Synthesis and antiviral (HIV-1, HBV) activities of 5-halo-6-methoxy(or azido)-5,6-dihydro-3'-fluoro-3'-deoxythymidine diastereomers. Potential prodrugs to 3'-fluoro-3'-deoxythymidine.
A new class of 5-halo-6-methoxy(or azido)-5,6-dihydro-3'-fluoro-3'- deoxythymidines (4-13) were investigated as potential anti-AIDS drugs. These 5,6-dihydro derivatives, which are also potential prodrugs to 3'-fluoro-3'-deoxythymidine (FLT), were designed to have properties which would enhance their duration of action, lipophilicity, and cephalic delivery to the central nervous system. The 5-halo-6-methoxy(or azido)-5,6-dihydro-3'-fluoro-3'-deoxythymidines, which differ in configuration at the C-5 and C-6 positions, were synthesized by the regiospecific addition of XR (X = Br, Cl, I; R = OMe, N3) to the 5,6-olefinic bond of FLT. These 5-halo-6-methoxy-5,6-dihydro derivatives are more lipophilic (P = 1.5-5.15 range) than the parent compound FLT (P = 0.5). Regeneration of the 5,6-olefinic bond to give FLT, upon incubation of the 5-halo-6-methoxy-5,6-dihydro compounds with glutathione, was dependent on the nature of the 5-halo substituent (I > Br > Cl). The ability of these 5-halo-6-methoxy(or azido)-5,6- dihydro compounds (4-13) to protect CEM cells against HIV-induced cytopathogenicity was evaluated. The C-5 halo substituent was a determinant of anti-HIV-1 activity where the approximately equipotent 5-iodo and 5-bromo were generally more potent than the 5-chloro derivatives of FLT. Compounds having the (5S,6S)-configuration were more potent than the corresponding (5R,6R)-diastereomer. The most potent anti-HIV-1 agents, which included the (5R,6R)-5-Br,6-OMe (4), (5S,6S)-5-Br,6-OMe (5), and (5S,6S)-5-I,6-OMe (10) derivatives of FLT, exhibited comparable activities to the reference drugs AZT and FLT. Although (5R,6R)-5-bromo-6-methoxy-5,6-dihydro-3'-fluoro-3'-deoxythymidine (4) inhibited hepatitis B virus replication at a 5-6-fold higher concentration (EC50) than the reference drug 2',3'-dideoxycytidine (DDC), it was 3-5-fold less cytotoxic (CC50) than DDC.


"Evolving nanoparticle gene delivery vectors for the liver: What has been learned in 30 years".
Nonviral gene delivery to the liver has been under evolution for nearly 30years. Early demonstrations established relatively simple nonviral vectors could mediate gene expression in HepG2 cells which understandably led to speculation that these same vectors would be immediately successful at transfecting primary hepatocytes in vivo. However, it was soon recognized that the properties of a nonviral vector resulting in efficient transfection in vitro were uncorrelated with those needed to achieve efficient nonviral transfection in vivo. The discovery of major barriers to liver gene transfer has set the field on a course to design biocompatible vectors that demonstrate increased DNA stability in the circulation with correlating expression in liver. The improved understanding of what limits nonviral vector gene transfer efficiency in vivo has resulted in more sophisticated, low molecular weight vectors that allow systematic optimization of nanoparticle size, charge and ligand presentation. While the field has evolved DNA nanoparticles that are stable in the circulation, target hepatocytes, and deliver DNA to the cytosol, breaching the nucleus remains the last major barrier to a fully successful nonviral gene transfer system for the liver. The lessons learned along the way are fundamentally important to the design of all systemically delivered nanoparticle nonviral gene delivery systems.


METABOLISM OF PHENOXYALKYL CARBOXYLIC ACIDS BY A FLAVOBACTERIUM SPECIES.
Macrae, I. C. (Cornell University, Ithaca, N.Y.), and M. Alexander. Metabolism of phenoxyalkyl carboxylic acids by a Flavobacterium species. J. Bacteriol. 86:1231-1235. 1963.-A Flavobacterium sp. isolated from soil and grown in media containing 4-(2,4-dichlorophenoxy) butyric acid metabolized omega-linked 2,4-dichlorophenoxyalkyl carboxylic acids in the series from 3-(2,4-dichlorophenoxy)propionic acid through 11-(2,4-dichlorophenoxy)undecanoic acid rapidly and without a preliminary induction phase. There was no detectable oxidation of 2,4-dichlorophenoxyacetic acid. Phenols and the fatty acids corresponding to the aliphatic side chains were liberated during the decomposition of the dichlorophenoxy alkanoates from propionate to octanoate. The data indicate that the initial step in the degradation of omega-linked 2,4-dichlorophenoxyalkyl carboxylic acids by the bacterium involves a cleavage of the ether linkage, a new mechanism for the microbial metabolism of these compounds.


Anxiety level of early- and late-stage prostate cancer patients.
Anxiety can worsen prostate cancer patients' decision making and quality of life. Early identification of anxiety disorders is thus very important for excellent prostate cancer treatment. This study aimed to determine the levels of anxiety in patients with early-stage prostate cancer compared with advanced-stage disease. This cross-sectional study was performed at the Department of Urology, 'Cipto Mangunkusumo' Hospital, Faculty of Medicine, University of Indonesia. The subjects were early-stage prostate cancer patients and advanced-stage prostate cancer patients with bone metastatic lesions proved by bone scan. Comparative analysis was done to analyze anxiety scores assessed by use of an 11-item modified Memorial Anxiety Scale for Prostate Cancer (MAX-PC) questionnaire. We also assessed the relationship of the MAX-PC score with age, prostate-specific antigen (PSA) value, number of bone metastases, and pain. Data were analyzed by using SPSS ver. 17 (SPSS Inc.). There were 34 subjects with early-stage prostate cancer and 34 subjects with advanced-stage prostate cancer. We found that the mean anxiety score was significantly lower (P=0.0001) in the early-stage prostate cancer group (8.32±3.65) than in the advanced-stage prostate cancer group (12.61±4.56). Nine subjects had a pathological MAX-PC score (≥16), of whom 1 subject had early-stage disease and 8 subjects had advanced-stage disease. Furthermore, there were significant positive correlations (P<0.001) between MAX-PC score and visual analogue scale pain score (r=0.633), PSA value (r=0.263), and number of bone metastatic lesions (r=0.464). However, the correlation between age and anxiety score was not significant (P=0.170). The MAX-PC anxiety score was significantly associated with the stage of prostate cancer. Furthermore, visual analogue scale pain score, PSA value, and number of bone metastatic lesions can also affect the MAX-PC anxiety score.


Intrinsic characteristics of activity: a comment on Kent's psychobiology.
Kent has made seven statements that should inspire responses from linguists, kinesiologists, and developmentalists, among others. His goal of reforming our current theoretical perspective on the development of speech will be accomplished, in part, by their corrections, elaborations, and further speculations. Not all of his statements have the same status or consequence for an evolving theory of development. Those on the anatomic and neurological differences between infants and adults are much less controversial than those on the initial separateness of the perception and production systems or those on the relation of rhythmic behavior to phonology. Across all the statements, two major topics merit discussion: 1) the relevant descriptive terms of the vocal behavior of infants and 2) the relation of vocal activity to other behavior.


Unleashing non-conjugated polymers as charge relay mediators.
The core factors affecting the efficiency of photocatalysis are predominantly centered on controllable modulation of anisotropic spatial charge separation/transfer and regulating vectorial charge transport pathways in photoredox catalysis, yet it still meets with limited success. Herein, we first conceptually demonstrate the rational design of unidirectional cascade charge transfer channels over transition metal chalcogenide nanosheets (TMC NSs: ZnIn2S4, CdS, CdIn2S4, and In2S3), which is synergistically enabled by a solid-state non-conjugated polymer, i.e., poly(diallyldimethyl ammonium chloride) (PDDA), and MXene quantum dots (MQDs). In such elaborately designed photosystems, an ultrathin PDDA layer functions as an intermediate charge transport mediator to relay the directional electron transfer from TMC NSs to MQDs that serve as the ultimate electron traps, resulting in a considerably boosted charge separation/migration efficiency. The suitable energy level alignment between TMC NSs and MQDs, concurrent electron-withdrawing capabilities of the ultrathin PDDA interim layer and MQDs, and the charge transport cascade endow the self-assembled TMC/PDDA/MQD heterostructured photosystems with conspicuously improved photoactivities toward anaerobic selective reduction of nitroaromatics to amino derivatives and photocatalytic hydrogen evolution under visible light irradiation. Furthermore, we ascertain that this concept of constructing a charge transfer cascade in such TMC-insulating polymer-MQD photosystems is universal. Our work would afford novel insights into smart design of spatial vectorial charge transport pathways by precise interface modulation via non-conjugated polymers for solar energy conversion.


Stochastic Optimal Control for Robot Manipulation Skill Learning Under Time-Varying Uncertain Environment.
In this article, a novel stochastic optimal control method is developed for robot manipulator interacting with a time-varying uncertain environment. The unknown environment model is described as a nonlinear system with time-varying parameters as well as stochastic information, which is learned via the Gaussian process regression (GPR) method as the external dynamics. Integrating the learned external dynamics as well as the stochastic uncertainties, the complete interaction system dynamics are obtained. Then the iterative linear quadratic Gaussian with learned external dynamics (ILQG-LEDs) method is presented to obtain the optimal manipulation control parameters, namely, the feedforward force, the reference trajectory, as well as the impedance parameters, subject to time-varying environment dynamics. The comparative simulation studies verify the advantages of the presented method, and the experimental studies of the peg-hole-insertion task prove that this method can deal with complex manipulation tasks.


Physicians Experiencing Intense Emotions While Seeing Their Patients: What Happens?
Physicians often deal with emotions arising from both patients and themselves; however, management of intense emotions when they arise in the presence of patients is overlooked in research. The aim of this study is to inspect physicians' intense emotions in this context, how these emotions are displayed, coping strategies used, adjustment behaviors, and the impact of the emotional reactions on the physician-patient relationship. A total of 127 physicians completed a self-report survey, built from a literature review. Participants were recruited in 3 different ways: through a snowball sampling procedure, via institutional e-mails, and in person during service meetings. Fifty-two physicians (43.0%) reported experiencing intense emotions frequently. Although most physicians (88.6%) tried to control their reactions, several reported not controlling themselves. Coping strategies to deal with the emotion at the moment included behavioral and cognitive approaches. Only the type of reaction (but not the emotion's valence, duration, relative control, or coping strategies used) seemed to affect the physician-patient relationship. Choking-up/crying, touching, smiling, and providing support were significantly associated with an immediate positive impact. Withdrawing from the situation, imposing, and defending oneself were associated with a negative impact. Some reactions also had an extended impact into future interactions. Experiencing intense emotions in the presence of patients was frequent among physicians, and the type of reaction affected the clinical relationship. Because many physicians reported experiencing long-lasting emotions, these may have important clinical implications for patients visiting physicians while these emotions last. Further studies are needed to clarify these results.


