Pharmacokinetic concepts and applications affecting the clinical laboratory: I. General concepts and applications.
This article (the first in a series of two papers on pharmacokinetic concepts and applications for the clinical laboratory) presents a general review of pharmacokinetic principles used in conjunction with assays of drug plasma concentrations to assist in developing safer and more efficacious drug dosage regimens for patients. The pharmacokinetic factors influencing drug therapy are discussed, followed by a consideration of the indications for, and limitations of, using drug plasma concentrations as a guide to treatment. Drugs commonly assayed by the clinical laboratory are noted and applications are presented.


The T11 (CD2) molecule is functionally linked to the T3/Ti T cell receptor in the majority of T cells.
Most mature human T lymphocytes express both the multichain T3 (CD3)/Ti T cell receptor for antigen (TCR), and the biochemically distinct 55-kDa T11 (CD2) glycoprotein. Stimulating the T11 molecule causes profound T cell proliferation and functional activation in vitro, but the relationship of T11-mediated activation to antigenic stimulation of T lymphocytes in vivo remains unknown. We now present evidence that T11 function is directly linked to TCR components in T3/Ti+ T11+ human T cells. First, we found that stimulating peripheral blood T cells with the mitogenic combination of anti-T11(2) cells with the mitogenic combination of anti-T11(2) plus anti-T11(3) monoclonal antibodies caused the phosphorylation of TCR T3 chains. The predominance of T3-gamma-phosphorylation that occurred in anti-T11(2) plus anti-T11(3)-treated T cells is similar to the pattern previously observed in antigen-stimulated T cell clones. Second, T11 function depended upon concurrent cell-surface expression of the TCR. Thus, when peripheral blood T cells were deprived of cell surface T3/Ti by anti-T3 modulation, anti-T11(2) plus anti-T11(3)-induced mitogenesis and transmembrane signal generation in the form of calcium mobilization were inhibited. The mechanism of TCR-T11 interdependence was investigated in a series of TCR-deficient variants of a T cell lymphoblastoid cell line. T3/Ti negative variants expressed cell surface T11, but anti-T11(2) plus anti-T11(3) failed to cause detectable calcium mobilization. The TCR-deficient variants also failed to express T11(3) activation epitopes after incubation with anti-T11(2) antibodies, suggesting that T11(3) expression is an essential and TCR-dependent intermediate in the T11 activation mechanism in these cells. Taken together, our results suggest that T11 function depends upon cell-surface expression of TCR in many T3/Ti+ T11+ T lymphocytes, and T11-mediated activation is intimately interconnected with TCR activation mechanisms. A model in which stimulating signals delivered via T11 may be a part of antigenic activation of T lymphocytes is presented.


Trial of atenolol and chlorthalidone for hypertension in black South Africans.
Twenty-four black patients (Zulus) with hypertension participated in a double-blind, placebo-controlled cross-over trial of the efficacy of a beta-blocking agent (atenolol) 100 mg once daily as compared with chlorthalidone 25 mg once daily. The two drugs were also given combined at these doses and the effects compared with those of the drugs given alone. Atenolol as sole treatment had no appreciable effect on blood pressure as compared with placebo. Chlorthalidone produced a small decrease, but this was not statistically significant. Combining the two drugs, however, produced a significant reduction in blood pressure (mean lying blood pressure p < 0.001; mean standing blood pressure p < 0.0002). These findings suggest that beta-blockers should not be regarded as baseline treatment of hypertension in blacks.


Good clinical practice and phytotherapy.
The GCP Guideline of the European Community on the performance of clinical trials became obligatory in June 1991. As the GCP standards have mainly been set for innovative drugs, there is a certain danger that these criteria could not be fulfilled by medicines used in phytotherapy. As regards, the chances and risks of the European guideline, especially for herbal medicines, the differences between chemically-defined and herbal drugs, as well as the extent, to which herbal medicines might be concerned by the guideline, have to be taken into account. Herbal medicines are different from chemically defined medicines in their character as well as in their medicinal use. They always contain a mixture of numerous substances. Data on preclinical investigations are often incomplete, whereas, on the other hand, physicians and patients have a long-term experience in applying these medicines. They are, in general, well-tolerated and therefore suitable for the treatment of chronic diseases. Due to a characteristic taste and smell, the production of placebos is often impossible. The GCP directive also contains basic elements concerning chemically defined drugs as well as herbal medicines in a similar way.


Lesion search and recognition by thymine DNA glycosylase revealed by single molecule imaging.
The ability of DNA glycosylases to rapidly and efficiently detect lesions among a vast excess of nondamaged DNA bases is vitally important in base excision repair (BER). Here, we use single molecule imaging by atomic force microscopy (AFM) supported by a 2-aminopurine fluorescence base flipping assay to study damage search by human thymine DNA glycosylase (hTDG), which initiates BER of mutagenic and cytotoxic G:T and G:U mispairs in DNA. Our data reveal an equilibrium between two conformational states of hTDG-DNA complexes, assigned as search complex (SC) and interrogation complex (IC), both at target lesions and undamaged DNA sites. Notably, for both hTDG and a second glycosylase, hOGG1, which recognizes structurally different 8-oxoguanine lesions, the conformation of the DNA in the SC mirrors innate structural properties of their respective target sites. In the IC, the DNA is sharply bent, as seen in crystal structures of hTDG lesion recognition complexes, which likely supports the base flipping required for lesion identification. Our results support a potentially general concept of sculpting of glycosylases to their targets, allowing them to exploit the energetic cost of DNA bending for initial lesion sensing, coupled with continuous (extrahelical) base interrogation during lesion search by DNA glycosylases.


Surgical treatment of metastatic liver tumors.
Liver resection for limited amounts of metastatic cancer should be recommended to highly selected patients. It will provide a significant chance for "cure" for patients with metastases from colorectal cancers and may provide palliation for a few others with very slow-growing tumors or hormone symptoms from endocrine tumors. The results of resection are compared with those of chemotherapy, radiation, arterial ligation, and other treatments. Selection criteria, none of which is absolute, include number of metastases, stage of primary tumor, interval between resection of primary tumor and discovery of liver metastasis, and proximity to vital structures. The presence of extrahepatic metastasis, even if resected, carries with it a grim prognosis and should probably preclude liver resection.


The Association of Inflammatory Bowel Disease with Postoperative Complications, Re-admissions and Emergency Department Visits Following Primary Total Hip Arthroplasty.
Inflammatory bowel disease (IBD) is a systemic inflammatory disorder of the gut. Few studies have evaluated whether patients with a history of IBD have worse outcomes following primary total hip arthroplasty (THA). Therefore, the purpose of this study was to evaluate whether IBD is associated with increased: (1) medical complications; (2) readmissions; and (3) emergency department (ED) visits. Using a nationwide claims database, patients with IBD undergoing primary THA were identified and matched to a comparison group according to age, sex and the Charlson Comorbidity Index. Outcomes assessed included the development of 90-day medical complications, 90-day re-admissions and 90-day ED visit rates. A p-value <0.0001 was considered statistically significant. Patients with IBD had a greater incidence and odds ratio of total medical complications (31.90% vs. 11.47%; OR 2.89; p < 0.0001) compared with matched controls. IBD patients had significantly higher incidence and odds ratio of developing acute kidney injury (5.46 vs. 1.46%; OR 3.92; p < 0.0001), cerebrovascular accident (1.32 vs. 0.35%; OR 3.79; p < 0.0001), pneumonia (4.02 vs. 1.30%; OR 3.19; p < 0.0001), respiratory failure (1.21 vs. 0.41%; OR 2.94; p < 0.0001), deep vein thrombosis (0.89% vs. 0.30%; OR 2.93; p < 0.0001), and other adverse events. IBD patients also had higher incidence and odds ratio of 90-day re-admissions (4.20% vs. 3.23%; OR 1.31; p < 0.0001) and ED visits (6.56% vs. 3.99%; OR 1.69; p < 0.0001). This study found that patients with IBD are at increased risk of 90-day medical complications, re-admissions, and ED visits. Due to its systemic nature, surgeons operating on these patients should be aware of the disease's extra-intestinal manifestations, and the potential postoperative risks in IBD patients. Providers should use this investigation when educating patients on potential risks of elective THA.


Racial differences in the prevalence of antenatal depression.
This study examined whether there were racial/ethnic differences in the prevalence of antenatal depression based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnostic criteria in a community-based sample of pregnant women. Data were drawn from an ongoing registry of pregnant women receiving prenatal care at a university obstetric clinic from January 2004 through March 2010 (N =1997). Logistic regression models adjusting for sociodemographic, psychiatric, behavioral and clinical characteristics were used to examine racial/ethnic differences in antenatal depression as measured by the Patient Health Questionnaire. Overall, 5.1% of the sample reported antenatal depression. Blacks and Asian/Pacific Islanders were at increased risk for antenatal depression compared to non-Hispanic White women. This increased risk of antenatal depression among Blacks and Asian/Pacific Islanders remained after adjustment for a variety of risk factors. Results suggest the importance of race/ethnicity as a risk factor for antenatal depression. Prevention and treatment strategies geared toward the mental health needs of Black and Asian/Pacific Islander women are needed to reduce the racial/ethnic disparities in antenatal depression.


Older adults lack SARS CoV-2 cross-reactive T lymphocytes directed to human coronaviruses OC43 and NL63.
Currently, infections with SARS-Coronavirus-2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, are responsible for substantial morbidity and mortality worldwide. Older adults subjects > 60 years of age account for > 95% of the over one million fatal cases reported to date. It is unclear why in this age group SARS-CoV-2 infection causes more severe disease than in young adults. We hypothesized that differences in SARS-CoV-2 cross-reactive cellular immunity induced after infection with human coronaviruses (HCoVs), like OC43 and NL63, were at the basis of the differential mortality (and morbidity) observed after SARS-CoV-2 infection, because a small proportion of HCoV-specific T cells cross-react with SARS-CoV-2. Our data demonstrate that pre-existing T cell immunity induced by circulating human alpha- and beta-HCoVs is present in young adult individuals, but virtually absent in older adult subjects. Consequently, the frequency of cross-reactive T cells directed to the novel pandemic SARS-CoV-2 was minimal in most older adults. To the best of our knowledge, this is the first time that the presence of cross-reactive T cells to SARS-CoV-2 is compared in young and older adults. Our findings provide at least a partial explanation for the more severe clinical outcome of SARS-CoV-2 infection observed in the elderly. Moreover, this information could help to design efficacious vaccines for this age group, aiming at the induction of cell-mediated immunity.


