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The central role of DNA damage in immunosenescence.
Ageing is the biggest risk factor for the development of multiple chronic diseases as well as increased infection susceptibility and severity of diseases such as influenza and COVID-19. This increased disease risk is linked to changes in immune function during ageing termed immunosenescence. Age-related loss of immune function, particularly in adaptive responses against pathogens and immunosurveillance against cancer, is accompanied by a paradoxical gain of function of some aspects of immunity such as elevated inflammation and increased incidence of autoimmunity. Of the many factors that contribute to immunosenescence, DNA damage is emerging as a key candidate. In this review, we discuss the evidence supporting the hypothesis that DNA damage may be a central driver of immunosenescence through senescence of both immune cells and cells of non-haematopoietic lineages. We explore why DNA damage accumulates during ageing in a major cell type, T cells, and how this may drive age-related immune dysfunction. We further propose that existing immunosenescence interventions may act, at least in part, by mitigating DNA damage and restoring DNA repair processes (which we term "genoprotection"). As such, we propose additional treatments on the basis of their evidence for genoprotection, and further suggest that this approach may provide a viable therapeutic strategy for improving immunity in older people.
Patient-reported symptoms and diagnostic journey in Multiple Myeloma.
INTRODUCTION: Late presentation of multiple myeloma (MM) heightens the risk of complication risks, including end-organ damage. This study aimed to: 1) detail the diagnostic journey of MM patients, encompassing symptoms, initial diagnoses, and healthcare professionals met; 2) establish the median duration from symptom onset to MM diagnosis; and 3) examine factors linked to timely MM diagnosis within 12 weeks. METHODS: A total of 300 adults self-reporting MM were analysed from the Rare and Undiagnosed Diseases cohort Study (RUDY). The RUDY study is a web-based platform, where participants provide dynamic consent and self-report their MM diagnosis and information about their diagnostic journey. This includes the estimated date of initial potential first symptoms, descriptions of these symptoms, the healthcare professionals they consulted, and other diagnoses received before the MM diagnosis. Descriptive statistics, combinatorial analyses and logistic regression analyses were used to describe and examine the diagnostic journey of individuals with MM. RESULTS: Overall, 52% of the participants reported other diagnoses before MM diagnosis, with musculoskeletal disorders (47.8%), such as osteoporosis, costochondritis, or muscle strains, being the most common. The most prevalent initial reported symptom was back pain/vertebral fractures (47%), followed by chest/shoulder pain, including rib pain and fractures (20%), and fatigue/tiredness (19.7%). 40% of participants were diagnosed by direct referral from primary care to haematology without seeing other healthcare professionals whilst 60% consulted additional specialists before diagnosis. The median time from symptom onset to MM diagnosis was 4 months (IQR 2-10 months, range 0-172). Seeing an Allied Healthcare Professional such as a physiotherapist, chiropractor or an osteopath (OR = 0.25, 95% CI [0.12, 0.47], p <0.001), experiencing infection symptoms (OR = 0.32, 95% CI [0.13, 0.76], p = 0.013), and having chest or shoulder pain (OR = 0.45, 95% CI [0.23, 0.86], p = 0.020) were associated with a lower likelihood of being diagnosed with MM within 12 weeks. Older age (OR = 1.04, 95% CI [1.02, 1.07], p = 0.001) was associated with a higher likelihood of diagnosis within 12 weeks. DISCUSSION: Developing resources for allied health professionals may improve early recognition of MM.
Predicting persistent back pain causing severe interference with daily activities among community-dwelling older adults: the OPAL cohort study.
BACKGROUND: Many older adults experience disabling back and leg pain. This study aimed to identify factors associated with back pain causing severe interference with daily activities over 2 years. METHODS: Participants were 2,109 community-dwelling adults (aged 65-100 years; mean age 74.2 (SD 6.3)) enrolled in a prospective cohort study who reported back pain at baseline and provided back pain data at 2 years follow-up. Baseline data included demographics, socio-economic factors, back pain presentation and age-associated adverse health states (e.g. frailty, falls, walking confidence). At 2 years follow-up, we asked if they were currently experiencing back pain and if so, asked participants to rate how much their back pain interfered with their daily activities on a scale of 0-10. Severe back pain interference was defined by a rating of 7 or more. The association between baseline factors and severe back pain interference at two years was assessed using logistic regression models. RESULTS: At two years, 77% of participants (1,611/2,109) still reported back pain, 25% (544/2,083) also reported leg pain and 14% (227/1,611) reported severe back pain interference with activities. Improvements in symptoms were observed over the two years follow-up in 880/2,109 participants (41.7%), 41.2% (869/2,109) of participants report no change and worsening symptoms was reported by 17.1% (360/2109) of participants. After adjusting for back pain troublesomeness at baseline, factors associated with reporting severe interference were adequacy of income (careful with money [OR 1.91; 95% CI 1.19-3.06]; prefer not to say [OR 2.22; 95% CI 1.11-4.43]), low endorsement of exercise in later life (OR 1.18; 95% CI 1.02-1.37), neurogenic claudication symptoms (OR 1.68 (95% CI 1.15-2.46)], multisite pain (OR 1.13; 95% CI 1.02-1.24) and low walking confidence (OR 1.15; 95% CI 1.08-1.22). CONCLUSION: After adjusting for baseline pain severity, we identified five factors that were associated with severe pain limitation at two years follow-up among a cohort of community dwelling older people reporting back and leg pain. These included other pain characteristics, walking confidence and attitude to activity in later life. We also identified a socioeconomic factor (perceived adequacy of income). Future research should focus on whether identifying individuals using these risk factors in order to intervene improves back pain outcomes for older people.
Diagnostic journey for individuals with fibrous dysplasia / McCune albright syndrome (FD/MAS).
