Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach with stage III/IV Hodgkin lymphoma.
Patients with advanced-stage Hodgkin lymphoma (HL) demonstrated excellent 2-year progression-free survival (PFS) after receiving positron emission tomography (PET)-adapted therapy on SWOG S0816. Patients received 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Patients achieving complete response (CR) on PET scan following cycle 2 of ABVD (PET2) continued 4 additional cycles of ABVD. Patients not achieving CR on PET2 were switched to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for 6 cycles. After a median follow-up of 5.9 years, a subset of 331 eligible patients with central review of PET2 was analyzed. PET2 was negative in 82% and positive in 18%. For all patients, the estimated 5-year PFS and OS was 74% (95% confidence interval [CI], 69%-79%) and 94% (95% CI, 91%-96%), respectively. For PET2- and PET2+ patients, the 5-year PFS was 76% (95% CI, 70%-81%) and 66% (95% CI, 52%-76%), respectively. Seven (14%) and 6 (2%) patients reported second cancers after treatment with eBEACOPP and ABVD, respectively (P = .001). Long-term OS of HL patients treated on S0816 remains high. Nearly 25% of PET2- patients experienced relapse events, demonstrating limitations ABVD therapy and of the negative predictive value of PET2. In PET2+ patients who received eBEACOPP, PFS was favorable, but was associated with a high rate of second malignancies compared with historical controls. Our results emphasize the importance of long-term follow-up, and the need for more efficacious and less toxic therapeutic approaches for advanced-stage HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00822120.


Playing games with multiple access channels.
Communication networks have multiple users, each sending and receiving messages. A multiple access channel (MAC) models multiple senders transmitting to a single receiver, such as the uplink from many mobile phones to a single base station. The optimal performance of a MAC is quantified by a capacity region of simultaneously achievable communication rates. We study the two-sender classical MAC, the simplest and best-understood network, and find a surprising richness in both a classical and quantum context. First, we find that quantum entanglement shared between senders can substantially boost the capacity of a classical MAC. Second, we find that optimal performance of a MAC with bounded-size inputs may require unbounded amounts of entanglement. Third, determining whether a perfect communication rate is achievable using finite-dimensional entanglement is undecidable. Finally, we show that evaluating the capacity region of a two-sender classical MAC is in fact NP-hard.


Investigation of the influence of a large steel plate on the magnetic field distribution of a magnetic proximity detection system.
A magnetic proximity detection system is mounted on a mobile mining machine to prevent underground workers from being pinned or struck by machine motion. The system generates magnetic fields around the machine to determine safe working distances. The miner-worn component measures the magnetic field in order to approximate location. Large masses of steel, such as those from mining equipment, can alter the magnetic field distribution. This affects the locational accuracy of the system, thus adversely impacting worker safety. To examine this problem, U.S. National Institute for Occupational Safety and Health researchers developed a method and test system to study the influence of a steel mass on the magnetic field distribution. The results show that a steel plate can strengthen the magnetic field perpendicular to the generator by up to 40 percent. Furthermore, they show that the degree of the influence on the field distribution is a function of distance. The results from this study can be used to further develop and improve the performance and reliability of electromagnetic proximity detection systems used in underground mining applications.


Response of superficial proximal convoluted tubule to decreased and increased renal perfusion pressure. In vivo microperfusion study in rats.
Although urinary sodium excretion is positively influenced by acute changes in renal perfusion pressure, micropuncture studies show highly conflicting results concerning the response of superficial proximal tubule sodium reabsorption to changes in renal perfusion pressure. In the present study, the changes of superficial proximal reabsorption to decreased and increased renal perfusion pressure were determined in rats by an in vivo microperfusion method. In vivo microperfusion was selected as the method to determine the proximal sodium reabsorption because this method made it possible to deliver a constant fluid and electrolyte load to the proximal tubule without the influence of possible changes of glomerular filtration rate. Renal perfusion pressure was decreased from normal pressure by inflating a suprarenal aortic cuff and was increased from the normal level by the occlusion of celiac and mesenteric arteries and the infrarenal aorta. Although fractional excretion of sodium (FENa) in the urine was decreased from 1.24 +/- 0.23% to 0.45 +/- 0.11% (n = 7, p less than 0.01) when renal perfusion pressure was decreased from 125 +/- 6 to 99 +/- 3 mm Hg, absolute tubular reabsorption by the superficial proximal convoluted tubules was not increased (from 4.4 +/- 0.5 to 4.2 +/- 0.3 nl/min/mm, n = 22). When the renal perfusion pressure was elevated from 126 +/- 4 to 149 +/- 4 mm Hg, tubular reabsorption by the superficial proximal tubules was decreased from 4.1 +/- 0.3 to 2.5 +/- 0.3 nl/min/mm (n = 36, p less than 0.01) with an accompanying increase in FENa (from 1.28 +/- 0.24% to 2.29 +/- 0.37%, n = 9, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Canadian Stroke Best Practice Recommendations: Hyperacute Stroke Care Guidelines, Update 2015.
The 2015 update of the Canadian Stroke Best Practice Recommendations Hyperacute Stroke Care guideline highlights key elements involved in the initial assessment, stabilization, and treatment of patients with transient ischemic attack (TIA), ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and acute venous sinus thrombosis. The most notable change in this 5th edition is the addition of new recommendations for the use of endovascular therapy for patients with acute ischemic stroke and proximal intracranial arterial occlusion. This includes an overview of the infrastructure and resources required for stroke centers that will provide endovascular therapy as well as regional structures needed to ensure that all patients with acute ischemic stroke that are eligible for endovascular therapy will be able to access this newly approved therapy; recommendations for hyperacute brain and enhanced vascular imaging using computed tomography angiography and computed tomography perfusion; patient selection criteria based on the five trials of endovascular therapy published in early 2015, and performance metric targets for important time-points involved in endovascular therapy, including computed tomography-to-groin puncture and computed tomography-to-reperfusion times. Other updates in this guideline include recommendations for improved time efficiencies for all aspects of hyperacute stroke care with a movement toward a new median target door-to-needle time of 30 min, with the 90th percentile being 60 min. A stronger emphasis is placed on increasing public awareness of stroke with the recent launch of the Heart and Stroke Foundation of Canada FAST signs of stroke campaign; reinforcing the public need to seek immediate medical attention by calling 911; further engagement of paramedics in the prehospital phase with prehospital notification to the receiving emergency department, as well as the stroke team, including neuroradiology; updates to the triage and same-day assessment of patients with transient ischemic attack; updates to blood pressure recommendations for the hyperacute phase of care for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The goal of these recommendations and supporting materials is to improve efficiencies and minimize the absolute time lapse between stroke symptom onset and reperfusion therapy, which in turn leads to better outcomes and potentially shorter recovery times.


Is a secondary procedure necessary in every case of failed endoscopic treatment for vesicoureteral reflux?
Endoscopic treatment (ET) has become a widely accepted procedure for treating vesicoureteral reflux (VUR). However, patients followed up after ET over long periods have reported persistent or recurrent VUR. We evaluated the natural course of failed ET in patients who required further treatments to help physicians in making decisions on the treatment of VUR. We retrospectively reviewed the medical records of patients who were diagnosed with VUR and underwent ET from January 2006 to December 2009. A total of 165 patients with 260 ureters underwent ET. We compared the parameters of the patients according to ET success or failure and evaluated the natural course of the patients after ET failure. Mean VUR grade and positive photon defect were higher in the failed ET group than in the successful ET group. Six months after the operation, persistent or recurrent VUR was observed in 76 ureters (29.2%), and by 16.3 months after the operation, VUR resolution was observed in 18 ureters (23.7%). Twenty-five ureters (32.9%) without complications were observed conservatively. Involuntary detrusor contraction was found in 1 of 9 (11.1%) among the secondary ET success group, whereas in the secondary ET failure group, 4 of 6 (66.7%) had accompanying involuntary detrusor contraction. Patients in whom ET fails can be observed for spontaneous resolution of VUR unless they have febrile urinary tract infection or decreased renal function. Urodynamic study may be helpful in deciding whether a secondary procedure after ET failure is necessary.


Computational approaches toward the design of pools for the in vitro selection of complex aptamers.
It is well known that using random RNA/DNA sequences for SELEX experiments will generally yield low-complexity structures. Early experimental results suggest that having a structurally diverse library, which, for instance, includes high-order junctions, may prove useful in finding new functional motifs. Here, we develop two computational methods to generate sequences that exhibit higher structural complexity and can be used to increase the overall structural diversity of initial pools for in vitro selection experiments. Random Filtering selectively increases the number of five-way junctions in RNA/DNA pools, and Genetic Filtering designs RNA/DNA pools to a specified structure distribution, whether uniform or otherwise. We show that using our computationally designed DNA pool greatly improves access to highly complex sequence structures for SELEX experiments (without losing our ability to select for common one-way and two-way junction sequences).


The economic value of time of informal care and its determinants (The CUIDARSE Study).
The main aims of this paper are to analyse the monetary value of informal care time using different techniques and to identify significant variables associated with the number of caregiving hours. A multicentre study in two Spanish regions in adult caregivers was conducted. A total sample of 604 people was available. A multivariate analysis was performed to identify the variables associated with the number of hours of caregiving time. In the monetary valuation of informal care provided, three approaches were used: replacement cost method, opportunity cost and contingent valuation (willingness to pay and willingness to accept). The main determinants of the amount of time of informal care provided were age, gender, the level of care receiver´s dependence and the professional care services received (at home and out of home). The value estimated for informal care time ranges from EUROS 80,247 (replacement cost method) to EUROS 14,325 (willingness to pay), with intermediate values of EUROS 27,140 and EUROS 29,343 (opportunity cost and willingness to accept, respectively). Several sensitivity analyses were performed over the base cases, confirming the previous results. Time of informal care represents a great social value, regardless of the applied technique. However, the results can differ strongly depending on the technique chosen. Therefore, the choice of technique of valuation is not neutral. Among the determinants of informal care time, the professional care received at home has a complementary character to informal care, while the formal care outside the home has a substitute character.


