Statins reduce amyloid-beta production through inhibition of protein isoprenylation.
Epidemiological evidence suggests that long term treatment with hydroxymethylglutaryl-CoA reductase inhibitors, or statins, decreases the risk for developing Alzheimer disease (AD). However, statin-mediated AD protection cannot be fully explained by reduction of cholesterol levels. In addition to their cholesterol lowering effects, statins have pleiotropic actions and act to lower the concentrations of isoprenoid intermediates, such as geranylgeranyl pyrophosphate and farnesyl pyrophosphate. The Rho and Rab family small G-proteins require addition of these isoprenyl moieties at their C termini for normal GTPase function. In neuroblastoma cell lines, treatment with statins inhibits the membrane localization of Rho and Rab proteins at statin doses as low as 200 nm, without affecting cellular cholesterol levels. In addition, we show for the first time that at low, physiologically relevant, doses statins preferentially inhibit the isoprenylation of a subset of GTPases. The amyloid precursor protein (APP) is proteolytically cleaved to generate beta-amyloid (Abeta), which is the major component of senile plaques found in AD. We show that inhibition of protein isoprenylation by statins causes the accumulation of APP within the cell through inhibition of Rab family proteins involved in vesicular trafficking. Moreover, inhibition of Rho family protein function reduces levels of APP C-terminal fragments due to enhanced lysosomal dependent degradation. Statin inhibition of protein isoprenylation results in decreased Abeta secretion. In summary, we show that statins selectively inhibit GTPase isoprenylation at clinically relevant doses, leading to reduced Abeta production in an isoprenoid-dependent manner. These studies provide insight into the mechanisms by which statins may reduce AD pathogenesis.


Differential protein phosphorylation in 3T3-L1 adipocytes in response to insulin versus platelet-derived growth factor. No evidence for a phosphatidylinositide 3-kinase-independent pathway in insulin signaling.
Insulin regulates glucose metabolism in adipocytes via a phosphatidylinositide 3-kinase (PI3K)-dependent pathway that appears to involve protein phosphorylation. However, the generation of phosphoinositides is not sufficient for insulin action, and it has been suggested that insulin regulation of glucose metabolism may involve both PI3K-dependent and -independent pathways, the latter being insulin specific. To test this hypothesis, we have designed a phosphoprotein screen to study insulin-specific phosphoproteins that may be either downstream or in parallel to PI3K. Nineteen insulin-regulated phosphospots were detected in the cytosol and high speed pellet fractions, only six of which were significantly regulated by platelet-derived growth factor. Importantly, almost all (92%) of the insulin-specific phosphoproteins identified using this approach were sensitive to the PI3K inhibitor wortmannin. Thus, we obtained no evidence for an insulin-specific, PI3K-independent signaling pathway. A large proportion (62%) of the insulin-specific phosphoproteins were enriched in the same high speed pellet fraction to which PI3K was recruited in response to insulin. Thus, our data suggest that insulin specifically stimulates the phosphorylation of a novel subset of downstream targets and this may in part be because of the unique localization of PI3K in response to insulin in adipocytes.


Effects of 3-thia fatty acids on feed intake, growth, tissue fatty acid composition, beta-oxidation and Na+,K+-ATPase activity in Atlantic salmon.
Atlantic salmon (Salmo salar) with an initial mass of 86 g were reared in 12 degrees C seawater for 8 weeks to a final average mass of 250 g. The fish were fed fish meal and fish oil-based diet supplemented with either 0%, 0.3% or 0.6% of tetradecylthioacetic acid (TTA), a 3-thia fatty acid. The specific growth rate (SGR) decreased with increasing dietary dose of TTA. The SGR of the group fed 0% of TTA (Control) was 1.8; that of the group fed 0.3% of TTA (TTA-L) was 1.7, and that of the group fed 0.6% of TTA (TTA-H) was 1.5. The mortality increased with increased dietary dose of TTA. The mitochondrial beta-oxidation capacity in the liver of fish fed the TTA diets was 1.5 to 2 times higher than that of the Control fish. TTA supplementation caused substantial changes in the fatty acid compositions of the phospholipids (PL), triacylglycerols (TAG) and free fatty acids (FFA) of gills, heart and liver. The percentages of n-3 fatty acids, particularly 22:6 n-3, increased in fish fed diets containing TTA, while the percentage of the saturated FAs 14:0 and 16:0 in the PL fractions of the gills and heart decreased. The sum of monounsaturated FAs in the PL and TAG fractions from liver was significantly higher in fish fed diets containing TTA. TTA itself was primarily incorporated into PL. Two catabolic products of TTA (sulphoxides of TTA) were identified, and these products were particularly abundant in the kidney. TTA supplementation had no significant effect on the activity of the membrane-bound enzyme Na(+),K(+)-ATPase.


Measurement of temperature and density using non-collective X-ray Thomson scattering in pulsed power produced warm dense plasmas.
We present the first experimental measurement of temperature and density of a warm dense plasma produced by a pulsed power driver at the Nevada Terawatt Facility (NTF). In the early phases of discharge, most of the mass remains in the core, and it has been challenging to diagnose with traditional methods, e.g. optical probing, because of the high density and low temperature. Accurate knowledge of the transport coefficients as well as the thermodynamic state of the plasma is important to precisely test or develop theoretical models. Here, we have used spectrally resolved non-collective X-ray Thomson scattering to characterize the dense core region. We used a graphite load driven by the Zebra current generator (0.6 MA in 200 ns rise time) and the Ti He-α line produced by irradiating a Ti target with the Leopard laser (30 J, 0.8 ns) as an X-ray probing source. Using this configuration, we obtained a signal-to-noise ratio ~2.5 for the scattered signal. By fitting the experimental data with predicted spectra, we measured T = 2±1.9 eV, ρ = 0.6±0.5 gr/cc, 70 ns into the current pulse. The complexity of the dense core is revealed by the electrons in the dense core that are found to be degenerate and weakly coupled, while the ions remain highly coupled.


Electric Pulse Stimulation of Myotubes as an In Vitro Exercise Model: Cell-Mediated and Non-Cell-Mediated Effects.
Regular exercise has emerged as one of the best therapeutic strategies to prevent and treat type-2-diabetes. Exercise-induced changes in the muscle secretome, consisting of myokines and metabolites, may underlie the inter-organ communication between muscle and other organs. To investigate this crosstalk, we developed an in vitro system in which mouse C2C12 myotubes underwent electric pulse stimulation (EPS) to induce contraction. Subsequently the effects of EPS-conditioned media (EPS-CM) on hepatocytes were investigated. Here, we demonstrate that EPS-CM induces Metallothionein 1/2 and Slc30a2 gene expression and reduces Cyp2a3 gene expression in rat hepatocytes. When testing EPS-CM that was generated in the absence of C2C12 myotubes (non-cell EPS-CM) no decrease in Cyp2a3 expression was detected. However, similar inductions in hepatic Mt1/2 and Slc30a2 expression were observed. Non-cell EPS-CM were also applied to C2C12 myotubes and compared to C2C12 myotubes that underwent EPS: here changes in AMPK phosphorylation and myokine secretion largely depended on EPS-induced contraction. Taken together, these findings indicate that EPS can alter C2C12 myotube function and thereby affect gene expression in cells subjected to EPS-CM (Cyp2a3). However, EPS can also generate non-cell-mediated changes in cell culture media, which can affect gene expression in cells subjected to EPS-CM too. While EPS clearly represents a valuable tool in exercise research, care should be taken in experimental design to control for non-cell-mediated effects.


Protective Adaptive Immunity Against Severe Acute Respiratory Syndrome Coronaviruses 2 (SARS-CoV-2) and Implications for Vaccines.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging human coronavirus responsible for coronavirus disease 2019 (COVID-19), a predominantly respiratory disease that has become a global pandemic. Millions of people worldwide are suffering from COVID-19, and hundreds of thousands of those infected have died. Nevertheless, many more people who have been infected with SARS-CoV-2 are asymptomatic or suffer a mild disease characterized by dry cough and mild fever. This new pandemic poses a threat to public health on a global scale, and an intervention to prevent continued spread of SARS-CoV-2 virus is of the utmost importance. To assess preventive and therapeutic strategies, it is imperative to understand the pathogenesis and immune response against SARS-CoV-2. In this review, we concentrate on the protective adaptive immune response elicited by this novel coronavirus as well as requirements for a successful vaccine inducing optimal protection.


The relevance of nurses' characteristics in learning behaviour therapy.
Factors that influence learning are of great interest to those concerned with health care. This is because they bear on the question of change in staff and patients. This study is a systematic investigation of the individual characteristics that the nurse brings to the learning situation and their association with change. The purpose of investigating this relationship is to clarify and pinpoint variables that may facilitate selection and predictions regarding learning. This in turn has great relevance for such aspects of nursing practice as patient teaching and in-service training. The study relates seven nurse variables to six measures of learning during an in-service course in behaviour therapy techniques for 65 qualified psychiatric nurses in the United Kingdom. The results suggest that some individual characteristics considered to impede learning, such as age, are unrelated. Other characteristics, such as academic qualifications, are expected to improve learning but were also found to be unrelated. The most significant associations were found for the relationship between prior knowledge and experience and measures of skill. The results are regarded as providing support for the argument of improved specification of both individual characteristics and learning. This improvement may lead in turn to modified nurse selection criteria, revised teaching methods, and to better patient care.


[Intensification of the excretory flow of plutonium-239 from the body in the late stage of its metabolism].
The paper deals with the effect of iron preparations on the excretion of plutonium 239 from a body at a later stage of the radionuclide metabolism. The experimental results show that oral administration of the iron preparation at a later stage of 239Pu metabolism enhances the radionuclide excretion both in urine and in faeces. On the basis of the results obtained the coefficients are calculated for 239Pu excretion in urine and faeces and for its content in the organs of deposition. This may be used for increasing the sensitivity of indirect dosimetry of plutonium-239 within the body.


