day, total FSH/HMG dosage and duration were the significant factors which independently predicted the likelihood of a live birth. These results suggested that atosiban treatment before fresh embryo transfer might not improve the live birth rate in RIF patients. The study had been approved by the Institutional Review Board of the hospital (2017 ethics No.43) and was registered under Clinicaltrials.gov with an identifier NCT02893722.


The structure-activity relationship of a new anti-arrhythmic agent 1-[2-acetoxy-3-(4-phenyl-1-piperazinyl)propyl]pyrrolidin-2-one.
This paper reports the synthesis of the new compound 1-[2-acetoxy-3-(4-phenyl-1-piperazinyl)propyl]pyrrolidin-2-one (Ac-MG-1). Preliminary pharmacological assessment revealed that Ac-MG-1 possesses anti-arrhythmic activity and a local anesthetic effect. The crystal structure of Ac-MG-1 was determined by X-ray diffraction, and conformational analysis was performed both for Ac-MG-1 and for other derivatives of (arylpiperazinyl)propylpyrrolidin-2-one.


Risk of Neonatal Short-Term Adverse Outcomes Associated with Noninfectious Intrapartum Hyperthermia: A Nested Case-Control Retrospective Study.
This study aimed to identify risk factors for adverse neonatal outcomes in neonates born to mothers with noninfectious intrapartum hyperthermia. A retrospective study was conducted of 460 singleton deliveries diagnosed with noninfectious intrapartum hyperthermia. Logistic regression was used to estimate the association between ante- and intrapartum risk factors and neonatal outcomes. The 460 singleton pregnant women were 19 to 43 years of age. They developed an intrapartum temperature of ≥37.5°C somewhere between 340/7 to 414/7 weeks' gestation; 437 (95%) were nulliparous. Meconium-stained amniotic fluid was associated with positive pressure ventilation or intubation ventilation (odds ratio [OR] = 5.940, 95% confidence interval [CI]: 2.038-17.318), birth depression (OR = 6.288, 95% CI: 2.273-17.399), and wet lung (OR = 2.747, 95% CI: 1.322-5.709). Induction of labor with artificial rupture of membranes (AROM; OR = 2.632, 95% CI: 1.325-5.228) was associated with neonatal infections. Maternal temperature ≥ 38°C was associated with neonate's artery blood gas pH < 7.3 (OR = 2.366, 95%CI: 1.067-5.246) and wet lung (OR = 2.909, 95% CI: 1.515-5.586). Maternal elevated C-reactive protein (CRP) was associated with neonatal infections (OR = 1.993, 95% CI: 1.260-3.154) and wet lung (OR = 2.600, 95% CI: 1.306-5.178). Meconium-stained amniotic fluid, induction of labor, maternal temperature ≥ 38°C, and elevated CRP during labor were risk factors for adverse neonatal outcomes.


Age-dependent control of lens growth by hypoxia.
The lens grows continuously throughout life, but the factors that influence the size of the adult lens are not known. Lens thickness is a significant risk factor for age-related cataract. It has been postulated that the hypoxic environment in the eye protects the lens from nuclear cataracts. The authors sought to determine whether the Po(2) in the eye regulates lens growth. Lens cell proliferation was determined by counting BrdU-labeled and total nuclei in the germinative zone in flatmounts of lens epithelia. Oxygen levels in the eye were altered by having rats breathe 11%, 21% (room air), or 60% oxygen. Oxygen levels in the vitreous were measured with a fiberoptic oxygen sensor. The BrdU-labeling index in the germinative zone declined from approximately 3.5% at 1 month to less than 0.7% at 8 months. Raising oxygen levels in the eyes of 1-month-old animals did not alter the rate of lens cell proliferation. Elevating intraocular oxygen in animals older than 1 month increased proliferation to the more rapid rate seen at 1 month. Decreasing oxygen levels below their normally low level did not affect the BrdU-labeling index at any age. Chronic exposure to increased oxygen led to the production of more lens fiber cells and larger lenses. Normal age-related decline in lens growth requires the low oxygen level normally present in the eye. Increases in lens cell number and mass may account for some of the increase in cataract risk caused by chronic exposure of the lens to elevated oxygen levels.


Oxidative balance scores and depressive symptoms: Mediating effects of oxidative stress and inflammatory factors.
Few studies have examined the combined effects of dietary and lifestyle factors on depressive symptoms. This study aimed to evaluate the association between oxidative balance score (OBS) and depressive symptoms and the underlying mechanisms. A total of 21,283 adults from the 2007 to 2018 National Health and Nutrition Examination Survey (NHANES) were included. Depressive symptoms were defined as a total score of ≥10 on the Patient's Health Questionnaire (PHQ-9). Twenty dietary and lifestyle factors were selected to calculate the OBS. Multivariable logistic regression analyses were used to evaluate the association between OBS and depression risk. Mediation analyses were conducted to explore the roles of oxidative stress and inflammatory markers. In multivariate model, a significant negative association was found between OBS and depression risk. Compared with those in OBS tertile 1, participants in tertile 3 had lower odds of developing depressive symptoms (OR:0.50; 95 % CI:0.40-0.62; P < 0.001). Restricted cubic splines showed a linear relationship between OBS and depression risk (P for nonlinearity = 0.67). Moreover, higher OBS was found to be associated with lower depression scores (β = -0.07; 95 % CI:-0.08, -0.05; P < 0.001). GGT concentrations and WBC counts mediated the association between OBS and depression scores by 5.72 % and 5.42 %, respectively (both P < 0.001), with a joint mediated effect of 10.77 % (P < 0.001). This study was a cross-sectional design making it difficult to infer a causal association. OBS is negatively associated with depression, which may be mediated in part by oxidative stress and inflammation.


Influence of insecticides flubendiamide and spinosad on biological activities in tropical black and red clay soils.
A laboratory experiment has been conducted to investigate the ecological toxicity of flubendiamide and spinosad at their recommended field rates and higher rates (1.0, 2.5, 5.0, 7.5, 10.0 kg ha-1) on cellulase, invertase and amylase in black and red clay soils after 10, 20, 30 and 40-day exposure under controlled conditions in groundnut (Arachis hypogaea L.) soils of Anantapur District, Andhra Pradesh, India. Flubendiamide and spinosad were stimulatory to the activities of cellulase, invertase and amylase at lower concentrations at 10-day interval. The striking stimulation in soil enzyme activities noticed at 2.5 kg ha-1, persists for 20 days in both soils. Overall, the higher concentrations (5.0-10.0 kg ha-1) of flubendiamide, and spinosad were toxic or innocuous to cellulase, invertase and amylase activities, respectively. The results of the present study thus, clearly, indicate that application of the insecticides in cultivation of groundnut, at field application rates improved the activities of cellulase, invertase and amylase in soils.


Diffuse pancreatic lesion mimicking autoimmune pancreatitis in an HIV-infected patient: successful treatment by antiretroviral therapy.
Pancreatitis is a common complication of acquired immunodeficiency syndrome. The most common causes of acute pancreatitis in an HIV population are medication and opportunistic infections. We report the case of a young, untreated, HIV-infected female who presented with acute pancreatitis of unknown origin. Unique to this case are the autoimmune pancreatitis-like features on imaging studies associated with renal mass-like lesions and lymph node involvement as well as the favorable outcome using highly active antiretroviral therapy alone. In HIV-infected patients, acute pancreatitis may present on imaging studies as autoimmune pancreatitis. In patients with uncontrolled HIV infection and imaging studies suggestive of autoimmune pancreatitis, direct HIV-related inflammation should be considered after exclusion of all other causes of pancreatitis.


