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Purpose The purpose of this study was to analyze the association between functioning and disability and quality of life (QoL) in older individuals with joint contractures in the geriatric care setting. More specifically, this study aimed to identify determinants of QoL out of a defined set of contracture-related categories of the International Classification of Functioning, Disability and Health (ICF). Methods Participants for this multicenter cross-sectional survey were recruited from acute geriatric rehabilitation hospitals, nursing homes, and community nursing facilities in Germany between February and October 2013. QoL was assessed using the validated German version of the EQ-5D index score and the EQ-5D visual analog scale (VAS). Manual and automatic variable selection methods were used to identify the most relevant variables out of 125 contracture-related ICF categories. Results A total of 241 eligible participants (34.9 % male, mean age 80.1 years) were included. The final models contained 14 ICF categories as predictors of the EQ-5D index score and 15 categories as predictors of the EQ-5D VAS. The statistically significant ICF categories from both models were 'muscle power functions (b730),' 'memory functions (b144),' 'taking care of plants (d6505),' 'recreation and leisure (d920),' 'religion and spirituality (d930),' 'drugs (e1101),' and 'products and technology for personal use in daily living (e115).' Conclusions We identified the most relevant ICF categories for older individuals with joint contractures and their health-related quality of life. These items describe potential determinants of QoL which may provide the basis for future health interventions aiming to improve QoL for the patients with joint contractures.

To conduct a pragmatic, randomized controlled trial to assess whether thiopurine methyltransferase (TPMT) genotyping prior to azathioprine reduces adverse drug reactions (ADRs). A total of 333 participants were randomized 1:1 to undergo genotyping prior to azathioprine or to commence treatment without genotyping. There was no difference in the primary outcome of stopping azathioprine due to an adverse reaction (ADR, p = 0.59) between the two study arms. ADRs were more common in older patients (p = 0.01). There was no increase in stopping azathioprine due to ADRs in heterozygotes compared with wild-type individuals. The single individual with TPMT variant homozygosity experienced severe neutropenia. Our work supports the strong evidence that individuals with TPMT variant homozygosity are at high risk of severe neutropenia, whereas heterozygotes are not at increased risk of ADRs at standard doses of azathioprine. Original submitted 5 January 2011; Revised submitted 18 February 2011

Aim: To conduct a pragmatic, randomized controlled trial to assess whether thiopurine methyltransferase (TPMT) genotyping prior to azathioprine reduces adverse drug reactions (ADRs). Methods: A total of 333 participants were randomized 1:1 to undergo TPMT genotyping prior to azathioprine or to commence treatment without genotyping. Results: There was no difference in the primary outcome of stopping azathioprine due to an adverse reaction (ADR, p = 0.59) between the two study arms. ADRs were more common in older patients (p = 0.01). There was no increase in stopping azathioprine due to ADRs in TPMT heterozygotes compared with wild-type individuals. The single individual with TPMT variant homozygosity experienced severe neutropenia. Conclusion: Our work supports the strong evidence that individuals with TPMT variant homozygosity are at high risk of severe neutropenia, whereas TPMT heterozygotes are not at increased risk of ADRs at standard doses of azathioprine. Original submitted 5 January 2011; Revised submitted 18 February 2011

Malnourishment, specifically overweight/obesity and undernourishment, affects more than 2.5 billion people worldwide, with the number affected ever-increasing. Concurrently, emerging viral diseases, particularly those that are mosquito-borne, have spread dramatically in the past several decades, culminating in outbreaks of several viruses worldwide. Both forms of malnourishment are known to lead to an aberrant immune response, which can worsen disease outcomes and reduce vaccination efficacy for viral pathogens such as influenza and measles. Given the increasing rates of malnutrition and spread of arthropod-borne viruses (arboviruses), there is an urgent need to understand the role of host nutrition on the infection, virulence, and transmission of these viruses. To address this gap in knowledge, we infected lean, obese, and undernourished mice with arthritogenic arboviruses from the genus Alphavirus and assessed morbidity, virus replication, transmission, and evolution. Obesity and undernourishment did not consistently influence virus replication in the blood of infected animals except for reductions in virus in obese mice late in infection. However, morbidity was increased in obese mice under all conditions. Using Mayaro virus (MAYV) as a model arthritogenic alphavirus, we determined that both obese and undernourished mice transmit virus less efficiently to mosquitoes than control (lean) mice. In addition, viral genetic diversity and replicative fitness were reduced in virus isolated from obese compared to lean controls. Taken together, nutrition appears to alter the course of alphavirus infection and should be considered as a critical environmental factor during outbreaks.

The use of rare earth elements has increased in recent years, leading to a rise in environmental concentrations. Despite the growth in number of studies regarding toxicity, knowledge gaps remain. For Daphnia magna , standardized test methods involve exposure periods of either 48 h or 21 days to assess toxicological effects. In this study, the exposure period was adjusted to 7 days to evaluate sublethal endpoints not measurable in 48-h tests. Additionally, this approach enabled us to obtain results within a shorter time frame than that required for 21-day tests. This study focused on the individual toxicity of lanthanum (La) and gadolinium (Gd) to Daphnia magna . We assessed mortality, feeding rate, somatic growth, and maturity under static conditions, modifying the media by adding MOPS buffer to maintain an initial pH of 6.8 and providing Raphidocelis subcapitata as a daily food source. Results showed that the solubility of La decreased considerably, with the highest recovery rate dropping from 133.33% at the start to 32.73% by the end of the 7-day exposure period. In contrast, Gd solubility remained stable, with a recovery rate of 86.88% at the start and 81.30% at the end of the test. Daily lethal concentrations (LC x ) were calculated, revealing LC 10 values on the first day, LC 20 on the second day, and LC 50 by the third day for La and the second day for Gd. By the test’s end, the LC 10 , LC 20 , and LC 50 values were 30.40, 78.96, and 403.67 µg L −1 for La, and 10.67, 33.73, and 241.28 µg L −1 for Gd. For the sublethal endpoints, maturity was the most sensitive endpoint with the EC 20 and EC 10 corresponding to 0.79 and 0.26 µg L −1 for La and 0.39 and 0.14 µg L −1 for Gd. Gd had a higher toxicity in all endpoints assessed. While a thorough comparison to existing literature remains challenging due to variations in endpoints assessed, the methodology employed in this study yielded a range of informative results. This approach provides a useful range-finding test for Daphnia magna toxicity assessments, particularly for preliminary screening, and may complement standardized methodologies.

