Single group multisite safety trial of sibling cord blood cell infusion to children with cerebral palsy: study protocol and rationale.
Cerebral palsy (CP) is the most common physical disability of childhood but has no cure. Stem cells have the potential to improve brain injury and are proposed as a therapy for CP. However, many questions remain unanswered about the most appropriate cell type, timing of infusions, dose required and associated risks. Therefore, human safety and efficacy trials are necessary to progress knowledge in the field. This is a single group study with sample size n=12 to investigate safety of single-dose intravenous 12/12 human leucocyte antigen-matched sibling cord blood cell infusion to children with CP aged 1-16 years without immune suppression. The study is similar to a 3+3 design, where the first two groups of participants have severe CP, and the final six participants include children with all motor severities. Children will be monitored for adverse events and the duration that donor cells are detected. Assessments at baseline, 3 and 12 months will investigate safety and preliminary evidence of change in gross motor, fine motor, cognitive and quality of life outcomes. Full approval was obtained from The Royal Children's Hospital Human Research Ethics Committee, and a clinical trial notification was accepted by Australia's Therapeutic Goods Administration. Participant guardian informed consent will be obtained before any study procedures. The main results of this study will be submitted for publication in a peer-reviewed journal. ACTRN12616000403437, NCT03087110.


Cyclooxygenase-2 alters transforming growth factor-beta 1 response during intestinal tumorigenesis.
Recent investigation suggests that cyclooxygenase-2 plays an important role in colorectal carcinogenesis. Transforming growth factor-beta1 (TGF-beta 1) is one of the most potent stimulators of cyclooxygenase-2 expression. A key step in intestinal tumorigenesis involves alteration of the normal cellular response to TGF-beta 1. We have hypothesized that overexpression of cyclooxygenase-2 alters intestinal epithelial response to TGF-beta 1. RIE-1 cells were stably transfected with rat cyclooxygenase-2 complementary DNA in either the sense (RIE-S) or antisense (RIE-AS) orientation. Tumor cell invasion was assessed with a modified Boyden collagen type I invasion assay in the presence of TGF-beta 1, antibody to urokinase plasminogen activator (uPA), or the selective cyclooxygenase-2 inhibitor SC-58125. Expression of uPA, uPA receptor, and plasminogen activator inhibitor-1 were determined by Western blot and enzyme-linked immunosorbent assay. RIE-1 and RIE-AS did not invade although RIE-S cells were minimally invasive at baseline. TGF-beta 1 had no effect on RIE-1 or RIE-AS invasion; however, TGF-beta 1 significantly upregulated RIE-S cell invasion. All 3 RIE cell lines produce minimal uPA under basal conditions. TGF-beta 1 upregulated uPA production only in the RIE-S cells. Both antibody to uPA and SC-58125 reversed TGF-beta-mediated RIE-S cell invasion. SC-58125 inhibited TGF-beta-mediated RIE-S uPA production. These results demonstrate that overexpression of cyclooxygenase-2 alters intestinal epithelial response to TGF-beta 1, which may be a mechanism by which cyclooxygenase-2 promotes colon carcinogenesis.


Use of Programmed Death Receptor-1 and/or Programmed Death Ligand 1 Inhibitors for the Treatment of Brain Metastasis of Lung Cancer.
The central nervous system (CNS) is regarded as an immune privileged environment; however, changes in the neuroimmunology paradigm have led to an increased interest in systematic immunotherapy in lung cancer therapy. The presence of the lymphatic system in the CNS as well as the physiological and biochemical changes in the blood-brain barrier in the tumor microenvironment suggests that immunocytes are fully capable of entering and exiting the CNS. Emerging clinical data suggest that inhibitors of programmed death receptor-1/programmed death ligand 1 (PD-1/PD-L1) can stimulate surrounding T cells and thus have antitumor effects in the CNS. For example, PD-1 antibody (pembrolizumab) monotherapy has displayed a 20-30% encephalic response rate in patients with brain metastases from malignant melanoma or non-small cell lung cancer. Combined application of nivolumab and ipilimumab anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 showed an encephalic response rate of 55% in patients with brain metastases of melanoma. Further evidence is required to verify these response rates and identify the mechanisms of curative effects and drug tolerance. While regional treatments such as whole-brain radiosurgery, stereotactic radiosurgery, and brain surgery remain the mainstream, PD-1/PD-L1 inhibitors display potential decreased neurotoxic effects. To date, five drugs have been approved for use in patients with encephalic metastases of lung carcinoma: the anti-PD-1 drugs, pembrolizumab and nivolumab, and the anti-PD-L1 agents, atezolizumab, durvalumab, and avelumab. In recent years, clinical trials of inhibitors in combination with other drugs to treat brain metastasis have also emerged. This review summarizes the biological principles of PD-1/PD-L1 immunotherapy for brain metastasis of lung cancer, as well as ongoing clinical trials to explore unmet needs.


Mesenchymal stem cells-derived exosomes: novel carriers for nanoparticle to combat cancer.
The advancement in novel cancer therapeutics brought a platform combining the properties of exosomes with nanoparticles to precision medicine. The novel therapeutic approach aim is cancer-targeted therapy. Exosomes from mesenchymal stem cells (MSCs-Exo) exhibit unique properties in cancer therapies, which makes them an ideal tool for delivering therapeutic agents into tumor cells. The key role of natural MSCs-Exo is controversial in cancer therapy; however, they can be engineered at their surface or cargo to serve as a smart drug delivery system for cancer-targeted therapy. In the last few years, researchers harnessed nanotechnology to enforce MSCs-Exo for cancer management including, tumor cell tracking, imaging, and tumor cell killing. Different nanoparticles such as gold nanoparticles have particularly been incorporated into MSCs-Exo, which showed an efficient accumulation at the site of tumor with improved anticancer impact. These findings indicate that a hybrid of exosomes-nanoparticles may serve as combination therapy for the effective removal of cancers. Although exhibiting impressive potential, the use of nanoparticle-loaded MSCs-Exo as a drug-delivery tool has been troubled by some challenges, therefore, translation to clinic prerequisites further scrutiny. In this review, we focus on nanoparticle-loaded MSCs-Exo as a new cancer therapy and discuss engineered MSC-Exo for target therapy.


Dihydropyridine-sensitive cell volume regulation in proximal tubule: the calcium window.
The mechanism underlying the activation of hypotonic cell volume regulation was studied in rabbit proximal straight tubule (PST). When isolated non-perfused tubules were exposed to hypotonic solution, cells swelled rapidly and then underwent a regulatory volume decrease (RVD). The extent of regulation after swelling was highly dependent on extracellular Ca concentration ([Ca2+]o), with a half-maximal inhibition (K1/2) for [Ca2+]o of approximately 100 microM. RVD was blocked by the Ca-channel blockers verapamil, lanthanum, and the dihydropyridines (DHP) nifedipine and nitrendipine, implicating voltage-activated Ca channels in the RVD response. Using the fura-2 fluorescence-ratio technique, we observed that cell swelling caused a sustained rise in intracellular Ca ([Ca2+]i) only when [Ca2+]o was normal (1 mM) but not when [Ca2+]o was low (1-10 microM). Furthermore, external Ca was required early on during swelling to induce RVD. If RVD was initially blocked by reducing [Ca2+]o or by addition of verapamil during hypotonic swelling, volume regulation could only be restored by subsequently inducing Ca entry within the first 1 min or less of exposure to hypotonic solution. These data indicate a "calcium window" of less than 1 min, during which RVD is sensitive to Ca, and that part of the Ca-dependent mechanism responsible for achieving RVD undergoes inactivation after swelling. It is concluded that RVD in rabbit PST is modulated by Ca via a DHP-sensitive mechanism in a time-dependent manner.


Early Fitting in Cochlear Implantation: Benefits and Limits.
Evaluation of a shortened delay time between surgical placement of the cochlear implant (CI) device and processor activation to less than 8 days (early CI fitting). Assessment of benefits and limits of early fitting in terms of medical, technical, audiological, and subjective outcome. Prospective. Tertiary referral center. Forty-one patients scheduled for cochlear implant surgery divided into early fit (EF, n = 21) and control group (CG, n = 19). Questionnaires were used to evaluate technical, medical, and subjective outcomes associated with early fitting. Additional, electrode impedance and speech recognition scores were measured. These data, collected preoperative, at first activation and after 3 months were compared with the CG with standard fitting. The medical and audiological status of the EF subjects allowed early fitting in nearly all patients (20/21). Evidence of pain, delayed wound healing, or other compromises was equal in both study groups. Speech recognition scores show comparable development over time for EF and CG. Average electrode impedance was significantly higher in the CG at first activation. Early fitting of the sound processor is feasible and did not compromise wound healing or generates additional pain. During the first month following surgery, reduction of wound swelling can be expected. Hence, regular inspection of magnet strength is recommended at follow-ups. Over all, early activation of their CI device was highly appreciated by nearly all patients.


Neo-sex chromosomes in the black muntjac recapitulate incipient evolution of mammalian sex chromosomes.
The regular mammalian X and Y chromosomes diverged from each other at least 166 to 148 million years ago, leaving few traces of their early evolution, including degeneration of the Y chromosome and evolution of dosage compensation. We studied the intriguing case of black muntjac, in which a recent X-autosome fusion and a subsequent large autosomal inversion within just the past 0.5 million years have led to inheritance patterns identical to the traditional X-Y (neo-sex chromosomes). We compared patterns of genome evolution in 35-kilobase noncoding regions and 23 gene pairs on the homologous neo-sex chromosomes. We found that neo-Y alleles have accumulated more mutations, comprising a wide variety of mutation types, which indicates cessation of recombination and is consistent with an ongoing neo-Y degeneration process. Putative deleterious mutations were observed in coding regions of eight investigated genes as well as cis-regulatory regions of two housekeeping genes. In vivo assays characterized a neo-Y insertion in the promoter of the CLTC gene that causes a significant reduction in allelic expression. A neo-Y-linked deletion in the 3'-untranslated region of gene SNX22 abolished a microRNA target site. Finally, expression analyses revealed complex patterns of expression divergence between neo-Y and neo-X alleles. The nascent neo-sex chromosome system of black muntjacs is a valuable model in which to study the evolution of sex chromosomes in mammals. Our results illustrate the degeneration scenarios in various genomic regions. Of particular importance, we report--for the first time--that regulatory mutations were probably able to accelerate the degeneration process of Y and contribute to further evolution of dosage compensation.


