Extrapair mating between relatives in the barn swallow: a role for kin selection?
Why do females of many species mate with more than one male? One of the main hypotheses suggests that female promiscuity is an insurance mechanism against the potential detrimental effects of inbreeding. Accordingly, females should preferably mate with less related males in multiple or extrapair mating. Here we analyse paternity, relatedness among mating partners, and relatedness between parents and offspring, in the socially monogamous North American barn swallow (Hirundo rustica erythrogaster). In contrast to the inbreeding avoidance hypothesis, we found that extrapair mating partners were more related than expected by random choice, and tended to be more related than social partners. Furthermore, extrapair mating resulted in genetic parents being more related to their extrapair young than to their withinpair young. We propose a new hypothesis for extrapair mating based on kin selection theory as a possible explanation to these findings.


Global Prevalence of Chronic Kidney Disease - A Systematic Review and Meta-Analysis.
Chronic kidney disease (CKD) is a global health burden with a high economic cost to health systems and is an independent risk factor for cardiovascular disease (CVD). All stages of CKD are associated with increased risks of cardiovascular morbidity, premature mortality, and/or decreased quality of life. CKD is usually asymptomatic until later stages and accurate prevalence data are lacking. Thus we sought to determine the prevalence of CKD globally, by stage, geographical location, gender and age. A systematic review and meta-analysis of observational studies estimating CKD prevalence in general populations was conducted through literature searches in 8 databases. We assessed pooled data using a random effects model. Of 5,842 potential articles, 100 studies of diverse quality were included, comprising 6,908,440 patients. Global mean(95%CI) CKD prevalence of 5 stages 13·4%(11·7-15·1%), and stages 3-5 was 10·6%(9·2-12·2%). Weighting by study quality did not affect prevalence estimates. CKD prevalence by stage was Stage-1 (eGFR>90+ACR>30): 3·5% (2·8-4·2%); Stage-2 (eGFR 60-89+ACR>30): 3·9% (2·7-5·3%); Stage-3 (eGFR 30-59): 7·6% (6·4-8·9%); Stage-4 = (eGFR 29-15): 0·4% (0·3-0·5%); and Stage-5 (eGFR<15): 0·1% (0·1-0·1%). CKD has a high global prevalence with a consistent estimated global CKD prevalence of between 11 to 13% with the majority stage 3. Future research should evaluate intervention strategies deliverable at scale to delay the progression of CKD and improve CVD outcomes.


Using the nursing delirium screening scale in assessing postoperative delirium: A meta-regression.
The nursing delirium screening scale (Nu-DESC) was developed for the rapid assessment of delirium, but little is known regarding the performance of the Nu-DESC in assessing postoperative delirium. The purpose of this systematic review and meta-analysis was to review and summarize the evidence of the diagnostic accuracy of the Nu-DESC in assessing postoperative delirium. The EMBASE, MEDLINE, Cochrane Library, CINAHL, and a Chinese e-Journal database were searched from the period of the inception of the Nu-DESC to June 18, 2020. Participants were adult (age ≥ 18 years) postoperative patients who received any type of surgery and any method of anesthesia. The quality assessment of diagnostic accuracy studies-2 was employed to assess the risk of bias among the selected studies, and meta-regression analyses were used to detect sources of between-study heterogeneity. Eleven studies involving 2062 postoperative patients in surgical settings were included. The Nu-DESC revealed a pooled sensitivity of 0.73 (95% confidence interval, 0.44-0.90) and a specificity of 0.93 (0.87-0.96). The area under the summary receiver operating characteristics curve was 0.94 (0.91-0.96), which also confirmed the accuracy of the Nu-DESC. Covariates, including the region of study and the standard reference used, were identified as possible sources of heterogeneity in the meta-regression. The findings of this review can update existing clinical guidelines for postoperative delirium. On the basis of its satisfactory diagnostic performance, we suggest that the Nu-DESC could be considered for nurses and allied health professionals for assessing postoperative delirium. However, because of the heterogeneity, the result of this meta-analysis should be considered with caution.


Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy.
The vacuolar H+-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in ATP6V0A1, the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four individuals. Here, we identified 17 individuals from 14 unrelated families with both with new and previously characterized variants in this gene, representing the largest cohort to date. Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals carried de novo missense variants and showed severe developmental and epileptic encephalopathy. The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction and severe developmental defect in Caenorhabditis elegans. Altogether, our findings further expand the neurological phenotype associated with variants in this gene and provide a direct link with endolysosomal acidification in the pathophysiology of ATP6V0A1-related conditions.


Effect of mannitol on cerebrovascular pressure reactivity in patients with intracranial hypertension.
Mannitol is commonly used in patients with increased intracranial pressure (ICP), but its effect on cerebrovascular pressure reactivity (CVPR) is uncertain. We analyzed the changes of pressure reactivity index (PRx) during the course of mannitol treatment. Twenty-one patients who received mannitol treatment for increased ICP were recruited prospectively. Continuous waveforms of arterial blood pressure (ABP) and ICP were collected simultaneously for 60 minutes (10 minutes at baseline and 50 minutes since mannitol administration) during 37 events of mannitol treatment. The correlation coefficients between the mean ABP and ICP were averaged every 10 minutes and labeled as the PRx. The linear correlation of six time points of PRx in each event was calculated to represent the trend of CVPR changes. The negative slope of correlation was defined as improvement in CVPR under mannitol treatment and vice versa. At baseline, the average of ICP was 26.0 ± 9.1 mmHg and the values of PRx were significantly correlated with ICP (p = 0.0044, r = 0.46). After mannitol administration, the average of ICP decreased significantly to 21.2 ± 11.1 mmHg (p = 0.036), and CVPR improved in 59.4 % of all events. Further analysis showed that low baseline cerebral perfusion pressure was the only hemodynamic parameter significant association with the improvement of CVPR after mannitol treatment (p = 0.039). Despite lowering ICP, mannitol may have diverse effects on CVPR in patients with intracranial hypertension. Our study suggests that mannitol infusion may have a beneficial effect on CVPR, particularly in those with a low cerebral perfusion pressure at baseline.


Ring-polymer molecular dynamical calculations for the F + HCl → HF + Cl reaction on the ground 12A' potential energy surface.
The reaction kinetics of the heavy-light-heavy abstraction reaction F + HCl → HF + Cl on the ground electronic state potential energy surface (PES) is investigated theoretically by a recently developed ring polymer molecular dynamics (RPMD) approach. First, a new PES is developed by the permutation invariant polynomial neural network (PIP-NN) approach based on 30 620 points sampled over a large configuration space from the latest and most accurate Deskevich-Hayes-Takahashi-Skodje-Nesbitt (DHTSN) PES (J. Chem. Phys., 2006, 124, 224303). Excellent fitting performance was achieved with only 521 parameters. The PIP-NN PES is 11 times faster than the DHTSN PES. Besides, the first analytical derivatives with respect to the coordinates of the atoms have been obtained for the PIP-NN PES. The RPMD rate coefficients on the PIP-NN PES are calculated and compared with available theoretical and experimental results. It is found that the experimental rate coefficients are significantly larger than the theoretical results on the DHTSN PES, due to its overestimated reaction barrier. We conclude that a reliable PES for this important heavy-light-heavy reaction is highly desirable.


Aldrin epoxidation, a highly sensitive indicator specific for cytochrome P-450-dependent mono-oxygenase activities.
Aldrin epoxidation was studied in rat liver microsomes. The assay is very sensitive; amounts of less than 1 microgram of microsomal protein were sufficient for activity determination. The very low background, stability of the metabolite, and the complete separation of substrate and metabolite permit estimation of mono-oxygenase activities of less than 1 pmol per mg of protein per min by a simple procedure. Pretreatment of animals with the mono-oxygenase inducer phenobarbital (PB) increased the epoxidation rate 3-fold, whereas 3-methylcholanthrene (MC) treatment markedly depressed enzyme activity. Induction with MC did not change the apparent Km of the reaction, which was 18 muM. The Km in microsomes from PB-treated animals was 28 muM. These data suggest that the same or (a) similar form(s) of mono-oxygenase catalyze(s) the epoxidation in the three different microsomal preparations. SKF 525-A, metyrapone, and 7,8-benzoflavone were almost similarly active as inhibitors in microsomes from control and inducer-treated rats. Sensitivity to these inhibitors was low; 0.7 mM SKF 525-A and 0.4 mM 7,8-benzoflavone were necessary to reduce enzyme activity by 50%, whereas 0.5 mM metyrapone caused an inhibition of 10-45%. The activity of aldrin epoxidation in untreated rats increased almost parallel to the activity of ethylmorphine demethylation between 3 and 10 weeks of age. The rate of benzo[a]pyrene hydroxylation remained unchanged during this period. The results demonstrate that aldrin epoxidation offers a selective and sensitive assay for the activity of mono-oxygenases dependent on cytochrome P-450 forms.


Balanced crossmodal excitation and inhibition essential for maximizing multisensory gain.
We examined whether and how the balancing of crossmodal excitation and inhibition affects intersensory facilitation. A neural network model, comprising lower-order unimodal networks (X, Y) and a higher-order multimodal network (M), was simulated. Crossmodal excitation was made by direct activation of principal cells of the X network by the Y network. Crossmodal inhibition was made in an indirect manner: the Y network activated glial cells of the X network. This let glial plasma membrane transporters export GABA molecules into the extracellular space and increased the level of ambient GABA. The ambient GABA molecules were accepted by extrasynaptic GABAa receptors and tonically inhibited principal cells of the X network. Namely, crossmodal inhibition was made through GABAergic gliotransmission. Intersensory facilitation was assessed in terms of multisensory gain: the difference between the numbers of spikes evoked by multisensory (XY) stimulation and unisensory (X-alone) stimulation. The maximal multisensory gain (XY-X) could be achieved at an intermediate noise level by balancing crossmodal excitation and inhibition. This result supports an experimentally derived conclusion: intersensory facilitation under noisy environmental conditions is not necessarily in accord with the principle of inverse effectiveness; rather, multisensory gain is maximal at intermediate signal-to-noise ratio (SNR) levels. The maximal multisensory gain was available at the weakest signal if noise was not present, indicating that the principle of inverse effectiveness is a special case of the intersensory facilitation model proposed here. We suggest that the balancing of crossmodal excitation and inhibition may be crucial for intersensory facilitation. The GABAergic glio-transmission-mediated crossmodal inhibitory mechanism effectively works for intersensory facilitation and on determining the maximal multisensory gain in the entire SNR range between the two extremes: low and high SNRs.


