Albuminuria Increases the Risks for Both Alzheimer Disease and Vascular Dementia in Community-Dwelling Japanese Elderly: The Hisayama Study.
Epidemiologic evidence has emerged to reveal an association of albuminuria and low estimated glomerular filtration rate (eGFR) with dementia, but the findings are inconsistent. In addition, there are limited studies addressing the association between albuminuria and Alzheimer disease (AD). A total of 1562 community-dwelling Japanese subjects aged ≥60 years without dementia were followed up for 10 years. The outcomes were incidence of all-cause dementia and its subtypes, namely, AD and vascular dementia (VaD). The hazard ratios for the outcomes were estimated according to urine albumin-creatinine ratio (UACR) and eGFR levels using a Cox proportional hazards model. During the follow-up, 358 subjects developed all-cause dementia (238 AD and 93 VaD). Higher UACR level was significantly associated with greater multivariable-adjusted risks of all-cause dementia (hazard ratios [95% confidence intervals]: 1.00 [reference], 1.12 [0.78-1.60], 1.65 [1.18-2.30], and 1.56 [1.11-2.19] for UACR of ≤6.9, 7.0-12.7, 12.8-29.9, and ≥30.0 mg/g, respectively), AD (1.00 [reference], 1.20 [0.77-1.86], 1.75 [1.16-2.64], and 1.58 [1.03-2.41], respectively), and VaD (1.00 [reference], 1.03 [0.46-2.29], 1.94 [0.96-3.95], and 2.19 [1.09-4.38], respectively). On the other hand, lower eGFR level was marginally associated with greater risk of VaD, but not AD. Subjects with UACR ≥12.8 mg/g and eGFR of <60 mL/min per 1.73 m2 had 3.3-fold greater risk of VaD than those with UACR <12.8 mg/g and eGFR of ≥60 mL/min per 1.73 m2. Albuminuria is a significant risk factor for the development of both AD and VaD in community-dwelling Japanese elderly. Moreover, albuminuria and low eGFR are mutually associated with a greater risk of VaD.


Reducing the health effect of natural hazards in Bangladesh.
Bangladesh, with a population of 151 million people, is a country that is particularly prone to natural disasters: 26% of the population are affected by cyclones and 70% live in flood-prone regions. Mortality and morbidity from these events have fallen substantially in the past 50 years, partly because of improvements in disaster management. Thousands of cyclone shelters have been built and government and civil society have mobilised strategies to provide early warning and respond quickly. Increasingly, flood and cyclone interventions have leveraged community resilience, and general activities for poverty reduction have integrated disaster management. Furthermore, overall population health has improved greatly on the basis of successful public health activities, which has helped to mitigate the effect of natural disasters. Challenges to the maintenance and reduction of the effect of cyclones and floods include rapid urbanisation and the growing effect of global warming. Although the effects of earthquakes are unknown, some efforts to prepare for this type of event are underway.


Medial prefrontal pathways for the contextual regulation of extinguished fear in humans.
The maintenance of anxiety disorders is thought to depend, in part, on deficits in extinction memory, possibly due to reduced contextual control of extinction that leads to fear renewal. Animal studies suggest that the neural circuitry responsible fear renewal includes the hippocampus, amygdala, and dorsomedial (dmPFC) and ventromedial (vmPFC) prefrontal cortex. However, the neural mechanisms of context-dependent fear renewal in humans remain poorly understood. We used functional magnetic resonance imaging (fMRI), combined with psychophysiology and immersive virtual reality, to elucidate how the hippocampus, amygdala, and dmPFC and vmPFC interact to drive the context-dependent renewal of extinguished fear. Healthy human participants encountered dynamic fear-relevant conditioned stimuli (CSs) while navigating through 3-D virtual reality environments in the MRI scanner. Conditioning and extinction were performed in two different virtual contexts. Twenty-four hours later, participants were exposed to the CSs without reinforcement while navigating through both contexts in the MRI scanner. Participants showed enhanced skin conductance responses (SCRs) to the previously-reinforced CS+ in the acquisition context on Day 2, consistent with fear renewal, and sustained responses in the dmPFC. In contrast, participants showed low SCRs to the CSs in the extinction context on Day 2, consistent with extinction recall, and enhanced vmPFC activation to the non-reinforced CS-. Structural equation modeling revealed that the dmPFC fully mediated the effect of the hippocampus on right amygdala activity during fear renewal, whereas the vmPFC partially mediated the effect of the hippocampus on right amygdala activity during extinction recall. These results indicate dissociable contextual influences of the hippocampus on prefrontal pathways, which, in turn, determine the level of reactivation of fear associations.


Pulmonary Artery Systolic Pressure Measured Intraoperatively by Right Heart Catheterization Is a Predictor of Kidney Transplant Recipient Survival.
BACKGROUND The effect of pulmonary artery systolic pressure (PASP) measured by Swan-Ganz right heart catheter (SG-RHC) on kidney transplant recipient survival has not been previously studied. The objective of this study was to assess the relationships between PASP measured via SG-RHC, done intraoperatively at the time of initiating anesthesia at the beginning of kidney transplant surgery, and patient survival. Multiple comorbidities, time on dialysis before the transplantation, and graft function were also analyzed in our study. MATERIAL AND METHODS This was a retrospective cohort study using data from all consecutive patients undergoing kidney transplant between January 1, 2005 and December 31, 2009 at Tampa General Hospital. Kidney transplant recipients were divided into 2 groups: Group 1 with PASP <35 mmHg and group 2 with PASP ≥35 mmHg. Patients and graft survival data, time on dialysis before transplant, and comorbidities were compared between the 2 groups. RESULTS Only 363 patients were found to have a documented PASP measurement at the time of anesthesia induction for the transplant surgery, and were included in the specific analysis of our study. Patients with PASP ≥35 mmHg showed a significant decrease in survival in comparison to patients having PASP values <35 mmHg (HR 1.88; 95% CI 1.012 to 3.47, P=0.04). There was a significant positive correlation between time on dialysis and PASP (rho 0.20; 95% CI 0.09 to 0.30, p<0.001), as well as a significant difference in median time on dialysis between PASP <35 vs. PASP ≥35 (22 vs. 29 months, p=0.004). There were no significant differences in graft failure between the 2 PASP groups (HR 0.34; 95% CI 0.12 to 1.01, P=0.05). CONCLUSIONS Patients with PASP ≥35 mmHg, measured intraoperatively by SG-RHC, showed significantly shorter survival in comparison to patients having PASP values <35 mmHg. This result suggests the need for a randomized controlled trial to address the importance of post-transplant pulmonary hypertension management in patient survival.


Designing high energy density flow batteries by tuning active-material thermodynamics.
The cost of electricity generated by wind and solar installations has become competitive with that generated by burning fossil fuels. While this paves the way for a carbon-neutral electrical grid, short- and long-term intermittency necessitates energy storage. Flow batteries are a promising technology to accommodate this need, with numerous advantages, including decoupled power and energy ratings, which imparts flexibility, thermal stability, and safety. Further, development of robust nonaqueous systems has the potential to greatly improve energy density, approaching that of lithium-ion batteries, while maintaining the advantages of flow systems. Herein we report a breakthrough on a bio-inspired nonaqueous redox flow battery (NRFB) electrolyte, which contains high-concentration active-material and maintains stability during deep cycling for extended time-periods. These advances are reinforced by thermodynamic considerations and computational investigations, which provide a clear path to further improvements. Electrochemical studies confirm that the active-material maintains its high stability at high concentration. This molecular scaffold clears two important hurdles in designing active-materials for nonaqueous electrolytes - low solubility and poor stability - providing an in-road to development of high-performance NRFB systems.


Randomised, double-blind and placebo-controlled study using new probiotic lactobacilli for strengthening the body immune defence against viral infections.
The aim of this study was to investigate whether consumption of Lactobacillus plantarum HEAL 9 (DSM 15312) and Lactobacillus paracasei 8700:2 (DSM 13434) could affect naturally acquired common cold infections in healthy subjects. A randomised, parallel, double-blind placebo-controlled study was performed to investigate whether intake of this probiotic mixture could reduce the risk of common cold episodes, number of days with common cold symptoms, frequency and severity of symptoms, and cellular immune response in common cold infections. A total of 272 subjects were supplemented daily with either 10(9) cfu (colony forming units) of probiotics (N = 135) or control (N = 137) for a 12-week period. The incidence of acquiring one or more common cold episode was reduced from 67% in the control group to 55% in the probiotic group (p < 0.05). Also, the number of days with common cold symptoms were significantly (p < 0.05) reduced from 8.6 days in the control group to 6.2 days, in the probiotic group, during the 12-week period. The total symptom score was reduced during the study period from a mean of 44.4 for the control group to 33.6 for the probiotic group. The reduction in pharyngeal symptoms was significant (p < 0.05). In addition, the proliferation of B lymphocytes was significantly counteracted in the probiotic group (p < 0.05) in comparison with the control group. In conclusion, intake of the probiotic strains Lactobacillus plantarum HEAL 9 (DSM 15312) and Lactobacillus paracasei 8700:2 (DSM 13434) reduces the risk of acquiring common cold infections.


Carboxyl-terminal domain III of the delta' subunit of DNA polymerase III holoenzyme binds DnaX and supports cooperative DnaX complex assembly.
The delta' subunit of the DNA polymerase-III holoenzyme is a key component of the DnaX complex; it is required for loading the beta(2) processivity factor onto a primed template. The x-ray crystal structure of delta' indicates a three domain C-shaped structure (Guenther, B., Onrust, R., Sali, A., O'Donnell, M., and Kuriyan, J. (1997) Cell 91, 335-345). In this study, we localized the DnaX-binding domain of delta' to its carboxyl-terminal domain III by quantifying protein-protein interactions using a series of delta' fusion proteins lacking specific domains. The fusion protein corresponding to domain III of delta' bound to DnaX with an affinity approaching that of full-length delta'. In contrast, a construct bearing delta' domains I-II did not bind DnaX at detectable levels. The presence of delta and chi psi strengthened the interaction of DnaX with full-length delta' and delta' domain III. Thus, domain III of delta' not only contains the DnaX-binding site, but also contains the elements required for positive cooperative assembly of the DnaX complex. A domain III-specific anti-delta' monoclonal antibody interfered with DnaX complex formation and abolished the replication activity of DNA polymerase III holoenzyme.