Effective intranasal cooling in an 80 year old patient with heatstroke.
Intranasal cooling by the evaporation of perflourcarbon is almost exclusively used for the induction of therapeutic hypothermia in post-resuscitation care. This method has proven to be effective and safe. This case presents a successful application to a patient with external heatstroke. The 80 year old male patient was found in deep coma (GCS 4) by emergency medical services (EMS) showing a core temperature around 42 °C. Despite of preclinical physical cooling, the patient showed a persistent temperature of 41.5 °C upon reaching the emergency department. After endotracheal intubation intranasal evaporation cooling was performed and the patient's core temperature was reduced efficiently. We recorded an excellent cooling rate of 2.8 °C per hour. 16 h later the patient was successfully extubated with a good neurological outcome. This case shows that although intranasal cooling is mostly known for post-resuscitation care, there is a sensible application in heatstroke with imminent cerebral oedema.


mRNA microarray profiling identifies a novel circulating HTRA2 for detection of gastric cancer.
mRNAs have been shown to be critical biomarkers or therapeutic targets for human diseases. However, only a few of them have been studied as blood-based biomarkers for gastric carcinoma (GC) detection. mRNA expression profiles for GC were screened using plasma samples from 10 GC patients with different TNM stages and 5 healthy individuals as controls. One candidate tumor-related mRNA named HTRA2 was then evaluated in GC samples with quantitative real-time polymerase chain reaction (qRT-PCR). TCGAportal, UALCAN, and TISCH database were used to explore the function of HTRA2 in GC. Finally, the effect generated by HTRA2 expression on cell proliferating, invading, and migrating processes was assessed in vitro with knockdown and over-expression strategies. HTRA2 displayed noticeable increase inside GC plasma compared with control cases. Higher expression of HTRA2 displayed a correlation to higher clinicopathological stage and worse prognosis. HTRA2 knocking down down-regulated GC cells' proliferating, invading, and migrating states, while HTRA2 over-expression exerted the inconsistent influence. HTRA2 protein, which may interact with PINK1, PARL, and CYCS, was mainly located in the mitochondria of cells and primarily involved cellular response and metabolic signaling pathway. Immune factors may interact with HTRA2 in GC, and HTRA2 was found noticeably linked with immunosuppressor such as CD274, IDO1, and TIGIT. One plasma HTRA2 can be an emerging diagnosis-related biomarker to achieve GC detecting process, but the particular regulatory effect still needs to be further explored.


Development of a non-heart-beating lung donor program with «Bithermia Preservation», and results after one year of clinical experience.
The number of lung transplantations that are performed in Spain continues to grow, with 235 transplant recipients 2010. Non-heart-beating donations have contributed to this upward progression. Our Lung Transplant Unit began its activity in October 2008 and during these last three years 97% of the transplant interventions performed have been successful. In order to increase the number of donations, we have developed a non-heart-beating donor program as part of the existing organs program in our hospital. In doing so, the development of a multi-organic preservation method (lung, liver and kidney), which we call «Bithermia Preservation», was necessary. This paper presents this methodology as well as the first year of clinical application experience. During this time, 3 patients have been transplanted using such non-heart-beating donations. None of them developed primary graft dysfunction; all the patients have been discharged and lead active lives without any evidence of bronchiolitis obliterans syndrome.


Supplementation of sulfur and folic acid improves performance of broiler chicken fed suboptimal concentrations of dietary methionine.
Supplementation of sulfur (S) and folic acid (FA) are known to spare the dietary requirement of methionine (Met) in chicken. An experiment was conducted to determine the effects of feeding graded concentrations of FA (0, 2, 4, 6, 8 mg kg-1 ) and two concentrations of S (0 and 2 g kg-1 ) in 5 × 2 factorial design. Diet without FA and S was considered as negative control (NC). Another diet with the recommended concentration of Met was considered as the positive control (PC). Each diet was offered ad libitum from day 1 to 42 to 10 pens of 20 male chicks each. Broilers fed the NC diet had lower body weight gain (BWG), high feed conversion ratio, lower ready-to-cook yield, higher lipid peroxidation and reduced concentrations of protein and albumin in serum. BWG improved with FA at day 21 and showed a trend of improvement at day 42. Similarly, BWG improved with S supplementation at day 42. The FA and S interaction indicated a significant reduction in lipid peroxidation with S supplementation at the majority of FA levels. Serum protein fractions increased with increased dietary FA content and increased further with S supplementation. Based on the results, it is concluded that the combination of FA (4 mg kg-1 ) and S (2 g kg-1 ) improved BWG. Similarly, the feed efficiency with 6 mg FA alone or with S was similar to the PC group. The improvement was probably due to the increase in protein accretion and reduction in lipid peroxidation with FA and S supplementation. © 2022 Society of Chemical Industry.


Synthesis, Characterization, and Evaluation of Difluoropyrido[4,3-b]indoles as Potential Agents for Acetylcholinesterase and Antiamnesic Activity.
Acetylcholinesterase (AChE) inhibitors are currently the most widely prescribed drugs for Alzheimer's disease. The high potential of indole compounds in medicinal chemistry led us to discover a novel series of fluoroindole compounds. The synthesis and pharmacological analysis of the difluoropyrido[4,3-b]indoles 11-34 are described. Compounds 11-34 were tested for AChE inhibition activity using a rat brain homogenate. Compounds 25-29 display a promising in vitro profile with an IC50 value range of 46-51.6 nM and show significant protective effect on scopolamine-induced amnesia. The present data indicate that compounds 25-29 may represent attractive potent molecules for the treatment of Alzheimer's disease.


[Use of Kenalog-40 in treating degenerative-dystrophic diseases of the locomotor apparatus].
Positive immediate (96%) and long-term (85%) results of treatment of some degenerative-dystrophic diseases of the locomotor system with corticosteroid drug Kenalog-40 allow it to be recommended as an effective medicine especially for deforming arthroses, scapulohumeral periarthritis, epicondylitis when other methods proved to be ineffective.


Preoperative predictors of cancerous involvement of the neurovascular bundles in patients with localized prostate cancer.
The purpose of this study was to identify preoperative variables that would be useful in objectively selecting prostate cancer patients for nerve-sparing prostatectomy. Twenty-six patients with clinical T1c-T2c cancers were evaluated for cancerous involvement in the region of the neurovascular bundles (NVB) from prostatectomy specimens. Preoperative prostate-specific antigen (PSA) and pathologic features in systematic biopsy specimens also were reviewed. A total of eight (31%) patients had cancerous involvement in the region of the NVB, including four on the right side, three on the left side and one on both sides. The percentage of each biopsy specimen occupied by the cancer was scored from zero to four and defined as the positive biopsy score. Preoperative PSA (P = 0.046), mean positive biopsy score (total sum of positive biopsy score divided by number of biopsy specimens; P = 0.001), number of cores containing cancer (P = 0.011), percentage of cores involved (P = 0.036) and maximum positive biopsy score (P < 0.001) were significant for predicting cancerous involvement in the NVB region using univariate analysis. However, only the mean positive biopsy score was independently significant according to multivariate analysis. To predict cancerous involvement in the region of each NVB, we found that ipsilateral mean positive biopsy score (total sum of corresponding positive biopsy score divided by number of ipsilateral biopsy specimens), number of cores involved on the ipsilateral side, percentage of cores involved on the ipsilateral side and maximum positive biopsy score on the ipsilateral side were significant predictive variables: the ipsilateral mean positive biopsy score being most appropriate for clinical practice. Ipsilateral mean positive biopsy score in systematic biopsy specimens can be an appropriate variable for selecting patients with localized prostate cancer for nerve-sparing prostatectomy.


How to train plastic surgeons of the future.
Plastic surgery is a competitive and over-subscribed career choice despite minimal medical school exposure. We quantify factors influencing career interest in plastic surgery, speciality appeal and workforce planning. These findings optimise and refine evidence-based plastic surgery training and postgraduate selection criteria. Medical students from two national plastic surgery courses complete a post-course questionnaire. Data categories included past experience and career interest in plastic surgery, sources of exposure, motivational factors, and sub-speciality interest. Data were recorded on modified Likert scales, with linear regression and t-test analyses performed. 175 students completed the questionnaire (81% response). Duration of medical student exposure to plastic surgery was significantly associated with career interest (Linear coefficient 0.12, 95% CI 0.08-0.17, P < 0.0001; r(2) = 0.15). 75 h experience is a significant cut-off to categorise students. Mean (95% CI) career interest is 31 percentage points higher in students with >75 h experience (89.2%, 83.2-95.2) compared to students with ≤75 h experience (58.1%, 52.9-63.3) (P < 0.0001). Influential sources included: (1) Operating Room (2) Consultant/Attending interaction (3) Resident interaction. Motivational factors towards a career in plastic surgery included operative satisfaction (91%), improving patient quality of life (89%), and reconstructive surgery (88%). Sub-speciality interests included: (1) Hand and Upper Limb (28%); (2) Cleft Lip and Palate (26%); (3) Burns (15%). This study identified influential and motivational factors upon a career in plastic surgery. Medical student exposure can be tailored to maximise positive educational exposure to optimise evidence-based plastic surgery training and workforce planning.


