The impact of adverse childhood experiences on DNA methylation age: a systematic review and meta-analysis.

Adverse childhood experiences (ACEs), such as abuse and neglect, are associated with poor health in adulthood. One proposed biological mechanism linking early adversity to health outcomes is epigenetic age acceleration (EAA), a measure of biological aging derived from DNA methylation. Understanding whether ACEs contribute to EAA might identify pathways linking early life stress to increased risk of morbidity and mortality.This systematic review and meta-analysis examined the relationship between cumulative ACE exposure and EAA in adults across 27 eligible observational studies from 1036 identified by comprehensive screening of the literature. Studies involved more female participants (median 56.6%) and employed a range of epigenetic clocks, most frequently Horvath, GrimAge, and PhenoAge. Risk of bias was assessed using the ROBINS-E tool, with most studies rated as having some concerns, primarily due to a lack of adjustment for key covariates. Meta-analyses of 6 studies using cumulative ACE exposure and standardised regression coefficients revealed no significant associations with EAA for first-generation clocks (Horvath: β =  - 0.03, 95% CI - 0.15 to 0.09; Hannum: β =  - 0.09, 95% CI - 0.41 to 0.23) or second-generation clocks (PhenoAge and GrimAge: both β = 0.21, 95% CIs spanning zero). Narrative synthesis of studies, including those that could not be considered in the meta-analyses, highlighted heterogeneous methodologies and mixed findings, particularly for individual ACEs and third generation clocks such as DunedinPACE. These findings suggest that while ACEs may influence biological aging, current evidence does not support a robust or consistent association with EAA. The study identifies the need for more consistent methodologies in future research

The UK Soft Drink Industry Levy and Inequalities in Caries-Related Extractions

This study evaluated the impact of the Soft Drinks Industry Levy (SDIL) on socioeconomic inequalities in hospital admissions for caries-related extractions in England. The study used monthly data on hospital admissions in NHS hospitals in England between March 2007 and December 2024 for 0- to 17-y-olds. Admission rates for caries-related extractions were standardised by population size (per 100,000 person-months) and stratified by area deprivation quintiles. The slope and relative indices of inequality (SII and RII) were used to evaluate the magnitude of the absolute and relative inequalities in admission rates by area deprivation. Admission rates for tonsillectomy were chosen as a negative control outcome. A segmented regression model was fitted with a parameterization that incorporated 4 key policy and contextual phases: SDIL announcement, implementation, COVID-19 lockdown, and postlockdown recovery. When the counterfactual and observed trends were compared, there were absolute reductions in the SII for caries-related extractions of 3.89 (95% CI: 2.38, 5.39) and 9.27 (95% CI: 7.15, 11.40) at 22 and 80 mo after implementation, corresponding to relative reductions of 9.16% (95% CI: 3.18, 15.13) and 25.54% (95% CI: 15.74, 35.34), respectively. There were also absolute reductions in the RII of 0.03 (95% CI: 0.01, 0.05) at 22 and 80 mo after implementation, corresponding to relative reductions of 13.52% (95% CI: 4.56, 22.48) and 12.74% (95% CI: 4.49, 20.99). No differences in SII or RII were observed for tonsillectomy admission rates. The introduction of the SDIL was associated with reductions in deprivation-related inequalities in admission rates for caries-related extractions among children in England.</jats:p

Investigating the effect of chemotherapy on heterogeneity and plasticity of colorectal cancer liver metastases