Wavelength shifts of dye lasing in microdroplets: effect of absorption change.
With addition of an absorber to dye-doped microdroplets, an absorption-dependent blue shift in the lasing spectra has been observed. The better the spectral overlap between the absorption and the fluorescence spectra of the dye, the larger the blue shift. The experimental observations are explained by a simple model of dye lasing in an optical cavity that includes losses because of the absorber and radiation leakage.


Improving the measurement of longitudinal change in renal function: automated detection of changes in laboratory creatinine assay.
Renal function is reported using the estimates of glomerular filtration rate (eGFR). However, eGFR values are recorded without reference to the particular serum creatinine (SCr) assays used to derive them, and newer assays were introduced at different time points across the laboratories in the United Kingdom. These changes may cause systematic bias in eGFR reported in routinely collected data, even though laboratory-reported eGFR values have a correction factor applied. An algorithm to detect changes in SCr that in turn affect eGFR calculation method was developed. It compares the mapping of SCr values on to eGFR values across a time series of paired eGFR and SCr measurements. Routinely collected primary care data from 20,000 people with the richest renal function data from the quality improvement in chronic kidney disease trial. The algorithm identified a change in eGFR calculation method in 114 (90%) of the 127 included practices. This change was identified in 4736 (23.7%) patient time series analysed. This change in calibration method was found to cause a significant step change in the reported eGFR values, producing a systematic bias. The eGFR values could not be recalibrated by applying the Modification of Diet in Renal Disease equation to the laboratory reported SCr values. This algorithm can identify laboratory changes in eGFR calculation methods and changes in SCr assay. Failure to account for these changes may misconstrue renal function changes over time. Researchers using routine eGFR data should account for these effects.


Peri-implantitis: a systematic review of recently published papers.
This systematic review considers possible etiologic factors and definitions of peri-implantitis as reported in the recent literature. An electronic search of databases plus a hand search of the most relevant journals published between January 2005 and September 2012 were performed. The electronic and manual searches yielded 640 and 14 titles, respectively. From the independent doublecheck of the titles and abstracts, 24 full texts were downloaded (18 clinical studies and 6 animal studies). After reading the full texts, 10 articles (4 clinical studies and 6 animal studies) were included in this review. None of the human articles selected provided sufficient evidence to address the research question, and no human clinical evidence is available to support a cause-effect relationship between peri-implantitis and bacterial accumulation and/or occlusal overload. The animal literature is also not unanimous regarding a specific peri-implantitis etiology. However, a correlation between periodontitis and smoking histories was cited as contributing to a higher incidence of peri-implantitis. The available scientific literature is characterized by an absence of a unanimous consensus regarding the etiology of peri-implantitis and its specific relationship to periodontitis. Furthermore, both the choice of the term peri-implantitis and its definition remain controversial.


COMPASS: Continuous Open Mouse Phenotyping of Activity and Sleep Status.
Background Disruption of rhythms in activity and rest occur in many diseases, and provide an important indicator of healthy physiology and behaviour. However, outside the field of sleep and circadian rhythm research, these rhythmic processes are rarely measured due to the requirement for specialised resources and expertise. Until recently, the primary approach to measuring activity in laboratory rodents has been based on voluntary running wheel activity. By contrast, measuring sleep requires the use of electroencephalography (EEG), which involves invasive surgical procedures and time-consuming data analysis. Methods Here we describe a simple, non-invasive system to measure home cage activity in mice based upon passive infrared (PIR) motion sensors. Careful calibration of this system will allow users to simultaneously assess sleep status in mice. The use of open-source tools and simple sensors keeps the cost and the size of data-files down, in order to increase ease of use and uptake. Results In addition to providing accurate data on circadian activity parameters, here we show that extended immobility of >40 seconds provides a reliable indicator of sleep, correlating well with EEG-defined sleep (Pearson's r >0.95, 4 mice). Conclusions Whilst any detailed analysis of sleep patterns in mice will require EEG, behaviourally-defined sleep provides a valuable non-invasive means of simultaneously phenotyping both circadian rhythms and sleep. Whilst previous approaches have relied upon analysis of video data, here we show that simple motion sensors provide a cheap and effective alternative, enabling real-time analysis and longitudinal studies extending over weeks or even months. The data files produced are small, enabling easy deposition and sharing. We have named this system COMPASS - Continuous Open Mouse Phenotyping of Activity and Sleep Status. This simple approach is of particular value in phenotyping screens as well as providing an ideal tool to assess activity and rest cycles for non-specialists.


Applicability of a noise-based model to estimate in-traffic exposure to black carbon and particle number concentrations in different cultures.
Several studies show that a significant portion of daily air pollution exposure, in particular black carbon (BC), occurs during transport. In a previous work, a model for the in-traffic exposure of bicyclists to BC was proposed based on spectral evaluation of mobile noise measurements and validated with BC measurements in Ghent, Belgium. In this paper, applicability of this model in a different cultural context with a totally different traffic and mobility situation is presented. In addition, a similar modeling approach is tested for particle number (PN) concentration. Indirectly assessing BC and PN exposure through a model based on noise measurements is advantageous because of the availability of very affordable noise monitoring devices. Our previous work showed that a model including specific spectral components of the noise that relate to engine and rolling emission and basic meteorological data, could be quite accurate. Moreover, including a background concentration adjustment improved the model considerably. To explore whether this model could also be used in a different context, with or without tuning of the model parameters, a study was conducted in Bangalore, India. Noise measurement equipment, data storage, data processing, continent, country, measurement operators, vehicle fleet, driving behavior, biking facilities, background concentration, and meteorology are all very different from the first measurement campaign in Belgium. More than 24h of combined in-traffic noise, BC, and PN measurements were collected. It was shown that the noise-based BC exposure model gives good predictions in Bangalore and that the same approach is also successful for PN. Cross validation of the model parameters was used to compare factors that impact exposure across study sites. A pooled model (combining the measurements of the two locations) results in a correlation of 0.84 when fitting the total trip exposure in Bangalore. Estimating particulate matter exposure with traffic noise measurements was thus shown to be a valid approach across countries and cultures.


Learning to hear: plasticity of auditory cortical processing.
Sensory experience and auditory cortex plasticity are intimately related. This relationship is most striking during infancy when changes in sensory input can have profound effects on the functional organization of the developing cortex. But a considerable degree of plasticity is retained throughout life, as demonstrated by the cortical reorganization that follows damage to the sensory periphery or by the more controversial changes in response properties that are thought to accompany perceptual learning. Recent studies in the auditory system have revealed the remarkably adaptive nature of sensory processing and provided important insights into the way in which cortical circuits are shaped by experience and learning.


Selective lamina dysregulation in granular retrosplenial cortex (area 29) after anterior thalamic lesions: an in situ hybridization and trans-neuronal tracing study in rats.
There is growing evidence that lesions of the anterior thalamic nuclei cause long-lasting intrinsic changes to retrosplenial cortex, with the potential to alter its functional properties. The present study had two goals. The first was to identify the pattern of changes in eight markers, as measured by in-situ hydridisation, in the granular retrosplenial cortex (area Rgb) following anterior thalamic lesions. The second was to use retrograde trans-neuronal tracing methods to identify the potential repercussions of intrinsic changes within granular retrosplenial cortex. In Experiment 1, adult rats received unilateral lesions of the anterior thalamic nuclei and were perfused 4 weeks later. Of the eight markers, four (c-fos, zif268, 5ht2rc, kcnab2) showed a very similar pattern of change, with decreased levels in superficial retrosplenial cortex (lamina II) in the ipsilateral hemisphere but little or no change in deeper layers (lamina V). A fifth marker (cox6b) showed a shift in activity levels in the opposite direction to the previous four markers. Three other markers (cox6a1, CD74, ncs-1) did not appear to change activity levels after surgery. The predominant pattern of change, a decrease in superficial cortical activity, points to potential alterations in plasticity and metabolism. In Experiment 2, wheat germ agglutin (WGA) was injected into the anterior thalamic nuclei in rats given different survival times, sometimes in combination with the retrograde, fluorescent tracer, Fast Blue. Dense aggregations of retrogradely labeled cells were always found in lamina VI of granular retrosplenial cortex, but additional labeled cells in lamina II were only found: (1) in WGA cases, that is never after Fast Blue injections, and (2) after longer WGA survival times (3 days). These layer II Rgb cells are likely to have been trans-neuronally labeled, revealing a pathway from lamina II of Rgb to those deeper retrosplenial cells that project directly to the anterior thalamic nuclei.


KL/KIT co-expression in mouse fetal oocytes.
The tyrosine kinase receptor, KIT, and its ligand, KL are important regulators of germ cell development. The aim of this study was to examine in detail the expression of the genes encoding these proteins (White and Steel, respectively) during the fetal period (14.5-18.5 days post coitum, dpc) and the two weeks after birth in mouse ovaries using the highly sensitive in situ reverse-transcriptase polymerase chain reaction (in situ RT-PCR). KL and KIT mRNAs were not detected in 14.5-15.5 dpc ovaries but, between 16.5 and 17.5 dpc, most of the oocytes in the outer regions of the ovaries positively stained for both mRNAs. The majority of the co-expressing oocytes were identified at the zygotene/pachytene stage of meiotic prophase I. At 18.5 dpc, positive staining for KL mRNA was present only in the somatic cells in the outer regions of the ovaries. At birth, faint KL mRNA-labelled somatic cells were mainly found in the central region of the ovaries and, by P7-14, a higher level of expression was detected in the follicle cells of one- and two-layered growing follicles. Between 17.5 dpc and birth, most of the oocytes expressed KIT mRNA and, from P7 onward, there was a considerable accumulation of transcripts in the growing oocytes. The results of in situ RT-PCR were confirmed by RT-PCR on purified populations of oocytes, and at protein level by means of immunohistochemistry. The co-expression of KL and KIT in a fraction of fetal oocytes suggests that the KL/KIT system, besides the well known paracrine functions on germ cells, may exert a novel autocrine role during the mid-stage of the oocyte meiotic prophase. The possibility that this autocrine loop plays a role in sustaining the survival of fetal oocytes in this stage is supported by the finding that the addition to the culture medium of anti-KL or anti-KIT antibodies led to a significant increase in oocyte apoptosis in the absence of exogenous KL.


