Group-specific component (Gc) variants of vitamin D binding protein differ in their affinity for vitamin D metabolites that modulate antimycobacterial immunity. We conducted studies to determine ...whether Gc genotype associates with susceptibility to tuberculosis (TB). The following subjects were recruited into case-control studies: in the UK, 123 adult TB patients and 140 controls, all of Gujarati Asian ethnic origin; in Brazil, 130 adult TB patients and 78 controls; and in South Africa, 281 children with TB and 182 controls. Gc genotypes were determined and their frequency was compared between cases versus controls. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were obtained retrospectively for 139 Gujarati Asians, and case-control analysis was stratified by vitamin D status. Interferon (IFN)-gamma release assays were also performed on 36 Gujarati Asian TB contacts. The Gc2/2 genotype was strongly associated with susceptibility to active TB in Gujarati Asians, compared with Gc1/1 genotype (OR 2.81, 95% CI 1.19-6.66; p = 0.009). This association was preserved if serum 25(OH)D was <20 nmol.L(-1) (p = 0.01) but not if serum 25(OH)D was > or =20 nmol.L(-1) (p = 0.36). Carriage of the Gc2 allele was associated with increased PPD of tuberculin-stimulated IFN-gamma release in Gujarati Asian TB contacts (p = 0.02). No association between Gc genotype and susceptibility to TB was observed in other ethnic groups studied.
The rate of survival after out-of-hospital cardiac arrest is low. It is not known whether this rate will increase if laypersons are trained to attempt defibrillation with the use of automated ...external defibrillators (AEDs).
We conducted a prospective, community-based, multicenter clinical trial in which we randomly assigned community units (e.g., shopping malls and apartment complexes) to a structured and monitored emergency-response system involving lay volunteers trained in cardiopulmonary resuscitation (CPR) alone or in CPR and the use of AEDs. The primary outcome was survival to hospital discharge.
More than 19,000 volunteer responders from 993 community units in 24 North American regions participated. The two study groups had similar unit and volunteer characteristics. Patients with treated out-of-hospital cardiac arrest in the two groups were similar in age (mean, 69.8 years), proportion of men (67 percent), rate of cardiac arrest in a public location (70 percent), and rate of witnessed cardiac arrest (72 percent). No inappropriate shocks were delivered. There were more survivors to hospital discharge in the units assigned to have volunteers trained in CPR plus the use of AEDs (30 survivors among 128 arrests) than there were in the units assigned to have volunteers trained only in CPR (15 among 107; P=0.03; relative risk, 2.0; 95 percent confidence interval, 1.07 to 3.77); there were only 2 survivors in residential complexes. Functional status at hospital discharge did not differ between the two groups.
Training and equipping volunteers to attempt early defibrillation within a structured response system can increase the number of survivors to hospital discharge after out-of-hospital cardiac arrest in public locations. Trained laypersons can use AEDs safely and effectively.
Background
People at high risk of developing melanoma are usually identified by pigmentary and naevus phenotypes.
Objective
We examined whether associations of these phenotypes with melanoma risk ...differed by ambient sun exposure or participant characteristics in two population‐based, case–control studies with comparable ancestry but different ambient sun exposure.
Methods
Data were analysed from 616 cases and 496 controls from the Australian Melanoma Family Study and 2012 cases and 504 controls from the Leeds (UK) case–control study. Questionnaire, interview and dermatological skin examination data were collected using the same measurement protocols. Relative risks were estimated as odds ratios using unconditional logistic regression, adjusted for potential confounders.
Results
Hair and skin colour were the strongest pigmentary phenotype risk factors. All associations of pigmentary phenotype with melanoma risk were similar across countries. The median number of clinically assessed naevi was approximately three times higher in Australia than Leeds, but the relative risks for melanoma associated with each additional common or dysplastic naevus were higher for Leeds than Australia, especially for naevi on the upper and lower limbs. Higher naevus counts on the head and neck were associated with a stronger relative risk for melanoma for women than men. The two countries had similar relative risks for melanoma based on self‐reported naevus density categories, but personal perceptions of naevus number differed by country. There was no consistent evidence of interactions between phenotypes on risk.
