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The relative importance and stability of disease burden causes over time: summarizing regional trends on disease burden for 290 causes over 28 years
Get PDFBackground:Since the Global Burden of Disease study (GBD) has become more comprehensive, data for hundreds of causes of disease burden, measured using Disability Adjusted Life Years (DALYs), have become increasingly available for almost every part of the world. However, undergoing any systematic comparative analysis of the trends can be challenging given the quantity of data that must be presented.Methods:We use the GBD data to describe trends in cause-specific DALY rates for eight regions. We quantify the extent to which the importance of‘major’DALY causes changes relative to‘minor’DALY causes over time by decomposing changes in the Gini coefficient into‘proportionality’ and ‘reranking’indices.Results:The fall in regional DALY rates since 1990 has been accompanied by generally positive proportionality indices and reranking indices of negligible magnitude. However, the rate at which DALY rates have been falling has slowed and, at the same time, proportionality indices have tended towards zero. These findings are clearest where the focus is exclusively upon non-communicable diseases. Notably, large and positive proportionality indices are recorded for sub-Saharan Africa over the last decade.Conclusion:The positive proportionality indices show that disease burden has become less concentrated around the leading causes over time, and this trend has become less prominent as the DALY rate decline has slowed. The recent decline in disease burden in sub-Saharan Africa is disproportionally driven by improvements in DALY rates for HIV/AIDS, as well as for malaria, diarrheal diseases, and lower respiratory infections
Glycan remodeled erythrocytes facilitate antigenic characterization of recent A/H3N2 influenza viruses
No full textDuring circulation in humans and natural selection to escape antibody recognition for decades, A/H3N2 influenza viruses emerged with altered receptor specificities. These viruses lost the ability to agglutinate erythrocytes critical for antigenic characterization and give low yields and acquire adaptive mutations when cultured in eggs and cells, contributing to recent vaccine challenges. Examination of receptor specificities of A/H3N2 viruses reveals that recent viruses compensated for decreased binding of the prototypic human receptor by recognizing α2,6-sialosides on extended LacNAc moieties. Erythrocyte glycomics shows an absence of extended glycans providing a rationale for lack of agglutination by recent A/H3N2 viruses. A glycan remodeling approach installing functional receptors on erythrocytes, allows antigenic characterization of recent A/H3N2 viruses confirming the cocirculation of antigenically different viruses in humans. Computational analysis of HAs in complex with sialosides having extended LacNAc moieties reveals that mutations distal to the RBD reoriented the Y159 side chain resulting in an extended receptor binding site.</p
External basic hyperthermia devices for preclinical studies in small animals
No full textPreclinical studies have shown that application of mild hyperthermia (40–43 °C) is a promising adjuvant to solid tumor treatment. To improve preclinical testing, enhance reproducibility, and allow comparison of the obtained results, it is crucial to have standardization of the available methods. Reproducibility of methods in and between research groups on the same techniques is crucial to have a better prediction of the clinical outcome and to improve new treatment strategies (for instance with heat‐sensitive nanoparticles). Here we provide a preclinically oriented review on the use and applicability of basic hyperthermia systems available for solid tumor thermal treatment in small animals. The complexity of these techniques ranges from a simple, low‐cost water bath approach, irradiation with light or lasers, to advanced ultrasound and capacitive heating devices.</p
Region-specific preservation of Purkinje cell morphology and motor behavior in the ATXN1[82Q] mouse model of spinocerebellar ataxia 1
No full textPurkinje cells are the primary processing units of the cerebellar cortex and display molecular heterogeneity that aligns with differences in physiological properties, projection patterns, and susceptibility to disease. In particular, multiple mouse models that feature Purkinje cell degeneration are characterized by incomplete and patterned Purkinje cell degeneration, suggestive of relative sparing of Purkinje cell subpopulations, such as those expressing Aldolase C/zebrinII (AldoC) or residing in the vestibulo-cerebellum. Here, we investigated a well-characterized Purkinje cell-specific mouse model for spinocerebellar ataxia type 1 (SCA1) that expresses human ATXN1 with a polyQ expansion (82Q). Our pathological analysis confirms previous findings that Purkinje cells of the vestibulo-cerebellum, i.e., the flocculonodular lobes, and crus I are relatively spared from key pathological hallmarks: somatodendritic atrophy, and the appearance of p62/SQSTM1-positive inclusions. However, immunohistological analysis of