MicroRNA-155 Modulates Macrophages' Response to Non-Tuberculous Mycobacteria through COX-2/PGE2 Signaling.
Non-tuberculous mycobacteria (NTM) have been recognized as a causative agent of various human diseases, including severe infections in immunocompromised patients, such as people living with HIV. The most common species identified is the Mycobacterium avium-intracellulare complex (MAI/MAC), accounting for a majority of infections. Despite abundant information detailing the clinical significance of NTM, little is known about host-pathogen interactions in NTM infection. MicroRNAs (miRs) serve as important post-transcriptional regulators of gene expression. Using a microarray profile, we found that the expression of miR-155 and cyclo-oxygenase 2 (COX-2) is significantly increased in bone-marrow-derived macrophages from mice and human monocyte-derived macrophages from healthy volunteers that are infected with NTM. Antagomir against miR-155 effectively suppressed expression of COX-2 and reduced Prostaglandin E2(PGE2) secretion, suggesting that COX-2/PGE2 expression is dependent on miR-155. Mechanistically, we found that inhibition of NF-κB activity significantly reduced miR-155/COX-2 expression in infected macrophages. Most importantly, blockade of COX-2, E-prostanoid receptors (EP2 and EP4) enhanced killing of MAI in macrophages. These findings provide novel mechanistic insights into the role of miR-155/COX-2/PGE2 signalling and suggest that induction of these pathways enhances survival of mycobacteria in macrophages. Defining host-pathogen interactions can lead to novel immunomodulatory therapies for NTM infections which are difficult to treat.


Prospective randomized trial between two doses of granulocyte colony-stimulating factor after ifosfamide, carboplatin, and etoposide in children with recurrent or refractory solid tumors: a children's cancer group report.
The objectives of this study were: 1) to compare the time to hematologic recovery (absolute neutrophil count [ANC] > or = 1,000/mm3 and platelet count > or = 100,000/mm3) in a randomized prospective study of two doses of granulocyte colony-stimulating factor (G-CSF) (5.0 vs. 10.0 microg/kg per day) after ifosfamide, carboplatin, and etoposide (ICE) chemotherapy; and 2) to determine the response rate (complete response [CR] + partial response [PR]) of ICE in children with refractory or recurrent solid tumors. From June 1992 until November 1994, 123 patients with recurrent or refractory pediatric solid tumors were treated with ifosfamide (1,800 mg/m2 per day x 5), carboplatin (400 mg/m2 per day x 2), and etoposide (100 mg/m2 per day x 5) and randomized to receive either 5.0 microg/kg per day or 10.0 microg/kg per day of G-CSF subcutaneously until recovery of ANC to > or = 1,000/mm3. The incidence of grade 4 neutropenia during the first course was 88%. Median time from the start of chemotherapy to ANC > or = 1,000/mm(-3) for all patients during courses 1 and 2 was 21 and 19 days, respectively. The incidence of developing platelet count < or = 20,000/mm3 during course 1 was 82%. The median time from the start of the course of chemotherapy to platelet recovery > or =100,000/mm3 for all patients during courses 1 and 2 was 27 days. There was no significant difference in the median time of ANC recovery, platelet recovery, or incidence of grade 4 neutropenia; and in the median days of fever and the incidence of infections requiring hospitalization and intravenous antibiotics during courses 1 and 2, there was no significant difference between the two doses of G-CSF. One hundred eighteen patients were evaluated for response to ICE. The overall response rate (CR + PR) in this study was 51% (90% confidence interval, 43%-59%). The CR rate for all diagnostic categories was 27%. The Kaplan-Meier estimates of 1-year and 2-year survival probabilities for all patients were 52% and 30%, respectively. In summary, this combination of chemotherapy (ICE) was associated with a high CR rate (27%) in children with recurrent or refractory solid tumors, but also with a high incidence of grade 4 neutropenia and thrombocytopenia. Doubling the dose of G-CSF from 5.0 to 10.0 microg/kg per day after ICE chemotherapy did not result in an enhancement of neutrophil or platelet recovery or the incidence of grade 4 neutropenia developing.


Routine high dose excretory urography.
Radiologic evaluation of 316 excretory urograms utilizing a single 50 ml injection of a 50 to 60 per cent tri-iodinated contrast medium indicated that these studies are of better quality than those previously obtained with the injection of 30 ml. The low incidence of side effects coincides with recent reports in the literature that this dosage level is safe. High dose intravenous drip infusion pyelography was necessary only in selected cases. High dose excretory urography is recommended for routine use.


Modification of oral contraceptive relationships on breast cancer risk by selected factors among younger women.
In a case-control study of 1647 breast cancer cases and 1501 population controls under 45 years of age, potential modifying effects of other risk factors on the relationship of oral contraceptives to breast cancer were examined. Among the total series of study subjects, the relationship of extended pill usage was greater in non-white than white women. Oral contraceptive associations, however, did not appear to be substantially modified by other risk factors, including parity, body size, or family history of breast cancer (apart from a somewhat enhanced relationship among subjects who reported a sister with breast cancer. Further, oral contraceptive relationships did not vary by a history of benign breast disease, although the majority of subjects began pill usage prior to the development of benign breast disease. Among the women under the age of 35, in whom oral contraceptive relationships were heightened (over a twofold excess risk for use of 5 years or longer), pill relationships were less modified by race than in the total series. Although among these younger subjects there was no effect of pill usage in heavy women, and an enhanced relationship among heavier consumers of alcoholic beverages, these interactive effects were not statistically significant. The findings of this study generally support no substantial variation in oral contraceptive relationships by other breast cancer risk factors, although some further attention might be warranted regarding possible modifying effects of race, body size, type of relative with breast cancer, and alcohol consumption.


Modulation of COUP-TF expression in a cnidarian by ectopic Wnt signalling and allorecognition.
COUP transcription factors are required for the regulation of gene expression underlying development, differentiation, and homeostasis. They have an evolutionarily conserved function, being a known marker for neurogenesis from cnidarians to vertebrates. A homologue of this gene was shown previously to be a neuronal and nematocyte differentiation marker in Hydra. However, COUP-TFs had not previously been studied in a colonial cnidarian. We cloned a COUP-TF homologue from the colonial marine cnidarian Hydractinia echinata. Expression of the gene was analysed during normal development, allorecognition events and ectopic Wnt activation, using in situ hybridisation and quantitative PCR. During normal Hydractinia development, the gene was first expressed in post-gastrula stages. It was undetectable in larvae, and its mRNA was present again in putative differentiating neurons and nematocytes in post-metamorphic stages. Global activation of canonical Wnt signalling in adult animals resulted in the upregulation of COUP-TF. We also monitored a strong COUP-TF upregulation in stolons undergoing allogeneic interactions. COUP-TF mRNA was most concentrated in the tissues that contacted allogeneic, non-self tissues, and decreased in a gradient away from the contact area. Interestingly, the gene was transiently upregulated during initial contact of self stolons, but dissipated rapidly following self recognition, while in non-self contacts high expression levels were maintained. We conclude that COUP-TF is likely involved in neuronal/nematocyte differentiation in a variety of contexts. This has now been shown to include allorecognition, where COUP-TF is thought to have been co-opted to mediate allorejection by recruiting stinging cells that are the effectors of cytotoxic rejection of allogeneic tissue. Our findings that Wnt activation upregulates COUP-TF expression suggests that Wnts' role in neuronal differentiation could be mediated through COUP-TF.


Robust optimization for HDR prostate brachytherapy applied to organ reconstruction uncertainty.
Recently, we introduced a bi-objective optimization approach based on dose-volume indices to automatically create clinically good HDR prostate brachytherapy plans. To calculate dose-volume indices, a reconstruction algorithm is used to determine the 3D organ shape from 2D contours, inevitably containing settings that influence the result. We augment the optimization approach to quickly find plans that are robust to differences in 3D reconstruction. Studied reconstruction settings were: interpolation between delineated organ contours, overlap between contours, and organ shape at the top and bottom contour. Two options for each setting yields 8 possible 3D organ reconstructions per patient, over which the robust model defines minimax optimization. For the original model, settings were based on our treatment planning system. Both models were tested on data of 26 patients and compared by re-evaluating selected optimized plans both in the original model (1 organ reconstruction, the difference determines the cost), and in the robust model (8 organ reconstructions, the difference determines the benefit). Robust optimization increased the run time from 3 to 6 min. The median cost for robust optimization as observed in the original model was -0.25% in the dose-volume indices with a range of [-0.01%, -1.03%]. The median benefit of robust optimization as observed in the robust model was 0.93% with a range of [0.19%, 4.16%]. For 4 patients, selected plans that appeared good when optimized in the original model, violated the clinical protocol with more than 1% when considering different settings. This was not the case for robustly optimized plans. Plans of high quality, irrespective of 3D organ reconstruction settings, can be obtained using our robust optimization approach. With its limited effect on total runtime, our approach therefore offers a way to account for dosimetry uncertainties that result from choices in organ reconstruction settings that is viable in clinical practice.


The pathobiological impact of cigarette smoke on pancreatic cancer development (review).
Despite extensive efforts, pancreatic cancer remains incurable. Most risk factors, such as genetic disposition, metabolic diseases or chronic pancreatitis cannot be influenced. By contrast, cigarette smoking, an important risk factor for pancreatic cancer, can be controlled. Despite the epidemiological evidence of the detrimental effects of cigarette smoking with regard to pancreatic cancer development and its unique property of being influenceable, our understanding of cigarette smoke-induced pancreatic carcinogenesis is limited. Current data on cigarette smoke-induced pancreatic carcinogenesis indicate multifactorial events that are triggered by nicotine, which is the major pharmacologically active constituent of tobacco smoke. In addition to nicotine, a vast number of carcinogens have the potential to reach the pancreatic gland, where they are metabolized, in some instances to even more toxic compounds. These metabolic events are not restricted to pancreatic ductal cells. Several studies show that acinar cells are also greatly affected. Furthermore, pancreatic cancer progenitor cells do not only derive from the ductal epithelial lineage, but also from acinar cells. This sheds new light on cigarette smoke-induced acinar cell damage. On this background, our objective is to outline a multifactorial model of tobacco smoke-induced pancreatic carcinogenesis.


