Differential expression of the gap junction proteins connexin45, -43, -40, -31, and -26 in mouse skin.
The expression of five different members of the gap junction multigene family, connexin (Cx)45, -43, -40, -31, and -26 was investigated in embryonic and adult mouse skin. For this purpose, polyclonal antibodies to Cx31 and Cx45 were raised by immunizing rabbits with fusion proteins of glutathione S-transferase and carboxy-terminal peptides including 65 amino acids of Cx31 or 138 c-terminal amino acids of Cx45, respectively. Here we describe characterization of the affinity-purified Cx31 antibodies in human HeLa cells, transfected with mouse Cx31 coding DNA, and in mouse keratinocyte-derived cell lines. In the epidermis of embryonic mice at day 19 of gestation Cx43 and -45 were detected in the basal layer, while the stratum spinosum showed expression of Cx43, -31 and -26. In the stratum granulosum we found expression of Cx31 and -26. In the epidermis of adult mice Cx43 and -31 were located similarly as in embryonic tissue, but Cx45 as well as Cx26 were not detected and in addition Cx40 was weakly expressed in the stratum basale. Furthermore, during hair development, Cx31 was detected in the inner epithelial root sheath and sebaceous glands of hair follicle. Cx43 and -40 were found in the outer epithelial root sheath and to a lesser extent in sebaceous glands. Cx31 was also demonstrated in Hel-37 and Hel-30, i.e. two related cell lines derived from mouse keratinocytes. Our results show that epidermal and follicular differentiation coincides with differential expression of five different connexin proteins, suggesting specific and coordinated function(s) of gap junctional communication during skin and hair development.


Potentially toxic elements in toys and children's jewelry: A critical review of recent advances in legislation and in scientific research.
Contamination by potentially toxic elements (PTEs) in children's toys and jewelry is an ongoing problem where PTEs can become bioavailable especially via oral pathway (ingestion as a whole or of parts, and mouthing) and may cause adverse health effects for children. In the present review, legislation updates from the last decade in the United States (U.S.), Canada, and the European Union (E.U.) on PTEs in toys and jewelry are presented. Then, a literature review mostly covering the last decade on the total concentration, bioavailability, children's exposure, and bioaccessibility of PTEs in toys and jewelry is provided. The U.S. and Canadian legislations mainly focus on lead (Pb) and cadmium (Cd) total/soluble concentration limits to prevent exposure and have received several updates within the last decade, extending particularly the covered span of children's products. It seems that the introduction, subsequent enforcement, and update of regulations in developed countries have shifted the problem towards developing countries. In terms of categories, metallic toys and children's jewelry still have the most severe PTE contamination and the presence of Pb and Cd in these articles is an ongoing issue. Some studies suggest that color can be used as an indicator for the potential presence of PTEs (linked to chemicals such as lead chromate, cadmium sulfide) but the evidence is not always clear. Another concern is vintage/second-hand toys and jewelry as those items might have been produced before the legislation was present. As total and bioaccessible concentrations of PTEs in toys and jewelry do not always correlate, approaches considering bioaccessibility (e.g. of the E.U.) are more scientifically appropriate and help with better estimation of risk from exposure. Studies on toy and jewelry contamination using in vitro bioaccessibility techniques has become more common, however, there is still no in vitro test specifically designed and validated for toys and jewelry.


Hepatitis B Vaccine Refusal in the Newborn Period.
Perinatal hepatitis B (HepB) infection is a serious condition in the pediatric population, with up to 90% of exposed infants progressing to chronic infection. The cornerstone of prevention is the birth dose of the HepB vaccine. In 2018, the Advisory Committee on Immunization Practices updated their guidelines for the birth dose of the HepB vaccine. These new guidelines included a refined timeline on when the HepB vaccine should be given, including for infants born to women with known HepB infection, unknown HepB status, and universal guidelines regardless of maternal HepB status. However, despite these guidelines, up to 25% of infants do not receive the birth dose of HepB vaccine. Individual provider commitment to administration of the vaccine remains fundamental, but institutional policies also have significant influence in ensuring appropriate vaccine administration for infants. [Pediatr Ann. 2021;50(8):e343-e347.].


[Superficial argentophilic structures of miracidium and cercaria of Schistosoma intercalatum (author's transl)].
Though it is presently admitted that Schistosoma intercalatum is a well individualized species, detailed studies of superficial argentophilic structures of the miracidium and chaetotaxy of the cercaria do not allow these larval stages to be distinguished from those of S. bovis. Therefore this emphasizes the close relationship between the two parasites.


Succession of fungi on dead and live wood in brackish water in Brunei.
We observed the sequence of fungi appearing on submerged wood of Hibiscus tiliaceus that initially was either dead or alive. Branches that were dead, but still attached to the tree, and live branches were cut from H. tiliaceus in the riparian vegetation in a brackish habitat on the Tutong River, Brunei. Branch segments were connected to the riverbank using monofilament line. Samples were examined for fungi before the branches were placed in the river and after the branches had been submerged 3 or 6 mo. Fifty taxa were found on the samples. Before being placed in the water different fungal assemblages were found on live as compared to deadwood. Branches that were alive when cut supported a distinctly different fungal assemblage after 3 mo in the water. Dead branches after 3 mo and both dead and initially live samples after 6 mo had been colonized by a fungal assemblage that is typical at this site. It is unknown whether the differences in colonization of dead and initially live wood can be attributed to differences in the substratum (i.e., the presence or absence of bark), inhibitory substances in more recently live wood or to assembly rules resulting from the different fungi that already were present in dead and live branches.


Physiological and Behavioral Responses to Calibrated Noxious Stimuli Among Individuals with Cerebral Palsy and Intellectual Disability.
As individuals with intellectual disability (ID) due to cerebral palsy (CP) are at high risk of experiencing pain, measuring their pain is crucial for adequate treatment. While verbal reports are the gold standard in pain measurements, they may not be sufficient in ID. The aim was to detect behavioral/autonomic responses that may indicate the presence and intensity of pain in individuals with CP and ID, using calibrated stimuli, here for the first time. Thirteen adults with CP and ID (CPID), 15 healthy controls (HC), and 5 adults with CP with no ID (CPNID). Subjects received pressure stimuli of various intensities. Self-reports (using a pyramid scale), facial expressions (retrospectively analyzed with Facial Action Coding System = FACS), and autonomic function (heart rate, heart rate variability, pulse, galvanic skin response) were analyzed. Self-reports and facial expressions but not the autonomic function exhibited stimulus-response relationship to pressure stimulation among all groups. The CPID group had increased pain ratings and facial expressions compared with controls. In addition, the increase in facial expressions along the increase in noxious stimulation was larger than in controls. Freezing in response to pain was frequent in CPID. 1) Individuals with CP and ID have increased responses to pain; 2) facial expressions and self-reports, but not autonomic variables can reliably indicate their pain intensity; 3) the pyramid scale is suitable for self-report in this population. Although facial expressions may replace verbal reports, increased facial expressions at rest among these individuals may mask pain, especially at lower intensities.


Long-term antithrombotic management patterns in Asian patients with acute coronary syndrome: 2-year observations from the EPICOR Asia study.
Despite guideline recommendations, dual antiplatelet therapy (DAPT) is frequently used for longer than 1 year after an acute coronary syndrome (ACS) event. In Asia, information on antithrombotic management patterns (AMPs), including DAPT post discharge, is sparse. This analysis evaluated real-world AMPs up to 2 years post discharge for ACS. There is wide variability in AMP use for ACS management in Asia. EPICOR Asia (NCT01361386) is a prospective observational study of patients discharged after hospitalization for an ACS in eight countries/regions in Asia, followed up for 2 years. Here, we describe AMPs used and present an exploratory analysis of characteristics and outcomes in patients who received DAPT for ≤12 months post discharge compared with >12 months. Data were available for 12 922 patients; of 11 639 patients discharged on DAPT, 2364 (20.3%) received DAPT for ≤12 months and 9275 (79.7%) for >12 months, with approximately 60% still on DAPT at 2 years. Patients who received DAPT for >12 months were more likely to be younger, obese, lower Killip class, resident in India (vs China), and to have received invasive reperfusion. Clinical event rates during year 2 of follow-up were lower in patients with DAPT >12 vs ≤12 months, but no causal association can be implied in this non-randomized study. Most ACS patients remained on DAPT up to 1 year, in accordance with current guidelines, and over half remained on DAPT at 2 years post discharge. Patients not on DAPT at 12 months are a higher risk group requiring careful monitoring.


Nonequilibrium Phonon Dynamics and Its Impact on the Thermal Conductivity of the Benchmark Thermoelectric Material SnSe.
Thermoelectric materials play a vital role in the pursuit of a sustainable energy system by allowing the conversion of waste heat to electric energy. Low thermal conductivity is essential to achieving high-efficiency conversion. The conductivity depends on an interplay between the phononic and electronic properties of the nonequilibrium state. Therefore, obtaining a comprehensive understanding of nonequilibrium dynamics of the electronic and phononic subsystems as well as their interactions is key for unlocking the microscopic mechanisms that ultimately govern thermal conductivity. A benchmark material that exhibits ultralow thermal conductivity is SnSe. We study the nonequilibrium phonon dynamics induced by an excited electron population using a framework combining ultrafast electron diffuse scattering and nonequilibrium kinetic theory. This in-depth approach provides a fundamental understanding of energy transfer in the spatiotemporal domain. Our analysis explains the dynamics leading to the observed low thermal conductivity, which we attribute to a mode-dependent tendency to nonconservative phonon scattering. The results offer a penetrating perspective on energy transport in condensed matter with far-reaching implications for rational design of advanced materials with tailored thermal properties.