Aberration-free dynamic focusing with a multichannel micromachined membrane deformable mirror.
We demonstrate aberration-free dynamic focusing with a low-cost 19-channel continuous-surface micromachined membrane deformable mirror (MMDM). A lookup table of the optimum control voltages for various focal lengths is obtained with an adaptive optics algorithm. Diffraction-limited imaging resolution is achieved owing to the capability of the MMDM for aberration compensation. The measured speed of the MMDM supports dynamic focusing operations at several hundred hertz. Our dynamic focusing approach is shown to function with either monochromatic or broadband optical sources.


Fendrix® compared to Engerix® in HIV-infected patients nonresponding to initial- and re-vaccination schedule.
In HIV-infected patients, the immunogenicity of hepatitis B vaccines is impaired. In this randomised controlled study (RCT), we investigated the effect of Fendrix® versus double-dose Engerix® vaccination in previously non-responsive HIV-infected subjects. Patients included those who were HIV-infected and non-responders to a primary (single-dose hepatitis B (HBV) vaccination) and a subsequent double-dose HBV revaccination schedule. Subjects were randomised 1:1 to receive Fendrix® (t = 0, 4, 8, 24 weeks) or double-dose Engerix® (t = 0, 4, 24 weeks) vaccinations. Primary efficacy, defined as anti-HBs response ≥ 10 IU/l, was evaluated at week 28 in both study arms. A subset of 48 patients non-responsive to HBV vaccination was selected, from a cohort of patients at our institution, who underwent HBV vaccination unsuccessfully either in a previous RCT or through standard care. The anti-HBs ≥ 10 IU/l response rate at week 28 in the Fendrix® arm and the Engerix® arm were 85.7% and 65.0%, respectively (p = 0.09). There was no significant difference between the two used vaccine types in the anti-HBs levels reached. In our institution, the overall response rate after initial standard-dose vaccination schedule and double-dose revaccination in our cohort was 75%. In this study, combining the effects of Fendrix and Engerix resulted in a 75% response rate in the 25% remaining non-responders on initial and double-dose revaccination series. This yielded an absolute 19% increase and an overall response to HBV vaccination in HIV-infected patients of around 94% in our cohort. These results together, suggest that continuing HBV vaccination in non-responders to a first course of single-dose vaccine and a double-dose revaccination scheme is worth the effort. No superiority of one of the investigated hepatitis B vaccines was shown in this cohort but an appropriate number of patients needed to achieve reliable answers was not achieved.


The Role of Ciliate Protozoa in the Rumen.
First described in 1843, Rumen protozoa with their striking appearance were assumed to be important for the welfare of their host. However, despite contributing up to 50% of the bio-mass in the rumen, the role of protozoa in rumen microbial ecosystem remains unclear. Phylogenetic analysis of 18S rDNA libraries generated from the rumen of cattle, sheep, and goats has revealed an unexpected diversity of ciliated protozoa although variation in gene copy number between species makes it difficult to obtain absolute quantification. Despite repeated attempts it has proven impossible to maintain rumen protozoa in axenic culture. Thus it has been difficult to establish conclusively a role of ciliate protozoa in rumen fiber degradation. The development of techniques to clone and express ciliate genes in λ phage, together with bioinformatic indices to confirm the ciliate origin of the genes has allowed the isolation and characterization of fibrolytic genes from rumen protozoa. Elimination of the ciliate protozoa increases microbial protein supply by up to 30% and reduces methane production by up to 11%. Our recent findings suggest that holotrich protozoa play a disproportionate role in supporting methanogenesis whilst the small Entodinium are responsible for much of the bacterial protein turnover. As yet no method to control protozoa in the rumen that is safe and practically applicable has been developed, however a range of plant extract capable of controlling if not completely eliminating rumen protozoa have been described.


The evolution of accelerated, partial breast irradiation as a potential treatment option for women with newly diagnosed breast cancer considering breast conservation.
Breast conservation therapy (BCT) is a safe, effective alternative to mastectomy for many women with newly diagnosed breast cancer. This approach involves local excision of the malignancy with tumor-free margins, followed by 5-7 weeks of external beam whole breast (WB) radiotherapy (XRT) to minimize the risk of an in-breast tumor recurrence (IBTR). Though clearly beneficial, the extended course of almost daily postoperative radiotherapy interrupts normal activities and lengthens care. Additional options are now available that shorten the radiotherapy treatment time to 1-5 days (accelerated) and focus an increased dose of radiation on just the breast tissue around the excision cavity (partial breast). Recent trials with accelerated, partial breast irradiation (APBI) have shown promise as a potential replacement to the longer, whole breast treatments for select women with early-stage breast cancer. Current APBI approaches include interstitial brachytherapy, intracavitary (balloon) brachytherapy, and accelerated external beam (3-D conformal) radiotherapy, all of which normally complete treatment over 5 days, while intraoperative radiotherapy (IORT) condenses the entire treatment into a single dose delivered immediately after tumor excision. Each approach has benefits and limitations. This study covers over 2 decades of clinical trials exploring APBI, discusses treatment variables that appear necessary for successful implementation of this new form of radiotherapy, compares and contrasts the various APBI approaches, and summarizes current and planned randomized trials that will shape if and how APBI is introduced into routine clinical care. Some of the more important outcome variables from these trials will be local toxicity, local and regional recurrence, and overall survival. If APBI options are ultimately demonstrated to be as safe and effective as current whole breast radiotherapy approaches, breast conservation may become an even more appealing choice, and the overall impact of treatment may be further reduced for certain women with newly diagnosed breast cancer.


The role of ankle-brachial index for predicting peripheral arterial disease.
The presence of peripheral arterial disease (PAD) is associated with higher cardiovascular morbidity and mortality, regardless of gender or its clinical form of presentation (symptomatic or asymptomatic). PAD is considered an independent predictor for cardiovascular mortality, more important for survival than clinical history of coronary artery disease. The ankle brachial index (ABI) is a sensitive and cost-effective screening tool for PAD. ABI is valuable for screening of peripheral artery disease in patients at risk and for diagnosing the disease in patients who present with lower-extremity symptoms. Compared to other diagnostic methods, ABI is superior because it is s a simple, noninvasive test, which could be routinely determined in all patients. Normal cut-off values for ABI are between 0.9 and 1.4. An abnormal ankle-brachial index- below 0.9-is a powerful independent marker of cardiovascular risk. There is an inverse correlation between ABI values, non-fatal cardiac events (myocardial infarction, stroke and heart failure exacerbation) and mortality (cardiovascular and global), the relation being nonlinear, patients with very low ABI (<0.3) having a significantly higher additional risk. Also, ABI values over 1.3-1.4 correlate with major adverse cardiovascular events. Therefore, ABI can be considered a generalized atherosclerotic predictor, identifying patients at high risk for developing cardio- or cerebrovascular events and should be incorporated into routine clinical practice.


Kinetic properties of the 2-oxoglutarate dehydrogenase complex from Azotobacter vinelandii evidence for the formation of a precatalytic complex with 2-oxoglutarate.
The 2-oxoglutarate dehydrogenase complex was purified from Azotobacter vinelandii. The complex consists of three components, 2-oxoglutarate dehydrogenase/decarboxylase (E1o), lipoate succinyltransferase (E2o) and lipoamide dehydrogenase (E3). Upon purification, the E3 component dissociates partially from the complex. From reconstitution experiments, the Kd for E3 was found to be 26 nM, about 30 times higher than that for the pyruvate dehydrogenase complex. The Km values for the substrates 2-oxoglutarate, CoA and NAD+ were found to be 0.15, 0.014 and 0.17 mM, respectively. The system has a high specificity for 2-oxoglutarate, which is determined by the action of both E1o and E2o. Above 4 mM substrate inhibition is observed. From steady-state inhibition experiments with substrate analogs, two substrate-binding modes are revealed at different degrees of saturation of the enzyme with 2-oxoglutarate. At low substrate concentrations (10(-6) to 10(-5) M), the binding mainly depends on the interaction of the enzyme with the substrate carboxyl groups. At a higher degree of substrate saturation (10(-4) to 10(-3) M) the relative contribution of the 2-oxo group in the binding increases. A kinetic analysis points to a single binding site for a substrate analog under steady state conditions. Saturation of this site with an analog indicates that two kinetically different complexes are formed with 2-oxoglutarate in the course of catalysis. From competition studies with analogs it is concluded that one of these complexes is formed at the site that is sterically identical to the substrate inhibition site. The data obtained are represented by a minimal scheme that considers formation of a precatalytic complex SE between the substrate and E1o before the catalytic complex ES, in which the substrate is added to the thiamin diphosphate cofactor, is formed. The incorrect orientation of the substrate molecule in SE or the occupation of this site by analogs is supposed to cause substrate or analog inhibition, respectively.


T1 and T2 alterations in the brains of patients with hepatic cirrhosis.
To determine whether previously reported T1-weighted MR hyperintensities in the brains of patients with hepatic cirrhosis are accompanied by changes in T2. We measured T1 and T2 in the brains of 10 patients with chronic liver disease and 7 age-matched healthy volunteers, using classic spin-echo sequences with multiple saturation recovery times and multiple echoes. Both T1 and T2 were shortened in the basal ganglia, cortex, and white matter of the patients, with the greatest shortening in the globus pallidus, where 1/T1 was increased by 0.76 s-1 or 74% and 1/T2 by 1.45 s-1 or 11%. The T1 changes were accompanied by T2 changes of greater magnitude that were not as visible because T2 is normally much shorter than T1, especially in the globus pallidus.


Large cerebellar lesion as original manifestation of transitional cell carcinoma of the bladder.
Patients with transitional cell carcinoma of the bladder classically present with irritative voiding symptoms or painless hematuria. Common sites of vascular metastases include the liver (38%), lung (36%), bone (27%), adrenal glands (21%), and intestine (13%). Vascular metastasis to the brain, without a prior history of chemotherapy, is extremely rare. To our knowledge, this is the first report of a patient with bladder transitional cell carcinoma whose original presentation was from a symptomatic, metastatic, cerebellar lesion.