[Role of cyclic AMP in the action of dopamine on the spontaneous and glutamate-induced activity of neostriatal neurons in the rat].
The influence of microionophoretically applied dopamine and dibutyril cAMP on the background and glutamate-evoked spike activity of neostriatum neurons was studied in acute experiments on rats immobilized by d-tubocurarine. The mean rate, stationarity, interspike interval histograms and autocorrelation functions for extracellularly recorded spike activity were measured. It was shown that dibutyril cAMP imitated the inhibiting dopamine effect on the background and glutamate-evoked spike activity of neostriatum neurons rather than the stimulating effect.


[Determination of lysine residue number, positive charge and molecular lengths of histone H1 and H5 by a method of incomplete succinylation].
A simple method for determination of lysine residue number and positive charge of histones H1 and H5 in the acetic acid -- urea system has been developed. The method is based on incomplete succinylation of lysine residues and allows an accurate determination of protein molecular length. The accuracy of the method has been demonstrated by determination of goose and chicken histones H5 and their fragments. The calibrating curve for determination of molecular lengths of histones H1 and H5 has been plotted. Using the incomplete succinylation method, a detailed analysis of Lymantria dispar histone H1 structure has been carried out. The method under discussion can be used for determining lysine residue number, positive charge and molecular length of practically any protein.


ACL deficiency affects stride-to-stride variability as measured using nonlinear methodology.
Previous studies suggested that the small fluctuations present in movement patterns from one stride to the next during walking can be useful in the investigation of various pathological conditions. Previous studies using nonlinear measures have resulted in the development of the "loss of complexity hypothesis" which states that disease can affect the variability and decrease the complexity of a system, rendering it less able to adjust to the ever changing environmental demands. The nonlinear measure of the Lyapunov Exponent (LyE) has already been used for the assessment of stride-to-stride variability in the anterior cruciate ligament (ACL) deficient knee in comparison to the contralateral intact knee. However, there is biomechanical evidence that after ACL rupture, adaptations are also present in the contralateral intact knee. Thus, our goal was to investigate stride-to-stride variability in the ACL deficient knee as compared to a healthy control knee. Seven subjects with unilateral ACL deficiency and seven healthy controls walked at their self-selected speed on a treadmill, while three-dimensional knee kinematics was collected for 80 consecutive strides. A nonlinear measure, the largest LyE was calculated from the resulted knee joint flexion-extension data of both groups. Larger LyE values signify increased variability and increased sensitivity to initial conditions. Our results showed that the ACL deficient group exhibited significantly less variable walking patterns than the healthy control. These changes are not desirable because they reflect decreases in system's complexity, which indicates narrowed functional responsiveness, according to the "loss of complexity hypothesis." This may be related with the increased future pathology found in ACL deficient patients. The methods used in the present paper showed great promise to assess the gait handicap in knee injured patients.


Clinical Theragnostic Relationship between Drug-Resistance Specific miRNA Expressions, Chemotherapeutic Resistance, and Sensitivity in Breast Cancer: A Systematic Review and Meta-Analysis.
Awareness of breast cancer has been increasing due to early detection, but the advanced disease has limited treatment options. There has been growing evidence on the role of miRNAs involved in regulating the resistance in several cancers. We performed a comprehensive systematic review and meta-analysis on the role of miRNAs in influencing the chemoresistance and sensitivity of breast cancer. A bibliographic search was performed in PubMed and Science Direct based on the search strategy, and studies published until December 2018 were retrieved. The eligible studies were included based on the selection criteria, and a detailed systematic review and meta-analysis were performed based on PRISMA guidelines. A random-effects model was utilised to evaluate the combined effect size of the obtained hazard ratio and 95% confidence intervals from the eligible studies. Publication bias was assessed with Cochran's Q test, I2 statistic, Orwin and Classic fail-safe N test, Begg and Mazumdar rank correlation test, Duval and Tweedie trim and fill calculation and the Egger's bias indicator. A total of 4584 potential studies were screened. Of these, 85 articles were eligible for our systematic review and meta-analysis. In the 85 studies, 188 different miRNAs were studied, of which 96 were upregulated, 87 were downregulated and 5 were not involved in regulation. Overall, 24 drugs were used for treatment, with doxorubicin being prominently reported in 15 studies followed by Paclitaxel in 11 studies, and 5 drugs were used in combinations. We found only two significant HR values from the studies (miR-125b and miR-4443) and our meta-analysis results yielded a combined HR value of 0.748 with a 95% confidence interval of 0.508-1.100; p-value of 0.140. In conclusion, our results suggest there are different miRNAs involved in the regulation of chemoresistance through diverse drug genetic targets. These biomarkers play a crucial role in guiding the effective diagnostic and prognostic efficiency of breast cancer. The screening of miRNAs as a theragnostic biomarker must be brought into regular practice for all diseases. We anticipate that our study serves as a reference in framing future studies and clinical trials for utilising miRNAs and their respective drug targets.


Global dissemination of influenza A virus is driven by wild bird migration through arctic and subarctic zones.
Influenza A viruses (IAV) circulate endemically among many wild aquatic bird populations that seasonally migrate between wintering grounds in southern latitudes to breeding ranges along the perimeter of the circumpolar arctic. Arctic and subarctic zones are hypothesized to serve as ecologic drivers of the intercontinental movement and reassortment of IAVs due to high densities of disparate populations of long distance migratory and native bird species present during breeding seasons. Iceland is a staging ground that connects the East Atlantic and North Atlantic American flyways, providing a unique study system for characterizing viral flow between eastern and western hemispheres. Using Bayesian phylodynamic analyses, we sought to evaluate the viral connectivity of Iceland to proximal regions and how inter-species transmission and reassortment dynamics in this region influence the geographic spread of low and highly pathogenic IAVs. Findings demonstrate that IAV movement in the arctic and subarctic reflects wild bird migration around the perimeter of the circumpolar north, favouring short-distance flights between proximal regions rather than long distance flights over the polar interior. Iceland connects virus movement between mainland Europe and North America, consistent with the westward migration of wild birds from mainland Europe to Northeastern Canada and Greenland. Though virus diffusion rates were similar among avian taxonomic groups in Iceland, gulls play an outsized role as sinks of IAVs from other avian hosts prior to onward migration. These data identify patterns of virus movement in northern latitudes and inform future surveillance strategies related to seasonal and emergent IAVs with potential public health concern.


Crystallization and preliminary crystallographic analysis of the autoinhibited form of the tandem SH3 domain of p47(phox).
p47(phox) is a cytosolic component of the phagocyte NADPH oxidase, which is responsible for the production of the superoxide which kills invasive microorgamisms. A recombinant form of a histidine-tagged tandem SH3 domain of the p47(phox)-containing polybasic autoinhibited region was expressed in Escherichia coli and purified and crystallized by the sitting-drop vapour-diffusion method at 293 K using polyethylene glycol 6000 as a precipitant. Diffraction data were collected to 2.15 A resolution at 100 K using synchrotron radiation. The crystal belongs to space group P4(1)2(1)2 or P4(3)2(1)2, with unit-cell parameters a = 100.02, c = 44.94 A. The presence of one molecule per asymmetric unit gives a crystal volume per protein mass (V(M)) of 2.6 A(3) Da(-1) and a solvent content of 52% by volume.


Visual fourier-transform spectroscopy with a single crystal plate.
This paper shows how a single Z-cut plate of uniaxial crystal can be used as a two-beam interferometer of Fourier-transform spectrometer. As a visual device, it permits easy identification of a set of achromatic fringes that can be seen in any two-beam interferometer when a white-light source is observed through it. These fringes apparently have not been described previously. They are expected when we understand that the white-light fringe pattern is in fact the Fourier transform of the spectral-sensitivity curve of the eye.


"Visible" 5d Orbital States in a Pleochroic Oxychloride.
Transition metal compounds sometimes exhibit attractive colors. Here, we report a new oxychloride, Ca3ReO5Cl2, that shows unusually distinct pleochroism; that is, the material exhibits different colors depending on the viewing direction. This pleochroism is a consequence of the coincidental complex crystal field splitting of the 5d orbitals of the Re6+ ion in a square-pyramidal coordination of low symmetry in the energy range of the visible spectrum. Since the relevant d-d transitions show characteristic polarization dependence according to the optical selection rule, the orbital states are "visible" in Ca3ReO5Cl2.


Hand and foot pressures in the aye-aye (Daubentonia madagascariensis) reveal novel biomechanical trade-offs required for walking on gracile digits.
Arboreal animals with prehensile hands must balance the complex demands of bone strength, grasping and manipulation. An informative example of this problem is that of the aye-aye (Daubentonia madagascariensis), a rare lemuriform primate that is unusual in having exceptionally long, gracile fingers specialized for foraging. In addition, they are among the largest primates to engage in head-first descent on arboreal supports, a posture that should increase loads on their gracile digits. We test the hypothesis that aye-ayes will reduce pressure on their digits during locomotion by curling their fingers off the substrate. This hypothesis was tested using simultaneous videographic and pressure analysis of the hand, foot and digits for five adult aye-ayes during horizontal locomotion and during ascent and descent on a 30 degrees instrumented runway. Aye-ayes consistently curled their fingers during locomotion on all slopes. When the digits were in contact with the substrate, pressures were negligible and significantly less than those experienced by the palm or pedal digits. In addition, aye-ayes lifted their hands vertically off the substrate instead of 'toeing-off' and descended head-first at significantly slower speeds than on other slopes. Pressure on the hand increased during head-first descent relative to horizontal locomotion but not as much as the pressure increased on the foot during ascent. This distribution of pressure suggests that aye-ayes shift their weight posteriorly during head-first descent to reduce loads on their gracile fingers. This research demonstrates several novel biomechanical trade-offs to deal with complex functional demands on the mammalian skeleton.


Reexamining the correlates of adolescent violent victimization: the importance of exposure, guardianship, and target characteristics.
The present study examines the relative contributions of various theoretical constructs to violent victimization by operationalizing multiple measures of exposure to motivated offenders, guardianship, and target characteristics. Using a nationally representative sample of American adolescents, we conducted principal components factor analysis and logistic regression analysis to examine whether such measures do in fact represent empirically distinct constructs and if they are each correlated with violent victimization risk. Findings suggest that both nondelinquent and delinquent routine activities which expose adolescents to motivated offenders increase risk of victimization. In terms of guardianship, parental attachment appears to protect adolescents from victimization, although direct parental control actually increases risk. Finally, only one of four target characteristics-psychological vulnerability-was significantly associated with violent victimization risk. We discuss the implications for theory and future research in light of the findings.


