Bayesian estimation of the diagnostic accuracy of a multiplex real-time PCR assay and bacteriological culture for 4 common bovine intramammary pathogens.
Bacteriological culture (BC) is the traditional method for intramammary infection diagnosis but lacks sensitivity and is time consuming. Multiplex real-time PCR (mr-PCR) enables testing the presence of several bacteria and reduces diagnosis time. Our objective was to estimate bacterial species-specific sensitivity (Se) and specificity of both BC and mr-PCR tests for detecting bacteria in milk samples from clinical mastitis cases and from apparently normal quarters, using a Bayesian latent class model. Milk samples from 1,014 clinical mastitis cases and 1,495 samples from apparently normal quarters were analyzed by BC and mr-PCR. Two positive culture definitions were used: ≥1 cfu/0.01 mL and ≥10 cfu/0.01 mL of the specified bacteria. The mr-PCR was designed to simultaneously detect Staphylococcus aureus, Streptococcus uberis, Escherichia coli, and Streptococcus agalactiae. The priors used in our Bayesian model were weakly informative, with BC priors using the best available error data. Results were compared with those obtained using uniform priors for mr-PCR to test robustness. Weak and uniform priors gave about the same posterior distributions except for Strep. uberis from normal quarters and Strep. agalactiae. Multiplex real-time PCR Se on milk from clinical mastitis were lower than mr-PCR Se on milk from normal quarters. Multiplex real-time PCR Se was higher than BC on milk from normal quarters. Multiplex real-time PCR Se was generally lower than BC on milk from clinical mastitis and it varied by clinical severity. The estimate specificities of detection for all pathogens were ≥99%, regardless of sample type. The effect of milk sample preservation before testing was evaluated and may have been a factor that affected our observed results. A significant association was observed between sample age and mr-PCR results leading to reduced detection of E. coli and Strep. agalactiae in nonclinical samples. Differences in sample age between conduct of BC and of mr-PCR did not concur with any apparent differences between Se estimates of the 2 tests. Further work should be done to extend these results to other PCR-based tests for detecting bacterial species in milk samples, for which presented results could be used as prior parameter distributions. Limits of sample handling and storage and the potential existence of substances in clinical case samples that may interfere with PCR reactions also are worth further investigation.


Highly concentrated collagen solutions leading to transparent scaffolds of controlled three-dimensional organizations for corneal epithelial cell colonization.
This study aimed at controlling both the organization and the transparency of dense collagen scaffolds making use of the lyotropic mesogen properties of collagen. Cholesteric or plywood-like liquid crystal phases were achieved using mixtures of acetic and hydrochloric acids as solvents. The critical pH at which the switch between the two phases occurred was around pH = 3. The use of the two acids led to fibrillated collagen I scaffolds, whose visual aspect ranged from opaque to transparent. Rheological investigations showed that viscoelastic properties of the plywood-like solutions were optimized for molding due to faster recovery. They also confirmed the correlation between the elastic modulus and the diameter of collagen fibrils obtained after fibrillogenesis under ammonia vapor. Human corneal epithelial cells, grown from donor limbal explants, were cultured both on transparent plywood-like matrices and on human amniotic membranes for 14 days. The development of corneal epithelium and the preservation of epithelial stem cells were checked by optical microscopy, colony formation assay, immuno-fluorescence and quantitative polymerase chain reaction. A higher level of amplification of limbal stem cells was obtained with collagen matrices compared with amniotic membranes, showing the high biocompatibility of our scaffolds. We therefore suggest that collagen solutions presenting both plywood-like organization and transparency might be of interest for biomedical applications in ophthalmology.


Bilirubin Is Inversely Associated With Cardiovascular Disease Among HIV-Positive and HIV-Negative Individuals in VACS (Veterans Aging Cohort Study).
Bilirubin may protect against cardiovascular disease (CVD) by reducing oxidative stress. Whether elevated bilirubin reduces the risk of CVD events among HIV+ individuals and if this differs from uninfected individuals remain unclear. We assessed whether bilirubin independently predicted the risk of CVD events among HIV+ and uninfected participants in VACS (Veterans Aging Cohort Study). We conducted a prospective cohort study using VACS participants free of baseline CVD. Total bilirubin was categorized by quartiles. CVD as well as acute myocardial infarction, heart failure, and ischemic stroke events were assessed. Cox regression was used to evaluate hazard ratios of outcomes associated with quartiles of total bilirubin in HIV+ and uninfected people after adjusting for multiple risk factors. There were 96 381 participants (30 427 HIV+); mean age was 48 years, 48% were black, and 97% were men. There were 6603 total incident CVD events over a mean of 5.7 years. In adjusted models, increasing quartiles of baseline total bilirubin were associated with decreased hazards of all outcomes (hazard ratio, 0.86; 95% confidence interval, 0.80-0.91). Among HIV+ participants, results persisted for heart failure, ischemic stroke, and total CVD, but nonsignificant associations were observed for acute myocardial infarction. VACS participants (regardless of HIV status) with elevated bilirubin levels had a lower risk of incident total CVD, acute myocardial infarction, heart failure, and ischemic stroke events after adjusting for known risk factors. Future studies should investigate how this apparently protective effect of elevated bilirubin could be harnessed to reduce CVD risk or improve risk estimation among HIV+ individuals.


Cadmium exposure in First Nations communities of the Northwest Territories, Canada: smoking is a greater contributor than consumption of cadmium-accumulating organ meats.
Traditional food consumption among northern populations is associated with improved nutrition but occasionally can also increase contaminant exposure. High levels of cadmium in the organs of moose from certain regions of the Northwest Territories, Canada, led to the release of consumption notices. These notices recommended that individuals limit their consumption of kidney and liver from moose harvested from the Southern Mackenzie Mountain. A human biomonitoring project was designed to better characterize exposure and risks from contaminants, including cadmium, among Dene/Métis communities of the Northwest Territories Mackenzie Valley, Canada. The project included a dietary assessment (food frequency questionnaire) to estimate moose and caribou organ (kidney and liver) consumption, as well as urine and blood sampling for the measurement of cadmium concentration using mass spectrometry. For a subset of the samples, urine cotinine was also quantified. The results from this biomonitoring research show that cadmium levels in urine (GM = 0.32 μg L-1) and blood (GM = 0.58 μg L-1) are similar to those observed in other populations in Canada. For the 38% of participants reporting eating game organs, current traditional food consumption patterns were not associated with cadmium biomarker levels. Instead, smoking appeared to be the main determinant of cadmium exposure. These results are supporting ongoing efforts at the community and territorial level to identify health priorities and design follow up plans in response to environmental monitoring data.


Ideal Cardiovascular Health and Carotid Atherosclerosis in a Mixed Cohort of HIV-Infected and Uninfected Ugandans.
Preventable cardiovascular disease (CVD) risk factors are responsible for the majority of CVD-related deaths, and are increasingly recognized as a cause of morbidity and mortality for HIV-infected persons taking antiretroviral therapy (ART). Simplified tools such as the American Heart Association's ideal cardiovascular health (iCVH) construct may identify and prognosticate CVD risk in resource-limited settings. No studies have evaluated iCVH metrics in sub-Saharan Africa or among HIV-infected adults. Thus, the central aim of this study was to compare levels of iCVH metrics and their correlations with carotid atherosclerosis for HIV-infected adults versus uninfected controls in a well-phenotyped Ugandan cohort. We analyzed the prevalence of iCVH metrics in a mixed cohort of HIV-infected persons on stable ART and uninfected, population-based comparators in Mbarara, Uganda. We also assessed the validity of iCVH by correlating iCVH values with common carotid intima media thickness (CCIMT). HIV-infected persons had a mean of 4.9 (SD 1.1) iCVH metrics at ideal levels versus 4.3 (SD 1.2) for uninfected controls (p = .002). This difference was largely driven by differences in blood pressure, blood glucose, and diet. In multivariable-adjusted linear regression models, each additional iCVH metric at an ideal level was associated with a significant 0.024 mm decrease in CCIMT (p < .001).HIV-infected persons on ART in rural Uganda had more iCVH metrics at ideal levels than uninfected persons. The difference appeared driven by factors that are putatively influenced by access to routine medical care. Composite scores of iCVH metrics were associated with subclinical atherosclerosis and more predictive of atherosclerosis for uninfected persons.


Stereo Photo Measured ONH Shape Predicts Development of POAG in Subjects With Ocular Hypertension.
To identify objective, quantitative optic nerve head (ONH) structural features and model the contributions of glaucoma. Baseline stereoscopic optic disc images of 1635 glaucoma-free participants at risk for developing primary open-angle glaucoma (POAG) were collected as part of the Ocular Hypertension Treatment Study. A stereo correspondence algorithm designed for fundus images was applied to extract the three-dimensional (3D) information about the ONH. Principal component analysis was used to identify ONH 3D structural features and the contributions of demographic features, clinical variables, and disease were modeled using linear regression and linear component analysis. The computationally identified features were evaluated based on associations with glaucoma and ability to predict which participants would develop POAG. The computationally identified features were significantly associated with future POAG, POAG-related demographics (age, ethnicity), and clinical measurements (horizontal and vertical cup-to-disc ratio, central corneal thickness, and refraction). Models predicting future POAG development using the OHTS baseline data and STEP features achieved an AUC of 0.722 in cross-validation testing. This was a significant improvement over using only demographics (age, sex, and ethnicity), which had an AUC of 0.599. Methods for identifying objective, quantitative measurements of 3D ONH structure were developed using a large dataset. The identified features were significantly associated with POAG and POAG-related variables. Further, these features increased predictive model accuracy in predicting future POAG. The results indicate that the computationally identified features might be useful in POAG early screening programs or as endophenotypes to investigate POAG genetics.