A mutant p21 cyclin-dependent kinase inhibitor isolated from a Burkitt's lymphoma.
The growth arrest mediated by p53 is caused at least in part by the p53 mediated expression of p21 (p21waf1/Cip1). Since only one-third of primary Burkitt's lymphomas (BL) demonstrate mutations in the p53 gene, we examined the structural integrity of the p21 coding region by single-strand conformational polymorphism and DNA sequence analysis to determine the extent to which this gene is mutated in BL. Of 34 BLs analyzed, a frequent change (38%) at codon 31 that replaced Ser with Arg was found in 13 samples, 10 of which were from Africa. This change at codon 31 is also detected in peripheral blood DNA from normal subjects and may thus represent a polymorphism. One BL cell line, DH978, carried a change at codon 63: Phe to Leu. This mutation was heterozygous, and both the wild-type and the mutated p21 mRNA were expressed in the tumor cell line. By transfection experiments, the mutant p21 was less efficient in suppressing clonogenicity than wild-type p21. To our knowledge, this is the only mutation described in p21. The availability of this mutant p21 should further help in functional studies of p21.


Facilitators and Barriers to Developing, Implementing, and Evaluating Healthy Vending Policies in Four Cities.
Vending machines are a common source of low-nutrient, energy-dense snacks, and beverages. Many cities are beginning to adopt healthy vending policies in public areas, but evidence regarding best practices for developing, implementing, and evaluating these healthy vending polices is limited. This study used a mixed-methods, multiple case study design to examine healthy vending policies and initiatives in four cities. Data were collected between August 2017 and December 2017. Research staff worked with a designated contact person to coordinate site visits to each city where observations of the vending machines were conducted. Semistructured interviews were conducted with multiple stakeholders from each site and documents, including policies, vendor contracts, and nutrition standards, were reviewed. The following elements were identified as being essential to a healthy vending policy or initiative: having a champion and support from leadership, internal and external partnerships, and clear communication. Conducting regular compliance checks of the vending machines and the ability to obtain sales data, especially pre- and post-healthy vending policy sales data, continues to be a challenge. Stakeholders across all cities reported that concerns about profit-loss from the vendor and city revenue and procurement departments are barriers to adopting healthy vending policies. More research and evaluation are needed, as results are mixed regarding the impact on overall revenue/profits. This study yielded a variety of resources and "lessons learned" from those who have developed and implemented healthy vending policies and initiatives. This information should be used by others looking to influence healthier snacking behaviors through vending machines.


Estimations of One Repetition Maximum and Isometric Peak Torque in Knee Extension Based on the Relationship Between Force and Velocity.
We aimed to investigate whether a linear regression formula based on the relationship between joint torque and angular velocity measured using a high-speed video camera and image measurement software is effective for estimating 1 repetition maximum (1RM) and isometric peak torque in knee extension. Subjects comprised 20 healthy men (mean ± SD; age, 27.4 ± 4.9 years; height, 170.3 ± 4.4 cm; and body weight, 66.1 ± 10.9 kg). The exercise load ranged from 40% to 150% 1RM. Peak angular velocity (PAV) and peak torque were used to estimate 1RM and isometric peak torque. To elucidate the relationship between force and velocity in knee extension, the relationship between the relative proportion of 1RM (% 1RM) and PAV was examined using simple regression analysis. The concordance rate between the estimated value and actual measurement of 1RM and isometric peak torque was examined using intraclass correlation coefficients (ICCs). Reliability of the regression line of PAV and % 1RM was 0.95. The concordance rate between the actual measurement and estimated value of 1RM resulted in an ICC(2,1) of 0.93 and that of isometric peak torque had an ICC(2,1) of 0.87 and 0.86 for 6 and 3 levels of load, respectively. Our method for estimating 1RM was effective for decreasing the measurement time and reducing patients' burden. Additionally, isometric peak torque can be estimated using 3 levels of load, as we obtained the same results as those reported previously. We plan to expand the range of subjects and examine the generalizability of our results.


Differences in right-to-left vs left-to-right interventricular conduction times in patients indicated to cardiac resynchronization therapy.
Differences in conduction times from right ventricle to left ventricle and from left ventricle to right ventricle respectively were observed during biventricular devices implantation when changing pacing vector direction. In this article the phenomenon of interventricular conduction time differences is described and assessed in relationship to various clinical and electrophysiological parameters. In 62 consecutive patients (9 females) interventricular conduction times between right and left ventricle in both directions were measured during cardiac resynchronization therapy device implantation procedure. Complex pacing protocol was performed. Investigated individuals was divided into 3 subgroups according to type of interventricular conduction pattern and statistically tested with various clinical data. Substantial differences in right-to-left vs left-to-right conduction times (> 5 ms, range 7-72 ms) were observed in 24 (39%) of all patients. They were more common in patients with dilated cardiomyopathy (20 of 38, 53%) compared to 4 (17%) of 24 patients with coronary artery disease (p = 0.011). The phenomenon occurred more often in hypertensive patients (p = 0.012). Other tested factors were nonsignificant. There are almost no data on this topic. The occurrence of conduction difference phenomenon is quite common in dilated cardiomyopathy while it is rare in coronary artery disease. We assume the diffuse nature of the disease and the way of remodeling of myocardium play the main role. Knowledge of this phenomenon could be useful in personalized cardiac resynchronization therapy optimization.


Predicting mental disorders from hypothalamic-pituitary-adrenal axis functioning: a 3-year follow-up in the TRAILS study.
Hypothalamic-pituitary-adrenal axis functioning, with cortisol as its major output hormone, has been presumed to play a key role in the development of psychopathology. Predicting affective disorders from diurnal cortisol levels has been inconclusive, whereas the predictive value of stress-induced cortisol concentrations has not been studied before. The aim of this study was to predict mental disorders over a 3-year follow-up from awakening and stress-induced cortisol concentrations. Data were used from 561 TRAILS (TRacking Adolescents' Individual Lives Survey) participants, a prospective cohort study of Dutch adolescents. Saliva samples were collected at awakening and half an hour later and during a social stress test at age 16. Mental disorders were assessed 3 years later with the Composite International Diagnostic Interview (CIDI). A lower cortisol awakening response (CAR) marginally significantly predicted new disorders [odds ratio (OR) 0.77, p = 0.06]. A flat recovery slope predicted disorders with a first onset after the experimental session (OR 1.27, p = 0.04). Recovery revealed smaller, non-significant ORs when predicting new onset affective or anxiety disorders, major depressive disorder, or dependence disorders in three separate models, corrected for all other new onsets. Our results suggest that delayed recovery and possibly reduced CAR are indicators of a more general risk status and may be part of a common pathway to psychopathology. Delayed recovery suggests that individuals at risk for mental disorders perceived the social stress test as less controllable and less predictable.


Health assessment of gasoline and fuel oxygenate vapors: developmental toxicity in mice.
CD-1 mice were exposed to baseline gasoline vapor condensate (BGVC) alone or to vapors of gasoline blended with methyl tertiary butyl ether (G/MTBE). Inhalation exposures were 6h/d on GD 5-17 at levels of 0, 2000, 10,000, and 20,000mg/m(3). Dams were evaluated for evidence of maternal toxicity, and fetuses were weighed, sexed, and evaluated for external, visceral, and skeletal anomalies. Exposure to 20,000mg/m(3) of BGVC produced slight reductions in maternal body weight/gain and decreased fetal body weight. G/MTBE exposure did not produce statistically significant maternal or developmental effects; however, two uncommon ventral wall closure defects occurred: gastroschisis (1 fetus at 10,000mg/m(3)) and ectopia cordis (1 fetus at 2000mg/m(3); 2 fetuses/1 litter at 10,000mg/m(3)). A second study (G/MTBE-2) evaluated similar exposure levels on GD 5-16 and an additional group exposed to 30,000mg/m(3) from GD 5-10. An increased incidence of cleft palate was observed at 30,000mg/m(3) G/MTBE. No ectopia cordis occurred in the replicate study, but a single observation of gastroschisis was observed at 30,000mg/m(3). The no observed adverse effect levels for maternal/developmental toxicity in the BGVC study were 10,000/2000mg/m(3), 20,000/20,000 for the G/MTBE study, and 10,000/20,000 for the G/MTBE-2 study.


Admixture Mapping of African-American Women in the AMBER Consortium Identifies New Loci for Breast Cancer and Estrogen-Receptor Subtypes.
Recent genetic admixture coupled with striking differences in incidence of estrogen receptor (ER) breast cancer subtypes, as well as severity, between women of African and European ancestry, provides an excellent rationale for performing admixture mapping in African American women with breast cancer risk. We performed the largest breast cancer admixture mapping study with in African American women to identify novel genomic regions associated with the disease. We conducted a genome-wide admixture scan using 2,624 autosomal ancestry informative markers (AIMs) in 3,629 breast cancer cases (including 1,968 ER-positive, 1093 ER-negative, and 601 triple-negative) and 4,658 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, a collaborative study of four large geographically different epidemiological studies of breast cancer in African American women. We used an independent case-control study to test for SNP association in regions with genome-wide significant admixture signals. We found two novel genome-wide significant regions of excess African ancestry, 4p16.1 and 17q25.1, associated with ER-positive breast cancer. Two regions known to harbor breast cancer variants, 10q26 and 11q13, were also identified with excess of African ancestry. Fine-mapping of the identified genome-wide significant regions suggests the presence of significant genetic associations with ER-positive breast cancer in 4p16.1 and 11q13. In summary, we identified three novel genomic regions associated with breast cancer risk by ER status, suggesting that additional previously unidentified variants may contribute to the racial differences in breast cancer risk in the African American population.