Conclusions
Classifying people at high risk of melanoma based on their number of naevi should ideally take into account their country of residence, type of counts (clinical or self‐reported), body site on which the naevus counts are measured and sex. The presence of naevi may be a stronger indicator of a genetic predisposition in the UK than in Australia based on less opportunity for sun exposure to influence naevus development.
IntroductionAndrogen deprivation therapy (ADT) is commonly used to treat men with locally advanced or metastatic prostate cancer. Men receiving ADT experience numerous side effects and frequently ...report unmet supportive care needs. An essential part of quality cancer care is survivorship care. To date, an optimal effective approach to survivorship care for men with prostate cancer on ADT has not been described. This protocol describes a randomised trial of tele-based nurse-led survivorship that addresses this knowledge gap: (1) determine the effectiveness of a nurse-led survivorship care intervention (PCEssentials), relative to usual care, for improving health-related quality of life (HR-QoL) in men with prostate cancer undergoing ADT and (2) evaluate PCEssentials implementation strategies and outcomes, including cost-effectiveness, compared with usual care.Methods and analysisThis is an effectiveness-implementation hybrid (type 1) trial with participants randomised to one of two arms: (1) minimally enhanced usual care and (2) nurse-led prostate cancer survivorship essentials (PCEssentials) delivered over four tele-based sessions, with a booster session 5 months after session 1. Eligible participants are Australian men with prostate cancer commencing ADT and expected to be on ADT for a minimum of 12 months. Participants are followed up at 3, 6 and 12 months postrecruitment. Primary outcomes are HR-QoL and self-efficacy. Secondary outcomes are psychological distress, insomnia, fatigue and physical activity. A concurrent process evaluation with participants and study stakeholders will be undertaken to determine effectiveness of delivery of PCEssentials.Ethics and disseminationEthics approval was obtained from the Metro South Health HREC (HREC/2021/QMS/79429). All participants are required to provide written informed consent. Outcomes of this trial will be published in peer-reviewed journals. The findings will be presented at conferences and meetings, local hospital departments, participating organisations/clinical services, and university seminars, and communicated at community and consumer-led forums.Trial registration numberACTRN12622000025730.
We consider the problem of inferring fold changes in gene expression from cDNA microarray data. Standard procedures focus on the ratio of measured fluorescent intensities at each spot on the ...microarray, but to do so is to ignore the fact that the variation of such ratios is not constant. Estimates of gene expression changes are derived within a simple hierarchical model that accounts for measurement error and fluctuations in absolute gene expression levels. Significant gene expression changes are identified by deriving the posterior odds of change within a similar model. The methods are tested via simulation and are applied to a panel of Escherichia coli microarrays.
Background and Purpose
Inhaled glucocorticoid (ICS)/long‐acting β2‐adrenoceptor agonist (LABA) combination therapy is a recommended treatment option for patients with moderate/severe asthma in whom ...adequate control cannot be achieved by an ICS alone. Previously, we discovered that LABAs can augment dexamethasone‐inducible gene expression and proposed that this effect may explain how these two drugs interact to deliver superior clinical benefit. Herein, we extended that observation by analysing, pharmacodynamically, the effect of the LABA, indacaterol, on glucocorticoid receptor (GR)‐mediated gene transcription induced by seven ligands with intrinsic activity values that span the spectrum of full agonism to antagonism.
Experimental Approach
BEAS‐2B human airway epithelial cells stably transfected with a 2× glucocorticoid response element luciferase reporter were used to model gene transcription together with an analysis of several glucocorticoid‐inducible genes.
Key Results
Indacaterol augmented glucocorticoid‐induced reporter activation in a manner that was positively related to the intrinsic activity of the GR agonist. This effect was demonstrated by an increase in response maxima without a change in GR agonist affinity or efficacy. Indacaterol also enhanced glucocorticoid‐inducible gene expression. However, the magnitude of this effect was dependent on both the GR agonist and the gene of interest.