CSF lactate alone is not a reliable indicator of bacterial ventriculitis in patients with ventriculostomies.
In a febrile patient with a ventriculostomy, diagnosing or excluding bacterial or microbial ventriculitis is difficult, as conventional markers in analysis of cerebrospinal fluid (CSF) are not applicable due to presence of blood and inflammation. CSF lactate has been shown to be a useful indicator of bacterial meningitis in CSF obtained via lumbar puncture, but little and heterogenous data exist on patients with ventriculostomies. We reviewed all CSF analyses obtained via ventriculostomy in patients admitted to our tertiary medical center between 2008 and 2013, and constructed receiver operating characteristic (ROC) curves to evaluate the accuracy of CSF lactate concentration in discriminating a positive CSF culture from a negative one in setting of ventriculostomy and prophylactic antibiosis. Among 467 CSF lactate values, there were 22 corresponding CSF cultures with bacterial growth. Sensitivities and specificities for CSF lactate at threshold values 3, 4, 5 and 6mmol/L showed sensitivity and specificity greater than 70% for CSF lactate threshold 4mmol/L. The lowest threshold value of 3mmol/L resulted in higher sensitivity of 81.8%, and the highest chosen threshold value resulted in high specificity of 94.2%, but these values had poor corresponding specificity and sensitivity, respectively. The area under the curve was 0.82 (95% CI 0.72, 0.91). Our data from a large sample of CSF studies in patients with ventriculostomy indicate that no single value of CSF lactate provided both sensitivity and specificity high enough to be regarded as reliable test.


Targeted Transcriptome and KRAS Mutation Analysis Improve the Diagnostic Performance of EUS-FNA Biopsies in Pancreatic Cancer.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis, and current diagnostic tests have suboptimal sensitivity. Incorporating standard cytology with targeted transcriptomic and mutation analysis may improve upon the accuracy of diagnostic biopsies, thus reducing the burden of repeat procedures and delays to treatment initiation. We reviewed the accuracy of 308 endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) diagnostic PDAC biopsies using a large multicenter clinical and biospecimen database, then performed RNA sequencing on 134 EUS-FNA biopsies spanning all stages of disease. We identified a transcriptomic diagnostic gene signature that was validated using external datasets and 60 further diagnostic EUS-FNAs. KRAS digital droplet PCR (ddPCR) analysis was performed and correlated with signature gene expression. The sensitivity of EUS-FNA cytology in diagnosing solid pancreatic masses in our retrospective cohort of 308 patients was 78.6% (95% confidence interval, 73.2%-83.2%). KRAS mutation analysis and our custom transcriptomic signature significantly improved upon the diagnostic accuracy of standard cytology to 91.3% in external validation sets and 91.6% in our validation cohort (n = 60). Exploratory ddPCR analysis of KRAS-mutant allele fraction (MAF%) correlated closely to signature performance and may represent a novel surrogate marker of tumor cellularity in snap-frozen EUS-FNA biopsies. Our findings support snap-frozen EUS-FNA biopsies as a feasible tissue source for the integrated genomic and transcriptomic analysis of patients presenting with PDAC from all tumor stages, including cases with nondiagnostic cytology. Our transcriptome-derived genetic signature in combination with tissue KRAS mutation analysis significantly improves upon the diagnostic accuracy of current standard procedures, and has potential clinical utility in improving the speed and accuracy of diagnosis for patients presenting with PDAC.


Analysis of 15 patients with systemic lupus erythematosus manifesting with negative immunofluorescence anti-nuclear antibodies after treatment.
The purpose of this study was to investigate the clinical and laboratorial characteristics of patients with systemic lupus erythematosus (SLE) manifesting with negative immunofluorescence anti-nuclear antibodies (IFANA) after treatment for the better understanding of negative conversion of IFANA. Demographic characteristics, clinical and laboratory data of hospitalized SLE patients between March 2006 and May 2011 were retrospectively reviewed. Fifteen cases with negative IFANA were identified in 960 patients. All of the 15 patients were severe, 11 patients manifested with nephritic range proteinuria and hypoalbuminemia, 8 patients were complicated with severe infection and all of the patients had been treated with glucocorticoid and immunosuppressant. Anti-ENA antibodies were positive in 4 of 15 patients. Eight patients died after average 1-year follow-up. Collectively, negative IFANA is mainly attributed to nephritic-range proteinuria; and large-dose glucocorticoid, immunosuppressant and severe infection are also important factors for negative IFANA. Antinuclear antibody can be detected in some SLE patients with negative IFANA by changing the detection method and titer. Negative conversion of IFANA often indicates unfavorable prognosis for severe patients.


A Knowledge-Based Platform for Assessing Potential Adverse Drug Reactions at the Point of Care: User Requirements and Design.
Even though Adverse Drug Reactions (ADRs) constitute a significant public health issue, there is a lack of Information & Communication Technologies (ICT) tools supporting Pharmacovigilance activities at the point of care. In this paper, we present the rationale of a Web-based platform to address this need. The driving user scenario of the proposed platform refers to a clinician who investigates information for a possible ADR as part of a specific patient treatment. The goal is to facilitate this assessment through appropriate tools for searching various relevant data sources, analysing the acquired data, aggregating the obtained evidence, and offering follow-up ADR monitoring over time in a systematic and user-friendly way. In this regard, we describe the adopted user requirements engineering methodology and illustrate the use of Knowledge Engineering (KE) as the platform's main technical paradigm to enable heterogeneous data integration and handle the complexity of the underlying information processing workflow.


Countrywide analysis of heat- and cold-related mortality trends in the Czech Republic: growing inequalities under recent climate warming.
Only little is known about trends in temperature-mortality associations among the most vulnerable subgroups, especially in the areas of central and eastern Europe, which are considered major climatic hotspots in terms of heatwave exposure. Thus, we aimed to assess trends in temperature-related mortality in the Czech Republic by sex, age and cause of death, and to quantify the temporal evolution of possible inequalities. We collected daily time series of all-cause (1987-2019) and cause-specific (1994-2019) mortality by sex and age category, and population-weighted daily mean 2-metre temperatures for each region of the Czech Republic. We applied a quasi-Poisson regression model to estimate the trends in region-specific temperature-mortality associations, with distributed lag non-linear models and multivariate random-effects meta-analysis to derive average associations across the country. We then calculated mortality attributable to non-optimal temperatures and implemented the indicator of sex- and age-dependent inequalities. We observed a similar risk of mortality due to cold temperatures for men and women. Conversely, for warm temperatures, a higher risk was observed for women. Results by age showed a clear pattern of increasing risk due to non-optimum temperatures with increasing age category. The relative risk (RR) related to cold was considerably attenuated in most of the studied subgroups during the study period, whereas an increase in the RR associated with heat was seen in the overall population, in women, in the age category 90+ years and with respect to respiratory causes. Moreover, underlying sex- and age-dependent inequalities experienced substantial growth. Our findings suggest ongoing adaptation to cold temperatures. Mal/adaptation to hot temperatures occurred unequally among population subgroups and resulted in growing inequalities between the sexes and among age categories.


Evaluating the fitness of PA/I38T-substituted influenza A viruses with reduced baloxavir susceptibility in a competitive mixtures ferret model.
Baloxavir is approved in several countries for the treatment of uncomplicated influenza in otherwise-healthy and high-risk patients. Treatment-emergent viruses with reduced susceptibility to baloxavir have been detected in clinical trials, but the likelihood of widespread occurrence depends on replication capacity and onward transmission. We evaluated the fitness of A/H3N2 and A/H1N1pdm09 viruses with the polymerase acidic (PA) I38T-variant conferring reduced susceptibility to baloxavir relative to wild-type (WT) viruses, using a competitive mixture ferret model, recombinant viruses and patient-derived virus isolates. The A/H3N2 PA/I38T virus showed a reduction in within-host fitness but comparable between-host fitness to the WT virus, while the A/H1N1pdm09 PA/I38T virus had broadly similar within-host fitness but substantially lower between-host fitness. Although PA/I38T viruses replicate and transmit between ferrets, our data suggest that viruses with this amino acid substitution have lower fitness relative to WT and this relative fitness cost was greater in A/H1N1pdm09 viruses than in A/H3N2 viruses.


Local signals with global impacts and clinical implications: lessons from the plasma membrane calcium pump (PMCA4).
Calcium has been unequivocally regarded as a key signal messenger in almost every cell type. Calcium regulates a number of important cellular functions including cell growth, myofilament contraction, cell survival and apoptosis as well as gene transcription. A complex regulatory mechanism of cellular calcium is needed to fine tune the precise calcium concentration in each subcellular location and also to transmit the signals carried by the calcium pool to the correct end target. In this article we will review the recently emerging role of the plasma membrane calcium/calmodulin dependent ATPase isoform 4 (PMCA4) in regulating calcium signalling. We will then focus on the function of this molecule in cardiomyocytes, in which PMCA4 forms protein-protein interactions with several key signalling molecules. Recent evidence has shown in vivo physiological functionalities and possible clinical implications of the PMCA4 signalling complex. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.


Prevalence, mean intensity and site preference of Caligus rotundigenitalis Yü, 1933 (Copepoda: Caligidae) on cage cultured crimson snapper (Lutjanus erythropterus Bloch, 1790) from Bukit Tambun, Penang, Malaysia.
Snapper had been cultured in Malaysia since 1980 due to the fry availability and the high demand. However, details on the caligids infestation were not properly documented. This study was carried out to determine the prevalence, mean intensity and site preference of Caligus rotundigenitalis (Caligidae, Siphonostomatoida) a parasitic copepod on cage cultured crimson snapper, Lutjanus erythropterus from Bukit Tambun, Penang, Malaysia. A total of 70 specimens of cultured snapper were examined based on different infestation sites such as head, body as well as operculum. The specimens were separated into three groups according to the size of the fish. C. rotundigenitalis was found to be the only species infesting L. erythropterus with the prevalence and the mean intensity of 81.4% and 5.6±4.4, respectively. There was a significant difference between the prevalence of site infestation of the body and inner operculum sites. The prevalence of C. rotundigenitalis was highest on inner operculum of the fish followed by the body and head. However, there was no significant difference in the distribution of C. rotundigenitalis over the different infestation sites derived from the three groups. The information obtained from this study can be used for more effective control measures of ectoparasitic copepod infestation in floating cages.