Chemotherapy is the most common treatment for colorectal cancer liver metastases (CRC LMs), which can significantly prolong patient survival. However, limited chemotherapy response and high rates of disease recurrence are common challenges contributing to poor patient outcome. A better understanding of how chemotherapy impacts specific cell types and states in LMs could aid development of improved therapeutic strategies for metastatic CRC. In this thesis, I aimed to characterise how chemotherapy alters the transcriptional and spatial landscape of cancer and tumour microenvironment cells in CRC LMs. Firstly, I analysed single-cell RNA-sequencing data from 87 CRC LM patients to annotate fine-grained cancer and tumour microenvironment cell subsets, characterising cellular heterogeneity across all major cellular compartments. Comparing transcriptional profiles and abundance of detailed subsets between chemotherapy-treated and untreated LMs revealed significant differences related to treatment. In treated LMs, greater abundance of dendritic cells and inflammatory macrophages, alongside increased expression of TNF-α signalling via NF-κB across multiple cell types, suggested an enhanced inflammatory response. Treated LMs also displayed reduced abundance of exhausted CD8 T cells and pro-tumoural SPP1+ macrophages suggesting that chemotherapy may alleviate immunosuppression. Comparisons based on responsiveness to chemotherapy elucidated that certain cancer cell states in better responding patients upregulated regenerative/fetal, apoptotic and inflammatory pathway signatures, and downregulated proliferation genes, compared to worse responders and untreated LMs. Therefore, the retention of cancer cells in a slower-cycling, regenerative state may relate to favourable chemotherapy outcome. Subsequent spatial mapping of fine-grained cell types using Visium spatial transcriptomics data of treated and untreated LMs supported differences in transcriptional pathways identified in single-cell data. Finally, bulk RNA-sequencing of CRC LM patient-derived organoids revealed that 5-fluorouracil, SN-38 and oxaliplatin chemotherapies induced inflammatory and regenerative signatures as an early response to treatment. Profiling recovery of patient-derived organoids after 5-fluorouracil treatment suggested transitions towards alternative non-canonical states that may relate to worse response to therapy. Overall, our results supported chemotherapy-induced alterations across cancer and tumour microenvironment cells in CRC LMs, which was dependent on patient response to chemotherapy. Our findings provide insights into the wide-ranging effects of chemotherapy at single-cell resolution that could inform identification of therapeutic targets

Intracortical inhibition, corticospinal excitability and voluntary activation in people with and without patellofemoral pain

Abstract The aims of this study were to investigate the intra‐rater reliability of peripheral nerve stimulation (PNS) and transcranial magnetic stimulation (TMS) in people with and without patellofemoral pain (PFP) and to compare nervous system function between these groups, using a case–control design. We sought people with and without PFP to participate in PNS and TMS testing to calculate maximal compound motor action potential, maximal force, voluntary activation (VA), active motor threshold (AMT), corticospinal excitability (CSE), silent period, and short‐interval intracortical inhibition. People with PFP also rated their current pain and function. Single‐measure intraclass correlation coefficients with 95% confidence intervals were used to determine intra‐rater reliability, with standard error of measurement and minimum detectable change calculated. Between‐group differences in PNS and TMS variables were determined using Student's two‐tailed, independent samples t ‐tests or Mann–Whitney U ‐tests. Twenty‐seven people without and 23 people with PFP completed PNS and TMS testing. For intra‐rater reliability, 18 people without and 17 people with PFP returned for a second testing session, and intraclass correlation coefficient values ranged from good to excellent (0.62–0.96). People with PFP demonstrated significantly lower VA ( P  &lt; 0.0001), higher AMT ( P  = 0.014) and lower CSE ( P  = 0.018). In conclusion, both PNS and TMS demonstrate acceptable intra‐rater reliability in people with and without PFP. Elevated AMT and reduced CSE indicate that people with PFP might have a hypoexcitable motor cortex–corticospinal pathway, and lower VA indicates reduced recruitment of high‐threshold motor units. These findings indicate that a neurophysiological mechanism might underpin the poor prognosis of PFP. </jats:p

Reducing self-harm in adolescents: the RISA-IPD comprehensive synopsis.

