Optimization of slice sensitivity profile for radiographic tomosynthesis.
Similar to other tomographic imaging modalities, the slice sensitivity profile (SSP) is an important image quality metric for radiographic tomosynthesis. In this study, the relationship between the acquisition angular range (Theta) and the SSP for the linear trajectory system was carefully investigated from both theoretical and experimental perspectives. A mathematical SSP model was derived for arbitrary points in the reconstructed volume. We used a newly developed flat-panel tomosynthesis prototype system to experimentally validate the mathematical model from 20 degrees (+/-10 degrees) to 60 degrees (+/-30 degrees) angular ranges. The SSP was measured by imaging an edge phantom placed at an angle with respect to the detector plane using the modulation transfer function degradation (MTF-d) method. In addition to the experiments, computer simulations were performed to investigate the relationship in a wider angular range (2.5 degrees to 60 degrees). Furthermore, image data from an anthropomorphic phantom were collected to corroborate the system analysis. All the images in this study were constructed using a 3D view-weighted cone-beam filtered backprojection algorithm (3D VW CB-FBP). The theoretical analysis reveals that the SSP of linear trajectory tomosynthesis is inversely proportional to tan(Theta/2). This theory was supported by both simulation (chi2=1.415, DF=7, p =0.985) and phantom experiment (r=0.999, p < 0.001) and was further confirmed by an analysis of the reconstructed images of an anthropomorphic phantom. The results imply that the benefit of narrower SSP by increasing angular range quickly diminishes once beyond 40 degrees. The advantages of the MTF-d method were also demonstrated.


Characteristics of Quinolone Resistance in Salmonella spp. Isolates from the Food Chain in Brazil.
Salmonella spp. is an important zoonotic pathogen related to foodborne diseases. Despite that quinolones/fluoroquinolones are considered a relevant therapeutic strategy against resistant isolates, the increase in antimicrobial resistance is an additional difficulty in controlling bacterial infections caused by Salmonella spp. Thus, the acquisition of resistance to quinolones in Salmonella spp. is worrisome to the scientific community along with the possibility of transmission of resistance through plasmids. This study investigated the prevalence of plasmid-mediated quinolone resistance (PMQR) in Salmonella spp. and its association with fluoroquinolone susceptibility in Brazil. We evaluated 129 isolates, 39 originated from food of animal sources, and 14 from environmental samples and including 9 from animals and 67 from humans, which were referred to the National Reference Laboratory of Enteric Diseases (NRLEB/IOC/RJ) between 2009 and 2013. These samples showed a profile of resistance for the tested quinolones/fluoroquinolones. A total of 33 serotypes were identified; S. Typhimurium (63) was the most prevalent followed by S. Enteritidis (25). The disk diffusion test showed 48.8% resistance to enrofloxacin, 42.6% to ciprofloxacin, 39.53% to ofloxacin, and 30.2% to levofloxacin. According to the broth microdilution test, the resistance percentages were: 96.1% to nalidixic acid, 64.3% to enrofloxacin, 56.6% to ciprofloxacin, 34.1% to ofloxacin, and 30.2% to levofloxacin. Qnr genes were found in 15 isolates (8 qnrS, 6 qnrB, and 1 qnrD), and the aac(6')-Ib gene in 23. The integron gene was detected in 67 isolates with the variable region between ±600 and 1000 bp. The increased detection of PMQR in Salmonella spp. is a serious problem in Public Health and must constantly be monitored. Pulsed-field gel electrophoresis was performed to evaluated clonal profile among the most prevalent serovars resistant to different classes of quinolones. A total of 33 pulsotypes of S. Typhimurium were identified with a low percentage of genetic similarity (≤65%). This result demonstrates the presence of high diversity in the resistant clones evaluated in this study.


Development and Characterization of a Fluorescent Tracer for the Free Fatty Acid Receptor 2 (FFA2/GPR43).
The free fatty acid receptor 2 (FFA2/GPR43) is considered a potential target for treatment of metabolic and inflammatory diseases. Here we describe the development of the first fluorescent tracer for FFA2 intended as a tool for assessment of thermodynamic and kinetic binding parameters of unlabeled ligands. Starting with a known azetidine FFA2 antagonist, we used a carboxylic acid moiety known not to be critical for receptor interaction as attachment point for a nitrobenzoxadiazole (NBD) fluorophore. This led to the development of 4 (TUG-1609), a fluorescent tracer for FFA2 with favorable spectroscopic properties and high affinity, as determined by bioluminescence resonance energy transfer (BRET)-based saturation and kinetic binding experiments, as well as a high specific to nonspecific BRET binding signal. A BRET-based competition binding assay with 4 was also established and used to determine binding constants and kinetics of unlabeled ligands.


The effect of carbon nanoparticles staining on lymph node tracking in colorectal cancer: A propensity score matching analysis.
The aim of this study was to evaluate the effect of carbon nanoparticles staining (CNS) on colorectal cancer (CRC) surgery, lymph node tracing and postoperative complications using propensity score matching (PSM). Patients who were diagnosed with CRC and underwent surgery were retrospectively collected from a single clinical center from Jan 2011 to Dec 2021. Baseline characteristics, surgical information and postoperative information were compared between the CNS group and the non-CNS group. PSM was used to eliminate bias. A total of 6,886 patients were enrolled for retrospective analysis. There were 2,078 (30.2%) patients in the CNS group and 4,808 (69.8%) patients in the non-CNS group. After using 1: 1 ratio PSM to eliminate bias, there were 2,045 patients left in each group. Meanwhile, all of their baseline characteristics were well matched and there was no statistical significance between the two groups (P > 0.05). In terms of surgical information and short-term outcomes, the CNS group had less intraoperative blood loss (P < 0.01), shorter operation time (P < 0.01), shorter postoperative hospital stay (P < 0.01), less metastatic lymph nodes (P = 0.013), more total retrieved lymph nodes (P < 0.01), more lymphatic fistula (P = 0.011) and less postoperative overall complications (P < 0.01) than the non-CNS group before PSM. After PSM, the CNS group had less intraoperative blood loss (P = 0.004), shorter postoperative hospital stay (P < 0.01) and more total retrieved lymph nodes (P < 0.01) than the non-CNS group. No statistical difference was found in other outcomes (P > 0.05). Preoperative CNS could help the surgeons detect more lymph nodes, thus better determining the patient's N stage. Furthermore, it could reduce intraoperative blood loss and reduce the hospital stay.


[Migration of an ingested foreign body (sewing needle) to the pancreas tail and spleen].
A case of a penetration of the stomach by a sewing needle with migration to the tail of the pancreas and the spleen in a 22-years old woman is reported. The patient was referred to us with a chief complaint of abdominal pain and nausea. A plain roentgenogram showed a needle in the upper left abdominal area. An contrast X ray and abdominal computed tomography scan revealed foreign body (broken needle) to be located at the hilum of the spleen. At laparotomy the needle in the spleen and tail of the pancreas was impossible to be extirpated safely which required splenectomy and partial resection of the pancreas. A perforation of the gastrointestinal tract by an ingested foreign body is difficult to presume when no peritonitis or abscess formation is observed. A plain X-ray and CT scan is useful to establish the diagnosis.


Effect of Cytochrome P450 Metabolites of Arachidonic Acid in Nephrology.
Thirty-five years ago, a third pathway for the metabolism of arachidonic acid by cytochrome P450 enzymes emerged. Subsequent work revealed that 20-hydroxyeicosatetraenoic and epoxyeicosatrienoic acids formed by these pathways have essential roles in the regulation of renal tubular and vascular function. Sequence variants in the genes that produce 20-hydroxyeicosatetraenoic acid are associated with hypertension in humans, whereas the evidence supporting a role for variants in the genes that alter levels of epoxyeicosatrienoic acids is less convincing. Studies in animal models suggest that changes in the production of cytochrome P450 eicosanoids alter BP. However, the mechanisms involved remain controversial, especially for 20-hydroxyeicosatetraenoic acid, which has both vasoconstrictive and natriuretic actions. Epoxyeicosatrienoic acids are vasodilators with anti-inflammatory properties that oppose the development of hypertension and CKD; 20-hydroxyeicosatetraenoic acid levels are elevated after renal ischemia and may protect against injury. Levels of this eicosanoid are also elevated in polycystic kidney disease and may contribute to cyst formation. Our review summarizes the emerging evidence that cytochrome P450 eicosanoids have a role in the pathogenesis of hypertension, polycystic kidney disease, AKI, and CKD.


Workplace well-being of Advanced Practice Nurses and patient outcomes.
Workplace well-being has been defined as a state of pleasure in doing your own job. Work engagement is an effective indicator to measure workplace well-being. To investigate the level of work engagement among the Advanced Practice Nurses and describe patient outcomes. A survey based on Utrecht Work Engagement Scale-17 (ranging 0-6) was administered to 11 Advanced Practice Nurses; data were collected in August 2021. Different outcomes were detected: incidence of pressure ulcers in COVID 19 patients; postoperative issues; number of cornea donations in eligible patients (from 2017 to 2020); number of preoperative stoma site marking. The results showed a median age of 48 [41-52] years, most of the partecipants were women (63.64%). Advanced Practice Nurses showed high levels of engagement as a whole (5.18 0.30) and on vigor (4.91 0.82), dedication (5.51 0.80) and absorption categories (5.12 0.68). 360 patients with COVID-19 were observed and only 17 of them (4,5%) had Pressure Ulcers (density incidence: 2,72ulcers/1000 patients day). Intervention by case manager completely solved the patient's problem in 10 cases (71.43%) during the postoperative period. A 13% increase in corneal donations was observed in eligible patients from 2017 to 2020. Preoperative stoma site marking was present in 103 (99.3%) of eligible patients. Advanced Practice Nurses present high levels of work engagement. Outcome results are coherent with the literature; a high level of work engagement seems to correlate with better patient outcomes. Postgraduate nursing training improves clinical outcomes for patients and process indicators. Healthcare organizations management should value workplace well-being of their Advanced Practice Nurses.


