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This article focuses on the new 6th edition TNM classification of colorectal cancer. The new 6th edition of the TNM staging classification of colorectal cancer changes the histological criteria for interpreting extramural tumour nodules. Changes to TNM staging in the 6th edition have replaced an objective criterion with one that is subjective and not reproducible by pathologists. Application of the new TNM classification "upstages" up to 11% of 13 colorectal cancers. This has implications for patient treatment, clinical trials and cancer intelligence.

Investigates how COX-2 levels change in the lung just before and just after birth. Results imply understanding of lung physiology in the adult; Mechanism subject to further investigation.

The management of hypoglycaemia is pivotal in the care of patients with insulinoma. Blood glucose monitoring and regulation needs careful attention pre- and peri-operatively for patients undergoing surgical resection and as part of the long-term management for patients with inoperable or metastatic disease. Hypoglycaemia symptoms are frequently pervasive and disabling, with many patients showing impaired hypoglycaemia awareness that can lead to life-threatening severe hypoglycaemia. Herein, we review the literature and describe our tertiary centre experience in the mutli-disciplinary management of hypoglycaemia for patients with proven insulinomas. We propose a stepwise algorithm for the management of hypoglycaemia, stratified by localised versus metastatic disease. We discuss our strategy for the nutritional management of hypoglycaemia, reviewing the evidence for the use of cornstarch products and artificial nutrition. We discuss pharmacological management including diazoxide, somatostatin receptor antagonists (SSAs), everolimus and glucocorticoids, in addition to other therapeutic interventions such as peptide receptor radionuclide therapy (PRRT) and endoscopic ablation., (© 2024 The Author(s). Clinical Endocrinology published by John Wiley & Sons Ltd.)

5-Methyldeoxycytidine (5mC) is a major epigenetic marker that regulates cellular functions in mammals. Endogenous lipid peroxidation can convert 5mC into 3,N4-etheno-5-methylcytosine (ϵ5mC). ϵ5mC is structurally similar to the mutagenic analog 3,N4-ethenocytosine (ϵC), which is repaired by AlkB family enzymes in the direct reversal repair (DRR) pathway and excised by DNA glycosylases in the base excision repair (BER) pathway. However, the repair of ϵ5mC has not been reported. Here, we examined the activities against ϵ5mC by DRR and BER enzymes and TET1-3, enzymes that modify the 5-methyl group in 5mC. We found that the etheno modification of 5mC blocks oxidation by TET1-3. Conversely, three human homologs in the AlkB family, ALKBH2, 3 and FTO were able to repair ϵ5mC to 5mC, which was subsequently modified by TET1 to 5-hydroxymethylcytosine. We also demonstrated that ALKBH2 likely repairs ϵ5mC in MEF cells. Another homolog, ALKBH5, could not repair ϵ5mC. Also, ϵ5mC is not a substrate for BER glycosylases SMUG1, AAG, or TDG. These findings indicate DRR committed by ALKBH2, 3 and FTO could reduce the detrimental effects of ϵ5mC in genetics and epigenetics and may work together with TET enzymes to modulate epigenetic regulations., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Interprofessional healthcare teams have become the benchmark for optimising athlete health and performance in high-stakes sports. Despite a history of utility as provider partners, chiropractors are currently a relatively underutilised human resource in this rapidly developing and challenging field. Consequently, our study explored the global experiences and distinct perspectives of elite-level career sports chiropractors. Through a qualitative explorative single case study, we purposively sampled and interviewed 15 chiropractors active in elite-level athletic contexts. ' Professional characteristics and competencies', 'Running the gamut of professional career development' and 'Navigating team development in a small organisational structure' emerged as the three key themes from the data. Our data indicate that chiropractors gain provider as members of the elite athletic health and performance management team as multirole manual medicine practitioners. However, thriving in a team-oriented practice, this context appears to be reliant on their capacity for development as part of a small organisational group., Competing Interests: None declared., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A controversial claim in recent dual process accounts of reasoning is that intuitive processes not only lead to bias but are also sensitive to the logical status of an argument. The intuitive logic hypothesis draws upon evidence that reasoners take longer and are less confident on belief-logic conflict problems, irrespective of whether they give the correct logical response. In this paper, we examine conflict detection under conditions in which participants are asked to either judge the logical validity or believability of a presented conclusion, accompanied by measures of eye movement and pupil dilation. The findings show an effect of conflict, under both types of instruction, on accuracy, latency, gaze shifts, and pupil dilation. Importantly, these effects extend to conflict trials in which participants give a belief-based response (incorrectly under logic instructions or correctly under belief instructions) demonstrating both behavioral and physiological evidence in support of the logical intuition hypothesis., (© 2023 The Authors. Cognitive Science published by Wiley Periodicals LLC on behalf of Cognitive Science Society (CSS).)

