Racial Variation of Carrying Angle of Elbow in North-East Indian Population: A Clinico-Radiological Study.

BACKGROUND: Carrying angle of elbow is the angle borne by the forearm to the arm in fully extended elbow and supinated forearm. Northeast Indian population being an amalgamation of diverse ethnicity of population, the researchers have felt the necessity of a reference value for this anthropometric parameter for pre-operative planning and template. The objective is to study the difference in carrying angle between males and females and its correlation with different parameters like age, sex, height, body mass index and handedness. MATERIALS AND METHODS: The study was conducted in Gauhati Medical College and Hospital on 384 persons with ages ranging from 20 to 74 years. Carrying angle was measured by goniometer and confirmed by radiography. RESULTS: Three hundred and forty-three were right handed while 41 individuals were left handed. In males, the mean carrying angle of the right elbow was found to be 12.55 ± 2.3° and of the left was found to be 12.27 ± 2.43°, while in females, the mean carrying angle of the right elbow was found to be 14.53 ± 2.34° and 14.06 ± 3.37° in the left (p < 0.05). Carrying angle is usually found significantly higher in dominant upper limb. There is no significant difference in carrying angle for northeast Indian population from the rest of the country. CONCLUSION: We have found that carrying angle is dependent on gender and on dominance of upper limb. The carrying angle variation in Northeastern Indian population is almost comparable with the population of the rest of our country except for some specific tribes which needs further analysis.

Infant Viral Respiratory Infection Nasal Immune-Response Patterns and Their Association with Subsequent Childhood Recurrent Wheeze.

RATIONALE: Recurrent wheeze and asthma are thought to result from alterations in early life immune development following respiratory syncytial virus (RSV) infection. However, prior studies of the nasal immune response to infection have assessed only individual cytokines, which does not capture the whole spectrum of response to infection. OBJECTIVES: To identify nasal immune phenotypes in response to RSV infection and their association with recurrent wheeze. METHODS: A birth cohort of term healthy infants born June to December were recruited and followed to capture the first infant RSV infection. Nasal wash samples were collected during acute respiratory infection, viruses were identified by RT-PCR, and immune-response analytes were assayed using a multianalyte bead-based panel. Immune-response clusters were identified using machine learning, and association with recurrent wheeze at age 1 and 2 years was assessed using logistic regression. MEASUREMENTS AND MAIN RESULTS: We identified two novel and distinct immune-response clusters to RSV and human rhinovirus. In RSV-infected infants, a nasal immune-response cluster characterized by lower non-IFN antiviral immune-response mediators, and higher type-2 and type-17 cytokines was significantly associated with first and second year recurrent wheeze. In comparison, we did not observe this in infants with human rhinovirus acute respiratory infection. Based on network analysis, type-2 and type-17 cytokines were central to the immune response to RSV, whereas growth factors and chemokines were central to the immune response to human rhinovirus. CONCLUSIONS: Distinct immune-response clusters during infant RSV infection and their association with risk of recurrent wheeze provide insights into the risk factors for and mechanisms of asthma development.

HIV-exposure, early life feeding practices and delivery mode impacts on faecal bacterial profiles in a South African birth cohort.

There are limited data on meconium and faecal bacterial profiles from African infants and their mothers. We characterized faecal bacterial communities of infants and mothers participating in a South African birth cohort. Stool and meconium specimens were collected from 90 mothers and 107 infants at birth, and from a subset of 72 and 36 infants at 4-12 and 20-28 weeks of age, respectively. HIV-unexposed infants were primarily exclusively breastfed at 4-12 (49%, 26/53) and 20-28 weeks (62%, 16/26). In contrast, HIV-exposed infants were primarily exclusively formula fed at 4-12 (53%; 10/19) and 20-28 weeks (70%, 7/10). Analysis (of the bacterial 16S rRNA gene sequences of the V4 hypervariable region) of the 90 mother-infant pairs showed that meconium bacterial profiles [dominated by Proteobacteria (89%)] were distinct from those of maternal faeces [dominated by Firmicutes (66%) and Actinobacteria (15%)]. Actinobacteria predominated at 4-12 (65%) and 20-28 (50%) weeks. HIV-exposed infants had significantly higher faecal bacterial diversities at both 4-12 (p = 0.026) and 20-28 weeks (p = 0.002). HIV-exposed infants had lower proportions of Bifidobacterium (p = 0.010) at 4-12 weeks. Maternal faecal bacterial profiles were influenced by HIV status, feeding practices and mode of delivery. Further longitudinal studies are required to better understand how these variables influence infant and maternal faecal bacterial composition.