The impact of intraluminal thrombus failure on the mechanical stress in the wall of abdominal aortic aneurysms.
The role of the intraluminal thrombus (ILT) in abdominal aortic aneurysm (AAA) rupture is controversial, and it is still not clear if an ILT increases or decreases AAA rupture risk. Specifically, signs of bleeding in the ILT are considered to increase AAA rupture risk. To further explore this hypothesis, intact AAAs (n = 4) with clear signs of fissures in the ILT, identified by computed tomography angiography (CTA) were investigated. Two different cases of ILT fissuring were investigated, where (1) ILT fissures were extracted directly from the CTA data and (2) a hypothetical fissure was introduced in the otherwise-intact ILT tissue. Wall stress distributions were predicted based on detailed Finite Element (FE) models. ILT fissures extracted from CTA data locally increase the mechanical stress in the underlying wall by up to 30%. The largest impact on wall stress was observed if the ILT crack reaches the aneurysm wall, or if it involves large parts of the ILT. By contrast, a concentric failure in the medial ILT, which does not reach the aneurysm wall, has almost no impact on wall stress distribution. Hypothetical ILT fissures that connect the lumen with the wall cause a twofold increase of the stress in the underlying wall. ILT fissures increase the stress in the underlying wall, whereas regions other than that remain unaffected. If ILT fissures reach the wall or involve large parts of the ILT, the resulting increase in wall stress could possibly cause AAA rupture.


Synthesis and Characterization of mRNA-Loaded Poly(Beta Aminoesters) Nanoparticles for Vaccination Purposes.
Vaccination has been one of the major successes of modern society and is indispensable in controlling and preventing disease. Traditional vaccines were composed of entire or fractions of the infectious agent. However, challenges remain, and new vaccine technologies are mandatory. In this context, the use of mRNA for immunizing purposes has shown an enhanced performance, as demonstrated by the speedy approval of two mRNA vaccines preventing SARS-CoV-2 infection. Beyond success in preventing viral infections, mRNA vaccines can also be used for therapeutic cancer applications. Nevertheless, the instability of mRNA and its fast clearance from the body due to the presence of nucleases makes its naked delivery not possible. In this context, nanomedicines, and specifically polymeric nanoparticles, are critical mRNA delivery systems. Thus, the aim of this article is to describe the protocol for the formulation and test of an mRNA vaccine candidate based on the proprietary polymeric nanoparticles. The synthesis and chemical characterization of the poly(beta aminoesters) polymers used, their complexation with mRNA to form nanoparticles, and their lyophilization methodology will be discussed here. This is a crucial step for decreasing storage and distribution costs. Finally, the required tests to demonstrate their capacity to in vitro transfect and mature model dendritic cells will be indicated. This protocol will benefit the scientific community working on vaccination because of its high versatility that enables these vaccines to prevent or cure a wide variety of diseases.


Discovering functional neuronal connectivity from serial patterns in spike train data.
Repeating patterns of precisely timed activity across a group of neurons (called frequent episodes) are indicative of networks in the underlying neural tissue. This letter develops statistical methods to determine functional connectivity among neurons based on nonoverlapping occurrences of episodes. We study the distribution of episode counts and develop a two-phase strategy for identifying functional connections. For the first phase, we develop statistical procedures that are used to screen all two-node episodes and identify possible functional connections (edges). For the second phase, we develop additional statistical procedures to prune the two-node episodes and remove false edges that can be attributed to chains or fan-out structures. The restriction to nonoverlapping occurrences makes the counting of all two-node episodes in phase 1 computationally efficient. The second (pruning) phase is critical since phase 1 can yield a large number of false connections. The scalability of the two-phase approach is examined through simulation. The method is then used to reconstruct the graph structure of observed neuronal networks, first from simulated data and then from recordings of cultured cortical neurons.


Intimate partner violence-related hospitalizations in Appalachia and the non-Appalachian United States.
The highly rural region of Appalachia faces considerable socioeconomic disadvantage and health disparities that are recognized risk factors for intimate partner violence (IPV). The objective of this study was to estimate the rate of IPV-related hospitalizations in Appalachia and the non-Appalachian United States for 2007-2011 and compare hospitalizations in each region by clinical and sociodemographic factors. Data on IPV-related hospitalizations were extracted from the State Inpatient Databases, which are part of the Healthcare Cost and Utilization Project. Hospitalization day, year, in-hospital mortality, length of stay, average and total hospital charges, sex, age, payer, urban-rural location, income, diagnoses and procedures were compared between Appalachian and non-Appalachian counties. Poisson regression models were constructed to test differences in the rate of IPV-related hospitalizations between both regions. From 2007-2011, there were 7,385 hospitalizations related to IPV, with one-third (2,645) occurring in Appalachia. After adjusting for age and rurality, Appalachian counties had a 22% higher hospitalization rate than non-Appalachian counties (ARR = 1.22, 95% CI: 1.14-1.31). Appalachian residents may be at increased risk for IPV and associated conditions. Exploring disparities in healthcare utilization and costs associated with IPV in Appalachia is critical for the development of programs to effectively target the needs of this population.


Flushing the vessel ends: the effect on ischemic free flap survival.
During vascular anastomosis of experimental ischemic free flaps it is common to observe that stagnant blood in the vessel ends has clotted. A study was performed to investigate if flushing away the stagnant blood on division of the vessels would increase flap survival. Flushing did not influence flap survival. Clinically, clot is rarely seen, except in conditions of prolonged ischemia or damaged vessels. Current surgical practice does not involve flushing the vessel ends upon division of the vessels and this approach is affirmed by our results.


Effects of vestibular and balance rehabilitation on sensory organization and dizziness handicap.
This retrospective study was undertaken to assess balance recovery and dizziness handicap in 32 patients after a vestibular and balance rehabilitation program. Outcomes were compared between 12 patients with peripheral vestibular disorders and 20 patients with central or mixed balance disorders. The patients were tested with posturography (sensory organization test [SOT]) and the Dizziness Handicap Inventory (DHI) before and after their therapy program. The vestibular SOT, composite SOT, and functional DHI scores obtained before and after exercise were significantly improved in both the peripheral and central groups. The visual SOT mean scores obtained before and after therapy were significantly different only for the group with central or mixed vestibular disorders. Changes in SOT scores were not directly correlated with changes in DHI scores. Outcome measures of vestibular rehabilitation protocols confirmed objective and subjective improvement of balance and dizziness handicap in patients with peripheral and central vestibular disorders.


Water intake in domestic rabbits (Oryctolagus cuniculus) from open dishes and nipple drinkers under different water and feeding regimes.
Rabbits (Oryctolagus cuniculus) are often presented suffering from urolithiasis. A high water intake is important in the prophylaxis of uroliths. We investigated the influence factors for water intake using 12 rabbits subjected to different feed and water regimes with practical relevance: Hay, fresh parsley, a seed mix and two different pelleted feed were offered in diverse combinations. Water was provided either by open dish or nipple drinker. Water was accessible ad libitum except for four treatments with 6 h or 12 h water access. Under the different feeding regimes, the drinker had no influence on water intake, but faecal dry matter content was significantly higher with nipple drinkers [60.0 ± 2.1 vs. 57.2 ± 2.1% of wet weight (mean ± 95% confidence interval), p = 0.003]. Dry food led to a higher drinking water intake but total water intake was still lower than with addition of 'fresh' food. With restricted water access, rabbits exhibited a significantly higher water intake with open dishes compared with nipple drinkers (54.9 ± 9.8 vs. 48.1 ± 8.2 g/kg(0.75) /day (mean ± 95% confidence interval), p = 0.04). High proportions of fresh parsley or hay in the diet enhanced total water intake and urine output, and led to lower urinary dry matter content and lower urinary calcium concentrations. Restricted access to drinkers led to a decreased total daily water intake and increased dry matter content of urine and faeces. For optimal water provision and urolith prophylaxis, we recommend a diet with a high 'fresh food' proportion as well as additionally hay ad libitum with free water access, offered in an open bowl.


The iPad and mobile technology revolution: benefits and challenges for individuals who require augmentative and alternative communication.
The iPad and other mobile technologies provide powerful new tools to potentially enhance communication for individuals with developmental disabilities, acquired neurogenic disorders, and degenerative neurological conditions. These mobile technologies offer a number of potential benefits, including: (a) increased awareness and social acceptance of augmentative and alternative communication (AAC), (b) greater consumer empowerment in accessing AAC solutions, (c) increased adoption of AAC technologies, (d) greater functionality and interconnectivity, and (e) greater diffusion of AAC research and development. However, there remain a number of significant challenges that must be addressed if these benefits are to be fully realized: (a) to ensure the focus is on communication, not just technology, (b) to develop innovative models of AAC service delivery to ensure successful outcomes, (c) to ensure ease of access for all individuals who require AAC, and, (d) to maximize AAC solutions to support a wide variety of communication functions. There is an urgent need for effective collaboration among key stakeholders to support research and development activities, and to ensure the successful implementation of mobile technologies to enhance communication outcomes for individuals who require AAC and their families.


Tunable trimers: using temperature and pressure to control luminescent emission in gold(I) pyrazolate-based trimers.
A systematic investigation into the relationship between the solid-state luminescence and the intermolecular Au⋅⋅⋅Au interactions in a series of pyrazolate-based gold(I) trimers; tris(μ2 -pyrazolato-N,N')-tri-gold(I) (1), tris(μ2 -3,4,5- trimethylpyrazolato-N,N')-tri-gold(I) (2), tris(μ2 -3-methyl-5-phenylpyrazolato-N,N')-tri-gold(I) (3) and tris(μ2 -3,5-diphenylpyrazolato-N,N')-tri-gold(I) (4) has been carried out using variable temperature and high pressure X-ray crystallography, solid-state emission spectroscopy, Raman spectroscopy and computational techniques. Single-crystal X-ray studies show that there is a significant reduction in the intertrimer Au⋅⋅⋅Au distances both with decreasing temperature and increasing pressure. In the four complexes, the reduction in temperature from 293 to 100 K is accompanied by a reduction in the shortest intermolecular Au⋅⋅⋅Au contacts of between 0.04 and 0.08 Å. The solid-state luminescent emission spectra of 1 and 2 display a red shift with decreasing temperature or increasing pressure. Compound 3 does not emit under ambient conditions but displays increasingly red-shifted luminescence upon cooling or compression. Compound 4 remains emissionless, consistent with the absence of intermolecular Au⋅⋅⋅Au interactions. The largest pressure induced shift in emission is observed in 2 with a red shift of approximately 630 cm(-1) per GPa between ambient and 3.80 GPa. The shifts in all the complexes can be correlated with changes in Au⋅⋅⋅Au distance observed by diffraction.