Mother's milk: an existential perspective on negative reactions to breast-feeding.
Drawing from an existential perspective rooted in terror management theory, four studies examined the hypothesis that breast-feeding women serve as reminders of the physical, animal nature of humanity and that such recognition is threatening in the face of one's unalterable mortality. Study 1 demonstrated that mortality salience (MS) led to more negative reactions toward a scenario depicting a woman breast-feeding her infant in public, and in Study 2, MS decreased liking and increased physical avoidance of a potential task partner described as breast-feeding in another room. Further supporting the hypothesis that such reactions are rooted in threats associated with human creatureliness, MS in conjunction with a breast-feeding prime led to an increase in the accessibility of creaturely related cognitions (Study 3) and priming human/animal similarities (i.e., creatureliness) led to increased negativity toward a magazine cover depicting a woman breast-feeding her child (Study 4). Implications of this research are discussed.


[Late adverse events after concurrent chemoradiation therapy in long-term survivors with non-small cell lung cancer].
Long-term survival in patients with non-small cell lung cancer( NSCLC) can be achieved more frequently with combined modality therapy. However, an increased risk of late treatment-related toxicities has been reported for this treatment strategy. We retrospectively evaluated NSCLC patients treated with chemoradiation therapy from January 1988 to January 2007. Patients who had survived for more than 5 years after treatment were included in an analysis of late adverse events (excluding radiation pneumonitis and pulmonary fibrosis). A total of 188 NSCLC patients treated with chemoradiation therapy were evaluated, with 25 patients having survived for more than 5 years. Of these patients, 4 had stage I disease, 4 had stage IIB disease, 1 had stage IIIA disease, 14 had stage IIIB disease, 1 had stage IV disease, and 1 had disease of unknown stage. The following grade 3 late adverse events were noted: skin ulceration( n=1), skin induration( n=1), brachial plexopathy( n=1), malignant neoplasm( n=1). Adequate management of late adverse events due to chemoradiation therapy is needed for long-term NSCLC survivors.


Characterization of the enterovirus 71 P1 polyprotein expressed in Pichia pastor as a candidate vaccine.
Human enterovirus 71 (EV71) plays an important role in hand, foot, and mouth disease (HFMD), which recently caused the death of hundreds of children in the Asia-Pacific region. However, there are no specific treatments available for EV71 infections; thus, a safe and effective vaccine is needed urgently. In this study, we developed an effective and economical method for producing EV71 polyprotein (P1 protein) in Pichia pastoris. Furthermore, we evaluated the potential of P1 protein as a candidate vaccine against EV71 virus. The data revealed that P1 protein induced persistent high cross-neutralization antibodies for different EV71 subtypes, and elicited significant splenocyte proliferation. The high levels of interleukin-10(IL-10) and interferon-gamma (IFN-γ) showed that P1 protein induced Th1 and Th2 immune responses. Interestingly, vaccinating female mice with the P1 protein conferred cross-protection against different EV71 subtypes to their neonatal offspring.Compared with heat-inactivated EV71, the P1 protein elicited improved humoral and cellular immune responses and showed good cross-protection with different EV71 subtypes. Therefore, the EV71-P1 protein produced by P. pastoris is a promising candidate vaccine against EV71.


Temporary confinement of loose-housed hyperprolific sows reduces piglet mortality.
The objective of this study was to investigate piglet mortality in a commercial setting where sows were accommodated in a loose-housed system with an option to confine the sow for a few days around farrowing and during early lactation. The study was conducted in a Danish piggery where records were obtained from 2,139 farrowings. Sows were randomly allocated to 1 of 3 treatments: loose-loose (LL), loose-confined (LC), and confined-confined (CC). In LL, sows were loose housed from the time they entered the farrowing pens to weaning. In LC, sows were loose housed until farrowing was finished and then confined to d 4 after farrowing. In CC, sows were confined at d 114 of gestation to d 4 after farrowing. All sows were loose housed from d 5 to weaning. Total piglet mortality was analyzed at batch level to include piglets fostered by nurse sows and at sow level to analyze the effects of confinement during different time periods. Total piglet mortality was greater in LL (26.0%) and LC (25.4%) compared with CC (22.1%; < 0.001). The proportion of stillborn piglets was not different between treatments ( = 0.21) but a larger proportion was crushed in LL (10.7%) compared with LC (9.7%; = 0.03), which again was greater than CC (7.8%; < 0.001). Piglet mortality before equalization was lower in CC (3.7%) than in LL (7.5%) and LC (7.0%; < 0.001). Confinement reduced mortality from litter equalization to d 4 (7.6% for LL vs. 6.7% for LC; = 0.01) but more so in CC (5.6%) than in LC ( < 0.001). From d 4 to weaning, LL had lower mortality (5.6%) than LC (6.9%) and CC (6.6%; = 0.01). A larger proportion of sows in CC were classified as "low mortality" compared with LL and LC both before ( < 0.001) and after ( = 0.002) litter equalization. The results in this study emphasize that the period of time from the birth of the first piglet to litter equalization is important in relation to piglet mortality. The results also suggest that confinement for 4 d after farrowing can reduce mortality in this specific period, but only confinement from d 114 of gestation to d 4 after farrowing reduced total piglet mortality.


Exploiting the Monomer-Feeding Mechanism of RAFT Emulsion Polymerization for Polymerization-Induced Self-Assembly of Asymmetric Divinyl Monomers.
We exploited the monomer-feeding mechanism of reversible addition-fragmentation chain transfer (RAFT) emulsion polymerization to achieve the successful polymerization-induced self-assembly (PISA) of asymmetric divinyl monomers. Colloidally stable cross-linked block copolymer nanoparticles with various morphologies, such as vesicles, were directly prepared at high solids. Morphologies of the cross-linked block copolymer nanoparticles could be controlled by varying the monomer concentration, degree of polymerization (DP) of the core-forming block, and length of the macro-RAFT agent. X-ray photoelectron spectroscopy (XPS) characterization confirmed the presence of unreacted vinyl groups within the obtained block copolymer nanoparticles, providing a landscape for further functionalization via thiol-ene chemistry. Finally, the obtained block copolymer nanoparticles were employed as additives to tune the mechanical properties of hydrogels. We expect that this study not only offers considerable opportunities for the preparation of well-defined cross-linked block copolymer nanoparticles, but also provides important insights into the controlled polymerization of multivinyl monomers.


Temozolomide therapy for resistant prolactin-secreting pituitary adenomas and carcinomas: a systematic review.
Pituitary tumors represent 10-15% of all intracranial tumors; of these, prolactinomas account for 40-50% of cases. Prolactinomas usually respond well to dopamine agonists (DA) as first-line therapy. However, treatment resistance remains a concern. Temozolomide (TMZ) is an oral alkylating agent that has shown promise in treating aggressive pituitary adenomas and carcinomas that are resistant to other therapies. To date, no control trials have been undertaken and only single case reports of pituitary tumors treated with TMZ have been published. A systematic literature search was conducted for studies reporting the use of TMZ for the treatment of prolactinomas that were resistant to standard therapy. In total, 42 reported cases were identified and included in our analysis: 23 cases of prolactin-secreting adenomas and 19 of prolactin-secreting carcinomas. Prior to TMZ administration, patients had exhibited tumor progression and had previously undergone various treatments including surgery, radiotherapy, and drug therapy. Tumor shrinkage was reported in 76% of patients. Reduced prolactin levels were observed in 75% of patients, while normalization of prolactin was reported in 8%. TMZ failure occurred in 20.6% of cases. Most patients exhibited no serious adverse effects. In conclusion, TMZ has potential for the treatment of highly aggressive and resistant prolactin-secreting adenomas and carcinomas, as demonstrated by tumor shrinkage or complete response and normalization of hormone hypersecretion, and exhibits good tolerability and few side effects.


Morphology and Optical Properties of Bare and Silica Coated Hybrid Silver Nanoparticles.
Owing to their wide applications in the field of optoelectronics, photonics, catalysis, and medicine; plasmonic metal nanoparticles are attaining considerable interest nowadays. The optical properties of these metal nanoparticles depend upon their size, shape, and surrounding medium. The present work studies the morphology and optical properties of bare silver nanoparticles and silica coated hybrid silver nanoparticles. Aqueous phase mediated synthesis and water-in-oil microemulsion mediated synthesis are two different wet chemical routes employed for nanosynthesis. Direct coating of silica is performed in water-in-oil microemulsion on pre-synthesized silver nanoparticles using tetraethyl orthosilicate as silica precursor. This study shows that using different wet chemical routes the size of the synthesized nanoparticles could be tuned. In addition, using reverse micelles as nanoreactors, the thickness of the silica shell around the core silver nanoparticles could be significantly controlled. Further, the optical properties of silver nanoparticles could be adjusted through the size and the surface coating.


Assessing procedural skills training in pediatric residency programs.
The objective of this study was to assess the opinions of pediatric program directors regarding procedural skills training of pediatric residents. We developed a survey based on the Residency Review Committee's guidelines for procedural training. It included items about the importance of 29 procedures encountered in pediatric training, estimates of residents' competence in performing them, and the teaching of procedural skills. The survey was sent to members of the Association of Pediatric Program Directors. The primary outcome was the perceived importance for residents to achieve competence in these procedures, rated on a 10-point Likert scale. Secondary outcomes included perception of resident competence to perform procedures and educational methods used by respondents for teaching procedural skills. Associations between demographic characteristics and perceived importance or competence were also assessed. Surveys were sent to 139 programs, and 112 responded. Thirteen procedures were rated 8 or higher by >75% of program directors. Seven skills that were prioritized by the Residency Review Committee did not achieve this level of consensus. Respondents reported that many residents failed to achieve competence by the end of training in 9 of 13 procedures that they rated as very important, including venipuncture, neonatal intubation, and administering injections. Residents who perform the majority of venipunctures and intravenous catheter placements at their institutions were more likely to be judged competent in performing these skills than residents who do not. The Residency Review Committee's list of procedures does not necessarily reflect the opinions of pediatric program directors on the most essential skills for trainees. Many residents may not develop competence in several important procedures by the end of residency, most notably vascular access and life-saving skills. A more robust and standardized method is needed for teaching procedural skills and for documenting competence.