Strain Level Streptococcus Colonization Patterns during the First Year of Life.

Pneumococcal pneumonia has decreased significantly since the implementation of the pneumococcal conjugate vaccine (PCV), nevertheless, in many developing countries pneumonia mortality in infants remains high. We have undertaken a study of the nasopharyngeal (NP) microbiome during the first year of life in infants from The Philippines and South Africa. The study entailed the determination of the Streptococcus sp. carriage using a lytA qPCR assay, whole metagenomic sequencing, and in silico serotyping of Streptococcus pneumoniae, as well as 16S rRNA amplicon based community profiling. The lytA carriage in both populations increased with infant age and lytA+ samples ranged from 24 to 85% of the samples at each sampling time point. We next developed informatic tools for determining Streptococcus community composition and pneumococcal serotype from metagenomic sequences derived from a subset of longitudinal lytA-positive Streptococcus enrichment cultures from The Philippines (n = 26 infants, 50% vaccinated) and South African (n = 7 infants, 100% vaccinated). NP samples from infants were passaged in enrichment media, and metagenomic DNA was purified and sequenced. In silico capsular serotyping of these 51 metagenomic assemblies assigned known serotypes in 28 samples, and the co-occurrence of serotypes in 5 samples. Eighteen samples were not typeable using known serotypes but did encode for capsule biosynthetic cluster genes similar to non-encapsulated reference sequences. In addition, we performed metagenomic assembly and 16S rRNA amplicon profiling to understand co-colonization dynamics of Streptococcus sp. and other NP genera, revealing the presence of multiple Streptococcus species as well as potential respiratory pathogens in healthy infants. A range of virulence and drug resistant elements were identified as circulating in the NP microbiomes of these infants. This study revealed the frequent co-occurrence of multiple S. pneumoniae strains along with Streptococcus sp. and other potential pathogens such as S. aureus in the NP microbiome of these infants. In addition, the in silico serotype analysis proved powerful in determining the serotypes in S. pneumoniae carriage, and may lead to developing better targeted vaccines to prevent invasive pneumococcal disease (IPD) in these countries. These findings suggest that NP colonization by S. pneumoniae during the first years of life is a dynamic process involving multiple serotypes and species.

Insights into study design and statistical analyses in translational microbiome studies.

Research questions in translational microbiome studies are substantially more complex than their counterparts in basic science. Robust study designs with appropriate statistical analysis frameworks are pivotal to the success of these translational studies. This review considers how study designs can account for heterogeneous phenotypes by adopting representative sampling schemes for recruiting the study population and making careful choices about the control population. Advantages and limitations of 16S profiling and whole-genome sequencing, the two primary techniques for measuring the microbiome, are discussed followed by an overview of bioinformatic processing of high-throughput sequencing data from these measurements. Practical insights into the downstream statistical analyses including data processing and integration, variable transformations, and data exploration are provided. The merits of regularization and ensemble modeling for analyzing microbiome data are discussed along with a recommendation for selecting modeling approaches based on data-driven simulations and objective evaluation. The review builds on several recent discussions of study design issues in microbiome research but with a stronger emphasis on the downstream and often-ignored aspects of statistical analyses that are crucial for bridging the gap between basic science and translation.

A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis.

