Datasets:

qualis2006

/

PUBMED_title_abstracts_2020_baseline

like 1

Sulfoxaflor, Zn2+ and their combinations disrupt the antioxidant and osmoregulatory (Ca2+-ATPase) system in Daphnia magna. The oxidative- and osmoregulatory stress-inducing potential of binary mixtures of sulfoxaflor (SUL), a recently developed sulfoximine insecticide, and Zn2+ was aimed to evaluate in Daphnia magna with different exposure regimes. Animals were exposed to different SUL concentrations (1.25, 2.5, 10, and 25 mg/L) for 7 days. In vivo 48 h and in vitro effects of single and binary mixtures of SUL (25 and 50 mg/L) and Zn2+ (40 µg/L) were also determined. Furthermore, Ca2+-ATPase, oxidative stress biomarkers (catalase, CAT; superoxide dismutase, SOD; glutathione peroxidase, GPX; glutathione S-transferase, GST; reduced glutathione, GSH; thiobarbituric acid reactive substances, TBARS), and morphometric characteristics were measured. Variable response patterns were observed due to exposure duration and regime, toxicant type, and concentration. Marked effects of SUL were observed, especially in subacute exposure, and 25 mg/L SUL concentration can be considered as a threshold level. Stimulation of GST activity was the most typical response, followed by declined SOD activity and GSH levels. GPX activity and TBARS levels responded differently depending upon the exposure type. Subacute and in vitro effects of SUL and Zn2+ produced similar responses except for some cases. Ca2+-ATPase activity was altered differently upon subchronic duration, though inhibited by in vitro SUL+Zn effect. Subchronic SUL exposure increased body weight and length up to 25 mg/L, contrary to the observed decrease at higher concentrations. Single and binary mixtures of SUL and Zn2+ caused damage to the antioxidant and osmoregulatory system due to their oxidative potential on cellular targets (biomarkers). The current data emphasized that investigating the SUL toxicity with the Zn2+ combination based on the multi-biomarker approach is essential in the realistic evaluation of SUL toxicity in toxicological research.

Professions, honesty, and income. Professional choices influence valued outcomes such as income, life satisfaction, and social status. However, public opinion polls consistently illustrate that an individual's profession also influences how honest one is perceived to be, and people are motivated to see themselves as honest for many reasons. Why would people choose professions that do not confer them with the benefits of honesty? Survey data reveals honesty perceptions to positively correlate with a profession's conferred prestige (i.e., perceived value to society) and negatively correlate with a profession's annual income. The tradeoff between income and honesty perceptions suggests a wage differential mechanism-employees may maintain a positive self-concept through increased income which compensates for costs incurred by working in a profession characterized by low honesty.

Prevalence and predictors of neurological manifestations in systemic AL amyloidosis. Immunoglobulin light chain (AL) amyloidosis is a life-threatening systemic disease due to plasma cell dyscrasias, which is characterized by amyloid deposition in various tissues. Neurological manifestations, in particular peripheral nervous system involvement, play a major role for quality of life and treatment decisions as frequently potentially neurotoxic drugs are used. We retrospectively investigated the prevalence of neurological manifestations, its risk factors and prognostic value in 155 consecutive patients with AL amyloidosis in a single German tertiary center between 2010 and 2021. Multiple logistic regression was performed to identify predictors of amyloid neuropathy and the impact of peripheral neuropathy on patient survival was assessed by Cox proportional hazard regression analysis. Nearly half of patients showed at least one of four neurological manifestations of AL amyloidosis which were frequent in our study: peripheral neuropathy (36.8%), carpal tunnel syndrome (12.9%), lumbar spinal stenosis (7.1%), and amyloid myopathy (3.9%). Male sex (OR 2.943, CI 1.152-8.139, p = 0.029) and cardiac involvement (OR 6.186, CI 1.449-43.38, p = 0.028) were independent predictors of peripheral neuropathy which was closely related to autonomic dysfunction in patients with AL amyloidosis. Peripheral neuropathy had no impact on survival (HR 0.952, CI 0.517-1.754, p = 0.876). Neurological involvement is common in systemic AL amyloidosis. Treatment decisions should take into account peripheral neuropathy, in particular in male patients with amyloid cardiomyopathy, but also amyloid myopathy that seems to be not as rare as previously suggested.

Elucidation of peripheral nerve myelination by bimodal waveform analysis. As the myelin sheath of the peripheral nerves is immaturely developed in children, a bimodal waveform may be evoked when sensory nerve conduction studies are performed in them. However, there has been no study regarding the relationship between age and the frequency of appearance of the bimodal waveform or the inter-peak latency. Herein, we examined how the bimodal waveform changes with age. A total of 218 sensory nerves (109 median and 109 ulnar nerves) in 86 children (0 to 15 years old) were analyzed. The frequency of the bimodal waveform and the distance-corrected inter-peak latency were examined with antidromic sensory nerve conduction studies of the upper limbs on proximal stimulation. The frequency of bimodal waveforms and distance-corrected inter-peak latency decreased with age. Analysis of the slope line of the scatter plot demonstrated that the bimodal waveform was present until the age of 15-16 years. The bimodal waveform of sensory nerves faded with growth. Given that development-associated temporal dispersion is considered to be the cause of the differences in the bimodal waveform, our findings suggest that the underlying cause of the bimodal waveform is an immature myelin sheath, which may not be fully developed until the age of 15-16 years.

A study of thin fuel slick combustion on wavy water. In-situ burning is a fast, cheap, and effective means for cleaning up spilled fuel in the environment. As in-situ burning grows in popularity as a viable way to clean up oil spills, it is increasingly important to study the combustion of liquid fuels floating on wavy water. This study analyzes the burning behavior of a liquid fuel floating on water with the interaction of waves. Nine wave profiles are evaluated with thin layers of kerosene poured into a circular, floating test pan in a rectangular freshwater-filled wave tank. Wave generation and wave absorbing equipment ensure linear wave composition for interaction with the burning pool. Water sublayer and fuel/water interface temperatures are measured for incorporation into a model. It is observed that waves reduce the burning rate and flame height. The burning rate is directly proportional to the steepness of the wave and decreases as steepness increases.

Association between anemic status on admission and clinical outcomes of acute large vessel occlusion. Anemia is a frequently observed condition, but its clinical impact on large vessel occlusion (LVO) remains unclear. We examined the association between anemic status on admission and clinical outcomes of LVO in a real-world setting. We conducted a post-hoc analysis of the RESCUE-Japan Registry 2, a nationwide registry which enrolled 2408 consecutive patients with LVO who were admitted within 24 h of onset. The patients were classified into anemia (<11 g/dL) and no-anemia (≥11 g/dL) groups according to their hemoglobin level on admission. The primary outcome was defined as a modified Rankin Scale of 0-2 at day 90. Among the 2373 patients with available baseline hemoglobin data, 307 (13.0%) were classified in the anemia group. Anemia was associated with a lower likelihood of the primary outcome (adjusted odds ratio [OR]: 0.68; 95% confidence interval [CI]: 0.47-0.98) and higher mortality within 90 days (adjusted OR: 1.48; 95% CI: 1.01-2.17). Subgroup analyses showed that the likelihood of achieving the primary outcome between the two groups was different between men and women (P for interaction = 0.049), those with Alberta Stroke Program Early CT Score (ASPECTS) <6 and ASPECTS ≥6 (P for interaction = 0.02), and those with National Institute of Health Stroke Scale (NIHSS) ≥16 and NIHSS < 16 (P for interaction = 0.005). Anemic state on admission was associated with poorer clinical outcomes of LVO in real-world clinical practice. The effects of anemic status were larger in LVO patients with lower NIHSS or higher ASPECTS.

Composition and functionality of bacterioplankton communities in marine coastal zones adjacent to finfish aquaculture. Finfish aquaculture is a fast-growing primary industry and is increasingly common in coastal ecosystems. Bacterioplankton is ubiquitous in marine environment and respond rapidly to environmental changes. Changes in bacterioplankton community are not well understood in semi-enclosed stratified embayments. This study aims to examine aquaculture effects in the composition and functional profiles of the bacterioplankton community using amplicon sequencing along a distance gradient from two finfish leases in a marine embayment. Results revealed natural stratification in bacterioplankton associated to NOx, conductivity, salinity, temperature and PO4. Among the differentially abundant bacteria in leases, we found members associated with nutrient enrichment and aquaculture activities. Abundant predicted functions near leases were assigned to organic matter degradation, fermentation, and antibiotic resistance. This study provides a first effort to describe changes in the bacterioplankton community composition and function due to finfish aquaculture in a semi-enclosed and highly stratified embayment with a significant freshwater input.

Jump landing among chronic ankle instability individuals who did or did not attend rehabilitation at the time of injury. The purpose was to compare vertical ground reaction forces and sagittal-plane energy dissipation patterns of the lower extremity during a single-limb jump-stabilization task between individuals with chronic ankle instability who did or did not attend rehabilitation after their initial ankle sprain. Cross-sectional. Research laboratory. Eight participants with chronic ankle instability who did and 12 participants who did not attend rehabilitation were enrolled. Normalized vertical ground reaction force data were used to calculate the average loading rate, time to peak force, and the peak force. Sagittal plane kinematics and joint moments at the ankle, knee, and hip, were used to calculate each joint's relative energy dissipation at 50, 100, 150, and 200 ms post-landing. Participants who attended rehabilitation had a slower average loading rate (P = 0.025) and smaller peak vertical ground reaction force (P = 0.025). The average relative energy dissipation at the knee was higher in those who attended rehabilitation at the 100 ms (P = 0.041), 150 ms (P = 0.046), and 200 ms (P = 0.042) time intervals. Attending rehabilitation after an ankle sprain may have a beneficial effect on jump-stabilization outcomes among individuals with chronic ankle instability.

Two-stage TKA for tuberculosis septic arthritis of the knee masquerading as pigmented villonodular synovitis: A case report. A 25-year-old female presented with left knee pain following arthroscopic synovectomy for presumed pigmented villonodular synovitis (PVNS). Radiographs and magnetic resonance imaging demonstrated tricompartmental arthritic changes. She underwent a two-stage procedure first involving antibiotic spacer implantation, followed 1 week later by spacer removal and definitive total knee arthroplasty (TKA) once initial intraoperative culture results were negative. Subsequent cultures confirmed tuberculosis septic arthritis. Repeat evaluation 1 year postoperatively showed no complications and patient satisfaction with left knee function. This is a unique case report in the United States describing 1-year outcomes following staged TKA for tuberculosis septic arthritis masquerading as PVNS.

Between-leg asymmetry in automatic postural responses to stance perturbations in people with Parkinson's disease. People with Parkinson's disease (PwPD) showed impairments of balance control which can be aggravated by the presence of higher interlateral postural asymmetry caused by a distinct dopaminergic loss in the substantia nigra between cerebral hemispheres. We evaluate asymmetries between the more and the less affected leg in PwPD in responses to unanticipated stance perturbations. Sixteen 16 PwPD participated in the experiment that consisted of recovering a stable upright stance, keeping the feet in place, in response to a perturbation caused by a sudden release of a load equivalent to 7 % of the participant's body mass. Anterior displacement and velocity of the center of pressure (CoP), the latency of gastrocnemius medialis muscle (GM) activation onset, rate of GM activation, and normalized magnitude of muscular activation were analyzed. Analysis revealed significantly rate (p = 0.04) and magnitude (p = 0.02) higher activation of GM in the less affected limb. No significant effects of the leg were found for GM activation latency or CoP-related variables. There is a higher contribution of the less affected leg in automatic postural responses in PwPD.

Center of pressure characteristics differ during single leg stance throughout pregnancy and compared to nulligravida individuals. Falls are common during pregnancy and present potential for injury to the pregnant individual and the baby. Do center of pressure characteristics during single leg stance differ between participants during and after pregnancy and nulligravida participants in the presence and absence of visual input? Nineteen pregnant participants completed testing during the second trimester, the third trimester, and 4-6 months post-partum. Matched, nulligravida females completed testing once. All participants performed single leg stance on a force platform on each limb for up to 20 s with eyes open and with eyes closed. Center of pressure characteristics were compared between pregnant and nulligravida females using three separate 2 × 2 mixed way ANOVAs, one for each pregnancy time point (second trimester, third trimester, and post-partum) with Bonferroni correction. Pregnant females demonstrated smaller single leg stance time with eyes closed during the third trimester. During the second and third trimester, pregnant participants demonstrated smaller sway and sway velocity across eyes open and eyes closed conditions. During the third trimester and post-partum, pregnant participants demonstrated greater median frequency of the center of pressure data. Pregnant participants also demonstrated smaller sample entropy in the anteroposterior direction during the second and third trimesters and in the mediolateral direction during the second trimester. The decreased total sway and sway velocity observed during pregnancy may reflect rigidity or a protective strategy during single limb stance. Additionally, center of pressure data were less smooth and more repetitive during pregnancy indicating robust differences in postural control strategies and potentially increased fall risk. Because single limb stance is a component of many activities of daily living, the single limb stance task may have clinical utility for testing or training balance in this population with a goal of decreasing falls.

Clavicular and scapular, but not spinal kinematics vary with scapular dyskinesis type during arm elevation and lowering in persons with neck pain. Scapular dyskinesis is often observed in patients with neck pain. However, it is unknown whether clavicular, scapular and spinal kinematics vary with different types of scapular dyskinesis during arm movement. Are there differences in clavicular, scapular and spinal kinematics during unilateral arm elevation and lowering among neck pain patients presenting with (i) scapular winging, (ii) with dysrhythmia, (iii) with no scapular abnormality and (iv) healthy controls? Sixty participants with neck pain (20 in each group) and 20 asymptomatic controls were recruited. The 3D kinematic data were measured during unilateral arm elevation and lowering at 30°, 60°, 90°, and 120° in the scapular plane. A three-way mixed-effects ANOVA was used to determine the main effects (group, phase and angle) and the interactions between three independent variables on the kinematic data. The neck pain group with scapular winging had decreased clavicular retraction and increased scapular internal rotation and anterior tilt compared to the other neck pain and control groups at all angles during both phases of arm movement (p < 0.01). The neck pain group with scapular dysrhythmia had decreased scapular upward rotation compared to all other groups (p < 0.01). Some alterations in the kinematics existed during the lowering phase compared to the raising phase for all groups (p < 0.05). Spinal kinematics were similar across all groups (p > 0.05). Specific patterns of clavicular and scapular kinematics were identified during arm movement relevant to the type of observed scapular dyskinesis in patients with neck pain. Such findings stand to inform more precise and relevant motor training in rehabilitation and improve understanding of the association between altered scapular kinematics and neck pain.

Substrate-free fluorescence ratiometric detection of serum acetylcholinesterase activity with a self-assembled CsPbBr3 perovskite nanocrystals/tetraphenylporphyrin tetrasulfonic acid nanocomposite. A dual-emission fluorescent nanoprobe was successfully constructed through self-assembling CsPbBr3 perovskite nanocrystals (CsPbBr3 PNCs) and tetraphenylporphyrin tetrasulfonic acid (TPPS). Acetylcholinesterase (AChE) is observed to directly quench the green fluorescence of CsPbBr3 PNCs at 520 nm in the absence of an enzyme substrate, but has no significant influence on the red emission of TPPS at 650 nm. The decreased value of the fluorescence intensities ratio at 520 to 650 nm (ΔF520/F650) is proportional to the logarithmic value of AChE activity ranging from 0.05 to 1.0 U/L. The limit of detection is as low as 0.0042 U/L. The relative standard deviation is 3.6% in eleven consecutive measurements of 0.2 U/L AChE. The method exhibits a good anti-interference capacity since it does not respond to most concomitant species. Satisfactory results are acquired for the determination of AChE activity in human serum samples.

Cadmium exposure causes mitochondrial fission and fusion disorder in the pig hypothalamus via the PI3K/AKT pathway. Cadmium (Cd) is the main environmental pollutant causing endocrine and nervous system dysfunction in animals. High doses of Cd cause cytotoxicity, including programmed necrosis and apoptosis, which has aroused widespread concern. Mitochondrial dynamics plays a key role in programmed necrosis and apoptosis of endocrine organs. Nevertheless, there is a lack of information on the relationship between Cd-induced programmed necrosis/apoptosis of the hypothalamus and the mitochondrial fusion-fission balance. Therefore, a hypothalamic injury model of Cd exposure was established by adding 20 mg/kg CdCl2 to the basic pig diet for 40 days. Analysis of the Cd toxicity mechanism was conducted by inductively coupled plasma mass spectrometry, hematoxylin and eosin staining, the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and quantitative reverse transcription-polymerase chain reaction, as well as western blot analyses. The results suggested that exposure to Cd inhibited the expression of PI3K and AKT, interfered with the balance of mitochondrial fusion and division, downregulated the expression of Mfn2, Mfn1, and OPA1, and upregulated the expression of Drp1 and Mff, which led to cell apoptosis and programmed necrosis in the pig hypothalamus. This study finds that cadmium exposure leads to mitochondrial fission and fusion dysfunction in porcine hypothalamus via the PI3K/AKT pathway.

