A Multicenter Phase 2 Study Incorporating High-Dose Rituximab into the CODOX-M/IVAC Regimen for Untreated Burkitt’s Lymphoma (BL): Examination of Correlative Serum and CSF Rituximab Levels

Background: Two-year survival rates for adult BL remain Methods: Twenty-five BL patients were enrolled. Patients had low-risk (LR) or high-risk (HR) disease; LR patients received 3 CODOX-M cycles, while HR had 4 alternating CODOX-M/IVAC cycles (Mead et al. Blood 2009). Rituximab (500mg/m2) was given x 2 doses each cycle. Correlative analyses of paired serum and CSF Rituximab levels were obtained for cycles 1+3 at 24+72 hours. Results: There were 20 HR and 5 LR patients and median age was 44 years (range, 23-70). 3 HR and 1 LR patient were HIV+, while 15% of HR patients had CNS disease. Additionally, 35% of HR patients had bulk \u3e10 cm and 40% had bone marrow involvement. Myelosuppression and mucositis appeared comparable with prior CODOX-M/IVAC data. The overall remission rate after 2 cycles was 100% with 67% complete remission. At 34-month median follow-up, 2-year PFS and OS rates for all patients were 86% and 86%, respectively (LR 2-year PFS and OS: both 100%; HR 2-year PFS and OS: both 82%). Further, the 2-year PFS and OS for HR, HIV-negative patients were 91% and 91%, respectively (disease-specific survival 100%). Two patients died from progressive disease (both HIV+ HR). The median serum and CSF rituximab levels for these patients were compared with patients without relapse (Table 1). Interestingly, cycle 1, 24-hour serum Rituximab levels were significantly higher among patients without relapse compared with the two patients who relapsed/died (P=0.042). Cycle 3, 24-hour Rituximab levels were of borderline significance (P=0.06). Conclusions: The integration of Rituximab into CODOX-M/IVAC was associated with excellent survival rates, especially for HIV-negative BL. Further investigation of the predictive value of serum Rituximab levels is warranted

Performance of Genotype Imputation for Rare Variants Identified in Exons and Flanking Regions of Genes

Genotype imputation has the potential to assess human genetic variation at a lower cost than assaying the variants using laboratory techniques. The performance of imputation for rare variants has not been comprehensively studied. We utilized 8865 human samples with high depth resequencing data for the exons and flanking regions of 202 genes and Genome-Wide Association Study (GWAS) data to characterize the performance of genotype imputation for rare variants. We evaluated reference sets ranging from 100 to 3713 subjects for imputing into samples typed for the Affymetrix (500K and 6.0) and Illumina 550K GWAS panels. The proportion of variants that could be well imputed (true r2>0.7) with a reference panel of 3713 individuals was: 31% (Illumina 550K) or 25% (Affymetrix 500K) with MAF (Minor Allele Frequency) less than or equal 0.001, 48% or 35% with 0.001<MAF< = 0.005, 54% or 38% with 0.005<MAF< = 0.01, 78% or 57% with 0.01<MAF< = 0.05, and 97% or 86% with MAF>0.05. The performance for common SNPs (MAF>0.05) within exons and flanking regions is comparable to imputation of more uniformly distributed SNPs. The performance for rare SNPs (0.01<MAF< = 0.05) was much more dependent on the GWAS panel and the number of reference samples. These results suggest routine use of genotype imputation for extending the assessment of common variants identified in humans via targeted exon resequencing into additional samples with GWAS data, but imputation of very rare variants (MAF< = 0.005) will require reference panels with thousands of subjects

Psychological interventions for the management of glycemic and psychological outcomes of Type 2 Diabetes Mellitus in China: a systematic review and meta-analyses of randomized controlled trials