Effective linkage from point of HIV testing to care and treatment in Tanga region, Tanzania.
Linkage to care and treatment is an important part of efforts to accelerate HIV prevention, treatment, care, and support. It offers an opportunity for PLHIV to receive information and services in a timely manner. Clients who present late for HIV care and treatment may miss out on timely initiation of prophylaxis and ART, which may accelerate disease progression and lead to an increased rate of HIV transmission within the community. The objective of this study was to determine the factors influencing effective linkages of newly diagnosed PLHIV from the point of testing to entry in care and treatment centres (CTCs) in Tanga Region, Tanzania. This cross-sectional study examined five clinics with a high volume of clients in each of the three districts in Tanga Region. All adults ages 18 years and above at the time of CTC enrolment, between 2010 and 2014, were eligible to participate in the study. The study engaged both secondary and primary data. To complement the secondary data, mixed methods were applied in primary data collection. Using a structured questionnaire, interviews with the sampled CTC clients while focus group discussions with healthcare providers and in-depth interviews with CTC clients. The qualitative data were analysed using a thematic analysis framework. The outcome of interest was whether a client enrolled in a CTC within three months of his or her first positive HIV test. A logistic regression model was used to determine factors associated with effective linkage of newly diagnosed HIV clients to CTC. A total of 16,041 adults from the three study districts were enrolled at a CTC from 2010 to 2014. A total of 1,096 clients from the sampled CTCs were recruited into the study for interview. The characteristics of these clients were representative of the larger group (16,041). The majority (72.4%) were female. More than half (52.1%) were married, and almost a quarter (21.2%) were single. The majority (59.6%) of participants completed primary education and almost half (45.1%) were subsistence farmers. The median CD4 count at enrolment was 218 (87-397) cells/mL with more than half (56.3%) having CD4 counts of less than 350 cells per millilitre (mL). Nearly all (91%) of the clients presented at a CTC within three months of receiving a positive HIV test. In a multivariate analysis, factors that remained significantly associated with early entry in CTC were level of education, CD4 count, and point of diagnosis. Participants' responses were consistent with many of the factors explained by participants to be barriers to effective linkages and referrals repeated in the FGDs and IDIs across the study sites. For instance, FGD respondent expressed that clients were worried about stigma from their relatives, which creates a delay in seeking treatment. Although the rate of early entry in care and treatment services is high, surprisingly was a marked increase in those who waited more than three months to seek treatment. To meet the target, issues such as disclosure and stigma need to be addressed.


Predictors of hospital stay and mortality in dengue virus infection-experience from Aga Khan University Hospital Pakistan.
Dengue virus infection (DVI) is very common infection. There is scarcity of data on factor associated with increased hospital stay and mortality in dengue virus infection (DVI). This study was done to know about factors associated with increased hospital stay and mortality in patients admitted with DVI. Out of 532 patients, two third (72.6%) had stay ≤3 days while one third (27.4%) had stay greater than 3 days. The mean length of hospital stay was 3.46 ± 3.45 days. Factors associated with increased hospital stay (>3 days) included AKI (acute kidney injury) (Odd ratio 2.98; 95% CI 1.66-5.34), prolonged prothrombin time (Odd ratio 2.03; 95% CI 1.07-3.84), prolonged activated partial thromboplastin time (aPTT) (Odd ratio 1.80; CI 95% 1.15-2.83) and increased age of > 41.10 years (Odd ratio 1.03; CI 95% 1.01-1.04).Mortality was 1.5%. High mortality was found in those with AKI (P <0.01), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) (P <0.001), respiratory failure (P0.01), prolong PT (P 0.001), prolong aPTT (P0.01) and increased hospital stay (P0.04). Increasing age, coagulopathy and acute kidney injury in patients with DVI is associated with increased hospital stay. Morality was more in patients with AKI, DHF and DSS, respiratory failure, coagulopathy and these patients had more prolonged hospitalization.


Spontaneous pneumothorax. Long-term results with tetracycline pleurodesis.
The aim of this prospective study was to determine the rate of recurrence for spontaneous pneumothorax (SP) after tetracycline pleurodesis (TCP), using that of observation, tube thoracostomy alone, and thoracotomy as references. From 1985 to the end of 1991, 78 patients were treated with tetracycline pleurodesis and 135 patients served as control subjects. Pleurodesis was induced by instillation of tetracycline and ascorbic acid through the pleural drain. The indication was any SP treated with tube thoracostomy, without active pulmonary infection. Follow-up period was from 13 to 95 months (mean, 45 months); follow-up rate was 94 percent. Post-therapy surgery was necessary for eight patients in whom pleurodesis failed due to presence of a persistent air leak. The ipsilateral recurrence rate of patients treated with TCP was 9 percent (6/66) and recurrence time ranged from 2 days to 9 months. The recurrence rate for patients treated with observation was 36 percent, 35 percent for those having chest tube alone, and none for those undergoing surgery. No death occurred as a direct result of this procedure and all patients could be released from the hospital. Eleven subjects died during the follow-up period; the mean follow-up until death was 37 months (range, 2 to 87 months). Five deaths were due to respiratory causes and six were due to extrapulmonary causes. Tetracycline pleurodesis has been shown to be a good alternative for the prevention of recurrence of SP. Its recurrence rate is lower than that of tube drainage but higher than that of surgical treatment.


Association of parity with birthweight and neonatal death in five sites: The Global Network's Maternal Newborn Health Registry study.
Nulliparity has been associated with lower birth weight (BW) and other adverse pregnancy outcomes, with most of the data coming from high-income countries. In this study, we examined birth weight for gestational age z-scores and neonatal (28-day) mortality in a large prospective cohort of women dated by first trimester ultrasound from multiple sites in low and middle-income countries. Pregnant women were recruited during the first trimester of pregnancy and followed through 6 weeks postpartum from Maternal Newborn Health Registry (MNHR) sites in the Democratic Republic of Congo (DRC), Guatemala, Belagavi and Nagpur, India, and Pakistan from 2017 and 2018. Data related to the pregnancy and its outcomes were collected prospectively. First trimester ultrasound was used for determination of gestational age; (BW) was obtained in grams within 48 h of delivery and later transformed to weight for age z-scores (WAZ) adjusted for gestational age using the INTERGROWTH-21st standards. 15,121 women were eligible and included. Infants of nulliparous women had lower mean BWs (males: 2676 gr, females: 2587 gr, total: 2634 gr) and gestational age adjusted weight for age z-scores (males: - 0.73, females: - 0.77, total: - 0.75,) than women with one or more previous pregnancies. The largest differences were between zero and one previous pregnancies among female infants. The associations of parity with BW and z-scores remained even after adjustment for maternal age, maternal height, maternal education, antenatal care visits, hypertensive disorders, and socioeconomic status. Nulliparous women also had a significantly higher < 28-day neonatal mortality rate (27.7 per 1,000 live births) than parous women (17.2 and 20.7 for parity of 1-3 and ≥ 4 respectively). Risk of preterm birth was higher among women with ≥ 4 previous pregnancies (15.5%) compared to 11.3% for the nulliparous group and 11.8% for women with one to three previous pregnancies (p = 0.0072). In this large sample from diverse settings, nulliparity was independently associated with both lower BW and WAZ scores as well as higher neonatal mortality compared to multiparity.


Carbon dioxide waveguide lasers with folds and tilted mirrors.
We present theoretical and experimental results for an rf-excited z-fold CO(2) waveguide laser. We describe how the output power, output rotational line(s) and transverse mode(s) vary as functions of elbow mirror tilt and obtain good agreement with predictions from a multimode matrix resonator model. Observations of multilining and/or multifrequency operation are partly explained by the near equality of gain/loss ratios for two or more resonator modes.


A randomised controlled trial of the effectiveness of a breastfeeding training DVD on improving breastfeeding knowledge and confidence among healthcare professionals in China.
Despite almost all babies being breastfed initially, the exclusive breastfeeding rate at six months is less than 30% in China. Improving professionals' knowledge and practical skill is a key government strategy to increase breastfeeding rates. This study aimed to test the effectiveness of a breastfeeding DVD training method for clinicians on improving their knowledge and confidence in the breastfeeding support skills of teaching mothers Positioning and Attachment (P & A) and Hand Expression (HE). A randomised controlled trial was conducted in three hospitals in Zhejiang province, China in 2014. Participants were recruited before their routine breastfeeding training course and randomly allocated to intervention group (IG) and control group (CG). The 15 min "Breastfeeding: Essential Support Skills DVD" was the intervention for IG and a vaginal delivery DVD was used for CG. All participants completed questionnaires of job information, knowledge and confidence in the two skills before (baseline) and immediately after viewing the DVD (post DVD). Out of 210 participants, 191 completed knowledge assessments before and after watching the DVD (IG n = 96, CG n = 95), with the response rate of 91.0%. At baseline, there are no significant differences in job variables, total knowledge scores and confident scores. The total knowledge score significantly increased post-DVD for IG (pre-DVD: M = 5.39, SD = 2.03; post-DVD: M = 7.74, SD = 1.71; t (95) = - 10.95, p < 0.01), but no significant change in total knowledge score for CG between pre- and post-DVD (pre-DVD: M = 5.67, SD = 1.70; post-DVD: M = 5.56, SD = 1.63; t (94) = 0.85). The total confidence scores were significantly higher post-DVD than pre-DVD in IG (pre-DVD: M = 66.49, SD = 11.27; post- DVD: M = 71.81, SD = 9.33; t (68) = - 4.92, p < 0.01), but no significant difference was seen in CG between pre- and post-DVD total confidence scores (pre-DVD: M = 68.33, SD = 11.08; post-DVD: M = 68.35, SD = 11.40; t (65) = - 0.25). Personal and job variables did not mediate these effects. The breastfeeding training DVD improved professionals' knowledge and confidence of the two breastfeeding support skills. However, the effect on professionals' practice and on breastfeeding outcomes needs to be examined in the future.


Towards IV drug standardization in critical care.
Local infusion practice within critical care has evolved over time, and one example of this is the wide variation in concentrations of drug infusions within critical care. While there are many similarities between critical care units, there are also many differences. Often drug infusions are used outside their product licence and, because of the diversity in practice, manufacturers are unlikely to license multiple preparations of even the most commonly used infusions. Critical care nurses spend many hours every day preparing and administering intravenous infusions. Much time could be saved if the infusions were available as a ready-to-use solution. This would also reduce the risk of errors that occur during the preparation and administration of medication infusions. This article describes a national project to achieve consensus on the strengths of drug infusions used within UK critical care units. Having agreed on standard solutions, it is hoped that manufacturers will seek licences for commonly used infusions and work towards mass production of these products. Off the shelf, ready-to-use infusions of commonly used medications could become a reality.


