Battery-free, wireless soft sensors for continuous multi-site measurements of pressure and temperature from patients at risk for pressure injuries.
Capabilities for continuous monitoring of pressures and temperatures at critical skin interfaces can help to guide care strategies that minimize the potential for pressure injuries in hospitalized patients or in individuals confined to the bed. This paper introduces a soft, skin-mountable class of sensor system for this purpose. The design includes a pressure-responsive element based on membrane deflection and a battery-free, wireless mode of operation capable of multi-site measurements at strategic locations across the body. Such devices yield continuous, simultaneous readings of pressure and temperature in a sequential readout scheme from a pair of primary antennas mounted under the bedding and connected to a wireless reader and a multiplexer located at the bedside. Experimental evaluation of the sensor and the complete system includes benchtop measurements and numerical simulations of the key features. Clinical trials involving two hemiplegic patients and a tetraplegic patient demonstrate the feasibility, functionality and long-term stability of this technology in operating hospital settings.


Overall survival and patient-reported outcome results from the placebo-controlled randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial of atezolizumab for newly diagnosed stage III/IV ovarian cancer.
To determine the impact on overall survival (OS) and patient-reported outcomes (PROs) of combining atezolizumab with standard therapy for newly diagnosed stage III/IV ovarian cancer. The placebo-controlled double-blind randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial (NCT03038100) assigned eligible patients to 3-weekly atezolizumab 1200 mg or placebo for 22 cycles with platinum-based chemotherapy and bevacizumab. Coprimary endpoints were progression-free survival (already reported) and OS in the PD-L1-positive and intent-to-treat (ITT) populations, tested hierarchically. Prespecified PRO analyses focused on disease-related abdominal pain and bloating symptoms (European Organisation for Research and Treatment of Cancer QLQ-OV28), functioning, and health-related quality of life (HRQoL) (QLQ-C30). After 38 months' median follow-up, the OS hazard ratio in the PD-L1-positive population was 0.83 (95% CI, 0.66-1.06; p = 0.13); median OS was not estimable with atezolizumab versus 49.2 months with placebo. The hazard ratio for OS in the ITT population was 0.92 (95% CI, 0.78-1.09; median 50.5 versus 46.6 months, respectively). At week 9, similar proportions of patients in both arms of the neoadjuvant cohort showed ≥10-point improvement from baseline in abdominal pain and bloating, functioning, and HRQoL. In the primary surgery cohort, similar proportions of patients in each arm had improved, stable, or worsened physical and role function and HRQoL from baseline over time. Neither cohort showed differences between arms in treatment-related symptoms or overall side-effect bother. Incorporation of atezolizumab into standard therapy for newly diagnosed ovarian cancer does not significantly improve efficacy or impose additional treatment burden for patients. gov registration: NCT03038100.


[Use of taurine in the treatment of experimental congestive heart failure].
The therapeutic effects of 2-aminoethanesulfonic acid (taurine) were tested in animals with congestive heart failure (HF) simulated by aortic valve damage. The drug given in a daily dose of 100 mg/kg for a month was shown to reduce mortality rates as compared to controls, to improve the animals' clinical condition, hemodynamic and myocardial contractility parameters. Taurine was found to exert a positive action on the heart response to stresses. The impaired response in the animals restored to heart rate stimulation, catecholamines and calcium loading. The mechanisms of the agent's action are discussed in the present paper. It is suggested that taurine-based taucard will be included into the arsenal of cardiotropic agents after its clinical trials are successfully completed.


Quantifying the Steric Effect on Metal-Ligand Bonding in Fe Carbene Photosensitizers with Fe 2p3d Resonant Inelastic X-ray Scattering.
Understanding the electronic structure and chemical bonding of transition metal complexes is important for improving the function of molecular photosensitizers and catalysts. We have utilized X-ray absorption spectroscopy (XAS) and resonant inelastic X-ray scattering (RIXS) at the Fe L3 edge to investigate the electronic structure of two Fe N-heterocyclic carbene complexes with similar chemical structures but different steric effects and contrasting excited-state dynamics: [Fe(bmip)2]2+ and [Fe(btbip)2]2+, bmip = 2,6-bis(3-methyl-imidazole-1-ylidine)pyridine and btbip = 2,6-bis(3-tert-butyl-imidazole-1-ylidene)pyridine. In combination with charge transfer multiplet and ab initio calculations, we quantified how changes in Fe-carbene bond length due to steric effects modify the metal-ligand bonding, including σ/π donation and π back-donation. We find that σ donation is significantly stronger in [Fe(bmip)2]2+, whereas the π back-donation is similar in both complexes. The resulting stronger ligand field and nephelauxetic effect in [Fe(bmip)2]2+ lead to approximately 1 eV destabilization of the quintet metal-centered 5T2g excited state compared to [Fe(btbip)2]2+, providing an explanation for the absence of a photoinduced 5T2g population and a longer metal-to-ligand charge-transfer excited-state lifetime in [Fe(bmip)2]2+. This work demonstrates how combined modeling of XAS and RIXS spectra can be utilized to understand the electronic structure of transition metal complexes governed by correlated electrons and donation/back-donation interactions.


Social connectedness as a determinant of mental health: A scoping review.
Public health and epidemiologic research have established that social connectedness promotes overall health. Yet there have been no recent reviews of findings from research examining social connectedness as a determinant of mental health. The goal of this review was to evaluate recent longitudinal research probing the effects of social connectedness on depression and anxiety symptoms and diagnoses in the general population. A scoping review was performed of PubMed and PsychInfo databases from January 2015 to December 2021 following PRISMA-ScR guidelines using a defined search strategy. The search yielded 66 unique studies. In research with other than pregnant women, 83% (19 of 23) studies reported that social support benefited symptoms of depression with the remaining 17% (5 of 23) reporting minimal or no evidence that lower levels of social support predict depression at follow-up. In research with pregnant women, 83% (24 of 29 studies) found that low social support increased postpartum depressive symptoms. Among 8 of 9 studies that focused on loneliness, feeling lonely at baseline was related to adverse outcomes at follow-up including higher risks of major depressive disorder, depressive symptom severity, generalized anxiety disorder, and lower levels of physical activity. In 5 of 8 reports, smaller social network size predicted depressive symptoms or disorder at follow-up. In summary, most recent relevant longitudinal studies have demonstrated that social connectedness protects adults in the general population from depressive symptoms and disorders. The results, which were largely consistent across settings, exposure measures, and populations, support efforts to improve clinical detection of high-risk patients, including adults with low social support and elevated loneliness.


Thermal noise in cells. A cause of spontaneous loss of cell function.
Background noise due to random thermal perturbations of molecules has a disruptive effect on all information handling systems, including cells and organisms. This thermal noise appears to be largely responsible for the spontaneous loss of proliferative cells in cell cultures. The rates at which proliferative cells are lost as a result of heat injury, in cultured hamster cells, have been measured at high temperatures and extrapolated down to 37 C. This gives an expected 0.2% loss per hour due to thermal injury at physiologic temperature. That such a loss does in fact occur can be shown by comparing cell generation time with population doubling time, when these cells are growing at physiologic temperatures. Apparently, internal thermal noise presents a primary hazard to the reliable functioning of the cell quite apart from the insults it receives from its external environment.


Case of suspected connective tissue disease presenting as chronic edema or swelling of face, neck, and upper trunk.
An adequate biopsy that includes the subcutaneous tissue is very helpful in the evaluation of patients with suspected connective tissue disease. However, the histologic features must often be correlated with the clinical features and other laboratory tests for a definitive diagnosis. An objective histologic diagnosis can usually be made in scleroderma, lupus erythematosus panniculitis, amyloidosis, and angioedema, and in diseases such as lepromatous leprosy and mycosis fungoids (which are sometimes confused with connective tissue diseases). Correlation with clinical features and, sometimes, other laboratory tests is often required to establish a diagnosis of scleredema, dermatomyositis, myxedema, and lichen myxedematosus. The features in cheilitis granulomatosa usually are not specific, but a biopsy is helpful to rule out other diseases.


The Complexity Of Billing And Paying For Physician Care.
The administrative costs of providing health insurance in the US are very high, but their determinants are poorly understood. We advance the nascent literature in this field by developing new measures of billing complexity for physician care across insurers and over time, and by estimating them using a large sample of detailed insurance "remittance data" for the period 2013-15. We found dramatic variation across different types of insurance. Fee-for-service Medicaid is the most challenging type of insurer to bill, with a claim denial rate that is 17.8 percentage points higher than that for fee-for-service Medicare. The denial rate for Medicaid managed care was 6 percentage points higher than that for fee-for-service Medicare, while the rate for private insurance appeared similar to that of Medicare Advantage. Based on conservative assumptions, we estimated that the health care sector deals with $11 billion in challenged revenue annually, but this number could be as high as $54 billion. These costs have significant implications for analyses of health insurance reforms.


Comparative study of the body surface electrocardiogram in double-muscled and conventional calves.
The purpose of this work was to study electrocardiographic features of double-muscled beef cattle. Electrocardiograms were recorded on one to six occasions from each of a group of 18 conventional calves of the Friesian breed and 29 double-muscled calves of the Belgian White and Blue breed. Ages of the calves at the times of examination ranged from eight to 348 days. The Holmes semi-orthogonal lead system was used. The waves and interval durations and the tridimensional P, QRS, and T modal vector orientation and amplitude were calculated. The magnitude of the cardiac vectors was significantly lower and the ventricular waves and QT interval duration significantly shorter in the double-muscled than in the conventional calves. The P modal vector pointed significantly less downwards and the QRS modal vector pointed significantly more forwards and less up- and rightwards in the Belgian White and Blue, than in the Friesian group. Most of the observed differences might be a consequence of the bodily, and more specifically the thoracic, conformation of the former calves. However, the lower cardiac vector magnitude and shorter wave and interval durations might also reflect lower cardiac mass in the double-muscled subjects.