Efficacy of Yiqi Yangyin Jiedu decoction in postoperative patients with thyroid cancer: A protocol for systematic review and meta-analysis.
There is no evidence-based data to confirm the efficacy of Yiqi Yangyin Jiedu Decoction (YYJD) in postoperative thyroid cancer patients. Therefore, in order to provide new evidence-based medical evidence for clinical treatment, we used this protocol to conduct a systematic review and meta-analysis to evaluate the efficacy and safety of YYJD in postoperative patients with thyroid cancer. This systematic review and meta-analysis has been prospectively registered in the PROSPERO (No. CRD42022365826). Six databases, including Medicine, Embase, Cochrane, CNKI, Wan Fang, and VIP, will be searched from their inception to February 1, 2023. Clinical controlled studies investigating the efficacy and safety of YYJD in patients after thyroid cancer surgery will all be considered for inclusion. The primary outcomes are tumor recurrence rate and overall survival. The secondary outcomes include treatment-related adverse effects, length of hospital stay, and patient satisfaction. All data will be analyzed using R version 3.4.3 to calculate pooled standardized mean differences for outcomes. Data that can not be retrieved will be interpreted from graphs using digital ruler software. The results of this paper will fill a gap in the literature regarding this project. We assume that the YYJD has a positive effect.


Comparison of human chromosome 21 conserved nongenic sequences (CNGs) with the mouse and dog genomes shows that their selective constraint is independent of their genic environment.
The analysis of conservation between the human and mouse genomes resulted in the identification of a large number of conserved nongenic sequences (CNGs). The functional significance of this nongenic conservation remains unknown, however. The availability of the sequence of a third mammalian genome, the dog, allows for a large-scale analysis of evolutionary attributes of CNGs in mammals. We have aligned 1638 previously identified CNGs and 976 conserved exons (CODs) from human chromosome 21 (Hsa21) with their orthologous sequences in mouse and dog. Attributes of selective constraint, such as sequence conservation, clustering, and direction of substitutions were compared between CNGs and CODs, showing a clear distinction between the two classes. We subsequently performed a chromosome-wide analysis of CNGs by correlating selective constraint metrics with their position on the chromosome and relative to their distance from genes. We found that CNGs appear to be randomly arranged in intergenic regions, with no bias to be closer or farther from genes. Moreover, conservation and clustering of substitutions of CNGs appear to be completely independent of their distance from genes. These results suggest that the majority of CNGs are not typical of previously described regulatory elements in terms of their location. We propose models for a global role of CNGs in genome function and regulation, through long-distance cis or trans chromosomal interactions.


[Anal tuberculosis. Report of a case].
We report a 70 years old man presenting with malaise, anal pain and progressive defecation difficulty, with a decrease in stool caliber. The patient had no contact or past history of tuberculosis. On physical examination, there was an ulcerated anal lesion with purulent discharge, that produced an anal stenosis. The patient had an erythrocyte sedimentation rate of 108 mm/h, images of active tuberculosis in both apical pulmonary lobes and a chronic tuberculous inflammation with caseation and epithelioid tubercles was observed in a biopsy of the anal lesion. Treatment with antituberculous drugs produced a categorical remission of anal lesions and after five months of therapy the patient is well.


A Smartphone Intervention for People With Serious Mental Illness: Fully Remote Randomized Controlled Trial of CORE.
People with serious mental illness (SMI) have significant unmet mental health needs. Development and testing of digital interventions that can alleviate the suffering of people with SMI is a public health priority. The aim of this study is to conduct a fully remote randomized waitlist-controlled trial of CORE, a smartphone intervention that comprises daily exercises designed to promote reassessment of dysfunctional beliefs in multiple domains. Individuals were recruited via the web using Google and Facebook advertisements. Enrolled participants were randomized into either active intervention or waitlist control groups. Participants completed the Beck Depression Inventory-Second Edition (BDI-II), Generalized Anxiety Disorder-7 (GAD-7), Hamilton Program for Schizophrenia Voices, Green Paranoid Thought Scale, Recovery Assessment Scale (RAS), Rosenberg Self-Esteem Scale (RSES), Friendship Scale, and Sheehan Disability Scale (SDS) at baseline (T1), 30-day (T2), and 60-day (T3) assessment points. Participants in the active group used CORE from T1 to T2, and participants in the waitlist group used CORE from T2 to T3. Both groups completed usability and accessibility measures after they concluded their intervention periods. Overall, 315 individuals from 45 states participated in this study. The sample comprised individuals with self-reported bipolar disorder (111/315, 35.2%), major depressive disorder (136/315, 43.2%), and schizophrenia or schizoaffective disorder (68/315, 21.6%) who displayed moderate to severe symptoms and disability levels at baseline. Participants rated CORE as highly usable and acceptable. Intent-to-treat analyses showed significant treatment×time interactions for the BDI-II (F1,313=13.38; P<.001), GAD-7 (F1,313=5.87; P=.01), RAS (F1,313=23.42; P<.001), RSES (F1,313=19.28; P<.001), and SDS (F1,313=10.73; P=.001). Large effects were observed for the BDI-II (d=0.58), RAS (d=0.61), and RSES (d=0.64); a moderate effect size was observed for the SDS (d=0.44), and a small effect size was observed for the GAD-7 (d=0.20). Similar changes in outcome measures were later observed in the waitlist control group participants following crossover after they received CORE (T2 to T3). Approximately 41.5% (64/154) of participants in the active group and 60.2% (97/161) of participants in the waitlist group were retained at T2, and 33.1% (51/154) of participants in the active group and 40.3% (65/161) of participants in the waitlist group were retained at T3. We successfully recruited, screened, randomized, treated, and assessed a geographically dispersed sample of participants with SMI entirely via the web, demonstrating that fully remote clinical trials are feasible in this population; however, study retention remains challenging. CORE showed promise as a usable, acceptable, and effective tool for reducing the severity of psychiatric symptoms and disability while improving recovery and self-esteem. Rapid adoption and real-world dissemination of evidence-based mobile health interventions such as CORE are needed if we are to shorten the science-to-service gap and address the significant unmet mental health needs of people with SMI during the COVID-19 pandemic and beyond. ClinicalTrials.gov NCT04068467; https://clinicaltrials.gov/ct2/show/NCT04068467.


A step forward towards the development of stable freeze-dried liposomes: a quality by design approach (QbD).
This study highlights the advantages of using a Quality by Design (QbD) approach in order to gain a more comprehensive understanding of the freeze-drying process of pravastatin-loaded long-circulating liposomes (LCL-PRAV). Within the QbD paradigm, the present study aimed to establish the design space for the optimization of freeze-dried LCL-PRAV by means of Design of Experiment (DOE). The encapsulated solute retention (ESR), the average particle size, and zeta potential after freeze-drying, the residual moisture content, the macroscopic cake appearance, the glass transition temperature (Tg) of the freeze-dried cake, and the primary drying time were defined as critical quality attributes (CQAs) for the freeze-dried final product. Further on, the influence of lyoprotectant type, freezing rate, shelf temperature during primary drying, and the presence of an annealing step on the CQAs was investigated through a 21-run D-optimal experimental design. Three-dimensional response surfaces were generated to complete the statistical analysis and for a better understanding of the influence of variables and their interactions on the responses. The developed model was then used to build the design space for the freeze-dried liposomes, within which the product quality was assured and the process variability was minimized.


The ETS gene ETV4 is required for anchorage-independent growth and a cell proliferation gene expression program in PC3 prostate cells.
Chromosomal abnormalities that give rise to elevated expression levels of the ETS genes ETV1, ETV4, ETV5, or ERG are prevalent in prostate cancer, but the function of these transcription factors in carcinogenesis is not clear. Previous work in cell lines implicates ERG, ETV1, and ETV5 as regulators of invasive growth but not transformation. Here we show that the PC3 prostate cancer cell line provides a model system to study the over-expression of ETV4. Migration assays, anchorage independent growth assays, and microarray analysis indicate that high ETV4 expression contributes to both transformation and cellular motility in PC3 cells. ETV4 directly bound the 5' and 3' MYC enhancers and modulated expression of both MYC and other cell proliferation genes, demonstrating a potential role in cell growth control. Despite this novel role for ETV4 in anchorage independent growth, ETV4 over-expression in normal prostate-derived RWPE-1 cells showed effects similar to ETV1 over-expression - increased cellular motility, and an up-regulation of genes encoding extracellular proteins as well as ones important for development, inflammation, and wound healing. Because ETV1 and ETV4 have similar roles when introduced to the same cellular background, we suggest that the requirement of high ETV4 expression for maintenance of the anchorage-independent growth in PC3 cells is due to a specific characteristic of this cell line rather than a function of ETV4 that is distinct from the other oncogenic ETS genes. Thus, the function of ETS genes in prostate cancer may differ based on other genetic alterations in a tumor.


Uncorrelated Component Analysis-Based Hashing.
The approximate nearest neighbor (ANN) search problem is important in applications such as information retrieval. Several hashing-based search methods that provide effective solutions to the ANN search problem have been proposed. However, most of these focus on similarity preservation and coding error minimization, and pay little attention to optimizing the precision-recall curve or receiver operating characteristic curve. In this paper, we propose a novel projection-based hashing method that attempts to maximize precision and recall. We first introduce an uncorrelated component analysis (UCA) transformation by examining precision and recall, and then propose a UCA-based hashing method. The proposed method is evaluated with a variety of data sets. The results show that UCA-based hashing outperforms state-of-the-art methods, and has computationally efficient training and encoding processes.


Wave-front tilt sensor with two quadrant detectors and its application to a laser beam pointing system.
A method that uses two quadrant detectors (QDs) for sensing wave-front tilt is described. The detectors are set at the front and back of the focal plane of the focusing optics. When the intensity distribution at the aperture of a telescope is not uniform because of atmospheric turbulence, the wave-front tilt can be measured more accurately with our two-QD method than with a conventional single-focal-plane QD. We proved this method to be effective by using it for fixed-star observation. Application of the method to a ground-to-satellite laser beam pointing system showed that it increases the intensity of the laser beam that is transmitted to a satellite.


