Miracle-dz/UniFAR-FTUs huggingface dataset:
An Evaluation of Provincial Infectious Disease Surveillance Reports in Ontario

Context: Public Health Ontario (PHO) publishes various infectious disease surveillance reports, but none have yet been formally evaluated. Objective: PHO evaluated its monthly and annual infectious disease surveillance reports to assess public health stakeholders' current perception of the products and to develop recommendations for improving future products. Design: An evaluation consisting of an online survey and a review of public Web sites of other jurisdictions with similar annual reports. Setting: For the online survey, stakeholder organizations targeted were the 36 local public health units and the Health health ministry in Ontario, Canada. Participants: Survey participants included epidemiologists, managers, directors, and other public health practitioners from participating organizations. Main Outcome Measures: Online survey respondents' awareness and access to the reports, their rated usefulness of reports and subsections, and suggestions for improving usefulness; timeliness of select annual reports from other jurisdictions based on the period from data described to report publication. Results: Among 57 survey respondents, between 74% and 97% rated each report as useful; the most common use was for situational awareness. Respondents ranked timeliness as the most important attribute of surveillance reports, followed by data completeness. Among 6 annual reports reviewed, the median time to publication was 11.5 months compared with 23.2 months for PHO. Conclusion: Recommendations based on this evaluation have already been applied to the monthly report (eg, focusing on the most useful sections) and have become key considerations when developing future annual reports and other surveillance reporting tools (eg, need to provide more timely reports). Other public health organizations may also use this evaluation to inform aspects of their surveillance report development and evaluation. The evaluation results have provided PHO with direction on how to improve its provincial infectious disease surveillance reporting moving forward, and formed a basis for future work in surveillance product development and evaluation.
Synthetic lethal targeting of DNA double‐strand break repair deficient cells by human apurinic/apyrimidinic endonuclease inhibitors

An apurinic/apyrimidinic (AP) site is an obligatory cytotoxic intermediate in DNA Base Excision Repair (BER) that is processed by human AP endonuclease 1 (APE1). APE1 is essential for BER and an emerging drug target in cancer. We have isolated novel small molecule inhibitors of APE1. In this study, we have investigated the ability of APE1 inhibitors to induce synthetic lethality (SL) in a panel of DNA double‐strand break (DSB) repair deficient and proficient cells; i) Chinese hamster (CH) cells: BRCA2 deficient (V‐C8), ATM deficient (V‐E5), wild type (V79) and BRCA2 revertant [V‐C8(Rev1)]. ii) Human cancer cells: BRCA1 deficient (MDA‐MB‐436), BRCA1 proficient (MCF‐7), BRCA2 deficient (CAPAN‐1 and HeLa SilenciX cells), BRCA2 proficient (PANC1 and control SilenciX cells). We also tested SL in CH ovary cells expressing a dominant‐negative form of APE1 (E8 cells) using ATM inhibitors and DNA‐PKcs inhibitors (DSB inhibitors). APE1 inhibitors are synthetically lethal in BRCA and ATM deficient cells. APE1 inhibition resulted in accumulation of DNA DSBs and G2/M cell cycle arrest. SL was also demonstrated in CH cells expressing a dominant‐negative form of APE1 treated with ATM or DNA‐PKcs inhibitors. We conclude that APE1 is a promising SL target in cancer.
Aluminium in food and daily dietary intake assessment from 15 food groups in Zhejiang Province, China

ABSTRACT Aluminium was measured in 2580 samples of 15 food groups and dietary exposure was estimated. Samples were purchased and analysed during 2010 to 2014. High aluminium levels were found in jellyfish (mean 4862 mg/kg), laver (mean 455.2 mg/kg) and fried twisted cruller (mean 392.4 mg/kg). Dietary exposure to aluminium was estimated for Zhejiang residents. The average dietary exposure to aluminium via 15 food groups in Zhejiang Province was 1.15 mg/kg bw/week, which is below the provisional tolerable weekly intake of 2 mg/kg bw /week. Jellyfish is the main Al contributor, providing 37.6% of the daily intake via these 15 food groups. This study provided new information on aluminium levels and assessment of aluminium (Al) dietary exposure in Zhejiang Province of China.
Runt‐related transcription factor 3 reverses epithelial–mesenchymal transition in hepatocellular carcinoma