Pilot Study: Detection of Gastric Cancer From Exhaled Air Analyzed With an Electronic Nose in Chinese Patients.
The aim of this pilot study is to investigate the ability of an electronic nose (e-nose) to distinguish malignant gastric histology from healthy controls in exhaled breath. In a period of 3 weeks, all preoperative gastric carcinoma (GC) patients (n = 16) in the Beijing Oncology Hospital were asked to participate in the study. The control group (n = 28) consisted of family members screened by endoscopy and healthy volunteers. The e-nose consists of 3 sensors with which volatile organic compounds in the exhaled air react. Real-time analysis takes place within the e-nose, and binary data are exported and interpreted by an artificial neuronal network. This is a self-learning computational system. The inclusion rate of the study was 100%. Baseline characteristics differed significantly only for age: the average age of the patient group was 57 years and that of the healthy control group 37 years ( P value = .000). Weight loss was the only significant different symptom ( P value = .040). A total of 16 patients and 28 controls were included; 13 proved to be true positive and 20 proved to be true negative. The receiver operating characteristic curve showed a sensitivity of 81% and a specificity of 71%, with an accuracy of 75%. These results give a positive predictive value of 62% and a negative predictive value of 87%. This pilot study shows that the e-nose has the capability of diagnosing GC based on exhaled air, with promising predictive values for a screening purpose.


Dietary broccoli sprouts protect against myocardial oxidative damage and cell death during ischemia-reperfusion.
Cruciferous vegetables are known for antioxidant and anti-carcinogenic effects. In the current study we asked whether dietary broccoli sprouts can protect the heart from ischemia-reperfusion. Rats were fed either control diet (sham and control groups) or a diet mixed with 2% dried broccoli sprouts for 10 days. After 10 days the isolated hearts were subjected to ischemia for 20 min and reperfusion for 2 h, and evaluated for cell death, oxidative damage, and Nrf2-regulated phase 2 enzyme activities. Broccoli sprouts feeding inhibited markers of necrosis (lactate dehydrogenase release) and apoptosis (caspase-3 activity) by 78-86%, and decreased indices of oxidative stress (thiobarbituric acid reactive substances and aconitase inactivation) by 82-116%. While broccoli sprouts increased total glutathione and activities of the phase 2 enzymes glutamate cysteine ligase and quinone reductase in liver, they did not affect these in ischemic-reperfused heart. While the mechanism is not clear, the results show that a relatively short dietary treatment with broccoli sprouts can strongly protect the heart against oxidative stress and cell death caused by ischemia-reperfusion.


Magnetic susceptibility of molecular carbon: nanotubes and fullerite.
Elemental carbon can be synthesized in a variety of geometrical forms, from three-dimensional extended structures (diamond) to finite molecules (C(60) fullerite). Results are presented here on the magnetic susceptibility of the least well-understood members of this family, nanotubes and C(60) fullerite. (i) Nanotubes represent the cylindrical form of carbon, intermediate between graphite and fullerite. They are found to have significantly larger orientation-averaged susceptibility, on a per carbon basis, than any other form of elemental carbon. This susceptibility implies an average band structure among nanotubes similar to that of graphite. (ii) High-resolution magnetic susceptibility data on C(60) fullerite near the molecular orientational-ordering transition at 259 K show a sharp jump corresponding to 2.5 centimeter-gram-second parts per million per mole of C(60). This jump directly demonstrates the effect of an intermolecular cooperative transition on an intramolecular electronic property, where the susceptibility jump may be ascribed to a change in the shape of the molecule due to lattice forces.


Recovery of classical chaoticlike behavior in a conservative quantum three-body problem.
Recovering trajectories of quantum systems whose classical counterparts display chaotic behavior has been a subject that has received a lot of interest over the last decade. However, most of these studies have focused on driven and dissipative systems. The relevance and impact of chaotic-like phenomena to quantum systems has been highlighted in recent studies which have shown that quantum chaos is significant in some aspects of quantum computation and information processing. In this paper we study a three-body system comprising of identical particles arranged so that the system's classical trajectories exhibit Hamiltonian chaos. Here we show that it is possible to recover very nearly classical-like, conservative, chaotic trajectories from such a system through an unravelling of the master equation. First, this is done through continuous measurement of the position of each system. Second, and perhaps somewhat surprisingly, we demonstrate that we still obtain a very good match between the classical and quantum dynamics by weakly measuring the position of only one of the oscillators.


Lip repositioning with or without myotomy: A randomized clinical trial.
Lip repositioning is a conservative surgical method for the correction of excess gingival display (EGD) by limiting the upward retraction of the lips. Lip repositioning presents a simple method for the treatment of gummy smile. The aim of this randomized clinical trial (RCT) was to assess lip repositioning, compared to lip repositioning with muscle severance for efficacy in treatment of EGD and resultant stability. A single-blinded, controlled, parallel-group RCT was performed. Twenty patients with EGD were enrolled in the study, treated with lip repositioning with and without muscle severance. Participants were assessed for EGD reduction, changes in lip length and result stability at 3, 6 and 12 months. Additionally, pain, swelling and satisfaction, were assessed. Classic lip repositioning was found capable of reducing EGD by 2.73 mm (SD ± 1.281), while lip repositioning with muscle severance offered an improved reduction in EGD with a mean reduction of 3.57mm (SD ± 1.62). Lip length, swelling and pain scores were found comparable between the two techniques. Lip repositioning is an effective method for treating EGD, however, muscle severance provides a more stable result at 12 months when compared to the classical technique. More studies are necessary to fully assess this procedure.


Atorvastatin affects interleukin-2 signaling by altering the lipid raft enrichment of the interleukin-2 receptor beta chain.
Although the immunomodulatory properties of statins are in part independent of their lipid-lowering effects, cholesterol is a major component of lipid rafts. We therefore studied the effects of atorvastatin (AS) on the raft enrichment of the interleukin-2 receptor (IL-2R) beta chain previously described by us and on early IL-2R signaling events in activated human T cells. We found that concomitant AS exposure during a 3-day stimulation with phytohemagglutinin (PHA) attenuates activation-associated events, such as the enhanced surface expression of the raft marker GM-1 and the induced expression of the activation marker CD25 (the IL-2R alpha chain). In contrast, brief AS treatment after PHA stimulation increased GM-1 surface expression and virtually abolished the selective raft enrichment of the IL-2R beta chain. Although this AS-associated increase in GM-1 expression resembled that seen in the presence of the raft-disrupting cholesterol chelator methyl-beta-cyclodextrin (MBCD), the two agents had contrasting effects on the tyrosine phosphorylation of the IL-2R beta chain by exogenous IL-2: MBCD essentially abolished this event, whereas AS tended to enhance it and shifted its occurrence out of rafts. We conclude that AS affects IL-2R signaling by altering the raft enrichment of the IL-2R beta chain and propose that this effect is one mechanism underlying the immunomodulatory properties of statins.


Primary care identification and referral to improve safety of women experiencing domestic violence (IRIS): protocol for a pragmatic cluster randomised controlled trial.
Domestic violence, which may be psychological, physical, sexual, financial or emotional, is a major public health problem due to the long-term health consequences for women who have experienced it and for their children who witness it. In populations of women attending general practice, the prevalence of physical or sexual abuse in the past year from a partner or ex-partner ranges from 6 to 23%, and lifetime prevalence from 21 to 55%. Domestic violence is particularly important in general practice because women have many contacts with primary care clinicians and because women experiencing abuse identify doctors and nurses as professionals from whom they would like to get support. Yet health professionals rarely ask about domestic violence and have little or no training in how to respond to disclosure of abuse. This protocol describes IRIS, a pragmatic cluster randomised controlled trial with the general practice as unit of randomisation. Our trial tests the effectiveness and cost-effectiveness of a training and support programme targeted at general practice teams. The primary outcome is referral of women to specialist domestic violence agencies. Forty-eight practices in two UK cities (Bristol and London) are randomly allocated, using minimisation, into intervention and control groups. The intervention, based on an adult learning model in an educational outreach framework, has been designed to address barriers to asking women about domestic violence and to encourage appropriate responses to disclosure and referral to specialist domestic violence agencies. Multidisciplinary training sessions are held with clinicians and administrative staff in each of the intervention practices, with periodic feedback of identification and referral data to practice teams. Intervention practices have a prompt to ask about abuse integrated in the electronic medical record system. Other components of the intervention include an IRIS champion in each practice and a direct referral pathway to a named domestic violence advocate. This is the first European randomised controlled trial of an intervention to improve the health care response to domestic violence. The findings will have the potential to inform training and service provision. ISRCTN74012786.


Does Current General Mental Health Status Relate to Current Smoking Status in Pregnant Women?
Research shows that smoking during pregnancy is related to mental health diagnoses. The purpose of this study was to assess whether current general mental health status is related to current smoking status in pregnant women after controlling for other factors related to both mental health and tobacco use during pregnancy. This cross-sectional analysis used 2017 Behavioral Risk Factor Surveillance Survey (BRFSS) data for 621 pregnant women aged 18-38 from Florida (N=136), Kansas (N=116), Minnesota (N=105), Nebraska (N=90), New York (N=78), and Utah (N=96). Multiple logistic regression analysis was used to assess the relationship between current mental health status and current tobacco use, while controlling for state, depression diagnosis, routine checkup, healthcare plan, age, marital status, ethnicity/race, education level, income level, and employment status. Overall, very few participants reported current smoking (6%) and about one-third reported low or moderate mental health status in the past 30 days. Adjusted results indicated that those who reported high mental health status were about 3 times less likely (OR=0.29, 95% CI=0.09, 0.88) to report current smoking status compared to those who reported low mental health status. Overall, current mental health status was highly related to current smoking status in pregnant women. Clinicians in obstetrics may expect a very low proportion of pregnant women to report smoking and up to one-third to report low or moderate current general mental health status. Given that current mental health issues and current tobacco use may harm both mother and child, be highly related in pregnant women, and change throughout the pregnancy, pregnant women should be screened automatically for both at each visit.