Utilizing oncology biosimilars to minimize the economic burden associated with cancer treatment: managed care considerations.
The high cost of therapies for treatment of cancer places a substantial burden on the United States healthcare system. In recent years, there has been increased attention to the cost-savings benefits associated with clinical uptake of biosimilars and their market availability, with several biosimilars with oncology-related indications currently available. Though the biosimilar development process has contributed to price reductions and increased patient access to care, misconceptions about biosimilar safety and efficacy as well as inconsistent prescribing patterns have emerged as main barriers to their use in clinical practice. However, this hesitation from a clinical standpoint is not necessarily matched by payers or formulary decision makers in the oncology space. Earlier detection of cancer and longer duration of therapy has spurred discussion about initiation of biosimilars for newly diagnosed patients requiring treatment, but incorporation of biosimilars into formularies and institution protocols remain a challenge. There is clear urgency within the healthcare system to initiate the inclusion of biosimilars into treatment pathways for cancer, and pharmacists who care for patients with cancer have an important role in providing consistent messaging to both healthcare professionals and patients about biosimilars.


The timetable of evolution.
The integration of fossils, phylogeny, and geochronology has resulted in an increasingly well-resolved timetable of evolution. Life appears to have taken root before the earliest known minimally metamorphosed sedimentary rocks were deposited, but for a billion years or more, evolution played out beneath an essentially anoxic atmosphere. Oxygen concentrations in the atmosphere and surface oceans first rose in the Great Oxygenation Event (GOE) 2.4 billion years ago, and a second increase beginning in the later Neoproterozoic Era [Neoproterozoic Oxygenation Event (NOE)] established the redox profile of modern oceans. The GOE facilitated the emergence of eukaryotes, whereas the NOE is associated with large and complex multicellular organisms. Thus, the GOE and NOE are fundamental pacemakers for evolution. On the time scale of Earth's entire 4 billion-year history, the evolutionary dynamics of the planet's biosphere appears to be fast, and the pace of evolution is largely determined by physical changes of the planet. However, in Phanerozoic ecosystems, interactions between new functions enabled by the accumulation of characters in a complex regulatory environment and changing biological components of effective environments appear to have an important influence on the timing of evolutionary innovations. On the much shorter time scale of transient environmental perturbations, such as those associated with mass extinctions, rates of genetic accommodation may have been limiting for life.


The anti-dermatophyte activity of Zataria multiflora essential oils.
Dermtophytes are a group of pathogenic fungi and the major cause of dermatophytosis in humans and animals. Fighting dermatophytes by natural essential oils is one important issue in new researches. In this investigation, we evaluated the anti-dermatophyte activities of three samples of Z. multiflora essential oils against dermatophytes along with analysis of chemical compositions of the essential oils and their anti-elastase activities on elastase production in dermatophytes. Carvacrol (1.5-34.4%), thymol (25.8-41.2%), carvacrol methyl ether (1.9-28.3%) and p-cymene (2.3-8.3%) were the main components of Z. multiflora essential oils. Z. multiflora essential oils (100ppm) inhibited the mycelium growth of dermatophytes (6±1.7-47.0±1.4%) and had the minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) values of 0.03-0.25μl/ml against dermatophytes. Essential oils inhibited elastase produced in dermatophytes and pure porcine elastase. Z. multiflora essential oils can be used as natural anti-dermatophyte agent for fighting dermatophytes in further preclinical and clinical studies.


[THE PROLIFERATIVE EFFECT OF DENDRITIC CELLS IN OVARIAN CANCER AND THE RELATIONSHIP WITH THE IGF SIGNALING PATHWAY].
Epithelial ovarian cancer (EOC) is the principal cause of death from gynecologic cancer in developed countries. While surgery and chemotherapy can improve survival, the mortality and morbidity rates remain significantly high. The insulin-like growth factor (IGF) axis has been shown to play an important part in carcinogenesis of several human malignancies. Preclinical studies reported a significant anti-proliferative activity of IGF1 receptor (IGF1R) inhibitors in ovarian malignancies, however, clinical studies have shown variable response rates. Recent data indicate that immunotherapy could hold promise in improving EOC treatment. Dendritic cells (DCs) which are antigen presenting cells evoke a positive immune response. Moreover, a recent study shows that IGF treatment can inhibit DC maturation. To investigate the involvement of IGF1R signaling in DCs and the effect of combined DCs and IGF1R inhibitor treatment on EOC cells growth. HL-60 leukemic cells were differentiated to DCs and ligand induced phosphorylated IGF1R levels were measured by Western blotting. Next, inhibition of IGF1R in DCs was applied and the effect of this inhibition on EOC cell lines ES2 and SKOV3 was examined using the migration assay method. The differentiation of HL-60 into DCs was associated with decreased levels of both IGF1R phosphorylation and total IGF1R protein. In addition, in-vitro growth assays (scratch assay) demonstrated an increased growth of both ES2 and SKOV3 cells into the scratch zone when co-cultured with DCs which were not pre-treated with IGF1R inhibitor as compared to treated DCs. Preliminary data suggest that DC differentiation is associated with IGF1R signaling downregulation. Moreover, inhibition of IGF1R signaling in DCs might decrease EOC growth.


Power-up: A Reanalysis of 'Power Failure' in Neuroscience Using Mixture Modeling.
Recently, evidence for endemically low statistical power has cast neuroscience findings into doubt. If low statistical power plagues neuroscience, then this reduces confidence in the reported effects. However, if statistical power is not uniformly low, then such blanket mistrust might not be warranted. Here, we provide a different perspective on this issue, analyzing data from an influential study reporting a median power of 21% across 49 meta-analyses (Button et al., 2013). We demonstrate, using Gaussian mixture modeling, that the sample of 730 studies included in that analysis comprises several subcomponents so the use of a single summary statistic is insufficient to characterize the nature of the distribution. We find that statistical power is extremely low for studies included in meta-analyses that reported a null result and that it varies substantially across subfields of neuroscience, with particularly low power in candidate gene association studies. Therefore, whereas power in neuroscience remains a critical issue, the notion that studies are systematically underpowered is not the full story: low power is far from a universal problem.SIGNIFICANCE STATEMENT Recently, researchers across the biomedical and psychological sciences have become concerned with the reliability of results. One marker for reliability is statistical power: the probability of finding a statistically significant result given that the effect exists. Previous evidence suggests that statistical power is low across the field of neuroscience. Our results present a more comprehensive picture of statistical power in neuroscience: on average, studies are indeed underpowered-some very seriously so-but many studies show acceptable or even exemplary statistical power. We show that this heterogeneity in statistical power is common across most subfields in neuroscience. This new, more nuanced picture of statistical power in neuroscience could affect not only scientific understanding, but potentially policy and funding decisions for neuroscience research.


Upregulation of mu opioid receptors by voluntary morphine administration in drinking water.
Morphine was provided to rats in drinking water for 21 days. Profound analgesic tolerance was detected both in hot-plate and tail-flick tests. The density of [3H]DAMGO binding sites increased by 76% in spinal cord membranes due to morphine exposure compared to those in opioid naive animals. Slightly augmented [3H]DAMGO binding was measured in the synaptic plasma membranes, with a concomitant decrease in the microsomal membranes, of morphine tolerant/dependent brains. These observations suggest that the regulation of spinal mu opioid receptors might be different from those in the brain. It is emphasized that the molecular changes underlying tolerance/dependence are influenced by several factors, such as the tissue or subcellular fractions used, besides the obvious importance of the route of drug administration. Results obtained after voluntary morphine intake further support the growing number of experimental data that chronic morphine does not internalize/downregulate the mu opioid receptors in the central nervous system.


Latin America and the Caribbean Code Against Cancer 1st Edition: 17 cancer prevention recommendations to the public and to policy-makers (World Code Against Cancer Framework).
Preventable risk factors are responsible of at least 40% of cases and almost 45% of all cancer deaths worldwide. Cancer is already the leading cause of death in almost half of the Latin American and the Caribbean countries constituting a public health problem. Cost-effective measures to reduce exposures through primary prevention and screening of certain types of cancers are critical in the fight against cancer but need to be tailored to the local needs and scenarios. The Latin America and the Caribbean (LAC) Code Against Cancer, 1st edition, consists of 17 evidence-based recommendations for the general public, based on the most recent solid evidence on lifestyle, environmental, occupational, and infectious risk factors, and medical interventions. Each recommendation is accompanied by recommendations for policymakers to guide governments establishing the infrastructure needed to enable the public adopting the recommendations. The LAC Code Against Cancer has been developed in a collaborative effort by a large number of experts from the region, under the umbrella strategy and authoritative methodology of the World Code Against Cancer Framework. The Code is a structured instrument ideal for cancer prevention and control that aims to raise awareness and educate the public, while building capacity and competencies to policymakers, health professionals, stakeholders, to contribute to reduce the burden of cancer in LAC.


Prenylated C6-C3 derivatives from the root of Illicium ternstroemioides with antiviral activity.
Six previously undescribed prenylated C6-C3 derivatives (1-6) were isolated from the root of Illicium ternstroemioides A. C. Smith. Their structures were elucidated based on extensive spectroscopic analyses (UV, IR, 1D and 2D NMR, and HRESIMS). The absolute configurations of 1-3 were determined using electronic circular dichroism (ECD), and Mo2(OAc)4 induced circular dichroism (ICD). Compound 3 exhibited weak activity against Coxsackievirus B3 with an IC50 value of 33.3 µM, and compound 5 exhibited more potent activity against Coxsackievirus B3 with an IC50 value of 6.4 µM.