Systematic impacts of fluoride exposure on the metabolomics of rats. Fluoride is widely present in the environment. Excessive fluoride exposure leads to fluorosis, which has become a global public health problem and will cause damage to various organs and tissues. Only a few studies focus on serum metabolomics, and there is still a lack of systematic metabolomics associated with fluorosis within the main organs. Therefore, in the current study, a non-targeted metabolomics method using gas chromatography-mass spectrometry (GC-MS) was used to research the effects of fluoride exposure on metabolites in different organs, to uncover potential biomarkers and study whether the affected metabolic pathways are related to the mechanism of fluorosis. Male Sprague-Dawley rats were randomly divided into two groups: a control group and a fluoride exposure group. GC-MS technology was used to identify metabolites. Multivariate statistical analysis identified 16, 24, 20, 20, 24, 13, 7, and 13 differential metabolites in the serum, liver, kidney, heart, hippocampus, cortex, kidney fat, and brown fat, respectively, in the two groups of rats. Fifteen metabolic pathways were affected, involving toxic mechanisms such as oxidative stress, mitochondrial damage, inflammation, and fatty acid, amino acid and energy metabolism disorders. This study provides a new perspective on the understanding of the mechanism of toxicity associated with sodium fluoride, contributing to the prevention and treatment of fluorosis.

Persistence behavior of chlorpyrifos and biological toxicity mechanism to cucumbers under greenhouse conditions. Chlorpyrifos, a broadly utilized insecticide, inhibits many cellular and physiological processes in plants. Here, the phyto-toxicity of chlorpyrifos on cucumber plants, as well as the dissipation kinetics of chlorpyrifos in leaves, were investigated. Those results showed that chlorpyrifos accumulated primarily in the leaves under normal agrochemical spraying conditions with the half-lives among 2.48-4.59 days. Residues of the primary metabolite, 3,5,6-trichloro-2-pyridinol (TCP), rapidly accumulated in plant tissues and soil with chlorpyrifos degradation. The application amount of chlorpyrifos had a significant effect on the persistence of chlorpyrifos and TCP in both plant and soil environments. Chlorpyrifos generated excessive reactive oxygen species (ROS) and malondialdehyde (MDA), which led to oxidative damage. High chlorpyrifos stress even inhibited antioxidant enzymes. The photosynthetic system and gas exchange were suppressed, which ultimately lead to inefficient light use under chlorpyrifos stress. Morphological results revealed that chlorpyrifos induced membrane damage and harmed organelles such as mitochondria and chloroplast. Noninvasive micro-test technology (NMT) showed that chlorpyrifos promoted intracellular Ca2+ influx and efflux of H+ and K+. The Ca2+ influx was significantly stimulated after both high and low chlorpyrifos treatment with the minimum value of - 336.33 pmol·cm-2·s-1 at 258 s and - 155.68 pmol·cm-2·s-1 at 288 s, respectively. Chlorpyrifos stress reversed the H+ influx to an efflux in cucumber mesophyll with the mean value of 0.45 ± 0.03 pmol·cm-2·s-1 and 0.19 ± 0.03 pmol·cm-2·s-1 in cucumber plants under low and high chlorpyrifos stress. High chlorpyrifos stress dramatically increase K+ efflux in cucumber leaves by 13.68 times higher than the control. We suggest that ion homeostasis destruction, accompanied by ROS, resulted in oxidative damage to the mesophyll cell of cucumber seedlings.

Distinct vulnerability to oxidative stress determines the ammonia sensitivity of crayfish (Procambarus clarkii) at different developmental stages. Red swamp crayfish (Procambarus clarkii) has increasingly become a high-value freshwater product in China. During the intensive cultivation, excessive ammonia exposure is an important lethal factor of crayfish. We investigated the toxic effects and mechanisms of ammonia on crayfish at two different developmental stages. A preliminary ammonia stress test showed a 96-h LC50 of 135.10 mg/L and 299.61 mg/L for Stage_1 crayfish (8.47 ± 1.68 g) and Stage_2 crayfish (18.33 ± 2.41 g), respectively. During a prolonged ammonia exposure (up to 96 h), serum acid phosphatase and alkaline phosphatase showed a time-dependent decrease. Histological assessment indicated the degree of hepatopancreatic injury, which was mainly characterized as tubule lumen dilatation, degenerated tubule, vacuolization and dissolved hepatic epithelial cell, increased with exposure time. Enhanced malondialdehyde level and reduced antioxidant capacity of hepatopancreas were also observed. The mRNA expression and activity of catalase and superoxide dismutase showed an initial up-regulation within 24 h, and then gradually down-regulated with the exposure time. In the post-treatment recovery period, the Stage_2 crayfish exerted a stronger antioxidant and detoxification capacity than that of the Stage_1 crayfish, and thus quickly recovered from the ammonia exposure. Our findings provide a further understanding of the adverse effects of ammonia stress and suggest guidelines for water quality management during crayfish farming.

Harnessing diversity of Lactococcus lactis from raw goat milk: Design of an indigenous starter for the production of Rocamadour, a French PDO cheese. Twenty-four strains of Lactococcus lactis isolated from raw goat milk collected in the Rocamadour PDO area were analysed by MLST typing and phenotypic characterisation. The strains were combined to design an indigenous starter for the production of Rocamadour PDO cheese. The strains were divided into three classes based on their technological properties: acidifying and proteolytic strains in class I (12/24 strains), slightly acidifying and non-proteolytic strains in class II (2/24 strains), and non-acidifying and non-proteolytic strains in class III (10/24 strains). Interestingly, all but three strains (21/24) produced diacetyl/acetoin despite not having citrate metabolism genes, as would classically be expected for the production of these aroma compounds. Three strains (EIP07A, EIP13D, and EIP20B) were selected for the indigenous starter based on the following inclusion/exclusion criteria: (i) no negative interactions between included strains, (ii) ability to metabolize lactose and at least one strain with the prtP gene and/or capable of producing diacetyl/acetoin, and (iii) selected strains derived from different farms to maximise genetic and phenotypic diversity. Despite consisting exclusively of L. lactis strains, the designed indigenous starter allowed reproducible cheese production with performances similar to those obtained with an industrial starter and with the sensory qualities expected of Rocamadour PDO cheese.

A high-resolution colorimetric immunoassay for tyramine detection based on enzyme-enabled growth of gold nanostar coupled with smartphone readout. In this work, a specific monoclonal antibody against tyramine was produced based on a new hapten design. Then, we developed a high-resolution multicolor colorimetric immunoassay for tyramine based on this antibody by integrating enzyme-induced multicolor generation with smartphone-assistant signal readout. The multicolor generation is due to the shift of the local surface plasmon resonance band of gold nanostructure controlled by alkaline phosphatase-induced the growth of gold nanostars. Quantitative detection of tyramine was achieved via analyzing the red/blue channel values of assay solution's image taken by a smartphone with the support of a color recognizer application. The limit of detection of this immunoassay for tyramine detection in beef, pork and yoghurt was 19.7 mg/kg or L. The average recoveries were between 83 % and 103 %., and the results were validated by high performance liquid chromatography to be reliable. Overall, this developed immunoassay provides a promising platform for on-site detection of tyramine.

Mycoprotein as novel functional ingredient: Mapping of functionality, composition and structure throughout the Quorn fermentation process. This study provides the first mapping of mycoprotein functionality, composition and structure throughout the Quorn fermentation process. The fermentation broth, RNA-reduced broth (RNA-broth), centrate and their centrifugation deposits and supernatants were characterised. The broth, RNA-broth and their deposits displayed high concentrations of fungal filaments, which contributed to their high gelling properties (with a 5,320 Pa elastic modulus reported for RNA-broth deposits gels). Foams prepared with RNA-broth and centrate supernatants via frothing exhibited high stability (380 min), with high concentrations of a foam-positive cerato-platanin reported in these samples. Emulsions prepared with the broth and broth supernatant showed high emulsifying activity and stability indexes (12.80 m2/g and 15.84 mins for the broth supernatant) and low oil droplet sizes (18.09 µm for the broth). This study identified previously unreported gelling, foaming and/or emulsifying properties for the different Quorn streams, highlighting opportunities to develop novel sustainable alternatives to animal-derived functional ingredients using mycoprotein material.

Mango 'criollo' by-products as a source of polyphenols with antioxidant capacity. Ultrasound assisted extraction evaluated by response surface methodology and HPLC-ESI-QTOF-MS/MS characterization. Ultrasound assisted extraction (UAE) was evaluated as a green procedure for the recovery of phenolic compounds with antioxidant capacity from underutilized mango 'criollo' (peel, pulp and seed). Magnetic stirred was performed as conventional extraction. Response surface methodology using a three-factor (% ethanol, amplitude and time) central composite design was used to maximize the extraction for total phenolic compounds (TPC), total flavonoids and antioxidant capacity. The operational conditions to maximize extraction were: peel, 46% ethanol/amplitude 60% (36 µm)/6.5 min; pulp, 25% ethanol/amplitude 75% (45 µm)/30 min; seed 49% ethanol/100% (60 µm) amplitude/20 min. The phenolic composition of the optimized extracts was characterized by HPLC-QTOF-MS/MS and 45 compounds were tentatively identified as xanthones (mangiferin), flavonoids (quercetin), ellagic acid, benzophenones (maclurin), gallate derivatives and gallotannins. UAE increased TPC extraction (33%); interestingly mangiferin extraction increased 53% in peel, similarly, ellagic acid increased up to 2.5 and 4.4 times in peel and seed extracts.

Headspace GC/MS and fast GC e-nose combined with chemometric analysis to identify the varieties and geographical origins of ginger (Zingiber officinale Roscoe). Food authenticity regarding different varieties and geographical origins is increasingly becoming a concern for consumers. In this study, headspace gas chromatography-mass spectrometry (HS-GC-MS) and fast gas chromatography electronic nose (fast GC e-nose) were used to successfully distinguish the varieties and geographical origins of dried gingers from seven major production areas in China. By chemometric analysis, a distinct separation between the two varieties of ginger was achieved based on HS-GC-MS. Furthermore, flavor information extracted by fast GC e-nose realized the discrimination of geographical origins, and some potential flavor components were selected as important factors for origin certification. Moreover, several pattern recognition algorithms were compared in varietal and regional identification, and random forest (RF) led to the highest accuracies for discrimination. Overall, a rapid and precise method combining multivariate chemometrics and algorithms was developed to determine varieties and geographical origins of ginger, and it could also be applied to other agricultural products.

Dietary alfalfa powder supplementation improves growth and development, body health, and meat quality of Tibetan sheep. The application of alfalfa powder (AP) in Tibetan sheep to explore its healthy effects and meat quality improvement potential has not been reported. Our study found that AP improved the growth performance, serum metabolism, and antioxidation of Tibetan sheep. The edible quality, sensory quality, and nutritional quality of longissimus dorsi (LD) were analyzed. We observed lower drip loss and hue angle of meat after AP supplementation. AP also increased the cooked meat percentage, pH24h, a*24h, chroma24h, and the contents of protein and fat. The targeted metabolomics profiling revealed that the contents of essential amino acids and flavor amino acids in mutton increased by AP treatments. AP also promoted the deposition of MUFA and PUFA. Therefore, as a promising botanical supplement, AP has a positive effect on the growth, development, and body health of Tibetan sheep, and is also conductive to providing healthy and nutritious high-quality livestock products.

Comparison of oxidation extent, structural characteristics, and oxidation sites of myofibrillar protein affected by hydroxyl radicals and lipid-oxidizing system. To compare the differences between direct protein oxidation (PO) and lipid-derived PO, the myofibrillar protein (MP) of obscure pufferfish was oxidatively modified by the hydroxyl radical oxidizing system (HOS) and the lipid-oxidizing system (LOS). The degree of oxidation, structural characteristics, and oxidation sites in MP were assessed. The results showed there was no significant thiol loss in LOS, compared with a 77.64% loss observed in case of the HOS. The secondary structure of MP was more vulnerable to HOS, but the tertiary structure was more susceptible to LOS. The cross-linking was largely attributed to the reversible disulfide links in HOS and the irreversible covalent linkages in LOS. Six amino acids and 10 specific oxidant products were identified in HOS. Only three amino acids and three specific oxidant products were identified in LOS. These findings may help deepen the understanding regarding the mechanism underlying PO in protein- and lipid-rich food materials.

Detection of protein oxidation products by fluorescence spectroscopy and trilinear data decomposition: Proof of concept. Current analytical methods studying protein oxidation modifications require laborious sample preparation and chromatographic methods. Fluorescence spectroscopy is an alternative, as many protein oxidation products are fluorescent. However, the complexity of the signal causes misinterpretation and quantification errors if single emission spectra are used. Here, we analyzed the entire fluorescence excitation-emission matrix using the trilinear decomposition method parallel factor analysis (PARAFAC). Two sample sets were used: a calibration set based on known mixtures of tryptophan, tyrosine, and four oxidation products, and a second sample set of oxidized protein solutions containing UV-illuminated β-lactoglobulin. The PARAFAC model succeeded in resolving the signals of the model systems into the pure fluorophore components and estimating their concentrations. The estimated concentrations for the illuminated β-lactoglobulin samples were validated by liquid chromatography-mass spectrometry. Our approach is a promising tool for reliable identification and quantification of fluorescent protein oxidation products, even in a complex protein system.

Effects of manual washing with three alkaline sterilizing agent solutions on egg quality during storage. This study aimed to investigate the abundance of microorganisms and quality of eggs washed with different washings (tap water, 0.03% calcium hypochlorite solution, 0.25% hydrogen peroxide solution, or 1% sodium percarbonate solution) and unwashed for 28-day storage. The results showed that the washing significantly decreased the abundance of microorganisms in all cases. Washing with one of the three alkaline sterilizing agent solutions significantly inhibited the deterioration of egg quality (evidenced by lower weight loss, air cell depth, albumen pH, yolk pH, and total volatile base nitrogen, but higher Haugh unit and yolk index) during storage, while washing with tap water showed opposite effects. The texture profile analysis and high-resolution scanning electron microscopy observation showed that all washings had slight negative effects on eggshell quality (eggshell breaking strength and microstructure), and washing with the alkaline sterilizing agent solution had no additional effects. The results might be attractive to egg preservation industry.

Hypoxemia in the presence or absence of systemic inflammation does not increase blood lactate levels in healthy volunteers. Elevated lactate levels are a sign of critical illness and may result from insufficient oxygen delivery. We investigated whether hypoxemia and/or systemic inflammation, results in increased lactate levels in healthy volunteers. 30 healthy volunteers were exposed to either 3.5 h of hypoxemia (FiO2 ± 11.5%), normoxemic endotoxemia (FiO2 21%, administration of 2 ng/kg endotoxin), or hypoxemic endotoxemia (n = 10 per group). Blood lactate, hemoglobin, SpO2, PaO2, PaCO2, pH, and hemodynamic parameters were serially measured. Hypoxemic treatment resulted in lower SpO2 (81.7 ± 2.6 and 81.4 ± 2.4% in the hypoxemia and hypoxemic endotoxemia groups, respectively) and hyperventilation with a PaCO2 decrease of 0.8 ± 0.5 and 1.5 ± 0.6 kPa and an increase in pH. Arterial oxygen content (CaO2) decreased by 20.5 ± 2.9 and 23.5 ± 4.4%, respectively. Lactate levels were slightly, but significantly higher in both hypoxemic groups compared with the normoxemic endotoxemia group over time (p < 0.0001 for both groups), but remained below 2.3 mmol/L in all subjects. Whereas PaO2 and SpO2 did not correlate with lactate levels, PaCO2, pH and CaO2 did. Hypoxemia, in the absence or presence of inflammation does not result in relevant increases of lactate. The small increases in lactate observed are likely to be due to hyperventilation-related decreases in glycolysis.

Metarhizium: an opportunistic middleman for multitrophic lifestyles. Metarhizium spp. mediate multiple interactions that are usually positive with respect to their long-term plant environment, and negative with respect to short-lived hosts. In particular, their ability to kill a wide range of insects maximizes protection to the plants and provides a resource of nitrogen that the fungus trades with the plant for carbon. Here, we highlight emerging concepts underlying Metarhizium-plant-insect interactions. Experiments on model systems have provided detailed mechanistic knowledge of how these fungi interact with plants and insects, and a greater understanding of the evolutionary forces driving these interactions. However, further integration of studies at the ecological and mechanistic level is needed to evaluate the importance of Metarhizium's multitrophic interactions to the structuring of natural communities.