Bioterrorism and electron microscopic differentiation of poxviruses from herpesviruses: dos and don'ts.
With increased threat of terrorism, much attention is being directed toward readiness for biodefense. Smallpox virus, a deadly and much feared organism, is among possible bioterrorism agents. Herpesviruses, such as the one that causes chickenpox and shingles, produce skin lesions that may resemble those seen early in smallpox infection. Electron microscopy (EM) is a rapid and reliable method for differentiating poxviruses from herpesviruses. However, before becoming involved in the monitoring of potential smallpox cases, a laboratory must consider several issues, including expertise in virus identification, capacity for handling biohazards, and health and immune status of laboratory staff.


Embryonic development in the reduced folate carrier knockout mouse is modulated by maternal folate supplementation.
The reduced folate carrier (RFC1) is a ubiquitously expressed integral membrane protein that mediates delivery of 5-methyltetrahydrofolate into mammalian cells. In this study, embryonic/fetal development is characterized in an RFC1 knockout mouse model in which pregnant dams receive different levels of folate supplementation. RFC1(+/-) males were mated to RFC1(+/-) females, and pregnant dams were treated with vehicle (control) or folic acid (25 or 50 mg/kg) by daily subcutaneous injection (0.1 mL/10 g bwt), beginning on E0.5 and continuing throughout gestation until the time of sacrifice. Without maternal folate supplementation, RFC1 nullizygous embryos die shortly postimplantation. Supplementation of pregnant dams with 25 mg/kg/day folic acid prolongs survival of mutant embryos until E9.5-E10.5, but they are developmentally delayed relative to wild-type littermates, display a marked absence of erythropoiesis, severe neural tube and limb bud defects, and failure of chorioallantoic fusion. Fgfr2 protein levels are significantly reduced or absent in the extraembryonic membranes of RFC1 nullizygous embryos. Maternal folate supplementation with 50 mg/kg/day results in survival of 22% of RFC1 mutants to E18.5, but they develop with multiple malformations of the eyelids, lungs, heart, and skin. High doses of daily maternal folate supplementation during embryonic/fetal development are necessary for early postimplantation embryonic viability of RFC1 nullizygous embryos, and play a critical role in chorioallantoic fusion, erythropoiesis, and proper development of the neural tube, limbs, lungs, heart, and skin.


Functional transfer of eukaryotic expression plasmids to mammalian cells by Listeria monocytogenes: a mechanistic approach.
Cystic fibrosis (CF) is one of the most common monogenic disorders in the caucasian population. Gene therapy for CF is principally feasible and bacterial transfer systems might provide novel possibilities for therapy. However, transfection efficiencies are low and need to be improved. Thus, more detailed understanding of the DNA transfer mechanism is necessary to systematically eliminate these restrictions. Functional transfer of GFP-CFTR (cystic fibrosis transmembrane conductance regulator) to eukaryotic cells using attenuated Listeria monocytogenes mediated gene transfer (bacteriofection) was shown by fluorescent microscopy, flow cytometry, immunoblotting and whole cell patch clamping. The characteristics of plasmid transfer were studied by use of electron and fluorescence microscopy, flow cytometry and Southern blotting. Polymerase chain reaction (PCR) was used to screen the genome of bacteriofected cells for cotransfer of chromosomal bacterial DNA. Correct intracellular localization and functionality of the GFP-CFTR fusion protein after bacteriofection was shown. Efficient bacterial lysis and release of bacterial content was demonstrated using antibiotics to kill intracellular bacteria. Although only low transfection rates were observed, high numbers of transferred plasmids were detected in host cells under these conditions. However, they were associated with high molecular weight entities and not available to cytosolic transcription. Cotransfer of bacterial genomic DNA was observed in transfectants but occurred at low frequencies. In this work we demonstrate that low rates of bacteria-mediated transfection are not due to poor invasion of bacteria, insufficient bacterial lysis, or plasmid DNA degradation. Our data suggest that the transferred plasmid DNA is associated with higher macromolecular structures inhibiting nuclear transport and transgene transcription.


Experimental measurement of dynamic fluid shear stress on the ventricular surface of the aortic valve leaflet.
Aortic valve (AV) calcification is a highly prevalent disease with serious impact on mortality and morbidity. The exact causes and mechanisms of AV calcification are unclear, although previous studies suggest that mechanical forces play a role. It has been clinically demonstrated that calcification preferentially occurs on the aortic surface of the AV. This is hypothesized to be due to differences in the mechanical environments on the two sides of the valve. It is thus necessary to characterize fluid shear forces acting on both sides of the leaflet to test this hypothesis. The current study is one of two studies characterizing dynamic shear stress on both sides of the AV leaflets. In the current study, shear stresses on the ventricular surface of the AV leaflets were measured experimentally on two prosthetic AV models with transparent leaflets in an in vitro pulsatile flow loop using two-component Laser Doppler Velocimetry (LDV). Experimental measurements were utilized to validate a theoretical model of AV ventricular surface shear stress based on the Womersley profile in a straight tube, with corrections for the opening angle of the valve leaflets. This theoretical model was applied to in vivo data based on MRI-derived volumetric flow rates and valve dimension obtained from the literature. Experimental results showed that ventricular surface shear stress was dominated by the streamwise component. The systolic shear stress waveform resembled a half-sinusoid during systole and peaks at 64-71 dyn/cm(2), and reversed in direction at the end of systole for 15-25 ms, and reached a significant negative magnitude of 40-51 dyn/cm(2). Shear stresses from the theoretical model applied to in vivo data showed that shear stresses peaked at 77-92 dyn/cm(2) and reversed in direction for substantial period of time (108-110 ms) during late systole with peak negative shear stress of 35-38 dyn/cm(2).


A Clinical Trial Comparing the Safety and Efficacy of Topical Tacrolimus versus Methylprednisolone in Ocular Graft-versus-Host Disease.
To evaluate the safety and efficacy of topical tacrolimus 0.05% versus topical methylprednisolone 0.5% in patients with ocular graft-versus-host disease (GVHD). Phase 1/2 prospective, randomized, double-masked clinical trial. Eighty eyes of 40 patients diagnosed with chronic ocular GVHD were enrolled. Forty patients with ocular GVHD were randomized; 24 patients were treated with topical tacrolimus 0.05% and 16 patients were treated with topical methylprednisolone 0.5% twice daily for 10 weeks, in addition to continuing their baseline treatment regimen. Safety was evaluated based on occurrence of adverse events. Tolerability was assessed based on subject reports of discomfort after drop instillation. Intraocular pressure (IOP) was monitored. The main efficacy end points were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1). Symptoms were evaluated using the Ocular Surface Disease Index (OSDI). After 10 weeks of treatment, no major adverse events occurred in either treatment group, and there was no significant difference in the composite tolerability scores between the 2 groups (P = 0.06). However, burning sensation was more pronounced with tacrolimus (P = 0.002). Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score at week 10 (55% vs. 23% reduction, respectively; P = 0.01) and achieved significant improvement in TBUT when compared with baseline (P < 0.001). Reduction in OSDI score achieved statistical significance with tacrolimus (27% reduction; P = 0.02), but was marginal with methylprednisolone (32% reduction; P = 0.06). Expression of ICAM-1 by ocular surface epithelium decreased significantly in both groups (tacrolimus, P = 0.003; methylprednisolone, P = 0.008), whereas HLA-DR expression decreased significantly only in the tacrolimus group (P = 0.03). Schirmer test scores did not change significantly in either group during the study; IOP increased significantly with methylprednisolone at week 10 (P = 0.04). Topical tacrolimus 0.05% is safe, generally well tolerated, and effective for the treatment of ocular GVHD without the hypertensive effects of topical corticosteroids.


Ultrasonographic assessment of fetal nuchal translucency (NT) at 11th and 14th week of gestation--Polish multicentre study.
THE AIMS OF THE STUDY WERE: To evaluate range and median values of NT in a large, unselected Polish population; to determine the value of the 95th percentile and the median values for NT for given weeks of late 1st trimester pregnancy and to determine the level of chromosomal aberration risk corresponding to the values of the 95th percentile in the examined groups; to examine the possible correlation between CRL, NT width as well as the mother's age with the risk of the most frequent chromosomal aberrations. We have retrospective analyzed 7,866 pregnant women. All fetuses of this women had NT measurement performed, as well as CRL and assessed of the most frequent chromosomal abnormalities. The group of pregnant women was divided into 2 subgroups: until and above 35 years old. All population group was divided into 3 subgroups depending on gestational age (11, 12 and above 13th weeks of gestation). The median of NT in all population group was 1.5 mm and 95th percentile was 2.4 mm, whilst in group with low risk median of NT and 95th percentile were the same and in group with high risk of chromosomal abnormalities respectively 1.5 mm and 2.5 mm. There were strong correlations between maternal age and the risk of most frequent chromosomal abnormalities from NT. The obtained results of median values and the 95th percentiles of NT in the examined group and the age groups under 35 and 35 plus are similar to these quoted by FMF. The risk levels of trisomy of 21st chromosome were similar to the reference values used by FMF. With gestational age, NT value increases in a non-linear way, therefore it is incorrect to use the term "a normal value" for NT, therefore, only the risk level calculated with the dedicated software using NT and CRL measurements with maternal age should be stated.


Influence of landscape and social interactions on transmission of disease in a social cervid.
The mechanisms of pathogen transmission are often social behaviours. These occur at local scales and are affected by landscape-scale population structure. Host populations frequently exist in patchy and isolated environments that create a continuum of genetic and social familiarity. Such variability has an important multispatial effect on pathogen spread. We assessed elk dispersal (i.e. likelihood of interdeme pathogen transmission) through spatially explicit genetic analyses. At a landscape scale, the elk population was composed of one cluster within a southeast-to-northwest cline spanning three spatially discrete subpopulations of elk across two protected areas in Manitoba (Canada). Genetic data are consistent with spatial variability in apparent prevalence of bovine tuberculosis (TB) in elk. Given the existing population structure, between-subpopulation spread of disease because of elk dispersal is unlikely. Furthermore, to better understand the risk of spread and distribution of the TB, we used a combination of close-contact logging biotelemetry and genetic data, which highlights how social intercourse may affect pathogen transmission. Our results indicate that close-contact interaction rate and duration did not covary with genetic relatedness. Thus, direct elk-to-elk transmission of disease is unlikely to be constrained to related individuals. That social intercourse in elk is not limited to familial groups provides some evidence pathogen transmission may be density-dependent. We show that the combination of landscape-scale genetics, relatedness and local-scale social behaviours is a promising approach to understand and predict landscape-level pathogen transmission within our system and within all social ungulate systems affected by transmissible diseases.