The capacity to evaluate logical arguments intuitively is a fundamental assumption of recent dual-process theories. One observation supporting this effect is the standard conflict effect on incongruent arguments under belief instruction. Conflict arguments are evaluated less accurately than non-conflict arguments, arguably because logic is intuitive and automatic enough to interfere with belief judgments. However, recent studies have challenged this interpretation by finding the same conflict effects when a matching heuristic cues the same response as logic, even on arguments with no logically valid structures. In this study, we test the matching heuristic hypothesis across 4 experiments (total N = 409) by manipulating the arguments propositions so that matching cues a response that is either (1) aligned or (2) misaligned with logic, or (3) cues no response at all. Consistent with the predictions of the matching heuristic, standard, reversed, and no conflict effects were found in those conditions, respectively. These results indicate that intuitively correct inferences which are assumed as evidence of logical intuitions are actually driven by a matching heuristic that cues responses aligned with logic. Alleged intuitive logic effects are reversed when the matching heuristic cues an opposing logical response or disappears when there are no matching cues. Therefore, it appears as though the operation of a matching heuristic, rather than an intuitive access to logic, drives logical intuitions., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Autoimmune Addison's disease (AAD) arises from a complex interplay between multiple genetic susceptibility polymorphisms and environmental factors. The first genome wide association study (GWAS) with patients from Scandinavian Addison's registries has identified association signals at four novel loci in the genes LPP, SH2B3, SIGLEC5, and UBASH3A. To verify these novel risk loci, we performed a case-control association study in our independent cohort of 420 patients with AAD from the across the UK. We report significant association of alleles of the LPP and UBASH3A genes [odds ratio (95% confidence intervals), 1.46 (1.21-1.75)and 1.40 (1.16-1.68), respectively] with AAD in our UK cohort. In addition, we report nominal association of AAD with SH2B3 [OR 1.18 (1.02-1.35)]. We confirm that variants at the LPP and UBASH3A loci confer susceptibility to AAD in a UK population. Further studies with larger patient cohorts are required to robustly confirm the association of SH2B3 and SIGLEC5/SPACA6 alleles., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology.)

Autoimmune Addison's disease (AAD) is defined as primary adrenal insufficiency due to immune-mediated destruction of the adrenal cortex. This destruction of steroid-producing cells has historically been thought of as an irreversible process, with linear progression from an ACTH-driven compensated phase to overt adrenal insufficiency requiring lifelong glucocorticoid replacement. However, a growing body of evidence suggests that this process may be more heterogeneous than previously thought, with potential for complete or partial recovery of glucocorticoid secretion. Although patients with persistent mineralocorticoid deficiency despite preserved or recovered glucocorticoid function are anecdotally mentioned, few well-documented cases have been reported to date. We present three patients in the United Kingdom who further challenge the long-standing hypothesis that AAD is a progressive, irreversible disease process. We describe one patient with a 4-year history of mineralocorticoid-only Addison's disease, a patient with spontaneous recovery of adrenal function and one patient with clinical features of adrenal insufficiency despite significant residual cortisol function. All three patients show varying degrees of mineralocorticoid deficiency, suggesting that recovery of zona fasciculata function in the adrenal cortex may occur independently to that of the zona glomerulosa. We outline the current evidence for heterogeneity in the natural history of AAD and discuss possible mechanisms for the recovery of adrenal function.