BACKGROUND: Copaxone is an efficacious and safe therapy that has demonstrated clinical benefit for over two decades in patients with relapsing forms of multiple sclerosis (MS). On an individual level, patients show variability in their response to Copaxone, with some achieving significantly higher response levels. The involvement of genes (e.g., HLA-DRB1*1501) with high inter-individual variability in Copaxone's mechanism of action (MoA) suggests the potential contribution of genetics to treatment response. This study aimed to identify genetic variants associated with Copaxone response in patient cohorts from late-phase clinical trials. METHODS: Single nucleotide polymorphisms (SNPs) associated with high and low levels of response to Copaxone were identified using genome-wide SNP data in a discovery cohort of 580 patients from two phase III clinical trials of Copaxone. Multivariable Bayesian modeling on the resulting SNPs in an expanded discovery cohort with 1171 patients identified a multi-SNP signature of Copaxone response. This signature was examined in 941 Copaxone-treated MS patients from seven independent late-phase trials of Copaxone and assessed for specificity to Copaxone in 310 Avonex-treated and 311 placebo-treated patients, also from late-phase trials. RESULTS: A four-SNP signature consisting of rs80191572 (in UVRAG), rs28724893 (in HLA-DQB2), rs1789084 (in MBP), and rs139890339 (in ZAK(CDCA7)) was identified as significantly associated with Copaxone response. Copaxone-treated signature-positive patients had a greater reduction in annualized relapse rate (ARR) compared to signature-negative patients in both discovery and independent cohorts, an effect not observed in Avonex-treated patients. Additionally, signature-positive placebo-treated cohorts did not show a reduction in ARR, demonstrating the predictive as opposed to prognostic nature of the signature. A 10% subset of patients, delineated by the signature, showed marked improvements across multiple clinical parameters, including ARR, MRI measures, and higher proportion with no evidence of disease activity (NEDA). CONCLUSIONS: This study is the largest pharmacogenetic study in MS reported to date. Gene regions underlying the four-SNP signature have been linked with pathways associated with either Copaxone's MoA or the pathophysiology of MS. The pronounced association of the four-SNP signature with clinical improvements in a ~10% subset of the MS patient population demonstrates the complex interplay of immune mechanisms and the individualized nature of response to Copaxone.

Differences in the Nasopharyngeal Microbiome During Acute Respiratory Tract Infection With Human Rhinovirus and Respiratory Syncytial Virus in Infancy.

Respiratory viruses alter the nasopharyngeal microbiome and may be associated with a distinct microbial signature. To test this hypothesis, we compared the nasopharyngeal microbiome of 135 previously healthy infants with acute respiratory infection due to human rhinovirus (HRV; n = 52) or respiratory syncytial virus (RSV; n = 83). The nasopharyngeal microbiome was assessed by sequencing the V4 region of the 16S ribosomal RNA. Respiratory viruses were identified by quantitative reverse-transcription polymerase chain reaction. We found significant differences in the overall taxonomic composition and abundance of certain bacterial genera between infants infected with HRV and those infected with RSV. Our results suggest that respiratory tract viral infections are associated with different nasopharyngeal microbial profiles.

Genetic variants in the mTOR pathway and interaction with body size and weight gain on breast cancer risk in African-American and European American women.

PURPOSE: Positive energy imbalance and growth factors linked to obesity promote the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway. As the obesity-breast cancer associations differ between European American (EA) and African-American (AA) women, we investigated genetic variants in the mTOR pathway and breast cancer risk in these two racial groups. METHODS: We examined 400 single-nucleotide polymorphisms (SNPs) in 31 mTOR pathway genes in the Women's Circle of Health Study with 1263 incident breast cancers (645 EA, 618 AA) and 1382 controls (641 EA, 741 AA). Multivariable logistic regression was performed separately within racial groups. Effect modification was assessed for measured body size and weight gain since age 20. RESULTS: In EA women, variants in FRAP1 rs12125777 (intron), PRR5L rs3740958 (synonymous coding), and CDKAL1 rs9368197 (intron) were associated with increased breast cancer risk, while variants in RPTOR rs9900506 (intron) were associated with decreased risk (nominal p-trend for functional and FRAP1 SNPs or p adjusted for correlated test [p ACT] < 0.05). For AA women, variants in RPTOR rs3817293 (intron), PIK3R1 rs7713645 (intron), and CDKAL1 rs9368197 were associated with decreased breast cancer risk. The significance for FRAP1 rs12125777 and RPTOR rs9900506 in EA women did not hold after correction for multiple comparisons. The risk associated with FRAP1 rs12125777 was higher among EAs who had body mass index ≥30 kg/m(2) (odds ratio = 7.69, 95 % CI 2.11-28.0; p-interaction = 0.007) and gained weight ≥35 lb since age 20 (odds ratio = 3.34, 95 % CI 1.42-7.85; p-interaction = 0.021), compared to their counterparts. CONCLUSIONS: The mTOR pathway may be involved in breast cancer carcinogenesis differently for EA and AA women.