Prognosticators of Functional Outcome After Supratentorial Minimally Invasive Intracranial Hemorrhage Evacuation With Tubular Retractor Systems.
Prognosticators of good functional outcome after minimally invasive surgical (MIS) intracranial hemorrhage (ICH) evacuation are poorly defined. This study aims to investigate clinical and radiographic prognosticators of poor functional outcome after MIS evacuation of ICH with tubular retractor systems. Single-center retrospective review of adult (age ≥18 years) patients who underwent surgical evacuation of a spontaneous supratentorial ICH evacuation using tubular retractors from 2013 to 2022 was performed. Clinical and radiographic factors, such as antiplatelet/anticoagulant use, initial NIH Stroke Scale, ICH score, premorbid modified Rankin Scale (mRS), intraventricular hemorrhage (IVH) severity according to the modified Graeb scale, and preoperative/postoperative ICH volume, were collected. The main outcome was poor functional outcome, defined as mRS score of 4-6 within 1 year postoperatively. Eighty-eight patients were included. Clinical follow-up data were available for 64 (73%) patients. Of those, 43 (67%) had a poor functional outcome. On multivariate Cox regression, postoperative ICH volume ≥15 mL (hazard ratio [HR] = 2.46 [95% CI: 1.25-4.87]; P = .010) and higher modified Graeb score (HR = 1.04 [95% CI: 1-1.1]; P = .035] significantly increased the risk of poor functional outcome. Elevated postoperative ICH volume was predicted by the presence of lobar ICH (vs nonlobar, OR = 3.32 [95% CI: 1.01-11.55]; P = .043) and higher preoperative ICH volume (OR = 1.05 [1.02-1.08]; P < .001). A minimum of 60% ICH evacuation yielded an improvement in mRS 4-6 rates (HR 0.3 [95% CI: 0.1-0.8], P = .013). In patients without IVH and with a >80% ICH evacuation, the rate of mRS 4-6 was 42% compared with 67% in the whole patient sample ( P = .017). Increased IVH volumes and residual postoperative ICH volumes are associated with poor functional outcome after MIS ICH evacuation. Postoperative ICH volume was associated with lobar ICH location as well as preoperative ICH volume. These factors may help to prognosticate patient outcomes and improve selection criteria for MIS ICH evacuation techniques.


Brazilian nursing journals: strengths, weaknesses and challenges.
To evaluate, qualitatively, the Brazilian nursing journals and identify their strengths and weaknesses when compared to international journals in the area. A historic approach regarding the period from 2012 to 2016. We included national nursing journals indexed in the SciELO Database and international journals with an impact factor above 1.0 and below 1.8 indexed in the WoS and Scopus databases. The national journals met SciELO requirements for internationalization and obtained visibility when they were included in international indexing bases. Their citations were mostly national, with the following mean values: 86% in Portuguese; 12% in Spanish and 2% in English. The excellence requirements of the national journals are being accomplished. The publication of articles in Spanish can impact on the increase of bibliometric indicators.


Dental Wear: Attrition, Erosion, and Abrasion-A Palaeo-Odontological Approach.
This paper reviews the surface ablation of early hominin teeth by attrition, abrasion, and erosive dental wear. The occurrence of these lesions is explored in a sample of South African fossil australopithecine dentitions revealing excessive wear. Interpretation of the nature of the dietary components causing such wear in the absence of carious erosion provides insight into the ecology of the Plio-pleistocene epoch (1-2 million years ago). Fossil teeth inform much of the living past by their retained evidence after death. Tooth wear is the ultimate forensic dental evidence of lives lived.


Protein dynamics and monomer-monomer interactions in AntR activation by electron paramagnetic resonance and double electron-electron resonance.
The Anthracis repressor (AntR) is a Mn(II)-activated DNA binding protein that is involved in the regulation of Mn(II) homeostasis in Bacillus anthracis. AntR is structurally and functionally homologous to Mn(II)-activated repressor from Bacillus subtillis (MntR). Our studies on AntR focus on metal-regulated activation of the protein. Line shape analysis of continuous wave electron paramagnetic resonance (EPR) spectra showed that metal binding resulted in a general reduction of backbone dynamics and that there were no further changes in backbone motion upon DNA binding. Double electron-electron resonance (DEER) pulsed EPR spectroscopy was used to measure distances between nitroxide spin labels strategically placed in dimeric AntR. The DEER data were analyzed assuming Gaussian distributions for discrete populations of spins. A structural model for AntR was built from homology to MntR, and the experimentally measured distances were simulated to distinguish between spin label and backbone motions. Together with the computational analysis, the DEER results for apo-AntR indicated relatively narrow conformational distributions for backbone residues at the dimer interface and near the metal binding site. No significant changes were observed on these sites in the presence of metal or DNA. On the other hand, the distribution of the conformers and the distances between the putative DNA binding helices decreased upon metal binding. These results suggest that the DNA binding region of AntR shows large amplitude backbone motions in the absence of metal, which may preclude sequence-specific binding to promoter sites. Metal binding narrows the range of conformations accessible in this region and shortens the mean distance between the DNA binding helices, probably resulting in alignment that optimizes promoter recognition and binding.


Mild phenotype due to inverse duplication 4p16.3 - P15.3 including the Wolf-Hirschhorn critical region.
Duplication of distal 4p results in a recognizable clinical phenotype. We report here on a 3 year old girl with a de novo inverse duplication of the chromosome segment 4p16.3-p15.3. The symptoms in this patient are milder than those of previously described patients with 4p duplication syndrome and include a deep hairline, deep-set eyes, short pug nose, full cheeks, simian crease, clinodactily of the fifth digit, no speech development and a moderate psychomotor retardation. Fluorescence in situ hybridization (FISH) using a chromosome 4 painting probe confirmed that the extra material is of chromosome 4 origin. Further analysis with the Wolf-Hirschhorn critical region probe demonstrated the duplication of this region. The lysosomal hydrolase alpha-L-iduronidase (IDUA) gene which is mutated in mucopolysaccaridosis type I (MPS I) and mapped to 4p16.3 might be responsible for some of the MPS like facial features. A phenotype-genotype correlation analysis in combination with literature review was undertaken to allow a further delineation of partial trisomy 4p syndromes.


Reflecting upon the Long-term Impact of COVID-19 on Cosmetic Plastic Surgery and Education.
As we enter a new year, this article serves as an opportunity to ponder on the impact of a worldwide pandemic on physicians and the field of plastic surgery, which began 4 years ago in January 2020. When looking at the data in the general-surgery and reconstructive literature, the surgical treatment of patients with COVID-19 appears safest 8 weeks after infection. It was also found that the so-called Zoom-boom crush of cosmetic surgery cases following pandemic lockdown appeared to be largely due to a backlog of cases. Cosmetic surgery, particularly facial cosmetic surgery, continues to increase in popularity year over year. However, the effects on plastic surgery training remain unclear. Even so, those affected by the pandemic seem more driven than ever to find job stability and security.


Immune checkpoint blockade induces distinct alterations in the microenvironments of primary and metastatic brain tumors.
In comparison with responses in recurrent glioblastoma (rGBM), the intracranial response of brain metastases (BrM) to immune checkpoint blockade (ICB) is less well studied. Here, we present an integrated single-cell RNA-Seq (scRNA-Seq) study of 19 ICB-naive and 9 ICB-treated BrM samples from our own and published data sets. We compared them with our previously published scRNA-Seq data from rGBM and found that ICB led to more prominent T cell infiltration into BrM than rGBM. These BrM-infiltrating T cells exhibited a tumor-specific phenotype and displayed greater activated/exhausted features. We also used multiplex immunofluorescence and spatial transcriptomics to reveal that ICB reduced a distinct CD206+ macrophage population in the perivascular space, which may modulate T cell entry into BrM. Furthermore, we identified a subset of progenitor exhausted T cells that correlated with longer overall survival in BrM patients. Our study provides a comprehensive immune cellular landscape of ICB's effect on metastatic brain tumors and offers insights into potential strategies for improving ICB efficacy for brain tumor patients.


The mechanical properties of simulated collagen fibrils.
Previous theoretical studies of the mechanical properties of tissues such as skin, bone and tendon, have used approaches based on composite materials and have tended to neglect the contribution of individual microscopic components. In this paper, we examine the relationship between the fine structure of a collagen fibril and its relative tensile strength. Collagen is a fibrous protein which provides associated tissues with the majority of their tensile strength. It is present in the form of elongated structures termed fibrils which are created by the self-assembly of rod-like collagen molecules in an entropy-driven process termed fibrillogenesis. Mutations that alter the primary structure of the collagen molecule, interfere with this assembly process and can lead to the potentially fatal brittle bone disease, osteogenesis imperfecta. Here we investigate the mechanical properties of a range of computer-generated aggregates. The aggregates, created by the diffusion limited aggregation of rods, were subjected to a simple tensile test based on local rules of damage accumulation. In the test, core samples are "extracted' from the aggregates, and the network of particles involved in the transmission of stress resolved. Increasing stress applied to the core leads to the removal of individual rods from this network; the tensile strength is determined from the force necessary to form a discontinuous network. Using this approach, we have shown that collagen fibril morphology is critical in determining its tensile strength. We suggest a possible mechanism to account for the increasing severity of osteogenesis imperfecta associated with the distance of mutation from the N-terminal of the collagen molecule.


International definitions of overweight and obesity for children: a lasting solution?
Definitions of overweight and obesity for children were published in 2000, derived by averaging the centiles of six countries equivalent to body mass index (BMI) at age 18 years of 25 and 30. For use in the UK it is unclear whether these present an advantage over equivalent definitions based on UK data. To compare the recently published international cut-off points for overweight and obesity in children with alternative cut-off points based on the UK 1990 reference data. Around 6000 white children aged 4-11 years from primary schools in 22 areas in England were measured in two cross-sectional surveys, in 1984 and 1994. Measurements included height and weight, from which BMI was calculated. Each child was classified as overweight or obese according to each cut-off point. The proposed international cut-off points exaggerate the difference in prevalence of overweight and obesity between English boys and girls in comparison to comparable measures based on UK data by up to 7%, and are not compatible with the UK reference charts for BMI. Using proposed UK cut-off points the prevalence of overweight in boys was 10.2% in 1984, rising to 13.8% in 1994, compared to 5.4 to 9.0% using the international definition. The limitations of the international definitions, due to averaging data from different countries and the choice of reference age, need to be known. The UK cut-off points here presented are compatible with the current UK reference curves.


Six-lepton Z' resonance at the Large Hadron Collider.
New physics models admit the interesting possibility of a Z' weak boson associated with an extra U(1) gauge symmetry and a Higgs boson that is heavy enough to decay into a pair of Z bosons. Then Z' production and decay via Z' --> ZH --> ZZZ has a distinctive LHC signal that is nearly background-free and reconstructs the H and Z' masses and widths. The Z' decay to 3 pairs of leptons is especially distinctive. The ZH decay mode exists even if the Z' is decoupled from leptons, which motivates an independent 6-lepton resonance search regardless of the dilepton search results.