Recent research suggests that reasoners are able to draw simple logical or probabilistic inferences relatively intuitively and automatically, a capacity that has been termed "logical intuition" (see, e.g., De Neys & Pennycook, 2019). A key finding in support of this interpretation is that conclusion validity consistently interferes with judgments of conclusion believability, suggesting that information about logical validity is available quickly enough to interfere with belief judgments. In this study, we examined whether logical intuitions arise because reasoners are sensitive to the logical features of a problem or another structural feature that just happens to align with logical validity. In three experiments ( N = 113, 137, and 254), we presented participants with logical (determinate) and pseudological (indeterminate) arguments and asked them to judge the validity or believability of the conclusion. Logical arguments had determinately valid or invalid conclusions, whereas pseudological arguments were all logically indeterminate, but some were pseudovalid (possible strong arguments) and others pseudoinvalid (possible weak arguments). Experiments 1 and 2 used simple modus ponens and affirming the consequent structures; Experiment 3 used more complex denying the antecedent and modus tollens structures. In all three experiments, we found that pseudovalidity interfered with belief judgments to the same extent as real validity. Altogether, these findings suggest that while people are able to draw inferences intuitively, and these inferences impact belief judgments, they are not logical intuitions. Rather, the intuitive inferences are driven by the processing of more superficial structural features that happen to align with logical validity. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A woman in her 50s with Turner syndrome was referred to the endocrine clinic, having been unaware of her diagnosis until she received a shielding letter from the UK government during the COVID-19 pandemic. Despite a neonatal diagnosis of Turner syndrome on her general practitioner record and despite having undergone laparoscopic examination for absent puberty and primary amenorrhoea aged 18 years, she had not received any prior hormone treatment or cardiovascular screening.Though Turner syndrome is rare, recent data from the UK Biobank suggest that it may be underdiagnosed. Clinicians should be aware of the clinical features and associated complications of Turner syndrome to avoid delayed diagnosis and missed opportunities for treatment.In this report, we discuss the clinical features of this rare syndrome and current guidelines for screening and treatment. We stress the importance of peer-to-peer support and information sharing through patient-led groups, such as the Turner Syndrome Support Society., Competing Interests: Competing interests: In the past 3 years, RQ has accepted Speaker’s honoraria from Bayer, Besins and Thornton & Ross., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro-a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening., (© 2022 Duncan et al.)

Classic dual process theories of human reasoning attribute explicit reasoning to effortful, deliberative thinking. According to these models, intuitive processes lack any access to the formal rules of logic and probability and hence rely exclusively on superficial problem features to determine a response. However, in recent years, researchers have demonstrated that reasoners are able to solve simple logical or probabilistic problems relatively automatically, a capability which has been called "logical intuition." In four experiments, we instructed participants to judge the validity (Experiments 1 and 4), likeability (Experiments 1, 2, and 3), and physical brightness (Experiments 2, 3, and 4) of the conclusion to several reasoning problems. Brightness judgements were made by evaluating the font shade brightness of the argument's conclusion. Participants were also asked to complete a range of individual differences measures, drawing on cognitive ability and cognitive style, to evaluate the extent to which "logical intuitions" were linked to measures of deliberative reasoning. The results showed that participants judged the conclusion of logically valid statements to be more valid, more likable, and more physically bright than invalid statements. Participants with higher cognitive ability and unlimited processing time showed greater effects of logical validity in their liking judgements (varied across experiments). However, these effects were absent in the brightness tasks, suggesting that logic effects observed under instructions to judge conclusion brightness are a purer measure of "logical intuition." We discuss the implications of our findings for recent dual process theories of human reasoning.