Precise Molecular Design of a Pair of New Regioisomerized Fluorophores With Opposite Fluorescent Properties.
Aggregation-induced emission (AIE) has attracted much attention in the past 2 decades. To develop novel AIE-active materials, ACQ-to-AIE transformation via regioisomerization is one of the most straightforward method. However, most of the reported ACQ-to-AIE transformations are achieved by migrating bulky units. In this work, a facile conversion was realized by migrating a small pyrrolidinyl group from para- to ortho-position on the rofecoxib scaffold. As a result, a pair of new isomers named MOX2 and MOX4 exhibited AIE behavior and ACQ activity, respectively. Moreover, MOX2 also showed solvatochromic, mechanochromic, and acidochromic properties with reversible multi-stimulus behavior. Single crystal X-ray analysis of MOX2 revealed that the molecular conformation and its packing mode were responsible for the AIE emission behavior. Further investigation indicated that MOX2 showed high lipid droplets staining selectivity. Taken together, the current work not only provides a new design philosophy for achieving ACQ-to-AIE conversion by migrating a small pyrrolidinyl group but also presents a promising candidate MOX2 for potential applications such as in security ink, optical recording and biological applications.


Effect of insulin on plasma triglyceride concentration in hepatectomized geese.
The effect of insulin on the removal of plasma triglycerides was tested in hepatectomized geese. In this preparation plasma triglyceride concentration decreases exponentially following hepatectomy. Infusion of insulin (0.001 U/kg/min. for 60 minutes) had no significant effect on the rate of disappearance of plasma triglycerides in the hepatectomized animals. The conclusion is, therefore, reached that insulin does not affect the removal of plasma triglycerides by the extrahepatic tissues in the goose.


Exploring epigenetic drugs as potential inhibitors of SARS-CoV-2 main protease: a docking and MD simulation study.
The COVID-19 pandemic has caused havoc around the globe since 2019 and is considered the largest global epidemic of the twentieth century. Although the first antiviral drug, Remdesivir, was initially introduced against COVID‑19, virtually no tangible therapeutic drugs exist to treat SARS-CoV-2 infection. FDA-approved Paxlovid (Nirmatrelvir supplemented by Ritonavir) was recently announced as a promising drug against the SARS-CoV-2 major protease (Mpro). Here we report for the first time the remarkable inhibitory potentials of lead epigenetic-targeting drugs (epi-drugs) against SARS-CoV-2 Mpro. Epi-drugs are promising compounds to be used in combination with cancer chemotherapeutics to regulate gene expression. The search for all known epi-drugs for the specific inhibition of SARS-CoV-2 Mpro was performed for the first time by consensus (three high-order program) molecular docking studies and end-state free energy calculations. Several epi-drugs were identified with highly comparable binding affinity to SARS-CoV-2 Mpro compared to Nirmatrelvir. In particular, potent histone methyltransferase inhibitor EPZ005687 and DNA methyltransferase inhibitor Guadecitabine were prominent as the most promising epi-drug inhibitors for SARS-CoV-2 Mpro. Long Molecular dynamics (MD) simulations (200 ns each) and corresponding MM-GBSA calculations confirmed the stability of the EPZ005687-Mpro complex with MM-GBSA binding free energy (ΔGbind) -48.2 kcal/mol (EPZ005687) compared to Nirmatrelvir (-44.7 kcal/mol). Taken together, the antiviral activities of the highlighted epi-drugs are reported beyond widespread use in combination with anti-cancer agents. The current findings therefore highlight as yet unexplored antiviral potential of epi-drugs suitable for use in patients struggling with chronic immunosuppressive disorders.Communicated by Ramaswamy H. Sarma.


Facilitating Growth Mixture Model Convergence in Preventive Interventions.
Growth mixture models (GMMs) are applied to intervention studies with repeated measures to explore heterogeneity in the intervention effect. However, traditional GMMs are known to be difficult to estimate, especially at sample sizes common in single-center interventions. Common strategies to coerce GMMs to converge involve post hoc adjustments to the model, particularly constraining covariance parameters to equality across classes. Methodological studies have shown that although convergence is improved with post hoc adjustments, they embed additional tenuous assumptions into the model that can adversely impact key aspects of the model such as number of classes extracted and the estimated growth trajectories in each class. To facilitate convergence without post hoc adjustments, this paper reviews the recent literature on covariance pattern mixture models, which approach GMMs from a marginal modeling tradition rather than the random effect modeling tradition used by traditional GMMs. We discuss how the marginal modeling tradition can avoid complexities in estimation encountered by GMMs that feature random effects, and we use data from a lifestyle intervention for increasing insulin sensitivity (a risk factor for type 2 diabetes) among 90 Latino adolescents with obesity to demonstrate our point. Specifically, GMMs featuring random effects-even with post hoc adjustments-fail to converge due to estimation errors, whereas covariance pattern mixture models following the marginal model tradition encounter no issues with estimation while maintaining the ability to answer all the research questions.


Pervasive epigenetic effects of Drosophila euchromatic transposable elements impact their evolution.
Transposable elements (TEs) are widespread genomic parasites, and their evolution has remained a critical question in evolutionary genomics. Here, we study the relatively unexplored epigenetic impacts of TEs and provide the first genome-wide quantification of such effects in D. melanogaster and D. simulans. Surprisingly, the spread of repressive epigenetic marks (histone H3K9me2) to nearby DNA occurs at >50% of euchromatic TEs, and can extend up to 20 kb. This results in differential epigenetic states of genic alleles and, in turn, selection against TEs. Interestingly, the lower TE content in D. simulans compared to D. melanogaster correlates with stronger epigenetic effects of TEs and higher levels of host genetic factors known to promote epigenetic silencing. Our study demonstrates that the epigenetic effects of euchromatic TEs, and host genetic factors modulating such effects, play a critical role in the evolution of TEs both within and between species.


Liver volume, as assessed by four ultrasonic crystals arranged to form a tetrahedron, decreases during anaphylactic shock in anesthetized rats.
We determined the hepatic volume change in anaphylactic hypotension by using four ultrasonic crystals in anesthetized rats. The hepatic volume was measured with four ultrasonic crystals arranged to form a tetrahedron on the liver surface. Before in vivo experiments, using isolated perfused rat liver preparations, we compared the measured liver volume changes with the whole-liver weight changes during hepatic blood flow rate changes and venoconstriction induced by norepinephrine. The measured relative change of the tetrahedron volume (V[utc]; percentage changes of the initial volume) was closely correlated with the liver weight change (W; percentage changes of the initial liver weight): V(utc) = 0.85W - 4.11 (r² = 0.67). Then, we measured the liver weight and the tetrahedron volume during hepatic anaphylaxis in isolated perfused liver excised from the rats sensitized with ovalbumin. An injection of the antigen into the perfusate caused anaphylactic venoconstriction, liver weight loss (1.1 ± 0.3 g; 9% ± 1%), and the tetrahedron volume reduction (12% ± 4%). Finally, we measured the liver volume change during anaphylactic hypotension in anesthetized ovalbumin-sensitized rats. When the antigen was i.v. injected into anesthetized rats, along with systemic hypotension and hepatic venoconstriction, the liver tetrahedron volume decreased by 6% ± 2% from baseline. In conclusion, we established a method to measure the hepatic volume by using four ultrasonic crystals forming a tetrahedron. Using this ultrasonic crystal method, we demonstrated that liver volume decreases during anaphylactic hypotension in anesthetized rats.


Field Inter-Rater Reliability of the Psychopathy Checklist-Revised.
Strong inter-rater reliability has been established for the Hare Psychopathy Checklist-Revised (PCL-R), specifically by examiners in research contexts. However, there is less support for inter-reliability in applied settings. This study examined archival data that included a sample of sex offenders ( n = 178) who entered federal custody between 1992 and 1998. The offenders were assessed using the PCL-R on two occasions. The first assessment occurred at Millhaven Institution, the intake unit for federally incarcerated offenders in the province of Ontario. The second assessment took place upon inmates' transfer to the Regional Treatment Center, which admits federal inmates with intense psychological and psychiatric needs. Intra-class correlation coefficients (ICCs) were calculated for item, total, factor, and facet scores. The ICC absolute agreement for the PCL-R total and factor scores from raters across both settings was slightly better than what has been previously reported by Hare. Results of this study show that the reliability of PCL-R scores in field settings can be comparable to those in research settings. Authors conclude by highlighting the importance of training, consultation, considering different scores for a given item, following the guidelines of the manual in addition to considering measures that enhance neutrality and reliability of findings in the criminal justice system.


Gene therapy of single-gene disorders: preface to the special section.
Gene therapy was introduced into clinical practice with great excitement, much publicity and considerable optimism in the early 1990s. Scientific evaluation of the early clinical trials has, however, greatly reduced the initial optimism. Follow-up studies have revealed that many early gene therapy trials mainly represented gene transfer into patients, possibly with short-term effects, but not true gene therapy where the course of the disease is permanently affected. This has lead to critical re-evaluation of the approaches taken. Clearly, more basic understanding is needed of the molecular mechanisms of the diseases treated. For this purpose, better animal models for human diseases are necessary. One of the biggest obstacles for gene therapy has been the lack of adequate vector systems. Development of new vectors for efficient and targeted delivery and uptake of therapeutic genes is a crucial area where progress needs to be made. The rationale for gene therapy depends largely on the type of disease to be treated. Recessively inherited single-gene disorders represent diseases where the concept of gene therapy--addition of a therapeutic gene to restore the lost function of two mutant alleles--is easily understood and rarely questioned. However, most gene therapy protocols are focused on multifactorial diseases such as malignancies where the therapeutic approach is quite different. While gene transfer technologies are being developed into truly effective gene therapy, the fight against inherited single-gene disorders also continues at population level by carrier screening and prenatal diagnostics where rapid methodological developments are taking place.


Underlying functions associated with keyboarding performance of elementary-school students.
Keyboarding (Typing) is a major writing mode in educational settings in addition to, or as an alternative to, handwriting. Therefore, it is important that occupational therapists become experts on this activity, to support students' performance. Yet, the knowledge of keyboarding performance of elementary-school students, and the underlying functions it entails, is limited. To compare keyboarding performance (speed and accuracy) of 4th-grade students in copying and dictation keyboarding tasks, and to examine the role of underlying functions in predicting keyboarding performance. The sample consisted of 57 4th-grade students, recruited from 2 elementary schools. Students were tested for reading speed, attention shifting, fine-motor skills, kinaesthetic awareness, and keyboarding performance. Keyboarding performance differed in the copying and dictation tasks. Reading speed was the major underlying function predicting keyboarding performance in both tasks. Additionally, kinaesthetic awareness had a low, negative correlation with dictation accuracy. When occupational therapists assess students' keyboarding performance, they should use various tasks. Additionally, therapists should consider students' reading speed and kinaesthetic awareness, as they may explain keyboarding performance. This knowledge may also support decision-making when considering keyboarding as an alternative writing mode for students with handwriting difficulties.