Characteristics of bovine hemoglobin as a potential source of hemoglobin-vesicles for an artificial oxygen carrier.
Hemoglobin-vesicles (HbV) have been developed for use as artificial O(2) carriers in which a purified Hb solution is encapsulated within a phospholipid bilayer membrane. In this study, bovine Hb (BHb) was tested as a source of HbV instead of human Hb (HHb). We compared the preparation process and characteristics of BHbV with those of HHbV. The purification of BHb was effectively performed simply with an ultrafiltration system including a process for removing virus and scrapie reagent. The removal ratio of the phospholipid components of bovine red blood cells was over 99.99%, and the protein purity was over 99.9%. The deoxygenated and carbonylated BHb showed denaturation transition temperatures at 83 and 87 degrees C, respectively, which are higher than those of HHb (80 and 78 degrees C, respectively), and resistant to pasteurization (60 degrees C, 10 h). The purified BHb was concentrated to over 40 g/dl, and encapsulated in a phospholipid bilayer membrane to form BHbV with a diameter of about 280 nm. The O(2) affinity (P(50)) of the BHbV was regulated by coencapsulation of an appropriate amount of Cl(-) (as NaCl), which binds to BHb as an allosteric effector, in the range 16-28 Torr, comparable to human blood (P(50) = 28 Torr). This is quite simple in comparison with HHb which requires phosphate derivatives such as pyridoxal 5'-phosphate as a replacement for 2,3-diphoshoglyceric acid. The viscosity and colloid osmotic pressure of the BHbV when suspended in 5% human serum albumin are 3.5 cP and 20 Torr, respectively, comparable to those of human blood. In conclusion, BHb can be used as a source for the production of HbV, not only because of its abundance in the cattle industry, but also because of the physicochemical advantages of the purification process, thermal stability, and regulation of O(2) affinity in comparison with HHb.


Sonographically guided intratendinous injection of hyperosmolar dextrose to treat chronic tendinosis of the Achilles tendon: a pilot study.
Chronic tendinosis of the Achilles tendon is a common overuse injury that is difficult to manage. We report on a new injection treatment for this condition. Thirty-six consecutive patients (25 men, 11 women; mean age, 52.6 years) with symptoms for more than 3 months (mean, 28.6 months) underwent sonography-guided intratendinous injection of 25% hyperosmolar dextrose every 6 weeks until symptoms resolved or no improvement was shown. At baseline and before each injection, clinical assessment was performed using a visual analogue scale (VAS) for pain at rest (VAS1), pain during normal daily activity (VAS2), and pain during or after sporting or other physical activity (VAS3). Sonographic parameters including tendon thickness, echogenicity, and neovascularity were also recorded. Posttreatment clinical follow-up was performed via telephone interview. Thirty-three tendons in 32 patients were successfully treated. The mean number of treatment sessions was 4.0 (range, 2-11). There was a mean percentage reduction for VAS1 of 88.2% (p < 0.0001), for VAS2 of 84.0% (p < 0.0001), and for VAS3 of 78.1% (p < 0.0001). The mean tendon thickness decreased from 11.7 to 11.1 mm (p < 0.007). The number of tendons with anechoic clefts or foci was reduced by 78%. Echogenicity improved in six tendons (18%) but was unchanged in 27 tendons (82%). Neovascularity was unchanged in 11 tendons (33%) but decreased in 18 tendons (55%); no neovascularity was present before or after treatment in the four remaining tendons. Follow-up telephone interviews of the 30 available patients a mean of 12 months after treatment revealed that 20 patients were still asymptomatic, nine patients had only mild symptoms, and one patient had moderate symptoms. Intratendinous injections of hyperosmolar dextrose yielded a good clinical response--that is, a significant reduction in pain at rest and during tendon-loading activities--in patients with chronic tendinosis of the Achilles tendon.


All-Arthroscopic Suprapectoral Versus Open Subpectoral Tenodesis of the Long Head of the Biceps Brachii Without the Use of Interference Screws.
To compare patient-reported outcomes and healing rates after open subpectoral and all-arthroscopic suprapectoral biceps tenodesis without the use of interference screws in patients with more than 2 years of follow-up. Patients with at least 2 years of follow-up who underwent open subpectoral biceps tenodesis or all-arthroscopic suprapectoral biceps tenodesis without concomitant rotator cuff repair, labral repair, or Mumford procedure were considered for enrollment in the study. They were evaluated for visual analog scale (VAS), American Shoulder and Elbow Surgeons (ASES) score, and satisfaction with function and biceps contour. Ultrasonography was performed to evaluate the integrity of the tenodesis site and measure biceps muscle diameters on each arm. Forty-nine patients were eligible for our study and of these, 38 were able to participate. Twenty-three patients had open subpectoral biceps tenodesis and 15 received all-arthroscopic suprapectoral biceps tenodesis. The average follow-up time was 4.5 years (range 2-9.1 years). There were no significant differences in anterior shoulder pain VAS, ASES scores, or satisfaction rates. The average anterior shoulder VAS was 0.7 ± 1.1 for the open group and 0.9 ± 1.8 for the arthroscopic group (P = .74). The mean ASES score for the open group was 90.6 ± 11.4 and 91.4 ± 13.9 for the arthroscopic group (P = .69). All patients had an intact tenodesis site on ultrasonography and the ratio of operative to nonoperative biceps diameters was 100.2% ± 12.8% for the open group and 99.1% ± 10.8% for the arthroscopic group (P = .66). There were no infections and no brachial plexus injuries in either group. Open subpectoral biceps tenodesis and all-arthroscopic suprapectoral biceps tenodesis are both successful surgeries with consistently positive outcomes. Tenodesis can be performed in either location without interference screw fixation with durable, reliable results. Level III, retrospective comparative trial.


The effectiveness of hylan G-F 20 in patients with knee osteoarthritis: an application of two sets of response criteria developed by the OARSI and one set developed by OMERACT-OARSI.
Secondary analyses of a previously conducted 1-year randomized controlled trial were performed to assess the application of responder criteria in patients with knee osteoarthritis (OA) using different sets of responder criteria developed by the Osteoarthritis Research Society International (OARSI) (Propositions A and B) for intra-articular drugs and Outcome Measures in Arthritis Clinical Trials (OMERACT)-OARSI (Proposition D). Two hundred fifty-five patients with knee OA were randomized to "appropriate care with hylan G-F 20" (AC+H) or "appropriate care without hylan G-F 20" (AC). A patient was defined as a responder at month 12 based on change in Western Ontario and McMaster Universities Osteoarthritis Index pain and function (0-100 normalized scale) and patient global assessment of OA in the study knee (at least one-category improvement in very poor, poor, fair, good and very good). All propositions incorporate both minimum relative and absolute changes. Results demonstrated that statistically significant differences in responders between treatment groups, in favor of hylan G-F 20, were detected for Proposition A (AC+H=53.5%, AC=25.2%), Proposition B (AC+H=56.7%, AC=32.3%) and Proposition D (AC+H=66.9%, AC=42.5%). The highest effectiveness in both treatment groups was observed with Proposition D, whereas Proposition A resulted in the lowest effectiveness in both treatment groups. The treatment group differences always exceeded the required 20% minimum clinically important difference between groups established a priori, and were 28.3%, 24.4% and 24.4% for Propositions A, B and D, respectively. This analysis provides evidence for the capacity of OARSI and OMERACT-OARSI responder criteria to detect clinically important statistically detectable differences between treatment groups.


Leadership and leadership development in healthcare settings - a simplistic solution to complex problems?
There is a trend in health systems around the world to place great emphasis on and faith in improving 'leadership'. Leadership has been defined in many ways and the elitist implications of traditional notions of leadership sit uncomfortably with modern healthcare organisations. The concept of distributed leadership incorporates inclusivity, collectiveness and collaboration, with the result that, to some extent, all staff, not just those in senior management roles, are viewed as leaders. Leadership development programmes are intended to equip individuals to improve leadership skills, but we know little about their effectiveness. Furthermore, the content of these programmes varies widely and the fact that many lack a sense of how they fit with individual or organisational goals raises questions about how they are intended to achieve their aims. It is important to avoid simplistic assumptions about the ability of improved leadership to solve complex problems. It is also important to evaluate leadership development programmes in ways that go beyond descriptive accounts.


Low-dose radiation exposure and atherosclerosis in ApoE⁻/⁻ mice.
The hypothesis that single low-dose exposures (0.025-0.5 Gy) to low-LET radiation given at either high (about 150 mGy/min) or low (1 mGy/min) dose rate would promote aortic atherosclerosis was tested in female C57BL/6J mice genetically predisposed to this disease (ApoE⁻/⁻). Mice were exposed either at an early stage of disease (2 months of age) and examined 3 or 6 months later or at a late stage of disease (8 months of age) and examined 2 or 4 months later. Changes in aortic lesion frequency, size and severity as well as total serum cholesterol levels and the uptake of lesion lipids by lesion-associated macrophages were assessed. Statistically significant changes in each of these measures were observed, depending on dose, dose rate and disease stage. In all cases, the results were distinctly non-linear with dose, with maximum effects tending to occur at 25 or 50 mGy. In general, low doses given at low dose rate during either early- or late-stage disease were protective, slowing the progression of the disease by one or more of these measures. Most effects appeared and persisted for months after the single exposures, but some were ultimately transitory. In contrast to exposure at low dose rate, high-dose-rate exposure during early-stage disease produced both protective and detrimental effects, suggesting that low doses may influence this disease by more than one mechanism and that dose rate is an important parameter. These results contrast with the known, generally detrimental effects of high doses on the progression of this disease in the same mice and in humans, suggesting that a linear extrapolation of the known increased risk from high doses to low doses is not appropriate.


Comparison of percutaneous intradiscal ozone injection with laser disc decompression in discogenic low back pain.
Intervertebral disc herniation with the pressure on the surrounding neural structures is one of the most important causes of chronic low back pain, which sometimes leads to open surgery. Reducing the pressure inside the disc with intradiscal intervention such as laser irradiation or ozone injection is a minimally invasive method and an alternative to surgery with satisfactory results. These two methods were compared with each other in this research. In this clinical trial, 40 patients with back pain radiating to lower limb due to lumbar intervertebral disc herniation were selected. These patients were randomly divided into two equal groups for percutaneous intradiscal intervention. The Laser Disc Decompression Group (LDG) (n=20) was exposed to 1500 J of laser irradiation into the disc center. In the Ozone Injection Group (OZG) patients (n=20), 6 mL of ozone 30 µg/mL was injected into the center of the disc. Considering the level of neural root involvement, both groups received 20 mg of triamcinolone injection via transforaminal epidural. Patients were followed up for 12 months regarding score on visual analogue scale and life performance improvement based on Oswestry Disability Index (ODI) and satisfaction level. According to the results, no difference was found between the two groups for ODI variable before intervention, whereas OZG showed better ODI scores in the measured time intervals. In LDG, only a significant difference in terms of ODI score was found between the times of before surgery and the first month. Intradiscal ozone injection could be an effective and cost-effective method for treatment of patients with discogenic back pain.