The Cognitive Reflection Test (CRT) has been used in thousands of studies across several fields of behavioural research. The CRT has fascinated scholars because it commonly elicits incorrect answers despite most respondents possessing the necessary knowledge to reach the correct answer. Traditional interpretations of CRT performance asserted that correct responding was the result of corrective reasoning involving the inhibition and correction of the incorrect response and incorrect responding was an indication of miserly thinking without feelings of uncertainty. Recently, however, these assertions have been challenged. We extend this work by employing novel eye-tracking techniques to examine whether people use corrective cognitive pathways to reach correct solutions, and whether heuristic respondents demonstrate gaze-based signs of uncertainty. Eye movements suggest that correct responding on the CRT is the result of intuitive not corrective cognitive pathways, and that heuristic respondents show signs of gaze-based uncertainty., (© 2021. The Psychonomic Society, Inc.)

Live attenuated viral vaccines (LAV) have saved millions of lives globally through their capacity to elicit strong, cross-reactive and enduring adaptive immune responses. However, LAV can also act as a Trojan horse to reveal inborn errors of immunity, thereby highlighting important protective elements of the healthy antiviral immune response. In the following article, we draw out these lessons by reviewing the spectrum of LAV-associated disease reported in a variety of inborn errors of immunity. We note the contrast between adaptive disorders, which predispose to both LAV and their wild type counterparts, and defects of innate immunity in which parenterally delivered LAV behave in a particularly threatening manner. Recognition of the underlying pathomechanisms can inform our approach to disease management and vaccination in a wider group of individuals, including those receiving immunomodulators that impact the relevant pathways., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The importance of infant social-emotional development for outcomes across the lifecourse has been amply demonstrated. Despite this, most screening measures of social-emotional development are designed for children 18 months of age and over, with a clear gap in earlier infancy. No systematic review has yet harvested the evidence for candidate indicators in the perinatal window. This paper examines modifiable risk and protective factors for two seminal early markers of social-emotional development: attachment security and behavioral regulation mid-infancy. We searched meta-analytic and longitudinal studies of developmental relationships between modifiable exposures in the perinatal window (pregnancy to 10 months postpartum) and attachment and behavioral regulation status measured between 12 and 18 months. Six electronic databases were used: ERIC, PsycINFO, Medline Complete, Informit, Embase, and Scopus. Twelve meta-analytic reviews and 38 original studies found replicated evidence for 12 indicators across infant, caregiving, and contextual domains predictive of infant behavioral regulation and attachment status between 12 and 18 months. Key among these were caregiving responsiveness, maternal mental health, couple relationship, and SES as a contextual factor. Perinatal factors most proximal to the infant had the strongest associations with social-emotional status. Beyond very low birthweight and medical risk, evidence for infant-specific factors was weaker. Risk and protective relationships were related but not always inverse. Findings from this review have the potential to inform the development of reliable tools for early screening of infant social-emotional development for application in primary care and population health contexts., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Limitations in spinal mobility are a characteristic feature of Axial Spondyloarthritis. Current clinical measurements of spinal mobility have shown low criterion-concurrent validity. This study sought to evaluate criterion-concurrent validity for a clinically feasible measurement method of measuring spine mobility using tri-axial accelerometers., Methods: Fifteen radiographic-Spondyloarthritis patients were recruited for this study. Two postural reference radiographs, followed by three trials in forward, left and right lateral bending were taken. For all trials, three measurements were collected: tape (Original Schober's, Modified Schober's, Modified-Modified Schober's, Lateral Spinal Flexion Test and Domjan Test), followed immediately by synchronized radiograph and accelerometer measurements at end range of forward and bilateral lateral flexion. The criterion-concurrent validity of all measurement methods was compared to the radiographic measures using Pearson's correlation coefficients. A Bland-Altman analysis was conducted to assess agreement., Results: In forward bending, the accelerometer method (r = 0.590, p = 0.010) had a stronger correlation to the radiographic measures than all tape measures. In lateral bending, the Lateral Spinal Flexion tape measure (r = 0.743, p = 0.001) correlated stronger than the accelerometer method (r = 0.556, p = 0.016). The Domjan test of bilateral bending (r = 0.708, p = 0.002) had a stronger correlation to the radiographic measure than the accelerometer method., Conclusions: Accelerometer measures demonstrated superior criterion-concurrent validity compared to current tape measures of spinal mobility in forward bending. While a moderate correlation exists between accelerometer and radiographs in lateral bending, the Lateral Spinal Flexion Test and Domjan Test were found to have the best criterion-concurrent validity of all tests examined in this study.