What next for preimplantation genetic screening? A clinician's perspective.
Preimplantation genetic screening (PGS) is a technique that has been introduced into clinical practice to screen and eliminate aneuploid embryos from transfer with the intention to improve implantation rates and decrease pregnancy wastage. Although practiced widely throughout the world, PGS unfortunately has been adopted without being subjected to rigorous scientific validation. Data from recent randomized trials have shed doubt on the efficacy of the procedure when used in women with advanced age, one of the target populations for PGS. Other purported indications for the application of this complicated technique such as recurrent implantation failure and recurrent spontaneous abortion have not been subjected to randomized controlled trials. For the best interest of patients, we feel it is timely for a debate regarding the efficacy and safety of PGS.


[Friedreich's disease: a real spectrum of clinical manifestations in terms of direct DNA diagnosis].
Friedreich's disease (FD) is autosomal-recessive form of hereditary ataxias conditioned by expansion of the trinucleotide GAA-repetitions in a new X25 gene. The study was performed in 20 patients from 13 families of different ethnic origin (Slavs, Turkmen, Moldavians, etc) with a suspicion to FD as well as in their 24 relatives who were clinically healthy. Direct DNA-diagnosis confirmed FD diagnosis in patients from 11 families; besides, a number of GAA-repetitions in the patients was in the range from 100 till 1200 (680 +/- 350). A molecular analysis revealed that FD severity was determined by a character of the mutation in each case: a classic form of the disease was characterized by the highest degree of the expansion of GAA-repetitions (more than 400), meanwhile atypic FD cases with late debut and slow progression were conditioned by either a small degree of the expansion of GAA-repetitions or by the presence of point mutations in one of the gene's alleles. A direct DNA-diagnosis permitted to determine a heterozygous carriage of the mutation in 3 clinically healthy individuals. Such cases are necessary to take into consideration in medico-genetic consultations.


The effect of dipyrone on survival of skin flaps.
The effect of dipyrone on the skin flap survival was studied in a model of an epigastric island flap with a random extension on the opposite side in 23 rats. Dipyrone was given intraperitoneally one hour before the skin flap was raised. At the end of the operation the depth of penetration of the fluorescein dye in the skin flap was assessed visually from photographic records and the flap survival area was measured by a grid method on the seventh postoperative day. There was a significant reduction in the amount of ischaemic necrosis of the skin flap after a single dose of dipyrone 50 mg/kg (p < 0.001). These data suggest that dipyrone is a useful agent in the prevention and treatment of ischaemia and necrosis of the skin flap.


Deubiquitylases from genes to organism.
Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.


Primary cultures of human chondrocytes are susceptible to low inocula of Staphylococcus aureus infection and undergo apoptosis.
Hypocellularity after joint infection has been attributed to the cytotoxic effects of pus, which can cause necrosis of chondrocytes. In this study, primary cultures of human chondrocytes lost their viability and underwent necrosis rapidly with high inocula of Staphylococcus aureus infection. Chondrocytes were shown to undergo apoptosis with low inocula of Staphylococcus aureus or their culture ultrafiltrate. These findings further support the hypothesis that residual bacterial toxins or triggered apoptotic processes in chondrocytes participate in the pathogenesis of post-infectious arthropathy.


Investigation of toxicity and performance deterioration of parylene-C packaged copper coils using accelerated test.
In this paper, to figure out the reliability of copper wire wound coil in an in vitro environment, performance deterioration and copper ion elution of coil was investigated using accelerated tests. Bare coils with enamel coating and parylene-C coated coils were immersed into the 75-degree Celsius phosphate-buffered saline for accelerated tests. Performance and elution of the copper ion were investigated using proper equipment. The parylene-C coating with a thickness of several um effectively depress the performance degradation and the elution of the copper ion. However, it has not reached a perfect level and research on additional packaging methods is needed. Coil for wireless power and data transfer is an important element in the design of implantable devices. Copper is the most widely used material for the design of coils in general. However, because of its cytotoxicity and high reactivity with water, the packaging capabilities should be investigated closely. In this paper, a method for evaluating the packaging performance when the coil is coated with parylene-C and the results are presented.


Out-of-hospital cardiac arrest: A systematic review of current risk scores to predict survival.
The arrest and the post-arrest period are an incredibly emotionally traumatic time for family and friends of the affected individual. There is a need to assess prognosis early in the patient pathway to offer objective, realistic and non-emotive information to the next-of-kin regarding the likelihood of survival. To present a systematic review of the clinical risk scores available to assess patients on admission following out-of-hospital cardiac arrest (OHCA) which can predict in-hospital mortality. A systematic search of online databases Embase, MEDLINE and Cochrane Central Register of Controlled Trials was conducted up until 20th November 2020. Out of 1,817 initial articles, we identified a total of 28 scoring systems, with 11 of the scores predicting mortality following OHCA included in this review. The majority of the scores included arrest characteristics (initial rhythm and time to return of spontaneous circulation) as prognostic indicators. Out of these, the 3 most clinically-useful scores, namely those which are easy-to-use, comprise of commonly available parameters and measurements, and which have high predictive value are the OHCA, NULL-PLEASE, and rCAST scores, which appear to perform similarly. Of these, the NULL-PLEASE score is the easiest to calculate and has also been externally validated. Clinicians should be aware of these risk scores, which can be used to provide objective, nonemotive and reproducible information to the next-of-kin on the likely prognosis following OHCA. However, in isolation, these scores should not form the basis for clinical decision-making.


Identification of a Novel Allosteric Inhibitory Site on Tryptophan Hydroxylase 1 Enabling Unprecedented Selectivity Over all Related Hydroxylases.
Pulmonary arterial hypertension (PAH) has demonstrated multi-serotonin receptor dependent pathologies, characterized by increased tone (5-HT1B receptor) and complex lesions (SERT, 5-HT1B, 5-HT2B receptors) of the pulmonary vasculature together with right ventricular hypertrophy, ischemia and fibrosis (5-HT2B receptor). Selective inhibitors of individual signaling elements - SERT, 5-HT2A, 5HT2B, and combined 5-HT2A/B receptors, have all been tested clinically and failed. Thus, inhibition of tryptophan hydroxylase 1 (TPH1), the rate limiting step in 5-HT synthesis, has been suggested as a more broad, and thereby more effective, mode of 5-HT inhibition. However, selectivity over non-pathogenic enzyme family members, TPH2, phenylalanine hydroxylase, and tyrosine hydroxylase has hampered therapeutic development. Here we describe the site/sequence, biochemical, and biophysical characterization of a novel allosteric site on TPH1 through which selectivity over TPH2 and related aromatic amino acid hydroxylases is achieved. We demonstrate the mechanism of action by which novel compounds selectively inhibit TPH1 using surface plasma resonance and enzyme competition assays with both tryptophan ligand and BH4 co-factor. We demonstrate 15-fold greater potency within a human carcinoid cell line versus the most potent known TPH1/2 non-specific inhibitor. Lastly, we detail a novel canine in vivo system utilized to determine effective biologic inhibition of newly synthesized 5-HT. These findings are the first to demonstrate TPH1-selective inhibition and may pave the way to a truly effective means to reduce pathologic 5-HT and thereby treat complex remodeling diseases such as PAH.


Levels of Adherence and Associated Factors Among Children on ART Over Time in Northwest, Ethiopia: Evidence from a Multicenter Follow-Up Study.
Despite the increased availability of antiretroviral therapy (ART), its success depends on a high level of adherence to a life-long antiretroviral therapy. However, the extent and factors associated with adherence to ART are not well known, especially in the current study setup. Therefore, this study aimed to assess the level of adherence and associated factors among children on ART in Northwest, Ethiopia. A retrospective follow-up study was conducted on human immunodeficiency virus (HIV)-infected children receiving ART at South Gondar public hospitals. Children receiving ART from January 1, 2015, to November 30, 2020, were included in the study. A computer-generated simple random sampling technique was employed. The data were entered into the EpiData version 3.1 and analyzed by STATA 14 statistical software. Bivariable logistic regression was fitted for each predictor variable. Moreover, those variables having a p-value ≤0.25 in bivariate analysis were fitted into a multivariable logistic regression model. P-value <0.05 was used to declare significance. A total of 363 HIV-infected children were involved in the study. From 363 HIV-infected children, the level of adherence to ART was found to be 78.2%, 95% CI (73.6, 82.2). TB co-infection [adjusted odds ratio (AOR) = 3.8, 95% CI (1.41, 10.1)], short duration on ART (AOR = 3.4, 95% CI (1.60, 7.20)), treatment failure (AOR = 10.2, 95% CI (3.95, 26.2)), and Zidovudine containing ART regimen (AOR = 3.5, 95% CI (1.1, 10.9)) were significant predictors of poor adherence. The current study showed that the level of adherence to ART was found to be low TB co-infection, short duration of ART, Zidovudine-containing ART regimen, and treatment failure were found to be significantly associated with poor adherence. Further studies on adherence rate and its determinants with multiple adherence measurements using prospective and multicenter studies were recommended.


Potential anticancer activity of tanshinone IIA against human breast cancer.
Tanshinone IIA is a derivative of phenanthrene-quinone isolated from Danshen, a widely used Chinese herbal medicine. It has antioxidant properties and cytotoxic activity against multiple human cancer cell lines, inducing apoptosis and differentiation of some human cancer cell lines. Our purpose was to confirm its anticancer activity on human breast cancer in vitro and in vivo and to elucidate the mechanism of its activity. Human breast cancer cells were tested in vitro for cytotoxicity, colony formation inhibition, BrdU incorporation and gene expression profiling after treatment with tanshinone IIA. Seven nude mice bearing human breast infiltrating duct carcinoma orthotopically were tested for anticancer activity and expression of caspase-3 in vivo by s.c. injection of tanshinone IIA at a dose of 30 mg/kg 3 times/week for 10 weeks. Tanshinone IIA demonstrated a dose- and time-dependent inhibitory effect on cell growth (IC50 = 0.25 microg/ml), and it significantly inhibited colony formation and BrdU incorporation of human breast cancer cells. Oligonucleotide microarray analysis identified 41 upregulated (1.22%) and 24 downregulated (0.71%) genes after tanshinone IIA treatment. Upregulated genes were involved predominantly in cycle regulation, cell proliferation, apoptosis, signal transduction and transcriptional regulation; and downregulated genes were associated mainly with apoptosis and extracellular matrix/adhesion molecules. A 44.91% tumor mass volume reduction and significant increase of casepase-3 protein expression were observed in vivo. Our findings suggest that tanshinone IIA might have potential anticancer activity on both ER-positive and -negative breast cancers, which could be attributed in part to its inhibition of proliferation and apoptosis induction of cancer cells through upregulation and downregulation of multiple genes involved in cell cycle regulation, cell proliferation, apoptosis, signal transduction, transcriptional regulation, angiogenesis, invasive potential and metastatic potential of cancer cells. ADPRTL1 might be the main target at which tanshinone IIA acted.


