Resident work hour limits and patient safety.
This study evaluates the effect of resident physician work hour limits on surgical patient safety. Resident work hour limits have been enforced in New York State since 1998 and nationwide from 2003. A primary assumption of these limits is that these changes will improve patient safety. We examined effects of this policy in New York on standardized surgical Patient Safety Indicators (PSIs). An interrupted time series analysis was performed using 1995 to 2001 Nationwide Inpatient Sample data. The intervention studied was resident work hour limit enforcement in New York teaching hospitals. PSIs included rates of accidental puncture or laceration (APL), postoperative pulmonary embolus or deep venous thrombosis (PEDVT), foreign body left during procedure (FB), iatrogenic pneumothorax (PTX), and postoperative wound dehiscence (WD). PSI trends were compared pre- versus postintervention in New York teaching hospitals and in 2 control groups: New York nonteaching hospitals and California teaching hospitals. A mean of 2.6 million New York discharges per year were analyzed with cumulative events of 33,756 (APL), 36,970 (PEDVT), 1,447 (FB), 10,727 (PTX), and 2,520 (WD). Increased rates over time (expressed per 1000 discharges each quarter) were observed in both APL (0.15, 95% confidence interval, 0.09-0.20, P<0.05) and PEDVT (0.43, 95% confidence interval, 0.03-0.83, P<0.05) after policy enforcement in New York teaching hospitals. No changes were observed in either control group for these events or New York teaching hospital rates of FB, PTX, or WD. Resident work hour limits in New York teaching hospitals were not associated with improvements in surgical patient safety measures, with worsening trends observed in APL and PEDVT corresponding with enforcement.


Pazopanib efficacy in renal cell carcinoma: evidence for predictive genetic markers in angiogenesis-related and exposure-related genes.
Pazopanib, an oral angiogenesis inhibitor, is approved for the treatment of advanced renal cell carcinoma (RCC). Response to pazopanib monotherapy varies between patients, and no validated biomarkers predictive of treatment outcome have been identified. We tested the hypothesis that this variability is partially dependent on germline genetic variants that may affect pazopanib exposure or angiogenesis pathways. Twenty-seven functional polymorphisms within 13 genes were evaluated in 397 patients with RCC. Genetic association with progression-free survival (PFS) and objective response rate (RR) was analyzed using the Cox proportional hazards model and proportional odds model, respectively. Three polymorphisms in IL8 and HIF1A and five polymorphisms in HIF1A, NR1I2, and VEGFA showed nominally significant association (P ≤ .05) with PFS and RR, respectively. Compared with the wild-type AA genotype (median PFS, 48 weeks), the IL8 2767TT variant genotype showed inferior PFS (27 weeks, P = .009). The HIF1A 1790AG genotype was associated with inferior PFS and reduced RR, compared with the wild-type GG genotype (median PFS, 20 v 44 weeks; P = .03; RR, 30% v 43%, P = .02). Reductions in RR were detected for the NR1I2 -25385TT genotype, compared with the wild-type CC genotype (37% v 50%, P = .03), and for the VEGFA -1498CC genotype compared with the TT genotypes (33% v 51%). Germline variants in angiogenesis- and exposure-related genes may predict treatment response to pazopanib monotherapy in patients with RCC. If validated, these markers may explain why certain patients fail antiangiogenesis therapy and they may support the use of alternative strategies to circumvent this issue.


Enabling a Disaster-Resilient Workforce: Attending to Individual Stress and Collective Trauma.
Superstorm Sandy forced the evacuation and extended shutdown of New York University Langone Medical Center. This investigation explored how nurses were impacted by the disasters and how they can best be supported in their nursing responsibilities. Sequential mixed methods were used to explore the psychosocial issues nurses experienced throughout the course of this natural disaster and its lingering aftermath. In-depth interviews were conducted from April to June 2013 with a subsample of nurses who participated in the evacuation deployment (n = 16). An anonymous, Internet-based cross-sectional survey sent to all registered nurses employed at the hospital at the time of the storm explored storm impact and recovery. Between July and September 2013, 528 surveys were completed. The qualitative data revealed challenges in balancing professional obligations and personal concerns. Accounts described dealing in the immediate recovery period with unexpected job changes and resultant work uncertainty. The storm's lingering aftermath did not signify restoration of their predisaster lifestyle for some, but necessitated coping with this massive storm's long-lasting impact on their personal lives and communal loss. Nurses working under the rapidly changing, uncontrolled, and potentially dangerous circumstances of a weather-related disaster are also experiencing concerns about their families' welfare and worries about personal loss. These multiple issues increase the psychosocial toll on nurses during a disaster response and impending recovery. Awareness of concerns and competing demands nurses experience in a disaster and aftermath can inform education and services to enable nurses to perform their critical functions while minimizing risk to patients and themselves.


Electrospun porous carbon nanofiber@MoS2 core/sheath fiber membranes as highly flexible and binder-free anodes for lithium-ion batteries.
Self-standing membranes of porous carbon nanofiber (PCNF)@MoS2 core/sheath fibers have been facilely obtained through a combination of electrospinning, high-temperature carbonization and the solvothermal reaction. PCNF fibers with porous channels are used as building blocks for the construction of hierarchical PCNF@MoS2 composites where thin MoS2 nanosheets are uniformly distributed on the PCNF surface. Thus, a three-dimensional open structure is formed, which provides a highly conductive pathway for rapid charge-transfer reactions, as well as greatly improving the surface active sites of MoS2 for fast lithiation/delithiation of Li(+) ions. The highly flexible PCNF@MoS2 composite membrane electrode exhibits synergistically improved electrochemical performance with a high specific capacity of 954 mA h g(-1) upon the initial discharge, a high rate capability of 475 mA h g(-1) even at a high current density of 1 A g(-1), and good cycling stability with almost 100% retention after 50 cycles, indicating its potential application as a binder-free anode for high-performance lithium-ion batteries.


REML/BLUP and sequential path analysis in estimating genotypic values and interrelationships among simple maize grain yield-related traits.
Methodologies using restricted maximum likelihood/best linear unbiased prediction (REML/BLUP) in combination with sequential path analysis in maize are still limited in the literature. Therefore, the aims of this study were: i) to use REML/BLUP-based procedures in order to estimate variance components, genetic parameters, and genotypic values of simple maize hybrids, and ii) to fit stepwise regressions considering genotypic values to form a path diagram with multi-order predictors and minimum multicollinearity that explains the relationships of cause and effect among grain yield-related traits. Fifteen commercial simple maize hybrids were evaluated in multi-environment trials in a randomized complete block design with four replications. The environmental variance (78.80%) and genotype-vs-environment variance (20.83%) accounted for more than 99% of the phenotypic variance of grain yield, which difficult the direct selection of breeders for this trait. The sequential path analysis model allowed the selection of traits with high explanatory power and minimum multicollinearity, resulting in models with elevated fit (R2 > 0.9 and ε < 0.3). The number of kernels per ear (NKE) and thousand-kernel weight (TKW) are the traits with the largest direct effects on grain yield (r = 0.66 and 0.73, respectively). The high accuracy of selection (0.86 and 0.89) associated with the high heritability of the average (0.732 and 0.794) for NKE and TKW, respectively, indicated good reliability and prospects of success in the indirect selection of hybrids with high-yield potential through these traits. The negative direct effect of NKE on TKW (r = -0.856), however, must be considered. The joint use of mixed models and sequential path analysis is effective in the evaluation of maize-breeding trials.


Assessing the impact of marine wind farms on birds through movement modelling.
Advances in technology and engineering, along with European Union renewable energy targets, have stimulated a rapid growth of the wind power sector. Wind farms contribute to carbon emission reductions, but there is a need to ensure that these structures do not adversely impact the populations that interact with them, particularly birds. We developed movement models based on observed avoidance responses of common eider Somateria mollissima to wind farms to predict, and identify potential measures to reduce, impacts. Flight trajectory data that were collected post-construction of the Danish Nysted offshore wind farm were used to parameterize competing models of bird movements around turbines. The model most closely fitting the observed data incorporated individual variation in the minimum distance at which birds responded to the turbines. We show how such models can contribute to the spatial planning of wind farms by assessing their extent, turbine spacing and configurations on the probability of birds passing between the turbines. Avian movement models can make new contributions to environmental assessments of wind farm developments, and provide insights into how to reduce impacts that can be identified at the planning stage.


Ribotype differences between clinical and environmental isolates of Burkholderia pseudomallei.
Burkholderia pseudomallei is isolated frequently from the soil in regions where the disease melioidosis occurs. However, recent surveys in Thailand have shown that the frequency of isolation of the organism from soil samples is not directly related to the incidence of melioidosis in an area. To determine whether strain populations of B. pseudomallei prevalent in soil are gentypically related to strains causing clinical disease, rRNA BamHI restriction fragment length polymorphisms (RFLP) of 139 soil environmental isolates and 228 human isolates were compared. Two groups of ribotype patterns were found. Group I comprised 37 different ribotype patterns which were characterised by five to eight hybridisation bands of 2.8- > 23 kb. All of these ribotypes were identified among the clinical isolates, and 18 of them were also found in 59 environmental isolates. Group II was represented by 12 ribotypes found only in environmental strains. These ribotype patterns comprised one to five bands in the size range 9- > 23 kb. All but one of the 73 isolates in this group grew on a minimal medium supplemented with L-arabinose. In contrast, only 3% of the 66 isolates from the environment with group I ribotype patterns could utilise this sugar as their sole energy source. These findings suggest that B. pseudomallei strains that utilise arabinose constitute a population that is genetically distinct from other environmental and clinical strains.


