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Graciela's Papi has been working in the United States for so long that she has almost forgotten his face, so when the box he promised for her seventh birthday does not arrive, she is very upset and nearly loses hope that he--and the rain--will someday return.

Individuals with type 2 diabetes mellitus (T2DM) have a higher fracture risk compared to those without T2DM despite having higher bone mineral density (BMD). Thus, T2DM may alter other aspects of resistance to fracture beyond BMD such as bone geometry, microarchitecture, and tissue material properties. We characterized the skeletal phenotype and assessed the effects of hyperglycemia on bone tissue mechanical and compositional properties in the TallyHO mouse model of early-onset T2DM using nanoindentation and Raman spectroscopy. Femurs and tibias were harvested from male TallyHO and C57Bl/6J mice at 26 weeks of age. The minimum moment of inertia assessed by micro-computed tomography was smaller (-26%) and cortical porosity was greater (+490%) in TallyHO femora compared to controls. In three-point bending tests to failure, the femoral ultimate moment and stiffness did not differ but post-yield displacement was lower (-35%) in the TallyHO mice relative to that in C57Bl/6J age-matched controls after adjusting for body mass. The cortical bone in the tibia of TallyHO mice was stiffer and harder, as indicated by greater mean tissue nanoindentation modulus (+22%) and hardness (+22%) compared to controls. Raman spectroscopic mineral:matrix ratio and crystallinity were greater in TallyHO tibiae than in C57Bl/6J tibiae (mineral:matrix +10%, p < 0.05; crystallinity +0.41%, p < 0.10). Our regression model indicated that greater values of crystallinity and collagen maturity were associated with reduced ductility observed in the femora of the TallyHO mice. The maintenance of structural stiffness and strength of TallyHO mouse femora despite reduced geometric resistance to bending could potentially be explained by increased tissue modulus and hardness, as observed at the tibia. Finally, with worsening glycemic control, tissue hardness and crystallinity increased, and bone ductility decreased in TallyHO mice. Our study suggests that these material factors may be sentinels of bone embrittlement in adolescents with T2DM.

Over recent decades, the southeastern United States (Southeast) has become increasingly well represented by the terrestrial climate proxy record. However, while the paleo proxy records capture the region's hydroclimatic history over the last several centuries, the understanding of near surface air temperature variability is confined to the comparatively shorter observational period (1895‐present). Here, we detail the application of blue intensity (BI) methods on a network of tree‐ring collections and examine their utility for producing robust paleotemperature estimates. Results indicate that maximum latewood BI (LWBI) chronologies exhibit positive and temporally stable correlations (r = 0.28–0.54, p < 0.01) with summer maximum temperatures. As such, we use a network of LWBI chronologies to reconstruct August‐September average maximum temperatures for the Southeast spanning the period 1760–2010 CE. Our work demonstrates the utility of applying novel dendrochronological techniques to improve the understanding of the multi‐centennial temperature history of the Southeast. Plain Language Summary Tree‐ring data are important sources of paleoclimate information, which allow for the longer‐term evaluation of modern climate values and trends. Compared to much of North America, the Southeastern United States (Southeast) contains substantially fewer paleoclimate records from tree rings, and no estimates of past temperature variability which extend before the observational period. Employing a recently developed technique, which uses light reflectance properties of wood to obtain a representative metric of tree‐ring density, we develop a network of temperature‐sensitive tree‐ring records across the Southeast. These records enable us to reconstruct late summer maximum temperatures across the region spanning the period 1760–2023 CE. As few ground‐based, pre‐instrumental temperature records previously existed for this region, our reconstruction allows for an improved understanding of the region's multi‐centennial climatic history. Key Points Maximum latewood blue intensity from tree rings can effectively be used to develop paleotemperature estimates for the southeastern US The fidelity of tree‐ring density parameters for paleoclimate reconstruction are influenced by disturbance regimes and microsite conditions Compared to the last 260 years, regional 20th‐century maximum late summer temperatures are not characterized by unprecedented positive trend

Purpose - The purpose of this study is to investigate whether the framework of brand credibility effects is applicable to service categories and to examine if brand credibility's impact differs according to service type and involvement level.Design methodology approach - Using a self-administered survey (n=385), this study tests the proposed model, including six latent constructs: brand credibility, perceived quality, perceived risk, information costs saved, perceived value for money, and purchase intention.Findings - The results indicate that brand credibility exerts a strong effect on purchase intention by increasing perceived quality, perceived value for money, and information costs saved, and by decreasing perceived risk across multiple service categories. The results also indicate that the magnitude of brand credibility's impact on purchase intention varies under different conditions with regard to utilitarian and hedonic services.Research limitations implications - This study is based on student samples with a limited number of service categories. Future research is needed to examine the generalizability of the proposed model by using non-student samples with different service classifications.Practical implications - Establishing brand credibility seems to be especially effective in utilitarian services when marketing communication campaigns have the consistency of brand attributes that invoke either value for money or lower service brand-related information efforts.Originality value - This study offers an initial attempt to explain how brand credibility influences its key outcomes under different service classes. Perceived value for money could be considered a new mediator of a causal relationship between brand credibility and purchase intention in service sectors.

Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab. In this 2-year trial, patients aged 8–35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0·5 U/kg per day and glycated haemoglobin A 1c (HbA 1C) of less than 6·5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697. 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group). Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in β-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children. MacroGenics, the Juvenile Diabetes Research Foundation, and Eli Lilly.

