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This article considers the question of the value and limits of the concept of discrimination for the ethics of migration by drawing attention to the need for a conceptualization of discrimination that can encompass forms of group-based disadvantage that are enabled and reproduced by the three central norms of our contemporary regime of global migration governance: the state’s right to unilateral control over its border regime, birthright citizenship and rights of (re)entry to one’s own state, and the individual right to leave a state. I sketch an historical account of the forging and yoking together of these norms as bound up with the history of European imperialism and argue that they function to enable the reproduction of the advantage of states of the Global North. I illustrate this argument by reference to the example of the transnational migration of medical professionals from sub-Saharan Africa and argue that this may amount to structural discrimination against the human right to health of the populations of these states of emigration before considering two responses to this condition: ‘no recruitment’ and ‘no disadvantage’.

Dieser Essay legt den Fokus auf den Kontext von und die Beziehung zwischen Kants ersten beiden Publikationen in der Berlinischen Monatsschrift: „Idee zu einer allgemeinen Geschichte in weltbürgerlicher Absicht“ und „Beantwortung der Frage: Was heißt Aufklärung?“. Seine Absicht ist nicht, einfach nur zu verstehen, was Kant in diesen Essays sagt, sondern zu rekonstruieren, was er macht, indem er die beiden Essays in dieser Zeitschrift, in dieser Reihenfolge, zu dieser Zeit veröffentlicht. Indem der Essay den geistesgeschichtlichen Kontext der Zeitschrift, in der Kant seine Essays publiziert, hinsichtlich seiner Beziehung zur Berliner Mittwochsgesellschaft und hinsichtlich des Aufklärungsverständnisses, das sie darstellt, rekonstruiert, argumentiere ich, dass eine zentrale Absicht von Kants Text darin besteht, dass er eine Kritik der ‚dogmatischen‘ Sichtweise bereitstellt und ein alternatives, „kritisches“ Verständnis anbietet. Es wird argumentiert, dass die frühere Veröffentlichung „Die Idee zu einer allgemeinen Geschichte“ eine zentrale Rolle einnimmt, um Orientierung für Kants Leserschaft auf den radikalen Blick der Aufklärung zu bieten, die er vorschlägt, und ihr ermöglicht, sich selbst als rationale, autonome Akteure zu begreifen, die in der Lage sind, das Projekt der Aufklärung fortzuführen. Der Argumentationsgang zielt darauf zu zeigen, dass Kants Essays eine Intervention darstellen, eine komplexe Arbeit der Anwaltschaft, die sich an Vormünder, die Öffentlichkeit und den Staat richtet.

Why are the reasons given in support of the declared aim of the current asylum policies in the UK, EU and USA of breaking the business model of smugglers expressed in humanitarian terms? It is, no doubt, tempting to simply dismiss this humanitarian rhetoric as hypocrisy, as the compliment that vice pays to virtue. Yet however justified that dismissal may be in particular cases, to turn away too quickly from this phenomenon would be to miss something of political significance in its form and to fail to register the historical entanglement of humanitarianism and border externalisation.

Two days before the UK Supreme Court declared the government’s Rwanda policy unlawful, PM Rishi Sunak rid himself of his Home Secretary, Suella Braverman. The sacking, the ruling, and the aftermath demonstrate both a key division in the Conservative Party and illustrate the choice it faces on the kind of politics it will promote after the next election: socially liberal technocratic nationalism (the Sunak option) or illiberal ‘culture war’ nationalism (the Braverman faction). The Supreme Court’s judgment raises the stakes in this conflict because its grounds for ruling the Rwanda Plan unlawful appear to provide ammunition for the radical illiberal wing of the Conservative Party.

Abstract Sex differences have been identified in many diseases associated with dysregulated immune responses, including Alzheimer’s disease (AD), for which approximately two-thirds of patients are women. An accumulating body of research indicates that microglia may play a causal role in the pathogenesis of this disease. We hypothesised that sex differences in the transcriptome of human myeloid cells may contribute to the sex difference observed in AD prevalence. To explore this, we assessed bulk and single-nuclear RNA sequencing data sets generated from four human derived myeloid cell populations: post-mortem microglial nuclei, peripheral monocytes, monocyte-derived macrophages (MDMs) and induced pluripotent stem cell derived microglial-like cells (MGLs). We found that expression of AD risk genes, gene signatures associated with the inflammatory response in AD, and genes related to proinflammatory immune responses were enriched in microglial nuclei isolated from aged female donors without ante-mortem neurological disease, relative to those from males. In addition, these inflammation-associated gene sets were found to be enriched in peripheral monocytes isolated from postmenopausal women and in MDMs obtained from premenopausal individuals relative to age-matched males. Expression of these gene sets did not differ in MDMs derived from women whose blood was sampled across the menstrual cycle or in MGLs cultured with 17β-oestradiol. This suggests that the observed gene set enrichments in myeloid cells from women were not being driven by acute hormonal influences. Together, these data support the hypothesis that the increased prevalence of AD in women may be partly explained by a myeloid cell phenotype biased towards expression of biological processes relevant to AD.

