Electrostatic potential on human leukocyte antigen: implications for putative mechanism of chronic beryllium disease.

The pathobiology of chronic beryllium disease (CBD) involves the major histocompatibility complex class II human leukocyte antigen (HLA). Although occupational exposure to beryllium is the cause of CBD, molecular epidemiologic studies suggest that specific (Italic)HLA-DPB1(/Italic) alleles may be genetic susceptibility factors. We have studied three-dimensional structural models of HLA-DP proteins encoded by these genes. The extracellular domains of HLA-DPA1*0103/B1*1701, *1901, *0201, and *0401, and HLA-DPA1*0201/B1*1701, *1901, *0201, and *0401 were modeled from the X-ray coordinates of an HLA-DR template. Using these models, the electrostatic potential at the molecular surface of each HLA-DP was calculated and compared. These comparisons identify specific characteristics in the vicinity of the antigen-binding pocket that distinguish the different HLA-DP allotypes. Differences in electrostatics originate from the shape, specific disposition, and variation in the negatively charged groups around the pocket. The more negative the pocket potential, the greater the odds of developing CBD estimated from reported epidemiologic studies. Adverse impact is caused by charged substitutions in positions 55, 56, 69, 84, and 85, namely, the exact same loci identified as genetic markers of CBD susceptibility as well as cobalt-lung hard metal disease. These findings suggest that certain substitutions may promote an involuntary cation-binding site within a putatively metal-free peptide-binding pocket and therefore change the innate specificity of antigen recognition

Technological capabilities to assess digital excellence in hospitals in high performing healthcare systems::an international eDelphi exercise

Background: Hospitals worldwide are developing ambitious digital transformation programs as part of broader efforts to create digitally advanced health care systems. However, there is as yet no consensus on how best to characterize and assess digital excellence in hospitals. Objective: Our aim was to develop an international agreement on a defined set of technological capabilities to assess digital excellence in hospitals. Methods: We conducted a two-stage international modified electronic Delphi (eDelphi) consensus-building exercise, which included a qualitative analysis of free-text responses. In total, 31 international health informatics experts participated, representing clinical, academic, public, and vendor organizations. Results: We identified 35 technological capabilities that indicate digital excellence in hospitals. These are divided into two categories: (a) capabilities within a hospital (n=20) and (b) capabilities enabling communication with other parts of the health and social care system, and with patients and carers (n=15). The analysis of free-text responses pointed to the importance of nontechnological aspects of digitally enabled change, including social and organizational factors. Examples included an institutional culture characterized by a willingness to transform established ways of working and openness to risk-taking. The availability of a range of skills within digitization teams, including technological, project management and business expertise, and availability of resources to support hospital staff, were also highlighted. Conclusions: We have identified a set of criteria for assessing digital excellence in hospitals. Our findings highlight the need to broaden the focus from technical functionalities to wider digital transformation capabilities

Process evaluation in a multisite, primary obesity-prevention trial in American Indian schoolchildren

We describe the development, implementation, and use of the process evaluation component of a multisite, primary obesity prevention trial for American Indian schoolchildren. We describe the development and pilot testing of the instruments, provide some examples of the criteria for instrument selection, and provide examples of how process evaluation results were used to document and refine intervention components. The theoretical and applied framework of the process evaluation was based on diffusion theory, social learning theory, and the desire for triangulation of multiple modes of data collection. The primary objectives of the process evaluation were to systematically document the training process, content, and implementation of 4 components of the intervention. The process evaluation was developed and implemented collaboratively so that it met the needs of both the evaluators and those who would be implementing the intervention components. Process evaluation results revealed that observation and structured interviews provided the most informative data; however, these methods were the most expensive and time consuming and required the highest level of skill to undertake. Although the literature is full of idealism regarding the uses of process evaluation for formative and summative purposes, in reality, many persons are sensitive to having their work evaluated in such an in-depth, context-based manner as is described. For this reason, use of structured, quantitative, highly objective tools may be more effective than qualitative methods, which appear to be more dependent on the skills and biases of the researcher and the context in which they are used

Strategies for measuring long-term control in atopic dermatitis trials: a systematic review

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease. There are no standardised methods for capturing long-term control of AD. Objective: To identify how long-term control has been captured in published randomised controlled trials (RCTs). Resultswill initiate consensus discussions on how best to measure long-term control in the core outcome set for AD. Methods: Systematic review of RCTs of AD treatments published between 2000 and 2013, with a follow-up period of ≥3 months, at least one outcome measure recorded at ≥3 time-points, full paper available, and published in English. Results: 101/ 353 RCTs were eligible. Methods to capture long-term control included: repeated measurement of AD outcomes (92 RCTs; 91%), use of AD medication (29 RCTs; 28.7%); and AD flares/remissions (26 RCTs; 25.7%). Repeated measurements of AD outcomes were typically collected 3 to 5 times during a trial, but analysis methods often failed to make best use of the data. Time to first flare was most commonly for trials including flare data (21/52). Medication-use was recorded based on quantity, potency and frequency of application. Limitations: Included RCT data only Conclusion: This review illustrates the difficulties in measuring long-term control, and points to the need for improved harmonization of outcomes

