Immunomodulatory effect of an isolated fraction from Tinospora crispa on intracellular expression of INF-γ, IL-6 and IL-8.
Immunomodulators are substances that modify immune system response to a threat. Immunomodulators modulate and potentiate the immune system, keeping it highly prepared for any threat. The immunomodulatory effect of the traditional medicine Tinospora crispa is investigated in this work. T. crispa ethanol extract was fractionated by using different solvents. The ethanol extract and effective isolated fraction were used to investigate the potential immunomodulatory effect of different T. crispa doses ranging from 25 μg/mL to 1000 μg/mL on RAW 246.7 cells by detecting intracellular INF-γ, IL-6, and IL-8 expressions. The antioxidant activity of T. crispa was evaluated through FRAP and DPPH. The total phenolic and total flavonoid contents were also quantified. Results show that T. crispa extract has higher antioxidant potential than ascorbic acid. The FRAP value of T. crispa extract is 11011.11 ± 1145.42 μmol Fe(+2)/g, and its DPPH inhibition percentage is 55.79 ± 7.9, with 22 μg/mL IC50. The results also reveal that the total phenolic content of T. crispa extract is 213.16- ± 1.31 mg GAE/g dry stem weight, and the total flavonoid content is 62.07- ± 39.76 mg QE/g dry stem weight. T. crispa crude extract and its isolated fraction significantly stimulate RAW264.7 cell viability (P ≤ 0.05) and intracellular INF-γ, IL-6, and IL-8 expressions. The results of LC-MS show that four of the active compounds detected in the T. crispa isolated fraction are cordioside, quercetin, eicosenoic acid (paullinic acid), and boldine. The results of this study obviously indicate that T. crispa has immunomodulatory effects through the stimulation of INF-γ, IL-6, and IL-8 expressions. LC-MS phytochemical analysis showed that the T. crispa fraction has cordioside, quercetin, eicosenoic acid (paullinic acid), and boldine, which may be responsible for the immunostimulator effect of T. crispa.


Potent inhibition of tau fibrillization with a multivalent ligand.
Small-molecule inhibitors of tau fibrillization are under investigation as tools for interrogating the tau aggregation pathway and as potential therapeutic agents for Alzheimer's disease. Established inhibitors include thiacarbocyanine dyes, which can inhibit recombinant tau fibrillization in the presence of anionic surfactant aggregation inducers. In an effort to increase inhibitory potency, a cyclic bis-thiacarbocyanine molecule containing two thiacarbocyanine moieties was synthesized and characterized with respect to tau fibrillization inhibitory activity by electron microscopy and ligand aggregation state by absorbance spectroscopy. Results showed that the inhibitory activity of the bis-thiacarbocyanine was qualitatively similar to a monomeric cyanine dye, but was more potent with 50% inhibition achieved at approximately 80nM concentration. At all concentrations tested in aqueous solution, the bis-thiacarbocyanine collapsed to form a closed clamshell structure. However, the presence of tau protein selectively stabilized the open conformation. These results suggest that the inhibitory activity of bis-thiacarbocyanine results from multivalency, and reveal a route to more potent tau aggregation inhibitors.


The radiological outcome in lumbar interbody fusion among rheumatoid arthritis patients: a 20-year retrospective study.
Clinical outcomes amongst Rheumatoid Arthritis (RA) patients have shown satisfactory results being reported after lumbar surgery. The increased adoption of the interbody fusion technique has been due to a high fusion rate and less invasive procedures. However, the radiographic outcome for RA patients after receiving interbody fusion has scarcely been addressed in the available literature. Patients receiving interbody fusion including ALIF, OLIF, and TLIF were examined for implant cage motion and fusion status at two-year follow-up. Parameters for the index correction level including ADH, PDH, WI, SL, FW, and FH were measured and compared at pre-OP, post-OP, and two-year follow-up. We enrolled 64 RA patients at 104 levels (mean 64.0 years old, 85.9% female) received lumbar interbody fusion. There were substantial improvement in ADH, PDH, WI, SL, FW, and FH after surgery, with both ADH and PDH having significantly dropped at two-year follow up. The OLIF group suffered from a higher subsidence rate with no significant difference in fusion rate when compared to TLIF. The fusion rate and subsidence rate for all RA patients was 90.4 and 28.8%, respectively. We revealed the radiographic outcomes of lumbar interbody fusions towards symptomatic lumbar disease in RA patients with good fusion outcome despite the relative high subsidence rate amongst the OLIF group. Those responsible for intra-operative endplate management should be more cautious to avoid post-OP cage subsidence.


Evaluation of national pandemic management policies-A hazard analysis of critical control points approach.
Analyses of pandemic preparedness policies revealed weaknesses in control systems of European nations. This reinforces the need to support countries in their endeavours to prevent and contain pandemics. A Hazard Analysis and Critical Control Points (HACCP) was applied to a generic plan to identify weaknesses in pandemic management policies, in order to develop recommendations for improving national pandemic management systems. Policy components considered in our analysis are command and control, early case detection and disease surveillance, and community containment management. The main critical areas identified in national pandemic control were: communication systems among all institutions and levels involved in pandemic management, guidelines and regulations describing how key personal and institutions should operate during a pandemic, training and dissemination of information to health care personnel involved in outbreak management. The HACCP analysis highlighted the need for agreed communication structures, clear division of responsibilities and harmonised policy guidelines at all levels of pandemic management. Being prepared is the key to successfully coordinate and implement response measures when a pandemic emerges.


Species-specific PCR for the identification of goat cashmere and sheep wool.
In order to establish rapid and species-specific method of goat cashmere and sheep wool identification, a polymerase chain reaction using specific primer pairs targeting mitochondrial D-loop was developed. The goat specific primers yielded a 294 bp PCR fragment and the sheep specific primers yielded three PCR fragments of which only the 404 bp fragment was found highly diagnostic. The specificity and reliability of the developed species-specific PCR assay was validated by considering as many as 500 cashmere and wool samples. The developed species-specific PCR was found effective in detecting mixed samples of cashmere and wool precisely with the relative content over 9.09%. The species-specific PCR method proved to be low cost, fast, easy and reliable alternative to determine the addition of sheep wool in goat cashmere.


Carvedilol prevents impairment of the counterregulatory response in recurrently hypoglycaemic diabetic rats.
It has been suggested that repeated activation of the adrenergic system during antecedent episodes of hypoglycaemia contributes to the development of counterregulatory failure. We previously reported that treatment with carvedilol, a non-specific β-blocker, prevented the development of counterregulatory failure and improved hypoglycaemia awareness in recurrently hypoglycaemic non-diabetic rats. The current study investigated whether carvedilol has similar benefits in diabetic rats. Recurrently hypoglycaemic streptozotocin-diabetic rats (STZ+RH) were treated with carvedilol for one week prior to undergoing a hypoglycaemic clamp. Hypoglycaemia awareness was evaluated in streptozotocin-diabetic rats made hypoglycaemia unaware using repeated injections of 2-deoxyglucose. Compared to hypoglycaemia-naïve STZ-diabetic controls, exogenous glucose requirements were more than doubled in the STZ+RH animals and this was associated with a 49% reduction in the epinephrine response to hypoglycaemia. Treating STZ+RH animals with carvedilol improved the epinephrine response to hypoglycaemia. Of note, neither recurrent hypoglycaemia nor carvedilol treatment affected the glucagon response in diabetic animals. Additionally, carvedilol treatment improved the feeding response to insulin-induced hypoglycaemia in diabetic animals made 'hypoglycaemia unaware' using repeated injections of 2-deoxyglucose, suggesting the treatment improved awareness of hypoglycaemia as well. Our data suggest that carvedilol may be useful in preventing impairments of the sympathoadrenal response and the development of hypoglycaemia unawareness during recurring episodes of hypoglycaemia in diabetic animals.


Probing the ground-state structural transition in small lithium clusters by quantum Monte Carlo simulations.
The ground-state structural transition in small lithium clusters Lin (n = 4 - 6) is analyzed based on the many-body expansion of the interaction energy using the total energy calculated by the fixed-node diffusion Monte Carlo (FN-DMC) simulations. The results show that the transition from 2D to 3D structure occurs through an intricate competition of attractive and repulsive interaction energies. As the structure dimensionality increases from 2D to 3D, the electron-correlation contribution to the interaction energy in the isomer of the ground-state structure is always the largest.


Effect of maternal multiple micronutrient supplements on cord blood hormones: a randomized controlled trial.
Fetal growth improves in pregnant women who take daily maternal multiple micronutrients [United Nations International Multiple Micronutrient Preparation (UNIMMAP)] rather than iron and folic acid (IFA) alone. Our objective was to test whether such an effect was mediated by changes in concentrations of cord hormones. In a double-blind, controlled trial carried out in Burkina Faso, we randomly assigned 1426 pregnant women to receive UNIMMAP or IFA supplements. We measured concentrations of insulin-like growth factor I (IGF-I), leptin, insulin, free thyroxine, and cortisol in cord serum in a subsample of 294 live single newborns. We performed mediation analysis with an Aroian test. UNIMMAP supplementation had no significant effect on cord hormone concentrations. However, UNIMMAP supplementation significantly affected concentrations of IGF-I (+30%; 95% CI: 8%, 52%; P = 0.009) and leptin in male newborns. In these infants, 51.1% (P = 0.08) of the effect of UNIMMAP supplementation on birth weight was mediated through IGF-I, whereas for female newborns, this proportion was negligible. UNIMMAP supplementation also increased cortisol concentrations by 36% (P = 0.009) in cord blood in primiparae (P for interaction = 0.02). Growth-retarded infants had 41.2% lower IGF-I (P < 0.0001) and 27.3% lower leptin (P = 0.04) than did infants with normal growth. Offspring of primiparae had reduced IGF-I and insulin concentrations, and their cortisol concentrations were 25% higher (P = 0.05). Male newborns had lower concentrations of IGF-I, leptin, and insulin than did female newborns. UNIMMAP supplementation had sex-specific effects on cord IGF-I and leptin concentrations that were of unclear clinical significance. Other pathways may have been involved in the action of UNIMMAP on fetal growth. The specific hormonal pattern in primiparae could be related to constrained fetal growth. Confirmatory studies are warranted. This trial was registered at clinicaltrials.gov as NCT00642408.


