Dyslexic doctors, an observation on current United Kingdom practice

Issue: Dyslexia is a common learning difficulty with an estimated prevalence of ten percent within the general population and two percent among junior doctors training in the United Kingdom. Despite dyslexia being common, there are still many challenges sufferers face in modern medical practice. Evidence: Multiple case studies have found there to be barriers that dyslexic doctors face throughout their training. Common activities that required reading or writing in time pressured situations in front of an audience can impose an additional pressure for dyslexic doctors. In addition to the difficulties with day to day work, criticism and mockery from other staff members can make suffers of dyslexia feel undermined. From personal experiences, the authors of this article have found barriers are particularly present with regards to sitting post- graduate examinations and getting support in a modern time pressure health service. Implications: The discrepancy in the prevalence of learning difficulties between the general population and doctors in training might be due to barriers in training and difficulties when starting work. Addressing challenges will help support current dyslexic doctors and also help support future generations. Rapidly developing technology in health care makes it easier to accommodate doctors with additional needs but the impact of this are yet to be studied. If the barriers are addressed it is likely to support not only doctors with dyslexia diagnosis but all health care professionals

Validation of a semi-automated technique to accurately measure abdominal fat distribution using CT and MRI for clinical risk stratification

Objective: A valid method for accurate quantification of abdominal fat distribution (AFD) using both CT and MRI is described. This method will be primarily useful in the prospective risk stratification of patients undergoing reconstructive breast surgery. Secondary applications in many other clinical specialities are foreseen. Methods: 15 sequential patients who had undergone breast reconstruction following both CT and MRI (30 scans) were retrospectively identified at our single centre. The AFD was quantified at the level of the L3 vertebra. Image analysis was performed by at least two independent operators using free software. Intra- and interobserver differences were assessed using Bland–Altman plots. Data were validated between imaging modalities by Pearson's correlation. Linear regression analyses were used to mathematically normalize results between imaging modalities. Results: The method was statistically independent of rater bias (intra: Pearson's R—0.954–1.00; inter: 0.799–0.999). Strong relationships between imaging modalities were demonstrated and are independent of time between imaging (Pearson's R 0.625–0.903). Interchangeable mathematical models to normalize between imaging modality are shown. Conclusion: The method described is highly reproducible and independent of rater bias. A strong interchangeable relationship exists between calculations of AFD on retrospective CT and MRI. Advances in knowledge: This is the first technique to be applicable to scans that are not performed sequentially or in a research setting. Analysis is semi-automated and results can be compared directly, regardless of imaging modality or patient position. This method has clinical utility in prospective risk stratification and will be applicable to many clinical specialities

Enhanced snoMEN Vectors Facilitate Establishment of GFP–HIF-1α Protein Replacement Human Cell Lines

The snoMEN (snoRNA Modulator of gene ExpressioN) vector technology was developed from a human box C/D snoRNA, HBII-180C, which contains an internal sequence that can be manipulated to make it complementary to RNA targets, allowing knock-down of targeted genes. Here we have screened additional human nucleolar snoRNAs and assessed their application for gene specific knock-downs to improve the efficiency of snoMEN vectors. We identify and characterise a new snoMEN vector, termed 47snoMEN, that is derived from box C/D snoRNA U47, demonstrating its use for knock-down of both endogenous cellular proteins and G/YFP-fusion proteins. Using multiplex 47snoMEM vectors that co-express multiple 47snoMEN in a single transcript, each of which can target different sites in the same mRNA, we document >3-fold increase in knock-down efficiency when compared with the original HBII-180C based snoMEN. The multiplex 47snoMEM vector allowed the construction of human protein replacement cell lines with improved efficiency, including the establishment of novel GFP–HIF-1α replacement cells. Quantitative mass spectrometry analysis confirmed the enhanced efficiency and specificity of protein replacement using the 47snoMEN-PR vectors. The 47snoMEN vectors expand the potential applications for snoMEN technology in gene expression studies, target validation and gene therapy

Hnf4α is a key gene that can generate columnar metaplasia in oesophageal epithelium

AbstractBarrett's metaplasia is the only known morphological precursor to oesophageal adenocarcinoma and is characterized by replacement of stratified squamous epithelium by columnar epithelium. The cell of origin is uncertain and the molecular mechanisms responsible for the change in cellular phenotype are poorly understood. We therefore explored the role of two transcription factors, Cdx2 and HNF4α in the conversion using primary organ cultures. Biopsy samples from cases of human Barrett's metaplasia were analysed for the presence of CDX2 and HNF4α. A new organ culture system for adult murine oesophagus is described. Using this, Cdx2 and HNF4α were ectopically expressed by adenoviral infection. The phenotype following infection was determined by a combination of PCR, immunohistochemical and morphological analyses. We demonstrate the expression of CDX2 and HNF4α in human biopsy samples. Our oesophageal organ culture system expressed markers characteristic of the normal SSQE: p63, K14, K4 and loricrin. Ectopic expression of HNF4α, but not of Cdx2 induced expression of Tff3, villin, K8 and E-cadherin. HNF4α is sufficient to induce a columnar-like phenotype in adult mouse oesophageal epithelium and is present in the human condition. These data suggest that induction of HNF4α is a key early step in the formation of Barrett's metaplasia and are consistent with an origin of Barrett's metaplasia from the oesophageal epithelium