A functional calcium-binding site in the metalloprotease domain of ADAMTS13.
ADAMTS13 regulates the multimeric size of von Willebrand factor (VWF). Its function is highly dependent upon Ca(2+) ions. Using the initial rates of substrate (VWF115, VWF residues 1554-1668) proteolysis by ADAMTS13 preincubated with varying Ca(2+) concentrations, a high-affinity functional ADAMTS13 Ca(2+)-binding site was suggested with K(D(app)) of 80 muM (+/- 15 muM) corroborating a previously reported study. When Glu83 or Asp173 (residues involved in a predicted Ca(2+)-binding site in the ADAMTS13 metalloprotease domain) were mutated to alanine, Ca(2+) dependence of proteolysis of the substrate was unaffected. Consequently, we sought and identified a candidate Ca(2+)-binding site in proximity to the ADAMTS13 active site, potentially comprising Glu184, Asp187, and Glu212. Mutagenesis of these residues within this site to alanine dramatically attenuated the K(D(app)) for Ca(2+) of ADAMTS13, and for D187A and E212A also reduced the V(max) to approximately 25% of normal. Kinetic analysis of the Asp187 mutant in the presence of excess Ca(2+) revealed an approximately 13-fold reduction in specificity constant, k(cat)/K(m), contributed by changes in both K(m) and k(cat). These results were corroborated using plasma-purified VWF as a substrate. Together, our results demonstrate that a major influence of Ca(2+) upon ADAMTS13 function is mediated through binding to a high-affinity site adjacent to its active site cleft.


[Clinical rhinomanometry].
Between 1971 and 1978 the author did 575 rhinomanometric examinations, using the Cottle rhinomanometer, Model FP-102. It was always a unilateral passive rhinomanometry. Results obtained on the rhinomanometer were compared with the patient's history and the clinical examination. For 423 cases (74%) the rhinomanometry confirmed the clinical data, and for 152 cases (26%) there was no relation between the two. It is concluded that for evaluation and choice of treatment the clinical history and examination are the only valuable criteria. Defects of the rhinomanometer are discussed. In medical rhinitis an effect was noticed which was exactly the contrary to that expected with a local decongestant. We believe that this equipment is not sufficiently developed to be currently useful in clinical work although rhinomanometry may have a role in research.


Ultrasonography for monitoring reproductive function in the bull.
Diagnostic ultrasonography has been widely used for examination of the reproductive tract of female cattle, but more sparingly in bulls. Typical clinical ultrasonographic examinations of bull testes are unlikely to affect semen quality or sperm production. The ultrasonographic anatomy of bull testes and accessory sex glands has been reported. Although testicular echogenicity increased (i.e. the parenchyma appeared more white) as a bull approached puberty, echogenicity was not superior to scrotal circumference as a predictor of puberty. Ultrasonography can be used to detect and characterize testicular pathology. It is noteworthy that areas of increased echogenicity (testicular fibrosis) are common, especially in young bulls, but are not associated with decreased semen quality (e.g. percentage of morphologically abnormal sperm). Neither visual evaluation nor computerized pixel analysis of testicular ultrasonic echotexture was consistently predictive of semen quality in bulls. Therefore, we concluded that the primary clinical use of ultrasonography in assessment of reproductive function in the bull is characterization of grossly detectable lesions in the testes and scrotum.


Serum beta-2-microglobulin in African Burkitt tumour, nasopharyngeal carcinoma and controls.
Serum beta2-microglobulin measurements were made in Burkitt lymphoma and nasopharyngeal carcinoma in Africans and infectious mononucleosis in Europeans. There was a significant increase of beta2-microglobulin levels in active Burkitt tumour compared to those in remission but young West African children have higher levels than that in Caucasians. Nasopharyngeal carcinoma can be associated with a raised beta2-microglobulin but the distribution is similar to that seen in other head and neck cancers. In 27 cases of infectious mononucleosis 74% have raised levels of serum beta2-microglobulin. The mechanism of production of high serum beta2-microglobulin levels in rural African children is as yet unknown.


Results of third-generation epirubicin/cisplatin/xeloda adjuvant chemotherapy in patients with radically resected gastric cancer.
The purpose of this study was to evaluate the efficacy and toxicity of a third-generation chemotherapy regimen in the adjuvant setting to radically operated patients with gastric cancer. This proposed new adjuvant regimen was also compared with a consecutive retrospective cohort of patients treated with the classic McDonald regimen. Starting in 2006, a non-randomized prospective phase II study was conducted at the Institute of Oncology of Cluj-Napoca on 40 patients with stage IB-IV radically resected gastric adenocarcinoma. These patients were administered a chemotherapy regimen already considered to be standard treatment in the metastatic setting: ECX (epirubicin, cisplatin, xeloda) and were compared to a retrospective control group consisting of 54 patients, treated between 2001 and 2006 according to McDonald's trial. In a previous paper, we reported toxicities and the possible predictive factors for these toxicities; in the present article, we report on the results concerning predictive factors on overall survival (OS) and disease free survival (DFS). The proposed ECX treatment was not less effective than the standard suggested by McDonald's trial. Age was an independent prognostic factor in multivariate analysis. N3 stage was an independent prognostic factor for OS and DFS. N ratio >70% was an independent predictive factor for OS and locoregional disease control. The resection margins were independent prognostic factors for OS and DFS. The proposed treatment is not less effective compared with the McDonald's trial. Age was an independent prognostic factor in multivariate analysis. N3 stage represented an independent prognostic factor and N ratio >70% was a predictive factor for OS and DFS. The resection margins were proven to be independent prognostic factors for OS and DFS.


Modeling digital pulse waveforms by solving one-dimensional Navier-stokes equations.
Mathematical modeling for composition distal arterial pulse wave in the blood vessels of the upper limbs was considered. Formation of distal arterial pulse wave is represented as a composition of forward and reflected pulse waves propagating along the arterial vessels. The formal analogy between pulse waves propagation along the human arterial system and the propagation of electrical oscillations in electrical transmission lines with distributed parameters was proposed. Dependencies of pulse wave propagation along the human arterial system were obtained by solving the one-dimensional Navier-Stokes equations for a few special cases.


[Takayasu's arteritis associated with acute myeloblastic leukemia].
We present one patient with acute myeloblastic leukemia diagnosed two months after the onset of Takayasu's arteritis. A 21-year old woman with a previous history of erythema nodosum and episcleritis was admitted for a left cervical mass. Diagnostic imaging showed an aneurism of the left extracranial internal carotid and a stenosis of the left subclavian artery. Histological findings of the carotid aneurism revealed a granulomatous giant cell arteritis consistent with Takayasu's arteritis. Two weeks after, she was discharged, elevated white cell count (440.000/mm3 ) was disclosed. A bone marrow aspirate documented an acute myeloid leukemia. The patient died of intracerebral hemorrhage. Leucocytoclastic vasculitis and polyarteritis nodosa occur in acute myeloid leukemia, but the association with Takayasu's arteritis is new. In our knowledge, only two documented cases of Takayasu's arteritis in association with acute myeloblastic leukemia have been published.


Aberrant iNOS signaling is under genetic control in rodent liver cancer and potentially prognostic for the human disease.
Mounting evidence underlines the role of inducible nitric oxide synthase (iNOS) in hepatocellular carcinoma (HCC) development, but its functional interactions with pathways involved in HCC progression remain uninvestigated. Here, we analyzed in preneoplastic and neoplastic livers from Fisher 344 and Brown Norway rats, possessing different genetic predisposition to HCC, in transforming growth factor-alpha (TGF-alpha) and c-Myc-TGF-alpha transgenic mice, characterized by different susceptibility to HCC, and in human HCC: (i) iNOS function and interactions with nuclear factor-kB (NF-kB) and Ha-RAS/extracellular signal-regulated kinase (ERK) during hepatocarcinogenesis; (ii) influence of genetic predisposition to liver cancer on these pathways and role of these cascades in determining a susceptible or resistant phenotype and (iii) iNOS prognostic value in human HCC. We found progressive iNos induction in rat and mouse liver lesions, always at higher levels in the most aggressive models represented by HCC of rats genetically susceptible to hepatocarcinogenesis and c-Myc-TGF-alpha transgenic mice. iNOS, inhibitor of kB kinase/NF-kB and RAS/ERK upregulation was significantly higher in HCC with poorer prognosis (as defined by patients' survival length) and positively correlated with tumor proliferation, genomic instability and microvascularization and negatively with apoptosis. Suppression of iNOS signaling by aminoguanidine led to decreased HCC growth and NF-kB and RAS/ERK expression and increased apoptosis both in vivo and in vitro. Conversely, block of NF-kB signaling by sulfasalazine or short interfering RNA (siRNA) or ERK signaling by UO126 caused iNOS downregulation in HCC cell lines. These findings indicate that iNOS cross talk with NF-kB and Ha-RAS/ERK cascades influences HCC growth and prognosis, suggesting that key component of iNOS signaling could represent important therapeutic targets for human HCC.


[Expression and significance of PCNA and p27 in benign prostate hypertrophy and prostate carcinoma].
To investigate the expression of PCNA and p27 in human benign prostate hypertrophy (BPH) and prostate carcinoma (PCa) and their effect on the genesis and progression of the tumor. The paraffin-embedded sections of 30 cases with BPH and 37 cases with PCa were collected. The expression of p27 and PCNA protein were examined by S-P immunohistochemical method. Comparative analysis for BPH and pathological grade and clinical stage of PCa was performed. The expression of PCNA in BPH (3.3%) was significantly lower than that in Pca (83.8%, P < 0.01). The expression of p27 in BPH (70.0%) was significantly higher than that in Pca (27.0%, P < 0.05). The expression of p27 was not correlated with histological grade and clinical stage in Pca (P > 0.05). An inverse correlation was found between p27 and PCNA expression in BPH (P < 0.01), while no correlation was found in Pca (P > 0.05). The loss or decreased expression of p27 protein may be related to the genesis of benign prostate hypertrophy, but not to the development of prostate carcinoma; the overexpression of PCNA may play an important role in the malignant behavior and progression of prostate carcinoma.