Loss or decreased expression of runt‐related transcription factor 3 (RUNX3), a tumor suppressor gene involved in gastric and other cancers, has been frequently observed in hepatocellular carcinoma (HCC). The objective of this study was to identify the regulatory mechanism of the epithelial–mesenchymal transition (EMT) by RUNX3 in HCC. Human HCC cell lines, Hep3B, Huh7, HLF and SK‐Hep1, were divided into low‐ and high‐EMT lines, based on their expression of TWIST1 and SNAI2, and were used in this in vitro study. Ectopic RUNX3 expression had an anti‐EMT effect in low‐EMT HCC cell lines characterized by increased E‐cadherin expression and decreased N‐cadherin and vimentin expression. RUNX3 expression has previously been reported to reduce jagged‐1 (JAG1) expression; therefore, JAG1 ligand peptide was used to reinduce EMT in RUNX3‐expressing low‐EMT HCC cells. Immunohistochemical analyses were performed for RUNX3, E‐cadherin, N‐cadherin and TWIST1 in 33 human HCC tissues, also divided into low‐ and high‐EMT HCC, based on TWIST1 expression. E‐cadherin expression was correlated positively and N‐cadherin expression was correlated negatively with RUNX3 expression in low‐EMT HCC tissues. Correlations between EMT markers and RUNX3 mRNA expression were analyzed using Oncomine datasets. Similarly, mRNA expression of E‐cadherin was also significantly correlated with that of RUNX3 in low‐EMT HCC, while mRNA expression of JAG1 was negatively correlated with that of RUNX3. These results suggest a novel mechanism by which loss or decreased expression of RUNX3 induces EMT via induction of JAG1 expression in low‐EMT HCC.
A novel RT‐PCR method for quantification of human papillomavirus transcripts in archived tissues and its application in oropharyngeal cancer prognosis

Oropharyngeal squamous cell carcinoma (SCC) is strongly associated with human papillomavirus (HPV) infection, which is distinctively different from most other head and neck cancers. However, a robust quantitative reverse transcription PCR (RT‐qPCR) method for comprehensive expression profiling of HPV genes in routinely fixed tissues has not been reported. To address this issue, we have established a new real‐time RT‐PCR method for the expression profiling of the E6 and E7 oncogenes from 13 high‐risk HPV types. This method was validated in cervical cancer and by comparison with another HPV RNA detection method (in situ hybridization) in oropharyngeal tumors. In addition, the expression profiles of selected HPV‐related human genes were also analyzed. HPV E6 and E7 expression profiles were then analyzed in 150 archived oropharyngeal SCC samples and compared with other variables and with patient outcomes. Our study showed that RT‐qPCR and RNA in situ hybridization were 100% concordant in determining HPV status. HPV transcriptional activity was found in most oropharyngeal SCC (81.3%), a prevalence that is higher than in previous studies. Besides HPV16, three other HPV types were also detected, including 33, 35 and 18. Furthermore, HPV and p16 had essentially identical expression signatures, and both HPV and p16 were prognostic biomarkers for the prediction of disease outcome. Thus, p16 mRNA or protein expression signature is a sensitive and specific surrogate marker for HPV transcriptional activity (all genotypes combined).
Effect of Intra-Venous Versus Intra-Arterial Leptin Infusion on Blood Pressure and Heart Rate

Objectives: In this study the effects of different Leptin concentrations on the blood pressure and heart rate in vivo in anesthetized rabbits were studied. Methods: Sixty Rabbits were divided into two groups, first group received Leptin intra-venously and other group received Leptin intra-arterially. Blood pressure and heart rate in were recorded before and after administration of Leptin. Results: A significant increase in mean arterial blood pressure (MABP) was seen after an intra-arterial injection of 3, 5 and 7 � g/kg of Leptin. This increase in MABP was monitored for different durations 10, 20 and 30 minutes after the infu- sion of each Leptin concentrations. The trend of the increase in MABP with time was demonstrated with all three concen- trations. Intra-venous infusion of Leptin caused a significant decrease in MABP after 10 minutes as well as after 20 and 30 minutes, with all three concentrations (3, 5, and 7 μg/Kg). Heart rate (HR) was not changed significantly at the end of 30 min of infusion. Conclusion: this in vivo study demonstrated that intra-venous Leptin infusion has a different effect on the MABP com- pared with intra-arterial infusion and this difference might be due to the site of action of Leptin.
Prevalence of Neuropsychiatric Symptoms in Elderly Patients with Dementia in Mungialde County (Basque Country, Spain)

