Patterning of B16 melanoma metastasis and colonization generally relates to tumor cell growth-stimulating or growth-inhibiting effects of organs and tissues.
The mouse B16 melanoma metastasizes first to the lungs and secondarily to systemic sites, involving mainly the adrenals, ovaries and pancreas. Systemic colonization effected by intracardiac injection of tumor cells establishes similar patterning, but in addition frequently colonizes the bones. To assess possible systemic site influences on metastasis and colony formation, the capacity of B16 melanoma cells to proliferate in these sites in vivo and in ex vivo explants following intracardiac injection was examined. Effects of cells isolated from these sites, and of organ- or tissue-conditioned medium, on growth of B16 cells in monolayer culture were also studied. Injected fluorochrome-labeled tumor cells initially distributed without site preference, but within 48 h had begun proliferating in the adrenals, ovaries and lungs, while remaining static in the pancreas and bones, and disappearing from the spleen, liver, kidneys, brain, and skeletal muscles. Mitogenic activity releasable in soluble form was associated with all favorable organs and tissues and was the predominant influence of those tissues on cultured tumor cells. In contrast, the overall effects of liver, spleen, kidney, and brain tissues were to inhibit tumor cell growth. Soluble growth-promoting activity enhanced clonogenic growth of isolated tumor cells stimulated by mouse serum, suggesting that metastasis or colony formation might be stimulated in favorable sites by those factors together with blood-borne growth factors. The observed effects of organ- and tissue-derived cells and soluble factors on tumor cells generally reflected the in vivo consequences of tumor cell entrapment in the corresponding sites. However, the failure of metastases to develop in the bones, which are favorable sites for colonization by the same cells, remains puzzling.


Variations in the soil micro-food web structure and its relationship with soil C and N mineralization during secondary succession of subalpine forests.
The soil micro-food web is an important network of belowground trophic relationships and it participates directly and indirectly in soil ecological processes. In recent decades, the roles of the soil micro-food web in regulating ecosystem functions in grasslands and agroecosystems have received much attention. However, the variations in the soil micro-food web structure and its relationship with ecosystem functions during forest secondary succession remain unclear. In this study, we investigated how forest secondary succession affected the soil micro-food web (including soil microbes and nematodes) and soil carbon and nitrogen mineralization across a successional sequence of "grasslands - shrublands - broadleaf forests - coniferous forests" in a subalpine region of southwestern China. With forest successional development, the total soil microbial biomass and the biomass of each microbial group generally increased. The significant influences of forest succession on soil nematodes were mainly reflected in several trophic groups with high colonizer-persister values (particularly bacterivore3, herbivore5 and omnivore-predator5) that are sensitive to environmental disturbance. The increases in the connectance and nematode genus richness, diversity, and maturity index indicated an increasingly stable and complex soil micro-food web with forest succession, which was closely related to soil nutrients, particularly the soil carbon contents. Additionally, we found that the soil carbon and nitrogen mineralization rates also exhibited generally increasing trends during forest succession, which had significant positive correlations with the soil micro-food web composition and structure. The path analysis results indicated that the variances in ecosystem functions induced by forest succession were significantly determined by soil nutrients and soil microbial and nematode communities. Overall, these results suggested that forest succession enriched and stabilized the soil micro-food web and promoted ecosystem functions via the increase in soil nutrients, and the soil micro-food web played an important role in regulating ecosystem functions during forest succession.


Correction: Effect of preterm birth on early neonatal, late neonatal, and postneonatal mortality in India.
[This corrects the article DOI: 10.1371/journal.pgph.0000205.].


Interaction between HMG proteins (1 + 2) and the negative regulatory region 1 (NCR1) in the 5'-flanking sequence of the human beta-globin gene.
The pattern of high mobility group proteins 1 and 2 (HMG1,2) interaction with the 5'-flanking sequence of the human beta-globin gene has been analyzed by scanning tunnelling microscopy (STM). A 200 bp negative regulatory region in the 5'-flanking sequence of the human beta-globin gene can be folded by HMG proteins 1 and 2 into a circular structure (diameter 70 +/- 6 A) with a linear tail which seems to be a left-handed double helix structure.


Differential diagnosis of the association of gastrointestinal symptoms and ST segment elevation, in the absence of chest pain.
This is a review of the underlying causes of the association of ST segment elevation and gastrointestinal symptoms such as abdominal pain, nausea, vomiting, and anorexia, in patients who do not have chest pain. The review was based on anecdotal reports in Googlescholar and Pubmed using the search terms, abdominal pain, nausea, vomiting, anorexia, ST elevation, myocardial infarction, and Takotsubo cardiomyopathy. Those patients who did not have acute myocardial infarction as the cause of the association of ST segment elevation and gastrointestinal symptoms were compared with counterparts with similar symptoms who had well authenticated acute myocardial infarction or Takotsubo cardiomyopathy as the underlying cause of ST segment elevation. The underlying causes of gastrointestinal symptoms which could be associated with ST segment elevation in the absence of either acute myocardial infarction or Takotsubo cardiomyopathy comprised pneumonia, pulmonary embolism, perforated gastric ulcer, intestinal obstruction, acute appendicitis, acute pancreatitis, acute cholecystitis, pheochromocytoma, bacterial meningitis, diabetic keto acidosis, and cannabis abuse. However, each of those disorders could also coexist either with acute myocardial infarction or with Takotsubo cardiomyopathy. The coexistence of ST segment elevation and gastrointestinal symptoms(without chest pain) was also documented in patients with esophageal perforation, mesenteric ischaemia, aortic dissection, Kounis syndrome, and in electrolyte disorders. In the context of presentation with gastroenterological symptoms but without concurrent chest pain, echocardiography appeared to be useful in distinguishing between "pseudo" myocardial infarction characterised by ST segment elevation in the absence of cardiac disease vs ST segment elevation attributable either to acute myocardial infarction or to Takotsubo cardiomyopathy.


Effects of collision cascade density on radiation defect dynamics in 3C-SiC.
Effects of the collision cascade density on radiation damage in SiC remain poorly understood. Here, we study damage buildup and defect interaction dynamics in 3C-SiC bombarded at 100 °C with either continuous or pulsed beams of 500 keV Ne, Ar, Kr, or Xe ions. We find that bombardment with heavier ions, which create denser collision cascades, results in a decrease in the dynamic annealing efficiency and an increase in both the amorphization cross-section constant and the time constant of dynamic annealing. The cascade density behavior of these parameters is non-linear and appears to be uncorrelated. These results demonstrate clearly (and quantitatively) an important role of the collision cascade density in dynamic radiation defect processes in 3C-SiC.


Testosterone effects on pain and brain activation patterns.
This study investigated whether pain and pain-related unpleasantness ratings were altered by blood testosterone levels. We also investigated whether activation of brain regions that represent pain intensity [primary somatosensory cortex (S1)] and pain-related unpleasantness [perigenual ACC (pACC) and orbitofrontal cortex (OFC)] were affected by blood testosterone levels. Twenty-six healthy men were recruited. Blood testosterone levels were measured before fMRI scanning. The participants were classified into two groups (high vs. low testosterone) according to their blood testosterone level (each group n = 13). The middle finger was immersed in a 50°C water bath (50°C, 30 s, five times) to induce identical noxious stimulation in all participants. The low testosterone group showed statistically significantly higher pain (P = 0.047), unpleasantness (P = 0.047), anxiety (P = 0.015), and fear ratings (P = 0.01) than the high testosterone group. Fear rating increased as pain rating rose and as testosterone level decreased (P < 0.001). When participants received noxious stimulation, the pACC and OFC were more highly activated in the low testosterone group compared to the high testosterone group. Activation of S1, a region related to pain intensity, did not differ between both groups. Compared to the high testosterone group, the low testosterone group had significant activation in the pACC and OFC, regions that represent pain-related unpleasantness, but not in S1 that represents pain intensity, leading to higher pain ratings. These findings emphasize the importance of considering the effects of testosterone levels when treating patients.


Ubiquitin-specific peptidase 22 overexpression may promote cancer progression and poor prognosis in human gastric carcinoma.
Ubiquitin-specific peptidase 22 (USP22) was recently identified as a new tumor cell marker, and previous studies demonstrated its expression in a variety of tumors and its correlation with tumor progression. Because tumor progression plays an important role in cancer, researchers are paying more attention to the correlation between USP22 expression and metastatic potential, resistance to chemotherapy, and patient prognosis. This study showed that USP22 is highly expressed in gastric cancer tissues, and significant differences in USP22 expression (P < 0.01) were identified between different types of gastric cancer (the highest expression was found in poorly differentiated adenocarcinomas). In addition USP22 expression was found to be correlated with the promotion of cancer evolution, tumor invasion, and lymph node metastasis. The C-myc protein was also shown to have synergistic effects with USP22 in gastric cancer tissue. On the basis of the results, USP22 expression may play an important role in gastric carcinoma tissue, particularly in precancerous lesions during the gastric cancer evolution process.


Acute Low-Dose Capsiate Supplementation Improves Upper Body Resistance Exercise Performance in Trained Men: A Randomized, Crossover and Double-Blind Study.
The purpose of this study was to compare the effects of two acute doses of Capsiate (CAP; 6 vs. 12 mg) on upper body resistance exercise performance in trained men. Using a randomized, crossover and double-blind design, 20 resistance-trained males were supplemented with low-dose CAP (6 mg), high-dose CAP (12 mg) or placebo 45 minutes before exercise. Subjects performed 4 sets of bench press with repetitions to failure at 70% 1 repetition maximum (1RM) and 2 minutes of rest between each set. The ratings of perceived exertion (RPE) and blood lactate were analyzed at baseline and after exercise. Total weight lifted was greater in the low CAP (2,454.6 ± 448.6 kg) compared to placebo (2,354.7 ± 458.6 kg, p = 0.039) and high CAP (2,309.3 ± 428.1 kg, p = 0.001). There was no significant difference between conditions for RPE (p = 0.155) and blood lactate (p = 0.434). In summary, 6 mg CAP increased total weight lifted and repetitions to failure on bench press exercise in trained men, while 12 mg did not present any effect.


Single- and double-color oligonucleotide primed in situ labeling (PRINS): applications in pathology.
Molecular cytogenetics is mostly performed by fluorescence in situ hybridization using long DNA probes that are generated by vector cloning. Oligonucleotide primed in situ labeling (PRINS) is a recent method that has been established for the detection of the centromeric or telomeric region in metaphase chromosomes. In this overview, we demonstrate the possible applications of PRINS and provide elaborated protocols for its use in intact interphase cells of routine cytological preparations, e.g., cell smears, touch preparations, and cytospins of non-neoplastic and neoplastic tissues. Moreover, the various modifications of the PRINS method, such as multi-color PRINS for targeting different chromosomes within one cell or the enzymatic detection of the PRINS product instead of the more commonly used fluorochromes, are discussed.