Mycobacterium gordonae pseudoinfection associated with a contaminated antimicrobial solution.
At Yale-New Haven Hospital, 46 specimens submitted for mycobacterial culture during an 8-week period in 1989 were positive for Mycobacterium gordonae, a nontuberculous acid-fast bacterium (AFB) of low pathogenicity. The specimens were submitted from 34 patients who came from various inpatient and outpatient services. Four patients were begun on antimycobacterial therapy on the basis of an AFB isolate which was later identified as M. gordonae. Isolation of M. gordonae was associated with use of the BACTEC TB system (BACTEC TB; Becton Dickinson Diagnostic Instrument Systems, Towson, Md.) and an antimicrobial solution, BACTEC PANTA PLUS (PANTA; Becton Dickinson Diagnostic Instrument Systems). The manufacturer reported that two lots (B9K1 and C9K1) of PANTA kits containing a single production lot (N8C1) of PANTA, which had been shipped to 173 laboratories, had been contaminated with M. gordonae. A survey of mycobacteriology laboratories in the United States revealed that, during April to July 1989, the M. gordonae isolation rate was 5.8/1,000 AFB specimens processed at laboratories that did not use BACTEC TB, 11.4/1,000 AFB specimens at laboratories that used BACTEC TB but not the implicated lot of PANTA, and 23.5/1,000 AFB specimens at laboratories that used BACTEC TB and the lot of implicated PANTA. Intrinsic contamination of PANTA was attributed to ineffective sterilization of water used in the manufacturing process and was not detected prior to product shipment because cultures for AFB were not part of the quality control regimen. This episode emphasizes that clinical laboratories can detect pseudoepidemics promptly if they are alert to abrupt increases in isolation rates, especially of unusual or generally nonpathogenic organisms.


Gene-disease network analysis reveals functional modules in mendelian, complex and environmental diseases.
Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult. We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. To assess the concept of modularity of human diseases, we performed a systematic study of the emergent properties of human gene-disease networks by means of network topology and functional annotation analysis. The results indicate a highly shared genetic origin of human diseases and show that for most diseases, including mendelian, complex and environmental diseases, functional modules exist. Moreover, a core set of biological pathways is found to be associated with most human diseases. We obtained similar results when studying clusters of diseases, suggesting that related diseases might arise due to dysfunction of common biological processes in the cell. For the first time, we include mendelian, complex and environmental diseases in an integrated gene-disease association database and show that the concept of modularity applies for all of them. We furthermore provide a functional analysis of disease-related modules providing important new biological insights, which might not be discovered when considering each of the gene-disease association repositories independently. Hence, we present a suitable framework for the study of how genetic and environmental factors, such as drugs, contribute to diseases. The gene-disease networks used in this study and part of the analysis are available at http://ibi.imim.es/DisGeNET/DisGeNETweb.html#Download.


Quantifying Lifecourse Drivers of International Migration: A Cross-national Analysis of Mexico and the United States.
Evaluating the long-term health consequences of migration requires longitudinal data on migrants and non-migrants to facilitate adjustment for time-varying confounder-mediators of the effect of migration on health. We merged harmonized data on subjects aged 50+ from the US-based Health and Retirement Study (HRS) and the Mexican Health and Aging Study (MHAS). Our exposed group includes MHAS-return migrants (n = 1555) and HRS Mexican-born migrants (n = 924). Our unexposed group includes MHAS-never migrants (n = 16,954). We constructed a lifecourse data set from birth (age 0) until either age at migration to the United States or age at study entry. To account for confounding via inverse probability of treatment weights (IPTW), we modeled the probability of migration at each year of life using time-varying pre-migration characteristics. We then evaluated the effect of migration on mortality hazard estimated with and without IPTW. Mexico to the United States migration was predicted by time-varying factors that occurred before migration. Using measured covariates at time of enrollment to account for selective migration, we estimated that, for women, migrating reduces mortality risk by 13%, although this estimate was imprecise and results were compatible with either large protective or deleterious associations (hazard ratio [HR] =0.87, 95% confidence interval [CI]: 0.60, 1.27). When instead using IPTWs, the estimated effect on mortality was similarly imprecise (HR = 0.98, 95% CI: 0.77, 1.25). The relationship among men was similarly uncertain in both models. Although time-varying social factors predicted migration, IPTW weighting did not affect our estimates. Larger samples are needed to precisely estimate the health effects of migration.


Fingerprinting the reactive toxicity pathways of 50 drinking water disinfection by-products.
A set of nine in vitro cellular bioassays indicative of different stages of the cellular toxicity pathway was applied to 50 disinfection by-products (DBPs) to obtain a better understanding of the commonalities and differences in the molecular mechanisms of reactive toxicity of DBPs. An Eschericia coli test battery revealed reactivity towards proteins/peptides for 64% of the compounds. 98% activated the NRf2-mediated oxidative stress response and 68% induced an adaptive stress response to genotoxic effects as indicated by the activation of the tumor suppressor protein p53. All DBPs reactive towards DNA in the E. coli assay and activating p53 also induced oxidative stress, confirming earlier studies that the latter could trigger DBP's carcinogenicity. The energy of the lowest unoccupied molecular orbital ELUMO as reactivity descriptor was linearly correlated with oxidative stress induction for trihalomethanes (r(2)=0.98) and haloacetamides (r(2)=0.58), indicating that potency of these DBPs is connected to electrophilicity. However, the descriptive power was poor for haloacetic acids (HAAs) and haloacetonitriles (r(2) (<) 0.06). For HAAs, we additionally accounted for speciation by including the acidity constant with ELUMO in a two-parameter multiple linear regression model. This increased r(2) to >0.80, indicating that HAAs' potency is connected to both, electrophilicity and speciation. Based on the activation of oxidative stress response and the soft electrophilic character of most tested DBPs we hypothesize that indirect genotoxicity-e.g., through oxidative stress induction and/or enzyme inhibition-is more plausible than direct DNA damage for most investigated DBPs. The results provide not only a mechanistic understanding of the cellular effects of DBPs but the effect concentrations may also serve to evaluate mixture effects of DBPs in water samples.


PRECEPT: an evidence assessment framework for infectious disease epidemiology, prevention and control.
Decisions in public health should be based on the best available evidence, reviewed and appraised using a rigorous and transparent methodology. The Project on a Framework for Rating Evidence in Public Health (PRECEPT) defined a methodology for evaluating and grading evidence in infectious disease epidemiology, prevention and control that takes different domains and question types into consideration. The methodology rates evidence in four domains: disease burden, risk factors, diagnostics and intervention. The framework guiding it has four steps going from overarching questions to an evidence statement. In step 1, approaches for identifying relevant key areas and developing specific questions to guide systematic evidence searches are described. In step 2, methodological guidance for conducting systematic reviews is provided; 15 study quality appraisal tools are proposed and an algorithm is given for matching a given study design with a tool. In step 3, a standardised evidence-grading scheme using the Grading of Recommendations Assessment, Development and Evaluation Working Group (GRADE) methodology is provided, whereby findings are documented in evidence profiles. Step 4 consists of preparing a narrative evidence summary. Users of this framework should be able to evaluate and grade scientific evidence from the four domains in a transparent and reproducible way.


A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors.
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome, characterized primarily by multiple tumors in the parathyroid glands, endocrine pancreas, and anterior pituitary. Other tumors, including gastrinoma, carcinoid, adrenal cortical tumors, angiofibroma, collagenoma, and lipoma, also occur in some patients. Individuals with MEN1 almost always have loss-of-function mutations in the MEN1 gene on chromosome 11, and endocrine tumors arising in these patients usually show somatic loss of the remaining wild-type allele. To examine the role of MEN1 in tumor formation, a mouse model was generated through homologous recombination of the mouse homolog Men1. Homozygous mice die in utero at embryonic days 11.5-12.5, whereas heterozygous mice develop features remarkably similar to those of the human disorder. As early as 9 months, pancreatic islets show a range of lesions from hyperplasia to insulin-producing islet cell tumors, and parathyroid adenomas are also frequently observed. Larger, more numerous tumors involving pancreatic islets, parathyroids, thyroid, adrenal cortex, and pituitary are seen by 16 months. All of the tumors tested to date show loss of the wild-type Men1 allele, further supporting its role as a tumor suppressor gene.


First Report of Aerial Blight of Peanut Caused by Rhizoctonia solani AG1-IA in Arkansas.
In early September 2012, symptoms similar to aerial blight were observed on runner peanut (cv. Georgia 09B) in a commercial field in Randolph County, Arkansas (3). Leaves within the canopy closest to the soil had water-soaked, gray to green lesions or tan to brown lesions. Localized areas of matted leaves with mycelium occurred on stems and hyphae extended along stems and newly affected leaves. Dark brown spherical sclerotia (1.5 to 4 mm diam.) were produced on the surface of symptomatic peanut tissue (3). Aerial blight symptoms were observed in two peanut fields (~4 to 6 ha) that were furrow irrigated. Symptomatic plants were localized in a single circular pattern (~20 × 25 m) near the lower end of each field with the final disease incidence of less than 5%. Isolations from surface-disinfected leaves on potato dextrose agar consistently yielded light brown to brown colonies with sclerotia typical of Rhizoctonia solani AG1-IA. The fungus was confirmed to be R. solani AG1 by anastomosis reaction (2) with known cultures of AG1-IA isolated from soybean and rice in Arkansas. Sequencing of the rDNA ITS region 5.8s with primers ITS1 and ITS4 (1) supported the identification of the R. solani isolates as AG1-IA. The BLAST search revealed that the sequence had a 96 to 97% maximum sequence identity to several R. solani AG1-IA isolates collected from rice sheaths in China and Arkansas. Eight-week-old peanut plants (cv. Georgia 09B) growing in pots were sprayed until runoff (2 ml/plant) with a solution containing approximately 1 × 105 hyphal fragments/ml. Five inoculated plants were placed in a humidity chamber within a greenhouse where temperatures ranged from 28 to 33°C. After 14 days, water soaked, gray to green or light brown lesions developed on all inoculated plants along with hyphal strands along inoculated sections of the peanut with dark brown sclerotia. None of the plants inoculated with sterile water expressed symptoms. Rhizoctonia solani was consistently reisolated from symptomatic tissue plated on PDA. Inoculations were repeated on peanut cv. Flavor Runner 458, Florida 07, FloRun 107, and Red River Runner with similar results. Although R. solani AG1-IA is a common pathogen on rice and soybean, causing sheath blight and aerial blight, respectively, to our knowledge this is the first report of aerial blight of peanut in the region. Currently, there is a renewed interest in peanut production in the state. Production practices include furrow irrigation, which can distribute floating sclerotia to peanut vines and the rotation practiced with soybean and, less frequently, rice, could potentially increase inoculum for the subsequent crop. Thus, this may be a significant disease problem in the region or Mid-South where peanut is planted after rice or soybean and furrow irrigated. References: (1) S. Kuninaga et al. Curr. Genet. 32:237, 1997. (2) G. C. MacNish et al. Phytopathology 83:922, 1993. (3) H. A. Melouk and P. A. Backman. Management of soilborne fungal pathogens. Pages 75-85 in: Peanut Health Management. H. A. Melouk and F. M. Stokes, eds. The American Phytopathological Society, St. Paul, MN, 1995.