Multiple hemangiomas (hemangiomatosis) of the cauda equina and spinal cord. Case report.
A case of multiple hemangiomas of the cauda equina nerve roots, conus medullaris, and lower spinal cord is described. The 74-year-old male patient presented with a 9-month history of progressive bilateral leg weakness. He had a history of lymphoma at the age of 39 years and renal cell carcinoma in his early 40s. Neither disease was evident at the time of this presentation. A magnetic resonance image revealed multiple enhancing nodules in the cauda equina region as well as on the pial surface of the lower thoracic spinal cord and conus medullaris. The patient underwent an L2-3 laminectomy. Cauda equina nerve roots were found to be studded with numerous purple nodules, the largest measuring 6 to 8 mm. The nodules were adherent to nerve roots from which they could not be resected. Two lesions were histologically examined and found to be capillary hemangiomas. Twelve months into an uneventful postoperative course, the patient is neurologically unchanged. This unique case might represent a distinct form of hemangiomatosis confined to the cauda equina nerve roots and spinal cord.


Bone mineral density following long-term use of antiepileptic drugs in a tropical Asian country.
The objective of this study was to investigate bone mineral density (BMD) in Thai epileptics who had been receiving long-term, antiepileptic drugs. Subjects were epileptic patients aged 15 to 50 years who had been taking antiepileptic drugs for longer than six months. All were free of disease and none was taking any medication that might interfere with bone metabolism other than antiepileptic drugs. BMD at the left femoral neck and spine was measured with dual energy X-ray absorptiometry. Demographic data, basic laboratory studies and history of clinical epilepsy were obtained. One hundred and thirty patients (63 males and 67 females) were included. Mean age (+ SD) was 31.9 +/- 9.7 year. There were 79 patients receiving monotherapy and 51 patients receiving polytherapy. All patients had normal serum calcium. Thirteen patients had slightly low serum phosphate levels. The BMD at the femoral neck had a mean Z-score - 0.15 +/- 1.17 and the mean Z-score at the lumbar spine was - 0.56 +/- 1.03. Thirty one patients had osteopenia at the spine and 30 patients at the femoral neck. Three patients had osteoporosis of the spine and 1 patient of the femoral neck. There was found to be no significant correlation between age, sex, body mass index, duration of treatment and type of antiepileptic drug with bone mineral density at the femur and spine. The mean BMD of long-term antiepileptic users was lower than that of the sex and age-adjusted mean.


Vacuum Assisted Closure (VAC) therapyTM as a swiss knife multi-tool for enteric fistula closure: tips and tricks: a pilot study.
Enterocutaneous fistulas (ECFs) are an uncommon surgical problem, but they are characterized by a difficult management. Vacuum-assisted closure (VAC) therapy is a method utilized for chronic and traumatic wound healing. At first, VAC therapy had been contraindicated in the treatment of intestinal fistulas, but as time went by, VAC therapy revealed itself to be a "Swiss knife multi-tool". This paper presents some clinical cases of enterocutaneous (ECF) and enteroatmospheric fistulas (EAF) treated with VAC therapy™. The history of 8 patients treated for complex fistulas was revised. Four of them presented with enterocutaneous and four with enteroatmospheric fistulas. All were treated with VAC therapy with variations elaborated to help in accelerated closure of intestinal wall lesions. Four out of four ECFs closed spontaneously. In the EAF group, in three cases the fistula turned slowly into an entero-cutaneous fistula, and in one out of four it closed spontaneously. The mean length of VAC therapy™ was 35.5 days and that of spontaneous closure was 36.4 days. The results of our study encourage the use of VAC therapy™ for the treatment of enterocutaneous fistulas. VAC therapy™ use has a double therapeutic value: (1) it promotes the healing of the skin and allows also the management of EAFs; (2) in selected cases, those in which it is possible to create a deep fistula tract ("well") it is possible to assist to a complete healing with closure of the ECFs.


Population differentiation in an annual legume: genetic architecture.
The presence or absence of epistasis, or gene interaction, is explicitly assumed in many evolutionary models. Although many empirical studies have documented a role of epistasis in population divergence under laboratory conditions, there have been very few attempts at quantifying epistasis in the native environment where natural selection is expected to act. In addition, we have little understanding of the frequency with which epistasis contributes to the evolution of natural populations. In this study we used a quantitative genetic design to quantify the contribution of epistasis to population divergence for fitness components of a native annual legume, Chamaecrista fasciculata. The design incorporated the contrast of performance of F2 and F3 segregating progeny of 18 interpopulation crosses with the F1 and their parents. Crosses were conducted between populations from 100 m to 2000 km apart. All generations were grown for two seasons in the natural environment of one of the parents. The F1 often outperformed the parents. This F1 heterosis reveals population structure and suggests that drift is a major contributor to population differentiation. The F2 generation demonstrated that combining genes from different populations can sometimes have unexpected positive effects. However, the F3 performance indicated that combining genes from different populations decreased vigor beyond that due to the expected loss of heterozygosity. Combined with previous data, our results suggest that both selection and drift contribute to population differentiation that is based on epistatic genetic divergence. Because only the F3 consistently expressed hybrid breakdown, we conclude that the epistasis documented in our study reflects interactions among linked loci.


The acceptability of self-administration of subcutaneous Depo-Provera.
Depo-Provera (depot medroxyprogesterone acetate, or DMPA) is an important contraceptive option for women worldwide. Currently, it is only available in intramuscular form requiring regular quarterly routine attendance at a health facility. A new subcutaneous preparation has been developed. This is self-administrable and could potentially reduce need for routine attendance to an annual visit. In a questionnaire survey of 176 women currently using DMPA, 67% would prefer to self-administer. Of the 33% who did not wish to self-administer, the most common reasons were a fear of needles (62%) and concern regarding incorrect administration (43%). In a second survey of 313 women not currently using DMPA, 64% of women said they would prefer to attend less often for contraceptive supplies. Twenty-six percent of women who had never used DMPA and 40% of ex-users would seriously consider DMPA if self-administration were possible. Our findings would suggest that the advent of subcutaneous self-administrable Depo-Provera with appropriate training and reminder system is likely to be beneficial and popular with many women.


Clinical experience with converting-enzyme inhibitors in hypertension.
Because the renin-angiotensin system frequently participates in sustaining severe forms of hypertension, early studies with the angiotensin-converting enzyme inhibitor captopril were concentrated in patients whose hypertension was refractory to previously available treatment. The effectiveness of captopril, both acutely and during long-term treatment, led to its widespread use for treatment-resistant hypertension. More recently, captopril's efficacy when used as monotherapy and its relative avoidance of symptomatic adverse effects have expanded its role to hypertension of all degrees of severity. A second converting-enzyme inhibitor, enalapril, has been approved for the treatment of hypertension. Its efficacy and clinical characteristics appear similar to those of captopril. In double-blind clinical trials, comparisons with beta-blocker or diuretic therapy have shown captopril to be equal in efficacy but to produce fewer side effects or metabolic changes. In mild-to-moderate essential hypertension it is effective when administered in twice-daily doses of 25 or 50 mg; higher doses do not usually increase its BP-lowering effects. The combination of captopril with a diuretic in low doses has been shown to be especially effective. In additional studies, once-daily doses have controlled BP in a majority of hypertensive patients, but this method of administering captopril has not yet been formally approved. In lower doses, captopril may be less effective in black patients than in white patients, but black patients appear to respond well if the doses are increased. Antihypertensive effects in elderly patients during captopril treatment are equal to those in the young. Converting-enzyme inhibitor therapy appears to have broad utility and a favorable side effect profile in the treatment of essential hypertension.


Replacement Process of Carbonate Apatite by Alveolar Bone in a Rat Extraction Socket.
The objective of this study was to investigate a bone graft substitute containing carbonate apatite (CO3Ap) to analyze bone replacement and the state of bone formation in vitro and in vivo compared with autogenous bone (AB) or control. An osteoclast precursor cell line was cultured with AB or CO3Ap, and morphological analysis using scanning electron microscopy and a tartrate-resistant acid phosphatase activity assay were performed. The right maxillary first and second molars of Wistar rats were extracted and compensated by AB or CO3Ap granules. Following implantation, the bone formation state was evaluated after 3, 5, 7, 14, and 28 days of surgery by micro-computed tomography and immunohistostaining. The osteoclast-like cell morphology was typical with many cell protrusions in the AB and CO3Ap groups. Additionally, the number of osteoclast-like cells formed in the culture increased in each group; however, there was no significant difference between the AB and CO3Ap groups. Five days after tooth extraction, osteoclasts were observed near CO3Ap. The bone thickness in the CO3Ap group was significantly increased than that in the control group and the bone formation in the CO3Ap group increased by the same level as that in the AB group. CO3Ap is gradually absorbed by osteoclasts in the extraction socket and is easily replaced by alveolar bone. The process of bone replacement by osteoclasts is similar to that of autologous bone. By observing the process of bone replacement in more detail, it may be possible to gain a better understanding of the bone formation and control the amount of bone after surgery.


[Prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in patients in long-term care in hospitals, rehabilitation centers and nursing homes of a rural district in Germany].
In recent years multi-resistant pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA) have been causing increasing problems in hospitals and nursing homes. In Germany area-wide and interdisciplinary studies of prevalence of MRSA have not previously been conducted. For this reason we investigated the its prevalence in a cross-sectional study, which included patients in hospitals, rehabilitation centers and nursing homes in a rural district in Germany. The MRSA prevalence was determined by obtaining cultures from the nose, throat and any existing skin lesions of each patient in medical institutions and nursing homes in the the Höxter district. The presence of methicillin resistance, Panton-Valentine leukocidin (PVL) gene were determined and and staphylococcal protein A (spa) typing was done. Potential risk factors for MRSA colonization were also determined. S. aureus was isolated from 319 of 1 083 patients (614 females, 469 males; median age 68,2 years) from five hospitals, five nursing homes und three rehabilitation centers. The MRSA prevalence was 2,5% (95% confidence interval (CI) 1,7-3,7%). In hospitals the MRSA prevalence was 3,4%, in the nursing homes 2,3% and in rehabilitation centers 1,2%, without any significant difference between these three establishments. The proportion of MRSA in all S. aureus isolates was 8,5%. The PVL gene was not detected. It was found by multivariate analysis that variables independently associated with evidence of MRSA were haemodialysis (odds ratio (OR) 11,2; 95% CI 1,9-67,4) and an acute infection in the six months before hospital admission (OR 6,5; 95% CI 1,5-29,2). The spa typing showed different regional distribution of the MRSA subtypes. With 30% the spa type t003 (ST225 clone; in Germany called "Rhine-Hessen strain") occurred most frequently, followed by t032 with 22,2% (ST22 clone, also called "Barnimer strain"). This first regional cross-sectional study provides supportive data for MRSA surveillance in Germany and the data provide a basis for additional preventative measures.


Future Impact of mRNA Therapy on Cardiovascular Diseases.
The silver lining of the recent pandemic was that it accelerated the emergence of messenger ribonucleic acid (mRNA) therapeutics. The great promise of mRNA therapeutics was highlighted by the speed at which the vaccines were created, tested, and proven to be relatively safe and highly effective. There are a wide variety of mRNA therapeutics now under development, and dozens of these are in clinical trials. These therapeutics are generating a major paradigm shift in medical therapy, including the treatment of cardiovascular disease. Most of the cardiovascular mRNA therapies are still in preclinical development, although a phase 2a trial of mRNA therapy for myocardial ischemia has been completed with promising results.1 The application of mRNA therapies to cardiovascular diseases is virtually limitless, and ongoing work includes mRNA therapies for myocardial ischemia, heart failure, arrhythmias, hypercholesterolemia, and arterial occlusive diseases. In addition, mRNA may be used to enhance cell therapies. In the future, mRNA therapies for cardiovascular disease are destined to supplant some of our current biologics and pharmacotherapies and will be used to treat previously untreatable cardiovascular diseases. Furthermore, mRNA therapies can be personalized, and they can be rapidly generated in current Good Manufacturing Practice facilities with a modest footprint, facilitating the rise of hospital-based regional centers of RNA therapeutics.


Selective bacterial adherence to oral epithelial surfaces and its role as an ecological determinant.
The possible relationship between the ability of Streptococcus species to adhere to oral epithelial cells and their natural distribution on epithelial surfaces within the mouth was studied. Strains of S. salivarius and S. sanguis, which are present in significant proportions on oral epithelial surfaces, were found to possess a definite capacity to adhere to epithelial cells obtained from cheek scrapings of humans, hamsters, and germ-free rats. In contrast, strains of S. mutans, which are found in only minor proportions, if at all, on oral epithelial surfaces exhibited feeble or no adherence to oral epithelial cells. S. salivarius cells attached well to human cheek cells over the range of pH 5 to 8. Its adherence was not found to be markedly influenced by saliva or by growth in sucrose broth. Several other types of bacteria were examined which also exhibited widely different abilities to attach to human cheek cells. Mixtures of streptomycin-labeled strains were introduced into the mouths of volunteers for study of the adherence of Streptococcus species to oral epithelial surfaces in vivo. Labeled S. salivarius and S. sanguis were recovered in high proportions from cheek and tongue surfaces, whereas the proportions of labeled S. mutans recovered from these surfaces were low in comparison to the original mixture. These data indicate that a correlation exists between the relative adherence of various Streptococcus species and their proportional distribution found naturally on oral epithelial surfaces. The ability of bacteria to adhere to surfaces is proposed as a critical ecological determinant affecting their colonization in environments with open surfaces exposed to bathing fluids.


Prevalence and risk factors for development of subscapularis and biceps pathology in shoulders with degenerative rotator cuff disease: a prospective cohort evaluation.
The prevalence of subscapularis and long head of biceps (LHB) in relation to the presence and severity of posterosuperior (PS) rotator cuff disease is not known. Subjects with asymptomatic rotator cuff tears were enrolled for this prospective longitudinal study (n = 354) and followed annually with shoulder ultrasonography and clinical evaluations to assess for the presence of subscapularis, LHB, and PS rotator cuff pathology and pain development. Subscapularis pathology developed in 14% of shoulders over a median follow-up of 5 years, with partial-thickness tearing occurring most commonly (83%). Age, sex, and hand dominance were not associated with subscapularis pathology. A greater proportion of concomitant full-thickness PS cuff tears were observed in shoulders that developed subscapularis tears (76% vs. 50%, P = .002). The PS cuff tear width (10 mm vs. 14 mm, P = .01) at the time of enrollment and both tear width (10 mm vs. 15 mm, P = .003) and length (12 mm vs. 15.5 mm, P = .02) at the time of diagnosis of subscapularis pathology were greater in subscapularis-torn shoulders. LHB pathology was prevalent in 34% of shoulders, with dislocation/subluxation occurring in 63% and higher prevalence in subscapularis-torn shoulders (71% vs. 12%, P < .01). Subscapularis-torn shoulders were more likely to develop pain (67% vs. 45%, P = .004), and concomitant PS cuff tear enlargement was associated with greater risk for pain development (76% vs. 36%, P = .01). The development of subscapularis and LHB pathology is significantly related to the size of the PS cuff tear. Subscapularis involvement is associated with greater risk of pain development in degenerative rotator cuff disease.


Protective effect of CpG-DNA against mastitis induced by Staphylococcus aureus infection in a rat model.
A mastitis model in rats, induced by Staphylococcus aureus infection, was established and the protective effect of CpG-DNA on this model was determined. A S. aureus suspension containing 2 x 10(3) CFU.mL(-1) (SL group), 2 x 10(5) CFU.mL(-1) (SH group) or 100 microL PBS (CON group) was inoculated into the mammary glands of rats 72 h after parturition. The rats were euthanized at 24 h post-infection. The histopathologic changes in mammary tissue from SL were mild, whereas the structural changes of the mammary gland from SH were severe and polymorphonuclear leukocytes (PMNs) accumulated in mammary alveoli. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and N-acetyl-beta-d-Glucosaminidase (NAGase) in mammary tissue from SH were significantly increased, however, those from SL were not significantly changed. Therefore, 2 x 10(5) CFU.mL(-1) was selected to test the potential protective effect of CpG-DNA on mammary glands. CpG-DNA (200 microg) or PBS (100 microL) controls were intramuscularly injected right after parturition of rats. At 72 h post-partum, 2 x 10(5) CFU.mL(-1)of S. aureus (100 microL) were inoculated into the mammary gland of all rats and at pre-infection (0 h), 8, 16, 24, 48 and 72 h after inoculation six rats were euthanatized. CpG-DNA induced more rapid migration of PMNs from blood to mammary tissue at the initial stage of infection, stimulated the secretion of IL-6 and TNF-alpha at different time points, reduced viable S. aureus in mammary tissue and decreased the activity of NAGase. CpG-DNA also promoted the expression of its specific receptor TLR-9 mRNA in mammary tissue. In conclusion, CpG-DNA protected against S. aureus mastitis in a rat model.


Electrical stimulation of the midbrain mediates metastatic tumor growth.
Pulmonary metastases were counted 10 days after female rats received tail-vein injections of Walker-256 carcinosarcoma cells. Previous observations that halothane anesthesia plus hind-limb amputation increases the number of metastases were confirmed. Amputation under the analgesia of electrical stimulation of the midbrain was found to increase metastatic activity. However, the stimulus-produced analgesia alone also increased the number of metastases. Systemically administered naloxone blocked the analgesic effect of midbrain stimulation but did not block the increase in the number of pulmonary metastases.


Individual exposure to Simulium bites and intensity of Onchocerca volvulus infection.
Onchocerca volvulus, the causative agent of river blindness, is transmitted through the black fly Simulium damnosum s.l., which breeds in turbulent river waters. To date, the number of flies attacking humans has only been determined by standard fly collectors near the river or the village. In our study, we counted the actual number of attacking and successfully feeding S. damnosum s.l. flies landing on individual villagers during their routine day-time activities in two villages of the Sudan-savannah and rainforest of Cameroon. We compared these numbers to the number of flies caught by a standard vector-collector, one positioned near the particular villager during his/her daily activity and the other sitting at the nearest Simulium breeding site. Using these data obtained by the two vector-collectors, we were able to calculate the Actual Index of Exposure (AIE). While the AIE in the savannah was on average 6,3%, it was 34% in the rainforest. The Effective Annual Transmission Potential (EATP) for individual villagers was about 20 fold higher in the rainforest compared to the savannah. Here we show for the first time that it is possible to determine the EATP. Further studies with more subjects are needed in the future. These data are important for the development of future treatment strategies.


