The genomics of sporadic and hereditary colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Over the past three decades, extensive efforts have sought to elucidate the genomic landscape of CRC. These studies reveal that CRC is highly heterogeneous at the molecular level, with different subtypes characterised by distinct somatic mutational profiles, epigenetic aberrations and transcriptomic signatures. This review summarises our current understanding of the genomic and epigenomic alterations implicated in CRC development and progression. Particular focus is given to how characterisation of CRC genomes is leading to more personalised approaches to diagnosis and treatment.

The effects of short-term, progressive exercise training on disease activity in smouldering multiple myeloma and monoclonal gammopathy of undetermined significance: a single-arm pilot study.

BACKGROUND: High levels of physical activity are associated with reduced risk of the blood cancer multiple myeloma (MM). MM is preceded by the asymptomatic stages of monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) which are clinically managed by watchful waiting. A case study (N = 1) of a former elite athlete aged 44 years previously indicated that a multi-modal exercise programme reversed SMM disease activity. To build from this prior case study, the present pilot study firstly examined if short-term exercise training was feasible and safe for a group of MGUS and SMM patients, and secondly investigated the effects on MGUS/SMM disease activity. METHODS: In this single-arm pilot study, N = 20 participants diagnosed with MGUS or SMM were allocated to receive a 16-week progressive exercise programme. Primary outcome measures were feasibility and safety. Secondary outcomes were pre- to post-exercise training changes to blood biomarkers of MGUS and SMM disease activity- monoclonal (M)-protein and free light chains (FLC)- plus cardiorespiratory and functional fitness, body composition, quality of life, blood immunophenotype, and blood biomarkers of inflammation. RESULTS: Fifteen (3 MGUS and 12 SMM) participants completed the exercise programme. Adherence was 91 ± 11%. Compliance was 75 ± 25% overall, with a notable decline in compliance at intensities > 70% V̇O2PEAK. There were no serious adverse events. There were no changes to M-protein (0.0 ± 1.0 g/L, P =.903), involved FLC (+ 1.8 ± 16.8 mg/L, P =.839), or FLC difference (+ 0.2 ± 15.6 mg/L, P =.946) from pre- to post-exercise training. There were pre- to post-exercise training improvements to diastolic blood pressure (- 3 ± 5 mmHg, P =.033), sit-to-stand test performance (+ 5 ± 5 repetitions, P =.002), and energy/fatigue scores (+ 10 ± 15%, P =.026). Other secondary outcomes were unchanged. CONCLUSIONS: A 16-week progressive exercise programme was feasible and safe, but did not reverse MGUS/SMM disease activity, contrasting a prior case study showing that five years of exercise training reversed SMM in a 44-year-old former athlete. Longer exercise interventions should be explored in a group of MGUS/SMM patients, with measurements of disease biomarkers, along with rates of disease progression (i.e., MGUS/SMM to MM). REGISTRATION: https://www.isrctn.com/ISRCTN65527208 (14/05/2018).

A dynamical measure of the black hole mass in a quasar 11 billion years ago.

Tight relationships exist in the local Universe between the central stellar properties of galaxies and the mass of their supermassive black hole (SMBH)1-3. These suggest that galaxies and black holes co-evolve, with the main regulation mechanism being energetic feedback from accretion onto the black hole during its quasar phase4-6. A crucial question is how the relationship between black holes and galaxies evolves with time; a key epoch to examine this relationship is at the peaks of star formation and black hole growth 8-12 billion years ago (redshifts 1-3)7. Here we report a dynamical measurement of the mass of the black hole in a luminous quasar at a redshift of 2, with a look back in time of 11 billion years, by spatially resolving the broad-line region (BLR). We detect a 40-µas (0.31-pc) spatial offset between the red and blue photocentres of the Hα line that traces the velocity gradient of a rotating BLR. The flux and differential phase spectra are well reproduced by a thick, moderately inclined disk of gas clouds within the sphere of influence of a central black hole with a mass of 3.2 × 108 solar masses. Molecular gas data reveal a dynamical mass for the host galaxy of 6 × 1011 solar masses, which indicates an undermassive black hole accreting at a super-Eddington rate. This suggests a host galaxy that grew faster than the SMBH, indicating a delay between galaxy and black hole formation for some systems.

Factors influencing medium- and long-term occupational impact following COVID-19.