The relaxant effect induced by Allium sativum L. bulb aqueous extract on rat isolated trachea.
Garlic plays an important role in complementary and alternative medicine. Most people believe in and use herbal products even when they have not been as thoroughly researched as garlic. Garlic is also known for its beneficial effects on the cardiovascular system. The relaxant effect of Allium sativum L. bulb aqueous extract (ASBAE) containing 0.06%-0.10% of allicin was studied on isolated smooth muscle of trachea of rats precontracted using acetylcholine (10(-5) M). It was found that ASBAE induced a dose-dependent relaxation with recorded EC (50) values of 71.87 ± 5.90 µg/mL (n = 7). Pretreatments with mepyramine (10(-7) M), methysergide (10(-7) M), caffeine (10(-6) M), theophylline (10(-6) M), nifedipine (10(-6) M), and dipyridamole (10(-6) M) did not alter ASBAE concentration-response curves. In turn, concentration-response curves to ASBAE were significantly shifted toward right in the presence of aspirin (3.10(-3) M), indomethacin (10(-6) M), prazosin (10(-6) M), and propranolol (10(-7) M). It is suggested that the recorded relaxation results are due to the release of prostaglandins E (1) and E (2) consecutively to α- and β-adrenoreceptor stimulation.


Phenotypic expression of bronchoalveolar lavage cells in lung rejection and infection.
The differentiation of episodes of lung allograft rejection from infection continues to be a problem. Bronchoalveolar lavage (BAL) has recently gained some success in the diagnosis and management of interstitial lung disease. To assess the usefulness of BAL in differentiating between lung allograft rejection and infection, we examined the differences in cellular subsets of BAL and peripheral blood (PBL) samples in a controlled canine model of rejection or pneumonia. Single-lung allotransplants were allowed to undergo rejection by withdrawing immunosuppressive agents (n = 6). In another group of dogs (n = 5), pneumonia was induced by transbronchial injection of Pseudomonas aeruginosa and melted agar followed by bronchial fulguration. Cells obtained from bronchoscopic BAL and PBL samples were labeled with functionally characterized cross-reactive murine monoclonal antibodies. Transthoracic needle biopsies and transbronchial biopsies were done to assess their adequacy in examining the rejecting or infected lungs and were compared with open lung biopsies. We found the following: (1) the percentage of DT2-labeled cells was significantly higher (p less than 0.05) in BAL samples from rejecting lungs compared with infected lungs; (2) the PBL/BAL ratio of DT2-labeled cell percentages was significantly higher in pneumonia (1.7 +/- 0.3) than rejection (0.5 +/- 0.2) (p less than 0.004); (3) the percentage of E11-labeled cells in PBL samples was significantly higher (p less than 0.02) in rejection than in infection; and (4) the ratio of WIG4 to DT2 cellular subset percentages in BAL samples from rejection (26.8 +/- 9.9) was significantly lower than from infection (61.0 +/- 22.9) (p less than 0.03). Transthoracic and transbronchial biopsies did not always yield representative specimens.(ABSTRACT TRUNCATED AT 250 WORDS)


Households and families: implications of changing census definitions for analyses using the ONS Longitudinal Study.
The ONS Longitudinal Study (LS) includes information from the 1971, 1981, 1991 and 2011 censuses. This article explains definitional differences over time, and their implications for household and family classifications.List of tables, 65.


A participatory approach to health promotion for informal sector workers in Thailand.
This study aims to promote occupational health in the informal sector in Thailand by using a participatory approach. The success of the intervention is based on an evaluation of the informal sector workers, a) knowledge, attitudes, and behaviors in occupational health and safety, b) work practice improvement, and c) working condition improvement. This study applies the Participatory Action Research (PAR) method. The participants of the study consisted of four local occupations in different regions of Thailand, including a ceramic making group in the North, a plastic weaving group in the Central region, a blanket making group in the Northeast, and a pandanus weaving group in the South. Data was collected using both qualitative and quantitative methods through questionnaires, industrial hygiene instruments, and group discussions. The results showed that the working conditions of the informal sector were improved to meet necessary standards after completing the participatory process. Also, the post-test average scores on 1) the occupational health and safety knowledge, attitudes and behaviors measures and 2) the work practice improvement measures were significantly higher than the pre-test average scores (P less than 0.05). The results demonstrate that the participatory approach is an effective tool to use when promoting the health safety of the informal sector and when encouraging the workers to voluntarily improve the quality of their own lives.


Transcription map of the early region of the Streptomyces bacteriophage phi C31.
Streptomyces coelicolor A3(2), lysogenised by the temperature-sensitive cts1 mutant of phi C31, can be synchronously induced into the lytic cycle by heat treatment. A transcription map of 10 kb of the phi C31 early gene cluster was deduced using low-resolution S1 nuclease mapping of RNA prepared 10 min after induction. At least nine early transcripts, early (e)RNAs 1-9, were localised reading exclusively rightwards with respect to the standard physical map of phi C31. The mRNAs were extensively overlapping, frequently initiating at the same place but terminating at different sites, and vice versa. Gene expression during the lytic cycle was tightly regulated; no transcription was observed before induction. Transcription was maximal at 10 min post-induction, and at 20 min, eRNAs 5 and 6 persisted whilst eRNAs 7-9 were severely reduced or absent. The pattern of transcription of the early region is consistent with the simultaneous activation of a large number of promoters and differential termination efficiency.


Background release and potential point sources of per- and polyfluoroalkyl substances to municipal wastewater treatment plants across Australia.
Wastewater treatment plants (WWTPs) are known to be significant sources of per- and polyfluoroalkyl substances (PFAS) to the environment. In this study, PFAS were measured in the influent of 76 municipal wastewater treatment plants (WWTPs) serving approximately 53% of the Australian population. Of fourteen target PFAS, twelve analytes including six C5-C10 perfluoroalkyl carboxylic acids (PFCAs), four C4-10 perfluoroalkyl sulfonic acids (PFSAs) and two fluorotelomer sulfonates (6:2 and 8:2 FTS) were detected. Of these, PFOS, PFHxS and PFHxA had the highest median concentrations. The per capita background release of Σ12 PFAS to WWTP influent in Australia was estimated to be 8.1-24 μg/d/per person. The background release was supplemented by contributions from catchment specific point sources (i.e., industry, airports, military bases, and landfills), whereby the number of industrial sites positively correlated with the per capita mass load of Σ12 PFAS (r = 0.5-0.63, p < 0.01). The per capita mass loads were extrapolated to the entire Australian population, with estimates suggesting that approximately 1 kg/d of Σ12 PFAS reach WWTPs in Australia (300-400 kg annually), with more than half of the PFAS (∼59%) attributed to background release and the remaining (∼41%) to catchment specific point sources. These data provide insight into the release of major PFAS to wastewater at a national scale in Australia.


Quantifying the potential dominance of immune-evading SARS-CoV-2 variants in the United States.
Recent evidence suggests that some new SARS-CoV-2 variants with spike mutations, such as P.1 (Gamma) and B.1.617.2 (Delta), exhibit partial immune evasion to antibodies generated by natural infection or vaccination. By considering the Gamma and Delta variants in a multi-variant transmission dynamic model, we evaluated the dominance of these variants in the United States (US) despite mounting vaccination coverage and other circulating variants. Our results suggest that while the dominance of the Gamma variant is improbable, the Delta variant would become the most prevalent variant in the US, driving a surge in infections and hospitalizations. Our study highlights the urgency for accelerated vaccination and continued adherence to non-pharmaceutical measures until viral circulation is driven low.


Retrospective case series to identify the most common conditions seen 'out-of-hours' by first-opinion equine veterinary practitioners.
The study aim was to describe conditions seen 'out-of-hours' in equine practice. This was a retrospective case series of first opinion 'out-of-hours' cases seen at two equine practices between 2011 and 2013. Data were retrieved on case presentation, diagnostic testing, treatment administered and outcome, and diseases categorised using a systems-based coding system. A hierarchical logistic regression, formulated using a generalised linear model, was used to identify clinical variables associated with a binary outcome of 'critical' cases (required hospitalisation or euthanasia or died). Data from 2602 cases were analysed. The most common reasons for 'out-of-hours' visits were colic (35 per cent, n=923/2620), wounds (20 per cent, n=511/2620) and lameness (11 per cent, n=288/2,620). The majority of cases required a single treatment (58 per cent, n=1475/2550), 26 per cent (n=656/2550) needed multiple treatments and 13 per cent (n=339/2550) were euthanased. Eighteen per cent (n=480/2602) of cases had a critical outcome. Increased heart rate at primary presentation was associated with critical outcome in both practices (Practice A, OR 1.07 (95 per cent confidence interval 1.06 to 1.09), Practice B OR 1.08 (95 per cent confidence interval 1.07 to 1.09; p<0.001)). Colic, wounds and lameness were the most common equine 'out-of-hours' conditions; 13 per cent of cases were euthanased. Further research is required into out-of-hours euthanasia decision-making.


Enhancement of mechanical properties and shape memory effect of Ti-Cr-based alloys via Au and Cu modifications.
The requirements for biomedical materials have been raised greatly due to the rapidly aging global population. Shape memory alloys (SMAs) are indeed promising materials for biomedical applications due to their controllable shape deformation via the manipulation of temperature and/or stress. This study investigated the enhancement of the fundamental mechanical properties and the shape memory effect (SME) in the Ti-Cr-based alloys via the modification of Au and Cu. The quaternary Ti-Cr-Au-Cu alloys were successfully manufactured by physical metallurgy methods and their phase constitutions, mechanical properties, SME, and superelastic (SE) behaviors have been investigated in this study. Cold-workability, which was enhanced by the introduction of the Au element, was elaborated by the phase constitutions of the alloys. The β-parent phase was stabilized to around body temperature by the introduction of the β-stabilizers of Cr, Au, and Cu, and the functionalities of the specimens were revealed at the operating temperature. Perfect SME at the shape recovery rate of 100% was practiced by the substitution of Au by Cu and the mechanical properties, such as strength and ductility, were also enhanced. Functional mappings of the fundamental mechanical properties, which could be a helpful tool for the investigations of the quaternary Ti-Cr-Au-Cu alloys, were constructed in this work.