HPLC-ESI-MS/MS of imidazole alkaloids in Pilocarpus microphyllus.
Pilocarpine, an important imidazole alkaloid, is extracted from the leaves of Pilocarpus microphyllus (Rutaceae), known in Brazil as jaborandi and used mainly for the treatment of glaucoma. Jaborandi leaves also contain other imidazole alkaloids, whose pharmacological and physiological properties are unknown, and whose biosynthetic pathways are under investigation. In the present study, a HPLC method coupled with ESI-MS(n) was developed for their qualitative and quantitative analysis. This method permits the chromatographic separation of the imidazole alkaloids found in extracts of jaborandi, as well as the MS/MS analysis of the individual compounds. Thus two samples: leaves of P. microphyllus and a paste that is left over after the industrial extraction of pilocarpine; were compared. The paste was found to contain significant amounts of pilocarpine and other imidazole alkaloids, but had a slightly different alkaloid profile than the leaf extract. The method is suitable for the routine analysis of samples containing these alkaloids, as well as for the separation and identification of known and novel alkaloids from this family, and may be applied to further studies of the biosynthetic pathway of pilocarpine in P. microphyllus.


Cold Water Immersion Directly and Mediated by Alleviated Pain to Promote Quality of Life in Indonesian with Gout Arthritis: A Community-based Randomized Controlled Trial.
Background: Gout arthritis is an autoinflammatory arthritis that generates chronic long-term pain. Pain impacts physical activities, joint mobility, stress, anxiety, depression, and quality of life. Cold-water immersion therapy reduces inflammation and pain associated with gout arthritis. However, cold-water immersion therapy has not been conducted among people worldwide with gout arthritis. Objective: To investigate the cold-water immersion intervention on pain, joint mobility, physical activity, stress, anxiety, depression, and quality of life among acute gout patients. Methods: A community-based randomized control trial design with two parallel-intervention groups: a cold-water immersion group (20-30°C 20 minutes/day for 4 weeks) and a control group. In total, 76 eligible participants in Tomohon City, Indonesia, were recruited using a multi-stage sampling method and were randomly assigned using block randomization. A generalized estimating equation model was used to analyze the results (coef. β) and produce 95% confidence intervals (CIs). A path analysis was used to analyze mediating effects. Results: Significant pain alleviation (β = -2.06; -2.42), improved joint mobility (β = 1.20, 1.44), physical activity (β = 2.05, .59), stress (β = -1.25; -1.35), anxiety (β = -.62; -1.37), and quality of life (β = 5.34; 9.93) were detected after cold-water immersion at the second-week, and were maintained to the fourth-week time point, compared to pre-intervention and the control group. Depression (β = -1.80) had decreased by the fourth week compared to the pre-test and control group. Cold-water immersion directly mediated alleviation of pain (β = -.46, p ≤ .001) and to promote the quality of life (β = .16, p = .01). Conclusions: Cold-water immersion decreased pain, stress, anxiety, and depression, and increased joint mobility, physical activity, and quality of life. It mediated alleviation of pain to increase the quality of life.


Retroviral vectors for analysis of viral mutagenesis and recombination.
Retrovirus population diversity within infected hosts is commonly high due in part to elevated rates of replication, mutation, and recombination. This high genetic diversity often complicates the development of effective diagnostics, vaccines, and antiviral drugs. This review highlights the diverse vectors and approaches that have been used to examine mutation and recombination in retroviruses. Retroviral vectors for these purposes can broadly be divided into two categories: those that utilize reporter genes as mutation or recombination targets and those that utilize viral genes as targets of mutation or recombination. Reporter gene vectors greatly facilitate the detection, quantification, and characterization of mutants and/or recombinants, but may not fully recapitulate the patterns of mutagenesis or recombination observed in native viral gene sequences. In contrast, the detection of mutations or recombination events directly in viral genes is more biologically relevant but also typically more challenging and inefficient. We will highlight the advantages and disadvantages of the various vectors and approaches used as well as propose ways in which they could be improved.


Cell-cycle regulators cdk2ap1 and bicalutamide suppress malignant biological interactions between prostate cancer and bone cells.
We examined whether the novel cell-cycle regulator cdk2-associated protein 1 (p12(cdk2ap1) or cdk2ap1), recently shown to regulate prostate cancer cell cycle and apoptosis, could have the capacity to reduce invasiveness and/or reduce malignant biological interactions between prostate cancer and bone cells. We also examined whether combining two cell-cycle arrest stimuli, cdk2ap1 plus bicalutamide (or casodex, CDX), could help enhance inhibition of prostate cancer cell phenotypes. We stably expressed cdk2ap1 in prostate cancer cell lines using lentiviral vectors, as well as several different co-culture assays to quantify cellular invasion, migration, and the effect of the treatments on interaction with the bone microenvironment. We have determined that cdk2ap1 can further augment the effects of CDX on cell-cycle arrest, growth inhibition, and cellular invasion. Using a coculture model, we observed that either cdk2ap1 or cdk2ap1/CDX combination were able to reduce chemotaxis towards osteoblasts, and also reduce the osteoblastic proliferative response to prostate cancer. Also modified by cdk2ap1 and CDX were several signaling pathways associated with prostate cancer/bone crosstalk mechanisms involved in prostate cancer progression. These results suggest that either cdk2ap1 or the cdk2ap1/CDX combination hold promise in regulating prostate cancer growth and malignant phenotypes, and potentially also in reducing procarcinogenic interactions with a bone microenvironment model, restoring malignant phenotypes and signaling to a more benign state.


The "triple whammy": Serious psychological distress, suicidal ideation, and substance misuse among transgender persons.
This paper examines the conjoint effects of serious psychological distress, suicidal ideation, and substance abuse among transgender adults. The principal aims are to determine the prevalence of this "triple whammy," identify the factors underlying the co-occurrence of all three problems, and to determine if there is evidence of syndemic effects underlying the "triple whammy." Data from the 2015 U.S. National Transgender Survey were used to examine the "triple whammy" relationship in a sample of 27,715 transgender Americans aged 18 or older. Odds ratios and multivariate logistic regression were performed to examine the data. 13.3 % of the study participants reported experiencing serious psychological distress, suicidal ideation, and substance abuse. The most potent predictors of the "triple whammy" were younger age, a greater number of anti-transgender experiences, and not reaching various transition milestones. Strong evidence emerged to indicate the presence of syndemic effects in operation. Experiencing the combination of adverse mental health and substance abuse was not uncommon in this population of transgender adults. Being young, experiencing a larger variety of types of anti-transgender discrimination, harassment, and violence, and not reaching specific transition milestones all had a significant impact on the odds that people would experience the "triple whammy." This was particularly true when these measures were examined in conjunction with one another, because of strong syndemic effects.


CT and MR imaging after placement of the GliaSite radiation therapy system to treat brain tumor: initial experience.
The GliaSite system delivers local, high radiation after brain tumor resection. We describe the imaging appearance of the device and the changes it causes. Eight patients with brain tumors were treated with this system. After surgery, all underwent MR imaging, and one underwent CT. Five were examined 1 month after radioactive unloading and every 2 months thereafter (total, 6-9 months). Initial studies were assessed for balloon appearance and complications; subsequent studies, for signal intensity and enhancement. Three patients underwent multivoxel proton MR spectroscopy, and one underwent MR perfusion study. Spectra were reviewed for metabolites suggesting tumor; perfusion studies were reviewed for increased relative cerebral blood volume and flow. CT showed the hyperattenuating balloon with considerable artifact. All MR images showed the device and adjacent brain. Follow-up studies showed enhancement and T2 hyperintensity in five patients. In one, enhancement progressively disappeared with no evidence of tumor recurrence. Another patient had progressive enhancement and low relative cerebral blood volume and flow; biopsy showed necrosis and inflammation. One patient had progressive enhancement and high choline levels (proved anaplastic astrocytoma). In another, T2 signal intensity and contrast enhancement progressed owing to tumor and bacterial infection. The last patient had a high choline level (proved radionecrosis); enhancement progressed over 5 months. In three, the device was removed early because of bleeding, mass effect, and therapeutic changes (no follow-up). Good balloon visualization was possible with MR imaging. After brachytherapy, all patients developed T2 hyperintensity; stable or progressive enhancement occurred with tumor recurrence and radionecrosis. High choline levels were suggestive of, but not necessarily diagnostic of, tumor.


A more gradual positive end-expiratory pressure increase reduces lung damage and improves cardiac function in experimental acute respiratory distress syndrome.
Increases in positive end-expiratory pressure (PEEP) or recruitment maneuvers may increase stress in lung parenchyma, extracellular matrix, and lung vessels; however, adaptative responses may occur. We evaluated the effects of PEEP on lung damage and cardiac function when increased abruptly, gradually, or more gradually in experimental mild/moderate acute respiratory distress syndrome (ARDS) induced by Escherichia coli lipopolysaccharide intratracheally. After 24 h, Wistar rats (n = 48) were randomly assigned to four mechanical ventilation strategies according to PEEP levels: 1) 3 cmH2O for 2 h (control); 2) 3 cmH2O for 1 h followed by an abrupt increase to 9 cmH2O for 1 h (no adaptation time); 3) 3 cmH2O for 30 min followed by a gradual increase to 9 cmH2O over 30 min then kept constant for 1 h (shorter adaptation time); and 4) more gradual increase in PEEP from 3 cmH2O to 9 cmH2O over 1 h and kept constant thereafter (longer adaptation time). At the end of the experiment, oxygenation improved in the shorter and longer adaptation time groups compared with the no-adaptation and control groups. Diffuse alveolar damage and expressions of interleukin-6, club cell protein-16, vascular cell adhesion molecule-1, amphiregulin, decorin, and syndecan were higher in no adaptation time compared with other groups. Pulmonary arterial pressure was lower in longer adaptation time than in no adaptation (P = 0.002) and shorter adaptation time (P = 0.025) groups. In this model, gradually increasing PEEP limited lung damage and release of biomarkers associated with lung epithelial/endothelial cell and extracellular matrix damage, as well as the PEEP-associated increase in pulmonary arterial pressure.NEW & NOTEWORTHY In a rat model of Escherichia coli lipopolysaccharide-induced mild/moderate acute respiratory distress syndrome, a gradual PEEP increase (shorter adaptation time) effectively mitigated histological lung injury and biomarker release associated with lung inflammation, damage to epithelial cells, endothelial cells, and the extracellular matrix compared with an abrupt increase in PEEP. A more gradual PEEP increase (longer adaptation time) decreased lung damage, pulmonary vessel compression, and pulmonary arterial pressure.