Cancer stem cells and tumor heterogeneity: Deciphering the role in tumor progression and metastasis. Tumor heterogeneity, in principle, reflects the variation among different cancer cell populations. It can be termed inter- or intra-tumoral heterogeneity, respectively, based on its occurrence in various tissues from diverse patients or within a single tumor. The intra-tumoral heterogeneity is one of the leading causes of cancer progression and treatment failure, with the cancer stem cells (CSCs) contributing immensely to the same. These niche cells, similar to normal stem cells, possess the characteristics of self-renewal and differentiation into multiple cell types. Moreover, CSCs contribute to tumor growth and surveillance by promoting recurrence, metastasis, and therapeutic resistance. Diverse factors, including intracellular signalling pathways and tumor microenvironment (TME), play a vital role in regulating these CSCs. Although a panel of markers is considered to identify the CSC pool in various cancers, further research is needed to discriminate cancer-specific CSC markers in those. CSCs have also been found to be promising therapeutic targets for cancer therapy. Several small molecules, natural compounds, antibodies, chimeric antigen receptor T (CAR-T) cells, and CAR-natural killer (CAR-NK) cells have emerged as therapeutic tools for specific targeting of CSCs. Interestingly, many of these are in clinical trials too. Despite being a much-explored avenue of research for years, and we have come to understand its nitty-gritty, there is still a tremendous gap in our knowledge concerning its precise genesis and regulation. Hence, a concrete understanding is needed to assess the CSC-TME link and how to target different cancer-specific CSCs by designing newer tools. In this review, we have summarized CSC, its causative, different pathways and factors regulating its growth, association with tumor heterogeneity, and last but not least, discussed many of the promising CSC-targeted therapies for combating cancer metastasis.

Relationship between zinc-related nutritional status and the progression of multiple sclerosis. Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. To investigate plasma and erythrocyte zinc status and its relationship to MS. Cross-sectional study, including 98 participants, distributed in groups: case (MS, n = 49), diagnosed with MS and control (n = 49), matched by age and sex with the case group. Zinc was analyzed by flame atomic absorption spectrophotometry, and superoxide dismutase (SOD) activity by spectrophotometry. Mean plasma zinc was 94.6 (22.1) μg/dL for MS patients and 81.5 (31.3) μg/dL for control group, with statistical difference (p = 0.023). The mean erythrocyte zinc was 83.6 (41.6) µg/gHb for case group and 72.6 (31.5) µg/gHb for control. Erythrocyte SOD activity was above reference values, significantly different for MS patients (p = 0.003). There was a significant direct correlation between erythrocyte zinc and SOD (r = 0.835; p < 0.001). SOD showed inverse correlation with MS outbreaks (r = -0.317; p = 0.027). Patients with MS have normal plasma and elevated erythrocyte zinc. Erythrocyte zinc showed positive correlation with SOD, which correlated inversely to outbreaks.

"You feel different in your body": Experiences of fatigue among children undergoing radiotherapy for cancer treatment. The aim of this research is to examine the experience and impact of radiotherapy related fatigue in children diagnosed with solid tumours. Children (n = 25) and parents (n = 19) participated in a semi-structured interview on the last week of radiotherapy treatment. The study sample included children who were 6 to 14 years of age, diagnosed with brain or solid tumour, and received radiotherapy as part of their treatment protocol over the period of 6 weeks. Interpretation of data was undertaken through the adoption of thematic analysis approach. Data revealed children's experience and response to fatigue while undergoing radiotherapy. Several recurring themes arose about their experience of fatigue/tiredness while undergoing radiotherapy. Two themes and eight sub themes, namely 'Experience of Fatigue' ("You feel Different in your body", Mood and Feeling, Activity and Occurrence) and 'Response to Fatigue' (Rest and Sleep, Activity, Mood and Concentration and Eating Habit) were identified. The findings illustrated significant fatigue on activity sleep, rest and mood of children undergoing radiotherapy. Monitoring and addressing fatigue and its consequences during radiotherapy treatment are essential to improve well-being of children with cancer.

Screening and characterizing flavone synthases and its application in biosynthesizing vitexin from naringenin by a one-pot enzymatic cascade. C-glycosylated flavonoids are important structural derivatives of flavonoids and have a variety of physiological activities. Flavone synthase is a key enzyme for producing C-glycosylated flavonoids. In this study, three flavone synthase genes were cloned, overexpressed and characterized in E. coli. By analyzing the enzymatic properties of the enzymes, Aethusa cynapium flavone synthase (AcFNS) was better than Apium graveolens flavone synthase (AgFNS) and Petroselinum crispum flavone synthase (PcFNS) in terms of catalytic ability, organic solvent tolerance and stability. Then, a one-pot enzymatic cascade was developed to synthesize vitexin from naringenin by using AcFNS, C-glycosyltransferase (TcCGT) from Trollius chinensis, and sucrose synthase (GmSUS) from Glycine max. The effects of enzyme ratios, substrate concentrations, cofactors, and reaction conditions on vitexin production were determined. The highest vitexin production reached 935.6 mg/L with a corresponding molar conversion of 78.7 % for (2 S)-naringenin. Thus, this is the first report of a one-pot enzymatic cascade for vitexin production from naringenin in vitro.

Efficient whole cell biotransformation of tyrosol from L-tyrosine by engineered Escherichia coli. An engineered Escherichia coli was constructed by co-expressing L-amino acid deaminase, α-keto acid decarboxylase, alcohol dehydrogenase, and glucose dehydrogenase through two plasmids for tyrosol production. The activity of the rate-limiting enzyme L-amino acid deaminase from Cosenzaea myxofaciens (CmAAD) toward tyrosine was improved by structure-guided modification. The enzyme activity of triple mutant CmAAD V438G/K147V/R151E toward tyrosine was ~5.12-fold higher than that of the wild-type CmAAD. Secondly, the plasmid copy numbers and the gene orders were optimized to improve the titer of tyrosol. Finally, the recombinant strain CS-6 transformed 10 mM tyrosine into 9.56 ± 0.64 mM tyrosol at 45 ℃, and the space-time yield reached 0.478 mM·L-1·h-1. This study proposes a novel idea for the efficient and natural production of tyrosol, which has great potential for industrial application.

Epigenetic gene alterations in metastatic solid tumours: results from the prospective precision medicine MOSCATO and MATCH-R trials. Although the role of epigenetic alterations in oncogenesis has been well studied, their prevalence in metastatic solid tumours is still poorly described. We therefore aimed at: (i) describing the presence of epigenetic gene alterations (EGA) - defined by an alteration in a gene encoding an epigenetic regulator; and (ii) evaluating their relationship with clinical characteristics and outcome in patients (pts) included in prospective molecular profiling trials. On-purpose tumour biopsies from pts with metastatic solid tumours enrolled in the Gustave Roussy-sponsored MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials were molecularly profiled using whole exome sequencing (WES). Alterations in 176 epigenetic genes were assessed and classified as pathogenic variants (PV) or non-pathogenic variants by a molecular tumour board. Clinical characteristics and outcome were collected. Between Dec 2011 and Oct 2016, WES was successfully performed in 292 pts presenting various solid tumours. We found 496 epigenetic gene alterations in 134 patients (49%), including 237 pathogenic variants in 86 patients; 63 tumour samples (47%) presented ≥3 EGAs. The median number of previous treatment lines was 3 (1-10). The most frequently altered genes were KMT2D and KMT2C (16% each), ARID1A and SETD2 (10% each) and KMT2A (8%).; 31% of EGA co-occurred with a driver gene alteration (p &amp;lt; 0.001). Outcome was not correlated with the presence of EGA. Epigenetic alterations occur frequently in metastatic solid tumours. With the current development of epigenetic modifiers, they increasingly represent actionable targets. Such genes should now be systematically analysed in molecular profiling studies.

Impact of pharmacodynamic biomarkers in immuno-oncology phase 1 clinical trials. Phase 1 immuno-oncology (IO) trials frequently involve pharmacodynamic (PD) biomarker assessments involving tumour biopsies and/or blood collection, with increasing use of molecular imaging. PD biomarkers are set to play a fundamental role in early drug development of immuno-oncology (IO) agents. In the IO era, the impact of PD biomarkers for confirmation of biologic activity and their role in subsequent drug development have not been investigated. Phase 1 studies published between January 2014 and December 2020 were reviewed. Studies that reported on-treatment PD biomarkers [tissue-derived (tissue-PD), blood-based (blood-PD) and imaging-based (imaging-PD)] were analysed. PD biomarker results and their correlation with clinical activity endpoints were evaluated. Authors' statements on the influence of PD biomarkers on further drug development decisions, and subsequent citations of PD biomarker study results were recorded. Among 386 trials, the most frequent IO agent classes evaluated were vaccines (32%) and PD-(L)1 inhibitors (25%). No PD biomarker assessments were reported in 100 trials (26%). Of the remaining 286, blood-PD, tissue-PD, and imaging-PD data were reported in 270 (94%), 94 (33%), and 12 (4%) trials, respectively. Assessments of more than one PD biomarker type were reported in 82 studies (29%). Similar proportions of blood-PD (9%), tissue-PD (7%), and imaging-PD studies (8%) had positive results that correlated with clinical activity. Results of 22 PD biomarker studies (8%) were referenced in subsequent clinical trials. Most phase 1 IO studies performed PD biomarker assessments. Overall, positive PD biomarker results were infrequently correlated with clinical activity or cited in subsequent trials, suggesting a limited impact on subsequent drug development. With emerging health regulatory emphasis on optimal dose selection based on PD activity, more informative and integrative multiplexed assays that capture the complexity of tumour-host immunity interactions are warranted to improve phase 1 IO trial methodology.

Placental dysfunction: The core mechanism for poor neurodevelopmental outcomes in the offspring of preeclampsia pregnancies. Preeclampsia (PE) is a leading condition threatening pregnant women and their offspring. The offspring of PE pregnancies have a high risk of poor neurodevelopmental outcomes and neuropsychological diseases later in life. However, the pathophysiology and pathogenesis of poor neurodevelopment remain undetermined. Abnormal placental functions are at the core of most PE cases, and recent research evidence supports that the placenta plays an important role in fetal brain development. Here, we summarize the relationship between abnormal fetal brain development and placental dysfunction in PE conditions, which include the dysfunction of nutrient and gas-waste exchange, impaired angiogenesis stimulation, abnormal neurotransmitter regulation, disrupted special protectors, and immune disorders. All these factors could lead to poor neurodevelopmental outcomes.

Placental protein 13 dilation of pregnant rat uterine vein is endothelium dependent and involves nitric oxide/calcium activated potassium channels signals. Accumulating evidence demonstrates the importance of the galectin protein Placental Protein 13 (PP13) in predicting Preeclampsia (PE), a gestational disorder that has no cure and is associated with a compromised uterine vascular adaptation to pregnancy. Uterine vasculature undergoes significant remodeling (growth in length and in circumference) during normal pregnancy to accommodate the increased blood volume to the feto-placental unit. The aim of this study was to demonstrate the role of PP13 on the uterine veins (UVs). PP13 was tested on UVs isolated from rat by using a pressurized myograph. The PP13 investigation was carried out in the presence of: a) nitric oxide synthases inhibitors (l-NAME + L-NNA, 2 x 10-4 M); b) small conductance Ca2+-activated K+ channels (SKca) inhibitor (Apamin, 10-7 M); c) intermediate conductance Ca2+-activated K+ channels (IKca) inhibitor (TRAM-34, 10-5 M); d) big conductance Ca2+-activated K+ channels (BKca) inhibitor (Paxilline, 10-5 M) and in the absence of endothelium. Our results showed that in late pregnancy, PP13 induced a significant dilation of UVs that is endothelium dependent. Further, PP13-dilation is mediated by the SKca - NO - BKca pathway. For the first time, this study provides evidence that in pregnancy, the UVs are dilated by PP13 and suggests SKCa as a potential target for treatments aimed at restoring pregnancy complication associated with deficiency in uterine adaptation.

Atypical knee jerk responses in high-risk children: A longitudinal EMG-study. We previously found that atypical responses to the knee jerk reflex, i.e., tonic responses (TRs), clonus and contralateral responses in very high-risk (VHR) infants were associated with cerebral palsy (CP) at 21 months. The current study aimed for a better understanding of pathophysiology of atypical knee jerk responses by evaluating whether infant atypical knee jerk responses are associated with CP and atypical knee jerk responses at school-age. 31 VHR-children, who had also been assessed longitudinally during infancy, and 24 typically developing children, were assessed at 7-10 years (school-age). We continuously recorded surface EMG of thigh muscles during knee jerk responses longitudinally during infancy and once at school-age. Neurological condition was assessed with age-appropriate neurological examinations. It included the diagnosis of CP at 21 months corrected age and school-age. CP's type and severity (Gross Motor Function Classification System (GMFCS)) were reported. Persistent TRs in infancy were associated with CP at school-age. TR prevalence decreased from infancy to childhood. At school-age it was no longer associated with CP. Clonus prevalence in VHR-children did not change with increasing age; it was significantly higher in children without than those with CP. Reflex irradiation was common in all school-age children, and its prevalence in contralateral muscles in VHR-children decreased between infancy and childhood. In infancy, TRs indicated an increased risk of CP, but at school-age TRs were not associated with CP. In general, spinal hyperexcitability, expressed as reflex irradiation and TRs, decreased between infancy and school-age.

Knowledge and teaching-learning methods regarding venous leg ulcers in nursing professionals and students: A scoping review. According to our scoping review questions, three aims were formulated to synthesize the evidence published on: (1) the content (2) the best or most appropriate teaching-learning methods for training nurses and undergraduate nursing students in venous leg ulcer care, and (3) to identify the level of knowledge in nurses and undergraduate nursing students about venous leg ulcer care. A venous leg ulcer can be defined as a skin lesion on the leg or foot that occurs in an area affected by ambulatory venous hypertension. Hence, nurse visits are the main driver of Venous Leg Ulcer-related healthcare costs. Optimal levels of knowledge obtained with appropriate methodologies tend to improve care. Nonetheless, the time devoted to chronic wound education in undergraduate nursing curricula has been considered insufficient and inadequate. For this scoping review, a search was performed in January 2021. To identify sources of evidence, a systematic search was conducted in MEDLINE, Embase, CINAHL, Web of Science, Scopus, Cuiden, ERIC and ScienceDirect. All types of evidence associated with knowledge, teaching and/or learning methods regarding venous leg ulcers in nursing were included. Finally, 19 documents were included. In these articles, the content mostly widely included in teaching-learning methods was compression therapy (14/19), anatomy, physiology, aetiology and/or pathophysiology (10/19) and topical treatment and care (8/19); various other topics were mentioned but less frequently. Teaching/learning methods and interventions were heterogeneous in modality, content, and duration but the majority showed better results after implementation. When looking at knowledge level, studies mainly focused on nursing staff. In general, it seems that there is a lack of knowledge and skills. Regarding our three pivotal questions: (1) There is no uniform type of content over the studies analysed and the most referred was compression therapy. (2) The educational interventions studied have demonstrated effectiveness, but there is insufficient data to determine which is the most effective. (3) This scoping review has highlighted the lack of knowledge among nurses and nursing students about venous leg ulcer care. Additionally, we felt that there is no ideal assessment tool to quantify knowledge, skills, attitude, confidence, and commitment in this context. A scoping review that synthesise the evidence on the level of knowledge and teaching-learning methods in nursing regarding of people with venous leg ulcers shows lack of knowledge and variability in programs.

Reward prediction errors, not sensory prediction errors, play a major role in model selection in human reinforcement learning. Model-based reinforcement learning enables an agent to learn in variable environments and tasks by optimizing its actions based on the predicted states and outcomes. This mechanism has also been considered in the brain. However, exactly how the brain selects an appropriate model for confronting environments has remained unclear. Here, we investigated the model selection algorithm in the human brain during a reinforcement learning task. One primary theory of model selection in the brain is based on sensory prediction errors. Here, we compared this theory with an alternative possibility of internal model selection with reward prediction errors. To compare these two theories, we devised a switching experiment from a first-order Markov decision process to a second-order Markov decision process that provides either reward- or sensory prediction error regarding environmental change. We tested two representative computational models driven by different prediction errors. One is the sensory prediction-error-driven Bayesian algorithm, which has been discussed as a representative internal model selection algorithm in the animal reinforcement learning task. The other is the reward-prediction-error-driven policy gradient algorithm. We compared the simulation results of these two computational models with human reinforcement learning behaviors. The model fitting result supports that the policy gradient algorithm is preferable to the Bayesian algorithm. This suggests that the human brain employs the reward prediction error to select an appropriate internal model in the reinforcement learning task.