Dose-rate considerations for the INTRABEAM electronic brachytherapy system: Report from the American association of physicists in medicine task group no. 292.
The purpose of this report is to provide detailed guidance on the dosimetry of the INTRABEAM® (Carl Zeiss Medical AG, Jena, Germany) electronic brachytherapy (eBT) system as it stands at the present time. This report has been developed by the members of American Association of Physicists in Medicine (AAPM) Task Group 292 and endorsed by the AAPM. Members of AAPM Task Group 292 on Electronic-Brachytherapy Dosimetry have reviewed pertinent publications and user manuals regarding the INTRABEAM system dosimetry and manufacturer-supplied dose calculation protocols. Formal written correspondence with Zeiss has also provided further clarification. Dose-rate calculations for the INTRABEAM system are highly dependent on choice of dosimetry protocol. Even with careful protocol selection, large uncertainties remain due to the incomplete characterization of the ionization chambers used for verification with respect to their energy dependence as well as manufacturing variations. There are two distinct sets of dose-rate data provided by Zeiss for the INTRABEAM system. One dataset (Calibration V4.0) is representative of the physical dose surrounding the source and the other dataset (TARGIT) has been adjusted to be consistent with a clinical trial named TARGIT (TARGeted Intraoperative RadioTherapy). The adjusted TARGIT doses are quite dissimilar to the physical doses, with differences ranging from 14% to 30% at the surface of a spherical applicator, depending on its diameter, and up to a factor of two at closer distances with the smaller needle applicators. In addition, ion chamber selection and associated manufacturing tolerances contribute to significant additional uncertainties. With these substantial differences in dose rates and their associated uncertainties, it is important for users to be aware of how each value is calculated and whether it is appropriate to be used for the intended treatment. If users intend to deliver doses that are the same as they were in 1998 at the onset of the TARGIT trial, then the TARGIT dose-rate tables should be used. The Calibration V4.0 dose rates may be more appropriate to use for applications other than TARGIT trial treatments, since they more closely represent the physical doses being delivered. Users should also be aware of the substantial uncertainties associated with the provided dose rates, which are due to beam hardening, chamber geometry, and selection of the point-of-measurement for a given ionization chamber. This report serves to describe the details and implications of the manufacturer-recommended dosimetry formalism for users of the INTRABEAM system.


Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling.
Vascular endothelial growth factor C (VEGF-C) stimulates tumor lymphangiogenesis (i.e., formation of lymphatic vessels) and metastasis to regional lymph nodes by interacting with VEGF receptor 3 (VEGFR-3). We sought to determine whether inhibiting VEGFR-3 signaling, and thus tumor lymphangiogenesis, would inhibit tumor metastasis. We used the highly metastatic human lung cancer cell line NCI-H460-LNM35 (LNM35) and its parental line NCI-H460-N15 (N15) with low metastatic capacity. We inserted genes by transfection and established a stable N15 cell line secreting VEGF-C and a LNM35 cell line secreting the soluble fusion protein VEGF receptor 3-immunoglobulin (VEGFR-3-Ig, which binds VEGF-C and inhibits VEGFR-3 signaling). Control lines were transfected with mock vectors. Tumor cells were implanted subcutaneously into severe combined immunodeficient mice (n = 6 in each group), and tumors and metastases were examined 6 weeks later. In another approach, recombinant adenoviruses expressing VEGFR-3-Ig (AdR3-Ig) or beta-galactosidase (AdLacZ) were injected intravenously into LNM35 tumor-bearing mice (n = 14 and 7, respectively). LNM35 cells expressed higher levels of VEGF-C RNA and protein than did N15 cells. Xenograft mock vector-transfected LNM35 tumors showed more intratumoral lymphatic vessels (15.3 vessels per grid; 95% confidence interval [CI] = 13.3 to 17.4) and more metastases in draining lymph nodes (12 of 12) than VEGFR-3-Ig-transfected LNM35 tumors (4.1 vessels per grid; 95% CI = 3.4 to 4.7; P<.001, two-sided t test; and four lymph nodes with metastases of 12 lymph nodes examined). Lymph node metastasis was also inhibited in AdR3-Ig-treated mice (AdR3-Ig = 0 of 28 lymph nodes; AdLacZ = 11 of 14 lymph nodes). However, metastasis to the lungs occurred in all mice, suggesting that LNM35 cells can also spread via other mechanisms. N15 tumors overexpressing VEGF-C contained more lymphatic vessels than vector-transfected tumors but did not have increased metastatic ability. Lymph node metastasis appears to be regulated by additional factors besides VEGF-C. Inhibition of VEGFR-3 signaling can suppress tumor lymphangiogenesis and metastasis to regional lymph nodes but not to lungs.


Efficient apoptosis requires feedback amplification of upstream apoptotic signals by effector caspase-3 or -7.
Apoptosis is a complex multi-step process driven by caspase-dependent proteolytic cleavage cascades. Dysregulation of apoptosis promotes tumorigenesis and limits the efficacy of chemotherapy. To assess the complex interactions among caspases during apoptosis, we disrupted caspase-8, -9, -3, -7, or -6 and combinations thereof, using CRISPR-based genome editing in living human leukemia cells. While loss of apical initiator caspase-8 or -9 partially blocked extrinsic or intrinsic apoptosis, respectively, only combined loss of caspase-3 and -7 fully inhibited both apoptotic pathways, with no discernible effect of caspase-6 deficiency alone or in combination. Caspase-3/7 double knockout cells exhibited almost complete inhibition of caspase-8 or -9 activation. Furthermore, deletion of caspase-3 and -7 decreased mitochondrial depolarization and cytochrome c release upon apoptosis activation. Thus, activation of effector caspase-3 or -7 sets off explosive feedback amplification of upstream apoptotic events, which is a key feature of apoptotic signaling essential for efficient apoptotic cell death.


Proteolytic processing of the peanut allergen Ara h 3.
The allergen Ara h 3 has been purified recently from peanuts. In contrast to recombinant Ara h 3, a 60 kDa single-chain polypeptide, the allergen isolated from its native source is extensively proteolytically processed. The characteristic proteolytic processing for 11S plant storage proteins of the glycinin family is observed for Ara h 3 yielding an acidic and a basic subunit, bound by a disulfide bridge. In addition to this, proteolytic truncation is observed for the acidic subunit but not for the basic subunit of Ara h 3. A series of Ara h 3 polypeptides ranging from 13-45 kDa was separated by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and each band was digested by trypsin. Peptides related to the bands were identified and a scheme positioning the different polypeptides in the Ara h 3 sequence has been constructed. Peptide analysis showed sequence heterogeneity at two positions indicating the presence of multiple genes encoding variant, but highly homologous Ara h 3 proteins. The pool of Ara h 3 polypeptides from its native source illustrated that allergen from the peanut is much more complex than the recombinant protein used for epitope mapping experiments. From several Ara h 3 truncation products one or more immunoglobulin E (IgE) binding sites had been removed. Characterization of the allergenicity of Ara h 3 should therefore also include IgE-binding studies with peanut-derived Ara h 3, providing the high degree of variation in the Ara h 3 protein structure, as this is what peanut-allergic individuals are confronted with.


Involvement of three meningococcal surface-exposed proteins, the heparin-binding protein NhbA, the α-peptide of IgA protease and the autotransporter protease NalP, in initiation of biofilm formation.
Neisseria meningitidis is a common and usually harmless inhabitant of the mucosa of the human nasopharynx, which, in rare cases, can cross the epithelial barrier and cause meningitis and sepsis. Biofilm formation favours the colonization of the host and the subsequent carrier state. Two different strategies of biofilm formation, either dependent or independent on extracellular DNA (eDNA), have been described for meningococcal strains. Here, we demonstrate that the autotransporter protease NalP, the expression of which is phase variable, affects eDNA-dependent biofilm formation in N. meningitidis. The effect of NalP was found in biofilm formation under static and flow conditions and was dependent on its protease activity. Cleavage of the heparin-binding antigen NhbA and the α-peptide of IgA protease, resulting in the release of positively charged polypeptides from the cell surface, was responsible for the reduction in biofilm formation when NalP is expressed. Both NhbA and the α-peptide of IgA protease were shown to bind DNA. We conclude that NhbA and the α-peptide of IgA protease are implicated in biofilm formation by binding eDNA and that NalP is an important regulator of this process through the proteolysis of these surface-exposed proteins.


Humanitarian Activities of Interplast Turkiye: 6 Years of Experience in Uzbekistan for Surgical Treatment of Cleft Patients and Related Secondary Deformities.
Cleft lip and palate (CL/P) is one of the leading congenital deformities among the world. Children born with CL/P experience problems with feeding, speech, hearing, and dentition. In developed countries, CL/P patients are receiving optimal health care involving multidisciplinary team approach and staged surgical operations, whereas in developing countries, there is severe shortage of both medical and financial sources. To overcome these limitations, humanitarian surgical missions are essential. The aim of this article is to share our experience of humanitarian surgical mission in Uzbekistan consisting of 6 consecutive visits between 2009 and 2014. The series of these humanitarian activities consisting of 6 consecutive visits was organized by the cooperation of Interplast Turkiye and governmental Turkish Coordination and Cooperation Agency. After initial evaluation, triage at the initial setting and prompt anesthesia evaluation among many more of them, 529 patients mostly with cleft, craniofacial, or congenital deformities were operated. The success of this type of mission is not solely based on the expertise of the team members, but also meticulous planning, patient selection, good coordination with the local colleagues and communication. At this point, caregivers attending from a culturally close and similar language-spoken countries will certainly have more advantages in achieving a mission. Volunteer surgical missions for congenital deformities can be an important relief for this burden in developing countries. Nevertheless, training the native surgeons and supporting the plastic surgery foundations in these countries are as important as providing the necessary health care by such humanitarian missions.