The introduction of the Illegal Migration Bill to the UK Parliament appears to be the latest outburst of the Conservative government’s increasing hysteria with respect to the small boat crossings of the Channel in which Brexit-released fantasies of post-imperial sovereign power are acted out in the form of half-baked legislative proposals. The politically inconvenient fact that most of the 15% of asylum seekers who reach UK territory in this way are found to have legitimate asylum or protection claims seems to be a particular source of rage with a leaked Conservative Party email to party members under Suella Braverman’s name blaming “an activist blob of leftwing lawyers, civil servants and the Labour Party” for boat crossings, which at least suggests she knows her audience. This is “Build the Wall” for an island nation and, like Trump’s project, its primary value is as a fantasy object than a practical project.

BackgroundMajor depressive disorder is a common mental disorder affecting 5% of adults worldwide. Early contact with health care services is critical for achieving accurate diagnosis and improving patient outcomes. Key symptoms of major depressive disorder (depression hereafter) such as cognitive distortions are observed in verbal communication, which can also manifest in the structure of written language. Thus, the automatic analysis of text outputs may provide opportunities for early intervention in settings where written communication is rich and regular, such as social media and web-based forums. ObjectiveThe objective of this study was 2-fold. We sought to gauge the effectiveness of different machine learning approaches to identify users of the mass web-based forum Reddit, who eventually disclose a diagnosis of depression. We then aimed to determine whether the time between a forum post and a depression diagnosis date was a relevant factor in performing this detection. MethodsA total of 2 Reddit data sets containing posts belonging to users with and without a history of depression diagnosis were obtained. The intersection of these data sets provided users with an estimated date of depression diagnosis. This derived data set was used as an input for several machine learning classifiers, including transformer-based language models (LMs). ResultsBidirectional Encoder Representations from Transformers (BERT) and MentalBERT transformer-based LMs proved the most effective in distinguishing forum users with a known depression diagnosis from those without. They each obtained a mean F1-score of 0.64 across the experimental setups used for binary classification. The results also suggested that the final 12 to 16 weeks (about 3-4 months) of posts before a depressed user’s estimated diagnosis date are the most indicative of their illness, with data before that period not helping the models detect more accurately. Furthermore, in the 4- to 8-week period before the user’s estimated diagnosis date, their posts exhibited more negative sentiment than any other 4-week period in their post history. ConclusionsTransformer-based LMs may be used on data from web-based social media forums to identify users at risk for psychiatric conditions such as depression. Language features picked up by these classifiers might predate depression onset by weeks to months, enabling proactive mental health care interventions to support those at risk for this condition.

ABSTRACT Human papillomavirus (HPV) E7 plays a major role in HPV-induced malignancy, perturbing cell cycle regulation, and driving cell proliferation. Major targets of cancer-causing HPV E7 proteins are the pRB family of tumor suppressors, which E7 targets for proteasome-mediated degradation and whose interaction is promoted through an acidic patch, downstream of the LXCXE motif in E7, that is subject to phosphorylation by casein kinase II (CKII). In this study we show that HPV-16 E7 targets the AP2-complex, which plays a critical role in cargo recognition in clathrin-mediated endocytosis. Intriguingly, HPV-16 E7 contains a specific amino acid sequence for AP2 recognition, and this overlaps the pRb LXCXE recognition sequence but involves completely different amino acid residues. HPV-16 E7 does this by binding to the AP2-μ2 adaptor protein subunit via residues 25-YEQL-28 within the LXCXE motif. Point mutations at Y25 within 22-LYCYE-26 suggest that the interaction of E7 with AP2-μ2 is independent from pRB binding. In cells, this interaction is modulated by acidic residues downstream of LXCXE, with the binding being facilitated by CKII-phosphorylation of the serines at positions 31 and 32. Finally, we also show that association of HPV-16 E7 with the AP2 adaptor complex can contribute to cellular transformation under low-nutrient conditions, which appears to be mediated, in part, through inhibition of AP2-mediated internalization of epidermal growth factor receptor (EGFR). This indicates that E7 can modulate endocytic transport pathways, with one such component, EGFR, most likely contributing toward the ability of E7 to induce cell transformation and malignancy. These studies define a new and unexpected role for HPV-16 E7 in targeting clathrin-mediated endocytosis. IMPORTANCE Despite being a very small protein, HPV-E7 has a wide range of functions within the infected cell, many of which can lead to cell transformation. High-risk HPV-E7 deregulates the function of many cellular proteins, perturbing cellular homeostasis. We show that a novel target of HPV-E7 is the clathrin-adaptor protein 2 complex (AP2) μ2 subunit, interacting via residues within E7’s pRB-binding region. Mutational studies show that an AP2 recognition motif is present in the CR2 region and is conserved in >50 HPV types, suggesting a common function for this motif in HPV biology. Mutational analysis suggests that this motif is important for cellular transformation, potentially modulating endocytosis of growth factor receptors such as EGFR, and thus being a novel activity of E7 in modulating clathrin-mediated endocytosis and cargo selection. This study has important implications for the molecular basis of E7 function in modulating protein trafficking at the cell surface.

In this paper I focus on Gillian Brock’s treatment of the case of refugees. After noting a potential distinction between our otherwise closely related theoretical approaches in which we view the refugee regime as a legitimacy repair (Owen) or legitimacy correction (Brock) mechanism, I draw a contrast between our ways of addressing this regime and argue that the difference between my historical approach and Brock’s presentist approach turns out to have implications for how we conceive what is due to refugees. Focusing on her advocacy of a developmental turn in refugee protection, I develop the concern that her articulation of this approach remains too closely tied to the humanitarian perspective of Betts and Collier in a way that underestimates the significance of political rights to refugee autonomy.