Optimization of protein identification from digests as analyzed by capillary isoelectric focusing-mass spectrometry.
Capillary isoelectric focusing (CIEF) is a high-resolution separation technique for the analysis of peptides and protein digests. When coupled to ion trap-mass spectrometry (CIEF-MS) the unique separation mechanism is combined with a highly efficient detection system. In an earlier report, we described aspects of separation and interfacing in connection to the analysis of a digest of set of standard proteins. Now, we report on different aspects of the process of protein identification. Sequest software parameters were optimized by using a standard protein digest. These settings were used for the analysis of periplasmic proteins from Escherichia coli. Since in CIEF peptides are focused according to their pI values, the mobilization time of a particular peptide is dependent on its pI value. Based on this relation, the identification of some peptides was facilitated. Furthermore, the Sequest settings that were used could be evaluated. In total, 159 proteins were identified in a single run.


Systemic Profile and Periodontal Condition of Hospitalized Women with High-Risk Pregnancy: A Cross-Sectional Study.
The physiological changes in mother-infant pairs during pregnancy increase the susceptibility to a series of infections, including those of the oral cavity. Therefore, the oral and systemic health of pregnant women is related to adverse pregnancy outcomes. This cross-sectional study aimed to evaluate the systemic profile and periodontal status of women with a high-risk pregnancy. Eighty-nine pregnant women at risk of preterm labor admitted to a hospital in southern Brazil were interviewed and received a periodontal examination. Data related to obstetric complications during pregnancy (pre-eclampsia, infections, medication use, and gestational diabetes) and systemic diseases were collected from medical records. The periodontal parameters of probing pocket depth, bleeding on probing, and clinical attachment level were evaluated. The data were tabulated, and statistical analysis was performed (p < 0.05). The mean age of participants was 24 years (SD = 5.62). Gingival bleeding was recorded in 91% of the participants. The prevalence of gingivitis was 31.46%, and periodontitis was 29.21%. No association between systemic conditions and periodontal disease was observed. Periodontal inflammation was not associated with the systemic profile during pregnancy. However, women with high-risk pregnancies showed higher levels of gingival inflammation, emphasizing the importance of dental care during pregnancy.


Derivation and Validation of a Clinical Score for Predicting Postoperative Atrial Fibrillation in Noncardiac Elective Surgery (the HART Score).
Postoperative atrial fibrillation (POAF) represents the most frequent cardiac arrhythmia in the surgical setting. It affects almost 3% of all patients over 45 years old who underwent noncardiovascular surgery and is associated with a higher risk of stroke, heart failure, myocardial infarction, and cardiac arrest. The study aimed to assess independent predictors of POAF and derive and validate a score for risk prediction in clinical practice. This was a retrospective cohort study including all consecutive candidates to all types of noncardiac elective surgery attending a cardiological preoperative assessment from 2016 to 2019. Exclusion criteria were a previous diagnosis of AF and the cancelation of the planned surgery. A total of 2,048 patients were enrolled (1350 men, aged 72 ± 12 years). A total of 44 patients experienced POAF (2.1%) - median 3 days (first to third quartile 2 to 4 days). Age (odds ratio [OR] 1.03 for each year, 95% confidence interval [CI] 1.01 to 1.07), hypertension (OR 3.43, 95% CI 1.22 to 9.63), thyroid dysfunction (OR 2.47, 95% CI 1.22 to 5.01), and intermediate or high-risk surgery (OR 18.28, 95% CI 2.51 to 33.09) resulted as independent predictors of POAF (all p <0.05). The Hypertension, Age, surgery Risk, and Thyroid dysfunction score (OR 2.59 for each point, 95% CI 1.79 to 3.75, p <0.001) was then created based on those 4 items. A cut-off score ≥6 had a 70% sensitivity and a 72% specificity in detecting POAF (area under the curve 0.76). Bootstrapping for internal validation confirmed the overall results (area under the curve 0.72). In conclusion, POAF complicates around 2% of all noncardiac surgery. A 4-item risk score, such as the Hypertension, Age, surgery Risk, and Thyroid dysfunction score, could be effective in implementing POAF screening and improving management.


Correction to: Asymptomatic unruptured intracranial aneurysms in the older people.
The article Asymptomatic unruptured intracranial aneurysms in the older people, written by Sang Woo Ha, Pahn Kyu Choi, Ji Eun Oh, Jung Soo Park and Hyun Goo Kang was originally published electronically on the publisher's internet portal (currently SpringerLink) on 29 October 2018 without open access.


Health technology assessment through the six sigma approach in abdominoplasty: Scalpel vs electrosurgery.
Abdominoplasty is a surgical procedure conducted to reduce excess abdominal skin and fat and improve body contouring. Despite being commonly performed, it is associated with a risk of complications such as infection, seroma, haematoma and wound dehiscence. To reduce the incidence of complications, different methods are used to create the abdominal flap, i.e., incision with a scalpel or electrosurgery. In this study, health technology assessment (HTA) using the Six Sigma methodology was conducted to compare these incision techniques in patients undergoing abdominoplasty. Two consecutively enroled groups of patients (33 in the scalpel group and 35 in the electrosurgery group) who underwent surgery at a single institution, the University of Campania "Luigi Vanvitelli", were analysed using the drain output as the main outcome for comparison of the incision techniques. While no difference was found regarding haematoma or seroma formation (no cases in either group), the main results also indicate a greater drain output (p-value<0.001) and a greater incidence of dehiscence (p-value=0.056) in patients whose incisions were made through electrosurgery. The combination of HTA and the Six Sigma methodology was useful to prove the possible advantages of creating skin incisions with a scalpel in full abdominoplasty, particularly a significant reduction in the total drain output and a reduction in wound healing problems, namely, wound dehiscence, when compared with electrosurgery, despite considering two limited and heterogeneous groups.


"Treasure Your Exceptions"-Studying Human Extreme Phenotypes to Illuminate Metabolic Health and Disease: The 2019 Banting Medal for Scientific Achievement Lecture.
The study of humans with genetic mutations which lead to a substantial disturbance of physiological processes has made a contribution to biomedical science that is disproportionate to the rarity of affected individuals. In this lecture, I discuss examples of where such studies have helped to illuminate two areas of human metabolism. First, the control of insulin sensitivity and its disruption in states of insulin resistance and second, the regulation of energy balance and its disturbances in obesity.


Micronutrient malnutrition and the pathogenesis of malarial anemia.
Malaria is a leading cause of morbidity and mortality worldwide, and anemia is a common and sometimes serious complication of Plasmodium falciparum infection. Although micronutrient malnutrition is usually highly prevalent in malaria endemic areas, the contribution of micronutrient deficiencies to malarial anemia is often overlooked. Recent investigation suggests that micronutrients such as vitamin A, vitamin E, and zinc, may improve the morbidity of malaria through immune modulation and alteration of oxidative stress. Micronutrients are also involved in the pathogenesis of anemia and likely play a role in malarial anemia, but many clinical trials have not specifically addressed the impact of micronutrient supplementation on malarial anemia. Further work is needed to assess the effect of both clinic and community-based micronutrient interventions on malarial anemia in infants, children, and pregnant women.


[The opening of the internal cervical os predicts cervical ripening better than Bishop's score in nulliparous women at 41 weeks gestation].
The objectif was to evaluate ultrasound measurement of the opening of the internal cervical os in the prediction of cervical ripening and to compare it with Bishop's score. We conducted a prospective study of 77 nulliparous women admitted to hospital in labor at 41w gestation, with Bishop's Score < 6, over a 10-month period, between July 2012 and April 2013. The measurement of the opening of the internal cervical os was performed using transvaginal ultrasound and Bishop's score was determined by clinical examination. All patients received prostaglandins for cervical ripening. Cervical ripening was successful among 63 patients (81%). Bishop's score and the opening of the internal cervical os were statistically associated with the success or failure of cervical ripening. The success rate of cervical ripening was 100% when the opening of the internal cervical os was equal to or greater than 5 mm (sensitivity: 54%, specificity: 86%). ROC curves showed that the measurement of the internal cervical os was more predictive of cervical ripening than Bishop's score (area under the curve: 0.733 and 0.704 respectively). Compared to Bishop's score, echographic measurement of the opening of the internal cervical os is more predictive of the success of cervical ripening in nulliparous women at 41 weeks of pregnancy with an unfavourable cervix.


Intracoronary radiotherapy with a 188Rhenium liquid-filled angioplasty balloon system in in-stent restenosis: a single-center, prospective, randomized, placebo-controlled, double-blind evaluation.
In cases of in-stent restenosis, intracoronary radiotherapy with beta-emitters and gamma-emitters has been shown to reduce the risk of repeat restenosis. The present randomised, placebo-controlled study addresses the question of whether intracoronary radiotherapy applied by the easy-to-handle Rhenium liquid-filled angioplasty balloon system is also able to reduce the angiographic re-restenosis rate in stents. At our center, from May 2000 to December 2003, 165 patients (mean age 64+/-10, median 65 years; 127 men, 38 women) with symptomatic in-stent restenosis underwent either intracoronary brachytherapy or sham procedure. Index clinical and angiographic parameters were largely comparable in both groups. Radiation therapy was performed with a standard percutaneous transluminal coronary angioplasty (PTCA) balloon catheter inflated with liquid Rhenium in the redilated in-stent restenosis for 240-890, mean 384+/-125 s with low pressure (3 atm) in order to reach 30 Gy at 0.5 mm depth of the vessel wall. In 82 patients, intracoronary radiotherapy was carried out without complications, but one of the 83 patients who underwent sham procedure suffered small myocardial infarction. During follow-up, stent thrombosis with subsequent non-Q-wave myocardial infarction occurred in one patient in each group (6 days and 8 months after the procedure, respectively). At 6 months after the index procedure, repeat angiography was performed in 156 of the 164 patients with successful procedure (rate 95%): restenosis (stenosis >50% in diameter) or reocclusion was observed in only 19 of 78 (=24%) patients of the radiation but in 31 of 78 (=40%) patients of the sham procedure group (P=0.04). Event-free survival (free of death, myocardial infarction, target vessel revascularization) at 1 year was 87% for patients being radiated and 74% for patients having undergone sham procedure (P=0.05). Intracoronary radiation therapy with the liquid-filled beta-emitting Rhenium balloon is not only easy to perform, safe, and comparably inexpensive but also an effective option to prevent repeat restenosis and the need for target vessel revascularization in cases of in-stent restenosis.