Respiratory Syncytial Virus whole-genome sequencing identifies convergent evolution of sequence duplication in the C-terminus of the G gene.

Respiratory Syncytial Virus (RSV) is responsible for considerable morbidity and mortality worldwide and is the most important respiratory viral pathogen in infants. Extensive sequence variability within and between RSV group A and B viruses and the ability of multiple clades and sub-clades of RSV to co-circulate are likely mechanisms contributing to the evasion of herd immunity. Surveillance and large-scale whole-genome sequencing of RSV is currently limited but would help identify its evolutionary dynamics and sites of selective immune evasion. In this study, we performed complete-genome next-generation sequencing of 92 RSV isolates from infants in central Tennessee during the 2012-2014 RSV seasons. We identified multiple co-circulating clades of RSV from both the A and B groups. Each clade is defined by signature N- and O-linked glycosylation patterns. Analyses of specific RSV genes revealed high rates of positive selection in the attachment (G) gene. We identified RSV-A viruses in circulation with and without a recently reported 72-nucleotide G gene sequence duplication. Furthermore, we show evidence of convergent evolution of G gene sequence duplication and fixation over time, which suggests a potential fitness advantage of RSV with the G sequence duplication.

Using Bayesian modelling to investigate factors governing antibiotic-induced Candida albicans colonization of the GI tract.

Receipt of broad-spectrum antibiotics enhances Candida albicans colonization of the GI tract, a risk factor for haematogenously-disseminated candidiasis. To understand how antibiotics influence C. albicans colonization, we treated mice orally with vancomycin or a combination of penicillin, streptomycin, and gentamicin (PSG) and then inoculated them with C. albicans by gavage. Only PSG treatment resulted in sustained, high-level GI colonization with C. albicans. Furthermore, PSG reduced bacterial diversity in the colon much more than vancomycin. Both antibiotic regimens significantly reduced IL-17A, IL-21, IL-22 and IFN-γ mRNA levels in the terminal ileum but had limited effect on the GI fungal microbiome. Through a series of models that employed Bayesian model averaging, we investigated the associations between antibiotic treatment, GI microbiota, and host immune response and their collective impact on C. albicans colonization. Our analysis revealed that bacterial genera were typically associated with either C. albicans colonization or altered cytokine expression but not with both. The only exception was Veillonella, which was associated with both increased C. albicans colonization and reduced IL-21 expression. Overall, antibiotic-induced changes in the bacterial microbiome were much more consistent determinants of C. albicans colonization than either the GI fungal microbiota or the GI immune response.

A systematic evaluation of high-dimensional, ensemble-based regression for exploring large model spaces in microbiome analyses.