We describe an effective approach to automated text digitisation with respect to natural history specimen labels. These labels contain much useful data about the specimen including its collector, country of origin, and collection date. Our approach to automatically extracting these data takes the form of a pipeline. Recommendations are made for the pipeline's component parts based on state-of-the-art technologies.Optical Character Recognition (OCR) can be used to digitise text on images of specimens. However, recognising text quickly and accurately from these images can be a challenge for OCR. We show that OCR performance can be improved by prior segmentation of specimen images into their component parts. This ensures that only text-bearing labels are submitted for OCR processing as opposed to whole specimen images, which inevitably contain non-textual information that may lead to false positive readings. In our testing Tesseract OCR version 4.0.0 offers promising text recognition accuracy with segmented images.Not all the text on specimen labels is printed. Handwritten text varies much more and does not conform to standard shapes and sizes of individual characters, which poses an additional challenge for OCR. Recently, deep learning has allowed for significant advances in this area. Google's Cloud Vision, which is based on deep learning, is trained on large-scale datasets, and is shown to be quite adept at this task. This may take us some way towards negating the need for humans to routinely transcribe handwritten text.Determining the countries and collectors of specimens has been the goal of previous automated text digitisation research activities. Our approach also focuses on these two pieces of information. An area of Natural Language Processing (NLP) known as Named Entity Recognition (NER) has matured enough to semi-automate this task. Our experiments demonstrated that existing approaches can accurately recognise location and person names within the text extracted from segmented images via Tesseract version 4.0.0.We have highlighted the main recommendations for potential pipeline components. The paper also provides guidance on selecting appropriate software solutions. These include automatic language identification, terminology extraction, and integrating all pipeline components into a scientific workflow to automate the overall digitisation process.

Abstract Background Referral letters from primary care contain a large amount of information that could be used to improve the appropriateness of the referral pathway for individuals seeking specialist opinion for knee or hip pain. The primary aim of this study was to evaluate the content of the referral letters to identify information that can independently predict an optimal care pathway. Methods Using a prospective longitudinal design, a convenience sample of patients with hip or knee pain were recruited from orthopaedic, specialist general practice and advanced physiotherapy practitioner clinics. Individuals completed a Knee or hip Osteoarthritis Outcome Score at initial consultation and after 6 months. Participant demographics, body mass index, medication and co-morbidity data were extracted from the referral letters. Free text of the referral letters was mapped automatically onto the Unified Medical Language System to identify relevant clinical variables. Treatment outcomes were extracted from the consultation letters. Each outcome was classified as being an optimal or sub-optimal pathway, where an optimal pathway was defined as the one that results in the right treatment at the right time. Logistic regression was used to identify variables that were independently associated with an optimal pathway. Results A total of 643 participants were recruited, 419 (66.7%) were classified as having an optimal pathway. Variables independently associated with having an optimal care pathway were lower body mass index (OR 1.0, 95% CI 0.9 to 1.0 p = 0.004), named disease or syndromes (OR 1.8, 95% CI 1.1 to 2.8, p = 0.02) and taking pharmacologic substances (OR 1.8, 95% CI 1.0 to 3.3, p = 0.02). Having a single diagnostic procedure was associated with a suboptimal pathway (OR 0.5, 95% CI 0.3 to 0.9 p

Summary: Background: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19. Methods: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK, between 19th June to 28th October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.1-10.0μg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). Findings: 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p

Cervical cancer (CC) is the primary cause of female cancer fatalities in low-middle-income countries (LMICs). Persistent infections from the human papillomavirus (HPV) can result in cervical cancer. However, numerous different factors influence the development and progression of cervical cancer. Transcriptomic knowledge of the mechanisms with which HPV causes cervical cancer pathogenesis is growing. Nonetheless, there is an existing gap hindering the development of therapeutic approaches and the improvement of patient outcomes. Alternative splicing allows for the production of numerous RNA transcripts and protein isoforms from a single gene, increasing the transcriptome and protein diversity in eukaryotes. Cancer cells exhibit astounding transcriptome modifications by expressing cancer-specific splicing isoforms. High-risk HPV uses cellular alternative splicing events to produce viral and host splice variants and proteins that drive cancer progression or contribute to distinct cancer hallmarks. Understanding how viruses utilize alternative splicing to drive pathogenesis and tumorigenesis is essential. Although research into the role of miRNAs in tumorigenesis is advancing, the function of other non-coding RNAs, including lncRNA and circRNA, has been understudied. Through their interaction with mRNA, non-coding RNAs form a network of competing endogenous RNAs (ceRNAs), which regulate gene expression and promote cervical cancer development and advancement. The dysregulated expression of non-coding RNAs is an understudied and tangled process that promotes cervical cancer development. This review will present the role of aberrant alternative splicing and immunosuppression events in HPV-mediated cervical tumorigenesis, and ceRNA network regulation in cervical cancer pathogenesis will also be discussed. Furthermore, the therapeutic potential of splicing disruptor drugs in cervical cancer will be deliberated.