Sarcopenia is associated with blood transfusions in head and neck cancer free flap surgery.
To determine if sarcopenia is a predictor of blood transfusion requirements in head and neck cancer free flap reconstruction (HNCFFR). A single-institution, retrospective review was performed of HNCFFR patients with preoperative abdominal imaging from 2014 to 2019. Demographics, comorbidities (modified Charlson Comorbidity Index [mCCI]), skeletal muscle index (cm2/m2), oncologic history, intraoperative data, and 30-day postoperative complications (Clavien-Dindo score [CD]) were collected. Binary logistic regression was performed to determine predictors of transfusion. Eighty (33.5%), 66 (27.6%), and 110 (46.0%) of n = 239 total patients received an intraoperative, postoperative, or any perioperative blood transfusion, respectively. Sixty-two (25.9%) patients had sarcopenia. Patients receiving intraoperative transfusions had older age (P = .035), more frequent alcoholism (P = .028) and sarcopenia (P < .001), greater mCCI (P < .001), lower preoperative hemoglobin (P < .001), reconstruction with flaps other than forearm (P = .003), and greater operative times (P = .001), intravenous fluids (P < .001), and estimated blood loss (EBL, P < .001). Postoperative transfusions were associated with major complications (CD ≥ 3; P < .001). Multivariate regression determined sarcopenia (P = .023), mCCI (P = .013), preoperative hemoglobin (P = .002), operative time (P = .036), and EBL (P < .001) as independent predictors of intraoperative transfusion requirements. Postoperative transfusions were predicted by preoperative hemoglobin (P = .007), osseous flap (P = .036), and CD ≥ 3 (P < .001). A perioperative transfusion was predicted by sarcopenia (P = .021), preoperative hemoglobin (P < .001), operative time (P = .008), and CD ≥ 3 (P = .018). Sarcopenia is associated with increased blood transfusions in HNCFFR. Patients should be counseled preoperatively on the associated risks, and the increased blood product requirement should be accounted in resource-limited scenarios. 4.


Correction of severe hemifacial atrophy with a free dermis-flat from the lower abdomen.
A case of hemifacial atrophy was corrected with a free dermal-fat flap, based on the inferior epigastric vessels. Microvascular anastomosis to the facial vessels was used. Ancillary "tailoring" procedures were done later to complete the work.


Marijuana effects on immunity: suppression of human natural killer cell activity of delta-9-tetrahydrocannabinol.
Delta-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, was tested for its ability to modulate human natural killer (NK) cell function. THC was toxic for peripheral blood lymphocytes at 20 micrograms/ml but not at 10 micrograms/ml or less. This component of marijuana also was inhibitory for NK activity against K562, a human tumor cell line at concentrations down to 5 micrograms/ml when pre-incubated with the effector cells. Suppression of NK function was dependent upon the concentration of THC and the length of time of pre-incubation but was independent of the ratio of effector to target cells. Prostaglandins were not involved in suppression of NK activity.


Study on the effect of municipal solid landfills on groundwater by combining the models of variable leakage rate, leachate concentration, and contaminant solute transport.
The landfill with low economic cost and technical barrier has become a popular option for municipal solid waste treatment, but it is likely to seriously pollute groundwater by solute leaching. In this study, the pollutants concentration model, leakage rate model, and the solute transport model were coupled to investigate the effect of municipal solid waste landfill on groundwater quality. Major results obtained are, (1) the leakage rate of leachate differs significantly among the landfilling stage, covering stage and completely covered stage as the leachate depth varies with the infiltration rainfall. The contact condition between HDPE and CCL was found to be a key factor in determining the leakage rate of leachate. Ensuring good connection between HPDE and CCL is thus critical in protecting groundwater from being polluted by landfill. (2) The NH3-N as a proxy for organic pollutants was generated via the degradation process, and Cl- as a proxy for inorganic pollutants is a leachable fraction of mobilized substances. The concentration of Cl- is higher than that of NH3-N before 7600 days, then the concentration of NH3-N becomes roughly stable while that of Cl- continues to decrease. (3) The load of NH3-N as a proxy for organic pollutants declines linearly downwards before the completely covering stage. The load of Cl- as a proxy for inorganic pollutants increased during the first five years, and then declined. (4) In the case study, the path of maximum pollutants concentration is perpendicular to the groundwater contour, and the maximum pollutants concentration has two peaks, occurring on 7106 days and 11,554 days, respectively. The change laws of maximum pollutants concentration are similar for different connections between HPDE and CCL.


Discovery of potent glycogen synthase kinase 3/cholinesterase inhibitors with neuroprotection as potential therapeutic agent for Alzheimer's disease.
In the present work, a novel series of pyridinethiazole bearing benzylpiperidine hybrids were designed and synthesized as dual-target inhibitors of GSK-3β/AChE. Among them, GD29 was the most promising candidate, with an IC50 value of 0.3 μM for hAChE and an IC50 value of 0.003 μM for hGSK-3β, respectively. The compounds exhibited good drug-like properties with optimal inhibitory enzyme activities. Moreover, GD29 showed anti-inflammatory properties at micromolar concentrations and displayed interesting neuroprotective profiles in an in vitro model of oxidative stress-induced neuronal death. Notably, the compounds also exhibited good permeability across the blood-brain-barrier (BBB) both in vitro. Central cholinomimetic activity was confirmed using a scopolamine-induced cognition impairment model in Institute of Cancer Research (ICR) mice upon oral administration. The current work identified optimized compounds and explored the therapeutic potential of glycogen synthase kinase 3/cholinesterase inhibition for the treatment of AD.


Comparison of bicuspid and tricuspid aortic valve repair.
The aim of this study was to compare the outcomes of tricuspid aortic valve (TAV) and bicuspid aortic valve (BAV) repair. We assessed mortality, freedom from reoperation and the rate of aortic valve regurgitation recurrence. Mortality in both groups was compared with expected survival, and risk factors for reoperation were identified. From January 2010 to April 2020, a total of 368 elective aortic valve repair procedures were performed, including 223 (60.6%) in patients with TAV. The perioperative mortality was 0.7% in the BAV group and 3.6% in the TAV group (P = 0.079). Estimated survival at 5 years in the BAV versus TAV group was 97 ± 3% vs 80 ± 6%, respectively (P < 0.001). Freedom from reoperation at 5 years in the TAV versus BAV group was 96 ± 3% vs 93 ± 4%, respectively (P = 0.28). Grade 2 or more aortic valve regurgitation was noted in 9.9% of BAV patients and 11% of TAV patients (P = 0.66). Reoperation was predicted by cusp perforation [hazard ratio 15.86 (4.44-56.61); P < 0.001], the use of pericardial patch [hazard ratio 8.58 (1.96-37.53); P = 0.004] and aortic valve annulus diameter >27.5 mm [hazard ratio 3.07 (0.99-9.58); P = 0.053]. BAV repair is as durable as TAV repair. BAV is not a predictor of a higher rate of reoperations. BAV repair yields survival comparable to expected. Cusp perforation, aortic valve annulus diameter >27.5 mm and the use of pericardial patch adversely impact long-term outcome of aortic valve repair.


5-Bromo-3-cyclo-pentyl-sulfinyl-2-methyl-1-benzofuran.
In the title compound, C(14)H(15)BrO(2)S, the cyclo-pentyl ring adopts an envelope conformation. In the cyclo-pentyl ring, two adjacent C atoms are disordered over two sets of sites with site-occupancy factors of 0.618 (11) and 0.382 (11). In the crystal, mol-ecules are linked through weak inter-molecular C-H⋯O hydrogen bonds.


Crystal structure of 3-{(E)-[(3,4-di-chloro-phen-yl)imino]-meth-yl}benzene-1,2-diol.
In the title Schiff base, C13H9Cl2NO2, which arose from the condensation of 3,4-di-chloro-aniline with 2,3-di-hydroxy-benzaldehyde, the dihedral angle between the aromatic rings is 44.74 (13)°. Intra-molecular O-H⋯O and O-H⋯N hydrogen bonds close S(5) and S(6) rings, respectively. In the crystal, inversion dimers linked by pairs of O-H⋯O hydrogen bonds generate R 2 (2)(10) loops. A weak C-H⋯π inter-action is also observed.


DFT study of superhalogen-doped borophene with enhanced nonlinear optical properties.
The concern of the present study is to investigate the nonlinear optical properties of superhalogen-doped borophene owing to its broad applications. The first principle study of the material for its nonlinear optical properties elaborated its use for electrical and optical applications. The superhalogen-based borophene in lithium ion-based batteries and medical appliances have made it one of the most potential materials for optoelectronics. First, hyperpolarizability (βo) of pure and doped B36 is computed, and the difference between their values was examined. The vertical ionization energy (VIE) was calculated for pure and doped systems. The interaction energy (Ei) for all combinations was computed. It would be expected to be one of the best materials to have high capacity and resistance. For all the calculations and to calculate the highest occupied molecular orbital and lowest unoccupied molecular orbital energy gap, the density functional theory (DFT) method was used. It is predicted that these combinations are more beneficial and can display better nonlinear optical (NLO) properties in electronic devices. Superhalogen-doped BF4 borophene-36 ground state optimized geometry, frontier molecular orbitals HOMO and LUMO, maximum absorption (λmax), density of states (DOS) analysis, and electrostatic potential diagram (MEP) are displayed here.


Pre-germination plasma treatment of seeds does not alter cotyledon DNA structure, nor phenotype and phenology of tomato and pepper plants.
The impact of cold radiofrequency plasma on CPDs formation, and the morphological and phenological development of tomato and pepper plants and fruits in greenhouse conditions was studied. Quality characteristics of fruits: total sugars, titratable acidity, pH and total solids were determined. Our results show that plasma treatment in the time ranges used for pre-sowing treatments, did not cause the formation of CPDs in the cotyledons, even when the testa was removed before treatment, as opposed to high UV radiation. In addition, plasma treatment did not have a negative effect on the morphology, phenology and quality parameters of plants and fruits that grew up from treated tomato and pepper seeds in the greenhouse.


Tolerance to acid in pH 5.0-grown organisms of potentially pathogenic gram-negative bacteria.
A wide range of potentially pathogenic species of Gram-negative bacteria were far more resistant to extreme acidity (pH 2.0-3.5) when cultured at pH 5.0 (habituated to acid) than after pH 7.0 culture. The differences were particularly great for Citrobacter spp., Enterobacter spp., Klebsiella spp. and for Vibrio parahaemolyticus; substantial habituation was also observed for Proteus mirabilis and Aeromonas formicans but the effect was less marked for Serratia marcescens and Acinetobacter calcoaceticus. Growth at pH 5.0 was substantially poorer than at pH 7.0 for most of the above species and also for Salmonella typhimurium and Salm. enteritidis but phosphate markedly enhanced growth at pH 5.0 for many of these species without affecting growth at pH 7.0.