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective population-based cohort study which recruited pregnant women in 1990-1992. The resource provides an informative and efficient setting for collecting data on the current coronavirus 2019 (COVID-19) pandemic. In early March 2020, a questionnaire was developed in collaboration with other longitudinal population studies to ensure cross-cohort comparability. It targeted retrospective and current COVID-19 infection information (exposure assessment, symptom tracking and reported clinical outcomes) and the impact of both disease and mitigating measures implemented to manage the COVID-19 crisis more broadly. Data were collected on symptoms of COVID-19 and seasonal flu, travel prior to the pandemic, mental health and social, behavioural and lifestyle factors. The online questionnaire was deployed across parent (G0) and offspring (G1) generations between 9 th April and 15 th May 2020. 6807 participants completed the questionnaire (2706 original mothers, 1014 original fathers/partners, 2973 offspring (mean age ~28 years) and 114 offspring partners). Eight (0.01%) participants (4 G0 and 4 G1) reported a positive test for COVID-19, 77 (1.13%; 28 G0 and 49 G1) reported that they had been told by a doctor they likely had COVID-19 and 865 (12.7%; 426 G0 and 439 G1) suspected that they have had COVID-19.  Using algorithmically defined cases, we estimate that the predicted proportion of COVID-19 cases ranged from 1.03% - 4.19% depending on timing during the period of reporting (October 2019-March 2020). Data from this first questionnaire will be complemented with at least two more follow-up questionnaires, linkage to health records and results of biological testing as they become available. Data has been released as: 1) a standard dataset containing all participant responses with key sociodemographic factors and 2) as a composite release coordinating data from the existing resource, thus enabling bespoke research across all areas supported by the study., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Northstone K et al.)

Prostate cancer is the second most common cancer diagnosed in men worldwide; however, few patients are affected by clinically significant disease within their lifetime. Unfortunately, the means to discriminate between patients with indolent disease and those who progress to aggressive prostate cancer is currently unavailable, resulting in over-treatment of patients. We therefore aimed to determine biomarkers of prostate cancer that can be used in the clinic to aid the diagnosis and prognosis. Immunohistochemistry analysis was carried out on prostate cancer specimens with a range of Gleason scores. Samples were stained and analysed for intensity of the Seven Transmembrane Epithelial Antigen of the Prostate (STEAP)-1, -2, -3, -4 and the Divalent Metal Transporter 1 (DMT1) proteins to determine suitable biomarkers for classification of patients likely to develop aggressive prostate cancer. Additionally, these proteins were also analysed to determine whether any would be able to predict future relapse using Kaplan Meier analysis. Data generated demonstrated that the protein expression levels of STEAP2 correlated significantly with Gleason score; furthermore, STEAP4 was a significant predictor of relapse. This data indicates that STEAP2 could be potential prognostic candidate for use in combination with the current prostate cancer detection methods and the presence of STEAP4 could be an indicator of possible relapse., Competing Interests: The authors have declared that no competing interests exist.