Fabrication of sensor based on polyvinyl alcohol functionalized tungsten oxide/reduced graphene oxide nanocomposite for electrochemical monitoring of 4-aminophenol.
4-aminophenol (4-AP) is one of the major environmental pollutants which is broadly exploited as drug intermediate in the pharmaceutical formulations. The extensive release of 4-AP in the environment without treatment has become a serious issue that has led several health effects on humans. This work describe the determination of 4-AP through a new chemically modified sensor based on polyvinyl alcohol functionalized tungsten oxide/reduced graphene oxide (PVA/WO3/rGO) nanocomposite. The fabricated nanocomposite was characterized through XRD and HR-TEM to confirm the crystalline structure with average size of 35.9 nm and 2D texture with ultra-fine sheets. The electrochemical characterization of fabricated sensor was carried out by electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) to ensure the charge transfer kinetics of modified sensor that revealed high conductivity of PVA/WO3/rGO/GCE. Under optimized conditions e.g. scan rate 80 mV/s, phosphate buffer (pH 6) as supporting electrolyte and potential window from -0.2 to 0.8 V, the prepared sensor showed excellent response for 4-AP. The linear dynamic range of developed method was optimized as 0.003-70 μM. The LOD of fabricated sensor based on PVA/WO3/rGO/GCE for 4-AP was calculated as 0.51 nM. The practical application of PVA/WO3/rGO/GCE was tested in real water and pharmaceutical samples. The fabricated sensor presented here, exhibited exceptional stability and sensitivity than the reported sensors and could be effectively used for the monitoring 4-AP without interferences.


A multicenter study of the safety and efficacy of naproxen: analysis of blood pressure.
A multicenter study was conducted to determine safety and efficacy of naproxen, 500 mg twice daily, administered for 4 weeks to osteoarthritis (OA) patients. OA symptoms improved in the study population. The study population included 97 patients, 43 of whom were 65 years of age or older. Forty-four of the 97 patients had a history of hypertension; 42 of these took antihypertensive medication before and during the study. Baseline blood pressure (BP) was measured in most patients while they were receiving their prior nonsteroidal antiinflammatory drug (NSAID) therapy; from that baseline, no increase in BP was seen in the hypertensive or normotensive patients after 4 weeks of naproxen therapy. In patients whose BP was controlled by antihypertensive agents, BP remained under control during naproxen therapy.


Occupational working conditions as risk factors for preterm birth in Benin, West Africa.
Although many studies from developed countries have established a relationship between various occupational working conditions during pregnancy and preterm birth, there is little data available in developing countries where both maternal physical labor during pregnancy and preterm birth are common. The aim of this study was to examine the association between difficult occupational working conditions of pregnant women and premature births in the Republic of Benin in West Africa. The case-control study included 99 women with preterm babies and 104 women with full-term babies. The participants were residents of the Republic of Benin who delivered between May 1, 2000 and April 30, 2002. Preterm delivery was defined as delivery prior to 37 completed weeks of gestation. The study sample was selected randomly from birth records. Data were collected both reviewing birth records and conducting semi-structured personal interviews with mothers. Logistic regression models were adjusted for mother's age, mother's education, health problems during pregnancy, and twin birth. Although working state of mother during pregnancy did not increase the risk for preterm delivery, carrying heavy loads more than 5 days per week was significantly associated with having a preterm baby (adjusted OR: 5.0; 95% CI: 1.38-18.8; P=0.018). Carrying heavy loads and having worked a lot more than 5 days per week was also significantly associated with preterm birth (adjusted OR: 6.88; 95% CI: 1.45-32.2; P=0.015). Reducing heavy loads carrying during pregnancy may also prevent preterm delivery in developing countries. Though replication of these data using a prospective design is needed, our results suggest that educating women about the risks associated with heavy labor during pregnancy is indicated.


Glycosylation-independent ERAD pathway serves as a backup system under ER stress.
During endoplasmic reticulum (ER)-associated degradation (ERAD), terminally misfolded proteins are retrotranslocated from the ER to the cytosol and degraded by the ubiquitin-proteasome system. Misfolded glycoproteins are recognized by calnexin and transferred to EDEM1, followed by the ER disulfide reductase ERdj5 and the BiP complex. The mechanisms involved in ERAD of nonglycoproteins, however, are poorly understood. Here we show that nonglycoprotein substrates are captured by BiP and then transferred to ERdj5 without going through the calnexin/EDEM1 pathway; after cleavage of disulfide bonds by ERdj5, the nonglycoproteins are transferred to the ERAD scaffold protein SEL1L by the aid of BiP for dislocation into the cytosol. When glucose trimming of the N-glycan groups of the substrates is inhibited, glycoproteins are also targeted to the nonglycoprotein ERAD pathway. These results indicate that two distinct pathways for ERAD of glycoproteins and nonglycoproteins exist in mammalian cells, and these pathways are interchangeable under ER stress conditions.


Athletic training in badminton players modulates the early C1 component of visual evoked potentials: a preliminary investigation.
One basic question in brain plasticity research is whether individual life experience in the normal population can affect very early sensory-perceptual processing. Athletes provide a possible model to explore plasticity of the visual cortex as athletic training in confrontational ball games is quite often accompanied by training of the visual system. We asked professional badminton players to watch video clips related to their training experience and predict where the ball would land and examined whether they differed from non-player controls in the elicited C1, a visual evoked potential indexing V1 activity. Compared with controls, the players made judgments significantly more accurately, albeit not faster. An early ERP component peaking around 65 ms post-stimulus with a scalp topography centering at the occipital pole (electrode Oz) was observed in both groups and interpreted as the C1 component. With comparable latency, amplitudes of this component were significantly enhanced for the players than for the non-players, suggesting that it can be modulated by long-term physical training. The results present a clear case of experience-induced brain plasticity in primary visual cortex for very early sensory processing.


Evaluation of a smartphone photoscreening app to detect refractive amblyopia risk factors in children aged 1-6 years.
To determine the specificity and sensitivity of a smartphone app (GoCheckKids [GCK] used as a photoscreening tool on the iPhone 7 to detect refractive amblyopia risk factors in children aged 1-6 years. A prospective, multicenter, 10-month evaluation of children aged 1-6 years old who underwent photoscreening with the GCK app to detect amblyopia risk factors. The first acceptable quality photograph of each study subject was evaluated by trained technicians using GCK's proprietary automated image processing algorithm to analyze for amblyopia risk factors. Trained graders, masked to the cycloplegic clinical data, remotely reviewed photographs taken with the app and compared results to the gold standard pediatric ophthalmology examinations using the 2013 American Association for Pediatric Ophthalmology & Strabismus amblyopia risk factor guidelines. Primary outcome was the ability of the GCK app to identify amblyopia risk factors compared to the cycloplegic refraction. There were 287 patient images analyzed. The overall sensitivity and specificity in detecting amblyopia risk factors were 76% and 85%, respectively using manual grading. The overall automated grading results had a sensitivity and sensitivity in detecting amblyopia risk factors of 65% and 83%, respectively. The GCK smartphone app is a viable photoscreening device for the detection of amblyopia risk factors in children aged 1-6 years.


Influences of COVID-19 pandemic on hospital-at-home functions in Finland - a questionnaire survey.
To investigate functions of Finnish hospital-at-home (HAH) during the first year of COVID19-pandemic 2020 compared with the previous year 2019. Retrospective questionnaire survey. Finnish HAHs from Northern, Eastern, Southern, Western and Central parts of Finland participated in a questionnaire web-based questionnaire survey. The numbers of patients, activities and staff in 2019 and 2020, participation in the care of COVID19 patients, availability of protective clothing, attitudes of patients towards home care and development of new practices in the corona era were asked using both predefined and free questions. questionnaire was sent to the nurses and physicians in charge of the HAHs (N = 13), 77% responded. The HAHs provided services to a total of 1,196,783 inhabitants in their municipalities. There were no significant changes in the numbers of patients, staff or activities between the years 2019 and 2020. Although nurses did viral tests, COVID19 patients were cared only in 40% of HAHs. Protective clothing was well available. New instructions for infection management were created. The COVID-19 pandemic did not largely influence the functions of the examined Finnish HAHs in 2020. Most activities and patients' characteristics remained unchanged from 2019. The role of HAHs should be further developed in Scandinavian countries, particularly during pandemics.Key PointsHospital-at-home (HAH) is a cost-effective model to provide hospital-like services.Data about the role of HAHs during COVID19 pandemics is lacking in the Nordic countries.This study shows that, the large Finnish municipal HAHs have been not influenced by pandemics.