Risk Factors Associated with the Development of Tuberculosis Among HIV-Infected Patients in Khartoum in 2010.
Tuberculosis (TB) screening among patients infected with Human Immunodeficiency Virus (HIV) is one of the approaches for controlling TB-HIV co-infection. The absence of typical TB symptoms among HIV-infected patients makes diagnosis challenging. Identifying predisposing risk factors of TB among HIV-infected patients could possibly guide TB diagnosis and treatment. This study was designed to identify some important factors associated with TB among HIV-infected patients and to quantify the strength of this association. In 2010, a case control study was conducted in Khartoum State, Sudan. Cases and controls were selected by simple random sampling with a 1:2 ratio; 97 cases and 194 controls were enrolled in the study. A logistic regression model was built to estimate and quantify the strength of the association between the study variables and the outcome; a p-value less than 0.05 was considered the cut-off point for a significant statistical association. Past history of TB, CD4 count < 200 cells/µl, late clinical stages, non-employment, and no formal education were found to be risk factors for developing TB among HIV-infected patients. The adjusted ORs and 95% CIs were (6.9: 3.75-12.99), (4.8: 1.57-15.26), (5.8: 1.88-17.96), (2.5: 1.26-5.03), and (2.5: 1.28-4.63), respectively. Poor adherence, marital status, age, and gender are not associated with developing TB among HIV patients. HIV patients who have at least one of the risk factors found in this analysis are at higher risk of TB; therefore, they should be screened more frequently and treated promptly, especially HIV patients with previous TB.


Changes in some psychophysiological parameters in speech information processing under masking noise effect.
The aim of the present work was to study the influence of masking broad-band (white), impulse and interrupted noise with intensities LAeq 60 and 90 dB(A) on the execution of some psychophysiological tasks. The following parameters were studied: pulse frequency and variation, breathing frequency and variation, vascular tone etc. The psychological tasks model different parts of the operators' activity and include: conduction of mathematical calculations at datum speed; test related to the information processing; complex optional task supplied by Piorkovski's device. After statistical processing of results by Student-Fischer's t test and monofactor dispersion analysis it was established that the masking noise effect was more strongly expressed in the execution of psychophysiological tasks connected with the main memory. Of all tested physiological parameters the changes in the peripheral circulation, expressed in elevated vascular tone of peripheral blood vessels, were the most significant.


Discrimination of cysteamine from mercapto amino acids through isoelectric point-mediated surface ligand exchange of β-cyclodextrin-modified gold nanoparticles.
The discrimination of cysteamine (CA) from mercapto amino acids (including glutathione, cysteine and homocysteine, GSH/Cys/Hcy) with high efficiency is essential to detect biothiols in a physiological environment. Herein, a nano-assembly was constructed by combining one-pot synthesized β-cyclodextrin-modified AuNPs and encapsulated rhodamine 6G (R6G-β-CD@AuNPs) without covalent modification. Interestingly, when the pH value of the tested solution was approximately the isoelectric point (pI) of the biothiol, the quenched fluorescence of R6G-β-CD@AuNPs was obviously restored by the introduction of the biothiol, which was due to the replacement of the R6G-β-CD composite by the biothiol on the surfaces of AuNPs via a stronger S-Au bond. The pI-mediated surface ligand exchange process was designed for the first time for the discrimination and detection of CA and GSH/Cys/Hcy at the pH values of 9.5 and 5.5, respectively. Under the optimized conditions, the enhanced fluorescence intensity displayed a good linear response to the concentration of each biothiol, with the detection limits of CA, GSH, Cys and Hcy calculated as 66.8, 417.6, 652.7 and 603.4 nM, respectively. The ingenious fabrication of the R6G-β-CD@AuNPs sensing platform eliminated the interferences from cholesterol by host-guest interactions and enabled high selectivity for the detection of biothiols in human serum samples. The pI-mediated sensing platform exhibits great potential for biothiol-related therapeutic drug monitoring.


Convenient Preparation of N-Acylbenzoxazines from Phenols, Nitriles, and DMSO Initiated by a Catalytic Amount of (COCl)2.
A convenient preparation method of N-acylbenzoxazines has been developed, in which phenols react with nitriles and dimethyl sulfoxide (DMSO) in the presence of a catalytic amount of (COCl)2 in CH3CN or chloroform to afford the corresponding N-acylbenzoxazines in moderate-to-good yields. DMSO acts as a source of HCHO, which is generated in situ from the decomposition of a methoxydimethylsulfonium salt. A regeneration cycle of the methoxydimethylsulfonium salt is proposed, which is initiated by a catalytic amount of (COCl)2.


Identification of phosphorylation sites on neurofilament proteins by nanoelectrospray mass spectrometry.
Neurofilament (NF) proteins are intermediate filaments found in the neuronal cytoskeleton. Phosphorylation of these proteins is considered an important factor in the assembly of filaments and determination of filament caliber and stability. Mammalian neurofilaments are composed of three polypeptide subunits, NF-L, NF-M, and NF-H, all of which are phosphorylated. Here we used techniques for the mass spectrometric sequencing of proteins from polyacrylamide gels to analyze in vivo phosphorylation sites on NF-M and NF-L. Neurofilaments were isolated from rat brain and enzymatically digested in gel. The resulting peptides were analyzed and sequence data obtained by nanoelectrospray mass spectrometry. Four phosphorylation sites have been found in the C-terminal domain of NF-M: serines 603, 608, 666, and 766. Two of these are found in lysine-serine-proline (KSP) motifs and two in the variant motifs, glutamic acid-serine-proline (ESP) and valine-serine-proline (VSP). Serine 55 in NF-L was not found to be phosphorylated, which confirms the possible role of phosphorylation and dephosphorylation of this site in early neurofilament assembly. The techniques used enable sequence data and characterization of posttranslational modifications to be obtained for each individual subunit directly from polyacrylamide gels.


Continuous low-dose human atrial natriuretic peptide promotes diuresis in oliguric patients after living donor liver transplantation.
Human atrial natriuretic peptide (ANP) is beneficial for the prophylaxis of acute renal failure (ARF) after liver transplantation (OLT). We evaluated renal function in OLT patients with or without ARF, describing cases unresponsive to loop diuretics successfully treated with continuous low-dose ANP infusion without hemodialysis. Twenty-seven consecutive adult-to-adult living donor liver transplantations (LDLTs) were performed in 26 patients. One case was excluded due to the need for continuous hemodialysis (HD) during the operation. Of the 26 cases, 6 (23%, group 2) developed ARF in the first 30 days after LDLT; the other 20 were ARF-free (group 1). The median follow-up was 24 months. No patient required either continuous or intermittent HD. Only one patient died due to multiple liver abscesses. Mean preoperative serum creatinine (sCr) value and intraoperative blood loss in group 2 were significantly higher than those in group 1. Three cases in group 2 failed to improve on high-dose loop diuretics with low-dose dopamine, exhibiting fluid overload. The remaining three cases in group 2 responded to conventional diuretic treatments. Continuous low-dose ANP was started 2, 4, or 5 days after LDLT, and urine output significantly increased after ANP administration. The serum creatinine values were 1.1, 1.2, and 1.1 at 1 month and 1.0, 0.9, and 0.6 mg/dL at 6 months after LDLT. Massive blood loss during the operation caused ARF, but did not affect renal function after LDLT. Continuous low-dose ANP improved renal function and diuresis for oliguric ARF patients, preventing the need for HD or continuous venovenous hemodialysis.


[Olygopeptide KND as a putative endogenous prototype of delta sleep inducing peptide (DSIP). Comparative study of biological properties].
We have undertaken a comparative study on physiological activity of well known neuropeptide DSIP (WAGGDASG E) and new closely related peptide KND (WKGGNASGE) in vivo assays. The sequence of K2, N5-DSIP (KND) was found recently by the computer search for DSIP homologous sequences in available nucleotide and protein databases at 324-332 site of Lysine-specific demethylase 3 B (EC 1.14.11, Swiss-Prot: Q7LBC6.1, 1-1761aa). This human lysine-specific histone demethylase is a representative of the recently discovered family of so called JmjC-domain-containing histone demethylases encoded by JMJD1B gene and ubiquitously expressed in tissues of various mammalian species. Biological investigations performed in this work confirm our preliminary data that DSIP-related peptide KND exhibits the similar biological properties in comparison with DSIP. Assessed by us antioxidative, anticonvulsive and behavioral effects of KND were even more expressed than in DSIP case. These results provide the additional evidences to support our suggestion that KND can be a possible endogenous prototype of "real" DSIP.


Time trends of 1,1,1-trichloroethane, trichloroethylene, and perchloroethylene in confined and unconfined aquifers of a groundwater system in northern Italy.
The concentrations of 1,1,1-trichloroethane, trichloroethylene, and perchloroethylene were recorded in a groundwater system of Northern Italy over the period 1985-1997. In the unconfined recharging aquifer these chemicals showed a remarkable overall decline which was accompanied by a five-fold reduction in their consumption (from approx. 250 to approx. 50 tons year-1) over the same period. The time trends for the confined aquifers indicated a steady decline for 1,1,1-trichloroethane which was accompanied by a constant concentration of trichloroethylene and an increasing presence of perchloroethylene. It is suggested that the confined aquifers are recording a contamination which took place in the unconfined recharging aquifer before monitoring period (1982) started. At present, in most of the study area 1,1,1-trichloroethane contamination is below the detection limit (0.1 microgram/L). For trichloroethylene and perchloroethylene, the average unconfined aquifer contamination accounts for approx. 1 +/- 1 and approx. 4 +/- 3 micrograms/L, respectively, while in the confined aquifers the average concentrations are approx. 8 +/- 3 and approx. 35 +/- 5 micrograms/L, respectively.


The activating dual phosphorylation of MAPK by MEK is nonprocessive.
Activation of mitogen-activated protein kinases (MAPKs), also known as extracellular-signal-regulated kinases (ERKs), by MAPK/extracellular protein kinase kinases (MEKs) requires phosphorylation at two sites. The first step in MAPK activation by MEK must be the formation of a MEK x MAPK enzyme-substrate complex, followed by phosphorylation producing monophosphorylated MAPK (pMAPK). Subsequently, one of two events may occur. (1) MEK catalyzes the second and fully activating phosphorylation of MAPK, producing ppMAPK (a processive mechanism). (2) The complex of MEK x pMAPK dissociates before the second phosphorylation occurs, full activation requiring a reassociation of pMAPK with MEK (a nonprocessive or distributive mechanism). Simulations indicate that these two mechanisms predict different kinetics of MAPK activation. Specifically, the nonprocessive mechanism predicts that there will be a paradoxical decrease in the rate of MAPK activation as the MAPK concentration is increased. The present study uses p42 MAPK, also known as ERK2, and MEK1 as representatives of their respective classes of enzymes. We find that increasing the ERK2 concentration decreases the rate of activation by a mechanism which does not involve inhibition of MEK1 function. The accumulation of the active, doubly phosphorylated ERK2 (ppERK2) was directly assessed using a phosphorylation-state-specific antibody. The rate of accumulation of ppERK2 is decreased by increasing the ERK2 concentration. Therefore, the mechanism of ERK2 activation by MEK1 in vitro is nonprocessive.