Association between Bolton discrepancy and Angle malocclusions.
This study aimed to assess and compare the overall and anterior ratios of tooth size discrepancies in all Angle malocclusion groups. The following null hypothesis (H0) was tested: no difference between tooth size discrepancies (overall and anterior) would be observed among Angle malocclusion groups. The sample comprised of 711 pre-orthodontic treatment study casts of Brazilian patients with a mean age of 17.42 years selected from private practices in Brazil. The casts were divided into 3 groups according to the type of malocclusion: Class I (n = 321), Class II (n = 324), and Class III patients (n = 66). The measurement of the greatest mesiodistal width of the teeth was performed using a centesimal precision digital caliper directly on the study casts, from the distal surface of the left first molar to the distal surface of the right first molar. The overall and anterior ratios between the maxillary and mandibular teeth were evaluated using Bolton's method. The following statistical tests were applied: chi-square, independent t-test, and one-way ANOVA. Results showed that all Angle malocclusions groups exhibited a ratio compatible with those recommended by Bolton. With respect to the overall and anterior ratios among the malocclusion groups, no statistically significant differences were found. The null hypothesis was accepted because the results showed no differences in the overall and anterior ratios of tooth size discrepancies among different Angle malocclusion groups.


Phosphatidylinositol 3-kinase and 4-kinase have distinct roles in intracellular trafficking of cellulose synthase complexes in Arabidopsis thaliana.
The oriented deposition of cellulose microfibrils in the plant cell wall plays a crucial role in various plant functions such as cell growth, organ formation and defense responses. Cellulose is synthesized by cellulose synthase complexes (CSCs) embedded in the plasma membrane (PM), which comprise the cellulose synthases (CESAs). The abundance and localization of CSCs at the PM should be strictly controlled for precise regulation of cellulose deposition, which strongly depends on the membrane trafficking system. However, the mechanism of the intracellular transport of CSCs is still poorly understood. In this study, we explored requirements for phosphoinositides (PIs) in CESA trafficking by analyzing the effects of inhibitors of PI synthesis in Arabidopsis thaliana expressing green fluorescent protein-tagged CESA3 (GFP-CESA3). We found that a shift to a sucrose-free condition accelerated re-localization of PM-localized GFP-CESA3 into the periphery of the Golgi apparatus via the clathrin-enriched trans-Golgi network (TGN). Treatment with wortmannin (Wm), an inhibitor of phosphatidylinositol 3- (PI3K) and 4- (PI4K) kinases, and phenylarsine oxide (PAO), a more specific inhibitor for PI4K, inhibited internalization of GFP-CESA3 from the PM. In contrast, treatment with LY294002, which impairs the PI3K activity, did not exert such an inhibitory effect on the sequestration of GFP-CESA3, but caused a predominant accumulation of GFP-CESA3 at the ring-shaped periphery of the Golgi apparatus, resulting in the removal of GFP-CESA3 from the PM. These results indicate that PIs are essential elements for localization and intracellular transport of CESA3 and that PI4K and PI3K are required for distinct steps in secretory and/or endocytic trafficking of CESA3.


Identification of two glioblastoma-associated stromal cell subtypes with different carcinogenic properties in histologically normal surgical margins.
Glioblastoma (GB) is a highly infiltrative tumor recurring within a few centimeters of the resection cavity in 85 % of cases, even in cases of complete tumor resection and adjuvant chemo/radiotherapy. We recently isolated GB-associated stromal cells (GASCs) from the GB peritumoral zone, with phenotypic and functional properties similar to those of the cancer-associated fibroblasts present in the stroma of carcinomas. In particular, GASCs promote blood vessel development and have tumor-promoting effects on glioma cells in vitro and in vivo. In this study, we characterized these cells further, by analyzing the transcriptome and methylome of 14 GASC and five control stromal cell preparations derived from non-GB peripheral brain tissues. We identified two subtypes of GASCs in surgical margins in GB patients: GASC-A and GASC-B. GASC-B promoted the development of tumors and endothelium, whereas GASC-A did not. A difference in DNA methylation may underlie these two subtypes. We identified various proteins as being produced in the procarcinogenic GASC-B. Some of these proteins may serve as prognostic factors for GB and/or targets for anti-glioma treatment. In conclusion, in this era of personalized therapy, the status of GASCs in GB-free surgical margins should be taken into account, to improve treatment and the prevention of recurrence.


Do Self-Regulated Learning Practices and Intervention Mitigate the Impact of Academic Challenges and COVID-19 Distress on Academic Performance During Online Learning?
The COVID-19 pandemic introduced significant disruptions and challenges to the learning environment for many post-secondary students with many shifting entirely to remote online learning. Barriers to academic success already experienced in traditional face-to-face classes may be compounded in the online environment and exacerbated by stressors related to the pandemic. In 2020-2021, post-secondary institutions were faced with the reality of rolling out fully online instruction with limited access to resources for assisting students in this transition. Instructional interventions that target students' ability to self-regulate their learning have been shown to improve academic performance and self-regulated learning (SRL) competencies have also been found to mediate the effect of SRL interventions on higher education. However, few studies have examined the efficacy of fully online SRL intervention on mitigating the impact of psychological distress and academic challenges on academic success. This study examined the moderating roles of self-regulatory practices and SRL intervention in buffering the influence of COVID-related psychological distress and academic challenges on academic outcomes (self-reported grade point average (GPA) and academic challenges) in a Canadian sample of undergraduate students (n = 496). We found (a) levels of metacognitive and motivational challenges fully mediated the impact of COVID distress on GPA, (b) SRL adapting practices moderated the impact of metacognitive challenges on GPA, and (c) semester-long SRL intervention buffered the impact of COVID distress on academic challenges and resulted in lower levels of social-emotional, cognitive, and metacognitive challenges for first year undergraduate students.


Structural changes in renal arterioles in Type I diabetic patients.
We aimed to obtain data on arteriolar structure in a follow-up study of microalbuminuric diabetic patients. Kidney biopsies were obtained at baseline and after 8 years in 18 Type I (insulin-dependent) diabetic patients. Albumin excretion rate, blood pressure and HbA(1C) were measured regularly, and the glomerular filtration rate (GFR) was measured at the time of the kidney biopsy. The biopsy was embedded into plastic blocks and serially sectioned with 1 microm sections. In levels 25 microm apart, afferent and efferent arteriolar profiles were identified and digitised in the electron microscope. The extra-cellular matrix as volume fraction of the media was measured, and estimates of thickness of matrix, media, endothelium and lumen were obtained. Baseline and follow-up biopsies were studied concomitantly. A large increase was seen in matrix volume fraction in afferent ( p = 0.0001) and in efferent arterioles ( p = 0.0004). Estimated thickness of media and matrix increased, whereas endothelial cell thickness decreased, over the 8 years. There was a correlation between the parameters of diabetic glomerulopathy and arteriolar parameters in the biopsies done at 8 years, basement membrane thickness compared with afferent matrix volume fraction: r = 0.74, p = 0.0005. Also aggravation of glomerulopathy and arteriolar structure over 8 years showed positive correlation. Arteriolar parameters correlated with the albumin excretion rate (AER) and inversely with GFR. The arteriolar accumulation of matrix parallels that taking place in glomeruli and shows association with functional parameters over 8 years in Type I diabetic patients with microalbuminuria. These changes are considered an important part of the structural lesions in the diabetic kidney underlying the development of diabetic nephropathy.


Experience with Yersinia enterocolitica at The Hospital for Sick Children, 1972-74.
Thirty-six cases of Yersinia enterocolitica infection were detected in the years 1972-74. The form of the illness in young children was acute gastroenteritis and in older children "appendicular syndrome". Improved isolation and identification techniques have increased the laboratory recognition of this enteric pathogen.


Perioperative risk and management in patients with pulmonary hypertension.
Pulmonary hypertension (PH) is a known risk factor for perioperative complications. Unlike in the case of cardiac surgery, PH is currently not listed as an independent risk factor for postoperative complications in guidelines for the management of noncardiac surgery. Despite the paucity of data, though, patients with PH are often counseled against having elective procedures because early and sudden postoperative deaths have been reported. Patients with PH are unable to accommodate alterations in right ventricular (RV) preload or afterload induced by fluid shifts, medications, or changes in the autonomic nervous system precipitated by hypoxia or hypercapnia. These factors become magnified in situations of added stress such as surgical intervention. Systemic hypotension and arrhythmias may precipitate RV ischemia, further worsening RV function. Patient and surgical characteristics and choice of anesthetic technique are crucial factors in perioperative management. The two main principles of perioperative management are the prevention of systemic hypotension (risk of RV ischemia) and the prevention of acute elevations in pulmonary arterial pressure (risk of RV failure). Close monitoring, optimization of systemic BP, pain control, oxygenation and ventilation, avoidance of exacerbating factors, and use of vasopressors and pulmonary vasodilators as necessary are essential elements of management. Understanding the pathophysiology, cause, and severity of PH in the individual perioperative patient allows accurate risk assessment, optimization of PH and RV function prior to surgery, and appropriate intraoperative and postoperative management.


Muscle activity and architecture as a predictor of hand-grip strength.
Grip strength is a powerful predictor of disability as well as a good indicator of physical activity. This study aimed to relate ultrasound (US) and electromyography (EMG) simultaneously to maximum hand-grip strength during an isometric contraction. This is a cross-sectional study. Data acquisition was done with a dynamometer, US and EMG. Outcome variables included maximum strength during the hand-grip gesture, maximum muscle activity and change in muscle thickness. A non-linear regression analysis was performed to analyse the relationship between all outcome variables. A total of 38 subjects (18 men and 20 women) participated in the study. The mean results for hand-grip strength were 25.50 (SD 6.55) kg of maximum strength, a change in muscle thickness of 1.83 (SD 0.75) mm and an EMG activity of 499.29 (SD 224.20) µV. Hand-grip strength had a high correlation with muscle thickness (R 2 = 0.61) and EMG activity (R 2 = 0.95). The correlation between maximum muscle activity and change in muscle thickness was R 2 = 0.83. The results of the present study demonstrate that this new method based on electromyographic activity and muscule architecture could be important in the development of the hand-grip test.