Influence of diet type on the kinetic disposition of fenbendazole in cattle and buffalo.
The plasma concentration profiles of fenbendazole (FBZ), FBZ-sulphoxide and FBZ-sulphone were measured following intraruminal administration of FBZ at 7.5 mg kg-1 body weight in cattle and buffalo offered 3 different diets: 100% dry mature sorghum hay, 100% green Pennisetum spp. and a 50:50 mix of these 2 diets. Changing the diet from dry to green fodder resulted in significantly lower systemic availability of FBZ and its metabolites in both species. Buffalo had a lower systemic availability of the drug than cattle on the dry diet and the difference between species increased when the diet included green fodder. It is suggested that decreased transit time of digesta on the green fodder reduced systemic concentrations by reducing the time available for gastrointestinal absorption of the drug.


Understanding the service needs of assault-injured, drug-using youth presenting for care in an urban Emergency Department.
Violence is a leading cause of injury among youth 15-24years and is frequently associated with drug use. To inform optimal violence interventions, it is critical to understand the baseline characteristics and intent to retaliate of drug-using, assault-injured (AI) youth in the Emergency Department (ED) setting, where care for violent injury commonly occurs. At an urban ED, AI youth ages 14-24 endorsing any past six-month substance use (n=350), and a proportionally-sampled substance-using comparison group (CG) presenting for non-assault-related care (n=250), were recruited and completed a baseline assessment (82% participation). Medical chart review was also conducted. Conditional logistic regression was performed to examine correlates associated with AI. Over half (57%) of all youth met the criteria for drug and/or alcohol use disorder, with only 9% receiving prior treatment. Among the AI group, 1 in 4 intended to retaliate, of which 49% had firearm access. From bivariate analyses, AI youth had poorer mental health, greater substance use, and were more likely to report prior ED visits for assault or psychiatric evaluation. Based on multivariable modeling, AI youth had greater odds of being on probation/parole (AOR=2.26; CI=1.28, 3.90) and having PTSD (AOR=1.88; CI=1.01, 3.50) than the CG. AI youth may have unmet needs for substance use and mental health treatment, including PTSD. These characteristics along with the risk of retaliation, increased ED service utilization, low utilization of other health care venues, and firearm access highlight the need for interventions that initiate at the time of ED visit.


Plants with Anti-Addictive Potential.
Drug addiction is prevalent among individuals of modern society, being a major cause of disability and premature loss of life. Although the drug addiction have profound social, economical and health impact in the world population, its management remains a challenge as available pharmacological treatments remains ineffective for most people. The limited efficacy and adverse effects have led to a search for alternative therapies to treat drug addiction. In this context, natural products are an important source for new chemical substances with a potential therapeutic applicability. Therefore, this chapter will present data obtained after an extensive literature search regarding the use of medicinal plants as a pharmacological alternative for drug addiction treatment.


Safety assessment of a three-dimensional-printed autologous omentum patch: An application on the kidneys as a new treatment approach.
Recently, the field of regenerative medicine has made great strides in the development of new treatments for various organ dysfunctions. One of the most promising new approaches is the use of three-dimensional (3D) printing and autologous tissues. In this study, we evaluated the safety of a 3D-printed autologous omentum patch to kidneys using large animals. A total of seven micropigs underwent transplantation of the 3D-printed autologous omentum patch. Twelve weeks after transplantation, the safety was evaluated by measuring body weight, blood, and the renal resistive index. In addition, biopsy samples were histologically analyzed. The results showed no surgical complications, renal functional hematological changes, or inflammatory responses. Therefore, this study provides important insights into direct therapy to kidneys with a 3D-printed patch made of autologous tissue. Furthermore, it has the potential for the development of new therapies for various organ dysfunction.


Gene expression profiles for a prognostic immunoscore in gastric cancer.
Increasing evidence has indicated an association between immune infiltration in gastric cancer and clinical outcome. However, reliable prognostic signatures, based on systematic assessments of the immune landscape inferred from bulk tumour transcriptomes, have not been established. The aim was to develop an immune signature, based on the cellular composition of the immune infiltrate inferred from bulk tumour transcriptomes, to improve the prognostic predictions of gastric cancer. Twenty-two types of immune cell fraction were estimated based on large public gastric cancer cohorts from the Gene Expression Omnibus using CIBERSORT. An immunoscore based on the fraction of immune cell types was then constructed using a least absolute shrinkage and selection operator (LASSO) Cox regression model. Using the LASSO model, an immunoscore was established consisting of 11 types of immune cell fraction. In the training cohort (490 patients), significant differences were found between high- and low-immunoscore groups in overall survival across and within subpopulations with an identical TNM stage. Multivariable analysis revealed that the immunoscore was an independent prognostic factor (hazard ratio 1·92, 95 per cent c.i. 1·54 to 2·40). The prognostic value of the immunoscore was also confirmed in the validation (210) and entire (700) cohorts. The proposed immunoscore represents a promising signature for estimating overall survival in patients with gastric cancer.


Pharmacokinetics of metamizol metabolites in healthy subjects after a single oral dose of metamizol sodium.
The linearity of the pharmacokinetics of the metamizol metabolites 4-methyl-amino-antipyrine (4-MAA), 4-amino-antipyrine (4-AA), 4-formyl-aminoantipyrine (4-FAA), and 4-acetyl-amino-antipyrine (4-AcAA) has been studied after administration to 15 healthy male volunteers of single oral doses of 750, 1500, and 3000 mg metamizol. The trial was open, randomized, and cross-over, with a one-week interval between dosing days. Metabolite concentrations in serum and urine were measured using reverse-phase HPLC. The mean Cmax of 4-MAA increased linearly with dose whereas its AUC was not proportional to dose after administration of 1500 and 3000 mg. With 4-AA, the increase in mean Cmax was linear, but the increase in AUC was not. The increases in mean Cmax and AUC for 4-FAA after doses of 1500 and 3000 mg were not proportional to the dose. The increases in mean Cmax and AUC for 4-AcAA were roughly proportional to the increase in dose. There were no significant differences in renal clearance between doses for any of the four metabolites. The observed non-linearities reflect the saturability of metabolic pathways. However, although they were statistically significant, the deviations from linearity were marginal and should not be of clinical relevance to the analgesic efficacy of metamizol in the dose range tested.


Functional characterization of three Azotobacter chroococcum alginate-modifying enzymes related to the Azotobacter vinelandii AlgE mannuronan C-5-epimerase family.
Bacterial alginate initially consists of 1-4-linked β-D-mannuronic acid residues (M) which can be later epimerized to α-L-guluronic acid (G). The family of AlgE mannuronan C-5-epimerases from Azotobacter vinelandii has been extensively studied, and three genes putatively encoding AlgE-type epimerases have recently been identified in the genome of Azotobacter chroococcum. The three A. chroococcum genes, here designated AcalgE1, AcalgE2 and AcalgE3, were recombinantly expressed in Escherichia coli and the gene products were partially purified. The catalytic activities of the enzymes were stimulated by the addition of calcium ions in vitro. AcAlgE1 displayed epimerase activity and was able to introduce long G-blocks in the alginate substrate, preferentially by attacking M residues next to pre-existing G residues. AcAlgE2 and AcAlgE3 were found to display lyase activities with a substrate preference toward M-alginate. AcAlgE2 solely accepted M residues in the positions - 1 and + 2 relative to the cleavage site, while AcAlgE3 could accept either M or G residues in these two positions. Both AcAlgE2 and AcAlgE3 were bifunctional and could also catalyze epimerization of M to G. Together, we demonstrate that A. chroococcum encodes three different AlgE-like alginate-modifying enzymes and the biotechnological and biological impact of these findings are discussed.


An eye for an 'I:' a critical assessment of artificial intelligence tools in migration and asylum management.
The promise of artificial intelligence has been originally to put technology at the service of people utilizing powerful information processors and 'smart' algorithms to quickly perform time-consuming data analysis. It soon though became apparent that the capacity of artificial intelligence to scrape and analyze big data would be particularly useful in surveillance policies. In the wider areas of migration and asylum management, increasingly sophisticated artificial intelligence tools have been used to register and manage vulnerable populations without much concern about the potential misuses of the data collected and the overall ethical and legal underpinnings of these operations. This article examines three cases in point. The first case investigates the United Nations High Commissioner for Refugees' decision to deploy a biometric matching engine engaging artificial intelligence to make accessing identification documents easier for both refugees and asylum seekers and the states and organizations they interact with. The second case focuses on the New Zealand government's introduction of artificial intelligence to improve border security and streamline immigration. The third case looks at data scraping and biometric recognition tools implemented by the United States government to track (and eventually deport) undocumented migrants. The article first shows how states and international organizations are increasingly turning to artificial intelligence tools to support the implementation of their immigration policies and programs. Subsequently, the article also outlines how even despite well-intentioned efforts, the decision to use artificial intelligence tools to increase efficiency and support the implementation of migration or asylum management policies and programs often involves jeopardizing or altogether sacrificing individuals' human rights, including privacy and security, and raises concerns about vulnerability and transparency.


Clinical characteristics of pediatric febrile urinary tract infection in Japan.
Febrile urinary tract infection (fUTI) is the most common serious bacterial infection in children. Despite this, there have been no studies examining the clinical features of pediatric fUTI in Japan. The purpose of this study was to describe the clinical characteristics of fUTI in Japanese children. A multicenter, retrospective, observational study was conducted at 21 hospitals in Japan. Children under the age of 15 years who were diagnosed with fUTI between 2008 and 2017 were included. The diagnostic criteria were a temperature over 38 °C and the presence of a single bacterial pathogen in urine culture. Patient characteristics were obtained from medical records. In total, 2,049 children were included in the study. The median age was 5 months, and 59.3% were male. It was found that 87.0% of the males and 53.2% of the females were under 1 year of age. The main causative pathogens identified were Escherichia coli and Enterococcus spp., accounting for 76.6% and 9.8% of infections, respectively. There was a male predominance of fUTI in Japanese children, particularly in infants. Enterococcus spp. were the second most frequent causative pathogen; therefore, Gram staining of urine samples is strongly recommended before initiating antibiotic therapy.


WASP-interacting protein (WIP): working in polymerisation and much more.
The migration of cells and the movement of some intracellular pathogens, such as Shigella and Vaccinia, are dependent on the actin-based cytoskeleton. Many proteins are involved in regulating the dynamics of the actin-based microfilaments within cells and, among them, WASP and N-WASP have a significant role in the regulation of actin polymerisation. The activity and stability of WASP is regulated by its cellular partner WASP-interacting protein (WIP) during the formation of actin-rich structures, including the immune synapse, filopodia, lamellipodia, stress fibres and podosomes. Here, we review the role of WIP in regulating WASP function by stabilising WASP and shuttling WASP to areas of actin assembly in addition to reviewing the WASP-independent functions of WIP.


