In reply

In Reply We thank Pimazoni-Netto et al for their letter and include our response to their concerns. In considering our published results, it is of tantamount importance that readers understand the tenets of comparative effectiveness research (CER)

Experimental infection of game animals with lumpy skin disease virus (prototype strain Neethling)

Calves of a giraffe, an impala, two buffaloes, and two adult black wildebeests were artificially infected with the Neethling type of lumpy skin disease virus. The giraffe and impala died with typical symptoms and lesions of the disease. Virological examinations confirmed the presence of lumpy skin disease virus in lesions of these animals. Histopathological studies revealed microscopic lesions typical of those reported in cattle suffering from lumpy skin disease. Both intracytoplasmic and intranuclear inclusions were noticed in various cell types and some additional histopathological changes are reported. Neither the wildebeests nor the buffaloes reacted clinically to artificial infection and they failed to show a rise in antibody titre subsequently.The journals have been scanned in colour with a HP 5590 scanner; 600 dpi. Adobe Acrobat v.11 was used to OCR the text and also for the merging and conversion to the final presentation PDF-format..mn201

Genetics of Obesity in Diverse Populations

Purpose of Review: The prevalence of obesity continues to rise, fueling a global public health crisis characterized by dramatic increases in type 2 diabetes, cardiovascular disease, and many cancers. In the USA, several minority populations, who bear much of the obesity burden (47% in African Americans and Hispanic/Latinos, compared to 38% in European descent groups), are particularly at risk of downstream chronic disease. Compounding these disparities, most genome-wide association studies (GWAS)—including those of obesity—have largely been conducted in populations of European or East Asian ancestry. In fact, analysis of the GWAS Catalog found that while the proportion of participants of non-European or non-Asian descent had risen from 4% in 2009 to 19% in 2016, African-ancestry participants are still just 3% of GWAS, Hispanic/Latinos are < 0.5%, and other ancestries are < 0.3% or not represented at all. This review summarizes recent developments in obesity genomics in US minority populations, with the goal of reducing obesity health disparities and improving public health programs and access to precision medicine. Recent Findings: GWAS of populations with the highest burden of obesity are essential to narrow candidate variants for functional follow-up, to identify additional ancestry-specific variants that contribute to individual genetic susceptibility, and to advance both public health and precision medicine approaches to obesity. Summary: Given the global public health burden posed by obesity and downstream chronic conditions which disproportionately affect non-European populations, GWAS of obesity-related traits in diverse populations is essential to (1) locate causal variants in GWAS-identified regions through fine mapping, (2) identify variants which influence obesity across ancestries through generalization, and (3) discover novel ancestry-specific variants which may be low frequency in European populations but common in other groups. Recent efforts to expand obesity genomic studies to understudied and underserved populations, including AAAGC, PAGE, and HISLA, are working to reduce obesity health disparities, improve public health, and bring the promise of precision medicine to all

Rapid conjugation of antibodies to toxins to select candidates for the development of anticancer Antibody-Drug conjugates (ADcs)

Antibody-Drug Conjugates (ADCs) developed as a targeted treatment approach to deliver toxins directly to cancer cells are one of the fastest growing classes of oncology therapeutics, with eight ADCs and two immunotoxins approved for clinical use. However, selection of an optimum target and payload combination, to achieve maximal therapeutic efficacy without excessive toxicity, presents a significant challenge. We have developed a platform to facilitate rapid and cost-effective screening of antibody and toxin combinations for activity and safety, based on streptavidin-biotin conjugation. For antibody selection, we evaluated internalization by target cells using streptavidin-linked antibodies conjugated to biotinylated saporin, a toxin unable to cross cell membranes. For payload selection, we biotinylated toxins and conjugated them to antibodies linked to streptavidin to evaluate antitumour activity and pre-clinical safety. As proof of principle, we compared trastuzumab conjugated to emtansine via streptavidin-biotin (Trastuzumab-SB-DM1) to the clinically approved trastuzumab emtansine (T-DM1). We showed comparable potency in reduction of breast cancer cell survival in vitro and in growth restriction of orthotopic breast cancer xenografts in vivo. Our findings indicate efficient generation of functionally active ADCs. This approach can facilitate the study of antibody and payload combinations for selection of promising candidates for future ADC development

Crystal structure, electronic, and magnetic properties of the bilayered rhodium oxide Sr3Rh2O7

