New role of fat-free mass in cancer risk linked with genetic predisposition.

Cancer risk is associated with the widely debated measure body mass index (BMI). Fat mass and fat-free mass measurements from bioelectrical impedance may further clarify this association. The UK Biobank is a rare resource in which bioelectrical impedance and BMI data was collected on ~ 500,000 individuals. Using this dataset, a comprehensive analysis using regression, principal component and genome-wide genetic association, provided multiple levels of evidence that increasing whole body fat (WBFM) and fat-free mass (WBFFM) are both associated with increased post-menopausal breast cancer risk, and colorectal cancer risk in men. WBFM was inversely associated with prostate cancer. We also identified rs615029[T] and rs1485995[G] as associated in independent analyses with both PMBC (p = 1.56E-17 and 1.78E-11) and WBFFM (p = 2.88E-08 and 8.24E-12), highlighting splice variants of the intriguing long non-coding RNA CUPID1 (LINC01488) as a potential link between PMBC risk and fat-free mass.

Twelve tips for designing and implementing peer-led assessment writing schemes in health professions education.

Peer-led assessment (PLA) has gained increasing prominence within health professions education as an effective means of engaging learners in the process of assessment writing and practice. Involving students in various stages of the assessment lifecycle, including item writing, quality assurance, and feedback, not only facilitates the creation of high-quality item banks with minimal faculty input but also promotes the development of students' assessment literacy and fosters their growth as teachers. The advantages of involving students in the generation of assessments are evident from a pedagogical standpoint, benefiting both students and faculty. However, faculty members may face uncertainty when it comes to implementing such approaches effectively. To address this concern, this paper presents twelve tips that offer guidance on important considerations for the successful implementation of peer-led assessment schemes in the context of health professions education.

Diversity of thought: public perceptions of genetic testing across ethnic groups in the UK.

Genetic testing is becoming rapidly more accessible to the general populous either through or outside healthcare systems. Few large-scale studies have been carried out to gauge public opinion in this growing area. Here, we undertook the largest cross-sectional study on genetic testing in the UK. The primary purpose of this study is to identify the differences in attitudes toward genetic testing across ethnic groups. A cohort of 6500 individuals from a diverse population completed a 72-item survey in a cross-sectional study. Responses between ethnic minority and white individuals in the UK were compared using a wilcoxon rank-sum and chi-square tests. The white cohort was approximately twice as likely to have taken a genetic test and 13% more had heard about genetic testing before the survey. The ethnic minority cohort appeared more apprehensive about the impact of genetic testing on employability. This study highlights that in the UK, significant differences in opinions regarding genetic testing exist between white individuals and ethnic minority individuals. There is an urgent need to develop more inclusive strategies to equally inform individuals from all backgrounds to avoid disparities in the utilisation of genetic testing.

Obesity: a perfect storm for carcinogenesis.

Obesity-related cancers account for 40% of the cancer cases observed in the USA and obesity is overtaking smoking as the most widespread modifiable risk factor for carcinogenesis. Here, we use the hallmarks of cancer framework to delineate how obesity might influence the carcinogenic hallmarks in somatic cells. We discuss the effects of obesity on (a) sustaining proliferative signaling; (b) evading growth suppressors; (c) resisting cell death; (d) enabling replicative immortality; (e) inducing angiogenesis; (f) activating invasion and metastasis; (g) reprogramming energy metabolism; and (h) avoiding immune destruction, together with its effects on genome instability and tumour-promoting inflammation. We present the current understanding and controversies in this evolving field, and highlight some areas in need of further cross-disciplinary focus. For instance, the relative importance of the many potentially causative obesity-related factors is unclear for each type of malignancy. Even within a single tumour type, it is currently unknown whether one obesity-related factor consistently plays a predominant role, or if this varies between patients or, even in a single patient with time. Clarifying how the hallmarks are affected by obesity may lead to novel prevention and treatment strategies for the increasingly obese population.