AMPAr GluA1 Phosphorylation at Serine 845 in Limbic System Is Associated with Cardiac Autonomic Tone.
The central autonomic network, which is connected to the limbic system structures including the amygdala (AMY) and anterior hippocampus (aHIP), regulates the sympathetic and parasympathetic modulation of visceromotor, neuroendocrine, pain, and behavior manifestations during stress responses. Heart rate variability (HRV) is useful to estimate the cardiac autonomic tone. The levels of phosphorylation on the Ser831 and Ser845 sites of the GluA1 subunit of the AMPAr (P-GluA1-Ser845 and P-GluA1-Ser831) are useful markers of synaptic plasticity. The relation between synaptic plasticity in the human limbic system structures and autonomic regulation in humans is unknown. This study investigated the association between HRV and neurochemistry biomarkers of synaptic plasticity in AMY and aHIP. HRV indices were obtained from the resting state electrocardiogram of patients with drug-resistant mesial temporal lobe epilepsy (MTLE, n = 18) and the levels of P-GluA1-Ser845 and P-GluA1-Ser831 in the AMY and aHIP resected during the epilepsy surgery. A backward stepwise multiple linear regression models were used to analyze the association between HRV and synaptic plasticity biomarkers controlling for imbalances in the distribution of sociodemographic, clinical, neuroimaging, and neurosurgical variables. P-GluA1-Ser845 levels in AMY show a negative association (p < 0.05) with the 3 investigated parasympathetic autonomic HRV indices (SDNN, rMSSD, and HF) predicting 24 to 40% of their variation. The final multiple linear regression models include disease duration and levels of P-GluA1-Ser845 and predict 24 to 56% of cardiac autonomic tone variation (p < 0.01). P-GluA1-Ser845 levels in AMY and aHIP are negatively associated with the resting HRV in MTLE-HS indicating that increased synaptic efficiency in amygdala is associated with a parasympathetic cardiac autonomic tone impairment. The results suggest that specific changes in synaptic plasticity may be involved in the brain-heart axis regulation by the limbic system.


Open-Label, Multi-Dose, Pilot Safety Study of Injection of OnabotulinumtoxinA Toward the Otic Ganglion for the Treatment of Intractable Chronic Cluster Headache.
The otic ganglion (OG) provides parasympathetic innervation to the cerebral circulation and cranial structures and may be involved in the pathophysiology of trigeminal autonomic headaches. This structure has never been targeted in any headache disorder. To investigate the safety of injecting onabotulinumtoxin A (BTA) toward the OG in 10 patients with intractable chronic cluster headache and to collect efficacy data. A total of 10 patients with chronic cluster headache were enrolled in this open-label, multi-dose pilot safety study. All patients were recruited and treated on an out-patient basis at St Olav's University Hospital (Norway). In 5 patients each, the OG was the injection target with 12.5 IU of BTA or 25 IU, respectively. The primary outcome measure was adverse events (AEs) and the main secondary outcome was the number of attacks per week measured at baseline and in the second month following injection. For the primary endpoint, we analyzed data for all 10 patients. There were a total of 17 AEs in 6 of the 10 patients. All AEs were considered mild and disappeared by the end of follow-up. The median number of attacks per week at baseline was 17.0 [7.8 to 25.8] vs 14.0 [7.3 to 20.0] in the second month following injection; difference: 3 (95%CI: -0.3 to 7.9), P = .063. Injection with BTA toward the OG appears to be safe. We did not find a statistically significant reduction in the number of attacks per week at month 2 after injection compared to the baseline. This study suggests that the OG is not an important target for the treatment of chronic cluster headache. A future study employing more precise targeting of the OG may be indicated.


Direct Synthesis of Acyl Fluorides from Carboxylic Acids with the Bench-Stable Solid Reagent (Me4N)SCF3.
A convenient, highly efficient, and selective transformation of aliphatic and aromatic carboxylic acids to acyl fluorides is reported. In contrast to established approaches that require toxic or volatile additives and base and reaction control (i.e., cooling, slow addition), this protocol allows for a straightforward access to various R-COF entities upon direct reaction with the bench-stable, solid reagent (Me4N)SCF3 at room temperature. The method is base- and additive-free, compatible with late-stage synthetic applications, high functional group tolerance, and facile target compound purification via filtration.


Detection of free radicals produced from the reaction of cytochrome P-450 with linoleic acid hydroperoxide.
The ESR spin-trapping technique was employed to investigate the reaction of rabbit cytochrome P-450 1A2 (P450) with linoleic acid hydroperoxide. This system was compared with chemical systems where FeSO4 or FeCl3 was used in place of P450. The spin trap 5, 5'-dimethyl-1-pyrroline N-oxide (DMPO) was employed to detect and identify radical species. The DMPO adducts of hydroxyl, O2-., peroxyl, methyl and acyl radicals were detected in the P450 system. The reaction did not require NADPH-cytochrome P-450 reductase or NADPH. The same DMPO-radical adducts were detected in the FeSO4 system. Only DMPO-.OH radical adduct and carbon-centred radical adducts were detected in the FeCl3 system. Peroxyl radical production was completely O2-dependent. We propose that polyunsaturated fatty acids are initially reduced to form alkoxyl radicals, which then undergo intramolecular rearrangement to form epoxyalkyl radicals. Each epoxyalkyl radical reacts with O2, forming a peroxyl radical. Subsequent unimolecular decomposition of this peroxyl radical eliminates O2-. radical.


Evolution of copper arsenate resistance for enhanced enargite bioleaching using the extreme thermoacidophile Metallosphaera sedula.
Adaptive laboratory evolution (ALE) was employed to isolate arsenate and copper cross-resistant strains, from the copper-resistant M. sedula CuR1. The evolved strains, M. sedula ARS50-1 and M. sedula ARS50-2, contained 12 and 13 additional mutations, respectively, relative to M. sedula CuR1. Bioleaching capacity of a defined consortium (consisting of a naturally occurring strain and a genetically engineered copper sensitive strain) was increased by introduction of M. sedula ARS50-2, with 5.31 and 26.29% more copper recovered from enargite at a pulp density (PD) of 1 and 3% (w/v), respectively. M. sedula ARS50-2 arose as the predominant species and modulated the proportions of the other two strains after it had been introduced. Collectively, the higher Cu2+ resistance trait of M. sedula ARS50-2 resulted in a modulated microbial community structure, and consolidating enargite bioleaching especially at elevated PD.


Regenerative Medicine in South Korea: Bridging the Gap Between Authorization and Reimbursement.
Regenerative medicine (RM) has considerable potential to address the needs of aging-related and uncurable diseases. However, its incorporation into reimbursement of health insurance benefits poses many challenges, including uncertain evidence and insufficient investment. This paper examines the wide gap between manufacturers, regulatory bodies, and health technology bodies regarding reimbursements for RMs focused cell therapy products. In this mixed-methods study, we first analyzed the sales of RMs approved in South Korea. In addition to exploring beliefs related to the market value of RMs, in-depth interviews were conducted with 24 experts (17 from bio-industries, two from the regulatory body, three from a health technology assessment (HTA) body, and two from the Pharmaceutical Benefit Coverage Assessment Committee [PBCAC]). Lastly, we surveyed PBCAC members about the market value of RMs. In total, 15 of the 20 developed cell therapy products are on the market in South Korea, and amounted to 0.24% of total pharmaceutical expenditures in 2018. We identified a wide gap between stakeholders and regulators regarding the market value and pricing of RMs. The interviewees from the pharmaceutical manufacturer association raised the issue of rising manufacturing costs and proposed a specific pricing policy for RMs. To bridge the gap between approval and reimbursement, stakeholders demand an alternative framework of value-based pricing. Conditional health insurance reimbursement may be an alternative to the traditional process in order to generate evidence of the effects of RMs using "risk-based" or "outcome-based" approaches.


Association between osteoporosis and cardiovascular disease in elderly people: evidence from a retrospective study.
This study aimed to investigate the associations between osteoporosis, biochemical indexes, bone mineral density (BMD), and cardiovascular disease. A cross-sectional study design was used to examine the relationships between these parameters. Logistic regression and correlation analyses were conducted to assess the associations between elevated levels of triglyceride, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), homocysteine, and the presence of osteoporosis. Additionally, correlations between BMD and biochemical indexes were analyzed. The incidence of cardiovascular disease and its correlation with BMD were evaluated. Receiver operating characteristic (ROC) analysis was performed to determine the utility of BMD in identifying cardiovascular disease. The results revealed that elevated triglyceride, total cholesterol, and LDL levels were positively associated with osteoporosis, while higher HDL levels and homocysteine were negatively associated. Correlation analysis demonstrated negative correlations between triglyceride levels and BMD, and positive correlations between total cholesterol and HDL levels with BMD. LDL levels showed a weak negative correlation, and homocysteine levels exhibited a strong negative correlation with BMD. The osteoporosis group had lower BMD and a higher incidence of cardiovascular disease compared to the non-osteoporosis group. Logistic regression analysis confirmed the correlation between lower BMD and increased risk of cardiovascular disease. This study provides evidence supporting the associations between osteoporosis, biochemical indexes, BMD, and cardiovascular disease. Aberrations in lipid profiles and homocysteine levels may contribute to osteoporosis development. Lower BMD, particularly in individuals with osteoporosis, appears to increase the risk of cardiovascular disease. BMD shows promise as a diagnostic tool for identifying individuals at risk of cardiovascular disease. Further research is needed to elucidate the underlying mechanisms and establish the clinical implications of these relationships. Future longitudinal studies are necessary to determine causality and long-term prognostic implications.


Interactions of graphene oxide and graphene nanoplatelets with the in vitro Caco-2/HT29 model of intestinal barrier.
Carbon-based nanomaterials are being increasingly used, demanding strong information to support their safety in terms of human health. As ingestion is one of the most important exposure routes in humans, we have determined their potential risk by using an in vitro model simulating the human intestinal barrier and evaluated the effects of both graphene oxide (GO) and graphene nanoplatelets (GNPs). A coculture of differentiated Caco-2/HT29 cells presenting inherent intestinal epithelium characteristics (i.e. mucus secretion, brush border, tight junctions, etc.) were treated with GO or GNPs for 24 h. Different endpoints such as viability, membrane integrity, NPs localization, cytokines secretion, and genotoxic damage were evaluated to have a wide view of their potentially harmful effects. No cytotoxic effects were observed in the cells that constitute the barrier model. In the same way, no adverse effects were detected neither in the integrity of the barrier (TEER) nor in its permeability (LY). Nevertheless, a different bio-adhesion and biodistribution behavior was observed for GO and GNPs by confocal microscopy analysis, with a more relevant uptake of GNPs. No oxidative damage induction was detected, either by the DCFH-DA assay or the FPG enzyme in the comet assay. Conversely, both GO and GNPs were able to induce DNA breaks, as observed in the comet assay. Finally, low levels of anti-inflammatory cytokines were detected, suggesting a weak anti-inflammatory response. Our results show the moderate/severe risk posed by GO/GNPs exposures, given the observed genotoxic effects, suggesting that more extensive genotoxic evaluations must be done to properly assess the genotoxic hazard of these nanomaterials.