Regulation and functional consequences of mGlu4 RNA editing.
Metabotropic glutamate receptor 4 (mGlu4) is one of eight mGlu receptors within the Class C G protein-coupled receptor superfamily. mGlu4 is primarily localized to the presynaptic membrane of neurons where it functions as an auto and heteroreceptor controlling synaptic release of neurotransmitter. mGlu4 is implicated in numerous disorders and is a promising drug target; however, more remains to be understood about its regulation and pharmacology. Using high-throughput sequencing, we have validated and quantified an adenosine-to-inosine (A-to-I) RNA editing event that converts glutamine 124 to arginine in mGlu4; additionally, we have identified a rare but novel K129R site. Using an in vitro editing assay, we then validated the pre-mRNA duplex that allows for editing by ADAR enzymes and predicted its conservation across the mammalian species. Structural modeling of the mGlu4 protein predicts the Q124R substitution to occur in the B helix of the receptor that is critical for receptor dimerization and activation. Interestingly, editing of a receptor homodimer does not disrupt G protein activation in response to the endogenous agonist, glutamate. Using an assay designed to specifically measure heterodimer populations at the surface, however, we found that Q124R substitution decreased the propensity of mGlu4 to heterodimerize with mGlu2 and mGlu7 Our study is the first to extensively describe the extent and regulatory factors of RNA editing of mGlu4 mRNA transcripts. In addition, we have proposed a novel functional consequence of this editing event that provides insights regarding its effects in vivo and expands the regulatory capacity for mGlu receptors.


Interleukin 4 acts on both high- and low-density murine B cell subpopulations to induce IgE and IgG1 synthesis in vitro.
Murine B cells were activated for 24 h with either lipopolysaccharide (LPS) or polyribosyl-ribitol-phosphate (PRP), followed by addition of interleukin 4 (IL-4) and the immunoglobulin isotypes secreted into the supernatant quantitated. Without IL-4, both LPS and PRP induced mainly IgM and IgG3 and no IgE secretion. Addition of IL-4 to both LPS- and PRP-activated cells decreased the IgM and IgG3 secretion and induced a large IgG1 production. In contrast to IgG1, only LPS-activated cells secreted large amounts of IgE, demonstrating that the nature of the polyclonal B cell activator also plays an important role in the IL-4 induced IgE formation. The effect of LPS and IL-4 on high- and low-density sIgM+/sIgD+ cells was also investigated. LPS and IL-4 induced IgG1 and IgE secretion by both populations. Low-density B cells from mice infected with the parasite Nippostrongylus brasiliensis formed more IgE than low-density B cells from normal mice, presumably because these mice have more in vivo preactivated B cells committed to IgE formation. The data show that IL-4 can act on both small high-density resting B cells as well as on in vivo preactivated low-density B cells to induce IgG1 and IgE secretion.


Application of the rpoS gene for species-specific detection of Vibrio vulnificus by real-time PCR.
Vibrio vulnificus is a causative agent of serious diseases in humans, resulting from the contact of wound with seawater or consumption of raw seafood. Several studies aimed at detecting V. vulnificus have targeted vvh as a representative virulence toxin gene belonging to the bacterium. In this study, we targeted the rpoS gene, a general stress regulator, to detect V. vulnificus. PCR specificity was identified by amplification of 8 V. vulnificus templates and by the loss of a PCR product with 36 non-V. vulnificus strains. The PCR assay had the 273-bp fragment and the sensitivity of 10 pg DNA from V. vulnificus. SYBR Green I-based real-time PCR assay targeting the rpoS gene showed a melting temperature of approximately 84 degrees for the V. vulnificus strains. The minimum level of detection by real-time PCR was 2 pg of purified genomic DNA, or 103 V. vulnificus cells from pure cultured broth and 103 cells in 1 g of oyster tissue homogenates. These data indicate that real-time PCR is a sensitive, species-specific, and rapid method for detecting this bacterium, using the rpoS gene in pure cultures and in infected oyster tissues.


Prevalence of oral mucosal disorders during pregnancy: A systematic review and meta-analysis.
To assess the prevalence of oral mucosal disorders during pregnancy. Observational studies were selected by two reviewers in a two-phase process. Search strategies were applied at CINAHL, LILACS, LIVIVO, PubMed, Scopus, Web of Science, Google Scholar, OpenGrey, and ProQuest. The risk of bias was assessed using the Joanna Briggs Institute's Critical Appraisal Checklist for Studies Reporting Prevalence Data. Synthesis of results was calculated by the software R Statistics version 3.5.1 (The R Foundation, Vienna, Austria). Confidence in cumulative evidence was assessed by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Fifteen studies met the eligibility criteria and were selected for qualitative synthesis and meta-analysis, of which 5935 participants were enrolled. The overall prevalence of oral mucosal disorders was 11.8%. Gingival hyperplasia (17.1%), morsicatio buccarum (10%), oral candidiasis (4.4%), pyogenic granuloma (3%), and benign migratory glossitis (2.8%) were the most prevalent lesions. The overall risk of bias was considered moderate, and the quality of evidence was very low. Disorders of the oral mucosa were present in approximately 1 out of 10 pregnant women. Gingival hyperplasia was the most prevalent lesion. Further studies should apply homogeneous methodology to improve the quality of evidence.


The Integration of Occlusion and Disparity Information for Judging Depth in Autism Spectrum Disorder.
In autism spectrum disorder (ASD), atypical integration of visual depth cues may be due to flattened perceptual priors or selective fusion. The current study attempts to disentangle these explanations by psychophysically assessing within-modality integration of ordinal (occlusion) and metric (disparity) depth cues while accounting for sensitivity to stereoscopic information. Participants included 22 individuals with ASD and 23 typically developing matched controls. Although adults with ASD were found to have significantly poorer stereoacuity, they were still able to automatically integrate conflicting depth cues, lending support to the idea that priors are intact in ASD. However, dissimilarities in response speed variability between the ASD and TD groups suggests that there may be differences in the perceptual decision-making aspect of the task.


Idarubicin-loaded methoxy poly(ethylene glycol)-b-poly(l-lactide-co-glycolide) nanoparticles for enhancing cellular uptake and promoting antileukemia activity.
Nanoparticle (NP)-based drug delivery approaches have tremendous potential for enhancing treatment efficacy and decreasing doses of chemotherapeutics. Idarubicin (IDA) is one of the most common chemotherapeutic drugs used in the treatment of acute myeloid leukemia (AML). However, severe side effects and drug resistance markedly limit the application of IDA. In this study, we encapsulated IDA in polymeric NPs and validated their antileukemia activity in vitro and in vivo. NPs with an average diameter of 84 nm was assembled from a methoxy poly(ethylene glycol)-b-poly(l-lactide-co-glycolide) (mPEG-PLGA). After loading of IDA, IDA-loaded mPEG-PLGA NPs (IDA/mPEG-PLGA NPs) were formed. The in vitro release data showed that the IDA/mPEG-PLGA NPs have excellent sustained release property. IDA/mPEG-PLGA NPs had exhibited the lower IC50 than pure IDA. Moreover, IDA/mPEG-PLGA NPs in the same concentration substantially induced apoptosis than did pure IDA. Most importantly, IDA/MPEG-PLGA NPs significantly decreased the infiltration of leukemia blasts and improved the overall survival of MLL-AF9-induced murine leukemia compared with free IDA. However, the blank NPs were nontoxic to normal cultured cells in vitro, suggesting that NPs were the safe carrier. Our data suggest that IDA/mPEG-PLGA NPs might be a suitable carrier to encapsulate IDA. Low dose of IDA/mPEG-PLGA NPs can be used as a conventional dosage for antileukemia therapy to reduce side effect and improve survival.


Different Doses of Nalbuphine Combined with Dexmedetomidine in Laparoscopic Oophorocystectomy.
BACKGROUND The goal of this study was to investigate different doses of nalbuphine combined with dexmedetomidine in the postoperative treatment of laparoscopic oophorocystectomy. MATERIAL AND METHODS This prospective single-blinded randomized controlled study included 219 patients with benign ovarian cysts who received laparoscopic oophorocystectomy from March 2017 to October 2019. Patients were randomized into 4 groups: low (0.5 mg/kg), middle (1.0 mg/kg), and high (1.5 mg/kg) doses of nalbuphine combined with dexmedetomidine (4 μg/kg) (LND, MND, and HND groups, respectively) and a control group with sufentanil (2.5 μg/kg), with different patient-controlled intravenous analgesia pump (PCIA) strategies. Rest and active visual analog scale (VAS) scores measured postoperative pain, and Ramsay scores were used to measure sedation. RESULTS The HND group showed the lowest rest and cough VAS scores at 2 h, 8 h, 12 h, and 24 h after surgery, the lowest PCIA pressing time within 48 h after surgery, and the highest Ramsay scores at 2 h, 8 h, 24 h and 48 h after surgery. Rest and cough VAS scores decreased with higher nalbuphine doses in a dose-dependent manner. One day after surgery, IL-1ß and IL-6 levels increased in all groups, with the lowest levels of IL-1ß and IL-6 in the HND group. Hospitalization time was significantly shorter in the HND group compared with the LND and MND groups. There were no significant differences in complications among groups. CONCLUSIONS Combined nalbuphine and dexmedetomidine improved postoperative pain and sedative conditions, reduced inflammation in a nalbuphine dose-dependent manner, and might facilitate patient recovery.


[Emotional dysregulation and autism spectrum disorders].
Autism spectrum disorders (ASD) are neurodevelopmental disorders that affect social communication and present stereotyped behaviours. They exhibit a wide range of phenotypic variability related with the capacity to use language for expression, cognitive skills and psychiatric comorbidities, among others. Psychiatric comorbidity is very frequent in ASD and in many cases it is multiple. Emotional dysregulation is related with ASD and with other psychiatric and neurodevelopmental disorders. Multiple comorbidity associated with ASD is the group that presents a high degree of functional inability, multiple pharmacology and hospital admissions. Emotional dysregulation could be the basis of the multiple comorbidity that exists in ASD and will require its own particular considerations in the diagnostic evaluation and treatment. To review emotional dysregulation, the currently held concept of it and its relationship with ASD. This work offers a review of the different definitions of emotional dysregulation, the associated cognitive and neurobiological mechanisms, the clinical presentation when associated to ASD, its role in psychiatric comorbidity and further considerations regarding psychological and pharmacological interventions. Emotional dysregulation could be associated to the multiple comorbidity present in persons with ASD, as well as being related with high rates of morbidity, hospital admissions and use of psychopharmaceuticals. Failure to identify and diagnose emotional dysregulation could be linked with low effectiveness and a large number of side effects in the case of comorbidity associated to ASD.


