Association of distal adenomas and hyperplastic polyp characteristics with long-term proximal colon cancer risk: a secondary, observational analysis of data from the UK Flexible Sigmoidoscopy Screening Trial

Objectives Colorectal cancer screening with flexible sigmoidoscopy focuses on the distal colorectum but it is unclear which distal polyps characteristics are associated with future proximal colon cancer incidence. We examined associations between distal adenoma or hyperplastic polyp characteristics and long-term incident proximal colon cancer. Methods In secondary, observational analyses of UK Flexible Sigmoidoscopy Screening Trial data, we obtained data on number and size of distal hyperplastic polyps (n=4,872) and adenomas (n=4,581), adenoma histology and dysplasia from endoscopy and pathology reports for screened asymptomatic participants. Adjusted hazard ratios (HR) and 95% confidence intervals (CIs) for the association between distal polyp characteristics and proximal colon cancer incidence were estimated using multivariable Cox proportional hazard models. Results Over a median of 20.7 years of follow-up (IQR 16.5–21.7), 110 proximal colon cancers were diagnosed among participants with distal adenomas and 96 were diagnosed among those with only distal hyperplastic polyps detected at baseline. Larger adenoma size (6-9mm vs. ≤5mm: HR 1.67 [95%CI: 1.07–2.59] and ≥10mm vs. ≤5mm: HR 2.08 [95%CI: 0.98–4.43]; p=0.037) and high-grade (vs. low-grade) adenoma dysplasia (HR 2.82, 95%CI: 1.34-5.93; p=0.012) at baseline were positively associated with proximal colon cancer incidence. No associations were observed for the number or histology of distal adenomas or the number or size of hyperplastic polyps and proximal colon cancer incidence. Conclusions We found some evidence that larger distal adenomas and those with high-grade dysplasia at baseline were positively associated with proximal colon cancer incidence. Larger studies are needed to confirm these findings

Rate-induced phenomena in dynamical systems with attracting limit cycles

We study the behaviour of dynamical systems under a time-dependent change of an external parameter. We are interested in phenomena induced by the parameter changing sufficiently quickly, and we refer to these as rate-induced phenomena. We investigate such rate-induced phenomena in continuous-time planar dynamical systems, where the underlying fixed-parameter autonomous dynamics have limit cycles attractors, extending the work of Alkhayuon and Ashwin [1]. We discover a new phenomena of rate-induced phase sensitivity, where the rate at which the parameter changes can trigger finite-time unpredictability in the dynamics. We also find that this new phenomenon interacts in an interesting way with the established notion of rate-induced tipping

A survey of the current experience of colonoscopy training for colorectal surgical trainees in the United Kingdom

Introduction The primary aim was to understand the current experience of colonoscopy training among general surgical trainees with a subspeciality interest in colorectal surgery. Methods An electronic survey was developed and disseminated by members of the Dukes’ Club (colorectal trainees network) and Association of Coloproctologists of Great Britain and Ireland (ACPGBI) colonoscopy subcommittee between February and April 2024 to assess key themes identified through formal and informal feedback from colorectal trainees of endoscopy training experience. Results The survey was completed by 196 participants.This included 13.3% from CT2-ST4, 28.6% from ST5-6, 36.5% from ST7-8, 13.3% from post CCT fellows, senior clinical fellows and SAS doctors and 8.7% from early years consultants. The median number of colonoscopies performed by respondents was 121.6 (range 0-8,000). Only 33.7% (66/196) reported having one dedicated training list per week and 56.6% (111/196) were not allocated to any regular training list. The barriers to training were service provision (71.9%), lack of dedicated training lists (69.9%) and access to training lists due to other trainees or health care professionals (42.3%). Only 25% of respondents had experience of immersion training but they consistently reported high numbers of colonoscopy during these periods, with 40% achieving more than 30 colonoscopies. Conslusion There is an urgent need to improve access to colonoscopy training. Regular endoscopy training lists and funding of academies and immersion training centrally are likely to greatly improve experience of colonoscopy training. Senior colorectral trainees should be prioritised to avoid delay in completion of training

Statistical learning to identify and characterise neurodevelopmental outcomes at 2 years in babies born preterm: model development and validation using population-level data from England and Wales