Free energy potential for aggregation of erythrocytes and phosphatidylcholine/phosphatidylserine vesicles in Dextran (36,500 MW) solutions and in plasma.
The free energy potential (affinity) for aggregation of human red blood cells and lipid vesicles in Dextran solutions and blood plasma has been quantitated by measuring to what extent a vesicle is encapsulated by the red cell surface. The free energy reduction per unit area of contact formation (affinity) was computed from the observation of the fractional extent of encapsulation at equilibrium with the use of a relation based on the elastic compliance of the red cell membrane as it is deformed to adhere to the vesicle surface. Micromanipulation methods were used to select and transfer single lipid vesicles (2-3 X 10(-4) cm diameter) from a chamber that contained the vesicle suspension to a separate chamber on the microscope stage that contained red cells in an EDTA buffer with Dextran or whole plasma. The vesicle and a red cell were maneuvered into close proximity and contact allowed to take place without forcing the cells together. To evaluate the effects of surface charge density and steric interactions on aggregation, vesicles were made from mixtures of egg phosphatidylcholine (PC) and bovine phosphatidylserine (PS) over a range of mole ratios (PC/PS)from (1:0) to (1:1); the vesicles were formed by rehydration in buffer. The Dextran solutions were made with a sharp-cut fraction of 36,500 MW in a concentration range of 0-10% by weight in grams (wt/wt). It was found that the Dextran 36,500 MW fraction produced aggregation behavior for red cells and vesicles similar to red cell-red cell aggregation in Dextran 70,000-150,000 MW fractions, when the vesicle surface charge density was comparable with that of normal red cells (i.e., PC/PS ratio of -3:1). This result indicated that Dextran molecules penetrate between the carbohydrate groups on the red cell surface and that either steric interactions between cell surface carbohydrates are important or many of the charge groups on red cells are superficial. Electrostatic repulsion effects were apparent, as no aggregation in Dextran 36,500 MW occurred for PC/PS ratios <2.6:1; the level of affinity increased with the PC content at a specific Dextran concentration. Affinities were measured in the range of 0-2 x 10-2 ergs/cm2. When adherent red cell-vesicle pairs were transferred into a Dextran-free buffer, the pair did not spontaneously separate.They maintained adhesive contact until forcibly parted, after which they would not read here. This demonstrates that Dextran forms a "cross-bridge" between the membrane surfaces. Red cell-vesicle aggregation was also tested in whole plasma, which normally yields affinity values in the range of 2-4 x 10-3 ergs/cm2 for red cell-red cell aggregation.However, no red cell-vesicle aggregation occurred in plasma, even for pure PC vesicles. This result indicates that either the aggregating plasma proteins (primarily fibrinogen) do not bind sufficiently to the lecithin surface, or they are shielded from binding to the surface by the presence of other nonaggregating components (perhaps albumin).


A Bayesian analysis of mouse infectivity data to evaluate the effectiveness of using ultraviolet light as a drinking water disinfectant.
Modelling disinfectant performance using Bayesian hierarchical methods can overcome problems with traditional methods and lead to improved estimates. Animal and cell-culture assays are used to estimate the degree of inactivation of a microorganism produced by a given disinfectant dose. Assay data traditionally are analyzed with logistic model or most probable number (MPN) method. These methods are limited particularly when assays show all (or no) animals or cells to be infected-estimates are reported as greater than (or less than) a measurement limit (i.e., censored data). The proposed Bayesian approach (1) properly models the propagation of uncertainty through the data analysis/modelling process, resulting in reduced model uncertainty, and (2) uses appropriate probability distribution models for the response variables, avoiding the censored data problem and more accurately describing statistical error when estimating dose-response behavior. This paper applies the Bayesian hierarchical models to logistic and MPN data from published papers for the ultraviolet (UV) inactivation of Cryptosporidium. Results are compared to those from three alternative models. The Bayesian model estimates a significantly lower UV dose for a given level of Cryptosporidium inactivation than the alternative models, due mainly to the reduced model uncertainty.


Outcome and Prognostic Factors of COVID-19 Infection in Swiss Cancer Patients: Final Results of SAKK 80/20 (CaSA).
Purpose: These are the final results of a national registry on cancer patients with COVID-19 in Switzerland. Methods: We collected data on symptomatic COVID-19-infected cancer patients from 23 Swiss sites over a one-year period starting on 1 March 2020. The main objective was to assess the outcome (i.e., mortality, rate of hospitalization, ICU admission) of COVID-19 infection in cancer patients; the main secondary objective was to define prognostic factors. Results: From 455 patients included, 205 patients (45%) had non-curative disease, 241 patients (53%) were hospitalized for COVID-19, 213 (47%) required oxygen, 43 (9%) invasive ventilation and 62 (14%) were admitted to the ICU. Death from COVID-19 infection occurred in 98 patients, resulting in a mortality rate of 21.5%. Age ≥65 years versus <65 years (OR 3.14, p = 0.003), non-curative versus curative disease (OR 2.42, p = 0.012), ICU admission (OR 4.45, p < 0.001) and oxygen requirement (OR 20.28, p < 0.001) were independently associated with increased mortality. Conclusions: We confirmed high COVID-19 severity and mortality in real-world cancer patients during the first and second wave of the pandemic in a country with a decentralized, high-quality, universal-access health care system. COVID-19-associated mortality was particularly high for those of older age in a non-curative disease setting, requiring oxygen or ICU care.


Review of methods to determine hand surface area of children less than six years old: a case study.
Various methods exist to determine the surface area of hands. The consistency of these methods is essential given that risk assessments utilize hand surface area (HSA) to quantify exposure to environmental contaminants. HSA is also utilized in the clinical setting to estimate size of burns, and to determine specific treatments and medication dosages. A reliable method of surface area measurement is important to guide these decisions, especially in children who are vulnerable to environmental contaminants and medication side effects. Despite this, fewer HSA-determining studies have been performed for children compared to adults. In this study, 122 children completed hand tracings, and the tracings were digitized using an ImageJ program to determine HSA. Six previously published methods of determining HSA were utilized based on the child's height, weight, and length and width of hand. Children were analyzed by age group including 0-2, 3-4, and 5-6 years. The HSA measurements determined by five of the six methods were statistically different from HSA determined using direct hand tracings/Image J methodology (p < 0.001). The single remaining study that did not differ significantly from the hand tracing method provided a uniform hand to total body surface area (TBSA) ratio for children of all ages. Based on these results, we propose a novel age-group-specific ratio utilizing the HSA results from hand tracings and TBSA calculations. The percentages of TBSA that reflect HSA for children aged 0-2, 3-4 and 5-6 years were 0.91%, 0.90% and 0.87%, respectively. These percentages should be considered for use in risk assessments and the clinical setting to guide treatment and prognosis.


Effects of plant downtime on the microbial community composition in the highly saline brine of a geothermal plant in the North German Basin.
The microbial biocenosis in highly saline fluids produced from the cold well of a deep geothermal heat store located in the North German Basin was characterized during regular plant operation and immediately after plant downtime phases. Genetic fingerprinting revealed the dominance of sulfate-reducing bacteria (SRB) and fermentative Halanaerobiaceae during regular plant operation, whereas after shutdown phases, sequences of sulfur-oxidizing bacteria (SOB) were also detected. The detection of SOB indicated oxygen ingress into the well during the downtime phase. High 16S ribosomal RNA (rRNA) and dsrA gene copy numbers at the beginning of the restart process showed an enrichment of bacteria, SRB, and SOB during stagnant conditions consistent with higher concentrations of dissolved organic carbon (DOC), sulfate, and hydrogen sulfide in the produced fluids. The interaction of SRB and SOB during plant downtimes might have enhanced the corrosion processes occurring in the well. It was shown that scale content of fluids was significantly increased after stagnant phases. Moreover, the sulfur isotopic signature of the mineral scales indicated microbial influence on scale formation.


Group B Streptococcus induces a caspase-dependent apoptosis in fetal rat lung interstitium.
Group B Streptococcus (GBS) is an important pathogen and is associated with sepsis and meningitis in neonates and infants. An ex vivo model that facilitates observations of GBS interactions with multiple host cell types over time was used to study its pathogenicity. GBS infections were associated with profound reductions in fetal lung; explant size, and airway branching. Elevated levels of apoptosis subsequent to GBS infections were observed by whole-mount confocal immunofluorescence using activated-caspase-3-antibodies and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assays. The caspase inhibitor Z-VAD-FMK abolished the increase in TUNEL-positive cells associated with GBS infections, indicating that the GBS-induced apoptosis was caspase-dependent. Digital image analyses revealed that both GBS and the active form of caspase-3 were distributed primarily within the lung interstitium, suggesting that these tissues are important targets for GBS. Antibodies to the active form of caspase-3 colocalized with both macrophage- and erythroblast-markers, suggesting that these hematopoietic cells are vulnerable to GBS-mediated pathogenesis. These studies suggest that GBS infections profoundly alter lung morphology and caspase-dependent hematopoietic cell apoptosis within the lung interstitium play roles in GBS pathophysiology in this model.