Neural extraction of multiscale essential structure for network dismantling. Diverse real world systems can be abstracted as complex networks consisting of nodes and edges as functional components. Percolation theory has shown that the failure of a few of nodes could lead to the collapse of a whole network, which brings up the network dismantling problem: How to select the least number of nodes to decompose a network into disconnected components each smaller than a predefined threshold? For its NP-hardness, many heuristic approaches have been proposed to measure and rank each node according to its importance to network structural stability. However, these measures are from a uniscale viewpoint by regarding one complex network as a flatted topology. In this article, we argue that nodes' structural importance can be measured in different scales of network topologies. Built upon recent deep learning techniques, we propose a self-supervised learning based network dismantling framework (NEES), which can hierarchically merge some compact substructures to convert a network into a coarser one with fewer nodes and edges. During the merging process, we design neural models to extract essential structures and utilize self-attention mechanisms to learn nodes' importance hierarchy in each scale. Experiments on real world networks and synthetic model networks show that the proposed NEES outperforms the state-of-the-art schemes in most cases in terms of removing the least number of target nodes to dismantle a network. The dismantling effectiveness of our neural extraction framework also highlights the emerging role of multi-scale essential structures.

Aqueous aggregation and deposition kinetics of fresh and carboxyl-modified nanoplastics in the presence of divalent heavy metals. The presence of heavy metals alters the colloidal stability and deposition of nanoplastics (NPs) in urban waters. Such processes are important to assess the mobility and fate of NPs and their associated heavy metals. Up to date, few studies have reported the impact of heavy metals on the colloidal behaviors of NPs and the involved mechanisms. In the study, time-resolved dynamic light scattering (DLS) and quartz crystal microbalance with dissipation (QCM-D) methods were used to assess the aggregation and deposition kinetics of polystyrene nanospheres with divalent heavy metals. For comparison, carboxyl-modified polystyrene nanospheres were used. Results reveal that heavy metals destabilized NPs more significantly than calcium ions. Spectroscopy and transmission electron microscopy analysis propose that heavy metals destabilized NPs via inner-sphere coordination with carboxyl groups and cation-π interactions, further leading to the formation of different dimensional aggregates. QCM-D results suggest that the deposition rate, irreversibility, and film compactness of NPs on silica surfaces first increased but further decreased as heavy metal concentration increased. Such deposition behaviors depended on the bridging effects between NPs and silica and aggregation-induced diffusion limitation. In that case, the destabilization and retention ability of heavy metals for NPs were related to their electronegativity and hydration shell thickness. In urban waters, the presence of natural organic matter (NOM) decreased the destabilization and retention ability of heavy metals, whereas heavy metals with environmentally relevant concentrations still enhanced the aggregation and deposition of NPs compared with other environmental cations. This study highlights the impact of heavy metal property on the colloidal behaviors of NPs, thus deepening our understanding of the mobility and fate of NPs associated with heavy metals in urban waters.

Recovery targets and timescales for Lough Neagh and other lakes. The framework, model and methods of Nürnberg were applied and evaluated in Lough Neagh and 19 other lakes in order to establish inflow phosphorus concentrations that support target lake values. Supporting concentrations, in the absence of an internal load, were derived and the effect of uncertainty in the model retention coefficient was relatively small, ±11-20 % in Lough Neagh and an average (n = 17) of ±9.7 % in the other lakes. There was further support for the model and methods from an independent estimate of the net internal load in Lough Neagh (13 % difference) and from another model in the other lakes (Supporting concentrations, which should be lower, were by an average of 11 mg P m-3). In the framework, steady state with the phosphorus load is assumed, but, based on a generic lake model, is not likely if the hydraulic residence time>0.5-0.8 yr and should lead to a decrease in phosphorus retention, which was found during three periods in Lough Neagh. Based on a compilation of internal load recovery times from 23 lakes in the literature, it could take between 8 and 20 years for lakes with an internal load to approach their targets.

Influence of chemical structure of organic micropollutants on the degradability with ozonation. The increasing environmental problems due to various organic micropollutants in water cause the search of suitable additional water treatment methods. Gaining experimental data for the large amount and variety of pollutants would consume a lot of time as well as economic and ecologic resources. An alternative approach is predictive quantitative structure-property relationship (QSPR) modeling, which establishes a correlation between the structural properties of a molecules with a biological, physical, or chemical property. Therefore, in this study, QSPR modeling has been conducted using extensive validation techniques and statistical test to investigate the structural influence on the degradability of organic micropollutants with ozonation. In contrast to most of the other studies, the underlying dataset - rate constants for 92 organic molecules - were obtained under standardized conditions with defined experimental parameters. QSPR modeling was executed using a combination of the software PaDEL for descriptor calculation and QSARINS for the modeling process respecting all five OECD-requirements for applicable QSAR/QSPR-models. The final model was selected using a multi-criteria decision-making tool to evaluate the model quality based on all calculated statistical quality parameters. The model included 10 selected descriptors and fingerprints and showed good regression abilities, predictive power, and stability (R² = 0.8221, CCCtr = 0.9024, Q²loo = 0.7436, R²ext = 0.8420, Q²F1 = 0.8104). The applicability domain of the QSPR model was defined and an interpretation of selected model descriptors has been connected to previous experimental studies. A significant influence of the interpretable descriptors was put into experimental context and compared with previous studies and models. For example, the molar refractivity as a measure of size and polarizability of a molecule and the occurrence of important substructures such as a formamide group seem to decrease the removal rate constant. The contribution of lone electrons entering into resonance as well as the occurrence of fused rings were identified as influences for the increase of the degradability of micropollutants by ozonation.

Unveiling the positive effect of mineral induced natural organic matter (NOM) on catalyst properties and catalytic dechlorination performance: An experiment and DFT study. Herein, we report the significant effects of natural organic matter contained in natural zeolite (Z-NOM) on the physicochemical characteristics of a Ni/Fe@natural zeolite (NF@NZ) catalyst and its decontamination performance toward the dechlorination of trichloroethylene (TCE). Z-NOM predominantly consists of humic-like substances and has demonstrable utility in the synthesis of bimetallic catalysts. Compared to NF@NZ600C (devoid of Z-NOM), NF@NZ had increased dispersibility and mobility and showed significant enhancement in the catalytic dechlorination of TCE owing to the encapsulation of Ni0/Fe0 nanoparticles by Z-NOM. The results of corrosion experiments, spectroscopic analyses, and H2 production experiments confirmed that Ni0 acted as an efficient cocatalyst with Fe0 to enhance the dechlorination of TCE to ethane, and Z-NOM-capped Ni0 showed improved adsorption of TCE and atomic hydrogen on their reactive sites and oxidation resistance. The density functional theory (DFT) studies have substantiated the improved adsorption of TCE due to the presence of NOM (especially by COOH structure) and the enhanced charge density at the Ni site in the Ni/Fe bimetal alloy for the stronger adsorption of hydrogen atoms that ultimately enhanced the TCE reduction reaction. These findings illustrate the efficiency of NOM containing natural minerals toward the synthesis of bimetallic catalysts for practical applications.

Development of a human iPSC line (SMBCi017-A) from a healthy donor. The human induced pluripotent stem cell (iPSC) line SMBCi017-A was derived from urine cells of a 20 year old male healthy control donor. The generated iPSCs had normal karyotype, expressed chromosomal stability pluripotency hallmarks and differentiated into the three primary germ layers.

Photochemical reactions of dissolved organic matter and bromide ions facilitate abiotic formation of manganese oxide solids. Manganese (Mn) oxide solids are ubiquitous in nature, acting as both electron donors and acceptors in diverse redox reactions in the environment. Reactions of Mn(III/IV) oxides with dissolved natural organic matter (DOM) are commonly described as reductive dissolutions that generate Mn2+(aq). In this study, we investigated the role of photochemical reactions of DOM in Mn2+(aq) oxidation and the resulting formation of Mn oxide solids. During the photolysis of DOM, reactive intermediates can be generated, including excited triplet state DOM (3DOM*), hydroxyl radicals (•OH), superoxide radicals (O2•-), hydrogen peroxide, and singlet oxygen. Among these, we found that O2•- radicals were mainly responsible for Mn oxidation. The solution pH controlled the formation of Mn oxide solids by affecting both Mn2+ oxidation by O2•- during photolysis of DOM and reductive dissolutions of Mn oxide solids by DOM. Further, with the addition of bromide ions (Br-), reactions between 3DOM* and Br-, together with reactions between •OH and Br-, can form reactive bromide radicals. The formed Br radicals also promoted Mn oxide formation. In DOM with more aromatic functional groups, more Mn2+ was oxidized to Mn oxide solids. This enhanced oxidation could be the result of promoted pathways from charge-transfer state DOM (DOM•+/•-) to O2•-. These new observations advance our understanding of natural Mn2+ oxidation and Mn(III/IV) oxide formation and highlight the underappreciated oxidative roles of DOM in the oxidation of metal ions in surface water illuminated by sunlight.

A critical review on induced totipotent stem cells: Types and methods. Totipotent stem cells are cells with the capacity to form an entire embryo. Many attempts have been made to convert other types of cells to totipotent stem cells which we called induced totipotent stem cells. Various aspects of these cells such as transcriptional and epigenetics networks are unique. By taking advantage of these aspects, efficient methods have been provided to induce totipotent stem cells. Although this advancement is significant, many aspects of induction such as the underlying mechanism remain to be elucidated. On the other hand, embryonic stem cells usually are the source of induction which raise important questions regarding if these methods are induction or promotion of 2C intrinsic totipotent cells in ESC culture. Here, we review the latest mouse progress in underling mechanism of induction of totipotent stem cells. In addition, we follow up on the progress of Blastoids derived from totipotent stem cells.

Generation of induced pluripotent stem cell line, ICGi033-A, by reprogramming peripheral blood mononuclear cells from a patient with Huntington's disease. Huntington's disease (HD) is a hereditary autosomal dominant neurodegenerative disease caused by the polyglutamine stretch expansion in the huntingtin (HTT) protein. In HD, dysregulation of multiple cellular processes occurs, resulting in the death of medium spiny neurons of striatum. A line of induced pluripotent stem cells (iPSCs) ICGi033-A was obtained from peripheral blood mononuclear cells of a patient carrying 77 CAG repeats in the HTT gene. The iPSCs express pluripotency markers, have a normal karyotype, and differentiate into three germ layers: endoderm, ectoderm, mesoderm.

The antibacterials ciprofloxacin, trimethoprim and sulfadiazine modulate gene expression, biomarkers and metabolites associated with stress and growth in gilthead sea bream (Sparus aurata). The high consumption and subsequent input of antibacterial compounds in marine ecosystems has become a worldwide problem. Their continuous presence in these ecosystems allows a direct interaction with aquatic organisms and can cause negative effects over time. The objective of the present study was to evaluate the effects of exposure to three antibacterial compounds of high consumption and presence in marine ecosystems (Ciprofloxacin CIP, Sulfadiazine SULF and Trimethoprim TRIM) on the physiology of the gilthead sea bream, Sparus aurata. Plasma parameters, enzymatic biomarkers of oxidative stress and damage and expression of genes related to stress and growth were assessed in exposed S. aurata specimens. For this purpose, sea bream specimens were exposed to individual compounds at concentrations of 5.2 ± 2.1 μg L-1 for CIP, 3.8 ± 2.7 μg L-1 for SULF and 25.7 ± 10.8 μg L-1 for TRIM during 21 days. Exposure to CIP up-regulated transcription of genes associated with the hypothalamic-pituitary-thyroid (HPT) (thyrotropin-releasing hormone, trh) and hypothalamic-pituitary-interrenal (HPI) axes (corticotropin-releasing hormone-binding protein, crhbp) in the brain, as well as altering several hepatic stress biomarkers (catalase, CAT; glutathione reductase, GR; and lipid peroxidation, LPO). Similar alterations at the hepatic level were observed after exposure to TRIM. Overall, our study indicates that S. aurata is vulnerable to environmentally relevant concentrations of CIP and TRIM and that their exposure could lead to a stress situation, altering the activity of antioxidant defense mechanisms as well as the activity of HPT and HPI axes.

Genetic overlap between dystonia and other neurologic disorders: A study of 1,100 exomes. Although shared genetic factors have been previously reported between dystonia and other neurologic conditions, no sequencing study exploring such links is available. In a large dystonic cohort, we aimed at analyzing the proportions of causative variants in genes associated with disease categories other than dystonia. Gene findings related to whole-exome sequencing-derived diagnoses in 1100 dystonia index cases were compared with expert-curated molecular testing panels for ataxia, parkinsonism, spastic paraplegia, neuropathy, epilepsy, and intellectual disability. Among 220 diagnosed patients, 21% had variants in ataxia-linked genes; 15% in parkinsonism-linked genes; 15% in spastic-paraplegia-linked genes; 12% in neuropathy-linked genes; 32% in epilepsy-linked genes; and 65% in intellectual-disability-linked genes. Most diagnosed presentations (80%) were related to genes listed in ≥1 studied panel; 71% of the involved loci were found in the non-dystonia panels but not in an expert-curated gene list for dystonia. Our study indicates a convergence in the genetics of dystonia and other neurologic phenotypes, informing diagnostic evaluation strategies and pathophysiological considerations.

Olaparib as maintenance treatment in patients with chemosensitive small cell lung cancer (STOMP): A randomised, double-blind, placebo-controlled phase II trial. Small cell lung cancer (SCLC) responds well to chemoradiotherapy but frequently relapses. Here, we evaluate activity and safety of the poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitor olaparib as maintenance treatment for patients with chemoresponsive SCLC. Eligible patients had complete or partial response to first line chemotherapy or chemoradiotherapy for SCLC. Patients were randomised 2:2:1:1 to olaparib 300 mg twice a day (BD), olaparib 200 mg three times a day (TDS), placebo BD or placebo TDS. The primary outcome was progression-free survival time (PFS). The trial design had 80% power to detect a 3-month difference in median PFS based on a one-sided 5% significance level. Secondary outcome measures included overall survival time (OS), adverse events and quality of life. ISRCTN 73164486, EudraCT 2010-021165-76. 220 patients were randomised: 74 placebo, 73 olaparib BD, 73 olaparib TDS. Median PFS (90% confidence interval (CI)) was 2·5 (1·8, 3·7), 3·7 (3·1, 4·6) and 3·6 (2·8, 4·7) months in the placebo, olaparib BD and TDS arms, respectively. There was no significant difference in PFS between olaparib and placebo for either BD (Hazard Ratio (HR) (90%CI) 0·76 (0·57, 1·02), P = 0·125 or TDS 0·86, (0·64, 1·15), P = 0·402. Common adverse events on olaparib were fatigue, nausea, anaemia, vomiting and anorexia. Of 214 patients who discontinued treatment before 24 months, toxicity was the reason cited for 66 (18 placebo, 24 olaparib BD, 24 olaparib TDS). This trial does not provide sufficient evidence that either the BD or TDS regimen for maintenance olaparib monotherapy improves PFS or OS in an unselected SCLC population to warrant further research. Toxicity for olaparib was similar to other studies.

Association of inflammatory bowel disease with suicidal ideation, suicide attempts, and suicide: A systematic review and meta-analysis. Inflammatory bowel disease (IBD) is associated with psychiatric comorbidities. However, the association between IBD and suicidal ideation or suicide attempts has not been well established. This study aimed to perform a systematic review and meta-analysis to elucidate the relationship between IBD and suicidal ideation, suicide attempts, and suicide. We systematically searched five electronic databases - PubMed, Embase, CENTRAL, Web of Science, and PsycINFO - from their inception to January 28, 2022. Quality assessment, data synthesis, subgroup analyses, sensitivity analyses, and publication bias assessment were performed on the included studies. We identified 28 studies with 1,047,755 patients with IBD. The pooled prevalence of suicidal ideation in patients with IBD was 17.3% (95% CI, 9.5%-25.2%). Patients with IBD were associated with an increased risk of suicide attempts (relative risk [RR], 1.39; 95% CI, 1.08-1.79) and suicide deaths (RR, 1.25; 95% CI, 1.09-1.43) than the controls without IBD. Patients with Crohn's disease subtypes, female IBD, pediatric-onset IBD, young adult IBD, and short-duration IBD had a particularly high risk for suicide. Patients with IBD had a high prevalence of suicidal ideation and a significantly higher likelihood of suicide attempts and suicide. Caring for patients with IBD, including their mental health needs, may require concerted efforts among gastroenterologists and other healthcare providers.