Abstract Background Knee injury and Osteoarthritis Outcome Score (KOOS) is an instrument used to quantify patients’ perceptions about their knee condition and associated problems. It is administered as a 42-item closed-ended questionnaire in which patients are asked to self-assess five outcomes: pain, other symptoms, activities of daily living, sport and recreation activities, and quality of life. We developed KLOG as a 10-item open-ended version of the KOOS questionnaire in an attempt to obtain deeper insight into patients’ opinions including their unmet needs. However, the open–ended nature of the questionnaire incurs analytical overhead associated with the interpretation of responses. The goal of this study was to automate such analysis. We implemented KLOSURE as a system for mining free–text responses to the KLOG questionnaire. It consists of two subsystems, one concerned with feature extraction and the other one concerned with classification of feature vectors. Feature extraction is performed by a set of four modules whose main functionalities are linguistic pre-processing, sentiment analysis, named entity recognition and lexicon lookup respectively. Outputs produced by each module are combined into feature vectors. The structure of feature vectors will vary across the KLOG questions. Finally, Weka, a machine learning workbench, was used for classification of feature vectors. Results The precision of the system varied between 62.8 and 95.3%, whereas the recall varied from 58.3 to 87.6% across the 10 questions. The overall performance in terms of F–measure varied between 59.0 and 91.3% with an average of 74.4% and a standard deviation of 8.8. Conclusions We demonstrated the feasibility of mining open-ended patient questionnaires. By automatically mapping free text answers onto a Likert scale, we can effectively measure the progress of rehabilitation over time. In comparison to traditional closed-ended questionnaires, our approach offers much richer information that can be utilised to support clinical decision making. In conclusion, we demonstrated how text mining can be used to combine the benefits of qualitative and quantitative analysis of patient experiences.

Abstract Background Copy number variants (CNVs) have been shown to increase risk for physical anomalies, developmental, psychiatric and medical disorders. Some of them have been associated with changes in weight, height, and other physical traits. As most studies have been performed on children and young people, these effects of CNVs in middle-aged and older people are not well established. The UK Biobank recruited half a million adults who provided a variety of physical measurements. We called all CNVs from the Affymetrix microarrays and selected a set of 54 CNVs implicated as pathogenic (including their reciprocal deletions/duplications) and that were found in five or more persons. Linear regression analysis was used to establish their association with 16 physical traits relevant to human health. Results 396,725 participants of white British or Irish descent (excluding first-degree relatives) passed our quality control filters. Out of the 864 CNV/trait associations, 214 were significant at a false discovery rate of 0.1, most of them novel. Many of these traits increase risk for adverse health outcomes: e.g. increases in weight, waist-to-hip ratio, pulse rate and body fat composition. Deletions at 16p11.2, 16p12.1, NRXN1 and duplications at 16p13.11 and 22q11.2 produced the highest numbers of significant associations. Five CNVs produced average changes of over one standard deviation for the 16 traits, compared to controls: deletions at 16p11.2 and 22q11.2, and duplications at 3q29, the Williams-Beuren and Potocki-Lupski regions. CNVs at 1q21.1, 2q13, 16p11.2 and 16p11.2 distal, 16p12.1, 17p12 and 17q12 demonstrated one or more mirror image effects of deletions versus duplications. Conclusions Carriers of many CNVs should be monitored for physical traits that increase morbidity and mortality. Genes within these CNVs can give insights into biological processes and therapeutic interventions.

We provide a rich multi-contrast microstructural MRI dataset acquired on an ultra-strong gradient 3T Connectom MRI scanner comprising 5 repeated sets of MRI microstructural contrasts in 6 healthy human participants. The availability of data sets that support comprehensive simultaneous assessment of test-retest reliability of multiple microstructural contrasts (i.e., those derived from advanced diffusion, multi-component relaxometry and quantitative magnetisation transfer MRI) in the same population is extremely limited. This unique dataset is offered to the imaging community as a test-bed resource for conducting specialised analyses that may assist and inform their current and future research. The Microstructural Image Compilation with Repeated Acquisitions (MICRA) dataset includes raw data and computed microstructure maps derived from multi-shell and multi-direction encoded diffusion, multi-component relaxometry and quantitative magnetisation transfer acquisition protocols. Our data demonstrate high reproducibility of several microstructural MRI measures across scan sessions as shown by intra-class correlation coefficients and coefficients of variation. To illustrate a potential use of the MICRA dataset, we computed sample sizes required to provide sufficient statistical power a priori across different white matter pathways and microstructure measures for different statistical comparisons. We also demonstrate whole brain white matter voxel-wise repeatability in several microstructural maps. The MICRA dataset will be of benefit to researchers wishing to conduct similar reliability tests, power estimations or to evaluate the robustness of their own analysis pipelines.