[Patients' experience of breast cancer treatment].
Medical treatments including chemotherapy, endocrine therapy, and antibody therapy effectively reduce the risk of recurrence after breast cancer and are also used against metastatic disease. This article reviews patients' experience of these treatments. Common side effects of chemotherapy include hair loss, nausea, hot flushes, mucositis, fatigue, and cognitive side effects. Overall quality of life, social relations, and sexuality may also be affected. Endocrine therapies are characterised by hot flushes, vaginal dryness, arthralgias, and reduced libido.


Stable isotope-mass spectrometric measurements of molecular fluxes in vivo: emerging applications in drug development.
Therapeutics require not only targets and chemical entities, but tools for measuring actions in vivo. Technologies for evaluating activities, filtering leads and predicting clinical response have lagged behind molecular discovery. 'Systems biology' has not provided systematic methods for predicting metabolic effects in complex systems. The flow of molecules through complex pathways, in contrast, reflects the connectivity relationships and emergent control features of fully assembled networks, but is a quantifiable therapeutic target. This strategy, which combines molecular specificity with intrinsic functional significance, requires different tools. Here, advances in critical pathway flux measurement utilizing stable isotopes and mass spectrometry are described. These include mass isotopomer analysis, heavy-water labeling techniques, secreted probes of intracellular processes, and analytic advances. Several fundamental advantages of kinetic measurements are demonstrated. Measurement of molecular fluxes represents a powerful addition to drug development technology.


Non-invasive Assessment of Changes in Corticomotoneuronal Transmission in Humans.
The corticospinal pathway is the major pathway connecting the brain with the muscles and is therefore highly relevant for movement control and motor learning. There exists a number of noninvasive electrophysiological methods investigating the excitability and plasticity of this pathway. However, most methods are based on quantification of compound potentials and neglect that the corticospinal pathway consists of many different connections that are more or less direct. Here, we present a method that allows testing excitability of different fractions of the corticospinal transmission. This so called H-reflex conditioning technique allows one to assess excitability of the fastest (monosynaptic) and also polysynaptic corticospinal pathways. Furthermore, by using two different stimulation sites, the motor cortex and the cervicomedullary junction, it allows not only differentiation between cortical and spinal effects but also assessment of transmission at the corticomotoneural synapse. In this manuscript, we describe how this method can be used to assess corticomotoneural transmission after low-frequency repetitive transcranial magnetic stimulation, a method that was previously shown to reduce excitability of cortical cells. Here we demonstrate that not only cortical cells are affected by this repetitive stimulation but also transmission at the corticomotoneuronal synapse at the spinal level. This finding is important for the understanding of basic mechanisms and sites of neuroplasticity. Besides investigation of basic mechanisms, the H-reflex conditioning technique may be applied to test changes in corticospinal transmission following behavioral (e.g., training) or therapeutic interventions, pathology or aging and therefore allows a better understanding of neural processes that underlie movement control and motor learning.


X-ray diffraction at the National Ignition Facility.
We report details of an experimental platform implemented at the National Ignition Facility to obtain in situ powder diffraction data from solids dynamically compressed to extreme pressures. Thin samples are sandwiched between tamper layers and ramp compressed using a gradual increase in the drive-laser irradiance. Pressure history in the sample is determined using high-precision velocimetry measurements. Up to two independently timed pulses of x rays are produced at or near the time of peak pressure by laser illumination of thin metal foils. The quasi-monochromatic x-ray pulses have a mean wavelength selectable between 0.6 Å and 1.9 Å depending on the foil material. The diffracted signal is recorded on image plates with a typical 2θ x-ray scattering angle uncertainty of about 0.2° and resolution of about 1°. Analytic expressions are reported for systematic corrections to 2θ due to finite pinhole size and sample offset. A new variant of a nonlinear background subtraction algorithm is described, which has been used to observe diffraction lines at signal-to-background ratios as low as a few percent. Variations in system response over the detector area are compensated in order to obtain accurate line intensities; this system response calculation includes a new analytic approximation for image-plate sensitivity as a function of photon energy and incident angle. This experimental platform has been used up to 2 TPa (20 Mbar) to determine the crystal structure, measure the density, and evaluate the strain-induced texturing of a variety of compressed samples spanning periods 2-7 on the periodic table.


Electroclinical semiology of the bilateral asymmetric tonic seizures observed in patients with supplementary sensorimotor area epilepsy confirmed by pre- and post-operative MRI.
To retrospectively reappraise characteristics of the electro-clinical seizure semiology of the bilateral asymmetric tonic seizure (BATS) in the patients with supplementary sensorimotor area (SSMA) epilepsy. From the retrospective analysis of the pre- and post-operative Magnetic Resonance Imaging (MRI) data involving 386 patients who received epilepsy surgery, 123 BATS were identified meeting the clinical criteria and included in the study. For comparison in four extremities involvement, limbs were paired and comparatively evaluated between the contralateral and ipsilateral sides, proximal and distal segments, and upper and lower limbs. For evaluation of sequential events, each tonic phase of the BATS was chronologically divided into 10 equal epochs. In each epoch, distribution of tonic events in 4 extremities and axes was visually evaluated and comparatively analyzed. Asymmetric tonic posturing was the most constant findings in 6 patients, whose upper limbs contralateral to epileptogenic cortex were kept in abduction in all 123 (100%) seizures and extension in 118 (95.9%) seizures. This type of asymmetry became visible and remained stable in the initial three epochs of the tonic phase in 107 out of 123 (87.0%) seizures. In each epoch, especially the initial one, the contralateral upper limbs were involved more frequently than those ipsilateral to the epileptogenic cortex (p < 0.05). By pairwise comparison, an earlier involvement of the contralateral side to epileptogenic cortex was visually observed in 53 out of 280 (18.9%) limb pairs, in which the ipsilateral limbs were preceded by the contralateral ones 4.6 (0.1-16.0) seconds earlier. Both of the proximal and distal segments were simultaneously involved in 260 out of 298 (87.2%) limb pairs, although the former were 4.3 (0.5-16.0) earlier than the latter in 34 out of 298 (11.4%) limb pairs. This study demonstrated that by studying the restricted epileptogenic lesion limited to pure SSMA, unilateral extension and abduction posturing in upper limb were the most prominent and valuable sign for the lesion lateralization in SSMA neurosurgery decision-making.


Normalization and Technical Variation in Gene Expression Measurements.
Using data from the Microarray Quality Control (MAQC) project, we demonstrate two data-analysis methods that shed light on the normalization of gene expression measurements and thereby on their technical variation. One is an improved method for normalization of multiple assays with mRNA concentrations related by a parametric model. The other is a method for characterizing limitations on the effectiveness of normalization in reducing technical variation. We apply our improved normalization to the four project materials as part of testing the linearity of the probe responses. We find that the lack of linearity is statistically significant but small enough that its sources cannot be easily identified. Applying our characterization method to assays of the same material, we show that there is a source of variation that cannot be eliminated by normalization and therefore must be dealt with by other means. Four high-density, single probe, one-color microarray platforms underlie our demonstration.


Dynamics of proinflammatory cytokines serum levels during viral hepatitis type A.
In this study we assessed the dynamics concerning IL-2, sLL-2R and IL-4 serum levels in the course of an acute viral hepatitis A infection. The study group consisted of 48 persons. The serum concentrations of IL-2, sIL-2R and IL-4 were assessed with the use of ELISA methods. In patients the assessments were done twice--in the first and third week of the hospitalisation. In the control group, which consisted of 24 healthy persons the assessments were done once. The obtained data were analysed with the use of c-Cochran and Cox statistical test. We observed a statistically important decrease in IL-2 and IL-4 serum levels in patients with acute viral hepatitis A infection in the first week of the hospitalisation compared to values observed in the control group. We also observed an increase in sIL-2R levels in the course of the disease. The dynamics of IL-2, sIL-2R and IL-4 serum levels in patients with acute hepatitis A infection was of a random type. The assessment of IL-2, sIL-2R and IL-4 serum levels can be helpful in examining the cellular response in viral hepatitis A infection.


[The disease caused by Clostridium difficile in geriatric patients].
The disease caused by the bacterium Clostridium difficile/Clostridium difficile associated disease/diarrhoea (CDAD) is becoming a serious problem especially in geriatric patients, who are now relatively often treated by broad-spectrum antibiotics. The goal of our study was to evaluate the occurrence of the risk factors and to evaluate the complex of relations and coherence which lead to the CDAD disease in a selected group of seniors treated at our institution. The retrospective study evaluated a group of 67 patients with diagnosed CDAD, who were hospitalized at the clinic of internal medicine, geriatrics and practical medicine, Faculty of Medicine and Faculty Hospital in Brno from January 2007 till October 2010. In the study 46 women (68.7%) and 21 men (31.3%) were included of the average age 78.8 +/- 10.3 years (56 till 96 years). The decisive moment in the diagnosis of CDAD was the discovery of enterotoxines A and B in faeces of the patients. The mean time of hospitalization of the patients suffering from CDAD was significantly higher (p = 0.01) in comparison with the control patients (24.63 +/- 16.34 vs. 11.5 +/- 10.7 days). Polymorbidity was also high in those patients. On average, each patient was ill with 11.3 diseases. The most frequent diseases were: high blood pressure (76.1% of the patients), ischemic heart disease 68.7% and the third most frequent diagnosis was the cerebrovascular disease 50.7%. We found that only 13 patients (19.4%) did not take the antibiotics at all, further 54 patients (80.6%) used one or more antibiotics. From the cohort of 67 patients 12 died (17.9%), the section was done in 7 patients, and colitis pseudomembranosa was proved in 3 of them. In 8 cases relapse of the colitis was proved. The infection of the clostridium is a very serious disease which increases the morbidity and mortality in geriatric patients. Besides the demands on the diagnostics and therapy, it influences also the duration of the hospitalization.


