Influence of peptidylarginine deiminase type 4 genotype and shared epitope on clinical characteristics and autoantibody profile of rheumatoid arthritis.

Background: Recent evidence suggests that distinction of subsets of rheumatoid arthritis (RA) depending on anticyclic citrullinated peptide antibody (anti-CCP) status may be helpful in distinguishing distinct aetiopathologies and in predicting the course of disease. HLA-DRB1 shared epitope (SE) and peptidylarginine deiminase type 4 (PADI4) genotype, both of which have been implicated in anti-CCP generation, are assumed to be associated with RA. Objectives: To elucidate whether PADI4 affects the clinical characteristics of RA, and whether it would modulate the effect of anti-CCPs on clinical course. The combined effect of SE and PADI4 on autoantibody profile was also analysed. Methods: 373 patients with RA were studied. SE, padi4_94C.T, rheumatoid factor, anti-CCPs and antinuclear antibodies (ANAs) were determined. Disease severity was characterised by cumulative therapy intensity classified into ordinal categories (CTI-1 to CTI-3) and by Steinbrocker score. Results: CTI was significantly associated with disease duration, erosive disease, disease activity score (DAS) 28 and anti-CCPs. The association of anti-CCPs with CTI was considerably influenced by padi4_94C.T genotype (C/C: ORadj=0.93, padj=0.92; C/T: ORadj=2.92, padj=0.093; T/T: ORadj=15.3, padj=0.002). Carriage of padi4_94T exhibited a significant trend towards higher Steinbrocker scores in univariate and multivariate analyses. An association of padi4_94C.T with ANAs was observed, with noteworthy differences depending on SE status (SE2: ORadj=6.20, padj,0.04; SE+: ORadj=0.36, padj=0.02) and significant heterogeneity between the two SE strata (p=0.006). Conclusions: PADI4 genotype in combination with anti- CCPs and SE modulates clinical and serological characteristics of RA

Impact of NOx vehicle emission standards failure on Air Quality in Europe

Vehicle exhaust emission standards have been tightened in the EU for several decades now, in order to protect health and the environment. This has led to a substantial decrease in total pollutant emissions, despite the growing volumes of passenger and freight transport. However, national emissions, particularly of NOx, exceed the ceilings accorded under the Gothenburg Protocol of the UNECE's Convention on Long-Range Transboundary Air Pollution (LRTAP) (EEA 2012) in twelve EU Member States. The main reasons for such exceedances are that more diesel cars have been sold than originally predicted when fixing the targets, and that diesel cars emit much more than expected under real-world driving conditions. The latter appears as a consequence of the effort to achieve high fuel efficiency. While this has largely helped to control CO2 emissions, it was to the detriment of NOx. In this study we estimate what the impact of the different vehicle emission standards has been so far and to predict what the impact of upcoming emission standards will be in the future, using the best current knowledge on road transport activity statistics and emission factors in Europe. We present several sensitivity calculations to reflect the considerable uncertainty about the real-driving NOx emissions of diesel light duty vehicles. The results of this work can be useful in designing both limits for upcoming standards but also in assessing the impact of deviating from such limits. This is necessary in both deciding on the next steps of emission control policy and to relevant air quality prediction models

Dental treatment on a German warship during a three-month deployment

Introduction: Despite routine dental screenings and treatments before military deployments, dental emergencies may arise due to acute infections, trauma or failed restorations. The purpose of this study is to evaluate the dental service during a three-month deployment on a German warship. Methods: A retrospective analysis of dental attendances and treatments in a German naval task group of three ships with an average total of 650 soldiers. Diagnosis, treatments performed, percentage of emergencies, routine procedures and numbers of appointments were recorded. Results: Out of 650 soldiers, there were 71 patients (10.92%) with a mean age of 25.1±5.3 years. Out of 136 treatments, 17.65% were for emergency treatment, which is equivalent to 3.69% of all servicemen of the task group. Combining the reasons for dental emergencies, 95.84% were caused by caries. Conclusions: The pre-screening of sailors before an overseas deployment is necessary to avoid severe dental treatments. Caries remains the main cause for dental emergencies, and medical doctors should be trained to treat caries lesions if a dentist is not on board

Constraining the uncertainty in emissions over India with a regional air quality model evaluation