The Oral Health Self-Care Behavior and Dental Attitudes among Nursing Home Personnel.
The need for nursing home care will increase for the next several decades. Rural areas will be impacted in particular, as many older adults live in rural areas. Daily oral infection control changes when a person moves from independent living to institutional living. Oral care to dependent individuals is influenced by many factors. The purpose of this study is to determine the association of oral health self-care behavior with dental attitudes in nursing home personnel in a rural state. A survey was provided to attendees at an oral health conference. Questions were asked to determine dental knowledge, oral health self-care behavior, and dental care attitudes. Of 128 long term care health care facilities' personnel invited, there were 31 attendees, and 21 of the attendees participated (67.7%). Nursing home personnel had a high level of dental knowledge. Oral health self-care behavior was independently influenced by dental knowledge (β=0.17; p=0.0444) and dental attitudes (β=0.55; p=.0081). Further investigation is needed to determine if oral health self-care attitudes and oral self-care behavior of nursing home personnel are factors in the provision of quality daily oral infection control for dependent nursing home residents living in rural areas.


Daily hypoxia increases basal monocyte HSP72 expression in healthy human subjects.
Heat shock protein 72 (HSP72) performs vital roles within the body at rest and during periods of stress. In vitro, research demonstrates HSP72 induction in response to hypoxia. Recently, in vivo, an acute hypoxic exposure (75 min at 2,980 m) was sufficient to induce significant increases in monocyte expressed HSP72 (mHSP72) and a marker of oxidative stress in healthy human subjects. The purpose of the current study was to identify the impact of 10 consecutive days of hypoxic exposures (75 min at 2,980 m) on mHSP72 and erythropoietin (EPO) expression, markers of oxidative stress, and maximal oxygen consumption in graded incremental aerobic exercise. Eight male subjects were exposed to daily normobaric hypoxic exposures for 75 min at 2,980 m for 10 consecutive days, commencing and ceasing at 0930 and 1045, respectively. This stressor was sufficient to induce significant increases in mHSP72, which was significantly elevated from day 2 of the hypoxic exposures until 48 h post-final exposure. Notably, this increase had an initial rapid (30% day on day compared to baseline) and final slow phase (16% day on day compared to baseline) of expression. The authors postulate that 7-day hypoxic exposure in this manner would be sufficient to induce near maximum hypoxia-mediated basal mHSP72 expression. Elevated levels of mHSP72 are associated with acquired thermotolerance and provide cross tolerance to non-related stressors in vivo, the protocol used here may provide a useful tool for elevating mHSP72 in vivo. Aside from these major findings, significant transient daily elevations were seen in a marker of oxidative stress, alongside sustained increases in EPO expression. However, no physiologically significant changes were seen in maximal oxygen consumption or time to exhaustion.


Bio-nanomuscle project: contractile properties of single actin filaments in an A-band motility assay system.
We have developed a new microscopic technique to measure the force generated on a single actin filament (FA) in the A-band in which the intact lattice structure composed of myosin thick filaments is maintained; we call this newly developed system "Bio-nanomuscle (or an A-band motility assay system)". The A-bands were prepared by selective removal of thin filaments from rabbit skeletal glycerinated myofibrils under optical microscope with the use of gelsolin (a severing and barbed (B)-end capping protein of FA) that was prepared from bovine serum. A polystyrene bead of 1 microm in diameter attached to the B-end of FA (through a gelsolin molecule attached to the surface of the bead) was trapped and manipulated with optical tweezers. The displacement of the bead up to 200 nm (corresponding to the force of approximately 40 pN) was determined by phase-contrast image analysis. At the initial stage of this study, the overlapping length of an FA with the A-band was determined from the fluorescence image of FA labeled with rhodamine-phalloidin (Rh-Ph) and the phase-contrast image, but we later improved the method of determination by moving the sample stage stepwise using the piezo actuator. The average force per overlap was subsequently estimated and the histogram was fitted with two Gaussian distributions. Each peak is supposed to correspond to the force developed by FA interacting outside or inside the A-band, and the peak value of the latter was estimated to be 140 pN/microm. From this value, the average force developed per each cross-bridge (CB; a two-headed myosin molecule) was determined to be 1.3 pN.


Modelling environmental factors correlated with podoconiosis: a geospatial study of non-filarial elephantiasis.
The precise trigger of podoconiosis - endemic non-filarial elephantiasis of the lower legs - is unknown. Epidemiological and ecological studies have linked the disease with barefoot exposure to red clay soils of volcanic origin. Histopathology investigations have demonstrated that silicon, aluminium, magnesium and iron are present in the lower limb lymph node macrophages of both patients and non-patients living barefoot on these clays. We studied the spatial variation (variations across an area) in podoconiosis prevalence and the associated environmental factors with a goal to better understanding the pathogenesis of podoconiosis. Fieldwork was conducted from June 2011 to February 2013 in 12 kebeles (administrative units) in northern Ethiopia. Geo-located prevalence data and soil samples were collected and analysed along with secondary geological, topographic, meteorological and elevation data. Soil data were analysed for chemical composition, mineralogy and particle size, and were interpolated to provide spatially continuous information. Exploratory, spatial, univariate and multivariate regression analyses of podoconiosis prevalence were conducted in relation to primary (soil) and secondary (elevation, precipitation, and geology) covariates. Podoconiosis distribution showed spatial correlation with variation in elevation and precipitation. Exploratory analysis identified that phyllosilicate minerals, particularly clay (smectite and kaolinite) and mica groups, quartz (crystalline silica), iron oxide, and zirconium were associated with podoconiosis prevalence. The final multivariate model showed that the quantities of smectite (RR = 2.76, 95% CI: 1.35, 5.73; p = 0.007), quartz (RR = 1.16, 95% CI: 1.06, 1.26; p = 0.001) and mica (RR = 1.09, 95% CI: 1.05, 1.13; p < 0.001) in the soil had positive associations with podoconiosis prevalence. More quantities of smectite, mica and quartz within the soil were associated with podoconiosis prevalence. Together with previous work indicating that these minerals may influence water absorption, potentiate infection and be toxic to human cells, the present findings suggest that these particles may play a role in the pathogenesis of podoconiosis and acute adenolymphangitis, a common cause of morbidity in podoconiosis patients.


Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders.
Patients with urea cycle disorders (UCDs) have an increased risk of neurological disease manifestation. Determining the effect of diagnostic and therapeutic interventions on the neurological outcome. Evaluation of baseline, regular follow-up and emergency visits of 456 UCD patients prospectively followed between 2011 and 2015 by the E-IMD patient registry. About two-thirds of UCD patients remained asymptomatic until age 12 days [i.e. the median age at diagnosis of patients identified by newborn screening (NBS)] suggesting a potential benefit of NBS. In fact, NBS lowered the age at diagnosis in patients with late onset of symptoms (>28 days), and a trend towards improved long-term neurological outcome was found for patients with argininosuccinate synthetase and lyase deficiency as well as argininemia identified by NBS. Three to 17 different drug combinations were used for maintenance therapy, but superiority of any single drug or specific drug combination above other combinations was not demonstrated. Importantly, non-interventional variables of disease severity, such as age at disease onset and peak ammonium level of the initial hyperammonemic crisis (cut-off level: 500 μmol/L) best predicted the neurological outcome. Promising results of NBS for late onset UCD patients are reported and should be re-evaluated in a larger and more advanced age group. However, non-interventional variables affect the neurological outcome of UCD patients. Available evidence-based guideline recommendations are currently heterogeneously implemented into practice, leading to a high variability of drug combinations that hamper our understanding of optimised long-term and emergency treatment.


Developing an Assessment Framework for Essential Internal Medicine Subspecialty Topics.
Assessing residents by direct observation is the preferred assessment method for infrequently encountered subspecialty topics, but this is logistically challenging. We developed an assessment framework for internal medicine (IM) residents in subspecialty topics, using tuberculosis diagnosis for proof of concept. We used a 4-step process at 8 academic medical centers that entailed (1) creating a 10-item knowledge assessment tool; (2) pilot testing on a sample of 129 IM residents and infectious disease fellow volunteers to evaluate validity evidence; (3) implementing the final tool among 886 resident volunteers; and (4) assessing outcomes via retrospective chart review. Outcomes included tool score, item performance, and rates of obtaining recommended diagnostics. Following tool development, 10 infectious disease experts provided content validity. Pilot testing showed higher mean scores for fellows compared with residents (7 [SD = 1.8] versus 3.8 [SD = 1.7], respectively, P < .001) and a satisfactory Kuder-Richardson Formula 20 (0.72). Implementation of the tool revealed a 14-minute (SD = 2.0) mean completion time, 61% (541 of 886) response rate, 4.4 (SD = 1.6) mean score, and ≤ 57% correct response rate for 9 of 10 items. On chart review (n = 343), the rate of obtaining each recommended test was ≤ 43% (113 of 261), except for chest x-rays (96%, 328 of 343). Our assessment framework revealed knowledge and practice gaps in tuberculosis diagnosis in IM residents. Adopting this approach may help ensure assessment is not limited to frequently encountered topics.


