Anti-mutated citrullinatedvimentin antibody for predicting the activity of rheumatoid arthritis

Background: Anti-citrullinated protein/peptide antibodies (ACPAs) are a heterogeneous family of autoantibodies, targeting citrullinated proteins. We investigated the relationship between serum levels of anti-mutated citrullinatedvimentin antibody (anti-MCV) and rheumatoid arthritis (RA) activity. Method: A total of 271 consecutive female patients with diagnosis of RA who met the ACR/EULAR criteria were enrolled. The disease activity was measured by the Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR). Anti-MCV was measured by enzyme-linked immunosorbent assay using a commercial kit with a cut-off value for positivity >20 U/mL. Results: Anti-MCV was positive in 153 (56.5%) patients. Disease in anti-MCV positive patients was significantly more active. A new composite index for predicting disease activity was constructed by replacing ESR with anti-MCV in the DAS28 model. There was a correlation between the absolute scores of DAS28-anti-MCV and DAS28-ESR scores. The new composite index best cut-off values corresponding to DAS28-ESR values of 2.6, 3.2, and 5.1 were 2.94, 3.17, and 4.87, respectively. The patients were re-categorized based on the new threshold values calculated by ROC curve analysis. There was agreement between the DAS28-anti-MCV categories and DAS28-ESR disease activity categories. Conclusions: Based on the correlation between anti-MCV levels with RA disease activity index, we conclude that anti-MCV may be a useful test to determine disease activity in RA

A brief review on DNA vaccines in the era of COVID-19

This article provides a brief overview of DNA vaccines. First, the basic DNA vaccine design strategies are described, then specific issues related to the industrial production of DNA vaccines are discussed, including the production and purification of DNA products such as plasmid DNA, minicircle DNA, minimalistic, immunologically defined gene expression (MIDGE) and Doggybone (TM). The use of adjuvants to enhance the immunogenicity of DNA vaccines is then discussed. In addition, different delivery routes and several physical and chemical methods to increase the efficacy of DNA delivery into cells are explained. Recent preclinical and clinical trials of DNA vaccines for COVID-19 are then summarized. Lastly, the advantages and obstacles of DNA vaccines are discussed

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

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A controversial large-scale project at the historic core of the city of Urmia in Iran, has been the starting point of the present study. The Imam Square project was enthusiastically proposed as a solution for the revitalization of the decayed areas in the historic city center. However, the failure of the first phase of the project has given rise to serious doubts about its progress for approximately eight years. The present study argues that without understanding the morphological logic of a city and its evolution through time in relation with its socio-cultural structure, any interventions on the historic urban context can be problematic. Urban morphology is used as a tool to analyze the traditional urban structure of Urmia and its transformation up to the present time. The analyses are done based on four periods of time and in different scales from the city level to the scale of the urban block. The analytical methods of Space Syntax are used to better understand how the morphological characteristics of the traditional town of Urmia have changed. A comparative study is conducted on the current Imam Square and the traditional Bugda Meydan located next to the project area. The Axial Map, Segment Map and Visual Graph analyses are used to prepare the models of measures: Integration HH and R3, Choice, Step Depth, Visual Integration and Visual Clustering Coefficient. The comparison of models and numerical values illustrates that the traditional urban structure of Urmia has been radically transformed since the early 20th century as a result of urban modernization. While the traditional Bugda Meydan possessed a unique place in the historic city, what are the reasons that Imam Square cannot achieve the same success in the contemporary Urmia? The methodology proposed in the thesis has been rarely applied to study an urban design project in the Iranian context. In order to provide the consistency and reliability of the results, the methods are applied to evaluate seven case studies from the Iranian cities. Meaningful results have been achieved particularly by the correlation between the measures of Visual Integration and Visual Clustering Coefficient by which the areas with maximum centrality and the potential for a place to be a node where activities concentrate can be identified. It is demonstrated that the methods can also be applied to other Iranian cities. The case studies have contributed to further development of the methodology of the research and to identify two configuration patterns according which the traditional meydans were organized. These patterns guaranteed the success of meydan as a multi-functional urban space in the traditional cities of Iran that needs to be considered in any contemporary intervention. The present study reveals the significance of urban morphology for a traditional city and provides a methodological approach to evaluate new urban design projects in the historic context.-Ph.D. - Doctoral Progra

İran’da Tarihi Şehir Merkezlerinde İki Meydan: Semnan’da Tirandaz Meydanı ve Hamadan’da İmam Meydanı Üzerine Kentsel Morfoloji ve Mekân Dizilimi Yöntemleriyle Karşılaştırmalı Bir İnceleme