BACKGROUND: Self-harm is common in adolescents and a major public health concern. Evidence for effective interventions is lacking. An individual participant data meta-analysis has potential to provide more reliable estimates of the effects of therapeutic interventions than conventional meta-analyses and to explore which treatments are best suited to certain groups. METHODS: A systematic review and individual participant data meta-analysis of randomised controlled trials of therapeutic interventions to reduce repeat self-harm in adolescents with a history of self-harm and who had presented to clinical services. We searched Cochrane Library, EMBASE, trial registers and other databases for randomised controlled trials published in January 2022. Eligible randomised controlled trials compared any therapeutic intervention against a control, aimed to reduce self-harm in adolescents (11-18 years old), with past self-harm presenting to clinical services, and collected outcome data on self-harm or suicide attempts. Interventions reviewed were grouped into nine categories: cognitive-behavioural therapy; dialectical behaviour therapy; family therapy; group therapy; mentalisation based, psychodynamic, cognitive analytic therapy; multisystemic therapy; problem-solving, psychoeducation, support; postcards, tokens, documents (postcards/tokens); and other single session, brief interventions. Control interventions were all either treatment as usual or enhanced treatment as usual and were not usually well described. There were no 'no treatment' controls except in the postcard/document/token studies. Primary outcome was repetition of self-harm at 12 months. Other outcomes included repetition of self-harm at other time points, overall mental health, depressive symptoms, thoughts of suicide, quality of life and death. Two-stage random-effects individual participant data meta-analyses were conducted overall and by intervention, and to examine interaction between treatment received and participant characteristics. Secondary analyses incorporated aggregate data from randomised controlled trials without individual participant data. Metaregression explored moderating study effects. RESULTS: We identified 39 eligible studies, from 10 countries, where we sought individual participant data (18 studies with full sample eligibility, 21 with partial sample eligibility). We obtained individual participant data from 26 studies of 3448 eligible participants. We used published data from a further seven studies where individual participant data were not available for a combined individual participant data aggregate data meta-analysis (698 participants). For our primary outcome, repetition of self-harm, only six studies were rated as low risk of bias. There was no evidence that intervention/s were more or less effective than controls at preventing repeat self-harm by 12 months using individual participant data (odds ratios 1.06, 95% confidence interval 0.86 to 1.31) or individual participant data + aggregate data (odds ratios 1.02, 95% confidence interval 0.82 to 1.27) and no evidence of heterogeneity of treatment effects on study and treatment factors. We found no evidence that intervention was more or less effective than control for secondary outcomes, except general psychopathology and suicidal ideation at 12 and 6 months, respectively. Across all interventions, participants with multiple prior self-harm episodes showed evidence of improved treatment effect on self-harm repetition 6-12 months after randomisation [odds ratios 0.33 (95% confidence interval 0.12 to 0.94), studies = 9, n = 1771]. Modest evidence suggesting differential treatment effects based on participants' age, gender, self-harm method, and anxiety levels are noted. LIMITATIONS: A significant limitation was missing individual participant data where authors were unable to share data; we offset this by including published data in secondary individual participant data plus aggregate meta-analysis. A wide range of interventions were evaluated and lacked replication. There was variability in the definitions and timings of outcomes, measures used for data collection, and available moderator data, with little consistency across studies. CONCLUSIONS: More attention needs to be paid to seeking appropriate consent from study participants for data-sharing. We found no evidence that any therapeutic intervention (overall or by intervention) was more or less effective than control for reducing repeat self-harm. We are therefore unable to recommend any specific intervention to prevent repetition of self-harm in adolescents. We observed evidence and trends indicating more effective interventions within specific subgroups. Analysis was constrained due to scarcity of data concerning common baseline characteristics, outcomes, and follow-up lengths. We recommend efficient, adaptive platform trial designs to tackle research questions and ascertain the most effective interventions for different groups, covering available treatments. FUNDING: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 17/117/11

Hörmander Type Fourier Multiplier Theorem and Nikolskii Inequality on Quantum Tori, and Applications

In this paper, we study Hörmander type Fourier multiplier theorem and the Nikolskii inequality on quantum tori. On the way to obtain these results, we also prove some classical inequalities such as the Paley, Hausdorff-Young-Paley, Hardy-Littlewood, and Logarithmic Sobolev inequalities on quantum tori. As applications we establish embedding theorems between Sobolev, Besov spaces as well as embeddings between Besov and Wiener and Beurling spaces on quantum tori. We also analyse β-versions of Wiener and Beurling spaces and their embeddings, and interpolation properties of all these spaces on quantum tori. As an application of the study, we also derive a version of the Nash inequality, and the time decay for solutions of a heat type equation