Primary hyperparathyroidism (PHPT) is characterised by the overproduction of parathyroid hormone (PTH) due to parathyroid hyperplasia, adenoma or carcinoma and results in hypercalcaemia and a raised or inappropriately normal PTH. Symptoms of hypercalcaemia occur in 20% of patients and include fatigue, nausea, constipation, depression, renal impairment and cardiac arrythmias. In the most severe cases, uraemia, coma or cardiac arrest can result. Primary hyperparathyroidism in pregnancy is rare, with a reported incidence of 1%. Maternal and fetal/neonatal complications are estimated to occur in 67 and 80% of untreated cases respectively. Maternal complications include nephrolithiasis, pancreatitis, hyperemesis gravidarum, pre-eclampsia and hypercalcemic crises. Fetal complications include intrauterine growth restriction; preterm delivery and a three to five-fold increased risk of miscarriage. There is a direct relationship between the degree of severity of hypercalcaemia and miscarriage risk, with miscarriage being more common in those patients with a serum calcium greater than 2.85 mmol/L. Neonatal complications include hypocalcemia. Herein, we present a case series of three women who were diagnosed with primary hyperparathyroidism in pregnancy. Case 1 was diagnosed with multiple endocrine neoplasia type 1 (MEN1) in pregnancy and required a bilateral neck exploration and subtotal parathyroidectomy in the second trimester of her pregnancy due to symptomatic severe hypercalcaemia. Both case 2 and case 3 were diagnosed with primary hyperparathyroidism due to a parathyroid adenoma and required a unilateral parathyroidectomy in the second trimester. This case series highlights the work-up and the tailored management approach to patients with primary hyperparathyroidism in pregnancy. Learning points: Primary hyperparathyroidism in pregnancy is associated with a high incidence of associated maternal fetal and neonatal complications directly proportionate to degree of maternal serum calcium levels. Parathyroidectomy is the definitive treatment for primary hyperparathyroidism in pregnancy and was used in the management of all three cases in this series. It is recommended when serum calcium is persistently greater than 2.75 mmol/L and or for the management of maternal or fetal complications of hypercalcaemia. Surgical management, when necessary is ideally performed in the second trimester. Primary hyperparathyroidism is genetically determined in ~10% of cases, where the likelihood is increased in those under 40 years, where there is relevant family history and those with other related endocrinopathies. Genetic testing is a useful diagnostic adjunct and can guide treatment and management options for patients diagnosed with primary hyperparathyroidism in pregnancy, as described in case 1 in this series, who was diagnosed with MEN1 syndrome. Women of reproductive age with primary hyperparathyroidism need to be informed of the risks and complications associated with primary hyperparathyroidism in pregnancy and pregnancy should be deferred and or avoided until curative surgery has been performed and calcium levels have normalised.

In the context of NHS workforce shortages, providers are increasingly looking to new models of care, diversifying the workforce and introducing new roles such as physician associates (PAs) into clinical teams. The current study used qualitative methods to investigate how PAs are integrated into a workforce in a region largely unfamiliar with the profession. We conducted an observational study examining factors that facilitated and challenged PA integration.  Findings suggest that the factors influencing PA integration relate to attributes of the individual, interpersonal relationships and organisational elements. From these, five key considerations have been derived which may aid organisations when planning to integrate new roles into the clinical workforce: prior to introducing PAs organisations should consider how to fully inform current staff about the PA profession; how to define the role of the PA within teams including clinical supervision arrangements; investment in educational and career development support for PAs; communication of remuneration to existing staff and conveying an organisational vision of PAs within the future workforce. Through consideration of these areas, organisations can facilitate role integration, maximising the potential of the workforce to contribute to sustainable healthcare provision.

The introduction of new professional roles to the multidisciplinary team has been heralded as a way to facilitate medical education in the face of increasing service pressures. However, concerns have been raised that the training of new healthcare professionals will dilute the availability of learning opportunities, thereby detracting from postgraduate medical education. As part of a mixed methods exploratory study, the experienced impact of newly qualified physician associates on medical training was explored. Within 6 months of newly qualified physician associates being introduced, half of junior doctors reported no overall impact on their training and a third felt that their training was enhanced by the presence of physician associates. A minority of trainees experienced dilution of training opportunities. The findings support the notion that new healthcare professionals do not detract from medical training and suggest that roles such as the physician associate have potential to enhance postgraduate medical education., (© Royal College of Physicians 2019. All rights reserved.)