Transdermal iontophoretic delivery of a liquid lipophilic drug by complexation with an anionic cyclodextrin.
Iontophoresis is now established as one of the methods of enhancing transdermal delivery of drugs. However, its application to enhance the delivery of highly lipophilic compounds is limited due to lack of any charge and poor water solubility of molecules. Propofol, a sedative and anesthetic drug was chosen as a model lipophilic drug in this study. Propofol was complexed with sulfobutyl ether-β-cyclodextrin (SCD), a β-cyclodextrin derivative carrying ionizable groups to render propofol amenable to iontophoresis. The phase solubility studies of propofol with SCD revealed an AL type curve indicating a stoichiometry of 1:1. The complex was characterized by UV-spectrophotometry and (1)HNMR. Transport studies were performed using Franz diffusion cells across porcine epidermis. The passive permeation flux of propofol was enhanced by fourfold due to complexation with SCD. Application of iontophoresis (0.5mA/cm(2)) to SCD-propofol solution enhanced the transport of propofol by an additional fourfold. The enhancement in the transport of propofol after complexation was found to be due to multiple mechanisms such as transport of intact complex, enhanced thermodynamic activity of drug at the interface and prolonged recovery of barrier disrupted due to iontophoresis. The pharmacokinetic studies were performed in Sprague-Dawley rats to assess the feasibility of transdermal iontophoretic delivery in vivo, of a lipophilic drug complexed with SCD.


Inhibitory activity of Plantago major L. on angiotensin I-converting enzyme.
Eight compounds were isolated from methanol extract of Plantago major L. leaves and investigated for their ability to inhibit angiotensin I-converting enzyme activity. Among them, compound 1 showed the most potent inhibition with rate of 28.06 ± 0.21% at a concentration of 100 μM. Compounds 2 and 8 exhibited weak activities. These results suggest that compound 1 might contribute to the ability of P. major to inhibit the activity of angiotensin I- converting enzyme.


Chest CT scan plus x-ray versus chest x-ray for the follow-up of completely resected non-small-cell lung cancer (IFCT-0302): a multicentre, open-label, randomised, phase 3 trial.
Even after resection of early-stage non-small-cell lung cancer (NSCLC), patients have a high risk of developing recurrence and second primary lung cancer. We aimed to assess efficacy of a follow-up approach including clinic visits, chest x-rays, chest CT scans, and fibre-optic bronchoscopy versus clinical visits and chest x-rays after surgery for resectable NSCLC. In this multicentre, open-label, randomised, phase 3 trial (IFCT-0302), patients aged 18 years or older and after complete resection of pathological stage I-IIIA NSCLC according to the sixth edition of the TNM classification were enrolled within 8 weeks of resection from 122 hospitals and tertiary centres in France. Patients were randomly assigned (1:1) to CT-based follow-up (clinic visits, chest x-rays, thoraco-abdominal CT scans, and fibre-optic bronchoscopy for non-adenocarcinoma histology) or minimal follow-up (visits and chest x-rays) after surgery for NSCLC, by means of a computer-generated sequence using the minimisation method. Procedures were repeated every 6 months for the first 2 years and yearly until 5 years. The primary endpoint was overall survival analysed in the intention-to-treat population. Secondary endpoints, also analysed in the intention-to-treat population, included disease-free survival. This trial is registered with ClinicalTrials.gov, NCT00198341, and is active, but not enrolling. Between Jan 3, 2005, and Nov 30, 2012, 1775 patients were enrolled and randomly assigned to a follow-up group (888 patients to the minimal follow-up group; 887 patients to the CT-based follow-up group). Median overall survival was not significantly different between follow-up groups (8·5 years [95% CI 7·4-9·6] in the minimal follow-up group vs 10·3 years [8·1-not reached] in the CT-based follow-up group; adjusted hazard ratio [HR] 0·95, 95% CI 0·83-1·10; log-rank p=0·49). Disease-free survival was not significantly different between follow-up groups (median not reached [95% CI not estimable-not estimable] in the minimal follow-up group vs 4·9 [4·3-not reached] in the CT-based follow-up group; adjusted HR 1·14, 95% CI 0·99-1·30; log-rank p=0·063). Recurrence was detected in 246 (27·7%) of 888 patients in the minimal follow-up group and in 289 (32·6%) patients of 887 in the CT-based follow-up group. Second primary lung cancer was diagnosed in 27 (3·0%) patients in the minimal follow-up group and 40 patients (4·5%) in the CT-based follow-up group. No serious adverse events related to the trial procedures were reported. The addition of thoracic CT scans during follow-up, which included clinic visits and chest x-rays after surgery, did not result in longer survival among patients with NSCLC. However, it did enable the detection of more cases of early recurrence and second primary lung cancer, which are more amenable to curative-intent treatment, supporting the use of CT-based follow-up, especially in countries where lung cancer screening is already implemented, alongside with other supportive measures. French Health Ministry, French National Cancer Institute, Weisbrem-Benenson Foundation, La Ligue Nationale Contre Le Cancer, and Lilly Oncology. For the French translation of the abstract see Supplementary Materials section.


Tilorone increases glucose uptake in vivo and in skeletal muscle cells by enhancing Akt2/AS160 signaling and glucose transporter levels.
Skeletal muscle plays a major role in whole-body glucose metabolism. Insulin resistance in skeletal muscle is characterized by decreased insulin-stimulated glucose uptake resulting from impaired intracellular trafficking and decreased glucose transporter 4 (GLUT4) expression. In this study, we illustrated that tilorone, a low-molecular-weight antiviral agent, improves glucose uptake in vitro and in vivo. Tilorone increased bone morphogenetic protein (BMP) signaling in C2C12 myoblasts, the transcription of multiple BMPs (BMP2, BMP4, BMP7, and BMP14), Smad4 expression, and the phosphorylation of BMP-mediated Smad1/5/8. The activation of Akt2/AS160 (TBC1D4) signaling, the critical regulator of GLUT4 translocation, was also increased, as well as the levels of GLUT4 and GLUT1, leading to enhanced uptake of the radioactively labeled glucose analog 18 F-fluoro-2-deoxyglucose (18 FDG). However, this excess glucose content did not result in increased ATP formation by mitochondrial respiration; both basal and ATP-linked respiration were diminished, thereby contributing to the induction of AMPK. In differentiated myotubes, AS160 phosphorylation and 18 FDG uptake also increased. Moreover, tilorone administration further increased insulin-stimulated phosphorylation of Akt2 and glucose uptake of myotubes indicating an insulin-sensitizing effect. Importantly, during in vivo experiments, the systemic administration of tilorone resulted in increased 18 FDG uptake of skeletal muscle, liver, and adipose tissue in C57BL/6 mice. Our results provide new perspectives for the treatment of type 2 diabetes, which has a limited number of treatments that regulate protein expression or translocation.


An Antiviral Drug-Peramivir: Degradation and Identification of Impurities and the Endorsement of an HPLC-MS Method.
Peramivir is a neuraminidase inhibitor that serves as a transition state analogue for influenza neuraminidase, inhibiting the formation of new viruses in infected cells, and has been approved for intravenous administration. To validate an HPLC method used to identify the degraded products of the antiviral drug peramivir. Herein, we report the identification of compounds formed after the degradation of peramivir through acid, alkali, peroxide, thermal, and photolytic degradation. At the level of toxicology, a technique was devised for the isolation and measurement of peramivir. A sensitive and reliable LC-tandem mass spectrometry technique for the quantitative measurement of Peramivir and its impurities was developed and verified in order to comply with the recommendations made by the International Council for Harmonisation (ICH). The proposed protocol was in the 50-750 µg/mL range. Relative Standard Deviation values of less than 2.0% indicated good recovery in the range of 98.36-102.57%. Within the studied range, the calibration curves demonstrated good linearity and, in addition, the fitting of correlation coefficient was more than 0.999 for every impurity. Quantitative analysis of contaminants revealed the high efficiency at a low level. Given its ability to separate degradation products, quantitative analysis is used to detect and quantify known and unknown impurities and degradants in the peramivir drug substance during routine analysis and stability studies. No significant degradation was found in peroxide and photolytic degradation studies. An HPLC method was developed and put to the test in order to analyze the behavior of the impurities of peramivir as they degraded when subjected to the stress conditions suggested by the ICH. Peramivir was found to be stable under peroxide and photolysis conditions but not stable or degradable when exposed to the acid, base, and thermal stress conditions. The method developed was extremely precise, linear, accurate, robust, and rugged. As a result, this technology has the potential to be used in the medication production process for regular impurity analysis as well as for the stability analysis of peramivir.


What do health care professionals know about childhood asthma?
The aim of this study was to examine the level of knowledge about childhood asthma in paediatric nurses, pharmacists and general practitioners to assess their potential value as sources of accurate information for patients with asthma. The main outcome measure was the score obtained on an asthma knowledge questionnaire which had been validated previously. The maximum possible score was 31. Eighty-three general practitioners had a mean score of 28.1 (range 14-31); 82 pharmacists scored a mean of 24.2 (range 15-30) and 30 paediatric nurses had a mean score of 25.5 (range 16-30). General practitioners scored well in most questions but had some worrying deficiencies, particularly in distinguishing preventive therapy from symptom relieving medication. Pharmacists and paediatric nurses had a number of problems in certain important areas. In particular pharmacists as a group were unaware of many of the clinical features of asthma, had misconceptions, such as the need to avoid cow's milk, and recorded incorrect responses to clinical scenarios of acute treatment. Paediatric nurses tended to overestimate the side effects of inhaled medications, and also the value of auscultation. They had poor knowledge of exercise-induced asthma. The data overall suggest that specific educational strategies should be devised for different groups of health professionals who manage children with asthma and suggest that poor knowledge on the part of health care providers may contribute to morbidity.


Chirp rate is independent of male condition in a synchronising bushcricket.
Males of the bushcricket Mecopoda elongata synchronise their chirps with neighbouring males, but because synchrony is imperfect, one male's chirp preceeds the other by some 50-200 ms. Since a male's intrinsic chirp rate is critical for the establishment of the leader role in a duet, and females prefer the leader in a choice situation, we investigated a possible condition dependence of this male trait. In a duet leader males are usually those calling at a higher intrinsic rate; therefore, we investigated whether calling at a higher rate indicates male condition. The calling metabolism was quantified in a respirometer; the factorial slope of males calling at a high rate was three times higher compared to males calling at lower rates. Males produce on average 3.4 singing bouts/per night, and there is a significant increase in chirp periods (CPs) with successive singing bouts. Call properties were investigated throughout a male's life; chirp period increases significantly with age. Two groups of males were reared on either a low- or a high-nutrition diet, and the influence of male condition on different song parameters was investigated. CPs in two feeding regimes did not differ significantly, although males of the low-nutrition diet group were significantly affected by nutrition with respect to mortality, a delayed last moult and reduced weight as adults. We therefore conclude that solo chirp rates do not reflect phenotypic male condition properly.