Protection of rhesus macaques from SIV infection by immunization with different experimental SIV vaccines.
The immunogenicity and efficacy of an inactivated whole SIVmac (32H) preparation adjuvanted with muramyl dipeptide (SIV-MDP) and a gp120-enriched SIVmac (32H) ISCOM preparation (SIV-ISCOM), were compared by immunizing four rhesus macaques (Macaca mulatta) four times with SIV-MDP and four others in the same way with SIV-ISCOM. Two monkeys immunized with whole inactivated measles virus (MV) adjuvanted with MDP (MV-MDP) and two monkeys immunized with MV-ISCOM served as controls. In the SIV-ISCOM-immunized monkeys higher SIV-specific serum antibody titres were found than in the SIV-MDP-immunized monkeys. In contrast to the MV-immunized monkeys all SIV-MDP- and SIV-ISCOM-immunized monkeys were protected against intravenous challenge 2 weeks after the last immunization with 10 median monkey infectious doses (MID50) of a cell-free SIVmac (32H) challenge stock propagated in the human T-cell line C8166. After 43 weeks the protected monkeys were reboosted and 2 weeks later rechallenged with 10 MID50 of the same virus produced in peripheral blood mononuclear cells (PBMC) from a rhesus macaque. None of these animals proved to be protected against this challenge. In a parallel experiment in which the same numbers of monkeys were immunized in the same way, the animals were challenged intravenously with 10 MID50 of PBMC from an SIVmac (32H)-infected rhesus macaque. Two out of four SIV-MDP- and two out of four SIV-ISCOM-immunized monkeys proved to be protected from SIV infection.


Perceptions of relationship satisfaction and addictive behavior: Comparing pornography and marijuana use.
Background and aims Research indicates that excessive pornography use can negatively impact romantic relationships. However, it is unclear whether these negative outcomes are different than negative outcomes produced by other compulsive or addictive behaviors, such as drug use. This study compared perceptions of relationship outcomes from either a romantic partner's excessive marijuana or pornography use. Furthermore, this study experimentally manipulated four factors potentially related to perceptions of relationship satisfaction and addictive behavior. Methods A total of 186 college-aged women read 16 scenarios describing heterosexual romantic relationships in which one partner used either pornography or marijuana. Each scenario varied on four variables: relationship commitment, secrecy of partner's behavior, frequency of partner's behavior, and context of partner's behavior. Results Results suggest that partner pornography and marijuana use are perceived to impact romantic relationships similarly and are influenced by similar factors, such as greater frequency, higher secrecy, and partner's availability for interaction. Conclusions Such findings are consistent with recommendations by professionals that compulsive pornography use be considered worthy of treatment intervention.


Monitoring Electron-Photon Dressing in WSe2.
Optical pumping of solids creates a nonequilibrium electronic structure where electrons and photons combine to form quasiparticles of dressed electronic states. The resulting shift of electronic levels is known as the optical Stark effect, visible as a red shift in the optical spectrum. Here we show that in a pump-probe setup we can uniquely define a nonequilibrium quasiparticle bandstructure that can be directly measurable with photoelectron spectroscopy. The dynamical photon-dressing (and undressing) of the many-body electronic states can be monitored by pump-probe time and angular-resolved photoelectron spectroscopy (tr-ARPES) as the photon-dressed bandstructure evolves in time depending on the pump-probe pulse overlap. The computed tr-ARPES spectrum agrees perfectly with the quasi-energy spectrum of Floquet theory at maximum overlap and goes to the equilibrium bandstructure as the pump-probe overlap goes to zero. Additionally, we show how this time-dependent nonequilibrium quasiparticle structure can be understood to be the bandstructure underlying the optical Stark effect. The extension to spin-resolved ARPES can be used to predict asymmetric dichroic response linked to the valley selective optical excitations in monolayer transition metal dichalcogenides (TMDs). These results establish the photon dressed nonequilibrium bandstructures as the underlying quasiparticle structure of light-driven steady-state quantum phases of matter.


Assessment of exposure to oak wood dust using gallic acid as a chemical marker.
The American Conference of Governmental Industrial Hygienists (ACGIH) has classified oak dust as a human carcinogen (A1), based on increased sinus and nasal cancer rates among exposed workers. The aims of this study were to investigate the use of gallic acid (GA) as a chemical marker of occupational exposure to oak dusts, to develop a high-performance liquid chromatography-diode array detector method to quantify GA and to apply the method in the analysis of oak dust samples collected in several factories. A high-performance liquid chromatography method was developed to detect GA in oak wood dust. The method was tested in the field, and GA was extracted from inhalable oak wood dust collected using the Institute of Occupational Medicine inhalable dust sampler in the air of five woodworking plants where only oak wood is used. A total of 57 samples with dust concentrations in the range of 0.27-11.14 mg/m(3) were collected. Five of these samples exceeded the Italian threshold limit value of 5 mg/m(3), and 30 samples exceeded the ACGIH TLV of 1 mg/m(3). The GA concentrations were in the range 0.02-4.18 µg/m(3). The total oak dust sampled was correlated with the GA content with a correlation coefficient (r) of 0.95. The GA in the tannic extracts of oak wood may be considered a good marker for this type of wood, and its concentration in wood dust sampled in the work environment is useful in assessing the true exposure to carcinogenic oak dust.


[Frequency of oral squamous cell carcinoma and oral epithelial dysplasia in oral and oropharyngeal mucosa in Chile].
Oral cancer in Chile corresponds approximately to 1.6% of all cancer cases. There are few studies about oral epithelial dysplasia and oral squamous cell carcinoma in the Chilean population. To determine the frequency of hyperkeratosis, mild, moderate and severe oral epithelial dysplasia, in situ carcinoma and squamous cell carcinoma of the oral and oropharyngeal mucosa in a registry of the Oral Pathology Reference Institute of the Faculty of Dentistry, Universidad de Chile, in a ten years period. Review of clinical records and pathological plates of 389 patients, obtained between 1990 and 2009. Cases were selected according to their pathological diagnosis, including hyperkeratosis, oral epithelial dysplasia, in situ carcinoma, squamous cell carcinoma and verrucous carcinoma. Forty four percent of cases were squamous cell carcinoma, followed by hyperkeratosis in 37% and mild epithelial dysplasia in 11%. Squamous cell carcinoma was more common in men aged over 50 years. Most of the potentially malignant disorders presented clinically as leukoplakia and squamous cell carcinoma were clinically recognized as cancer. In this study, men aged over 50 years are the highest risk group for oral cancer. Early diagnosis is deficient since most of these lesions were diagnosed when squamous cell carcinoma became invasive. Leukoplakia diagnosis is mostly associated with hyperkeratosis and epithelial dysplasia, therefore biopsy of these lesions is mandatory to improve early diagnosis.


Differential regulation of the PGC family of genes in a mouse model of Staphylococcus aureus sepsis.
The PGC family of transcriptional co-activators (PGC-1alpha [Ppargc1a], PGC-1beta [Ppargc1b], and PRC [Pprc]) coordinates the upregulation of mitochondrial biogenesis, and Ppargc1a is known to be activated in response to mitochondrial damage in sepsis. Therefore, we postulated that the PGC family is regulated by the innate immune system. We investigated whether mitochondrial biogenesis and PGC gene expression are disrupted in an established model of Staphylococcus aureus sepsis both in mice with impaired innate immune function (TLR2-/- and TLR4-/-) and in wild-type controls. We found an early up-regulation of Ppargc1a and Ppargc1b post-infection (at 6 h) in WT mice, but the expression of both genes was concordantly dysregulated in TLR2-/- mice (no increase at 6 h) and in TLR4-/- mice (amplified at 6 h). However, the third family member, PRC, was regulated differently, and its expression increased significantly at 24 h in all three mouse strains (WT, TLR2-/-, and TLR4-/-). In silico analyses showed that Ppargc1a and Ppargc1b share binding sites for microRNA mmu-mir-202-3p. Thus, miRNA-mediated post-transcriptional mRNA degradation could account for the failure to increase the expression of both genes in TLR2-/- mice. The expression of mmu-mir-202-3p was measured by real-time PCR and found to be significantly increased in TLR2-/- but not in WT or TLR4-/- mice. In addition, it was found that mir-202-3p functionally decreases Ppargc1a mRNA in vitro. Thus, both innate immune signaling through the TLRs and mir-202-3p-mediated mRNA degradation are implicated in the co-regulation of Ppargc1a and Ppargc1b during inflammation. Moreover, the identification of mir-202-3p as a potential factor for Ppargc1a and Ppargc1b repression in acute inflammation may open new avenues for mitochondrial research and, potentially, therapy.


Behavioral weight loss and physical activity intervention in obese adults with asthma. A randomized trial.
The effect of weight loss on asthma in obese adults warrants rigorous investigation. To examine an evidence-based, practical, and comprehensive lifestyle intervention targeting modest weight loss and increased physical activity for asthma control. The trial randomized 330 obese adults with uncontrolled asthma to receive usual care enhanced with a pedometer, a weight scale, information about existing weight management services at the participating clinics, and an asthma education DVD, or with these tools plus the 12-month intervention. The primary outcome was change in Asthma Control Questionnaire (ACQ) scores from baseline to 12 months. Participants (mean [SD] age, 47.6 [12.4] yr) were 70.6% women, 20.0% non-Hispanic black, 20.3% Hispanic/Latino, and 8.2% Asian/Pacific Islander. At baseline, they were obese (mean [SD] body mass index, 37.5 [5.9] kg/m(2)) and had uncontrolled asthma (Asthma Control Test score, 15.1 [3.8]). Compared with control subjects, intervention participants achieved significantly greater mean weight loss (±SE) (intervention, -4.0 ± 0.8 kg vs. control, -2.1 ± 0.8 kg; P = 0.01) and increased leisure-time activity (intervention, 418.2 ± 110.6 metabolic equivalent task-min/wk vs. control, 178.8 ± 109.1 metabolic equivalent task-min/wk; P = 0.05) at 12 months. But between-treatment mean (±SE) differences were not significant for ACQ changes (intervention, -0.3 ± 0.1 vs. control, -0.2 ± 0.1; P = 0.92) from baseline (mean [SD], 1.4 [0.8]), nor for any other clinical asthma outcomes (e.g., spirometric results and asthma exacerbations). Among all participants regardless of treatment assignment, weight loss of 10% or greater was associated with a Cohen d effect of 0.76 and with 3.78 (95% confidence interval, 1.72-8.31) times the odds of achieving clinically significant reductions (i.e., ≥0.5) on ACQ as stable weight (<3% loss or gain from baseline). The effects of other weight change categories were small. Moderately and severely obese adults with uncontrolled asthma can safely participate in evidence-based lifestyle intervention for weight loss and active living. The modest average weight and activity improvements are comparable to those shown to reduce cardiometabolic risk factors in studies of similar interventions in other populations but are not associated with significant net benefits for asthma control or other clinical asthma outcomes in the current population. Instead, weight loss of 10% or greater may be required to produce clinically meaningful improvement in asthma. Clinical trial registered with www.clinicaltrials.gov (NCT00901095).