transgene expression revealed that spared Purkinje cells do not express mutant ATXN1 protein, indicating the sparing of Purkinje cells can be explained by an absence of transgene expression. Additionally, we found that Purkinje cells in other cerebellar lobules that typically express AldoC, not only display severe pathology but also show loss of AldoC expression. The relatively preserved flocculonodular lobes and crus I showed a substantial fraction of Purkinje cells that expressed the mutant protein and displayed pathology as well as loss of AldoC expression. Despite considerable pathology in these lobules, behavioral analyses demonstrated a relative sparing of related functions, suggestive of sufficient functional cerebellar reserve. Together, the data indicate that mutant ATXN1 affects both AldoC-positive and AldoC-negative Purkinje cells and disrupts normal parasagittal AldoC expression in Purkinje cells. Our results show that, in a mouse model otherwise characterized by widespread Purkinje cell degeneration, sparing of specific subpopulations is sufficient to maintain normal performance of specific behaviors within the context of the functional, modular map of the cerebellum.</p
Bypassing Institutional Barriers
No full textChina is often viewed as an emerging experimental base for transit-oriented development (TOD) practices because of its rapid urban growth and development of mass transit networks. The implementation of TOD can be heavily influenced by institutional barriers to urban growth. However, some newly emerging types of TOD practice allow planners and decision-makers to bypass some of the institutional barriers and achieve a certain degree of integrated development. Current academic literature, however, has little to say on how these informal institutional solutions go around these barriers. This article aims to fill this gap by examining three different types of TOD practice as applied in Guangzhou and Shenzhen. We analysed and compared the origins and effects of abovementioned informal institutional arrangements under entrepreneurial governance. We found that land value capturing can replace the existing governance mode in which local government heavily relies on revenue from land-leasing and realise better integration of transit and land development. We conclude with several suggestions for institutional reform based on these new types of TOD experiments.</p
In uveal melanoma, angiopoietin-2 but not angiopoietin-1 is increased in high-risk tumors, providing a potential druggable target
No full textUveal melanoma (UM) metastasize haematogeneously, and tumor blood vessel density is an important prognostic factor. We hypothesized that proangiogenic factors such as angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), two targetable cytokines, might play a role in tumor development and metastatic behavior. mRNA levels of ANG-1 and ANG-2 were determined in 64 tumors using an Illumina HT-12 v4 mRNA chip and compared to clinical, pathologic, and genetic tumor parameters. Tissue expression was also determined by immunohistochemistry (IHC). Samples of aqueous humor were collected from 83 UM-containing enucleated eyes and protein levels that were determined in a multiplex proximity extension assay. High tissue gene expression of ANG-2, but not of ANG-1, was associated with high tumor thickness, high largest basal diameter, involvement of the ciliary body, and with UM-related death (ANG-2 mRNA p < 0.001; ANG-2 aqueous protein p < 0.001). The presence of the ANG-2 protein in aqueous humor correlated with its mRNA expression in the tumor (r = 0.309, p = 0.03). IHC showed that ANG-2 was expressed in macrophages as well as tumor cells. The presence of ANG-2 in the tumor and in aqueous humor, especially in high-risk tumors, make ANG-2 a potential targetable cytokine in uveal melanoma.</p
Equity-specific effects of interventions to promote physical activity among middle-aged and older adults
No full textBackground: Reducing inequalities in physical activity (PA) and PA-associated health outcomes is a priority for public health. Interventions to promote PA may reduce inequalities, but may also unintentionally increase them. Thus, there is a need to analyze equity-specific intervention effects. However, the potential for analyzing equity-specific effects of PA interventions has not yet been sufficiently exploited. The aim of this study was to set out a novel equity-specific re-analysis strategy tried out in an international interdisciplinary collaboration. Methods: The re-analysis strategy comprised harmonizing choice and definition of outcomes, exposures, socio-demographic indicators, and statistical analysis strategies across studies, as well as synthesizing results. It was applied in a collaboration of a convenience sample of eight European PA intervention studies in adults aged ≥45 years. Weekly minutes of moderate-to-vigorous PA was harmonized as outcome. Any versus no intervention was harmonized as exposure. Gender, education, income, area deprivation, and marital status were harmonized as socio-demographic indicators. Interactions between the intervention and socio-demographic indicators on moderate-to-vigorous PA were analyzed using multivariable