Epigallocatechin-3-gallate attenuates cyclophosphamide-induced damage in mouse ovarian tissue via suppressing inflammation, apoptosis, and expression of phosphorylated Akt, FOXO3a and rpS6.
This study was conducted to evaluate the protective effects of epigallocatechin-3-gallate (EGCG) against ovarian toxicity in cyclophosphamide-treated mice and to verify the possible involvement of phosphorylated Akt, FOXO3a and rpS6 in the EGCG actions. Mice received saline solution (i.p.; control) or a single dose of cyclophosphamide (200 mg/kg body weight, i.p.) or mice were pretreated with N-acetylcysteine (150 mg/kg body weight, i.p.; positive control) or with EGCG (5, 25 or 50 mg/kg body weight, i.p.) once daily for three days followed by injection with single dose of cyclophosphamide (200 mg/kg body weight, i.p.). Thereafter, the mice were euthanized, and the ovaries were harvested and destined to histological (follicular morphology and activation), immunohistochemistry (cleaved caspase-3 and TNF-α) and fluorescence (mitochondrial activity and GSH concentrations) analyses. Furthermore, we examined the participation of p-Akt, p-FOXO3a and p-rpS6 in the protective effects of EGCG in cyclophosphamide-induced ovarian damage by immunohistochemical staining. The results showed that pretreatment with N-acetylcysteine or EGCG at 25 and 50 mg/kg before cyclophosphamide administration preserved the normal follicular morphology, prevented primordial follicle loss, reduced atresia, inflammation, and mitochondrial damage, and increased GSH concentrations compared to the only cyclophosphamide treatment. Additionally, pretreatment with 25 mg/kg EGCG regulated phosphorylated Akt, FOXO3a and rpS6 after cyclophosphamide treatment. In conclusion, short-time pretreatment with 25 mg/kg EGCG can prevent follicle loss in cyclophosphamide-treated mice by reducing oxidative damage, inflammation, and apoptosis, and regulating of p-Akt, p-FOXO3a and p-rpS6.


Cell-Cell Contact Area Affects Notch Signaling and Notch-Dependent Patterning.
During development, cells undergo dramatic changes in their morphology. By affecting contact geometry, these morphological changes could influence cellular communication. However, it has remained unclear whether and how signaling depends on contact geometry. This question is particularly relevant for Notch signaling, which coordinates neighboring cell fates through direct cell-cell signaling. Using micropatterning with a receptor trans-endocytosis assay, we show that signaling between pairs of cells correlates with their contact area. This relationship extends across contact diameters ranging from micrometers to tens of micrometers. Mathematical modeling predicts that dependence of signaling on contact area can bias cellular differentiation in Notch-mediated lateral inhibition processes, such that smaller cells are more likely to differentiate into signal-producing cells. Consistent with this prediction, analysis of developing chick inner ear revealed that ligand-producing hair cell precursors have smaller apical footprints than non-hair cells. Together, these results highlight the influence of cell morphology on fate determination processes.


Population pharmacokinetic modeling and simulation of maribavir to support dose selection and regulatory approval in adolescents with posttransplant refractory cytomegalovirus.
Maribavir was approved by the US Food and Drug Administration for the treatment of patients aged ≥12 years and weighing ≥35 kg with posttransplant cytomegalovirus infection/disease refractory (with/without resistance) to valganciclovir, ganciclovir, cidofovir, or foscarnet, with an oral dose of 400 mg twice daily. With no pediatric clinical data available and difficulty in trial recruitment, population pharmacokinetic modeling and simulations were conducted to predict the pharmacokinetics and inform maribavir dosing in adolescents.


[Efficacy of second-line treatment based on moxifloxacin triple therapy for Helicobacter pylori infection].
To evaluate the efficacy and tolerability of moxifloxacin-based triple therapy as an alternative second-line treatment for Helicobacter pylori (H. pylori) infection. A total of 109 patients, in whom the initial standard PPI triple therapy had failed to eradicate Hp infection, were included. Patients were randomized to one of the following 7-day treatment regimens: (1) rabeprazole 10 mg twice a day, moxifloxacin 400 mg/day and amoxicillin 1000 mg twice a day; and (2) rabeprazole 10 mg twice a day, bismuth salts 150 mg three times a day; clarithromycin 500 mg twice a day, metronidazole 400 mg twice a day. The eradication rates and side-effect rates of these two regimens were compared. The eradication rates were 75.5% (40/53) and 83.3% (40/48) with moxifloxacin-based triple therapy, and 62.5% (35/56) and 71.4% (35/49) with bismuth-based quadruple therapy by intention-to-treat and per-protocol analyses (both P > 0.05) respectively. The 7-day moxifloxacin-based triple therapy has a high eradication rate with fewer side-effects. This regimen can be a safe and effective option as second-line treatment for H. pylori infection.


[Augmentation cystoplasty: Perioperative management for urologic nurses].
Augmentation cystoplasty (AC) is a surgical option to restore a good capacity bladder reservoir able to fill at low pressure. The authors present the main principles for perioperative management for urologic nurses. AC is usually made with a piece of ileum patched to the bladder. Patient education programs are very important and are usually managed by urologic nurses. It begins in preoperative phase with the self-catheterization learning and continue in the postoperative phase with advises and prevention of the urinary mucus. AC are tricky surgeries but management and education of patients by urological nurses are key points to avoid chronic infection, stones or AC perforation.


Prevention of epidural fibrosis in rats by local or systemic administration of citicoline.
The objective of this study was to investigate the effect of citicoline administration on epidural fibrosis which is a frequent complication of lumbar disc surgery with no effective treatment or preventive surgical technique. Sixty Sprague-Dawley female rats undergoing L4-5 right hemilaminotomy and annular fenestration were arranged in three groups: rats in Group 1 (control group) and Group 2 (topical citicoline group) were applied 0,9% saline and 100 μM citicoline on surgical area, respectively, while rats in Group 3 (systemic citicoline group) received 600 μmol/kg citicoline intraperitoneally. Rats were sacrificed four weeks later and their vertebral colons were removed en bloc. Groups were evaluated according to histological criteria and results were compared using statistical tools. Compared with control group, significantly less epidural fibrosis, dural adhesion, fibroblast cell density, foreign body reaction, and medulla spinalis retraction were observed in groups treated with topical and systemic citicoline (groups 2 and 3) (p < 0,001). No significant difference was found with regard to measured parameters between two treatment groups (p > 0,05). Our study demonstrates for the first time in the literature that citicoline may be effective for preventing postoperative epidural fibrosis. However, its mechanism of action and clinical effectiveness must be further investigated.


Effects of simvastatin on serum adiponectin: a meta-analysis of randomized controlled trials.
Effects of simvastatin on serum level of adiponectin, a protein conferring benefits in both cardiovascular and metabolic system, are not fully determined. A meta-analysis of randomized controlled trials (RCTs) was performed. Studies were identified by searching of Pubmed, Embase, and the Cochrane Library databases. Heterogeneity among the RCTs was determined by Cochrane's Q test and I2 statistics. Meta-analysis was performed with random-effect model or fixed-effect model according to the heterogeneity. Meta-regression and subgroup analyses were performed to analyze the source of heterogeneity. Twelve RCTs with 16 comparisons and 1042 patients were included. Overall, serum adiponectin was not significantly affected by simvastatin (WMD: 0.42 μg/mL; 95% CI, -0.66-1.50 μg/mL). However, significant heterogeneity was detected (Cochrane's Q test: p < 0.01; I2 = 83%). Subsequent meta-regression analyses indicated that treatment duration was a significant determinant of the effects of simvastatin treatment on serum adiponectin (Coefficient 0.04, p = 0.03). Subgroup analyses demonstrated that simvastatin treatment was associated with increased adiponectin in studies with treatment duration of 12 weeks (WMD: 3.65 μg/mL; p < 0.01), but not in studies with treatment duration of ≤ 8 weeks (WMD: -0.20 μg/mL; p = 0.38). The different between the two stratums was significant (p < 0.01). Treatment with simvastatin of 12 weeks may increase the serum level adiponectin in patients at risk for cardiovascular diseases, but not for the short term treatment of ≤ 8 weeks.


Protective effects of quercetin-loaded microcapsules on the enteric nervous system of diabetic rats.
Quercetin-loaded microcapsules (QLM) promote controlled release and higher bioavailability of quercetin, an antioxidant and neuroprotective agent. We evaluated the antioxidant effect of QLM on enteric innervation and in the oxidative status of the ileum of diabetic rats. Wistar adult rats (Rattus norvegicus) were used in six groups containing normoglycemic (N), diabetic (D) and either normoglycemic or diabetic groups treated with QLM at a dose of 10 mg/kg (NQ10 and DQ10, respectively) or 100 mg/kg (NQ100 and DQ100, respectively). DQ10 e DQ100 did not prevent overall neuronal loss in the total and cholinergic populations. Nitrergic population showed differences regarding the treatments: DQ10 preserved neurons in the nitrergic population whilst DQ100 increased nitrergic loss. Evaluation of the redox status showed pro-oxidant effects in NQ100 by t-butyl-induced chemiluminescence analysis. We observed a reduction in the carbonylic content and an increase of low molecular weight antioxidants for DQ10 e DQ100. Therefore, QLM treatment at a dose of 10 mg/kg acted positively on nitrergic neurons reducing oxidative damage induced by diabetes.


Schizophrenia and processing of facial emotions: sex matters.
The aim of this study was to examine sex differences in emotion processing in patients with schizophrenia and control subjects. To this end, 53 patients with schizophrenia (28 men and 25 women), and 42 controls (21 men and 21 women) were assessed with the use of a facial affect recognition morphing task. Accuracy and sensitivity scores were measured. Women performed better than men in labelling negative emotions. On the same task, patients performed worse than control subjects, irrespective of sex, although the largest degree of impairment was seen in male patients. In conclusion, emotion perception was disproportionally affected in men with schizophrenia relative to women. This may explain, in part, why women with schizophrenia are less impaired in social life than men suffering from this illness.


METTL3-mediated LINC00657 promotes osteogenic differentiation of mesenchymal stem cells via miR-144-3p/BMPR1B axis.
N6-methyladenosine (m6A) modification plays a crucial role in the progression of osteoporosis (OP). The study aimed to explore the effects of methyltransferase-like 3 (METTL3) in OP. The levels of METTL3, LINC00657, miR-144-3p and BMPR1B were detected using qPCR. Osteogenesis was assessed using alizarin red and alkaline phosphatase (ALP) staining assays. The protein expression of Bglap, Runx2 and Col1a1 was measured by western blot. The targets of LINC00657 and miR-144-3p were screened by bioinformatic analysis. The interaction between miR-144-3p and LINC00657 or BMPR1B was analyzed by dual-luciferase reporter assay and RNA pull-down assay. The results showed that METTL3 was downregulated in OP. METTL3 mediated m6A methylation of LINC00657 to promote the development of osteogenesis. Further study indicated that LINC00657 functioned as a ceRNA to upregulate BMPR1B via sponging miR-144-3p. Additionally, BMPR1B knockdown alleviated the effects of METTL3 on osteogenesis of bone marrow mesenchymal stem cells (BMSCs). Taken together, METTL3 facilitated osteogenic differentiation of BMSCs via the LINC00657/miR-144-3p/BMPR1B axis. Our findings may provide a novel insight of m6A methylation in the development of OP.