Rethinking hiker preparedness: Association of carrying "10 essentials" with adverse events and satisfaction among day-hikers.
Many trusted organizations recommend a particular set of gear for hikers. Termed the "10 essentials," the importance of these items to wilderness preparedness has not been critically evaluated. We sought to better understand the value of these items in day hiker preparedness by assessing the association between carried items, the occurrence of adverse events, and satisfaction. A cross-sectional survey study was conducted at Mount Monadnock (NH) over 4 non-consecutive days. Adults finishing a day hike were invited to participate. The survey assessed items carried, adverse events, satisfaction, and whether hikers felt prepared for the adverse events that occurred. The primary outcome was the occurrence of an adverse event. A total sample of 961 hikers reported 1686 adverse events. Hikers felt prepared for 89% of the events experienced. The most common adverse events reported were thirst (62%), hunger (50%), feeling cold (18%), and needing rain gear (11%). Medical events such as sprains and lacerations made up 18% of all adverse events. Carrying more items was associated with an increased likelihood of reporting an adverse event and a decreased likelihood of adverse events that the hiker was not prepared for, without a change in satisfaction rates. Carrying more items did not translate into improved satisfaction for day hikers, but was associated with fewer events for which the hiker was unprepared. Other than adverse events related to hunger, thirst, weather, and minor medical events, adverse events were unlikely during this day hike. Nutrition, hydration, and insulation were the items reported as most often needed, followed by a kit to treat minor medical events, while the remaining 6 items were infrequently used.


Resonance characteristic and its ionic basis of rat mesencephalic trigeminal neurons.
Intrinsic resonant frequency properties of neurons in the brain provide a basis for different behavioral states and determine the responding modality (i.e. excitability) of different neurons. Previously, three types of excitability behaviors in rat Mesencephalic V neurons were found. To investigate the different resonant frequency and ionic current mechanisms underlying different resonances among three types of excitability, we performed whole-cell patch recordings and applied ZAP current on Mesencephalic V cells (N=70) in rat slices. The results show that: Class 2 neurons (30/30) have two resonances with U-shaped voltage dependence. One is a high frequency resonance (75.4 ± 2.11 Hz) significant at depolarized potentials (about -50 mV) and the other is a low frequency resonance (5.46 ± 0.31 Hz) significant at hyperpolarized potentials (about -70 mV). Voltage clamp experiments reveal two non-inactivating currents operating in the subthreshold voltage range: (1) 4-aminopyridine sensitive K(+) current, which activates at membrane potentials positive than -60 mV and was blocked by 4-AP (50 µM), was underlying the high frequency resonance of Class 2 neuron; (2) h-current, which activates negative than -60mV and was blocked by the hyperpolarization-activated cyclic nucleotide-gated channel blocker ZD7288 (10 µM), was underlying the low frequency resonance. Class 1 neurons do not show voltage-dependence resonant behaviors (10/10). Class 3 neurons (23/30) have two resonances, which are similar with Class 2 in both resonant frequency and currents. Our results provide clear evidence for the existence of multiple kinds of frequency resonances and how the relationship between the resonant frequency and the ionic current is based in Mesencephalic V neurons.


Characterization of the root and canal anatomy of maxillary premolar teeth in an Iraqi subpopulation: a cone beam computed tomography study.
This study aims to evaluate the number of roots and root canal morphology types of maxillary premolars in relation to a patient's gender and age in an Iraqi population using two classification systems. Cone beam computed tomography (CBCT) scans of 1116 maxillary premolars from 385 patients were evaluated for the number of roots and root canal morphology types according to Vertucci's classification and Ahmed et al. classification systems. Differences in the number of roots and root canal morphology types with regard to tooth type, patients' gender and age groups were evaluated and the degree of bilateral symmetry was determined. Chi-squared test was used for statistical analysis. About 51.1% of the 1st premolars were double rooted. The majority (87.9%) of the 2nd premolars were single rooted. The three-rooted form presented in only 1.2% and 0.7% of the 1st and 2nd premolars, respectively. Vertucci Type IV (Ahmed et al. code 2MaxP B1P1) and Vertucci Type I (Ahmed et al. code 1MaxP1) were the most common canal morphology types in the 1st and 2nd premolars, respectively. Females showed a lower number of roots and a higher prevalence of Vertucci Type I configuration (P < 0.05). Younger age groups showed a higher prevalence of Vertucci Type I configuration (P < 0.05). Bilateral symmetry was seen in more than half of the maxillary premolars. There is a considerable variation in the number of roots and root canal configurations of maxillary premolars in the studied Iraqi population, with a significant difference by gender and age groups. Ahmed et al. classification provided more accurate presentation of the root and canal anatomy in maxillary premolars compared to Vertucci's classification.


Template specificity of Qbeta and SP phage RNA replicases as studied by replication of small variant RNAs.
Template specificity of two RNA-dependent RNA polymerases (Qbeta and SP RNA replicases) was examined using "variant RNAs" as template. Three variant RNAs, one (8S) generated by Qbeta replicase and two (6S and 5.2S) generated by SP replicase, were isolated from the reaction mixtures incubated in the absence of exogenous template RNA. All these RNAs were found to be active as template for both Qbeta and SP replicases, though homologous RNA exhibited activities about three times higher than heterologous RNA with either enzyme, in agreement with the results obtained in phage RNA-dependent reactions. In these reactions, faithful replication of variant RNA was observed, and the amount of RNA synthesized was in a many-fold excess over the template RNA added. We also found that the heterologous RNA-dependent reactions were suppressed by increasing the concentration of salts or decreasing the concentration of substrates. Under such conditions, replication of heterologous variant RNA was almost completely suppressed, while the amount of homologous variant RNA synthesized was only reduced to 50% of that synthesized under the standard conditions. Thus the template specificity of the two RNA replicases seems to be expressed more strictly in these replication systems.


Non-everted oxygenated rat intestinal segments as a measure of neutral detergent fiber effects on iron absorption.
Iron absorption in the presence of varying amounts and sizes of dietary fiber was measured. A method using non-everted rat intestinal segments perfused in oxygen was refined. Neutral detergent fiber (NDF), a component of dietary fiber, was extracted from cooked pinto bean (Phaseolus vulgaris). The NDF did not affect iron absorption in intestinal segments from iron replete rats. However, 4 and 6 mg of NDF/ml significantly decreased iron absorption in the intestinal segments from anemic rats. NDF with a smaller particle size of 0.125 mm increased iron absorption relative to that absorbed with 0.180 mm particles. Histological examination validated using non-everted intestinal segments perfused with oxygen as a method for studying dietary effects on iron absorption. Segments which are not everted are less prone to damage. Perfusion with oxygen maintained metabolic activity in the tissue during the experiment.


TOSDS: Tenant-centric Object-based Software Defined Storage for Multitenant SaaS Applications.
Enormous amounts of unstructured data such as images, videos, emails, sensors' data and documents of multiple types are being generated daily by varied applications. Apart from the challenges related to collection or processing of this data, its efficient storage is also a significant challenge since this data do not conform to any predefined storage model. Therefore, any enterprise dealing with huge unstructured data requires a scalable storage system that can provide data durability and availability at a low cost. The paper proposes a tenant-centric approach to develop an object-based software defined storage system for SaaS multi-tenant applications. We present TOSDS (Tenant-centric Object-based Software Defined Storage), a system that can efficiently meet the storage requirements of users or tenants with diverse needs who are using a multitenant SaaS application. The experimental verification of TOSDS illustrates its effectiveness in storage utilization as well as tenant isolation.


Wilson's disease--unusual features.
Two cases of Wilson's disease with unusual features are reported. In one case neurological abnormality was the presenting feature without any clinical involvement of the liver. In the other case, neurologic manifestations were associated with rickets and cholelithiasis, a result of chronic hemolytic state. Apart from clinical profile both the cases were diagnosed by grossly reduced serum ceruloplasmin level. However, Kayser-Fleischer rings were found in each case.


Immunohistochemistry for LEF1 and SOX11 adds diagnostic specificity in small B-cell lymphomas.
Lymphocyte enhancer-binding factor 1 (LEF1) and SRY-Box 11 (SOX11) are highly sensitive and specific for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL) including the cyclin D1-negative subtype, respectively. We assessed the utility of these markers in a large cohort of small B-cell lymphomas (SBCLs) on varied sample types. Immunohistochemistry (IHC) was performed for LEF1 and SOX11 on 354 SBCLs (129 CLL/SLLs, 33 MCLs, 142 marginal zone lymphomas [MZLs]-nodal MZL [NMZL]: 40, extranodal MZL [ENMZL]: 28, splenic MZL [SMZL]: 74 cases-and 50 lymphoplasmacytic lymphomas [LPLs]/Waldenstrom macroglobulinemias [WMs]). Ninety-eight percent of CLL/SLLs were LEF1 positive. SOX11 showed good sensitivity (82%) and excellent specificity for MCL (99%), with only 2 of 142 MZLs (both SMZLs) showing SOX11 expression. The low sensitivity for SOX11 was on account of inclusion of 4 non-nodal cases. All 50 LPL/WMs were negative for both LEF1 and SOX11. The expression of SOX11 and LEF1 was not always mutually exclusive, as 2 confirmed MCLs expressed both markers. LEF1 and SOX11 have excellent utility as diagnostic markers especially for atypical CD5-positive SBCLs.


The development of electrocortical activity in the fetal and neonatal guinea pig.
We have developed techniques for chronic recording of electrocortical activity in the fetal and neonatal guinea pig with subsequent power spectral analysis. Thirty-four unanesthesized, unrestrained pregnant Hartley guinea pigs were studied 1 to 14 days following surgical procedures. Twelve neonatal animals instrumented during the first week of life were studied at 3 to 30 days. Spontaneous, undifferentiated electrocortical activity was recorded from the youngest fetuses studied, with high-voltage slow activity appearing at 50 days' gestation. Cycling electrocortical activity and sleep spindles could be observed in the late-term fetal and neonatal animals, with rapid eye movements and behavioral state defined in the latter. Power spectral analysis demonstrated more predominant delta activity, faster beta frequencies, and better-developed sleep spindles in the neonatal animal as compared to the fetus.


Genuine and simulated suicide notes: An analysis of content.
The present study examined genuine and simulated suicide notes aiming to identify the measures of content that best differentiate between the two. Thirty-three genuine and thirty-three simulated suicide notes were content-analysed and data subjected to smallest space analysis (SSA), a Multidimensional Scaling Procedure. The core of all suicide notes was discovered to be constructed with the use of three variables: expressions of love, positive construction of partner and apologies. Furthermore, four different genuine suicide note themes ('planned escape', 'negative affect and self-mitigation', 'positive affect and failed relationship', 'lack of self-acceptance') and three simulated suicide note themes ('escape', 'positive affect and self-blame', 'purposeless life') were identified revealing that authentic suicide note themes were more internally consistent and clearer to interpret.