Prevention of vaginal SHIV transmission in macaques by a coitally-dependent Truvada regimen.
Daily pre-exposure prophylaxis (PrEP) with Truvada (a combination of emtricitabine (FTC) and tenofovir (TFV) disoproxil fumarate (TDF)) is a novel HIV prevention strategy recently found to prevent HIV transmission in men who have sex with men and heterosexual couples. We previously showed that a coitally-dependent Truvada regimen protected macaques against rectal SHIV transmission. Here we examined FTC and tenofovir TFV exposure in vaginal tissues after oral dosing and assessed if peri-coital Truvada also protects macaques against vaginal SHIV infection. The pharmacokinetic profile of emtricitabine (FTC) and tenofovir (TFV) was evaluated at first dose. FTC and TFV levels were measured in blood plasma, rectal, and vaginal secretions. Intracellular concentrations of FTC-triphosphate (FTC-TP) and TFV-diphosphate (TFV-DP) were measured in PBMCs, rectal tissues, and vaginal tissues. Efficacy of Truvada in preventing vaginal SHIV infection was assessed using a repeat-exposure vaginal SHIV transmission model consisting of weekly exposures to low doses of SHIV162p3. Six pigtail macaques with normal menstrual cycles received Truvada 24 h before and 2 h after each weekly virus exposure and six received placebo. Infection was monitored by serology and PCR amplification of SHIV RNA and DNA. As in humans, the concentration of FTC was higher than the concentration of TFV in vaginal secretions. Also as in humans, TFV levels in vaginal secretions were lower than in rectal secretions. Intracellular TFV-DP concentrations were also lower in vaginal tissues than in rectal tissues. Despite the low vaginal TFV exposure, all six treated macaques were protected from infection after 18 exposures or 4 full menstrual cycles. In contrast, all 6 control animals were infected. We modeled a peri-coital regimen with two doses of Truvada and showed that it fully protected macaques from repeated SHIV exposures. Our results open the possibility for simplified PrEP regimens to prevent vaginal HIV transmission in women.


Self-regulated learning and academic performance in medical education.
Medical schools aim to graduate medical doctors who are able to self-regulate their learning. It is therefore important to investigate whether medical students' self-regulated learning skills change during medical school. In addition, since these skills are expected to be helpful to learn more effectively, it is of interest to investigate whether these skills are related to academic performance. In a cross-sectional design, the Self-Regulation of Learning Self-Report Scale (SRL-SRS) was used to investigate the change in students' self-regulated learning skills. First and third-year students (N = 949, 81.7%) SRL-SRS scores were compared with ANOVA. The relation with academic performance was investigated with multinomial regression analysis. Only one of the six skills, reflection, significantly, but positively, changed during medical school. In addition, a small, but positive relation of monitoring, reflection, and effort with first-year GPA was found, while only effort was related to third-year GPA. The change in self-regulated learning skills is minor as only the level of reflection differs between the first and third year. In addition, the relation between self-regulated learning skills and academic performance is limited. Medical schools are therefore encouraged to re-examine the curriculum and methods they use to enhance their students' self-regulated learning skills. Future research is required to understand the limited impact on performance.


Dose - response relationship between noise exposure and the risk of occupational injury.
Many workers worldwide experience fatality and disability caused by occupational injuries. This study examined the relationship between noise exposure and occupational injuries at factories in Korea. A total of 1790 factories located in northern Gyeonggi Province, Korea was evaluated. The time-weighted average levels of dust and noise exposure were taken from Workplace Exposure Assessment data. Apart occupational injuries, sports events, traffic accidents, and other accidents occurring outside workplaces were excluded. The incidences of occupational injury in each factory were calculated by data from the Korea Workers' Compensation and Welfare Services. Workplaces were classified according to the incidence of any occupational injuries (incident or nonincident workplaces, respectively). Workplace dust exposure was classified as <1 or ≥ 1 mg/m³ , and noise exposure as <80, 80-89, or >90 dB. Workplaces with high noise exposure were significantly associated with being incident workplaces, whereas workplaces with high dust exposure were not. The odds ratios (95% confidence intervals) derived from a logistic regression model were 1.68 (1.27-2.24) and 3.42 (2.26-5.17) at 80-89 dB and ≥ 90 dB versus <80 dB. These associations remained significant when in a separate analysis according to high or low dust exposure level. Noise exposure increases the risk of occupational injury in the workplace. Furthermore, the risk of occupational injury increases with noise exposure level in a dose-response relationship. Therefore, strategies for reducing noise exposure level are required to decrease the risk of occupational injury.


BCL-2 inhibition with ABT-737 prolongs survival in an NRAS/BCL-2 mouse model of AML by targeting primitive LSK and progenitor cells.
Myelodysplastic syndrome (MDS) transforms into an acute myelogenous leukemia (AML) with associated increased bone marrow (BM) blast infiltration. Using a transgenic mouse model, MRP8[NRASD12/hBCL-2], in which the NRAS:BCL-2 complex at the mitochondria induces MDS progressing to AML with dysplastic features, we studied the therapeutic potential of a BCL-2 homology domain 3 mimetic inhibitor, ABT-737. Treatment significantly extended lifespan, increased survival of lethally irradiated secondary recipients transplanted with cells from treated mice compared with cells from untreated mice, with a reduction of BM blasts, Lin-/Sca-1(+)/c-Kit(+), and progenitor populations by increased apoptosis of infiltrating blasts of diseased mice assessed in vivo by technicium-labeled annexin V single photon emission computed tomography and ex vivo by annexin V/7-amino actinomycin D flow cytometry, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, caspase 3 cleavage, and re-localization of the NRAS:BCL-2 complex from mitochondria to plasma membrane. Phosphoprotein analysis showed restoration of wild-type (WT) AKT or protein kinase B, extracellular signal-regulated kinase 1/2 and mitogen-activated protein kinase patterns in spleen cells after treatment, which showed reduced mitochondrial membrane potential. Exon specific gene expression profiling corroborates the reduction of leukemic cells, with an increase in expression of genes coding for stem cell development and maintenance, myeloid differentiation, and apoptosis. Myelodysplastic features persist underscoring targeting of BCL-2-mediated effects on MDS-AML transformation and survival of leukemic cells.


Improving the linkages between air pollution epidemiology and quantitative risk assessment.
Air pollution epidemiology plays an integral role in both identifying the hazards of air pollution as well as supplying the risk coefficients that are used in quantitative risk assessments. Evidence from both epidemiology and risk assessments has historically supported critical environmental policy decisions. The extent to which risk assessors can properly specify a quantitative risk assessment and characterize key sources of uncertainty depends in part on the availability, and clarity, of data and assumptions in the epidemiological studies. We discuss the interests shared by air pollution epidemiology and risk assessment communities in ensuring that the findings of epidemiological studies are appropriately characterized and applied correctly in risk assessments. We highlight the key input parameters for risk assessments and consider how modest changes in the characterization of these data might enable more accurate risk assessments that better represent the findings of epidemiological studies. We argue that more complete information regarding the methodological choices and input data used in epidemiological studies would support more accurate risk assessments-to the benefit of both disciplines. In particular, we suggest including additional details regarding air quality, demographic, and health data, as well as certain types of data-rich graphics. Relatively modest changes to the data reported in epidemiological studies will improve the quality of risk assessments and help prevent the misinterpretation and mischaracterization of the results of epidemiological studies. Such changes may also benefit epidemiologists undertaking meta-analyses. We suggest workshops as a way to improve the dialogue between the two communities.


Maternal fat supplementation during late pregnancy and lactation influences the development of hepatic steatosis in offspring depending on the fat source.
In this study we investigate the effects of maternal supplementation with different fat sources (margarine, olive oil, or butter) during pregnancy and lactation on offspring metabolic health in adulthood and under obesogenic conditions. In adulthood and under a high-fat (HF) diet, the margarine group showed lower body fat content than the butter group and was also protected against the increase in hepatic lipid content occurring in the other groups, whereas the butter group showed signs of more advanced hepatic steatosis. Under an HF diet, all fat-supplemented animals showed greater hepatic expression levels of fatty acid oxidation-related genes compared to their normal-fat diet counterparts, with higher levels in the margarine group. Under these conditions, the margarine group also showed higher white adipose tissue mRNA levels of adipogenic genes than the other fat-supplemented groups. Thus, compared to other fat sources, offspring from margarine-supplemented dams seem to be more protected from metabolic alterations related to the HF diet, particularly concerning hepatic fat accumulation.


Longer prior exposure to zidovudine/lamivudine-containing combination antiretroviral therapy, age, and male gender are each associated with reduced subcutaneous adipose tissue.
Whether zidovudine (AZT)-associated lipoatrophy occurrence differs by concomitant exposure to protease (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) remains unclear. Baseline body composition data from a randomized trial in subjects stable on first-line AZT-based therapy were used to explore this issue. In this substudy of the PREPARE trial, centrally read baseline whole-body dual energy x-ray aborptiometry (DXA) and single-slice abdominal CT scans were analyzed with respect to duration and type of prior AZT/lamivudine (3TC) combination antiretroviral therapy (cART), including by multivariate linear regression adjusted for age, gender, ethnicity, body mass index (BMI), and nadir CD4. DXA and CT, from 134 and 136 patients, respectively [87% male; 82% Caucasian; mean (SD) age, 45.6 years (10); BMI, 24.3 kg/m² (3.2)], were analyzed. Prior AZT/3TC cART exposure was 5.5 (2.2) years. Seventy-eight and 27 patients had concomitantly and exclusively used NNRTIs and PIs, respectively. AZT/3TC cART, AZT/3TC/NNRTI, and AZT/3TC/PI, respectively, were associated with the presence of a mean (95% CI) of 247 g (-438 to -56; P = .012), 267 g (-467 to -66; P = .010), and 216 g (-430 to -1.7; P = .048) less baseline limb fat per additional year of prior exposure. Although abdominal subcutaneous (SAT) adipose tissue was likewise less with longer AZT/3TC cART, this was only significant for AZT/3TC/ NNRTI but not AZT/3TC/PI. Visceral adipose tissue (VAT) amount was not clearly associated to prior treatment. Increased age and male gender were independently associated with lower limb fat and SAT, but more VAT. Longer exposure to AZT/3TC, regardless of whether in combination with PI or NNRTI, as well as increased age and male gender are independently associated with lower limb fat mass.