Behavior Problems in Low-Income Young Children Screened in Pediatric Primary Care.
Screening of behavior problems in young children in pediatric primary care is essential to timely intervention and optimizing trajectories for social-emotional development. Identifying differential behavior problem trajectories provides guidance for tailoring prevention and treatment. To identify trajectories of behavior problems in children 2 to 6 years of age screened in pediatric primary care. This retrospective cohort study identified trajectories of behavior problems and demographic and clinical correlates. Data were collected as part of routine care in 3 pediatric primary care offices and 3 school-based health centers in Ohio serving a primarily low-income population. In total, 15 218 children aged 2 to 6 years with well-child visits between July 13, 2016, and January 31, 2022, were included. Caregivers completed the Strengths and Difficulties Questionnaire (SDQ) at annual well-child visits. Trajectory groups were identified using latent growth mixture modeling of SDQ total difficulties scores, and relative risk ratio (RRR) of various demographic (eg, race) and clinical (eg, depression in caregiver) variables were assessed by multinomial logistic regression analysis. Of 15 281 children (51.3% males), 10 410 (68.1%) were African American or Black, 299 (2.0%) were Asian, 13 (0.1%) were American Indian or Alaska Native, 876 (5.7%) were multiracial, 26 (0.2%) were Native Hawaiian and Other Pacific Islander, 2829 (18.5%) were White, and 39 (0.02%) were categorized as other. In addition, 944 (6.2%) identified as Hispanic and 14 246 (93.2%) as non-Hispanic. Four behavior problem trajectory groups reflecting severity were identified: low-stable (LS; 10 096 [66.1%]), moderate-decreasing (MD; 16.6%), low-increasing (LI; 13.1%), and high-increasing (HI; 4.3%). Relative to the LS group, patients in each elevated group were more likely to be male (HI RRR, 1.87 [95% CI, 1.55-2.26]; MD RRR, 1.55 [95% CI, 1.41-1.71]; and LI RRR, 1.94 [95% CI, 1.70-2.21]), White (HI RRR, 2.27 [95% CI, 1.83-2.81]; MD RRR, 1.28 [95% CI, 1.13-1.45]; and LI RRR, 1.54, [95% CI, 1.32-1.81]), publicly insured (HI RRR, 0.49 [95% CI, 0.28-0.84]; MD RRR, 0.56 [95% CI, 0.43-0.73]; and LI RRR, 0.50 [95% CI, 0.35-0.73]), have a social need (HI RRR, 3.07 [95% CI, 2.53-3.73]; MD RRR, 2.02 [95% CI, 1.82-2.25]; and LI RRR, 2.12 [95% CI, 1.84-2.44]), and have a caregiver with depression (HI RRR, 1.66 [95% CI, 1.38-2.00]; MD RRR, 1.44 [95% CI, 1.31-1.58]; and LI RRR, 1.39 [95% CI, 1.23-1.58]). Relative to the LI group, patients in the MD group were less likely to be male (RRR, 0.80; 95% CI, 0.68-0.93). The substantial portion of young children with increased behavior problems observed in this cohort study underscores the need for screening in pediatric primary care. Caregivers with depression and family social needs warrant prioritization in early prevention and treatment to alter elevated trajectories.


The medical and social science basis for a national infant care leave policy.
In a review of work in psychology, psychiatry, neonatology, and sociology, the birth or adoption of an infant emerges as a sensitive period in which parents need time for role adaptation. Evidence points to the need for job-protected leave without financial loss so that parents can meet the material and emotional needs of their family in general, and the developmental needs of their new infant in particular, during the early postpartum period.


Calcifying aponeurotic fibroma around posterior tibialis tendon in an elderly patient with flatfoot: A case report.
Calcifying aponeurotic fibroma (CAF) is a rare benign fibroblastic tumor that is commonly in the hand or foot of children or adolescents. A 74-year-old female presented with a progressive pain on the medial foot for 3 years ago. The pain aggravated while walking or in a standing position for more than 20 minutes. She also complained of skin contact along the medial aspect of the foot while trying to wear a shoe. Physical examination revealed a firm, immobile, nontender mass accompanied with flexible flatfoot. On the single heel raise test, loss of the balance and intensification of the pain were observed. Faintly calcified soft tissue mass is shown in plain radiographs without bone involvement. Magnetic resonance imaging revealed a subcutaneous mass with ill-defined circumscribed subcutaneous mass adherent to the thickened PTT. The patient underwent a complete excisional biopsy, followed by medial displacement calcaneal osteotomy. The excised mass was diagnosed to be CAF on the histologic examination. At the 1-year follow-up, patient remained asymptomatic with no evidence of recurrence and all the radiographic parameters demonstrating flat foot improved. This is the first case of CAF located at PTT presenting with both foot pain and functional disability. In this case, complete excision of the causative structure along with alignment correction can contribute to successful postoperative outcome.


Time-dependent oxidative stress caused by benznidazole.
Benznidazole (BZN) is a nitroimidazole derivative which has a notable trypanocide activity, and it is the only drug used in Brazil and Argentina for the treatment of Chagas' disease. The drug in current use is thought to act, at least in part, by inducing oxidative stress within the parasite. Imidazolic compounds are involved in the production of reactive oxygen species (ROS). In order to evaluate the effect of BZN on ROS production and on the antioxidant status of the host, male rats were treated for different periods of time (2, 4, 6, 10 and 30 days) with 40 mg BZN/kg body weight. After treatment, biomarkers of oxidative stress such as the activities of catalase (CAT), superoxide dismutase (SOD), glutathione-S-transferase (GST) and glutathione reductase (GR), and also thiobarbituric acid reactive species (TBARS), reduced glutathione (GSH), total glutathione (TG) and oxidized glutathione (GSSG) concentrations, were measured in crude hepatic homogenates. Our results revealed that BZN is able to cause tissue damage as shown by increased TBARS content, inhibition of some antioxidants and induction of other antioxidants in a concentration- and time-dependent manner. The tissue damage measured as TBARS increased up to the 10th day of treatment. GST activity was inhibited during the BZN treatment. On the other hand, CAT and GR showed similar increased activities at the beginning, followed by decreased activities at the end of the treatment. After 30 days of treatment, GR activity remained low while CAT activity was high, compared to controls. The SOD activities remained unchanged throughout the experimental period. GSH showed lower values at the beginning of BZN treatment but the hepatic concentrations were enhanced at the end of the experimental period. Total glutathione showed a similar profile, and oxidized glutathione showed higher values in rats treated with BZN. In conclusion, these results indicate that, at therapeutic doses, BZN treatment elicits an oxidative stress in rat hepatocytes.


The relationship between clinical outcomes and quality of life in first-episode mania: a longitudinal analysis.
Despite growing attention to the relationship between bipolar disorder (BD) and quality of life (QoL), there remains a lack of information about QoL in the early stages of BD, and about the course of QoL in people with BD over time. Here, we report on QoL and symptomatic outcomes over a 1.5-year period in a Canadian sample of first-episode mania patients. Patients (n = 63) with DSM-IV-TR BD type I recovering from a recent episode of mania were recruited from a university-based hospital setting in Vancouver, BC, Canada and assessed at six monthly intervals for 18 months. In addition to symptomatic and cognitive assessments, two self-report QoL scales [the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and the Medical Outcomes Study Short Form 36 (SF-36)] were administered. Baseline QoL scores were high, with mean Q-LES-Q scores at 70% of the maximum possible score; QoL continued to show a trend towards improvement over time. Multiple hierarchical regressions were used to explore predictors of QoL over time, finding that: (i) length of illness and severity of depressive symptoms at baseline predicted Q-LES-Q scores at both baseline and six months; (ii) the number of previous depressive episodes and severity of depression at baseline and 12 months all predicted QoL at 12 months; and (iii) only severity of depressive symptoms at 12 months predicted QoL at 18 months. Our observation that QoL in patients who have recently experienced an episode of mania can be relatively preserved offers hope, both for healthcare providers and for those newly diagnosed. Further, that severity of depressive symptoms even in the early stages of the disease was the consistent predictor of QoL suggests that depressive symptoms need to be aggressively treated to improve QoL.


Sequence-dependent nucleotide dynamics revealed by intercalated ring rotation in DNA-bisnaphthalimide complexes.
Bisnaphthalimide intercalators are anti-tumour agents composed of two planar rings linked by a flexible diazanonylene chain. The intercalated rings of three bisnaphthalimide analogues complexed to DNA are found here to undergo 180 degrees rotating motions that do not affect the diazanonylene linker atoms bound to the major groove. These ring rotations are detected by NMR spectroscopy in a broad range of sequence contexts and duplex lengths. A comparative analysis of the frequency and activation energies of such excited states in different complexes and conditions indicates that these motions (i) are unrelated to drug dissociation; (ii) are a consequence of concerted, sequence-dependent nucleotide movements taking place on the millisecond time scale; and (iii) may occur inside the DNA duplexes. The rotation frequencies range from 2 to 25 s(-1) at 25 degrees C, depending on DNA composition and the size of the rotating rings. The detected nucleotide dynamics are likely to play an important role in the binding kinetics of the numerous proteins and drugs that require base unstacking when interacting with DNA.


Rituximab as a monotherapy or in combination therapy for the treatment of non-paraneoplastic autoimmune retinopathy.
To examine the efficacy of rituximab as a monotherapy or in combination therapy for the treatment of patients with non-paraneoplastic autoimmune retinopathy. Twelve eyes of six patients with non-paraneoplastic autoimmune retinopathy who were treated with rituximab and had at least 6 months of follow-up were included. Demographic data, clinical data, visual field parameters, electroretinography parameters, and anti-retinal and anti-optic nerve autoantibody bands were collected from the Massachusetts Eye Research and Surgery Institution database between September 2010 and January 2015. Changes in visual acuity, visual field parameters, electroretinography parameters, and anti-retinal and anti-optic nerve autoantibody bands from the initial visit to the most recent visit were examined. From the initial visit to the last visit, visual acuity was stable in eight (66.7%) eyes. Visual field was stable in six (50%) eyes and improved in two (16.7%) eyes. Electroretinography was stable or improved in eight (66.7%) eyes. The average number of anti-retinal and anti-optic nerve antibody bands was reduced. Stabilization and/or improvement of visual acuity, visual field parameters, and electroretinography parameters were observed in a high number of patients (75%) on rituximab, as a monotherapy (one patient) or in combination therapy.