Nitric oxide modulates ozone-induced cell death, hormone biosynthesis and gene expression in Arabidopsis thaliana.
Nitric oxide (NO) is involved together with reactive oxygen species (ROS) in the activation of various stress responses in plants. We have used ozone (O₃) as a tool to elicit ROS-activated stress responses, and to activate cell death in plant leaves. Here, we have investigated the roles and interactions of ROS and NO in the induction and regulation of O₃-induced cell death. Treatment with O₃ induced a rapid accumulation of NO, which started from guard cells, spread to adjacent epidermal cells and eventually moved to mesophyll cells. During the later time points, NO production coincided with the formation of hypersensitive response (HR)-like lesions. The NO donor sodium nitroprusside (SNP) and O₃ individually induced a large set of defence-related genes; however, in a combined treatment SNP attenuated the O₃ induction of salicylic acid (SA) biosynthesis and other defence-related genes. Consistent with this, SNP treatment also decreased O₃-induced SA accumulation. The O₃-sensitive mutant rcd1 was found to be an NO overproducer; in contrast, Atnoa1/rif1 (Arabidopsis nitric oxide associated 1/resistant to inhibition by FSM1), a mutant with decreased production of NO, was also O₃ sensitive. This, together with experiments combining O₃ and the NO donor SNP suggested that NO can modify signalling, hormone biosynthesis and gene expression in plants during O₃ exposure, and that a functional NO production is needed for a proper O₃ response. In summary, NO is an important signalling molecule in the response to O₃.


[Surgical treatment of incessant atrial tachycardia: description of a case].
A 50 year old woman with no evidence of structural heart disease was referred for ectopic incessant repetitive atrial tachycardia uncontrolled by medical therapy. Intracavitary and transesophageal simultaneous recordings revealed the earliest atrial electrical activity to be located in the left atrium. Intraoperative electrophysiologic mapping demonstrated that the site of earliest atrial activation was in a small diverticulum of the left atrial appendage. Excision of the appendage and isolation of left atrium was carried out with restoration of sinus rhythm. The patient was arrhythmia-free till 24 months later. Surgical treatment appears to be an effective therapeutic option for drug-resistant ectopic atrial tachycardia.


Norfloxacin versus co-trimoxazole in the treatment of acute bacterial diarrhoea: a placebo controlled study.
The bacteriological and clinical efficacy of norfloxacin 400 mg b.i.d. was compared to those of co-trimoxazole (160 mg of trimethoprim plus 800 mg of sulphamethoxazole) b.i.d. and placebo b.i.d. for the treatment of acute bacterial diarrhoea in a randomized double-blind trial. Of a total of 450 patients with acute diarrhoea, 303 had positive bacterial cultures and were evaluable for efficacy. The time to elimination of pathogens was significantly (p less than 0.001) shorter in the norfloxacin group than in the co-trimoxazole and placebo groups. At completion of treatment, bacteriological cure was found in 97.9%, 72.4% and 38.2% of patients treated with norfloxacin, co-trimoxazole and placebo, respectively. All pathogens were susceptible to norfloxacin and none of them developed resistance to norfloxacin during treatment. In the co-trimoxazole group, resistance to that antibiotic increased from 2% at inclusion to 65.6% at the end of treatment (p less than 0.001). In patients with shigellosis or cholera, the mean time to normalization of bowel movements was significantly shorter in the norfloxacin and co-trimoxazole groups than in the placebo group (p less than 0.05 and p less than 0.01, respectively). There were no significant differences between groups with respect to adverse events reported. In conclusion, norfloxacin was well tolerated and highly effective in the treatment of acute bacterial diarrhoea.


Acupuncture beyond the endorphin concept?
Traditional acupuncture has been used for treating a variety of health conditions. In contrast, Western physicians limited acupuncture to the alleviation of pain. Concomitant with a recent view that not all kinds of pain are within the reach of acupuncture-induced relief, it has been suggested that some conditions other than pain can be effectively treated by this method. Increased release of the neuropeptide beta-endorphin was proposed to explain the antinociceptive function of acupuncture. Even if correct beta-endorphin cannot account for the effect of acupuncture in other conditions. Endorphins might be interacting with cytokines, some of which (e.g. interleukin-10) downregulate the inflammatory component of disorders in which acupuncture may be useful. We present a speculative notion of the view that acupuncture may amplify the interaction between neuropeptides and cytokines. A non-invasive approach, such as immune-committed cells harvested from blood of acupuncture-treated patients, could be used to examine this hypothesis. Inclusion of a placebo group might support the credibility of acupuncture.


Outcomes after traumatic injury in patients with preexisting psychiatric illness.
Patients with psychiatric illness have been shown to experience higher rates of traumatic injury. Injury patterns, treatment decisions, and outcomes have not been well characterized in patients with psychiatric illness after injury, in particular those who undergo acute surgical intervention. The purpose of this analysis was to determine mortality, complications, and surgical intervention rates in patients with psychiatric illness after traumatic injury. This is a retrospective study of trauma patients ≥18 years old admitted to LAC + USC Medical Center between January 2008 and March 2015. Patients with psychiatric diagnoses were identified using ICD-9 diagnosis codes. Multivariate logistic regression analyses taking into account demographic and injury characteristics were used to identify associations between psychiatric comorbidity, injury mechanism, surgical interventions, and outcomes in patients after injury. A total of 26,502 patients were analyzed. Of these, 3,040 (11.5%) had a documented psychiatric comorbidity (2.0% depressive disorder, 0.8% bipolar disorder, 1.3% schizophrenia, 0.5% anxiety disorder, 3.2% substance use disorder). Patients with psychiatric illness were significantly older (49.6 years vs. 42.0 years, p < 0.001), had a lower proportion of penetrating injuries (13.8% vs. 18.1%, p < 0.001), and had a higher incidence of self-inflicted injuries (11.6% vs. 0.72%, p < 0.001). No difference in gender distribution was observed (74.2% men vs. 74.4% men, p = 0.80). Overall mortality was similar in both groups (adjusted odds ratio [aOR], 0.73; p = 0.07). Patients with psychiatric illness were significantly less likely to undergo acute surgical intervention within 6 hours of emergency department admission (aOR, 0.64; p < 0.001). Time from ED arrival to consent for acute surgical intervention was similar in both groups (94.8 min vs. 93.0 min, p = 0.84). No significant difference in mortality after acute surgical intervention was observed (aOR, 0.26; p = 0.10). Psychiatric illness was associated with a significantly higher likelihood of developing complications (aOR, 1.90; p < 0.001) and longer hospital lengths of stay (10.6 days vs. 6.2 days, p < 0.001). Trauma patients with comorbid psychiatric illness were observed to have lower rates of acute surgical interventions, higher complication rates, and longer hospital lengths of stay. Further studies are needed to better characterize the causative factors underlying these associations. Epidemiological, level III.


[Norwegian scabies, a rare diagnosis in Tunisia].
Norwegian scabies is a particular form of scabies, rarely reported in Tunisia. It habitually occurs in immunocompromised hosts, with prolonged immunosuppressive therapy, congenital immune disease, HIV-1 infection or neoplasm. We report an observation of norwegian scabies, occuring in a woman with prolounged systemic corticosteroid therapy. A 65-year-old woman, with a long history of obstructive bronchoneumopathy and bronchiectasis, treated with systemic corticosteroids for 5 years, was referred with a mild pruriginous and scaly erythroderma. This dermatosis developed within 5 months, with fever and impairing of health. Skin parasitological exams showed a massive infestation by sarcoptes. Histologic findings revealed multiple sarcoptes scabiei and eggs in the stratum corneum. The patient was treated with benzyl benzoate during 48 hours. She died rapidly with acute respiratory distress. basing on this observation of norwegian scabies occuring in an old immunocompromised woman, we put the accent on this particular form of scabies, often misappreciated, and incite to practice skin and nail parasitological exams in case of mild pruriginous, chronic scaly erythroderma. developing in immunocompromised patients.


Aldosterone-Producing Adenomas: Histopathology-Genotype Correlation and Identification of a Novel CACNA1D Mutation.
Mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 are thought to cause the excessive autonomous aldosterone secretion of aldosterone-producing adenomas (APAs). The histopathology of KCNJ5 mutant APAs, the most common and largest, has been thoroughly investigated and shown to have a zona fasciculata-like composition. This study aims to characterize the histopathologic spectrum of the other genotypes and document the proliferation rate of the different sized APAs. Adrenals from 39 primary aldosteronism patients were immunohistochemically stained for CYP11B2 to confirm diagnosis of an APA. Twenty-eight adenomas had sufficient material for further analysis and were target sequenced at hot spots in the 5 causal genes. Ten adenomas had a KCNJ5 mutation (35.7%), 7 adenomas had an ATP1A1 mutation (25%), and 4 adenomas had a CACNA1D mutation (14.3%). One novel mutation in exon 28 of CACNA1D (V1153G) was identified. The mutation caused a hyperpolarizing shift of the voltage-dependent activation and inactivation and slowed the channel's inactivation kinetics. Immunohistochemical stainings of CYP17A1 as a zona fasciculata cell marker and Ki67 as a proliferation marker were used. KCNJ5 mutant adenomas showed a strong expression of CYP17A1, whereas ATP1A1/CACNA1D mutant adenomas had a predominantly negative expression (P value =1.20×10-4). ATP1A1/CACNA1D mutant adenomas had twice the nuclei with intense staining of Ki67 than KCNJ5 mutant adenomas (0.7% [0.5%-1.9%] versus 0.4% [0.3%-0.7%]; P value =0.04). Further, 3 adenomas with either an ATP1A1 mutation or a CACNA1D mutation had >30% nuclei with moderate Ki67 staining. In summary, similar to KCNJ5 mutant APAs, ATP1A1 and CACNA1D mutant adenomas have a seemingly specific histopathologic phenotype.


Relation of bone mineral density and content to mineral content and density of the fat-free mass.
Differences in the mineral fraction of the fat-free mass (M(FFM)) and in the density of the FFM (D(FFM)) are often inferred from measures of bone mineral content (BMC) or bone mineral density (BMD). We studied the relation of BMC and BMD to the M(FFM) and D(FFM) in a heterogeneous sample of 216 young men (n = 115) and women (n = 101), which included whites (n = 155) and blacks (n = 61) and collegiate athletes ( n = 132) and nonathletes (n = 84). Whole body BMC and BMD were determined by dual-energy X-ray absorptiometry (DXA; Hologic QDR-1000W, enhanced whole body analysis software, version 5.71). FFM was estimated using a four-component model from measures of body density by hydrostatic weighing, body water by deuterium dilution, and bone mineral by DXA. There was no significant relation of BMD to M(FFM) (r = 0.01) or D(FFM) (r = -0.06) or of BMC to M(FFM) (r = -0.11) and a significant, weak negative relation of BMC to D(FFM) (r = -0.14, P = 0.04) in all subjects. Significant low to moderate relationships of BMD or BMC to M(FFM) or D(FFM) were found within some gender-race-athletic status subgroups or when the effects of gender, race, and athletic status were held constant using multiple regression, but BMD and BMC explained only 10-17% of the variance in M(FFM) and 0-2% of the variance in D(FFM) in addition to that explained by the demographic variables. We conclude that there is not a significant positive relation of BMD and BMC to M(FFM) or D(FFM) in young adults and that BMC and BMD should not be used to infer differences in M(FFM) or D(FFM).