Pseudo-template molecularly imprinted polymeric fiber solid-phase microextraction coupled to gas chromatography for ultrasensitive determination of 2,4,6-trihalophenol disinfection by-products. 2,4,6-trihalorophenol disinfection by-products (DBPs) have strong toxicity to be needed for monitoring. In this study, two kind of molecularly imprinted polymeric fibers were prepared using 2,4,6-trichlorophenol as template and tricuronic phloroglucinol (MOP) as pseudo-template, respectively. The two fibers were assembled as solid phase microextraction (SPME) fiber to extract 2,4,6-trihalophenol DBPs from water and detect them by gas chromatography coupled to electron capture detector (GC-ECD). The results of F-test and t-test stated that there are significant difference in the analytical results of 2,4,6-trichlorophenol between using the fiber based on 2, 4, 6-trichlorophenol as template and MOP as pseudo-template. It was found that the carry-over of template (2,4,6-trichlorophenol) leaked from the fiber in GC thermal desorption, resulting in the wrong quantitative analytical result for 2,4,6-trichlorophenol in water. Hence, molecularly imprinted polymeric fibers based on MOP as pseudo-template was applied for the determination of 2,4,6-trihalophenol DBPs in water combined with GC-ECD. The selectivity of the fiber for 2,4,6-trihalophenol DBPs was investigated and demonstrated. Under the optimized condition, the method has much lower limit of detection (0.5-1.1 pg mL-1) than most reported methods. The method was applied for the determination of 2,4,6-trihalophenol DBPs in environmental water and the relative recoveries were found to be in the range from 77.1% to 105.6% and the relative standard deviation was 0.5-9.4%. 2,4,6-tribromophenol was found at concentration of 0.054 ng mL-1 in a swimming pool.

Synthesis of carbon dots-based covalent organic nanomaterial as stationary phase for open tubular capillary electrochromatography. The transformation of zero-dimensional carbon dots (CDs) to cross-linked nanomaterials is rare. In this work, a novel carbon dots-based covalent organic nanomaterial (CON CDs-TAPB) consisted of 1,3,5-tris(4-aminophenyl)-benzene (TAPB) and carbon dots (CDs) through facile Schiff-base reaction was synthesized and then employed as a stationary phase for open-tubular capillary electrochromatography (OT-CEC). The CON CDs-TAPB and the CDs-TAPB coated column were characterized through Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), UV-spectra experiments and X-ray photoelectron spectroscopy (XPS). Thanks to CON CDs-TAPB unique structure and abundant accessibility and interaction sites, the prepared column exhibited a satisfactory separation ability towards analytes including parabens, phenolic compounds. Among all analytes, the highest column efficiency was over 1.6 × 105 plates·m-1. In addition, affording methylbenzene loading capacity of 156.9 pmole, surpassing most of those materials-based OT-CEC reported thus far. Thus, the prepared carbon dots-based covalent organic nanomaterial (CON CDs-TAPB) gave a potential as a stationary phase in the separation science.

Sensitive determination of auxins in environmental water and peach beverage by hyper crosslinked polymer-based solid-phase extraction with high performance liquid chromatography-fluorescence detection. As plant regulators, auxins can promote plant growth. However, they have toxicity and may cause harm to humans. Due to their low concentrations in food sample matrices, the enrichment and analysis of trace auxins in food samples is a challenging work. In this work, a series of hyper crosslinked polymers (HCPs) were synthesized by Friedel-Crafts acylation to extract four auxins (indole-3-acetic acid, indole-3-propionic acid, indole-3-butyric acid and 1-naphthylacetic acid). Among these HCPs, the QP-TC-HCP, synthesized from p-quaterphenyl (QP) and terephthaloyl chloride (TC), showed the best adsorption performance for the auxins. It was then applied as the adsorbent for the solid-phase extraction of the auxins from environmental water and peach beverage samples, followed by high performance liquid chromatography-fluorescence detection. Under the optimized conditions, the limits of detection were 3.0-12.0 pg mL-1 for environmental water and 18.0-36.0 pg mL-1 for peach beverage sample. The method recoveries of the auxins for the spiked samples were in the range of 85.0-110.0%. The established method provided an alternative approach for the determination of auxins in food samples. In addition, different types of organic compounds were tested for the extraction by the QP-TC-HCP to assess its application potential and adsorption mechanism. It was concluded that the QP-TC-HCP had better extraction performance for the compounds with certain hydrophilicity and more hydrogen bonding sites.

CC chemokine receptor 5 antagonist alleviates inflammation by regulating IFN-γ/IL-10 and STAT4/Smad3 signaling in a mouse model of autoimmune encephalomyelitis. Multiple sclerosis (MS) is an immunopathological disease that causes demyelination and recurrent episodes of T cell-mediated immune attack in the central nervous system. Experimental autoimmune encephalomyelitis (EAE) is a well-established mouse model of MS. The roles of T cells in MS/EAE have been well investigated, but little is known about the role of CCR5+ cells. In the present study, we investigated whether treatment with DAPTA, a selective CCR5 antagonist, could modulate the progression of EAE in the SJL/J mice. EAE mice were treated with DAPTA (0.01 mg/kg) intraperitoneally daily from day 14 to day 42, and the clinical scores were evaluated. We further investigated the effects of DAPTA on IFN-γ-, TGF-β-, IL-10-, IL-17A-, IL-22-, T-bet, STAT4-, RORγT-, AhR-, Smad3-, and Foxp3-expressing CCR5+ spleen cells using flow cytometry analysis. We further explored the effects of DAPTA on mRNA/protein expression of IFN-γ, IL-10, IL-17A, IL-22, TGF-β, T-bet, STAT4, RORγT, AhR, Foxp3, and NF-H in the brain tissue. The severity of clinical scores decreased in DAPTA-treated EAE mice as compared to that in the EAE control mice. Moreover, the percentage of CCR5+IFN-γ+, CCR5+T-bet+, CCR5+STAT4+, CCR5+IL-17A+, CCR5+RORγt+, CCR5+IL-22+, and CCR5+AhR+ cells decreased while CCR5+TGF-β+, CCR5+IL-10+, CCR5+Smad3+, and CCR5+Foxp3+ increased in DAPTA-treated EAE mice. Furthermore, DAPTA treatment significantly mitigated the EAE-induced expression of T-bet, STAT4, IL-17A, RORγT, IL-22, and AhR but upregulated Foxp3, IL-10, and NF-H expression in the brain tissue. Taken together, our data demonstrated that DAPTA could ameliorate EAE progression through the downregulation of the inflammation-related cytokines and transcription factors signaling, which may be useful for the clinical therapy of MS.

Diffusion coefficients of an extensive set of pharmaceutical compounds in supercritical fluid chromatography over a wide range of mobile phase compositions. Diffusion data are essential for adequate analysis of the kinetic separation performance of any chromatographic system. Unfortunately, for Supercritical Fluid Chromatography (SFC), very little data is available of the diffusion coefficients in mobile phases typically used in contemporary methods, i.e. with a non-negligible amount of polar modifier such as methanol. In this work, a relative simple method which only requires minor modifications to a standard commercially available SFC instrument is used to determine the diffusion coefficient of an extensive set of pharmaceutical compounds in the range of 10-50 vol% of modifier (methanol) in CO2. By using a traditional SFC column, the solute is first separated from the sample solvent plug, before entering a long capillary, where the band broadening can be linked to its diffusion coefficient using the Taylor-Aris equation. By using two UV-detectors, before and after the capillary, the effect of the dispersion in the column can be eliminated and the true volumetric flow rate determined. It was found that in the investigated range of conditions, the change in mobile phase viscosity in a first approximation allows to predict the variation in diffusion coefficient. Chemical structure and more particularly functional groups can however have a significant effect on the diffusion coefficient.

Development of magnetic molecularly imprinted solid-phase extraction and ultra-high performance liquid chromatography tandem mass spectrometry for rapid and selective determination of urinary diphenyl phosphate of college students. Organophosphate esters (OPEs), known as novel alternative flame retardants, are a class of environmental endocrine disruptors. Long-term exposure to OPEs may bring a non-negligible health risk to human. Urinary OPE metabolites (mOPEs) are generally used as biomarkers to evaluate the internal exposure to OPEs. Diphenyl phosphate (DPHP), the main metabolite of aryl-OPEs, exhibited high detection rates and concentrations in urine samples. To establish a selective and simple analytical method for biomonitoring urinary DPHP, a specific magnetic molecular imprinted polymer (MMIP) was fabricated via a sol-gel method. Under optimum magnetic solid-phase extraction (MSPE) conditions, the resultant MMIP exhibited selective recognition ability, ideal adsorption capacity and good reusability on urinary DPHP enrichment. The developed MSPE method coupled with ultra-high performance liquid chromatography tandem mass spectrometry (U-HPLC-MS/MS) exhibited good precision and accuracy (spiked recoveries of 85.8%-109% with relative standard deviations (RSDs) ranged from 5.1%-13%), low detection limit of 0.035 ng/mL, and negligible matrix inhibition. Then we used this proposed method to detect urinary DPHP levels of recruited 30 college students and investigate the time variability and potential determinants. All urine samples revealed the presence of DPHP at a median concentration of 0.56 μg/g Creatinine (Cr). Moderate reproducibility of DPHP level was observed in first morning urine samples (ICC>0.40). Significant correlations were found between urinary DPHP levels and gender (β=0.72; 95% CI: 0.48∼0.96), sampling time (β=0.36; 95% CI: 0.08∼0.65) as well as the frequency for take-out food (β=0.45; 95% CI: 0.07∼0.74) (p< 0.05). Hence, a fast and sensitive MSPE-U-HPLC-MS/MS method was successfully built to quantify urinary DPHP.

Skill-mix change and outcomes in primary care: Longitudinal analysis of general practices in England 2015-2019. Increasing the employment of staff with new clinical roles in primary care has been proposed as a solution to the shortages of GPs and nurses. However, evidence of the impacts this has on practice outcomes is limited. We examine how outcomes changed following changes in skill-mix in general practices in England. We obtained annual data on staff in 6,296 English general practices between 2015 and 2019 and grouped professionals into four categories: GPs, Nurses, Health Professionals, and Healthcare Associate Professionals. We linked 10 indicators of quality of care covering the dimensions of accessibility, clinical effectiveness, user experiences and health system costs. We used both fixed-effect and first-differences regressions to model changes in staff composition and outcomes, adjusting for practice and population factors. Employment increased over time for all four staff groups, with largest increases for Healthcare Professionals (from 0.04 FTE per practice in 2015 to 0.28 in 2019) and smallest for Nurses who experienced a 3.5 percent growth. Increases in numbers of GPs and Nurses were positively associated with changes in practice activity and outcomes. The introduction of new roles was negatively associated with patient satisfaction: a one FTE increase in Health Professionals was associated with decreases of 0.126 [-0.175, -0.078] and 0.116 [-0.161, -0.071] standard deviations in overall patient satisfaction and satisfaction with making an appointment. Pharmacists improved medicine prescribing outcomes. All staff categories were associated with higher health system costs. There was little evidence of direct complementarity or substitution between different staff groups. Introduction of new roles to support GPs does not have straightforward effects on quality or patient satisfaction. Problems can arise from the complex adaptation required to adjust practice organisation and from the novelty of these roles to patients. These findings suggest caution over the implementation of policies encouraging more employment of different professionals in primary care.

A combined cowhide/gelatine soft tissue simulant for ballistic studies. The ballistic resistance of a combined soft tissue simulant was studied, consisting of gelatine as a simulant for human muscle tissue and tanned cowhide (leather) as a simulant for human skin. The simulant was manufactured by applying cowhide to liquid ballistic gelatine, as the gelatine solidified in its mould. Combining a skin and muscle tissue simulant in this adhered way opens the possibility to produce purpose-built proxies for human body parts in ballistic studies or for forensic shooting incident reconstructions. Ballistic resistance of adhered cowhide - (bonded) to solidifying ballistic gelatine - was compared to that of the same material applied on gelatine blocks in loose condition. Ballistic resistance of tanned cowhide was found to be more consistent in adhered condition. This enhanced consistency is a benefit, increasing reproducibility of results in ballistic studies. Additionally, two ways to assess ballistic resistance of a skin simulant were described and compared. Logistic regression, from a number of measured velocities and associated (non)perforations is recommended for testing ballistic resistance.

Dantrolene reduces platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell proliferation and neointimal formation following vascular injury in mice. Dantrolene is a ryanodine receptor blocker that is used clinically for treatment of malignant hyperthermia. This study was conducted using murine aortic vascular smooth muscle cells (MOVAS) and a mouse arterial injury model to investigate the inhibitory effect of dantrolene on smooth muscle cell proliferation and migration. We investigated whether dantrolene suppressed platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell proliferation and migration in vitro. The effect of dantrolene on smooth muscle phenotype was evaluated using immunostaining. In addition, smooth muscle cell proliferation and phenotype switching were tested by applying dantrolene around blood vessels using a mouse arterial injury model. Dantrolene inhibited PDGF-induced cell proliferation and migration of MOVAS. Dantrolene also inhibited the switch from contractile to synthetic phenotype both in vitro and in vivo. Dantrolene is effective at inhibiting vascular smooth muscle cell proliferation, migration, and neointimal formation following arterial injury in mice.

Identification and structural analysis of a selective tropomyosin receptor kinase C (TRKC) inhibitor. Tropomyosin receptor kinases (TRKs) are a family of TRKA, TRKB and TRKC isoforms. It has been widely reported that TRKs are implicated in a variety of tumors with several Pan-TRK inhibitors currently being used or evaluated in clinical treatment. However, off-target adverse events frequently occur in the clinical use of Pan-TRK inhibitors, which result in poor patient compliance, even drug discontinuation. Although a subtype-selectivity TRK inhibitor may avert the potential off-target adverse events and can act as a more powerful tool compound in the biochemical studies on TRKs, the high sequence similarities of TRKs hinder the development of subtype-selectivity TRK inhibitors. For example, no selective TRKC inhibitor has been reported. Herein, a selective TRKC inhibitor (L13) was disclosed, with potent TRKC inhibitory activity and 107.5-/34.9-fold selectivity over TRKA/B (IC50 TRKA/B/C = 1400 nM, 454 nM, 13 nM, respectively). Extensive molecular dynamics simulations illustrated that key interactions of L13 with the residues and diversely conserved water molecules in the ribose regions of different TRKs may be the structural basis of selectivity. This will provide inspiring insights into the development of subtype-selectivity TRK inhibitors. Moreover, L13 could serve as a tool compound to investigate the distinct biological functions of TRKC and a starting point for further research on drugs specifically targeting TRKC.

Synthesis of antiplasmodial 2-aminothieno[3,2-d]pyrimidin-4(3H)-one analogues using the scaffold hopping strategy. Gamhepathiopine (also known as M1), is a multi-stage acting antiplasmodial 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hydrochloride that was first described in 2015. The development of this compound is limited by poor microsomal stability, insufficient aqueous solubility and low intestinal permeability. In order to obtain new optimized derivatives, we conducted a scaffold hopping strategy from compound M1, resulting in the synthesis of 20 new compounds belonging to six chemical series. All the compounds were tested on the K1 multi-resistant strain of Plasmodium falciparum and the human HepG2 cell-line, to evaluate their antiplasmodial activity and their cytotoxicity. Analogues' biological results also highlighted the mandatory presence of a heteroatom at position 5 of the thieno[3,2-d]pyrimidin-4(3H)-one moeity for the antiplasmodial activity. However, modifications at position 7 were detrimental for the antiplasmodial activity. We identified furane bioisostere 3j as a promising candidate, showing good blood stage antiplasmodial activity, better water solubility and highly improved intestinal permeability in the PAMPA assay.

Exploring the druggability of oxidized low-density lipoprotein (ox-LDL) receptor, LOX-1, a proatherogenic drug target involved in atherosclerosis. Lectin-like oxidized low-density lipoprotein (ox-LDL) receptor 1 (LOX-1) is a vital scavenger receptor involved in ox-LDL binding, internalization, and subsequent proatherogenic signaling leading to cellular dysfunction and atherosclerotic plaque formation. Existing data suggest that modulation of ox-LDL - LOX-1 interaction can prevent or slow down atherosclerosis. Therefore, we utilized computational methods such as multi-solvent simulation and characterized two top-ranked druggable sites. Using systematic molecular docking followed by atomistic molecular dynamics simulation, we have identified and shortlisted small molecules from the NCI library that target two key binding sites. We demonstrate, using surface plasmon resonance (SPR), that four of the shortlisted molecules bind one-on-one to the purified C-terminal domain (CTLD) of LOX-1 receptor with high affinity (KD), ranging from 4.9 nM to 20.1 μM. Further, we performed WaterMap analysis to understand the role of individual water molecules in small molecule binding and the LOX-1-ligand complex stability. Our data clearly show that LOX-1 is druggable with small molecules. Our study provides strategies to identify novel inhibitors to attenuate ox-LDL - LOX-1 interaction.