[Three dimensional fluorescence excitation-emission matrix spectrum of dissolved organic substance in marine microalgaes growth process].
The three-dimensional fluorescence spectrum was used to detect the changes in dissolved organic substances from the cultured Skeletonema costatum , Alexandrium tamarense, Alexandrium mimutum, Scrippsiella trochodea, Prorocentrum donghaiense and Prorocentrum micans. The result indicates that all of the miroalgaes can produce FDOM in the growth courses. Diatom such as Skeletonema costatum can produce humic-like FDOM. However dinoflagellate can produce protein-like FDOM at exponential growth phase. When the algae grows into decadency phase, the intensity of humic-like and protein-like fluorescence augments rapidly, which may be due to a mass of FDOM realeased by the old or dead cell fragmentation and the degradation of bacteria by using non-FDOM. The fluorescent intensity of Alexandrium tamarense, Alexandrium mimutum, Prorocentrum donghaiense and Prorocentrum micans can reduce at anaphase of decadency phase because of the degradation of bacteria and light. The same genus of algae can produce similar FDOM, for example: Alexandrium tamarense, and Alexandrinum mimutum, Prorocentrum donghaiense and Prorocentrum micans, but the positions of the fluorescence peaks are different.


Diverticular disease is associated with increased risk of subsequent arterial and venous thromboembolic events.
Diverticular disease and cardiovascular disease share several risk factors. Inflammation associated with diverticular disease could predispose to cardiovascular disease. We assessed the association between a diagnosis of diverticular disease and subsequent arterial and venous thromboembolic events, adjusting for related comorbidities to explore a possible causal relationship. We identified 77,065 incident cases of diverticular disease from 1980-2011 from Danish nationwide medical registries; these were matched for age and sex with 302,572 population comparison cohort members. Individuals with a history of cardiovascular disease were excluded. We used Cox proportional hazards regression to compute incidence rate ratios, comparing the incidence of acute myocardial infarction, stroke, venous thromboembolism, and subarachnoid hemorrhage in patients with diverticular disease with those of the population cohort members, adjusting for age, sex, obesity, diabetes, hyperlipidemia, chronic obstructive pulmonary disease, connective tissue disease, renal disease, and treatments and medications. The adjusted incidence rate ratios for patients with diverticular disease, compared with population cohort members, were 1.11 (95% confidence interval [CI], 1.07-1.14) for acute myocardial infarction, 1.11 (95% CI, 1.08-1.15) for overall stroke, 1.36 (95% CI, 1.30-1.43) for overall venous thromboembolism, and 1.27 (95% CI, 1.09-1.48) for subarachnoid hemorrhage. The relative risk of each event remained increased after we adjusted for changes in aspirin use or for endoscopy or colorectal surgery after the diagnosis of diverticular disease. These findings also held after excluding the first year of follow-up and limiting the analysis to patients with diverticulitis. On the basis of an analysis of Danish medical registries, a diagnosis of diverticular disease is associated with a modest increase in risk of arterial and venous thromboembolic events after adjustment for related disorders.


Infection control in the intensive care unit: expert consensus statements for SARS-CoV-2 using a Delphi method.
During the current COVID-19 pandemic, health-care workers and uninfected patients in intensive care units (ICUs) are at risk of being infected with SARS-CoV-2 as a result of transmission from infected patients and health-care workers. In the absence of high-quality evidence on the transmission of SARS-CoV-2, clinical practice of infection control and prevention in ICUs varies widely. Using a Delphi process, international experts in intensive care, infectious diseases, and infection control developed consensus statements on infection control for SARS-CoV-2 in an ICU. Consensus was achieved for 31 (94%) of 33 statements, from which 25 clinical practice statements were issued. These statements include guidance on ICU design and engineering, health-care worker safety, visiting policy, personal protective equipment, patients and procedures, disinfection, and sterilisation. Consensus was not reached on optimal return to work criteria for health-care workers who were infected with SARS-CoV-2 or the acceptable disinfection strategy for heat-sensitive instruments used for airway management of patients with SARS-CoV-2 infection. Well designed studies are needed to assess the effects of these practice statements and address the remaining uncertainties.


[Evaluation experiences of the supplementary care sector: contributions of integrality].
This work identifies aspects of comprehensiveness in the proposals for healthcare evaluation of the Agência Nacional de Saúde Suplementar (ANS) in Brazil, and of the National Commitee Quality Assurance (NCQA) in the U.S.A. The investigation was based on a documental analysis of the proposals found in the websites of both institutions in the second semester of 2006. The data were systemized according to pre-established attributes, building an analytical matrix for evaluating the following three dimensions: management practices and service organization; quality of knowledge and of practices of the health workers; and quality of the control practices of the society. In the Brazilian case there was an emphasis on the first and the third dimensions. The evaluation focalized the operators; the health plans were not evaluated. In the American case there was a balance between the three sets of attributes and the evaluation was focused on the health plans. Both proposals measured the satisfaction of the beneficiaries and made the results of the evaluations available in their websites. In conclusion we emphasize the importance of evaluative concepts and approaches for measuring the integrality of private health plan operators in the Brazilian supplementary health sector.


Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart disease.
Congenital heart diseases are traditionally considered to be multifactorial in pathogenesis resulting from environmental and genetic interactions that determine penetrance and expressivity within a genetically predisposed family. Recent evidence suggests that genetic contributions have been significantly underestimated. However, single gene defects occur only in a minority of cases, and multigenetic causes of congenital heart diseases have not been fully demonstrated. Here, we show that interactions between alleles of 3 Pbx genes, which encode homeodomain transcription factors, are sufficient to determine the phenotypic presentation of congenital heart diseases in mice. A major role is served by Pbx1, whose inactivation results in persistent truncus arteriosus. Reduction or absence of Pbx2 or Pbx3 leads to Pbx1 haploinsufficiency and specific malformations that resemble tetralogy of Fallot, overriding aorta with ventricular septal defect, and bicuspid aortic valves. Disruption of Meis1, which encodes a Pbx DNA-binding partner, results in cardiac anomalies that resemble those caused by Pbx mutations. Each of the observed cardiac defects represents developmental abnormalities affecting distinct stages of cardiac outflow tract development and corresponds to specific types of human congenital heart disease. Thus, varied deficiencies in the Pbx gene family produce a full spectrum of cardiac defects involving the outflow tract, providing a framework for determining multigenetic causes of congenital heart anomalies.


Angiographic characteristics of ruptured paraclinoid aneurysms: risk factors for rupture.
The diagnosis and treatment of unruptured paraclinoid aneurysms has been increasing with the recent advent of diagnostic tools and less invasive endovascular therapeutic options. Considering the low incidence of rupture, investigation of the characteristics of ruptured paraclinoid aneurysm is important to predict rupture risk of the paraclinoid aneurysms. The objective of this study is to evaluate probable factors for rupture by analyzing the characteristics of ruptured paraclinoid aneurysms. A total of 2,276 aneurysms (1,419 ruptured and 857 unruptured) were diagnosed and treated endovascularly or microsurgically between 2001 and 2011. Among them, 265 were paraclinoid aneurysms, of which 37 were ruptured. Removing 12 blister-like aneurysms, 25 ruptured and 228 unruptured saccular aneurysms were included and the medical records and radiological images were retrospectively analyzed. Of 25 aneurysms, 16 (64.0%) were located in the superior direction. Five were inferior located lesions (20%) and four were medially located lesions (16.0%). Laterally located lesions were not found. The mean size of aneurysms was 9.4 ± 5.6 mm. Ten aneurysms (40.0%) were ≥ 10 mm in size. Thirteen aneurysms (52.0%) were lobulated. The superiorly located aneurysms were larger than the other aneurysms (10.3 ± 5.8 mm vs. 7.7 ± 4.9 mm) and more frequently lobulated (ten of 16 vs. three of nine). In a comparative analysis, the ruptured aneurysms were located more in the superior direction compared with unruptured aneurysms (64 vs. 23.2%, p < 0.0001). Large aneurysms (36.0 vs. 7.9%, p < 0.0001), longer fundus diameter (mean 9.4 ± 5.6 vs. 4.8 ± 3.3 mm, p = 0.001), dome-to-neck ratio (mean 1.8 ± 0.9 vs. 1.2 ± 0.5, p < 0.0001), and lobulated shape aneurysms were more likely to be ruptured aneurysms (13 of 25 ruptured aneurysms, 52.0%, p = 0.001). Rupture risk of the paraclinoid aneurysm is very low. However, superiorly located paraclinoid aneurysms appear more likely to rupture than other locations. Angiographically, more conservative indication for the treatment of paraclinoid aneurysm should be recommended except for superior located lesions.


Systems biology approach to understanding post-traumatic stress disorder.
Post-traumatic stress disorder (PTSD) is a psychological disorder affecting individuals that have experienced life-changing traumatic events. The symptoms of PTSD experienced by these subjects-including acute anxiety, flashbacks, and hyper-arousal-disrupt their normal functioning. Although PTSD is still categorized as a psychological disorder, recent years have witnessed a multi-directional research effort attempting to understand the biomolecular origins of the disorder. This review begins by providing a brief overview of the known biological underpinnings of the disorder resulting from studies using structural and functional neuroimaging, endocrinology, and genetic and epigenetic assays. Next, we discuss the systems biology approach, which is often used to gain mechanistic insights from the wealth of available high-throughput experimental data. Finally, we provide an overview of the current computational tools used to decipher the heterogeneous types of molecular data collected in the study of PTSD.