Chyluria treated with renal autotransplantation: a case report.
We report a rare case of chyluria in a patient from an area not endemic to filariasis. Initial surgical treatment consisted of stripping of the renal pedicle, following which the patient was free of symptoms for 3 months. Recurrence was noted and renal autotransplantation was performed. Chyluria has not recurred 12 months after the second operation. The etiology and various treatments of chyluria are discussed.


Alagille syndrome (arteriohepatic dysplasia) and del(20)(p11.2)
We report on a boy with Alagille syndrome. Chromosome analysis on a peripheral blood lymphocyte culture showed a de novo deletion of the short arm of chromosome 20 with a 46,XY,del(20)(p11.2) chromosome constitution. This is the second report of a del(20p) in a patient with Alagille syndrome. The possible localisation of this autosomal dominant syndrome on 20p is discussed.


Radiographic Diagnosis in the Pediatric Dental Patient.
This article emphasizes the selection criteria for radiographic acquisition in children due to the greater sensitivity of children for radiation compared with adults. Diagnosis of common pediatric dental conditions, including dental caries, periodontitis, dental anomalies, cysts, tumors, and traumatic dental conditions, are discussed with relevant clinical scenarios.


Analysis of Instrument Motion and the Impact of Residency Level and Concurrent Distraction on Laparoscopic Skills.
Using a laparoscopic box trainer fitted with motion analysis trackers and software, we aim to identify differences between junior and senior residents performing the peg transfer task, and the impact of a distracting secondary task on performance. General surgery residents were asked to perform the laparoscopic peg transfer task on a trainer equipped with a motion tracker. They were also asked to perform the laparoscopic task while completing a secondary task. Extreme velocity and acceleration events of instrument movement in the 3 rotational degrees of freedom were measured during task completion. The number of extreme events, defined as velocity or acceleration exceeding 1 SD above or below their own mean, were tabulated. The performance of junior residents was compared to senior residents. Simulation learning institute, Beaumont Hospital, Royal Oak, Michigan. Thirty-seven general surgery residents from Beaumont Hospital, Royal Oak. When completing the primary task alone, senior residents executed significantly fewer extreme motion events specific to acceleration in pitch (16.63 vs. 20.69, p = 0.04), and executed more extreme motion events specific to velocity in roll (16.14 vs. 15.11, p = 0.038), when compared to junior residents. With addition of a secondary task, senior residents had fewer extreme acceleration events specific to pitch, (14.69 vs. 22.22, p < 0.001). While junior and senior residents completed the peg transfer task with similar times, motion analysis identified differences in extreme motion events between the groups, even when a secondary task was added. Motion analysis may prove useful for real-time feedback during laparoscopic skill acquisition.


Hormone replacement therapy and WONCA/COOP functional status: a cross-sectional population-based study of women in Israel.
Current indications for hormone replacement therapy (HRT) for menopausal women include symptom relief, but recent studies have raised concerns about the safety of HRT. Little data are available on the effect of HRT on functional status of women taking hormonal preparations after menopause. To assess the association between hormonal replacement therapy and functional status in menopausal women. A cross-sectional survey, population-based study of 682 menopausal women between the ages of 50 and 70 years registered with six family physicians in central Israel. The main outcome measure was the functional status measured by the WONCA/COOP charts. A total of 587 women (86%) completed questionnaires. Univariate analysis showed an association between current use of HRT and improved functional status. However this association was diminished in a regression analysis which controlled for sociodemographic status and health variables. The contribution of HRT to functional status was small but was found to be significant in the domains of general health status (1.9%, p<0.002), sleep (0.9%, p<0.044), physical activities (2.1%, p<0.001) and feelings (1.0%, p<0.033). The contribution of HRT to daily activities, social activities, change in health status and pain was not significant. HRT use had a small contribution to improved functional status in half of the domains measured by the WONCA/COOP charts.


Treatment with antidepressants and lithium is associated with increased risk of treatment with antiparkinson drugs: a pharmacoepidemiological study.
To estimate the risk for persons treated with antidepressants or lithium of subsequent treatment with antiparkinson drugs (APD). The Danish national prescription database supplied data on all persons who received antidepressants, lithium, or antidiabetics (first control group). A second control group was included comprising persons from the general population. Outcome was purchase of APD and the study period was 1995 to 1999. In total, 1 293 789 persons were included. The rate ratio of treatment with APD after treatment with antidepressants was 2.27 (95% CI 2.14 to 2.42) for men and 1.50 (95% CI 1.43 to 1.58) for women. Figures for lithium were almost identical. Persons treated with antidepressants or lithium are at increased risk of subsequently treatment with APD, showing an association between anxiety/affective disorder and Parkinson's disease.


Development and Validation of a Practical Model to Identify Patients at Risk of Bleeding After TAVR.
No standardized algorithm exists to identify patients at risk of bleeding after transcatheter aortic valve replacement (TAVR). The aim of this study was to generate and validate a useful predictive model. Bleeding events after TAVR influence prognosis and quality of life and may be preventable. Using machine learning and multivariate regression, more than 100 clinical variables from 5,185 consecutive patients undergoing TAVR in the prospective multicenter RISPEVA (Registro Italiano GISE sull'Impianto di Valvola Aortica Percutanea; NCT02713932) registry were analyzed in relation to Valve Academic Research Consortium-2 bleeding episodes at 1 month. The model's performance was externally validated in 5,043 TAVR patients from the prospective multicenter POL-TAVI (Polish Registry of Transcatheter Aortic Valve Implantation) database. Derivation analyses generated a 6-item score (PREDICT-TAVR) comprising blood hemoglobin and serum iron concentrations, oral anticoagulation and dual antiplatelet therapy, common femoral artery diameter, and creatinine clearance. The 30-day area under the receiver-operating characteristic curve (AUC) was 0.80 (95% confidence interval [CI]: 0.75-0.83). Internal validation by optimism bootstrap-corrected AUC was 0.79 (95% CI: 0.75-0.83). Score quartiles were in graded relation to 30-day events (0.8%, 1.1%, 2.5%, and 8.5%; overall p <0.001). External validation produced a 30-day AUC of 0.78 (95% CI: 0.72-0.82). A simple nomogram and a web-based calculator were developed to predict individual patient probabilities. Landmark cumulative event analysis showed greatest bleeding risk differences for top versus lower score quartiles in the first 30 days, when most events occurred. Predictivity was maintained when omitting serum iron values. PREDICT-TAVR is a practical, validated, 6-item tool to identify patients at risk of bleeding post-TAVR that can assist in decision making and event prevention.


Extracellular vesicles carry miR-27a-3p to promote drug resistance of glioblastoma to temozolomide by targeting BTG2.
Glioblastoma (GBM) is the most common central nervous system tumor. Temozolomide (TMZ) is a commonly used drug for GBM management. This study explored the mechanism of extracellular vesicles (EVs) regulating TMZ-resistance in GBM. LN229 cells were inducted into TMZ-resistant LN229r strain by stepwise induction. After the intervention of miR-27a-3p expression, cell viability of GBM cells treated with different concentrations of TMZ was detected by MTT and IC50 value was calculated. Cell proliferation and apoptosis were detected by colony formation and flow cytometry. EVs extracted from LN18 cells were identified and the internalization of EVs by LN229r cells was evaluated. The 100 μmol/L TMZ-treated LN229r cells were treated with EVs or EVs with downregulated miR-27a-3p to verify the effect of EVs-carried miR-27a-3p on TMZ resistance. The binding relation between BTG2 and miR-27a-3p was verified. miR-27a-3p and BTG2 expressions in GBM cells and EVs were detected by RT-qPCR. The BTG2 effect on TMZ-resistance in GBM was verified. The xenograft tumor nude mouse model was established by injecting LN229r cells and treated with EVs and 100 μmol/L TMZ. miR-27a-3p was highly expressed in LN229r cells. IC50 value and proliferation of LN229r cells with silenced miR-27a-3p were decreased and apoptosis was increased, indicating that miR-27a-3p silencing reduced the drug-resistant cell LN229r resistance to TMZ. LN18-derived EVs could be internalized by LN229r cells, and release its encapsulated miR-27a-3p into LN229r cells and increase miR-27a-3p expression. EV treatment increased LN229r cell proliferation and reduced apoptosis, while EVs with silenced miR-27a-3p showed the opposite trend. miR-27a-3p targeted BTG2. BTG2 overexpression reduced LN229r cell resistance to TMZ. In vivo, after EVs treatment, tumor volume and weight, Ki67-positive rate, and miR-27a-3p were increased, while BTG2 expression was decreased. GBM-derived EVs were internalized by GBM cells, released miR-27a-3p into GBM cells, upregulated miR-27a-3p expression, and targeted BTG2, thus promoting TMZ resistance.


Rectal cancer patients benefit from implementation of a dedicated colorectal cancer center in a Veterans Affairs Medical Center.
A dedicated colorectal cancer (CRC) center was created in a Veterans Affairs Medical Center with the intent of improving quality of patient care and multidisciplinary cooperation. Retrospective and prospective databases before and after creation of the CRC center, respectively, were created. Patients entered in each database included those requiring surgical intervention for CRC treatment. Statistical analyses included Fisher's exact, chi-square, and unpaired Student t tests as well as analysis of variance. The overall quality of care of CRC patients has improved as evidenced by a larger percentage of complete, margin-negative resections (P <.05) as well as an increase in the number of lymph nodes excised at surgery (P <.0001). Furthermore, a multidisciplinary approach is clearly beneficial as evidenced by the increased number of CRC patients receiving appropriate multidisciplinary therapy (P <.0001). A dedicated CRC center has significantly improved quality of care for CRC patients.