The influence of heptane-1,2,3-triol on the size and shape of LDAO micelles. Implications for the crystallisation of membrane proteins.
The presence of small amphiphiles has been found to be necessary in the crystallization of several membrane-protein/surfactant complexes. It has been suggested that the role of the small amphiphile may be to reduce the size of the surfactant belt around the protein, making the formation of crystals easier. Thus far it was not known if this would involve changes in micellar size in general or whether the small amphiphile would merely replace LDAO during crystal growth. In the present study we have used small angle neutron scattering to study mixed micelles of lauryldimethyl amine oxide (LDAO; hydrogenated and deuterated) and heptane-1,2,3-triol (HP). Our results show that with increasing overall HP concentrations mixed LDAO/HP micelles of decreasing mass and radius are formed. The composition of these micelles has been determined. HP thus may decrease the size of the surfactant belt around a protein before crystallisation by insertion into a host micelle. As HP is a 'small amphiphile' compared to the surfactants used for solubilization of membrane proteins, the curvature of the host micelle will be increased by its insertion.


Heteroatom coordination induces electric field polarization of single Pt sites to promote hydrogen evolution activity.
Herein, we reported a kind of single Pt site (Pt-SA) stabilized on an MXene support (Pt-SA/MXene) via the formation of Pt-O and Pt-Ti bonds to effectively catalyze the hydrogen evolution reaction (HER). Due to the local electric field polarization derived from its unique asymmetric coordination, Pt-SA/MXene displays remarkably higher catalytic HER activity in an alkaline electrolyte. In detail, the Pt-SA/MXene electrocatalyst only needs a low overpotential of 33 mV to reach a current density of 10 mA cm-2 and maintains the performance over 27 h. Besides, Pt-SA/MXene also has a competitive mass activity, 23.5 A mgPt-1, at an overpotential of 100 mV, which is 29.4 times greater than that of the commercial Pt/C counterpart. Density functional theory (DFT) calculations revealed that the polarized electric field could efficiently tailor the electronic structure of Pt-SA/MXene and reduce the energy barrier of adsorption/desorption of the H* intermediate step, further improving its HER catalytic activity.


Risk factors for the development of endometrial fluid in women undergoing IVF: A retrospective cohort study✰.
Presence of endometrial fluid (EF) is a poorly understood pathology and remains a challenge for clinicians, as very little data exists to explain its consequences and treatment. Our objective was to investigate risk factors for EF during IVF. This retrospective cohort study included all women with a freeze all embryos cycle (FAE) for EF between 2010 and 2016 at a university-affiliated private IVF center. Controls (2:1) were randomly selected out of the database of our fresh autologous IVF cycles during the same period. Main outcome measures were possible risk factors for EF, comprising polycystic ovarian syndrome (PCOS), ovarian hyperstimulation syndrome (OHSS), previous pelvic or endometrial surgery (polypectomy or synechia removal), cesarean section, myomas and severe endometriosis. A logistic regression model was used to assess independent risk factors for EF. Out of 9000 IVF cycles, 1204 were FAE cycles, among which we identified 86 EF cases. We then selected 171 controls. Independent risk factors for presence of EF were a history of previous myomectomy (adjusted odds ratio (aOR) 19.77, 95%CI [4.01-97.53]), severe endometriosis (aOR 5.97, 95%CI [2.09-17.05]), PCOS (aOR 5.72, 95%CI [2.66-12.33]) and previous cesarean section (aOR 5.17, 95%CI [1.84-14.49]). Our results are not only confirming the association between PCOS, severe endometriosis, previous cesarean procedure and EF, but also reporting for the first time an association between previous myomectomy and EF.


Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor.
Apixaban is a potent, highly selective, reversible, oral, direct factor Xa (fXa) inhibitor in development for thrombosis prevention and treatment. The preclinical pharmacokinetic (PK) attributes of apixaban feature small volume of distribution (Vd), low systemic clearance (CL), and good oral bioavailability. Apixaban is well absorbed in rat, dog, and chimpanzee, with absolute oral bioavailability of approximately 50% or greater. The steady-state Vd of apixaban is approximately 0.5, 0.2, and 0.17 l/kg in rats, dogs, and chimpanzees, while CL is approximately 0.9, 0.04, and 0.018 l/h/kg, respectively. In vitro metabolic clearance of apixaban is also low. Renal clearance comprises approximately 10-30% of systemic clearance in rat, dog, and chimpanzee. Anti-fXa activity, prothrombin time (PT), and HEPTEST(®) clotting time (HCT) prolongation correlated well with plasma apixaban concentration in rat, dog and chimpanzee. There was no lag time between apixaban plasma concentration and the pharmacodynamic (PD) markers, suggesting a rapid onset of action of apixaban. The PK/PD analyses were performed using an inhibitory E (max) model for anti-fXa assay and a linear model for PT and HCT assays. The IC(50) values for anti-fXa activity were 0.73 ± 0.03 and 1.5 ± 0.15 μM for rat and dog, respectively. The apparent K ( i ) values for PT were approximately 1.7, 6.6, and 4.8 μM for rat, dog and chimpanzee, respectively. The apparent K ( i ) for HCT was approximately 1.3 μM for dog. Apixaban exhibits desirable PK and PD properties for clinical development with good oral bioavailability, small Vd, low CL, and direct, predictable, concentration-dependent PD responses.


LncRNA CARMN overexpression promotes prognosis and chemosensitivity of triple negative breast cancer via acting as miR143-3p host gene and inhibiting DNA replication.
Triple negative breast cancer (TNBC) is a subtype of breast cancer with poor prognosis and lack of effective treatment target. Here we screened differentially expressed lncRNAs through bioinformatics analysis and identified CARMN as a downregulated lncRNA which is lowest expressed in TNBC. We aimed to identify the potential role and molecular mechanisms of CARMN in TNBC. Predictive value of CARMN was explored in breast cancer cohorts. TNBC cell lines with CARMN overexpression or CARMN silence and were used for in vitro and in vivo experiments. RNA-seq of CARMN overexpressed cells was performed for exploring downstream of CARMN. CARMN is downregulated at different phase of malignant transformation of breast tissue. CARMN can predict both better prognosis and higher response rate of cisplatin-based neoadjuvant chemotherapy in breast cancer. A nomogram is built to predict cisplatin-based chemotherapy response in breast cancer. Through in vitro and in vivo studies, we confirmed CARMN can also inhibit tumorigenesis and enhance sensitivity to cisplatin in TNBC cells. RNA-seq and further experiments revealed CARMN can inhibit DNA replication. MCM5, an important DNA replication initiation factor, is the most downregulated gene in DNA replication pathway following CARMN overexpression. We confirmed CARMN can produce miR143-3p from its exon5 which is DROSHA and DICER dependent, resulting binding and decrease of MCM5. Moreover, suppressing miR143-3p can weaken function of CARMN in suppressing tumorigenesis and promoting chemosensitivity. Our results indicated lncRNA CARMN is a predictive biomarker of better prognosis and enhanced cisplatin sensitivity in TNBC. CARMN is the host gene of miR143-3p which downregulates MCM5, causing inhibited DNA replication.


A case of acute eosinophilic granulocytic leukemia with PML-RAR alpha fusion gene expression and response to all-trans retinoic acid.
A typical case of eosinophilic granulocytic leukemia with PML-RAR alpha fusion gene expression is reported. The patient achieved complete remission after oral administration of all-trans retinoic acid without any exposure to cytotoxic agents. The facts strongly suggest that the genetic event occurred at the level of pluripotent stem cells.


Genome Resource of Ancylobacter pratisalsi E130T: A Novel Plant-Growth-Promoting Bacterium Isolated from the Rhizosphere.
Ancylobacter pratisalsi sp. nov. strain E130T is a Gram-negative, nonmotile, aerobic, and rod-shaped bacterium that was recently isolated from the rhizosphere of Plantago winteri Wirtg. from a natural salt meadow. This strain was described as novel species in genus Ancylobacter; however, information about its complete genome has yet not been reported. In this study, its genome was completely sequenced by PacBio SMRT cell platform, analyzed, and compared with other selected complete genome sequences of Ancylobacter to elucidate its potential plant growth promotion abilities. The genomic analysis revealed that the genome of strain E130T consists of one circular DNA chromosome of 4,618,530 bp with a GC content of 66% and one plasmid of 159,741 bp with a GC content of 64.13%. The entire genome contains 4,322 predicted coding genes, 49 transfer RNAs, and 6 ribosomal RNA genes. Genome analysis identified a siderophore natural product biosynthesis cluster, which produces fuscachelin. Knockout of several key genes in this cluster significantly reduces the plant-growth-promotion ability of the strain E130T. In addition to plant-growth promotion, the strain E130T can grow well on 5% NaCl (wt/vol), indicating that this strain is a potential bioresource for successful production of economic crops in alkaline soil.


Surface properties of Staphylococcus saprophyticus and Staphylococcus epidermidis as studied by adherence tests and two-polymer, aqueous phase systems.
S. saprophyticus is an established pathogen in man, devoided of characteristics associated with pathogenicity in Staphylococcus aureus. The ability of this species to attach to cells from regions, viz. the urinary tract, where it acts as an invador and to cells from areas where it is known as a commensal, was compared to its behaviour in this respect with another staphylococcal species, viz. S. epidermidis. S. saprophyticus showed a preferenital adherence to human exfoliated urogenital cells, when compared with its ability to attach to skin and buccal cells from man and also when compared with procine cells from these regions. The profound ability to adhere to human exfoliated urogenital epithelial cells by far exceeded that of S. epidermidis, while no such species difference was found when testing porcine cells (S. saprophyticus is unknown as a urogenital tract pathogen in pigs). When studied in a two-polymer, aqueous phase system, S. saprophyticus and S. epidermidis were found to have a negative surface charge at pH 7.2, but the former carried a considerably higher surface charge density. Both staphylococcal species exhibited a poor hydrophobic interaction liability. These physico-chemical surface characteristics are briefly discussed with regard to the differential bacteria-cell interactions of these species.


A simple method of characterizing mitochondrial ribonucleic acid.
A simple method of isolating and characterizing RNA from L-cell mitochondria is described. The mitochondrial fraction is lysed by sodium dodecyl sulphate, and the RNA fractionated by sucrose-density-gradient centrifugation. The efficacy of proteinase K in preventing ribonuclease activity is also demonstrated.