Alternative splicing is deregulated in cancer and alternatively spliced products can be linked to cancer hallmarks. Targeting alternative splicing could offer novel effective cancer treatments. We investigated the effects of the crude extract of a South African medicinal plant, Cotyledon orbiculata, on cell survival of colon (HCT116) and esophageal (OE33 and KYSE70) cancer cell lines. Using RNASeq, we discovered that the extract interfered with mRNA regulatory pathways. The extract caused hnRNPA2B1 to splice from the hnRNPB1 to the hnRNPA2 isoform, resulting in a switch in the BCL2L1 gene from Bcl-xL to Bcl-xS causing activation of caspase-3-cleavage and apoptosis. Similar splicing effects were induced by the known anti-cancer splicing modulator pladienolide B. Knockdown of hnRNPB1 using siRNA resulted in decreased cell viability and increased caspase-3-cleavage, and over-expression of hnRNPB1 prevented the effect of C. orbiculata extract on apoptosis and cell survival. The effect of the hnRNPA2/B1 splicing switch by the C. orbiculata extract increased hnRNPA2B1 binding to Bcl-xl/s, BCL2, MDM2, cMYC, CD44, CDK6, and cJUN mRNA. These findings suggest that apoptosis in HCT116, OE33, and KYSE cancer cells is controlled by switched splicing of hnRNPA2B1 and BCL2L1, providing evidence that hnRNPB1 regulates apoptosis. Inhibiting this splicing could have therapeutic potential for colon and esophageal cancers. Targeting hnRNPA2B1 splicing in colon cancer regulates splicing of BCL2L1 to induce apoptosis. This approach could be a useful therapeutic strategy to induce apoptosis and restrain cancer cell proliferation and tumor progression. Here, we found that the extract of Cotyledon orbiculata, a South African medicinal plant, had an anti-proliferative effect in cancer cells, mediated by apoptosis induced by alternative splicing of hnRNPA2B1 and BCL2L1.

Abstract As human‐elephant conflict (HEC) increases, a better understanding of the human dimensions of these conflicts and non‐violent mitigation methods are needed to foster long‐term coexistence. In this study, we conducted household questionnaires (n = 296) to assess the prevalence of HEC and attitudes towards elephants in four rural villages in Thailand. In addition, we evaluated a pilot beehive fence as a sustainable solution for HEC. The majority of the households reported seeing or hearing elephants near their property at least once a week (84.9%) and experienced negative impacts from elephants in the last 5 years, (81.0%). The beehive fence deterred 88.4% of individual elephants (n = 155) and 64.3% of elephant groups (n = 28) that approached the fence. Most elephants (70.7%) exhibited behaviors suggesting heightened attentiveness or alarm. The farm owner reported economic and social benefits of the beehive fence. By contributing to farmer income and reducing crop damage caused by wild elephants, beehive fencing may provide an important locally‐managed complement to regional HEC mitigation methods.

Abstract Background Nifedipine is a generic, well-known and commonly-prescribed dihydropyridine calcium channel blocker used in the treatment of hypertension and Prinzmetal’s angina. A known but very rare and serious adverse effect of nifedipine is clinically-apparent hepatitis which can take months to resolve. Case presentation Here we present a case of nifedipine-induced hepatitis in a 78-year-old Caucasian female with no prior history of liver or autoimmune disease. We discuss our investigative and management approach, and present a review of prior cases. We offer an approach for patients who present with signs of acute liver injury with jaundice and high elevations in serum transaminases. Conclusion Not much is known about nifedipine-induced hepatitis due to its rare occurrence. Its prevalence is unknown. The disease appears to afflict older men and women. It can present acutely (within days) or subacutely (within 4–8 weeks after medication start) and in an idiosyncratic manner. Chronic or latent cases have also been described, some diagnosed as late as 3 years after medication start. Common symptoms include jaundice, nausea, chills, rigors, diaphoresis, fatigue, and abdominal pain. Laboratory investigations often reveal profound elevations in AST, ALT, GGT, and conjugated bilirubin. Peripheral blood smear may demonstrate eosinophilia. Histology from liver biopsy typically demonstrates infiltration of immune cells, cholestasis, and a picture of steatohepatitis. Treatment involves immediate discontinuation of the drug with supportive care. Thus far, all published instances of nifedipine-induced hepatitis were self-limiting without mortality due to fulminant liver failure. However, this disease can take months to resolve. There is no randomized evidence for other treatments such as corticosteroids.

Cancer is a multifaceted disease that involves several molecular mechanisms including changes in gene expression. Two important processes altered in cancer that lead to changes in gene expression include altered microRNA (miRNA) expression and aberrant splicing events. MiRNAs are short non-coding RNAs that play a central role in regulating RNA silencing and gene expression. Alternative splicing increases the diversity of the proteome by producing several different spliced mRNAs from a single gene for translation. MiRNA expression and alternative splicing events are rigorously regulated processes. Dysregulation of miRNA and splicing events promote carcinogenesis and drug resistance in cancers including breast, cervical, prostate, colorectal, ovarian and leukemia. Alternative splicing may change the target mRNA 3′UTR binding site. This alteration can affect the produced protein and may ultimately affect the drug affinity of target proteins, eventually leading to drug resistance. Drug resistance can be caused by intrinsic and extrinsic factors. The interplay between miRNA and alternative splicing is largely due to splicing resulting in altered 3′UTR targeted binding of miRNAs. This can result in the altered targeting of these isoforms and altered drug targets and drug resistance. Furthermore, the increasing prevalence of cancer drug resistance poses a substantial challenge in the management of the disease. Henceforth, molecular alterations have become highly attractive drug targets to reverse the aberrant effects of miRNAs and splicing events that promote malignancy and drug resistance. While the miRNA–mRNA splicing interplay in cancer drug resistance remains largely to be elucidated, this review focuses on miRNA and alternative mRNA splicing (AS) events in breast, cervical, prostate, colorectal and ovarian cancer, as well as leukemia, and the role these events play in drug resistance. MiRNA induced cancer drug resistance; alternative mRNA splicing (AS) in cancer drug resistance; the interplay between AS and miRNA in chemoresistance will be discussed. Despite this great potential, the interplay between aberrant splicing events and miRNA is understudied but holds great potential in deciphering miRNA-mediated drug resistance.