To Create a Safe and Healthy Place for Children: The Associations of Green Open Space Characteristics With Children's Use.
Green open space (GOS) is an important outdoor resource for the well-being of children by providing places for physical activity (PA), especially in the highly urbanized environment. The COVID-19 lockdowns have made children have more sedentary time than before due to less access to public places. This article aims to examine the associations of GOS characteristics (environmental and surrounding) and children's use (visitation and PA pattern) to provide evidence for promoting their PA during the pandemic. This study employed the method of GPS positioner, accelerometer, and survey to measure the children's actual use in GOS. A total of 179 children participated in the study and 10 GOSs were selected. The children were provided with the accelerometers and GPS positioners to track their walking steps, duration, and locations. The environmental characteristics and 1 km buffer of the selected GOSs were explored as extended study area. Results showed that 49.16% of children reported more visitations than before the pandemic, and 48.60% of them preferred to go on weekdays during the pandemic. Both environmental and surrounding characteristics could affect the visitation pattern. The size (p < 0.000), residential ratio (p < 0.000), and intersection density (p < 0.000) were found as the factors significantly associated with visitation pattern. The children's PA pattern was mainly associated with the environmental characteristics of size (p < 0.000), sports, and playground proportion (p < 0.000). The locations of children's PA were mainly around square, playground, sheltered place, and waterside areas. COVID-19 has transformed the children's use of GOS, as well as their relationship with GOS. The large GOS was more likely to promote PA and its use by the children. The environmental and surrounding characteristics of GOS could affect their use pattern, whereas their PA pattern was mainly associated with the environmental characteristics. The findings suggest that GOS characteristics could be an effective solution to respond the challenge from the pandemic, and promote their visitation and PA.


[Stressful experiences in social relationships and ill health].
Based on a large scale population study, associations between experienced non-reciprocity in social relationships and three health indicators (depressive symptoms, self-rated health, sleeping problems) are analysed. The norm of reciprocity is commonly defined as the obligation to return actions or services provided by another person. We use baseline survey data of the Heinz Nixdorf Recall Study. Participants (n = 4814) were randomly selected from mandatory lists of residency from three adjacent cities of the Ruhrregion (Germany) with a response rate of 55.8 %. Non-reciprocity is measured by a questionnaire containing three scales: "partnership", "parent-child", and "non-specific relationships". Depressive symptoms are assessed by the German short version of the CES-D scale, self-rated health by a single widely tested item and sleeping problems by an index consisting of three items. Associations are explored using logistic regression analyses with age, education, occupational position and two indicators of social support as control variables. Results show that men and women who experience non-reciprocity in social relationships have significantly elevated risks of depressive symptoms, poor self-rated health and sleeping problems. Associations decrease after controlling for age, education, occupational position and social support but remain significant in most cases. The reciprocity approach proposed here offers the opportunity to systematically explore negative aspects of social relationships and resulting health consequences.


Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic.
The implementation of automation in the multistep flow synthesis is essential for transforming laboratory-scale chemistry into a reliable industrial process. In this review, we briefly introduce the role of automation based on its application in synthesis viz. auto sampling and inline monitoring, optimization and process control. Subsequently, we have critically reviewed a few multistep flow synthesis and suggested a possible control strategy to be implemented so that it helps to reliably transfer the laboratory-scale synthesis strategy to a pilot scale at its optimum conditions. Due to the vast literature in multistep synthesis, we have classified the literature and have identified the case studies based on few criteria viz. type of reaction, heating methods, processes involving in-line separation units, telescopic synthesis, processes involving in-line quenching and process with the smallest time scale of operation. This classification will cover the broader range in the multistep synthesis literature.


Focus: Structure and dynamics of the interfacial layer in polymer nanocomposites with attractive interactions.
In recent years it has become clear that the interfacial layer formed around nanoparticles in polymer nanocomposites (PNCs) is critical for controlling their macroscopic properties. The interfacial layer occupies a significant volume fraction of the polymer matrix in PNCs and creates strong intrinsic heterogeneity in their structure and dynamics. Here, we focus on analysis of the structure and dynamics of the interfacial region in model PNCs with well-dispersed, spherical nanoparticles with attractive interactions. First, we discuss several experimental techniques that provide structural and dynamic information on the interfacial region in PNCs. Then, we discuss the role of various microscopic parameters in controlling structure and dynamics of the interfacial layer. The analysis presented emphasizes the importance of the polymer-nanoparticle interactions for the slowing down dynamics in the interfacial region, while the thickness of the interfacial layer appears to be dependent on chain rigidity, and has been shown to increase with cooling upon approaching the glass transition. Aside from chain rigidity and polymer-nanoparticle interactions, the interfacial layer properties are also affected by the molecular weight of the polymer and the size of the nanoparticles. In the final part of this focus article, we emphasize the important challenges in the field of polymer nanocomposites and a potential analogy with the behavior observed in thin films.


Important Variables When Screening for Students at Suicidal Risk: Findings from the French Cohort of the SEYLE Study.
Due to early detection of mental ill-health being an important suicide preventive strategy, the multi-centre EU funded "Saving and Empowering Young Lives in Europe" (SEYLE) study compared three school-based mental health promotion programs to a control group. In France, 1007 students with a mean age of 15.2 years were recruited from 20 randomly assigned schools. This paper explores the French results of the SEYLE's two-stage screening program (ProfScreen) and of the cross-program suicidal emergency procedure. Two-hundred-thirty-five ProfScreen students were screened using 13 psychopathological and risk behaviour scales. Students considered at risk because of a positive finding on one or more scales were offered a clinical interview and, if necessary, referred for treatment. A procedure for suicidal students (emergency cases) was set up to detect emergencies in the whole cohort (n = 1007). Emergency cases were offered the same clinical interview as the ProfScreen students. The interviewers documented their reasons for referrals in a short report. 16,2% of the ProfScreen students (38/235) were referred to treatment and 2,7% of the emergency cases (27/1007) were also referred to treatment due to high suicidal risk. Frequent symptoms in those students referred for evaluation were depression, alcohol misuse, non-suicidal self-injuries (NSSI), and suicidal behaviours. According to the multivariate regression analysis of ProfScreen, the results show that the best predictors for treatment referral were NSSI (OR 2.85), alcohol misuse (OR 2.80), and depressive symptoms (OR 1.13). Analysis of the proportion for each scale of students referred to treatment showed that poor social relationships (60%), anxiety (50%), and suicidal behaviours (50%) generated the highest rate of referrals. Qualitative analysis of clinician's motivations to refer a student to mental health services revealed that depressive symptoms (51%), anxiety (38%), suicidal behaviours (40%), and negative life events (35%) were the main reasons for referrals. Thus, not only the classical psychopathological symptoms, such as depression, anxiety, and suicidal behaviours, but also negative life events and poor social relationships (especially isolation) motivate referrals for treatment.


Genetics of host response in leprosy.
In this review, we discuss recently accumulated data, analysing genetic influence on leprosy outcome. Most leprosy-related epidemiological studies are based on the comparison of frequencies of genetic markers in case-control designs using candidate genes, mainly on immunological pathways. Genomic scans using family-based designs also identified some chromosome regions to be tested for association with leprosy. The results have suggested that different genes are implicated in resistance/susceptibility to leprosy, such as tumour necrosis factor-alpha (TNFalpha), interleukin (IL)-10, vitamin D receptor (VDR), and parkin, although some of the results obtained in different populations are controversial. In spite of the recent advances in genomics and genetic epidemiology we have experienced, the results must be confirmed using better designed epidemiological studies to directly pinpoint the genes responsible for leprosy outcome. Furthermore, there is a clear requirement of functional/biological data in order to validate epidemiological findings. In this way, these genetic markers could be used to screen high-risk populations introducing gene testing as diagnostic and prognostic tools to interrupt the chain of transmission and prevent neurological damage.


The social and mental impact on healthcare workers: A comparative and cross-sectional study during two waves of the COVID-19 pandemic in Taiwan.
The coronavirus disease 2019 (COVID-19) pandemic has caused a heavily burden on healthcare workers (HCWs) worldwide. The aim of this study was to compare differences in psychological and social impact between two waves of the pandemic among first- and second-line HCWs in Taiwan. The current study derived data from two cross-sectional surveys conducted in 2020 and 2021. Levels of depression, sleep disturbance, psychological distress, social impact, and demographic variables were collected through self-reported questionnaires. The independent t test was used to compare differences in scores between the first and second wave of the pandemic. Differences between first- and second-line HCWs were also analyzed. A total of 711 HCWs in the first wave and 560 HCWs in the second wave were recruited. For the first- and second-line HCWs, the social impact during the second wave was higher than during the first wave, and they expressed a higher intention to maintain social distancing and were more aware of the pandemic overseas in the second wave. The first-line HCWs had a trend of worse sleep quality during the second wave. In addition, sleep quality was worse in the first-line HCWs than in the second-line HCWs during both waves. The second-line HCWs expressed a greater desire to seek COVID-19-related information than the first-line HCWs during the first wave, and more intended to maintain social distancing during the second wave. Our results show the importance of evaluating the social and mental health burden of HCWs, and especially first-line workers.


Molecular Dynamics Simulations of Amide Functionalized Imidazolium Bis(trifluoromethanesulfonyl)imide Dicationic Ionic Liquids.
In the present study, the structure and dynamics of three dicationic ionic liquids (DILs) with a functional amide group in the imidazolium ring with bis(trifluoromethanesulfonyl)imide, [TFSI]- anion has been studied by molecular dynamics (MD) simulations. Densities, radial distribution functions (RDFs), combined distribution functions (CDFs), spatial distribution functions, mean-square displacements (MSD), and self-diffusivities for the ions have been calculated from the MD simulations. The calculated densities for [C4(amim)2][TFSI]2 at different temperatures agreed well with the experimental values. The calculated RDFs and CDFs show that the anions are well organized around the amide group and imidazolium rings and the favorite sites of interaction of the [TFSI]- ion are the hydrogen atoms of the amide group and hydrogen atoms of the imidazolium ring of the cation. The calculated MSDs indicated that the diffusion coefficients of the studied DILs are 1 order of magnitude smaller than those of DILs with a comparable molar mass.


Effects of Combined Lysosomal and Mitochondrial Photodamage in a Non-small-Cell Lung Cancer Cell Line: The Role of Paraptosis.
We previously reported that a low level of lysosomal photodamage potentiated the phototoxic effect of subsequent mitochondrial photodamage mediated by the benzoporphyrin derivative (BPD) in murine hepatoma 1c1c7 cells. This was attributed to release of Ca2+ from damaged lysosomes and a calpain-mediated conversion of the autophagy-related protein ATG5 to a pro-apoptotic fragment. We now report a comparison of these results with those obtained with the human non-small-cell lung cancer A549 cell line. A549 cells contained lower levels of ATG5 and were less responsive than 1c1c7 cultures to the PDT combination. A rapid appearance of caspase 3/7 activation together with formation of condensed chromatin indicated initiation of apoptosis in both cell lines, but to a lesser extent in A549 cultures. Both cell lines became highly vacuolated within 16 h of combination PDT or an equivalent phototoxic dose from BPD alone. The vacuole periphery was labeled with a fluorescent probe for the endoplasmic reticulum (ER), and vacuole formation was prevented by presence of the protein synthesis inhibitor cycloheximide. These effects are characteristics of a caspase-independent death mode termed paraptosis previously associated with ER stress. These studies suggest that paraptosis may be a more frequent outcome of PDT than has hitherto been realized.