A methodological survey of the analysis, reporting and interpretation of Absolute Risk ReductiOn in systematic revieWs (ARROW): a study protocol.
Clinicians, providers and guideline panels use absolute effects to weigh the advantages and downsides of treatment alternatives. Relative measures have the potential to mislead readers. However, little is known about the reporting of absolute measures in systematic reviews. The objectives of our study are to determine the proportion of systematic reviews that report absolute measures of effect for the most important outcomes, and ascertain how they are analyzed, reported and interpreted. We will conduct a methodological survey of systematic reviews published in 2010. We will conduct a 1:1 stratified random sampling of Cochrane vs. non-Cochrane systematic reviews. We will calculate the proportion of systematic reviews reporting at least one absolute estimate of effect for the most patient-important outcome for the comparison of interest. We will conduct multivariable logistic regression analyses with the reporting of an absolute estimate of effect as the dependent variable and pre-specified study characteristics as the independent variables. For systematic reviews reporting an absolute estimate of effect, we will document the methods used for the analysis, reporting and interpretation of the absolute estimate. Our methodological survey will inform current practices regarding reporting of absolute estimates in systematic reviews. Our findings may influence recommendations on reporting, conduct and interpretation of absolute estimates. Our results are likely to be of interest to systematic review authors, funding agencies, clinicians, guideline developers and journal editors.


Plasmodium vivax: transmission-blocking immunity in a malaria-endemic area of Colombia.
Plasmodium vivax transmission-blocking activity was assessed in sera from acutely infected patients from a malaria-endemic area in Colombia. We measured reduction in the number of oocysts that developed in the midguts of Anopheles albimanus mosquitoes artificially fed with blood from these patients. Of 88 mosquito batches that developed infections when parasites were mixed with normal AB human serum, one-third (36.4%) showed full transmission-blocking activity (>or= 90% inhibition) when mixed with autologous sera, 29.6% showed partial activity (50-89%), 17.0% did not block transmission (0-50%), and 17% did not enhance transmission. Transmission-blocking activity correlated with antibody titer by an immunofluorescent antibody test and decreased with the serial dilution of the sera. This activity disappeared at a 1:4 dilution in most sera tested. Afro-Colombian individuals showed lower activity than other ethnic groups and febrile patients produced stronger inhibition than those without fever.


A Babesia bovis gene syntenic to Theileria parva p67 is expressed in blood and tick stage parasites.
Completion of the Babesia bovis (T2Bo strain) genome provides detailed data concerning the predicted proteome of this parasite, and allows for a bioinformatics approach to gene discovery. Comparative genomics of the hemoprotozoan parasites B. bovis and Theileria parva revealed a highly conserved syntenic block of genes flanking the p67 gene of T. parva, a sporozoite stage-specific vaccine candidate against East Coast fever (ECF). The syntenic gene in B. bovis, designated bov57, encodes a protein of limited amino acid sequence identity (11.8%) to p67. Monoclonal antibodies were produced against recombinant BOV57 and were used to demonstrate expression of BOV57 in merozoite and kinete stages of the T2Bo strain of B. bovis. Transcript levels of bov57 in kinetes were increased 100-fold in comparison to msa-1, a previously identified gene encoding an erythrocyte stage surface protein. Amino acid sequence comparisons between the T2Bo strain and two attenuated and virulent strains from Argentina and Australia revealed a high degree of sequence conservation in BOV57 among these geographically and pathogenically divergent isolates (97% amino acid sequence identity). Additional genomic comparisons show that the bov57 gene locus is also conserved in Babesia bigemina and Babesia equi. While not identifiable through amino acid or nucleotide sequence similarity, the conserved gene order within this locus in multiple piroplasms may suggest a critical function adapted for each species' unique host and life-cycle.


Australian mental health caregiver burden: a smallest space analysis.
To explore Australian mental health carers' prioritisation of key elements of caregiving and establish the extent to which particular issues contribute to carer burden. Cross-sectional survey. All Australian States and Territories. Responses were received from 231 Australian mental health caregivers. The Involvement Evaluation Questionnaire was used to assess caregiver burden. Smallest space analysis identified three distinct regions, which we conceptualise as: 1) promoting the safety and health of mental health consumers; 2) impact of caring on caregivers' personal lives and 3) enabling daily living functional recovery of mental health consumers. The analysis demonstrates that carers are most concerned with enabling daily living functional recovery, for which the mean value was considerably higher than the personal impact and promoting safety and health regions. In terms of the individual questionnaire items, the issues of most importance are assisting with self-care, worrying about consumers' future, finances and general health, encouraging consumer involvement in activities and concerns over the treatment consumers are receiving. Caregiving often came at significant personal cost. The burden that results from caring for mental health consumers could perhaps be alleviated through the expansion of psychiatric disability services, increasing government financial support and providing tailored psychosocial interventions that meet the needs of families.


Influence of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice.
The effects of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice have been investigated using a versatile procedure for encapsulating doxorubicin inside liposomes. In this procedure, vesicles exhibiting transmembrane pH gradients (acidic inside) were employed to achieve drug trapping efficiencies in excess of 98%. Drug-to-lipid ratios as high as 0.3:1 (wt:wt) could be obtained in a manner that is relatively independent of lipid composition and vesicle size. Egg phosphatidylcholine (EPC)/cholesterol (55:45; mol/mol) vesicles sized through filters with a 200-nm pore size and loaded employing transmembrane pH gradients to achieve a doxorubicin-to-lipid ratio of 0.3:1 (wt/wt) increased the LD50 of free drug by approximately twofold. Removing cholesterol or decreasing the drug-to-lipid ratio in EPC/cholesterol preparations led to significant decreases in the LD50 of liposomal doxorubicin whereas, the LD50 increased 4- to 6-fold when distearoylphosphatidylcholine was substituted for EPC. The results suggest that the stability of liposomally entrapped doxorubicin in the circulation is an important factor in the toxicity of this drug in liposomal form. In contrast, the antitumor activity of liposomal doxorubicin is not influenced dramatically by alterations in lipid composition. Liposomal doxorubicin preparations of EPC, EPC/cholesterol (55:45; mol:mol), EPC/egg phosphatidylglycerol (EPG)/cholesterol (27.5:27.5:45; mol:mol), and distearoylphosphatidylcholine/cholesterol (55:45; mol:mol) all demonstrated similar efficacy to that of free drug when given at doses of 20 mg/kg and below. Higher dose levels of the less toxic formulations could be administered, leading to enhanced increases in life span (ILS) values. Variations in vesicle size, however, strongly influenced the antitumor activity of liposomal doxorubicin. At a dose of 20 mg/kg, large EPC/cholesterol systems are significantly less effective than free drug (with ILS values of 65% and 145%, respectively). In contrast, small systems sized through filters with a 100-nm pore size are more effective than free drug, resulting in an ILS of 375% and a 30% long term (greater than 60 days) survival rate when administered at a dose of 20 mg/kg. Similar size-dependent effects are observed for distearoylphosphatidylcholine/cholesterol systems.


Autolysin mediated adherence of Staphylococcus aureus with Fibronectin, Gelatin and Heparin.
Major autolysin (Atl) of Staphylococcus aureusis a cell surface associated peptidoglycan hydrolase with amidase and glucosaminidase domains. Atl enzymes (amidase and glucosaminidase) are known to participate in biofilm formation and also can bind with host matrices. Earlier studies demonstrated the binding of Atlwithfibronectin, thrombospondin 1, vitronectin and heat shock cognate protein Hsc70. Here, we have shown, Atl mediates attachment of S.aureus to heparin and gelatine as well. The atl mutant strain demonstrated around 2.5 fold decreased adherence with fibronectin, gelatin and heparin coated microtiter plates. The microscopic studies confirmed the reduced binding of atl mutant with them compared to its parental wild type and complemented mutant strains. Amidase and glucosaminidase were expressed as N-terminal histidine tagged proteins from Escherichia coli, purified and refolded. We found refolded amidase bind with fibronectin, gelatin and heparin; whereas refolded glucosaminidase binds with only fibronectin and heparin but not gelatin. These results reemphasize Atl as one of the crucial proteins from Staphylococcus that facilitate their binding with multiple host cellular components during colonization and infection.


Clinical Application of Liquid Biopsy in Targeted Therapy of Metastatic Colorectal Cancer.
Background. Colorectal cancers (CRC) shed DNA into blood circulation. There is growing evidence that the analysis of circulating tumor DNA can be effectively used for monitoring of disease, to track tumor heterogeneity and to evaluate response to treatment. Case Presentation. Here, we describe two cases of patients with advanced CRC. The first case is about a patient with no available tissue for analysis of RAS mutation status. Liquid biopsy revealed RAS-wild-type and the therapy with anti-EGFR (epidermal growth factor receptor) monoclonal antibody cetuximab could be initiated. In the second case, the mutational profile of a patient with initial wild-type RAS-status was continually tracked during the course of treatment. An acquired KRAS exon 3 mutation was detected. The number of KRAS mutated fragments decreased continuously after the discontinuation of the therapy with EGFR-specific antibodies. Conclusion. Liquid biopsy provides a rapid genotype result, which accurately reproduces the current mutation status of tumor tissue. Furthermore, liquid biopsy enables close monitoring of the onset of secondary resistance to anti-EGFR therapy.


An Energy-Efficient Secure Routing and Key Management Scheme for Mobile Sinks in Wireless Sensor Networks Using Deployment Knowledge.
For many sensor network applications such as military or homeland security, it is essential for users (sinks) to access the sensor network while they are moving. Sink mobility brings new challenges to secure routing in large-scale sensor networks. Previous studies on sink mobility have mainly focused on efficiency and effectiveness of data dissemination without security consideration. Also, studies and experiences have shown that considering security during design time is the best way to provide security for sensor network routing. This paper presents an energy-efficient secure routing and key management for mobile sinks in sensor networks, called SCODEplus. It is a significant extension of our previous study in five aspects: (1) Key management scheme and routing protocol are considered during design time to increase security and efficiency; (2) The network topology is organized in a hexagonal plane which supports more efficiency than previous square-grid topology; (3) The key management scheme can eliminate the impacts of node compromise attacks on links between non-compromised nodes; (4) Sensor node deployment is based on Gaussian distribution which is more realistic than uniform distribution; (5) No GPS or like is required to provide sensor node location information. Our security analysis demonstrates that the proposed scheme can defend against common attacks in sensor networks including node compromise attacks, replay attacks, selective forwarding attacks, sinkhole and wormhole, Sybil attacks, HELLO flood attacks. Both mathematical and simulation-based performance evaluation show that the SCODEplus significantly reduces the communication overhead, energy consumption, packet delivery latency while it always delivers more than 97 percent of packets successfully.