Background: Routine screening colonoscopy is on the rise and pathologists have to deal with the ever larger numbers of excised colonic polyps. It is very important to optimize the patients’ individual treatment and further surveillance. Pathologists play a critical role in management, as most of the clinical decisions concerning colonic polyp management are based on pathologic findings. One of the most important clinical issues in colonic adenomas is the diagnosis of malignancy and reporting its different aspects by the pathologist. The histologic type and the extent of carcinoma within a malignant polyp have considerable impact on the decisions of gastroenterologists and surgeons for further management. Therefore, the most recent literature regarding the diagnosis and reporting of the different features of malignant polyps was reviewed. Data Acquisition: There is growing literature regarding the different pathologic features and reporting of malignant colonic polyps, and in this review, published articles that are listed on Google Scholar and Pub Med are discussed. Conclusion: Diagnosis of malignant colon polyp requires the presence of tumor cells that are penetrating beyond the muscular mucosa into submucosa (pT1). As well as establishing a diagnosis of malignant polyp, it is very important to report the size of the invasive component, the presence or absence of lymphovascular invasion, the degree of tumor differentiation and the distance of the carcinoma from the line of resection. Other important features that may be reported include: the presence or absence of tumor budding, the depth of tumor cell penetration into the submucosa, and results of immunohistochemistry for mismatch repair proteins and BRAF.

Background and Aims: Ultrasound (US)-guided infraclavicular approach for axillary vein (AXV) cannulation has gained popularity in the last decade. Material and Methods: In this manikin study, we evaluated the feasibility of a training model for teaching AXV cannulation. The learning pattern with this technique was assessed among attending anesthesiologists and residents in training. Results: A faster learning pattern was observed for AXV cannulation among the attending anesthesiologists and residents in training, irrespective of their prior experience with US. It was evident that a training modality for this technique could be easily established with a phantom model and that hands-on training motivates trainees to embrace US-based central venous cannulation. Conclusion: A teaching model for US-guided infraclavicular longitudinal in-plane AXV cannulation can be established using a phantom model. A focused educational program would result in an appreciable change in preference in embracing US-based cannulation techniques among residents.

Thymic Treg cell differentiation occurs via a two-step process. Step one generates Treg cell progenitors (TregP) and is driven by strong TCR interactions with antigens presented in the thymus. Step two is initiated by activation of STAT5 via IL-2, or IL-15, leading to mature Treg cells capable of emigrating from the thymus and mediating immune tolerance and homeostasis in peripheral tissues. Herein we describe an in vitro TregP cell differentiation assay that models the second, cytokine dependent, step of thymic Treg cell development. It can be utilized with relative ease to determine if a population of thymocytes represents a potential progenitor population for Treg cells as well as test how different cytokines or chemical inhibitors modulate the differentiation of known TregP cell populations into mature Treg cells.

To track recent thymic emigrants (RTEs) or study T cell development in the thymus, intra-thymic injection of a cellular tag or precursor cells for various T cell lineages is often desired. However, the traditional surgical approach to expose the thymus for intra-thymic injection is time-consuming and can cause a high level of pain and stress to animals, which might disrupt immune homeostasis, potentially confounding the results. Here, we introduce an ultrasound guided intra-thymic injection procedure, which is non-surgical and minimally invasive to animals. This technique is relatively easy to learn and offers an efficient and accurate tool to track RTEs or perform intra-thymic transfer of various cell types to investigate their differentiation.

This essay develops, within the terms of the recent New York Declaration, an account of the shared responsibility of states to refugees and of how the character of that responsibility effects the ways in which it can be fairly shared. However, it also moves beyond the question of the general obligations that states owe to refugees to consider ways in which refugee choices and refugee voice can be given appropriate standing with the global governance of refuge. It offers an argument for the normative significance of refugee’s reasons for choosing states of asylum and linked this to consideration of a refugee matching system and to refugee quota trading conceived as responsibility-trading, before turning to the issue of the inclusion of refugee voice in relation to the justification of the norms of refugee governance and in relation to the institutions and practices of refugee governance through which those norms are given practical expression.

The translocator protein (TSPO) is a mitochondrial membrane protein, of as yet uncertain function. Its purported high expression on activated macrophages, has lent utility to TSPO targeted molecular imaging in the form of positron emission tomography (PET), as a means to detect and quantify inflammation in vivo. However, existing literature regarding TSPO expression on human activated macrophages is lacking, mostly deriving from brain tissue studies, including studies of brain malignancy, and inflammatory diseases such as multiple sclerosis. Here, we utilized three human sources of monocyte derived macrophages (MDM), from THP-1 monocytes, healthy peripheral blood monocytes and synovial fluid monocytes from patients with rheumatoid arthritis, to undertake a detailed investigation of TSPO expression in activated macrophages. In this work, we demonstrate a consistent down-regulation of TSPO mRNA and protein in macrophages activated to a pro-inflammatory, or 'M1' phenotype. Conversely, stimulation of macrophages to an M2 phenotype with IL-4, dexamethasone or TGF-β1 did not alter TSPO expression, regardless of MDM source. The reasons for this are uncertain, but our study findings add some supporting evidence for recent investigations concluding that TSPO may be involved in negative regulation of inflammatory responses in macrophages.