Risk factors for drug-related problems in a general hospital: A large prospective cohort.
To identify risk factors for potential Drug-Related Problems (DRP) at admission in hospitalized patients. Prospective cohort study conducted in adults patients hospitalized (May 2016 to May 2018) in a general tertiary care hospital in Brazil. Potential DRP were detected by daily review of 100% of electronic medication orders by hospital pharmacists and classified by the Pharmaceutical Care Network Europe classification system (PCNE version 6.2). For the identification of risk factors of potential DRP, backward stepwise logistic regression was used to identify the set of independent predictors among over 120 variables collected in the initial 48 hours after admission in a training set consisting of 2/3 of the study population. The model was validated in the remaining sample. The study population consisted of 1686 patients aged 52.0+/- 18.3 years-old, 51.4% females, with a median length of stay of 3.24 days, and 4.5% in-hospital mortality. The cumulative incidence of potential DRP was 14.5%. Admission for elective surgery and main diagnosis of disease of the circulatory system were associated with reduced risk of DRP (OR 0.41 and 0.57, respectively, p<0.05). The independent risk factors of DRP are heart rate ≥ 80 bpm (OR 1.41, p = 0.05), prescription of more than seven drugs in day 2 (OR 1.63, p = 0.05), prescription in day 1 of drugs of the Anatomical Therapeutic Chemical Code (ATC) class A (alimentary tract and metabolism, OR 2.24, p = 0.003), prescription in day 2 of two or more ATC class A drugs (OR = 3.52, p<0.001), and in day 1 of ATC class J drugs (antiinfectives for systemic use, OR 1.97, p = 0.001). In the validation set, the c-statistic of the predictive model was 0.65, the sensitivity was 56.1% and the specificity was 65.2%. This study identified seven independent risk factors of potential DRP in patients hospitalized in a general hospital that have fair predictive performance for utilization in clinical practice.


Chiral self-recognition: direct spectroscopic detection of the homochiral and heterochiral dimers of propylene oxide in the gas phase.
In this report, we describe rotational spectroscopic and high-level ab initio studies of the 1:1 chiral molecular adduct of propylene oxide dimer. The complexes are bound by weak secondary hydrogen bonds, that is, the O(epoxy)...H-C noncovalent interactions. Six homochiral and six heterochiral conformers were predicted to be the most stable configurations where each monomer acts as a proton acceptor and a donor simultaneously, forming two six- or five-membered intermolecular hydrogen-bonded rings. Rotational spectra of six, that is, three homochiral and heterochiral conformer pairs, out of the eight conformers that were predicted to have sufficiently large permanent electric dipole moments were measured and analyzed. The relative conformational stability order and the signs of the chiral recognition energies of the six conformers were determined experimentally and were compared to the ab initio computational results. The experimental observations and the ab initio calculations suggest that the concerted effort of these weak secondary hydrogen bonds can successfully lock the subunits in a particular orientation and that the overall binding strength is comparable to a classic hydrogen bond.


[Antibiotic sensitivity of gram-negative bacteria in intensive care units in Switzerland].
The sensitivity to the major antimicrobial agents of consecutively isolated gram-negative rods in intensive care units in Switzerland was investigated. A majority of strains originated from clinical specimens where infection or colonization could not be distinguished from each other. A total of 1024 isolates from 482 patients were tested by a standardized microtiter method. Of the beta-lactam antibiotics, imipenem (92% of bacteria sensitive), ceftazidime (90%), and aztreonam (85%) showed the greatest activity. 94% of the isolates were sensitive to ciprofloxacin, and 93% and 91% to amikacin and tobramycin respectively. There where considerable differences locally and in time, probably reflecting small outbreaks due to resistant bacteria and because selective pressure is locally dependent on the antimicrobial agents used. 122 patients were observed for an extended period. In 67 (55%) the same gram-negative rods persisted for up to 42 days without development of resistance. In 41 patients (34%) there was a change to other more resistant bacteria, especially to multi-resistant Pseudomonas aeruginosa, Flavobacterium meningo-septicum, Xanthomonas maltophilia or Enterobacter cloacae. In 12 patients (10%) bacteria of the same species with resistance to additional antimicrobial agents were observed.


[Breastfeeding reduces risk of obesity among children 12 months of age].
Many studies suggest that some breastfeeding may be a protective factor against obesity. Our aim was to evaluate whether exclusive breastfeeding for six months, as recommended by the Danish National Board of Health, prevents obesity among children. A literature search found four epidemiological studies comparing children who were exclusively breastfed for six months with children who were never breastfed. Exclusive breastfeeding for six months reduced the risk of obesity among children 12 months of age. In children aged 3-14 years the result was inconsistent.


What impact does trauma have on the at-risk mental state? A systematic literature review.
Identification of individuals with an at-risk mental state (ARMS) who are at a heightened risk of developing psychosis allows researchers and clinicians to identify what factors are associated with poorer outcomes and transitions to psychosis. A number of socioenvironmental factors are linked to an increase risk of developing psychosis, of which childhood trauma is widely acknowledged. The current review aims to examine what impact trauma has on the ARMS by reviewing reported relationships between trauma variables and transition to psychosis, ARMS severity, adaptive functioning and comorbid symptomology from both cross sectional and prospective design studies. A literature search was conducted for all relevant original research articles published in the English language up to December 2015 using 3 electronic databases: PsycINFO, Web of Science and PubMed. A total of 6 papers met the inclusion criteria and were included in the current review. Trauma was found to have a significant impact on the ARMS observed through reported relationships between trauma variables and transition to psychosis, ARMS severity, adaptive functioning and comorbid symptomology. Sexual trauma demonstrated the most consistent trauma variable to impact the ARMS. Individuals with an ARMS who have experienced sexual trauma are at a heightened risk of poorer outcomes and transitions to psychosis. Further prospective design studies are required to examine this observation further.


Visfatin attenuates the ox-LDL-induced senescence of endothelial progenitor cells by upregulating SIRT1 expression through the PI3K/Akt/ERK pathway.
Endothelial progenitor cells (EPCs) play an important role in aging-associated senescence, thereby potentially contributing to vascular pathologies. Visfatin, identified as a new adipocytokine, is closely associated with the senescence of human cells. However, the effects of visfatin on the oxidized low-density lipoprotein (ox-LDL)-induced senescence of EPCs has not yet been explored, to the best of our knowledge. For this purpose, in the present study, we examined the effects of visfatin in ox-LDL-stimulated EPCs as well as the underlying mechanism responsible for these effects. We found that visfatin attenuated the ox-LDL-induced senescence of EPCs by repressing β-galactosidase expression and recovering telomerase activity. Western blot analysis confirmed that visfatin induced a dose-dependent increase in sirtuin 1 (SIRT1) expression in EPCs and ox-LDL exposure decreased SIRT1 expression. Silencing SIRT1 abolished the inhibition of EPC senescence and the suppression of p53 expression induced by visfatin. Moreover, visfatin attenuated the inhibition of phosphorylation of Akt, phosphoinositide-3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) induced by ox-LDL. Taken together, these findings suggest that the treatment of EPCs with visfatin markedly attenuates the ox-LDL-induced senescence of EPCs by upregulating SIRT1 expression through the PI3K/Akt/ERK pathway.


Do Transsacral-transiliac Screws Across Uninjured Sacroiliac Joints Affect Pain and Functional Outcomes in Trauma Patients?
Patients with pelvic ring displacement and instability can benefit from surgical reduction and instrumentation to stabilize the pelvis and improve functional outcomes. Current treatments include iliosacral screw or transsacral-transiliac screw, which provides greater biomechanical stability. However, controversy exists regarding the effects of placement of a screw across an uninjured sacroiliac joint for pelvis stabilization after trauma. Does transsacral-transiliac screw fixation of an uninjured sacroiliac joint increase pain and worsen functional outcomes at minimum 1-year followup compared with patients undergoing standard iliosacral screw fixation across the injured sacroiliac joint in patients who have sustained pelvic trauma? All patients between ages 18 and 84 years who sustained injuries to the pelvic ring (AO/OTA 61 A, B, C) who were surgically treated between 2011 and 2013 at an academic Level I trauma center were identified for selection. We included patients with unilateral sacroiliac disruption or sacral fractures treated with standard iliosacral screws across an injured hemipelvis and/or transsacral-transiliac screws placed in the posterior ring. Transsacral-transiliac screws were generally more likely to be used in patients with vertically unstable sacral injuries of the posterior ring as a result of previous reports of failures or in osteopenic patients. We excluded patients with bilateral posterior pelvic ring injuries, fixation with a device other than a screw, previous pelvic or acetabular fractures, associated acetabular fractures, and ankylosing spondylitis. Of the 110 patients who met study criteria, 53 (44%) were available for followup at least 12 months postinjury. Sixty patients were unable to be contacted by phone or mail and seven declined to participate in the study. Outcomes were obtained by members of the research team using the visual analog scale (VAS) pain score for both posterior sacroiliac joints, Short Musculoskeletal Functional Assessment (SMFA), and Majeed scores. Patients completed the forms by themselves when able to return to the clinic. A phone interview was performed for others after they received the outcome forms by mail or email. There were no differences between iliosacral and transsacral-transiliac in terms of VAS injured (2.9 ± 2.9 versus 3.0 ± 2.8, mean difference = 0.1 [95% confidence interval, -1.6 to 1.7], p = 0.91), VAS uninjured (1.8 ± 2.4 versus 2.0 ± 2.6, mean difference = 0.2 [-1.3 to 1.6], p = 0.82), Majeed (80.3 ± 19.9, 79.3 ± 17.5, mean difference = 1.0 [-11.6 to 9.6], p = 0.92), SMFA Function (22.8 ± 22.2, 21.0 ± 17.6, mean difference = 1.8 [-13.2 to 9.6], p = 0.29, and SMFA Bother (24.3 ± 23.8, 29.7 ± 23.4, mean difference = 5.4 [-7.8 to 18.6], p = 0.42). Placement of fixation across a contralateral, uninjured sacroiliac joint resulted in no differences in pain and function when compared with standard iliosacral screw placement across an injured hemipelvis at least 1 year after instrumentation. When needed for biomechanical stability, transsacral-transiliac fixation across an uninjured sacroiliac joint can be used without expectation of positive or negative effects on pain or functional outcomes at minimum 1-year followup. Level III, therapeutic study.