Development and reliability of a classification system for gross motor function in children with metachromatic leucodystrophy.
Motor deterioration is a key feature of late infantile and juvenile metachromatic leucodystrophy (MLD). Assessment of the disease course implies the need for a standardized description of motor decline. The aim of this study was to establish a classification system for gross motor function in MLD and to assess its interrater reliability. The Gross Motor Function Classification in MLD (GMFC-MLD) was modelled analogous to the Gross Motor Function Classification System in cerebral palsy. Motor data from 59 individuals (27 male; 32 female) with MLD (21 late infantile; 38 juvenile) born between 1970 and 2007 were gathered from a nationwide survey and classified by six independent raters. Median age at onset was 17 months (range 9-27 mo) for the late infantile group and 74 months (35-168 mo) for the juvenile group. The GMFC-MLD consists of seven levels and is applicable from the age of 18 months. It represents all clinically relevant stages from normal (level 0) to loss of all gross motor function (level 6). The kappa coefficient was 0.90 for overall rater agreement. There were no significant differences between level-specific kappa coefficients. The GMFC-MLD is a highly reliable, feasible tool for standardized assessment of gross motor function in MLD which can be used for the description of the natural course of the disease and for evaluation of therapeutic options such as stem cell transplantation and enzyme replacement, both of which are topics of current research.


ROMA, an algorithm for ovarian cancer.
Improvement of survival in ovarian cancer may be achieved through early diagnosis and modification of treatment. Although abnormalities in the adnexal region are frequently observed in transvaginal ultrasound, interpretation may be equivocal in some cases. If neoplastic tumor is suspected, a wide range of tests and algorithms may be applied. Risk of Malignancy Algorithm (ROMA), as first described by Moore in 2009, is one of the most popular approaches. The clinical utility of this regression model has been demonstrated in both pre- (75.6% sensitivity and 74.8% specificity) and post-menopausal (92.3% sensitivity and 74.7% specificity) women. These findings have been independently confirmed in a number of publications. The sensitivity and specificity of ROMA may, however, be improved with inclusion of supplemental data, such as age and ultrasound findings. Because of its simplicity, ROMA is a reliable tool characterized by high accuracy and reproducibility to stratify patients into a high or a low ovarian cancer risk.


Comparative long-term outcomes of laparoscopic hepatectomy and radiofrequency ablation for hepatocellular carcinoma located in the anterolateral segments of the liver.
Laparoscopic liver resection (LLR) is considered the standard surgical approach for resecting small hepatocellular carcinomas (HCC) located in the anterolateral segments of the liver. However, few studies have compared LLR and radiofrequency ablation (RFA) in such cases. We retrospectively compared the short- and long-term outcomes of 101 patients who underwent LLR and 264 patients who underwent RFA because of a newly diagnosed single, small (≤4 cm) HCC located in the anterolateral segments of the liver. By applying 1:1 propensity score matching, we matched 61 patients in both groups. Although the 5-year overall survival rates were similar (83.6% vs 84.5%; P = .913), the 5-year disease-free survival rate was greater in the LLR group (56.4% vs 41.8%; P = .009). In patients with an α-fetoprotein level of ≥100 ng/mL, the 5-year overall (100% vs 80.0%; P = .022) and disease-free survival (76.6% vs 45.5%; P = .006) rates were greater in the LCC group. For patients with a single, small HCC located in the anterolateral segments of the liver, LLR was associated with similar complication and overall survival rates, but better disease-free survival compared with RFA. LLR may be recommended for patients with higher α-fetoprotein levels.


Brefeldin A sensitive mechanisms contribute to endocytotic membrane retrieval and vesicle recycling in cerebellar granule cells.
The recycling of synaptic vesicle (SV) proteins and transmitter release occur at multiple sites along the axon. These processes are sensitive to inhibition of the small GTP binding protein ARF1, which regulates the adaptor protein 1 and 3 complex (AP-1/AP-3). As the axon matures, SV recycling becomes restricted to the presynaptic bouton, and its machinery undergoes a complex process of maturation. We used the styryl dye FM1-43 to highlight differences in the efficiency of membrane recycling at different sites in cerebellar granule cells cultured for 7 days in vitro. We used Brefeldin A (BFA) to inhibit AP-1/AP-3-mediated recycling and to test the contribution of this pathway to the heterogeneity of the responses when these cells are strongly stimulated. Combining imaging techniques and ultrastructural analyses, we found a significant decrease in the density of functional boutons and an increase in the presence of endosome-like structures within the boutons of cells incubated with BFA prior to FM1-43 loading. Such effects were not observed when BFA was added 5 min after the end of the loading step, when endocytosis was almost fully completed. In this situation, vesicles were found closer to the active zone (AZ) in boutons exposed to BFA. Together, these data suggest that the AP-1/AP-3 pathway contributes to SV recycling, affecting different steps in all boutons but not equally, and thus being partly responsible for the heterogeneity of the different recycling efficiencies. Cover Image for this issue: doi. 10.1111/jnc.13801.


TRIM31 facilitates K27-linked polyubiquitination of SYK to regulate antifungal immunity.
Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase, which plays an essential role in both innate and adaptive immunity. However, the key molecular mechanisms that regulate SYK activity are poorly understood. Here we identified the E3 ligase TRIM31 as a crucial regulator of SYK activation. We found that TRIM31 interacted with SYK and catalyzed K27-linked polyubiquitination at Lys375 and Lys517 of SYK. This K27-linked polyubiquitination of SYK promoted its plasma membrane translocation and binding with the C-type lectin receptors (CLRs), and also prevented the interaction with the phosphatase SHP-1. Therefore, deficiency of Trim31 in bone marrow-derived dendritic cells (BMDCs) and macrophages (BMDMs) dampened SYK-mediated signaling and inhibited the secretion of proinflammatory cytokines and chemokines against the fungal pathogen Candida albicans infection. Trim31-/- mice were also more sensitive to C. albicans systemic infection than Trim31+/+ mice and exhibited reduced Th1 and Th17 responses. Overall, our study uncovered the pivotal role of TRIM31-mediated K27-linked polyubiquitination on SYK activation and highlighted the significance of TRIM31 in anti-C. albicans immunity.


Real-Life Experience of Tralokinumab for the Treatment of Adult Patients with Severe Atopic Dermatitis: A Multicentric Prospective Study.
Tralokinumab, the first fully human monoclonal antibody that binds specifically to interleukin-13, was safe and effective for treating atopic dermatitis (AD) in clinical trials, but real-life experience is still limited. The objective of this study was to evaluate the effectiveness and safety of tralokinumab in severe AD in a real-life multicenter prospective cohort. Adult patients with severe AD were enrolled between January 2022 and July 2022 and received tralokinumab subcutaneously for 16 weeks. Objective and subjective scores were collected at baseline, weeks 6 and 16. Adverse events were reported throughout the study. Twenty-one patients were included. An improvement of at least 75% on the Eczema Area and Severity Index (EASI 75) was achieved in 66.7% of patients at week 16. The median objective and subjective scores at week 16 were significantly (p < 0.001) lower than those at baseline. Combination with cyclosporine was sometimes necessary at the beginning of treatment, and addition of upadacitinib was required for some patients with very severe disease during the treatment. The most frequent adverse events were flares of eczema (23.8%) and reactions at injection site (19.0%). No cases of conjunctivitis were reported. Four patients (19.0%) discontinued treatment. Tralokinumab is an effective first-line biotherapy for severe AD. However, therapeutic response may be progressive. Safety data were reassuring. Atopic dermatitis flares or reactions at the injection site may lead to discontinuation of treatment. A history of conjunctivitis on dupilumab is not a contraindication to the initiation of tralokinumab.


Matrix model for collective phenomena in electron beam's longitudinal phase space.
The possibility to predict, characterize and minimize the presence of spurious harmonic content in the longitudinal profile of high brightness electron beams, namely the microbunching instability, has become vital to ensure accurate modeling and reliable operation of radiofrequency and plasma-based linear accelerators such as those driving free-electron lasers. Recently, the impact of intrabeam scattering (IBS) on the instability has been experimentally demonstrated by the authors. This work complements that experimental study by extending existing theories in a self-consistent, piece-wise calculation of IBS in single pass linacs and multi-bend transfer lines. New expressions for the IBS are introduced in two different semi-analytical models of microbunching. The accuracy of the proposed models and the range of beam parameters to which they apply is discussed. The overall modeling turns out to be a fast comprehensive tool for the optimization of linac-driven free-electron lasers.


The Term Newborn: Congenital Infections.
Maternal pathogens can be transmitted to the fetus resulting in congenital infection with sequelae ranging from asymptomatic infection to severe debilitating disease and still birth. The TORCH pneumonic (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus) is used widely, but it provides a limited description of the expanding list of pathogens associated with congenital infection. This article focuses on the evaluation and management of infants with common congenital infections such as cytomegalovirus, and infections that warrant early diagnosis and treatment to prevent serious complications, such as toxoplasmosis, human immunodeficiency virus, and syphilis. Zika virus and Chagas disease remain uncommon.


Short-term effectiveness of an outcomes research training curriculum within a coordinated program.
The fourth edition of the Commission on Accreditation for Dietetics Education Standards of Education mandated outcomes research training. Our objective was to determine the short-term effectiveness (<5 years) of the outcomes research training curriculum in the Coordinated Program in Dietetics (CP) at the University of Missouri-Columbia, which exceeds these minimum standards. Toward this end, a survey tool was administered to University of Missouri-Columbia CP graduates before the implementation of the fourth edition of Standards of Education and to University of Missouri-Columbia CP graduates with two semesters of outcomes research training; graduates of two other CPs from different universities from the same years were also surveyed. Graduates who went through CPs after implementation of the fourth edition of the Standards of Education showed notable improvement in attitudes, interest, and participation in most of the outcomes research skills queried, compared with those who completed their education under the earlier standards; knowledge was only slightly improved. Of these areas, only enhancements in attitudes and interest were consistently more pronounced in food and nutrition professionals trained using the University of Missouri-Columbia's outcomes research curriculum compared with other CP graduates. Both the Commission on Accreditation for Dietetics Education and program directors can use the findings described herein to further assess and develop the research competencies and/or to strengthen their programs.


Migraine-associated vertigo.
This article presents a brief overview of migraine-associated vertigo for the practicing otolaryngologist. Discussion includes the definition of migraine-associated vertigo and its pathophysiology, clinical features, demographics, findings on physical examination, use of otologic and vestibular testing, differential diagnosis, treatment, and prognosis.