Modular encoding and decoding models derived from bayesian canonical correlation analysis.
Neural encoding and decoding provide perspectives for understanding neural representations of sensory inputs. Recent functional magnetic resonance imaging (fMRI) studies have succeeded in building prediction models for encoding and decoding numerous stimuli by representing a complex stimulus as a combination of simple elements. While arbitrary visual images were reconstructed using a modular model that combined the outputs of decoder modules for multiscale local image bases (elements), the shapes of the image bases were heuristically determined. In this work, we propose a method to establish mappings between the stimulus and the brain by automatically extracting modules from measured data. We develop a model based on Bayesian canonical correlation analysis, in which each module is modeled by a latent variable that relates a set of pixels in a visual image to a set of voxels in an fMRI activity pattern. The estimated mapping from a latent variable to pixels can be regarded as an image basis. We show that the model estimates a modular representation with spatially localized multiscale image bases. Further, using the estimated mappings, we derive encoding and decoding models that produce accurate predictions for brain activity and stimulus images. Our approach thus provides a novel means of revealing neural representations of stimuli by automatically extracting modules, which can be used to generate effective prediction models for encoding and decoding.


Enzymatic processing of uracil glycol, a major oxidative product of DNA cytosine.
A major stable oxidation product of DNA cytosine is uracil glycol (Ug). Because of the potential of Ug to be a strong premutagenic lesion, it is important to assess whether it is a blocking lesion to DNA polymerase as is its structural counterpart, thymine glycol (Tg), and to evaluate its pairing properties. Here, a series of oligonucleotides containing Ug or Tg were prepared and used as templates for a model enzyme, Escherichia coli DNA polymerase I Klenow fragment (exo-). During translesion DNA synthesis, Ug was bypassed more efficiently than Tg in all sequence contexts examined. Furthermore, only dAMP was incorporated opposite template Ug and Tg and the kinetic parameters of incorporation showed that dAMP was inserted opposite Ug more efficiently than opposite Tg. Ug opposite G and A was also recognized and removed in vitro by the E. coli DNA repair glycosylases, endonuclease III (endo III), endonuclease VIII (endo VIII), and formamidopyrimidine DNA glycosylase. The steady state kinetic parameters indicated that Ug was a better substrate for endo III and formamidopyrimidine DNA glycosylase than Tg; for endonuclease VIII, however, Tg was a better substrate.


A digital framework to build, visualize and analyze a gene expression atlas with cellular resolution in zebrafish early embryogenesis.
A gene expression atlas is an essential resource to quantify and understand the multiscale processes of embryogenesis in time and space. The automated reconstruction of a prototypic 4D atlas for vertebrate early embryos, using multicolor fluorescence in situ hybridization with nuclear counterstain, requires dedicated computational strategies. To this goal, we designed an original methodological framework implemented in a software tool called Match-IT. With only minimal human supervision, our system is able to gather gene expression patterns observed in different analyzed embryos with phenotypic variability and map them onto a series of common 3D templates over time, creating a 4D atlas. This framework was used to construct an atlas composed of 6 gene expression templates from a cohort of zebrafish early embryos spanning 6 developmental stages from 4 to 6.3 hpf (hours post fertilization). They included 53 specimens, 181,415 detected cell nuclei and the segmentation of 98 gene expression patterns observed in 3D for 9 different genes. In addition, an interactive visualization software, Atlas-IT, was developed to inspect, supervise and analyze the atlas. Match-IT and Atlas-IT, including user manuals, representative datasets and video tutorials, are publicly and freely available online. We also propose computational methods and tools for the quantitative assessment of the gene expression templates at the cellular scale, with the identification, visualization and analysis of coexpression patterns, synexpression groups and their dynamics through developmental stages.


Short-term weight change and fluctuation as risk factors for type 2 diabetes in Finnish male smokers.
Risk of weight change and fluctuation for type 2 diabetes was studied in a prospective study among 20,952 Finnish male smokers aged 50-69 years. Baseline data on lifestyle and medical history were collected, and height and weight measured. Weight was measured thrice after the baseline, 1 year apart. Weight change was defined as the slope of the regression line fitted to the four measurements and weight fluctuation as the root-mean-square-error deviation from this line. Incident cases of diabetes were identified from a national medication reimbursement register; 535 cases up to 9 years' follow-up. The Cox proportional hazards model served to estimate relative risk [RR, 95% confidence interval (CI)]. Weight gain and fluctuation associated with higher risk for diabetes, multivariate RR = 1.77, 95% CI 1.44-2.17, for weight gain of at least 4 kg compared with those of weight change less than 4 kg, and RR = 1.64, 95% CI 1.24-2.17 in the highest weight fluctuation quintile compared to the lowest. These RRs remained similar when weight change and fluctuation were adjusted for each other. Large weight fluctuation increased the risk of diabetes both in men who gained weight (>or=4 kg), had stable weight (+/- <4 kg), and lost weight (>or=4 kg); RR = 2.17, 95% CI 1.60-2.94, RR = 1.47, 95% CI 1.14-1.91, and RR = 2.04, 95% CI 1.47-2.83, respectively, compared to those with stable weight and moderate fluctuation. Short-term weight gain and large weight fluctuation are independent risk factors for diabetes.


An MEDT study of the carbenoid-type [3 + 2] cycloaddition reactions of nitrile ylides with electron-deficient chiral oxazolidinones.
The molecular mechanism of the carbenoid-type [3 + 2] cycloaddition (32CA) reactions of a nitrile ylide (NY) with a non-chiral and a chiral oxazolidinone has been studied within Molecular Electron Density Theory (MEDT) at the MPWB1K/6-31G(d) computational level. Topological analysis of the Electron Localisation Function (ELF) of the NY shows that it presents a carbenoid structure. The high nucleophilic character of the NY together with the electrophilic character of the non-chiral oxazolidinone favour a polar 32CA reaction with a very low activation energy, the reaction being completely meta/endo selective. A Bonding Evolution Theory (BET) study of the molecular mechanism makes it possible to characterise a two-stage one-step carbenoid-type mechanism. Non-Covalent Interactions (NCI) analysis of the 32CA reaction between the NY and chiral oxazolidinone correctly explains the diastereoselectivity experimentally observed.


Properties and modulation of cardiac calcium channels.
Voltage-dependent calcium channels are widely distributed in excitable membranes and are involved in the regulation of many cellular functions. These channels can be modulated by neurotransmitters and drugs. There is one particular type of calcium channel in cardiac cells (L-type) whose gating is affected in different ways by beta-adrenoceptor and 1,4-dihydropyridine agonists. We have analysed single calcium channel currents (i) in myocytes from rat hearts in the absence and presence of isoproterenol or 8-bromo-cAMP. We have found that both compounds have similar effects on calcium channel properties. They increase the overall open state probability (po) of individual calcium channels while i remains unaffected. Analysis of the gating kinetics of calcium channels showed: a slight increase in the mean open times of calcium channels, a reduction in time intervals between bursts of channel openings, an increase in burst length and a prominent reduction in failures of calcium channels to open upon depolarization. These kinetic changes caused by isoproterenol and 8-bromo-cAMP can account for the increase in po. Since the macroscopic calcium current, ICa, can be described by ICa = N X po X i, the increase in po accounts for the well-known increase in ICa by beta-adrenergic catecholamines. Cyclic AMP-dependent phosphorylation of calcium channels is a likely metabolic step involved in this modulation. Another class of drug that modulates calcium channel gating is the 1,4-dihydropyridines which can either enhance or reduce ICa, either by prolonging the open state of the channels or by facilitating the inactivated state. Both effects depend strongly on membrane potential and are independent of cyclic AMP-dependent phosphorylation reactions.


Emergence of a Novel Coronavirus (COVID-19): Protocol for Extending Surveillance Used by the Royal College of General Practitioners Research and Surveillance Centre and Public Health England.
The Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) and Public Health England (PHE) have successfully worked together on the surveillance of influenza and other infectious diseases for over 50 years, including three previous pandemics. With the emergence of the international outbreak of the coronavirus infection (COVID-19), a UK national approach to containment has been established to test people suspected of exposure to COVID-19. At the same time and separately, the RCGP RSC's surveillance has been extended to monitor the temporal and geographical distribution of COVID-19 infection in the community as well as assess the effectiveness of the containment strategy. The aims of this study are to surveil COVID-19 in both asymptomatic populations and ambulatory cases with respiratory infections, ascertain both the rate and pattern of COVID-19 spread, and assess the effectiveness of the containment policy. The RCGP RSC, a network of over 500 general practices in England, extract pseudonymized data weekly. This extended surveillance comprises of five components: (1) Recording in medical records of anyone suspected to have or who has been exposed to COVID-19. Computerized medical records suppliers have within a week of request created new codes to support this. (2) Extension of current virological surveillance and testing people with influenza-like illness or lower respiratory tract infections (LRTI)-with the caveat that people suspected to have or who have been exposed to COVID-19 should be referred to the national containment pathway and not seen in primary care. (3) Serology sample collection across all age groups. This will be an extra blood sample taken from people who are attending their general practice for a scheduled blood test. The 100 general practices currently undertaking annual influenza virology surveillance will be involved in the extended virological and serological surveillance. (4) Collecting convalescent serum samples. (5) Data curation. We have the opportunity to escalate the data extraction to twice weekly if needed. Swabs and sera will be analyzed in PHE reference laboratories. General practice clinical system providers have introduced an emergency new set of clinical codes to support COVID-19 surveillance. Additionally, practices participating in current virology surveillance are now taking samples for COVID-19 surveillance from low-risk patients presenting with LRTIs. Within the first 2 weeks of setup of this surveillance, we have identified 3 cases: 1 through the new coding system, the other 2 through the extended virology sampling. We have rapidly converted the established national RCGP RSC influenza surveillance system into one that can test the effectiveness of the COVID-19 containment policy. The extended surveillance has already seen the use of new codes with 3 cases reported. Rapid sharing of this protocol should enable scientific critique and shared learning. DERR1-10.2196/18606.