Efficacy, Safety, and Pharmacoeconomic Analysis of Adalimumab and Secukinumab for Moderate-to-Severe Plaque Psoriasis: A Single-Center, Real-World Study.
A growing number of biologics have recently been approved in China for psoriasis treatment, and some of these are eligible for Chinese medical insurance, resulting in a significant increase in the number of patients receiving these biologics. Nevertheless, real-world data on the efficacy and safety of biologics for treating moderate-to-severe plaque psoriasis in Chinese patients are limited, and relevant pharmacoeconomic studies are lacking. Therefore, we performed a prospective, single-center study to evaluate the efficacy and safety of adalimumab (ADA) and secukinumab (SEC) in real-world practice. A cost-effectiveness analysis (CEA) was also conducted. Participants were enrolled between January 2019 and December 2020 at the West China Hospital, Sichuan University. Baseline and follow-up assessments were conducted, and an appropriate statistical analysis was performed. A total of 183 patients were included. At week 12, the number of patients achieving a psoriasis area and severity index reduction of 75% (PASI 75) with SEC treatment was higher than that with ADA and methotrexate (MTX) (SEC versus ADA versus MTX, 90.59% versus 58.70% versus 17.14%, respectively). Adverse events (AEs) were reported in 44.83% and 56.36% of patients in the SEC and ADA groups, respectively. The cost-effectiveness ratio in the SEC group was 46,311.83 Chinese yuan(CNY), compared with 17,580.92 CNY in the ADA group. In real-world practice, SEC and ADA are effective and safe for moderate-to-severe plaque psoriasis treatment in Chinese patients. On the basis of drug prices during our study period without considering access to health insurance, ADA was more cost-effective in real-world practice. Adalimumab and secukinumab are two monoclonal antibodies used for the treatment of psoriasis, which target different cytokines in the pathogenesis. A growing number of biologics have recently been approved in China for psoriasis treatment including adalimumab and secukinumab, which are eligible for Chinese medical insurance, resulting in a significant increase in the number of patients receiving these biologics. With the purpose of evaluating its efficacy and safety in the real world, we registered the data of eligible patients in West China Hospital, Sichuan University over the past two years and conducted statistical analysis. In order to provide different therapeutic strategies for patients based on case-specific needs and access to financial resources, we performed pharmacoeconomic analyses to evaluate the cost-effectiveness of the two drugs. Our study demonstrated that adalimumab and secukinumab were effective and safe for moderate-to-severe plaque psoriasis in Chinese patients in the real-world practice. Based on drug prices during our study period and without taking into consideration access to health insurance, ADA was more cost-effective in real-world practice.


Genetic Control of Floral Architecture: Insights into Improving Crop Yield.
Selection of plants with traits that are beneficial for cultivation and consumption has been a common practice for thousands of years; however, combination of these traits can be detrimental too, for instance by leading to undesirable branching and yield loss in tomato. The findings from Soyk et al. in this issue of Cell help understand how to bypass such negative effects and improve crop productivity.


Antitumor agents. Part 218: Cappamensin A, a new In vitro anticancer principle, from Capparis sikkimensis.
A new inhibitor of in vitro tumor cell replication, cappamensin A (1) (2H-1,4-benzoxazin-3(4H)-one, 6-methoxy-2-methyl-4-carbaldehyde), was isolated from the roots of Capparis sikkimensis subsp. formosana using bioactivity-guided fractionation. The structure of 1 was established by spectroscopic methods, including 2D NMR analyses. Compound 1 displayed significant in vitro anticancer activity against ovarian (1A9), lung (A549), ileocecal (HCT-8), breast (MCF-7), nasopharyngeal (KB), and vincristine resistant (KB-VIN) human tumor cell lines with ED(50) values </=4 microgram/mL (mean GI(50) value of 15.1 microM).


Comparison of the effects of hydrogen peroxide and x-ray irradiation on toxicity, mutation, and DNA damage/repair in mammalian cells (V-79).
Hydrogen peroxide is not detectably mutagenic at the hypoxanthine-guanine phosphoribosyl transfer locus (measured as 6-thioguanine resistance) in V-79 Chinese hamster lung cells, yet is cytotoxic with a Do dose of 240 muM. X-ray, by contrast, is both mutagenic and cytotoxic with a Do dose of 260 rad for cytotoxicity. The number of DNA single-strand breaks induced at equitoxic doses is much greater for hydrogen peroxide than it is for X-ray. Single-strand breaks are repaired with initial t 1/2 values of 5.0 min for X-ray and 6.8 min for hydrogen peroxide; after 12.5 min X-ray repair becomes biphasic, whereas H2O2 repair remains linear. Hydrogen peroxide does not induce either DNA-protein or DNA-DNA crosslinks, although X-ray has been previously shown to induce DNA-protein crosslinks. Hydroxyl radicals scavengers reduce the number of DNA single-strand breaks induced by hydrogen peroxide and X-ray, which implies that hydroxyl radicals may mediate the formation of these breaks. Because of hydroxyl radicals are produced by both agents, yet only X-ray is mutagenic, we conclude that hydroxyl radicals are not necessarily mutagenic in V-79 cells. The implications of these findings for the detection of carcinogens and mutagens is discussed.


Vertebral hemangioma causing spinal cord compression during pregnancy.
Hemangiomas of bone are extremely common vascular tumors that are most commonly discovered as incidental findings in the vertebral column. Infrequently, these benign lesions may cause local or radicular pain and neurologic deficits, from myeloradiculopathy to paralysis. This report describes the occurrence of a symptomatic vertebral hemangioma during pregnancy, in order to illustrate current methods for diagnosis and treatment of these lesions when associated with spinal cord compression. The possible mechanisms by which they may become symptomatic during pregnancy are reviewed.


Concentrative uptake of digoxin by slices of chicken renal cortex.
The purpose of this investigation was to define, under controlled in vitro conditions, the processes contributing to the uptake and accumulation of [3H]digoxin by incubated slices of chicken renal cortex. Progressive uptake was evident in time-course experiments with the slice-to-medium concentration ratio (S/M) reaching 5.25 after 120 min. No metabolism was evident. Increasing the ratio of unlabeled to labeled digoxin resulted in a concentration-dependent decrease in relative uptake of the label, suggesting saturability. Incubation under conditions of metabolic inhibition reduced digoxin S/M by about 50%, indicating that both energy-requiring and passive mechanisms contribute to the overall accumulation process. The structural nature of the uptake process was explored by incubating digoxin in the presence of potential inhibitors of transport. The organic cation quinine and the non-glycosidic steroids digoxigenin and spironolactone were without effect even at greater than 1000-fold excess compared to digoxin. Similarly, the sugar digitoxose had no inhibitory activity on digoxin accumulation by the slices. On the other hand, the glycosides digitoxin, digoxigenin-bis-digitoxoside and digoxigenin-mono-digitoxoside inhibited dogoxin uptake in a concentration-dependent manner. These results indicate a structural preference for an intact glycoside rather than for either the steroidal or sugar portion of the molecule alone. An inhibitory effect of ouabain and a stimulatory effect of reduced medium potassium concentration suggest a possible role for Na+,K(+)-ATPase in the uptake of digoxin by the renal cortex.


Synthesis and characterization of a stable cyclic gem-bis(phosphaylide): a 4π-electron three-membered heterocycle.
The mixed P,S-bisylide 1 reacts with phosphenium salts, affording phosphoniophosphinocarbenes, with elimination of diphenyl sulfide. Using a more compact cyclic phosphenium cation, the reaction leads to the formation of an original three-membered heterocycle featuring a gem-bisylide function. This molecule represents the first isolable analogue of the phosphirenyl anion derivative.


The relationship between psychological, cognitive, and contextual factors and rehabilitation outcomes in Achilles tendinopathy: A prospective feasibility cohort study.
This study aimed to investigate the feasibility of conducting a full-scale study investigating the influence of patient-related factors on rehabilitation outcomes in Achilles tendinopathy (AT). A secondary aim was to investigate preliminary relationships between patient-related factors and clinical outcomes at 12- and 26- weeks. feasibility cohort. Australian healthcare settings. Participants with AT receiving physiotherapy in Australia were recruited via treating physiotherapists and online. Data were collected online at baseline, 12- and 26-weeks. Progression criteria for a full-scale study were recruitment rate of ≥10 per month, conversion rate ≥20%, and response rate to questionnaires ≥80%. The relationship between patient-related factors and clinical outcomes was investigated using Spearman's rho correlation coefficient. The average recruitment rate was 5/month, conversion rate was 97%, and response rate to questionnaires was ≥97% at all timepoints. There was a fair to moderate correlation (rho = 0.225 to 0.683) between patient-related factors and clinical outcomes at the 12-week, but no to weak correlation at the 26-week (rho = 0.002 to 0.284). Feasibility outcomes suggest a future full-scale cohort study is feasible with the caveat of utilizing strategies to improve recruitment rate. Preliminary bivariate correlations at 12-weeks warrant further investigations in larger studies.


Using a computer presentation program and a web-based program to teach the core rotation in obstetrics and gynecology.
To describe the curriculum modification of required PowerPoint (Microsoft Office PowerPoint 2003, Microsoft Corporation, Redmond, Washington) presentations by medical students during the core obstetrics-gynecology rotation. A retrospective review of 90 medical students' PowerPoint presentations, grades and evaluations from 2000 to 2004. Descriptive and correlation tests were used as appropriate. Most Association for Professors of Gynecology and Obstetrics (APGO) objectives were covered by the students' PowerPoint presentations; sections on breast disorders and human sexuality were minimally covered. The students' PowerPoint presentations were posted on the clerkship official website in 2004 and have been accessed by students as educational material. Overall, 70-90% of students found the curriculum useful and thought that it improved their educational experience in obstetrics-gynecology; however, about one third did not think they obtained assistance from the faculty and did not find it easy obtaining the required material. There was a significant positive correlation between PowerPoint presentation grades with the oral (r = 0.408, p = 0.000), National Board of Medical Examiners Obstetrics-Gynecology examination (r = 0.362, p = 0.000) and clinical (r = 0.329, p = 0.002) scores. Also, the PowerPoint presentation curriculum was shown to effectively teach many of the segments of Accreditation Council of Graduate Medical Educators (ACGME) competency. A PowerPoint presentation by students is useful in enhancing educational experience and can be used to cover APGO educational objectives and ACGME competency.


Henry's law constants and mass transfer coefficients for methyl bromide and 1,3-dichloropropene applied to Florida sandy field soil.
Methyl bromide, a pre-emergent soil fumigant, is scheduled to be phased out in the US by 2005, with exceptions for critical use. Comparison of some of the physical constants related to distribution and retention for methyl bromide (MBr) to other fumigants yields a useful quantification of possible alternatives. In this study, the atmospheric and subsurface dissipation of methyl bromide as well as (Z)- and (E)-1,3-dichloropropene (1,3-D) isomers in Telone II were examined. The Henry's law constants of the three chemicals at soil temperature and their mass transfer coefficients for movement through an agricultural mulch of UV-resistant, high-density polyethylene (PE) were evaluated using field data. At the soil temperature of 16.4 degrees C, calculated Henry's law constant gave a fumigant ranking of MBr (0.21)>>(Z)-1,3-D (0.041)>(E)-1,3-D (0.027). Since rapid subsurface distribution of a fumigant is highly dependent on the amount in the gas phase, the greater value for Henry's law constant implies faster distribution throughout the soil. After distribution through the soil, retention of the fumigant becomes imperative. Calculation of the fumigant's mass transfer coefficients through PE from field data gave a ranking of the three chemicals: MBr (1.08 cm/h)<(E)-1,3-D (3.25 cm/h)<(Z)-1,3-D (4.13 cm/h). With mass transfer coefficients of this magnitude, it was concluded that PE film was an inadequate barrier for retaining these fumigants in an agricultural setting.