Background: Determination of the prevalence of neuropsychiatric symptoms in elderly patients with dementia inMungialde. Methods: 108 subjects with dementia, who participated in a door-to-door epidemiological study, were included. The 12-item Spanish version of the Neuropsychiatric Inventory was used to evaluate these symptoms. Results: The prevalence of at least 1 neuropsychiatric symptom was found to be 76.90% for all dementia types, 73.50% in patients with Alzheimer’s disease (AD), 80% for the Parkinson-Lewy body dementia complex (PLBD), 78.60% for vascular dementia (VD) and 100% for frontotemporal dementia (FTD). Apathy was found to be the most prevalent symptom for all dementia types and in patients with AD (53.70 and 54.30%, respectively). The next most prevalent symptoms were anxiety, depression and sleep disturbances (35.20, 32.40 and 30.60%) for all dementia types, and anxiety and depression (32.10 and 30.90%) in patients with AD. The most prevalent symptoms in patients with PLBD were apathy, appetite changes, sleep disturbances and agitation (50% each); in patients with VD they were apathy, depression and anxiety (42.90% each), and in patients with FTD they were apathy, anxiety and aberrant motor activity (100% each). Conclusions: Neuropsychiatric symptoms were found to be prevalent in patients with dementia, irrespective of dementia type.
Cell type specific interleukin‐6 induced responses in tumor keratinocytes and stromal fibroblasts are essential for invasive growth

Interleukin‐6 (IL‐6) is one of the major inflammatory interleukins that has been linked to cancer progression. In our model for human skin squamous cell carcinoma (SCC), IL‐6 expression is strongly upregulated upon progression from benign tumors to highly malignant, metastasizing SCCs. We now demonstrate that IL‐6 promotes malignant and invasive tumor growth in human skin SCCs by inducing cell type specific cytokine profiles in tumor keratinocytes and stromal fibroblasts, activating the latter towards a tumor associated fibroblast (TAF) phenotype. In three‐dimensional organotypic cocultures in vitro invasive growth of IL‐6 overexpressing tumor keratinocytes, is associated with increased expression of matrix metalloproteinase‐2 (MMP‐2), MMP‐14 and tissue inhibitor of metalloproteinases‐2, and clearly depends on IL‐6 activated fibroblasts. IL‐6‐induced secretion of monocyte chemotactic protein‐1 (MCP‐1) in tumor keratinocytes and of hepatocyte growth factor in fibroblasts is crucial for regulating expression and activation of MMP‐2. This functional role of IL‐6 is confirmed in vivo. Here MMP‐14 and MMP‐2 expression occur exclusively in surface transplants of IL‐6 overexpressing keratinocytes and fibroblasts are identified as important source of MMP‐2. Our data indicate that tumor keratinocytes derived IL‐6 activates stromal fibroblasts towards a TAF phenotype, promoting tumor invasion via enhanced expression and activation of MMP‐2.
Skeletal Muscle Fatigue

Abstract Skeletal muscle fatigue is a complex problem which deserves attention from physiotherapists and other clinical practitioners. This article will discuss the findings of recent literature to explore some of the main mechanisms thought to underlie fatigue in skeletal muscles. These mechanisms may be peripheral in origin, occurring within the muscle fibres themselves, or central, affecting the neural control of muscle contraction. Peripheral mechanisms of fatigue include metabolic factors such as the availability and utilization of metabolic substrates (e.g. glycogen, phosphocreatine and adenosine triphosphate) during muscle activity as well as the influence of muscle pH on both metabolism and muscle contractile properties. Impairment in neuromuscular transmission and excitation–contraction coupling may also cause muscle fatigue. Central fatigue mechanisms include both psychological and physiological factors which may influence motor cortex activity and hence muscle force output. Pathological factors which may cause abnormal muscle fatigue are also discussed.
Psychiatric disorders and labour force activity