Induction of Xenopus oocyte meiotic maturation by the dbl oncogene product.
The dbl oncogene was originally identified by transfection of NIH3T3 cells with DNA from a human diffuse B-cell lymphoma. The dbl oncogene product is a cytoplasmic phosphoprotein distributed between the cytosolic and cytoskeletal matrix-associated membrane fractions. Nucleotide sequence analysis has indicated that the predicted dbl product is very hydrophilic with no detectable similarity to known oncogene products. We have more recently discovered that a region of dbl essential for its transforming activity shows significant sequence similarity to a yeast cell cycle gene, CDC24, which is involved in cell polarity and bud formation in the division cycle of Saccharomyces cerevisiae. This sequence similarity suggests a possible role for dbl in cell division. We report here that the dbl oncogene product is able to induce maturation of Xenopus oocytes. Germinal vesicle breakdown (GVBD) was observed when oocytes were microinjected with the soluble fraction of SF9 insect cells infected with a dbl recombinant baculovirus as well as with the in vitro-transcribed dbl mRNA. Moreover, extracts of oocytes microinjected with dbl mRNA showed activation of H1 histone kinase activity. These findings define a new biologic activity of the dbl product and provide the opportunity to analyse dbl interactions with other components of signaling pathways involved in oocyte maturation.


In Vitro Model for Hepatotoxicity Studies Based on Primary Human Hepatocyte Cultivation in a Perfused 3D Bioreactor System.
Accurate prediction of the potential hepatotoxic nature of new pharmaceuticals remains highly challenging. Therefore, novel in vitro models with improved external validity are needed to investigate hepatic metabolism and timely identify any toxicity of drugs in humans. In this study, we examined the effects of diclofenac, as a model substance with a known risk of hepatotoxicity in vivo, in a dynamic multi-compartment bioreactor using primary human liver cells. Biotransformation pathways of the drug and possible effects on metabolic activities, morphology and cell transcriptome were evaluated. Formation rates of diclofenac metabolites were relatively stable over the application period of seven days in bioreactors exposed to 300 µM diclofenac (300 µM bioreactors (300 µM BR)), while in bioreactors exposed to 1000 µM diclofenac (1000 µM BR) metabolite concentrations declined drastically. The biochemical data showed a significant decrease in lactate production and for the higher dose a significant increase in ammonia secretion, indicating a dose-dependent effect of diclofenac application. The microarray analyses performed revealed a stable hepatic phenotype of the cells over time and the observed transcriptional changes were in line with functional readouts of the system. In conclusion, the data highlight the suitability of the bioreactor technology for studying the hepatotoxicity of drugs in vitro.


A modified panel of sentinel congenital anomalies for potential use in mutation epidemiology based on birth defects registry data.
Since 1983, several authors have used panels of "sentinel" congenital anomalies that might serve as indicators of the human genome mutation rate. The current study suggests a considerably updated panel, and applies it to public health birth defects registry data to determine the potential number of de novo cases. Data were taken from deliveries in 1999-2009 from the Texas Birth Defects Registry, an active surveillance program. Cases with one of the conditions or syndromes in the panel were identified using codes and text searches. Frequencies and birth prevalence were calculated for the overall panel and subcategories within it. Of the 60 conditions appearing in previous papers on sentinel phenotypes, 21 (35%) were used in the current study along with 27 new phenotypes. We found 1,694 cases. Of those, 1,100 exhibited phenotypes thought to arise de novo in at least 90% of the cases ("all/almost all" subpanel), and 594 considered de novo in roughly 50-90% of cases ("most" subpanel). Chromosomal deletion disorders were present in 523 cases and imprinting disorders in 243. After adjusting for maternal age, occurrence of cases in the total panel, "most" subpanel, and imprinting disorders subpanel were significantly associated with paternal age. Our panel of sentinel phenotypes differs from previous panels due to evolved knowledge of genetic disorders, different approaches with respect to interviewing, and different operational definitions. It is hoped that using an overall panel as well as subpanels may maximize statistical power as well as suggest potential mechanisms.


Evaluating the impact of an intensive education workshop on evidence-informed decision making knowledge, skills, and behaviours: a mixed methods study.
Health professionals require a unique set of knowledge and skills in order to meet increasing expectations to use research evidence to inform practice and policy decisions. They need to be able to find, access, interpret, and apply the best available research evidence, along with information about patient preferences, clinical expertise, and the clinical context and resources, to such decisions. This study determined preferences for continuing education following an intensive educational workshop and evaluated the impact of the workshop on evidence informed decision making (EIDM) knowledge, skills, and behaviours. An explanatory mixed methods, longitudinal study design was implemented among a convenience sample of various health care professionals attending the workshop. EIDM knowledge, skills, and behaviours were quantitatively measured at baseline and six month follow-up, with EIDM knowledge and skills measured additionally immediately following the educational workshop (post-test measurement). To determine participants preferences for continuing education, data were collected using quantitative survey (post-test measurement) and qualitative (individual telephone interviews after six-month follow-up) methods. EIDM knowledge and skills increased significantly from baseline to immediately following the intervention [5.6, 95% CI (3.7, 7.4), P < 0.001] and from baseline to six-month follow-up [3.7, 95% CI (2.1, 5.3), P < 0.001], with a significant decrease from immediately following the intervention to six-month follow-up [-1.9, 95% CI (-3.5, -0.3), P 0.018]. EIDM behaviours increased, but not significantly, from baseline to six-month follow-up [1.7, 95% CI (-0.3, 3.8), P 0.095]. At baseline and six-month follow-up there was a weak, non-significant positive correlation between EIDM knowledge and skills and EIDM behaviours (r = 0.29, P 0.069 and r = 0.24, P 0.136, respectively). Over time there was a shift in preferences for timing and frequency of online continuing education strategies. Willingness to participate in continuing education, however, remained evident. An intensive educational workshop shows promise for increasing EIDM knowledge and skills. Increasing EIDM knowledge and skills may promote the capacity of health professionals to use research evidence when making practice and policy decisions and, in turn, lead to positive patient outcomes.


A Solid-State Luminescent Cd(II) Supramolecular Coordination Framework Based on Mixed Luminophores as a Sensor for Discriminatively Selective Detection of Amine Vapors.
A novel Cd(II) supramolecular coordination framework containing mixed functionalized luminophore ligands, namely, [Cd(AS)2(phen)2]EtOH or 1 (where AS = 4-aminosalicylate, phen = 1,10-phenanthroline, EtOH = ethanol), was successfully synthesized as a solid-state luminescent sensor for the detection of amine vapors. The single-crystal X-ray diffraction analysis revealed that 1 possesses a three-dimensional (3D) supramolecular framework enclosing ethanol molecule in the lattice. The supramolecular structure is well-stabilized by various noncovalent intermolecular interactions through functional groups of ligands. Compound 1 shows an intense yellow solid-state emission and displays a reversibly discriminative luminescent response to NH3 and ethylenediamine (EDA) vapors through very large blue-shifted luminescent spectra with distinguishable emission colors under UV light. This work reports the first time for selective luminescent sensing of NH3 and EDA vapors with considerably different emission color change. A sensing mechanism has been confirmed by density functional theory and time-dependent density functional theory calculations that agrees well with the experimental results. Also, 1 exhibits a good recyclability over five cycles for sensing of NH3 and EDA vapors.


1-Hydroxyanthraquinones Containing Aryl Substituents as Potent and Selective Anticancer Agents.
A series of 1,2-, 1,4-disubstituted or 1,2,4-trisubstituted anthraquinone-based compounds was designed, synthesized, characterized and biologically evaluated for anticancer efficacy. 2- or 4-arylated 1-hydroxy-9,10-antraquinones (anthracene-9,10-diones) were prepared by Suzuki-Miyaura cross-coupling reaction of 1-hydroxy-2-bromoanthraquinone, 1-hydroxy-4-iodoanthraquinone or 1-hydroxy-2,4-dibromoanthraquinone with arylboronic acids. The cross-coupling reaction of 2,4-dibromo-9,10-anthraquinone with arylboronic acids provide a convenient approach to 2,4-bis arylated 1-hydroxyanthraquinones with a variety of aryl substituent in the 2 and 4 position. The cytotoxicity of new anthraquinone derivatives was evaluated using the conventional MTT assays. The data revealed that six of the aryl substituted compounds among the entire series 3, 15, 16, 25, 27, 28 were comparable potent with the commercially available reference drug doxorubicin on the human glioblastoma cells SNB-19, prostate cancer DU-145 or breast cancer cells MDA-MB-231 and were relatively safe towards human telomerase (h-TERT)immortalized lung fibroblasts cells. The results suggested that the in vitro antitumor activity of synthesized 2-aryl, 4-aryl- and 2,4-diaryl substituted 1-hydroxyanthraquinones depends on the nature of the substituent within the cyclic backbone. Docking interaction of 2-, 4-substituted and 2,4-disubstituted 1-hydroxyanthraquinones indicates intercalative mode of binding of compounds with DNA topoisomerase. The interaction with the DNA of 4-aryl-13, 15, 16 and 4-(furan-3-yl)-23 1-hydroxyanthraquinones was experimentally confirmed through a change in electroforetic mobility. Further experiments with 1-hydroxy-4-phenyl-anthraquinone 13 demonstrated that the compound induced cell cycle arrest at sub-G1 phase in DU-145 cells in the concentration 1.1 μM, which is probably achieved by inducing apoptosis. 4-Arylsubstituted 1-hydroxyanthraquinones 13 and 16 induced the enhancement of DNA synthesis on SNB19 cell lines.


Inferences on the phylogeography of the fungal pathogen Heterobasidion annosum, including evidence of interspecific horizontal genetic transfer and of human-mediated, long-range dispersal.
Fungi in the basidiomycete species complex Heterobasidion annosum are significant root-rot pathogens of conifers throughout the northern hemisphere. We utilize a multilocus phylogenetic approach to examine hypotheses regarding the evolution and divergence of two Heterobasidion taxa associated with pines: the Eurasian H. annosum sensu stricto and the North American H. annosum P intersterility group (ISG). Using DNA sequence information from portions of two nuclear and two mitochondrial loci, we infer phylogenetic relationships via parsimony, Bayesian and median-joining network analysis. Analysis of isolates representative of the entire known geographic range of the two taxa results in monophyletic sister Eurasian and North American lineages, with North America further subdivided into eastern and western clades. Genetically anomalous isolates from the Italian presidential estate of Castelporziano are always part of a North American clade and group with eastern North America, upholding the hypothesis of recent, anthropogenically mediated dispersal. P ISG isolates from Mexico have phylogenetic affinity with both eastern and western North America. Results for an insertion in the mitochondrial rDNA suggest this molecule was obtained from the Heterobasidion S ISG, a taxon sympatric with the P ISG in western North America. These data are compatible with an eastern Eurasian origin of the species, followed by dispersal of two sister taxa into western Eurasia and into eastern North America over a Beringean land bridge, a pattern echoed in the phylogeography of other conifer-associated basidiomycetes.