The effects of malaria chemoprophylaxis given by traditional birth attendants on the course and outcome of pregnancy.
A trial of malaria chemoprophylaxis given by traditional birth attendants was undertaken in a rural area of The Gambia where access to antenatal clinics is difficult. Women received one or more doses of Maloprim or placebo from a traditional birth attendant during 1049 of 1208 pregnancies (87%) recorded in 16 villages over a 3-year period. Primigravidae who received Maloprim had a lower parasite rate and a significantly higher mean packed cell volume than primigravidae who received placebo, and their babies were significantly heavier (6% low birth weight vs 22%). In multigravidae chemoprophylaxis reduced malaria parasitaemia but it had no beneficial effect on haemoglobin level and much less effect on birth weight than was observed in primigravidae. However, the mean birth weight of babies born to grandemultigravidae who received chemoprophylaxis was significantly higher than that of babies born to grandemultigravidae who did not.


Acute pancreatitis patient registry to examine novel therapies in clinical experience (APPRENTICE): an international, multicenter consortium for the study of acute pancreatitis.
We have established a multicenter international consortium to better understand the natural history of acute pancreatitis (AP) worldwide and to develop a platform for future randomized clinical trials. The AP patient registry to examine novel therapies in clinical experience (APPRENTICE) was formed in July 2014. Detailed web-based questionnaires were then developed to prospectively capture information on demographics, etiology, pancreatitis history, comorbidities, risk factors, severity biomarkers, severity indices, health-care utilization, management strategies, and outcomes of AP patients. Between November 2015 and September 2016, a total of 20 sites (8 in the United States, 5 in Europe, 3 in South America, 2 in Mexico and 2 in India) prospectively enrolled 509 AP patients. All data were entered into the REDCap (Research Electronic Data Capture) database by participating centers and systematically reviewed by the coordinating site (University of Pittsburgh). The approaches and methodology are described in detail, along with an interim report on the demographic results. APPRENTICE, an international collaboration of tertiary AP centers throughout the world, has demonstrated the feasibility of building a large, prospective, multicenter patient registry to study AP. Analysis of the collected data may provide a greater understanding of AP and APPRENTICE will serve as a future platform for randomized clinical trials.


A least-squares deconvolution technique for the photoelectric Fabry-Perot spectrometer.
A method is described for deconvolving into Voigt profiles a spectrum obtained with a Fabry-Perot spectrometer. This technique removes many of the limitations of some recently discussed schemes for analytically describing such spectroscopic data and reducing it to Voigt profiles. The use of a digital computer is assumed for all computations. The analytical description of the spectrometer includes all the important instrumental parameters as well as four adjustable profile parameters (position, amplitude, Lorentzian width, and Gaussian width) for each line present in the source spectrum. A least-squares adjustment of all nonfixed profile parameters is performed such that the sum of the individually fitted lines reproduces the recorded spectrum. This technique has been successfully applied to the thirteen fine structure components of the 4686-A line of He ii obtained with a double etalon Fabry-Perot spectrometer.


Dispersion flattening in a W fiber.
An exhaustive and simple method for dispersion flattening in double-clad single-mode fibers is presented. The idea is to generate all such fibers with a certain cutoff wavelength and then find, by one-dimensional minimization and direct inspection, fibers yielding minimum dispersion. As examples, the root mean square chromatic dispersion over the wavelength range (1.25, 1.60 µm) is minimized for a W fiber and also for a triangular-index fiber with a depressed inner cladding. The material dispersion is included through a Sellmeier refractive-index formula. The full vector solution of Maxwell's equations is used. It is found, as is well known, that the W fiber is capable of dispersion flattening. The validity of the numerical results presented depends on the validity of the approximate refractive-index model used.


Teleconsultation and Training of VHA Providers on Transgender Care: Implementation of a Multisite Hub System.
The Veterans Health Administration (VHA) is piloting a national program providing teleconsultation and training to clinicians to increase knowledge and comfort with treating transgender veterans and to expand clinical capacity. This program is based on Project ECHO and uses specialist expertise to train and educate front-line clinicians. Over time, the front-line clinicians increase knowledge and skills, enabling them to provide care locally and obviate need for patient travel. This program is innovative in its national scope, interdisciplinary team model, and multihub structure. This article describes development of the program and initial results for the first cohort of learners. Five interdisciplinary clinical teams participated in the 14-session, 7-month program. Most teams had some experience treating transgender veterans prior to participation. The teams completed at least 12 of 14 sessions. Thirteen of 33 participants completed an evaluation. In general, respondents found the teleconsultation program very helpful and credited the experience with improving their team functioning. Furthermore, respondents reported a significant increase in confidence to treat transgender veterans by the end of the program (59% versus 83%). We explored whether it is possible to recruit VHA clinical teams to participate in lengthy training on a low prevalence but complex condition. Early results support the feasibility and effectiveness of this national VHA teleconsultation and training program for transgender care. Lessons learned from the first group of learners have been applied to two concurrent groups with positive results.


A prospective study of hearing preservation in untreated vestibular schwannomas.
The authors previously published a systematic review of the English language literature regarding the natural history of untreated vestibular schwannomas (VSs). This analysis found that the best predictor of future hearing loss was tumor growth > 2.5 mm/year on serial imaging, a factor that doubled the rate of hearing loss. In this paper the authors present an analysis of prospectively collected outcomes in patients with untreated VS from their institution that confirms their previous findings. Clinical, radiographic, and audiometric data for all patients evaluated for VS at the authors' institution over a 22-year period were prospectively collected in a database. All patients in this database who had serviceable hearing (American Academy of Otolaryngology-Head and Neck Surgery Grade A or B) on initial presentation were selected, and underwent serial observation. Magnetic resonance imaging and audiometric data were analyzed, and the time from presentation until hearing loss was analyzed using Kaplan-Meier analysis. Fifty-nine patients with VS who initially presented with serviceable hearing were treated conservatively over this period. Consistent with the authors' previous findings, patients with a tumor growth rate > 2.5 mm/year at any point during follow-up lost their hearing at a much faster rate than those who had slower growing tumors. The median time to hearing loss was 7.0 years in those patients with tumor growth rate > 2.5 mm/year compared to 14.8 years in the other patients (p < 0.0001). The estimated median time to hearing loss in the 3 initial tumor size groups was 11.6 years in the intracanalicular group, 10.3 years in the group with 0.1-1 cm extension into the CPA cistern, and 9.3 years in the group with > 1 cm extension into the CPA cistern (p value nonsignificant). Initial tumor size, age at diagnosis, and neurofibromatosis Type 2 status did not affect the time to loss of serviceable hearing. Interestingly, many patients who were followed up for more than a decade eventually lost their hearing, regardless of whether the tumor displayed any documented interval growth. The authors confirmed the findings of their systematic review of the literature using a prospectively followed group of patients with untreated VS. Collectively, these data suggest that the expectation for more rapid hearing loss should be communicated to patients, and the decision for surgical or other intervention should be made in the context of the known risk of continued observation of fast growing tumors.


Age dependency of risk factors for cognitive decline.
Risk factors for cognitive decline might depend on chronological age. The aim of the study was to explore the age dependency of risk factors for cognitive decline in cognitively healthy subjects aged 55-85 years at baseline. We included 2527 cognitively healthy subjects from the Longitudinal Aging Study Amsterdam (LASA). Median follow-up was 9.1 (IQR: 3.2-19.0) years. The association of genetic and cardiovascular risk factors, depressive symptoms, inflammation markers and lifestyle risk factors with decline in MMSE and memory function was tested using spline regression analyses. Subjects were on average 70.1 (SD 8.8) years old at baseline. Based on a spline regression model, we divided our sample in three age groups: ≤70 years (young-old), > 70-80 years (old) and > 80 years (oldest-old). The association of LDL cholesterol, homocysteine, hypertension, history of stroke, depressive symptoms, interleukin-6, a1-antichymotrypsin, alcohol use and smoking with cognitive decline significantly differed between the age groups. In general, the presence of these risk factors was associated with less cognitive decline in the oldest-old group compared to the young-old and old group. The negative effect of various risk factors on cognitive decline decreases with higher age. A combination of epidemiological factors, such as the selection towards healthier subjects during follow-up, but also risk factor specific features, for example ensuring the cerebral blood flow in case of hypertension, explain this diminished association at higher age. It is important to take these age differences into account when applying preventive strategies to avert cognitive decline.


Sustained signalling by PTH modulates IP3 accumulation and IP3 receptors through cyclic AMP junctions.
Parathyroid hormone (PTH) stimulates adenylyl cyclase through type 1 PTH receptors (PTH1R) and potentiates the Ca(2+) signals evoked by carbachol, which stimulates formation of inositol 1,4,5-trisphosphate (IP3). We confirmed that in HEK cells expressing PTH1R, acute stimulation with PTH(1-34) potentiated carbachol-evoked Ca(2+) release. This was mediated by locally delivered cyclic AMP (cAMP), but unaffected by inhibition of protein kinase A (PKA), exchange proteins activated by cAMP, cAMP phosphodiesterases (PDEs) or substantial inhibition of adenylyl cyclase. Sustained stimulation with PTH(1-34) causes internalization of PTH1R-adenylyl cyclase signalling complexes, but the consequences for delivery of cAMP to IP3R within cAMP signalling junctions are unknown. Here, we show that sustained stimulation with PTH(1-34) or with PTH analogues that do not evoke receptor internalization reduced the potentiated Ca(2+) signals and attenuated carbachol-evoked increases in cytosolic IP3. Similar results were obtained after sustained stimulation with NKH477 to directly activate adenylyl cyclase, or with the membrane-permeant analogue of cAMP, 8-Br-cAMP. These responses were independent of PKA and unaffected by substantial inhibition of adenylyl cyclase. During prolonged stimulation with PTH(1-34), hyperactive cAMP signalling junctions, within which cAMP is delivered directly and at saturating concentrations to its targets, mediate sensitization of IP3R and a more slowly developing inhibition of IP3 accumulation.