BACKGROUND: Significant numbers of individuals struggle to return to work following acute coronavirus disease 2019 (COVID-19). The UK Military developed an integrated medical and occupational pathway (Defence COVID-19 Recovery Service, DCRS) to ensure safe return to work for those with initially severe disease or persistent COVID-19 sequalae. Medical deployment status (MDS) is used to determine ability to perform job role without restriction ('fully deployable', FD) or with limitations ('medically downgraded', MDG). AIMS: To identify which variables differ between those who are FD and MDG 6 months after acute COVID-19. Within the downgraded cohort, a secondary aim is to understand which early factors are associated with persistent downgrading at 12 and 18 months. METHODS: Individuals undergoing DCRS had comprehensive clinical assessment. Following this, their electronic medical records were reviewed and MDS extracted at 6, 12 and 18 months. Fifty-seven predictors taken from DCRS were analysed. Associations were sought between initial and prolonged MDG. RESULTS: Three hundred and twenty-five participants were screened, with 222 included in the initial analysis. Those who were initially downgraded were more likely to have post-acute shortness of breath (SoB), fatigue and exercise intolerance (objective and subjective), cognitive impairment and report mental health symptoms. The presence of fatigue and SoB, cognitive impairment and mental health symptoms was associated with MDG at 12 months, and the latter two, at 18 months. There were also modest associations between cardiopulmonary function and sustained downgrading. CONCLUSIONS: Understanding the factors that are associated with initial and sustained inability to return to work allows individualized, targeted interventions to be utilized.

Academic Department of Military Rehabilitation (ADMR): avoiding the pitfalls of 'the Walker Dip'.

A key research theme identified during the 2021 Strategic Delivery Plan (SDP) for Defence Medical Services (DMS) Research was preventing and treating musculoskeletal injury (MSKI). MSKI is a significant burden to military populations globally, reducing both operational strength and force readiness. It is therefore essential that research is conducted to gain a greater understanding of the epidemiology, aetiology and risk factors associated with MSKI to develop targeted prevention strategies and rehabilitation interventions. The Academic Department of Military Rehabilitation (ADMR) and the recently established MSKI research-theme working group must use a combination of balance and flexibility when coordinating research priorities to ensure they align and reflect both higher level DMS and UK Defence Rehabilitation practitioner-driven priorities. This article describes the response ADMR have taken to meet and align with the requirements of the 2021 SDP.

A moderated mediation analysis on the influence of social support and cognitive flexibility in predicting mental wellbeing in elite sport.

The purpose of this study was to examine the mechanism by which social support influences mental wellbeing. Using the thriving through relationships model to provide a theoretical underpinning, cognitive flexibility was hypothesised as a mediator. Additionally, the research examined the consistency of this pathway between elite athletes, retired athletes, and non-athletes. Survey responses from a sample of 247 participants (n = 49 elite athletes, n = 61 retired athletes, n = 137 convenience sample; of which 127 (51.4%) were males were included in the analysis. Initial mediation analysis revealed a significant indirect pathway from social support to mental wellbeing through cognitive flexibility. Moderated mediation analysis revealed this pathway was significant for retired athletes and the convenience sample, but not for elite athletes. Results provide additional insight into the mechanisms by which social support influences wellbeing. Cognitive flexibility interventions may not be as effective for elite athletes.

Coulomb Blockade in a Nonthermalized Quantum Dot.

We investigate nonequilibrium transport properties of a quantum dot in the Coulomb blockade regime under the condition of negligible inelastic scattering during the dwelling time of the electrons in the dot. Using the quantum kinetic equation we show that the absence of thermalization leads to a double step in the distribution function of electrons on the dot, provided that it is symmetrically coupled to the leads. This drastically changes nonlinear transport through the dot resulting in an additional (compared to the thermalized case) jump in the conductance at voltages close to the charging energy, which could serve as an experimental manifestation of the absence of thermalization.

Head injury in older adults presenting to the ambulance service: who do we convey to the emergency department, and what clinical variables are associated with an intracranial bleed? A retrospective case-control study.