Responsiveness of the Countermovement Jump and Handgrip Strength to an Incremental Running Test in Endurance Athletes: Influence of Sex.
The present study analyzed the acute effects of an incremental running test on countermovement jump (CMJ) and handgrip strength performance in endurance athletes, considering the effect of post-exercise recovery time and sex. Thirty-three recreationally trained long-distance runners, 20 men and 13 women, participated voluntarily in this study. The participants performed the Léger test, moreover, the CMJ and handgrip strength tests were carried out before and after the running test and during different stages of recovery (at the 1st min of recovery (posttest1), 5th min of recovery (posttest2), and 10th min of recovery (posttest3)). Two-way analysis of variance revealed a significant improvement in the CMJ (pre-posttest1, p = 0.001) and handgrip strength (pre-posttest2, p = 0.017) during recovery time. The Pearson's Chi-2 test showed no significant relationship (p ≥ 0.05) between sex and post-activation potentiation (PAP). A linear regression analysis pointed to heart rate recovery as a predictive factor of CMJ improvement (PAP). In conclusion, despite significant fatigue reached during the Léger test, the long-distance runners did not experience an impaired CMJ and handgrip strength performance, either men or women, achieving an improvement (PAP) in posttest conditions. The results obtained showed no significant relationship between sex and PAP. Moreover, significant effect of recovery after running at high intensity on CMJ performance and handgrip strength was found. Finally, the data suggest that PAP condition can be predicted by heart rate recovery in endurance runners.


On the dynamic nature of Mo sites for methane dehydroaromatization.
The mechanism of methane activation on Mo/HZSM-5 is not yet fully understood, despite the great interest in methane dehydroaromatization (MDA) to replace aromatics production in oil refineries. It is difficult to assess the exact nature of the active site due to fast coking. By pre-carburizing Mo/HZSM-5 with carbon monoxide (CO), the MDA active site formation was isolated from coke formation. With this a clear 13C NMR signal solely from the active site and not obscured by coke was obtained, and it revealed two types of likely molecular Mo (oxy-)carbidic species in addition to the β-Mo2C nanoparticles often mentioned in the literature. Furthermore, separating the active site formation from coking by pre-carburization helped us examine how methane is activated on the catalytic site by carrying out MDA using isotopically labelled methane (13CH4). Carbon originating from the pre-formed carbide was incorporated into the main products of the reaction, ethylene and benzene, demonstrating the dynamic behavior of the (oxy-)carbidic active sites.


Characterization of a Mycobacterium tuberculosis peptide that is recognized by human CD4+ and CD8+ T cells in the context of multiple HLA alleles.
The secreted Mycobacterium tuberculosis 10-kDa culture filtrate protein (CFP)10 is a potent T cell Ag that is recognized by a high percentage of persons infected with M. tuberculosis. We determined the molecular basis for this widespread recognition by identifying and characterizing a 15-mer peptide, CFP10(71-85), that elicited IFN-gamma production and CTL activity by both CD4(+) and CD8(+) T cells from persons expressing multiple MHC class II and class I molecules, respectively. CFP10(71-85) contained at least two epitopes, one of 10 aa (peptide T1) and another of 9 aa (peptide T6). T1 was recognized by CD4(+) cells in the context of DRB1*04, DR5*0101, and DQB1*03, and by CD8(+) cells of A2(+) donors. T6 elicited responses by CD4(+) cells in the context of DRB1*04 and DQB1*03, and by CD8(+) cells of B35(+) donors. Deleting a single amino acid from the amino or carboxy terminus of either peptide markedly reduced IFN-gamma production, suggesting that they are minimal epitopes for both CD4(+) and CD8(+) cells. As far as we are aware, these are the shortest microbial peptides that have been found to elicit responses by both T cell subpopulations. The capacity of CFP10(71-85) to stimulate IFN-gamma production and CTL activity by CD4(+) and CD8(+) cells from persons expressing a spectrum of MHC molecules suggests that this peptide is an excellent candidate for inclusion in a subunit antituberculosis vaccine.


Coffee consumption and risk of rheumatoid arthritis.
Recent reports have suggested an association between consumption of coffee or decaffeinated coffee and the risk of rheumatoid arthritis (RA), although data are sparse and somewhat inconsistent. Furthermore, existing studies measured dietary exposures and potential confounders only at baseline and did not consider possible changes in diet or lifestyle over the followup period. We studied whether coffee, decaffeinated coffee, total coffee, tea, or overall caffeine consumption was associated with the risk of RA, using the Nurses' Health Study, a longitudinal cohort study of 121,701 women. Information on beverage consumption was assessed with a food frequency questionnaire (FFQ) that was completed every 4 years, from baseline in 1980 through 1998. Among the 83,124 women who completed the FFQ at baseline, the diagnosis of incident RA (between 1980 and 2000) was confirmed in 480 women by a connective tissue disease screening questionnaire and medical record review for American College of Rheumatology criteria. Relationships between intake of various beverages and the risk of RA were assessed in age-adjusted models and in multivariate Cox proportional hazards models including the cumulative average intake of each beverage during the followup period, adjusted for numerous potential confounders. In addition, for direct comparisons with prior reports, multivariate analyses were repeated using only baseline beverage information. We did not find a significant association between decaffeinated coffee consumption of >/=4 cups/day (compared with no decaffeinated coffee consumption) and subsequent risk of incident RA, in either an adjusted multivariate model (relative risk [RR] 1.1, 95% confidence interval [95% CI] 0.5-2.2) or a multivariate model using only baseline reports of decaffeinated coffee consumption (RR 1.0, 95% CI 0.6-1.7). Similarly, there was no relationship between cumulative caffeinated coffee consumption and RA risk (RR 1.1, 95% CI 0.8-1.6 for >/=4 cups per day versus none) or between tea consumption and RA risk (RR 1.1, 95% CI 0.7-1.8 for >3 cups/day versus none). Total coffee and total caffeine consumption were also not associated with the risk of RA. In this large, prospective study, we find little evidence of an association between coffee, decaffeinated coffee, or tea consumption and the risk of RA among women.


Quality of Life and Life Satisfaction in Former Athletes: A Systematic Review and Meta-Analysis.
Sport participation has many physical and psychosocial benefits, but there is also an inherent risk of injury, subsequent osteoarthritis and psychological challenges that can negatively impact quality of life (QOL). Considering the multifaceted impacts of sport participation on QOL across the lifespan, there is a need to consolidate and present the evidence on QOL in former sport participants. To evaluate QOL and life satisfaction in former sport participants, and determine what factors are associated with QOL and life satisfaction in this population. Eight electronic databases were systematically searched in July 2018 to retrieve all articles that evaluated QOL or life satisfaction in former sport participants. Two authors independently screened titles/abstracts and full texts, extracted data, and appraised methodological quality using a modified Downs and Black Checklist. Random-effects meta-analysis estimated pooled mean and 95% confidence intervals (Cis) for Mental Component Scores (MCS) and Physical Component Scores (PCS) derived from the SF-12, SF-36, VR-12 and VR-36 measures. MCS and PCS were pooled for all former sport participants, as well as professional- and collegiate-athlete subgroups. Data that were inappropriate for meta-analysis (i.e. EQ-5D, PROMIS and life-satisfaction outcomes) were collated and reported descriptively. Seventeen articles evaluated QOL or life satisfaction in a total of 6692 former athletes [eight studies (n = 4255) former professional athletes; six studies (n = 1946) former collegiate athletes; two studies (n = 491) included both] with a mean age ranging from 21 to 66 years. Most studies were cross-sectional (15 of 17 articles) and 12 studies had a moderate risk of bias (n = 1 high-risk, n = 4 low-risk). Unpublished data were provided for five studies. Meta-analysis of seven studies resulted in a pooled PCS mean (95% CI) of 50.0 (46.6-53.3) [former professional athletes from two studies: 46.7 (42.1-51.2), former collegiate athletes from five studies: 51.2 (48.4-53.9)] and a pooled MCS of 51.4 (50.5-52.2) [former professional athletes: 52.7 (51.3-54.2), former collegiate athletes: 50.9 (50.0-51.8)]. Factors associated with worse QOL or life satisfaction in former athletes included involuntary retirement from sport (three studies), collision/high-contact sport compared with low/no-contact sport (three studies), three or more concussions compared with no/fewer concussions (two studies), increased body mass index (BMI) (worse PCS, three studies), and osteoarthritis or musculoskeletal issues (worse PCS and MCS, three studies; worse PCS but not MCS, two studies). Former athletes had similar PCS and better MCS, compared to general-population norms. Former athletes with impaired PCS reported better MCS than population norms, highlighting the need to use an instrument that differentiates between physical and mental components of QOL in former sport participants. Factors associated with worse QOL that may explain between-study variation include involuntary retirement, collision/high contact sports, concussion, BMI and osteoarthritis. CRD42018104319.


Large-scale binding of α-crystallin to cell membranes of aged normal human lenses: a phenomenon that can be induced by mild thermal stress.
With age, large amounts of crystallins become associated with fiber cell membranes in the human lens nucleus, and it has been proposed that this binding of protein may lead to the obstruction of membrane pores and the onset of a barrier to diffusion. This study focused on membrane binding within the barrier region and the outermost lens cortex. Human lenses across the age range were used, and the interaction of crystallins with membranes was examined using sucrose density gradient centrifugation, two-dimensional gel electrophoresis, and amine-reactive isobaric tagging technology. Lipids were quantified using shotgun lipidemics. Binding of proteins to cell membranes in the barrier region was found to be different from that in the lens nucleus because in the barrier and outer cortical regions, only one high-density band formed. Most of the membrane-associated protein in this high-density band was α-crystallin. Mild thermal stress of intact young lenses led to pronounced membrane binding of proteins and yielded a sucrose density pattern in all lens regions that appeared to be identical with that from older lenses. α-Crystallin is the major protein that binds to cell membranes in the barrier region of lenses after middle age. Exposure of young human lenses to mild thermal stress results in large-scale binding of α-crystallin to cell membranes. The density gradient profiles of such heated lenses appear to be indistinguishable from those of older normal lenses. The data support the hypothesis that temperature may be a factor responsible for age-related changes to the human lens.