What Are the Applications and Limitations of Artificial Intelligence for Fracture Detection and Classification in Orthopaedic Trauma Imaging? A Systematic Review.
Artificial-intelligence algorithms derive rules and patterns from large amounts of data to calculate the probabilities of various outcomes using new sets of similar data. In medicine, artificial intelligence (AI) has been applied primarily to image-recognition diagnostic tasks and evaluating the probabilities of particular outcomes after treatment. However, the performance and limitations of AI in the automated detection and classification of fractures has not been examined comprehensively. In this systematic review, we asked (1) What is the proportion of correctly detected or classified fractures and the area under the receiving operating characteristic (AUC) curve of AI fracture detection and classification models? (2) What is the performance of AI in this setting compared with the performance of human examiners? The PubMed, Embase, and Cochrane databases were systematically searched from the start of each respective database until September 6, 2018, using terms related to "fracture", "artificial intelligence", and "detection, prediction, or evaluation." Of 1221 identified studies, we retained 10 studies: eight studies involved fracture detection (ankle, hand, hip, spine, wrist, and ulna), one addressed fracture classification (diaphyseal femur), and one addressed both fracture detection and classification (proximal humerus). We registered the review before data collection (PROSPERO: CRD42018110167) and used the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). We reported the range of the accuracy and AUC for the performance of the predicted fracture detection and/or classification task. An AUC of 1.0 would indicate perfect prediction, whereas 0.5 would indicate a prediction is no better than a flip-of-a-coin. We conducted quality assessment using a seven-item checklist based on a modified methodologic index for nonrandomized studies instrument (MINORS). For fracture detection, the AUC in five studies reflected near perfect prediction (range, 0.95-1.0), and the accuracy in seven studies ranged from 83% to 98%. For fracture classification, the AUC was 0.94 in one study, and the accuracy in two studies ranged from 77% to 90%. In two studies AI outperformed human examiners for detecting and classifying hip and proximal humerus fractures, and one study showed equivalent performance for detecting wrist, hand and ankle fractures. Preliminary experience with fracture detection and classification using AI shows promising performance. AI may enhance processing and communicating probabilistic tasks in medicine, including orthopaedic surgery. At present, inadequate reference standard assignments to train and test AI is the biggest hurdle before integration into clinical workflow. The next step will be to apply AI to more challenging diagnostic and therapeutic scenarios when there is absence of certitude. Future studies should also seek to address legal regulation and better determine feasibility of implementation in clinical practice. Level II, diagnostic study.


Speed encoding in human visual cortex revealed by fMRI adaptation.
In macaque visual cortex, the conventional view is that image motion is initially detected by direction-sensitive neurons that are tuned in terms of local spatial and temporal frequency (TF), from which speed is encoded later. We used functional magnetic resonance imaging (fMRI) adaptation to seek evidence for speed or TF tuning in human visual cortex. Drifting sine-wave gratings were presented in pairs (S1: adapter, 100% contrast; S2: probe, 15, 40 or 80% contrast). In each trial, either speed or TF was the same for S1 and S2, whereas the other dimension changed. We investigated whether the response was weaker (adapted) for repetitions of the same speed, indicating speed coding, or for repetitions of TF, indicating TF coding. For high-contrast (80%) probes, we observed clear speed coding in MT and MST with similar but weaker trends in several earlier visual areas. For medium- and low contrast probes, our data indicated a trend towards temporal frequency coding in most visual areas studied. In a second experiment, we adjusted stimuli in terms of perceived rather than physical speed and found a trend for speed coding even for low-contrast probes. Our results suggest that speed coding dominates in MT/MST for high contrast stimuli, and possibly also in other visual areas and/or at lower contrasts.


Ameliorative effects of lotus seedpod proanthocyanidins on cognitive deficits and oxidative damage in senescence-accelerated mice.
We investigated the effects of lotus seedpod proanthocyanidins (LSPC) administration by oral gavage for 3 months on body weight, learning and memory deficits using Y-maze test, oxidative stress and antioxidative enzyme activity in brain and serum of the senescence-accelerated mice (SAMP8) and the senescence-resistant mice (SAMR1). Mice of each group were weighed weekly. Brain was obtained from SAMP8 and SAMR1 (the control mouse for SAMP8) at 6 months of age and serum was available from SAMP8 and SAMR1 at 3, 4, 5 and 6 months of age. The results of body weight showed that 90mg/kg LSPC administration significantly increased body weight at 5.5 and 6 months of age in SAMP8 when compared with control SAMP8 of the same age. Y-maze test indicated that learning and memory abilities of mice were deteriorated significantly at 6 months of age in SAMP8 compared with age-matched SAMR1, but were remarkably improved after LSPC (60, 90, 120mg/kg body weight) administration beginning at 3 months of ages. Malondialdehyde (MDA), nitric oxide (NO) and nitric oxide synthase (NOS) exhibited significant increases mostly at 5 and 6 months of age in SAMP8. Glutathione (GSH), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities decreased significantly mostly at 5 and 6 months of age in SAMP8. LSPC (60, 90, 120mg/kg body weight) administration beginning at 3 months of ages decreased MDA, NO content and lowered NOS activity in the brain and serum of SAMP8. Furthermore, LSPC significantly increased GSH level and augmented GPx, SOD activity in the brain and serum of SAMP8. These results suggest that an age-related increase in brain tissue vulnerability to oxidation and deterioration in learning and memory abilities in SAM that can be modified by LSPC, most likely through the ability of LSPC to scavenge oxygen free radicals and to stimulate antioxidant enzyme activity.


The fine details of evolution.
Charles Darwin's theory of evolution was based on studies of biology at the species level. In the time since his death, studies at the molecular level have confirmed his ideas about the kinship of all life on Earth and have provided a wealth of detail about the evolutionary relationships between different species and a deeper understanding of the finer workings of natural selection. We now have a wealth of data, including the genome sequences of a wide range of organisms, an even larger number of protein sequences, a significant knowledge of the three-dimensional structures of proteins, DNA and other biological molecules, and a huge body of information about the operation of these molecules as systems in the molecular machinery of all living things. This issue of Biochemical Society Transactions contains papers from oral presentations given at a Biochemical Society Focused Meeting to commemorate the 200th Anniversary of Charles Darwin's birth, held on 26-27 January 2009 at the Wellcome Trust Conference Centre, Cambridge. The talks reported on some of the insights into evolution which have been obtained from the study of protein sequences, structures and systems.


Antimicrobial plant metabolites: structural diversity and mechanism of action.
Microbial infectious diseases continue to be one of the leading causes of morbidity and mortality. It has been estimated that microbial species comprise about 60% of the Earth's biomass. This, together with the fact that their genetic, metabolic and physiological diversity is extraordinary, makes them a major threat to the health and development of populations across the world. Widespread antibiotic resistance, the emergence of new pathogens in addition to the resurgence of old ones, and the lack of effective new therapeutics exacerbate the problems. Thus, the need to discover and develop new antimicrobial agents is critical to improve mankind's future health. Plant secondary metabolites (PSMs) offer particular promise in this sense. Plant Kingdom could be considered a rich source of the most diverse structures (e.g. there are more than 12,000 known alkaloids, more than 8,000 phenolic compounds and over 25,000 different terpenoids), many of which were proven to possess strong antimicrobial properties (e.g. thymol, eurabienol, etc.). In many instances, PSMs can be easily isolated from the plant matrix, either in pure state or in the form of mixtures of chemically related compounds. What is also important is that the development of bacterial resistance toward natural plant products (that are generally regarded as eco-friendly) has been thus far documented in a very limited number of cases (e.g. for reserpine). Having all of the mentioned advantages of PSMs as potential antimicrobials in mind, a major question arises: why is it that there are still no commercially available or commonly used antibiotics of plant origin? This review tries to give a critical answer to this question by considering potential mechanisms of antimicrobial action of PSMs (inhibition of cell wall or protein synthesis, inducing leakage from the cells by tampering with the function of the membranes, interfering with intermediary metabolisms or DNA/RNA synthesis/function), as well as their physical and chemical properties (e.g. hydrophilicity/lipophilicity, chemical stability). To address the possible synergistic/antagonistic effects between PSMs and with standard antibiotics, special attention has been given to the antimicrobial activity of PSM-mixtures (e.g. essential oils, plant extracts). Moreover, possible ways of overcoming some of PSMs molecular limitations in respect to their usage as potential antibiotics were also discussed (e.g. derivatization that would enable fine tuning of certain molecular characteristics).


Feasibility and effects of a combined adjuvant high-intensity interval/strength training in breast cancer patients: a single-center pilot study.
To evaluate feasibility of an exercise intervention consisting of high-intensity interval endurance and strength training in breast cancer patients. Twenty-six women with nonmetastatic breast cancer were consecutively assigned to the exercise intervention- (n= 15, mean age 51.9 ± 9.8 years) and the control group (n = 11, mean age 56.9 ± 7.0 years). Cardiopulmonary exercise testing that included lactate sampling, one-repetition maximum tests and a HADS-D questionnaire were used to monitor patients both before and after a supervised six weeks period of either combined high-intensity interval endurance and strength training (intervention group, twice a week) or leisure training (control group). Contrarily to the control group, endurance (mean change of VO2, peak 12.0 ± 13.0%) and strength performance (mean change of cumulative load 25.9 ± 11.2%) and quality of life increased in the intervention group. No training-related adverse events were observed. Our guided exercise intervention could be used effectively for initiation and improvement of performance capacity and quality of life in breast cancer patients in a relatively short time. This might be especially attractive during medical treatment. Long-term effects have to be evaluated in randomized controlled studies also with a longer follow-up. Implications for Rehabilitation High-intensity interval training allows improvement of aerobic capacity within a comparable short time. Standard leisure training in breast cancer patients is rather suitable for the maintenance of performance capacity and quality of life. Guided high-intensity interval training combined with strength training can be used effectively for the improvement of endurance and strength capacity and also quality of life. After exclusion of contraindications, guided adjuvant high-intensity interval training combined with strength training can be safely used in breast cancer patients.