Applying Computational Fluid Dynamics in the Development of Smart Ripening Rooms for Traditional Cheeses.
Traditional ewe's cheese producers face certain challenges caused by fluctuating environmental parameters inside the ripening room, which lead to lack of homogeneity in the final product. The present research discusses the application of computer fluid dynamics for simulating the distribution of environmental parameters, predicting the airflow pattern, and identifying critical areas where such parameters could cause reduced cheese quality. A new monitoring system was developed including presence sensors, temperature and humidity dataloggers, pneumatic actuators, microcontrollers, and microcomputers connected remotely for control, data visualization, and processing. The validation of the computer simulation and monitoring system was made with a batch of 40 ewe's cheeses distributed in three different zones inside a prototype ripening room and ripened for 35 days. At 35 days, a physical, chemical, and microbiological characterization of cheeses was made for evaluation of the influence of environmental conditions on cheese quality. The comparison between simulated and local measurements showed close agreement, especially concerning air velocity inside the stacks of cheese. The results of Pearson's correlation analysis and PCA concluded that temperature affected the appearance of the rind, hardness, number and area occupied by holes. Humidity affected aw and mFeret. Air velocity affected pH and the circularity of gas holes.


Comparison of the kinetics of cycling of the transferrin receptor in the presence or absence of bound diferric transferrin.
The kinetics of cycling of the transferrin receptor in A431 human epidermoid-carcinoma cells was examined in the presence or absence of bound diferric transferrin. In order to investigate the properties of the receptor in the absence of transferrin, the cells were maintained in defined medium without transferrin. It was demonstrated that Fab fragments of a monoclonal anti-(transferrin receptor) antibody (OKT9) did not alter the binding of diferric 125I-transferrin to the receptor or change the accumulation of [59Fe]diferric transferrin by cells. OKT9 125I-Fab fragments were prepared and used as a probe for the function of the receptor. The first-order rate constants for endocytosis (0.16 +/- 0.02 min-1) and exocytosis (0.056 +/- 0.003 min-1) were found to be significantly lower for control cells than the corresponding rate constants for endocytosis (0.22 +/- 0.02 min-1) and exocytosis (0.065 +/- 0.004 min-1) measured for cells incubated with 1 microM-diferric transferrin (mean +/- S.D., n = 3). The cycling of the transferrin receptor is therefore regulated by diferric transferrin via an increase in both the rate of endocytosis and exocytosis. Examination of the accumulation of OKT9 125I-Fab fragments indicated that diferric transferrin caused a marked decrease in the amount of internalized 125I-Fab fragments associated with the cells after 60 min of incubation at 37 degrees C. Diferric transferrin therefore increases the efficiency of the release of internalized 125I-Fab fragments compared with cells incubated without diferric transferrin. These data indicate that transferrin regulates the sorting of the transferrin receptor at the cell surface and within endosomal membrane compartments.


Cortical responses to thermal pain depend on stimulus size: a functional MRI study.
Cortical activity patterns to thermal painful stimuli of two different sizes were examined in normal volunteers using functional magnetic resonance imaging (fMRI). Seven right-handed subjects were studied when the painful stimulus applied to the right hand fingers covered either 1,074-mm(2)-area large stimulator or 21-mm(2)-area small stimulator. Stimulus temperatures were adjusted to give rise to equivalent moderately painful ratings. fMRI signal increases and decreases were determined for the contralateral parietal and motor areas. When the overall activity in these regions was compared across subjects, increased fMRI activity was observed over more brain volume with the larger stimulator, whereas decreased fMRI activity was seen in more brain volume for the smaller stimulator. The individual subject and group-averaged activity patterns indicated regional specific differences in increased and decreased fMRI activity. The small stimulator resulted in decreased fMRI responses throughout the upper body representation in both primary somatosensory and motor cortices. In contrast, no decreased fMRI signals were seen in the secondary somatosensory cortex and in the insula. In another seven volunteers, the effects of the size of the thermal painful stimulus on vibrotactile thresholds were examined psychophysically. Painful stimuli were delivered to the fingers and vibrotactile thresholds were measured on the arm just distal to the elbow. Consistent with the fMRI results in the primary somatosensory cortex, painful thermal stimuli using the small stimulator increased vibrotactile thresholds on the forearm, whereas similarly painful stimuli using the large stimulator had no effect on forearm vibrotactile thresholds. These results are discussed in relation to the cortical dynamics for pain perception and in relation to the center-surround organization of cortical neurons.


Programmed Death-1 Pathway in Orbital Invasion of Cutaneous Carcinomas.
The programmed death-1 pathway negatively regulates the immune system. Previous reports have indicated worse tumor-related outcomes with increased expression of the ligand for this pathway. This study was undertaken to assess the role of the PD pathway in cutaneous malignancies that invade the orbit. Immunohistochemical staining for the programmed death-1 receptor and ligand was performed on exenteration specimens of invasive cutaneous orbital malignancies (n = 12) and nodular basal cell carcinoma (n = 10). The numbers of positively-staining cells/40× field were counted across 5 consecutive fields, and statistical analyses were performed to compare the differences between the 2 groups. Programmed death-1 receptor positivity was seen in means of 30.9 cells/40× field and 62.4 cells/40× field for nodular basal cell carcinomas and invasive malignancies, respectively (p = 0.0046). A mean of 4.54 cells/40× field stained positively for the programmed death-1 ligand in nodular basal cell carcinoma, whereas a mean of 46.4 cells/40× field stained positively for programmed cell death ligand-1 in orbital invasive cutaneous carcinomas (p = 0.0015). Both of these differences were statistically significant. Both the programmed death-1 receptor and its ligand are enriched in invasive cutaneous malignancies. This finding indicates that negative regulation of the immune system likely prohibits tumor surveillance, and facilitates increasing aggressiveness and invasion of cutaneous malignancies.


The adenine nucleotide translocase: a central component of the mitochondrial permeability transition pore and key player in cell death.
In addition to its normal function, the adenine nucleotide translocase (ANT) forms the inner membrane channel of the mitochondrial permeability transition pore (MPTP). Binding of cyclophilin-D (CyP-D) to its matrix surface (probably on Pro(61) on loop 1) facilitates a calcium-triggered conformational change converting it from a specific transporter to a non-specific pore. The voltage dependent anion channel (VDAC) binds to the outer face of the ANT, at contact sites between the inner and outer membranes, and together VDAC, ANT and CyP-D probably represent the minimum MPTP configuration. The evidence for this is critically reviewed as is the structure and molecular mechanism of the carrier in its normal physiological mode. This provides helpful insights into MPTP regulation by adenine nucleotides, membrane potential and ANT ligands such as carboxyatractyloside and bongkrekic acid. Oxidative stress activates the MPTP by glutathione-mediated cross-linking of Cys(159) and Cys(256) on matrix-facing loops of the ANT that inhibits ADP binding and enhances CyP-D binding. Molecular modeling of the loop containing the ADP binding site suggests an arrangement of aspartate and glutamate residues that may provide a calcium binding site. There are other proteins that may bind to the ANT, modulating MPTP opening and hence cell death. These included members of the Bax/Bcl-2 family (both oncoproteins and tumor suppressors) and viral proteins. Vpr from HIV-1 can bind to ANT and convert it into a pro-apoptotic pore, whereas vMIA from cytomegalovirus interacts to inhibit opening. Thus the ANT may provide a molecular link between physiopathological mechanisms of infection and the regulation of MPTP function and so represents a potential therapeutic target.


Editorial: Acknowledging complexity and heterogeneity in causality--implications of recent insights into neuropsychology of childhood disorders for clinical practice.
From a clinical perspective research that tries to unravel the causal processes that underpin mental health problems can often seem esoteric and far removed from day to day clinical decision making. Indeed even though there are now a plethora of evidence based clinical guidelines that aim to support the translational process it still takes many years for new scientific understanding of a condition to permeate routine clinical practice, via this route. At the same time, however, a clinician's personal and informal interpretation of what is causing their patients' problems can have very important clinical implications and impact directly on; their formulation of a patient's presentation, the way in which they transmit this to the patient and their family and any treatment decisions that are made. Clinicians who are able to stay up to date with the latest evidence and scientific debate about what is and is not known about the underlying causes of mental health problems should be at an advantage in this regard. But for the busy clinician, 'just' staying up to date with the huge amount of new directly related to this topic is in itself a big ask in itself - critically appraising this evidence, in a balanced way, another thing altogether. To facilitate this process it is necessary for researchers to make every effort to include a balanced, clear and relevant discussion of the translational implications of their findings. In particular they must try to avoid overselling a message that may attract a lot of initial attention but that may, in time, prove to be a false dawn or an over simplification.


High-intensity Statin Treatments in Clinically Stable Patients on Aspirin Monotherapy 12 Months After Drug-eluting Stent Implantation: A Randomized Study.
Current guidelines on the treatment of blood cholesterol recommend continuous maintenance of high-intensity statin treatment in drug-eluting stent (DES)-treated patients. However, high-intensity statin treatment is frequently underused in clinical practice after stabilization of DES-treated patients. Currently, the impact of continuous high-intensity statin treatment on the incidence of late adverse events in these patients is unknown. We investigated whether high-intensity statin treatment reduces late adverse events in clinically stable patients on aspirin monotherapy 12 months after DES implantation. Clinically stable patients who underwent DES implantation 12 months previously and received aspirin monotherapy were randomly assigned to receive either high-intensity (40mg atorvastatin, n = 1000) or low-intensity (20mg pravastatin, n = 1000) statin treatment. The primary endpoint was adverse clinical events at 12-month follow-up (a composite of all death, myocardial infarction, revascularization, stent thrombosis, stroke, renal deterioration, intervention for peripheral artery disease, and admission for cardiac events). The primary endpoint at 12-month follow-up occurred in 25 patients (2.5%) receiving high-intensity statin treatment and in 40 patients (4.1%) receiving low-intensity statin treatment (HR, 0.58; 95%CI, 0.36-0.92; P = .018). This difference was mainly driven by a lower rate of cardiac death (0 vs 0.4%, P = .025) and nontarget vessel myocardial infarction (0.1 vs 0.7%, P = .033) in the high-intensity statin treatment group. Among clinically stable DES-treated patients on aspirin monotherapy, high-intensity statin treatment significantly reduced late adverse events compared with low-intensity statin treatment. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01557075.