Rare but active taxa contribute to community dynamics of benthic biofilms in glacier-fed streams.
Glaciers harbour diverse microorganisms, which upon ice melt can be released downstream. In glacier-fed streams microorganisms can attach to stones or sediments to form benthic biofilms. We used 454-pyrosequencing to explore the bulk (16S rDNA) and putatively active (16S rRNA) microbial communities of stone and sediment biofilms across 26 glacier-fed streams. We found differences in community composition between bulk and active communities among streams and a stronger congruence between biofilm types. Relative abundances of rRNA and rDNA were positively correlated across different taxa and taxonomic levels, but at lower taxonomic levels, the higher abundance in either the active or the bulk communities became more apparent. Here, environmental variables played a minor role in structuring active communities. However, we found a large number of rare taxa with higher relative abundances in rRNA compared with rDNA. This suggests that rare taxa contribute disproportionately to microbial community dynamics in glacier-fed streams. Our findings propose that high community turnover, where taxa repeatedly enter and leave the 'seed bank', contributes to the maintenance of microbial biodiversity in harsh ecosystems with continuous environmental perturbations, such as glacier-fed streams.


Has the economic crisis widened the intraurban socioeconomic inequalities in mortality? The case of Barcelona, Spain.
There is considerable evidence demonstrating socioeconomic inequalities in mortality, some of which focuses on intraurban inequalities. However, all the studies assume that the spatial variation of inequalities is stable over the time. We challenge this assumption and propose two hypotheses: (i) have spatial variations in socioeconomic inequalities in mortality at an intraurban level changed over time? and (ii) as a result of the economic crisis, has the gap between such disparities widened? In this paper, our objective is to assess the effect of the economic recession on the spatio-temporal variation of socioeconomic inequalities in mortality in Barcelona (Catalonia, Spain). We used a spatio-temporal ecological design to analyse mortality inequalities at small area level in Barcelona. Mortality data and socioeconomic indicators correspond to the years 2005 and 2008-2011. We specified spatio-temporal ecological mixed regressions for both men and women using two indicators, neighbourhood and year. We allowed the coefficients of the socioeconomic variables to differ according to the levels and explicitly took into account spatio-temporal adjustment. For men and women both absolute and, above all, relative risks for mortality have increased since 2009. In relative terms, this means that the risk of dying has increased much more in the most economically deprived neighbourhoods than in the more affluent ones. Although the geographical pattern in relative risks for mortality in neighbourhoods in Barcelona remained very stable between 2005 and 2011, socioeconomic inequalities in mortality at an intraurban level have surged since 2009.


Ongoing unraveling of a continental fauna: decline and extinction of Australian mammals since European settlement.
The highly distinctive and mostly endemic Australian land mammal fauna has suffered an extraordinary rate of extinction (>10% of the 273 endemic terrestrial species) over the last ∼200 y: in comparison, only one native land mammal from continental North America became extinct since European settlement. A further 21% of Australian endemic land mammal species are now assessed to be threatened, indicating that the rate of loss (of one to two extinctions per decade) is likely to continue. Australia's marine mammals have fared better overall, but status assessment for them is seriously impeded by lack of information. Much of the loss of Australian land mammal fauna (particularly in the vast deserts and tropical savannas) has been in areas that are remote from human population centers and recognized as relatively unmodified at global scale. In contrast to general patterns of extinction on other continents where the main cause is habitat loss, hunting, and impacts of human development, particularly in areas of high and increasing human population pressures, the loss of Australian land mammals is most likely due primarily to predation by introduced species, particularly the feral cat, Felis catus, and European red fox, Vulpes vulpes, and changed fire regimes.


Controlling single-molecule junction conductance by molecular interactions.
For the rational design of single-molecular electronic devices, it is essential to understand environmental effects on the electronic properties of a working molecule. Here we investigate the impact of molecular interactions on the single-molecule conductance by accurately positioning individual molecules on the electrode. To achieve reproducible and precise conductivity measurements, we utilize relatively weak π-bonding between a phenoxy molecule and a STM-tip to form and cleave one contact to the molecule. The anchoring to the other electrode is kept stable using a chalcogen atom with strong bonding to a Cu(110) substrate. These non-destructive measurements permit us to investigate the variation in single-molecule conductance under different but controlled environmental conditions. Combined with density functional theory calculations, we clarify the role of the electrostatic field in the environmental effect that influences the molecular level alignment.


Extracellular matrix scaffolds for treatment of large volume muscle injuries: A review.
Large muscular or musculotendinous defects present a dilemma because of the inadequacies of current treatment strategies. Extracellular matrices (ECM) are potential clinically applicable regenerative biomaterials. This review summarizes information from the preclinical literature evaluating the use of ECM for muscle regeneration in animal models of volumetric muscle loss (VML). Literature review. Animal models of VML in which surgical repair was performed with an ECM product, with or without added cell populations. PubMed, Google Scholar, CAB abstracts, and Scopus were searched for preclinical studies using ECM in animal models of VML. The search terms "extracellular matrix," "VML," "muscle regeneration," "cell seeded," and "scaffold" identified 40 articles that met inclusion criteria of an animal model of VML in which surgical repair was performed with an ECM product, with or without added cell populations. Key skeletal muscle repair mechanisms and experimental findings on scaffold type, VML location, and experimental animal species were summarized. Satellite cells and basal lamina are key endogenous contributors to skeletal muscle regeneration. ECM as a dynamic tissue component may provide structural integrity, signaling molecules, and a 3-dimensional topography conducive to muscle regeneration. Preclinical models of muscle repair most commonly used mice and rats (88%). Most experimental lesions were created in abdominal wall (33%), anterior tibialis (33%), latissimus dorsi (10%), or quadriceps (10%) muscles. Matrices varied markedly in source and preparation. Experimental outcomes of ECM and cell-seeded ECM implantation for muscle regeneration in VML were highly variable and dependent on matrix tissue source, preparation method, and anatomic site of injury. Scar tissue formation likely contributes to load transfer. Nonappendicular lesions had better regenerative results compared with appendicular VML. The preponderance of current evidence supports the use of ECM for muscle defect repair only in specific instances, such as nonappendicular and/or partial-thickness defects. Consequently, clinical use of ECM in veterinary patients requires careful consideration of the specific ECM product, lesion size and location, and loading circumstances.


The changing world of oncology drug development-A global pharmaceutical company's perspective.
Recent approvals for oncology drugs have seen an increasing proportion directed to specific genetic targets identified with an associated companion diagnostic test. In addition, there is a wave of drugs directed against immune 'checkpoints' which promise to transform the way cancer is treated in the next decade. We can increase the probability of success in drug development based on a thorough mechanistic understanding of how a target drug affects cancer biology and the specific biological and genotypic context in which it operates. This article compares and contrasts the discovery and development of gefitinib-the first EGFR tyrosine kinase inhibitor and AZD9291, an irreversible inhibitor of both sensitizing and resistant mutated EGFR. This demonstrates how the better understanding we now have of the genetic changes driving the cancer growth and the biochemical structure and function of the mutated proteins, has led to a much faster developmental path with higher likelihood of success in pivotal trials. An emerging trend in response to the challenge of the increasing segmentation of cancers based on their genetic makeup is the development of 'basket' studies which include one or more screening tests for multiple genetic aberrations and the direction of patients to one of several arms of a clinical trial based on the specific aberration in their tumor. In the face of both the wealth of genetic information about cancer and the challenges of drug development, collaboration across academia and industry is vital. There is great potential to benefit from more 'open innovation' to address some of these challenges and opportunities. Far from there being a decline in innovation in pharmaceutical development, I see that we are in one of the most exciting times in cancer drug development with innovation in every aspect of how we discover and develop new therapies.


Deficits in neuromuscular control of the trunk predict knee injury risk: a prospective biomechanical-epidemiologic study.
Female athletes are at significantly greater risk of anterior cruciate ligament (ACL) injury than male athletes in the same high-risk sports. Decreased trunk (core) neuromuscular control may compromise dynamic knee stability. (1) Increased trunk displacement after sudden force release would be associated with increased knee injury risk; (2) coronal (lateral), not sagittal, plane displacement would be the strongest predictor of knee ligament injury; (3) logistic regression of factors related to core stability would accurately predict knee, ligament, and ACL injury risk; and (4) the predictive value of these models would differ between genders. Cohort study (prognosis); Level of evidence, 2. In this study, 277 collegiate athletes (140 female and 137 male) were prospectively tested for trunk displacement after a sudden force release. Analysis of variance and multivariate logistic regression identified predictors of risk in athletes who sustained knee injury. Twenty-five athletes (11 female and 14 male) sustained knee injuries over a 3-year period. Trunk displacement was greater in athletes with knee, ligament, and ACL injuries than in uninjured athletes (P < .05). Lateral displacement was the strongest predictor of ligament injury (P = .009). A logistic regression model, consisting of trunk displacements, proprioception, and history of low back pain, predicted knee ligament injury with 91% sensitivity and 68% specificity (P = .001). This model predicted knee, ligament, and ACL injury risk in female athletes with 84%, 89%, and 91% accuracy, but only history of low back pain was a significant predictor of knee ligament injury risk in male athletes. Factors related to core stability predicted risk of athletic knee, ligament, and ACL injuries with high sensitivity and moderate specificity in female, but not male, athletes.