Increased risk of Eustachian tube disorders in patients with sleep-disordered breathing.
Sleep-disordered breathing (SDB) and Eustachian tube disorders (ETDs) share the same risk factors. The specific aim of this study was to determine the correlation between these 2 conditions and to determine whether treatments for SDB reduce the risk of ETD.This is a retrospective and large population-based cohort study. According to Taiwan's National Health Insurance Research Database, out of 1,000,000 insured patients, 24,251 patients were newly diagnosed with SDB from year 2000 through 2009. The control group for this study comprised 96,827 patients without SDB who were randomly selected from the same database at a ratio of 1:4, frequency matched for sex, age, and index year of SDB. The incidence of developing ETD was compared between these 2 groups; the main covariates were demographic data, interventions, and medical comorbidities.There was an increased risk of developing ETD among the SDB cohort compared with the control group (hazard ratio = 1.51, 95% confidence interval = 1.41-1.63). Compared with SDB patients who did not receive treatment, those who received the treatment, that is, pharyngeal or nasal surgery, CPAP, or multiple modalities (both surgery and CPAP), had a significantly reduced risk of developing ETD.This study showed that patients with SDB are at an increased risk of developing ETD and other comorbidities. The risk of developing ETD can be reduced by implementing prompt treatment for SDB. Multidisciplinary evaluation including ETD should be conducted in the management of patients presenting with SDB.


Impact of Lean on patient cycle and waiting times at a rural district hospital in KwaZulu-Natal.
Prolonged waiting time is a source of patient dissatisfaction with health care and is negatively associated with patient satisfaction. Prolonged waiting times in many district hospitals result in many dissatisfied patients, overworked and frustrated staff, and poor quality of care because of the perceived increased workload. The aim of the study was to determine the impact of Lean principles techniques, and tools on the operational efficiency in the outpatient department (OPD) of a rural district hospital. The study was conducted at the Catherine Booth Hospital (CBH) - a rural district hospital in KwaZulu-Natal, South Africa. This was an action research study with pre-, intermediate-, and post-implementation assessments. Cycle and waiting times were measured by direct observation on two occasions before, approximately two-weekly during, and on two occasions after Lean implementation. A standardised data collection tool was completed by the researcher at each of the six key service nodes in the OPD to capture the waiting times and cycle times. All six service nodes showed a reduction in cycle times and waiting times between the baseline assessment and post-Lean implementation measurement. Significant reduction was achieved in cycle times (27%; p < 0.05) and waiting times (from 11.93 to 10 min; p = 0.03) at the Investigations node. Although the target reduction was not achieved for the Consulting Room node, there was a significant reduction in waiting times from 80.95 to 74.43 min, (p < 0.001). The average efficiency increased from 16.35% (baseline) to 20.13% (post-intervention). The application of Lean principles, tools and techniques provides hospital managers with an evidence-based management approach to resolving problems and improving quality indicators.


Mechanism-Based Classification of PAH Mixtures to Predict Carcinogenic Potential.
We have previously shown that relative potency factors and DNA adduct measurements are inadequate for predicting carcinogenicity of certain polycyclic aromatic hydrocarbons (PAHs) and PAH mixtures, particularly those that function through alternate pathways or exhibit greater promotional activity compared to benzo[a]pyrene (BaP). Therefore, we developed a pathway-based approach for classification of tumor outcome after dermal exposure to PAH/mixtures. FVB/N mice were exposed to dibenzo[def,p]chrysene (DBC), BaP, or environmental PAH mixtures (Mix 1-3) following a 2-stage initiation/promotion skin tumor protocol. Resulting tumor incidence could be categorized by carcinogenic potency as DBC >> BaP = Mix2 = Mix3 > Mix1 = Control, based on statistical significance. Gene expression profiles measured in skin of mice collected 12 h post-initiation were compared with tumor outcome for identification of short-term bioactivity profiles. A Bayesian integration model was utilized to identify biological pathways predictive of PAH carcinogenic potential during initiation. Integration of probability matrices from four enriched pathways (P < .05) for DNA damage, apoptosis, response to chemical stimulus, and interferon gamma signaling resulted in the highest classification accuracy with leave-one-out cross validation. This pathway-driven approach was successfully utilized to distinguish early regulatory events during initiation prognostic for tumor outcome and provides proof-of-concept for using short-term initiation studies to classify carcinogenic potential of environmental PAH mixtures. These data further provide a 'source-to-outcome' model that could be used to predict PAH interactions during tumorigenesis and provide an example of how mode-of-action-based risk assessment could be employed for environmental PAH mixtures.


A novel and effective acupuncture modality as a complementary therapy to acute pain relief in inpatients with rib fractures.
Pain control has been emphasized as a priority for both practitioners and inpatients with rib fractures, since analgesia could only offer limited relief from severe pain. A prospective and randomized controlled trial was conducted to analyze the efficacy and efficiency of acupuncture in acute pain relief for inpatients with rib fractures. A total of 58 inpatients were recruited and allocated to two groups, receiving identical doses of conventional oral analgesics as well as filiform needles as treatment and thumbtack intradermal (TI) needles placed upon the skin surface as a control, respectively, via novel acupuncture modality once daily for three consecutive days. The effect of pain relief was evaluated during activities that induce pain, and sustained maximal inspiration (SMI) lung volumes and sleep quality were assessed. The patients treated with filiform needles had more effective pain relief than those in the TI needle group during deep breathing, coughing, and turning over the body (p < 0.05), and the effect persisted for at least 6 h in most patients. Sustained maximal inspiration lung volumes and sleep quality did not show improvement through every acupuncture intervention, and they could not respond accurately to pain relief via acupuncture. The active evaluation could provide a more adaptive model for assessing pain intensity due to rib fractures. This novel acupuncture modality in which the needle insertion sites are corresponding to the pain spots can be a safe and viable therapy for relieving pain in inpatients with rib fractures.


Life-threatening serotonin toxicity due to a citalopram-fluconazole drug interaction: case reports and discussion.
To discuss two cases of life-threatening serotonin toxicity due to a drug interaction between citalopram and fluconazole and to review the pertinent literature. A Medline search without date limitation was conducted using the terms serotonin syndrome, serotonin toxicity, fluconazole and citalopram. Fluconazole inhibits CYP2C19. Citalopram is a substrate for 2C19 and inhibition of its metabolism may result in serotonin toxicity. Serotonin toxicity in oncology patients may not present with the classic constellation of signs typically described in the literature. Delirium may be the only presenting feature. Current level of evidence for treatment of serotonin toxicity is level 4 or 5 (case series and expert opinion). Nevertheless, there is a strong theoretical basis for treating serotonin toxicity in medical patients with a 5H(2A) blocker such as cyproheptadine. Consultation-liaison psychiatrists and oncologists should be aware of this preventable and underrecognized interaction. Citalopram should be stopped or substituted prior to the concurrent administration of fluconazole, and in the event of toxicity, treatment with cyproheptadine has a favorable risk-benefit ratio despite a lack of randomized controlled data to support its use.


Antinociceptive pharmacology of N-(4-chlorobenzyl)-N'-(4-hydroxy-3-iodo-5-methoxybenzyl) thiourea, a high-affinity competitive antagonist of the transient receptor potential vanilloid 1 receptor.
The transient receptor potential vanilloid 1 receptor (TRPV1) is expressed predominantly in a subset of primary afferent nociceptors. Due to its specific anatomical location and its pivotal role as a molecular integrator for noxious thermal and chemical stimuli, there is considerable interest to develop TRPV1 antagonists for the treatment of pain. Recently, N-(4-chlorobenzyl)-N'-(4-hydroxy-3-iodo-5-methoxybenzyl) thiourea (IBTU) was synthesized, and it was found in vitro to be a high-affinity competitive antagonist of cytoplasmic, but not intracellular, TRPV1. In this study, we examined the in vivo antinociceptive activity of IBTU in several acute and inflammatory pain models in mice. Our emphasis was on nociceptive pathways that are likely mediated by TRPV1, including capsaicin-, noxious heat-, and proton (including inflammation)-induced nociception tests. Capsazepine was used as a positive control in these experiments. IBTU dose-dependently blocked the capsaicin-induced nociception, confirming its antagonism at TRPV1 in vivo. By itself, IBTU produced significant antinociception, because it significantly prolonged the tail-flick latency in a dose-dependent manner. IBTU also blocked both early and late phases of the formalin-induced flinching response as well as acetic acid-induced writhing behavior. Moreover, IBTU inhibited the complete Freund's adjuvant-induced persistent hyperalgesia. Taken together, these data demonstrate that IBTU acts as a TRPV1 antagonist in vivo, and they suggest that it may be of therapeutic use for the treatment of pain.


A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening.
High-throughput and virtual screening are widely used to discover novel leads for drug design. On examination, many screening hits appear non-drug-like: they act noncompetitively, show little relationship between structure and activity, and have poor selectivity. Attempts to develop these peculiar molecules into viable leads are often futile, and much time can be wasted on the characterization of these "phony" hits. Despite their common occurrence, the mechanism of action of these promiscuous molecules remains unknown. To investigate this problem, 45 diverse screening hits were studied. Fifteen of these were previously reported as inhibitors of various receptors, including beta-lactamase, malarial protease, dihydrofolate reductase, HIV Tar RNA, thymidylate synthase, kinesin, insulin receptor, tyrosine kinases, farnesyltransferase, gyrase, prions, triosephosphate isomerase, nitric oxide synthase, phosphoinositide 3-kinase, and integrase; 30 were from an in-house screening library of a major pharmaceutical company. In addition to their original targets, 35 of these 45 compounds were shown to inhibit several unrelated model enzymes. These 35 screening hits included compounds, such as fullerenes, dyes, and quercetin, that have repeatedly shown activity against diverse targets. When tested against the model enzymes, the compounds showed time-dependent but reversible inhibition that was dramatically attenuated by albumin, guanidinium, or urea. Surprisingly, increasing the concentration of the model enzymes 10-fold largely eliminated inhibition, despite a 1000-fold excess of inhibitor; a well-behaved competitive inhibitor did not show this behavior. One model to explain these observations was that the active form of the promiscuous inhibitors was an aggregate of many individual molecules. To test this hypothesis, light scattering and electron microscopy experiments were performed. The nonspecific inhibitors were observed to form particles of 30-400 nm diameter by both techniques. In control experiments, a well-behaved competitive inhibitor and an inactive dye-like molecule were not observed to form aggregates. Consistent with the hypothesis that the aggregates are the inhibitory species, the particle size and IC(50) values of the promiscuous inhibitors varied monotonically with ionic strength; a competitive inhibitor was unaffected by changes in ionic strength. Unexpectedly, aggregate formation appears to explain the activity of many nonspecific inhibitors and may account for the activity of many promiscuous screening hits. Molecules acting via this mechanism may be widespread in drug discovery screening databases. Recognition of these compounds may improve screening results in many areas of pharmaceutical interest.