Current Interventions for Controlling Pathogenic Escherichia coli.
This review examined scientific reports and articles published from 2007 to 2016 regarding the major environmental sources of pathogenic Escherichia coli and the routes by which they enter the human gastrointestinal tract. The literature describes novel techniques used to combat pathogenic E. coli transmitted to humans from livestock and agricultural products, food-contact surfaces in processing environments, and food products themselves. Although prevention before contamination is always the best "intervention," many studies aim to identify novel chemical, physical, and biological techniques that inactivate or eliminate pathogenic E. coli cells from breeding livestock, growing crops, and manufactured food products. Such intervention strategies target each stage of the food chain from the perspective of "Farm to Table food safety" and aim to manage major reservoirs of pathogenic E. coli throughout the entire process. Issues related to, and recent trends in, food production must address not only the safety of the food itself but also the safety of those who consume it. Thus, research aims to discover new "natural" antimicrobial agents and to develop "multiple hurdle technology" or other novel technologies that preserve food quality. In addition, this review examines the practical application of recent technologies from the perspective of product quality and safety. It provides comprehensive insight into intervention measures used to ensure food safety, specifically those aimed at pathogenic E. coli.


Synthesis and characterization of copper(II) 4'-phenyl-terpyridine compounds and catalytic application for aerobic oxidation of benzylic alcohols.
The reactions between 4'-phenyl-terpyridine (L) and nitrate, acetate or chloride Cu(II) salts led to the formation of [Cu(NO3)2L] (1), [Cu(OCOCH3)2L]·CH2Cl2 (2·CH2Cl2) and [CuCl2L]·[Cu(Cl)(μ-Cl)L]2 (3), respectively. Upon dissolving 1 in mixtures of DMSO-MeOH or EtOH-DMF the compounds [Cu(H2O){OS(CH3)2}L](NO3)2 (4) and [Cu(HO)(CH3CH2OH)L](NO3) (5) were obtained, in this order. Reaction of 3 with AgSO3CF3 led to [CuCl(OSO2CF3)L] (6). The compounds were characterized by ESI-MS, IR, elemental analysis, electrochemical techniques and, for 2-6, also by single crystal X-ray diffraction. They undergo, by cyclic voltammetry, two single-electron irreversible reductions assigned to Cu(II) → Cu(I) and Cu(I) → Cu(0) and, for those of the same structural type, the reduction potential appears to correlate with the summation of the values of the Lever electrochemical EL ligand parameter, which is reported for the first time for copper complexes. Complexes 1-6 in combination with TEMPO (2,2,6,6-tetramethylpiperidinyl-1-oxyl radical) can exhibit a high catalytic activity, under mild conditions and in alkaline aqueous solution, for the aerobic oxidation of benzylic alcohols. Molar yields up to 94% (based on the alcohol) with TON values up to 320 were achieved after 22 h.


Orchitis in roosters with reduced fertility associated with avian infectious bronchitis virus and avian metapneumovirus infections.
The pathogenesis of infection involving both infectious bronchitis virus (IBV) and avian metapneumovirus (aMPV) causes reproductive damage in hens after viral replication in the epithelium of the oviduct, resulting in loss of cilia and degeneration and necrosis of the epithelial and glandular cells. Although IBV has been indicated as a possible cause of the formation of calcium stones in the epididymus of roosters, a definitive association has not been confirmed. This report describes the detection of IBV and aMPV in the testes of roosters from a Brazilian poultry broiler breeder's flock with epididymal stones and low fertility. Samples of testis, trachea, and lungs from breeder males aged 57 wk were positive for IBV by reverse transcriptase-polymerase chain reaction (RT-PCR), and virus isolation and testis samples were also positive for aMPV by RT-PCR. The inoculation of testis samples into embryonated chicken eggs via the allantoic cavity resulted in curled, hemorrhagic, and stunted embryos typical of IBV infection. The allantoic fluid was positive by RT-PCR aimed to amplify the region coding for the S1 subunit of the IBV S gene, but it was not positive for aMPV. Sequence analysis of the amplified fragment revealed a close relationship with European IBV genotype D274, previously unreported in Brazil. These results indicate that IBV and perhaps aMPV are likely to have played a role in the pathogenesis of the testicular disease described and should be regarded as factors that can influence male fertility disease in chickens.


Effective spin model for the spin-liquid phase of the Hubbard model on the triangular lattice.
We show that the spin-liquid phase of the half-filled Hubbard model on the triangular lattice can be described by a pure spin model. This is based on a high-order strong coupling expansion (up to order 12) using perturbative continuous unitary transformations. The resulting spin model is consistent with a transition from three-sublattice long-range magnetic order to an insulating spin-liquid phase, and with a jump of the double occupancy at the transition. Exact diagonalizations of both models show that the effective spin model is quantitatively accurate well into the spin-liquid phase, and a comparison with the Gutzwiller projected Fermi sea suggests a gapless spectrum and a spinon Fermi surface.


N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression.
Recent studies suggested that interruption of the interaction of advanced glycation end products (AGEs), with the signal-transducing receptor receptor for AGE (RAGE), by administration of the soluble, extracellular ligand-binding domain of RAGE, reversed vascular hyperpermeability and suppressed accelerated atherosclerosis in diabetic rodents. Since the precise molecular target of soluble RAGE in those settings was not elucidated, we tested the hypothesis that predominant specific AGEs within the tissues in disorders such as diabetes and renal failure, N(epsilon)-(carboxymethyl)lysine (CML) adducts, are ligands of RAGE. We demonstrate here that physiologically relevant CML modifications of proteins engage cellular RAGE, thereby activating key cell signaling pathways such as NF-kappaB and modulating gene expression. Thus, CML-RAGE interaction triggers processes intimately linked to accelerated vascular and inflammatory complications that typify disorders in which inflammation is an established component.


From hemicrania lunaris to hemicrania continua: an overview of the revised International Classification of Headache Disorders.
The International Headache Society's (IHS) Classification of Headache Disorders, published in 1988, is largely responsible for stimulating the rapid scientific and therapeutic advances that have revolutionized the field of headache. By establishing consistent operational diagnostic criteria for primary and secondary headache disorders, the IHS Classification has facilitated epidemiological and genetic studies as well as the multinational clinical trials that provide the basis for our present treatment guidelines. Fifteen years after its original release, a revised 2nd edition has been unveiled. Modifications are small but significant. We hope to introduce clinicians to the salient changes in the 2nd edition by highlighting the newly included headache types, acknowledging the renamed headache types, and reviewing the modifications in diagnostic criteria for existing headache types. Physicians involved in the care of headache patients need to be aware of these changes and should continue to consult the IHS criteria to ensure accurate diagnosis, to continue to refine the diagnostic criteria, and to contribute to the body of knowledge necessary to make further advances in the classification as well as in the field of headache.


Targeted Regulation of Nuclear Lamins by Ubiquitin and Ubiquitin-Like Modifiers.
Nuclear lamins (NLs) are essential components of the animal cell nucleus involved in the regulation of a plethora of molecular and cellular processes. These include the nuclear envelope assembly and stability, mechanotransduction and chromatin organization, transcription, DNA replication, damage repair, and genomic integrity maintenance. Mutations in NLs can lead to the development of a wide range of distinct disease phenotypes, laminopathies, consisting of cardiac, neuromuscular, metabolic and premature aging syndromes. In addition, alterations in the expression of nuclear lamins were associated with different types of neoplastic diseases. Despite the importance and critical roles that NLs play in the diverse cellular activities, we only recently started to uncover the complexity of regulatory mechanisms governing their expression, localization and functions. This integrative review summarizes and discusses the recent findings on the emerging roles of ubiquitin and ubiquitin-like modifiers (ULMs) in the regulation of NLs, highlighting the intriguing molecular associations and cross-talks occurring between NLs and these regulatory molecules under physiological conditions and in the disease states.


Systematic triage in the emergency department using the Australian National Triage Scale: a pilot project.
The objective of this study was to evaluate the validity in Belgium of the National Triage Scale for judgement of the urgency of a patient's condition and making a case-mix description of the patient profiles in the different urgency categories. The study is of a descriptive retrospective and descriptive correlational design and was carried out in the emergency department at the University Hospital Gasthuisberg in Leuven, Belgium. The urgency of patients arriving at the emergency department was evaluated during one randomly selected shift a day over 12 weeks in 1997 by one of the four triage-educated nurses, using an instrument based on the National Triage Scale. Patient identification and outcome parameters were retrieved from the existing computer system. The data were mainly analysed using the Ridit analysis. Overall 3650 patients were evaluated: Category 1, 4.19%; Category 2, 24.44%; Category 3, 39.32%; Category 4, 27.97%; Category 5, 4.08%. Any similarity between sentinel diagnoses as well as between the admission percentages in this pilot study and the reference from Australia (Z = 0.827; p > 0.05) was noted. Different aspects influenced the triage nurses while determining the degree of urgency. Urgency categories profiles revealed a significant effect of age (Kruskall-Wallis = 530.5; p = 0.000). Higher categories of urgency resulted in a higher degree of admission (t (df = 3640) = 643.45; p = 0.000). It is concluded that a resemblance between the pilot study and the reference confirms the predictive validity of the scale used. Patient profiles in the different urgency categories give a description of the emergency department population.


Laparoscopic gastrectomy in obese patients with gastric cancer.
The aim of this study was to assess the surgical and survival outcomes of laparoscopic gastrectomy in obese patients with gastric cancer. All obese patients (body mass index/BMI ≥30 kg/m2) who underwent laparoscopic gastrectomy for gastric cancer with radical intent from January 2008 to September 2016 were compared with non-obese patients undergoing similar surgery. The patient short- and long-term outcomes (overall [OS] and disease-free survival [DFS]) were reviewed. Fifty-seven obese and 153 non-obese patients underwent laparoscopic gastrectomy for gastric cancer. Operating times were not significantly different. The conversion rate was higher in obese patients than in non-obese patients. Postoperative 30-day morbidity was greater in obese patients than in non-obese patients. The duration of postoperative hospital stay was similar for laparoscopically completed cases (9 days for obese patients vs 8 days for non-obese patients), but in the obese-converted group it was 13 days. Pathological data were equivalent between obese and non-obese patients. The 5-year OS and DFS was similar between the two groups. Laparoscopic gastrectomy for gastric cancer in obese patients is technically feasible and oncologically safe. However, a higher postoperative 30-day morbidity and conversion rate was observed in obese patients.