Novel multisubstrate inhibitors of mammalian purine nucleoside phosphorylase.
In an effort to develop potent multisubstrate-analog inhibitors of purine nucleoside phosphorylase (PNP), three nucleoside phosphonates were designed utilizing structural information from the previously reported structures of complexes of bovine PNP with substrates and products. The nucleoside phosphonates contain an acetal linkage at the O2' and O3' positions and a two-C-atom spacer between the ribose and phosphate moieties. The linkage enables the compounds to simultaneously occupy the purine-, ribose- and phosphate-binding sites. The chemical syntheses, inhibition profiles and structural characterization of these novel multisubstrate analog inhibitors with bovine PNP are described.


Transgenic zebrafish model of DUX4 misexpression reveals a developmental role in FSHD pathogenesis.
Facioscapulohumeral dystrophy type 1 (FSHD-1) is the most common autosomal dominant form of muscular dystrophy with a prevalence of ∼1 in 8000 individuals. It is considered a late-onset form of muscular dystrophy and leads to asymmetric muscle weakness in the facial, scapular, trunk and lower extremities. The prevalent hypothesis on disease pathogenesis is explained by misexpression of a germ line, primate-specific transcription factor DUX4-fl (double homeobox 4, full-length isoform) linked to the chromosome 4q35. In vitro and in vivo studies have demonstrated that very low levels of DUX4-fl expression are sufficient to induce an apoptotic and/or lethal phenotype, and therefore modeling of the disease has proved challenging. In this study, we expand upon our previously established injection model of DUX4 misexpression in zebrafish and describe a DUX4-inducible transgenic zebrafish model that better recapitulates the expression pattern and late onset phenotype characteristic of FSHD patients. We show that an induced burst of DUX4 expression during early development results in the onset of FSHD-like phenotypes in adulthood, even when DUX4 is no longer detectable. We also utilize our injection model to study long-term consequences of DUX4 expression in those that fail to show a developmental phenotype. Herein, we introduce a hypothesis that DUX4 expression during developmental stages is sufficient to induce FSHD-like phenotypes in later adulthood. Our findings point to a developmental role of DUX4 misexpression in the pathogenesis of FSHD and should be factored into the design of future therapies.


Acute pancreatitis as a cause of sudden or unexpected death in Northern Ireland.
Utilising incomplete data supplied by the Hospital Inpatient Analysis, the annual incidence of acute pancreatitis in Northern Ireland was estimated to be about 170 cases per million population. The annual mortality rate for the years 1974-1983, using figures obtained from the Registrar-General for Northern Ireland, was 12.3 cases per million. An increase in both incidence and mortality from acute pancreatitis was demonstrated during the study. There was 191 deaths from pancreatitis during the study period and in 27 of these the diagnosis was made only at postmortem examination. Of the undiagnosed fatalities, 10 occurred in individuals with a history of alcohol abuse. Eight of the 27 undiagnosed cases had not sought medical attention, five had presented with a systemic complication of acute pancreatitis, and a further five had only minor gastrointestinal tract symptoms prior to death. The diagnosis of acute pancreatitis requires a high index of suspicion and should be considered in acutely ill patients, particularly those with a history of alcohol abuse, who fail to respond to appropriate therapy.


Analysis of early ventral telencephalic defects in mice lacking functional Gli3 protein.
The transcription factor Gli3 is expressed throughout developing telencephalon. Previous studies have focused on Gli3's role in dorsal telencephalon, which is greatly reduced in size in Gli3(Xt/Xt) mutants. We examined the effects of loss of Gli3 on early development of ventral telencephalon. Ventral telencephalon was defined in both wildtypes and Gli3(Xt/Xt) mutants on the basis of its expression of Olig2, Nkx2.1, Mash1, and Foxg1 and its lack of expression of Pax6. We found that at embryonic day (E)10.5 the volume of the ventral telencephalon is about 50% greater in Gli3(Xt/Xt) mutants than in wildtypes. By E12.5, however, the volume of the ventral telencephalon is about 20% lower in Gli3(Xt/Xt) mutants than in wildtypes. We observed a significant increase in the number of both apoptotic cells and newly differentiated neurons in the E10.5 Gli3(Xt/Xt) ventral telencephalon, suggesting that increased cell death and withdrawal of cells from the cell cycle might account for the failure of the Gli3(Xt/Xt) ventral telencephalon to grow normally by E12.5. We found no changes in the lengths of the cell cycles of proliferating ventral telencephalic cells at E10.5. We used marker analysis and optical projection tomography to assess the Gli3(Xt/Xt) forebrain in three dimensions and found that the Gli3(Xt/Xt) diencephalon is shifted relatively rostrally. We conclude that in the absence of Gli3 an abnormally large portion of the newly formed telencephalon is specified to a ventral fate but this then suffers impaired growth, due to defects of cell differentiation and death, contributing to severe distortion of the forebrain.


Purification of a base-specific ribonuclease Ru from Rhizopus niveus.
A base-specific ribonuclease (RNase) Ru (EC 184.108.40.206) was isolated and purified from Rhizopus niveus in a yield of 17% by the procedures of acetone precipitation, column chromatography on Duolite A-2, DEAE-cellulose, CM-cellulose, and 2'(3')-aminohexyl-5'-UMP-agarose. The enzyme was shown to be homogeneous by polyacrylamide disc electrophoresis. The amino- and carboxyl-terminal amino acids of the enzyme were determined to be an arginine and an aspartic acid, respectively. The enzyme has a base specificity: it released only 3'-UMP from yeast RNA or poly(U) and, in addition, small amounts of 3'-CMP from poly(C).


Plasticity of Pax-5(-/-) pre-B I cells.
In Pax-5 deficient mice, B cell development is blocked at the pre-B I cell stage. In contrast to their wild type counterparts, Pax-5(-/-) pre-B I cells posses an extraordinary developmental plasticity showing hematopoietic stem cell features such as pluripotency and self renewing capacity. Here we review the in vitro and in vivo evidence of this intriguing phenomenon.


The effect of ion implantation on field emission property of nanodiamond films.
Nanocrystalline diamond films prepared by microwave plasma enhanced chemical vapor deposition (MPECVD) were implanted using 110 keV nitrogen ions under fluence ranging from 10(13)-10(14) ions/cm2. Scanning Electron Microscopy (SEM) and Raman spectroscopy were used to analyze the changes in the surface of the films before and after ion implantation. Results show that with nitrogen ion implantation in nanocrystalline diamond film cause to decrease in diamond crystallinity. The field emission measurement shows a sharp increase in current density with increase in dose. The ion implantation also alters the turn on field. It is observed that the structural damage caused by ion implantation plays a significant role in emission behaviour of nanocrystalline diamonds.


The bacterial type III secretion system as a target for developing new antibiotics.
Antibiotic resistance in pathogens requires new targets for developing novel antibacterials. The bacterial type III secretion system (T3SS) is an attractive target for developing antibacterials as it is essential in the pathogenesis of many Gram-negative bacteria. The T3SS consists of structural proteins, effectors, and chaperones. Over 20 different structural proteins assemble into a complex nanoinjector that punctures a hole on the eukaryotic cell membrane to allow the delivery of effectors directly into the host cell cytoplasm. Defects in the assembly and function of the T3SS render bacteria non-infective. Two major classes of small molecules, salicylidene acylhydrazides and thiazolidinones, have been shown to inhibit multiple genera of bacteria through the T3SS. Many additional chemically and structurally diverse classes of small molecule inhibitors of the T3SS have been identified as well. While specific targets within the T3SS of a few inhibitors have been suggested, the vast majority of specific protein targets within the T3SS remain to be identified or characterized. Other T3SS inhibitors include polymers, proteins, and polypeptides mimics. In addition, T3SS activity is regulated by its interaction with biologically relevant molecules, such as bile salts and sterols, which could serve as scaffolds for drug design.


A Comprehensive Review of US FDA-Approved Immune Checkpoint Inhibitors in Urothelial Carcinoma.
Few effective treatment options are available for patients with advanced or metastatic urothelial carcinoma (UC) after unsuccessful first-line platinum-based chemotherapy. To date, immune checkpoint inhibitors are novel therapeutic agents for UC treatment. From May 2016 to May 2017, five anti-PD-1/PD-L1 monoclonal antibodies received accelerated or regular approval from the US Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic UC. The present comprehensive review presents the background information of these five US FDA-approved anticancer agents to provide a basic but concise understanding of these agents for advanced studies. We summarize their immune checkpoint mechanisms, clinical efficacy, recommended usage protocols, adverse events, and the limitations of the PD-L1 biomarker assays.


Quantum Tunneling Contribution for the Activation Energy in Microwave-Induced Reactions.
In this study, a quantum approach is presented to explain microwave-enhanced reaction rates by considering the tunneling effects in chemical reactions. In the Arrhenius equation, the part of the Hamiltonian relative to the interaction energy during tunneling, between the particle that tunnels and the electrical field defined in the medium, whose spatial component is specified by its rms value, is taken into account. An approximate evaluation of the interaction energy leads to a linear dependence of the effective activation energy on the applied field. The evaluation of the rms value of the field for pure liquids and reaction mixtures, through their known dielectric properties, leads to an appreciable reduction in the activation energies for the proton transfer process in these liquids. The results indicate the need to move toward the use of more refined methods of modern quantum chemistry to calculate more accurately field-induced reaction rates and effective activation energies.


Mapping and direct valuation: do they give equivalent EQ-5D-5L index scores?
Utility values of health states defined by health-related quality of life instruments can be derived from either direct valuation ('valuation-derived') or mapping ('mapping-derived'). This study aimed to compare the utility-based EQ-5D-5L index scores derived from the two approaches as a means to validating the mapping function developed by van Hout et al for the EQ-5D-5L instrument. This was an observational study of 269 breast cancer patients whose EQ-5D-5L index scores were derived from both methods. For comparing discriminatory ability and responsiveness to change, multivariable regression models were used to estimate the effect sizes of various health indicators on the index scores. Agreement and test-retest reliability were examined using intraclass correlation coefficient (ICC). Whenever appropriate, the 90% confidence intervals (90% CI) were compared to predefined equivalence margins. The mean difference in and ICC between the valuation- and mapping-derived EQ-5D-5L index scores were 0.015 (90% CI = 0.006 to 0.024) and 0.915, respectively. Discriminatory ability and responsiveness of the two indices were equivalent in 13 of 15 regression analyses. However, the mapping-derived index score was lower than the valuation-derived index score in patients experiencing extreme health problems, and the test-retest reliability of the former was lower than the latter, for example, their ICCs differed by 0.121 (90% CI = 0.051 to 0.198) in patients who reported no change in performance status in the follow-up survey. This study provided the first evidence supporting the validity of the mapping function for converting EQ-5D-5L profile data into a utility-based index score.