[Cell cycle parameters and proliferative activity in chorioallantois tissues at various stages in chick embryo development].
Two peculiarities of cell population kinetics are characteristic of the provisional tissues of the chick embryo chorioallantois. The one is that the proliferative pool is relatively small at relatively early stages of embryogenesis (8 day incubation). The other is that at the final stages of embryogenesis, when proliferative activity in the embryo cell populations is still high, the cell reproduction is practically stopped. The process of tissue differentiation in chorioallantois, on the one hand, is accompanied with a withdrawal of a considerable part of cells from the cycle of reproduction, but on the other hand this differentiation affects the cells that have remained in the proliferative compartment which is reflected in modifications of either the cell cycle structure or the cell population composition.


[A cross-sectional study of health status and the development of their offspring among woman workers exposed to hazards at factories in Dalian].
A cross-sectional study of health status and the development of their offspring among 3,555 woman workers exposed to a variety of hazardous factors at 14 factories was conducted in 1988 in Dalian. 2,054 woman workers who were not exposed to any kind of the Hazards were used as control group. The relative risk (RR) and the attributive risk (AR) were used to compare the incidence of the study group with that of the control. There are statistically significant excesses of irregular menstruation rate, abortion rate premature and still birth rate in the study group. The rate of congenital malformations of the offsprings of women exposed to benzene is significantly high and so are women working in chemical industry, but it is not significantly different between those exposed to lead and the control group. The incidence of gynecopathy among the study group women consistently is higher than the control group indicating that the hazards in factories can adversely affect the menstruation, reproduction, and the development of their offspring of woman workers.


"Game on!" Teaching gamification principles for library instruction to health sciences information professionals using interactive, low-tech activities and design-thinking modalities.
Gamification is correlated with increased motivation and engagement of learners and is increasingly being incorporated into library instruction. Opportunities for librarians to learn and practice principles of gamification can be helpful for those desiring to incorporate gamification into instruction. This report describes the development and delivery of an interactive special content session at MLA '18, the 2018 Medical Library Association annual meeting in Atlanta, Georgia, focusing on principles of low-tech game design for health sciences library classroom instruction. The special content session, titled "Design, Play, Learn: A Special Content Session to Design a Game for Database Instruction," was designed and delivered using multimodal instruction (e.g., flipped classroom, didactic component, active learning) that also incorporated principles of design thinking. A pre- and post-survey was given to all participants at the beginning and end of the session to measure confidence and desire to incorporate gamification into instruction and as a formative feedback indicator for instructors. Participants reported increased confidence and desire to use games for library instruction after participating in the session. A selection of games was uploaded to a shared content folder designed for course participants as an ongoing repository for ideas and communication. For librarians who are interested in incorporating principles of gamification into library instruction, attending a relatively short hands-on workshop can facilitate learning and confidence around prototyping and creating games for use in library instruction. We intend to improve upon the workshop and offer it again in additional contexts, based on direct observations of the session and participant feedback.


Social mindfulness predicts concern for nature and immigrants across 36 nations.
People cooperate every day in ways that range from largescale contributions that mitigate climate change to simple actions such as leaving another individual with choice - known as social mindfulness. It is not yet clear whether and how these complex and more simple forms of cooperation relate. Prior work has found that countries with individuals who made more socially mindful choices were linked to a higher country environmental performance - a proxy for complex cooperation. Here we replicated this initial finding in 41 samples around the world, demonstrating the robustness of the association between social mindfulness and environmental performance, and substantially built on it to show this relationship extended to a wide range of complex cooperative indices, tied closely to many current societal issues. We found that greater social mindfulness expressed by an individual was related to living in countries with more social capital, more community participation and reduced prejudice towards immigrants. Our findings speak to the symbiotic relationship between simple and more complex forms of cooperation in societies.


Digital imaging by parents: an aid to the diagnosis of inguinal hernia in infants and children.
The aim of the study is to see the feasibility of utilisation of digital imaging by parents in the diagnosis of inguinal hernia in children, and reduce the rate of occasional negative groin exploration. During a two and a half year period, 155 inguinal hernias were diagnosed and operated on in our university teaching hospital. The diagnosis was based on the history and physical examinations of all patients. In 21 patients, the diagnosis was made based on the examination of history alone, as they did not demonstrate the hernia at presentation. In the last year, digital imaging by parents was utilised to aid in the diagnosis of difficult cases. There were ten cases, in addition to the history and physical examinations, that were confirmed by this method. All hernias were confirmed at exploration during surgery. Out of 155 inguinal hernias, 21 (13.5 percent) were diagnosed by history alone, of which four (2.5 percent) had negative exploration, eight (5.1 percent) were positive for hernia, supported with digital imaging by parents' pictures, and nine (5.8 percent) were positive at exploration, without any additional means of diagnosis. History-taking and physical examinations are the mainstay of diagnosis of inguinal hernia in children. The capture of a digital image of the presenting complaint by the patients' parents, can be used as an additional aid in the diagnosis of difficult cases to demonstrate inguinal hernia, as demonstrated in a selected group of children.


Behavior of Germanium and Silicon Nanowire Anodes with Ionic Liquid Electrolytes.
The electrochemical behavior of binder-free, germanium and silicon nanowires as high-capacity anode materials for lithium-ion battery systems is investigated in an ionic liquid electrolyte. Cyclic voltammetry, cycling tests, and impedance spectroscopy reveal a highly reversible lithium alloying/dealloying process, as well as promising compatibility between the Ge and Si materials and the electrolyte components. Reversible capacities of 1400 and 2200 mA h g-1 are delivered by the Ge and Si anodes, respectively, matching the values exhibited in conventional organic solutions. Furthermore, impressive extended cycling performance is obtained in comparison to previous research on Li alloying anodes in ionic liquids, with capacity retention overcoming 50% for Si after 500 cycles and 67% for Ge after 1000 cycles, at a current rate of 0.5C. This stable long-term cycling arises due to the ability of the electrolyte formulation to promote the transformation of the nanowires into durable porous network structures of Ge or Si nanoligaments, which can withstand the extreme volume changes associated with lithiation/delithiation. Remarkable capacity is exhibited also by composite Ge and Si nanowire electrodes. Preliminary tests with lithium cobalt oxide cathodes clearly demonstrate the feasibility of Ge and Si nanowires in full batteries.


Effects of Canagliflozin on Fatty Liver Indexes in Patients with Type 2 Diabetes: A Meta-analysis of Randomized Controlled Trials.
Non-alcoholic fatty liver disease (NAFLD) affects about 75% of patients with type 2 diabetes mellitus (T2DM). We conducted a meta-analysis to determine the effect of canagliflozin on fatty liver indexes in T2DM patients. A literature search of PubMed, Embase and Cochrane was conducted up to March 30, 2017. The liver function test and lipid profile were extracted from randomized controlled trials (RCTs) to evaluate the effect of canagliflozin on fatty liver. Weighted mean differences (WMDs) or relative risks and 95% confidence intervals (CIs) were computed by using either fixed or random-effects models. Sensitivity analysis and publication bias were evaluated. Our results showed that canagliflozin decreased serum concentrations of alanine amino transferase (WMD: -11.68 [95% CI: -18.95, -10.95]; P<0.001), aspartate amino transferase (WMD: -7.50 [95% CI: -10.61, -4.38]; P<0.001), gamma-glutamyl transferase (WMD: -15.17 [95% CI: -17.73, -12.61]; P<0.001), triglycerides (WMD: -0.10 [95% CI: -0.15, -0.05]; P<0.001) but increased low-density lipoprotein cholesterol (WMD: 0.1 [95% CI: 0.06, 0.13]; P<0.001), high-density lipoprotein cholesterol (WMD: 0.06 [95% CI: 0.05, 0.07]; P<0.001) at week 26 or 52. Our results indicated that canagliflozin may have a protective effect on fatty liver in T2DM patients. The limitation was that the liver biopsy was hard to obtain in published studies. More RCTs specified on NAFLD are needed to get further information. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.


Genome-wide survey of V-ATPase genes in Drosophila reveals a conserved renal phenotype for lethal alleles.
V-ATPases are ubiquitous, vital proton pumps that play a multiplicity of roles in higher organisms. In many epithelia, they are the major energizer of cotransport processes and have been implicated in functions as diverse as fluid secretion and longevity. The first animal knockout of a V-ATPase was identified in Drosophila, and its recessive lethality demonstrated the essential nature of V-ATPases. This article surveys the entire V-ATPase gene family in Drosophila, both experimentally and in silico. Adult expression patterns of most of the genes are shown experimentally for the first time, using in situ hybridization or reporter gene expression, and these results are reconciled with published expression and microarray data. For each subunit, the single gene identified previously by microarray, as upregulated and abundant in tubules, is shown to be similarly abundant in other epithelia in which V-ATPases are known to be important; there thus appears to be a single dominant "plasma membrane" V-ATPase holoenzyme in Drosophila. This provides the most comprehensive view of V-ATPase expression yet in a multicellular organism. The transparent Malpighian tubule phenotype first identified in lethal alleles of vha55, the gene encoding the B-subunit, is shown to be general to those plasma membrane V-ATPase subunits for which lethal alleles are available, and to be caused by failure to accumulate uric acid crystals. These results coincide with the expression view of the gene family, in which 13 of the genes are specialized for epithelial roles, whereas others have spatially or temporally restricted patterns of expression.