[The effect of the concentration and nature of 1-1-valent electrolytes on acid-base equilibrium in solutions of DNA].
The effect of concentration of LiCl, NaCl, KCl and NH4Cl on the potentiometric titration curves of chicken erythrocyte DNA has been studied. Two inflections have been found in the titration curves at pH 5 and pH 8, respectively. The ionization constant corresponding to the second inflection is slightly increased when the concentrations of NaCl, KCl and NH4Cl are increased. Both constants are increased when the concentration of LiCl is increased. It has also been found that the addition of LiCl to the DNA solution lowers the pH of the solution but the addition of the other investigated salts causes an increase of the pH of DNA solutions. The results found are used for discussion of the nature of acid groups of DNA.


A survey of preconceptional folic acid use in a group of Canadian women.
Randomized controlled trials have demonstrated that periconceptional folic acid supplementation has a dramatic effect in reducing neural tube defects, one of the most serious congenital anomalies. Unfortunately, supplementation tends to be suboptimal in disadvantaged populations. The primary objective was to determine patient factors associated with a lack of use of periconceptional folic acid among Canadian women in a multi-ethnic, urban setting. Our secondary objective was to assess patient knowledge about folic acid tablet supplementation and its link to reduced birth defects. We undertook a cross-sectional study to survey postpartum Toronto women on their use and knowledge of periconceptional folic acid. Of the 383 women surveyed, only 28% took folic acid or a multivitamin containing folic acid during the periconceptional period. Multivariate analysis revealed that the use of periconceptional folic acid was more common among women of Jewish descent (adjusted relative risk [RR] 0.3; 95% confidence interval [CI], 0.04-0.9) and those who had 1 or no children (adjusted RR 0.6; 95% CI, 0.4-0.8). Not taking folic acid was associated with unplanned pregnancy (adjusted RR 1.5; 95% CI, 1.4-1.6) and a lack of knowledge about when folic acid should be taken (adjusted RR 1.8; 95% CI, 1.6-1.8). Ethnic background is an independent predictor of periconceptional folic acid use.


Gastrointestinal mucins of Fut2-null mice lack terminal fucosylation without affecting colonization by Candida albicans.
Posttranslational modification of apomucins by the sequential action of glycosyltransferases is required to produce mature mucins. The Secretor gene (FUT2) encodes an alpha(1,2)fucosyltransferase (EC 188.8.131.52) that catalyzes addition of terminal alpha(1,2)fucose residues on mucins and other molecules in mucosal epithelium. Mutant mice containing targeted replacement of Fut2 with the bacterial reporter gene lacZ were studied to determine the affect of the loss of Fut2 on glycosylation of mucins in the gastrointestinal tract. By whole organ X-gal staining, lacZ activity is prominently expressed in the foveolar pit and chief cells of the glandular stomach, Brunner's glands of the duodenum, and goblet cells in the large intestine of Fut2-LacZ-null mice. Staining with Aleuria aurantia agglutinin demonstrates loss of L-fucosylated epithelial glycans throughout the gastrointestinal tract of Fut2-LacZ-null mice, however, histologic appearance of the tissues appears normal. Analysis of oligosaccharides released from insoluble colonic mucins, largely Muc2, by mass spectrometry shows complete lack of terminal fucosylation of O-linked oligosaccharides in Fut2-LacZ-null mice. Precursor glycans accumulate with no evidence of compensation by other fucosyltransferases or sialyltransferases on mucin glycosylation. Because Candida albicans has been reported to adhere to intestinal mucins creating a potential reservoir associated with vaginitis, Fut2-LacZ-null and wild-type mice were inoculated by gastric lavage with C. albicans. We observe no difference in colonization between genotypes suggesting mucin terminal fucosylation does not significantly influence C. albicans-host interaction in the intestine, highlighting that infections caused by the same organism at different mucosal surfaces are not equal.


Characterisation of sulphonylurea and ATP-regulated K+ channels in rat pancreatic A-cells.
We have monitored whole-cell and single channel ATP-sensitive K+ (KATP) currents in isolated rat glucagon-secreting pancreatic A-cells. Tolbutamide produced a concentration-dependent decrease in the whole-cell KATP conductance (Ki = 6 microM) and initiated action potential firing. The K+ channel opener diazoxide, but not cromakalim or pinacidil, inhibited electrical activity and increased the whole-cell K+ conductance fourfold. ATP applied to the intracellular face of the membrane inhibited KATP channel activity with a Ki of 17 microM, an effect that could be counteracted by Mg-ADP and Mg-GDP. GTP and UTP did not affect KATP channel activity. Phosphatidylinositol 4,5-bisphosphate activated KATP channels inhibited by ATP after a delay of 90 s. In situ hybridisation demonstrated the expression of the mRNA encoding KATP channel subunits Kir6.2 and SUR1 but not Kir6.1 and SUR2. We conclude that rat pancreatic A-cells express KATP channels with the nucleotide-, sulphonylurea- and K+ channel-opener sensitivities expected for a channel formed by Kir6.2 and SUR1 subunits.


Traceable Research Data Sharing in a German Medical Data Integration Center With FAIR (Findability, Accessibility, Interoperability, and Reusability)-Geared Provenance Implementation: Proof-of-Concept Study.
Secondary investigations into digital health records, including electronic patient data from German medical data integration centers (DICs), pave the way for enhanced future patient care. However, only limited information is captured regarding the integrity, traceability, and quality of the (sensitive) data elements. This lack of detail diminishes trust in the validity of the collected data. From a technical standpoint, adhering to the widely accepted FAIR (Findability, Accessibility, Interoperability, and Reusability) principles for data stewardship necessitates enriching data with provenance-related metadata. Provenance offers insights into the readiness for the reuse of a data element and serves as a supplier of data governance. The primary goal of this study is to augment the reusability of clinical routine data within a medical DIC for secondary utilization in clinical research. Our aim is to establish provenance traces that underpin the status of data integrity, reliability, and consequently, trust in electronic health records, thereby enhancing the accountability of the medical DIC. We present the implementation of a proof-of-concept provenance library integrating international standards as an initial step. We adhered to a customized road map for a provenance framework, and examined the data integration steps across the ETL (extract, transform, and load) phases. Following a maturity model, we derived requirements for a provenance library. Using this research approach, we formulated a provenance model with associated metadata and implemented a proof-of-concept provenance class. Furthermore, we seamlessly incorporated the internationally recognized Word Wide Web Consortium (W3C) provenance standard, aligned the resultant provenance records with the interoperable health care standard Fast Healthcare Interoperability Resources, and presented them in various representation formats. Ultimately, we conducted a thorough assessment of provenance trace measurements. This study marks the inaugural implementation of integrated provenance traces at the data element level within a German medical DIC. We devised and executed a practical method that synergizes the robustness of quality- and health standard-guided (meta)data management practices. Our measurements indicate commendable pipeline execution times, attaining notable levels of accuracy and reliability in processing clinical routine data, thereby ensuring accountability in the medical DIC. These findings should inspire the development of additional tools aimed at providing evidence-based and reliable electronic health record services for secondary use. The research method outlined for the proof-of-concept provenance class has been crafted to promote effective and reliable core data management practices. It aims to enhance biomedical data by imbuing it with meaningful provenance, thereby bolstering the benefits for both research and society. Additionally, it facilitates the streamlined reuse of biomedical data. As a result, the system mitigates risks, as data analysis without knowledge of the origin and quality of all data elements is rendered futile. While the approach was initially developed for the medical DIC use case, these principles can be universally applied throughout the scientific domain.


Antigenic profile of muscularis mucosae and muscularis propria of the urinary bladder.
Differentiation between the muscularis mucosae (MM) and muscularis propria (MP) of the bladder remains challenging. To identify MM- and MP-specific antigens that could be of potential value for staging of urothelial carcinoma in a pilot study. The expression of 12 protein antigens in 11 human bladder specimens was examined. There were 5 post radical cystectomy specimens and 6 normal bladder autopsy specimens. Antibodies against actin, caldesmon, type IV collagen, cytokeratin, desmin, elastin, fibronectin, filamin, laminin, miotilin, smoothelin, and vimentin were used. Slides were stained with immunohistochemical reagents and assessed using light microscopy. The intensity of the immune reaction within MM and MP was evaluated in a four-level scale as negative and weakly, moderately or strongly positive. The presence of MM was noticed in 63.6% of specimens. The expression of desmin, filamin, and smoothelin was stronger within MP compared to MM in all cases. Stronger reaction with anti-type IV collagen antibodies was noticed within MP in 80% of the cases. In the whole study group, the expression of vimentin was stronger within MM than MP. MM and MP cells are of different antigenic characteristics. This can be used in the microscopic diagnostics of selected cases. The results need to be validated in a series of specimens from transurethral resection.


Microsomal epoxide hydrolase (EPHX1) polymorphisms are associated with aberrant promoter methylation of ERCC3 and hematotoxicity in benzene-exposed workers.
Benzene is an important industrial chemical and widespread environmental pollutant known to induce leukemia and other blood disorders. To be carcinogenic, benzene must be metabolized to produce toxic metabolites. To investigate whether single nucleotide polymorphisms (SNPs) in the metabolic enzyme genes are associated with benzene-induced alterations in DNA methylation and hematotoxicity, we genotyped four commonly studied SNPs in three metabolic enzymes genes CYP1A1, EPHX1 and NQO1; and analyzed promoter DNA methylation status in 11 genes which have been reported to be associated with benzene-induced hematotoxicity (BLM, CYP1A1, EPHX1, ERCC3, NQO1, NUDT1, p15, p16, RAD51, TP53 and WRAP53) in 77 benzene-exposed workers and 25 unexposed controls in China. ERCC3, a DNA repair gene, showed a small but statistically significant increase of promoter DNA methylation in the exposed group compared with the unexposed group (mean ± SD: 4.73 ± 3.46% vs. 3.63 ± 1.96%, P = 0.048). We also observed that an increased number of C allele for rs1051740 in EPHX1 was associated with decreased ERCC3 methylation levels in benzene-exposed workers (P(trend) = 0.001), but not in unexposed controls (P(trend) = 0.379). Interestingly, another EPHX1 SNP (rs2234922) was associated with lower white blood cell (WBC) counts (P(trend) = 0.044) in benzene-exposed workers. These associations remained the same when ERCC3 promoter methylation and WBCs were dichotomized according to the 90th percentile (≥6%) of methylation levels in controls and a leucopenia cutoff (<4 × 10(9) /L), respectively. Our findings suggest that benzene exposure may be associated with hypermethylation in ERCC3, and that genetic variants in EPHX1 may play an important role in epigenetic changes and hematotoxicity among benzene-exposed workers.