Monitoring inflammation (including fever) in acute brain injury.
Inflammation is an important part of the normal physiologic response to acute brain injury (ABI). How inflammation is manifest determines if it augments or hinders the resolution of ABI. Monitoring body temperature, the cellular arm of the inflammatory cascade, and inflammatory proteins may help guide therapy. This summary will address the utility of inflammation monitoring in brain-injured adults. An electronic literature search was conducted for English language articles describing the testing, utility, and optimal methods to measure inflammation in ABI. Ninety-four articles were included in this review. Current evidence suggests that control of inflammation after ABI may hold promise for advances in good outcomes. However, our understanding of how much inflammation is good and how much is deleterious is not yet clear. Several important concepts emerge form our review. First, while continuous temperature monitoring of core body temperature is recommended, temperature pattern alone is not useful in distinguishing infectious from noninfectious fever. Second, when targeted temperature management is used, shivering should be monitored at least hourly. Finally, white blood cell levels and protein markers of inflammation may have a limited role in distinguishing infectious from noninfectious fever. Our understanding of optimal use of inflammation monitoring after ABI is limited currently but is an area of active investigation.


A modular tethering complex for endosomal recycling.
How proteins migrate through the interconnected organelles of the endolysosomal system is poorly understood. A piece of the puzzle has been added with the identification of a complex of tethering factors that functions in the recycling of proteins towards the cell surface.


Obesity and its Link to Undiagnosed Diabetes Mellitus and Hypertension in Rural Parts of Western India.
Obesity and overweight are becoming major health concerns worldwide. Hence, we studied the association between overweight and obesity with new-onset diabetes and hypertension in a selected rural population. Community health workers made house-to-house visits, inviting adults >20 years of age who were at a higher risk of diabetes, from a predefined rural area of Maharashtra, to visit a mobile diabetes clinic operating in a hub and spoke manner. Sociodemographic data and anthropometric measurements were recorded. BMI and waist circumference was classified according to the WHO recommended cutoffs for Asians. Subjects with capillary blood fasting glucose of ≥126 mg/dL or random glucose of ≥200 mg/dL by glucometer were diagnosed as diabetes and blood pressure of ≥140/90 mmHg by sphygmomanometer were diagnosed as hypertension. Subjects with a known history of diabetes mellitus and hypertension were excluded. Out of 29,324 total population, 16.5% of subjects were overweight and 26.4% were obese. Mean ± SD of BMI of the participants was 22.9 ± 4.1 kg/m2 in males and 22.4 ± 4.2 kg/m2 in females. Around 35% of males and 30.5% of females had a high waist circumference of ≥90 cm and ≥80 cm, respectively, 20.5% of subjects had newly diagnosed hypertension, and 11.4% of subjects had newly diagnosed diabetes mellitus. The occurrence of newly diagnosed hypertension and diabetes showed an increasing trend with increasing BMI. Our community-based screening suggested a high prevalence of overweight and obesity in rural India. There was a high prevalence of newly diagnosed hypertension and diabetes in this population.


Psychological, cognitive factors and contextual influences in pain and pain-related suffering as revealed by a combined qualitative and quantitative assessment approach.
Previous psychophysiological research suggests that pain measurement needs to go beyond the assessment of Pain Intensity and Unpleasantness by adding the evaluation of Pain-Related Suffering. Based on this three-dimensional approach, we attempted to elucidate who is more likely to suffer by identifying reasons that may lead individuals to report Pain and Pain-Related Suffering more than others. A sample of 24 healthy participants (age range 18-33) underwent four different sessions involving the evaluation of experimentally induced phasic and tonic pain. We applied two decision tree models to identify variables (selected from psychological questionnaires regarding pain and descriptors from post-session interviews) that provided a qualitative characterization of the degrees of Pain Intensity, Unpleasantness and Suffering and assessed the respective impact of contextual influences. The overall classification accuracy of the decision trees was 75% for Intensity, 77% for Unpleasantness and 78% for Pain-Related Suffering. The reporting of suffering was predominantly associated with fear of pain and active cognitive coping strategies, pain intensity with bodily competence conveying strength and resistance and unpleasantness with the degree of fear of pain and catastrophizing. These results indicate that the appraisal of the three pain dimensions was largely determined by stable psychological constructs. They also suggest that individuals manifesting higher active coping strategies may suffer less despite enhanced pain and those who fear pain may suffer even under low pain. The second decision tree model revealed that suffering did not depend on pain alone, but that the complex rating-related decision making can be shifted by situational factors (context, emotional and cognitive). The impact of coping and fear of pain on individual Pain-Related Suffering may highlight the importance of improving cognitive coping strategies in clinical settings.


The metalloproteinase stromelysin-1 (transin) mediates PC12 cell growth cone invasiveness through basal laminae.
Matrix metalloproteinases have been implicated in various extracellular matrix remodeling events that occur during normal development and in a number of pathologies. In previous work with PC12 rat pheochromocytoma cells, we found that the matrix metalloproteinase stromelysin-1 (ST1) was highly induced by nerve growth factor (NGF), but not by epidermal growth factor (EGF). Here, we show that ST1 immunoreactivity is present in growth cones of NGF-treated PC12 cells, but not EGF-treated or untreated cells. To determine whether ST1 expression confers neurite invasiveness, three lines of PC12 cells were produced that constitutively express ST1 antisense mRNA. These lines expressed and secreted significantly reduced levels of ST1 protein, as determined by immunoblot and immunocytochemical methods, but otherwise responded normally to NGF-treatment by elaborating neurites. We found, however, that the neurites of these ST1 antisense cells showed a significantly reduced ability to penetrate a Matrigel reconstituted basal lamina, as compared to the parental cells, suggesting that ST1 confers neurite invasiveness. Finally, we show that ST1 is also expressed in vivo in sections through Embryonic Day 15 rat embryos, including neurons of both the peripheral and central nervous systems. These data indicate that ST1 may play a role in axonal growth in vivo, including a role in growth cone invasiveness.


Quantitative trait loci in a bacterially induced model of inflammatory bowel disease.
Inflammatory bowel diseases (IBDs) are complex disorders caused by a combination of environmental, microbial, and genetic factors. Genome-wide association studies in humans have successfully identified multiple genes and loci associated with disease susceptibility, but the mechanisms by which these loci interact with each other and/or with environmental factors (i.e., intestinal microbiota) to cause disease are poorly understood. Helicobacter hepaticus-induced intestinal inflammation in mice is an ideal model system for elucidating the genetic basis of IBD susceptibility in a bacterially induced system, as there are significant differences in H. hepaticus-induced disease susceptibility among inbred mouse strains. Infected A/J mice develop acute overexpression of proinflammatory cytokines followed 2-3 months later by chronic cecal inflammation, whereas infected C57BL/6 mice fail to develop cecal inflammation or increased cytokine expression. The goal of this project was to use quantitative trait locus (QTL) mapping to evaluate genetic factors that contribute to the differential disease susceptibility between these two mouse strains. Using acute cecal IL-12/23p40 expression as a biomarker for disease susceptibility, QTL analysis of H. hepaticus-infected F(2) mice revealed involvement of multiple loci. The loci with the strongest association were located on Chromosome 3 and Chromosome 17, with logarithm of odds (LOD) scores of 6.89 and 3.09, respectively. Cecal expression of IL-12/23p40 in H. hepaticus-infected C57BL/6J-Chr3(A/J)/NaJ chromosome substitution mice had an intermediate phenotype, significantly higher than in resistant C57BL/6 but lower than in susceptible A/J mice, confirming the importance of this locus to the immune response to H. hepaticus infection.


A selective effect of parietal damage on letter identification in mixed case words.
We investigated the reading of cAsE mIxInG and contrast reduction on word reading in patients with unilateral parietal lesions and attentional deficits. We show that, compared with control participants, the patients produce selective increases in lateralised errors when reading mixed case relative to same case words. However, there were not reliable increases in lateralised errors when words were degraded by low contrast. The patients also showed some increases in contralesional errors at a task aimed at feature processing in words (a gap detection task), but these effects were not increased for mixed case stimuli and errors were reduced relative to the word reading task. The results are consistent with mixed case words stressing attention-demanding letter identification, drawing-out an impairment in the patients in attending to contralesional stimuli. On the other hand, effects of contrast reduction are accommodated without necessarily recruiting attentional processes mediated by the posterior parietal lobe.


A longitudinal study of Neospora caninum infection on a dairy farm in New Zealand.
A 600-cow New Zealand dairy herd experienced an abortion storm in 1997 and was monitored (blood sampling at about 3-month intervals) from May 1997 until January 1999. Abortion risk reached 9% in 1997 and was highest in heifers at 19%. The abortion risk decreased in 1998 to 3.2% (still somewhat higher than during the years prior to the outbreak). The serological reaction pattern for Neospora caninum showed an association with abortion risk only around the time of the 1997 outbreak when seropositive cows were 4.2 times more likely to abort than negative ones. Over the whole study period, only 27% of cows that were sampled on all nine visits always tested negative. Offspring from dams which had positive tests for Neospora caninum were 2.4 times more likely to abort than those from dams testing consistently negative. Controlling for age and breed, seropositive cows produced more milk than those that were consistently negative. Infection might have been present endemically within this herd prior to the epidemic, but in 1997 an additional factor appeared to have triggered the outbreak.


Efficient phototrophic production of a high-value sesquiterpenoid from the eukaryotic microalga Chlamydomonas reinhardtii.
The heterologous expression of terpene synthases in microbial hosts has opened numerous possibilities for bioproduction of desirable metabolites. Photosynthetic microbial hosts present a sustainable alternative to traditional fermentative systems, using freely available (sun)light and carbon dioxide as inputs for bio-production. Here, we report the expression of a patchoulol synthase from Pogostemon cablin Benth in the model green microalga Chlamydomonas reinhardtii. The sesquiterpenoid patchoulol was produced from the alga and was used as a marker of sesquiterpenoid production capacity. A novel strategy for gene loading was employed and patchoulol was produced up to 922±242µgg-1 CDW in six days. We additionally investigated the effect of carbon source on sesquiterpenoid productivity from C. reinhardtii in scale-up batch cultivations. It was determined that up to 1.03mgL-1 sesquiterpenoid products could be produced in completely photoautotrophic conditions and that the alga exhibited altered sesquiterpenoid production metabolism related to carbon source.