The bilayered rhodium oxide Sr3Rh2O7 was synthesized by high-pressure and high-temperature heating techniques. The single-phase polycrystalline sample of Sr3Rh2O7 was characterized by measurements of magnetic susceptibility, electrical resistivity, specific heat, and thermopower. The structural characteristics were investigated by powder neutron diffraction study. The rhodium oxide Sr3Rh2O7 [Bbcb, a = 5.4744(8) A, b = 5.4716(9) A, c = 20.875(2) A] is isostructural to the metamagnetic metal Sr3Ru2O7, with five 4d electrons per Rh, which is electronically equivalent to the hypothetic bilayered ruthenium oxide, where one electron per Ru is doped into the Ru-327 unit. The present data show the rhodium oxide Sr3Rh2O7 to be metallic with enhanced paramagnetism, similar to Sr3Ru2O7. However, neither manifest contributions from spin fluctuations nor any traces of a metamagnetic transition were found within the studied range from 2 K to 390 K below 70 kOe.Comment: To be published in PR

Evidence for Association between SH2B1 Gene Variants and Glycated Hemoglobin in Nondiabetic European American Young Adults: The Add Health Study

Glycated hemoglobin (HbA1c) is used to classify glycaemia and type 2 diabetes (T2D). Body mass index (BMI) is a predictor of HbA1c levels and T2D. We tested 43 established BMI and obesity loci for association with HbA1c in a nationally representative multiethnic sample of young adults from the National Longitudinal Study of Adolescent to Adult Health [Add Health: age 24–34 years; n = 5641 European Americans (EA); 1740 African Americans (AA); 1444 Hispanic Americans (HA)] without T2D, using two levels of covariate adjustment (Model 1: age, sex, smoking, and geographic region; Model 2: Model 1 covariates plus BMI). Bonferroni adjustment was made for 43 SNPs and we considered P &lt; 0.0011 statistically significant. Means (SD) for HbA1c were 5.4% (0.3) in EA, 5.7% (0.4) in AA, and 5.5% (0.3) in HA. We observed significant evidence for association with HbA1c for two variants near SH2B1 in EA (rs4788102, P = 2.2 × 10−4; rs7359397, P = 9.8 × 10−4) for Model 1. Both results were attenuated after adjustment for BMI (rs4788102, P = 1.7 × 10−3; rs7359397, P = 4.6 × 10−3). No variant reached Bonferroni-corrected significance in AA or HA. These results suggest that SH2B1 polymorphisms are associated with HbA1c, largely independent of BMI, in EA young adults

Moderate to vigorous physical activity interactions with genetic variants and body mass index in a large US ethnically diverse cohort

Summary What is already known about this subject Genome-Wide Association Studies have successfully identified numerous genetic loci that influence body mass index in European-descent middle-aged adults. Adolescence is a high-risk period for the development of adult obesity and severe obesity. Physical activity is one of the most promising behavioural candidates for preventing and reducing weight gain, particularly among youth. What this study adds An examination of the joint association between 41 of the well-established obesity susceptibility single-nucleotide polymorphisms with <5 vs. ≥5 bouts of moderate to vigorous physical activity (MVPA) per week in relation to body mass index (BMI)-for-age Z-score in a nationally representative sample of European American, African-American and Hispanic American adolescents. Three nominally significant interactions (P < 0.05) varied by race/ethnicity. Overall, the estimated effect of the risk allele on BMI-for-age Z-score was greater in individuals with <5 than those with ≥5 bouts MVPA per week. Background Little is known about the interaction between genetic and behavioural factors during lifecycle risk periods for obesity and how associations vary across race/ethnicity. Objective The objective of this study was to examine joint associations of adiposity-related single-nucleotide polymorphisms (SNPs) and moderate to vigorous physical activity (MVPA) with body mass index (BMI) in a diverse adolescent cohort. Methods Using data from the National Longitudinal Study of Adolescent Health (n = 8113: Wave II 1996; ages 12-21, Wave III; ages 18-27), we assessed interactions of 41 well-established SNPs and MVPA with BMI-for-age Z-scores in European Americans (EA; n = 5077), African-Americans (AA; n = 1736) and Hispanic Americans (HA; n = 1300). Results Of 97 assessed, we found nominally significant SNP-MVPA interactions on BMI-for-age Z-score in EA at GNPDA2 and FTO and in HA at LZTR2/SEC16B. In EA, the estimated effect of the FTO risk allele on BMI-for-age Z-score was lower (β = -0.13; 95% confidence interval [CI]: 0.08, 0.18) in individuals with ≥5 vs. <5 (β = 0.24; CI: 0.16, 0.32) bouts of MVPA per week (P for interaction 0.02). Race/ethnicity-pooled meta-analysis showed nominally significant interactions for SNPs at TFAP2B, POC5 and LYPLAL1. Conclusions High MVPA may attenuate underlying genetic risk for obesity during adolescence, a high-risk period for adult obesity