Gray Matter and Functional Connectivity in Anterior Cingulate Cortex are Associated with the State of Mental Silence During Sahaja Yoga Meditation.
Some meditation techniques teach the practitioner to achieve the state of mental silence. The aim of this study was to investigate brain regions that are associated with their volume and functional connectivity (FC) with the depth of mental silence in long-term practitioners of Sahaja Yoga Meditation. Twenty-three long-term practitioners of this meditation were scanned using Magnetic Resonance Imaging. In order to identify the neural correlates of the depth of mental silence, we tested which gray matter volumes (GMV) were correlated with the depth of mental silence and which regions these areas were functionally connected to under a meditation condition. GMV in medial prefrontal cortex including rostral anterior cingulate cortex were positively correlated with the subjective perception of the depth of mental silence inside the scanner. Furthermore, there was significantly increased FC between this area and bilateral anterior insula/putamen during a meditation-state specifically, while decreased connectivity with the right thalamus/parahippocampal gyrus was present during the meditation-state and the resting-state. The capacity of long-term meditators to establish a durable state of mental silence inside an MRI scanner was associated with larger gray matter volume in a medial frontal region that is crucial for top-down cognitive, emotion and attention control. This is furthermore corroborated by increased FC of this region during the meditation-state with bilateral anterior insula/putamen, which are important for interoception, emotion, and attention regulation. The findings hence suggest that the depth of mental silence is associated with medial fronto-insular-striatal networks that are crucial for top-down attention and emotional control.


Immunogenetics of autoimmune thyroid diseases: A comprehensive review.
Both environmental and genetic triggers factor into the etiology of autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT). Although the exact pathogenesis and causative interaction between environment and genes are unknown, GD and HT share similar immune-mediated mechanisms of disease. They both are characterized by the production of thyroid autoantibodies and by thyroidal lymphocytic infiltration, despite being clinically distinct entities with thyrotoxicosis in GD and hypothyroidism in HT. Family and population studies confirm the strong genetic influence and inheritability in the development of AITD. AITD susceptibility genes can be categorized as either thyroid specific (Tg, TSHR) or immune-modulating (FOXP3, CD25, CD40, CTLA-4, HLA), with HLA-DR3 carrying the highest risk. Of the AITD susceptibility genes, FOXP3 and CD25 play critical roles in the establishment of peripheral tolerance while CD40, CTLA-4, and the HLA genes are pivotal for T lymphocyte activation and antigen presentation. Polymorphisms in these immune-modulating genes, in particular, significantly contribute to the predisposition for GD, HT and, unsurprisingly, other autoimmune diseases. Emerging evidence suggests that single nucleotide polymorphisms (SNPs) in the immunoregulatory genes may functionally hinder the proper development of central and peripheral tolerance and alter T cell interactions with antigen presenting cells (APCs) in the immunological synapse. Thus, susceptibility genes for AITD contribute directly to the key mechanism underlying the development of organ-specific autoimmunity, namely the breakdown in self-tolerance. Here we review the major immune-modulating genes that are associated with AITD and their potential functional effects on thyroidal immune dysregulation.


Compliance of clinical trial registries with the World Health Organization minimum data set: a survey.
Since September 2005 the International Committee of Medical Journal Editors has required that trials be registered in accordance with the World Health Organization (WHO) minimum dataset, in order to be considered for publication. The objective is to evaluate registries' and individual trial records' compliance with the 2006 version of the WHO minimum data set. A retrospective evaluation of 21 online clinical trial registries (international, national, specialty, pharmaceutical industry and local) from April 2005 to February 2007 and a cross-sectional evaluation of a stratified random sample of 610 trial records from the 21 registries. Among 11 registries that provided guidelines for registration, the median compliance with the WHO criteria were 14 out of 20 items (range 6 to 20). In the period April 2005-February 2007, six registries increased their compliance by six data items, on average. None of the local registry websites published guidelines on the trial data items required for registration. Slightly more than half (330/610; 54.1%, 95% CI 50.1% - 58.1%) of trial records completed the contact details criteria while 29.7% (181/610, 95% CI 26.1% - 33.5%) completed the key clinical and methodological data fields. While the launch of the WHO minimum data set seemed to positively influence registries with better standardisation of approaches, individual registry entries are largely incomplete. Initiatives to ensure quality assurance of registries and trial data should be encouraged. Peer reviewers and editors should scrutinise clinical trial registration records to ensure consistency with WHO's core content requirements when considering trial-related publications.


Systematic error detection in experimental high-throughput screening.
High-throughput screening (HTS) is a key part of the drug discovery process during which thousands of chemical compounds are screened and their activity levels measured in order to identify potential drug candidates (i.e., hits). Many technical, procedural or environmental factors can cause systematic measurement error or inequalities in the conditions in which the measurements are taken. Such systematic error has the potential to critically affect the hit selection process. Several error correction methods and software have been developed to address this issue in the context of experimental HTS 1234567. Despite their power to reduce the impact of systematic error when applied to error perturbed datasets, those methods also have one disadvantage - they introduce a bias when applied to data not containing any systematic error 6. Hence, we need first to assess the presence of systematic error in a given HTS assay and then carry out systematic error correction method if and only if the presence of systematic error has been confirmed by statistical tests. We tested three statistical procedures to assess the presence of systematic error in experimental HTS data, including the χ2 goodness-of-fit test, Student's t-test and Kolmogorov-Smirnov test 8 preceded by the Discrete Fourier Transform (DFT) method 9. We applied these procedures to raw HTS measurements, first, and to estimated hit distribution surfaces, second. The three competing tests were applied to analyse simulated datasets containing different types of systematic error, and to a real HTS dataset. Their accuracy was compared under various error conditions. A successful assessment of the presence of systematic error in experimental HTS assays is possible when the appropriate statistical methodology is used. Namely, the t-test should be carried out by researchers to determine whether systematic error is present in their HTS data prior to applying any error correction method. This important step can significantly improve the quality of selected hits.


Incipient de novo genes can evolve from frozen accidents that escaped rapid transcript turnover.
A recent surge of studies have suggested that many novel genes arise de novo from previously noncoding DNA and not by duplication. However, most studies concentrated on longer evolutionary time scales and rarely considered protein structural properties. Therefore, it remains unclear how these properties are shaped by evolution, depend on genetic mechanisms and influence gene survival. Here we compare open reading frames (ORFs) from high coverage transcriptomes from mouse and another four mammals covering 160 million years of evolution. We find that novel ORFs pervasively emerge from noncoding regions but are rapidly lost again, while relatively fewer arise from the divergence of coding sequences but are retained much longer. We also find that a subset (14%) of the mouse-specific ORFs bind ribosomes and are potentially translated, showing that such ORFs can be the starting points of gene emergence. Surprisingly, disorder and other protein properties of young ORFs hardly change with gene age in short time frames. Only length and nucleotide composition change significantly. Thus, some transcribed de novo genes resemble 'frozen accidents' of randomly emerged ORFs that survived initial purging. This perspective complies with very recent studies indicating that some neutrally evolving transcripts containing random protein sequences may be translated and be viable starting points of de novo gene emergence.


Risk factors for outbreaks of infectious salmon anemia in farmed Atlantic salmon, Salmo salar.
Infectious salmon anemia (ISA) is a viral disease occurring in farmed Atlantic salmon (Salmo salar) that is characterized by lethargy, anorexia, anemia and death. To control the disease in New Brunswick, Canada, 7.5 million fish from outbreak cages have been destroyed since 1997. Despite changes made by farmers, 2002 was the worst year ever for ISA losses in the region. We evaluated the associations between potential risk factors and ISA outbreaks in the Atlantic-salmon sites in New Brunswick. This was a multilevel study in which the site-level design was a retrospective cohort study while the cage-level design was a modified case-cohort study. The questionnaire was divided into site-level questions, cage-level questions and hatchery information. The important factors identified by this study can be categorized as environmental, farmer controlled or industry controlled according to the capacity to change or eliminate them. Environmental risk factors such as increasing the depth of the net (if nets were <or=9 m, odds ratio (OR)=3.34) and decreasing the depth of water underneath the net (if depth of water underneath the net >3m, OR=3.34) are for the most part dictated by site location. Wild pollock (Pollachius virens) in the cage reflects the number of wild pollock that live in the site location. If there were >or=1000 pollock in the cage, the odds of disease in the cage increased 4.43-fold. Risk factors that are under farm control include increasing the number of times that the salmon are treated for sea lice (OR=3.31 if lice treatments are <or=2 times), transferring small smolts into seawater (OR=2.40 if smolts weighed >99 g) and improving on the adaptation of smolts to seawater to reduce post-transfer mortalities (OR=4.52 if there was at least one cage with post-transfer mortalities >5%). The industry-controlled factors need to be addressed by the industry as a whole. Organizing boat travel to minimize the time and frequency of boats travelling to or by sites currently is being reviewed. This will be extremely important because the OR=9.43 if processing boats travel within 1 km of the site and the OR=4.03 if the site has dry feed delivered by the feed company. Because the hazard ratio increased stepwise from 1 if the nearest neighbor with ISA was >or=5 km up to 5.5 if the nearest site with ISA was within 0.5 km, increasing the distance between sites might be necessary for effective control.


Impact of frequency of internet use on development of brain structures and verbal intelligence: Longitudinal analyses.
Excessive internet use is shown to be cross sectionally associated with lower cognitive functioning and reduced volume of several brain areas. However, the effects of daily internet use on the development of verbal intelligence and brain structures have not been investigated. Here, we cross sectionally examined the effects of the frequency of internet use on regional gray/white matter volume (rGMV/rWMV) and verbal intelligence as well as their longitudinal changes after 3.0 ± 0.3 (standard deviation) years in a large sample of children recruited from the general population (mean age, 11.2 ± 3.1 years; range, 5.7-18.4 years). Although there were no significant associations in cross sectional analyses, a higher frequency of internet use was found to be associated with decrease of verbal intelligence and smaller increase in rGMV and rWMV of widespread brain areas after a few years in longitudinal analyses. These areas involve areas related to language processing, attention and executive functions, emotion, and reward. In conclusion, frequent internet use is directly or indirectly associated with decrease of verbal intelligence and development to smaller gray matter volume at later stages.