INTRODUCTION: China has the largest number of type 2 diabetes mellitus (T2DM) cases globally, and T2DM management has become a critical public health issue in China. Individuals with T2DM have an increased risk of developing mental health disorders, psychological disturbances, and functional problems associated with living with their condition. Previous systematic reviews have demonstrated that, generally, psychological interventions are effective in the management of T2DM-related outcomes; however, these reviews have predominantly included studies conducted within English-speaking countries and have not determined the efficacy of the varying types of psychological interventions. As such, this paper aims to synthesize evidence and quantify the efficacy of psychological therapies for the management of glycemic and psychological outcomes of T2DM in China, relative to control conditions. METHODS: A systematic search (MEDLINE, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, and Wangfang Data) for all years to December 2014 identified all available literature. Eligibility criteria included: peer-reviewed journal articles, randomized controlled trials (RCTs) assessing the efficacy of a psychological therapy for the management of T2DM, adult participants (&ge;18&thinsp;years) diagnosed with T2DM or non-insulin-dependent diabetes mellitus, and Chinese speaking participants only (in mainland China). Outcome measures were glycated hemoglobin, blood glucose concentration, depression, anxiety, and quality of life. Effect sizes were pooled using a random effects model. Negative effect sizes corresponded to positive outcomes favoring the intervention. RESULTS: Forty-five RCTs were eligible for the meta-analyses. Cognitive behavioral therapy (CBT) and motivational interviewing (MI) were more effective than the control condition in the reduction of glycated hemoglobin [CBT: -0.97 (95% CI -1.37 to -0.57); MI: -0.71 (95% CI -1.00 to -0.43)]. CBT and client-centered therapy (CCT) were also associated with reductions in depression and blood glucose concentration, and CBT was associated with reductions in anxiety. CONCLUSION: Psychological interventions, namely, CBT, MI, and CCT are effective in improving certain T2DM-related outcomes in China. Considerable levels of heterogeneity and unclear risk of bias associated with most included RCTs suggest caution when interpreting results. In China, where the burden of T2DM is increasing significantly, psychological interventions may provide promising approaches to assist in the management of T2DM to delay the progression of T2DM related outcomes

The PROblem Gambling RESearch Study (PROGRESS) research protocol: a pragmatic randomised controlled trial of psychological interventions for problem gambling.

INTRODUCTION: International prevalence rates for problem gambling are estimated at 2.3%. Problem gambling is a serious global public health concern due to adverse personal and social consequences. Previous research evaluating the effectiveness of psychological interventions for the treatment of problem gambling has been compromised by methodological limitations, including small sample sizes and the use of waitlist control groups. This article describes the study protocol for a pragmatic randomised controlled trial (RCT) evaluating the effectiveness of cognitive-behavioural therapy (CBT), behaviour therapy (BT), motivational interviewing (MI) against a non-directive supportive therapy (NDST) control, in treating problem gambling. METHODS AND ANALYSIS: This study was a mixed-methods design, with a parallel group, pragmatic RCT as the primary component, and embedded qualitative studies conducted alongside. A total of 297 participants were recruited from the community in Victoria, Australia. Individuals aged 18 years and over, could communicate in English and wished to receive treatment for a gambling problem were eligible. Participants were randomly allocated in to 1 of the 4 psychological interventions: CBT, BT, MI and NDST. Repeated measures were conducted at pretreatment and post-treatment, and 6 and 12 months post-treatment. The statistical analysis will use an intention-to-treat approach. Multilevel mixed modelling will be used to examine changes in the primary outcome measures: gambling symptom severity, using the Gambling Symptom Assessment Scale, and gambling behaviours (frequency, time and expenditure). Secondary outcomes are depression, anxiety, stress and alcohol use. Individual semistructured qualitative interviews were conducted at pretreatment and post-treatment and 12 months post-treatment for a subset of participants (n=66). ETHICS AND DISSEMINATION: This study was approved by the Victorian Department of Justice, Monash University and the University of Melbourne Human Research Ethics Committees. Findings will be reported in a government report, peer-reviewed publications and conference presentations

Genome-wide Association Study of Platelet Count Identifies Ancestry-Specific Loci in Hispanic/Latino Americans

Platelets play an essential role in hemostasis and thrombosis. We performed a genome-wide association study of platelet count in 12,491 participants of the Hispanic Community Health Study/Study of Latinos by using a mixed-model method that accounts for admixture and family relationships. We discovered and replicated associations with five genes (ACTN1, ETV7, GABBR1-MOG, MEF2C, and ZBTB9-BAK1). Our strongest association was with Amerindian-specific variant rs117672662 (p value = 1.16 × 10−28) in ACTN1, a gene implicated in congenital macrothrombocytopenia. rs117672662 exhibited allelic differences in transcriptional activity and protein binding in hematopoietic cells. Our results underscore the value of diverse populations to extend insights into the allelic architecture of complex traits

Flexibility but no coordination of visits in provisioning riflemen

Parental care strategies occupy a continuum from fixed investments that are consistent across contexts to flexible behaviour that largely depends on external social and environmental cues. Determining the flexibility of care behaviour is important, as it influences the outcome of investment games between multiple individuals caring for the same brood. We investigated the repeatability of provisioning behaviour and the potential for turn taking among breeders and helpers in a cooperatively breeding bird, the rifleman, Acanthisitta chloris. First, we examined whether nest visit rate is an accurate measure of investment by assessing whether carers consistently bring the same size of food, and whether food size is related to nest visit rate. Our results support the use of visit rate as a valid indicator of parental investment. Next, we calculated the repeatability of visit rate and food size to determine whether these behaviours are fixed individual traits or flexible responses to particular contexts. We found that riflemen were flexible in visit rate, supporting responsive models of care over ‘sealed bids’. Finally, we used runs tests to assess whether individual riflemen alternated visits with other carers, indicative of turn taking. We found little evidence of any such coordination of parental provisioning. We conclude that individual flexibility in parental care appears to arise through factors such as breeding status and brood demand, rather than as a real-time response to social partners