Entomotoxic Activity of Prasiola crispa (Antarctic Algae) in Nauphoeta cinerea Cockroaches: Identification of Main Steroidal Compounds.
Prasiola crispa is a macroscopic green algae found in abundance in Antarctica ice free areas. Prasiola crispan-hexaneextract (HPC) induced insecticidal activity in Nauphoeta cinerea cockroaches after 24 h of exposure. The chemical analysis of HPC revealed the presence of the followingphytosterols: β-sitosterol, campesterol and stigmasterol. The incubation of cockroach semi-isolated heart preparations with HPC caused a significant negative chronotropic activity in the heartbeats. HPC affected the insect neuromuscular function by inducing a complete inhibition of the cockroach leg-muscle twitch tension. When the isolated phytosterols were injected at in vivo cockroach neuromuscular preparations, there was a progressive inhibition of muscle twitches on the following order of potency: β-sitosterol > campesterol > stigmasterol. HPC also provoked significant behavioral alterations, characterized by the increase or decrease of cockroach grooming activity, depending on the dose assayed. Altogether, the results presented here corroborate the insecticide potential of Prasiola crispa Antarctic algae. They also revealed the presence of phytosterols and the involvement of these steroidal compounds in the entomotoxic activity of the algae, potentially by modulating octopaminergic-cholinergic pathways. Further phytochemical-combined bioguided analysis of the HPC will unveil novel bioactive compounds that might be an accessory to the insecticide activity of the algae.


Effect of exogenous adenosine and monensin on glycolytic flux in isolated perfused normoxic rat hearts: role of pyruvate kinase.
We studied the effect of exogenous adenosine in isolated perfused normoxic rat hearts on glycolytic flux through pyruvate kinase (PK). We compared its effect with that of myxothiazol, an inhibitor of mitochondrial ATP production. Moreover, we tested whether an increase of membrane ionic flux with monensin is linked to a stimulation of glycolytic flux through PK. After a 20-min stabilization period adenosine, myxothiazol or monensin were administrated to the perfusate continuously at various concentrations during 10 min. The contraction was monitored and the lactate production in coronary effluents evaluated. The amount of adenine nucleotides and phosphoenolpyruvate was measured in the frozen hearts. Myxothiazol induced a decrease of the left ventricular developed pressure (LVDP : -40%) together with a stimulation of glycolytic flux secondary to PK activation. In contrast, adenosine primarily reduced heart rate (HR: -30%) with only marginal effects on LVDP. This was associated with an inhibition of glycolysis at the level of PK. The Na+ ionophore monensin affected HR (+14%) and LVDP (+25%). This effect was associated with a stimulation of glycolysis secondary to the stimulation of PK. These results provide new information of action of adenosine in the heart and support the concept of a direct coupling between glycolysis and process regulating sarcolemmal ionic fluxes.


A novel grading system for clear cell renal cell carcinoma incorporating tumor necrosis.
Grading of renal cell carcinoma (RCC) has prognostic significance, and there is recent consensus by the International Society of Urological Pathology (ISUP) that for clear cell and papillary RCC, grading should primarily be based on nucleolar prominence. Microscopic tumor necrosis also predicts outcome independent of tumor grading. This study was undertaken to assess whether the incorporation of microscopic tumor necrosis into the ISUP grading system provides survival information superior to ISUP grading alone. Data on 3017 patients treated surgically for clear cell RCC, 556 for papillary RCC, and 180 for chromophobe RCC were retrieved from the Mayo Clinic Registry. Median follow-up periods were 8.9, 9.7, and 8.5 years, respectively. Four proposed grades were defined: grade 1: ISUP grade 1+ISUP grade 2 without necrosis; grade 2: ISUP grade 2 with necrosis+ISUP grade 3 without necrosis; grade 3: ISUP grade 3 with necrosis+ISUP grade 4 without necrosis; grade 4: ISUP grade 4 with necrosis or sarcomatoid/rhabdoid tumors. There was a significant difference in survival between each of the grades for clear cell RCC, and the concordance index was superior to that of ISUP grading. The proposed grading system also outperformed the ISUP grading system when cases were stratified according to the TNM stage. Similar results were not obtained for papillary RCC or chromophobe RCC. We conclude that grading for clear cell RCC should be based on nucleolar prominence and necrosis, that ISUP grading should be used for papillary RCC, and that chromophobe RCC should not be graded.


The antidiabetic drug acarbose suppresses age-related lesions in C57BL/6 mice in an organ dependent manner.
Acarbose (Acb) is an antidiabetic drug used to reduce blood glucose by inhibiting the conversion of complex carbohydrates into simple sugars. It has also shown promise as an anti-aging drug by increasing lifespan in mice but studies have not been reported on the effects of short-term treatment in aging mice. To address this question, 20-month-old C57BL/6 male and female mice were given a standard diet, or a diet supplemented with 1000 ppm Acb for 3 months. After this period, mice were assessed for age-related lesions as readouts for the delay in the progression of aging. Results showed there was a significant decrease in lesions of the heart and kidney in mice treated with Acb suggesting that Acb can suppress cardiac and renal pathology associated with increasing age.


Risk of Early Childhood Obesity in Offspring of Women with Preeclampsia: A Population-Based Study.
Preeclampsia (PE) is a major disease of pregnancy, with various short- or long-term complications for both the mother and offspring. We focused on the body mass index (BMI) of offspring and compared the incidence of obesity during early childhood between PE- and non-PE-affected pregnancies. Women with singleton births (n = 1,697,432) were identified from the Korea National Health Insurance database. The outcomes of offspring at 30-80 months of age were analyzed. The effects of PE on BMI and the incidence of obesity in the offspring were compared. The incidence of low birth weight (LBW) offspring was higher in the PE group (n = 29,710) than that in the non-PE group (n = 1,533,916) (24.70% vs. 3.33%, p < 0.01). However, BMI was significantly higher in the PE-affected offspring than that in non-PE-affected offspring. After adjusting for various factors, the risk of obesity was higher in the PE-affected offspring (odds ratio = 1.34, 95% confidence interval = 1.30-1.38). The BMI and incidence of obesity were higher during early childhood in the PE-affected offspring, even though the proportion of LBW was higher. These results may support the basic hypotheses for the occurrence of various cardiovascular and metabolic complications in PE-affected offspring. In addition, early-age incidence of obesity could influence PE management and child consultation in clinical applications.


Right atrial mural thrombi: An autopsy study of an under-diagnosed complication at an unusual site.
Right atrial mural thrombi (RAMT) are often seen in association with cardiac diseases or foreign bodies. Unusual locations at the flutter isthmus and the atrial appendage prompted us to evaluate our 2-year autopsy data on such thrombi. In the 2-year retrospective autopsy, the clinical and autopsy records of patients with RAMT were reviewed, with particular reference to the presence of central venous catheter (CVC), its site of insertion, its type, material and size, its duration of placement, and the drugs infused through the catheter. Of the 940 autopsies performed in 2 years, RAMT was seen in 24 hearts and was related to an insertion of a CVC in 23 patients (95.8%). The risk and/or associated factors for this complication were tunneled and polyethylene catheters, Intensive Care Unit admission, infused drugs, underlying cardiac diseases, and pregnancy. A noteworthy feature was the location of the thrombi in the flutter isthmus in 16 hearts (66.7%) and atrial appendage in another six hearts. Localized endocarditis/myocarditis and pulmonary thromboembolism were observed in six and four patients, respectively. This autopsy study, which has a high incidence of catheter-related RAMT, does not reflect the true incidence but reiterates the importance of guided insertion of central venous and prompt recognition of thrombus formation.


Systematic review with meta-analysis of studies comparing primary duct closure and T-tube drainage after laparoscopic common bile duct exploration for choledocholithiasis.
With advances in laparoscopic instrumentation and acquisition of advanced laparoscopic skills, laparoscopic common bile duct exploration (LCBDE) is technically feasible and increasingly practiced by surgeons worldwide. Traditional practice of suturing the dochotomy with T-tube drainage may be associated with T-tube-related complications. Primary duct closure (PDC) without a T-tube has been proposed as an alternative to T-tube placement (TTD) after LCBDE. The aim of this meta-analysis was to evaluate the safety and effectiveness of PDC when compared to TTD after LCBDE for choledocholithiasis. A systematic literature search was performed using PubMed, EMBASE, MEDLINE, Google Scholar, and the Cochrane Central Register of Controlled Trials databases for studies comparing primary duct closure and T-tube drainage. Studies were reviewed for the primary outcome measures: overall postoperative complications, postoperative biliary-specific complications, re-interventions, and postoperative hospital stay. Secondary outcomes assessed were: operating time, median hospital expenses, and general complications. Sixteen studies comparing PDC and TTD qualified for inclusion in our meta-analysis, with a total of 1770 patients. PDC showed significantly better results when compared to TTD in terms of postoperative biliary peritonitis (OR 0.22, 95% CI 0.06-0.76, P = 0.02), operating time (WMD, -22.27, 95% CI -33.26 to -11.28, P < 0.00001), postoperative hospital stay (WMD, -3.22; 95% CI -4.52 to -1.92, P < 0.00001), and median hospital expenses (SMD, -1.37, 95% CI -1.96 to -0.77, P < 0.00001). Postoperative hospital stay was significantly decreased in the primary duct closure with internal biliary drainage (PDC + BD) group when compared to TTD group (WMD, -2.68; 95% CI -3.23 to -2.13, P < 0.00001). This comprehensive meta-analysis demonstrates that PDC after LCBDE is feasible and associated with fewer complications than TTD. Based on these results, primary duct closure may be considered as the optimal procedure for dochotomy closure after LCBDE.


Anti-stokes Raman study of vibrational cooling dynamics in the primary photochemistry of rhodopsin.
Picosecond Stokes and anti-Stokes Raman spectra are used to probe the structural dynamics and reactive energy flow in the primary cis-to-trans isomerization reaction of rhodopsin. The appearance of characteristic ethylenic, hydrogen out-of-plane (HOOP), and low-wavenumber photoproduct bands in the Raman spectra is instrument-response-limited, consistent with a subpicosecond product appearance time. Intense high and low-frequency anti-Stokes peaks demonstrate that the all-trans photoproduct is produced vibrationally hot on the ground-state surface. Specifically, the low-frequency modes at 282, 350, and 477 cm(-1) are highly vibrationally excited (T > 2000 K) immediately following isomerization, revealing that these low-frequency motions directly participate in the reactive curve-crossing process. The anti-Stokes modes are characterized by a approximately 2.5 ps temporal decay that coincides with the conversion of photorhodopsin to bathorhodopsin. This correspondence shows that the photo-to-batho transition is a ground-state cooling process and that energy storage in the primary visual photoproduct is complete on the picosecond time scale. Finally, unique Stokes vibrations at 290, 992, 1254, 1290, and 1569 cm(-1) arising from the excited state of rhodopsin are observed only at 0 ps delay.