A Suite of Engineered GFP Molecules for Oligomeric Scaffolding.
Applications ranging from synthetic biology to protein crystallization could be advanced by facile systems for connecting multiple proteins together in predefined spatial relationships. One approach to this goal is to engineer many distinct assembly forms of a single carrier protein or scaffold, to which other proteins of interest can then be readily attached. In this work we chose GFP as a scaffold and engineered many alternative oligomeric forms, driven by either specific disulfide bond formation or metal ion addition. We generated a wide range of spatial arrangements of GFP subunits from 11 different oligomeric variants, and determined their X-ray structures in a total of 33 distinct crystal forms. Some of the oligomeric GFP variants show geometric polymorphism depending on conditions, while others show considerable geometric rigidity. Potential future applications of this system are discussed.


The influence of ethnic group composition on focus group discussions.
Focus groups are commonly used to explore participants' experiences in health and social care research. Although it is suggested that having demographically homogenous groups may help put participants at ease, the evidence is sparse.The aims of the paper are to: explore the impact of relative ethnic homogeneity and heterogeneity of focus group participants on the group discussions; improve understanding of homogeneity and heterogeneity in focus groups; suggest ways to operationalise concepts such as being 'more comfortable' with other focus group participants. Digitally recorded focus groups were undertaken with family carers of stroke survivors and were later transcribed and analysed using framework analysis. Groups were designated as more or less ethnically homogenous. More homogenous groups included, for example, only White British or Asian Indian participants whilst more heterogeneous groups comprised a mixture of, for example, Asian, White British and Black Caribbean participants. Forty-one carers participated in seven focus groups. Analysis revealed differences in discussions around ethnicity between the more or less ethnically homogenous groups. For example, participants in more ethnically homogenous focus groups were more likely to say ethnicity might influence perceptions of social care services. On the other hand, more heterogeneous groups emphasised similarity in carers' experiences, irrespective of ethnicity. Participants in the more homogenous groups were also more likely to make potentially controversial comments relating to ethnic differences. Additionally they appeared to be more at ease with each other discussing the topic. For example, they spontaneously mentioned ethnic differences earlier in these groups.In contrast, analysis of topics not specifically related to ethnicity, such as the difficult experiences of being a carer, produced no discernible patterns when comparing more and less homogenous focus groups. Considerations around focus group participant demographic homogeneity and heterogeneity are complex and these terms may be most usefully applied only in relative terms.Data derived from more homogenous groups complement data from more heterogeneous groups providing different perspectives. Depending on the focus of the discussion, having characteristics in common, such as being a carer can override other differences.


Recurrent Strokes due to Transient Vasospasms of the Extracranial Internal Carotid Artery.
Vasospasms of the intracranial arteries are a well-known complication of subarachnoid hemorrhage and are also frequently encountered in other disorders such as migraine, cerebral vasculitis or reversible cerebral vasoconstriction syndrome. In contrast, recurrent spontaneous vasospasms of the extracranial circulation appear to be extremely rare and have most often been associated with migraine. We present a patient with recurrent strokes due to spontaneous transient vasospastic occlusions of the internal carotid artery (ICA) without migraine over a time period of at least 13 years. Initially, the patient had presented with a bilateral ICA occlusion and a cerebral infarct on the right side. While the right ICA remained occluded, a reopening of the left ICA could be detected 3 days after this initial event. In subsequent years, both duplex sonography and magnetic resonance angiography revealed recurrent occlusions of the left ICA, which resolved spontaneously within days. This case and other rare previous reports indicate that recurrent non-migrainous vasospasms of the extracranial carotid artery likely reflect a distinct entity which can cause ischemic strokes.


Osteosarcopenia.
Osteosarcopenia is a newly described syndrome that describes the co-existence of osteoporosis and sarcopenia, two chronic musculoskeletal conditions associated with ageing. Osteoporosis, a condition of low bone mass and micro-architectural deterioration of bone, and sarcopenia, the loss of muscle mass, strength and function, often co-exist in a frail subset of the elderly population, leading to significantly worsened outcomes than seen in either condition alone. These include a greater risk of falls, fractures and institutionalization, and significant socioeconomic costs. With our ageing population, osteosarcopenia is a public health concern that will become increasingly relevant in the future. Its aetiology is multifactorial, with mechanical, biochemical, genetic and lifestyle factors all contributing to involution of the 'bone-muscle unit'. Improved understanding of the interactions between muscle and bone could facilitate the development of new therapeutic agents which target muscle and bone as one. Together with existing pharmacological, nutritional and exercise-based therapies, this should enable a more holistic approach to osteosarcopenia in the future.


SYMNET: an optical interconnection network for scalable high-performance symmetric multiprocessors.
We address the primary limitation of the bandwidth to satisfy the demands for address transactions in future cache-coherent symmetric multiprocessors (SMPs). It is widely known that the bus speed and the coherence overhead limit the snoop/address bandwidth needed to broadcast address transactions to all processors. As a solution, we propose a scalable address subnetwork called symmetric multiprocessor network (SYMNET) in which address requests and snoop responses of SMPs are implemented optically. SYMNET not only has the ability to pipeline address requests, but also multiple address requests from different processors can propagate through the address subnetwork simultaneously. This is in contrast with all electrical bus-based SMPs, where only a single request is broadcast on the physical address bus at any given point in time. The simultaneous propagation of multiple address requests in SYMNET increases the available address bandwidth and lowers the latency of the network, but the preservation of cache coherence can no longer be maintained with the usual fast snooping protocols. A modified snooping cache-coherence protocol, coherence in SYMNET (COSYM) is introduced to solve the coherence problem. We evaluated SYMNET with a subset of Splash-2 benchmarks and compared it with the electrical bus-based MOESI (modified, owned, exclusive, shared, invalid) protocol. Our simulation studies have shown a 5-66% improvement in execution time for COSYM as compared with MOESI for various applications. Simulations have also shown that the average latency for a transaction to complete by use of COSYM protocol was 5-78% better than the MOESI protocol. SYMNET can scale up to hundreds of processors while still using fast snooping-based cache-coherence protocols, and additional performance gains may be attained with further improvement in optical device technology.


Using qualitative research to explore intervention mechanisms: findings from the trial of the Learning Together whole-school health intervention.
This study reports on qualitative research conducted within a randomised controlled trial to explore possible intervention mechanisms. It focuses on the 'Learning Together' whole-school intervention delivered in secondary schools in England from 2014 to 2017 aiming to prevent bullying and aggression and improve student health. Intervention schools received staff training in restorative practice, a social and emotional learning curriculum, and an external facilitator and manual to convene and run a student/staff action group tasked with coordinating the intervention, focusing this on local needs. Informed by realist approaches to evaluation, we analysed qualitative data to explore intervention mechanisms and how these might interact with school contexts to generate outcomes. Qualitative analysis drew on 45 interviews and 21 focus groups across three case-study schools and employed thematic content analysis to explore how intervention resources were taken up and used by local actors, how participants described the intervention mechanisms that then ensued, and how these might have generated beneficial outcomes. The thematic content analysis identified three social mechanisms that recurred in participant accounts: (1) building student commitment to the school community, (2) building healthy relationships by modelling and teaching pro-social skills, and (3) de-escalating bullying and aggression and enabling re-integration within the school community. Our analysis provides in-depth exploration of possible mechanisms and the contextual contingencies associated with these, allowing refinement of the initial intervention theory of change. ISRCTN registry 10751359 . Registered on 11 March 2014.


The effects of cardiopulmonary bypass on fibrin formation and lysis: is a normal fibrinolytic response essential?
Fibrinolytic activity in blood is regulated by a dynamic process that includes control of production, secretion, inhibition, and clearance of fibrinolytic proteins. The concentration of active tissue plasminogen activator (tPA) in the region of the thrombus controls the rate of fibrinolytic activation. We have developed a first-generation kinetic model that can be used to simulate the effects of secretion, inhibition, and clearance reactions on the concentrations of active tPA, active plasminogen activator inhibitor type 1 (PAI-1), and tPA/PAI-1 complex in the circulation. This model was used to estimate the rate and pattern of secretion of tPA and PAI-1 in individual subjects. We also undertook a laboratory evaluation of fibrinolysis in patients with a history of myocardial infarction. Elevated PAI-1 activity in the absence of elevations in other acute-phase proteins suggested an intrinsic increase in PAI-1 secretion in patients post-myocardial infarction. Cardiopulmonary bypass (CPB) results in a major increase in fibrinolytic activity that has been associated with an increased risk for hemorrhage. Fibrinolytic proteins were sampled from patients both during surgery and for 2 days postoperatively. Total tPA antigen rose throughout CPB and returned to baseline in the post-operative period. PAI-1 activity fell during the initial bypass and by the end of bypass had returned to baseline. On the first to second postoperative day there was a large increase in PAI-1 activity and a significant decrease in tPA activity. These data suggest that during this period there is a window of risk for a thromboembolic event. There was, however, a large individual variability in patient response to CPB.


"Chipping away": non-consumer researcher perspectives on barriers to collaborating with consumers in mental health research.
Collaboration between researchers who have lived experience of mental illness and services (consumer researchers) and mental health researchers without (other mental health researchers) is an emergent development in research. Inclusion of consumer perspectives is crucial to ensuring the ethics, relevancy and validity of mental health research; yet widespread and embedded consumer collaboration of this nature is known to be impeded by attitudinal and organisational factors. Limited research describes consumer researchers' experiences of barriers. Other mental health researchers are key players in the co-production process yet there is also a paucity of research reporting their views on barriers to collaborating with consumers. To explore other researchers' views and experiences on partnering with consumer mental health researchers in Australia and New Zealand. Exploratory qualitative design. Eleven semi-structured interviews were conducted with mental health researchers. Interviews were recorded, transcribed and thematically analysed. Four themes concerning barriers to collaborating with consumers (hierarchies, status quo, not understanding, paternalism), and one theme on addressing the barriers (constantly chipping away) were identified. It is suggested that multifaceted strategies for advancing collaboration with consumers are most effective. It is imperative to attend to several barriers simultaneously to redress the inherent power disparity.