linear regression and random-effects meta-analysis. Results: The collaborative experience shows that the novel re-analysis strategy can be applied to investigate equity-specific effects of existing PA interventions. Across our convenience sample of studies, no consistent pattern of equity-specific intervention effects was found. Pooled estimates suggested that intervention effects did not differ by gender, education, income, area deprivation, and marital status. Conclusions: To exploit the potential for equity-specific effect analysis, we encourage future studies to apply the strategy to representative samples of existing study data. Ensuring sufficient representation of ‘hard to reach’ groups such as the most disadvantaged in study samples is of particular importance. This will help to extend the limited evidence required for the design and prioritization of future interventions that are most likely to reduce health inequalities.</p
The role of tobacco smoking and illicit drug use in adolescent acute alcohol intoxication
No full textBackground: This study aims to determine the prevalence of tobacco smoking and illicit drug use among Dutch adolescents admitted to hospital for acute alcohol intoxication treatment. Furthermore, socio-demographic predictors for smoking and illicit drug use in the sample population will be studied. The relationship between illicit drug use and specific characteristics of intoxication, such as blood alcohol concentration (BAC) and duration of reduced consciousness is also investigated. Methods: The national Dutch Paediatric Surveillance Unit was used to prospectively register cases of acute alcohol intoxication from 2007 through 2017. Cases were included if they met the following inclusion criteria: BAC > 0.0 g/L, aged between 10 to 18 years old and requiring hospital treatment due to reduced consciousness. Questionnaires were sent to paediatricians to obtain clinical information. Results: During the period 2007–2017, 5322 cases that met the inclusion criteria were reported. In this patient group, the prevalence of tobacco smoking was 22.2% (CI 21.0–23.5%), while the prevalence of illicit drug use was 11.8% (CI 10.9–12.7%). The predictors for smoking were the absence of alcohol-specific parental rule-setting, lower educational level, non-traditional family structure and positive drug screening. The predictors for illicit drug use were the absence of alcohol-specific parental rule-setting and smoking. Illicit drug use was also associated with a lower BAC at the time of admission. Conclusions: Assessing smoking and illicit drug use among adolescents admitted for acute alcohol intoxication is important in acute cases of intoxication, for outpatient follow-up and for the purposes of prevention. The relationship between simultaneous illicit drug use and a lower BAC is of relevance for paediatricians’ attempts to diagnose acute intoxication. With respect to outpatient follow-up and preventive measures, it is important to be aware that adolescents’ alcohol consumption, tobacco and illicit drug use are related and, ultimately, increase the odds of using other substances.</p
Combination Therapy, a Promising Approach to Enhance the Efficacy of Radionuclide and Targeted Radionuclide Therapy of Prostate and Breast Cancer
No full textIn recent years, radionuclide therapy (RT) and targeted radionuclide therapy (TRT) have gained great interest in cancer treatment. This is due to promising results obtained in both preclinical and clinical studies. However, a complete response is achieved in only a small percentage of patients that receive RT or TRT. As a consequence, there have been several strategies to improve RT and TRT outcomes including the combination of these treatments with other well-established anti-cancer therapies, for example, chemotherapy. Combinations of RT and TRT with other therapies with distinct mechanisms of action represent a promising strategy. As for prostate cancer and breast cancer, the two most prevalent cancer types worldwide, several combination-based therapies have been evaluated. In this review, we will provide an overview of the RT and TRT agents currently used or being investigated in combination with hormone therapy, chemotherapy, immunotherapy, and external beam radiation therapy for the treatment of prostate cancer and breast cancer
Recommendations for Clinical CYP2D6 Genotyping Allele Selection
No full textThe goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing, and to determine a minimal set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations on a minimal panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories in designing assays for PGx testing. When developing these recommendations, the Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations with regard to PGx testing. The ultimate goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This document is focused on clinical CYP2D6 PGx testing that may be applied to all cytochrome P450 2D6–metabolized medications. These recommendations are not meant to be interpreted as prescriptive but to provide a reference guide for clinical laboratories that may be either implementing PGx testing or reviewing and updating their existing platform.</p