– The purpose of this paper is to explore and review the range and quality of international epidemiological and observational studies reporting impacts of psychiatric disorders on labour force activity. This information is needed to explore the relative priority of different diagnostic groups for more intensive forms of vocational rehabilitation. , – The authors provide an overview of the current literature. A systematic review of papers measuring labour force variables and psychiatric disorders across a range of countries is conducted. These results are compared to OECD background unemployment rates during the same period. The results for each diagnostic category included are aggregated and compared to the other diagnostic categories. , – The proportions of people employed decreased with the more severe disorder categories, indicating that severe psychiatric illnesses are contributing to employment struggles for people with these illnesses, across countries. , – This review is exploratory and shows that there is little consistency in reporting of labour force variables. Future research should endeavour to utilise internationally agreed definitions of labour force activity. , – This conclusion is relevant to matching community residents with psychiatric disorders to the more intensive and costly forms of vocational rehabilitation. , – To our knowledge, no previous review has examined diagnostic categories of psychiatric disorders by labour force activity internationally while taking into account background unemployment. This review found an employment gradient related to severity of diagnostic category that will be of interest to clinicians and policy makers.
Occupational Therapy Intervention Process Model – Den ergotherapeutischen Prozess strukturieren

Seit gerade mal einem Jahr ist ein neues ergotherapeutisches Modell auf dem Markt! Bisher jedoch nur in englischer Sprache erhältlich. Verschaffen Sie sich hier einen ersten Eindruck vom Occupational Therapy Intervention Process Model, welches die Klientenzentrierung und die Betätigung in den Vordergrund stellt. Barbara Dehnhardt
MiR‐137 functions as a tumor suppressor in neuroblastoma by downregulating KDM1A

Neuroblastoma is the most common extracranial solid tumor of childhood, and accounts for ∼15% of all childhood cancer deaths. The histone demethylase, lysine‐specific demethylase 1 (KDM1A, previously known as LSD1), is strongly expressed in neuroblastomas, and overexpression correlates with poor patient prognosis. Inducing differentiation in neuroblastoma cells has previously been shown to down regulate KDM1A, and siRNA‐mediated KDM1A knockdown inhibited neuroblastoma cell viability. The microRNA, miR‐137, has been reported to be downregulated in several human cancers, and KDM1A mRNA was reported as a putative target of miR‐137 in colon cancer. We hypothesized that miR‐137 might have a tumor‐suppressive role in neuroblastoma mediated via downregulation of KDM1A. Indeed, low levels of miR‐137 expression in primary neuroblastomas correlated with poor patient prognosis. Re‐expressing miR‐137 in neuroblastoma cell lines increased apoptosis and decreased cell viability and proliferation. KDM1A mRNA was repressed by miR‐137 in neuroblastoma cells, and was validated as a direct target of miR‐137 using reporter assays in SHEP and HEK293 cells. Furthermore, siRNA‐mediated KDM1A knockdown phenocopied the miR‐137 re‐expression phenotype in neuroblastoma cells. We conclude that miR‐137 directly targets KDM1A mRNA in neuroblastoma cells, and activates cell properties consistent with tumor suppression. Therapeutic strategies to re‐express miR‐137 in neuroblastomas could be useful to reduce tumor aggressiveness.
Knowledge, behaviors and practices of community and hospital pharmacists towards biosimilar medicines: Results of a French web-based survey

ABSTRACT This study's aims were: 1) to extract a comprehensive overview of the knowledge, experience and opinions of both community pharmacists and hospital pharmacists regarding biosimilar medicines in France; and 2) to identify the perceived problems and solutions to promoting their prescription. A 2015 web-based survey was conducted by the Observatoire des Médicaments, des Dispositifs Médicaux et de l'Innovation Thérapeutique of Alsace. A total of 802 pharmacists responded to the survey. Many (536, 66.8%, [95% confidence interval (CI) 63.6–70.1]) indicated that they were not familiar with biosimilars. Half of community pharmacists (95% CI 42.7–57.3) stated that they were not at all informed about biosimilar drugs, compared with 15.7% (95% CI 12.9–18.6) of hospital pharmacists. Almost all respondents (781, 97.4%, [95% CI 96.3–98.5]) had at least one pending question on biosimilars. Most of the questions were related to the manufacturing process, safety, substitution rules and the international non-proprietary name prescription. At the time of the study, 467 pharmacists (58.2%, [95% CI 54.8–61.6]) had already validated a prescription for a biosimilar drug, mainly for filgrastim. These latter were more comfortable in explaining the benefit of biosimilar medicines to the patient. Pharmacists were rather favorable to biosimilar drugs, and about 9 of 10 quoted healthcare cost savings as incentives to their prescription. However, many did not agree with allowing biosimilar substitution. “Patients' wishes to be treated with the originator” and “indication extrapolation” were the two main constraints identified. The survey highlighted the need to provide French pharmacists with accurate and comprehensive information regarding biosimilar medicines.
Evidence for intermolecular domain exchange in the Fab domains of dimer and oligomers of an IgG1 monoclonal antibody