Simple and ultrastable all-inclusive pullulan tablets for challenging bioassays.
Many biodetection systems employ labile enzymes and substrates that need special care, making it hard to routinely use them for point-of-care or field applications. In this work we provide a simple solution to this challenging problem through the creation of all-inclusive pullulan assay tablets. The proposed tablet system not only enhances the long-term stability of both enzymes and organic substrates, but also simplifies the assay procedure. The enhanced stability is attributed to two factors: the restriction of the molecular motion of proteins and impermeability to molecular oxygen afforded by the tables. These tablets dissolve rapidly upon addition to testing samples, making the test very easy to perform. Using the ATP-detecting luciferase-luciferin system as an example, we show that the tablet-based assay can achieve highly sensitive detection of ATP in biological samples and that the activity of the assay tablets remains unchanged for over a month at room temperature.


Panax notoginseng Root Cell Death Caused by the Autotoxic Ginsenoside Rg1 Is Due to Over-Accumulation of ROS, as Revealed by Transcriptomic and Cellular Approaches.
Panax notoginseng is a highly valuable medicinal herb, but its culture is strongly hindered by replant failure, mainly due to autotoxicity. Deciphering the response mechanisms of plants to autotoxins is critical for overcoming the observed autotoxicity. Here, we elucidated the response of P. notoginseng to the autotoxic ginsenoside Rg1 via transcriptomic and cellular approaches. Cellular analyses demonstrated that Rg1 inhibited root growth by disrupting the cell membrane and wall. Transcriptomic analyses confirmed that genes related to the cell membrane, cell wall decomposition and reactive oxygen species (ROS) metabolism were up-regulated by Rg1 stress. Further cellular analyses revealed that Rg1 induced ROS ([Formula: see text] and H2O2) accumulation in root cells by suppressing ascorbate peroxidase (APX) and the activities of enzymes involved in the ascorbate-glutathione (ASC-GSH) cycle. Exogenous antioxidants (ASC and gentiobiose) helped cells scavenge over-accumulated ROS by promoting superoxide dismutase (SOD) activity and the ASC-GSH cycle. Collectively, the autotoxin Rg1 caused root cell death by inducing the over-accumulation of ROS, and the use of exogenous antioxidants could represent a strategy for overcoming autotoxicity.


Reduced Insulin/Insulin-Like Growth Factor Receptor Signaling Mitigates Defective Dendrite Morphogenesis in Mutants of the ER Stress Sensor IRE-1.
Neurons receive excitatory or sensory inputs through their dendrites, which often branch extensively to form unique neuron-specific structures. How neurons regulate the formation of their particular arbor is only partially understood. In genetic screens using the multidendritic arbor of PVD somatosensory neurons in the nematode Caenorhabditis elegans, we identified a mutation in the ER stress sensor IRE-1/Ire1 (inositol requiring enzyme 1) as crucial for proper PVD dendrite arborization in vivo. We further found that regulation of dendrite growth in cultured rat hippocampal neurons depends on Ire1 function, showing an evolutionarily conserved role for IRE-1/Ire1 in dendrite patterning. PVD neurons of nematodes lacking ire-1 display reduced arbor complexity, whereas mutations in genes encoding other ER stress sensors displayed normal PVD dendrites, specifying IRE-1 as a selective ER stress sensor that is essential for PVD dendrite morphogenesis. Although structure function analyses indicated that IRE-1's nuclease activity is necessary for its role in dendrite morphogenesis, mutations in xbp-1, the best-known target of non-canonical splicing by IRE-1/Ire1, do not exhibit PVD phenotypes. We further determined that secretion and distal localization to dendrites of the DMA-1/leucine rich transmembrane receptor (DMA-1/LRR-TM) is defective in ire-1 but not xbp-1 mutants, suggesting a block in the secretory pathway. Interestingly, reducing Insulin/IGF1 signaling can bypass the secretory block and restore normal targeting of DMA-1, and consequently normal PVD arborization even in the complete absence of functional IRE-1. This bypass of ire-1 requires the DAF-16/FOXO transcription factor. In sum, our work identifies a conserved role for ire-1 in neuronal branching, which is independent of xbp-1, and suggests that arborization defects associated with neuronal pathologies may be overcome by reducing Insulin/IGF signaling and improving ER homeostasis and function.


Assisting role redesign: a qualitative evaluation of the implementation of a podiatry assistant role to a community health setting utilising a traineeship approach.
Increasing demands for podiatry combined with workforce shortages due to attrition, part-time working practices and rural healthcare shortages means that in some geographic areas in Australia there are insufficient professionals to meet service demand. Although podiatry assistants have been introduced to help relieve workforce shortages there has been little evaluation of their impact on patient, staff and/or service outcomes. This research explores the processes and outcomes of a 'trainee' approach to introducing a podiatry assistant (PA) role to a community setting in the Australian Capital Territory (ACT) Government Health Service Directorate. A qualitative methodology was employed involving interviews and focus groups with service managers, qualified practitioners, the assistant, service users and consumer representatives. Perspectives of the implementation process; the traineeship approach; the underlying mechanisms that help or hinder the implementation process; and the perceived impact of the role were explored. Data were analysed using the Richie and Spencer Framework approach. Although the impact of the PA role had not been measured at the time of the evaluation, the implementation of the PA traineeship was considered a success in terms of enabling the transfer of a basic foot-care service from nursing back to podiatry; releasing Enrolled Nurses (ENs) from foot-care duties; an increase in the number of treatments delivered by the podiatry service; and high levels of stakeholder satisfaction with the role. It was perceived that the transfer of the basic foot-care role from nursing to podiatry through the use of a PA impacted on communication and feedback loops between the PA and the podiatry service; the nursing-podiatry relationship; clinical governance around the foot-care service; and continuity of care for clients through the podiatry service. The traineeship was considered successful in terms of producing a PA whose skills were shaped by and directly met the needs of the practitioners with whom they worked. However, the resource intensiveness of the traineeship model was acknowledged by most who participated in the programme. This research has demonstrated that the implementation of a PA using a traineeship approach requires good coordination and communication with a number of agencies and staff and substantial resources to support training and supervision. There are added benefits of the new role to the podiatry service in terms of regaining control over podiatric services which was perceived to improve clinical governance and patient pathways.


Comparison of clinically diagnosed asthma with parental assessment of children's asthma in a questionnaire.
Epidemiological evaluations of the prevalence of asthma are usually based on written questionnaires (WQs) in combination with validation by clinical investigation. In the present investigation, we compared parental assessment of asthma among their preschool children in response to a WQ with the corresponding medical records in the same region. An International Study of Asthma and Allergies in Childhood (ISAAC)-based WQ was answered by 75% of the parents of 6295 children aged 1-6 yr. Clinically diagnosed asthma, recorded in connection with admissions to the hospital or a visit to any of the outpatient clinics in the same region, were analysed in parallel. Finally, a complementary WQ was sent to the parents of children identified as asthmatic by either or both of this approaches. In response to the WQ 5.9% were claimed to suffer from asthma diagnosed by a doctor. According to the medical records, the prevalence of clinically diagnosed asthma was 4.9%. The estimated prevalence among children requiring treatment for their asthma was 4.4%. The sensitivity of the WQ was 77%, the specificity 97.5%. In the 1-2 yr age group the sensitivity was only 22%. This WQ was able to identify 54% of the children with a medical record of asthma. Forty percent of the children claimed by their parents to be asthmatic had no medical record of asthma. An ISAAC-based parentally completed WQ provided an acceptable estimation of the prevalence of asthma in children 2-6 yr of age, although only half of the individual patients identified in this manner are the same as those identified clinically.


Is There an Association Between COVID-19 Mortality and the Renin-Angiotensin System? A Call for Epidemiologic Investigations.
Mortality from coronavirus disease 2019 (COVID-19) is strongly associated with cardiovascular disease, diabetes, and hypertension. These disorders share underlying pathophysiology related to the renin-angiotensin system (RAS) that may be clinically insightful. In particular, activity of the angiotensin-converting enzyme 2 (ACE2) is dysregulated in cardiovascular disease, and this enzyme is used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to initiate the infection. Cardiovascular disease and pharmacologic RAS inhibition both increase ACE2 levels, which may increase the virulence of SARS-CoV-2 within the lung and heart. Conversely, mechanistic evidence from related coronaviruses suggests that SARS-CoV-2 infection may downregulate ACE2, leading to toxic overaccumulation of angiotensin II that induces acute respiratory distress syndrome and fulminant myocarditis. RAS inhibition could mitigate this effect. With conflicting mechanistic evidence, we propose key clinical research priorities necessary to clarify the role of RAS inhibition in COVID-19 mortality that could be rapidly addressed by the international research community.


Seven In Absentia Homolog 2 (SIAH2) downregulation is associated with tamoxifen resistance in MCF-7 breast cancer cells.
A significant percentage of estrogen receptor (ER)-positive breast cancers are resistant to tamoxifen therapy. Seven in Absentia Homolog 2 (SIAH2), an E3 ubiquitin protein ligase, has been shown to be associated with resistance to antiestrogens. We sought to assess its role in the resistance of a breast cancer cell line, MCF-7, to the ER antagonist, tamoxifen. A bioinformatic approach was used for the analysis of SIAH2 expression in breast cancer. MCF-7 and MDA-MB-231, which are ER-positive and -negative breast cancer cell lines, respectively, were used for in vitro studies. SIAH2 and ER-α were selectively knocked down in these cell lines with small-interfering RNAs. Knockdowns were confirmed with Western blot analysis and quantitative real-time polymerase chain reaction. Cells with SIAH2 knockdown were treated with tamoxifen and compared with controls. Knockdown of SIAH2 followed by treatment with tamoxifen resulted in a significant decrease in the sensitivity of treated ER-positive cells. Of note, knockdown of SIAH2 resulted in downregulation of ER-α, whereas knockdown of ER-α had minimal effect on SIAH2. Consistent with this result, the bioinformatic analysis of clinical data revealed that SIAH2 expression is significantly correlated with ER positivity in human breast cancers, and low SIAH2 expression is associated with a poorer response to tamoxifen. SIAH2 appears to be an important modulator of tamoxifen sensitivity in ER-positive MCF-7 cells, mediated, at least in part, through regulation of ER-α expression. Low expression of SIAH2 may be one of the mechanisms that contribute to tamoxifen resistance in human breast cancer.