Six-transmembrane epithelial antigen of the prostate-2 (STEAP2) expression is increased in prostate cancer when compared to normal prostate, suggesting STEAP2 may drive prostate cancer progression. This study aimed to establish the functional role of STEAP2 in prostate tumourigenesis and evaluate if its knockdown resulted in reduced invasive potential of prostate cancer cells. PC3 and LNCaP cells were transfected with STEAP2 siRNA and proliferation, migration, invasion and gene expression analyses were performed. STEAP2 immunohistochemistry was applied to assess the protein expression and localisation according to Gleason score in 164 prostate cancer patients. Invasion significantly decreased in both cell lines following STEAP2 knockdown. PC3 proliferation and migration capacity significantly reduced, while LNCaP cell morphology and growth characteristics were altered. Additionally, STEAP2 downstream targets associated with driving invasion were identified as MMP3, MMP10, MMP13, FGFR4, IL1β, KiSS1 and SERPINE1 in PC3 cells and, MMP7 in LNCaP cells, with CD82 altered in both. In patient tissues, STEAP2 expression was significantly increased in prostate cancer samples and this significantly correlated with Gleason score. These data demonstrate that STEAP2 drives aggressive prostate cancer traits by promoting proliferation, migration and invasion and significantly influencing the transcriptional profile of ten genes underlying the metastatic cascade.

Background: Despite previous identification of pre-operative clinical and radiological predictors of post-operative paediatric cerebellar mutism syndrome (CMS), a unifying pre-operative risk stratification model for use during surgical consent is currently lacking. The aim of the project is to develop a simple imaging-based pre-operative risk scoring scheme to stratify patients in terms of post-operative CMS risk., Methods: Pre-operative radiological features were recorded for a retrospectively assembled cohort of 89 posterior fossa tumour patients from two major UK treatment centers (age 2-23yrs; gender 28 M, 61 F; diagnosis: 38 pilocytic astrocytoma, 32 medulloblastoma, 12 ependymoma, 1 high grade glioma, 1 pilomyxoid astrocytoma, 1 atypical teratoid rhabdoid tumour, 1 hemangioma, 1 neurilemmoma, 2 oligodendroglioma). Twenty-six (29%) developed post-operative CMS. Based upon results from univariate analysis and C4.5 decision tree, stepwise logistic regression was used to develop the optimal model and generate risk scores., Results: Univariate analysis identified five significant risk factors and C4.5 decision tree analysis identified six predictors. Variables included in the final model are MRI primary location, bilateral middle cerebellar peduncle involvement (invasion and/or compression), dentate nucleus invasion and age at imaging >12.4 years. This model has an accuracy of 88.8% (79/89). Using risk score cut-off of 203 and 238, respectively, allowed discrimination into low (38/89, predicted CMS probability <3%), intermediate (17/89, predicted CMS probability 3-52%) and high-risk (34/89, predicted CMS probability ≥52%)., Conclusions: A risk stratification model for post-operative paediatric CMS could flag patients at increased or reduced risk pre-operatively which may influence strategies for surgical treatment of cerebellar tumours. Following future testing and prospective validation, this risk scoring scheme will be proposed for use during the surgical consenting process.

Aim: Emergency departments are characterised by a fast-paced, quick turnover and high acuity workload, therefore appropriate staffing is vital to ensure positive patient outcomes. Models of care are frameworks in which safe and effective patient-to-nurse ratios can be ensured. The aim of this study was to implement a supportive and transparent model of emergency nursing care that provides structure - regardless of nursing staff profile, business or other demands; improvement to nursing workloads; and promotes individual responsibility and accountability for patient care., Method: A convergent parallel mixed-method approach was used. Quantitative data were analysed using descriptive statistics and the qualitative data used a thematic analysis to identify recurrent themes., Results: Data post-implementation of the model of emergency nursing care indicate improved staff satisfaction in relation to workload, patient care and support structures., Conclusion: The development and implementation of a model of care in an emergency department improved staff workload and staff's perception of their ability to provide care., Competing Interests: None declared, (©2017 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.)