Effects of Two Cannabidiol Oil Products on Self-Reported Stress Relief: A Quasi-Experimental Study.
Estimated rates of past-month cannabidiol (CBD) use in the general public are 13-26% and emerging research examines CBD as a potential adjunct treatment for several medical conditions, including stress-related disorders (e.g., depression, anxiety, and chronic pain). However, little is known about the effects of different CBD products on self-reported stress. The present study compared the effects of two delta-9-tetrahydrocannabinol (THC)-free CBD tincture products - (1) an isolate CBD oil and (2) a broad spectrum CBD oil - on self-ratings of effectiveness of the product and ability to manage stress. This quasi-experimental study reports on a total of 374 participants who completed either a 30- or 60-day regimen. Participants were instructed to use a 1,000 mg CBD isolate product at will, and then switch over to a 1,000 mg broad spectrum product for the remainder of the regimen (i.e., next 15 or 30 days). Self-reported effectiveness of the product and its ability to help manage stress was compared between the isolate and broad spectrum products. We also examined overall impression, quality, taste, and adverse effects of each product. Overall, both products were rated to be highly effective and able to assist with stress management. Participants reported that the broad spectrum product's effectiveness (p < 0.001) and ability to reduce stress (p < 0.001) as greater than the isolate product across both regimens. However, participants preferred the taste of the isolate product over that of the broad spectrum across regimens (p < 0.05). For the 30-day regimen, participants reported a more positive overall impression of the isolate as compared to the broad spectrum (p < 0.001); however, overall impression did not differ between the products in the 60-day regimen. There was no difference in adverse effects or quality between the products, across both regimens. These results fit with prior studies suggesting anti-stress effects of CBD. Ratings were higher for the broad spectrum as compared to the isolate product, which is consistent with prior data suggesting that cannabinoids can work synergistically to maximize benefits. Nonetheless, more controlled studies are needed to explore these effects in nonclinical and clinical populations.


Effects of fatigue and kinesiophobia on functional capacity, physical activity and quality of life in Parkinson's disease.
The aim of this study was to investigate the effects of fatigue and fatigue-related kinesiophobia on functional capacity, physical activity and quality of life in patients with Parkinson's disease. Twenty patients with Parkinson's disease were included in the study. The fatigue severity was assessed by the Fatigue Severity Scale, kinesiophobia by the Tampa Kinesiophobia Scale, functional capacity with the Six-Minute Walk Test, and quality of life was evaluated by the Parkinson's Disease Questionnaire. In addition, the physical activity level of each patient, such as the number of steps, active energy expenditure and total energy expenditure, were recorded for one week with an activity monitor mounted on the patients' arms. The mean age of the patients (10 female/10 male) was 69.85 ± 9.38. According to the multiple regression analysis, a significant correlation was found between fatigue with 6-min walking test score (P = 0.039) and number of steps (P = 0.030). Also, a significant correlation was found between kinesiophobia with total energy expenditure (P = 0.013) and quality of life (P = 0.042). While fatigue was a significant determinant for functional capacity and number of steps, kinesiophobia was a significant determinant for total energy expenditure and quality of life. Fatigue and kinesiophobia are emphasized less compared to other findings in Parkinson's disease. However, fatigue and kinesiophobia symptoms negatively affect the functional capacity, physical activity and quality of life of patients. The results of this study revealed the need to evaluate fatigue and kinesiophobia, and the need to use physiotherapy and rehabilitation interventions to reduce these symptoms.


Extracorporeal membrane oxygenation support may be a lifesaving modality in patients with burn and severe acute respiratory distress syndrome: Experience of Formosa Water Park dust explosion disaster in Taiwan.
Extracorporeal membrane oxygenation (ECMO) has been reported to improve outcomes in patients with refractory respiratory failure. These successful experiences have stimulated interest in using ECMO as a potential therapy for patients with acute pulmonary failure resulting from burn and inhalation lung injury. Current literature has supported the use of ECMO in critically-ill, pediatric burn patients. On the other hand, it is controversial to apply ECMO in adult burn patients, and the evidence is limited by the shortcomings of small sample size. We share our successful experience of ECMO treatment in the casualties of the Formosa Water Park Dust Explosion Disaster. We investigated the data from the dust explosion event, which happened on June 27, 2015, in New Taipei, Taiwan. The medical records of five patients with severe acute respiratory distress syndrome receiving ECMO were evaluated. The mean study subject age was 21.8 years, with a mean total body surface area burned of 82.9%. The average time to ECMO setup was 48.6 days. Survivors and non-survivors averaged four days and 77.7 days, respectively. The overall mortality rate was 40%. Three survivors were discharged without any ECMO-related complications or pulmonary sequelae after one year of follow up. ECMO may be a lifesaving modality for burn patients with severe lung injury who are nonresponsive to maximal medical management, especially for young patients with early ECMO intervention.


A neural network model for the development of simple and complex cell receptive fields within cortical maps of orientation and ocular dominance.
Prenatal development of the primary visual cortex leads to simple cells with spatially distinct and oriented ON and OFF subregions. These simple cells are organized into spatial maps of orientation and ocular dominance that exhibit singularities, fractures, and linear zones. On a finer spatial scale, simple cells occur that are sensitive to similar orientations but opposite contrast polarities, and exhibit both even-symmetric and odd-symmetric receptive fields. Pooling of outputs from oppositely polarized simple cells leads to complex cells that respond to both contrast polarities. A neural network model is described which simulates how simple and complex cells self-organize starting from unsegregated and unoriented geniculocortical inputs during prenatal development. Neighboring simple cells that are sensitive to opposite contrast polarities develop from a combination of spatially short-range inhibition and high-gain recurrent habituative excitation between cells that obey membrane equations. Habituation, or depression, of synapses controls reset of cell activations both through enhanced ON responses and OFF antagonistic rebounds. Orientation and ocular dominance maps form when high-gain medium-range recurrent excitation and long-range inhibition interact with the short-range mechanisms. The resulting structure clarifies how simple and complex cells contribute to perceptual processes such as texture segregation and perceptual grouping.


Radiation force and torque on an elliptical cylinder illuminated by a TE-polarized non-paraxial focused Gaussian light sheet with arbitrary incidence.
Predicting and computing the optical radiation force and torque experienced by an elliptical cylinder illuminated by a structured finite light-sheet beam in two dimensions (2D) remains a challenge from the standpoint of light-matter interactions in electromagnetic (EM) optics, tweezers, laser trapping, and scattering theory. In this work, the partial-wave series expansion method in cylindrical coordinates (which utilizes standard Bessel and Hankel wave functions) is proposed, verified, and validated. Exact expressions for the longitudinal and transverse radiation force components (per length) as well as the axial radiation torque component (per length) are derived analytically without any approximations. The example of a TE-polarized non-paraxial focused Gaussian light sheet illuminating a perfect electrically conducting (PEC) elliptical cylinder is considered. The scattering coefficients of the elliptical cylinder are determined by imposing the Neumann boundary condition and numerically solving a linear system of equations by matrix inversion. The structural functions are determined using a single numerical angular integration procedure to enforce the orthogonality and thus validity of the solution, making the proposed method semi-analytical. Calculations are performed for the non-dimensional longitudinal and transverse radiation force efficiencies (or functions) as well as the axial radiation torque efficiency. Emphases are given to varying the ellipticity of the cylindrical particle, its non-dimensional size, the non-paraxial beam waist (i.e., focusing), and the angle of incidence in the polar plane. Suitable convergence plots confirm the validity of the partial-wave series method to evaluate accurately the radiation force and torque with no limitation to a particular frequency range or particle size. The results are mostly relevant in understanding the fundamentals of the optical/EM radiation force and torque theories for structured focused light sheets and related applications dealing with the interactions of EM waves with elongated tubular particles with elliptical surfaces in particle manipulation and other areas. The analogy with the acoustical counterpart is also noted, which shows the universal character of the radiation force and torque phenomena.


Automatic generation of computable implementation guides from clinical information models.
Clinical information models are increasingly used to describe the contents of Electronic Health Records. Implementation guides are a common specification mechanism used to define such models. They contain, among other reference materials, all the constraints and rules that clinical information must obey. However, these implementation guides typically are oriented to human-readability, and thus cannot be processed by computers. As a consequence, they must be reinterpreted and transformed manually into an executable language such as Schematron or Object Constraint Language (OCL). This task can be difficult and error prone due to the big gap between both representations. The challenge is to develop a methodology for the specification of implementation guides in such a way that humans can read and understand easily and at the same time can be processed by computers. In this paper, we propose and describe a novel methodology that uses archetypes as basis for generation of implementation guides. We use archetypes to generate formal rules expressed in Natural Rule Language (NRL) and other reference materials usually included in implementation guides such as sample XML instances. We also generate Schematron rules from NRL rules to be used for the validation of data instances. We have implemented these methods in LinkEHR, an archetype editing platform, and exemplify our approach by generating NRL rules and implementation guides from EN ISO 13606, openEHR, and HL7 CDA archetypes.


An Overview of Emergent Order in Far-from-Equilibrium Driven Systems: From Kuramoto Oscillators to Rayleigh-Bénard Convection.
Soft-matter systems when driven out of equilibrium often give rise to structures that usually lie in between the macroscopic scale of the material and microscopic scale of its constituents. In this paper we review three such systems, the two-dimensional square-lattice Ising model, the Kuramoto model and the Rayleigh-Bénard convection system which when driven out of equilibrium give rise to emergent spatio-temporal order through self-organization. A common feature of these systems is that the entities that self-organize are coupled to one another in some way, either through local interactions or through a continuous media. Therefore, the general nature of non-equilibrium fluctuations of the intrinsic variables in these systems are found to follow similar trends as order emerges. Through this paper, we attempt to find connections between these systems, and systems in general which give rise to emergent order when driven out of equilibrium. This study, thus acts as a foundation for modeling a complex system as a two-state system, where the states: order and disorder can coexist as the system is driven away from equilibrium.