Single-Trial EEG Analysis Predicts Memory Retrieval and Reveals Source-Dependent Differences.
We used pattern classifiers to extract features related to recognition memory retrieval from the temporal information in single-trial electroencephalography (EEG) data during attempted memory retrieval. Two-class classification was conducted on correctly remembered trials with accurate context (or source) judgments vs. correctly rejected trials. The average accuracy for datasets recorded in a single session was 61% while the average accuracy for datasets recorded in two separate sessions was 56%. To further understand the basis of the classifier's performance, two other pattern classifiers were trained on different pairs of behavioral conditions. The first of these was designed to use information related to remembering the item and the second to use information related to remembering the contextual information (or source) about the item. Mollison and Curran (2012) had earlier shown that subjects' familiarity judgments contributed to improved memory of spatial contextual information but not of extrinsic associated color information. These behavioral results were similarly reflected in the event-related potential (ERP) known as the FN400 (an early frontal effect relating to familiarity) which revealed differences between correct and incorrect context memories in the spatial but not color conditions. In our analyses we show that a classifier designed to distinguish between correct and incorrect context memories, more strongly involves early activity (400-500 ms) over the frontal channels for the location distinctions, than for the extrinsic color associations. In contrast, the classifier designed to classify memory for the item (without memory for the context), had more frontal channel involvement for the color associated experiments than for the spatial experiments. Taken together these results argue that location may be bound more tightly with the item than an extrinsic color association. The multivariate classification approach also showed that trial-by-trial variation in EEG corresponding to these ERP components were predictive of subjects' behavioral responses. Additionally, the multivariate classification approach enabled analysis of error conditions that did not have sufficient trials for standard ERP analyses. These results suggested that false alarms were primarily attributable to item memory (as opposed to memory of associated context), as commonly predicted, but with little previous corroborating EEG evidence.


Cardiovascular effects of sub-daily levels of ambient fine particles: a systematic review.
While the effects of daily fine particulate exposure (PM) have been well reviewed, the epidemiological and physiological evidence of cardiovascular effects associated to sub-daily exposures has not. We performed a theoretical model-driven systematic non-meta-analytical literature review to document the association between PM sub-daily exposures (< or =6 hours) and arrhythmia, ischemia and myocardial infarction (MI) as well as the likely mechanisms by which sub-daily PM exposures might induce these acute cardiovascular effects. This review was motivated by the assessment of the risk of exposure to elevated sub-daily levels of PM during fireworks displays. Medline and Elsevier's EMBase were consulted for the years 1996-2008. Search keywords covered potential cardiovascular effects, the pollutant of interest and the short duration of the exposure. Only epidemiological and experimental studies of adult humans (age > 18 yrs) published in English were reviewed. Information on design, population and PM exposure characteristics, and presence of an association with selected cardiovascular effects or physiological assessments was extracted from retrieved articles. Of 231 articles identified, 49 were reviewed. Of these, 17 addressed the relationship between sub-daily exposures to PM and cardiovascular effects: five assessed ST-segment depression indicating ischemia, eight assessed arrhythmia or fibrillation and five considered MI. Epidemiologic studies suggest that exposure to sub-daily levels of PM is associated with MI and ischemic events in the elderly. Epidemiological studies of sub-daily exposures suggest a plausible biological mechanism involving the autonomic nervous system while experimental studies suggest that vasomotor dysfunction may also relate to the occurrence of MI and ischemic events. Future studies should clarify associations between cardiovascular effects of sub-daily PM exposure with PM size fraction and concurrent gaseous pollutant exposures. Experimental studies appear more promising for elucidating the physiological mechanisms, time courses and causes than epidemiological studies which employ central pollution monitors for measuring effects and for assessing their time course. Although further studies are needed to strengthen the evidence, given that exposure to sub-daily high levels of PM (for a few hours) is frequent and given the suggestive evidence that sub-daily PM exposures are associated with the occurrence of cardiovascular effects, we recommend that persons with cardiovascular diseases avoid such situations.


Knockout of an azorhizobial dTDP-L-rhamnose synthase affects lipopolysaccharide and extracellular polysaccharide production and disables symbiosis with Sesbania rostrata.
A nonpolar mutation was made in the oac2 gene of Azorhizobium caulinodans. oac2 is an ortholog of the Salmonella typhimurium rfbD gene that encodes a dTDP-L-rhamnose synthase. The knockout of oac2 changed the lipopolysaccharide (LPS) pattern and affected the extracellular polysaccharide production but had no effect on bacterial hydrophobicity. Upon hot phenol extraction, the wild-type LPS partitioned in the phenol phase. The LPS fraction of ORS571-oac2 partitioned in the water phase and had a reduced rhamnose content and truncated LPS molecules on the basis of faster migration in detergent gel electrophoresis. Strain ORS571-oac2 induced ineffective nodule-like structures on Sesbania rostrata. There was no clear demarcation between central and peripheral tissues, and neither leghemoglobin nor bacteroids were present. Light and electron microscopy revealed that the mutant bacteria were retained in enlarged, thick-walled infection threads. Infection centers emitted a blue autofluorescence under UV light. The data indicate that rhamnose synthesis is important for the production of surface carbohydrates that are required to sustain the compatible interaction between A. caulinodans and S. rostrata.


Evaluation of filesystem provenance visualization tools.
Having effective visualizations of filesystem provenance data is valuable for understanding its complex hierarchical structure. The most common visual representation of provenance data is the node-link diagram. While effective for understanding local activity, the node-link diagram fails to offer a high-level summary of activity and inter-relationships within the data. We present a new tool, InProv, which displays filesystem provenance with an interactive radial-based tree layout. The tool also utilizes a new time-based hierarchical node grouping method for filesystem provenance data we developed to match the user's mental model and make data exploration more intuitive. We compared InProv to a conventional node-link based tool, Orbiter, in a quantitative evaluation with real users of filesystem provenance data including provenance data experts, IT professionals, and computational scientists. We also compared in the evaluation our new node grouping method to a conventional method. The results demonstrate that InProv results in higher accuracy in identifying system activity than Orbiter with large complex data sets. The results also show that our new time-based hierarchical node grouping method improves performance in both tools, and participants found both tools significantly easier to use with the new time-based node grouping method. Subjective measures show that participants found InProv to require less mental activity, less physical activity, less work, and is less stressful to use. Our study also reveals one of the first cases of gender differences in visualization; both genders had comparable performance with InProv, but women had a significantly lower average accuracy (56%) compared to men (70%) with Orbiter.


Doping control using high and ultra-high resolution mass spectrometry based non-targeted metabolomics-a case study of salbutamol and budesonide abuse.
We have detected differences in metabolite levels between doped athletes, clean athletes, and volunteers (non athletes). This outcome is obtained by comparing results of measurements from two analytical platforms: UHPLC-QTOF/MS and FT-ICR/MS. Twenty-seven urine samples tested positive for glucocorticoids or beta-2-agonists and twenty samples coming from volunteers and clean athletes were analyzed with the two different mass spectrometry approaches using both positive and negative electrospray ionization modes. Urine is a highly complex matrix containing thousands of metabolites having different chemical properties and a high dynamic range. We used multivariate analysis techniques to unravel this huge data set. Thus, the several groups we created were studied by Principal Components Analysis (PCA) and Partial Least Square regression (PLS-DA and OPLS) in the search of discriminating m/z values. The selected variables were annotated and placed on pathway by using MassTRIX.


Morphological changes in textile fibres exposed to environmental stresses: atomic force microscopic examination.
The ability of the atomic force microscope (AFM) to investigate the nanoscopic morphological changes in the surfaces of fabrics was examined for the first time. This study focussed on two natural (cotton and wool), and a regenerated cellulose (viscose) textile fibres exposed to various environmental stresses for different lengths of times. Analyses of the AFM images allowed us to measure quantitatively the surface texture parameters of the environmentally stressed fabrics as a function of the exposure time. It was also possible to visualise at the nanoscale the finest details of the surfaces of three weathered fabrics and clearly distinguish between the detrimental effects of the imposed environmental conditions. This study confirmed that the AFM could become a very powerful tool in forensic examination of textile fibres to provide significant fibre evidence due to its capability of distinguishing between different environmental exposures or forced damages to fibres.


Influence of renal biomarker variability on the design and interpretation of occupational or environmental studies.
To quantify and identify sources of within- and between-subject variability of microalbumin, N-acetyl-beta-D-glucosaminidase (NAG) and alanine aminopeptidase (AAP), three biomarkers used for early detection of renal injury, and to assess the consequences of this variability for the design and power of epidemiological studies. Urinary excretion of microalbumin, NAG, AAP and creatinine as well as blood pressure (BP) were measured three times over a 2-year period among 142 healthy male workers. To minimise physiopathological and analytical sources of variation, standardised methods were used for urine collection and assays, and severe exclusion criteria were applied. At the first and third examinations, subjects completed the same questionnaire, providing information about their personal characteristics, tobacco and alcohol consumption, and health. A linear mixed model was used to estimate the within- and between-subject variance components and to analyse the relation between subjects' characteristics and the biomarkers. No change in the mean value of any of the biomarkers was observed over the 2-year period. Intra-class correlation coefficients between repeated measurements were 0.53, 0.57 and 0.56 for microalbumin, NAG and AAP, respectively; the between-subject variance was slightly higher than the within-subject variance. Subjects' age, BP, body mass index and smoking and drinking habits explained 7.2%, 12.5% and 4.2% of the total variance of microalbumin, NAG and AAP, respectively. In this healthy population of male workers, day-to-day differences in biomarker values appeared to be nearly as great as differences between subjects. The within-subject variance of these biomarkers is not high enough to justify systematic repeated measurements in epidemiological surveys. But, in some situations where the number of subjects is limited, measuring the subjects twice may improve study power by reducing the total variance by about 25% for each biomarker. Taking the above covariates into account would slightly improve study power and the accuracy of parameter estimates for NAG, but would add little to the analysis of microalbumin and AAP.