A prospective study of serum amyloid A in relation to plasma administration in neonatal foals. SAA is a commonly used biomarker for measuring acute inflammation in equine practice, and the administration of prophylactic plasma to foals is a routine practice in large breeding farms. Despite this, limited information is available on the values of SAA in healthy or sick neonatal foals following this common procedure. A prospective study was conducted with 31 foals from a veterinary hospital in Texas in one year. Enrolled foals were part of a foaling program, where a prophylactic hyperimmunized plasma was administered 12 h after birth. Blood was collected for SAA measurements at birth and at 12 h (pre-plasma), 13 h (post-plasma), 24 h, 48 h, 72 h, and 96 h. Eight of the foals were clinically ill prior to plasma administration, and 23 foals were clinically normal. The mean SAA of all foals at birth was 1 μg/mL, increased to 11 μg/mL at 12 h (pre-plasma), and at 13 h (post-plasma) was 155 μg/mL. At 13 h, 65% of normal foals and 63% of sick foals had an SAA value >100 μg/mL. Transient but substantial increases in SAA following prophylactic plasma administration were frequently observed in this study. Veterinarians evaluating neonatal foals for clinical disease in the field should be cognizant of the timing of blood sampling in relation to plasma administration.

Photo-enhanced upcycling H2O2 into hydroxyl radicals by IR780-embedded Fe3O4@MIL-100 for intense nanocatalytic tumor therapy. Reactive oxygen species (ROS)-based nanocatalytic tumor therapy is alluring owing to the capability to generate highly cytotoxic ∙OH radicals from tumoral H2O2. However, the antitumor efficacy is highly dependent on the radical generation efficiency and challenged by the high levels of antioxidative glutathione (GSH) in cancer cells. Herein, we report an IR-780 decorated, GSH-depleting Fe3O4@MIL-100 (IFM) nanocomposite for photo-enhanced tumor catalytic therapy by extensive production of ∙OH, which is realized by an integration of excellent peroxidase-like activity of IFM, selective upregulation of tumoral H2O2 by β-lapachone, and localized hyperthermia by near infrared light irradiation. IFM shows potentiated antiproliferative effect in 4T1 cancer cells by ∙OH overproduction and glutathione scavenging, inducing intracellular redox dyshomeostasis and cell death by concurrent apoptosis and ferroptosis. In vivo antitumor investigation further demonstrates photoacoustic and fluorescence imaging-guided combinational therapy with a tumor inhibition rate of 96.4%. This study provides a strategy of photo-enhanced nanocatalytic tumor therapy by tumor-specific H2O2 amplification and hyperthermia.

A photoactivatable theranostic probe for simultaneous oxidative stress-triggered multi-color cellular imaging and photodynamic therapy. Simultaneous in situ monitoring critical organelles upon oxidative stress and implementing therapeutics utilizing oxidative stress are of vital importance and remain challenging task. Herein, we rationally design and facilely synthesized a photoactivatable fluorescent probe bearing 1,4-dihydropyridine moiety with aggregation-induced emission (AIE) tendency, namely TPA-DHPy, which can rapidly transform into its pyridine counterpart TPA-Py via photo-oxidative dehydrogenation showing strong polarity sensitivity and largely red-shifted emission. TPA-DHPy- and TPA-Py-based type I/type II photosensitization is able to effectively generate reactive oxygen species to induce in situ oxidative stress under white light irradiation. TPA-DHPy can be taken up by cancer cells, and gradually light up lipid droplets (LDs) and endoplasmic reticulum (ER) during photoactivatable process, as well as in situ monitoring difference and alteration of their microenvironment upon oxidative stress by means of multi-color fluorescence imaging in lambda mode. Furthermore, the in situ generated TPA-Py is capable of further destroying the functions of LDs and ER with prolonging the irradiation time, and remarkably inhibiting tumor growth under white light irradiation by the way of photodynamic therapy. This study thus offers useful insights into designing a new generation of theranostic agents towards imaging-guided precise cancer therapy.

Design, synthesis and activity evaluation of isopropylsulfonyl-substituted 2,4- diarylaminopyrimidine derivatives as FAK inhibitors for the potential treatment of pancreatic cancer. A series of isopropylsulfonyl-substituted 2,4-diarylaminopyrimidine derivatives were designed and synthesized as FAK inhibitors to evaluate their biological activity against pancreatic cancer. One of the most promising compound, 9h, effectively interfered with FAK-mediated phosphorylation and suppressed the proliferation of human pancreatic cancer AsPC-1 cells with half maximal inhibitory concentration (IC50) values of 0.1165 nM and 0.1596 μM, respectively. In addition, 9h also exhibited relatively low toxicity against immortalized normal human liver L-02 cells, indicating its low hepatotoxicity at an equivalent dosage. Furthermore, the elucidation of the mechanism of action revealed that compound 9h effectively inhibited cell migration and inhibited the proliferation of AsPC-1 by blocking the cell cycle at the G2/M phase. Moreover, 9h also demonstrated efficacy in inhibiting tumor growth in a murine AsPC-1 cell xenograft model at the dosage of 10 mg/kg without losing noticeable body weight. All these findings provide important clues for the identification of potent FAK inhibitors.

Investigation on the chemical recovery and stability of a newly developed method for 137Cs measurement in marine biota Scomber Japonicus. Seven sets of experiments based on a newly developed Mincing-Digesting method for 137Cs measuring in marine biota Scomber Japonicus were conducted to investigate the method's stability and chemical recovery. The results show the chemical recovery of radiocesium for aqueous parts is 68.77 ± 11.2%, which is relatively stable with R2 = 0.97, means this value could be used when measuring the Scomber Japonicus or other marine biota belonging to the same category and having similar muscular tissue and cellular structure. Meanwhile, the Minimum Detectable Activity (MDA) of the method is 0.013Bq/kg-ww which is comparable with that of the conventional method, means that the method could be further developed as a reliable and efficient way to measure other radionuclides in other marine biotas in the future if more experiments were conducted.

Production of cultured meat from pig muscle stem cells. Cultured meat is meat for consumption produced in a more sustainable way. It involves cell harvesting and expansion, differentiation into myotubes, construction into muscle fibres and meat structuring. We isolated 5.3 × 104 porcine muscle stem cells from 1 g of neonatal pig muscle tissue. According to calculations, we need to expand muscle stem cells 106-107 times to produce 100 g or 1 kg of cultured meat. However, the cells gradually lost the ability to express stemness and mature muscle cell markers (PAX7, MyHC). To tackle this critical issue and maintain cell function during cell expansion, we found that long-term culture with (100 μM) l-Ascorbic acid 2-phosphate (Asc-2P) accelerated cell proliferation while preserving the muscle cell differentiation. We further optimized a scalable PDMS mold. Porcine muscle stem cells formed structurally-organized myotubes similar to muscle fibres in the mold. Asc-2P enhanced porcine muscle cells grown as 3D tissue networks that can produce a relatively large 3D tissue networks as cultured meat building blocks, which showed improved texture and amino acid content. These results established a realistic workflow for the production of cultured meat that mimics the pork meat structurally and is potentially scalable for industry.

Comparison of serum tryptase as a diagnostic oncological marker in canine versus human mast cell neoplasms. Canine mast cell tumors (MCTs) are a promising translational model for human mast cell neoplasms with striking similarities such as the Darier's sign and mutations in the KIT gene. Whereas mast cell neoplasms are rare in humans, MCTs are the most frequent malignant neoplasms of the skin in dogs. In human systemic mastocytosis, serum tryptase is an important diagnostic criterion. Surprisingly, serum tryptase levels were not yet investigated in dogs with MCTs. Therefore, the aim of this study was to investigate whether serum tryptase levels in dogs with cutaneous MCTs were elevated compared to those of a non-MCT control group. As a secondary aim, it was investigated whether surgical manipulation caused an increase in serum tryptase in canine MCT patients. A total of 48 serum samples were collected from dogs with different grades of cutaneous MCTs (n = 24) and non-MCT controls (n = 24). In dogs with cutaneous MCTs, blood was collected prior to and within 1 h after surgery. Serum tryptase levels were measured using a commercially available canine-specific ELISA kit. No significant difference in serum tryptase levels was found between cutaneous MCT patients and non-MCT controls, nor in these levels before versus after surgery. Our findings in canine cutaneous MCTs are in accordance with human cutaneous mastocytosis, where serum tryptase levels tend to remain within the normal range. However, despite various similarities between aggressive mast cell tumors in dogs and humans, serum tryptase cannot be considered a diagnostic biomarker in dogs with cutaneous MCTs as part of a comparative oncologic strategy.

Capturing the mechanics of clathrin-mediated endocytosis. Clathrin-mediated endocytosis enables selective uptake of molecules into cells in response to changing cellular needs. It occurs through assembly of coat components around the plasma membrane that determine vesicle contents and facilitate membrane bending to form a clathrin-coated transport vesicle. In this review we discuss recent cryo-electron microscopy structures that have captured a series of events in the life cycle of a clathrin-coated vesicle. Both single particle analysis and tomography approaches have revealed details of the clathrin lattice structure itself, how AP2 may interface with clathrin within a coated vesicle and the importance of PIP2 binding for assembly of the yeast adaptors Sla2 and Ent1 on the membrane. Within cells, cryo-electron tomography of clathrin in flat lattices and high-speed AFM studies provided new insights into how clathrin morphology can adapt during CCV formation. Thus, key mechanical processes driving clathrin-mediated endocytosis have been captured through multiple techniques working in partnership.

Factors influencing of quality of life in adolescent idiopathic scoliosis. Adolescent idiopathic scoliosis (AIS) is the lateral and horizontal deformity of the vertebral column which occurs idiopathically during adolescence. The aim of this study is to identify independent predictors of quality of life in AIS patients. In total, 31 adolescent patients diagnosed with AIS aged between 10 and 18 years old were included in the study. The scoliosis severity was determined for each patient according to the Cobb method, and their scoliosis perception using the Walter Reed Visual Assessment Scale, a pain assessment was conducted based on the Visual Analog Scale, quality of life using the Scoliosis Research Society-22 questionnaire, and depression level according to the Children's Depression Scale. Multiple Linear Regression analysis was then performed in order to determine the independent determinants of health-related quality of life. According to the Linear Regression analysis results, children's depression scale, walter reed visual assessment scale, cobb, and anterior trunk rotation explained 52.7% of the variance as independent determinants of SRS-22. The study examined the determinants affecting the quality of life in AIS patients. The results of the study showed that scoliosis severity, perception of cosmetic deformity, degree of rotation, and depression level to be predictors of quality of life in AIS patients. "This trail registered with NCT05242601."

The validity of the cervical rotation lateral flexion test in predicting benefit after manipulation treatment to the first and second rib. Prospective cohort study. The cervical rotation lateral flexion (CRLF) test is frequently used in clinical practice to determine whether a thrust manipulation targeting the first rib should be performed. To evaluate the predictive validity of the CRLF test and manual examination in determining whether patients with neck pain are likely to benefit from manipulative treatment to the first and second rib. A physical examination incorporating the CRLF test was performed on 50 participants with neck pain followed by manipulation treatment to the first and second ribs. Clinical improvement was assessed immediately and one week after treatment. Participants who experienced at least a 30% improvement in their Neck Disability Index (NDI) score were considered "improved." Predictive validity was assessed by calculating sensitivity, specificity, and negative and positive likelihood ratios. Neither the CRLF test nor manual examination were predictive of clinical improvement after manipulative treatment to the first and second rib. However, being male, of older age, and exhibiting T1 and/or T2 restricted end-feel were associated with improved neck related-disability at one-week follow-up. The CRLF test does not appear to be helpful in determining whether patients with neck pain are likely to benefit from manipulative treatment to the first and second rib. Other factors from the history and clinical examination may be more helpful when selecting manipulative treatment including age and gender and possibly the presence of T1/T2 restricted end-feel.

A Call for Kindness, Connection, and Science. This personal narrative describes our family's struggle with my adult son's substance use disorder (SUD). Years of traditional tough love treatment programs worsened his SUD and our relationship. When he experienced drug induced psychosis and was hospitalized, I realized I needed to change my approach and understand his behaviors. I reached out to the recovery community and spoke with many individuals who had walked in my son's shoes. They described feelings of loneliness, self-loathing, and hopelessness while being on the receiving end of tough love. They further described the contrast between those negative feelings, and the life affirming hope associated with communication, empathy, and inclusion. I became inspired to research programs that are based on communication, science, and connection, rather than isolation, judgment, and punishment. Family and community are powerful tools and can motive change. An evidence-based program called CRAFT (Community Reinforcement and Family Training) encourages relationships and teaches families skills to connect with their loved ones by effectively communicating and reinforcing positive behaviors, even in the context of unhealthy behaviors. Receiving praise for healthy behavior, recognition for good work, or even a positive acknowledgement for taking baby steps toward self-care can activate the same dopamine-producing reward system as drugs. Individuals with SUD can learn how to feel good in ways that do not involve using substances. Traditional patient-focused treatment programs, which encourage separation, punishment, and distance should not be considered the only approach to treatment. Loved ones are not powerless. While we can't make a person change, we can contribute to making them want to change. We have more influence than we once thought possible and need to proactively seek out empirically supported family-based programs that reinforce these approaches.

The relationship between plasma biomarkers and amyloid PET in dementia with Lewy bodies. Amyloid-β (Aβ) deposition is common in dementia with Lewy bodies (DLB) and has been associated with more rapid disease progression. An effective biomarker that identified the presence of significant brain Aβ in people with DLB may be useful to identify and stratify participants for research studies and to inform prognosis in clinical practice. Plasma biomarkers are emerging as candidates to fulfil this role. Thirty-two participants with DLB had brain amyloid (18F-florbetapir) PET, of whom 27 also had an MRI to enable the calculation of 18F-florbetapir SUVR. Plasma Aβ42/40, phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) were measured using single molecule array (Simoa). The plasma biomarkers were investigated for correlation with 18F-florbetapir SUVR, discriminant ability to identify Aβ-positive cases based on a predefined SUVR threshold of 1.10 and correlation with subsequent cognitive decline over one year. All four plasma markers significantly correlated with 18F-florbetapir SUVR (|β| = 0.40-0.49; p < .05). NfL had the greatest area under the receiver operating characteristic curve to identify Aβ-positive cases (AUROC 0.84 (95% CI 0.66, 1); β = 0.46, p = .001), whereas Aβ42/40 had the smallest (AUROC 0.73 (95% CI 0.52, 0.95); β = -0.47, p = .01). Accuracy was highest when combining all four biomarkers (AUROC 0.92 (95% CI 0.80, 1)). Lower plasma Aβ42/40 was significantly associated with more rapid decline in cognition (β = 0.53, p < .01). Plasma biomarkers have the potential to identify Aβ deposition in DLB. Further work in other cohorts is required to determine and validate optimal cut-offs for these biomarkers.

Folic acid supplementation in pregnant women with hepatitis B surface antigen improves infant hepatitis B surface antibody mediated by infant IL-4. Immunoprophylaxis has not completely eliminated hepatitis B virus (HBV) infection due to hyporesponsiveness to hepatitis B vaccine (HepB). We explored the impact of folic acid supplementation (FAS) in pregnant women with positive hepatitis B surface antigen (HBsAg) on their infant hepatitis B surface antibody (anti-HBs) and the mediation effect of infant interleukin-4 (IL-4). We recruited HBsAg-positive mothers and their neonates at baseline. Maternal FAS was obtained via a questionnaire, and neonatal anti-HBs and IL-4 were detected. Follow-up was performed at 11-13 months of age of infants, when anti-HBs and IL-4 were measured. We applied univariate and multivariate analyses. A mediation effect model was performed to explore the mediating role of IL-4. A total of 399 mother-neonate pairs were enrolled and 195 mother-infant pairs were eligible for this analysis. The infant anti-HBs geometric mean concentrations in the maternal FAS group were significnatly higher than those in the no-FAS group (383·8 mIU/ml, 95 % CI: 294·2 mIU/ml to 500·7 mIU/ml v. 217·0 mIU/ml, 95 % CI: 147·0 mIU/ml to 320·4 mIU/ml, z = -3·2, P = 0·001). Infants born to women who took folic acid (FA) within the first trimester were more likely to have high anti-HBs titres (adjusted β-value = 194·1, P = 0·003). The fold change in IL-4 from neonates to infants partially mediated the beneficial influence of maternal FAS on infant anti-HBs (24·7 % mediation effect) after adjusting for confounding factors. FAS during the first trimester to HBsAg-positive mothers could facilitate higher anti-HBs levels in infants aged 11-13 months partly by upregulating IL-4 in infants.