Test-retest variability of high resolution positron emission tomography (PET) imaging of cortical serotonin (5HT2A) receptors in older, healthy adults.
Position emission tomography (PET) imaging using [18F]-setoperone to quantify cortical 5-HT2A receptors has the potential to inform pharmacological treatments for geriatric depression and dementia. Prior reports indicate a significant normal aging effect on serotonin 5HT2A receptor (5HT2AR) binding potential. The purpose of this study was to assess the test-retest variability of [18F]-setoperone PET with a high resolution scanner (HRRT) for measuring 5HT2AR availability in subjects greater than 60 years old. Six healthy subjects (age range = 65-78 years) completed two [18F]-setoperone PET scans on two separate occasions 5-16 weeks apart. The average difference in the binding potential (BPND) as measured on the two occasions in the frontal and temporal cortical regions ranged between 2 and 12%, with the lowest intraclass correlation coefficient in anterior cingulate regions. We conclude that the test-retest variability of [18F]-setoperone PET in elderly subjects is comparable to that of [18F]-setoperone and other 5HT2AR radiotracers in younger subject samples.


ARPC1B binds WASP to control actin polymerization and curtail tonic signaling in B cells.
Immune cells exhibit low-level, constitutive signaling at rest (tonic signaling). Such tonic signals are required for fundamental processes, including the survival of B lymphocytes, but when they are elevated by genetic or environmental causes, they can lead to autoimmunity. Events that control ongoing signal transduction are, therefore, tightly regulated by submembrane cytoskeletal polymers like F-actin. The actin-binding proteins that underpin the process, however, are poorly described. By investigating patients with ARPC1B deficiency, we report that ARPC1B-containing ARP2/3 complexes are stimulated by Wiskott Aldrich Syndrome protein (WASP) to nucleate the branched actin networks that control tonic signaling from the B cell receptor (BCR). Despite an upregulation of ARPC1A, ARPC1B-deficient cells were not capable of WASP-mediated nucleation by ARP2/3, and this caused the loss of WASP-dependent structures, including podosomes in macrophages and lamellipodia in B cells. In the B cell compartment, ARPC1B deficiency also led to weakening of the cortical F-actin cytoskeleton that normally curtails the diffusion of BCRs and ultimately resulted in increased tonic lipid signaling, oscillatory calcium release from the endoplasmic reticulum (ER), and phosphorylated Akt. These events contributed to skewing the threshold for B cell activation in response to microbial-associated molecular patterns (MAMPs). Thus, ARPC1B is critical for ARP2/3 complexes to control steady-state signaling of immune cells.


Hepatitis B and C in Switzerland - healthcare provider initiated testing for chronic hepatitis B and C infection.
Hepatitis B and hepatitis C are contagious liver diseases caused by the hepatitis B virus (HBV) and the hepatitis C virus (HCV), respectively. In particular, chronic infection with HBV or HCV is a major public health problem throughout Europe. The majority of persons chronically infected (65%-75%) are not aware of their infection status until symptoms of advanced liver disease appear. In addition, the peak in the number of patients suffering from advanced stages of the disease, such as cirrhosis and hepatocellular carcinoma, has not yet been reached. In order to reduce the current and future morbidity and mortality associated with chronic HBV or HCV infection, the timely detection of chronically infected persons, with follow-up and case management, is crucial. However, the current screening strategies in Europe and Switzerland have to be considered as inadequate to detect the majority of chronically infected persons. Hence, we emphasise the importance of an alternative approach: the healthcare provider initiated identification of HBV or HCV infection in defined risk groups. This entails determining whether a person is not only at risk of being chronically infected, but also at risk of becoming infected with HBV or HCV and, if necessary, testing for HBV or HCV infection.


Alternate pathways for NADH oxidation in Thermus thermophilus using type 2 NADH dehydrogenases.
Type 2 NADH dehydrogenase (NDH-2) is a single-subunit membrane-associated flavoenzyme that is part of the respiratory chain of many prokaryotes. The enzyme catalyzes the electron transfer from NADH to quinone but is not directly coupled to the generation of a proton motive force. The purpose of the current work is to compare two different NDH-2s that are encoded in strains of Thermus thermophilus. The aerobic T. thermophilus HB27 strain expresses one NDH-2 that has been previously isolated and characterized. In this work it is shown that a gene, which is misannotated as an NADH oxidase, encodes this enzyme. Unlike HB27, strain NAR1 of T. thermophilus is capable of partial denitrification, and in addition its genome contains the nrcN gene that encodes a second putative NDH-2. Of particular interest is the fact that nrcN is part of an operon (nrcDEFN) that is proposed to encode a protein complex specifically required for nitrate reduction. In this work, the nrcN gene has the activity expected of a NDH-2, and functions independently of other components of the putative Nrc complex. The biochemical properties of the two NDH-2 enzymes are compared. Efforts to demonstrate that NrcN is part of a multiprotein complex were not successful. However, the NrcE protein was expressed in Escherichia coli and shown to be a membrane-bound protein containing heme B.


THE INACTIVATION OF PENICILLINS F, G, K, AND X BY HUMAN AND RABBIT SERUM.
1. Penicillins F, G, K, and X were all inactivated by human and rabbit serum, but two qualitatively distinct mechanisms were apparently involved. 2. One was a slow inactivation of all four penicillins by a relatively thermostable serum component which was not demonstrably affected by heating for 60 minutes at 56 degrees C. (a) In both human and rabbit serum this general inactivation of penicillin behaved like a pseudo first order reaction, with a velocity constant of 0.05-0.07 for penicillin X, and 0.09-0.11 for penicillins F and G. (b) The percentage of penicillins F, G, and X inactivated per hour was independent of their concentration over the range 0.4 to 50 micrograms per cc., averaging 9.5, 10, and 6.5 per cent, respectively, in human serum, and 9,8.5, and 5 per cent in rabbit serum. (c) The rate of inactivation varied linearly with the concentration of the serum factor. (d) Penicillin X was consistently and significantly less susceptible to inactivation than any of the other penicillins. Although minor differences were observed between F and G, these were not consistent, and are of questionable significance. 3. Superimposed on this slow inactivation of penicillins F, G, K, and X by a thermostable serum component was a much faster inactivation observed only with penicillin K. (a) In both rabbit and human serum, the serum factor responsible for this inactivation was highly thermolabile, and was almost completely destroyed within 5 minutes at 56 degrees C., leaving only a thermostable component, not affected by further heating. (b) The inactivation of K by this thermolabile component was not a first order reaction, but varied with the concentration of both serum and penicillin. At high concentrations of K, the rate of inactivation due to the thermolabile factor was negligible, and penicillin K was destroyed no more rapidly than F, G, or X. The rate of inactivation increased as the concentration of penicillin was reduced. At penicillin K concentrations of 50, 10, 2, and 0.4 micrograms per cc., the hourly destruction in rabbit serum averaged 10, 16, 21, and 54 per cent. The corresponding figures in human serum were 10, 11, 14, and 54 per cent. The reservations entailed by the large serum error at the lower concentrations of penicillin are discussed in the text. 4. The temperature coefficient for the inactivation of penicillin K by fresh human or rabbit serum was 2.5 for each 10 degrees C. No significant inactivation was observed in 24 hours at 20 degrees C.; and this was true also of penicillins F, G, and X. 5. Heparinized plasma was just as active as serum, washed red blood cells had no effect, and the activity of whole blood was referable to its plasma content. 6. The nature of the serum factors responsible for these two types of penicillin inactivation are under present study. 7. The urinary excretion of penicillin is so rapid that the slow destruction of penicillins F, G, and X in the circulating blood as here described is of secondary significance therapeutically. It nevertheless must contribute to their rapid disappearance from the blood; and the fact that X is inactivated more slowly than either F or G could be reflected in higher and more sustained blood levels than are afforded by the latter two species. There are some reports that such is the case (15-17), and the following paper provides further evidence for the superiority of penicillin X in this respect over the other species so far studied. The serum inactivation of penicillin K, at a rate which increases as its concentration falls, should be reflected in significantly lower and more evanescent blood levels than are observed with penicillins F, G, or X. As will be discussed in the following paper, this has been found to be the case, and provides a simple explanation for its paradoxically low therapeutic activity in vivo (8-11).


Implementing bedside rounds to improve patient-centred outcomes: a systematic review.
Bedside rounds (BR) have been proposed as an ideal method to promote patient-centred hospital care, but there is substantial variation in their implementation and effects. Our objectives were to describe the implementation of BR in hospital settings and determine their effect on patient-centred outcomes. Data sources included Ovid MEDLINE, Ovid Embase, Scopus and Ovid Cochrane Central Registry of Clinical Trials from database inception through 28 July 2017. We included experimental studies comparing BR to another form of rounds in a hospital-based setting (ie, medical/surgical unit, intensive care unit (ICU)) and reporting a quantitative patient-reported or objectively measured clinical outcome. We used random effects models to calculate pooled Cohen's d effect size estimates for the patient knowledge and patient experience outcome domains. Twenty-nine studies met inclusion criteria, including 20 from adult care (17 non-ICU, 3 ICU), and nine from paediatrics (5 non-ICU, 4 ICU), the majority of which (n=23) were conducted in the USA. Thirteen studies implemented BR with cointerventions as part of a 'bundle'. Studies most commonly reported outcomes in the domains of patient experience (n=24) and patient knowledge (n=10). We found a small, statistically significant improvement in patient experience with BR (summary Cohen's d=0.09, 95% CI 0.04 to 0.14, p<0.001, I2=56%), but no significant association between BR and patient knowledge (Cohen's d=0.21, 95% CI -0.004 to -0.43, p=0.054, I2=92%). Risk of bias was moderate to high, with methodological limitations most often relating to selective reporting, low adherence rates and missing data. BR have been implemented in a variety of hospital settings, often 'bundled' with cointerventions. However, BR have demonstrated limited effect on patient-centred outcomes.