Kin selection, not group augmentation, predicts helping in an obligate cooperatively breeding bird.
Kin selection theory has been the central model for understanding the evolution of cooperative breeding, where non-breeders help bear the cost of rearing young. Recently, the dominance of this idea has been questioned; particularly in obligate cooperative breeders where breeding without help is uncommon and seldom successful. In such systems, the direct benefits gained through augmenting current group size have been hypothesized to provide a tractable alternative (or addition) to kin selection. However, clear empirical tests of the opposing predictions are lacking. Here, we provide convincing evidence to suggest that kin selection and not group augmentation accounts for decisions of whether, where and how often to help in an obligate cooperative breeder, the chestnut-crowned babbler (Pomatostomus ruficeps). We found no evidence that group members base helping decisions on the size of breeding units available in their social group, despite both correlational and experimental data showing substantial variation in the degree to which helpers affect productivity in units of different size. By contrast, 98 per cent of group members with kin present helped, 100 per cent directed their care towards the most related brood in the social group, and those rearing half/full-sibs helped approximately three times harder than those rearing less/non-related broods. We conclude that kin selection plays a central role in the maintenance of cooperative breeding in this species, despite the apparent importance of living in large groups.


Mobile Health in Urology: The Good, the Bad and the Ugly.
Our aim is to present the current position of mobile health (mHealth) and the delivery of healthcare services via mobile communication devices in urology. We conducted a literature review of urology mHealth papers on PubMed. Results indicate that mHealth is becoming ubiquitous in contemporary healthcare systems. Although its potential has been shown, urology lags behind other areas, representing just 0.1% of the 300,000 available medical apps in the Apple App Store and Google Play Store. Furthermore, there is a lack of expert healthcare professional involvement in app development. To avoid harm, it is critical that the scientific accuracy, patient privacy, and user safety of urology mHealth applications are assured. This is because there is no globally enforced medical app regulation, compulsory scientific guidelines, nor mandatory industry standards. Urologists, either individually or via scientific organizations, should have a pivotal position in the design, development, review, certification, and recommendation of apps. mHealth holds great potential in urology, as it can aid multiple stakeholders: citizens, patients, healthcare professionals, health organizations, and public authorities (e.g., Ministry of Health). Even though it is mostly used to improve existing medical activities at present, the future will include revolutionary and ground-breaking technology solutions. This innovative field should be seen by urologists as an opportunity to provide greater care to our patients and better tools and knowledge to our peers.


Synergistic Reinforcement of Immunogenic Cell Death and Transformation of Tumor-Associated Macrophages via an M1-type Macrophage Membrane-Camouflaged Ferrous-Supply-Regeneration Nanoplatform.
The immune system's role in tumor growth and spread has led to the importance of activating immune function in tumor therapy. We present a strategy using an M1-type macrophage membrane-camouflaged ferrous-supply-regeneration nanoplatform (M1mDDTF) to synergistically reinforce immunogenic cell death (ICD) and transform tumor-associated macrophages (TAMs) against tumors. The M1mDDTF nanoparticles consist of doxorubicin-loaded dendritic mesoporous silica nanoparticles chelated with FeIII-tannic acid (FeIIITA) and coated with M1-type macrophage membranes. In the acidic tumor microenvironment, FeIIITA releases Fe2+ and generates ·OH, aided by near infrared irradiation for enhanced doxorubicin release. Furthermore, the M1mDDTF nanoplatform not only directly kills tumor cells but stimulates ICD, which can increase the proportion of CD86+ CD80+ cells and promote dendritic cell maturation. Particularly, the M1mDDTF nanoplatform can also promote the gradual polarization of TAMs into the M1-type and promote tumor cell killing. This study demonstrates the safety and multifunctionality of M1mDDTF nanoparticles, highlighting their potential for clinical tumor treatment. STATEMENT OF SIGNIFICANCE: : Malignant tumors are a global concern and a major cause of death. Nanoparticles' passive targeting is ineffective and hindered by reticuloendothelial system clearance. Therefore, enhancing nanoparticle accumulation in tumors while minimizing toxicity is a challenge. Coating nanoparticles with cell membranes enhances biocompatibility, immune evasion, and specific targeting. This approach has led to the development of numerous cell membrane-mimicking nanomaterials with remarkable properties and functions. This study developed an M1-type macrophage membrane-camouflaged ferrous-supply-regeneration nanoplatform, boosting immunogenic cell death and transforming tumor-associated macrophages. Tannic acid in the tumor microenvironment reduced Fe3+ to Fe2+, generating ·OH. M1mDDTF nanosystem induced M1-type macrophage polarization, inhibiting tumor growth and triggering immune cell death. Safe and versatile, these M1mDDTF nanoparticles hold promise for clinical tumor treatment.


Vaccinomics to design a multi-epitope-based vaccine against monkeypox virus using surface-associated proteins.
In 2022, the ongoing multi-country outbreak of monkeypox virus-now occurring outside Africa, too is a global health concern. Monkeypox is a zoonotic virus, which causes disease mainly in animals, and then it is transferred to humans. Recently, in the monkeypox epidemic, a large number of human cases emerged while the global health community worked to tackle the outbreak and save lives. Herein, a multi-epitope-based vaccine is designed against monkeypox virus using two surface-associated proteins: MPXVgp002 accession number > YP_010377003.1 and MPXVgp008 accession number > YP_010377007.1 proteins. These proteins were utilized for B- and T-cell epitopes prediction. The epitopes were further screened, and the screen filtered KCKDNEYRSR, RSCNTTHNR, and RTRRETGAS with the antigenicity scores of 0.5279, 0.5604, and 0.7628, respectively. Overall, the epitopes can induce immunity in 99.74% population of the world. Further, GPGPG linkers were used for joining the epitopes and EAAAK linker was used for adjuvant attachment. It has a three-dimensional structure modelled for retaining the structural stability. Three pairs of amino acid residues that were able to make disulfide bonds were chosen: Gly1-Ser82, Cys7-Tyr10, and Phe51-Ile55. Molecular docking of vaccine was done with toll-like receptors, viz., 2, 3, 4, and 8 immune cell receptors. The docking results revealed that the vaccine as potential molecule due to its better binding affinity with toll-like receptors 2, 3, 4 and 8. Top complex in docking in with each receptor was selected based on lowest energy scores- -888.7 kcal/mol (TLR-2), -976.3 kcal/mol (TLR-3), -801.9 kcal/mol (TLR-4), and -955.4 kcal/mol (TLR-4)-were subjected to simulation. The docked complexes were evaluated in 500 ns of MD simulation. Throughout the simulation time, no significant deviation occurred. This confirmed that the vaccine as potential vaccine candidate to interact with immune cell receptors. This interaction is important for the immune system activation. In conclusion, the proposed vaccine construct against monkeypox could induce an effective immune response and speed up the vaccine development process. However, the study is completely based on the computational approach, hence, the experimental validation is required.Communicated by Ramaswamy H. Sarma.


A conformal multi-port MIMO patch antenna for 5G wireless devices.
This paper presents a multiple-input-multiple-output (MIMO) antenna array with low-profile and flexible characteristics. Multiple microstrip patches are arranged in the E-plane configuration and decoupled by shorted quarter-wavelength stubs. The antenna has a small element spacing of 0.032 λ, where λ is a free-space wavelength at the center frequency. To demonstrate the feasibility of the proposed concept, a 1 × 4 MIMO array prototype is fabricated. The measured results on the fabricated prototype demonstrate that the MIMO antenna has good operation features at 4.8 GHz with a reflection coefficient of less than -10 dB and an isolation of better than 20 dB. Besides, good radiation patterns and broadside gain of around 4.5 dBi are also attained. The antenna also works in the bending mode and has the capability of extending to large-scale MIMO arrays. Such attractive features prove the utility of the proposed antenna in various modern electronic devices.


Elevated triglyceride levels are associated with increased risk for major adverse cardiovascular events in statin-naïve rheumatoid arthritis patients: A nationwide cohort study.
To investigate the association between the four components of the lipid profile (total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)) at baseline and composite major adverse cardiovascular events (MACEs) in statin-naïve rheumatoid arthritis (RA) patients with no previous history of cardiovascular events. This nationwide population-based cohort study was performed on a total of 15,216 statin-naïve RA patients. The end point was a composite of clinical events, including myocardial infarction (MI), stroke, coronary revascularization, and cardiovascular death. We compared the incidence of and risk for clinical events according to each lipid variable. During follow-up (median 4.70 years), the incidence of MACE per 1000 person-years was 7.27. Among the four lipid components, only higher baseline TG levels were significantly associated with increased risk for composite MACE in RA subjects. The risk for composite MACE was significantly higher in the third (adjusted hazard ratio (HR), 1.35 [95% confidence interval (CI), 1.03-1.78]) and highest quartiles (adjusted HR, 1.74 [95%CI, 1.33-2.28]) of baseline TG level versus the lowest quartile. In statin-naïve RA patients, increased TG level is associated with increased risk for MACE. Therefore, screening and intervention for increased TG level may be clinically beneficial in this population.


Reduced nociceptive responses in mice with alloxan induced hyperglycemia after garlic (Allium sativum Linn.) treatment.
Administration of ethanol (95%) extract (45 mg/kg body wt/day for 28 days) of garlic (A. sativum) to alloxan induced diabetic (ALX-D) mice significantly lowered the serum glucose levels, nociceptive response in tail-flick, hotplate, allodynia, formalin test and relative thickness, weight of hind paw in formalin induced Paw oedema test, over 28 days, thus, showing the reversal trend in hyperglycemia and hyperalgesia compared to ALX-D mice. The reversal of hyperglycemia and hyperalgesia was progressive and more effective as duration of extract administration increased. The results suggest therapeutic potential of ethanol extract of garlic for anti-hyperglycemic and anti-nociceptive effects in diabetes.


Does the medial orbitofrontal cortex have a role in social valuation?
It has been claimed that social behaviour changes after lesions of the ventromedial prefrontal cortex (vmPFC). However, lesions in humans are rarely restricted to a well defined cortical area. Although vmPFC lesions usually include medial orbitofrontal cortex (mOFC), they typically also affect subgenual and/or perigenual anterior cingulate cortex. The purpose of the current study is to investigate the role of mOFC in social valuation and decision-making. We tested four macaque monkeys prior to and after focal lesions of mOFC. Comparison of the animals' pre- and postoperative performance revealed that, unlike lesions of anterior cingulate gyrus (ACCg), lesions of mOFC did not induce alterations in social valuation. MOFC lesions did, however, induce mild impairments in a probabilistic two-choice decision task, which were not seen after ACCg lesions. In summary, the double dissociation between the patterns of impairment suggest that vmPFC involvement in both decision-making and social valuation may be mediated by distinct subregions centred on mOFC and ACCg respectively.