How do patients view the role of the primary care physician in inpatient care?
As hospitalized patients are increasingly cared for by physicians who are not their primary care physicians, discontinuity of care occurs when patients are sickest. We sought to determine hospitalized patients' knowledge, preferences, and satisfaction regarding the involvement of their primary care physician in their inpatient care. We conducted a cross-sectional questionnaire of 73 patients cared for by inpatient physicians and 12 relatives of such patients on an inpatient general medical service in a teaching hospital. Eligible patients were those admitted to the care of an inpatient physician other than their primary care provider (PCP), who stayed in the hospital for >1 day. If these patients were too sick to be interviewed or did not speak English, a relative knowledgeable about their medical care was interviewed. In all, 87% of patients had a primary care physician. Of these, 33% had some contact with their PCP while in the hospital. A total of 66% of respondents were satisfied with the contact they or their relative had with the PCP. Some 61% of respondents knew that communication had occurred between the inpatient and PCP. Respondents generally had positive opinions of their hospital care. However, most agreed that patients receive better care from and have more trust in physicians they have known for a long time, compared with those they have just met. About 50% of respondents believed that a PCP (rather than a separate hospital physician) should inform a patient of a serious diagnosis or discuss choices between medical and surgical management. Patients under the care of an inpatient physician want contact with their PCP and want good communication between the PCP and hospital doctors. Systems should be established to facilitate communication between in patient and primary care physicians, and between PCPs and patients.


Dry powder inhaler formulation comparison: Study of the role of particle deposition pattern and dissolution.
The composition, morphology and dissolution profile of particles and micro-sized agglomerates delivered upon inhalation may have a significant impact on the product clinical effect. However, although several efforts are ongoing, a methodology that considers deposition structures and dissolution performance evaluation in a biorelevant set-up is not yet standardized. The goal of this work is to apply a collection and dissolution methodology able to discriminate dry powder inhaler (DPI) formulations in terms of deposition structures and dissolution profile in vitro. Hence, Fluticasone Propionate (FP) engineered particles and formulated products (used as a case study) were collected employing a breath simulator and characterized regarding (i) aerodynamic particle size distribution; (ii) deposited microstructures; and (iii) dissolution/absorption profiles using the DissolvIt® bio-relevant dissolution equipment. The results indicated that the particle engineering technology had an impact on the generated and deposited microstructures, here associated to the differences on surface properties of jet milled and wet polished particles quantified by the specific surface area. Differences on surface properties modulate particle interactions, resulting in agglomerates of drug substance and excipient upon actuation with significant different morphologies, observed by microscope, as well as quantified by Marple cascade impactor. These observations allow for a further understanding of the DPI aerosolization and deposition mechanisms. The dissolution and absorption assessment indicates that the presence of lactose may accelerate the drug substance dissolution kinetics, and the FP dissolution can be significantly enhanced when formulated as a spray-dried dispersion particle. Ultimately, the results suggest dissolution testing can be an essential tool to both optimize an innovator DPI and de-risk generics development.


Rising incidence and prevalence of primary biliary cirrhosis: a large population-based study.
Large population-based studies are much needed to accurately establish the epidemiology of primary biliary cirrhosis (PBC). We aimed to collect all PBC patients in a geographically defined area to evaluate the epidemiology of PBC and examine the possible association of PBC with smoking, age at menarche, age at first pregnancy and number of pregnancies. All PBC patients between 2000 and 2008 were identified in a geographically defined area of the Netherlands, comprising 50% of the Dutch population. Four independent hospital databases were searched in 44 hospitals. Medical records were reviewed on site verifying diagnosis and for collection of clinical data. Age- and gender matched controls were recruited from the outpatient clinics of four participating hospitals. Patients and controls were asked to fill out a questionnaire regarding family history, previous and current smoking behaviour and fertility status. Nine hundred and ninety-two PBC patients fulfilled all inclusion criteria, resulting in a mean incidence of 1.1 per 100 000; 0.3 in men and 1.9 in women. On January 1st 2008 the point prevalence was 13.2 per 100 000 inhabitants. Incidence and prevalence rates were increasing over time (P < 0.001). No geographical differences in disease distribution were observed. Smoking behaviour, age at menarche, age at first pregnancy, gravidity and number of children were not significantly different between cases and controls. Incidence and prevalence rates of PBC are increasing over time. PBC was not found to be associated with smoking, age at menarche, age at first pregnancy or number of pregnancies.


Sildenafil in Left Ventricular Assist Device Is Safe and Well-Tolerated.
Right heart failure is a potentially devastating complication of mechanical circulatory support, occurring at a rate of 0.49 events per 100 patient-months. Pulmonary vasodilators such as phosphodiesterase-5 inhibitors (PDE5i) have been frequently used to unload the right ventricle in left ventricular assist device (LVAD) patients, but there is scant evidence to support this practice., The purpose of this analysis is to provide additional data regarding the safety and efficacy of the PDE5i sildenafil in a real world population of patients supported with LVADs at Washington University in St. Louis. Sildenafil use was not associated with differences in gastrointestinal (GI) bleeding, stroke, mortality, heart failure (HF) admission, or orthotopic heart transplantation (OHT).


Novel targets for malaria therapy.
Malaria has emerged as one of the most debilitating parasitic infection with about 500 million cases reported annually and one million deaths worldwide. Currently, Plasmodium falciparum has developed resistance to almost all classes of antimalarials, thus precluding the use of those agents which once formed the cornerstone of malaria therapy. In lieu of this phenomenon, and taking into consideration the absence of an effective vaccine for malaria, the only way to combat the deadly parasite is to enrich the antimalarial cache with new molecules acting on fresh targets in the parasite. After potential targets have been validated, these targets can be used as basis for screening compounds to identify new leads followed by lead optimization. This review discusses novel targets of the malaria parasite that can be utilized to treat the disease.


Angiography in the diagnosis and staging of pelvic neoplasms.
The efficacy of arteriography in the staging of pelvic neoplasms was examined in 447 patients. It was found to be most useful in defining advanced neoplastic disease, improving accuracy of staging in these patients by about 18%. In patients with early pelvic neoplastic disease, arteriography reduced the number of false positives.


Estimating causal dependencies in networks of nonlinear stochastic dynamical systems.
The inference of causal interaction structures in multivariate systems enables a deeper understanding of the investigated network. Analyzing nonlinear systems using partial directed coherence requires high model orders of the underlying vector-autoregressive process. We present a method to overcome the drawbacks caused by the high model orders. We calculate the corresponding statistics and provide a significance level. The performance is illustrated by means of model systems and in an application to neurological data.


Does aircraft noise exposure increase the risk of hypertension in the population living near airports in France?
The largest study until now around 6 major European airports, the HYENA (HYpertension and Exposure to Noise near Airports) study, reported an excess risk of hypertension related to long-term aircraft noise exposure. The DEBATS (Discussion on the health effects of aircraft noise) study investigated the relationship between this exposure and the risk of hypertension in men and in women near French airports. Blood pressure of 1244 participants older than 18 years of age was measured. Information about health, socioeconomic and lifestyle factors was collected by means of a face-to-face questionnaire performed at home by an interviewer. Aircraft noise exposure was assessed for each participant's home address using noise maps. They were calculated with the Integrated Noise Model with a 1 dB(A)-resolution. The major potential confounders being risk factors for hypertension were included in the logistic regression models: age, occupational activity, body mass index, physical activity and alcohol consumption. After adjustment for the main potential confounders, an exposure-response relationship was evidenced between the risk of hypertension and aircraft noise exposure at night for men only. A 10-dB(A) increase in Lnight was associated with an OR of 1.34 (95% CI 1.00 to 1.97). These findings contribute to the overall evidence suggesting that aircraft noise exposure at night-time may increase the risk of hypertension in men. Hypertension is a well-known and established risk factor for cardiovascular disease. The association reported in the present study between aircraft noise and hypertension implies that aircraft noise might be a risk factor also for cardiovascular disease.


Flagellar targeting of an arginine kinase requires a conserved lipidated protein intraflagellar transport (LIFT) pathway in Trypanosoma brucei.
Both intraflagellar transport (IFT) and lipidated protein intraflagellar transport (LIFT) pathways are essential for cilia/flagella biogenesis, motility, and sensory functions. In the LIFT pathway, lipidated cargoes are transported into the cilia through the coordinated actions of cargo carrier proteins such as Unc119 or PDE6δ, as well as small GTPases Arl13b and Arl3 in the cilium. Our previous studies have revealed a single Arl13b ortholog in the evolutionarily divergent Trypanosoma brucei, the causative agent of African sleeping sickness. TbArl13 catalyzes two TbArl3 homologs, TbArl3A and TbArl3C, suggesting the presence of a conserved LIFT pathway in these protozoan parasites. Only a single homolog to the cargo carrier protein Unc119 has been identified in T. brucei genome, but its function in lipidated protein transport has not been characterized. In this study, we exploited the proximity-based biotinylation approach to identify binding partners of TbUnc119. We showed that TbUnc119 binds to a flagellar arginine kinase TbAK3 in a myristoylation-dependent manner and is responsible for its targeting to and enrichment in the flagellum. Interestingly, only TbArl3A, but not TbArl3C interacted with TbUnc119 in a GTP-dependent manner, suggesting functional specialization of Arl3-GTPases in T. brucei These results establish the function of TbUnc119 as a myristoylated cargo carrier and support the presence of a conserved LIFT pathway in T. brucei.


Clinical risk factors for primary graft failure following lung transplantation.
s: Primary graft failure (PGF) is a devastating acute lung injury syndrome following lung transplantation. We sought to identify donor, recipient, and operative risk factors for its development. We conducted a cohort study of 255 consecutive lung transplant procedures performed between October 1991 and July 2000. We defined PGF as follows: (1) diffuse alveolar opacities exclusively involving allograft(s) and developing within 72 h of transplant, (2) a ratio of PaO(2) to fraction of inspired oxygen < 200 beyond 48 h postoperatively, and (3) no other secondary cause of graft dysfunction identified. Risk factors were assessed individually and adjusted for confounding using multivariable logistic regression models. Tertiary-care academic medical center. The overall incidence was 11.8% (95% confidence interval [CI], 7.9 to 15.9). Following multivariable analysis, the risk factors independently associated with development of PGF were as follows: a recipient diagnosis of primary pulmonary hypertension (PPH; adjusted odds ratio [OR], 4.52; 95% CI, 1.29 to 15.9; p = 0.018), donor female gender (adjusted OR, 4.11; 95% CI, 1.17 to 14.4; p = 0.027), donor African-American race (adjusted OR, 5.56; 95% CI, 1.57 to 19.8; p = 0.008), and donor age < 21 years (adjusted OR, 4.06; 95% CI, 1.34 to 12.3; p = 0.013) and > 45 years (adjusted OR, 6.79; 95% CI, 1.61 to 28.5; p = 0.009). Recipient diagnosis of PPH, donor African-American race, donor female gender, and donor age are independently and strongly associated with development of PGF.