Investigators used plasmapheresis and low-dose intravenous immune globulin to desensitize HLA-incompatible patients before transplantation and compared their survival rate with that of controls. Live-donor transplantation after desensitization provided a survival benefit. Renal-replacement therapy can be achieved by means of transplantation or dialysis. Transplantation offers clear benefits in terms of longevity, lifestyle, and savings in health care costs. 1 – 4 However, organs are scarce, and the rate of death among patients on the kidney-transplant waiting list is high. In 2008, of the 82,000 patients on the waiting list in the United States, 16,520 received a renal transplant, whereas 4800 died while waiting for one. 5 Patients who have become sensitized to HLA as a result of previous transplantation, pregnancy, or blood transfusion have an increased likelihood of a positive cross-match, indicating the presence of . . .

Ethnic variation in the genes The power of the latest massively parallel synthetic DNA sequencing technologies is demonstrated in two major collaborations that shed light on the nature of genomic variation with ethnicity. The first describes the genomic characterization of an individual from the Yoruba ethnic group of west Africa. The second reports a personal genome of a Han Chinese, the group comprising 30% of the world's population. These new resources can now be used in conjunction with the Venter, Watson and NIH reference sequences. A separate study looked at genetic ethnicity on the continental scale, based on data from 1,387 individuals from more than 30 European countries. Overall there was little genetic variation between countries, but the differences that do exist correspond closely to the geographic map. Statistical analysis of the genome data places 50% of the individuals within 310 km of their reported origin. As well as its relevance for testing genetic ancestry, this work has implications for evaluating genome-wide association studies that link genes with diseases. Understanding the genetic structure of human populations is of fundamental interest to medical, forensic and anthropological sciences. Advances in high-throughput genotyping technology have markedly improved our understanding of global patterns of human genetic variation and suggest the potential to use large samples to uncover variation among closely spaced populations 1 , 2 , 3 , 4 , 5 . Here we characterize genetic variation in a sample of 3,000 European individuals genotyped at over half a million variable DNA sites in the human genome. Despite low average levels of genetic differentiation among Europeans, we find a close correspondence between genetic and geographic distances; indeed, a geographical map of Europe arises naturally as an efficient two-dimensional summary of genetic variation in Europeans. The results emphasize that when mapping the genetic basis of a disease phenotype, spurious associations can arise if genetic structure is not properly accounted for. In addition, the results are relevant to the prospects of genetic ancestry testing 6 ; an individual’s DNA can be used to infer their geographic origin with surprising accuracy—often to within a few hundred kilometres.

This is the first randomized controlled diet intervention trial to investigate both the amount and type of carbohydrate on symptomatic gastroesophageal reflux disease (GERD). Ninety-eight veterans with symptomatic GERD were randomly assigned to high total/high simple, high total/low simple, low total/high simple, or low total/low simple carbohydrate diet for 9 weeks. The primary outcomes were esophageal acid exposure time (AET) and total number of reflux episodes derived from 24-hour ambulatory pH monitoring. Secondary outcomes were esophageal reflux symptoms rated using the Gastroesophageal Reflux Disease Questionnaire (GERDQ) and GERD Symptom Assessment Scale (GSAS). Half of the subjects were White and half African American (mean age, 60.0 ± 12.5 years; mean body mass index, 32.7 ± 5.4 kg/m 2 ). There was a significant main effect of diet treatment on AET ( P = 0.001) and on the total number of reflux episodes ( P = 0.003). The change in AET in the high total/low simple group (-4.3% ± 3.8%) differed significantly from the high total/high simple control group (+3.1% ± 3.7%), (P = 0.04). The reduction in simple sugar intake averaged 62 g less per day. Subjects' ratings of symptoms improved in all carbohydrate modification groups, including significant reductions in heartburn frequency, heartburn severity, acid taste in the mouth, lump/pain in the throat or chest, and sleep disturbance. A modification of dietary carbohydrate intake that targeted a substantial reduction in the intakes of simple sugars improved pH monitoring outcomes and symptoms of GERD that profoundly affect daily life. These findings provide a feasible and clinically applicable contribution to the limited objective data existing for efficacious dietary recommendations in the routine treatment and management of GERD.

Background Low pass sequencing has been proposed as a cost-effective alternative to genotyping arrays to identify genetic variants that influence multifactorial traits in humans. For common diseases this typically has required both large sample sizes and comprehensive variant discovery. Genotyping arrays are also routinely used to perform pharmacogenetic (PGx) experiments where sample sizes are likely to be significantly smaller, but clinically relevant effect sizes likely to be larger. Results To assess how low pass sequencing would compare to array based genotyping for PGx we compared a low-pass assay (in which 1x coverage or less of a target genome is sequenced) along with software for genotype imputation to standard approaches. We sequenced 79 individuals to 1x genome coverage and genotyped the same samples on the Affymetrix Axiom Biobank Precision Medicine Research Array (PMRA). We then down-sampled the sequencing data to 0.8x, 0.6x, and 0.4x coverage, and performed imputation. Both the genotype data and the sequencing data were further used to impute human leukocyte antigen (HLA) genotypes for all samples. We compared the sequencing data and the genotyping array data in terms of four metrics: overall concordance, concordance at single nucleotide polymorphisms in pharmacogenetics-related genes, concordance in imputed HLA genotypes, and imputation r 2 . Overall concordance between the two assays ranged from 98.2% (for 0.4x coverage sequencing) to 99.2% (for 1x coverage sequencing), with qualitatively similar numbers for the subsets of variants most important in pharmacogenetics. At common single nucleotide polymorphisms (SNPs), the mean imputation r 2 from the genotyping array was 0.90, which was comparable to the imputation r 2 from 0.4x coverage sequencing, while the mean imputation r 2 from 1x sequencing data was 0.96. Conclusions These results indicate that low-pass sequencing to a depth above 0.4x coverage attains higher power for association studies when compared to the PMRA and should be considered as a competitive alternative to genotyping arrays for trait mapping in pharmacogenetics.