Pathways: a culturally appropriate obesity-prevention program for American Indian schoolchildren

Pathways, a culturally appropriate obesity prevention study for third-, fourth-, and fifth-grade American Indian schoolchildren includes an intervention that promotes increased physical activity and healthful eating behaviors. The Pathways intervention, developed through a collaboration of universities and American Indian nations, schools, and families, focuses on individual, behavioral, and environmental factors and merges constructs from social learning theory with American Indian customs and practices. We describe the Pathways program developed during 3 y of feasibility testing in American Indian schools, with special emphasis on the activities developed for the third grade; review the theoretical and cultural underpinnings of the program; outline the construction process of the intervention; detail the curriculum and physical education components of the intervention; and summarize the formative assessment and the school food service and family components of the intervention

Triple-Nucleoside Regimens versus Efavirenz-Containing Regimens for the Initial Treatment of HIV-1 Infection

BACKGROUND Regimens containing three nucleoside reverse-transcriptase inhibitors offer an alternative to regimens containing nonnucleoside reverse-transcriptase inhibitors or protease inhibitors for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection, but data from direct comparisons are limited. METHODS This randomized, double-blind study involved three antiretroviral regimens for the initial treatment of subjects infected with HIV-1: zidovudine-lamivudine-abacavir, zidovudine-lamivudine plus efavirenz, and zidovudine-lamivudine-abacavir plus efavirenz. RESULTS We enrolled a total of 1147 subjects with a mean baseline HIV-1 RNA level of 4.85 log10(71,434) copies per milliliter and a mean CD4 cell count of 238 per cubic millimeter were enrolled. A scheduled review by the data and safety monitoring board with the use ofprespecified stopping boundaries led to a recommendation to stop the triple-nucleoside group and to present the results in the triple-nucleoside group in comparison with pooled data from the efavirenz groups. After a median follow-up of 32 weeks, 82 of 382 subjects in the triple-nucleoside group (21 percent) and 85 of 765 ofthose in the combined efavirenz groups (11 percent) had virologic failure; the time to virologic failure was significantly shorter in the triple-nucleoside group (P<0.001). This difference was observed regardless of the pretreatment HIV-1 RNA stratum (at least 100,000 copies per milliliter or below this level; P≤0.001 for both comparisons). Changes in the CD4 cell count and the incidence of grade 3 or grade 4 adverse events did not differ significantly between the groups. CONCLUSIONS In this trial of the initial treatment of HIV-1 infection, the triple-nucleoside combination ofabacavir, zidovudine, and lamivudine was virologically inferior to a regimen containing efavirenz and two or three nucleosides

Comparison of Sequential Three-Drug Regimens as Initial Therapy for HIV-1 Infection

BACKGROUND The optimal sequencing ofantiretroviral regimens for the treatment of infection with human immunodeficiency virus type 1 (HIV-1) is unknown. We compared several different antiretroviral treatment strategies. METHODS This multicenter, randomized, partially double-blind trial used a factorial design to compare pairs of sequential three-drug regimens, starting with a regimen including zidovudine and lamivudine or a regimen including didanosine and stavudine in combination with either nelfinavir or efavirenz. The primary end point was the length of time to the failure ofthe second three-drug regimen. RESULTS A total of 620 subjects who had not previously received antiretroviral therapy were followed for a median of 2. 3 years. Starting with a three-drug regimen containing efavirenz combined with zidovudine and lamivudine (but not efavirenz combined with didanosine and stavudine) appeared to delay the failure ofthe second regimen, as compared with starting with a regimen containing nelfinavir (hazard ratio for failure ofthe second regimen, 0.71; 95 percent confidence interval, 0.48 to 1.06), as well as to delay the second virologic failure (hazard ratio, 0.56; 95 percent confidence interval, 0.29 to 1.09), and significantly delayed the failure ofthe first regimen (hazard ratio, 0.39) and the firstvirologic failure (hazard ratio, 0.34). Starting with zidovudine and lamivudine combined with efavirenz (but not zidovudine and lamivudine combined with nelfinavir) appeared to delay the failure of the second regimen, as compared with starting with didanosine and stavudine (hazard ratio, 0.68), and significantly delayed both the first and the second virologic failures (hazard ratio for the firstvirologic failure, 0.39; hazard ratio for the second virologic failure, 0.47), as well as the failure ofthe first regimen (hazard ratio, 0.35). The initial use of zidovudine, lamivudine, and efavirenz resulted in a shorter time to viral suppression. CONCLUSIONS The efficacy ofantiretroviral drugs depends on how they are combined. The combination of zidovudine, lamivudine, and efavirenz is superior to the other antiretroviral regimens used as initial therapy in this study

A Roadmap for HEP Software and Computing R&D for the 2020s

Particle physics has an ambitious and broad experimental programme for the coming decades. This programme requires large investments in detector hardware, either to build new facilities and experiments, or to upgrade existing ones. Similarly, it requires commensurate investment in the R&D of software to acquire, manage, process, and analyse the shear amounts of data to be recorded. In planning for the HL-LHC in particular, it is critical that all of the collaborating stakeholders agree on the software goals and priorities, and that the efforts complement each other. In this spirit, this white paper describes the R&D activities required to prepare for this software upgrade.Peer reviewe