Exposure to wastewater effluent affects fish behaviour and tissue-specific uptake of pharmaceuticals.
Pharmaceutical active compounds (PhACs) are increasingly being reported in wastewater effluents and surface waters around the world. The presence of these products, designed to modulate human physiology and behaviour, has created concern over whether PhACs similarly affect aquatic organisms. Though laboratory studies are beginning to address the effects of individual PhACs on fish behaviour, few studies have assessed the effects of exposure to complex, realistic wastewater effluents on fish behaviour. In this study, we exposed a wild, invasive fish species-the round goby (Neogobius melanostomus)-to treated wastewater effluent (0%, 50% or 100% effluent dilutions) for 28days. We then determined the impact of exposure on fish aggression, an important behaviour for territory acquisition and defense. We found that exposure to 100% wastewater effluent reduced the number of aggressive acts that round goby performed. We complimented our behavioural assay with measures of pharmaceutical uptake in fish tissues. We detected 11 of 93 pharmaceutical compounds that we tested for in round goby tissues, and we found that concentration was greatest in the brain followed by plasma, then gonads, then liver, and muscle. Fish exposed to 50% and 100% effluent had higher tissue concentrations of pharmaceuticals and concentrated a greater number of pharmaceutical compounds compare to control fish exposed to no (0%) effluent. Exposed fish also showed increased ethoxyresorufin-O-deethylase (EROD) activity in liver tissue, suggesting that fish were exposed to planar halogenated/polycyclic aromatic hydrocarbons (PHHs/PAHs) in the wastewater effluent. Our findings suggest that fish in effluent-dominated systems may have altered behaviours and greater tissue concentration of PhACs. Moreover, our results underscore the importance of characterizing exposure to multiple pollutants, and support using behaviour as a sensitive tool for assessing animal responses to complex contaminant mixtures, like wastewater effluent.


The reason for the low Ca2+-sensitivity of thin filaments associated with the Glu41Lys mutation in the TPM2 gene is "freezing" of tropomyosin near the outer domain of actin and inhibition of actin monomer switching off during the ATPase cycle.
The E41K mutation in TPM2 gene encoding muscle regulatory protein beta-tropomyosin is associated with nemaline myopathy and cap disease. The mutation results in a reduced Ca2+-sensitivity of the thin filaments and in muscle weakness. To elucidate the structural basis of the reduced Ca2+-sensitivity of the thin filaments, we studied multistep changes in spatial arrangement of tropomyosin (Tpm), actin and myosin heads during the ATPase cycle in reconstituted fibers, using the polarized fluorescence microscopy. The E41K mutation inhibits troponin's ability to shift Tpm to the closed position at high Ca2+, thus restraining the transition of the thin filaments from the "off" to the "on" state. The mutation also inhibits the ability of S1 to shift Tpm to the open position, decreases the amount of the myosin heads bound strongly to actin at high Ca2+, but increases the number of such heads at low Ca2+. These changes may contribute to the low Ca2+-sensitivity and muscle weakness. As the mutation has no effect on troponin's ability to switch actin monomers on at high Ca2+ and inhibits their switching off at low Ca2+, the use of reagents that increase the Ca2+-sensitivity of the troponin complex may not be appropriate to restore muscle function in patients with this mutation.


The neural correlates of subjective value during intertemporal choice.
Neuroimaging studies of decision-making have generally related neural activity to objective measures (such as reward magnitude, probability or delay), despite choice preferences being subjective. However, economic theories posit that decision-makers behave as though different options have different subjective values. Here we use functional magnetic resonance imaging to show that neural activity in several brain regions--particularly the ventral striatum, medial prefrontal cortex and posterior cingulate cortex--tracks the revealed subjective value of delayed monetary rewards. This similarity provides unambiguous evidence that the subjective value of potential rewards is explicitly represented in the human brain.


Guided mode resonance flat-top bandpass filter for terahertz telecom applications.
In this work, we design and experimentally demonstrate a novel terahertz (THz) filter exhibiting a flattened spectral response in the atmospheric transmission window around the central frequency of 300 GHz. The innovative concept behind this filter is the coupling of Fabry-Perot and guided mode resonances. The latter arise from a two-dimensional patch array patterned on an aluminum layer deposited on a low loss cyclo-olefin polymer. The filter experimental performance shows high transmittance in the flat-top band, with less than 3 dB losses, and high out-of-band rejection, as theoretically expected. This kind of component provides a cost-effective, functional solution for narrowband filtering in emerging THz devices and systems with possible applications in wireless telecommunications.


Retinal architecture predicts pupillary reflex metrics in MS.
To study the relation of retinal nerve fiber layer thinning to clinical and physiologic measures of visual function in patients with MS or neuromyelitis optica and unilateral optic neuropathy. We studied a cohort of control subjects (n = 64) and patients (n = 24) with evidence of unilateral thinning of their average retinal nerve fiber layer as measured by optical coherence tomography in order to characterize the relationship between ganglion cell axonal degeneration and its impact upon vision and pupillary light reflex metrics using infrared pupillometry. When compared to the normal fellow eye, and with respect to normal subjects' eyes, we confirmed significant abnormalities in retinal nerve fiber layer thickness, total macular volume, low-contrast letter acuity, and pupillary reflex metrics in the eye with the thinner retinal nerve fiber layer. For each -5% change in pupil diameter, there was a corresponding 7.1 Amicrom reduction in the average retinal nerve fiber layer thickness. There was a significant difference between the pupillary metric of percent change in diameter and a decrease in low-contrast letter acuity (P < 0.001). Each -5% change in pupil diameter was associated with a substantial 3.4 line loss of low-contrast letter acuity (P < 0.001). Each -5% change in pupil diameter was associated with a 0.2 mm(2) decrease in total macular volume (P < 0.001). These findings further corroborate the hypothesis that the retina can be utilized as a model to advance our understanding of the mechanisms of axonal and neurodegeneration, and the corresponding impact of these processes upon the pathophysiology of MS and related disorders.


Interactive network analytical tool for instantaneous bespoke interrogation of food safety notifications.
The globalization of food supply necessitates continued advances in regulatory control measures to ensure that citizens enjoy safe and adequate nutrition. The aim of this study was to extend previous reports on network analysis relating to food notifications by including an optional filter by type of notification and in cases of contamination, by type of contaminant in the notified foodstuff. A filter function has been applied to enable processing of selected notifications by contaminant or type of notification to i) capture complexity, ii) analyze trends, and iii) identify patterns of reporting activities between countries. The program rapidly assesses nations' roles as transgressor and/or detector for each category of contaminant and for the key class of border rejection. In the open access demonstration version, the majority of notifications in the Rapid Alert System for Food and Feed were categorized by contaminant type as mycotoxin (50.4%), heavy metals (10.9%) or bacteria (20.3%). Examples are given demonstrating how network analytical approaches complement, and in some cases supersede, descriptive statistics such as frequency counts, which may give limited or potentially misleading information. One key feature is that network analysis takes the relationship between transgressor and detector countries, along with number of reports and impact simultaneously into consideration. Furhermore, the indices that compliment the network maps and reflect each country's transgressor and detector activities allow comparisons to be made between (transgressing vs. detecting) as well as within (e.g. transgressing) activities. This further development of the network analysis approach to food safety contributes to a better understanding of the complexity of the effort ensuring food is safe for consumption in the European Union. The unique patterns of the interplay between detectors and transgressors, instantly revealed by our approach, could supplement the intelligence gathered by regulatory authorities and inform risk based sampling protocols.


Aetiology of lateral progression of arthritis following Oxford medial unicompartmental knee replacement: a case-control study.
The aim of this case-control study is to assess for predictive factors that may determine development of lateral compartment progression after Oxford medial unicompartmental knee replacement. Twenty-eight patients who were revised as a result of lateral osteoarthritis progression were matched to 52 alive and unrevised patients. Body mass index, intra-operative findings, postoperative leg alignment, meniscal bearing size and histological findings have been analysed. Radiological analysis was carried out on the immediate postoperative radiographs by two blinded observers to assess the severity of arthritis in the lateral compartment. The measurements of the components positions were converted into binary figures as to whether they were inside or outside the recommended limits for analysis. Conditional logistic regression was used to identify important predictors of progression, taking into account the case-control grouping. The results shows that the condition of the lateral compartment is a significant predictor for developing subsequent lateral compartment arthrosis (OR 2.627, p = 0.019). The study showed no relationship between progression of arthritis and component position (OR [0.5-1.18], p [0.21-1]). Nor have it demonstrated that BMI (OR 1.06, p = 0.61), postoperative leg alignment (OR 1.26, p = 0.636), meniscal bearing size (1.32, p = 0.307) or presence of chondrocalcinosis (OR 0.35, p = 0.36) have any association with lateral osteoarthritis progression. This study showed the importance of excluding radiographic evidence of lateral compartment osteoarthritis on the preoperative radiograph prior to medial unicompartmental knee replacement. We have not been able to show any relationship between progression of arthritis and component position. Level of proof Case-control study, level III.


Optical Imaging Reveals Liver Metabolic Perturbations in Mblac1 Knockout Mice.
Metabolic changes have been extensively documented in brain tissue undergoing neurodegeneration, including Parkinson's disease and Alzheimer's disease (AD). Mutations in the C. elegans swip-10 gene result in dopamine (DA) dependent motor dysfunction accompanied by DA neuron degeneration. Recently, the putative human ortholog of swip-10 (MBLAC1) was implicated as a risk factor in AD, that like PD, has been associated with mitochondrial dysfunction. Interestingly, the AD risk associated with MBLAC1 arises in subjects with cardiovascular morbidity, suggesting the possibility of a broader functional insult arising from reduced MBLAC1 protein expression, and one possibly linked to metabolic alterations. Our current studies, utilizing Mblac1 knockout (KO) mice, seeks to determine whether mitochondrial respiration is affected in peripheral tissues of these animals in this model. To initiate these studies, we quantified the levels of mitochondrial coenzymes, NADH, FAD, and their redox ratio (NADH/FAD, RR) in the livers of wild type (WT) mice and their homozygous KO littermates, using 3D optical cryo-imaging. We found that Mblac1 KO mice exhibited a greater oxidized redox state compared to WT mice. When compared to the WT group, the redox ratio of KO mice was decreased by 46.32%, driven predominantly by significantly lower NADH levels (more oxidized state). We speculate that, as seen with C. elegans swip-10 mutants, that loss of MBLAC1 protein results in deficits in tricarboxylic acid cycle (TCA) production of NADH and FAD TCA that leads to diminished cellular ATP production and oxidative stress. Such observations are consistent with changes that in the central nervous system (CNS) could support neurodegeneration and in the periphery account for comorbidities.