Adiponectin-Mediated Analgesia and AntiInflammatory Effects in Rat

The adipose tissue-derived protein, adiponectin, has significant anti-inflammatory properties in a variety of disease conditions. Recent evidence that adiponectin and its receptors (AdipoR1 and AdipoR2) are expressed in central nervous system, suggests that it may also have a central modulatory role in pain and inflammation. This study set out to investigate the effects of exogenously applied recombinant adiponectin (via intrathecal and intraplantar routes; 10–5000 ng) on the development of peripheral inflammation (paw oedema) and pain hypersensitivity in the rat carrageenan model of inflammation. Expression of adiponectin, AdipoR1 and AdipoR2 mRNA and protein was characterised in dorsal spinal cord using real-time polymerase chain reaction (PCR) and Western blotting. AdipoR1 and AdipoR2 mRNA and protein were found to be constitutively expressed in dorsal spinal cord, but no change in mRNA expression levels was detected in response to carrageenan-induced inflammation. Adiponectin mRNA, but not protein, was detected in dorsal spinal cord, although levels were very low. Intrathecal administration of adiponectin, both pre- and 3 hours post-carrageenan, significantly attenuated thermal hyperalgesia and mechanical hypersensitivity. Intrathecal administration of adiponectin post-carrageenan also reduced peripheral inflammation. Intraplantar administration of adiponectin pre-carrageenan dose-dependently reduced thermal hyperalgesia but had no effect on mechanical hypersensitivity and peripheral inflammation. These results show that adiponectin functions both peripherally and centrally at the spinal cord level, likely through activation of AdipoRs to modulate pain and peripheral inflammation. These data suggest that adiponectin receptors may be a novel therapeutic target for pain modulation

Risk of Bowel Obstruction in Patients Undergoing Neoadjuvant Chemotherapy for High-risk Colon Cancer

Objective: This study aimed to identify risk criteria available before the point of treatment initiation that can be used to stratify the risk of obstruction in patients undergoing neoadjuvant chemotherapy (NAC) for high-risk colon cancer. Background: Global implementation of NAC for colon cancer, informed by the FOxTROT trial, may increase the risk of bowel obstruction. Methods: A case-control study, nested within an international randomized controlled trial (FOxTROT; ClinicalTrials.gov: NCT00647530). Patients with high-risk operable colon cancer (radiologically staged T3-4 N0-2 M0) that were randomized to NAC and developed large bowel obstruction were identified. First, clinical outcomes were compared between patients receiving NAC in FOxTROT who did and did not develop obstruction. Second, obstructed patients (cases) were age-matched and sex-matched with patients who did not develop obstruction (controls) in a 1:3 ratio using random sampling. Bayesian conditional mixed-effects logistic regression modeling was used to explore clinical, radiologic, and pathologic features associated with obstruction. The absolute risk of obstruction based on the presence or absence of risk criteria was estimated for all patients receiving NAC. Results: Of 1053 patients randomized in FOxTROT, 699 received NAC, of whom 30 (4.3%) developed obstruction. Patients underwent care in European hospitals including 88 UK, 7 Danish, and 3 Swedish centers. There was more open surgery (65.4% vs 38.0%, P=0.01) and a higher pR1 rate in obstructed patients (12.0% vs 3.8%, P=0.004), but otherwise comparable postoperative outcomes. In the case-control–matched Bayesian model, 2 independent risk criteria were identified: (1) obstructing disease on endoscopy and/or being unable to pass through the tumor [adjusted odds ratio: 9.09, 95% credible interval: 2.34–39.66] and stricturing disease on radiology or endoscopy (odds ratio: 7.18, 95% CI: 1.84–32.34). Three risk groups were defined according to the presence or absence of these criteria: 63.4% (443/698) of patients were at very low risk (10%). Conclusions: Safe selection for NAC for colon cancer can be informed by using 2 features that are available before treatment initiation and identifying a small number of patients with a high risk of preoperative obstruction

Once (but not twice) upon a time: Narrative inoculation against conjunction errors indirectly reduces conspiracy beliefs and improves truth discernment

Psychological inoculation has proven effective at reducing susceptibility to misinformation. We present a novel storytelling approach to inoculation against susceptibility to the conjunction fallacy (dmeta‐analysis = 0.82), a known cognitive predictor of conspiracy beliefs. In Study 1 (Pilot; N = 161), a narrative inoculation (vs. control) reduced susceptibility to conjunction errors, and in turn, conspiracy beliefs regarding government malfeasance. In Study 2 (main experiment; N = 141; pre‐registered), two separate narrative inoculations (vs. control) directly reduced susceptibility to conjunction errors, and indirectly reduced conspiracy beliefs regarding extra‐terrestrial cover‐ups. In addition, the inoculation messages improved detection of both real and fake news (‘truth discernment’). We discuss theoretical and practical implications, including the use of inoculation to induce critical thinking styles, and tailoring inoculations that may suit storytelling mediums