Handling missing data in rest-activity time series measured by actimetry.
A handling procedure of off-wrist episodes in actimetry time series of motor activity is presented using two records (regular vs. irregular sleep-wake cycle and daytime activity) of 14 consecutive days sampled in 1-minute epochs. We generated single missing value (NA) intervals of 1 h, 2 h, 4 h, 6 h, 12 h, and 24 h as well as random NA episodes following probabilistic rules to simulate real-life off-wrist episodes. Then, we replaced these episodes with "zeroes" (i.e., the default of immobility records), mean or median of the remaining 13 days corresponding to the missing bins. Single missing episodes of up to 12 h resulted in less than 5% variation from the original values. The irregular series showed higher variability in acrophase, MESOR, L5, M10 and RA compared to the regular series. Random missing allocation simulating real-life off-wrist episodes resulted in significant changes in most parameters, and the imputation of zeroes significantly increased the variance; however, replacing NA with mean or median resulted in patterns similar to those of NA. We recommend replacing 'zeroes' with NA whenever possible, given the risk of inflating invariance using zeroes. If the parameters cannot be computed in the presence of NA, we recommend using the weekly mean of corresponding timepoints.


An open, multisite pilot study of cognitive therapy for depressed adolescents.
In a 12-session open trial of cognitive therapy, depressed adolescent outpatients showed significant decreases in depressive symptomatology, although there was less improvement in a subgroup with comorbid attention-deficit hyperactivity or schizoid personality disorder. Decreases on measures of depressive symptoms and depressotypic cognition were maintained up to 5 months after acute-phase treatment. Outcome was not associated with age, gender, other comorbid diagnoses, concurrent use of antidepressants, duration of acute-phase therapy, or participation in subsequent booster sessions. Data suggest that cognitive therapy is a promising intervention for depressed adolescents and provide a rationale for pursuit of controlled cognitive therapy trials with this population.


Effects of Ethacrynic Acid Addition to Diet on Fitness and Development in the Psocid Liposcelis bostrychophila Badonnel.
Fertility life table provides a comprehensive description of arthropod population dynamics by the estimation of parameters about arthropod population growth potential. It can also clarify the sublethal effects of chemicals on insects. Ethacrynic acid (EA), an inhibitor of glutathione S-transferases, is a diuretic compound that has been confirmed to modulate drug resistance in organisms. In this study, the effects of EA on growth and development of Liposcelis bostrychophila Badonnel were investigated in the laboratory to explore the potential possibilities of EA as an active agent to manage insecticide-resistant psocids. The treatment of psocids was obtained by feeding on the routine diet containing 3% EA for three successive generations, and psocids on routine diet served as control. The results indicated that EA possessed some negative effects on the life-table parameters of the psocid in F1 and F2 generations. The addition of EA to diet stunted psocids growth by lengthening development time and increasing mortality with a greater effect in the F2 generation. In the third generation of psocids on EA diet, it seemed there was a return to normal. Psocid fitness was influenced by addition of EA to standard diet. Using rm values, the fitness for EA diet in F1, F2, and F3 compared with the counterpart of routine diet was calculated as 0.80, 0.74, and 0.87, respectively.


Enhancement of tissue factor expression by vein segments exposed to coronary arterial hemodynamics.
Although saphenous vein is the most reliable conduit for arterial interposition procedures in the coronary circulation, graft thrombosis remains a clinical problem. We hypothesized that an important factor in early graft thrombosis is sudden change in the hemodynamic environment of the vein as it is placed in the coronary circulation. We used an ex vivo perfusion system to study freshly excised segments of human saphenous vein (HSV) and pig internal jugular vein. For coronary graft (CAVG) simulation, sections of HSV were subjected to arterial pulsatile pressure and flow and twisting and stretching to mimic deformations caused by the beating heart. Using functional and immunohistochemical assays, we investigated the effect of these conditions on expression of tissue factor (TF), an important prothrombotic surface molecule. In each of 11 experiments (6 human, 5 porcine), vein segments from a single donor were subjected to venous conditions (VEN), CAVG perfusion, or no perfusion. Expression of TF was measured as the amount of factor Xa generated per unit area of luminal vein surface. VEN perfusion did not cause a significant change in mean TF expression over nonperfused control values (human: 14.3 +/- 1.5 versus 11.4 +/- 2.3 U/cm2, p = 0.31; pig: 11.6 +/- 1.5 versus 12.5 +/- 1.4 U/cm2, p = 0.70). CAVG perfusion led to significant enhancement of TF expression over VEN perfusion (human: 36.8 +/- 6.2 versus 14.3 +/- 1.5 U/cm2, p < 0.05; pig: 40.0 +/- 9.9 versus 11.6 +/- 1.5 U/cm2, p < 0.05). Immunohistochemical analysis showed positive TF staining on the luminal side of a CAVG-stimulated HSV segment, but not on a VEN-stimulated segment. In four additional studies, HSV segments were subjected to arterial perfusion without twist and stretch to mimic lower extremity arterial interposition grafts. TF expression for lower extremity venous graft perfusion was significantly higher than for VEN perfusion (25.3 +/- 2.5 versus 14.3 +/- 1.5, p < 0.01) but not significantly different from CAVG perfusion. Our studies in a unique perfusion system suggest that exposure of vein to coronary arterial hemodynamic conditions results in elevated expression of the important prothrombotic molecule TF. This phenomenon may contribute to early graft thrombosis.


Continuously Constructive Deep Neural Networks.
Traditionally, deep learning algorithms update the network weights, whereas the network architecture is chosen manually using a process of trial and error. In this paper, we propose two novel approaches that automatically update the network structure while also learning its weights. The novelty of our approach lies in our parameterization, where the depth, or additional complexity, is encapsulated continuously in the parameter space through control parameters that add additional complexity. We propose two methods. In tunnel networks, this selection is done at the level of a hidden unit, and in budding perceptrons, this is done at the level of a network layer; updating this control parameter introduces either another hidden unit or layer. We show the effectiveness of our methods on the synthetic two-spiral data and on three real data sets of MNIST, MIRFLICKR, and CIFAR, where we see that our proposed methods, with the same set of hyperparameters, can correctly adjust the network complexity to the task complexity.


Effect of cancer-associated fibroblasts on radiosensitivity of cancer cells.
Solid tumors are composed of tumor epithelial cells and the stroma, which are seemingly separate but actually related through cell-cell and cell-matrix interactions. These interactions can promote tumor evolution. Cancer-associated fibroblasts (CAFs) are the most abundant non-neoplastic cells in the stroma and also among the most important cell types interacting with cancer cells. Particularly, cancer cells promote the formation and maintenance of CAFs by secreting various cytokines. The activated CAFs then synthesize a series of growth factors to promote tumor cell growth, invasion and metastasis. More importantly, the presence of CAFs also interferes with therapeutic efficacy, bringing severe challenges to radiotherapy. This review summarizes the effect of CAFs on the radiosensitivity of tumor cells and underscores the need for further studies on CAFs in order to improve the efficacy of antitumor therapy.


Collateral ligament laxity of the knee. Long-term comparison between plateau fractures and normal.
Bilateral varus-valgus knee-stress roentgenograms were made in 208 patients with unilateral single tibial-plateau fracture. Martin's so-called clear space was used to measure the laxity of the collateral ligaments and statistical analysis showed no increased laxity in the possibility injured ligaments. A vacuum phenomenon was produced in 36 per cent and ligament calcification was noted in 16 per cent of the knees tested.


Individuals with sickle cell disease have a significantly greater vasoconstriction response to thermal pain than controls and have significant vasoconstriction in response to anticipation of pain.
The painful vaso-occlusive crises (VOC) that characterize sickle cell disease (SCD) progress over hours from the asymptomatic steady-state. SCD patients report that VOC can be triggered by stress, cold exposure, and, pain itself. We anticipated that pain could cause neural-mediated vasoconstriction, decreasing regional blood flow and promoting entrapment of sickle cells in the microvasculature. Therefore, we measured microvascular blood flow in the fingers of both hands using plethysmography and laser-Doppler flowmetry while applying a series of painful thermal stimuli on the right forearm in 23 SCD patients and 25 controls. Heat pain applied to one arm caused bilateral decrease in microvascular perfusion. The vasoconstriction response started before administration of the thermal pain stimulus in all subjects, suggesting that pain anticipation also causes significant vasoconstriction. The time delay between thermal pain application and global vasoconstriction ranged from 5 to 15.5 seconds and increased with age (P < .01). Although subjective measures, pain threshold and pain tolerance were not different between SCD subjects and controls, but the vaso-reactivity index characterizing the microvascular blood flow response to painful stimuli was significantly higher in SCD patients (P = .0028). This global vasoconstriction increases microvascular transit time, and may promote entrapment of sickle cells in the microvasculature, making vaso-occlusion more likely. The rapidity of the global vasoconstriction response indicates a neural origin that may play a part in the transition from steady-state to VOC, and may also contribute to the variability in VOC frequency observed in SCD patients.


Improving empirical antibiotic treatment using TREAT, a computerized decision support system: cluster randomized trial.
Appropriate antibiotic treatment decreases mortality, while superfluous treatment is associated with antibiotic resistance. We built a computerized decision support system for antibiotic treatment (TREAT) targeting these outcomes. Prospective cohort study comparing TREAT's advice to physician's treatment followed by a cluster randomized trial comparing wards using TREAT (intervention) versus antibiotic monitoring without TREAT (control). We included patients suspected of harbouring bacterial infections in three hospitals (Israel, Germany and Italy). The primary outcome, appropriate antibiotic treatment, was assessed among patients with microbiologically documented infections (MDI). Length of hospital stay, adverse events, mortality (interventional trial) and antibiotic costs (both studies), including costs related to future antibiotic resistance, were compared among all included patients. Among 1203 patients included in the cohort study (350 with MDI), TREAT prescribed appropriate empirical antibiotic treatment significantly more frequently than physicians (70% versus 57%, P < 0.001) using less broad-spectrum antibiotics at half physicians' antibiotic costs. The randomized trial included 2326 patients, 570 with MDI. The rate of appropriate empirical antibiotic treatment was higher in intervention versus control wards [73% versus 64%, odds ratio (OR): 1.48, 95% confidence interval (CI): 0.95-2.29, intention to treat, adjusted for location and clustering]. For patients treated according to TREAT's advice in intervention wards, the difference with controls was highly significant (OR: 3.40, 95% CI: 2.25-5.14). Length of hospital stay, costs related to future resistance and total antibiotic costs were lower in intervention versus control wards. TREAT improved the rate of appropriate empirical antibiotic treatment while reducing antibiotic costs and the use of broad-spectrum antibiotic treatment.