A biorepository for ophthalmic surgical specimens.
Biorepositories are collections of surgically obtained human tissues for current and future investigations of disease mechanisms, therapeutics, and diagnostics. In ophthalmology, a critical challenge is how to interface the operating room with the laboratory. To attain standards required for basic research, clinical and research teams must cooperate to collect, annotate, and store specimens that yield consistent results required for advanced molecular techniques. We developed an efficient platform for obtaining vitreous and other eye tissues from the operating room and transferring them to the lab. The platform includes a mobile lab cart for on-site tissue processing, a multi-user, web-based database for point-of-care phenotypic capture, and an integrated data tracking system for long-term storage. These biorepository instruments have proven essential for our studies in ophthalmic disease proteomics. This system can be implemented in other operating rooms and laboratories for a variety of biological tissues.


Sildenafil Potentiates the Therapeutic Efficacy of Docetaxel in Advanced Prostate Cancer by Stimulating NO-cGMP Signaling.
Docetaxel plays an indispensable role in the management of advanced prostate cancer. However, more than half of patients do not respond to docetaxel, and those good responders frequently experience significant cumulative toxicity, which limits its dose duration and intensity. Hence, a second agent that could increase the initial efficacy of docetaxel and maintain tolerability at biologically effective doses may improve outcomes for patients. We determined phosphodiesterase 5 (PDE5) expression levels in human and genetically engineered mouse (GEM) prostate tissues and tumor-derived cell lines. Furthermore, we investigated the therapeutic benefits and underlying mechanism of PDE5 inhibitor sildenafil in combination with docetaxel using in vitro, Pten conditional knockout (cKO), derived tumoroid and xenograft prostate cancer models. PDE5 expression was higher in both human and mouse prostate tumors and cancer cell lines compared with normal tissues/cells. In GEM prostate-derived cell lines, PDE5 expression increased from normal prostate (wild-type) epithelial cells to androgen-dependent and castrated prostate-derived cell lines. The addition of physiologically achievable concentrations of sildenafil enhanced docetaxel-induced prostate cancer cell growth inhibition and apoptosis in vitro, reduced murine 3D tumoroid growth, and in vivo tumorigenicity as compared with docetaxel alone. Furthermore, sildenafil enhanced docetaxel-induced NO and cGMP levels thereby augmenting antitumor activity. Our results demonstrate that sildenafil's addition could sensitize docetaxel chemotherapy in prostate cancer cells at much lesser concentration than needed for inducing cell death. Thus, the combinatorial treatment of sildenafil and docetaxel may improve anticancer efficacy and reduce chemotherapy-induced side-effects among patients with advanced prostate cancer.


[Home Daily Hemodialysis with NxStage System One: monocentric italian casistic results].
NxStage System One is a new dialytic technology based on easy setup, simplicity of use and reduced dimensions, which is increasingly in use worldwide for home hemodialysis treatments. The system utilizes a low amount of dialysate, usually 15-30 liters according to anthropometric patients' values. The dialysate is supplied at very low flux, generally about 1/3 of blood flow, in order to obtain an elevated saturation of dialysate for solutes. In these conditions the clearance of urea will be almost equal to dialysate flow rate. In order to achieve an obptimal weekly clearance evaluated by Std Kt/V the dialysis sessions are repeated six times a week. In this way a good control of blood voleme can be reached. In this paper we report our experience of treatment with NxStage System One in 12 patients from May 2011 to Dicember 2016.


A tale of two epidemics: gay men's mental health and the biomedicalisation of HIV prevention and care in Toronto.
There is mounting urgency regarding the mental health of gay, bisexual and other men who have sex with men (GBM). We examined how GBM are understanding the relationship between HIV and their mental health given the increasing biomedicalisation of HIV prevention and care. Our Grounded Theory analysis derived from qualitative interviews with 24 GBM living in Toronto, Canada, including both HIV-negative and HIV-positive men. Participants understood biomedical advances, such as undetectable viral load and pre-exposure prophylaxis (PrEP), as providing some relief from HIV-related distress. However, they offered ambivalent perspectives on the biomedicalisation of HIV. Some considered non-HIV-specific stressors (e.g. unemployment, racial discrimination) more significant than HIV-related concerns. These men expressed HIV-related distress as being under control due to biomedical advances or as always negligible when compared to non-HIV-specific stressors. Others emphasised the ongoing mental health implications of HIV (e.g. enduring risk and stigma). We describe a tension between optimistic responses to biomedicine's ability to ease the psychosocial burdens associated with HIV and the inability for biomedicine to address the social and economic determinants driving the dual epidemics of HIV and mental distress amongst GBM. We argue for more socio-material analysis over further sexual behavioural analysis of GBM mental health disparities.


Diagnosis and treatment of hypothermia.
Although hypothermia is most common in patients who are exposed to a cold environment, it can develop secondary to toxin exposure, metabolic derangements, infections, and dysfunction of the central nervous and endocrine systems. The clinical presentation of hypothermia includes a spectrum of symptoms and is grouped into the following three categories: mild, moderate, and severe. Management depends on the degree of hypothermia present. Treatment modalities range from noninvasive, passive external warming techniques (e.g., removal of cold, wet clothing; movement to a warm environment) to active external rewarming (e.g., insulation with warm blankets) to active core rewarming (e.g., warmed intravenous fluid infusions, heated humidified oxygen, body cavity lavage, and extracorporeal blood warming). Mild to moderate hypothermia is treated easily with supportive care in most clinical settings and has good patient outcomes. The treatment of severe hypothermia is more complex, and outcomes depend heavily on clinical resources. Prevention and recognition of atypical presentations are essential to reducing the rates of morbidity and mortality associated with this condition.


Should serial monitoring of procalcitonin be done routinely in critically ill patients of ICU: A systematic review and meta-analysis.
Sepsis is a life-threatening condition with dysregulated host response to infection. It is a major determinant of mortality in the intensive care unit (ICU). Procalcitonin (PCT) is widely investigated for prognosis in patients with sepsis. Most of the studies have cited that elevated PCT concentrations and PCT non-clearance are associated with poor outcomes in patients with sepsis and some studies have cited as having no additional benefit. Most of the studies have evaluated single PCT measurement and correlated with prognosis and outcome in septic patients. Limited literature is there about serial PCT levels and its impact on the outcome of patients with sepsis. We searched literature through PubMed, Embase, Web of Knowledge, and the Cochrane Library from 2007 to 2017 and present a systematic review and meta-analysis of studies evaluating the utility of serial measurement of PCT for prognosis in critically ill patients. Articles that assessed PCT non-clearance as a marker of mortality data were included. The primary objective of this meta-analysis was to pool the results of all the available studies on serial PCT non-clearance as a mortality predictor and formulate overall area under receiver operating curve (AUROC). To find out the overall proportion of mortality in PCT non-clearance was our secondary objective. To detect the mortality using PCT non-clearance, ROC curve analysis was done. Area under curve (AUC) of the studies was varying between 0.52 and 0.86. Overall AUC was observed 0.711 (95% confidence interval (CI): 0.662-0.760) under fixed effect model and 0.708 (95% CI: 0.648-0.769) under random effect model. There was moderate variation among the studies, i.e., I2 50.80% (95% CI: 0.00-80.42%). The overall proportion of mortality was 37.54% with much heterogeneity (I2 88.24%) among the studies. PCT non-clearance is a fair predictor of mortality. Further studies are needed to define optimal cut off point for PCT non-clearance in ICU patients with sepsis.


Adsorption deformation of microporous composites.
We study here the behavior of flexible adsorbent materials, or soft porous crystals, when used in practical applications as nanostructured composites such as core-shell particles or mixed matrix membranes. Based on simple models and the well-established laws of elasticity, we demonstrate how the presence of a binder results in an attenuation of the adsorption-induced stress and deformation. In the case where the adsorbent undergoes adsorption-induced structural transitions, such as the gate opening phenomenon occurring in some metal-organic frameworks, we show that the presence of the binder will result in shifts of the adsorption-induced transition pressures.


Adaptive clinical trial designs with blinded selection of binary composite endpoints and sample size reassessment.
For randomized clinical trials where a single, primary, binary endpoint would require unfeasibly large sample sizes, composite endpoints (CEs) are widely chosen as the primary endpoint. Despite being commonly used, CEs entail challenges in designing and interpreting results. Given that the components may be of different relevance and have different effect sizes, the choice of components must be made carefully. Especially, sample size calculations for composite binary endpoints depend not only on the anticipated effect sizes and event probabilities of the composite components but also on the correlation between them. However, information on the correlation between endpoints is usually not reported in the literature which can be an obstacle for designing future sound trials. We consider two-arm randomized controlled trials with a primary composite binary endpoint and an endpoint that consists only of the clinically more important component of the CE. We propose a trial design that allows an adaptive modification of the primary endpoint based on blinded information obtained at an interim analysis. Especially, we consider a decision rule to select between a CE and its most relevant component as primary endpoint. The decision rule chooses the endpoint with the lower estimated required sample size. Additionally, the sample size is reassessed using the estimated event probabilities and correlation, and the expected effect sizes of the composite components. We investigate the statistical power and significance level under the proposed design through simulations. We show that the adaptive design is equally or more powerful than designs without adaptive modification on the primary endpoint. Besides, the targeted power is achieved even if the correlation is misspecified at the planning stage while maintaining the type 1 error. All the computations are implemented in R and illustrated by means of a peritoneal dialysis trial.


Plain tobacco packaging: progress, challenges, learning and opportunities.
The aim of this paper is to overview progress made with respect to the adoption of plain (or standardised) packaging, key challenges faced, evaluative evidence and opportunities for extending this policy. It has been a decade since Australia became the first country to require tobacco products to be sold in plain packaging; after slow initial uptake, 16 countries have now fully implemented this policy. Since 2020, plain packaging laws have become more comprehensive in some countries, expanding coverage beyond traditional tobacco products to include heated tobacco, tobacco accessories (rolling papers) and other nicotine-containing products (e-cigarettes). Laws have also become more innovative: some now ban non-biodegradable filters, include provision for a periodic change of the pack colour or require both plain packaging and health-promoting pack inserts. The tobacco industry has and will continue to use multi-jurisdictional strategies to oppose this policy. Evaluations suggest that plain packaging has improved health outcomes and has not burdened retailers, although research is limited to early policy adopters and important gaps in the literature remain. While the power of packaging as a sales tool has diminished in markets with plain packaging, tobacco companies have exploited loopholes to continue to promote their products and have increasingly focused on filter innovations. Opportunities exist for governments to strengthen plain packaging laws.