Positive and negative selection of functional mouse CD4 cells by porcine MHC in pig thymus grafts.
Specific tolerance to discordant xenogeneic donors can be achieved by grafting of fetal pig thymic and liver tissue (FP THY/LIV) to T cell and NK cell-depleted, thymectomized (ATX) mice. Mouse CD4+ T cells develop in FP THY/LIV grafts, and demonstrate remarkably normal immune function, including host-restricted responses to keyhole limpet hemocyanin. We have therefore studied the role of host MHC class II in the development of mouse T cells in FP THY/LIV grafts by comparing their development in ATX MHC class II-deficient (IIKO) and wild-type (H-2b) mice. Mouse CD4+ T cells repopulated T/NK cell-depleted, ATX IIKO mice after grafting with FP THY/LIV, indicating that pig MHC can positively select mouse CD4 cells. Expression of TCR, MHC class I, Qa-2, heat-stable Ag, and CD45RB among double-positive and CD4 single-positive (SP) graft thymocytes in wild-type recipients was similar to that in normal mouse thymi, whereas CD4 SP thymocytes in grafts of IIKO mice showed increased Qa-2 and decreased heat-stable Ag expression, suggesting an increased level of maturity. Double-positive cells in grafts of IIKO mice also expressed higher than normal levels of Qa-2. Deletion within the grafts of Vbeta3+, Vbeta5.1/5.2+, and Vbeta11+ but not Vbeta6+, Vbeta7+, or Vbeta8.1/8.2+ mouse CD4 SP thymocytes in ATX IIKO mice demonstrated that swine leukocyte Ag participates in negative selection of the T cell repertoire. Therefore, porcine MHC mediates positive and negative selection of mouse thymocytes, but host class II MHC molecules also regulate thymocyte maturation in xenogeneic thymic grafts.


Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases.
The minichromosome maintenance (MCM) 2-7 helicase complex functions to initiate and elongate replication forks. Cell cycle checkpoint signaling pathways regulate DNA replication to maintain genomic stability. We describe four lines of evidence that ATM/ATR-dependent (ataxia-telangiectasia-mutated/ATM- and Rad3-related) checkpoint pathways are directly linked to three members of the MCM complex. First, ATM phosphorylates MCM3 on S535 in response to ionizing radiation. Second, ATR phosphorylates MCM2 on S108 in response to multiple forms of DNA damage and stalling of replication forks. Third, ATR-interacting protein (ATRIP)-ATR interacts with MCM7. Fourth, reducing the amount of MCM7 in cells disrupts checkpoint signaling and causes an intra-S-phase checkpoint defect. Thus, the MCM complex is a platform for multiple DNA damage-dependent regulatory signals that control DNA replication.


Distress and resilience among unintentional injuries survivors in Kenya: A qualitative study.
Unintentional injuries such as road traffic injuries constitute a major facet of health and disability in low- and middle-income countries. Survivors of moderate or severe unintentional injuries are at risk of psychological distress, although many people show resilience during recovery. This article describes the experience and contributing factors of psychological distress and resilience over the course of recovery among unintentional injury survivors in urban Kenya. We examined the various social and mental health consequences over the course of injury and recovery through conducting in-depth interviews with 28 survivors of unintentional injuries in Nairobi, Kenya, 4-8 months after the injury. Respondents were purposively sampled based on reported depressive and anxiety symptoms through structured questionnaire interviews in the parent study. Inductive thematic coding was performed on transcribed and translated interviews using ATLAS.ti, upon which the conservation of resources theory was identified as the most relevant theory to facilitate the understanding and presentation of the findings. Several types of resource loss were described, including financial, property, condition (e.g., employment, marriage), and physical health resources at different phases of recovery. Social support (in terms of materials and emotional support) through family, friends, neighbors, church members, spirituality, personal resources, and improvement in physical condition contributed to the adaptation and resilience. Potential interventions on building a more formalized follow-up support system and provision of social services early in the treatment phase is important to prevent additional resource losses to help reduce distress and improve psychosocial and physical functioning. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


Comparative study of changes in maternal and perinatal morbidity inequalities among migrant and native women over time, between 2008 and 2014 in France.
An increased risk of severe maternal morbidity and mortality has been described in migrant women, particularly in those born in sub-Saharan Africa. The mechanisms in question are poorly identified and rarely studied specifically. To compare changes in maternal and perinatal morbidity inequalities among migrant and native women over time, between 2008 and 2014. A retrospective, single-centre study carried out at the Maternity Unit of the University of Caen Hospital in France. All women who gave birth in 2008 or 2014 were included. Twin pregnancies and delivery before reaching 22 weeks of pregnancy were excluded. Pre-pregnancy characteristics and maternal and perinatal morbidities were collected from the university hospital's medical and administrative database. We compared the maternal and perinatal morbidity in 2008 and 2014 of women born in France to the morbidity of women born abroad. Secondly, we compared these migrant women between 2008 and 2014 to see if changes in the characteristics of migrant women were associated with a change in the type of maternal and perinatal complications. Of the 3,038 and 3,001 women included in 2008 and 2014, respectively, 272 (9.0 %) and 385 (12.8 %) women were migrants. Compared to women born in France, we found two times more severe postpartum hemorrhages in women born in sub-Saharan Africa (aOR = 2.1[1.1-3.9]) and a significant increase in the risk of gestational diabetes in women born in North Africa (aOR = 1.9[1.2-2.9]). We found a significant increase in the risk of severe postpartum hemorrhage (aOR = 2.1[1.5-3.0]) and gestational diabetes (aOR = 3.0[2.5-3.7]) in 2014 compared to 2008. We did not find a significant difference in perinatal morbidity between 2008 and 2014. We noted a significant increase in the risk of severe postpartum hemorrhage in women born in sub-Saharan Africa and gestational diabetes in women born in North Africa compared to those born in France, and these risks increase in 2014 relative to 2008.


Imaging guided trials of the angiogenesis inhibitor sunitinib in mouse models predict efficacy in pancreatic neuroendocrine but not ductal carcinoma.
Preclinical trials in mice represent a critical step in the evaluation of experimental therapeutics. Genetically engineered mouse models (GEMMs) represent a promising platform for the evaluation of drugs, particularly those targeting the tumor microenvironment. We evaluated sunitinib, an angiogenesis inhibitor that targets VEGF and PDGF receptor signaling, in two GEMMs of pancreatic cancer. Sunitinib did not reduce tumor burden in pancreatic ductal adenocarcinoma (PDAC), whereas tumor burden was reduced in the pancreatic neuroendocrine tumor (PNET) model, the latter results confirming and extending previous studies. To explore the basis for the lack of pathologic response in PDAC, we used noninvasive microbubble contrast-enhanced ultrasound imaging, which revealed that sunitinib reduced blood flow both in PDAC and in PNET, concomitant with a reduction in vessel density; nevertheless, PDAC tumors continued to grow, whereas PNET were growth impaired. These results parallel the response in humans, where sunitinib recently garnered FDA and European approval in PNET, whereas two antiangiogenic drugs failed to demonstrate efficacy in PDAC clinical trials. The demonstration of on-target activity but with discordant benefit in the PDAC and PNET GEMMs illustrates the potential value of linked preclinical and clinical trials.


Cancer patients' perceptions of their participation and own resources after receiving information about discontinuation of active tumour treatment.
The focus of most studies on informational needs has been on primary cancer diagnosis. The aim of this study was to explore how cancer patients in a palliative care setting perceived their own participation and resources after receiving information about the discontinuation of active tumour treatment. Thirty cancer patients admitted to a hospital-based home-care unit participated in the study. Semi-structured interviews were conducted and analysed using a phenomenographic method. The patients described their own participation as being either verbally passive or active, in order to receive more information or to avoid information. Furthermore, previous knowledge, at different levels, was described as important: 1) Unsuspecting naive, 2) apprehensive suspicious, 3) well prepared. Patients' own resources included a sense of wellbeing, a sense of security and individual strength. In conclusion, patients' previous knowledge and own resources are important components for their capacity to take part in the dialogue when receiving information.


Theoretical background, first stage development and adaptation of a novel Integrative Adapt Therapy (IAT) for refugees.
Refugees are confronted with the task of adapting to the long-term erosion of psychosocial systems and institutions that in stable societies support psychological well-being and mental health. We provide an overview of the theoretical principles and practical steps taken to develop a novel psychotherapeutic approach, Integrative Adapt Therapy (IAT), which aims to assist refugees to adapt to these changes. This paper offers the background informing ongoing trials of IAT amongst refugees from Myanmar. A systematic process was followed in formulating the therapy and devising a treatment manual consistent with the principles of the Adaptation and Development After Persecution and Trauma (ADAPT) model. The process of development and refinement was based on qualitative research amongst 70 refugees (ten from West Papua and 60 Rohingya from Myanmar). The therapeutic process was then piloted by trained interventionists amongst a purposively selected sample of 20 Rohingya refugees in Malaysia. The final formulation of IAT represented an integration of the principles of the ADAPT model and evidence-based techniques of modern therapies in the field, including a transdiagnostic approach and the selective use of cognitive behavioural treatment elements such as problem-solving and emotional regulation techniques. The steps outlined in refining the manual are outlined in relation to work amongst West Papuan refugees, and the process of cultural and contextual modifications described during early piloting with Rohingya refugees in Malaysia. IAT integrates universal principles of the ADAPT model with the particularities of the culture, history of conflict and living context of each refugee community; this synthesis of knowledge forms the basis for participants gaining insights into their personal patterns of psychosocial adaptation to the refugee experience. Participants then apply evidence-based techniques to improve their capacity to adapt to the serial psychosocial changes they have encountered in their lives as refugees. The overarching goal of IAT is to provide refugees with a coherent framework that assists in making sense of their experiences and their emotional and interpersonal reactions to the challenges they confront within the family and community context. As such, the principles of a general model (ADAPT) are used as a springboard for making concrete, manageable and meaningful life changes at the individual level, a potentially novel approach for psychosocial interventions in the field.