How the TCR balances sensitivity and specificity for the recognition of self and pathogens.
The T cell repertoire is generated during thymic development in preparation for the response to antigens from pathogens. The T cell repertoire is shaped by positive selection, which requires recognition by the T cell antigen receptor (TCR) of complexes of self peptide and major histocompatibility complex proteins (self-pMHC) with low affinity, and negative selection, which eliminates T cells with TCRs that recognize self-pMHC with high affinity. This generates a repertoire with low affinity for self-pMHC but high affinity for foreign antigens. The TCR must successfully engage both of these ligands for development, homeostasis and immune responses. This review discusses mechanisms underlying the interaction of the TCR with peptide-major histocompatibility complex ligands of varying affinity and highlights signaling mechanisms that enable the TCR to generate different responses to very distinct ligands.


The role of polymorphonuclear leukocytes in the resistance to cutaneous Leishmaniasis.
The massive infiltration by polymorphonuclear leukocytes (PMN) soon after skin infection with Leishmania major suggests that PMN could participate in reducing parasite load and controlling the spreading of leishmanial infection. Yet, direct evidence for the participation of PMN in host defense against L. major was lacking. We investigated L. major infection in susceptible and resistant mice treated with the monoclonal (mAb) antibody RB6-8C5 that depletes the population of mature neutrophils and eosinophils. Both BALB/c and C57BL/6 mice depleted of PMN show accelerated parasite spreading and more severe footpad swelling than similarly infected untreated mice. In addition, significant higher parasite numbers were found in the lesion draining lymph nodes from PMN-depleted C57BL/6 mice. Histopathological analysis of the paw confirmed neutrophils containing ingested parasites as the dominant cell type in the infiltrate of the first days after infection and the nearly absolute neutrophil depletion in mAb-treated mice. Our data show the importance of PMN in early control of parasite load and parasitism spreading in cutaneous leishmaniasis.


Protocol for a feasibility randomised controlled study of a multicomponent intervention to promote a sustainable return to work of workers on long-term sick leave - PROWORK: PROmoting a Sustainable and Healthy Return to WORK.
The cost of sickness absence has major social, psychological and financial implications for individuals and organisations. Return-to-work (RTW) interventions that support good quality communication and contact with the workplace can reduce the length of sickness absence by between 15 and 30 days. However, initiatives promoting a sustainable return to work for workers with poor mental health on long-term sickness absence across small, medium and large enterprises (SMEs and LEs) are limited. This paper describes the protocol of a pilot randomised controlled trial (RCT) to test the feasibility of implementing a RTW intervention across SMEs and LEs across all sectors. A two-arm feasibility RCT with a 4-month intervention will be conducted in SMEs and LE enterprises from the Midlands region, UK. At least 8 organisations (4 controls and interventions), and at least 60 workers and/or managers, will be recruited and randomised into the intervention and control group (30 interventions, 30 controls). Workers on long-term sickness absence (LTSA) (between 8 and 50 days) and managers with a worker on LTSA will be eligible to participate. The intervention is a behavioural change programme, including a managers and workers RTW toolkit, focused on supporting sickness absence and RTW through the provision of knowledge, problem-solving, action planning, goal setting and positive communication that leads to a sustainable RTW. Organisations assigned to the control group will continue with their usual practice. Measurements of mental health, RTW, work outcomes, quality-of-life, workplace support and communication and other demographic data will be taken at baseline, 2 months and 4 months. Feasibility will be assessed based on recruitment, retention, attrition, completion of measures and intervention compliance for which specific process and research outcomes have been established. A process evaluation will explore the experiences and acceptability of the intervention components and evaluation measures. Exploratory economic evaluation will be conducted to further inform a definitive trial. This is a novel intervention using a worker-manager approach to promote a sustainable return to work of workers on long-term sick leave due to poor mental wellbeing. If this intervention is shown to be feasible, the outcomes will inform a larger scale randomised control trial. ISRCTN90032009 (retrospectively registered, date registered 15th December 2020).


In vitro and in vivo characterization of a novel, highly potent p53-MDM2 inhibitor.
Small molecule inhibitors of the p53-MDM2 protein complex are under intense investigation in clinical trials as anti-cancer agents, including our first generation inhibitor NVP-CGM097. We recently described the rational design of a novel pyrazolopyrrolidinone core as a new lead structure and now we report on the synthesis and optimization of this to provide a highly potent lead compound. This new compound displayed excellent oral efficacy in our preclinical mechanistic in vivo model and marked a significant milestone towards the identification of our second generation clinical candidate NVP-HDM201.


NEMPD: a network embedding-based method for predicting miRNA-disease associations by preserving behavior and attribute information.
As an important non-coding RNA, microRNA (miRNA) plays a significant role in a series of life processes and is closely associated with a variety of Human diseases. Hence, identification of potential miRNA-disease associations can make great contributions to the research and treatment of Human diseases. However, to our knowledge, many existing computational methods only utilize the single type of known association information between miRNAs and diseases to predict their potential associations, without focusing on their interactions or associations with other types of molecules. In this paper, we propose a network embedding-based method for predicting miRNA-disease associations by preserving behavior and attribute information. Firstly, a heterogeneous network is constructed by integrating known associations among miRNA, protein and disease, and the network representation method Learning Graph Representations with Global Structural Information (GraRep) is implemented to learn the behavior information of miRNAs and diseases in the network. Then, the behavior information of miRNAs and diseases is combined with the attribute information of them to represent miRNA-disease association pairs. Finally, the prediction model is established based on the Random Forest algorithm. Under the five-fold cross validation, the proposed NEMPD model obtained average 85.41% prediction accuracy with 80.96% sensitivity at the AUC of 91.58%. Furthermore, the performance of NEMPD is also validated by the case studies. Among the top 50 predicted disease-related miRNAs, 48 (breast neoplasms), 47 (colon neoplasms), 47 (lung neoplasms) were confirmed by two other databases. The proposed NEMPD model has a good performance in predicting the potential associations between miRNAs and diseases, and has great potency in the field of miRNA-disease association prediction in the future.


Reviewing performance of NSF/ANSI 53 certified water filters for lead removal.
Properly certified NSF/ANSI 53 water filters are distributed as a temporary measure to protect residents from risk of exposure to elevated lead (Pb) levels resulting from water system changes and various activities. Water consumers and other stakeholders have raised questions on the performance of these filters in field settings, particularly in cases where water Pb levels exceeded the NSF/ANSI 53 challenge water level of 150 µg/L and when Pb phosphate nanoparticles (≤ 200 nm) were present in drinking water. This literature review summarizes findings from 23 studies that evaluated the ability of NSF/ANSI 53 post-2007 certified filters to reduce soluble and/or particulate Pb from water. The studies in total examined 1,486 faucet-mounted, 25 under-the-sink, and 167 pitcher filters, with 1,528 filters used in field studies and 150 filters in laboratory studies. This review found that filter performance varied with different filter type, test water source, and initial unfiltered total Pb concentration. 99% (1,512/1,528) of the filters used in field studies removed Pb to at or below the certification benchmark of pre-2019, 10 µg/L or post-2019, 5 µg/L. In contrast, 61% (91/150) of the filters used in laboratory studies reduced Pb to the benchmark. Laboratory filters were often tested under conditions beyond what they were certified to handle. Pb concentration, particle form and size, improper operation and maintenance of certified water filters were attributed to reported filter failures. This information is intended to help water utilities, regulators, and others make decisions regarding the deployment of water filters to the public when drinking water Pb exposure concerns have been raised.


Mycobiota and mycotoxins in malted barley and brewer's spent grain from Argentinean breweries.
To evaluate mycobiota and aflatoxins B(1) (AFB(1)), B(2) (AFB(2)), G(1) (AFG(1)), G(2) (AFG(2)) and fumonisin B(1) (FB(1)) contamination in different malted barley types and brands and brewer's grain collected from a major Argentinean brewery. Total fungal counts were performed using the plate count method. Aflatoxin B(1), AFB(2), AFG(1), AFG(2) and Zearalenone (ZEA) analyses were performed by thin-layer chromatography (TLC). Fumonisin B(1) was determined by HPLC. Eighty-three percentage of the malted barley (100% M1, 50% M2 and 100% M3) and 61% of brewer's grain samples had a count >1 × 10(4) CFU g(-1). Yeasts were isolated from all malt and brewer's grain samples. Genera containing some of the most important mycotoxin producer species--Fusarium ssp., Aspergillus ssp., Penicillium ssp. and Alternaria ssp.--were isolated from the analysed samples, along with other environmental saprophytic fungi such as Geotrichum ssp., Mucorales and Cladosporium ssp. All samples were contaminated with 104-145 μg kg(-1) FB(1). Eighteen per cent of brewer's grain samples were contaminated with 19-44.52 μg kg(-1) AFB(1). Aflatoxin B(2), AFG(1), AFG(2) and ZEA were not detected in any of the analysed samples. Fungal and mycotoxin contamination in malt and brewer's grain is an actual risk for animal and human health. This study may be useful for assessing the risk of mycotoxins in Argentinean beers and especially in animal feeds.