Point-of-Care Ultrasound to Detect Acute Large Vessel Occlusions in Stroke Patients: A Proof-of-Concept Study. A primary admission of patients with suspected acute ischemic stroke and large vessel occlusion (LVO) to centers capable of providing endovascular stroke therapy (EVT) may induce shorter time to treatment and better functional outcomes. One of the limitations in this strategy is the need for accurately identifying LVO patients in the prehospital setting. We aimed to study the feasibility and diagnostic performance of point-of-care ultrasound (POCUS) for the detection of LVO in patients with acute stroke. We conducted a proof-of-concept study and selected 15 acute ischemic stroke patients with angiographically confirmed LVO and 15 patients without LVO. Duplex ultrasonography (DUS) of the common carotid arteries was performed, and flow profiles compatible with LVO were scored independently by one experienced and one junior neurologist. Among the 15 patients with LVO, 6 patients presented with an occlusion of the carotid-T and 9 patients presented with an M1 occlusion. Interobserver agreement between the junior and the experienced neurologist was excellent (kappa = 0.813, p < 0.001). Flow profiles of the CAA allowed the detection of LVO with a sensitivity of 73%, a positive predictive value of 92 and 100%, and a c-statistics of 0.83 (95%CI = 0.65-0.94) and 0.87 (95%CI = 0.69-0.94) (experienced neurologist and junior neurologist, respectively). In comparison with clinical stroke scales, DUS was associated with better trade-off between sensitivity and specificity. POCUS in acute stroke setting is feasible, it may serve as a complementary tool for the detection of LVO and is potentially applicable in the prehospital phase.

[New era of accurate diagnosis of hemophagocytic lymphohistiocytosis]. Hemophagocytic lymphohistiocytosis is a rapidly progressive and highly fatal disease with no specific clinical manifestations and multiple potential etiologies. Timely initiation of appropriate treatment is the key to improvement of the prognosis. Timely, accurate, and complete diagnosis of hemophagocytic lymphohistiocytosis requires the three-step principle, which is suspected diagnosis, confirmed diagnosis, and etiological diagnosis. With the development of new diagnostic technologies and methods, the establishment of a standardized diagnostic system and the construction of clinical pathways for hemophagocytic lymphohistiocytosis, the diagnostic efficiency of the fatal disease has been continuously improved, and hemophagocytic lymphohistiocytosis has entered an era of standardized, path-based and individualized accurate diagnosis.

[Precise diagnosis and treatment of hemophagocytic lymphohistiocytosis guided by cytokine patterns]. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening entity which presents as multi-organ dysfunction caused by overactivated T cell and macrophage and overwhelming hyperinflammation. Cytokine storm is the key pathophysiology of HLH. Due to the diversity of the underlying diseases, the difference of disease severity and the non-specific clinical manifestation, the early diagnosis and standardized treatment is a great challenge for clinicians. According to previous clinical studies, serum cytokine measurement is helpful for rapid diagnosis of HLH and the differentiation of HLH from other diseases caused by hypercytokinemia, and it perfoms well to clarify subtypes of HLH, to stratify patients with different risks and to predict the prognosis and outcome. Thus, serum cytokine measurement could be a useful tool for the precise diagnosis and treatment of HLH.

An ABA-serotonin module regulates root suberization and salinity tolerance. Suberin in roots acts as a physical barrier preventing water/mineral losses. In Arabidopsis, root suberization is regulated by abscisic acid (ABA) and ethylene in response to nutrient stresses. ABA also mediates coordination between microbiota and root endodermis in mineral nutrient homeostasis. However, it is not known whether this regulatory system is common to plants in general, and whether there are other key molecule(s) involved. We show that serotonin acts downstream of ABA in regulating suberization in rice and Arabidopsis and negatively regulates suberization in rice roots in response to salinity. We show that ABA represses transcription of the key gene (OsT5H) in serotonin biosynthesis, thus promoting root suberization in rice. Conversely, overexpression of OsT5H or supplementation with exogenous serotonin represses suberization and reduces tolerance to salt stress. These results identify an ABA-serotonin regulatory module controlling root suberization in rice and Arabidopsis, which is likely to represent a general mechanism as ABA and serotonin are ubiquitous in plants. These findings are of significant importance to breeding novel crop varieties that are resilient to abiotic stresses and developing strategies for production of suberin-rich roots to sequestrate more CO2 , helping to mitigate the effects of climate change.

[Perspectives on recent monkeypox outbreak in non-endemic areas]. Monkeypox is a rare infectious disease caused by the monkeypox virus, which used to occur endemically in central and western Africa. As of 25th May, a total of 219 recently confirmed cases of monkeypox have been reported from 19 non-endemic countries. This outbreak unusually takes place in non-endemic areas for monkeypox virus and has exhibited features of high risk of human-to-human transmission. Onset of multiple human monkeypox cases may be related to the decreased level of herd cross-immunity after the cessation of smallpox vaccination. Moreover, behavioral patterns in specific populations may account for the human-to-human transmission in this outbreak. Currently, possibility of global epidemic of monkeypox is extremely low, but China should be cautious about risks of importation of monkeypox cases. The key to prevention and control is to establish a surveillance system to identify suspicious cases and close contacts as soon as possible.

[Evaluation of CD107a and perforin expression detection in the diagnosis of primary hemophagocytic lymphohistiocytosis]. Objective: To evaluate the efficacy of rapid immunological indicator-degranulation function (CD107a) and perforin expression in the diagnosis of primary hemophagocytic lymphohistiocytosis (pHLH). Methods: The clinical data of 295 HLH patients who underwent genetic screening from April 2015 to June 2020 in Beijing Friendship Hospital, Capital Medical University, Beijing Jingdu Children's Hospital and Beijing Children's Hospital, Capital Medical University was collected and analyzed. The fitness of CD107a and Perforin expression with genetic screening was compared to evaluate the sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) of the two indicators, and the receiver operating characteristic (ROC) curves were generated and used to determine the optimal threshold (cut-off values) of CD107a and Perforin expression assays that would identify pHLH patients with a maximum sensitivity and specificity (Youden index). Results: In all 295 patients included, there were 156 males and 139 females, aged from 2 months to 70 years, with a median age of 18 years. In terms of distinguishing the type of pHLH associated with degranulation gene defect from all other genetic screening results, in the CD107a testing, the ROC curve was generated and showed an area under the curve (AUC) of 0.920 (P<0.001), and the optimal cut-off value was determined to be 7.15% with a sensitivity of 83.3% and specificity of 89.2% when the corresponding Youden index was maximized. The PPV and NPV were 33.3% and 98.8%, respectively. CD107a>10% had an accuracy of 81.6% in judging patients without degranulation-related gene defect and negative genetic screening results. In addition, in terms of distinguishing the type of familial hemophagocytic lymphohistiocytosis type 2 (FHL2) from all other genetic screening results, the sensitivity, specificity, PPV and NPV of the Perforin expression testing were 88.2%, 64.2%, 20.3% and 98.1%, respectively, based on the normal laboratory test value (≥ 81%). The ROC curve was established to further optimize the cut-off value. The AUC was 0.933 (P<0.001). The cut-off value corresponding to the maximum Youden index was 62.34%, and the sensitivity remained at 88.2%. While the specificity, PPV and NPV rose to 91.5%, 51.7% and 98.7%, respectively. Conclusions: CD107a and Perforin assays have good significance of early prediction for pHLH involved in impaired cytotoxic function. Selecting appropriate cut-off values can provide basis for accurate clinical diagnosis.

[Two-dimensional equivalent mechanical modeling and finite element analysis of normal female pelvic floor system]. Objective: To construct the geometric model of the pelvic floor by a two-dimensional equivalent mechanics method, and to explore the effect of the shape and position of pelvic floor organs and tissues on the biomechanical properties of the pelvic floor under different abdominal pressure. Methods: A 28-year-old healthy and symmetrical married infertile female volunteer was included. The pelvic floor tissue was scanned in the supine position using a 3.0T magnetic resonance scanner (Philips Company, Holland). Based on the method of magnetic resonance imaging (MRI) two-dimensional parameter measurement and computer aided design, the geometric model and finite element model of the female pelvic floor were established, and the biomechanical characteristics of the pelvic floor support system under different abdominal pressure were analyzed. Results: In this study, four different working conditions of the pelvic floor force were simulated under 60, 99, 168, and 208 cmH2O (1 cmH2O=0.098 kPa) abdominal pressure loads. The trend was as follows: under the abdominal pressure load, the retrograde flexion of the uterus occurred, the cervical, the middle and upper vaginal segment and the levator anus muscle had the characteristic change of mechanical axial direction pointing to the sacrum and coccyx, and the deformation of the levator anus muscle in the horizontal direction was greater than that in the vertical direction. With the increase of the abdominal pressure, the maximum stress values of the pelvic floor whole system of healthy subjects under four different working conditions were 0.194 3, 0.389 6, 0.557 1, and 0.627 5 MPa, respectively, and the maximum displacement values were 10, 14, 21 and 25 mm, respectively. The maximum stress values of the cervical and vaginal middle and upper segment were 0.111 7, 0.161 8, 0.250 6, and 0.304 1 MPa, respectively, and the maximum displacement values were 3, 6, 9, and 11 mm, respectively. The maximum stress of the perineal body was 0.063 4, 0.119 6, 0.235 2, and 0.288 0 MPa, and the maximum displacement was 1, 2, 4, and 5 mm. The maximum stress values of the levator anus muscle were 0.194 3, 0.389 6, 0.557 1, and 0.627 5 MPa, and the maximum displacement values were 2, 4, 7, and 8 mm, respectively. The maximum stress and maximum displacement of pelvic organs increased with the increase of the abdominal pressure under different working conditions. The stress axial relationship of normal female pelvic floor was that the middle and upper segment of uterus and vagina mainly acted on the sacrococcyx and the levator anus muscle, and the lower vaginal segment acts on the perineal body. Conclusions: The two-dimensional equivalent mechanical modeling and finite element analysis of the female pelvic floor system can accurately reflect the biomechanical characteristics of the female pelvic floor, and the resultant stress direction of the pelvic organs points to the sacrum and coccyx. The sacrum and coccyx, levator anus and perineal body play important stress supporting roles in the pelvic floor system.

[Clinical features and prognostic factors of severe hemophagocytic syndrome in children]. Objective: To explore the clinical characteristics, prognostic risk factors and effective treatment of severe hemophagocytic syndrome (HPS) in children, so as to provide reference for the clinical diagnosis and treatment of the disease. Methods: The clinical data of 83 children with severe HPS admitted in Affiliated Hospital of Zunyi Medical University from January 2014 to April 2021 were collected, and their clinical characteristics, prognosis and prognostic risk factors were analyzed. The children were divided into central nervous system (CNS) dysfunction group and non-CNS dysfunction group according to whether they were accompanied with CNS dysfunction, and were divided into blood purification group and non-blood purification group according to whether they received blood purification, then the survival differences were compared. Results: Among the 83 children, there were 43 males and 40 females, aged[M(Q1,Q3)] 36(15,27)months. A total of 51 children were induced by infection, among which 41 children (80.4%) were infected with EB virus. All the children were accompanied by multiple organ dysfunction (MODS), and dysfunction of the blood system (72.3%), liver (71.1%), respiratory system (53.0%) and CNS (37.3%) were common. By the end of follow-up, 40 cases (48.2%) survived, 38 cases (45.8%) died, and 5 cases (6.0%) were lost to follow-up. CNS dysfunction was a risk factor (HR=3.358, 95%CI: 1.445-7.803, P=0.005) and blood purification was a protective factor (HR=0.362, 95%CI: 0.179-0.730, P=0.005) affecting the prognosis of children. The mortality of CNS dysfunction group was statistically higher than that of non-CNS dysfunction group (74.2% vs 28.8%) (P<0.001); The mortality of blood purification group was statistically lower than that of non-blood purification group (31.0% vs 61.0%) (P=0.010). Conclusions: Severe HPS in children was dangerous and had a poor overall prognosis. CNS dysfunction was a risk factor for death. Blood purification could significantly improve the prognosis and improve the survival rate of children.

[Ruxolitinib combined with liposomal doxorubicin, etoposide, methylprednisolone+/-PEG-asparaginase in treatment of relapsed/refractory pediatric hemophagocytic lymphohistiocytosis]. Objective: To investigate the efficacy and safety of ruxolitinib, liposomal doxorubicin, etoposide, methylprednisolone+/-PEG-asparaginase (RU-DEP+/-L) in the treatment of relapsed/refractory (R/R) pediatric hemophagocytic lymphohistiocytosis (HLH). Methods: The clinical data of R/R pediatric HLH, who accepted the RU-DEP+/-L regimen at Beijing Children's Hospital from January 2018 to December 2019 was retrospectively analyzed. Results: A total of 16 patients were included in this study, including 13 males and 3 females, aged[M(Q1,Q3)] 1 (1, 2) years at diagnosis. Thirteen patients were diagnosed with Epstein-Barr virus (EBV)-HLH, 2 with EBV-induced primary HLH, and 1 with unclear etiology, among which 3 patients were co-infected with CMV. After the first-line treatment, 11 patients had no response, and 5 patients relapsed after complete response. Nine patients received the RU-L-DEP regimen, and 7 patients received the RU-DEP regimen. The overall response rate and complete response of RU-DEP+/-L treatment were 10/16 and 3/16, respectively. The negative conversion rate of plasma EBV-DNA was 7/15. The median follow-up time was 35.1 (2.4, 40.7) months, and 9/16 patients were survival. The 3-year overall survival rate after RU-DEP+/-L treatment in response and accepted hematopoietic stem cell transplantation (HSCT) was higher than that without response and did not receive HSCT (P=0.048). Among the 16 patients, 9 had varying degrees of myelosuppression, and 13 had an infection. Conclusions: RU-DEP+/-L can be used as a salvage treatment in R/R pediatric HLH, which can provide a bridge to HSCT and play an important role in the control of HLH. The main adverse reactions are myelosuppression and infection, which can be tolerated.

[Clinical characteristics and prognosis of lymphoma-associated hemophagocytic syndrome]. Subjective To investigate clinical characteristics, treatment, and prognosis of lymphoma-associated hemophagocytic syndrome (LAHS) patients. Methods: The clinical data of patients diagnosed with LAHS from January 2010 to October 2021 in West China Hospital were retrospectively analyzed. Clinical characteristics, treatment, overall response rate (ORR), and overall survival (OS) were investigated. Univariate and multivariate analysis of potential factors were conducted. Results: Of all 94 patients included, 59 were male and 35 were female. The age at hemophagocytic lymphohistiocytosis (HLH) diagnosis was (40.5±17.3) years. Seventy-four cases were T/NK cell lymphoma; 15 were B cell lymphoma; 5 were Hodgkin lymphoma. The age at HLH diagnosis of T/NK cell LAHS patients was (37.9±16.2) years, while that of B cell LAHS patients was (55.9±14.0) years. T/NK cell LAHS patients were significantly younger than B cell LAHS patients (P<0.001). Baseline fibrinogen of T/NK cell LAHS patients was 1.34 (0.86, 2.44) g/L, while that of B cell LAHS patients was 2.20 (1.75, 4.25) g/L. T/NK cell LAHS patients showed significantly lower fibrinogen levels than B cell LAHS patients (P=0.008). Combined treatment of anti-HLH and anti-lymphoma treatment was conducted in 35 patients; anti-HLH treatment was conducted in 31 patients; anti-lymphoma treatment was conducted in 8 patients; glucocorticoid treatment was conducted in 7 patients. ORR was 49.4%, and the median OS was 61 days for overall patients. Patients who received anti-HLH treatment and turned to anti-lymphoma treatment early displayed the best ORR and OS, significantly higher than those of anti-HLH patients (69.0 vs 38.7%, P=0.019, and 192.0 vs 24.5 days, P=0.028, respectively), which were also insignificantly higher than those of anti-lymphoma patients. Extranodal NK/T-cell lymphoma or aggressive natural killer cell leukemia was the risk factor of LAHS prognosis (HR=0.113, 95%CI: 0.018-0.728, P=0.022). Conclusions: Prognosis of LAHS patients is poor. Anti-lymphoma treatment should be initiated as soon as HLH is rapidly controlled.

[Significance of aspergillus fumigatus-specific IgG in the diagnosis of allergic bronchopulmonary aspergillosis]. The data of 18 patients with allergic bronchopulmonary aspergillosis (ABPA) who received aspergillus fumigatus-specific IgG detection from 2015 to 2021 in Peking University Third Hospital were retrospectively analyzed. Among them, 11 were male and 7 were female, aged 18-79 years. All patients had a history of asthma or symptoms of cough and asthma, and aspergillus fumigatus-specific IgE was positive; 16 patients had total serum IgE>500 U/ml, of which 13 patients had total serum IgE>1 000 U/ml. Among other diagnostic indicators, peripheral blood eosinophils were >0.5×109/L in 16 cases; lung CT showed bronchiectasis in 15 cases; serum aspergillus fumigatus-specific IgG was positive (>120 AU/ml) in 10 cases. There was no significant difference in serum total IgE level, peripheral blood eosinophil count, and bronchiectasis ratio between positive and negative cases of aspergillus fumigatus-specific IgG (all P>0.05). In this study, the positive rate of aspergillus fumigatus-specific IgG in patients with ABPA was more than 50%, which has auxiliary value in the diagnosis of ABPA.