New Caregiver Diagnoses of Severe Depression and Child Asthma Controller Medication Adherence.
Children with asthma who have depressed caregivers are known to be less adherent to medication regimes. However, it is less clear how adherence responds to a caregiver's new diagnosis of severe depression or whether there is a similar relationship with other serious caregiver diagnoses. The hypothesis is that adherence worsens both with new diagnoses of depression and possibly with new diagnoses of other serious conditions. This study follows a cohort of 341,444 continuously insured children with asthma before and after a caregiver's new diagnosis of severe depression or another serious health condition. The effect of a new depression diagnosis on a child's medication adherence is compared to the effect of new diagnoses of other common caregiver chronic conditions including diabetes, cancer, congestive heart failure, coronary artery disease, and chronic obstructive pulmonary disease. Results show that children's medication adherence declines following a caregiver's new diagnosis of severe depression, but that it also declines following a caregiver's new diagnosis of diabetes. There is no association with new diagnoses of the other caregiver chronic conditions examined. Children whose caregivers have a new diagnosis of depression or diabetes may be at increased risk of deterioration in their medication adherence. These caregivers may benefit from additional support and follow-up. The relationship between caregivers' health and children's medication adherence is complex and deserves further study.


Radiation dose from cigarette tobacco.
The radioactivity in tobacco leaves collected from 15 different regions of Greece before cigarette production was studied in order to estimate the effective dose from cigarette tobacco due to the naturally occurring primordial radionuclides, such as (226)Ra and (210)Pb of the uranium series and (228)Ra of the thorium series and or man-made radionuclides, such as (137)Cs of Chernobyl origin. Gamma-ray spectrometry was applied using Ge planar and coaxial type detectors of high resolution and high efficiency. It was concluded that the annual effective dose due to inhalation for adults (smokers) for (226)Ra varied from 42.5 to 178.6 microSv y(-1) (average 79.7 microSv y(-1)), while for (228)Ra from 19.3 to 116.0 microSv y(-1) (average 67.1 microSv y(-1)) and for (210)Pb from 47.0 to 134.9 microSv y(-1) (average 104.7 microSv y(-1)), that is the same order of magnitude for each radionuclide. The sum of the effective doses of the three natural radionuclides varied from 151.9 to 401.3 microSv y(-1) (average 251.5 microSv y(-1)). The annual effective dose from (137)Cs of Chernobyl origin was three orders of magnitude lower as it varied from 70.4 to 410.4 nSv y(-1) (average 199.3 nSv y(-1)).


[Chronic effects of fluorides on the pituitary-thyroid system in industrial workers].
Radioimmunologic study of thyrotropin and thyroid hormones in the blood of those engaged in fluorine production showed moderate functional changes of the hypophysis-thyroid gland system, not accompanied by clinical manifestations of hypo- or hyperthyreosis and caused by disorders of the regulatory chain and fluorine impact on thyroid hormones' metabolism at the level of target cells. Elevation of calcitonin concentration in workers' blood indicated stimulation of thyroid gland parafollicular cells. Phase states in the hypophysis-thyroid gland system were detected along with the dependence of some hormones' concentration on the duration of workers' contact with fluorine compounds and the stage of fluorosis.


The study of antimicrobial, anti-cancer, anti-inflammatory and α-glucosidase inhibitory activities of Nigronapthaphenyl, isolated from an extract of Nigrospora sphaerica.
A new compound, nigronapthaphenyl, was extracted from the endophytic fungus Nigrospora sphaerica isolated from a mangrove plant Bruguiera gymnorrhyza. The structure of the compound was elucidated by analysis of 1D and 2D NMR spectra and mass spectrometric data. It was tested in vitro for its antimicrobial activity, cytotoxicity, anti-inflammatory activity and for its ability to inhibit α-glucosidase. Nigronapthaphenyl showed antibacterial activities against Bacillus subtilis TISTR 088 and Bacillus cereus TISTR 688 with MIC values of 4 and 2 μg/mL respectively. Cytotoxicity against colon cancer cell line HCT 116 was found to be an IC50 value of 9.62 ± 0.5 μM . This further showed potential anti-inflammatory activity amounting to an IC50 of 6.2 ± 0.5 μM and also α-glucosidase inhibitory activity, with an IC50 value of 6.9 ± 0.5 μM.


[Investigation of the Clinical Significance of Anti-Dense Fine Speckled 70 (anti-DFS70) Autoantibody and Determination of Accompanying Pathologies].
Autoantibodies targeting nuclear and cytoplasmic autoantigens are used as markers in the diagnosis and classification of systemic autoimmune rheumatic diseases (SARD). The dense fine speckled (DFS) pattern is characterized by the fine-granular fluorescence of the nuclei in the interphase and the metaphase chromatin. DFS70 antibodies have been reported in healthy individuals, various autoimmune disorders, infection, cancer and inflammatory conditions. But there is still lack of information about its clinical significance. This study aimed to investigate the clinical significance of anti-DFS70 autoantibodies and the determination of accompanying pathologies. A total of 5710 serum samples routinely requested for ANA screening were tested between 2017 and 2019. Antinuclear antibody (ANA) and dsDNA were performed by indirect immunofluorescence method (IIF) (Euroimmun, Germany). Immunoblot (IB) method was used for the extractable nuclear antigen profile (ENA) (Euroimmun, Germany). Demographic and clinical data, were investigated from the medical records. Among 5710 samples tested for ANA, 23.7% were ANA positive by IIF. Mean age of the patients were 47.9 and 79.5% were female. Only 8.1% of the study group had SARD. The frequency of DFS pattern by ANA-IIF was 6.0% (342/5710), (mean age ± SD= 44.4 ± 16.7, 88% female). DFS70 pattern-positive patients were sub-grouped according to their diagnosis. SARD were detected 10.8% (mean age ± SD= 55.12 ± 14.10) in DFS70 pattern positive patient group (RA 6.1%, SS 2.6%, SLE 0.9%, SSc 0.6%, UCTD 0.6%). Autoantibodies accompanying anti-DFS70 antibody were determined as Ro-52, SS-A, nucleosome, histone, AMA-M2, dsDNA, respectively. Non-SARD diseases were determined in 89.2% of the patients with positive DFS70 pattern. Non-SARD diseases were detected as musculoskeletal complaints (47.4%), other rheumatic diseases like fibromyalgia (14.3%), dermatological diseases (9.4%), gastrointestinal system diseases (5.6%), hematological disorders (3.8%), thyroid /parathyroid diseases (3.5%), allergic diseases (2.3%), neurological diseases (2.3%) and neoplasia (breast cancer) (0.6%). The anti-DFS70 autoantibody is widely used to exclude the diagnosis of SARD in the absence of concomitant SARD-related autoantibodies. It has been observed that anti-DFS70 autoantibody may be associated with non-SARD rheumatic diseases and in many diseases (dermatological, gastrointestinal system, hematological, thyroid diseases) related to other systems. Therefore it is essential to evaluate these pathologies in patients positive for anti-DFS70 antibodies.


[Epoetin alfa in radiotherapy].
Sixty per cent of oncologic patients need radiation therapy for cure or palliation. In fact, in most neoplastic diseases, a better local control positively impacts on disease-free survival and overall survival. The efficacy of radiotherapy depends on several factors: while some are tumor-related, others are host-related. Radiobiological phenomena are also important: ionizing radiation is responsible for cell damage (double rupture of DNA chains), mostly an indirect mechanism with the formation of free radicals. Their toxic action is enhanced by the oxygen partial pressure at the cellular level. A number of studies have confirmed that good tissue oxygenation is a function of a high hemoglobin level in the peripheral blood (Hb > or = 13 g/dL). Unfortunately, these values are rarely present in oncologic patients due to the disease-related toxicosis as well as to the therapy induced hematologic toxicity. The treatment of anemia is free of risk for the recent developments in technology which with gene cloning and the technique of recombinant DNA has allowed the production of human recombinant erythropoietin. Erythropoietin is produced by the interstitial cells of renal tubules in response to hypoxia. It prevents apoptosis and promotes erythroid proliferation and differentiation with consequent reticulocyte release and hemoglobin synthesis. It is not completely understood whether the efficacy of radiotherapy depends on hemoglobin values present at the start of irradiation (often less than 12-13 g/dL) or on the higher ones observed during and at the end of radiotherapy. Therefore, preventive systemic erythropoietin therapy in non anemic patients in terms of costs/benefits is at present non sustainable. To the contrary, in patients undergoing radiotherapy to extended fields or aggressive multimodal treatments, for the higher risk of anemia, the early use of this treatment can be hypothesized in case of initial anemia to improve therapy compliance and prevent negative conditioning of results. Keeping in mind that grade 1 minimum toxicity for red cells, according to the Radiation Therapy Oncology Group (RTOG) is equal to 11 gHb/dL we think that this value can be considered as cutoff to start erythropoietin therapy.


Age-specific social mixing of school-aged children in a US setting using proximity detecting sensors and contact surveys.
Comparisons of the utility and accuracy of methods for measuring social interactions relevant to disease transmission are rare. To increase the evidence base supporting specific methods to measure social interaction, we compared data from self-reported contact surveys and wearable proximity sensors from a cohort of schoolchildren in the Pittsburgh metropolitan area. Although the number and type of contacts recorded by each participant differed between the two methods, we found good correspondence between the two methods in aggregate measures of age-specific interactions. Fewer, but longer, contacts were reported in surveys, relative to the generally short proximal interactions captured by wearable sensors. When adjusted for expectations of proportionate mixing, though, the two methods produced highly similar, assortative age-mixing matrices. These aggregate mixing matrices, when used in simulation, resulted in similar estimates of risk of infection by age. While proximity sensors and survey methods may not be interchangeable for capturing individual contacts, they can generate highly correlated data on age-specific mixing patterns relevant to the dynamics of respiratory virus transmission.