Nano Biomass Material functionalized by β-CD@Ce(NO)3 as a high performance adsorbent to removal of fluorine from wastewater.
Fluorine pollution has become one of the key issues of water pollution, and the adsorption materials for efficient removal of fluorine ions have attracted much attention. It is rarely reported that the self-synthesized biomass materials were functionalized by the β-CD@Ce(NO)3. This paper mainly proposed a new synthetic method of the self-synthesized biomass materials were modified by the β-CD@Ce(NO)3 and removal of fluorine ions. The effects of this materials on the adsorption efficiency of fluorine ions under different conditions were explored, and the kinetic and thermodynamic simulations were carried out. The results show that the self-synthesized biomass materials were modified by the β-CD@Ce(NO)3 has significant pore structure, large specific surface area and multi-functional group. Adsorption experiment showed that the reaction reached adsorption equilibrium at 30 min. The removal rate of fluorine ions reached 93.13%, and the fluorine ions adsorption capacity was 37.25 mg/g under neutral conditions. The material can be recycled for more than 5 times, and the adsorption efficiency remains above 94%. The adsorption kinetics accorded with the pseudo second-order model and the adsorption isotherm equation is in line with the Langmuir isotherm adsorption model. PO43- and CO32- have the most impact on fluorine ions adsorption. This method reduces the synthesis cost of high-performance adsorption materials and improves the adsorption performance, which is conducive to the popularization and application in the future.


Efficient synthesis of chiral 1,1'-binaphthalenes by the asymmetric suzuki-miyaura reaction: dramatic synthetic improvement by simple purification of naphthylboronic acids.
Naphthylboronic acids prepared as reported in the literature are contaminated with HCl. A very simple purification prior to their use in Suzuki-Miyaura couplings has been found to be crucial, rendering efficient some reactions that had been reported in the literature either to fail or to give extremely poor yields. With this improvement, parent boronic acids can be used instead of esters at moderate temperatures, and bromo derivatives can be used instead of iodo derivatives. Convenient access to chiral sterically hindered binaphthalene derivatives has been achieved through the use of boronic acids, bromonaphthalenes, and ferrocenylphosphane ligands. The products were obtained in good yields (95-55 %) and with good enantioselectivities (90-50 %). Bulkier ligands are less efficient in the coupling of hindered partners.


Lack of observed association between high plasma osteoprotegerin concentrations and ischemic stroke risk in a healthy population.
Several studies suggest that osteoprotegerin (OPG) concentrations may be associated with the risk of ischemic stroke, but no large prospective studies have been conducted. We conducted a nested case-control study within a large cohort to elucidate a possible relation. The study was done within a follow-up study including 57 053 men and women. Baseline data included OPG concentrations, lifestyle factors, and medical history. Median length of follow-up was 3.1 years. We assessed the relationship between OPG and stroke risk using conditional logistic regression to adjust for known risk factors (smoking, blood pressure, cholesterol, diabetes, body mass index, alcohol use, polyunsaturated fatty acids, and education). We identified 254 cases with verified incident acute ischemic stroke and 254 age- and sex-matched controls. Median plasma OPG concentration among cases was 1.84 microg/L (25th-75th percentile 1.45-2.30 microg/L) compared with 1.87 microg/L (1.49-2.27 microg/L) in the control group. The adjusted odds ratio was 0.87 (95% CI 0.46-1.63) comparing participants in the highest quartile of OPG concentrations with those in the lowest quartile. These findings provide no support for the hypothesis that plasma OPG concentrations are associated with an increased risk of ischemic stroke. This result could indicate a different pathogenic process in stroke development from that in ischemic heart disease, where OPG is a strong predictor.


Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus.
To assess factors associated with primary and secondary non-response to rituximab in systemic lupus erythematosus (SLE) and evaluate management of secondary non-depletion non-response (2NDNR). 125 patients with SLE treated with rituximab over 12 years were studied prospectively. A major clinical response was defined as improvement of all active British Isles Lupus Assessment Group (BILAG)-2004 domains to grade C/better and no A/B flare. Partial responders were defined by one persistent BILAG B. B-cell subsets were measured using highly sensitive flow cytometry. Patients with 2NDNR, defined by infusion reaction and defective depletion, were treated with ocrelizumab or ofatumumab. 117 patients had evaluable data. In cycle 1 (C1), 96/117 (82%) achieved BILAG response (major=50%, partial=32%). In multivariable analysis, younger age (OR 0.97, 95% CI 0.94 to 1.00) and B-cell depletion at 6 weeks (OR 3.22, 95% CI 1.24 to 8.33) increased the odds of major response. Complete depletion was predicted by normal complement and lower pre-rituximab plasmablasts and was not associated with increased serious infection post-rituximab. Seventy-seven (with data on 72) C1 responders were retreated on clinical relapse. Of these, 61/72 (85%) responded in cycle 2 (C2). Of the 11 C2 non-responders, nine met 2NDNR criteria (incidence=12%) and tested positive for anti-rituximab antibodies. Lack of concomitant immunosuppressant and higher pre-rituximab plasmablasts predicted 2NDNR. Five were switched to ocrelizumab/ofatumumab, and all depleted and responded. Treatment with anti-CD20 agents can be guided by B-cell monitoring and should aim to achieve complete depletion. 2NDNR is associated with anti-rituximab antibodies, and switching to humanised agents restores depletion and response. In SLE, alternative anti-CD20 antibodies may be more consistently effective.


A diet supplemented with n-3 polyunsaturated fatty acids influences the metabomscic and endocrine response of rabbit does and their offspring.
The aim of the present study was to evaluate the productive, endocrine, and metabomscic responses as well as oxidative stress of rabbit does and their offspring when fed a diet supplemented with -3 PUFA during their first productive cycle. To this aim, a total of 105 rabbit does were fed ad mscibitum from d 60 to 172 of age 2 isoenergetic and isoproteic diets differing in fatty acid composition. The control diet ( = 52 does) contained 45.9 g/kg of -3 of the total fatty acids and the enriched diet ( = 53 does) contained 149.2 g/kg of -3 of the total fatty acids. Both experimental groups had similar feed intake during rearing, pregnancy, and lactation. The enrichment of diet had no effect on ultrasonographic assessment of does on d 9 and 16 of pregnancy, with an embryonic vesicle number and fetus and placenta size similar between groups ( > 0.05). Even though there were no major effects ( > 0.05) on fertimscity, duration of gestation, and number born amscive and stillborn kits at parturition, mscive kits from enriched does were longer (71.6 ± 2.42 vs. 79.5 ± 2.13 mm; < 0.05) and tended to be heavier (42.5 ± 3.94 vs. 50.8 ± 3.47 g; = 0.07) than those from control does ( < 0.05). The 2 groups had similar milk production and mortamscity values during lactation; consequently, there were no differences between diets in ADG, mscitter weight, and number of weaned kits ( > 0.05). In enriched does, higher plasma leptin and estradiol concentrations than in control does ( < 0.05) were observed. In addition, enriched females also had lower total and high-density mscipoprotein cholesterol (HDL-c) than control females during lactation ( < 0.05). Regarding offspring, the enrichment of diet with PUFA caused a hypermscipidemic status (greater values of plasma triglycerides, total cholesterol, and HDL-c; < 0.05) at 1 d postpartum (dpp), compared with the control group, that disappeared at 32 dpp. Supplemented does before parturition and their offspring at 1 dpp had greater oxidative stress than those in the control group. In conclusion, an increase of -3 PUFA concentration in the diet of rabbit does and, consequently, of their offspring during a productive cycle alters their mscipid profile and the indicators of oxidative stress, without major endocrine modifications or improvements in the productive variables.


Block training in group analysis: the Norwegian program.
Block training in group psychotherapy makes it possible to train professionals living far apart and to import conductors to an area or country lacking sufficient expertise. This article reports experience with such a training program in Norway. Training is given in blocks of 5 weekends a year, each weekend containing small group therapy, supervision, theory courses, lectures, and large group experiences. The participants were questioned about their personal and professional gains from the training. These findings and the effect of the program in relation to stated goals are discussed.


3D microtomographic characterization of precision extruded poly-epsilon-caprolactone scaffolds.
One of the dominant approaches to tissue engineering is the seeding of biodegradable, biocompatible polymer scaffolds with progenitor cells prior to 3D culture or implantation. The microarchitecture of these scaffolds has direct effects upon the ability of cells to attach, migrate, and differentiate. Microtomographic (micro-CT) scanners enable high-speed 3D characterization of the salient features of these polymer scaffolds. A micro-CT scan followed by 3D reconstruction of serial image sections can determine porosity, pore size, pore interconnectivity, strut size, and overall 3D microarchitecture. In this study, four polymer samples with different microarchitectures were manufactured through precision extrusion deposition free-form fabrication and subsequently characterized through micro-CT analysis. A desktop micro-CT scanner was used to examine each sample at approximately 19.1-micron resolution. 2D analyses and 3D reconstructions of core regions of each sample were performed. These results illustrate that qualitative and quantitative analysis of polymer scaffolds is possible using micro-CT and 3D reconstruction techniques.


An HD-GYP cyclic di-guanosine monophosphate phosphodiesterase with a non-heme diiron-carboxylate active site.
The intracellular level of the ubiquitous bacterial secondary messenger, cyclic di-(3',5')-guanosine monophosphate (c-di-GMP), represents a balance between its biosynthesis and degradation, the latter via specific phosphodiesterases (PDEs). One class of c-di-GMP PDEs contains a characteristic HD-GYP domain. Here we report that an HD-GYP PDE from Vibrio cholerae contains a non-heme diiron-carboxylate active site, and that only the reduced form is active. An engineered D-to-A substitution in the HD dyad caused loss of c-di-GMP PDE activity and of two iron atoms. This report constitutes the first demonstration that a non-heme diiron-carboxylate active site can catalyze the c-di-GMP PDE reaction and that this activity can be redox regulated in the HD-GYP class.


Reactivity of murine and human recombinant LPS-binding protein (LBP) within LPS and gram negative bacteria.
The serum lipopolysaccharide (LPS) binding protein, LBP, has been shown to greatly enhance cellular responses to low concentrations of LPS. Purified LBP facilitates the transfer of LPS to membrane-bound or soluble CD14; the CD14/LPS complex then triggers a signal in responsive cells. We have cloned and sequenced a cDNA encoding murine LBP, and produced recombinant murine LBP using a baculovirus expression system. Using either a solid-phase or a cytofluorometric assay, recombinant murine and human LBP were found to bind avidly to free LPS, but only weakly to live bacteria from most LPS-containing Gram negative strains. Binding correlated loosely with the length and composition of the polysaccharide O chains. However, recombinant LBP did bind well to all heat-killed bacterial preparations. These findings suggest that LBP could be implicated in the response to killed but not live Gram negative bacteria.