Regulation of transferrin receptor mRNA expression. Distinct regulatory features in erythroid cells.
In proliferating non-erythroid cells, the expression of transferrin receptors (TfR) is negatively regulated by the amount of intracellular iron. Fe-dependent regulation of TfR occurs post-transcriptionally and is mediated by iron-responsive elements (IRE) located in the 3' untranslated region of the TfR mRNA. IREs are recognized by a specific cytoplasmic binding protein (IRE-BP) that, in the absence of Fe, binds with high affinity to TfR mRNA, preventing its degradation. While TfR numbers are positively correlated with proliferation in non-erythroid cells, in hemoglobin-synthesizing cells, their numbers increase during differentiation and are, therefore, negatively correlated with proliferation. This suggests a distinct regulation of erythroid TfR expression and evidence, as follows, for this was found in the present study. (a) With nuclear run-on assays, our experiments show increased TfR mRNA transcription following induction of erythroid differentiation of murine erythroleukemia (MEL) with Me2SO. (b) Me2SO treatment of MEL cells does not increase IRE-BP activity which is, however, increased in uninduced MEL cells by Fe chelators. (c) Following induction of MEL cells, there is an increase in the stability of TfR mRNA, whose level is only slightly affected by iron excess. (d) Heme-synthesis inhibitors, such as succinylacetone and isonicotinic acid hydrazide, which inhibit numerous aspects of erythroid differentiation, also inhibit TfR mRNA expression in induced MEL cells. However, heme-synthesis inhibition does not lead to a decrease in TfR mRNA levels in uninduced MEL cells. Thus, these studies indicate that TfR gene expression is regulated differently in hemoglobin synthesizing as compared to uninduced MEL cells.


ER stress disrupts Ca2+-signaling complexes and Ca2+ regulation in secretory and muscle cells from PERK-knockout mice.
Disruption of protein synthesis and folding results in ER stress, which is associated with the pathophysiology of diverse diseases affecting secretory and muscle cells. Cells are protected against ER stress by activation of the unfolded protein response (UPR) that is regulated by the protein kinase PERK, which phosphorylates the translation initiation factor 2 eIF2alpha to attenuate protein synthesis. PERK-/- cells are unable to modulate ER protein load and experience high levels of ER stress. In addition to its role in protein synthesis, the ER also orchestrates many signaling events essential for cell survival, prominent among which is Ca2+ signaling. It is not known, however, whether there is a relationship between ER stress and the function of the Ca2+-signaling pathway in muscle and non-muscle cells. To directly address this question we characterized Ca2+ signaling in the secretory pancreatic and parotid acinar cells and in urinary bladder smooth muscle (UBSM) cells obtained from PERK-/- and wild-type mice. Deletion of PERK that results in high levels of ER stress, and distention and fragmentation of the ER slowed the rate of agonist-mediated Ca2+ release from the ER and reduced Ca2+-induced Ca2+ release, although IP3 production, localization of the IP3 receptors, IP3-mediated Ca2+ release, Ca(v)1.2 current and RyRs activity remained unaltered. On the other hand, ER stress disrupted the integrity of the Ca2+-signaling complexes in both secretory and UBSM cells, as revealed by markedly reduced co-immunoprecipitation of plasma membrane- and ER-resident Ca2+-signaling proteins. These findings establish a relationship between the unfolding protein response, ER stress and Ca2+ signaling and highlight the importance of communication within the terminal ER-plasma membrane microdomain for propagation of the Ca2+ signal from the plasma membrane into the cell.


Appendicular osteosarcoma in small-breed dogs: 51 cases (1986-2011).
To describe outcomes for small-breed dogs with appendicular osteosarcoma. Multi-institutional retrospective case series. 51 small-breed dogs. Records from participating Veterinary Society of Surgical Oncology members were searched for dogs that weighed ≤ 15 kg (33 lb) with a histologic diagnosis of appendicular osteosarcoma. The Kaplan-Meier method was used to determine median survival times (MSTs), and Cox regression was performed to identify variables associated with survival time. Tumors were most commonly located on the humerus (n = 15) and femur (14). Of the 51 study dogs, 9 were treated nonsurgically, 16 underwent amputation of the affected limb only, and 26 underwent curative-intent treatment, with MSTs of 112, 257, and 415 days, respectively. The MST did not differ significantly between dogs in the amputation-only and curative-intent groups. For dogs in the nonsurgical group, MST decreased significantly as the tumor histologic score increased. For dogs in the amputation-only group, MST decreased as body weight increased. For the small-breed dogs with appendicular osteosarcoma of the present study, tumor histologic grade and mitotic index were subjectively lower and MST following amputation of the affected limb without adjuvant chemotherapy was longer, compared with those for similarly affected larger dogs. Results indicated no significant advantage in MST for dogs that underwent curative-intent treatment versus dogs that underwent amputation only, and further investigation of the importance of adjuvant chemotherapy is warranted.


Patterns in PARTNERing across Public Health Collaboratives.
Inter-organizational networks represent one of the most promising practice-based approaches in public health as a way to attain resources, share knowledge, and, in turn, improve population health outcomes. However, the interdependencies and effectiveness related to the structure, management, and costs of these networks represents a critical item to be addressed. The objective of this research is to identify and determine the extent to which potential partnering patterns influence the structure of collaborative networks. This study examines data collected by PARTNER, specifically public health networks (n = 162), to better understand the structured relationships and interactions among public health organizations and their partners, in relation to collaborative activities. Combined with descriptive analysis, we focus on the composition of public health collaboratives in a series of Exponential Random Graph (ERG) models to examine the partnerships between different organization types to identify the attribute-based effects promoting the formation of network ties within and across collaboratives. We found high variation within and between these collaboratives including composition, diversity, and interactions. The findings of this research suggest common and frequent types of partnerships, as well as opportunities to develop new collaborations. The result of this analysis offer additional evidence to inform and strengthen public health practice partnerships.


The public library as therapeutic landscape: a qualitative case study.
The idea of the therapeutic landscape has been widely used to describe the relationship between place and improvements in mental health. This paper uses data from a qualitative study conducted with people with mental health problems to outline the role of the public library as a therapeutic landscape. It situates the public library as a space that is simultaneously familiar and welcoming, comforting and calming, and empowering. Further, the paper reflects on the impact of proposed library closures in light of these previously hidden benefits, thinking about the library's role as an environment and not as a service provider.


Reliable Strategy for Analysis of Complex Biosensor Data.
When using biosensors, analyte biomolecules of several different concentrations are percolated over a chip with immobilized ligand molecules that form complexes with analytes. However, in many cases of biological interest, e.g., in antibody interactions, complex formation steady-state is not reached. The data measured are so-called sensorgram, one for each analyte concentration, with total complex concentration vs time. Here we present a new four-step strategy for more reliable processing of this complex kinetic binding data and compare it with the standard global fitting procedure. In our strategy, we first calculate a dissociation graph to reveal if there are any heterogeneous interactions. Thereafter, a new numerical algorithm, AIDA, is used to get the number of different complex formation reactions for each analyte concentration level. This information is then used to estimate the corresponding complex formation rate constants by fitting to the measured sensorgram one by one. Finally, all estimated rate constants are plotted and clustered, where each cluster represents a complex formation. Synthetic and experimental data obtained from three different QCM biosensor experimental systems having fast (close to steady-state), moderate, and slow kinetics (far from steady-state) were evaluated using the four-step strategy and standard global fitting. The new strategy allowed us to more reliably estimate the number of different complex formations, especially for cases of complex and slow dissociation kinetics. Moreover, the new strategy proved to be more robust as it enables one to handle system drift, i.e., data from biosensor chips that deteriorate over time.


Purification and characterization of human metallocarboxypeptidase Z.
Carboxypeptidase Z (CPZ) is a recently discovered member of the metallocarboxypeptidase gene family that has an N-terminal domain related to the Wnt/wingless binding domain of frizzled receptors and other proteins. To further characterize the enzymatic properties of CPZ, the enzyme was purified using Arg- and heparin-affinity columns. CPZ has a neutral pH optimum, and is inhibited by chelating agents and several divalent cations (Zn2+, Mn2+, Cd2+, Cu2+, Hg2+). Active site-directed inhibitors of several other metallocarboxypeptidases also inhibit CPZ activity with moderate potency. CPZ cleaves substrates with C-terminal Arg residues, preferring peptides with an Ala in the penultimate position. No activity is detected toward substrates with an Ile-Arg or a Pro-Arg sequence. The Km for dansyl-Phe-Ala-Arg and dansyl-Pro-Ala-Arg are both approximately 2 mM. Taken together, these data suggests a selective role for CPZ in the processing of extracellular peptides or proteins.


ABCD3 and ABCD3-I scores are superior to ABCD2 score in the prediction of short- and long-term risks of stroke after transient ischemic attack.
Several risk scores have been developed to predict the stroke risk after transient ischemic attack (TIA). However, the validation of these scores in different cohorts is still limited. The objective of this study was to elucidate whether these scores were able to predict short-term and long-term risks of stroke in patients with TIA. From the Fukuoka Stroke Registry, 693 patients with TIA were followed up for 3 years. Multivariable-adjusted Cox proportional hazards model was used to assess the hazard ratio of risk factors for stroke. The discriminatory ability of each risk score for incident stroke was estimated by using C-statistics and continuous net reclassification improvement. The multivariable-adjusted Cox proportional hazards model revealed that dual TIA and carotid stenosis were both significant predictors for stroke after TIA, whereas abnormal diffusion-weighted image was not. ABCD3 (C-statistics 0.61) and ABCD3-I (C-statistics 0.66) scores improved the short-term predictive ability for stroke (at 7 days) compared with the ABCD2 score (C-statistics 0.54). Addition of intracranial arterial stenosis (at 3 years, continuous net reclassification improvement 30.5%; P<0.01) and exclusion of abnormal diffusion-weighted imaging (at 3 years, continuous net reclassification improvement 24.0%; P<0.05) further improved the predictive ability for stroke risk until 3 years after TIA. The present study demonstrates that ABCD3 and ABCD3-I scores are superior to the ABCD2 score for the prediction of subsequent stroke in patients with TIA. Addition of neuroimaging in the ABCD3 score may enable prediction of long-term stroke risk after TIA.