Light Pollution Changes the Toxicological Effects of Cadmium on Microbial Community Structure and Function Associated with Leaf Litter Decomposition.
Artificial light at night (ALAN/A) can not only alter the behavior and communication of biological organisms, it can also interact with other stressors. Despite its widespread use and the numerous potential ecological effects, little is known about the impact of ALAN on plant litter decomposition under cadmium (Cd) pollution in aquatic ecosystems. In an indoor microcosm experiment, we tested single and combined effects of ALAN and Cd on the activities and community structure of fungi associated with plant litter. The results showed that ALAN and/or Cd can change both water and leaf litter characteristics. ALAN exposure not only altered fungal community structure and their correlations, but also increased the activities of alkaline phosphatase, β-glucosidase, and cellobiohydrolase. The leaf litter decomposition rate was 71% higher in the A-Cd treatment than that in the N-Cd treatment, indicating that the presence of ALAN weakened the negative impact of Cd on leaf litter decomposition. These results suggested that ALAN exposure mitigated the negative effect of Cd on leaf litter decomposition, contributing to the duel effect of ALAN on leaf litter decomposition. Overall, the results expand our understanding of ALAN on the environment and highlight the contribution of ALAN to Cd toxicity in aquatic ecosystems.


Neural and non-neural related properties in the spastic wrist flexors: An optimization study.
Quantifying neural and non-neural contributions to increased joint resistance in spasticity is essential for a better understanding of its pathophysiological mechanisms and evaluating different intervention strategies. However, direct measurement of spasticity-related manifestations, e.g., motoneuron and biophysical properties in humans, is extremely challenging. In this vein, we developed a forward neuromusculoskeletal model that accounts for dynamics of muscle spindles, motoneuron pools, muscle activation and musculotendon of wrist flexors and relies on the joint angle and resistant torque as the only input measurement variables. By modeling the stretch reflex pathway, neural and non-neural related properties of the spastic wrist flexors were estimated during the wrist extension test. Joint angle and resistant torque were collected from 17 persons with chronic stroke and healthy controls using NeuroFlexor, a motorized force measurement device during the passive wrist extension test. The model was optimized by tuning the passive and stretch reflex-related parameters to fit the measured torque in each participant. We found that persons with moderate and severe spasticity had significantly higher stiffness than controls. Among subgroups of stroke survivors, the increased neural component was mainly due to a lower muscle spindle rate at 50% of the motoneuron recruitment. The motoneuron pool threshold was highly correlated to the motoneuron pool gain in all subgroups. The model can describe the overall resistant behavior of the wrist joint during the test. Compared to controls, increased resistance was predominantly due to higher elasticity and neural components. We concluded that in combination with the NeuroFlexor measurement, the proposed neuromusculoskeletal model and optimization scheme served as suitable tools for investigating potential parameter changes along the stretch-reflex pathway in persons with spasticity.


Silencing suppressor protein VPg of a potyvirus interacts with the plant silencing-related protein SGS3.
Viral genome-linked protein (VPg) of potyviruses is involved in multiple steps of the potyvirus infection cycle, including viral multiplication and movement in plants. Recently, we showed that VPg of Potato virus A (PVA; genus Potyvirus) suppresses sense-mediated RNA silencing, which is linked to one or both nuclear or nucleolar localization. Here, we studied interactions between VPg and components of the plant RNA silencing pathway. Results showed that VPg interacts with the SGS3 protein of Solanum tuberosum and Arabidopsis thaliana, as shown by yeast two-hybrid analysis and bimolecular fluorescence complementation assays. VPg-SGS3 interactions co-localized with small cytoplasmic bodies that contained plant RNA-dependent RNA polymerase 6 (RDR6) (likely SGS3/RDR6 bodies). The N-terminal zinc finger (ZF) domain of SGS3 was the main determinant of the VPg interaction. Our data also suggest that the ZF domain controls SGS3 localization. SGS3 homodimerization was controlled by multiple protein regions. The VPg-SGS3 interaction appeared beneficial for PVA, as viral RNA levels correlated positively with sgs3 mRNA levels in the SGS3-silenced and SGS3-overexpressing leaves of Nicotiana benthamiana. The data support the idea that VPg acts as a suppressor of RNA silencing and suggest that an interaction with SGS3 may be important, especially in suppression of sense-mediated RNA silencing.


Race, care seeking, and utilization for chronic back and neck pain: population perspectives.
We analyzed a statewide survey of individuals with chronic back and neck pain to determine whether prevalence and care use varied by patient race or ethnicity. We conducted a telephone survey of a random sample of 5,357 North Carolina households in 2006. Adults with chronic (>3 months duration or >24 episodes of pain per year), impairing back or neck pain were identified and were asked to complete a survey about their health and care utilization. 837 respondents (620 white, 183 black, 34 Latino) reported chronic back or neck pain. Whites and blacks had similar rates of chronic back pain. Back pain prevalence was lower in Latinos (10.4% [9.3-11.6] vs 6.3% [3.8-8.8]), likely due to their younger age; and the prevalence of chronic, disabling neck pain was lower in blacks (2.5% [1.9-3.1] vs 1.1% [.04-1.9]). Blacks had higher pain scores in the previous 3 months (5.2 vs 5.9 P < .05), and higher Roland disability scores (0-23 point scale): 14.2 vs 16.8, P < .05. Care seeking was similar among races (83% white, 85% black, 72% Latino). Use of opioids was also similar between races, at 49% for whites, 52% for blacks, and trended lower at 35% for Latinos. We found few racial/ethnic differences in care seeking, treatment use, and use of narcotics for the treatment of chronic back and neck pain. This article presents new, population-based data on the issue of racial and ethnic disparities in neck- and back-pain prevalence and care. Few disparities were found; care quality issues may affect all ethnic groups similarly. Previous findings of disparities in chronic-pain management may be decreasing, or may perhaps be site specific.


Group Physical Activity Intervention for Childhood Cancer Survivors: A Pilot Study.
Inadequate physical activity (PA) in childhood cancer survivors may lead to compromised health outcomes. The purpose of this pilot study was to evaluate the feasibility and effect of a PA intervention in childhood cancer survivors ages 8-12 who report < 1 hour of moderate-to-vigorous physical (MVPA) per day. Twenty survivors were randomized to a 6-month group PA intervention or to a control group. A pre/post measure of MVPA was completed by all participants, and a pre/post measure of self-efficacy was completed by the intervention group. Analysis included measures of feasibility, change in percentage of awake time spent in MVPA, self-efficacy scores, and correlations in MVPA and self-efficacy. All feasibility parameters were confirmed. Increases in percent of awake time spent in MVPA were seen in 67% of the intervention group and 14% of the control group. A medium effect size (r = 0.55) was calculated for the correlation between change in MVPA and change in total self-efficacy scores; the largest effect size (r = 0.62) was found for the subscale for adequacy. Increases in MVPA can be seen in childhood cancer survivors who participate in a group intervention that includes support of self-efficacy.


Phospholipase A2 and 3H-hemicholinium-3 binding sites in rat brain: a potential second-messenger role for fatty acids in the regulation of high-affinity choline uptake.
The involvement of phospholipase A2 (PLA2) and fatty acid release in the regulation of sodium-dependent high-affinity choline uptake in rat brain was assessed in vitro through the use of the specific binding of 3H-hemicholinium-3 (3H-HCh-3). Addition of arachidonic acid and other unsaturated fatty acids to rat striatal membranes in vitro resulted in a dose-dependent, temperature-independent activation of 3H-HCh-3 binding. Scatchard analysis revealed that these changes in binding result from a 2-fold increase in the affinity and capacity of 3H-HCh-3 binding. Saturated fatty acids, lysophospholipids, and phospholipids did not affect specific 3H-HCh-3 binding. Addition of defatted BSA to membranes, which had been treated previously with arachidonic acid, completely reversed the increase in specific 3H-HCh-3 binding. However, several inhibitors of fatty acid metabolism, including nordihydroguaiaretic acid, indomethacin, catalase, and superoxide dismutase, did not alter arachidonic acid-induced changes in 3H-HCh-3 binding, suggesting that unsaturated fatty acids, and not their metabolites, are directly responsible for the observed activation of specific 3H-HCh-3 binding. Additionally, unsaturated fatty acids dose-dependently inhibited high-affinity 3H-choline uptake in rat striatal synaptosomes, apparently due to the disruption of synaptosomal integrity. The phospholipase A2 inhibitors quinacrine hydrochloride, trifluoperazine, and 4-bromophenacylbromide dose-dependently inhibited potassium depolarization-induced activation of specific 3H-HCh-3 binding in slices of rat brain in vitro. Similarly, both quinacrine and trifluoperazine inhibited the metabolism of phospholipids and the release of fatty acids evoked by either elevated KCl or calcium ionophore A23187. These results support the involvement of PLA2 and subsequent fatty acid release in the increase of 3H-HCh-3 binding in cholinergic neurons and suggest that activation of PLA2 may be the penultimate step in regulating the velocity of sodium-dependent choline transport.


Initial experience with new intraluminal devices for GERD, Barrett's esophagus, and obesity.
Transoral intraluminal surgery is less painful. However, endoscopic antireflux procedures have been unsuccessful, endoscopic foregut mucosal excision procedures are often difficult to perform, and endoscopic intra-luminal suturing is both imprecise and too shallow. We have endeavored to correct these deficiencies and report here new devices for GERD, obesity, and Barrett's mucosal excision. A retrospective review of ex vivo and in vivo animal experiments using sharp blade mucosal excision for esophageal and gastric mucosa and a suturing device with transverse needles designed to full thickness penetrate the gastric wall were completed. A total of 338 excisions were performed in 134 ex vivo tissue experiments and in 119 in vivo attempts. Suture needle testing was performed in ex vivo human stomachs and porcine stomachs and in in vivo canine and baboon stomachs. One excision perforation (0.9%) occurred in a live animal. Satisfactory mucosal excision depth for the Barrett's device was reproducible. Progressive suture actuation reliability improved from 83% during ex vivo testing to 96.7% in in vivo experiments. The results demonstrate feasibility, reliability, and safety for gastric and esophageal mucosal excision. Suturing reliability improved and further studies will be performed to finalize the instrument designs, the operative techniques, and the other device applications.