Introduction.ARFI is a new technique that uses acoustic push pulse to generate tissue displacement resulting in shear wave propagation, can be used to measure elasticity of tissue. We aim to assess feasibility of ARFI as a non-invasive method to measure liver fibrosis compared to histological fibrosis scores and to compare our results with the published pooled-meta-analysis cut off values.Material and methods. Prospective study to compare median velocities of ARFI shear wave measurements (Virtual Touch Imaging™ ACUSON S2000, Siemens, Mountain View CA) with Batts and Ludwig liver fibrosis scoring system F0-F4.Results. 70 patients (mean = 49 years) were included. Etiologies were chronic hepatitis C (n = 43), chronic hepatitis B (n = 7) and others (n = 20). Median ARFI values (m/sec) for fibrosis stages and inflammatory stages measured were F0: 1.52, 1.42; F1: 1.50, 1.37; F3: 2.36, 2.41 and F4: 2.61. Areas under the curve for grade 3 = 0.875, stage 3 = 0.867; grade 2 = 0.4, stage 2 = 0.3.Using the cut-off ARFI value of 1.34 m/s for F ≥ 2 suggested in the meta-analysis, we found sensitivity of detecting true F > 2 is 68%, specificity 66%, PPV 74% and NPV 59%. For F ≥ 3 using the cut-off ARFI value of 1.55 m/s, we found sensitivity of 95%, specificity 86%, PPV 74% and NPV 98%. No stage 4 was compared due to insufficient cases.Conclusion. ARFI has strong correlation with higher fibrosis scores compared to lower. When compared to the pooled meta-analysis cut off values, the sensitivity and specificity for detecting true F ≥ 3 are higher than that of F ≥ 2.

Debates concerning the ‘democratic deficit’ have been a prevalent feature of the normative literature on the European Union, but rather less attention has been paid to ‘demos problems’ constructed by the normative ordering of the EU and what such problems reveal about the nature of democratic citizenship in the EU, the character of the EU as a normative order and the institutional character of the relationship between the constitution of the EU as a normative order and as a structure of political incentives. This article addresses this topic by focusing on one such ‘demos problem’.

This essay considers the role of the ‘all affected interests’ principle in democratic theory, focusing on debates concerning its form, substance and relationship to the resolution of the democratic boundary problem. It begins by defending an ‘all actually affected’ formulation of the principle against Goodin's ‘incoherence argument’ critique of this formulation, before addressing issues concerning how to specify the choice set appropriate to the principle. Turning to the substance of the principle, the argument rejects Nozick's dismissal of its intuitive appeal and considers the two arguments advanced in favour of the principle as a criterion of democratic inclusion: the interlinked interests argument and the tracking power argument. It is shown that neither of these arguments can substantiate a view of the principle as a criterion of democratic inclusion, although both ground a constitutional understanding of the principle as specifying the scope of a duty of justification. It is then proposed that the principle can play an important role in a two-stage resolution of the democratic boundary problem in which it addresses the question of who is entitled to inclusion in the ‘pre-political’ demos that determines whether to constitute a polity. The second stage of this resolution requires an answer to the question of who should constitute the ‘political demos’, that is, the demos of a constituted polity and it is argued that a version of the “all subjected persons” principle can appropriately play this role.

Background and aims. Acoustic Radiation Force Impulse Imaging (ARFI) is a novel non invasive technique studying the localized mechanical properties of tissue by utilising short, high intensity acoustic pulses (shear wave pulses) to assess the mechanical response (tissue displacement), providing a measure of tissue elasticity. The aim of this study is to investigate the feasibility of ARFI imaging as a non-invasive method for the assessment of liver fibrosis compared to liver biopsy scores.Materials and methods. A prospective blind comparison study of ARFI elastography (Virtual Touch Imaging™, ACUSON S2000 Ultrasound Unit, Siemens, Mountain View CA) in a consecutive series of patients who underwent liver biopsy for assessment of fibrosis in chronic liver disease. ARFI shear-wave propagation velocity was measured in meters per second. Mean ARFI velocities were compared with both Batts-Ludwig (F0 to F4) and Modified Ishak scores (F0 to F4) for fibrosis in liver biopsy findings. Twenty-one patients with chronic liver disease (Hepatitis C (HCV) = 16, Hepatitis B (HBV) = 1, both HCV and HBV = 1 Alcoholic liver disease (ALD) = 1, others = 2) underwent ARFI and liver biopsy on the same day.Results. The Spearman correlation coefficients between the median values of the ARFI measurements and the histological fibrosis stage of the Modified Ishak score and Batts-Lud-≥ wig score were both highly significant (p < 0.01) with rho = 0.69 and rho = 0.72 respectively. The median ARFI (total 180 replications; minimum 5, maximum 10 measurements per patients) velocities for our study population range from 0.92 to 4.17 m/sec. Areas under the receiver operating characteristic curve for the accuracy of ARFI imaging was 1.00 and 0.35, for the diagnosis of moderate fibrosis (histologic fibrosis stage, F ≥ 2) and 0.85 and 0.85 respectively for Ishak and Batts-Ludwig score, for the diagnosis of cirrhosis.Conclusion. ARFI imaging has a strong correlation with the fibrosis stage of both Batts-Ludwig and shak score in chronic liver disease. It’s accuracy in prediction of severe fibrosis and cirrhosis is maximal in comparison with earlier stages.