Intermittent change in ventricular size in patients with ventriculo-peritoneal shunts is a recognised complication but definitive imaging evidence is rare. We report a 3 years old boy with a medullary astrocytoma and ventriculo-peritoneal shunt placement who demonstrated intermittent ventriculomegaly during a single MRI scan.

Pseudokinases and pseudophosphatases possess the ability to bind substrates without catalyzing their modification, thereby providing a mechanism to recruit potential phosphotargets away from active enzymes. Since many of these pseudoenzymes possess other characteristics such as localization signals, separate catalytic sites, and protein-protein interaction domains, they have the capacity to influence signaling dynamics in local environments. In a similar manner, the targeting of signaling enzymes to subcellular locations by A-kinase-anchoring proteins (AKAPs) allows for precise and local control of second messenger signaling events. Here, we will discuss how pseudoenzymes form 'pseudoscaffolds' and compare and contrast this compartment-specific regulatory role with the signal organization properties of AKAPs. The mitochondria will be the focus of this review, as they are dynamic organelles that influence a broad range of cellular processes such as metabolism, ATP synthesis, and apoptosis., (© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Scapular orientation is highly dependent on axioscapular muscle function. This study examined the impact of neck muscle fatigue on scapular and humeral kinematics in participants with and without subclinical neck pain (SCNP) during humeral elevation., Methods: Ten SCNP and 10 control participants performed three unconstrained trials of dominant arm humeral elevation in the scapular plane to approximately 120 degrees before and after neck extensor muscle fatigue. Three-dimensional scapular and humeral kinematics were measured during the humeral elevation trials., Results: Humeral elevation plane angle showed a significant interaction between groups (SCNP vs controls) and trial (pre- vs post-fatigue) (p=0.001). Controls began the unconstrained humeral elevation task after fatigue in a more abducted position, (p=0.002). Significant baseline differences in scapular rotation existed between the two groups (Posterior/Anterior tilt, p=0.04; Internal/External Rotation, p=0.001)., Discussion: SCNP contributed to altered scapular kinematics. Neck muscle fatigue influenced humeral kinematics in controls but not the SCNP group; suggesting that altered scapular motor control in the SCNP group resulted in an impaired adaption further to the neck muscle fatigue., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

High-cost, medically complex patients have been a challenging population to manage in the US health care system, in terms of both improving health outcomes and containing costs. This paper evaluated the economic impact of Care One, an intensive care management program (data analysis, evaluation, empanelment, specialist disease management, nurse case management, and social support) designed to target the most expensive 1% of patients in a university health care system. Data were collected for a cohort of high-cost, medically complex patients (N = 753) who received care management and a control group (N = 794) of similarly complex health system users who did not receive access to the program. A pre-post empirical model estimated the Care One program to be associated with a per-patient reduction in billed charges of $92,227 (95% confidence interval [CI]: $83,988 to $100,466). A difference-in-difference model, which utilized the control group, estimated a per-patient reduction in billing charges of $44,504 (95% CI: $29,195 to $59,813). Results suggest that care management for high-cost, medically complex patients in primary care can reduce costs compared to a control group. In addition, significant reversion to the mean is found, providing support for the use of a difference-in-difference estimator when evaluating health programs for high-cost, medically complex patients.

Lake Ontario once supported a large complex of Atlantic Salmon (Salmo salar) populations that became extinct prior to scientific study. Since the 1860s, research efforts to conserve and reintroduce a sustainable population of Atlantic Salmon have focused on determining whether Lake Ontario's original salmon populations had migrated to the Atlantic Ocean as part of their lifecycle (anadromy), stayed in the lake year-round (potamodromy), or both. We used stable carbon, nitrogen, and sulfur isotope analyses of archaeological bones and historical museum-archived salmon scales to show that the original salmon populations from Lake Ontario completed their entire lifecycle without migrating to the Atlantic Ocean. With a time depth of more than 500 years, our findings provide a unique baseline with significant potential for informing modern restocking and conservation efforts.