Cytokine changes in cerebrospinal fluid following vascular surgery on the thoracic aorta.

There is growing evidence that surgery can drive an inflammatory response in the brain. However, the mechanisms behind this response are incompletely understood. Here, we investigate the hypotheses that 1. Cerebrospinal fluid (CSF) cytokines increase after vascular surgery and 2. That these changes in CSF cytokines are interrelated. Patients undergoing either open or endovascular elective surgery of the thoracic aorta were invited to participate in this study. Cerebrospinal fluid samples were taken before surgery and on the first post-operative day. These were analysed for the presence of ten cytokines by immunoassay to examine for post-operative changes in cytokine levels. After surgery, there were significant increases in six out of the ten measured CSF cytokines (IL-1ß, 2, 6, 8, 10 and 13). This included changes in both putative pro-inflammatory (IL-1ß, 6 and 8) and putative anti-inflammatory (IL-2, 10 and 13) cytokines. The greatest increases occurred in IL-6 and IL-8, which showed a 63-fold and a 31-fold increase respectively. There was strong intercorrelation between CSF cytokines after the operation. Following surgery on the thoracic aorta, there was a marked increase in CSF cytokines, consistent with a potential role in neuroinflammation. The ten measured cytokines showed intercorrelation after the operation, indicating that a balance between multiple pro- and anti-inflammatory cytokines may be present.

Cytokine changes in cerebrospinal fluid and plasma after emergency orthopaedic surgery.

Neuroinflammation after surgery and its contribution to peri-operative neurocognitive disorders (PND) is not well understood. Studying the association between central and peripheral cytokines and neuroinflammation is a prelude to the development of treatments for PND. Here, we investigate the hypotheses that there is a greater cytokine response in cerebrospinal fluid (CSF) than plasma after orthopaedic surgery, and that plasma cytokine levels are directly related to CSF cytokine levels, indicating that plasma cytokine levels may have potential as biomarkers of neuroinflammation. Patients admitted with a fractured neck of femur were invited to participate in this study. Participants had a spinal catheter inserted just prior to induction of anaesthesia. Samples of blood and CSF were taken before, immediately after, and on the first day following emergency surgery. The catheter was then removed. Samples were analysed for the presence of ten cytokines by immunoassay. A spinal catheter was successfully inserted in 11 participants during the 18-month study period. Five plasma cytokines (IL-4, IL-6, IL-10, IL-12p70 and IL-13) rose significantly following surgery, whereas all ten CSF cytokines rose significantly (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IFN-γ and TNF-α) (adjusted-p < 0.05). Central (CSF) cytokine levels were consistently higher than their peripheral (plasma) counterparts after surgery, with some patients having a particularly marked neuroinflammatory response. The greatest increases occurred in IL-8 in CSF and IL-6 in plasma. There were significant, strong positive correlations between several of the measured cytokines in the CSF after surgery, but far fewer in plasma. There was no significant correlation between cytokine levels in the plasma and CSF at each of the three time points. To our knowledge, this is the first study to analyse paired samples of plasma and CSF for cytokine levels before and after emergency orthopaedic surgery. This study demonstrates that following surgery for a fractured neck of femur, there is a far greater rise in cytokines in the CSF compared to plasma. The lack of correlation between peripheral and central cytokines suggests measurement of peripheral cytokines are not necessarily related to which patients may have a large neuroinflammatory response.

Detection and quantification of antibody to SARS CoV 2 receptor binding domain provides enhanced sensitivity, specificity and utility.