Clinical features and phylogenetic analysis of severe hand-foot-and-mouth disease caused by Coxsackievirus A6.
Coxsackievirus A6 (CA6) infection may lead to high hand-foot-and-mouth disease (HFMD) aggregation in children. We aimed to analyze the clinical and phylogenetic features of severe CA6-associated pediatric HFMD. The clinical and laboratory features of 206 and 55 children with mild and severe CA6-associated HFMD, respectively, were summarized. The CA6 phylogenetic tree was depicted using combinatorial analysis of the VP1-encoding regions and neighbor-joining method. CA6 was the major pathogen both in mild and severe HFMD in 2017. Most CA6-associated severe HFMD cases showed high fever, skin rash, age younger than 36 months, and elevated white blood cell and C-reactive protein levels, and there were no significant differences compared to the mild cases (p > 0.05). The severe cases were significantly more likely (p < 0.05) to show male sex, long fever duration, decreased oral intake, tonsil enlargement, diarrhea, vomiting, elevated levels of creatine kinase and blood glucose, and positive fecal occult-blood test results. Severe complications included aseptic meningitis (29/55, 52.7%) and pulmonary edema (6/55, 10.9%) were observed in severe cases. Furthermore, genetic analyses showed all CA6 isolates belonged to lineage E2, and two amino acid changes of V174I and T283A in VP1 may be associated with the severity of HFMD. CA6 has become a major cause of HFMD with severe systemic disorders. V174I and T283A of VP1 may be associated with the severity of CA6 infection. These findings could raise awareness of the clinical importance of CA6 infection among practitioners.


A Potential MRI Agent and an Anticancer Drug Encapsulated within CPMV Virus-Like Particles.
Virus nanoparticles have been extensively studied over the past decades for theranostics applications. Viruses are well-characterized, naturally occurring nanoparticles that can be produced in high quantity with a high degree of similarity in both structure and composition. The plant virus Cowpea Mosaic Virus (CPMV) has been innovatively used as a nanoscaffold. Utilization of the internal cavity of empty Virus-Like Particles (VLPs) for the inclusion of therapeutics within the capsid has opened many opportunities in drug delivery and imaging applications. The encapsidation of magnetic materials and anticancer drugs was achieved. SuperscriptCPMV denotes molecules attached to the external surface of CPMV and CPMVSubscript denotes molecules within the interior of the capsid. Here, the generation of novel VLPs incorporating iron-platinum nanoparticles TCPMVFePt and cisplatin (Cis) (TCPMVCis) is reported. TCPMVCis exhibited a cytotoxic IC50 of TCPMVCis on both A549 and MDA-MB-231 cell lines of 1.8 μM and 3.9 μM, respectively after 72 hours of incubation. The TCPMVFePt were prepared as potential MRI contrast agents. Cisplatin loaded VLP (TCPMVCis) is shown to enhance cisplatin cytotoxicity in cancer cell lines with its potency increased by 2.3-folds.


Spatial and temporal characterization of cyanobacteria blooms in the Mississippi Sound and their relationship to the Bonnet Carré Spillway openings.
During the spring and summer of 2019, an unprecedented cyanobacterial harmful algal bloom (cyanoHAB) was responsible for beach advisories on 25 beaches along the Mississippi Sound for over 3 months. Due to the preceding heavy rainfall and flooding within the Mississippi River watershed, for the first time in history, the Bonnet Carré Spillway (BCS) opened twice in one year during 2019. The coastal cyanoHAB coincided with the second BCS opening. The main objectives of this study were: (1) to investigate the potential for using the National Aeronautics and Space Administration (NASA) ocean color standard Cyanobacteria Index (CIcyano) algorithm to characterize the spatial and temporal extent of the 2019 cyanoHAB; (2) to couple the CIcyano data with river discharge, salinity, and modeled-wind data to study the conditions leading to the cyanoHAB and factors aiding the advection and persistence of the bloom within the Mississippi Sound, including a possible relationship to the BCS; (3) to further investigate the relationship with the BCS by repeating the methods using data from 2018, which was a year when the BCS was opened but no evidence of cyanoHABs was reported along the Mississippi coast. Weekly means and monthly frequency CIcyano images, river discharge, salinity, and modeled-wind data from February to September of 2018 and 2019 were analyzed, which coincide with three BCS openings. In March 2018, a cyanobacteria bloom was observed within Lake Pontchartrain coinciding with the BCS opening; however, the month-long bloom was contained to the lake. Two distinct cyanoHABs were observed in 2019 and both blooms were advected into the Mississippi Sound, and likely contributed to the 3-month-long beach water advisories of 2019 along the Mississippi coastline. From March to mid-July 2019, salinity at stations within the Mississippi Sound was consistently near zero indicating high levels of freshwater. During that time, winds were predominantly northwestward, preventing the BCS waters from flushing into the Mississippi Shelf and resulting in BCS waters remaining longer within the estuarine lakes and Mississippi Sound. Although the BCS had an undeniable impact on the presence of the coastal cyanoHAB of 2019, other variables including wind direction, water flow, mixing, and persistence of freshwater within the Sound can determine the intensity and extent of the cyanoHABs. Coupling in situ phytoplankton information from freshwater water bodies to the marine continuum along with water flow, wind data, and satellite imagery could help identify cyanoHABs at early stages and forecast their trajectory and potential impacts on coastal areas.


Hertzian contact response of dentin with loading rate and orientation.
To test the hypothesis that dentin Hertzian contact response varies with loading rate and tubule orientation. Sound teeth (n=12) were cut either parallel or perpendicular to the axial direction to expose dentin (n=6 each). The cut specimens were embedded (poly-methyl-methacrylate (PMMA) and divided into two groups: (GL) load applied parallel to dentin tubule direction and (GP) load applied perpendicular to tubule direction. A 1.5mm diameter tungsten-carbide ball was used for Hertzian contact testing with a maximum load of 150 N load and loading rates of 0.1, 1, 100, and 1000 N/s on each specimen. Indented specimens were observed microscopically and photomicrographs acquired. Hertzian contact diameter and modulus were analysed (p<0.05) by one-way ANOVA and Tukey test. There were significant differences (p<0.05) in Hertzian response with respect to loading rate for GL (0.1N/s versus 1000 N/s, 0.1N/s versus 100 N/s, 1N/s versus 1000 N/s, and 1N/s versus 100 N/s), and GP (0.1N/s versus 1000 N/s, 0.1N/s versus 100 N/s, and 1N/s versus 1000 N/s). Contact modulus was higher for GL compared to GP at all loading rates (p<0.05). The results suggest that dentin contact modulus is loading rate dependent. Tubule orientation of dentin did not influence contact modulus values (p>0.05).


Amplification for hearing-impaired children: basic considerations.
The importance of the selection of proper amplification for the hearing impaired child is discussed including goals of amplification, specific methods of choosing amplification, and test procedures including speech audiometry. Evaluation controversies discussed include: monaural versus binaural amplification; body worn versus post auricular hearing aids; maximum output; and special hearing aid modifications.


Mannitol to prevent cisplatin-induced nephrotoxicity in patients with squamous cell cancer of the head and neck (SCCHN) receiving concurrent therapy.
The purpose of this study is to compare the incidence and severity of nephrotoxicity in patients receiving cisplatin with saline hydration vs. saline hydration with mannitol. Retrospective chart review of all patients receiving a starting dose of cisplatin 100 mg/m(2) with concurrent radiation for SCCHN between January 1, 2009 and March 1, 2013. All patients received pre and post hydration each with 1 l of 0.9 % saline. The mannitol group received 12.5 g of mannitol in the prehydration fluid. The primary outcome was to compare the rate of grade 3 or greater serum creatinine (SCr) increase in patients receiving saline hydration vs. the addition of mannitol; additional parameters of interest included creatinine clearance, electrolyte disturbances, dose changes, and discontinuation of cisplatin. Data from 139 patients (80 % male) with a median age of 56 years (range 22 to 75 years) were collected; 88 received mannitol and 51 received saline alone. On multivariable analysis, the mannitol group was less likely to have grade 3 SCr increase than saline only group (OR 0.16; 95 % CI 0.04-0.65; p value = 0.01). There were no grade 4 SCr increase events. Rates of hypomagnesemia and hypokalemia were similar across groups. Grade 3 hyponatremia was more likely to occur in the mannitol group as compared to saline alone group (41 vs 22 %; p = 0.026). The addition of mannitol to saline hydration decreased the incidence of grade 3 increases in SCr in this cohort of patients and may increase rates of hyponatremia. Further investigations of methods to lessen cisplatin-induced nephrotoxicity are needed.