Is gross proteinuria a risk factor for the incidence of proliferative diabetic retinopathy?
To examine the relationship between gross proteinuria, measured at the initial examination, and the 4-year incidence of proliferative diabetic retinopathy (PDR) in a population-based study in Wisconsin. Gross proteinuria was measured by reagent strip. Diabetic retinopathy was determined from stereoscopic fundus photographs in a masked fashion using the modified Airlie House classification scheme. In the younger-onset group taking insulin (n = 693), the relative risk of proliferative retinopathy developing in those with gross proteinuria at baseline was 2.32 (95% confidence interval [CI]: 1.40,3.83) compared with those without gross proteinuria. For the older-onset group taking insulin, the relative risk was 2.02 (95% CI: 0.91,4.44), and for those not taking insulin it was 1.13 (95% CI: 0.15,8.50). After controlling for other risk variables, the relationship was of borderline statistical significance (P = 0.052) in the younger-onset group with no or early nonproliferative retinopathy at baseline. These data suggest that gross proteinuria is a risk indicator for proliferative retinopathy in younger-onset patients with diabetes. These patients might benefit from having regular ophthalmologic evaluation.


Signal flow and pathways in response to early Wallerian degeneration after rat sciatic nerve injury.
Wallerian degeneration (WD) remains a subject of critical research interest in modern neurobiology. WD is a process which a large number of genes are differentially regulated, especially the early response to activate nerve degeneration and regeneration, but the precise mechanisms remain elusive. In this study, we report the signal pathways, key regulate recurrent neural networks and signal flow in the early WD. The data indicated that there are several kinds of up- or down-regulated genes, relating to the regulation of response to stimulus, signal transmission via phosphorylation event, immune response, apoptosis and regulation of cell communication. KEGG pathway analysis revealed activity mainly relating to cytokine-cytokine receptor interaction, MAPK signaling pathway, Jak-STAT signaling pathway, ErbB signaling pathway and TGF-beta signaling pathway involved in the recurrent neural networks that were regulated by the key factors, Cldn-14, Cldn-15, ITG, BID and BIRC3. These results will help to much better understand information relating to the early response to WD and provide us with a firmer basis in future investigations on the molecular mechanisms of WD that regulate nerve degeneration and/or regeneration.


Assessing dose of the representative person for the purpose of radiation protection of the public. ICRP publication 101. Approved by the Commission in September 2005.
The Commission intended that its revised recommendations should be based on a simple, but widely applicable, system of protection that would clarify its objectives and provide a basis for the more formal systems needed by operating managers and regulators. The recommendations would establish quantified constraints, or limits, on individual dose from specified sources. These dose constraints apply to actual or representative people who encounter occupational, medical, and public exposures. This report updates the previous guidance for estimating dose to the public. Dose to the public cannot be measured directly and, in some cases, it cannot be measured at all. Therefore, for the purpose of protection of the public, it is necessary to characterise an individual, either hypothetical or specific, whose dose can be used for determining compliance with the relevant dose constraint. This individual is defined as the 'representative person'. The Commission's goal of protection of the public is achieved if the relevant dose constraint for this individual for a single source is met and radiological protection is optimised. This report explains the process of estimating annual dose and recognises that a number of different methods are available for this purpose. These methods range from deterministic calculations to more complex probabilistic techniques. In addition, a mixture of these techniques may be applied. In selecting characteristics of the representative person, three important concepts should be borne in mind: reasonableness, sustainability, and homogeneity. Each concept is explained and examples are provided to illustrate their roles. Doses to the public are prospective (may occur in the future) or retrospective (occurred in the past). Prospective doses are for hypothetical individuals who may or may not exist in the future, while retrospective doses are generally calculated for specific individuals. The Commission recognises that the level of detail afforded by its provision of dose coefficients for six age categories is not necessary in making prospective assessments of dose, given the inherent uncertainties usually associated with estimating dose to the public and with identification of the representative person. It now recommends the use of three age categories for estimating annual dose to the representative person for prospective assessments. These categories are 0-5 years (infant), 6-15 years (child), and 16-70 years (adult). For practical implementation of this recommendation, dose coefficients and habit data for a 1-year-old infant, a 10-year-old child, and an adult should be used to represent the three age categories. In a probabilistic assessment of dose, whether from a planned facility or an existing situation, the Commission recommends that the representative person should be defined such that the probability is less than about 5% that a person drawn at random from the population will receive a greater dose. If such an assessment indicates that a few tens of people or more could receive doses above the relevant constraint, the characteristics of these people need to be explored. If, following further analysis, it is shown that doses to a few tens of people are indeed likely to exceed the relevant dose constraint, actions to modify the exposure should be considered. The Commission recognises the role that stakeholders can play in identifying characteristics of the representative person. Involvement of stakeholders can significantly improve the quality, understanding, and acceptability of the characteristics of the representative person and the resulting estimated dose.


Post Graduate Students' Experiences with Research Ethics: A South African Perspective.
The strict adherence to ethical principles (namely respect for persons, beneficence/non-maleficence and justice) when conducting research involving human participants is the bedrock of research. There has been little research on students' experiences with the research ethics process and how these students incorporate ethical standards into their research work, despite previous research looking into teaching methodologies, curricula, and the educational environment for postgraduate students. The purpose of the study was to investigate postgraduate students' experiences with research ethics during their research project. A sample of 11 participants was used. Through online interviews, this qualitative study, underpinned by the interpretivist paradigm, collected data from postgraduate students from different disciplines and universities in South Africa between June and August 2021. The findings showed different perspectives on the training received in research ethics, and on support and guidance received from supervisors, and the application of research ethics principles in their research projects. Most participants indicated gaps in the teaching and support they received and had not read their university research ethics policies. By focusing on students' experiences in a developing country and different disciplines, the study contributes to the body of knowledge on postgraduate student experiences. Furthermore, the findings suggest that there is need for more research ethics training amongst postgraduate students in South Africa.


Direct and indirect striatal efferent pathways are differentially influenced by low and high dyskinetic drugs: behavioural and biochemical evidence.
Clinical evidence suggests that stimulation of the D(1) rather than D(2) dopamine receptor is related to the development of dyskinesias in Parkinson's disease (PD). We evaluated, in the 6-hydroxydopamine rat model of PD, sensitization of contralateral turning (SCT) behaviour and abnormal involuntary movements (AIMs) as behavioural parameters of dyskinetic response, and changes in zif-268 mRNA expression in striatonigral and striatopallidal neurons on subchronic administration of the D(2)/D(3) agonist ropinirole, defined as a mild dyskinetic drug in the clinic. Results were compared with previous findings on repeated L-dopa treatment. Ropinirole displayed a mild dyskinetic response characterized by SCT only, which contrasted with the presence of SCT in association with AIMs elicited by repeated L-dopa. Zif-268 mRNA levels were decreased in both striatonigral and striatopallidal neurons by ropinirole, in contrast to hyper-expression of zif-268 mRNA selectively induced by L-dopa in striatonigral neurons. Unbalanced responsiveness of striatal efferent neurons might represent a molecular correlate of high dyskinetic potential and AIMs in rats; in contrast, a balanced striatal output might underlie the low dyskinetic potential displayed by ropinirole.


Unconventional Bladder Preservation: Factors Predicting Failure to Receive Definitive Surgery following Chemotherapy for Nonmetastatic Muscle Invasive Bladder Cancer in the National Cancer Database.
Neoadjuvant chemotherapy is an important adjunct to cystectomy for managing muscle invasive bladder cancer. Using the National Cancer Database we investigated factors that predict failure to undergo surgery following multi-agent chemotherapy for nonmetastatic muscle invasive bladder cancer. We performed a cohort study in patients diagnosed with cT2-4aN0M0 urothelial cell carcinoma of the bladder between 2004 and 2013 who underwent multi-agent chemotherapy. We excluded those with surgery prior to chemotherapy, clinical T4b disease and those who received radiotherapy. Socioeconomic and clinical predictors, including time from diagnosis to treatment, were analyzed using logistic regression for the receipt of surgery after chemotherapy. Cox proportional hazards modeling was applied to perform time dependent analysis. Of the 4,640 patients who met our study inclusion and exclusion criteria 4,244 (91%) proceeded to surgery. Negative predictors of surgery included African American or Hispanic race (OR 0.58, p = 0.007 and 0.48, p = 0.002, respectively), increasing age (OR 0.44, p <0.001) and greater time between diagnosis and chemotherapy initiation (fourth quartile greater than 59 days, OR 0.51, p <0.001). African American race (HR 0.79, p <0.001), Medicare (HR 0.86, p <0.001) and other government insurance (HR 0.73, p <0.001) were associated with delayed chemotherapy. Increasing age, African American or Hispanic race and longer time to chemotherapy predicted failure to undergo surgery. Furthermore, African American race was associated with delayed chemotherapy. Chemotherapy was also delayed in patients on Medicare or other government insurance. Longer time to neoadjuvant chemotherapy is a modifiable risk factor that should be closely observed in multimodal cancer treatment.


Infant's physiological response to short heat stress during sauna bath.
Thermoregulatory response to Finnish sauna bath was investigated in 47 infants (age 3 - 14 month). Before taking a short sauna bath lasting 3 min, the infants stayed in a swimming pool for 15 min. Under these conditions sauna bathing did not increase the rectal temperature. Unexpectedly rectal temperature even decreased by 0.2 degrees C (p < 0.05) probably due to redistribution of cold peripheral blood into the core of the body. Mean systolic and diastolic arterial blood pressure and mean heart rate remained unchanged after sauna bathing. The blood pressure amplitude decreased significantly after the swimming period from 47 mm Hg to 38 mm Hg (p < 0.05) and rose again after sauna bathing to 42 mm Hg. All infants tolerated short heat exposure in the sauna without side effects. The circulatory adjustment was efficient. Even young infants were able to cope with the acute circulatory changes imposed by heat stress. Adequate thermoregulatory and cardiovascular adaptive responses to sauna bathing could be shown for the first time in infants between 3 and 14 months of age.