To evaluate uncertainty in the spatial distribution of air emissions over India, we compare satellite and surface observations with simulations from the U.S. Environmental Protection Agency (EPA) Community Multi-Scale Air Quality (CMAQ) model. Seasonally representative simulations were completed for January, April, July, and October 2010 at 36 km × 36 km using anthropogenic emissions from the Greenhouse Gas-Air Pollution Interaction and Synergies (GAINS) model following version 5a of the Evaluating the Climate and Air Quality Impacts of Short-Lived Pollutants project (ECLIPSE v5a). We use both tropospheric columns from the Ozone Monitoring Instrument (OMI) and surface observations from the Central Pollution Control Board (CPCB) to closely examine modeled nitrogen dioxide (NO2) biases in urban and rural regions across India. Spatial average evaluation with satellite retrievals indicate a low bias in the modeled tropospheric column (-63.3%), which reflects broad low-biases in majority non-urban regions (-70.1% in rural areas) across the sub-continent to slightly lesser low biases reflected in semi-urban areas (-44.7%), with the threshold between semi-urban and rural defined as 400 people per km2. In contrast, modeled surface NO2 concentrations exhibit a slight high bias of +15.6% when compared to surface CPCB observations predominantly located in urban areas. Conversely, in examining extremely population dense urban regions with more than 5000 people per km2 (dense-urban), we find model overestimates in both the column (+57.8) and at the surface (+131.2%) compared to observations. Based on these results, we find that existing emission fields for India may overestimate urban emissions in densely populated regions and underestimate rural emissions. However, if we rely on model evaluation with predominantly urban surface observations from the CPCB, comparisons reflect model high biases, contradictory to the knowledge gained using satellite observations. Satellites thus serve as an important emissions and model evaluation metric where surface observations are lacking, such as rural India, and support improved emissions inventory development

Distinct polyadenylation landscapes of diverse human tissues revealed by a modified PA-seq strategy

Background: Polyadenylation is a key regulatory step in eukaryotic gene expression and one of the major contributors of transcriptome diversity. Aberrant polyadenylation often associates with expression defects and leads to human diseases. Results: To better understand global polyadenylation regulation, we have developed a polyadenylation sequencing (PA-seq) approach. By profiling polyadenylation events in 13 human tissues, we found that alternative cleavage and polyadenylation (APA) is prevalent in both protein-coding and noncoding genes. In addition, APA usage, similar to gene expression profiling, exhibits tissue-specific signatures and is sufficient for determining tissue origin. A 3? untranslated region shortening index (USI) was further developed for genes with tandem APA sites. Strikingly, the results showed that different tissues exhibit distinct patterns of shortening and/or lengthening of 3? untranslated regions, suggesting the intimate involvement of APA in establishing tissue or cell identity. Conclusions: This study provides a comprehensive resource to uncover regulated polyadenylation events in human tissues and to characterize the underlying regulatory mechanism

Rationality as the Rule of Reason

The demands of rationality are linked both to our subjective normative perspective (given that rationality is a person-level concept) and to objective reasons or favoring relations (given that rationality is non-contingently authoritative for us). In this paper, I propose a new way of reconciling the tension between these two aspects: roughly, what rationality requires of us is having the attitudes that correspond to our take on reasons in the light of our evidence, but only if it is competent. I show how this view can account for structural rationality on the assumption that intentions and beliefs as such involve competent perceptions of downstream reasons, and explore various implications of the account

Diagnostic errors by medical students: results of a prospective qualitative study

Background: Diagnostic errors occur frequently in daily clinical practice and put patients' safety at risk. There is an urgent need to improve education on clinical reasoning to reduce diagnostic errors. However, little is known about diagnostic errors of medical students. In this study, the nature of the causes of diagnostic errors made by medical students was analyzed. Methods: In June 2016, 88 medical students worked on eight cases with the chief complaint dyspnea in a laboratory setting using an electronic learning platform, in summary 704 processed cases. The diagnostic steps of the students were tracked and analyzed. Furthermore, after each case the participants stated their presumed diagnosis and explained why they came to their diagnostic conclusion. The content of these explanations was analyzed qualitatively. Results: Based on the diagnostic data gathering process and the students' explanations, eight different causes could be identified of which the lack of diagnostic skills (24%) and inadequate knowledge base (16%) were the most common. Other causes that often contributed to a diagnostic error were faulty context generation (15%) and premature closure (10%). The causes of misdiagnosis varied per case. Conclusions: Inadequate skills/knowledge and faulty context generation are the major problems in students' clinical reasoning process. These findings are valuable for improving medical education and thus reducing the frequency of diagnostic errors in students' later everyday clinical practice