Did food increase fertility? Evaluation of !Kung and Herero history.
Low fertility among nomadic !Kung foragers of the northern Kalahari Desert of Botswana has been hypothesized to be an adaptation to scarcity of food. However, a comparison of !Kung fertility before and after a transition to a more sedentary lifestyle indicates that more food did not increase fertility. An examination of the fertility of neighboring sedentary Bantu-speaking Herero pastoralists during the same period also indicates that low female reproductive rates in this region are not unique to the !Kung. Herero fertility has increased dramatically in recent decades, probably in response to the control of sexually transmitted diseases in northwestern Botswana. More food appears to have substantially increased !Kung reproductive success by reducing infant and child mortality rates to levels observed among the Herero. These findings suggest that low !Kung fertility and mortality reflect contact with the Herero, who began expanding in large numbers into !Kung territory in the 1950s. This study emphasizes the need for a more rigorous comparative perspective in anthropology to understand better the significance of findings from restricted populations, and I suggest that evolutionary ecology would benefit from shifting some of its current focus on fertility to mortality.


Removal of Cr(III), Ni(II) and Cu(II) by poly(gamma-glutamic acid) from Bacillus subtilis NX-2.
Poly(gamma-glutamic acid) (gamma-PGA) derived from Bacillus subtilis NX-2 was investigated as a sorbent for heavy metal ions in batch adsorption experiments. The results showed that the heavy metal adsorption capacity of gamma-PGA enhanced with the increase of pH, in the following order: Cr(III) > Cu(II) > Ni(II), within the pH range 3-5. The Langmuir sorption model effectively described the metal sorption of y-PGA through the experiments of isotherm sorption, and it was deduced that the affinity of gamma-PGA for metals was following the sequence: Cr(III) > Cu(II) > Ni(II). Gamma-PGA was also used to trap trace amounts of heavy metals from the electroplating wastewater, which were difficult to be entirely removed by the traditional hydroxide precipitation method. The results showed that Cr(III) and Ni(II) in the electroplating effluent decreased from 3.07 and 9.46 mg/l to 0.15 and 1.01 mg/l, respectively, and the treated solutions reached the effluent standard. Therefore, gamma-PGA is satisfactory as a well biosorbent for the removal of heavy metals. The adsorption mechanism of gamma-PGA binding heavy metals was also studied using HyperChem simulation and FT-IR.


Contribution of Eat1 and Other Alcohol Acyltransferases to Ester Production in Saccharomyces cerevisiae.
Esters are essential for the flavor and aroma of fermented products, and are mainly produced by alcohol acyl transferases (AATs). A recently discovered AAT family named Eat (Ethanol acetyltransferase) contributes to ethyl acetate synthesis in yeast. However, its effect on the synthesis of other esters is unknown. In this study, the role of the Eat family in ester synthesis was compared to that of other Saccharomyces cerevisiae AATs (Atf1p, Atf2p, Eht1p, and Eeb1p) in silico and in vivo. A genomic study in a collection of industrial S. cerevisiae strains showed that variation of the primary sequence of the AATs did not correlate with ester production. Fifteen members of the EAT family from nine yeast species were overexpressed in S. cerevisiae CEN.PK2-1D and were able to increase the production of acetate and propanoate esters. The role of Eat1p was then studied in more detail in S. cerevisiae CEN.PK2-1D by deleting EAT1 in various combinations with other known S. cerevisiae AATs. Between 6 and 11 esters were produced under three cultivation conditions. Contrary to our expectations, a strain where all known AATs were disrupted could still produce, e.g., ethyl acetate and isoamyl acetate. This study has expanded our understanding of ester synthesis in yeast but also showed that some unknown ester-producing mechanisms still exist.


Sustainability in e-commerce packaging: A review.
Online purchasing, and hence e-commerce packaging production and use, have grown steadily in recent years, and so has their environmental impact as a result. This paper reviews the evolution of packaging over the last century through a compilation of scientific literature on e-commerce packaging focusing on its environmental side. The primary aims were to identify research gaps in e-commerce packaging and to propose new research lines aimed at reducing its environmental impact. A systematic search of abstracts was conducted to identify articles dealing with sustainability in e-commerce packaging in order to better understand changes in materials and formats, identify problems such as oversizing and allow prospective readers to become acquainted with the latest innovations in materials, sustainability and logistics. Based on existing research, packaging materials and technology evolved rapidly until the 1990s. Later, however, it has become increasingly difficult to further reduce their cost and environmental impact. Also, some packaging products continue to be made from non-renewable materials and thus restrict growth of e-commerce. Further research is needed with a view to producing new packages from renewable sources such as cellulose-containing materials, which are widely available in nature, or from recycled cellulose-based materials such as cartonboard. Improving distribution processes with new, more effective tools could additionally help alleviate the environmental impact of packaging. Similarly, new production processes such as additive manufacturing and 3D printing might help optimize package volume and shape, thereby facilitating more sustainable production through, for example, reduced CO2 emissions. Currently available technology can be useful to rethink the whole e-commerce packaging paradigm, which has changed very little over the past few decades.


The role of system Xc- in methamphetamine-induced dopaminergic neurotoxicity in mice.
The cystine/glutamate antiporter (system Xc-, Sxc) transports cystine into cell in exchange for glutamate. Since xCT is a specific subunit of Sxc, we employed xCT knockout mice and investigated whether this antiporter affected methamphetamine (MA)-induced dopaminergic neurotoxicity. MA treatment significantly increased striatal oxidative burdens in wild type mice. xCT inhibitor [i.e., S-4-carboxy-phenylglycine (CPG), sulfasalazine] or an xCT knockout significantly protected against these oxidative burdens. MA-induced increases in Iba-1 expression and Iba-1-labeled microglial immunoreactivity (Iba-1-IR) were significantly attenuated by CPG or sulfasalazine administration or xCT knockout. CPG or sulfasalazine significantly attenuated MA-induced TUNEL-positive cell populations in the striatum of Taconic ICR mice. The decrease in excitatory amino acid transporter-2 (or glutamate transporter-1) expression and increase in glutamate release were attenuated by CPG, sulfasalazine or xCT knockout. In addition, CPG, sulfasalazine or xCT knockout significantly protected against dopaminergic loss (i.e., decreases in tyrosine hydroxylase expression and immunoreactivity, and an increase in dopamine turnover rate) induced by MA. However, CPG, sulfasalazine or xCT knockout did not significantly affect the impaired glutathione system [i.e., decrease in reduced glutathione (GSH) and increase in oxidized glutathione (GSSG)] induced by MA. Our results suggest that Sxc mediates MA-induced neurotoxicity via facilitating oxidative stress, microgliosis, proapoptosis, and glutamate-related toxicity.


National trends in asthma visits and asthma pharmacotherapy, 1978-2002.
Research is limited on physicians' compliance with recent clinical guidelines for asthma treatment. Our purpose was to investigate the relationships among clinical guidelines, asthma pharmacotherapy, and office-based visits through use of nationally representative data. Nationally representative data on prescribing patterns by office-based US physicians were extracted from the National Disease and Therapeutic Index. We tracked 1978-2002 trends in the frequency of asthma visits and patterns of asthma pharmacotherapy, focusing on the use of controller and reliever medications. The estimated annual number of asthma visits in the United States increased continuously from 1978 through 1990 (18 million visits); since 1990, it has remained relatively stable. Controller medication use increased 8-fold between 1978 and 2002, inhaled corticosteroids manifesting the biggest increases. The use of reliever medications, particularly short-acting oral beta(2)-agonists, decreased modestly over this period. The aggregate use of controllers (83% of visits) superseded that of relievers (80%) for the first time in 2001. Improved appropriateness of asthma pharmacotherapy was also suggested by an increase in the controller-to-reliever ratio, which reached 92% in 2002. Xanthines, which once dominated asthma therapy (63% of visits in 1978), were used in only 2% of visits in 2002. More recent drug entrants have been adopted rapidly, single-entity long-acting inhaled beta(2)-agonists being used in 9% of visits and leukotriene modifiers in 24% of visits in 2002. Asthma pharmacotherapy has changed extensively in the past 25 years. Practices over the last decade are increasingly consistent with evidence-based guidelines. These changes in medication use might have contributed to the lack of a recent increase in asthma visits.


Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders.
In recent years, more awareness is raised about sex-specific dilemmas in inherited bleeding disorders. However, no large studies have been performed to assess differences in diagnosis, bleeding phenotype and management of men and women with bleeding disorders. Therefore, we investigated sex differences in a large cohort of well-defined patients with autosomal inherited bleeding disorders (von Willebrand disease (VWD), rare bleeding disorders (RBDs) and congenital platelet defects (CPDs)). We included patients from three nationwide cross-sectional studies on VWD, RBDs and CPDs in the Netherlands, respectively the WiN, RBiN and TiN study. In all studies a bleeding score (BS) was obtained, and patients filled in an extensive questionnaire on the management and burden of their disorder. We included 1092 patients (834 VWD; 196 RBD; 62 CPD), of whom 665 (60.9%) were women. Women were more often referred because of a bleeding diathesis than men (47.9% vs 36.6%, p = 0.002). Age of first bleeding was similar between men and women, respectively 8.9 ± 13.6 (mean ±sd) years and 10.6 ± 11.3 years (p = 0.075). However, the diagnostic delay, which was defined as time from first bleeding to diagnosis, was longer in women (11.6 ± 16.4 years) than men (7.7 ± 16.6 years, p = 0.002). Similar results were found when patients referred for bleeding were analyzed separately. Of women aging 12 years or older, 469 (77.1%) had received treatment because of sex-specific bleeding. Women with autosomal inherited bleeding disorders are more often referred for bleeding, have a longer diagnostic delay, and often require treatment because of sex-specific bleeding. The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda), and CSL Behring (unrestricted grant).