Study of serological and clinical factors among juvenile rheumatoid arthritis cases admitted to Mofid Children's Hospital and Imam Hossein Hospital, Tehran, Iran.
Juvenile Rheumatoid Arthritis is the most common rheumatologic disease of childhood period. The aim of study was to compare ANA positive and ANA negative cases. This observation study was performed as correlation research. All cases with diagnosis ofJRA who visited Mofid Children's Hospital and Imam Hossein Hospital were included in this study. Duration of this study was from 2006, 1 October till 2008, 31 October. All patients were examined carefully by an experienced pediatric rheumatologist. Age, sex, disease onset, age at diagnosis, RF, ANA, HLA-B27, ESR, type of disease, disease activity, and duration of inactivity were included in this study. ANA titer was measured by immunoflurocence technique. Patients were categorized according to sex, ANA, and type of disease and then group was compared with each other. Data was analyzed by SPSS Ver. 16 (Chicago, IL, USA). This study was approved by Ethical Committee of university. In this study, 61 cases were enrolled. Twenty five cases (41%) were males and 36 cases were females. Mean of age at disease onset was 6.1 +/- 3.1 (Range 6 months to 12.5 years). Mean of age at disease diagnosis was 6.7 +/- 3.2. Mean of age at time of study was 7.6 +/- 3.5 (1.4 to 14 years). From all cases, 38 cases were oligoarticular, 18 cases were polyarticular and 5 cases were systemic onset. From 61 cases, 22 (36.1%) cases, had ANA positive JRA. Of these cases, 14 cases were oligoarticular and 8 cases were polyarticular. Except for sex and morning stiffness, there is significant correlation between type of disease and ANA,RF,HLA-B27, response to treatment, early onset erosion, subcutaneous nodule, and uveitis (P < 0.05). There is significant correlation between sex and ANA, RF, HLA-B27, early erosion, response to treatment, subcutaneous treatment, and uveitis (P < 0.05). There is significant correlation between ANA seropositivity and HLA-B27, early erosion, response to treatment, uveitis and subcutaneous nodule. Our results showed that there is significant correlation among ANA and other factors except morning stiffness. Another prospective study is recommended.


Triptans in the Italian population: a drug utilization study and a literature review.
Previous studies performed in selected populations show a poor utilization of triptans for migraine. The objectives of our study were to establish patterns of triptans utilization in a large sample, covering 1/10 of Italian population (5.57 millions), and to perform a review of published studies on this topic. We investigated drug prescription database collected during 2006 from 33 health authorities distributed in 8 different regions. About 0.6% of the subjects received at least one prescription of triptans in 1 year: 77.7% were females and 22.3% males. Age distribution shows that 9.5% of patients were aged above 65, and received prescriptions for 8.2% of packages. The review of the literature suggests that these percentages of utilization are common to several countries, and shows that occasional triptan users who received only one prescription in 1 year are a large percentage (40-60%); moreover, a minor population of triptan users utilize a large amount of total triptans. Finally triptans are frequently prescribed in people aged above 65 years, a population in which triptans are contraindicated or not recommended. Our study and the analyzed ones indicate suboptimal treatment of migraine patients with triptans and also an incorrect use in some patients (triptan abusers, elderly).


Gender and age differences in absolute and relative handgrip strength of the Turkish population aged 8-27 years.
We aimed to investigate the impact of anthropometric variables on absolute and relative hand grip strength (HGS) and associations among them in gender-specific age groups and also to evaluate normative HGS values adjusted to body mass index (BMI), fat free mass (FFM) and fat free mass index (FFMI) in healthy subjects as a function of age group and gender. A total of 567 volunteers (n=271 boys, 10.89±1.16 years, and n=296 girls, 10.86±1.07 years) participated in this study. Three consecutive trials for both hands were performed; the highest value was used as the HGS. There were no significant differences between genders in both anthropometric and strength values except FFM, FFMI and left-side grip strength (LSGS) in the 8-12 age group even though HGS values were normalized. FFM (r=0.80, r=0.86, p<0.01) and FFMI (r=0.57, r=0.76, p<0.01) had strong relationship with HGS in both females and males, respectively. The results of this study show that both age-dependent increases in HGS and gender differences are strongly associated with changes in FFM and FFMI. For this purpose, we suggest using FFM or FFMI-corrected HGS values to compare or constitute standard data as a guide for practitioners when interpreting grip strength measurements.


Working memory effects of gap-predictions in normal adults: an event-related potentials study.
The current study examined the relationship between verbal memory span and the latency with which a filler-gap dependency is constructed. A previous behavioral study found that low span listeners did not exhibit antecedent reactivation at gap sites in relative clauses, in comparison to high verbal memory span subjects (Roberts et al. in J Psycholinguist Res 36(2):175-188, 2007), which suggests that low span subjects are delayed at gap filling. This possibility was examined in the current study. Using an event-related potentials paradigm, it was found that low span subjects have an onset latency delay of about 200 ms in brain responses to violations of syntactic expectancies after the gap site, thus providing a time course measure of the delay hypothesized by previous literature.


Allergic manifestation 15 years after early intervention with hydrolyzed formulas--the GINI Study.
Data on the long-term impact of hydrolyzed formulas on allergies are scarce. To assess the association between early intervention with hydrolyzed formulas in high-risk children and allergic outcomes in adolescence. GINI trial participants (n = 2252) received one of four formulas in the first four months of life as breastmilk substitute if necessary: partial or extensive whey hydrolyzate (pHF-W, eHF-W), extensive casein hydrolyzate (eHF-C) or standard cow's milk formula (CMF) as reference. Associations between these formulas and the cumulative incidence and prevalence of parent-reported physician-diagnosed asthma, allergic rhinitis (AR) and eczema, as well as spirometric indices and sensitization, were examined using generalized linear models. Between 11 and 15 years, the prevalence of asthma was reduced in the eHF-C group compared to CMF (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.26-0.89), which is consistent with the spirometric results. The cumulative incidence of AR was lower in eHF-C (risk ratio (RR) 0.77, 95% CI 0.59-0.99]) and the AR prevalence in pHF-W (OR 0.67, 95% CI 0.47-0.95) and eHF-C (OR 0.59, 95% CI 0.41-0.84). The cumulative incidence of eczema was reduced in pHF-W (RR 0.75, 95% CI 0.59-0.96) and eHF-C (RR 0.60, 95% CI 0.46-0.77), as was the eczema prevalence between 11 and 15 years in eHF-C (OR 0.42, 95% CI 0.23-0.79). No significant effects were found in the eHF-W group on any manifestation,nor was there an effect on sensitization with any formula. In high-risk children, early intervention using different hydrolyzed formulas has variable preventative effects on asthma, allergic rhinitis and eczema up to adolescence.


Arabidopsis MKKK20 is involved in osmotic stress response via regulation of MPK6 activity.
Plants have developed various regulatory pathways to adapt to environmental stresses. In this study, we identified Arabidopsis MKKK20 as a regulator in the response to osmotic stress. mkkk20 mutants were found to be sensitive to high concentration of salt and showed higher water loss rates than wild-type (WT) plants under dehydration conditions. In addition, mkkk20 mutants showed higher accumulation of superoxide, a reactive oxygen species (ROS), compared to WT plants under high salt condition. In contrast, transgenic plants overexpressing MKKK20 displayed tolerance to salt stress. MKKK20 transcripts were increased by the treatments with NaCl, mannitol, MV, sorbitol, and cold, suggesting that MKKK20 is involved in the response to osmotic, ROS, and cold stresses. In-gel kinase assay showed that MKKK20 regulates the activity of MPK6 under NaCl, cold, and H(2)O(2) treatments. Taken together, our results suggest that MKKK20 might be involved in the response to various abiotic stresses, especially osmotic stress, through its regulation of MPK6 activity.