ABSTRACT Recombinant protein therapeutics have become increasingly useful in combating human diseases, such as cancer and those of genetic origin. One quality concern for protein therapeutics is the content and the structure of the aggregated proteins in the product, due to the potential immunogenicity of these aggregates. Collective efforts have led to a better understanding of some types of protein aggregates, and have revealed the diversity in the structure and cause of protein aggregation. In this work we used a broad range of analytical techniques to characterize the quinary structure (complexes in which each composing unit maintains native quaternary structure) of the stable non-covalent dimer and oligomers of a monoclonal IgG1λ antibody. The results supported a mechanism of intermolecular domain exchange involving the Fab domains of 2 or more IgG molecules. This mechanism can account for the native-like higher order (secondary, tertiary and disulfide bonding) structure, the stability of the non-covalent multimers, and the previously observed partial loss of the antigen-binding sites without changing the antigen-binding affinity and kinetics of the remaining sites (Luo et al., 2009, mAbs 1:491). Furthermore, the previously observed increase in the apparent affinity to various Fcγ receptors (ibid), which may potentially promote immunogenicity, was also explained by the quinary structure proposed here. Several lines of evidence indicated that the formation of multimers by the mechanism of intermolecular domain exchange took place mostly during expression, not in the purified materials. The findings in this work will advance our knowledge of the mechanisms for aggregation in therapeutic monoclonal antibodies.
Vemurafenib reverses immunosuppression by myeloid derived suppressor cells

Myeloid derived suppressor cells (MDSCs) suppress innate and adaptive immunity, thereby limiting anti‐tumor immune responses in cancer patients. In patients with advanced melanoma, the phenotype and function of MDSCs remains controversial. In our study, we further explored two distinct subpopulations of MDSCs and investigated the impact of Vemurafenib on these cells. Flow cytometry analysis revealed that in comparison to healthy donors and patients with localized disease, PBMCs from patients with metastatic melanoma showed an increased frequency of CD14+HLA‐DR−/low monocytic MDSCs (moMDSCs) and of a previously unrecognized population of CD14−CD66b+Arginase1+ granulocytic MDSCs (grMDSCs). In vitro, both populations suppressed autologous T‐cell proliferation, which was tested in CFSE‐based proliferation assays. Vemurafenib treatment of melanoma patients reduced the frequency of both moMDSCs and grMDSCs. According to our in vivo finding, conditioned medium (CM) from Vemurafenib treated melanoma cells was less active in inducing moMDSCs in vitro than CM from untreated melanoma cells. In conclusion, patients with advanced melanoma show increased levels of moMDSCs, and of a population of CD14−CD66b+Arginase1+ grMDSCs. Both MDSCs are distinct populations capable of suppressing autologous T‐cell responses independently of each other. In vitro as well as in vivo, Vemurafenib inhibits the generation of human moMDSCs. Thus, Vemurafenib decreases immunosuppression in patients with advanced melanoma, indicating its potential as part of future immunotherapies.
Andrews' Diseases of the Skin: Clinical Dermatology

This textbook is designed to be a "compact, concise, single volume. clinically oriented working text" for all physicians. This is an ambitious and worthwhile goal. The book includes brief chapters on pathophysiology and cutaneous diagnosis, in addition to more than 1,000 pages devoted to clinical dermatology. The material is organized along traditional dermatologic lines, though sometimes in a confusing fashion. For instance, Reiter's syndrome is included in the section on bacterial infections, and endocrine diseases, hypertrophies, atrophies, and dermal elastosis are grouped in a single chapter. The black-and-white photographs are generally of good quality, and as might be expected there are relatively few photographs of the histology. The style is conversational, and the text is easily readable. There are numerous references by name in the text to the work of various authors; unfortunately, many of these are not included in the full list of literature cited at the end of