Human secretory immunoglobulin A may contribute to biofilm formation in the gut.
It is critical, both for the host and for the long-term benefit of the bacteria that colonize the gut, that bacterial overgrowth with subsequent bacterial translocation, which may lead to sepsis and death of the host, be avoided. Secretory IgA (sIgA) is known to be a key factor in this process, agglutinating bacteria and preventing their translocation in a process termed 'immune exclusion'. To determine whether human sIgA might facilitate the growth of normal enteric bacteria under some conditions, the growth of human enteric bacteria on cultured, fixed human epithelial cells was evaluated in the presence of sIgA or various other proteins. Human sIgA was found to facilitate biofilm formation by normal human gut flora and by Escherichia coli on cultured human epithelial cell surfaces under conditions in which non-adherent bacteria were repeatedly washed away. In addition, the presence of sIgA resulted in a 64% increase in adherence of E. coli to live cultured epithelial cells over a 45-min period. Mucin, another defence factor thought to play a key role in immune exclusion, was found to facilitate biofilm formation by E. coli. Our findings suggest that sIgA may contribute to biofilm formation in the gut.


Fura-2 measurement of cytosolic free Ca2+ concentration in corpus allatum cells of larval Manduca sexta.
Cytosolic free Ca2+ has been implicated in the regulation of the larval corpus allatum (CA) of the tobacco hornworm Manduca sexta since agents presumed to cause changes in intracellular Ca2+ concentrations affect both basal and neuropeptide-modulated synthesis/release of the juvenile hormones. To determine whether differences in cytosolic free [Ca2+] in CA cells were associated with different levels of gland activity, methods were developed for dissociating CA cells with the retention of biosynthetic activity and for uptake by the dissociated cells of the fluorescent Ca2+ indicator Fura-2. Digitized fluorescence microscopy of the Fura-2-loaded cells enabled measurement of intracellular Ca2+ levels in individual cells. Intracellular free Ca2+ levels were measured in CA cells from selected days during the fifth larval stadium and were found to be highest when the CA were biosynthetically active. Treatment of CA cells from day 6 with the Ca2+ ionophore ionomycin elevated the intracellular Ca2+ level, corroborating the involvement of elevated intracellular [Ca2+] in ionophore effects on juvenile hormone (JH) and JH acid synthesis. The results of the study are considered in relation to our knowledge of the role of Ca2+ in the function of endocrine gland cells.


First-in-human evaluation of a novel sirolimus-eluting ultra-high molecular weight APTITUDE bioresorbable scaffold: 9- and 24-month imaging and clinical results of the RENASCENT II trial.
The novel sirolimus-eluting ultra-high molecular weight APTITUDE bioreabsorbable vascular scaffold (BRS) displays higher mechanical strength, expansion capabilities and resistance to fracture compared to other BRS technologies. RENASCENT II is a prospective, multicentre first-in-human clinical study evaluating the clinical performance of the APTITUDE BRS in the treatment of single de novo coronary lesions among patients undergoing percutaneous coronary intervention. The APTITUDE BRS was tested in a prospective study in two countries (Italy and Colombia). Study objectives were angiographic in-scaffold late lumen loss (IS-LLL) measured by quantitative coronary angiography (QCA) and target vessel failure (TVF) defined as the composite rate of cardiac death, target vessel myocardial infarction (TV-MI) or ischaemia-driven target lesion revascularisation (TLR) at 9 and 24 months. A total of 60 patients were enrolled. All patients underwent lesion predilatation and 46 patients (76.7%) underwent post-dilatation. Clinical device and procedural success were 98.3% (59/60 patients) and 100%, respectively. Angiographic late lumen loss was 0.19±0.26 mm at 9 months and 0.3±0.41 mm at 24 months. At 9 months, TVF occurred in 2/59 patients (3.4%) due to TV-MI but there was no TLR. No further cases of TVF, MACE or stent thrombosis were reported up to 24-month follow-up. In this multicentre prospective study, the APTITUDE BRS was shown to be safe and effective in the treatment of single coronary lesions at 24-month clinical follow-up.


First clinical results with a new telemetric intracranial pressure-monitoring system.
The knowledge of intracranial pressure (ICP) is the basis of an appropriate neurosurgical treatment. Because clinical, fundoscopic, or radiological data alone are often elusive, a pre- or postoperative long-term monitoring of the ICP itself is desirable. We describe the first clinical experiences with a new telemetric ICP-monitoring device. The transducer of this telemetric intraparenchymal pressure probe is placed under the galea over the calvaria. ICP can be monitored via a special telemetric reader, placed over the intact skin, and the ICP values are stored in a small portable computer. The system does not require an intensive care environment and can be used in any ward or even at home. The system was successfully applied in 10 patients (age, 3-56 years) in whom raised ICP due to hydrocephalus, shunt dysfunction, endoscopic third ventriculostomy failure, craniostenosis, or pseudotumor cerebri was suspected. Continuous telemetric monitoring of ICP was performed for 2 to 24 weeks. In 7 patients, increased ICP values could be excluded, and further surgical maneuvers were avoided. In 3 patients, repeated plateaus or continuously raised ICP indicated surgery resulting in a normalization of ICP. This new telemetric system was safe and effective for ICP measurement over a long period, including home monitoring. For the patients, it was easy to handle, and reliable data could be recorded over many weeks. Based on this preliminary experience, the authors consider the new system extremely advantageous in surgical decision making in particularly difficult cases of suspected abnormalities of ICP.


Digital Health Opportunities to Improve Primary Health Care in the Context of COVID-19: Scoping Review.
The COVID-19 pandemic brought social, economic, and health impacts, requiring fast adaptation of health systems. Although information and communication technologies were essential for achieving this objective, the extent to which health systems incorporated this technology is unknown. The aim of this study was to map the use of digital health strategies in primary health care worldwide and their impact on quality of care during the COVID-19 pandemic. We performed a scoping review based on the Joanna Briggs Institute manual and guided by the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) Extension for Scoping Reviews. A systematic and comprehensive three-step search was performed in June and July 2021 in multidisciplinary health science databases and the gray literature. Data extraction and eligibility were performed by two authors independently and interpreted using thematic analysis. A total of 44 studies were included and six thematic groups were identified: characterization and geographic distribution of studies; nomenclatures of digital strategies adopted; types of information and communication technologies; characteristics of digital strategies in primary health care; impacts on quality of care; and benefits, limitations, and challenges of digital strategies in primary health care. The impacts on organization of quality of care were investigated by the majority of studies, demonstrating the strengthening of (1) continuity of care; (2) economic, social, geographical, time, and cultural accessibility; (3) coordination of care; (4) access; (5) integrality of care; (6) optimization of appointment time; (7) and efficiency. Negative impacts were also observed in the same dimensions, such as reduced access to services and increased inequity and unequal use of services offered, digital exclusion of part of the population, lack of planning for defining the role of professionals, disarticulation of actions with real needs of the population, fragile articulation between remote and face-to-face modalities, and unpreparedness of professionals to meet demands using digital technologies. The results showed the positive and negative impacts of remote strategies on quality of care in primary care and the inability to take advantage of the potential of technologies. This may demonstrate differences in the organization of fast and urgent implementation of digital strategies in primary health care worldwide. Primary health care must strengthen its response capacity, expand the use of information and communication technologies, and manage challenges using scientific evidence since digital health is important and must be integrated into public service.


Clinical and Haematological Manifestations of Typhoid Fever in Children in Eastern Turkey.
Typhoid fever can involve various organs, leading to a wide range of presentations: from uncomplicated to complicated typhoid fever. The haematological changes are common in typhoid fever and include anaemia, leucopaenia, thrombocytopaenia and bleeding diathesis. This study was undertaken in order to determine the clinical and haematological presentation of typhoid fever in children. In this study, records of children and adolescents with typhoid fever aged under or equal to 16 years, admitted to Yuzuncu Yil University Hospital between 2010 and 2014, were analysed retrospectively. The cases (56%) were admitted to our hospital in July and October. Major symptoms of patients were abdominal pain (24%), arthralgia (21%) and fever (11%). In our study, decreased mean platelet volume (31%), eosinopaenia 20%), abnormal platelet count (19%), anaemia (16%), leucocytosis (16%) and eosinophilia (12%) were the most common haematological findings in the children. Typhoid fever is predominant in children at school age with a slight male predominance. Decreased mean platelet volume and abdominal pain might be useful as early diagnostic clues.


Berberine reduces the occurrence of neonatal necrotizing enterocolitis by reducing the inflammatory response.
Necrotizing enterocolitis (NEC) is a life-threatening disease that occurs in premature infants. The aim of the present study was to investigate the effects of berberine, an isoquinoline alkaloid mainly used to treat digestive diseases, in a rat model of NEC. NEC models were established in newborn rats via inhalation of N2 for 90 sec every 4 h and oral administration of 4 mg/kg/day lipopolysaccharides on days 0 and 1. Berberine was administered via oral gavage. In the NEC model group, Toll-like receptor (TLR)4, nuclear factor NF-κB (NF-κB), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10 were upregulated. Symptoms of NEC in the berberine intervention group were significantly relieved, with a clear reduction in the incidence of NEC compared with the NEC group. TLR4, NF-κB, iNOS, TNF-α, IL-6 and IL-10 expression was decreased following berberine intervention. Furthermore, the expression of mucin-2 (MUC2) and RNA polymerase σ factor SigA (SIgA) were decreased in the NEC model group and increased following berberine intervention, when compared with the untreated group. It was also demonstrated that the incidence of NEC was reduced following berberine administration, possibly owing to changes in the inflammatory responses. The results of the current study support a potential therapeutic role of berberine for the treatment of NEC.