General anesthesia for intussusception reduction by enema.
Intussusception is the most frequent cause of bowel obstruction in children. Although enema is usually used as the initial treatment, surgery may be required in more than 50% of patients. General anesthesia (GA) has been suggested to increase the rate of enema success. The purpose of this study was to evaluate whether GA increases the success rate of reduction by air enema. In this retrospective single-center study from 1989 to the end of June 2008, patients receiving air enema for intussusception reduction were studied. Multivariable analysis using propensity score was performed to compare the success rate between patients receiving sedation or GA. The success rate of air enema increased from 72% in 1989 to the current rate of 90%. When time elapsed between first symptoms and enema was >12 h, the success rate decreased significantly (Odds Ratio 0.67 [0.56-0.81], P < 0.0001). When patients were matched by propensity score, GA significantly increased the likelihood of success (OR 5.66 [2.85-12.89], P = 0.013). Air enema performed under GA allows intussusception reduction in more than 90% of patients.


The protein corona and its effects on nanoparticle-based drug delivery systems.
In most cases, once nanoparticles (NPs) enter the blood, their surface is covered by biological molecules, especially proteins, forming a so-called protein corona (PC). As a result, what the cells of the body "see" is not the NPs as formulated by the chemists, but the PC. In this way, the PC can influence the effects of the NPs and even mask the desired effects of the NP components. While this can argue for trying to inhibit protein-nanomaterial interactions, encapsulating NPs in an endogenous PC may increase their clinical usefulness. In this review, we briefly introduce the concept of the PC, its formation and its effects on the behavior of NPs. We also discuss how to reduce the formation of PCs or exploit them to enhance NP functions. Studying the interactions between proteins and NPs will provide insights into their clinical activity in health and disease. STATEMENT OF SIGNIFICANCE: The formation of protein corona (PC) will affect the operation of nanoparticles (NPs) in vivo. Since there are many proteins in the blood, it is impossible to completely overcome the formation of PC. Therefore, the use of PCs to deliver drug is the best choice. De-opsonins adsorbed on NPs can reduce macrophage phagocytosis and cytotoxicity of NPs, and prolong their circulation in blood. Albumin, apolipoprotein and transferrin are typical de-opsonins. In present review, we mainly discuss how to optimize the delivery of nanoparticles through the formation of albumin corona, transferrin corona and apolipoprotein corona in vivo or in vitro.


Vitamin B₁₂ deficiency: an unusual cause of vocal fold palsy.
We report an extremely rare case of vocal fold palsy secondary to vitamin B12 deficiency. Case report and English-Language review of the world literature concerning vitamin B12 deficiency and its neurological manifestations. We discuss the physiological role of vitamin B and its specific relationship to the presented patient's symptoms. We describe a rare instance of a patient presenting with bilateral lower limb weakness and unilateral vocal fold palsy, as a manifestation of vitamin B12 deficiency. Quick recognition and treatment resulted in a full recovery. To our knowledge, this is the first reported case of unilateral vocal fold palsy secondary to vitamin B12 deficiency. Central and peripheral neuropathies have been described; however, other than the optic nerve, the cranial nerves are very rarely affected. It is important to consider vitamin B12 deficiency as a cause, as speedy identification and treatment can help prevent permanent neurological damage.


Artificial intelligence-enabled automatic segmentation of skull CT facilitates computer-assisted craniomaxillofacial surgery.
The image segmentation of skull CT is the cornerstone for the computer-assisted craniomaxillofacial surgery in multiple aspects. This study aims to introduce an AI-enabled automatic segmentation and propose its prospect in facilitating the computer-assisted surgery. Three patients enrolled in a clinical trial of computer-assisted craniomaxillofacial surgery were randomly selected for this study. The preoperative helical CT scans of the head and neck region were subjected to the AI-enabled automatic segmentation in Mimics Viewer. The performance of AI segmentation was evaluated based on the requirements of computer-assisted surgery. All three patients were successfully segmented by the AI-enabled automatic segmentation. The performance of AI segmentation was excellent regarding key anatomical structures. The overall quality of bone surface was satisfying. The median DICE coefficient was 92.4% for the maxilla, and 94.9% for the mandible, which fulfilled the requirements of computer-assisted craniomaxillofacial surgery. The AI-enabled automatic segmentation could facilitate the preoperative virtual planning and postoperative outcome verification, which formed a feedback loop to enhance the current workflow of computer-assisted surgery. More studies are warranted to confirm the robustness of AI segmentation with more cases.


The application of rapid kinetic techniques to the transport of thymidine and 3-O-Methylglucose into Mammalian cells in suspension culture.
Techniques are described by which the transport of nutrients into mammalian cells in suspension can be measured at intervals of 1.5 seconds. By application of these techniques, the existence of a saturable (Km = 85 muM), non-concentrative, transport system for thymidine was demonstrated in Novikoff rat hepatoma cells depleted of ATP. At concentrations of thymidine less than the Km, this system operated at velocities sufficient to nearly completely equilibrate intra- and extra-cellular thymidine pools within 8 seconds. In phosphorylating cells, the transport system operated with similar rapidity, so that intracellular phosphorylation was rate-limiting for the incorporation of thymidine into nucleotides. Uptake of 3-O-methylglucose occurred at comparable velocities, attaining 90% of equilibrium between internal and external pools within 25 seconds. Uptake of cytosine by simple diffusion was 100 times slower.


Outcomes of Extracorporeal Membrane Oxygenation in Acute Respiratory Distress Syndrome Following Traumatic Injury: A Propensity-Matched Analysis.
The purpose of this study is to evaluate the overall occurrence of inhospital mortality in trauma patients who were placed on extracorporeal membrane oxygenation following the complication of the acute respiratory distress syndrome. Observational cohort study. The data of all patients who were traumatically injured and developed the complication of acute respiratory distress syndrome were accessed from the Trauma Quality Improvement Program database from the calendar years of 2013 to 2016. Patients 16 years old and less than 90 years old were included in the study. Variables included patient demography, Injury Severity Score, Glasgow Coma Scale score, Abbreviated Injury Scale score, and outcomes. Extracorporeal membrane oxygenation. Propensity-matched analysis was performed between two groups: patients placed on extracorporeal membrane oxygenation and patients placed on conventional mode of ventilation. The primary outcome was inhospital mortality. Out of 6,121 patients who developed acute respiratory distress syndrome, 118 patients (1.93%) were placed on extracorporeal membrane oxygenation. The pair matched analysis showed significant difference between the two groups (extracorporeal membrane oxygenation vs conventional mode of ventilation) for overall inhospital mortality (35.6% vs 14.4%; p < 0.001). There were significant differences found between the two groups for the median hospital length of stay (41 [35-49] vs 27 [24-33]), ICU days (35 [30-41] vs 19 [17-24]), and ventilator days (30 [27-34] vs 15 [13-18]). All p values are less than 0.001. Approximately 2% of acute respiratory distress syndrome patients were placed on extracorporeal membrane oxygenation. The overall inhospital mortality remained high despite patients being placed on extracorporeal membrane oxygenation.


How the gut and liver hibernate.
For hibernating mammals, the transition from summer active to winter hibernation seasons come with significant remodeling at cellular, organ and whole organism levels. This review summarizes and synthesizes what is known about hibernation-related remodeling in the gastrointestinal tract of the thirteen-lined ground squirrel, including intestinal and hepatic physiology and the gut microbiota. Hibernation alters intestinal epithelial, immune and cell survival pathways in ways that point to a protective phenotype in the face of prolonged fasting and major fluctuations in nutrient and oxygen delivery during torpor-arousal cycles. The prolonged fasting associated with hibernation alters lipid metabolism and systemic cholesterol dynamics, with both the gut and liver participating in these changes. Fasting also affects the gut microbiota, altering the abundance, composition and diversity of gut microbes and impacting the metabolites they produce in ways that may influence hibernation-related traits in the host. Finally, interventional studies have demonstrated that the hibernation phenotype confers resistance to experimental ischemia-reperfusion injury in both gut and liver, suggesting potential therapeutic roadmaps. We propose that the plasticity inherent to hibernation biology may contribute to this stress tolerance, and in the spirit of August Krogh, makes hibernators particularly valuable for study to identify solutions to certain problems.


Mutagenicity of carcinogenic azo dyes and their derivatives.
The mutagenicity of N,N-dimethyl-4-aminoazobenzene and N-methyl-4-aminoazobenzene and their derivatives was shown on Salmonella typhimurium TA100 and TA98. S-9 Mix, obtained from rat liver after injection of polychlorinated biphenyl, was abligatory for their mutagenic action. N-Acetoxy-N-methyl-4-aminoazobenzene and N-benzoyloxy-N-methyl-4-aminoazobenzene and their 4'-methoxycarbonyl derivatives were also mutagenic on TA100 and TA98 and did not require metabolic activation by S-9 Mix. It is suggested that the carcinogenic effects of azo dyes may involve modification of DNA.


[Inhibition of interferon action by glycoprotein hormones].
The antiviral action of human interferon is inhibited by thyrotropin and chorionic gonadotropin. These findings suggest that interferon and these hormones share common binding sites on the cell surface.


Stress During Pregnancy Associated with Newborn Low Birth Weight: Experiences from the State of Rhode Island.
Prenatal stress is a known risk for poor birth outcomes. This study specifically looked at reported stress during pregnancy and low birth weight (LBW) in Rhode Island. Pregnancy Risk Assessment Monitoring System (PRAMS) data from 2016 to 2018 for the state of Rhode Island was utilized. Stress during most recent pregnancy was dichotomized as: 'none to minimal' and 'moderate to high.' LBW was defined as less than 2,500 g. Multivariable regression analysis was performed, accounting for complex survey design. In this cohort, 24% of pregnant people reported moderate to high stress leading to an adjusted odds of 1.70 (95% CI 1.43-2.03) of having a LBW newborn compared to those with none to minimal stress. Primiparity, previous preterm birth, racism, smoking history, and history of chronic medical problems were also associated with LBW newborns. We recommend screening and provision of support services for stress in all settings where pregnant people access care.