Deep Learning of Multimodal Ultrasound: Stratifying the Response to Neoadjuvant Chemotherapy in Breast Cancer Before Treatment.
Not only should resistance to neoadjuvant chemotherapy (NAC) be considered in patients with breast cancer but also the possibility of achieving a pathologic complete response (PCR) after NAC. Our study aims to develop 2 multimodal ultrasound deep learning (DL) models to noninvasively predict resistance and PCR to NAC before treatment. From January 2017 to July 2022, a total of 170 patients with breast cancer were prospectively enrolled. All patients underwent multimodal ultrasound examination (grayscale 2D ultrasound and ultrasound elastography) before NAC. We combined clinicopathological information to develop 2 DL models, DL_Clinical_resistance and DL_Clinical_PCR, for predicting resistance and PCR to NAC, respectively. In addition, these 2 models were combined to stratify the prediction of response to NAC. In the test cohort, DL_Clinical_resistance had an AUC of 0.911 (95%CI, 0.814-0.979) with a sensitivity of 0.905 (95%CI, 0.765-1.000) and an NPV of 0.882 (95%CI, 0.708-1.000). Meanwhile, DL_Clinical_PCR achieved an AUC of 0.880 (95%CI, 0.751-0.973) and sensitivity and NPV of 0.875 (95%CI, 0.688-1.000) and 0.895 (95%CI, 0.739-1.000), respectively. By combining DL_Clinical_resistance and DL_Clinical_PCR, 37.1% of patients with resistance and 25.7% of patients with PCR were successfully identified by the combined model, suggesting that these patients could benefit by an early change of treatment strategy or by implementing an organ preservation strategy after NAC. The proposed DL_Clinical_resistance and DL_Clinical_PCR models and combined strategy have the potential to predict resistance and PCR to NAC before treatment and allow stratified prediction of NAC response.


Selective adaptation in networks of cortical neurons.
A key property of neural systems is their ability to adapt selectively to stimuli with different features. Using multisite electrical recordings from networks of cortical neurons developing ex vivo, we show that neurons adapt selectively to different stimuli invading the network. We focus on selective adaptation to frequent and rare stimuli; networks were stimulated at two sites with two different stimulus frequencies. When both stimuli were presented within the same period, neurons in the network attenuated their responsiveness to the more frequent input, whereas their responsiveness to the rarely delivered stimuli showed a marked average increase. The amplification of the response to rare stimuli required the presence of the other, more frequent stimulation source. By contrast, the decreased response to the frequent stimuli occurred regardless of the presence of the rare stimuli. Analysis of the response of single units suggests that both of these effects are caused by changes in synaptic transmission. By using synaptic blockers, we find that the increased responsiveness to the rarely stimulated site depends specifically on fast GABAergic transmission. Thus, excitatory synaptic depression, the inhibitory sub-network, and their balance play an active role in generating selective gain control. The observation that selective adaptation arises naturally in a network of cortical neurons developing ex vivo indicates that this is an inherent feature of spontaneously organizing cortical networks.


Male Breast Cancer: Therapy-Induced Toxicities, Psychological Distress, and Individual Patient Goals during Oncological Inpatient Rehabilitation.
Male breast cancer (MBC) is a rare malignancy that accounts for less than 1% of all cancers in men and less than 1% of all breast cancers worldwide. Understandably, due to the low incidence of this rare cancer, there is a lack of prospective clinical data. The aim of this retrospective study was the analysis of therapy-induced toxicities as well as the assessment of psychological distress in the affected men during oncological inpatient rehabilitation. Fifty-one MBC patients were evaluated for the presence of treatment-induced side effects, toxicities, and psychological distress (using German version of the 11-stage NCCN distress thermometer; cut-off ≥5) during oncological indoor rehabilitation. The collected data were checked for correlation with sociodemographic and clinical factors (SPSS 22). The mean age was 62.0 ± 10.6 years, in 96% a hormone-dependent breast tumor (ER+), and in over 75%, overweight or obesity (BMI >25/>30) was diagnosed. Most reported side effects included weakness/fatigue (74.5%), arthralgia after surgery/chemotherapy (43.1%), chemotherapy-induced polyneuropathy (36.3%), and/or lymphedema (13.7%). Psychological distress was detected in 24 cases (47.0%; ≥5), in 13 cases even with significantly high levels (25.5%; ≥7). There was no correlation between psychological distress and clinical factors such as age, performed treatment (e.g., chemotherapy), or therapy-induced side effects (e.g., lymphedema) in our small collective. Psychological distress and somatic side effects are common in MBC. These data demonstrate the importance of routine screening for psychological distress and the high need for psycho-oncological therapy (regardless of gender) in multimodal oncological rehabilitation.


Determination of melatonin content in traditional Thai herbal remedies used as sleeping aids.
Melatonin content was screened in leaves of seven edible herbs used as sleeping aids in Thai traditional medicine. These plants are Piper nigrum L, Sesbania glandiflora (L.) Desv., Sesbania sesban (L.) Merr., Senna tora (L.) Roxb., Moringa oleifera Lam., Momordica charantia L. and Baccaurea ramiflora Lour. Dried leaves were extracted by sonication in methanol for six hours at room temperature, and then melatonin was purified by C18 solid phase extraction (SPE). Melatonin was then quantified by a validated RP-C18 HPLC method with fluorescent detection. Melatonin contents in extracts of B. ramiflora, S. glandiflora, M. charantia, S. tora and S. sesban were 43.2, 26.3, 21.4, 10.5 and 8.7 ng/g of dry sample weight, respectively. The highest melatonin content was from P. nigrum extract (1092.7 ng/g of dry sample weight). Melatonin was not detected in the extract of M. oleifera. Melatonin identification was confirmed by ELISA. Melatonin was found in six of the seven herbs in the traditional Thai sleeping recipe. One of these, P. nigrum, exhibited an encouragingly high amount of melatonin.


Implication of human endogenous retrovirus envelope proteins in placental functions.
Human endogenous retroviruses (ERVs) represent 8% of the total human genome. Although the majority of these ancient proviral sequences have only retained non-coding long terminal repeats (LTRs), a number of "endogenized" retroviral genes encode functional proteins. Previous studies have underlined the implication of these ERV-derived proteins in the development and the function of the placenta. In this review, we summarize recent findings showing that two ERV genes, termed Syncytin-1 and Syncytin-2, which encode former envelope (Env) proteins, trigger fusion events between villous cytotrophoblasts and the peripheral multinucleated syncytiotrophoblast layer. Such fusion events maintain the stability of this latter cell structure, which plays an important role in fetal development by the active secretion of various soluble factors, gas exchange and regulation of fetomaternal immunotolerance. We also highlight new studies showing that these ERV proteins, in addition to their localization at the cell surface of cytotrophoblasts, are also incorporated on the surface of various extracellular microvesicles, including exosomes. Such exosome-associated proteins could be involved in the various functions attributed to these vesicles and could provide a form of tropism. Additionally, through their immunosuppressive domains, these ERV proteins could also contribute to fetomaternal immunotolerance in a local and more distal manner. These various aspects of the implication of Syncytin-1 and -2 in placental function are also addressed in the context of the placenta-related disorder, preeclampsia.


Analysis of risk factors leading to postoperative urethral stricture and bladder neck contracture following transurethral resection of prostate.
To determine risk factors of postoperative urethral stricture (US) and vesical neck contracture (BNC) after transurethral resection of prostate (TURP) from perioperative parameters. 373 patients underwent TURP in a Chinese center for lower urinary tract symptoms suggestive of benign prostatic obstruction (LUTS/BPO), with their perioperative and follow-up clinical data being collected. Univariate analyses were used to determine variables which had correlation with the incidence of US and BNC before logistic regression being applied to find out independent risk factors. The median follow-up was 29.3 months with the incidence of US and BNC being 7.8% and 5.4% respectively. Resection speed, reduction in hemoglobin (ΔHb) and hematocrit (ΔHCT) levels, incidence of urethral mucosa rupture, re-catheterization and continuous infection had significant correlation with US, while PSA level, storage score, total prostate volume (TPV), transitional zone volume (TZV), transitional zone index (TZI), resection time and resected gland weight had significant correlation with BNC. Lower resection speed (OR=0.48), urethral mucosa rupture (OR=2.44) and continuous infection (OR=1.49) as well as higher storage score (OR=2.51) and lower TPV (OR=0.15) were found to be the independent risk factors of US and BNC respectively. Lower resection speed, intraoperative urethral mucosa rupture and postoperative continuous infection were associated with a higher risk of US while severer storage phase symptom and smaller prostate size were associated with a higher risk of BNC after TURP.


Clinical Implementation of Prolonged Liver Preservation and Monitoring Through Normothermic Machine Perfusion in Liver Transplantation.
Normothermic machine perfusion (NMP) bears the potential for significant prolongation of liver preservation before transplantation. Although safety and feasibility have been recently published, no data are available describing the significant challenges of establishing NMP programs outside clinical studies. We herein present our experience and propose a multidisciplinary approach for liver NMP in the clinical routine. In February 2018, liver NMP was introduced for routine use in marginal organs, logistic challenges, and complex recipients at our institution. In a multidisciplinary effort among transplant coordinators, perfusionists, transplant surgeons, anesthesia, nurses, blood bank as well as laboratory staff, a clinical routine was established and 34 NMP cases were performed without critical incidents or organ loss. Nine livers were discarded due to poor organ quality and function observed during NMP. Twenty-five livers were successfully transplanted after preservation of up to 38 h. The extended criteria donors rate was 100% and 92% in discarded and transplanted livers, respectively. Nighttime procedures and parallel transplantations were eventually omitted. Graft and patient survival was 88% at 20 mo. No cholangiopathy was observed despite the use of extended criteria donor organs in 92% of cases. NMP in a multidisciplinary approach enables a safe prolongation of liver preservation and overnight organ care. A first field test of NMP indicates safety and benefit of this approach.