Validation of the English Version of the Scale for Psychosocial Factors in Food Allergy and the Relationship with Mental Health, Quality of Life, and Self-Efficacy.
Background. The Scale for Psychosocial Factors in Food Allergy (SPS-FA) is based on the biopsychosocial model of health and was developed and validated in Chile to measure the interaction between psychological variables and allergy symptoms in the child. We sought to validate this scale in an English speaking population and explore its relationship with parental quality of life, self-efficacy, and mental health. Methods. Parents (n = 434) from the general population in the UK, who had a child with a clinical diagnosis of food allergy, completed the SPS-FA and validated scales on food allergy specific parental quality of life (QoL), parental self-efficacy, and general mental health. Findings. The SPS-FA had good internal consistency (alphas = .61-.86). Higher scores on the SPS-FA significantly correlated with poorer parental QoL, self-efficacy, and mental health. All predictors explained 57% of the variance in SPS-FA scores with QoL as the biggest predictor (β = .52). Discussion. The SPS-FA is a valid scale for use in the UK and provides a holistic view of the impact of food allergy on the family. In conjunction with health-related QoL measures, it can be used by health care practitioners to target care for patients and evaluate psychological interventions for improvement of food allergy management.


Intra-Arrest Induction of Hypothermia via Large-Volume Ice-Cold Saline for Sudden Cardiac Arrest: The New York City Project Hypothermia Experience.
Therapeutic hypothermia, the standard for post-resuscitation care of out-of-hospital sudden cardiac arrest (SCA), is an area that the most recent resuscitation guidelines note "has not been studied adequately." We conducted a two-phase study examining the role of intra-arrest hypothermia for out-of-hospital SCA, first standardizing the resuscitation and transport of patients to resuscitation centers where post-resuscitation hypothermia was required and then initiating hypothermia during out-of-hospital resuscitation efforts. The primary end points were return of spontaneous circulation (ROSC), sustained ROSC, survival to hospital admission, and survival to discharge. Comparing the cohort of standard hospital-initiated hypothermia (Phase I) with the prehospital-initiated hypothermia via large-volume ice-cold saline (LVICS) infusion (Phase II), no difference was noted for any end point: ROSC (56.4% vs. 53.4%, p = 0.51; 95% confidence interval [CI]: -5.7 to 11.4), sustained ROSC (46.9% vs. 42.8%, p = 0.38; 95% CI: -4.7 to 12.4), hospital admission (44.7% vs. 37.7%, p = 0.13; 95% CI: -1.9 to 15.4), hospital discharge among those surviving to admission (40.0% vs. 28.0%, p = 0.08; 95% CI: -1.5 to 27.8), or neurological outcome among those surviving to discharge (76.0% vs. 71.4%, p = 0.73; 95% CI: -26.9 to 38.7). Patients presenting in ventricular fibrillation were more likely to survive to hospital discharge in both phases, although a trend toward worsened early outcomes (ROSC, sustained ROSC, and survival to admission) with intra-arrest hypothermia was noted in this subgroup. Multivariable regression analyses failed to demonstrate any survival benefit associated with the intra-arrest initiation of hypothermia via LVICS. Our study, the largest study of intra-arrest initiation of hypothermia published to date, failed to demonstrate any effect on survival for out-of-hospital SCA patients, confirming findings of previously published smaller studies. We therefore do not recommend the use of intra-arrest cooling via LVICS infusion as part of routine out-of-hospital SCA resuscitative efforts.


Polio supplementary immunization activities and equity in access to vaccination: evidence from the demographic and health surveys.
Every year, large numbers of children are vaccinated against polio during supplementary immunization activities (SIAs). Such SIAs have contributed to the >99% decline in the incidence of poliovirus cases since the beginning of the Global Polio Eradication Initiative. It is not clear, however, how much they have also contributed to reducing poverty-related inequalities in access to oral polio vaccine (OPV). We investigated whether the gap in coverage with 3 doses of OPV between children in the poorest and wealthiest households was reduced by SIA participation. To do so, we used data from 25 demographic and health surveys (DHS) conducted in 20 countries since 2002. We found that, in several countries as well as in pooled analyses, poverty-related inequalities in 3-dose OPV coverage were significantly lower among children who had participated in SIAs over the 2 years before a DHS than among other children. SIAs are an important approach to ensuring equitable access to immunization services and possibly other health services.


Do existing research summaries on health systems match immunisation managers' needs in middle- and low-income countries? Analysis of GAVI health systems strengthening support.
The GAVI Alliance was created in 2000 to increase access to vaccines. More recently, GAVI has supported evidence-based health systems strengthening to overcome barriers to vaccination. Our objectives were: to explore countries' priorities for health systems strengthening; to describe published research summaries for each priority area in relation to their number, quality and relevance; and to describe the use of national data from surveys in identifying barriers to immunisation. From 44 health systems strengthening proposals submitted to GAVI in 2007 and 2008, we analysed the topics identified, the coverage of these topics by existing systematic reviews and the use of nation-wide surveys with vaccination data to justify the needs identified in the proposals. Thirty topics were identified and grouped into three thematic areas: health workforce (10 topics); organisation and management (14); and supply, distribution and maintenance (6). We found 51 potentially relevant systematic reviews, although for the topic that appeared most frequently in the proposals ('Health information systems') no review was identified. Thematic and geographic relevance were generally categorised as "high" in 33 (65%) and 25 (49%) reviews, respectively, but few reviews were categorised as "highly relevant for policy" (7 reviews, 14%). With regard to methodological quality, 14 reviews (27%) were categorised as "high".The number of topics that were addressed by at least one high quality systematic review was: seven of the 10 topics in the 'health workforce' thematic area; six of the 14 topics in the area of 'organisation and management'; and none of the topics in the thematic area of 'supply, distribution and maintenance'. Only twelve of the 39 countries with available national surveys referred to them in their proposals. Relevant, high quality research summaries were found for few of the topics identified by managers. Few proposals used national surveys evidence to identify barriers to vaccination. Researchers generating or adapting evidence about health systems need to be more responsive to managers' needs. Use of available evidence from local or national surveys should be strongly encouraged.


Temporal recalibration during asynchronous audiovisual speech perception.
We investigated the consequences of monitoring an asynchronous audiovisual speech stream on the temporal perception of simultaneously presented vowel-consonant-vowel (VCV) audiovisual speech video clips. Participants made temporal order judgments (TOJs) regarding whether the speech-sound or the visual-speech gesture occurred first, for video clips presented at various different stimulus onset asynchronies. Throughout the experiment, half of the participants also monitored a continuous stream of words presented audiovisually, superimposed over the VCV video clips. The continuous (adapting) speech stream could either be presented in synchrony, or else with the auditory stream lagging by 300 ms. A significant shift (13 ms in the direction of the adapting stimulus in the point of subjective simultaneity) was observed in the TOJ task when participants monitored the asynchronous speech stream. This result suggests that the consequences of adapting to asynchronous speech extends beyond the case of simple audiovisual stimuli (as has recently been demonstrated by Navarra et al. in Cogn Brain Res 25:499-507, 2005) and can even affect the perception of more complex speech stimuli.


CCNU, etoposide, and prednimustine (CEP) in refractory Hodgkin's disease.
Starting in February 1980, 58 patients with Hodgkin's disease refractory to both MOPP and ABVD received as third-line chemotherapy a combination of CCNU or lomustine, etoposide, and prednimustine (CEP). Complete response (CR) was achieved in 40% of cases and partial response (PR) in 14%. The median duration of CR was greater than 15 months, and the median survival of complete responders was longer than 24 months. In addition, CEP alternating with ABVD was given to 21 patients refractory to MOPP chemotherapy. In this series, CR was documented in 67% of patients with a median duration of 24+ months and a median survival of 36+ months. Treatment was generally well tolerated, and all acute side effects were reversible. Present findings indicate that CEP is an effective regimen in patients refractory to MOPP and ABVD.


Definition, conservation and epigenetics of housekeeping and tissue-enriched genes.
Housekeeping genes (HKG) are constitutively expressed in all tissues while tissue-enriched genes (TEG) are expressed at a much higher level in a single tissue type than in others. HKGs serve as valuable experimental controls in gene and protein expression experiments, while TEGs tend to represent distinct physiological processes and are frequently candidates for biomarkers or drug targets. The genomic features of these two groups of genes expressed in opposing patterns may shed light on the mechanisms by which cells maintain basic and tissue-specific functions. Here, we generate gene expression profiles of 42 normal human tissues on custom high-density microarrays to systematically identify 1,522 HKGs and 975 TEGs and compile a small subset of 20 housekeeping genes which are highly expressed in all tissues with lower variance than many commonly used HKGs. Cross-species comparison shows that both the functions and expression patterns of HKGs are conserved. TEGs are enriched with respect to both segmental duplication and copy number variation, while no such enrichment is observed for HKGs, suggesting the high expression of HKGs are not due to high copy numbers. Analysis of genomic and epigenetic features of HKGs and TEGs reveals that the high expression of HKGs across different tissues is associated with decreased nucleosome occupancy at the transcription start site as indicated by enhanced DNase hypersensitivity. Additionally, we systematically and quantitatively demonstrated that the CpG islands' enrichment in HKGs transcription start sites (TSS) and their depletion in TEGs TSS. Histone methylation patterns differ significantly between HKGs and TEGs, suggesting that methylation contributes to the differential expression patterns as well. We have compiled a set of high quality HKGs that should provide higher and more consistent expression when used as references in laboratory experiments than currently used HKGs. The comparison of genomic features between HKGs and TEGs shows that HKGs are more conserved than TEGs in terms of functions, expression pattern and polymorphisms. In addition, our results identify chromatin structure and epigenetic features of HKGs and TEGs that are likely to play an important role in regulating their strikingly different expression patterns.