Spectral sharpening of color sensors: diagonal color constancy and beyond.
It has now been 20 years since the seminal work by Finlayson et al. on the use of spectral sharpening of sensors to achieve diagonal color constancy. Spectral sharpening is still used today by numerous researchers for different goals unrelated to the original goal of diagonal color constancy e.g., multispectral processing, shadow removal, location of unique hues. This paper reviews the idea of spectral sharpening through the lens of what is known today in color constancy, describes the different methods used for obtaining a set of sharpening sensors and presents an overview of the many different uses that have been found for spectral sharpening over the years.


Elevated seawater PCO₂ differentially affects branchial acid-base transporters over the course of development in the cephalopod Sepia officinalis.
The specific transporters involved in maintenance of blood pH homeostasis in cephalopod molluscs have not been identified to date. Using in situ hybridization and immunohistochemical methods, we demonstrate that Na(+)/K(+)-ATPase (soNKA), a V-type H(+)-ATPase (soV-HA), and Na(+)/HCO(3)(-) cotransporter (soNBC) are colocalized in NKA-rich cells in the gills of Sepia officinalis. mRNA expression patterns of these transporters and selected metabolic genes were examined in response to moderately elevated seawater Pco(2) (0.16 and 0.35 kPa) over a time course of 6 wk in different ontogenetic stages. The applied CO(2) concentrations are relevant for ocean acidification scenarios projected for the coming decades. We determined strong expression changes in late-stage embryos and hatchlings, with one to three log2-fold reductions in soNKA, soNBCe, socCAII, and COX. In contrast, no hypercapnia-induced changes in mRNA expression were observed in juveniles during both short- and long-term exposure. However, a transiently increased ion regulatory demand was evident during the initial acclimation reaction to elevated seawater Pco(2). Gill Na(+)/K(+)-ATPase activity and protein concentration were increased by ~15% during short (2-11 days) but not long-term (42-days) exposure. Our findings support the hypothesis that the energy budget of adult cephalopods is not significantly compromised during long-term exposure to moderate environmental hypercapnia. However, the downregulation of ion regulatory and metabolic genes in late-stage embryos, taken together with a significant reduction in somatic growth, indicates that cephalopod early life stages are challenged by elevated seawater Pco(2).


Downstream Microvascular Thrombosis in Cortical Venules Is an Early Response to Proximal Cerebral Arterial Occlusion.
Previous experimental studies have shown that downstream microvascular thromboinflammation is involved in brain damage from acute ischemic stroke. Using intravital microscopy, we investigated and characterized the sequence of downstream microvascular thromboinflammation in an ischemia/reperfusion acute ischemic stroke model. Rats underwent transient monofilament middle cerebral artery (MCA) occlusion. Cerebral microcirculation in the MCA territory was exposed through a craniotomy and analyzed using real-time intravital imaging coupled with laser Doppler interferometry. Leukocytes, platelets, fibrinogen, and blood-brain barrier permeability were analyzed by intravenous injection of fluorescent antibodies and bovine serum albumin. MCA occlusion induced a sudden and profound drop in downstream microvascular blood flow associated with leukocyte margination in the venous compartment. Leukocyte margination fostered fibrinogen deposition and thrombosis in postcapillary venules. Either in venules or arterioles, blood flow was not fully restored after MCA recanalization. Furthermore, venular thrombi persisted despite MCA recanalization, and leukocyte extravasation continued to develop in venules in association with blood-brain barrier disruption. Finally, microhemorrhages were occasionally observed, colocalizing with thrombosed venules characterized by marked leukocyte margination. We showed that microvascular thrombosis in transient monofilament MCA occlusion and blood-brain barrier disruption are initiated immediately after occlusion and are propagated through the venous compartment in close association with marginating leukocytes. MCA occlusion-induced downstream microvascular thromboinflammation response was responsible for incomplete reperfusion after MCA recanalization and delayed microhemorrhages.


Physical activity and screen-based media use: cross-sectional associations with health-related quality of life and the role of body satisfaction in a representative sample of German adolescents.
Purpose: Although it is widely accepted that physical activity (PA) positively, and screen-based media use (SBM) negatively, affects well-being, there is a lack of studies relating PA and SBM to health-related quality of life (HRQoL) in adolescents. We examined these associations in German adolescents for different HRQoL subdomains and explored the role of body satisfaction as a possible mediator. Methods: The 11-17-year-old subsample of the German Health Interview and Examination Survey (2003-2006) was analysed (N = 6813; 51.3% male). Cross-sectional associations of self-reported PA frequency and amount of daily SBM with HRQoL subscale scores (according to KINDL-R) were examined by hierarchical linear regression models, adjusting for the clustering of the sample and for a variety of possible confounders. The size and significance of indirect effects via body (dis)satisfaction (BDS) were examined by mediation analyses. Results: Higher PA frequency was significantly associated with higher HRQoL on nearly all subscales and dose-response-relationships were observable. Variations were greatest in terms of social well-being in boys (effect size d = 0.59) and physical well-being in girls (d = 0.43). Higher SBM was related to lower HRQoL on all subscales in girls and on some subscales in boys, with the largest effects for school functioning in both genders (d = 0.31 and 0.37, respectively). The mediated effects for PA and SBM were significant in both genders, but the sizes and the proportions of total effects mediated by body satisfaction were rather small. Conclusions: Higher PA frequency was associated with higher self-reported HRQoL, and higher SBM was associated with lower self-reported HRQoL in both genders, even after adjusting for relevant covariates. The results support the assumption of independent health impacts of both behaviours, although no causal relationship can be confirmed with these cross-sectional data. Mechanisms other than body satisfaction must largely account for the effects of PA and SBM on well-being.


Influence of FCGR3A genotype on the therapeutic response to rituximab in rheumatoid arthritis: an observational cohort study.
To determine whether a polymorphism in the Fcγ receptor type IIIA (FCGR3A-F158V), influencing immunoglobulin G binding affinity, relates to the therapeutic efficacy of rituximab in rheumatoid arthritis (RA) patients. Observational cohort study. Three university hospital rheumatology units in Sweden. Patients with established RA (n=177; 145 females and 32 males) who started rituximab (Mabthera) as part of routine care. Response to rituximab therapy in relation to FCGR3A genotype, including stratification for sex. The frequency of responders differed significantly across FCGR3A genotypes (p=0.017 in a 3×2 contingency table). Heterozygous patients showed the highest response rate at 83%, as compared with patients carrying 158FF (68%) or 158VV (56%) (p=0.028 and 0.016, respectively). Among 158VV patients, response rates differed between male and female patients (p=0.036), but not among 158FF or 158VF patients (p=0.72 and 0.46, respectively). Therapeutic efficacy of rituximab in RA patients is influenced by FCGR3A genotype, with the highest response rates found among heterozygous patients. This may suggest that different rituximab mechanisms of action in RA are optimally balanced in FCGR3A-158VF patients. Similar to the previously described associations with RA susceptibility and disease course, the impact of 158VV on rituximab response may be influenced by sex.


Medical physics practice in the next decade.
Impressive advances in computers and materials science have fueled a broad-based confluence of basic science breakthroughs. These advances are making us reformulate our learning, teaching and credentialing methodologies and research and development frontiers. We are now in the age of molecular medicine. In the entire field of health care, a paradigm shift from population-based solutions to individual specific care is taking place. These trends are reshaping the practice of medical physics. In this short presentation, examples are given to illustrate developments in image-guided intensity-modulated and adaptive helical tomotherapy, enhanced application of intensity modulation radiotherapy (IMRT) using adaptive radiotherapy and conformal avoidance. These advances include improved normal tissue sparing and permit dose reconstruction and verification, thereby allowing significant biologically effective dose escalation and reduced radiation toxicity. The intrinsic capability of helical TomoTherapy for megavoltage CT imaging for IMRT image-guidance is also discussed. Finally developments in motion management are described.


Online learning control using adaptive critic designs with sparse kernel machines.
In the past decade, adaptive critic designs (ACDs), including heuristic dynamic programming (HDP), dual heuristic programming (DHP), and their action-dependent ones, have been widely studied to realize online learning control of dynamical systems. However, because neural networks with manually designed features are commonly used to deal with continuous state and action spaces, the generalization capability and learning efficiency of previous ACDs still need to be improved. In this paper, a novel framework of ACDs with sparse kernel machines is presented by integrating kernel methods into the critic of ACDs. To improve the generalization capability as well as the computational efficiency of kernel machines, a sparsification method based on the approximately linear dependence analysis is used. Using the sparse kernel machines, two kernel-based ACD algorithms, that is, kernel HDP (KHDP) and kernel DHP (KDHP), are proposed and their performance is analyzed both theoretically and empirically. Because of the representation learning and generalization capability of sparse kernel machines, KHDP and KDHP can obtain much better performance than previous HDP and DHP with manually designed neural networks. Simulation and experimental results of two nonlinear control problems, that is, a continuous-action inverted pendulum problem and a ball and plate control problem, demonstrate the effectiveness of the proposed kernel ACD methods.


Association between Allergies and Hypercholesterolemia: A Systematic Review.
There is controversy in the literature regarding the potential relationship between atopic predisposition (AP) and serum cholesterol levels. To this purpose, we reviewed human studies that investigated this possible link. Following PRISMA guidelines, a literature search of PubMed and Science Direct for peer-reviewed journal articles in English from January 2003, with updates through to August 2016, was conducted. Relevant publications were reviewed that included pediatric and adult populations. Information on the study design, sample, intervention, comparators, outcome, time frame, and risk of bias were abstracted for each article. Of 601 reviewed reports, 18 were included in this systematic review. Fifteen studies assessed the relationship between AP and serum cholesterol levels. Due to the lack both of observational and cross-sectional studies from the literature search at this time (only 8 studies also analyzed confounding factors) there is a high possibility of confounding variables (familial and genetic predisposition, age, gender, BMI, comorbidity, and medication status) that could not be ruled out. Existing studies are heterogeneous, making it difficult to draw broad conclusions. Future studies and more detailed analyses, considering confounding variables and including a larger and homogeneous population, are needed to strengthen the argument for a link between lipid metabolism and atopy.