OBJECTIVE: Most older adults with traumatic brain injuries (TBI) reach the emergency department via the ambulance service. Older adults, often with mild TBI symptoms, risk being under-triaged and facing poor outcomes. This study aimed to identify whether sufficient information is available on the scene to an ambulance clinician to identify an older adult at risk of an intracranial haemorrhage following a head injury. METHODS: This was a retrospective case-control observational study involving one regional ambulance service in the UK and eight emergency departments. 3545 patients aged 60 years and over presented to one regional ambulance service with a head injury between the 1st of January 2020 and the 31st of December 2020. The primary outcome was an acute intracranial haemorrhage on head computed tomography (CT) scan in patients conveyed to the emergency department (ED). A secondary outcome was factors associated with conveyance to the ED by the ambulance clinician. RESULTS: In 2020, 2111 patients were conveyed to the ED and 162 patients were found to have an intracranial haemorrhage on their head CT scan. Falls from more than 2 m (adjusted odds ratio (aOR) 3.45, 95% CI 1.78-6.40), chronic kidney disease (CKD) (aOR 2.80, 95% CI 1.25-5.75) and Clopidogrel (aOR 1.98, 95% CI 1.04-3.59) were associated with an intracranial haemorrhage. Conveyance to the ED was associated with patients taking anticoagulant and antiplatelet medication or a visible head injury or head injury symptoms. CONCLUSION: This study highlights that while most older adults with a head injury are conveyed to the ED, only a minority will have an intracranial haemorrhage following their head injury. While mechanisms of injury such as falls from more than 2 m remain a predictor, this work highlights that Clopidogrel and CKD are also associated with an increased odds of tICH in older adults following a head injury. These findings may warrant a review of current ambulance head injury guidelines.

Renal replacement and extracorporeal therapies in critical care: current and future directions.

There are a wide number of indications for extracorporeal therapies in the critical care environment. A common indication seen by the acute physician is continuous renal replacement therapy (CRRT) in a proportion of patients with acute kidney injury. It is therefore important that acute physicians have a sound understanding of the principles of CRRT in the acutely unwell patient. This review will outline the indications for its use, commonly used methods and anticoagulation considerations. It will discuss when to start and stop CRRT as well as describing potential treatment complications. This review will also discuss the role of therapeutic plasma exchange in critical care and novel extracorporeal therapies including blood purification in sepsis and carbon dioxide removal in acute respiratory distress syndrome and acute exacerbations of obstructive lung disease. Extracorporeal membrane oxygenation is outside of the scope of this article.

Ultrasound compared with projection radiography for the detection of soft tissue foreign bodies - A technical note.

INTRODUCTION: Soft tissue foreign bodies (STFBs) present a diagnostic challenge depending on their composition. Untreated complications can arise, namely infection through to loss of function. General (projection) radiography is recommended as the first line imaging examination. However, some STFBs are radiolucent, leading to false negative radiographs. The aim of this in vitro study was to compare ultrasound with projection radiographs for the detection of a range of different types of STFB. METHOD: Ethical approval (for use of participants to evaluate images) was granted by the Higher Education Institute's departmental Ethics Committee. Seven hand phantoms were created from a water, gelatine and psyllium mix. A different STFB (radiolucent and radiopaque) was inserted into six phantoms, with the seventh being a control. Ultrasound and projection radiograph images were generated of each phantom. Participants (academics and radiography students) reviewed all images. RESULTS: 50 responses were received from a study population of approximately 400, (10 academics, 40 students). The ability of ultrasound to detect radiolucent foreign bodies performs well compared with projection radiography: sensitivity 94% versus 9%, specificity 90% versus 88%. For radiopaque foreign bodies the data was more mixed: sensitivity 96% versus 99%, specificity 90% versus 88%. DISCUSSION: These data suggest that ultrasound is superior to projection radiography for the detection of radiolucent STFBs. Limitations include the lack of formal postgraduate ultrasound training within the study population and a lack of simulated bony structure within the hand phantoms. IMPLICATIONS FOR PRACTICE: Ultrasound has the potential to be a useful modality in the detection of STFBs, particularly radiolucent objects. There are associated challenges such as conducting ultrasound in the vicinity of a wound, but further exploration of this application of ultrasound is warranted.

Coulomb staircase in an asymmetrically coupled quantum dot.

We investigate the Coulomb blockade in quantum dots asymmetrically coupled to the leads for an arbitrary voltage bias focusing on the regime where electrons do not thermalise during their dwell time in the dot. By solving the quantum kinetic equation, we show that the current-voltage characteristics are crucially dependent on the ratio of the Fermi energy to charging energy on the dot. In the standard regime when the Fermi energy is large, there is a Coulomb staircase which is practically the same as in the thermalised regime. In the opposite case of the large charging energy, we identify a new regime in which only one step is left in the staircase, and we anticipate experimental confirmation of this finding.