Accurate and sensitive detection of antibody to SARS-CoV-2 remains an essential component of the pandemic response. Measuring antibody that predicts neutralising activity and the vaccine response is an absolute requirement for laboratory-based confirmatory and reference activity. The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA), providing the most sensitive format has been exploited in a novel hybrid manner employing a solid-phase S1 preferentially presenting RBD, coupled with a labelled RBD conjugate, used in a two-step sequential assay for detection and measurement of antibody to RBD (anti-RBD). This class and species neutral assay showed a specificity of 100 % on 825 pre COVID-19 samples and a potential sensitivity of 99.6 % on 276 recovery samples, predicting quantitatively the presence of neutralising antibody determined by pseudo-type neutralization and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine and in humans immunised with both AstraZeneca and Pfizer vaccines. This assay detects anti-RBD at presentation with illness, demonstrates its elevation with disease severity, its sequel to asymptomatic infection and its persistence after the loss of antibody to the nucleoprotein (anti-NP). It also provides serological confirmation of prior infection and offers a secure measure for seroprevalence and studies of vaccine immunisation in human and animal populations. The hybrid DABA also displays the attributes necessary for the detection and quantification of anti-RBD to be used in clinical practice. An absence of detectable anti-RBD by this assay predicates the need for passive immune prophylaxis in at-risk patients.

The Association Between Antibody Response to Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Post-COVID-19 Syndrome in Healthcare Workers.

It is currently unknown how post-COVID-19 syndrome (PCS) may affect those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This longitudinal study includes healthcare staff who tested positive for SARS-CoV-2 between March and April 2020, with follow-up of their antibody titers and symptoms. More than half (21 of 38) had PCS after 7-8 months. There was no statistically significant difference between initial reverse-transcription polymerase chain reaction titers or serial antibody levels between those who did and those who did not develop PCS. This study highlights the relative commonality of PCS in healthcare workers and this should be considered in vaccination scheduling and workforce planning to allow adequate frontline staffing numbers.

Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non-Small Cell Lung Cancer.

PURPOSE: Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed. RESULTS: Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change -28% [95% confidence interval (CI), -58.2 to -4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, -6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%-74%) lower in cohort 1 compared with cohort 2 (P = 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported. CONCLUSIONS: This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.

Asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in a Rehabilitation Facility: Evolution of the Presence of Nasopharyngeal SARS-CoV-2 and Serological Antibody Responses.

At the start of the UK coronavirus disease 2019 epidemic, this rare point prevalence study revealed that one-third of patients (15 of 45) in a London inpatient rehabilitation unit were found to be infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but asymptomatic. We report on 8 patients in detail, including their clinical stability, the evolution of their nasopharyngeal viral reverse-transcription polymerase chain reaction (RT-PCR) burden, and their antibody levels over time, revealing the infection dynamics by RT-PCR and serology during the acute phase. Notably, a novel serological test for antibodies against the receptor binding domain of SARS-CoV-2 showed that 100% of our asymptomatic cohort remained seropositive 3-6 weeks after diagnosis.

Pediatric Drowning: A Standard Operating Procedure to Aid the Prehospital Management of Pediatric Cardiac Arrest Resulting From Submersion.

OBJECTIVES: Drowning is one of the leading causes of death in children. Resuscitating a child following submersion is a high-pressure situation, and standard operating procedures can reduce error. Currently, the Resuscitation Council UK guidance does not include a standard operating procedure on pediatric drowning. The objective of this project was to design a standard operating procedure to improve outcomes of drowned children. METHODS: A literature review on the management of pediatric drowning was conducted. Relevant publications were used to develop a standard operating procedure for management of pediatric drowning. RESULTS: A concise standard operating procedure was developed for resuscitation following pediatric submersion. Specific recommendations include the following: the Heimlich maneuver should not be used in this context; however, prolonged resuscitation and therapeutic hypothermia are recommended. CONCLUSIONS: This standard operating procedure is a potentially useful adjunct to the Resuscitation Council UK guidance and should be considered for incorporation into its next iteration.

Formative student-authored question bank: perceptions, question quality and association with summative performance.