Background Children born preterm face elevated risks of neurodevelopmental impairments across domains. Prior studies have relied on expert-imposed typologies within single domains. This study applies statistical learning to a national database to identify transdomain clusters and their maternal and neonatal predictors. Methods Latent class analysis (LCA) was used to derive transdomain clusters from parent-reported visual, auditory, neuromotor, and communication impairments in preterm-born children at two years corrected age using the UK National Neonatal Research Database data (N=27,261). Replication was conducted in an independent sample from Wales (N=975). Clusters were clinically validated using cerebral palsy diagnosis, Bayley Scales of Infant and Toddler Development (3rd edition), and global neurodevelopmental delay. Random forest identified cluster-specific and shared predictors. Findings Four homogeneous clusters were derived (silhouette score = 0.71) and replicated in Wales with high balanced accuracy (93%): (1) typically developing (84.8%), (2) communication impairments (8.4%), (3) neuro-motor impairments (4.1%), and (4) multiple neuro-morbidity (2.7%). Clusters had high clinical validity and were distinguishable by shared and cluster-specific predictors. Neonatal brain injuries were most predictive of neuro-motor and multiple neuro-morbidity clusters. Birthweight, gestational age, socio-economic deprivation, and sex were stronger predictors of the communication cluster than preterm co-morbidities. Interpretation This study provides first evidence of the transdomain nature of neurodevelopmental impairments after preterm birth using LCA. The finding that socio-demographic and perinatal factors rather than co-morbidities increase the risk of communication impairment highlights the importance of environmental modification alongside clinical interventions. Applying data-driven approaches to routinely collected data may offer a cost-effective way to stratify at-risk children and inform targeted support strategies. Funding UKRI Medical Research Council

SpbR controls lipoteichoic acid length by directly inhibiting signal peptidase SpsB in <i>Staphylococcus aureus<i>

Staphylococcus aureus is a Gram-positive pathogen that causes life threatening infections. Its cell envelope contains anionic polymers called teichoic acids that are required for cell viability. Teichoic acids come in two forms and are made by different biosynthetic pathways. One form, lipoteichoic acid (LTA), is anchored in the cell membrane; the other form, wall teichoic acid (WTA), is covalently linked to the peptidoglycan cell wall. Although the LTA and WTA biosynthetic pathways have been characterized, regulation of teichoic acid production is not well understood. Here, we identified SpbR (SAOUHSC_00965), a polytopic membrane protein similar to a eukaryotic CAAX protease, as a new factor that controls LTA levels in S. aureus cells. We show that loss of SpbR results in short LTAs and a synthetically sick phenotype when WTA biosynthesis is prevented, whereas overexpressing SpbR results in elongated LTAs. Mechanistically, we find that SpbR physically associates with the type I signal peptidase SpsB, which cleaves LtaS, the polymerase that assembles LTA on the extracellular side of the membrane, and we show that this physical interaction inhibits SpsB cleavage of LtaS both in vivo and in vitro. Although the phenotypes investigated here are dominated by SpbR’s effects on LtaS, it also inhibits cleavage of other SpsB substrates. Based on its role in regulating the activity of SpsB, we named this factor SpbR (Signal peptidase b Regulator). To the best of our knowledge, SpbR is the first known factor that directly modulates the activity of a type I signal peptidase in bacteria

The relationship of baseline high-sensitivity C-reactive protein with incident cardiovascular events and all-cause mortality over 20 years

Background: The prediction of future cardiovascular events in those with risk factors is important for the appropriate optimisation of preventative therapies for those at greatest risk. The value of high sensitivity C-reactive Protein (hsCRP) has been questioned in this regard. The objectives of this post-hoc analysis of a randomised controlled trial were to investigate the usefulness of baseline serum hsCRP for predicting very long-term cardiovascular events in patients with hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy Study. Methods: The ASCOT Legacy Study reports events up to 20 years of follow-up of the UK participants in the Lipid Lowering Arm of the original ASCOT trial. We examined outcomes related to serum hsCRP levels measured using a commercial ELISA, in tertiles or continuously, adjusting for classical cardiovascular risk factors as well as treatment allocation within ASCOT. The primary outcome was non-fatal myocardial infarction (MI) and fatal coronary heart disease (CHD); whilst secondary outcomes were all-cause mortality, total coronary events and procedures, total cardiovascular events and stroke. Findings: After excluding 3286 participants without hsCRP data, 5294 participants were included in the final cohort. The highest tertile of hsCRP was associated with the following outcomes compared to the lowest tertile: non-fatal myocardial infarction (MI) and fatal CHD (HR 1.32 [1.05–1.67]); total coronary events and procedures (HR 1.27 [1.09–1.47]); total cardiovascular events (HR 1.22 [1.08–1.37]); and all-cause mortality (HR 1.25 [1.10–1.42]). However, there was insufficient evidence regarding the association between hsCRP levels and stroke events. Addition of hsCRP in tertiles resulted in an improved net reclassification index for the prediction of non-fatal MI and fatal CHD at 20 years (9.68%, p < 0.0001). Interpretation: Higher baseline serum hsCRP levels can independently predict cardiovascular events and all-cause mortality at long-term follow-up in stable patients with hypertension. Funding: British Heart Foundation Clinical Research Fellowship (FS/17/16/32560), Wellcome Trust Clinical Research Fellowship (220572/Z/20/Z), and Sansour Fund at Imperial Healthcare Charity. The substudy of ASCOT Biomarker Programme was supported by Pfizer, New York, NY, USA. Infrastructure support was provided by the NIHR Imperial Biomedical Research Centre as well as the Imperial British Heart Foundation Research Excellence Award (4) (RE/24/130023)