Meydanlar, geleneksel İran şehrinde farklı fiziksel ve işlevsel özelliklere sahip önemli kentsel unsurlardır. Başkentlerdeki ana meydan idari öneme sahipken, diğer şehirlerde genellikle ticari faaliyetlerin olduğu bir kamusal alan olmuştur. 20. yüzyılın başlarından itibaren, İran şehirlerinin geleneksel kent yapısı üzerine modern sokak ağı uygulanarak dönüştürülmeye başlatıldı. Şehirlerin morfolojik mantığı pervasız müdahalelerle değişti ve geleneksel kent unsurları birbirleriyle olan ilişkilerini kaybettiler. Bu çalışma, İran’ın geleneksel iki şehri olan Semnan ve Hamadan’daki iki meydanı analiz ederek eski ve yeninin karşılıklı etkilerini değerlendirmeyi amaçlamaktadır. Kentsel morfoloji, bir yöntem olarak, kentlerin geçmiş ve şimdiki mekânsal yapısını ve meydanların bu yapılarda durumunu belirlemek için kullanılacaktır. Semnan’da bulunan Tirandaz Meydan, eskiden iç içe geçmiş çok sayıda açık ve kapalı alan içeren kentsel kompleksin bir parçasıydı. Kentsel modernizasyonundan sonra, Tirandaz Meydan’ın morfolojik karakteri tamamen değişti. Öte yandan, Hamadan’ın tarihi merkezinde, kentin yeni kamusal odak noktası olması için modern bir meydan yayalaştırılmıştır. Hamadan’ın İmam meydanı, araba trafiğini kolaylaştırmak için ilk modernizasyon hareketi tarafından 20. yüzyılın başlarında inşa edildi. Mekan dizimi analiz yöntemi, geleneksel bir meydanın mekânsal özelliklerinin modern kentte nasıl değiştiğini, ve işlevsel olarak değiştirilmiş modern bir meydanın şehrin tarihi çekirdeğini nasıl etkilediğini anlamak için kullanılacaktır. Eksenel Harita analizi, modernleşme sürecinde geleneksel kentlerin entegrasyon modelinin nasıl değiştiğini incelemek için yapılacaktır. Hamadan için, İmam Meydanı’ndaki araç trafiği sınırlamalarından önceki ve sonraki durumları arasında “Choice” ve “Integration HH” analiz metodları ile karşılaştırma yapılmıştır. Modeller, İmam meydanının trafik yükünü artırarak tarihi dokuya olumsuz bir etki yaptığını göstermektedir. Görsel Grafik analizi, modern kentte, Semnan’daki Tirandaz Meydanının mekansal özelliklerinin nasıl değiştiğini anlamak için yapılmıştır. “Visual Integration” ve “Visual Clustering Coefficient” ölçümleri, görünürlüğünü ve kamu faaliyetleri potansiyelini değerlendirmek için kullanılmıştır. Başarılı bir kamusal alan için bu niteliklerin her ikisi de gerekli olduğundan, bunların korelasyonu “scatter plot” diyagramı ile yapılacaktır. Sonuçlar, geleneksel Tirandaz Meydan’ın çağdaş Semnan’da merkeziyetini ve kamusal alan olma potansiyelini kaybettiğini ortaya koyuyor. Modern sokaklar, şehrin yeni ticari aksları olmak için kapalı çarşı gibi geleneksel kentsel unsurlarla yakın rekabet içindedir. Semnan’ın tarihi kapalı çarşıdan bağımsız Tirandaz Meydan’ı modern caddeye bağlanmış ve tarihi sosyo-ekonomik rolü tamamen otopark yerine dönüşmüştür. Meydanda yaya akışı azaldığından, geleneksel perakendecilerin yerini toptan satış mağazaları almıştır. Hamadan’da modern caddelerin sosyal aktiviteler açısından yüksek potansiyeli, geleneksel mahalleler dikkate alınmadan yeni bir meydan yapmak için kullanıldı. Araştırmanın sonuclarına göre, kalan tarihi evlerin yarı özel alanı, artan araba trafiği tarafından ihlal edilmektedir

MicroRNA expression studies: challenge of selecting reliable reference controls for data normalization

Accurate determination of microRNA expression levels is a prerequisite in using these small non-coding RNA molecules as novel biomarkers in disease diagnosis and prognosis. Quantitative PCR is the method of choice for measuring the expression levels of microRNAs. However, a major obstacle that affects the reliability of results is the lack of validated reference controls for data normalization. Various non-coding RNAs have previously been used as reference controls, but their use may lead to variations and lack of comparability of microRNA data among the studies. Despite the growing number of studies investigating microRNA profiles to discriminate between healthy and disease stages, robust reference controls for data normalization have so far not been established. In the present article, we provide an overview of different reference controls used in various diseases, and highlight the urgent need for the identification of suitable reference controls to produce reliable data. Our analysis shows, among others, that RNU6 is not an ideal normalizer in studies using patient material from different diseases. Finally, our article tries to disclose the challenges to find a reference control which is uniformly and stably expressed across all body tissues, fluids, and diseases