Discontinuity of marginal artery at splenic flexure and rectosigmoid junction: A systematic review and meta-analysis.

AIM: The aim of this study was to provide comprehensive evidence-based assessment of the discontinuity of the marginal artery at the splenic flexure (SF) and the rectosigmoid junction (RSJ). METHOD: A systematic review was conducted of literature published to 26 December 2022 in the electronic databases PubMed, SCOPUS and Web of Science to identify studies eligible for inclusion. Data were extracted and pooled into a meta-analysis using the Metafor package in R. The primary outcomes were the pooled PPEs of the marginal artery at the SF and the RSJ. The secondary outcome was the size of vascular anastomoses. RESULTS: A total of 21 studies (n = 2,864 patients) were included. The marginal artery was present at the splenic flexure in 82% (95% CI: 62-95) of patients. Approximately 81% (95% CI: 63-94%) of patients had a large macroscopic anastomosis, while the remainder (19%) had small bridging ramifications forming the vessel. The marginal artery was present at the RSJ in 82% (95% CI: 70-91%) of patients. CONCLUSION: The marginal artery may be absent at the SF and the RSJ in up to 18% of individuals, which may confer a higher risk of ischaemic colitis. As a result of high interstudy heterogeneity noted in our analysis, further well-powered studies to clarify the prevalence of the marginal artery at the SF and the RSJ, as well as its relationship with other complementary colonic collaterals (intermediate and central mesenteric), are warranted.

UK-wide risk factor study of broiler carcases highly contaminated with Campylobacter.

Campylobacter is a major cause of food poisoning and is typically the most common cause of gastroenteritis in the UK. Data collected at broiler farm and abattoir level, for slaughter batches that were sampled for UK-wide monitoring, were used to generate two epidemiological risk factor models. A total of 483 batches slaughtered between January 2016 and March 2017 were used in the analysis, coming from 19 abattoirs representing more than 85% of UK broiler production. For each selected slaughter batch, one carcase was sampled after primary chilling and 10 randomly sampled birds had caecal samples collected at the evisceration point. Samples were used for Campylobacter identification and quantification. Two multivariable mixed-effects models were designed, one with the binary outcome for the detection of a highly contaminated (>1000 colony forming units (CFU)/g) Campylobacter-positive carcase, whereas the other used the Campylobacter colony count (CFU/g) carcase outcome. The results suggest that caecal colonization within the batch was a key factor for the occurrence of Campylobacter on carcases, and many factors that were identified in the model were also likely to be related to colonization or related to the risk of introduction of Campylobacter from partial depopulation (referred to as thinning) of ~30% of the flock approximately 1 week before full flock depopulation events. The amount of neck skin in the sample was another key factor identified and was included in both models as a risk factor. The models have also identified other factors which may be related to the general health and husbandry on-farm (use of prebiotics or vaccines, and identification of the product used for drinking line cleaning), whereas the other factors may identify control points related to transmission within a farm. The identification of these variables could help focus control efforts on-farm, especially for relatively easy improvements, such as improving the provision of house-specific bird-weighing buckets/cages in houses.

Use of symptom-guided physical activity and exercise rehabilitation for COVID-19 and other postviral conditions.

There are many similarities in symptoms between postviral conditions, including clinical features such as fatigue, reduced daily activity and postexertional symptom exacerbation. Unfavourable responses to exercise have influenced the wider debate on how to reintegrate physical activity (PA) and exercise while simultaneously managing symptoms during recovery from post-COVID-19 syndrome (or Long COVID). This has resulted in inconsistent advice from the scientific and clinical rehabilitation community on how and when to resume PA and exercise following COVID-19 illness. This article provides commentary on the following topics: (1) controversies surrounding graded exercise therapy as a treatment modality for post-COVID-19 rehabilitation; (2) evidence supporting PA promotion, resistance exercise and cardiorespiratory fitness for population health, and the consequences of physical inactivity in patients with complex rehabilitation needs; (3) population-based challenges for UK Defence Rehabilitation practitioners for the management of postviral conditions; and (4) 'symptom guided PA and exercise rehabilitation' as an appropriate treatment option for managing individuals with multifaceted medical needs.

Evaluation of the current guidelines for the management of haemorrhoidal disease using the Appraisal of Guidelines Research and Evaluation II instrument.