Perfluorooctane Sulfonate-Induced Hepatic Steatosis in Male Sprague Dawley Rats Is Not Attenuated by Dietary Choline Supplementation.
Perfluorooctane sulfonate (PFOS) is an environmentally persistent chemical. Dietary 100 ppm PFOS fed to male mice and rats for 4 weeks caused hepatic steatosis through an unknown mechanism. Choline deficient diets can cause hepatic steatosis. A hepatic choline:PFOS ion complex was hypothesized to cause this effect in mice. This study tested whether dietary choline supplementation attenuates PFOS-induced hepatic steatosis in rats. Sprague Dawley rats (12/sex/group) were fed control, choline supplemented (CS), 100 ppm PFOS, or 100 ppm PFOS + CS diets for 3 weeks. Male rats fed both PFOS-containing diets had decreased serum cholesterol and triglycerides (TGs) on days 9, 16, and/or 23 and increased hepatic free fatty acids and TG (ie, steatosis). Female rats fed both PFOS diets had decreased serum cholesterol on days 9 and 16 and decreased hepatic free fatty acid and TG at termination (ie, no steatosis). Liver PFOS concentrations were similar for both sexes. Liver choline concentrations were increased in male rats fed PFOS (±CS), but the increase was lower in the PFOS + CS group. Female liver choline concentrations were not altered by any diet. These findings demonstrate a clear sex-related difference in PFOS-induced hepatic steatosis in the rat. Additional evaluated mechanisms (ie, nuclear receptor activation, mRNA upregulation, and choline kinase activity inhibition) did not appear to be involved in the hepatic steatosis. Dietary PFOS (100 ppm) induced hepatic steatosis in male, but not female, rats that was not attenuated by choline supplementation. The mechanism of lipid accumulation and the sex-related differences warrant further investigation.


Guidelines for overcoming hospital managerial challenges: a systematic literature review.
The need to respond to accreditation institutes' and patients' requirements and to align health care results with increased medical knowledge is focusing greater attention on quality in health care. Different tools and techniques have been adopted to measure and manage quality, but clinical errors are still too numerous, suggesting that traditional quality improvement systems are unable to deal appropriately with hospital challenges. The purpose of this paper is to grasp the current tools, practices, and guidelines adopted in health care to improve quality and patient safety and create a base for future research on this young subject. A systematic literature review was carried out. A search of academic databases, including papers that focus not only on lean management, but also on clinical errors and risk reduction, yielded 47 papers. The general characteristics of the selected papers were analyzed, and a content analysis was conducted. A variety of managerial techniques, tools, and practices are being adopted in health care, and traditional methodologies have to be integrated with the latest ones in order to reduce errors and ensure high quality and patient safety. As it has been demonstrated, these tools are useful not only for achieving efficiency objectives, but also for providing higher quality and patient safety. Critical indications and guidelines for successful implementation of new health managerial methodologies are provided and synthesized in an operative scheme useful for extending and deepening knowledge of these issues with further studies. This research contributes to introducing a new theme in health care literature regarding the development of successful projects with both clinical risk management and health lean management objectives, and should address solutions for improving health care even in the current context of decreasing resources.


Interventions for reading difficulties: a comparison of response to intervention by ELL and EFL struggling readers.
This article explores whether struggling readers from different primary language backgrounds differ in response to phonologically based remediation. Following random assignment to one of three reading interventions or to a special education reading control program, reading and reading-related outcomes of 166 struggling readers were assessed before, during, and following 105 intervention hours. Struggling readers met criteria for reading disability, were below average in oral language and verbal skills, and varied in English as a first language (EFL) versus English-language learner (ELL) status. The research-based interventions proved superior to the special education control on both reading outcomes and rate of growth. No differences were revealed for children of EFL or ELL status in intervention outcomes or growth during intervention. Oral language abilities at entry were highly predictive of final outcomes and of reading growth during intervention, with greater language impairment being associated with greater growth.


Characterization of volatile production during storage of lettuce (Lactuca sativa) seed.
The duration that seeds stay vigorous during storage is difficult to predict but critical to seed industry and conservation communities. Production of volatile compounds from lettuce seeds during storage was investigated as a non-invasive and early detection method of seed ageing rates. Over 30 volatile compounds were detected from lettuce seeds during storage at 35 degrees C at water contents ranging from 0.03 to 0.09 g H(2)O g(-1) dw. Both qualitative and quantitative differences in volatile composition were noted as a function of water content, and these differences were apparent before signs of deterioration were visible. Seeds stored at high water content (L >or=0.06 g H(2)O g(-1) dw) emitted molecular species indicative of glycolysis (methanol+ethanol), and evidence of peroxidation was apparent subsequent to viability loss. Seeds containing less water (0.03-0.05 g H(2)O g(-1) dw) produced volatiles indicative of peroxidation and survived longer compared with seeds stored under more humid conditions. Production of glycolysis-related by-products correlated strongly with deterioration rate when measured as a function of water content. This correlation may provide a valuable non-invasive means to predict the duration of the early, asymptomatic stage of seed deterioration.


Somatostatin Receptor PET/CT Imaging for the Detection and Staging of Pancreatic NET: A Systematic Review and Meta-Analysis.
We investigated the diagnostic performance of Somatostatin Receptor Positron Emission Tomography/Computed Tomography (SSR-PET/CT) for the detection of primary lesion and initial staging of pancreatic neuroendocrine tumors (pNETs). A comprehensive literature search up to January 2020 was performed selecting studies in presence of: sample size ≥10 patients; index test (i.e., 68Ga-DOTATOC or 68Ga-DOTANOC or 68Ga-DOTATATE PET/CT); and outcomes (i.e., detection rate (DR), true positive, true negative, false positive, and false-negative). The methodological quality was evaluated with QUADAS-2. Pooled DR and pooled sensitivity and specificity for the identification of the primary tumor were assessed by a patient-based and a lesion-based analysis. Thirty-eight studies were selected for the qualitative analysis, while 18 papers were included in the meta-analysis. The number of pNET patients ranged from 10 to 142, for a total of 1143 subjects. At patient-based analysis, the pooled sensitivity and specificity for the assessment of primary pNET were 79.6% (95% confidence interval (95%CI): 71-87%) and 95% (95%CI: 75-100%) with a heterogeneity of 59.6% and 51.5%, respectively. Pooled DR for the primary lesion was 81% (95%CI: 65-90%) and 92% (95%CI: 80-97%), respectively, at patient-based and lesion-based analysis. In conclusion, SSR-PET/CT has high DR and diagnostic performances for primary lesion and initial staging of pNETs.


Designing Human Immunodeficiency Virus Counselling and Testing Services to Maximize Uptake Among High School Learners in South Africa: What Matters?
Increasing human immunodeficiency virus (HIV) testing in South Africa is vital for the HIV response. Targeting young people is important as they become sexually active and because HIV risk rapidly increases as youth enter their 20s. This study aims to increase the understanding of high school learners' preferences regarding the characteristics of HIV testing service delivery models and to inform policy makers and implementers regarding potential barriers to and facilitators of HIV testing. An attitudinal survey was used to examine HIV testing preferences among 248 high school learners in KwaZulu-Natal. Statistical tests were used to identify the most favored characteristics of testing service delivery models and examine key differences in preferences based on demographic characteristics and testing history. Most learners were found to prefer testing offered at a clinic on a Saturday (43%), using a finger prick test (59%), conducted by a doctor (61%) who also provides individual counselling (60%). Shorter testing times were preferred, as well as a monetary incentive to cover any associated expenses. Time, location, the type of test, and who conducts the test were most important. However, stratified analysis suggests that preferences diverge, particularly around gender, grade, but also sexual history and previous testing experience. Human immunodeficiency virus testing services can be improved in line with preferences, but there is no single optimal design that caters to the preferences of all learners. It is unlikely that a "one-size-fits-all" approach will be effective to reach HIV testing targets. A range of options may be required to maximize coverage.


Liliequist membrane: radiological evaluation, clinical and therapeutic implications.
In a simplistic and succinct way, Liliequist membrane may be understood as a projection formed by an arachnoid membrane extending from the dorsum sellae to the mammillary bodies. In spite of being well known to neurosurgeons, many radiologists neither know this anatomical structure nor give importance to its study. The imaging evaluation of this membrane is feasible and may be interesting for a better preoperative planning; postoperative evaluation of third ventriculostomies; and understanding of suprasellar arachnoid cysts and perimesencephalic hemorrhage. The present article illustrates the anatomy of the membrane, with emphasis on imaging findings, besides describing its possible clinical and surgical implications.


Characterization of the csmD and csmE genes from Chlorobium tepidum. The CsmA, CsmC, CsmD, and CsmE proteins are components of the chlorosome envelope.
The csmD and csmE genes, encoding two proteins of the chlorosome envelope, have been cloned and sequenced from the green sulfur bacterium Chlorobium tepidum. The csmD gene predicts a hydrophobic protein of 113 amino acids with a molecular mass of 11.1 kDa. The csmE gene was identified immediately upstream from csmD; the csmE gene predicts a protein of 82 amino acids (9.0 kDa) which is 49% identical to CsmA (Chung et al. (1994) Photosynthesis Res 41: 261-275). The CsmE protein is post-translationally processed, most likely in a manner similar to CsmA. The csmE and csmD genes are cotranscribed as a dicistronic mRNA but can also be cotranscribed with an open reading frame upstream from csmE that predicts a protein with sequence similarity to the CheY and SpoOF subclass of regulatory proteins. The CsmA, CsmC, CsmD, and CsmE proteins were overproduced in Escherichia coli, purified, and used to raise polyclonal antibodies in rabbits. Protease susceptibility mapping and agglutination experiments using these antibodies indicate that all four proteins are exposed at the surface of isolated chlorosomes and hence are probably components of the chlorosome envelope. Additionally, antigalactose antibodies were used to confirm that the galactosyl moiety of monogalactosyl diglycerol is exposed at the chlorosome surface; this is consistent with the notion that these lipids are components of the chlorosome envelope.


Physiotherapy in critical care in australia.
A physiotherapist is part of the multidisciplinary team in most intensive care units in Australia. Physiotherapists are primary contact practitioners and use a comprehensive multisystem assessment that includes the respiratory, cardiovascular, neurological, and musculoskeletal systems to formulate individualized treatment plans. The traditional focus of treatment has been the respiratory management of both intubated and spontaneously breathing patients. However, the emerging evidence of the longstanding physical impairment suffered by survivors of intensive care has resulted in physiotherapists re-evaluating treatment priorities to include exercise rehabilitation as a part of standard clinical practice. The goals of respiratory physiotherapy management are to promote secretion clearance, maintain or recruit lung volume, optimize oxygenation, and prevent respiratory complications in both the intubated and spontaneously breathing patient. In the intubated patient, physiotherapists commonly employ manual and ventilator hyperinflation and positioning as treatment techniques whilst in the spontaneously breathing patients there is an emphasis on mobilization. Physiotherapists predominantly use functional activities for the rehabilitation of the critically ill patient in intensive care. While variability exists between states and centers, Australian physiotherapists actively treat critically ill patients targeting interventions based upon research evidence and individualized assessment. A trend toward more emphasis on exercise rehabilitation over respiratory management is evident.