Duration and dose of chemotherapy and dental development.
Given the susceptibility of developing tissues to drugs, even small doses of anticancer drugs may affect odontogenesis. Although any toxic effect is transient, the treatment regimens are based on repeated drug administration. The study aimed to establish the impact of antineoplastic therapy on the occurrence of longterm adverse dental effects in a dose-dependent manner in young survivors treated for cancer before 10 years of age. In total, 37 cancer survivors treated with antineoplastic therapy before 10 years of age underwent a dental examination with a thorough analysis of panoramic radiographs. A total of 236 teeth with 243 different developmental abnormalities were revealed in 28 survivors. Agenesis, tooth size reduction, taurodontia, and enamel and root abnormalities were diagnosed. All survivors received multi-agent chemotherapy, with the most frequently used drugs being vincristine (VCR), doxorubicin (DXR), cyclophosphamide (CP), ifosfamide (IF), etoposide (VP-16), carboplatin (CBDCA), cisplatin (CDDP), and actinomycin-D (ActD). A detailed analysis of medical records was also performed to assess the relationship between the treatment duration as well as the cumulative drug dose administered and the occurrence of particular disturbances. When analyzing the treatment duration and the drug doses in the affected and non-affected participants, there were no statistically significant differences between the survivors with different disturbances within most of the specific drug groups. In some groups, the mean cumulative treatment dose was significantly higher in the non-affected patients. According to Spearman's rho, no significant relationships were observed. In the present study, no significant differences in terms of treatment duration or drug doses were observed between the patients with particular abnormalities. The developmental stage of tooth formation during chemotherapy is likely the most important factor influencing dental changes. For future research with respect to different treatment protocols, an analysis of a more homogenous group of survivors is warranted.


The effect of sensitization and coping style on post-traumatic stress symptoms and quality of life: two longitudinal studies.
The present study investigated the effects of multiple trauma exposure and coping style on post-traumatic stress symptoms and quality of life. It was hypothesized that sensitization would occur in subjects repeatedly exposed to life-threatening situations (study 1), and different coping styles would act as a resilience or facilitating factor in symptom development (study 2). The results showed that the single-exposure group revealed a decrease in trauma specific stress reactions from three weeks to four months, with a persistent reduction at 12-month follow-up, while the repeated-exposure group showed an increase in symptom reporting over the 12-month period. The same pattern emerged for perceived quality of life-measured by the General Health Questionnaire (GHQ-30). The second study revealed a correlation between scores on avoidant-focused coping style and the Impact of Event Scale-avoidance dimension, Post-traumatic Symptom Scale and GHQ-30. Furthermore, only subjects with a dominant coping style of emotion-focused or task-focused coping showed a reduction in trauma-specific symptom scores over time.


Traffic lights detection and tracking for HD map creation.
HD-maps are one of the core components of the self-driving pipeline. Despite the effort of many companies to develop a completely independent vehicle, many state-of-the-art solutions rely on high-definition maps of the environment for localization and navigation. Nevertheless, the creation process of such maps can be complex and error-prone or expensive if performed via ad-hoc surveys. For this reason, robust automated solutions are required. One fundamental component of an high-definition map is traffic lights. In particular, traffic light detection has been a well-known problem in the autonomous driving field. Still, the focus has always been on the light state, not the features (i.e., shape, orientation, pictogram). This work presents a pipeline for lights HD-map creation designed to provide accurate georeferenced position and description of all traffic lights seen by a camera mounted on a surveying vehicle. Our algorithm considers consecutive detection of the same light and uses Kalman filtering techniques to provide each target's smoother and more precise position. Our pipeline has been validated for the detection and mapping task using the state-of-the-art dataset DriveU Traffic Light Dataset. The results show that our model is robust even with noisy GPS data. Moreover, for the detection task, we highlight how our model can correctly identify even far-away targets which are not labeled in the original dataset.


Cardiac function in experimental uremia.
In acutely uremic animals, the contractile force of the heart is consistently increased; such an increase can be dissociated from changes of afterload or catecholaminergic drive. It is associated with diminished sarcolemmal Na,K-ATPase activity in the heart which, in turn, may be related to increased levels of endogenous digitalis-like substances (endigens) that have been postulated to represent a natriuretic factor. In patients with chronic uremia, myocardial contractility is usually normal, but occasionally there may be heart failure unrelated to pre-existing hypertension, coronary heart disease, anemia, fluid overload, or other recognizable factors. So far, the experimental basis for this clinical observation is uncertain. Possible causes for the clinical syndrome include an excess of parathyroid hormone or cardiodepressor substances. There is experimental evidence of impaired cardiac response to beta adrenergic agonists, e.g., decreased isoproterenol-dependent calcium uptake, diminished inotropic and chronotropic responses. In acutely uremic rats, cardiac cyclic AMP levels are high but can be reversed by beta blockers. Heart calcium content is variable and heart weight is constantly increased in acutely uremic rats, despite decreased skeletal muscle mass. The change in heart weight is not related to anemia, to an excess of parathyroid hormone, or to sympathetic activity; its cause remains unknown. Experimental studies to date have shown a variety of abnormalities, but do not provide a uniform concept of the mechanisms or an explanation for the cardiac dysfunction so often observed in patients with uremia.


Clinically Important Deterioration (CID) and Ageing in COPD: A Systematic Review and Meta-Regression Analysis According to PRISMA Statement.
Clinically important deterioration (CID) is a composite endpoint developed to quantify the impact of pharmacological treatment in clinical trials for Chronic Obstructive Pulmonary Disease (COPD), also showing a prognostic value. CID is defined as any of the following condition: forced expiratory volume in 1 s decrease ≥100 mL from baseline, and/or St. George's Respiratory Questionnaire total score increase ≥4-unit from baseline, and/or the occurrence of a moderate-to-severe exacerbation of COPD. Although most COPD patients experience a clinical worsening as they get older, to date, no specific studies assessed the correlation between ageing and CID in COPD. Therefore, the aim of this study was to investigate the impact of ageing on CID in COPD patients. Data obtained from 55219 COPD patients were extracted from 17 papers, mostly post-hoc analyses. A pairwise meta-analysis and a meta-regression analysis were performed according to PRISMA-P guidelines to quantify the impact of pharmacological therapy on CID and to determine whether ageing might modulate the risk of CID in COPD patients. Inhaled treatments resulted generally effective in reducing the risk of CID in COPD (relative risk: 0.81, 95% confidence interval 0.79-0.84; P < 0.001). The meta-regression analysis indicated a trend toward significance (P = 0.063) in the linear relationship between age and the risk of CID. Of note, age significantly (P < 0.05) increased the risk of CID when associated with lower post-bronchodilator FEV1. These results were not affected by a significant risk of bias. This quantitative synthesis suggests that inhaled therapy is effective in reducing the risk of CID in COPD, although such a protective effect may be affected in older patients with impaired lung function. Further studies specifically designed on CID in COPD are needed to confirm these results.


Chronic Condition Combinations and Productivity Loss Among Employed Nonelderly Adults (18 to 64 Years).
We examined the relationship between specific chronic condition combinations and productivity loss measured by missed work days among nonelderly employed adults with at least two physical chronic conditions of arthritis, diabetes mellitus, heart disease, and hypertension. We analyzed data from the Medical Expenditure Panel Survey for the years 2004 to 2012. Adults with arthritis/diabetes/heart disease had the highest average missed work days (14.42). In the adjusted model, compared with adults with arthritis/hypertension, adults with diabetes/heart disease and arthritis/heart disease/hypertension had significantly higher missed work days, while adults with diabetes/hypertension had significantly lower missed work days. Specific chronic condition combinations have a high burden of disease in terms of productivity loss. Workplace health programs that address multiple health conditions at the same time should be implemented to reduce missed work days.


Quality at the point of service: profiles of practice in after-school settings.
A unique observational data set was used to explore quality at the point of service in after-school programs. Staff practices in after-school settings were represented on a series of unidimensional scales closely indexed to staff behavior. In order to account for heterogeneity of staff performances, pattern-centered methods were used to construct profiles of common staff practices. Results revealed six pedagogy profiles that were classified in terms of three broad types of performances delivered by after-school staff: (1) positive youth development, (2) staff-centered, and (3) low-quality. Staff membership in these profiles was not related to youth-staff ratio. However, results revealed significant differences between the profiles on the content of the offering and the age of youth in the setting.


LG-ESSs and HG-ESSs: underlying molecular alterations and potential therapeutic strategies.
Endometrial stromal tumors (ESTs) include endometrial stromal nodule (ESN), low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), and undifferentiated uterine sarcoma (UUS). Since these are rare tumor types, there is an unmet clinical need for the systematic therapy of advanced LG-ESS or HG-ESS. Cytogenetic and molecular advances in ESTs have shown that multiple recurrent gene fusions are present in a large proportion of LG-ESSs, and HG-ESSs are identified by the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon (YWHAE)-family with sequence similarity 22 (FAM22) fusion. Recently, a group of ESSs harboring both zinc finger CCCH domain-containing protein 7B (ZC3H7B)-B-cell lymphoma 6 corepressor(BCOR) fusion and internal tandem duplication (ITD) of the BCOR gene have been provisionally classified as HG-ESSs. In this review, we firstly describe current knowledge about the molecular characteristics of recurrent aberrant proteins and their roles in the tumorigenesis of LG-ESSs and HG-ESSs. Next, we summarize the possibly shared signal pathways in the tumorigenesis of LG-ESSs and HG-ESSs, and list potentially actionable targets. Finally, based on the above discussion, we propose a few promising therapeutic strategies for LG-ESSs and HG-ESSs with recurrent gene alterations.


Simple, low-cost fabrication of semi-circular channel using the surface tension of solder paste and its application to microfluidic valves.
This work presents a simple, low-cost method to fabricate semi-circular channels using solder paste, which can amalgamate the cooper surface to form a half-cylinder mold using the surface tension of Sn-Pd alloy (the main component in solder paste). This technique enables semi-circular channels to be manufactured with different dimensions. These semi-circular channels will then be integrated with a polymethylmethacrylate frame and machine screws to create miniaturized, portable microfluidic valves for sequential liquid delivery and particle synthesis. This approach avoids complicated fabrication processes and expensive facilities and thus has the potential to be a useful tool for lab-on-a-chip applications.