Genetic Diversity and Association Studies in US Hispanic/Latino Populations: Applications in the Hispanic Community Health Study/Study of Latinos

US Hispanic/Latino individuals are diverse in genetic ancestry, culture, and environmental exposures. Here, we characterized and controlled for this diversity in genome-wide association studies (GWASs) for the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We simultaneously estimated population-structure principal components (PCs) robust to familial relatedness and pairwise kinship coefficients (KCs) robust to population structure, admixture, and Hardy-Weinberg departures. The PCs revealed substantial genetic differentiation within and among six self-identified background groups (Cuban, Dominican, Puerto Rican, Mexican, and Central and South American). To control for variation among groups, we developed a multi-dimensional clustering method to define a “genetic-analysis group” variable that retains many properties of self-identified background while achieving substantially greater genetic homogeneity within groups and including participants with non-specific self-identification. In GWASs of 22 biomedical traits, we used a linear mixed model (LMM) including pairwise empirical KCs to account for familial relatedness, PCs for ancestry, and genetic-analysis groups for additional group-associated effects. Including the genetic-analysis group as a covariate accounted for significant trait variation in 8 of 22 traits, even after we fit 20 PCs. Additionally, genetic-analysis groups had significant heterogeneity of residual variance for 20 of 22 traits, and modeling this heteroscedasticity within the LMM reduced genomic inflation for 19 traits. Furthermore, fitting an LMM that utilized a genetic-analysis group rather than a self-identified background group achieved higher power to detect previously reported associations. We expect that the methods applied here will be useful in other studies with multiple ethnic groups, admixture, and relatedness

Detailed Molecular and Immune Marker Profiling of Archival Prostate Cancer Samples Reveals an Inverse Association between TMPRSS2:ERG Fusion Status and Immune Cell Infiltration

Prostate cancer is a significant global health issue and limitations to current patient management pathways often result in over- or under-treatment. New ways to stratify patients are urgently needed. We conducted a feasibility study of such novel assessments looking for associations between genomic changes and lymphocyte infiltration. An innovative workflow utilizing an in-house targeted sequencing panel, immune cell profiling using an image analysis pipeline, RNA-Seq, and exome sequencing in select cases was tested. Gene fusions were profiled by RNA-seq in 27/27 cases and a significantly higher TIL count was noted in tumors without a TMPRSS2:ERG fusion compared to those with the fusion (P = 0.01). Although this finding was not replicated in a larger validation set (n=436) of The Cancer Genome Atlas images, there was a trend in the same direction. Differential expression analysis of TIL-High and TIL-Low tumors revealed the enrichment of both innate and adaptive immune response pathways. Mutations in mismatch repair genes (MLH1 and MSH6 mutations in 1/27 cases) were identified. We describe a potential immune escape mechanism in TMPRSS2:ERG fusion positive tumors. Detailed profiling, as shown here, can provide novel insights into tumor biology. Likely differences with findings with other cohorts are related to methods used to define region of interest, but this warrants further study in a larger cohort

Ancestral Components of Admixed Genomes in a Mexican Cohort

For most of the world, human genome structure at a population level is shaped by interplay between ancient geographic isolation and more recent demographic shifts, factors that are captured by the concepts of biogeographic ancestry and admixture, respectively. The ancestry of non-admixed individuals can often be traced to a specific population in a precise region, but current approaches for studying admixed individuals generally yield coarse information in which genome ancestry proportions are identified according to continent of origin. Here we introduce a new analytic strategy for this problem that allows fine-grained characterization of admixed individuals with respect to both geographic and genomic coordinates. Ancestry segments from different continents, identified with a probabilistic model, are used to construct and study “virtual genomes” of admixed individuals. We apply this approach to a cohort of 492 parent–offspring trios from Mexico City. The relative contributions from the three continental-level ancestral populations—Africa, Europe, and America—vary substantially between individuals, and the distribution of haplotype block length suggests an admixing time of 10–15 generations. The European and Indigenous American virtual genomes of each Mexican individual can be traced to precise regions within each continent, and they reveal a gradient of Amerindian ancestry between indigenous people of southwestern Mexico and Mayans of the Yucatan Peninsula. This contrasts sharply with the African roots of African Americans, which have been characterized by a uniform mixing of multiple West African populations. We also use the virtual European and Indigenous American genomes to search for the signatures of selection in the ancestral populations, and we identify previously known targets of selection in other populations, as well as new candidate loci. The ability to infer precise ancestral components of admixed genomes will facilitate studies of disease-related phenotypes and will allow new insight into the adaptive and demographic history of indigenous people