Dynamic light scattering Monte Carlo: a method for simulating time-varying dynamics for ordered motion in heterogeneous media.
Few methods exist that can accurately handle dynamic light scattering in the regime between single and highly multiple scattering. We demonstrate dynamic light scattering Monte Carlo (DLS-MC), a numerical method by which the electric field autocorrelation function may be calculated for arbitrary geometries if the optical properties and particle motion are known or assumed. DLS-MC requires no assumptions regarding the number of scattering events, the final form of the autocorrelation function, or the degree of correlation between scattering events. Furthermore, the method is capable of rapidly determining the effect of particle motion changes on the autocorrelation function in heterogeneous samples. We experimentally validated the method and demonstrated that the simulations match both the expected form and the experimental results. We also demonstrate the perturbation capabilities of the method by calculating the autocorrelation function of flow in a representation of mouse microvasculature and determining the sensitivity to flow changes as a function of depth.


Variations of the contractile apparatus in smooth and striated muscles. X-ray diffraction studies at rest and in contraction.
Structural information is presented for three muscle systems-mammalian smooth muscle at rest and partially active, living toad striated muscle at rest and contracting, and glycerinated rabbit psoas muscle under various conditions of pH and ionic environment. In the smooth muscle no evidence of organized myosin filaments has been found. In the striated muscle the myosin-to-actin distance can vary widely, according to sarcomere length and to muscle treatment, both at rest and during contraction. In the discussion it is suggested that muscle should be considered as a colloidal system and that there need not necessarily be any chemical bonding (cross-linking) involved in the contractile process.


Uniqueness of the anterior dentition three-dimensionally assessed for forensic bitemark analysis.
The uniqueness of the human dentition (UHD) is an important concept in the comparative process in bitemark analysis. During this analysis, the incisal edges of the suspects' teeth are matched with the bitemarks collected from the victim's body or crime scenes. Despite playing an essential part to exclude suspects, the UHD contained in the involved incisal tooth edges remains an assumption on bitemark level. The present study was aimed, first, to investigate three-dimensionally (3D) the UHD within different quantities of dental material from the incisal edges; second, to test these outcomes in a bidimensional (2D) simulation. Four-hundred forty-five dental casts were collected to compose 4 study groups: I - randomly-selected subjects, II - orthodontically treated subjects, III - twins and IV - orthodontically treated twins. Additionally, 20 dental casts were included to create threshold groups on subjects from whom the dental impressions were taken at 2 different moments (Group V). All the dental casts were digitalized with an automated motion device (XCAD 3D® (XCADCAM Technology®, São Paulo, SP, Brazil). The digital cast files (DCF) were integrated in Geomagic Studio® (3D Systems®, Rock Hill, SC, USA) software package (GS) for cropping, automated superimposition and pair-wise comparisons. All the DCF were cropped remaining 3 mm (part 1), 2 mm (part 2) and 1 mm (part 3) from the incisal edges of the anterior teeth. For a 2D validation, slices of 1 mm, not including incisal edges (part 4), were also cropped. These procedures were repeated in Group V, creating specific thresholds for each of the study parts. The 4 study groups were compared with its respective threshold using ANOVA test with statistical significance of 5%. Groups I, II and III did not differ from the corresponding threshold (Group V) in all study parts (p > 0.05). Scientific evidence to support the UHD was not observed in the current study. Bitemark analysis should not be disregarded but considered carefully when the suspects present similar dental alignment and morphology, such as in orthodontically treated subjects and twins, respectively.


Microneedle delivery of H5N1 influenza virus-like particles to the skin induces long-lasting B- and T-cell responses in mice.
A simple method suitable for self-administration of vaccine would improve mass immunization, particularly during a pandemic outbreak. Influenza virus-like particles (VLPs) have been suggested as promising vaccine candidates against potentially pandemic influenza viruses, as they confer long-lasting immunity but are not infectious. We investigated the immunogenicity and protective efficacy of influenza H5 VLPs containing the hemagglutinin (HA) of A/Vietnam/1203/04 (H5N1) virus delivered into the skin of mice using metal microneedle patches and also studied the response of Langerhans cells in a human skin model. Prime-boost microneedle vaccinations with H5 VLPs elicited higher levels of virus-specific IgG1 and IgG2a antibodies, virus-specific antibody-secreting cells, and cytokine-producing cells up to 8 months after vaccination compared to the same antigen delivered intramuscularly. Both prime-boost microneedle and intramuscular vaccinations with H5 VLPs induced similar hemagglutination inhibition titers and conferred 100% protection against lethal challenge with the wild-type A/Vietnam/1203/04 virus 16 weeks after vaccination. Microneedle delivery of influenza VLPs to viable human skin using microneedles induced the movement of CD207(+) Langerhans cells toward the basement membrane. Microneedle vaccination in the skin with H5 VLPs represents a promising approach for a self-administered vaccine against viruses with pandemic potential.


Structure⁻Activity Relationship of Piplartine and Synthetic Analogues against Schistosoma mansoni and Cytotoxicity to Mammalian Cells.
Schistosomiasis, caused by helminth flatworms of the genus Schistosoma, is an infectious disease mainly associated with poverty that affects millions of people worldwide. Since treatment for this disease relies only on the use of praziquantel, there is an urgent need to identify new antischistosomal drugs. Piplartine is an amide alkaloid found in several Piper species (Piperaceae) that exhibits antischistosomal properties. The aim of this study was to evaluate the structure–function relationship between piplartine and its five synthetic analogues (19A, 1G, 1M, 14B and 6B) against Schistosoma mansoni adult worms, as well as its cytotoxicity to mammalian cells using murine fibroblast (NIH-3T3) and BALB/cN macrophage (J774A.1) cell lines. In addition, density functional theory calculations and in silico analysis were used to predict physicochemical and toxicity parameters. Bioassays revealed that piplartine is active against S. mansoni at low concentrations (5⁻10 µM), but its analogues did not. In contrast, based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, piplartine exhibited toxicity in mammalian cells at 785 µM, while its analogues 19A and 6B did not reduce cell viability at the same concentrations. This study demonstrated that piplartine analogues showed less activity against S. mansoni but presented lower toxicity than piplartine.


MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients.
Standard therapy for glioblastoma (GBM) is temozolomide (TMZ) administration, initially concurrent with radiotherapy (RT), and subsequently as maintenance therapy. The radiologic images obtained in this setting can be difficult to interpret since they may show radiation-induced pseudoprogression (psPD) rather than disease progression. Patients with histologically confirmed GBM underwent radiotherapy plus continuous daily temozolomide (75 mg/m(2)/d), followed by 12 maintenance temozolomide cycles (150 to 200 mg/m(2) for 5 days every 28 days) if magnetic resonance imaging (MRI) showed no enhancement suggesting a tumor; otherwise, chemotherapy was delivered until complete response or unequivocal progression. The first MRI scan was performed 1 month after completing combined chemoradiotherapy. In 103 patients (mean age, 52 years [range 20 to 73 years]), total resection, subtotal resection, and biopsy were obtained in 51, 51, and 1 cases, respectively. MGMT promoter was methylated in 36 patients (35%) and unmethylated in 67 patients (65%). Lesion enlargement, evidenced at the first MRI scan in 50 of 103 patients, was subsequently classified as psPD in 32 patients and early disease progression in 18 patients. PsPD was recorded in 21 (91%) of 23 methylated MGMT promoter and 11 (41%) of 27 unmethylated MGMT promoter (P = .0002) patients. MGMT status (P = .001) and psPD detection (P = .045) significantly influenced survival. PsPD has a clinical impact on chemotherapy-treated GBM, as it may express the glioma killing effects of treatment and is significantly correlated with MGMT status. Improvement in the early recognition of psPD patterns and knowledge of mechanisms underlying this phenomenon are crucial to eliminating biases in evaluating the results of clinical trials and guaranteeing effective treatment.


Synthesis and Characterization of the Rare-Earth Hybrid Double Perovskites: (CH3NH3)2KGdCl6 and (CH3NH3)2KYCl6.
Two hybrid rare-earth double perovskites, (CH3NH3)2KGdCl6 and (CH3NH3)2KYCl6, have been synthesized by a solution evaporation method and their structures determined by variable temperature single-crystal X-ray diffraction. The diffraction results show that at room temperature both perovskites adopt a rhombohedral structure with R3̅m symmetry, as found previously for (MA)2KBiCl6, and lattice parameters of a = 7.7704(5) Å and c = 20.945(2) Å for (MA)2KGdCl6 and a = 7.6212(12) Å and c = 20.742(4) Å for (MA)2KYCl6. Both phases exhibit a rhombohedral-to-cubic phase transition on heating to ∼435 K for (MA)2KYCl6 and ∼375 K for (MA)2KGdCl6. Density functional calculations on the rhombohedral phase indicate that both materials have large direct band gaps, are mechanically stable, and, in the case of (MA)2KGdCl6, could exhibit magnetic ordering at low temperatures.


Effect of Genetic Polymorphisms on the Pharmacokinetics of Gefitinib in Healthy Chinese Volunteers.
Gefitinib is the first generation drug of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) metabolized by the cytochrome P450 and transported by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). In the present study, the pharmacokinetics of gefitinib in healthy Chinese volunteers was investigated and the effect of genetic polymorphisms on its variability was evaluted.Forty-five healthy volunteers were admimistered a single dose of gefitinib and the blood samples were used for quantifying the concentration of gefitinib and genotyping fifteen single-nucleotide polymorphisms of cytochrome P450 enzymes (CYP3A4, CYP3A5, CYP2D6, CYP2C9 and CYP2C19) and drug transporters (ABCB1 and ABCG2).CYP3A5*3 (rs776746) polymorphism showed a significant influence, with higher gefitinib AUC0-t in carrier of CC genotype than in CT/TT genotype (BH-adjusted p value <0.05). For CYP2C9*3 (rs1057910), significant differences in pharmacokinetics of gefitinib were detected between carriers of AA and AC genotypes, with higher AUC0-t, AUC0-∞ and Cmax in carrier of AC genotype than in AA genotype (BH-adjusted p value <0.05). No associations were found between SNPs in CYP3A4, CYP2D6, CYP2C19, ABCB1, ABCG2 and the pharmacokinetics of gefitinib.The SNPs in CYP3A5*3 (rs776746) and CYP2C9*3 (rs1057910) were found to be associated with altered gefitinib pharmacokinetics in healthy Chinese volunteers.