BACKGROUND: Microbiome studies incorporate next-generation sequencing to obtain profiles of microbial communities. Data generated from these experiments are high-dimensional with a rich correlation structure but modest sample sizes. A statistical model that utilizes these microbiome profiles to explain a clinical or biological endpoint needs to tackle high-dimensionality resulting from the very large space of variable configurations. Ensemble models are a class of approaches that can address high-dimensionality by aggregating information across large model spaces. Although such models are popular in fields as diverse as economics and genetics, their performance on microbiome data has been largely unexplored. RESULTS: We developed a simulation framework that accurately captures the constraints of experimental microbiome data. Using this setup, we systematically evaluated a selection of both frequentist and Bayesian regression modeling ensembles. These are represented by variants of stability selection in conjunction with elastic net and spike-and-slab Bayesian model averaging (BMA), respectively. BMA ensembles that explore a larger space of models relative to stability selection variants performed better and had lower variability across simulations. However, stability selection ensembles were able to match the performance of BMA in scenarios of low sparsity where several variables had large regression coefficients. CONCLUSIONS: Given a microbiome dataset of interest, we present a methodology to generate simulated data that closely mimics its characteristics in a manner that enables meaningful evaluation of analytical strategies. Our evaluation demonstrates that the largest ensembles yield the strongest performance on microbiome data with modest sample sizes and high-dimensional measurements. We also demonstrate the ability of these ensembles to identify microbiome signatures that are associated with opportunistic Candida albicans colonization during antibiotic exposure. As the focus of microbiome research evolves from pilot to translational studies, we anticipate that our strategy will aid investigators in making evaluation-based decisions for selecting appropriate analytical methods.

Associations between estrogen receptor-negative breast cancer and timing of reproductive events differ between African American and European American women.

The effects of reproductive factors on breast cancer risk seem to differ by estrogen receptor (ER) status. Menarche and first live birth (FLB) tend to occur at younger ages in African Americans (AA) than European Americans (EA), and could play a role in breast cancer disparities. In the Women's Circle of Health Study, a case-control study of breast cancer in EA and AA women, in-person interviews were conducted to collect epidemiologic data, including reproductive histories. Data on ER status, abstracted from pathology reports, were available for 814 AA and 538 EA breast cancer cases, and were analyzed with 1015 AA and 715 EA controls, to evaluate associations between subgroups and age at menarche, age at FLB, and the interval between those ages. Among AA women, later age at menarche (≥14 years) was associated with reduced risk of both ER(+) and ER(-) breast cancer, with ORs strongest for ER(-) disease [OR = 0.57; 95% confidence interval (CI), 0.37-0.88]; associations were weaker and nonsignificant for EA women. There were no significant associations with age at FLB, but AA women with a FLB within 15 years of menarche had increased risk of ER(-) disease (OR = 2.26; 95% CI, 1.29-3.95), with no significant associations among EAs. In our data, earlier age at menarche and shorter intervals until FLB are associated with ER(-) breast cancer in AA women; differential distributions by race of these and other reproductive risk factors could contribute to the higher prevalence of ER(-) breast cancer in AA women. Cancer Epidemiol Biomarkers Prev; 23(6); 1115-20. ©2014 AACR.

Parity and breastfeeding among African-American women: differential effects on breast cancer risk by estrogen receptor status in the Women's Circle of Health Study.

PURPOSE: It has long been held that parity reduces risk of breast cancer. However, accumulating evidence indicates that the effects of parity, as well as breastfeeding, may vary according to estrogen receptor (ER) status. We evaluated these associations in a case-control study among African-American women in New York City and New Jersey. METHODS: In the Women's Circle of Health Study, including 786 African-American women with breast cancer and 1,015 controls, data on reproductive histories were collected from in-person interviews, with tumor characteristics abstracted from pathology reports. We calculated number of live births and months breastfeeding for each child, and examined each in relation to breast cancer by ER status, and for triple-negative (TN) breast cancer. RESULTS: Although associations were not statistically significant, having children was associated with reduced risk of ER+ breast cancer [odds ratio (OR) 0.82, 95 % confidence interval (CI) 0.58-1.16], but increased risk of ER- tumors, with associations most pronounced for TN breast cancer (OR 1.81, 95 % CI 0.93-3.51). Breastfeeding gave no additional benefit for ER+ cancer, but reduced the risk of ER- disease associated with parity. CONCLUSIONS: Accumulating data from a number of studies, as well as our own in African-American women, indicate that the effects of parity and breastfeeding differ by ER status. African-American women are more likely to have children and not to breastfeed, and to have ER- and TN breast cancer. It is possible that breastfeeding in this population could reduce risk of more aggressive breast cancers.