Conclusions and Implications
These data suggest that indacaterol activates a molecular rheostat, which increases the transcriptional competency of GR in an agonist‐ and gene‐dependent manner without apparently changing the relationship between fractional GR occupancy and response. These findings provide a platform to rationally design ICS/LABA combination therapy that is based on the generation of agonist‐dependent gene expression profiles in target and off‐target tissues.
Summary
Background
Structured exergaming with prescribed moderate intensity physical activity has reduced adiposity among adolescents. The extent to which adolescents reduce adiposity when allowed to ...self‐select intensity level is not known.
Objective
The objective of the study was to examine the influence of exergaming on adolescent girls' body composition and cardiovascular risk factors.
Methods
This randomized controlled trial assigned 41 overweight and obese girls aged 14 to 18 years to group‐based dance exergaming (36 h over 3 months) or to a self‐directed care control condition. Body size and composition were measured by anthropometry, dual‐energy X‐ray absorptiometry %fat and bone mineral density {BMD} and magnetic resonance imaging. Cardiovascular risk factors included blood pressure, cholesterol, triglycerides, glucose and insulin.
Results
Attrition was 5%. Using analysis of covariance controlling for baseline value, age and race, there were no significant condition differences. Per protocol (attended >75%), the intervention group significantly decreased abdominal subcutaneous adiposity and increased trunk and spine BMD (ps < 0.05). Per protocol (>2600 steps/session), the intervention group significantly decreased leg %fat and decreased abdominal subcutaneous and total adiposity (ps < 0.05).
Conclusion
Exergaming reduced body fat and increased BMD among those adolescent girls who adhered. Further research is required before exergaming is recommended in clinical settings.
The increasing trend of population growth along with the rapid groundwater-based agricultural expansion and decreasing trend of mean annual rainfall in the Northwest region of Bangladesh has been ...exacerbating the declination of groundwater for further expansion. Therefore, the present study attempts to demarcate the potential groundwater abstraction zones from the assessment of potential recharge and available recharge. Potential recharge was obtained with commonly used geospatial-based weighted linear combination (WLC) technique. Here, WLC analysis was based on eight factors related to physiographic (e.g. drainage density, lineament density, slope), geomorphologic (e.g. geomorphology, lithology, soil), land use and land cover (LULC) and hydrology (i.e. rainfall). Available net recharge was assessed for the period 1993–2017 by employing the water table fluctuation method. Finally, the resultant map on potential abstraction was characterized into five different classes, viz. ‘very low’, ‘low’, ‘moderate’, ‘high’ and ‘very high’. The derived map reveals that ‘very high’ potential zone is distributed along the Teesta river floodplain, especially the northeastern part. In contrast, the Barind Tract (i.e. the southwestern and the southcentral parts) area shows ‘very low’ groundwater prospect. Such fused interpretations are expected to contribute to the planning of integrated management of water resources.
Protein structure prediction is an important but unsolved problem in biological science. Predicted structures vary much with energy functions and structure-mapping spaces. In our simplified ab initio ...protein structure prediction methods, we use hydrophobic-polar (HP) energy model for structure evaluation, and 3-dimensional face-centred-cubic lattice for structure mapping. For HP energy model, developing a compact hydrophobic-core (H-core) is essential for the progress of the search. The H-core helps find a stable structure with the lowest possible free energy.
In order to build H-cores, we present a new Spiral Search algorithm based on tabu-guided local search. Our algorithm uses a novel H-core directed guidance heuristic that squeezes the structure around a dynamic hydrophobic-core centre. We applied random walks to break premature H-cores and thus to avoid early convergence. We also used a novel relay-restart technique to handle stagnation.
We have tested our algorithms on a set of benchmark protein sequences. The experimental results show that our spiral search algorithm outperforms the state-of-the-art local search algorithms for simplified protein structure prediction. We also experimentally show the effectiveness of the relay-restart.
PDF