PURPOSE OF THE STUDY: There are few studies on the value of authoring questions as a study method, the quality of the questions produced by students and student perceptions of student-authored question banks. Here we evaluate PeerWise, a widely used and free online resource that allows students to author, answer and discuss multiple-choice questions. STUDY DESIGN: We introduced two undergraduate medical student cohorts to PeerWise (n=603). We looked at their patterns of PeerWise usage; identified associations between student engagement and summative exam performance; and used focus groups to assess student perceptions of the value of PeerWise for learning. We undertook item analysis to assess question difficulty and quality. RESULTS: Over two academic years, the two cohorts wrote 4671 questions, answered questions 606 658 times and posted 7735 comments. Question writing frequency correlated most strongly with summative performance (Spearman's rank: 0.24, p=<0.001). Student focus groups found that: (1) students valued curriculum specificity; and (2) students were concerned about student-authored question quality. Only two questions of the 300 'most-answered' questions analysed had an unacceptable discriminatory value (point-biserial correlation <0.2). CONCLUSIONS: Item analysis suggested acceptable question quality despite student concerns. Quantitative and qualitative methods indicated that PeerWise is a valuable study tool.

And you try and tell the medical students of today that and they won't believe ya.

Older clinicians typically engage in reflections on their own early careers and indeed whichever generation of clinician you talk to, their medical school and early career experiences were more challenging than the last. We draw on inspiration from Monty Python and specifically the Four Yorkshiremen to illustrate this point. However, as we strive to lay the foundations of learning that avoids the adage 'whatever doesn't kill you, makes you stronger', we must remember that medics are competitive… even at complaining.

A novel student-led approach to multiple-choice question generation and online database creation, with targeted clinician input.

PROBLEM: Multiple-choice questions (MCQs) are the main method of assessing medical student knowledge. As a result there is a high demand from medical students for formative MCQs. However, teaching staff rarely have the time or incentive to develop high-quality formative questions, focusing instead on material for high-stakes assessments. INTERVENTION: We have developed a novel student-led approach involving an interactive online question database, created by medical students for medical students. We adopted a staged approach to create an online bank of formative MCQ questions. First, students write MCQs following a standardized format. Questions are then peer-reviewed by other students, discussing relevant clinical topics, guidelines, and journals to improve question quality. The questions are then scrutinized by specialist doctors and academics. Next, questions are piloted online. Finally, question performance is evaluated statistically. This 5-stage student-led process produced a bank of more than 200 MCQs in three months. CONTEXT: This intervention was carried out by two final-year medical student leads at Cardiff University School of Medicine, UK. Final-year students were recruited to write and peer-review questions, and senior content specialists were recruited from the department. After piloting and evaluation of the questions, the question bank was made available as a learning resource to all medical students at Cardiff University. OUTCOME: Objective analysis of the created MCQs (discrimination indices and distractor analysis) indicated that the random sample of questions piloted were of high quality. When the questions were made available as online tests to approximately 600 students, usage data revealed that 2,800 tests were taken over a 3-month period, indicating that the resource was popular. In addition, subjective feedback from students question writers/reviewers was gathered via free text feedback forms and was invariably positive. We plan to continue the question generation process in Cardiff and would encourage other medical schools to adopt this approach. LESSONS LEARNED: Our 5-stage approach can generate a large volume of high-quality MCQs, addressing the demand from students for formative MCQ questions, with minimal teaching staff input. The project's benefits go beyond the creation of the resource, as involving students in the writing, review, and presentation of questions itself is useful pedagogically.

UK medical selection: lottery or meritocracy?

From senior school through to consultancy, a plethora of assessments shape medical careers. Multiple methods of assessment are used to discriminate between applicants. Medical selection in the UK appears to be moving increasingly towards non-knowledge-based testing at all career stages. We review the evidence for non-knowledge-based tests and discuss their perceived benefits. We raise the question: is the current use of non-knowledge-based tests within the UK at risk of undermining more robust measures of medical school and postgraduate performance?