Chikungunya virus (CHIKV) is a mosquito-borne RNA virus that poses an emerging threat to humans. In a manner similar to other RNA viruses, CHIKV encodes an error-prone RNA polymerase which, in addition to producing full-length genomes, gives rise to truncated, non-functional genomes, which have been coined defective viral genomes (DVGs). DVGs have been intensively studied in the context of therapy, as they can inhibit viral replication and dissemination in their hosts. In this work, we interrogate the influence of viral RNA secondary structures on the production of CHIKV DVGs. We experimentally map RNA secondary structures of the CHIKV genome using selective 2′-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP), which couples chemical labelling with next-generation sequencing. We correlate the inferred secondary structure with preferred deletion sites of CHIKV DVGs. We document an increased probability of DVG generation with truncations at unpaired nucleotides within the secondary structure. We then generated a CHIKV mutant bearing synonymous changes at the nucleotide level to disrupt the existing RNA secondary structure (CHIKV-D2S). We show that CHIKV-D2S presents altered DVG generation compared to wild-type virus, correlating with the change in RNA secondary structure obtained by SHAPE-MaP. Our work thus demonstrates that RNA secondary structure impacts CHIKV DVG production during replication.

Purpose Patients with pancreatic ductal adenocarcinoma (PDAC) have yet to experience significant benefits from targeted therapy. Olaparib is currently the only active substance in BRCA-mutated PDACs that successfully influences the DNA repair of carcinoma cells. H2AX belongs to the histone family and is known as a part of the DNA repair system. The inhibition of γ-H2AX could lead to the inhibition of mitotically active tumor cells. Therefore, we aimed to evaluate the predictive value of the γ-H2AX in patients with PDAC. Methods All included patients ( n  = 311) received a pancreatic resection with curative intention in one of our PANCALYZE study centers. Subsequently, they were enrolled in a standardized follow-up protocol. Immunohistochemical stainings for γ-H2AX were conducted on tissue microarrays. Results Patients exhibiting high levels of γ-H2AX expression experience more frequent R1 resections, indicating advanced tumor stages in this subgroup. Additionally, patients with high γ-H2AX expression demonstrated significantly poorer survival compared to those with low expression (median OS: 15 vs. 25 months, p  < 0.001). In multivariate analyses, high γ-H2AX expression could be identified as an independent risk factor for worse patient survival. Moreover, high γ-H2AX expression could be more frequently observed in the more aggressive basal-like subtype. Conclusion γ-H2AX can be characterized as a predictive biomarker for poorer patient survival. Consequently, upcoming clinical trials focused on the efficacy of targeted therapies influencing the DNA repair system and radiotherapy should evaluate γ-H2AX as a potential biomarker for therapy response. Furthermore, γ-H2AX may serve as a viable target for treatment in the future.

Purpose Rising incidence of pancreatic ductal adenocarcinoma (PDAC) bind with insufficient therapy options showcases a great medical challenge. Further biomarkers are required to identify patients, who will benefit from more aggressive therapy. Methods 320 patients were included by the PANCALYZE study group. Cytokeratin 6 (CK6) immunohistochemical staining as a putative marker for the basal-like subtype of PDAC was performed. The correlation between CK6 expression patterns and survival data, as well as various markers of the (inflammatory) tumor microenvironment, were analyzed. Results We divided the study population based on the expression pattern of CK6. Patients with a high CK6 tumor expression had a significantly shorter survival ( p  = 0.013), confirmed in a multivariate cox regression model. CK6-expression is an independent marker for a decreased overall survival (HR = 1.655, 95% CI 1.158–2.365, p  = 0.006). In addition, the CK6-positive tumors showed significantly less plasma cell infiltration and more cancer-associated fibroblasts (CAFs) expressing Periostin and SMA. Conclusions CK6 could be considered as an independent biomarker for a shorter overall survival. CK6 is a clinically easily accessible biomarker for the identification of the basal-like subtype of PDAC. Therefore, it could be taken into consideration in deciding for the more aggressive therapy regimes. Prospectively, studies addressing the chemosensitive characteristics of this subtype are required.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples.

We report the discovery of a transient equivalent hydrogen column density with an absorption edge at ∼3.8 kiloelectron volts in the spectrum of the prompt x-ray emission of gamma-ray burst (GRB) 990705. This feature can be satisfactorily modeled with a photoelectric absorption by a medium located at a redshift of ∼0.86 and with an iron abundance of ∼75 times the solar one. The transient behavior is attributed to the strong ionization produced in the circumburst medium by the GRB photons. The high iron abundance points to the existence of a burst environment enriched by a supernova along the line of sight. The supernova explosion is estimated to have occurred about 10 years before the burst. Our results agree with models in which GRBs originate from the collapse of very massive stars and are preceded by a supernova event.