Variation in macrophage-migration-inhibitory-factor immunoreactivity during porcine gestation.
The localization and activity of macrophage migration inhibitory factor (MIF) was investigated in the interhemal region of the noninvasive, diffuse, folded epitheliochorial placenta and in the nonpregnant uterus of the pig. MIF, a proinflammatory cytokine with many actions on macrophages and monocytes, may play an important role in materno-fetal immuno-tolerance during placental establishment, modulation, and growth. Immunohistochemical staining with anti-human MIF polyclonal antibodies was carried out on placental sections from 11 stages of gestation (16-95 days postcoitus) and on nonpregnant uterus at 13 days postestrus. Western blot analysis confirmed the specificity of the anti-human MIF polyclonal antibodies on pig tissues. MIF staining was intense in both the trophoblast and maternal epithelium in the early stages; in the later stages, it decreased dramatically in the maternal epithelium but remained high in the trophoblast. The uterine glands showed immunoreactivity at all stages, and the maternal and fetal epithelial linings of the areolar cavity showed high reactivity at Day 25. The vasculature also showed staining for MIF, and an intense to moderate staining was shown in the nonpregnant uterus, mostly in the surface and glandular epithelium. The high activity of MIF in the maternal and fetal tissues throughout placentation and its expression in the nonpregnant uterus indicate a regulatory role for MIF during embryo receptivity and epitheliochorial placentation.


p38gamma MAPK regulation of glucose transporter expression and glucose uptake in L6 myotubes and mouse skeletal muscle.
Skeletal muscle expresses at least three p38 MAPKs (alpha, beta, gamma). However, no studies have examined the potential regulation of glucose uptake by p38gamma, the isoform predominantly expressed in skeletal muscle and highly regulated by exercise. L6 myotubes were transfected with empty vector (pCAGGS), activating MKK6 (MKK6CA), or p38gamma-specific siRNA. MKK6CA-transfected cells had higher rates of basal 2-deoxy-d-[3H]glucose (2-DG) uptake (P < 0.05) but lower rates of 2,4-dinitrophenol (DNP)-stimulated glucose uptake, an uncoupler of oxidative phosphorylation that operates through an insulin-independent mechanism (P < 0.05). These effects were reversed when MKK6CA cells were cotransfected with p38gamma-specific siRNA. To determine whether the p38gamma isoform is involved in the regulation of contraction-stimulated glucose uptake in adult skeletal muscle, the tibialis anterior muscles of mice were injected with pCAGGS or wild-type p38gamma (p38gammaWT) followed by intramuscular electroporation. Basal and contraction-stimulated 2-DG uptake in vivo was determined 14 days later. Overexpression of p38gammaWT resulted in higher basal rates of glucose uptake compared with pCAGGS (P < 0.05). Muscles overexpressing p38gammaWT showed a trend for lower in situ contraction-mediated glucose uptake (P = 0.08) and significantly lower total GLUT4 levels (P < 0.05). These data suggest that p38gamma increases basal glucose uptake and decreases DNP- and contraction-stimulated glucose uptake, partially by affecting levels of glucose transporter expression in skeletal muscle. These findings are consistent with the hypothesis that activation of stress kinases such as p38 are negative regulators of stimulated glucose uptake in peripheral tissues.


Seasonality as a driver of pH1N12009 influenza vaccination campaign impact.
Although the most recent respiratory virus pandemic was triggered by a Coronavirus, sustained and elevated prevalence of highly pathogenic avian influenza viruses able to infect mammalian hosts highlight the continued threat of pandemics of influenza A virus (IAV) to global health. Retrospective analysis of pandemic outcomes, including comparative investigation of intervention efficacy in different regions, provide important contributions to the evidence base for future pandemic planning. The swine-origin IAV pandemic of 2009 exhibited regional variation in onset, infection dynamics and annual infection attack rates (IARs). For example, the UK experienced three severe peaks of infection over two influenza seasons, whilst Australia experienced a single severe wave. We adopt a seasonally forced 2-subtype model for the transmission of pH1N12009 and seasonal H3N2 to examine the role vaccination campaigns may play in explaining differences in pandemic trajectories in temperate regions. Our model differentiates between the nature of vaccine- and infection-acquired immunity. In particular, we assume that immunity triggered by infection elicits heterologous cross-protection against viral shedding in addition to long-lasting neutralising antibody, whereas vaccination induces imperfect reduction in susceptibility. We employ an Approximate Bayesian Computation (ABC) framework to calibrate the model using data for pH1N12009 seroprevalence, relative subtype dominance, and annual IARs for Australia and the UK. Heterologous cross-protection substantially suppressed the pandemic IAR over the posterior, with the strength of protection against onward transmission inversely correlated with the initial reproduction number. We show that IAV pandemic timing relative to the usual seasonal influenza cycle influenced the size of the initial waves of pH1N12009 in temperate regions and the impact of vaccination campaigns.


Status quo of hybrid coronary revascularization for multi-vessel coronary artery disease.
Hybrid coronary revascularization (HCR) combines bypass grafting of the left anterior descending (LAD) coronary artery with percutaneous coronary intervention (PCI) of non-LAD vessels. HCR has been performed as an alternative to CABG or multi-vessel PCI in thousands of patients since the late 1990s. In this review article, we provide an overview on patient selection, procedural sequence and timing, use of surgical techniques and anti-platelet agents. Additionally, patient recovery, satisfaction, costs and clinical outcomes of individual studies after HCR are evaluated. Future directions are also discussed, including the need for adequately powered randomized trials.


The characteristics and extent of food industry involvement in peer-reviewed research articles from 10 leading nutrition-related journals in 2018.
There is emerging evidence that food industry involvement in nutrition research may bias research findings and/or research agendas. However, the extent of food industry involvement in nutrition research has not been systematically explored. This study aimed to identify the extent of food industry involvement in peer-reviewed articles from a sample of leading nutrition-related journals, and to examine the extent to which findings from research involving the food industry support industry interests. All original research articles published in 2018 in the top 10 most-cited nutrition- and dietetics-related journals were analysed. We evaluated the proportion of articles that disclosed involvement from the food industry, including through author affiliations, funding sources, declarations of interest or other acknowledgments. Principal research findings from articles with food industry involvement, and a random sample of articles without food industry involvement, were categorised according to the extent to which they supported relevant food industry interests. 196/1,461 (13.4%) articles reported food industry involvement. The extent of food industry involvement varied by journal, with The Journal of Nutrition (28.3%) having the highest and Paediatric Obesity (3.8%) having the lowest proportion of industry involvement. Processed food manufacturers were involved in the most articles (77/196, 39.3%). Of articles with food industry involvement, 55.6% reported findings favourable to relevant food industry interests, compared to 9.7% of articles without food industry involvement. Food industry involvement in peer-reviewed research in leading nutrition-related journals is commonplace. In line with previous literature, this study has shown that a greater proportion of peer-reviewed studies involving the food industry have results that favour relevant food industry interests than peer-reviewed studies without food industry involvement. Given the potential competing interests of the food industry, it is important to explore mechanisms that can safeguard the integrity and public relevance of nutrition research.


[18F]fluorodeoxyglucose-positron emission tomography in patients with medulloblastoma.
We evaluated the [(18)F]fluorodeoxyglucose (FDG) accumulation during positron emission tomography (PET) in patients with medulloblastoma and examined the relationship of intensity of uptake with patient outcome after the initial scan. Magnetic resonance imaging and FDG-PET scans of brain and spine were used to assess FDG uptake by visual grade (qualitative analysis) and metabolic activity ratios (T(max)/G(mean) and T(max)/W(mean)). Patients were divided into two groups based on either confirmation of tumor by biopsy and/or death resulting from progressive disease after the initial FDG-PET scan (Group A) or no intervention for the suspected lesion shown on magnetic resonance imaging after the initial FDG-PET scan but currently alive without evidence of disease (Group B). Twenty-two patients with either recurrent (n = 21) or newly diagnosed (n = 1) medulloblastoma underwent brain (n = 18) or whole-body (n = 4) FDG-PET scans after magnetic resonance imaging evidence of suspected tumor. The median qualitative analysis was 3 (range, 0-4) in 17 Group A patients compared with 0 (range, 0-1) in 5 Group B patients (P = 0.0003). The mean T(max)/G(mean) and T(max)/W(mean) ratios for 16 Group A patients were 1.3 (range, 0.1-3.8) and 2.10 (range, 0.4-5.2), respectively, compared with 0.80 (range, 0.20-1.5) and 1.3 (range, 0.5-1.9) in 5 Group B patients (P = 0.2 for both parameters, not significant). There was a significant negative correlation between increased FDG uptake and survival. Higher qualitative analysis and T(max)/W(mean) were associated with significantly poorer 2-year overall survival after the initial scan (71% versus 15% for qualitative analysis grade of <3 versus > or =3, P = 0.001; 46% versus 0% for T(max)/W(mean) < or =2.5 versus >2.5, P = 0.004). Increased FDG uptake is observed in medulloblastoma and is correlated negatively with survival.


Early prosthetic joint infection: outcomes with debridement and implant retention followed by antibiotic therapy.
Recent expert reviews recommend a conservative surgical strategy - debridement and irrigation, antibiotics and implant retention (DAIR) - for most early post-surgical prosthetic joint infections (PJI). However, differences exist in published series regarding success rates with DAIR, and the size of most series is small. In this prospective multicenter cohort study of early PJI managed by DAIR, factors associated with failure of the DAIR were analyzed. Out of 139 early PJI, 117 cases managed with DAIR were studied For 67 patients (57.3%), infection was cured and the implant was salvaged with definite antimicrobial therapy. In 35 (29.9%) DAIR failed and removal of the prosthesis was necessary during follow-up. Finally, 15 patients (12.8%) needed chronic suppressive antimicrobial therapy due to suspected or confirmed persistent infection. Infections due to methicillin-resistant S. aureus (72.7% failed; p 0.05) and those treated at one of the hospitals (80.0% failed; p <0.05) had worse outcomes, but only this last variable was associated with treatment failure following multivariate analysis. Seventy-four per cent of patients who were successfully treated by DAIR and only 32.7% of the failures were able to walk without help or with one stick at the last follow-up visit (p <0.05). In conclusion, a substantial proportion of patients with an early PJI may be successfully treated with DAIR and definite antimicrobial therapy. In more than half of these, the infection can be cured. Since identification of factors associated with failure of DAIR is not simple, we recommend offering DAIR to most patients with early PJI.


