Specific Alterations in Complement Protein Activity of Little Brown Myotis (Myotis lucifugus) Hibernating in White-Nose Syndrome Affected Sites

White-nose syndrome (WNS) is the most devastating condition ever reported for hibernating bats, causing widespread mortality in the northeastern United States. The syndrome is characterized by cutaneous lesions caused by a recently identified psychrophilic and keratinophylic fungus (Geomyces destructans), depleted fat reserves, atypical behavior, and damage to wings; however, the proximate cause of mortality is still uncertain. To assess relative levels of immunocompetence in bats hibernating in WNS-affected sites compared with levels in unaffected bats, we describe blood plasma complement protein activity in hibernating little brown myotis (Myotis lucifugus) based on microbicidal competence assays using Escherichia coli, Staphylococcus aureus and Candida albicans. Blood plasma from bats collected during mid-hibernation at WNS-affected sites had higher bactericidal ability against E. coli and S. aureus, but lower fungicidal ability against C. albicans when compared with blood plasma from bats collected at unaffected sites. Within affected sites during mid-hibernation, we observed no difference in microbicidal ability between bats displaying obvious fungal infections compared to those without. Bactericidal ability against E. coli decreased significantly as hibernation progressed in bats collected from an affected site. Bactericidal ability against E. coli and fungicidal ability against C. albicans were positively correlated with body mass index (BMI) during late hibernation. We also compared complement activity against the three microbes within individuals and found that the ability of blood plasma from hibernating M. lucifugus to lyse microbial cells differed as follows: E. coli>S. aureus>C. albicans. Overall, bats affected by WNS experience both relatively elevated and reduced innate immune responses depending on the microbe tested, although the cause of observed immunological changes remains unknown. Additionally, considerable trade-offs may exist between energy conservation and immunological responses. Relationships between immune activity and torpor, including associated energy expenditure, are likely critical components in the development of WNS

Common Genetic Variants, Acting Additively, Are a Major Source of Risk for Autism

Background: Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods: By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results: By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions: Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability

Common genetic variants, acting additively, are a major source of risk for autism

Abstract Background Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.http://deepblue.lib.umich.edu/bitstream/2027.42/112370/1/13229_2012_Article_55.pd

Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

SummaryWe have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6–12.0, p = 2.4 × 10-7). We estimate there are 130–234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

UAV LiDAR Survey for Archaeological Documentation in Chiapas, Mexico

Airborne laser scanning has proven useful for rapid and extensive documentation of historic cultural landscapes after years of applications mapping natural landscapes and the built environment. The recent integration of unoccupied aerial vehicles (UAVs) with LiDAR systems is potentially transformative and offers complementary data for mapping targeted areas with high precision and systematic study of coupled natural and human systems. We report the results of data capture, analysis, and processing of UAV LiDAR data collected in the Maya Lowlands of Chiapas, Mexico in 2019 for a comparative landscape study. Six areas of archaeological settlement and long-term land-use reflecting a diversity of environments, land cover, and archaeological features were studied. These missions were characterized by areas that were variably forested, rugged, or flat, and included pre-Hispanic settlements and agrarian landscapes. Our study confirms that UAV LiDAR systems have great potential for broader application in high-precision archaeological mapping applications. We also conclude that these studies offer an important opportunity for multi-disciplinary collaboration. UAV LiDAR offers high-precision information that is not only useful for mapping archaeological features, but also provides critical information about long-term land use and landscape change in the context of archaeological resources