Long COVID-19 syndrome as a fourth phase of SARS-CoV-2 infection.
The SARS-CoV-2 pandemic has affected in the last two years a large number of subjects, with a high cost in terms of morbidity and mortality. The scientific community made progress in understanding risk factors, pathophysiology, clinical manifestations, diagnosis and treatment of acute SARS-CoV-2 infection. In the last months, another condition has become evident and caught the attention of the scientific community: the so-called long COVID syndrome. The pathophysiology of this condition is not known, even if some hypothesis have been made but not demonstrated yet. Long COVID is characterized by a very heterogeneous group of subacute and/or chronic symptoms and signs that follow the acute phase of SARS-CoV-2 infection and have a very variable duration. The presence of this syndrome in an individual is not dependent from the severity of the acute SARS-CoV-2 infection. Because of the extreme clinical heterogeneity, and also due to the lack of a shared and specific definition of the disease, it is very difficult to know the real prevalence and incidence of this condition. Some risk factors for the development of the disease have been identified: advanced age, elevated body mass index, comorbidities, specific symptoms of acute COVID-19 (in particular dyspnea), number of symptoms in the acute phase and female sex. The number of individuals affected by long COVID is high, even if it occurs only in a part of the subjects who had COVID-19. Therefore, long COVID constitutes now a major health issue and has to be managed in order to ensure an adequate access to care for all the people that need it. "Post COVID" clinics have been created in various countries, especially in Europe, for the management of people affected by long COVID syndrome. Guidelines have been written to help clinicians. An important role in the management of long COVID patients is played by the general practitioner, directly or indirectly linked to post COVID hospital clinics. The extreme heterogeneity of clinical presentation needs a patient-tailored, multidisciplinary approach. As NHS guidelines say, the three principal of care for long COVID patients are personalized care, multidisciplinary support and rehabilitation. More studies are needed in order to know better the pathophysiology of the disease. It is also necessary to create standardized and shared definitions of the disease, in order to better understand the epidemiology, the diagnostic criteria and to offer the right treatment to all the individuals who need it, without social or economic diffeences.


The Age-Related Growth of Mastoid Air Cells in Infancy: A Retrospective Cross-Sectional Study.
To investigate the normal growth and development of mastoid pneumatization volume from 5 to 12 months for pediatric otosurgeons. Retrospective chart review. A tertiary referral center. This study evaluated age-dependent changes in mastoid air cell volume in 94 (188 ears) patients aged 5 to 12 months without a history of middle ear disease. Volume reconstruction was based on high-resolution computed tomography images using a three-dimensional reconstruction that is considered normal by radiologists. One-way analysis of variance and linear regression were used to determine the relationship between the volume and age in male and female subjects. Forty-eight scans were from male and 46 from female patients. In the age group from 5 to 12 months, the mastoid pneumatization was independent of age ( p > 0.05). There were no significant volume differences found between the age groups. Neither male/female nor right/left significant differences were observed in relation to the algebraic data of the mastoid air cells volume ( p > 0.05). Based on this analytic study, we are the first to use three-dimensional volume quantification based on high-resolution computed tomography in such large samples of early infancy. Because of its potential role as a susceptibility factor for otitis media and other otologic problems, it is important to describe the growth and development of mastoid pneumatization. More extensive clinical studies are needed to give a comprehensive insight into the air cell volume across age groups in different populations.


Effects of a compound Trichoderma agent on Coptis chinensis growth, nutrients, enzyme activity, and microbial community of rhizosphere soil.
Root rot diseases are prevalent in many Coptis chinensis Franch. production areas, perhaps partially due to the overuse of synthetic fertilizers. Synthetic fertilizers can also lead to soil degradation. Trichoderma is widely used in biofertilizers and biopesticides. This study applied a combination of four Trichoderma species (compound Trichoderma agent, CTA) to C. chinensis and evaluated its effects on growth, as well as rhizosphere soil nutrients, enzyme activities, and microbial community structure. The purpose of this study was to estimate the potential of using CTA as a biofertilizer for C. chinensis, and determine if it could, at least partially, replace synthetic fertilizers to control root rot disease and maintain soil fertility. CTA, compound fertilizer and sterile water were applied to C. chinensis plants. After 60 days, the soluble sugar, soluble protein, chlorophyll of leaves, and individual weight of each plant were measured. The rhizosphere soil nutrient content, enzymatic activity, and the microbial community were also determined. The results were analyzed to evaluate the effect of CTA on C. chinensis growth and soil fertility. CTA increased the soluble protein, chlorophyll, and individual weight of C. chinensis plants while compound fertilizer decreased chlorophyll. CTA increased the activities of urease and catalase in rhizosphere soil, whereas the compound fertilizer decreased urease, catalase, and alkaline phosphatase activities. CTA elevated soil pH, while compound fertilizer reduced it. CTA had no significant effects on soil nutrients and organic matter. CTA decreased the fungal number and alpha-diversity of fungi and bacteria, and both the fungal and bacterial communities were significantly different from the other two. CTA increased B/F value, which improved the rhizosphere microbial community. Both CTA and the compound fertilizer significantly altered the soil microbial community. The relative abundance of Ascomycota was higher and Basidiomycota was lower after CTA treatment than after the other two treatments, indicating that the soil treated with CTA was healthier than that of the other two treatments. CTA decreased harmful Ilyonectria mors-panacis and Corynebacterium sp. And increased beneficial Ralstonia picketti. Trichoderma spp. could exist in C. chinensis rhizosphere soil for a long time. The functional prediction results demonstrated that CTA reduced some rhizosphere phytopathogenic fungi. Correlation analysis showed that CTA elevated rhizosphere pH and enzyme activities. In summary, synthetic fertilizers damaged soil fertility, and the overuse of them might be responsible for root rot disease, while CTA could promote C. chinensis growth, improve soil and decrease the incidence and severity of C. chinensis root rot disease. Therefore, as a biofertilizer, CTA can, at least partially, replace synthetic fertilizers in C. chinensis production. Combining it with organic fertilizer will increase the potential of Trichoderma.


[Effects of mucolytic agents and macrolides in the treatment of COPD].
Mucolytic agents and macrolides have been used in the treatment of patients with chronic obstructive pulmonary disease (COPD). These drugs improve symptoms, such as sputum, and quality of life in COPD patients and reduce the frequency of COPD exacerbation. Mucolytic agents have various biological effects, such as reduction of mucin production, improvement of goblet cell hyperplasia and mucociliary transport, reduction of airway inflammation, and anti-oxidant and anti-viral effects. Similarly, in addition to antimicrobial effects, macrolides have biological effects, including reduction of mucin production and airway inflammation induced by airway infection, improvement of mucociliary transport, and anti-bacterial and anti-viral effects. These biological effects may be associated with clinical benefits of mucolvtic agents and macrolides in the treatment of COPD patients.


Tablet fragmentation without a disintegrant: A novel design approach for accelerating disintegration and drug release from 3D printed cellulosic tablets.
Fused deposition modelling (FDM) 3D printing has shown the most immediate potential for on-demand dose personalisation to suit particular patient's needs. However, FDM 3D printing often involves employing a relatively large molecular weight thermoplastic polymer and results in extended release pattern. It is therefore essential to fast-track drug release from the 3D printed objects. This work employed an innovative design approach of tablets with unique built-in gaps (Gaplets) with the aim of accelerating drug release. The novel tablet design is composed of 9 repeating units (blocks) connected with 3 bridges to allow the generation of 8 gaps. The impact of size of the block, the number of bridges and the spacing between different blocks was investigated. Increasing the inter-block space reduced mechanical resistance of the unit, however, tablets continued to meet pharmacopeial standards for friability. Upon introduction into gastric medium, the 1 mm spaces gaplet broke into mini-structures within 4 min and met the USP criteria of immediate release products (86.7% drug release at 30 min). Real-time ultraviolet (UV) imaging indicated that the cellulosic matrix expanded due to swelling of hydroxypropyl cellulose (HPC) upon introduction to the dissolution medium. This was followed by a steady erosion of the polymeric matrix at a rate of 8 μm/min. The design approach was more efficient than a comparison conventional formulation approach of adding disintegrants to accelerate tablet disintegration and drug release. This work provides a novel example where computer-aided design was instrumental at modifying the performance of solid dosage forms. Such an example may serve as the foundation for a new generation of dosage forms with complicated geometric structures to achieve functionality that is usually achieved by a sophisticated formulation approach.


Metal-free visible-light-enabled vicinal trifluoromethyl dithiolation of unactivated alkenes.
The difunctionalization of alkenes involving a trifluoromethylthio group (SCF3) for the conversion of versatile and readily available olefins into structurally more complex molecules has been successfully studied. However, the disproportionate dithiolation of alkenes is unknown. Herein, a transition-metal-free protocol is presented for the vicinal trifluoromethylthio-thiolation of unactivated alkenes via a radical process under mild conditions with a broad substrate scope and excellent tolerance.


Craniomandibular pain, oral parafunctions, and psychological stress in a longitudinal case study.
In a single case study, the most frequently suggested contributing factors to craniomandibular pain, viz., oral parafunctions and psychological stress, were studied in more detail. During a 13-week study period, questionnaires were completed, in which, among others, jaw muscle pain, bruxism behaviour, and experienced/anticipated stress were noted. During about 40% of the nights, nocturnal masticatory muscle activity (NMMA) was recorded, using single-channel electromyography (EMG). The number of NMMA events per recorded hour was scored, using a detection threshold of 10% of the maximum voluntary contraction level. This threshold was established in a separate study, in which EMG was compared with polysomnography. Stepwise regression analyses indicated, that morning jaw muscle pain could be explained by evening jaw muscle pain for 64% and by alcohol intake for another 2%. In turn, evening jaw muscle pain was explained by daytime clenching for 56% and by vacuum sucking of the tongue for an additional 6%. Finally, daytime clenching was significantly explained by experienced stress for 30%. Data of the recorded nights showed, that variations in NMMA did not contribute to variations in morning jaw muscle pain. This case study corroborates the paradigm that experienced stress may be related to daytime clenching and, in turn, to evening and morning jaw muscle pain.