Synthesis, molecular modeling studies, and pharmacological activity of selective A(1) receptor antagonists.
We present a combined computational study aimed at identifying the three-dimensional structural properties required for different classes of compounds to show antagonistic activity toward the A(1) adenosine receptor (AR). Particularly, an approach combining pharmacophore mapping, molecular alignment, and pseudoreceptor generation was applied to derive a hypothesis of the interaction pathway between a set of A(1) AR antagonists taken from the literature and a model of the putative A(1) receptor. The pharmacophore model consists of seven features and represents an improvement of the N(6)-C8 model, generally reported as the most probable pharmacophore model for A(1) AR agonists and antagonists. It was used to build up a pseudoreceptor model able to rationalize the relationships between structural properties and biological data of, and external to, the training set. In fact, to further assess its statistical significance and predictive power, the pseudoreceptor was employed to predict the free energy of binding associated with compounds constituting a test set. While part of these molecules was also taken from the literature, the remaining compounds were designed and synthesized by our research group. All of the new compounds were tested for their affinity toward A(1), A(2a), and A(3) AR, showing interesting antagonistic activity and A(1) selectivity.


Incidence and 30-day case fatality for acute myocardial infarction in England in 2010: national-linked database study.
There are limited national population-based epidemiological data on acute myocardial infarction (AMI) in England, making the current burden of disease, and clinical prognosis, difficult to quantify. The aim of this study was to provide national estimates of incidence and 30-day case fatality rate (CFR) for first and recurrent AMI in England. Population-based study using person-linked routine hospital and mortality data on 79 896 individuals of any age, who were admitted to hospital for AMI or who died suddenly from AMI in 2010. Of 82 252 AMI events in 2010, 83% were first. Age-standardized incidence of first AMI per 100 000 population was 130 (95% CI 129-131) in men and 55.9 (95% CI 55.3-56.6) in women. Age-standardized 30-day overall CFRs including sudden AMI deaths for men and women, respectively, were 32.4% (95% CI 32.0-32.9) and 30.3% (95% CI 29.8-30.9) for first AMI and 29.7% (95% CI 28.7-30.7) and 26.7% (95% CI 25.5-27.9) for recurrent AMI. Age-standardized hospitalized 30-day CFR was 12.0% (95% CI 11.6-12.3) for men and 12.3% (95% CI 11.9-12.7) for women. While the majority of AMIs are not fatal, of those that are, two-thirds occur as sudden AMI deaths. About one in six of all AMIs are recurrent events. These findings reinforce the importance of primary and secondary prevention in reducing AMI morbidity and mortality.


Multiscale mechanics of the lateral pressure effect on enhancing the load transfer between polymer coated CNTs.
While individual carbon nanotubes (CNTs) are known as one of the strongest fibers ever known, even the strongest fabricated macroscale CNT yarns and fibers are still significantly weaker than individual nanotubes. The loss in mechanical properties is mainly because the deformation mechanism of CNT fibers is highly governed by the weak shear strength corresponding to sliding of nanotubes on each other. Adding polymer coating to the bundles, and twisting the CNT yarns to enhance the intertube interactions are both efficient methods to improve the mechanical properties of macroscale yarns. Here, we perform molecular dynamics (MD) simulations to unravel the unknown deformation mechanism in the intertube polymer chains and also local deformations of the CNTs at the atomistic scale. Our results show that the lateral pressure can have both beneficial and adverse effects on shear strength of polymer coated CNTs, depending on the local deformations at the atomistic scale. In this paper we also introduce a bottom-up bridging strategy between a full atomistic model and a coarse-grained (CG) model. Our trained CG model is capable of incorporating the atomistic scale local deformations of each CNT to the larger scale collect behavior of bundles, which enables the model to accurately predict the effect of lateral pressure on larger CNT bundles and yarns. The developed multiscale CG model is implemented to study the effect of lateral pressure on the shear strength of straight polymer coated CNT yarns, and also the effect of twisting on the pull-out force of bundles in spun CNT yarns.


Body composition by photon absorptiometry.
Whole-body dual photon measurements of body composition were made in 9 controls, 15 athletes and 5 patients with eating disorders. Measurements of lean body mass, mineral mass and fat mass were accurate. Lean body mass and fat mass were measured with reliabilities of about 0.8 kg while for total body bone mineral mass, the reliability was about 60 g. Women had a smaller lean body mass and a greater fat mass than men. Women with eating disorders had the same body composition as males. Measurements of body composition by dual photon absorptiometry are safe and reliable.


Copy number and SNP arrays in clinical diagnostics.
The ability of chromosome microarray analysis (CMA) to detect submicroscopic genetic abnormalities has revolutionized the clinical diagnostic approach to individuals with intellectual disability, neurobehavioral phenotypes, and congenital malformations. The recognition of the underlying copy number variant (CNV) in respective individuals may allow not only for better counseling and anticipatory guidance but also for more specific therapeutic interventions in some cases. The use of CMA technology in prenatal diagnosis is emerging and promises higher sensitivity for several highly penetrant, clinically severe microdeletion and microduplication syndromes. Genetic counseling complements the diagnostic testing with CMA, given the presence of CNVs of uncertain clinical significance, incomplete penetrance, and variable expressivity in some cases. While oligonucleotide arrays with high-density exonic coverage remain the gold standard for the detection of CNVs, single-nucleotide polymorphism (SNP) arrays allow for detection of consanguinity and most cases of uniparental disomy and provide a higher sensitivity to detect low-level mosaic aneuploidies.


Raising awareness of unspecified living kidney donation: an ELPAT view.
Living donor kidney transplantation (LDKT) is the preferred treatment for patients with end-stage renal disease and unspecified living kidney donation is morally justified. Despite the excellent outcomes of LDKT, unspecified kidney donation (UKD) is limited to a minority of European countries due to legal constraints and moral objections. Consequently, there are significant variations in practice and approach between countries and the contribution of UKD is undervalued. Where UKD is accepted as routine, an increasing number of patients in the kidney exchange programme are successfully transplanted when a 'chain' of transplants is triggered by a single unspecified donor. By expanding the shared living donor pool, the benefit of LDKT is extended to patients who do not have their own living donor because a recipient on the national transplant list always completes the chain. Is there a moral imperative to increase the scope of UKD and how could this be achieved? An examination of the literature and individual country practices was performed to identify the limitations on UKD in Europe and recommend strategies to increase transplant opportunities. Primary limitations to UKD, key players and their roles and responsibilities were identified. Raising awareness to encourage the public to volunteer to donate is appropriate and desirable to increase UKD. Recommendations are made to provide a framework for increasing awareness and engagement in UKD. The public, healthcare professionals, policy makers and society and religious leaders have a role to play in creating an environment for change.


TADs are 3D structural units of higher-order chromosome organization in Drosophila.
Deciphering the rules of genome folding in the cell nucleus is essential to understand its functions. Recent chromosome conformation capture (Hi-C) studies have revealed that the genome is partitioned into topologically associating domains (TADs), which demarcate functional epigenetic domains defined by combinations of specific chromatin marks. However, whether TADs are true physical units in each cell nucleus or whether they reflect statistical frequencies of measured interactions within cell populations is unclear. Using a combination of Hi-C, three-dimensional (3D) fluorescent in situ hybridization, super-resolution microscopy, and polymer modeling, we provide an integrative view of chromatin folding in Drosophila. We observed that repressed TADs form a succession of discrete nanocompartments, interspersed by less condensed active regions. Single-cell analysis revealed a consistent TAD-based physical compartmentalization of the chromatin fiber, with some degree of heterogeneity in intra-TAD conformations and in cis and trans inter-TAD contact events. These results indicate that TADs are fundamental 3D genome units that engage in dynamic higher-order inter-TAD connections. This domain-based architecture is likely to play a major role in regulatory transactions during DNA-dependent processes.


Cerebrospinal Fluid Total Protein Reference Intervals Derived from 20 Years of Patient Data.
Reference intervals are vital for interpretation of laboratory results. Many existing reference intervals for cerebrospinal fluid total protein (CSF-TP) are derived from old literature because of the invasive nature of sampling. The objective of this study was to determine reference intervals for CSF-TP using available patient data. Twenty years of hospital database information was mined for previously reported CSF-TP results. Associated demographic, laboratory, and clinical diagnosis (International Classification of Diseases 9/10 codes) details were extracted. CSF-TP results included 3 different analytical platforms: the Siemens Vista 1500, Beckman Lx20, and Roche Hitachi 917. From an initial data set of 19591 samples, the following exclusion criteria were applied: incomplete data, white blood cells (WBCs) >5 × 106/L, red blood cells (RBCs) >50 × 106/L, and glucose <2.5 mmol/L. Patient charts were reviewed in detail to exclude 60 different conditions for which increases in CSF-TP would be expected. A total of 6068 samples were included; 63% of the samples were from females. Continuous reference intervals were determined using quantile regression. Age- and sex-partitioned intervals were established using the quantile regression equation and splitting age-groups into 5-year bins. CSF-TP showed a marked age dependence, and males had significantly higher CSF-TP than females across all ages. CSF-TP results from the 3 different instruments and manufacturers showed small (approximately 0.04 g/L), but statistically significant, differences. CSF-TP showed weak, but again statistically significant, correlation with WBC and RBC but was independent of serum total protein and creatinine. The age dependence of CSF-TP supports that age-partitioned reference intervals will be more accurate than a single cutoff, particularly in patients with advancing age.