Formyl-methyl-methylenetetrahydrofolate synthetase-(combined). An ovine protein with multiple catalytic activities.
Formyltetrahydrofolate synthetase, methenyltetrahydrofolate cyclohydrolase, and methylenetetrahydrofolate dehydrogenase in sheep liver co-purify 200-fold to yield a homogeneous preparation containing a single protein species observed on discontinuous polyacrylamide gel electrophoresis in the presence of dodecyl sulfate. The synthetase and dehydrogenase activities migrate with the single protein band observed on polyacrylamide gel electrophoresis in two discontinuous buffer systems near pH 8. The protein sediments with a single symmetrical boundary with sedimentation coefficient (S20,w) = 8.30 S and elutes from molecular exclusion chromatography columns at a position corresponding to a diffusion coefficient (D20,w) = 3.99 X 10(-7) cm2 sec-1. Dodecyl sulfate-polyacrylamide gel electrophoresis of the protein intramolecularly cross-linked with dimethylsuberimidate shows one protein species of Mr = 218,000 in addition to the species of Mr = 108,500 characteristic of the unmodified protein. NH2-terminal analysis of the protein using 5-dimethylaminonaphthalene-1-sulfonyl (dansyl) chloride in the presence of dodecyl sulfate results in the recovery of a single dansyl amino acid, alanine. The three activities are thus shown to reside in a protein composed of two apparently identical subunits, and the trivial name formyl-methenyl-methylenetetrahydrofolate synthetase(combined) is proposed for this enzyme to suggest the multiple catalytic activities associated with the single protein species.


Requirement for oxytocin augmentation in spontaneous parturition is associated with the maternal serum steroid hormones assessed by liquid chromatography coupled to the tandem mass spectrometry.
The aim of research was to evaluate the maternal serum concentration of selected endogenous steroid hormones during spontaneous parturition at term and to determinate their association with the need for oxytocin augmentation. Blood of 108 healthy pregnant women whose parturition started with the regular spontaneous uterine contractions was drawn at the beginning of the labor. Liquid chromatography coupled to the tandem mass spectrometry device was utilized for measurement of sex hormone binding globulin, aldosterone, androstenedione, cortisol, cortisone, corticosterone, dehydroepiandrosterone, dehydroepiandrosteron sulphate, 17-hydroxyprogesterone, progesterone, and testosterone. Mann-Whitney U test, chi-square test, univariate and multivariate logistic regression, and receiver operating characteristic (ROC) analysis were used for the data analysis. Reference ranges of the selected hormones assessed by liquid chromatography coupled to the tandem mass spectrometry in maternal serum were established. Statistically significant differences in the serum concentration of corticosterone, dehydroepiandrosterone, and androstenedione between mothers requiring oxytocin augmentation and the rest of women having spontaneous parturition were found (p = 0.002, p = 0.008, and p = 0.04, respectively). Concentrations were lower in the group of mothers who required oxytocin infusion for progression of labor. ROC analysis showed that all the mothers with dehydroepiandrosterone serum concentration above 21.6 nmol/L have lower chance to use oxytocin infusion for the labor progression ( area under the curve (AUC) = 0.649, sensitivity = 71.7%, specificity = 59.6%, p = 0.006). This research provided reference ranges for the selected maternal serum steroid hormones at the beginning of parturition. Association of corticosterone, dehydroepiandrosterone, and androstenedione with the need for the oxytocin infusion usage has been established. Dehydroepiandrosterone could be potential predictor of oxytocin infusion augmentation for progression of the parturition.


Towards effective offloading mechanisms in fog computing.
Fog computing is considered a formidable next-generation complement to cloud computing. Nowadays, in light of the dramatic rise in the number of IoT devices, several problems have been raised in cloud architectures. By introducing fog computing as a mediate layer between the user devices and the cloud, one can extend cloud computing's processing and storage capability. Offloading can be utilized as a mechanism that transfers computations, data, and energy consumption from the resource-limited user devices to resource-rich fog/cloud layers to achieve an optimal experience in the quality of applications and improve the system performance. This paper provides a systematic and comprehensive study to evaluate fog offloading mechanisms' current and recent works. Each selected paper's pros and cons are explored and analyzed to state and address the present potentialities and issues of offloading mechanisms in a fog environment efficiently. We classify offloading mechanisms in a fog system into four groups, including computation-based, energy-based, storage-based, and hybrid approaches. Furthermore, this paper explores offloading metrics, applied algorithms, and evaluation methods related to the chosen offloading mechanisms in fog systems. Additionally, the open challenges and future trends derived from the reviewed studies are discussed.


In silico investigations of possible routes of assembly of ORF 3a from SARS-CoV.
ORF 3a of human severe acute respiratory syndrome corona virus (SARS-CoV) has been identified as a 274 amino acid membrane protein. When expressed in Xenopus oocytes the protein forms channels. Based on bioinformatics approaches the topology has been identified to include three transmembrane domains (TMDs). Since structural models from experiments are still lacking, computational methods can be challenged to generate such models. In this study, a 'sequential approach' for the assembly is proposed in which the individual TMDs are assembled one by one. This protocol is compared with a concerted protocol in which all TMDs are assembled simultaneously. The role of the loops between the TMDs during assembly of the monomers into a bundle is investigated. Molecular dynamics simulations for 20 ns are performed as a short equilibration to assess the bundle stability in a lipid environment. The results suggest that bundles are likely with the second TMD facing the putative pore. All the putative bundles show water molecules trapped within the lumen of the pore with only occasional events of complete crossing.


How does childhood maltreatment influence cardiovascular disease? A sequential causal mediation analysis.
Childhood maltreatment has been consistently associated with cardiovascular disease (CVD). However, the mechanisms of this relationship are not yet fully understood. We explored the relative contribution of anxiety/depression, smoking, body mass index (BMI) and inflammation (C-reactive protein, CRP) to the association between childhood maltreatment and CVD in men and women aged 40-69 years in the UK. We used data from 40 596 men and 59 511 women from UK Biobank. To estimate the indirect effects of childhood maltreatment (physical, sexual and emotional abuse, and emotional and physical neglect) on incident CVD via each of the mediators, we applied a sequential mediation approach. All forms of maltreatment were associated with increased CVD risk [hazard ratios (HRs) ranging from 1.09 to 1.27]. Together, anxiety/depression, smoking, BMI and inflammation (indexed by CRP) mediated 26-90% of the association between childhood maltreatment and CVD, and the contribution of these mediators differed by type of maltreatment and sex. Anxiety/depression mediated the largest proportion of the association of sexual abuse, emotional abuse and emotional neglect with CVD (accounting for 16-43% of the total effect), especially in women. In men, BMI contributed the most to the indirect effect of associations of physical abuse and physical neglect with CVD; in women, anxiety/depression and BMI had similar contributions. These findings add to the understanding of how childhood maltreatment affects CVD risk and identify modifiable mediating factors that could potentially reduce the burden of CVD in people exposed to maltreatment in early life.


Impact of gender, partner status, and race on locoregional failure and overall survival in head and neck cancer patients in three radiation therapy oncology group trials.
We investigated the impact of race, in conjunction with gender and partner status, on locoregional control (LRC) and overall survival (OS) in three head and neck trials conducted by the Radiation Therapy Oncology Group (RTOG). Patients from RTOG studies 9003, 9111, and 9703 were included. Patients were stratified by treatment arms. Covariates of interest were partner status (partnered vs. non-partnered), race (white vs. non-white), and sex (female vs. male). Chi-square testing demonstrated homogeneity across treatment arms. Hazards ratio (HR) was used to estimate time to event outcome. Unadjusted and adjusted HRs were calculated for all covariates with associated 95% confidence intervals (CIs) and p values. A total of 1,736 patients were analyzed. Unpartnered males had inferior OS rates compared to partnered females (adjusted HR = 1.22, 95% CI, 1.09-1.36), partnered males (adjusted HR = 1.20, 95% CI, 1.09-1.28), and unpartnered females (adjusted HR = 1.20, 95% CI, 1.09-1.32). White females had superior OS compared with white males, non-white females, and non-white males. Non-white males had inferior OS compared to white males. Partnered whites had improved OS relative to partnered non-white, unpartnered white, and unpartnered non-white patients. Unpartnered males had inferior LRC compared to partnered males (adjusted HR = 1.26, 95% CI, 1.09-1.46) and unpartnered females (adjusted HR = 1.30, 95% CI, 1.05-1.62). White females had LRC superior to non-white males and females. White males had improved LRC compared to non-white males. Partnered whites had improved LRC compared to partnered and unpartnered non-white patients. Unpartnered whites had improved LRC compared to unpartnered non-whites. Race, gender, and partner status had impacts on both OS and locoregional failure, both singly and in combination.


The effects of non-weight-bearing and limited motion on the tensile properties of the meniscus.
Recent clinical studies have suggested that many of the complications of prolonged immobilization after knee surgery can be prevented by permitting early motion while minimizing loading of healing tissues. The purpose of this study was to determine the effects of such a regimen on the tensile properties of the meniscus. The right knee of 10 skeletally mature sheep received a sham operation after which the hindlimb was placed in a harness that prevented weight bearing while permitting limited knee motion. The left knee served as the nonoperated control. Twelve weeks after surgery, paired specimens from the medial meniscus of each limb were tested in tension with the load parallel to the circumferentially oriented collagen fibers. No significant differences in the modulus, tensile strength, and ultimate strain between treated and control medial menisci were identified. Our data thus suggest that preventing weight bearing while permitting even limited motion of the knee will prevent any detrimental effect on the tensile properties of the meniscus in the circumferential direction.


PROMPT intervention for children with severe speech motor delay: a randomized control trial.
Currently, there is limited information on the intervention efficacy for children with speech motor delay (SMD). This randomized control trial (RCT) study examined the effectiveness of Prompts for Restructuring Oral Muscular Phonetic Targets (PROMPT) intervention to improve the outcomes in children with SMD. We hypothesized that children with SMD receiving PROMPT intervention would improve more in the measured outcomes than those waitlisted and receiving home training. Using a two-arm, parallel group, RCT, 49 children with SMD were allocated to either an intervention group (N = 24) that received 45 min of PROMPT intervention two times a week for 10 weeks or were waitlisted for the same duration and received only home training instructions (N = 25). Outcome measures for speech motor control, articulation, speech intelligibility (word and sentence levels), and functional communication were assessed at baseline and at a 10-week follow-up. PROMPT intervention was associated with notable improvements in speech motor control, speech articulation, and word-level speech intelligibility. Intervention allocation yielded weak improvements in sentence-level speech intelligibility and functional communication. PROMPT intervention is a clinically effective intervention approach for children with SMD. Currently, there is limited information on the intervention efficacy for children with SMD. We report on the findings of a phase III intervention efficacy study on children with SMD using an RCT design. PROMPT intervention is a clinically effective intervention approach for children with SMD. Results of the study will be fundamental to the delivery of effective services for this population. These findings may facilitate the development of an evidence-based care pathway for children with severe speech sound disorders.