Human AZFb deletions cause distinct testicular pathologies depending on their extensions in Yq11 and the Y haplogroup: new cases and review of literature

Genomic AZFb deletions in Yq11 coined “classical” (i.e. length of Y DNA deletion: 6.23 Mb) are associated with meiotic arrest (MA) of patient spermatogenesis, i.e., absence of any postmeiotic germ cells. These AZFb deletions are caused by non-allelic homologous recombination (NAHR) events between identical sequence blocks located in the proximal arm of the P5 palindrome and within P1.2, a 92 kb long sequence block located in the P1 palindrome structure of AZFc in Yq11. This large genomic Y region includes deletion of 6 protein encoding Y genes, EIFA1Y, HSFY, PRY, RBMY1, RPS4Y, SMCY. Additionally, one copy of CDY2 and XKRY located in the proximal P5 palindrome and one copy of BPY1, two copies of DAZ located in the P2 palindrome, and one copy of CDY1 located proximal to P1.2 are included within this AZFb microdeletion. It overlaps thus distally along 2.3 Mb with the proximal part of the genomic AZFc deletion. However, AZFb deletions have been also reported with distinct break sites in the proximal and/or distal AZFb breakpoint intervals on the Y chromosome of infertile men. These so called “non-classical” AZFb deletions are associated with variable testicular pathologies, including meiotic arrest, cryptozoospermia, severe oligozoospermia, or oligoasthenoteratozoospermia (OAT syndrome), respectively. This raised the question whether there are any specific length(s) of the AZFb deletion interval along Yq11 required to cause meiotic arrest of the patient’s spermatogenesis, respectively, whether there is any single AZFb Y gene deletion also able to cause this “classical” AZFb testicular pathology? Review of the literature and more cases with “classical” and “non-classical” AZFb deletions analysed in our lab since the last 20 years suggests that the composition of the genomic Y sequence in AZFb is variable in men with distinct Y haplogroups especially in the distal AZFb region overlapping with the proximal AZFc deletion interval and that its extension can be “polymorphic” in the P3 palindrome. That means this AZFb subinterval can be rearranged or deleted also on the Y chromosome of fertile men. Any AZFb deletion observed in infertile men with azoospermia should therefore be confirmed as “de novo” mutation event, i.e., not present on the Y chromosome of the patient’s father or fertile brother before it is considered as causative agent for man’s infertility. Moreover, its molecular length in Yq11 should be comparable to that of the “classical” AZFb deletion, before meiotic arrest is prognosed as the patient’s testicular pathology

Assessing the macroeconomic impacts of individual behavioral changes on carbon emissions

© 2019, The Author(s). In the last decade, instigated by the Paris agreement and United Nations Climate Change Conferences (COP22 and COP23), the efforts to limit temperature increase to 1.5 °C above pre-industrial levels are expanding. The required reductions in greenhouse gas emissions imply a massive decarbonization worldwide with much involvement of regions, cities, businesses, and individuals in addition to the commitments at the national levels. Improving end-use efficiency is emphasized in previous IPCC reports (IPCC 2014). Serving as the primary ‘agents of change’ in the transformative process towards green economies, households have a key role in global emission reduction. Individual actions, especially when amplified through social dynamics, shape green energy demand and affect investments in new energy technologies that collectively can curb regional and national emissions. However, most energy-economics models—usually based on equilibrium and optimization assumptions—have a very limited representation of household heterogeneity and treat households as purely rational economic actors. This paper illustrates how computational social science models can complement traditional models by addressing this limitation. We demonstrate the usefulness of behaviorally rich agent-based computational models by simulating various behavioral and climate scenarios for residential electricity demand and compare them with the business as usual (SSP2) scenario. Our results show that residential energy demand is strongly linked to personal and social norms. Empirical evidence from surveys reveals that social norms have an essential role in shaping personal norms. When assessing the cumulative impacts of these behavioral processes, we quantify individual and combined effects of social dynamics and of carbon pricing on individual energy efficiency and on the aggregated regional energy demand and emissions. The intensity of social interactions and learning plays an equally important role for the uptake of green technologies as economic considerations, and therefore in addition to carbon-price policies (top-down approach), implementing policies on education, social and cultural practices can significantly reduce residential carbon emissions