Serum vitamin D levels in patients with obstructive sleep apnea syndrome and level changes after continuous positive airway pressure therapy.
Patients with obstructive sleep apnea syndrome (OSAS) have been found to exhibit lower serum vitamin D levels, even when the control groups are matched for confounding conditions. However, contradictory studies are also present. This study aimed to compare serum 25-hydroxyvitamin D (25(OH)D) levels between adult patients with OSAS and non-apneic controls and to evaluate the changes in 25(OH)D levels after 3 and 12 months of continuous positive airway pressure (CPAP) therapy. The study was comprised of 30 patients with OSAS and 30 controls. Serum 25(OH)D levels were determined at baseline and after 3 and 12 months of CPAP therapy in all patients with OSAS. For analysis, patients with OSAS were divided into subgroups by adherence, with adherence defined as CPAP usage for > 4 h per night on at least 70% of nights. The 25(OH)D levels were not significantly different between OSAS and control groups at baseline. 25(OH)D levels did not change after 3 and 12 months of CPAP therapy. Patients who were CPAP-adherent showed less reduction in 25(OH)D levels compared with non-adherent ones (21.18 ± 9.3 vs. 12.13 ± 3.8 ng/mL, p = 0.022) after 1 year. The 25(OH)D levels were significantly correlated with higher daily CPAP usage at 3 and 12 months. Mean daily CPAP usage was a significant predictor of serum 25(OH)D levels at 12 months. Patients with OSAS who demonstrated good CPAP adherence showed significantly higher 25(OH)D levels after 1 year compared with those not adequately using CPAP. Long-term good CPAP adherence and highly daily CPAP usage positively affected 25(OH)D levels in patients with OSAS.


Visualization and analysis of mural thrombogenesis on collagen, polyurethane and nylon.
Visualization and analysis of mural thrombogenesis on collagen-coated glass, polyurethane and nylon was discussed. Epi-fluorescent video microscopy was used to visualize thrombotic events at a protein or polymer surface in contact with flowing whole blood. Digital image processing was used to analyse the real-time microscopic images obtained, resulting in measurements of morphological features and the number of platelets that compose each thrombus. The three-dimensional structures of the thrombi were also estimated. A photodiode was used to measure integrated end-point platelet accumulation at different axial positions along the surface. Additionally, the convection-diffusion equations were solved to estimate the concentrations of adenosine diphosphate, thromboxane A2, and thrombin generated by activated platelets at the blood-contacting surface.


National surveys of UK and Italian neonatal units highlighted significant differences in the use of non-invasive respiratory support.
This study compared how non-invasive respiratory support (NRS) was provided in neonatal units in Italy and the UK. An NRS questionnaire was sent to tertiary neonatal centres, identified by national societies, from November 2015 to May 2016. Responses were received from 49/57 (86%) UK units and 103/115 (90%) Italian units. NRS was started in the delivery room by 61% of UK units and 85% of Italian units. In neonatal intensive care units, 33% of UK units used nasal high-flow therapy (HFT) as primary support, compared to 3% in Italy. Nasal continuous positive airway pressure (CPAP) was used in 57% of UK units and 90% of Italian units. The commonest starting flow rate on nasal HFT for term and preterm infants was 6 L/min in the UK, while Italian units mainly used this flow for term infants. In the UK, 67% of units decreased nasal HFT by 1 L/min per day. In Italy, infants on nasal CPAP were weaned by 1 cm H2 O per day in 39% of units. The way that NRS was managed for very preterm infants differed between the UK and Italy, reflecting a lack of evidence on optimal NRS and the use of local protocols.


Acceptance and Commitment Training for Veterans with Polytrauma: A randomized controlled trial protocol.
Mild traumatic brain injury (mTBI) is a signature wound of Veterans of operations in Iraq and Afghanistan (i.e., OIF/OEF/OND). Most Veterans with mTBI also experience stress-based psychopathology (e.g., depression, posttraumatic stress disorder) and chronic pain. This combination - referred to as polytrauma - results in detrimental long-term effects on social, occupational, and community reintegration. This study will compare the efficacy of a one-day Acceptance and Commitment Training plus Education, Resources, and Support (ACT+ERS) workshop to a one-day active control group (ERS) on symptoms of distress and social, occupational, and community reintegration. We will also examine mediators and moderators of treatment response. This is an ongoing randomized clinical trial. 212 OIF/OEF/OND Veterans with polytrauma are being recruited. Veterans are randomly assigned to a one-day ACT+ERS or a one-day ERS workshop with two individualized booster sessions approximately two- and four-weeks post-workshop. Veterans complete assessments prior to the workshop and again at six weeks, three months, and six months post-workshop. Of note, workshops were converted to a virtual format due to the COVID-19 pandemic. The primary outcomes are symptoms of distress and reintegration; secondary outcomes are post-traumatic stress disorder symptoms and pain interference. Secondary analyses will assess whether changes in avoidance at three months mediate changes in distress and reintegration at six months. Facilitating the psychological adjustment and reintegration of Veterans with polytrauma is critical. The results of this study will provide important information about the impact of a brief intervention for Veterans with these concerns.


Transforming urban environmentsIf the Past Teaches, What Does the Future Learn? John T. Murphy and Carole L. Crumley, Eds. TU Delft Publishing, 2022. 124 pp.
Resilient cities of the past hold lessons for creating adaptable communities of the future.


Improvement of granulocyte adherence and in vivo granulocyte delivery by ascorbic acid in renal transplant patients.
Delivery of polymorphonuclear cells (PMN) to sites of bacterial invasion is a critical step in host defense. Renal transplant patients have a defect in PMN delivery caused by glucocorticoid immunosuppressive therapy that leads to increased susceptibility to infection. Because inhibited granulocyte adherence is often associated with poor delivery, the effects of propranolol and of ascorbic acid were measured for both of these functions. Propranolol caused a short-lived increase in adherence and no change in delivery in normal volunteers, so it was not studied in transplant patients. Ascorbic acid also failed to affect adherence in normal controls, but increased depressed adherence in transplant patients from a mean value of 27.7% to 48.0% when given daily for 3-4 weeks. PMN delivery increased to normal following 3-6 weeks of ascorbic acid, 4 g/day in a similar group of patients with low adherence prior to treatment. Pretreatment delivery was 3.06 X 10(5) and rose to 1.18 X 10(6) PMN after treatment (P less than 0.02), with no change noted in graft function. Thus, ascorbic acid treatment may improve PMN host defense in renal transplant patients.


Detection of a New Tert-Leucinate Synthetic Cannabinoid 5F-MDMB-PICA and Its Metabolites in Human Hair: Application to Authentic Cases.
Methyl 2 -[ [ 1- (5- fluoropentyl) indole - 3- carbonyl] amino] -3, 3- dimethyl - butanoate (5F-MDMB-PICA) is a new synthetic cannabinoid characterized by valinate or tert-leucinate moieties. In recent years, 5F-MDMB-PICA has been abused in the form of "spice-like" herbal incenses or electronic cigarette oil. A UHPLC-MS/MS method was developed to detect 5F-MDMB-PICA and its metabolites in human hair. Approximately 20 mg of hair was weighed and pulverized with methanol below 4°C. After ultrasonication, centrifugation and filtration, 200 μL of supernatant was placed into an autosampler vial and analyzed on a Waters Acquity UPLC HSS T3 column (100 mm × 2.1 mm, 1.8 μm particle size) using an acetonitrile-20 mmol/L ammonium acetate (0.1% formic acid, 5% acetonitrile) gradient with a run time of 8 min. The limit of detection (LOD) ranged from 0.5 to 5 pg/mg, and the lower limit of quantitation (LLOQ) ranged from 1 to 5 pg/mg. The method was shown to be linear over a concentration range of 1-200 pg/mg. The linear correlation (R 2) of the calibration curves for all analytes was >0.999. The accuracy varied from 95.4 to 107.4%, while the intra- and inter-day precision RSD values were 0.7-10.6% and 1.7-12.2%, respectively. Recoveries were within the range of 61.1-93.3%, and matrix effects were in the range of 19.1-102.6%. The validated method was successfully applied to the identification and quantification of 5F-MDMB-PICA and its metabolites in hair from authentic forensic cases.


[IgA endomysium antibodies. Detection in children with celiac disease].
Epidemiology of coeliac disease gives rise to the search for a non-invasive, reliable screening test. We looked for IgA anti-endomysial antibodies (IgA-EmA) in 103 sera of 90 children (age: 2 months-13.9 years) using an indirect immunofluorescence method on monkey oesophagus sections. In 44 patients, the diagnosis of coeliac disease was confirmed fulfilling new criteria of the European Society of Pediatric Gastroenterology and Nutrition. All 24 coeliac disease patients with an initial flat mucosa had IgA-EmA (sensitivity 100%). In 36% of coeliac disease patients adhering to a gluten-free diet we found IgA-EmA. None of 46 patients in whom coeliac disease had been excluded by jejunal biopsy had IgA-EmA (specificity 100%). The sera of 102 blood-donors were used as controls and showed a test specificity of 99%. In coeliac disease patients, the titer of IgA-EmA declined during gluten-free diet by 0.66 steps/month on average, and rose 1.76 steps/month during gluten challenge. These results confirm the diagnostic significance of IgA-EmA for patients with suspected coeliac disease and their value for monitoring treatment even in young children (below 2 years).


Breast cancer and Poland's syndrome: a case report and literature review.
Poland's syndrome is a rare congenital development malformation characterized by unilateral chest wall hypoplasia and ipsilateral hand abnormalities. It is also known to be associated with some malignant diseases. We herein report a case of Poland's syndrome associated with invasive ductal carcinoma of breast, and review the literatures to investigate the clinical characteristics of breast cancer with Poland's syndrome.


Preparation of Anionic Surfactant-Based One-Dimensional Nanostructured Polyaniline Fibers for Hydrogen Storage Applications.
Polyaniline fibers were prepared in the presence of anionic surfactant in an ice medium to nucleate in one dimension and were compared to bulk polyaniline prepared at an optimum temperature. Fourier-transform infrared spectroscopy (FTIR) and X-ray powder diffraction (XRD) were used to investigate the structural analysis of the prepared samples. A conductivity study reveals that polyaniline fibers have high conductivity compared to bulk polyaniline. Hydrogen storage measurements confirm that the polyaniline fibers adsorbed approximately 86% of the total actual capacity of 8-8.5 wt% in less than 9 min, and desorption occurs at a lower temperature, releasing approximately 1.5 wt% of the hydrogen gases when the pressure is reduced further to 1 bar.


Reprogramming bacteriophage host range: design principles and strategies for engineering receptor binding proteins.
Bacteriophages (phages) use specialized tail machinery to deliver proteins and genetic material into a bacterial cell during infection. Attached at the distal ends of their tails are receptor binding proteins (RBPs) that recognize specific molecules exposed on host bacteria surfaces. Since the therapeutic capacity of naturally occurring phages is often limited by narrow host ranges, there is significant interest in expanding their host range via directed evolution or structure-guided engineering of their RBPs. Here, we describe the design principles of different RBP engineering platforms and draw attention to the mechanisms linking RBP binding and the correct spatial and temporal attachment of the phage to the bacterial surface. A deeper understanding of these mechanisms will directly benefit future engineering of more effective phage-based therapeutics.