Breakup of 17^{17}F on 208^{208}Pb near the Coulomb barrier

Angular distributions of oxygen produced in the breakup of $^{17}$F incident on a $^{208}$Pb target have been measured around the grazing angle at beam energies of 98 and 120 MeV. The data are dominated by the proton stripping mechanism and are well reproduced by dynamical calculations. The measured breakup cross section is approximately a factor of 3 less than that of fusion at 98 MeV. The influence of breakup on fusion is discussed.Comment: 7 pages, 8 figure

Screen time behaviours may interact with obesity genes, independent of physical activity, to influence adolescent BMI in an ethnically diverse cohort

Background There has been little investigation of gene-by-environment interactions related to sedentary behaviour, a risk factor for obesity defined as leisure screen time (ST; i.e. television, video and computer games). Objective To test the hypothesis that limiting ST use attenuates the genetic predisposition to increased body mass index (BMI), independent of physical activity. Design Using 7642 wave II participants of the National Longitudinal Study of Adolescent Health, (Add Health; mean=16.4 years, 52.6% female), we assessed the interaction of ST (hweek-1) and 41 established obesity single nucleotide polymorphisms (SNPs) with age- and sex-specific BMI Z-scores in 4788 European-American (EA), 1612 African-American (AA) and 1242 Hispanic American (HA) adolescents. Results Nominally significant SNP ST interaction were found for FLJ35779 in EA, GNPDA2 in AA and none in HA (EA: beta [SE]=0.016[0.007]), AA: beta [SE]=0.016[0.011]) per 7hweek-1 ST and one risk allele in relation to BMI Z-score. Conclusions While for two established BMI loci, we find evidence that high levels of ST exacerbate the influence of obesity susceptibility variants on body mass; overall, we do not find strong evidence for interactions between the majority of established obesity loci. However, future studies with larger sample sizes, or that may build on our current study and the growing published literature, are clearly warranted

Glucose self-monitoring in non-insulin-treated patients with type 2 diabetes in primary care settings: A randomized trial

IMPORTANCE The value of self-monitoring of blood glucose (SMBG) levels in patients with non-insulin-treated type 2 diabetes has been debated. OBJECTIVE To compare 3 approaches of SMBG for effects on hemoglobin A1c levels and health-related quality of life (HRQOL) among people with non-insulin-treated type 2 diabetes in primary care practice. DESIGN, SETTING, AND PARTICIPANTS The Monitor Trial studywas a pragmatic, open-label randomized trial conducted in 15 primary care practices in central North Carolina. Participants were randomized between January 2014 and July 2015. Eligible patients with type 2 non-insulin-treated diabetes were: older than 30 years, established with a primary care physician at a participating practice, had glycemic control (hemoglobin A1c) levels higher than 6.5%but lower than 9.5%within the 6 months preceding screening, as obtained from the electronic medical record, and willing to comply with the results of random assignment into a study group. Of the 1032 assessed for eligibility, 450 were randomized. INTERVENTIONS No SMBG, once-daily SMBG, and once-daily SMBG with enhanced patient feedback including automatic tailored messages delivered via the meter. MAIN OUTCOMES AND MEASURES Coprimary outcomes included hemoglobin A1c levels and HRQOL at 52 weeks. RESULTS A total of 450 patients were randomized and 418 (92.9%) completed the final visit. There were no significant differences in hemoglobin A1c levels across all 3 groups (P = .74; estimated adjusted mean hemoglobin A1c difference, SMBG with messaging vs no SMBG, -0.09%; 95%CI, -0.31% to 0.14%; SMBG vs no SMBG, -0.05%; 95%CI, -0.27%to 0.17%). There were also no significant differences found in HRQOL. There were no notable differences in key adverse events including hypoglycemia frequency, health care utilization, or insulin initiation. CONCLUSIONS AND RELEVANCE In patients with non-insulin-treated type 2 diabetes, we observed no clinically or statistically significant differences at 1 year in glycemic control or HRQOL between patients who performed SMBG compared with those who did not perform SMBG. The addition of this type of tailored feedback provided through messaging via ameter did not provide any advantage in glycemic control