Platelet-aggregating activity of type I and type III collagens from human aorta and chicken skin.
Human or chicken type III collagen dissolved in 0.1 M-acetic acid was much more potent than type I collagen at inducing platelet aggregation. After incubation in 0.38M-Na2HPO4 to promote fibrillogenesis, the platelet-aggregating activity of both collagen types increased, and type I was then virtually equiactive with type III. Preincubation in cell-free plasma increased the activity of chicken but not that of human collagen. The platelet-aggregating activity of type III collagen did not appear to depend on the integrity of the intrachain disulphide bonds.


Female inheritance of malarial lap genes is essential for mosquito transmission.
Members of the LCCL/lectin adhesive-like protein (LAP) family, a family of six putative secreted proteins with predicted adhesive extracellular domains, have all been detected in the sexual and sporogonic stages of Plasmodium and have previously been predicted to play a role in parasite-mosquito interactions and/or immunomodulation. In this study we have investigated the function of PbLAP1, 2, 4, and 6. Through phenotypic analysis of Plasmodium berghei loss-of-function mutants, we have demonstrated that PbLAP2, 4, and 6, as previously shown for PbLAP1, are critical for oocyst maturation and sporozoite formation, and essential for transmission from mosquitoes to mice. Sporozoite formation was rescued by a genetic cross with wild-type parasites, which results in the production of heterokaryotic polyploid ookinetes and oocysts, and ultimately infective Deltapblap sporozoites, but not if the individual Deltapblap parasite lines were crossed amongst each other. Genetic crosses with female-deficient (Deltapbs47) and male-deficient (Deltapbs48/45) parasites show that the lethal phenotype is only rescued when the wild-type pblap gene is inherited from a female gametocyte, thus explaining the failure to rescue in the crosses between different Deltapblap parasite lines. We conclude that the functions of PbLAPs1, 2, 4, and 6 are critical prior to the expression of the male-derived gene after microgametogenesis, fertilization, and meiosis, possibly in the gametocyte-to-ookinete period of differentiation. The phenotypes detectable by cytological methods in the oocyst some 10 d after the critical period of activity suggests key roles of the LAPs or LAP-dependent processes in the regulation of the cell cycle, possibly in the regulation of cytoplasm-to-nuclear ratio, and, importantly, in the events of cytokinesis at sporozoite formation. This phenotype is not seen in the other dividing forms of the mutant parasite lines in the liver and blood stages.


Quality of Nursing Work Life among Nurses in Saudi Arabia: A Descriptive Cross-Sectional Study.
Background: Quality of working life (QWL) is a multidimensional concept that describes an employee's satisfaction with several work life elements. Quality of nurse working life is considered as a stepping stone for health services improvement, as it affects job satisfaction which, in turn, affects the performance of nurses. Understanding and investigating the nurses' quality of work life in Saudi Arabia is needed for improvement actions. Objectives: This study aimed to examine the quality of nursing work life (QNWL) among nurses working in Saudi Arabia and to determine the association between demographic variables and quality of work life among nurses. Methods: It was a cross-sectional design using Brooks' quality of nursing work life survey. It was distributed among nurses over the kingdom of Saudi Arabia. Results: There were 860 nurses participating in the study. The mean total score for the participants was 174.5+/- 30.3, indicating moderate to high QNWL. The highest score achieved by the nurses was for the work world context (4.29) while the lowest score was for work design dimension (3.92). The study revealed that nationality, income, and shift duration, having a dependent person, and having family accompany the nurse as significant factors affecting the quality of work life among the nurses. Conclusion: A novel contribution of the current study was that the demographic characteristics of the participants, including nationality, income, having family accompany the nurse, having an independent child, or spouse or parents, and shift duration, tended to have a statistically significant correlation with QNWL. The comprehensive results of this study have practical implications whereby authority bodies can create regulatory plans for enhancing satisfaction and performance over the sole utilization of job satisfaction measurements and can thereby improve nurses' retention and turnover rates.


Recursive confidence band construction for an unknown distribution function.
Given a sample X1,...,Xn of independent observations from an unknown continuous distribution function F, the problem of constructing a confidence band for F is considered, which is a fundamental problem in statistical inference. This confidence band provides simultaneous inferences on all quantiles and also on all of the cumulative probabilities of the distribution, and so they are among the most important inference procedures that address the issue of multiplicity. A fully nonparametric approach is taken where no assumptions are made about the distribution function F. Historical approaches to this problem, such as Kolmogorov's famous () procedure, represent some of the earliest inference methodologies that address the issue of multiplicity. This is because a confidence band at a given confidence level 1-α allows inferences on all of the quantiles of the distribution, and also on all of the cumulative probabilities, at that specified confidence level. In this paper it is shown how recursive methodologies can be employed to construct both one-sided and two-sided confidence bands of various types. The first approach operates by putting bounds on the cumulative probabilities at the data points, and a recursive integration approach is described. The second approach operates by providing bounds on certain specified quantiles of the distribution, and its implementation using recursive summations of multinomial probabilities is described. These recursive methodologies are illustrated with examples, and R code is available for their implementation.


Death in the field: teaching paramedics to deliver effective death notifications using the educational intervention "GRIEV_ING".
Emergency medical services (EMS) personnel are rarely trained in death notification despite frequently terminating resuscitation in the field. As research continues to validate guidelines for the termination of resuscitation (TOR) and reputable organizations such as NAEMSP lend support to such protocols, death notification in the field will continue to increase. We sought to test the hypothesis that a learning module, GRIEV_ING, which teaches a structured method for death notification, will improve the confidence, competency, and communication skills of EMS personnel in death notification. The GRIEV_ING didactic session consisted of a 90-minute education session composed of a didactic lecture, small group breakout session, and role-plays. This was both preceded and followed by a 15-minute case role-play using trained standardized survivors. To assess performance we used a pre-post design with 3 quantitative measures: confidence, competency, and, communication. Paramedics from the local EMS agency participated in the education as a part of continuing education. Pre-post differences were measured using a paired t-test and McNemar's test. Thirty EMS personnel consented and participated. Confidence and competency demonstrated statistically significant improvements: confidence (percent change in scores = 11.4%, p < 0.0001) and competency (percent change in scores = 13.9%, p = 0.0001). Communication skill scores were relatively unchanged in pre-post test analysis (percent change in scores = 0.4, p = 0.9). This study demonstrated that educating paramedics to use a structured communication model based on the GRIEV_ING mnemonic improved confidence and competence of EMS personnel delivering death notification.


Synthesis of all stereoisomers of 3,3'-dimethoxy-7,7'-epoxylignane-4,4'-diol and their plant growth inhibitory activity.
All stereoisomers of 3,3'-dimethoxy-7,7'-epoxylignane-4,4'-diol were synthesized to examine the effect of stereochemistry on their plant growth inhibitory activity using lettuce and Italian ryegrass. The effect of structural modifications such as dehydroxylation, methoxylation and hydroxylation at the 9- and 9'-positions of the lignans on the activity was also studied. Most of the epoxylignanes showed higher plant growth inhibitory potency against ryegrass than against lettuce, and the inhibitory activity varied depending on the configurations of each position of the tetrahydrofuran ring (7-, 7'-, 8-, and 8'-positions of the epoxylignanes). Among the 9,9'-position-modified derivatives, the dehydroxy derivatives showed the highest potency. These results suggested that the plant growth inhibitory activity should be influenced by the structure of the epoxylignanes.


A regularized model-based optimization framework for pan-sharpening.
Pan-sharpening is a common postprocessing operation for captured multispectral satellite imagery, where the spatial resolution of images gathered in various spectral bands is enhanced by fusing them with a panchromatic image captured at a higher resolution. In this paper, pan-sharpening is formulated as the problem of jointly estimating the high-resolution (HR) multispectral images to minimize an objective function comprised of the sum of squared residual errors in physically motivated observation models of the low-resolution (LR) multispectral and the HR panchromatic images and a correlation-dependent regularization term. The objective function differs from and improves upon previously reported model-based optimization approaches to pan-sharpening in two major aspects: 1) a new regularization term is introduced and 2) a highpass filter, complementary to the lowpass filter for the LR spectral observations, is introduced for the residual error corresponding to the panchromatic observation model. To obtain pan-sharpened images, an iterative algorithm is developed to solve the proposed joint minimization. The proposed algorithm is compared with previously proposed methods both visually and using established quantitative measures of SNR, spectral angle mapper, relative dimensionless global error in synthesis, Q, and Q4 indices. Both the quantitative results and visual evaluation demonstrate that the proposed joint formulation provides superior results compared with pre-existing methods. A software implementation is provided.


Let the healers heal.
There has been an increase in the incidence of attacks on doctors in recent times. It is important that some measures are taken to ensure the safety of doctors at the workplace, because only when they feel safe will they be able to treat their patients without any hesitation or fear. We call upon all concerned authorities to ensure a safe hospital environment for better healthcare, and we also suggest remedial steps to that end.


Management development in health care setting: a training model for hospital managers.
This study was conducted to design an on job-training model for the managers of the Iranian Social Security Organization (ISSO) hospitals and any other similar setting. A five dimensional model (i.e. knowledge, ability, managerial skills, personality attributes and attitudes) with 187 components was designed. The model was validated through seeking the view of experts and a field test. For the field test, a survey was done on 31 ISSO hospital managers to explore their views on the structure of the model and its components. The managers were asked to score each component on a five- point Likert scale as they thought it would affect their job performance. The model with 5 dimensions and 165 components was verified in the field test, and 104 out of 165 components of this model got high, 52 medium and nine low mean scores for influencing job performance of the managers. These findings reveal that most of the components selected in this project are justified to be included in the model. It also reflects the managers' needs for any formal and informal training program in future. The needs of hospital managers at work go far beyond the knowledge and skills, which they have gained, via formal education in school. Therefore, in designing a training program for this group of professionals one should consider a multi-dimensional model in which "knowledge, ability, managerial skills, personality, and attitude dimensions" are all taken under consideration.