Distribution of craniomandibular disorders, occlusal factors and oral parafunctions in a paediatric population.
The aim of this work was to gather clinical data on craniomandibular (CMD)/temporomandibular joint (TMJ) disorders in a paediatric population. The clinical study population comprised patients with TMJ disorders who were being treated in the orthognathic ambulatory clinic of the University of Naples, where an instrumental and clinical study was performed. Data were recorded for extra and intraoral findings, Angles classification and malocclusions. Radiographic examinations were carried out. Study models were fabricated for evaluation. TMJs were assessed by palpation as well as masseter, temporal, suprahyoid, sternocleidomastoid, suboccipital, paravertebral and trapezius muscles to evaluate any possible pain. Auscultation of the TMJ was used to determine presence of articular sounds and their type (cracks, crunches, clicks) by the use of a stethoscope. Pain localisation was evaluated according to these movements taking into account site, intensity, frequency, and duration. Episodes of headache were recorded according to its intensity (mild, moderate, intense), frequency (daily, weekly, monthly), site (top of the head, occiput, temple, frontal, overorbital region, back of the head) and the duration of the episodes (in minutes, hours or whether constant). A substantial number of the 106 patients included in the study showed a malocclusion with prevalence in Angles Class II cases. Bruxism, onychophagy, TMJ pain, headache, mouth opening partial inability, mastication difficulty and articular sound were the most representative symptoms. The identification and recognition of factors, such as malocclusions and parafunctions, are considered fundamental to early diagnosis of TMJ problems, which is the most useful way to avoid a dysfunctional state of the stomatognathic system.


Role of nutritional composition in the development and survival of Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) on artificial diet and natural hosts.
Helicoverpa armigera is a pest of several crops causing significant economic impact. We evaluated the insect development on different vegetative and reproductive structures of cotton, maize, and soybean compared to artificial diet. One hundred individuals were evaluated per structure (cotton leaves and bolls; maize leaves, grains, and silk; soybean leaves and pods) and artificial diet. Centesimal analyses were performed on quantifiable nutrient contents in diets. The viability of immatures (eggs, larvae, and pupae) ranged from 30% on maize leaf to 74% on cotton bolls, while on the artificial diet, it was 70%. Maize, cotton, and soybean leaves provided viability of 30, 37, and 42%, respectively, revealing these leaves tissues are less favorable to the development of H. armigera immatures compared to 'reproductive tissues'. Centesimal composition of diets compared 14 common components in all diets, which correlated significantly with larval and pupal stages and/or pupal weight. Of the 12 dietary components that significantly affected larval development time, half were negatively correlated, indicating a decrease in developmental time from their increments. In general, when insects were confined separately to substrates, the artificial diet was the most suitable for H. armigera development compared to the evaluated natural diets. However, in natural conditions, the variability of available hosts must be considered. In addition, it is acceptable for moths to select more suitable hosts for oviposition, while their larvae move to other more suitable tissues of the same plant or even migrate to other plants.


Antidepressants substantially affect basic REM sleep characteristics in narcolepsy-cataplexy patients.
Antidepressants substantially affect REM sleep characteristics and trigger manifestations of REM sleep behavior disorder (RBD) in the general, non-narcoleptic, population. Antidepressants are also frequently administrated in an attempt to suppress cataplexy. We investigated the role of antidepressants in the development of RBD in narcolepsy with cataplexy (NC) patients. Seventy-five patients diagnosed with NC were assessed by a structured interview (focused on RBD manifestations and the use of antidepressants) and night video-polysomnography followed by the multiple sleep latency test. Of all 75 NC patients (36 male, 39 female; mean age 46.1±18.5 years), 34 cases had a history of antidepressant use (45.3%; 18 male, 16 female). In this antidepressant-positive group, 13 patients suffered from RBD (38.2%). Among antidepressant-naïve patients, only 5 subjects (12.2%) were diagnosed with RBD. Polysomnographic data showed significantly increased REM latency (p<0.01) and reduced percentage of REM sleep (p<0.01) in the antidepressant-positive group, as well as more periodic limb movements during sleep (p=0.01). NC patients with a history of antidepressant use showed a three-fold higher occurrence of RBD in comparison to antidepressant-naïve patients.


A phase I dose-escalation and pharmacokinetic study of a micellar nanoparticle with entrapped docetaxel (CPC634) in patients with advanced solid tumours.
CPC634 is docetaxel entrapped in core-cross linked polymeric micelles. In preclinical studies, CPC634 demonstrated enhanced pharmacokinetics and improved therapeutic index. This phase I dose escalation study is the first-in-human study with CPC634. adult patients with advanced solid tumours received CPC634 intravenously either 3-weekly (Q3W) (part 1, dose range 15-100 mg/m2), 2-weekly (Q2W) (part 2, 45 mg/m2) or Q3W with dexamethasone premedication (part 3, 60 mg/m2). thirty-three patients were enrolled. Skin toxicity was dose limiting (DLT) at ≥60 mg/m2 in part 1 and at 45 mg/m2 in part 2 and was the most common CPC634 related grade ≥ 3 adverse event (24%). With dexamethasone premedication no DLTs were observed at 60 mg/m2 Q3W. CPC634 exhibited a dose-proportional pharmacokinetic profile. At 60 mg/m2, the plasma area under the curve was 4067.5 ± 2974.0 ng/h/mL and the peak plasma level 217.3 ± 91.9 ng/mL with a half-life of 39.7 ± 9.4 h for released docetaxel. CPC634 could be administered safely upon pretreatment with dexamethasone. Cumulative skin toxicity was the main DLT. The recommended phase 2 dose was determined at 60 mg/m2 Q3W with dexamethasone premedication.


Problematic Use of the Internet and Well-Being among Youth from a Global Perspective: A Mediated-Moderated Model of Socio-Emotional Factors.
Problematic Use of the Internet (PUI) is characterized as the inability to control one's internet use or as an excessive use of the internet that may result in social, psychological, and emotional difficulties (Fernandes et al., 2019). It is regarded nowadays as an increasingly worrisome public heath issue, especially among youth. This study explored the contexts in which youth PUI occurs and its associations with socio-emotional functioning that may lead to a decrease in one's sense of well-being. We conducted this exploration among 783 middle school students from the US (425 students; 54.27%) and Israel (358 students; 45.73%). The overall age of both samples ranged between 12 and 16 (M = 13.94, SD = 1.59). In the Israeli sample, 49.1% of the students were girls and 50.9% were boys, whereas in the US sample, 48.8% were girls and 51.2% were boys. The study examined the role of depressive mood, loneliness, resilience, self-control, and school engagement in mediating the relationship between PUI and well-being, and how country of origin might moderate these relationships. Results indicate PUI was related to lower well-being only for the US sample. Yet, for both samples, higher loneliness was related to lower well-being, and higher school engagement was related to higher well-being. A moderated mediation analysis revealed the socio-emotional variables were all mediators in these associations, but differently for each country sample. The study results are discussed according to key factors required for developing intervention programs for coping with youth PUI behaviors.


Intraluminal fibrosis in interstitial lung disorders.
The histopathologic and ultrastructural features of intraluminal organizing and fibrotic changes were studied in open lung biopsies and autopsy specimens from 373 patients with interstitial lung disorders, including hypersensitivity pneumonitis (n = 44), idiopathic pulmonary fibrosis (n = 92), collagen-vascular diseases (n = 20), chronic eosinophilic pneumonia (n = 10), pulmonary histiocytosis X (n-90), pulmonary sarcoidosis (n = 62), pneumoconioses (n = 25), Legionnaire's disease (n = 5), drug- and toxin-induced pneumonitis (n = 4), radiation-induced pneumonitis (n = 2), lymphangioleiomyomatosis (n = 11), and chronic organizing pneumonia of unknown cause (n = 8). Three patterns of intraluminal organization and fibrosis were recognized: 1) intraluminal buds, which partially filled the alveoli, alveolar ducts and/or distal bronchioles; 2) obliterative changes, in which loose connective tissue masses obliterated the lumens of alveoli, alveolar ducts or distal bronchioles, and 3) mural incorporation of previously intraluminal connective tissue masses, which fused with alveolar, alveolar ductal, or bronchiolar structures and frequently became reepithelialized. All three patterns had common morphologic features, suggesting that, regardless of their severity, they resulted from a common pathogenetic mechanism, ie, the migration of activated connective tissue cells, through defects in the epithelial lining and its basement membrane, from the interstitial into the intraluminal compartment. Intraluminal buds were observed most frequently in hypersensitivity pneumonitis, chronic eosinophilic pneumonia, and organizing pneumonia of unknown cause. Mural incorporation and, to a lesser extent, obliterative changes were observed in most interstitial disorders and were very prominent in idiopathic pulmonary fibrosis. Mural incorporation and obliterative changes play an important role in pulmonary remodeling, especially when several adjacent alveoli and/or other air spaces are involved. Under these circumstances, intraluminal organization can mediate the fusion of adjacent alveolar structures by intraluminal connective tissue.


[Diphtheroids and nontoxigenic Corynebacterium diphtheriae in the etiology of diphtheria].
The review raises a problem of cooperation between a laboratory and clinics for diphtheria diagnosis. According to scientific literature nontoxigenic diphtheroids cause different nosocomial infections of immunocompromised patients. Nontoxigenic Corynebacterium diphtheriae may cause such systemic infections as septic arthritis and endocarditis in people belonging to unsecured strata of the society. A toxin which can be produced not only by C. diphtheriae but also by diphtheroids is the sole reason of diphtheric inflammation. The role of the C. diphtheriae nontoxigenic strains should be elucidated by the improving of standard methods and introduction of the methods of molecular biology for the toxigenicity assay of diphtheria strains (e.g. polymerase chain reaction). But a complexity of gene expression and difficulties in distinguishing between the infection and the microorganism colonization of a vaccinated person reserve the last word in the diagnosis of diphtheria for a clinical physician.


Diversity is in my veins: role of bone morphogenetic protein signaling during venous morphogenesis in zebrafish illustrates the heterogeneity within endothelial cells.
Endothelial cells are a highly diverse group of cells which display distinct cellular responses to exogenous stimuli. Although the aptly named vascular endothelial growth factor-A signaling pathway is hailed as the most important signaling input for endothelial cells, additional factors also participate in regulating diverse aspects of endothelial behaviors and functions. Given this heterogeneity, these additional factors seem to play a critical role in creating a custom-tailored environment to regulate behaviors and functions of distinct subgroups of endothelial cells. For instance, molecular cues that modulate morphogenesis of arterial vascular beds can be distinct from those that govern morphogenesis of venous vascular beds. Recently, we have found that bone morphogenetic protein signaling selectively promotes angiogenesis from venous vascular beds without eliciting similar responses from arterial vascular beds in zebrafish, indicating that bone morphogenetic protein signaling functions as a context-dependent regulator during vascular morphogenesis. In this review, we will provide an overview of the molecular mechanisms that underlie proangiogenic effects of bone morphogenetic protein signaling on venous vascular beds in the context of endothelial heterogeneity and suggest a more comprehensive picture of the molecular mechanisms of vascular morphogenesis during development.