Low dose intoxication and a crisis of regulatory models. Chemical mutagens in the Deutsche Forschungsgemeinschaft (DFG), 1963-1973.
Regulation and the prevention of danger are among the main characteristics of the modern state. However, the idea and the conceptualization of what danger is have changed over time. The genealogy of these changes shows that the history of social change and the history of knowledge are well connected. The 1970s marked the start of a social transformation of Western industrialized societies. This article proposes that this transformation was connected with basic epistemic reconfigurations and that the genealogy of risk played a significant role. This thesis is explored through the example of DFG advisory politics. Beginning in the 1960s, the DFG expert commissions that had been established to make policy and regulation recommendations began to focus more and more on the health effects of environmental pollution. The Commission for Questions of Mutagenicity played a particularly interesting role because its recommendations resulted in the foundation of a research institution run by the DFG, the Central Laboratory for Mutagenicity Testing (CML). The challenges faced by the CML in mutagenic research and testing effected a crisis of the expert-based advisory politics of the Mutagenicity Commission and a fundamental shift in the way scientific (regulatory) knowledge was perceived and valued politically. The pattern of this crisis calls to mind the constellation of the "risk society", but as will be shown, the (re)balancing of science and politics/society presented here is more adequately understood within the framework of political epistemology.


In vitro and ex vivo suppression by aminoglycosides of PCDH15 nonsense mutations underlying type 1 Usher syndrome.
Type 1 Usher syndrome (USH1) is a recessively inherited condition, characterized by profound prelingual deafness, vestibular areflexia, and prepubertal onset of retinitis pigmentosa (RP). While the auditory component of USH1 can be treated by cochlear implants, to date there is no effective treatment for RP. USH1 can be caused by mutations in each of at least six genes. While truncating mutations of these genes cause USH1, some missense mutations of the same genes cause nonsyndromic deafness. These observations suggest that partial or low level activity of the encoded proteins may be sufficient for normal retinal function, although not for normal hearing. In individuals with USH1 due to nonsense mutations, interventions enabling partial translation of a full-length functional protein may delay the onset and/or progression of RP. One such possible therapeutic approach is suppression of nonsense mutations by small molecules such as aminoglycosides. We decided to test this approach as a potential therapy for RP in USH1 patients due to nonsense mutations. We initially focused on nonsense mutations of the PCDH15 gene, underlying USH1F. Here, we show suppression of several PCDH15 nonsense mutations, both in vitro and ex vivo. Suppression was achieved both by commercial aminoglycosides and by NB30, a new aminoglycoside-derivative developed by us. NB30 has reduced cytotoxicity in comparison to commercial aminoglycosides, and thus may be more efficiently used for therapeutic purposes. The research described here has important implications for the development of targeted interventions that are effective for patients with USH1 caused by various nonsense mutations.


Randomized, non-inferiority trial evaluating the efficacy of a novel teat sealant in pasture grazed dairy cows.
The intramammary infusion at the end of lactation of a bismuth subnitrate internal teat sealant (ITS), with no antibiotic component has been shown to be an effective means of reducing new intra-mammary infections (IMI) over the dry period. There has, however, been very few comparative studies between different brands of ITS under grazed pasture conditions. The objectives of this study were, therefore, to determine if a new bismuth subnitrate internal teal sealant (Shutout®, MSD Animal Health, Wellington, New Zealand) was non-inferior to Teatseal (Zoetis, Auckland, New Zealand) regarding endpoints such as a) detection of the ITS product after calving, b) clinical mastitis during the dry period and early lactation, and c) subclinical mastitis at 30-60 d-in-milk. A total of 1105 mixed age cattle were enrolled across 2 farms comparing 2 ITS products for detection of the ITS at calving and prevention of clinical and subclinical mastitis. Both ITS contained 65% (2.6 g) bismuth salts emulsified in ≤ 1.4 g of mineral oil (Shutout® as Investigational Product; IVP and Teatseal as control product; CP). At dry off, treatment was allocated to every second cow. All cows met industry best practice criteria for using ITS treatment without antibiotics. Outcomes included detection of ITS at first stripping of the udder by the farmer, clinical mastitis (CM) from dry-off to 30 d following calving and subclinical mastitis (SCM) at 30-60 d following calving. For ITS detection, a generalized mixed linear regression model was used to model the data, with clustering of quarters within cow accounted for by including cow as a random intercept. CM was analyzed at the cow-level using a Fisher's exact test, and SCC was modeled using a negative binomial distribution. The IVP was non-inferior to the CP for ITS detection following calving. There were 1344/1800 (71.5%) of quarters with ITS detection in the IVP in comparison to 1076/1604 (67.1%) of quarters in the CP treated group. The quarter-level CM incidence risk was low (45 cases out 4324 quarters; 1.04%). The overall cow-level CM risk was 4.1% (44/1081), with 20/540 (3.7%) cases in animals in the IVP group and 24/541 (4.4%) cases in animals in the CP group. The IVP was non-inferior to the CP for cow-level mastitis incidence. The median SCC for all animals was 23,000 cells/mL, with a mean of 92,000 cells/mL. The back-transformed estimated marginal mean estimated SCC was 84,800 (95% CI 75,200 - 95,600) cells/mL for animals in the IVP group, and 98,800 (95% CI 87,600 - 111,300) cells/mL for animals in the CP group. The IVP was, therefore, non-inferior for all outcomes measured.


A nomogram to predict conversion of laparoscopic surgery to laparotomy for Choledocholithiasis.
Laparoscopic surgery is effective for treating common bile duct (CBD) stones. However, it has high requirements for surgeons and the risk of conversion to laparotomy cannot be ignored. However, when conditions during surgery are not favorable, persisting with laparoscopic procedures blindly can lead to serious complications. Our study aimed to establish a nomogram model for predicting conversion of laparoscopic to laparotomy for choledocholithiasis. A total of 867 patients who were diagnosed with choledocholithiasis and underwent laparoscopic surgery were randomly divided into a training group (70%, n = 607) and a validation group (30%, n = 260). A nomogram was constructed based on the results of logistic regression analysis. The area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA) were used to assess the predictive performance of the nomogram. Previous upper abdominal surgery, maximum diameter of stone ≥12 mm, medial wall of the duodenum stone, thickening of the gallbladder wall, thickening of CBD wall, stone size/CBD size ≥0.75, and simultaneous laparoscopic hepatectomy were included in the nomogram. The AUC values were 0.813 (95% CI: 0.766-0.861) and 0.804 (95% CI: 0.737-0.871) in the training and validation groups, respectively. The calibration curve showed excellent consistency between the nomogram predictions and actual observations. DCA showed a positive net benefit for the nomogram. We constructed a nomogram with a good ability to predict conversion to open surgery in laparoscopic surgery for choledocholithiasis, which can help surgeons to make a reasonable operation plan before surgery and timely convert to laparotomy during operation to reduce potential harm to the patient.


Complications of mandibular distraction osteogenesis for congenital deformities: a systematic review of the literature and proposal of a new classification for complications.
A systematic review of English and non-English language articles on the complications of mandibular distraction osteogenesis (MDO) for patients with congenital deformities was performed, in accordance with the PRISMA statement. Search terms expressing distraction osteogenesis were used in 'AND' combination with search terms comprising 'mandible' and terms for complication, failure, and morbidity. A search using PubMed (National Library of Medicine, NCBI), EMBASE, and the Cochrane Central Register of Controlled Trials yielded 644 articles published between 1966 and mid October 2013. Clinical articles that reported complications related to MDO were included. Finally 81 articles on MDO in congenital deformities were eligible and were screened in detail. Complications including minor infection (6.0%), device-related problems (7.3%), skeletal open bite (2.4%), hypertrophic scar formation (2.1%), facial nerve palsy (1.8%), neurosensory disturbances of the inferior alveolar nerve (1.9%), and (fibrous) non-union (0.7%) were seen. A new index for more detailed classification of complications in MDO is proposed based on six categories that indicate the impact of the complication and its further treatment or final results. The proposed complication index may be a useful tool to classify complications related to MDO.


Copper at the crossroads: Assessment of the interactions between low-carbon energy transition and supply limitations.
This article aims to assess the impact of copper availability on the energy transition and to determine whether copper could become critical due to the high copper content of low-carbon technologies compared to conventional technologies. In assessing copper availability through to 2050, we rely on our linear programming world energy-transport model, TIAM-IFPEN. We examine two climate scenarios (2 °C and 4 °C) with two mobility shape, implemented with a recycling chain. The penetration of low-carbon technologies in the transport and energy sectors (electric vehicles and low-carbon power generation technologies) is likely to significantly increase copper demand by 2050. To investigate how tension over copper resources can be reduced in the energy transition context, we consider two public policy drivers: sustainable mobility and recycling practices. Results show that in the most stringent scenario, the cumulative primary copper demand between 2010 and 2050 is found to be 89.4% of the copper resources known in 2010. They also pinpoint the importance of China and Chile in the future evolution of the copper market.


Comparative genomic analysis of vertebrate Hox3 and Hox4 genes.
We used a comparative genomic approach to identify putative cis-acting regulatory sequences of the zebrafish hoxb3a and hoxb4a genes. We aligned genomic sequences spanning the clustered Hoxb1 to Hoxb5 genes from pufferfish, mice, and humans with the zebrafish hoxba and hoxbb cluster sequences. We identified multiple blocks of conserved sequences in non-coding regions within and surrounding the Hoxb3/b4 gene locus; a subset of these blocks are conserved in the zebrafish hoxbb cluster, despite loss of hoxb3/b4 genes. Overall, we find that the architecture of the Hoxb3/b4 loci and of the conserved sequence elements is very similar in teleosts and mammals. Our analyses also revealed two alternative transcripts of the zebrafish hoxb3a gene and an exon sequence unusually located 10 kb upstream of adjacent hoxb4a; an equivalent murine Hoxb3 exon has not yet been confirmed. We show that many of the Hoxb3/b4 conserved non-coding sequences correlate with functional neural enhancers previously described in the mouse. Further, within the conserved non-coding sequences we have identified binding sites for transcription factors, including Kreisler/Valentino, Krox20, Hox, and Pbx, some of which had not been previously described for the mouse. Finally, we demonstrate that the regulatory sequences of zebrafish hoxa3a are divergent with respect to the mouse ortholog Hoxa3, or the paralog hoxb3a. Despite limited conservation of regulatory sequences, zebrafish hoxa3a and hoxb3a genes share very similar expression profiles.