Critiquing imaginaries of 'the public' in UK dialogue around animal research: Insights from the Mass Observation Project.
With an established history of controversy in the UK, the use of animals in science continues to generate significant socio-ethical discussion. Here, the figure of 'the public' plays a key role. However, dominant imaginaries of 'the public' have significant methodological and ethical problems. Examining these, this paper critiques three ways in which 'the public' is currently constructed in relation to animal research; namely as un- or mis-informed; homogenous; and holding fixed and extractable views. In considering an alternative to such imaginaries, we turn to the Mass Observation Project (MOP), a national life-writing project in the UK. In its efforts to generate writing which is typically reflexive, its recognition of the plurality and performativity of identity, and embrace of knowledge as situated yet fluid, the MOP offers lessons for approaching views towards animal research and the role of publics in dialogue around the practice. In considering the MOP, we underline the need to acknowledge the role of method in shaping both what publics are able to articulate, and which positions they are able to articulate from. Finally, we stress the need for future dialogue around animal research to involve publics beyond one-way measurements of 'public opinion' and instead work to foster a reciprocity which enables them to act as collaborators in and coproducers of animal research policy, practice, and dialogue.


Cost and cost-effectiveness analysis of a community mobilisation intervention to reduce intimate partner violence in Kampala, Uganda.
Intimate partner violence (IPV) poses a major public health concern. To date there are few rigorous economic evaluations of interventions aimed at preventing IPV in low-income settings. This study provides a cost and cost effectiveness analysis of SASA!, a community mobilisation intervention to change social norms and prevent IPV. An economic evaluation alongside a cluster randomised controlled trial. Both financial and economic costs were collected retrospectively from the provider's perspective to generate total and unit cost estimates over four years of intervention programming. Univariate sensitivity analysis is conducted to estimate the impact of uncertainty in cost and outcome measures on results. The total cost of developing the SASA! Activist Kit is estimated as US$138,598. Total intervention costs over four years are estimated as US$553,252. The annual cost of supporting 351 activists to conduct SASA! activities was approximately US$389 per activist and the average cost per person reached in intervention communities was US$21 over the full course of the intervention, or US$5 annually. The primary trial outcome was past year experience of physical IPV with an estimated 1201 cases averted (90% CI: 97-2307 cases averted). The estimated cost per case of past year IPV averted was US$460. This study provides the first economic evaluation of a community mobilisation intervention aimed at preventing IPV. SASA! unit costs compare favourably with gender transformative interventions and support services for survivors of IPV. ClinicalTrials.gov # NCT00790959.


Comparing image search behaviour in the ARRS GoldMiner search engine and a clinical PACS/RIS.
Information search has changed the way we manage knowledge and the ubiquity of information access has made search a frequent activity, whether via Internet search engines or increasingly via mobile devices. Medical information search is in this respect no different and much research has been devoted to analyzing the way in which physicians aim to access information. Medical image search is a much smaller domain but has gained much attention as it has different characteristics than search for text documents. While web search log files have been analysed many times to better understand user behaviour, the log files of hospital internal systems for search in a PACS/RIS (Picture Archival and Communication System, Radiology Information System) have rarely been analysed. Such a comparison between a hospital PACS/RIS search and a web system for searching images of the biomedical literature is the goal of this paper. Objectives are to identify similarities and differences in search behaviour of the two systems, which could then be used to optimize existing systems and build new search engines. Log files of the ARRS GoldMiner medical image search engine (freely accessible on the Internet) containing 222,005 queries, and log files of Stanford's internal PACS/RIS search called radTF containing 18,068 queries were analysed. Each query was preprocessed and all query terms were mapped to the RadLex (Radiology Lexicon) terminology, a comprehensive lexicon of radiology terms created and maintained by the Radiological Society of North America, so the semantic content in the queries and the links between terms could be analysed, and synonyms for the same concept could be detected. RadLex was mainly created for the use in radiology reports, to aid structured reporting and the preparation of educational material (Lanlotz, 2006) [1]. In standard medical vocabularies such as MeSH (Medical Subject Headings) and UMLS (Unified Medical Language System) specific terms of radiology are often underrepresented, therefore RadLex was considered to be the best option for this task. The results show a surprising similarity between the usage behaviour in the two systems, but several subtle differences can also be noted. The average number of terms per query is 2.21 for GoldMiner and 2.07 for radTF, the used axes of RadLex (anatomy, pathology, findings, …) have almost the same distribution with clinical findings being the most frequent and the anatomical entity the second; also, combinations of RadLex axes are extremely similar between the two systems. Differences include a longer length of the sessions in radTF than in GoldMiner (3.4 and 1.9 queries per session on average). Several frequent search terms overlap but some strong differences exist in the details. In radTF the term "normal" is frequent, whereas in GoldMiner it is not. This makes intuitive sense, as in the literature normal cases are rarely described whereas in clinical work the comparison with normal cases is often a first step. The general similarity in many points is likely due to the fact that users of the two systems are influenced by their daily behaviour in using standard web search engines and follow this behaviour in their professional search. This means that many results and insights gained from standard web search can likely be transferred to more specialized search systems. Still, specialized log files can be used to find out more on reformulations and detailed strategies of users to find the right content.


Evaluation of the Total Design Method in a survey of Japanese dentists.
This study assessed the application of the Total Design Method (TDM) in a mail survey of Japanese dentists. The TDM was chosen because survey response rates in Japan are unacceptably low and the TDM had previously been used in a general population survey. Four hundred and seventy eight dentist members of the Okayama Medical and Dental Practitioner's Association were surveyed. The nine-page, 27-item questionnaire covered dentist job satisfaction, physical practice, and dentist and patient characteristics. Respondents to the first mailing or the one-week follow-up postcard were defined as early responders; others who responded were late responders. Responder bias was assessed by examining age, gender and training. The overall response rate was 46.7% (223/478). The response rates by follow-up mailing were, 18% after the first mailing, 35.4% after the follow-up postcard, 42.3% after the second mailing, and 46.7% after the third mailing. Respondents did not differ from non-respondents in age or gender, nor were there differences between early and late responders. The application of TDM in this survey of Japanese dentists produced lower rates of response than expected from previous Japanese and US studies.


Pay for performance programs in Australia: a need for guiding principles.
Pay-for-performance (P4P) programs which reward clinical providers with incentive payments based on one or more measures of quality of care are now common in the United States and the United Kingdom and it is likely they will attract increasing interest in Australia. However, empirical evidence demonstrating effectiveness of such programs is limited and many existing programs have not had rigorous outcome evaluation. To maximise success, future P4P programs should incorporate the lessons and insights obtained from previous experience. Based on a review of published trials, program evaluations and position statements, the following principles that may guide future program design and implementation were synthesised: 1) formulate a rationale and a business case for P4P; 2) use established evidence-based performance measures; 3) use rigorous and verifiable methods of data collection and analysis; 4) define performance targets using absolute and relative thresholds; 5) use rewards that are sufficient, equitable and transparent; 6) address appropriateness of provider responses and avoid perverse incentives; 7) implement communication and feedback strategies; 8) use existing organisational structures to implement P4P programs; 9) attribute credit for performance to participants in ways that foster population-based perspectives; and 10) invest in outcomes and health service research. Recommendations flowing from these principles relevant to Australian settings are provided.


mVps34 deletion in podocytes causes glomerulosclerosis by disrupting intracellular vesicle trafficking.
Recent studies have suggested that autophagy is a key mechanism in maintaining the integrity of podocytes. The mammalian homologue of yeast vacuolar protein sorting defective 34 (mVps34) has been implicated in the regulation of autophagy, but its role in podocytes is unknown. We generated a line of podocyte-specific mVps34-knockout (mVps34(pdKO)) mice, which were born at Mendelian ratios. These mice appeared grossly normal at 2 weeks of age but exhibited growth retardation and were significantly smaller than control mice by 6 weeks of age, with no difference in ratios of kidney to body weight. mVps34(pdKO) mice developed significant proteinuria by 3 weeks of age, developed severe kidney lesions by 5-6 weeks of age, and died before 9 weeks of age. There was striking podocyte vacuolization and proteinaceous casts, with marked glomerulosclerosis and interstitial fibrosis by 6 weeks of age. Electron microscopy revealed numerous enlarged vacuoles and increased autophagosomes in the podocytes, with complete foot process effacement and irregular and thickened glomerular basement membranes. Immunoblotting of isolated glomerular lysates revealed markedly elevated markers specific for lysosomes (LAMP1 and LAMP2) and autophagosomes (LC3-II/I). Immunofluorescence staining confirmed that the enlarged vacuoles originated from lysosomes. In conclusion, these results demonstrate an indispensable role for mVps34 in the trafficking of intracellular vesicles to protect the normal cellular metabolism, structure, and function of podocytes.


Benchmarking of protein carbonylation analysis in Caenorhabditis elegans: specific considerations and general advice.
Oxidative stress has been extensively studied due to its correlation with cellular disorders and aging. In proteins, one biomarker of oxidative stress is the presence of carbonyl groups, such as aldehyde and ketone, in specific amino acid side chains such as lysine, proline, arginine and threonine, so-called protein carbonylation (PC). PC study is now a growing field in general and medical science since PC accumulation is associated with various pathologies and disorders. At present, enzyme-linked immunosorbent assays (ELISA) seem to be the most robust method of quantifying the presence of carbonyl groups in proteins, despite having some recognised caveats. In parallel, gel-based approaches present cross-comparison difficulties, along with other technical problems. As generic PC analyses still suffer from poor homogeneity, leading to cross-data analysis difficulties and poor results overlap, the need for harmonisation in the field of carbonyl detection is now widely accepted. This study aims to highlight some of the technical challenges in proteomic gel-based multiplexing experiments when dealing with PC in difficult samples like those from Caenorhabditis elegans, from protein extraction to carbonyl detection. We demonstrate that some critical technical parameters, such as labelling time, probe concentration, and total and carbonylated protein recovery rates, should be re-addressed in a sample-specific way. We also defined a procedure to cost-effectively adapt CyDye™-hydrazide-based protocols to specific samples, especially when the experimental interest is focused on studying differences between stimulating conditions with a maximised signal-to-noise ratio. Moreover, we have improved an already-existing powerful solubilisation buffer, making it potentially useful for hard-to-solubilise protein pellets. Lastly, the depicted methodology exemplifies a simple way of normalising carbonyl-related signal to total protein in SDS-PAGE multiplexing experiments. Within that scope, we also proposed a simple way to quantify carbonyl groups by on-gel spotting diluted dye-containing labelling buffer. Proof of the robustness of the procedure was also highlighted by the high linear correlation between the level of carbonyls and the ultraviolet exposure duration of whole worms (R2=0.993). Altogether, these results will help to standardise existing protocols in the growing field of proteomic carbonylation studies.