[Efficacy and safety of omalizumab in patients with refractory allergic asthma: a meta-analysis]. Objective: To evaluate the efficacy and safety of omalizumab in patients with refractory allergic asthma using meta-analysis. Methods: We searched databases including PubMed, Web of Science, Embase and the website of ClinicalTrials. gov registry for randomized controlled trials (RCTs), using the search terms: ("anti-IgE" OR "anti-immunoglobulin E" OR "anti-IgE antibody" OR "omalizumab" OR "rhuMAb-E25" OR "Xolair") AND ("allergic asthma"). The time was up to September 19th 2020. Review Manager 5.4 software and Stata16 software were used to calculate pooled RR or WMD, perform heterogeneity test, and assess publication bias. Results: Fifteen RCTs with 6 316 patients in total (omalizumab, n=3 469; placebo, n=2 847) met our selection criteria. Comparing with placebo, omalizumab reduced the risk of asthma exacerbations during both stable-inhaled corticosteroid (ICS) phase (RR=0.69, 95%CI: 0.63-0.75, P<0.001; I2=39.0%, P=0.090) and ICS-reduction phase (RR=0.55, 95%CI: 0.46-0.66, P<0.001; I2=41.0%, P=0.180), reduced emergency visits (RR=0.53, 95%CI: 0.38-0.73, P<0.001; I2=0, P=0.420), made a significant reduction in dosage of ICS (RR=1.35, 95%CI: 1.25-1.45, P<0.001; I2=22.0%, P=0.280) and even withdrew from ICS completely (RR=1.80, 95%CI: 1.41-2.31, P<0.001; I2=57.0%, P=0.070). Omalizumab significantly improved asthma-related quality of life (RR=1.81, 95%CI: 1.51-2.17). The use of rescue bronchodilators was significantly reduced in the omalizumab group (RR=0.78, 95%CI: 0.67-0.92) but there was no significant difference in the dosage of rescue bronchodilators (puff per day) (WMD=-0.32, 95%CI: -0.77-0.13). Patients taking omalizumab did not increase the frequency of any adverse events (RR=1.01, 95%CI: 0.98-1.03) and serious adverse events (RR=0.89, 95%CI: 0.74-1.06). Conclusions: Omalizumab is an ideal adjunctive treatment for refractory allergic asthma with good efficacy and safety. Further randomized controlled trials are needed to determine the appropriate duration of treatment.

TRIM26 inhibits hepatitis B virus replication by promoting HBx degradation and TRIM26 genetic polymorphism predicts PegIFNα treatment response of HBeAg-positive chronic hepatitis B Patients. Hepatitis B virus (HBV) infection is a serious global health burden. TRIM26 has been reported to affect hepatitis C virus replication. To manifest the role of TRIM26 on HBV replication and explore if there are single-nucleotide polymorphisms (SNPs) in TRIM26 associated with response to pegylated interferon-alpha (PegIFNα) treatment in patients with chronic hepatitis B (CHB). We investigated the effect and mechanism of TRIM26 on HBV replication in vitro. The association between SNPs in TRIM26 and PegIFNα treatment response was evaluated in two independent cohorts including 238 and 707 patients with HBeAg-positive CHB. Knockdown of TRIM26 increased, while overexpression of TRIM26 inhibited, HBV replication. Co-immunoprecipitation assays and immunofluorescence showed that TRIM26 interacted and co-localised with HBx. Co-transfection of HBx-HIS and TRIM26-FLAG plasmids in Huh7 cells showed that TRIM26 inhibited the expression of HBx. Furthermore, TRIM26 inhibited HBV replication by mediating HBx ubiquitination degradation, and TRIM26 SPRY domain was responsible for the interaction and degradation of HBx. Besides, IFN increased TRIM26 expression. TRIM26 rs116806878 was associated with response to PegIFNα in two CHB cohorts. Moreover, a polygenic score integrating TRIM26 rs116806878, STAT4 rs7574865 and CFB rs12614 (previously reported to be associated with response to PegIFNα) was related to response to PegIFNα in CHB. TRIM26 inhibits HBV replication; IFN promotes TRIM26 expression. TRIM26 exerts an inhibitory effect on HBx by promoting ubiquitin-mediated degradation of HBx. Furthermore, TRIM26 rs116806878 is a potential predictive biomarker of response to PegIFNα in patients with CHB.

[Occurrence and recovery of adverse drug reactions of preventive treatment in elderly population with latent tuberculosis infection]. Objective: To evaluate the occurrence and recovery of adverse drug reactions (ADRs) of preventive treatment in the elderly population with latent tuberculosis infection (LTBI). Methods: A total of 2 583 elderly patients with LTBI were recruited in Zhongmu, Henan Province from July 1 to October 17, 2015. Face-to-face surveys and physical examinations were used to obtain the basic information of the participants, and the body mass index (BMI) was calculated. Fasting venous blood was collected from the participants for blood biochemical and routine blood tests. The random numbers were generated by Excel 2010, and the participants were divided into group A (1 284 cases) and group B (1 299 cases) by simple randomization. Both group A and group B received combination treatment of isoniazid and rifapentine. Group A was treated for 8 weeks with weekly doses of isoniazid at 15 mg/kg and 900 mg for those with body weight ≤50 and>50 kg, respectively, and the doses of rifapentin were 750 and 900 mg, respectively. Group B was treated twice a week for 6 weeks, the doses of isoniazid in patients with body weight ≤50 and>50 kg were [600-(50-body weight)×15] (rounded up) and 600 mg, respectively, and the doses of rifapentin were 600 and 450 mg, respectively. During the treatment period, doctors observed, inquired about and recorded symptoms related to ADRs, and blood biochemical and routine blood tests were performed at 4 weeks after taking the drug, the end of the treatment, and 3 months after the end of the treatment. The patients with ADRs were treated accordingly by severity. The ADRs and graded treatment outcomes of LTBI patients in group A and group B were compared. Results: The age［M（Q1，Q3）］of the participants was 60 (55,65) years old, and 54.7% (1 412/2 583) were males. There were no statistical differences in age, gender, BMI and baseline biochemical indexes between groups A and B (all P values>0.05). The incidence of ADRs in group A and group B were 18.5% (237/1 279) and 16.3% (209/1 279), respectively, and those with alanine aminotransferase (ALT)≥5 ULN accounted for 0.8% (7/931) and 1.1% (11/987), aspartate aminotransferase (AST)≥5 ULN accounted for 0.3% (3/931) and 0.3% (3/987), respectively, and there were no statistically significant differences (all P values>0.05). There were 7 and 11 patients with ALT≥5 ULN in group A and group B, respectively, and 3 patients with AST≥5 ULN for each group, respectively. After treatment, except for 2 patients with ALT≥5 ULN in group B, ALT and AST levels in all the other patients returned to normal. There were 15 and 10 patients with abnormal white blood cell count in group A and group B, respectively, and 10 and 9 patients returned to normal after treatment. Conclusion: LTBI preventive treatment has a high incidence of adverse drug reactions, but it can be effectively controlled through active monitoring and graded management.

[Assessment of MS-Score and HScore in timeliness of diagnosis of macrophage activation syndrome associated with adult-onset Still's disease]. The data of 33 patients with adult-onset still's disease (AOSD)-associated macrophage activation syndrome (MAS) were retrospectively collected from January 2013 to December 2020 in Peking Union Medical College Hospital. Hemophagocytic lymphohistiocytosis (HLH)-2004 criteria, macrophage activation syndrome/juvenile idiopathic arthritis (MS-Score) and hemophagocytic syndrome diagnostic score (HScore) were used to diagnose AOSD-associated MAS, respectively. The time of diagnosis of AOSD-associated MAS by MS-Score was 19.0 (4.5, 31.0) days [M (Q1,Q3)] earlier than by HLH-2004 criteria, and 13.5 (0.5, 21.5) days earlier than by HScore (both P<0.05). The difference was not statistically significant between the time of diagnosis of AOSD-associated MAS by Hscore and by HLH-2004 criteria (P>0.05). There was significant difference among the three criteria (P<0.001). MS-Score can be used to diagnose AOSD-associated MAS earlier than HLH-2004 criteria, while the timeliness of HScore is not certain.

[Multidisciplinary regenerative treatment and mechanisms for rescuing a severe calciphylaxis patient with human amnion-derived mesenchymal stem cells]. Calciphylaxis is a rare disease with severe pain and high-mortality due to cutaneous ischemic necrosis and infection that currently lacks proved effective therapies. The occurrence of calciphylaxis in end stage kidney disease (ESKD) patients is known as calcific uremic arteriolopathy (CUA), which is characterized histologically by dermal microvessel calcification, intimal fibroplasia and microthrombosis. Here we innovatively treated a severe CUA patient with human amnion-derived mesenchymal stem cells (hAMSCs). A 34-year-old uremic woman was presented with progressive, painful malodorous ulcers in buttocks and mummified lower limbs. Skin pathological features supported the diagnosis of calciphylaxis. The patient was refractory to conventional multidisciplinary symptomatic therapies. With the approval of our hospital ethics committee, she was treated with hAMSCs including intravenous and local intramuscular injection, and external application of hAMSC culture supernatant to the wound area. During 15-month follow-up, the patient had regeneration of skin and soft tissues, with improved blood biochemical, inflammatory, mineral and bone metabolic indices and immunoregulation effects. After 15-month hAMSC treatment, the score of pain visual analog scale (VAS) decreased from 10 to 0, Bates-Jensen wound assessment tool (BWAT) score decreased from 65 to 13, and wound-quality of life (Wound-QoL) questionnaire score decreased from 68 to 0. We propose that hAMSC treatment is promising for CUA patients. The therapy is potentially involved in the multiple beneficial effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, modulating adverse inflammatory and immunologic responses, promoting re-epithelialization and restoring skin integrity.

Lifetime Exposure to Welding Fumes and Risk of Some Rare Cancers. We investigated the association between exposure to welding fumes and the risk of biliary tract, male breast, bone, and thymus cancer, as well as cancer of the small intestine, eye melanoma, and mycosis fungoides, among men in a European, multicenter case-control study. From 1995-1997, 644 cases and 1,959 control subjects from 7 countries were studied with respect to information on welding and potential confounders. We linked the welding histories of the participants with a measurement-based exposure matrix to calculate lifetime exposure to welding fumes. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models, conditional on country and 5-year age groups, and adjusted for education and relevant confounders. Regular welding was associated with an increased risk of cancer of the small intestine (OR = 2.30, 95% CI: 1.17, 4.50). Lifetime exposure to welding fumes above the median of exposed controls was associated with an increased risk of cancer of the small intestine (OR = 2.00, 95% CI: 1.07, 3.72) and male breast (OR = 2.07, 95% CI: 1.14, 3.77), and some elevation in risk was apparent for bone cancer (OR = 1.92, 95% CI: 0.85, 4.34) with increasing lifetime exposure to welding fumes. Welding fumes could contribute to an increased risk of some rare cancers.

Teaching presence predicts cyberloafing during online learning: From the perspective of the community of inquiry framework and social learning theory. Cyberloafing exists extensively in online learning and impairs learning, yet little is known about how course-related factors affect it. The community of inquiry framework maintains that learning is affected by teaching presence, according to which, we assume that teaching presence impacts cyberloafing, which is mediated by social presence, cognitive presence, and lack of attention, and moderated by normative influence. This study examined the effect of teaching presence on cyberloafing and its underlying mechanisms - the mediating roles of social presence, cognitive presence and lack of attention, and the moderating roles of normative influence. Participants were 814 university students who were taking video-centric asynchronous online courses. Self-report instruments were adopted, and data were analysed using structural equation modelling. Teaching presence was negatively associated with cyberloafing. Social presence (positively), cognitive presence (negatively), and lack of attention (negatively) mediated the relation, respectively. Social presence, cognitive presence and lack of attention were also serial mediators of the association (i.e., teaching presence → social presence → cognitive presence → cyberloafing; teaching presence → cognitive presence → lack of attention → cyberloafing; teaching presence → social presence → cognitive presence → lack of attention → cyberloafing), and these sequential mediating effects were negative. Moreover, normative influence could aggravate the negative effect of cognitive presence on lack of attention, the positive effect of social presence on cyberloafing, and the positive effect of lack of attention on cyberloafing. Theoretical and practical implications of the findings for learning and teaching are discussed.

Transporting a Prediction Model for Use in a New Target Population. We considered methods for transporting a prediction model for use in a new target population, both when outcome and covariate data for model development are available from a source population that has a different covariate distribution compared with the target population and when covariate data (but not outcome data) are available from the target population. We discuss how to tailor the prediction model to account for differences in the data distribution between the source population and the target population. We also discuss how to assess the model's performance (e.g., by estimating the mean squared prediction error) in the target population. We provide identifiability results for measures of model performance in the target population for a potentially misspecified prediction model under a sampling design where the source and the target population samples are obtained separately. We introduce the concept of prediction error modifiers that can be used to reason about tailoring measures of model performance to the target population. We illustrate the methods in simulated data and apply them to transport a prediction model for lung cancer diagnosis from the National Lung Screening Trial to the nationally representative target population of trial-eligible individuals in the National Health and Nutrition Examination Survey.

Time and sequence of emergence of the deciduous dentition in dogs and its applicability for age estimation. This study investigated the influence of several covariates on the time and sequence of deciduous dentition emergence in puppies. Data were obtained in a longitudinal study, with some cross-sectional observations, of 1001 puppies of 53 dog breeds. A parametric proportional hazards survival model was used to estimate median emergence time and evaluate the effect of the covariates. No significant differences were found between the left and right sides of a puppy's dentition, but differences were statistically significant for the earlier appearance of maxillary incisors and canines and later appearance of maxillary premolars compared with their mandibular counterparts. The tendency for delayed onset and completion of emergence in female compared to male puppies was statistically but not clinically significant. The differences between puppies of breeds of different size or skull type were both statistically and clinically significant, with small and brachycephalic breeds showing later emergence times, longer clinical eruption times and more individual variation. Per quadrant, regardless of dog breed, canines or incisors were usually the first teeth to emerge and fully erupt, followed by premolars in the order Pd3 > 4 > 2. The maxillary canines and incisors usually emerged earlier than mandibular canines. Age estimation standards for breed size groups are presented based on the number of emerged teeth per quadrant. To assess whether a puppy has reached the legally required minimum age of 8 weeks to leave the litter, the best predictive capability using the data from this study is obtained when assessing the emergence status of the deciduous third premolars.

Extremely rare occurrence of multiple cranial fasciitis: A case report. Cranial fasciitis (CF) is a rare, rapidly growing, benign fibroproliferative lesion of the skull in the pediatric population. It is characterized by benign mesenchymal proliferation of spindle cells arranged as short, intersecting loose fascicles within a fibromyxoid stroma, and mostly appears as a single mass. A surgical excision with clear surgical margins is definitively curative for CF. Up to date only two cases with multiple CF have been reported in the literature. In this report, we describe a 1-year-old girl with multiple locations of CF, as the first case to be reported in the Turkish population. The radiological and morphological findings of our case were comparable with the observations of the two previous reports in the literature. Histopathological examination remains to be the gold-standard for differential diagnosis of CF, as the treatment of this lesion differs from other malignancies of the skull in the pediatric population.

Ludvig Dahl's psychiatric genetic studies in his 1859 monograph: "Contribution to the knowledge of insanity in Norway". In 1859, Ludvig Dahl, a Norwegian alienist, wrote a rarely referenced book entitled "Contribution to The Knowledge of Insanity." In it, he describes a highly innovative psychiatric genetics research project with severable notable features. First, while the vast majority of 19th century psychiatric genetic studies were based on asylum hospital records, Dahl did field work to find cases of mental illness in certain defined areas within Norway, using census data, key-informants, record reviews, and personal interviews especially of suspected affected individuals. Second, for the first time in the history of psychiatric genetics, and perhaps more broadly in medical genetics, Dahl studied and graphed extensive pedigrees covering up to seven generations demonstrating a high density of psychiatric illness. Third, he proposed and conducted the first controlled investigation of familial aggregation of insanity. A 126 member 5-generation pedigree that he studied contained 8 individuals with confirmed insanity compared to 16 cases in the remaining 2,974 individuals in the Parish, a relative risk of nearly 12. Dahl also noted the co-segregation within pedigrees of mental handicap, deaf-mutism, and insanity. He evaluated familial-environmental sources of familial aggregation and noted, among nonpsychotic family members in his pedigrees, personalities that might reflect a "disposition" to insanity.