Perinatal mental health in India in the states of Haryana and Telangana: a district level situational analysis

Background: Women in the perinatal phase are at an increased risk of experiencing mental health problems, but in low and middle-income countries such as India, perinatal mental health (PMH) care provision is often scarce. This situational analysis presents the formative findings of the SMARThealth Pregnancy and Mental Health (PRAMH) project (Votruba et al.). It investigates the nature and availability of maternal mental health policies, legislation, systems, and services, as well as relevant context and community in India on a national, state (Haryana and Telangana) and district (Faridabad and Siddipet) level. Findings : A desktop, scoping review and informal interviews with mental health experts were conducted. Socio-demographic and maternal health indicators vary between Haryana and Telangana. No specific national PMH policy or plan is available. General mental health services exist at a district level within Siddipet and Faridabad but no specific PMH services have been identified. Implications: National and state level plans and policies will be critical in establishing services to bridge the existing PMH treatment gap. The findings from this situational analysis will inform the development of a future intervention for PMH in rural communities in Telangana and Haryana

A comment on monetary policy and rational asset price bubbles

Gal´ı (2014) showed that a monetary policy rule that raises interest rates when bubbles exceed some steady-state benchmark can paradoxically lead to larger deviations from that steady state. This comment shows that a central bank that wants to dampen the current value of a bubble can always do so by setting a higher-than-expected interest rate, although it may have to raise the rate aggressively. This is a different point from the one in the Miao, Shen and Wang (2019) comment on Gal´ı’s paper. They showed that when the central bank targets a different steady state than the one Gal´ı considered, raising interest rates when bubbles exceed this alternative steady-state leads to (weakly) smaller deviations from steady state. We study how the set of equilibria changes when a central bank sets an interest rate above what markets expect rather than when it sets out to target a different steady state

Enhancing autophagy by redox regulation extends lifespan in Drosophila

Dysregulation of redox homeostasis is implicated in the ageing process and the pathology of age-related diseases. To study redox signalling by H2O2 in vivo, we established a redox-shifted model by manipulating levels of the H2O2-degrading enzyme catalase in Drosophila. Here we report that ubiquitous over-expression of catalase robustly extends lifespan in females. As anticipated, these flies are strongly resistant to a range of oxidative stress challenges, but interestingly are sensitive to starvation, which could not be explained by differences in levels of energy reserves. This led us to explore the contribution of autophagy, which is an important mechanism for organismal survival in response to starvation. We show that autophagy is essential for the increased lifespan upon catalase up-regulation, as the survival benefits are completely abolished upon global autophagy knock-down. Furthermore, using a specific redox-inactive knock-in mutant, we highlight the in vivo role of a key regulatory cysteine residue in Atg4a, which is required for the lifespan extension in our catalase model. Altogether, these findings confirm the redox regulation of autophagy in vivo as an important modulator of longevity

Are food taxes for healthy eating acceptable? A survey of public attitudes in the UK

Introduction Appropriately designed food taxes can improve diet quality and health. Fiscal levers are used in several countries to combat the rise in obesity and diet-related diseases. This study aims to investigate public attitudes, knowledge and policy preferences regarding food taxes for promoting healthy eating in the UK. Methods A survey was administered through YouGov Plc to a nationally representative sample of 2125 adults, gathering information on: acceptability and support for different types of food taxes, awareness and knowledge of existing taxes and preferences for the characteristics of possible new taxes. Results Overall, 48% of respondents support higher taxes on unhealthy foods, rising to 72% if taxes made healthy foods more affordable. Respondents with high socioeconomic status and those living in London showed the highest support. Respondents had limited awareness of existing food and beverage taxes and prioritised discretionary items such as cakes and crisps for possible increased taxation. Conclusions The survey shows a high level of support for taxing unhealthy foods, as well as concern for the affordability of healthy foods. A carefully designed holistic approach to food taxation can be part of a wider public health strategy and can be favourably met by the general population in the UK