Systematic review of adherence to the standards for reporting of diagnostic accuracy studies (STARD) 2015 reporting guideline in cerebral aneurysm imaging diagnostic accuracy studies.
Diagnostic neuroimaging plays an essential role in guiding clinical decision-making in the management of patients with cerebral aneurysms. Imaging technologies for investigating cerebral aneurysms constantly evolve, and clinicians rely on the published literature to remain up to date. Reporting guidelines have been developed to standardise and strengthen the reporting of clinical evidence. Therefore, it is essential that radiological diagnostic accuracy studies adhere to such guidelines to ensure completeness of reporting. Incomplete reporting hampers the reader's ability to detect bias, determine generalisability of study results or replicate investigation parameters, detracting from the credibility and reliability of studies. The purpose of this systematic review was to evaluate adherence to the Standards for Reporting of Diagnostic Accuracy Studies (STARD) 2015 reporting guideline amongst imaging diagnostic accuracy studies for cerebral aneurysms. A systematic search for cerebral aneurysm imaging diagnostic accuracy studies was conducted. Journals were cross examined against the STARD 2015 checklist and their compliance with item numbers was recorded. The search yielded 66 articles. The mean number of STARD items reported was 24.2 ± 2.7 (71.2% ± 7.9%), with a range of 19 to 30 out of a maximum number of 34 items. Taken together, these results indicate that adherence to the STARD 2015 guideline in cerebral aneurysm imaging diagnostic accuracy studies was moderate. Measures to improve compliance include mandating STARD 2015 adherence in instructions to authors issued by journals.


Post-infection treatment with the E protein inhibitor BIT225 reduces disease severity and increases survival of K18-hACE2 transgenic mice infected with a lethal dose of SARS-CoV-2.
The Coronavirus envelope (E) protein is a small structural protein with ion channel activity that plays an important role in virus assembly, budding, immunopathogenesis and disease severity. The viroporin E is also located in Golgi and ER membranes of infected cells and is associated with inflammasome activation and immune dysregulation. Here we evaluated in vitro antiviral activity, mechanism of action and in vivo efficacy of BIT225 for the treatment of SARS-CoV-2 infection. BIT225 showed broad-spectrum direct-acting antiviral activity against SARS-CoV-2 in Calu3 and Vero cells with similar potency across 6 different virus strains. BIT225 inhibited ion channel activity of E protein but did not inhibit endogenous currents or calcium-induced ion channel activity of TMEM16A in Xenopus oocytes. BIT225 administered by oral gavage for 12 days starting 12 hours before infection completely prevented body weight loss and mortality in SARS-CoV-2 infected K18 mice (100% survival, n = 12), while all vehicle-dosed animals reached a mortality endpoint by Day 9 across two studies (n = 12). When treatment started at 24 hours after infection, body weight loss, and mortality were also prevented (100% survival, n = 5), while 4 of 5 mice maintained and increased body weight and survived when treatment started 48 hours after infection. Treatment efficacy was dependent on BIT225 dose and was associated with significant reductions in lung viral load (3.5 log10), virus titer (4000 pfu/ml) and lung and serum cytokine levels. These results validate viroporin E as a viable antiviral target and support the clinical study of BIT225 for treatment and prophylaxis of SARS-CoV-2 infection.


Aberrant regulation of NMDA receptors by dopamine D4 signaling in rats after phencyclidine exposure.
Dopaminergic dysfunction in the prefrontal cortex (PFC) has been implicated in the pathophysiology of schizophrenia. On the other hand, administration of the NMDAR antagonist phencyclidine (PCP) impairs PFC functions and induces a broad range of schizophrenic-like symptoms, thus has been widely used as an animal model for schizophrenia. This study sought to determine the mechanism by which PCP may alter the dopaminergic functions in PFC. In control rats, activation of dopamine D4 receptors produced a significant suppression of NMDA receptor transmission in PFC pyramidal neurons, which was dependent on the inhibition of active CaMKII. However, in PCP-treated rats, the D4 modulation of NMDA receptors was significantly impaired, with the concomitant loss of D4 regulation of CaMKII activity. In contrast, the D4 modulation of voltage-dependent Ca2+ channels was intact following PCP administration. Furthermore, treatment with the antipsychotic drug clozapine restored the D4 regulation of NMDA receptors in PCP-treated rats. These findings suggest that the selective disruption of the interaction between D4 and NMDA receptors in the PCP model, which is attributable to the impaired D4-mediated downstream signaling, may contribute to the aberrant PFC neuronal activity in schizophrenia.


Single-center trials in neonatology: Issues to consider.
Single-center randomized controlled trials confer certain advantages over multi-center trials, in that they are cheaper and easier to design and conduct. However, recent research suggests that single-center trials are likely to overestimate treatment effects. There are notable examples in neonatology where results from multi-center trials have contradicted results of single-center studies. In this paper we discuss issues around external generalizability of single-center studies, and methodological issues that may cause bias.


Burnout and depression in nurses: A systematic review and meta-analysis.
Nurses work in stressful and demanding settings and often suffer from depression and burnout. Despite overlapping symptoms, research has been inconclusive regarding the discriminant validity of measures of burnout with regard to measures of depression. Such inconclusive discriminant validity might cause clinicians to fail to recognize and manage depression separately from burnout. This meta-analysis aimed to clarify the distinctiveness of burnout as a separate construct by examining the size of the relationship between burnout and depression among nurses as well as potential moderators. A stepwise method was used by searching 4 databases (PubMed, CINAHL, PsycINFO, and EMBASE) to retrieve published papers in English examining the relationship between burnout and depression among nurses and reporting the effect sizes of their findings. We identified a total of 37 eligible studies. The pooled estimate showed a positive association between burnout and depression among nurses (r = 0.403, 95% CI [0.327, 0.474], p < 0.0001) and a slightly higher correlation coefficient for the Emotional Exhaustion subscale of the Maslach Burnout Inventory (MBI) measure (0.494, 95% CI [0.41, 0.57]). This review confirms a large burnout - depression correlation in nursing samples, adding to existing literature encompassing a variety of occupations. Future studies should focus on path analysis to assess the causal relationship as well as investigate potential moderators.


Abortion care in Ireland: Developing legal and ethical frameworks for conscientious provision.
This article celebrates the remarkable changes which have occurred in the provision of abortion care in Ireland following the vote to remove the restrictive Eighth Amendment to the Constitution of Ireland in May 2018. However, it also identifies ways in which the emerging legal, ethical and clinical landscape is still impeding the conscientious provision of abortion care. It argues that in order to address these impediments, more attention needs to be paid to the ethical context for conscientious provision. This requires political leadership as well as ongoing leadership by professional bodies to develop both the clinical and the ethical guidance for conscientious provision.


Funding source and conflict of interest disclosures by authors and editors in gastroenterology specialty journals revisited.
A survey of journals published in the field of Gastroenterology conducted 5 years ago showed marked variability in reporting of conflicts of interest or funding sources in these journals. To re-examine reporting of conflicts of interest and funding sources for original articles and editorials in Gastroenterology and Hepatology journals. We evaluated all original articles and editorials in 15 leading journals (determined by impact factor-Thomson Reuter Science Citation Index) devoted to Gastroenterology and Hepatology for disclosures of conflicts and for editor's self disclosures. We examined each journal's editorial policy by contacting the journal directly if the information was not revealed on the Web site or print versions of the journal. Of the 1574 articles evaluated, a total of 1207 (77%) reported the presence or absence of a potential conflict of interest and 1047 (67%) reported the presence or absence of funding sources. A total of 3 of the 15 (20%) journals (American Journal of Gastroenterology, Gastroenterology, and Alimentary Pharmacology and Therapeutics reported the presence or absence of funding sources in all their published original articles. Only 5 of 15 (33%) journals (Gut, Gastrointestinal Endoscopy, American Journal of Gastroenterology, Neurogastroenterology & Motility and Alimentary Pharmacology and Therapeutics) publicly disclosed the conflicts of interest of the editors. (i) Funding sources and conflicts of interest are still reported variably in the GI literature. (ii) Editorials and review articles are influential, but have poor reporting of conflicts of interest. (iii) Editors of many journals still do not report their conflicts of interest.


Divided Infringement in the Limelight of the Patent Battle Field.
Diagnostic patents usually comprise multiple steps and can be jointly implemented by different parties. However, in the USA, joint implementation may render diagnostic patents unenforceable in light of recent court opinions. Here, I explain how inappropriate claim drafting may render a diagnostic patent vulnerable to joint implementation.


Modeling of MEMS resonator piezoelectric disc by means of an equicharge current source method.
The Legendre polynomial method has been extended to the modeling of MEMS resonator disc with current excitation (equicharge current source). Formulation is given that allows the electric current source to be taken into account. A unique formalism has been developed which allows for both harmonic and modal analyses. Numerical results such as normalized electric input impedance, resonant and anti-resonant frequencies, dispersion curves and displacement profiles are presented and compared with those obtained by using voltage excitation in order to check the accuracy and range of applicability of the proposed approach.