Heterogeneity of prognostic studies of 24-hour blood pressure variability: systematic review and meta-analysis.
In addition to mean blood pressure, blood pressure variability is hypothesized to have important prognostic value in evaluating cardiovascular risk. We aimed to assess the prognostic value of blood pressure variability within 24 hours. Using MEDLINE, EMBASE and Cochrane Library to April 2013, we conducted a systematic review of prospective studies of adults, with at least one year follow-up and any day, night or 24-hour blood pressure variability measure as a predictor of one or more of the following outcomes: all-cause mortality, cardiovascular mortality, all cardiovascular events, stroke and coronary heart disease. We examined how blood pressure variability is defined and how its prognostic use is reported. We analysed relative risks adjusted for covariates including the appropriate mean blood pressure and considered the potential for meta-analysis. Our analysis of methods included 24 studies and analysis of predictions included 16 studies. There were 36 different measures of blood pressure variability and 13 definitions of night- and day-time periods. Median follow-up was 5.5 years (interquartile range 4.2-7.0). Comparing measures of dispersion, coefficient of variation was less well researched than standard deviation. Night dipping based on percentage change was the most researched measure and the only measure for which data could be meaningfully pooled. Night dipping or lower night-time blood pressure was associated with lower risk of cardiovascular events. The interpretation and use in clinical practice of 24-hour blood pressure variability, as an important prognostic indicator of cardiovascular events, is hampered by insufficient evidence and divergent methodologies. We recommend greater standardisation of methods.


Discovery of new potential antimalarial compounds using virtual screening of ZINC database.
Falcipain-3 (FP-3) is a cysteine protease of the malaria parasite Plasmodium falciparum which is a promising and attractive target enzyme for antiparasitic chemotherapy. In this study, a support vector machine (SVM) model based on fingerprint-based descriptors was developed on a dataset of 239 FP-3 inhibitors to identify the most active antimalarial compounds among the active compounds provided from similarity search. The satisfactory classification performance achieved by the SVM model shows its ability to use it as a further filter to distinguish the most active compounds. The accuracy in prediction for the training, test and external validation sets were 97.39%, 94.74% and 90.6%, respectively. Furthermore, the performance of the model was examined by plotting the receiver operating characteristic (ROC) curve, and the area under the ROC curve was 0.96 for the modeling set. The ability of a virtual screening scheme to scaffold hopping or lead hopping is known as a key ability of an effective method for virtual screening. Three diverse reference FP-3 structures were chosen as active antimalarial compounds to search the lead-like database of ZINC and retrieve the most similar compounds. Compounds having Tanimoto similarity coefficient above 0.8 were extracted for further analysis by classification model. The SVM model rendered five most active compounds and they were also analyzed by ADME/Tox and diversity measures. Maximum property-based distance between extracted compounds was found to be 0.70, which shows the importance of applying multiple diverse reference compounds in the similarity searching.


Horizontal propagation of excitation in rat visual cortical slices revealed by optical imaging.
Optical imaging with high spatial and temporal resolution of neural activity in rat cortical slices was used to investigate the dynamics of signal transmission through neural connections in the visual cortex. When inhibition due to gamma-aminobutyric acid was slightly suppressed, horizontal propagation of excitation in both the supra- and infragranular layers became prominent. This propagation was not affected by vertical cuts in either the supra- or infragranular layer, which suggests that excitation is at least partially conveyed horizontally by reciprocal vertical connections between neurons in these layers.


Outcomes of influenza A(H1N1)pdm09 virus infection: results from two international cohort studies.
Data from prospectively planned cohort studies on risk of major clinical outcomes and prognostic factors for patients with influenza A(H1N1)pdm09 virus are limited. In 2009, in order to assess outcomes and evaluate risk factors for progression of illness, two cohort studies were initiated: FLU 002 in outpatients and FLU 003 in hospitalized patients. Between October 2009 and December 2012, adults with influenza-like illness (ILI) were enrolled; outpatients were followed for 14 days and inpatients for 60 days. Disease progression was defined as hospitalization and/or death for outpatients, and hospitalization for >28 days, transfer to intensive care unit (ICU) if enrolled from general ward, and/or death for inpatients. Infection was confirmed by RT-PCR. 590 FLU 002 and 392 FLU 003 patients with influenza A (H1N1)pdm09 were enrolled from 81 sites in 17 countries at 2 days (IQR 1-3) and 6 days (IQR 4-10) following ILI onset, respectively. Disease progression was experienced by 29 (1 death) outpatients (5.1%; 95% CI: 3.4-7.2%) and 80 inpatients [death (32), hospitalization >28 days (43) or ICU transfer (20)] (21.6%; 95% CI: 17.5-26.2%). Disease progression (death) for hospitalized patients was 53.1% (26.6%) and 12.8% (3.8%), respectively, for those enrolled in the ICU and general ward. In pooled analyses for both studies, predictors of disease progression were age, longer duration of symptoms at enrollment and immunosuppression. Patients hospitalized during the pandemic period had a poorer prognosis than in subsequent seasons. Patients with influenza A(H1N1)pdm09, particularly when requiring hospital admission, are at high risk for disease progression, especially if they are older, immunodeficient, or admitted late in infection. These data reinforce the need for international trials of novel treatment strategies for influenza infection and serve as a reminder of the need to monitor the severity of seasonal and pandemic influenza epidemics globally. ClinicalTrials.gov Identifiers: FLU 002--NCT01056354, FLU 003--NCT01056185.


A systematic review and meta-analysis of randomized controlled trials investigating the effects of supplementation with Nigella sativa (black seed) on blood pressure.
Several reports suggest a beneficial effect of Nigella sativa on cardiometabolic risk factors, including blood pressure (BP). However, the magnitude of the BP-lowering effect of N. sativa remains controversial. We aimed to calculate this effect size of N. sativa through a systematic review and meta-analysis of randomized controlled trials (RCTs). PubMed, Cochrane Collaboration Library, and SCOPUS were used as data sources of RCTs published before 30 August 2015 (in English only) comparing N. sativa treatment with placebo or standard treatment. We used random effect models to estimate the difference in BP reductions, I index and χ statistics to measure and test the interstudy heterogeneity. Random effect metaregression models were applied to explore the associations between BP reduction and duration of treatment, dosage of N. sativa, and type of black seed as potential confounders. Publication bias was evaluated using funnel plot and Egger's regression asymmetry test. Total 11 RCTs, including 860 hypertensive or normotensive individuals were eligible, of which 10 compared N. sativa versus placebo and one versus standard treatment. SBP and DBP means decreased from 132.85 to 125.19 mmHg and from 82.63 to 77.74 mmHg after mean treatment duration of 8.3 weeks in N. sativa groups, respectively. The difference in reductions as compared with control/standard groups were -3.26 (-5.10, -1.42; I = 59%) mmHg in SBP and -2.80 (-4.28, -1.32; I = 60%) mmHg in DBP. Pharmaceutical preparations of N. sativa in powder and oil demonstrated a different lowering effect (in favour of the former) on both SBP and DBP. No association was observed between SBP lowering and time on treatment, N. sativa dosage or type of N. sativa. The results of Egger's test did not indicate any publication bias. Our meta-analysis suggests that short-term treatment with N. sativa powder can significantly reduce SBP and DBP levels. More evidence is needed, however, to strengthen the available evidence and to further explore the long-term BP-lowering effect of N. sativa.


Genetic aspects of intracellular motility: cortical localization and insertion of trichocysts in Paramecium tetraurelia.
Wild-type and selected mutants of Paramecium tetraurelia were subjected to detailed analysis of the trichocyst phenotype. The characteristics of morphology, saltatory motility, and cortical insertion of trichocysts were found to be genetically distinguishable. In mutants with defective trichocyst saltatory motility, other intracellular motility systems (i.e. mitochondrial saltatory motility, and cyclosis) appeared to be unaffected. Saltatory motility appears to be an essential intermediate step in the functional development of the trichocyst, since it serves to transport the trichocyst from its site of assembly, deep in the cytoplasm, to the cortex, where it is inserted and becomes discharge-competent. If trichocyst saltatory motility is lost, as in the mutants ndA and tam8, then trichocysts are not transported to the cortex and are therefore not inserted. However, the successful transport of a trichocyst to the cortex does not guarantee the proper insertion of that trichocyst, as in the case of the mutant am. Apparently there are independent steps involved specifically with trichocyst insertion. The gross morphology of the trichocyst appears to be independent of its saltatory motility, and to a degree, independent of cortical insertion.


Text messaging as adjunct to community-based weight management program.
Increasing obesity rates are still a public health priority. The primary aim of this study was to evaluate the effect of tailored text messages on body weight change in overweight and obese adults in a community-based weight management program. A secondary aim was to detect behavioral changes in the same population. The study design was quasi-experimental with pretest and posttest analysis, conducted over 12 weeks. A total of 28 participants were included in the analysis. Body weight, eating behaviors, exercise and nutrition self-efficacy, attitude toward mobile technology, social support, and physical activity were assessed at baseline and at 12 weeks. Text messages were sent biweekly to the intervention but not to the control group. At 12 weeks, the intervention group had lost significant weight as compared with the control group. There was a trend toward an improvement in eating behaviors, exercise, and nutrition self-efficacy in the intervention group, with no significant difference between groups. A total of 79% of participants stated that text messages helped in adopting healthy behaviors. Tailored text messages appear to enhance weight loss in a weight management program at a community setting. Large-scale and long-term intervention studies are needed to confirm these findings.