Background: Haemorrhoids are a very common disease and many professional societies have produced guidelines for their treatment. The aim of this study is to appraise the quality of the existing guidelines in the management of haemorrhoids. Methods: A systematic search of the literature was conducted in the EMBASE, Google Scholar, Cochrane library, and PubMed databases. The quality of guidelines was independently appraised using the Appraisal of Guidelines Research and Evaluation II (AGREE II) instrument by five of the authors. Results: Six guidelines of varying quality were identified and included in this study. The highest scoring guidelines were the SICCR (Società Italiana di Chirurgia Colorectale, which is Italian Society of Colorectal Surgery), ESCP (European Society of Coloproctology) and ASCRS (American Society of Colon and Rectal Surgeons) guidelines, scoring 86% each overall. There was considerable variability across not just the studies but across the different domains. The highest scoring domains were domain VI: editorial independence (median =95% across all studies) and domain I: Scope & Purpose (85%). The lowest scores were observed in domain V: Applicability (48%) and domain II: Stakeholder Involvement (41%). Only three of the six gained unanimous support for their use, whilst two of the guidelines were unanimously declared not suitable for clinical use. Conclusions: With the notable exception of three guidelines (SICCR, ESCP and ASCRS), the general quality of haemorrhoid guidelines is poor. Stakeholder (especially patient) involvement and instructions on how to implement recommendations is lacking from the majority of guidelines. This is an area that requires urgent attention if we are to improve guidelines in haemorrhoid management.

Changing characteristics of post-COVID-19 syndrome: Cross-sectional findings from 458 consultations using the Stanford Hall remote rehabilitation assessment tool.

BACKGROUND: In the UK, there have been multiple waves of COVID-19, with a five-tier alert system created to describe the transmission rate and appropriate restrictions. While acute mortality decreased, there continued to be a significant morbidity, with individuals suffering from persistent, life-restricting symptoms for months to years afterwards. A remote rehabilitation tool was created at the Defence Medical Rehabilitation Centre (DMRC) Stanford Hall to assess post-COVID-19 symptoms and their impact on the UK military.This study aims to understand changes in post-COVID-19 syndrome between wave 1 and wave 2, identify interactions between alert level and symptoms and investigate any predictive nature of acute symptoms for postacute symptomology in a young, physically active population. METHODS: Cross-sectional study of 458 consecutive remote rehabilitation assessments performed at DMRC Stanford Hall between 2 April 2020 and 29 July 2021. Consultations were coded, anonymised, and statistical analysis was performed to determine associations between acute and postacute symptoms, and between symptoms, alert levels and waves. RESULTS: 435 assessments were eligible; 174 in wave 1 and 261 in wave 2. Post-COVID-19 syndrome prevalence reduced from 43% to 2% between the waves. Acutely, widespread pain was more prevalent in wave 2 (p<0.001). Postacutely, there was increased anxiety (p=0.10) in wave 1 and increased sleep disturbance (p<0.001), memory/concentration issues (p<0.001) and shortness of breath/cough (p=0.017) in wave 2. Increasing alert level was associated with increased postacute symptom prevalence (p=0.046), with sleep disturbance increasing at higher alert level (p=0.016). Acute symptoms, including fatigue, sleep disturbance and myalgia, were associated with multiple postacute symptoms. CONCLUSIONS: This study reports the overall prevalence and symptom burden in the UK military in the first two waves of COVID-19. By reporting differences in COVID-19 in different waves and alert level, this study highlights the importance of careful assessment and contextual understanding of acute and postacute illnesses for individual management plans.

Defence Medical Rehabilitation Centre (DMRC) COVID-19 Recovery Service.

Coronavirus disease 2019 (COVID-19) causes significant mortality and morbidity, with an unknown impact in the medium to long term. Evidence from previous coronavirus epidemics indicates that there is likely to be a substantial burden of disease, potentially even in those with a mild acute illness. The clinical and occupational effects of COVID-19 are likely to impact on the operational effectiveness of the Armed Forces. Collaboration between Defence Primary Healthcare, Defence Secondary Healthcare, Defence Rehabilitation and Defence Occupational Medicine resulted in the Defence Medical Rehabilitation Centre COVID-19 Recovery Service (DCRS). This integrated clinical and occupational pathway uses cardiopulmonary assessment as a cornerstone to identify, diagnose and manage post-COVID-19 pathology.