In this paper, I argue that the sociocultural structuring property of whiteness has been utilized to marginalize President Obama and effectively undermine his presidential authority. Whiteness functions in a largely invisible and ostensibly deracialized way to normalize the interests, needs, and values of whites, while at the same time marginalizing and devaluing the voice of people of color. Analyzing the health care debate through this theoretical lens generates insights into how the debate reproduced the system of racial oppression, and how whiteness functions in political discourse.

BACKGROUND: Barrett’s esophagus (BE) with dysplasia may progress to esophageal adenocarcinoma. Photodynamic therapy is a promising treatment for BE.

Complex hand dexterity is fundamental to our interactions with the physical, social and cultural environment. Dexterity can be an expression of creativity and precision in a range of activities, including musical performance. Little is understood about complex hand dexterity or how virtuoso expertise is acquired, due to the versatility of movement combinations available to complete any given task. This has historically limited progress of the field because of difficulties in measuring movements of the hand. Recent developments in methods of motion capture and analysis mean it is now possible to explore the intricate movements of the hand and fingers. These methods allow us insights into the neurophysiological mechanisms underpinning complex hand dexterity and motor learning. They also allow investigation into the key factors that contribute to injury, recovery and functional compensation.The application of such analytical techniques within musical performance provides a multidisciplinary framework for purposeful investigation into the process of learning and skill acquisition in instrumental performance. These highly skilled manual and cognitive tasks present the ultimate achievement in complex hand dexterity. This paper will review methods of assessing instrumental performance in music, focusing specifically on biomechanical measurement and the associated technical challenges faced when measuring highly dexterous activities.

OBJECTIVE: To determine the rate of Helicobacter pylori eradication following bismuth-based triple therapy with colloidal bismuth subcitrate, tetracycline hydrochloride and metronidazole.

A 25-year-old white woman was diagnosed with Crohn’s disease involving the small and large intestines. She had a complex clinical course that required treatment with multiple pharmacological agents, including intravenous, oral and rectal corticosteroids. She also received parenteral nutrition with lipid emulsions. Finally, repeated intestinal resections and drainage of perianal abscesses were required. Her disease was complicated by gallstones, urolithiasis and hip pain. After osteonecrosis was diagnosed, joint replacements were performed. Review of the pathological sections from the resected hip, however, resulted in detection of granulomatous inflammation with multinucleated giant cells - the histological ’footprint’ of Crohn’s disease in the gastrointestinal tract. Because prior specialized perfusion fixation pathological studies of the intestine in Crohn’s disease have shown that granulomas are located in the walls of blood vessels, a possible mechanism for the pathogenesis of osteonecrosis in Crohn’s disease is chronic microvascular ischemia of bone.

Two cases of cutaneous metastases from hepatocellular carcinoma (HCC) are reported. Both patients had been diagnosed with HCC at least one year before the appearance of skin lesions. The lesions presented as small reddish nodules in both patients, with a large additional vascular lesion in one of the patients. Cutaneous metastases from HCC are very rare. However, these two cases suggest that patients with HCC and presenting with skin nodules should have biopsies performed to confirm the diagnosis.

Este artículo describe los objetivos, enfoques y desarrollo del proyecto interuniversitario titulado “Entre líneas: Lectura comprensiva de textos literarios en lengua extranjera” financiado por la Agencia de Gestión de Ayudas Universitarias y de la Investigación (MQD 00121) y destinado a la mejora de la calidad docente en el ámbito de la enseñanza de la literatura. Con el objetivo de contrarrestar el excesivo interés que nuestros alumnos han manifestado por aspectos esencialmente superficiales de los textos literarios y de facilitar la comprensión de cuestiones textuales más complejas, este proyecto ha priorizado sistemáticamente la cuestión de la narratividad en la enseñanza de la literatura, lo que ha ayudado a los alumnos a acercarse a la asignatura a través de técnicas más sofisticadas de acuerdo con las exigencias de sus estudios de grado. El artículo analiza las diferentes fases de ejecución del proyecto en relación con el problema de fondo que ha impulsado la iniciativa y avanza hacia algunas conclusiones provisionales.

There is little doubt that the contemporary rise of populist forms of politics, especially those of the right, have targeted immigration as a key issue – and, more generally, political parties of left and right have responded to, and often stoked, perceived public concerns (however ill-founded) concerning immigration through efforts designed to highlight and demarcate the privileges of citizenship. In his timely response to this phenomenon, Liav Orgad aims to offer an account of majority rights that is, he thinks, missing from contemporary political theory and that can differentiate justifiable and unjustifiable ways in which the majority culture can defend its dominant standing and, hence, the rights it should (and should not) possess.