BACKGROUND: Reducing delayed diagnosis is a significant healthcare priority for individuals with rare diseases. Fibrous Dysplasia/ McCune Albright Syndrome (FD/MAS) is a rare bone disease caused by somatic activation mutations of NASA. FD/MAS has a broad clinical phenotype reflecting variable involvement of bone, endocrine and other tissues, distribution and severity. The variable phenotype is likely to prolong the diagnostic journey for patients further. AIM: To describe the time from symptom onset to final diagnosis in individuals living with FDMAS. METHODS: We used the UK-based RUDY research database ( www.rudystudy.org ), where patients self-report their diagnosis of FD/MAS. Participants are invited to complete the diagnostic journey based on the EPIRARE criteria. RESULTS: 51 individuals diagnosed with FD/MAS were included in this analysis. Among them, 70% were female, and the median age was 51.0 years (IQR 34.5-57.5]. 12 (35%) individuals reported McCune Albright Syndrome, 11 (21.6%) craniofacial and 11(21.6%) for each of poly- and mono-ostotic FD and 6 (11.8%) did not know their type of FD/MAS. Pain was the commonest first symptom (58.8%), and 47.1% received another diagnosis before the diagnosis of FD/MAS. The median time to final diagnosis from the first symptom was two years with a wide IQR (1,18) and range (0-59 years). Only 12 (23.5%) of individuals were diagnosed within 12 months of their first symptoms. The type of FD/MAS was not associated with the reported time to diagnosis. Significant independent predictors of longer time to final diagnosis included older current age, younger age at first symptom and diagnosis after 2010. CONCLUSION: Individuals with FDMAS have a variable time to diagnosis that can span decades. This study highlights the need for further research on how to improve diagnostic pathways within Orthopaedic and Ear, Nose and Throat (ENT)/Maxillofacial services. Our data provides a baseline to assess the impact of novel NHS diagnostic networks on reducing the diagnostic odyssey.
The role of COVID-19 vaccines in preventing post-COVID-19 thromboembolic and cardiovascular complications.
OBJECTIVE: To study the association between COVID-19 vaccination and the risk of post-COVID-19 cardiac and thromboembolic complications. METHODS: We conducted a staggered cohort study based on national vaccination campaigns using electronic health records from the UK, Spain and Estonia. Vaccine rollout was grouped into four stages with predefined enrolment periods. Each stage included all individuals eligible for vaccination, with no previous SARS-CoV-2 infection or COVID-19 vaccine at the start date. Vaccination status was used as a time-varying exposure. Outcomes included heart failure (HF), venous thromboembolism (VTE) and arterial thrombosis/thromboembolism (ATE) recorded in four time windows after SARS-CoV-2 infection: 0-30, 31-90, 91-180 and 181-365 days. Propensity score overlap weighting and empirical calibration were used to minimise observed and unobserved confounding, respectively.Fine-Gray models estimated subdistribution hazard ratios (sHR). Random effect meta-analyses were conducted across staggered cohorts and databases. RESULTS: The study included 10.17 million vaccinated and 10.39 million unvaccinated people. Vaccination was associated with reduced risks of acute (30-day) and post-acute COVID-19 VTE, ATE and HF: for example, meta-analytic sHR of 0.22 (95% CI 0.17 to 0.29), 0.53 (0.44 to 0.63) and 0.45 (0.38 to 0.53), respectively, for 0-30 days after SARS-CoV-2 infection, while in the 91-180 days sHR were 0.53 (0.40 to 0.70), 0.72 (0.58 to 0.88) and 0.61 (0.51 to 0.73), respectively. CONCLUSIONS: COVID-19 vaccination reduced the risk of post-COVID-19 cardiac and thromboembolic outcomes. These effects were more pronounced for acute COVID-19 outcomes, consistent with known reductions in disease severity following breakthrough versus unvaccinated SARS-CoV-2 infection.
French translation and transcultural adaptation of the shoulder pain and disability index (SPADI).
BACKGROUND: A French version of the Shoulder Pain and Disability Index (SPADI) is currently unavailable for clinical and research use in French-speaking countries. OBJECTIVES: To translate and transculturally adapt the Shoulder Pain And Disability Index (SPADI) from English to French language. DESIGN: Translation and transcultural adaptation of a Patient-Reported Outcome Measure. METHODS: Following international guidelines for translating and adapting PROMs, we carried out a seven-step process involving 15 contributors. The forward translation was performed by five independent native French speakers, while five independent native English speakers conducted the blinded back-translation. A bilingual expert committee synthesized the translations, and three healthcare professionals participated in the pre-test phase. Ten patients were involved in pre-testing to evaluate the pre-final version. RESULTS: A final French version of the SPADI was achieved after making seven adjustments across the 18 items, instructions, and examples on the Likert scale. Changes were implemented only if at least 20% of the pre-test participants suggested modifications to enhance readability or coherence. Face validity was assessed by the expert committee. CONCLUSION: The French version of the SPADI is now available, enabling condition-specific self-assessment and quantitative follow-up of shoulder pain and function in both clinical practice and research. Although psychometric properties of this version are yet to be assessed, future studies are expected to confirm the preservation of the original tool's validity and reliability.
Antibiotic usage in chronic rhinosinusitis: analysis of national primary care electronic health records.
BACKGROUND: The aim of this study was to analyse rates of antibiotic usage in chronic rhinosinusitis (CRS) in primary care in England and Wales and to identify trends in the choice of antibiotics prescribed. METHODS: We used linked data from primary care EHRs, with diagnoses coded using the Read terminology (Clinical Practice Research Datalink) from consenting general practices, with (2) hospital care administrative records (Hospital Episode Statistics, HES recorded using ICD-10). RESULTS: From the total of 88,317 cases of CRS identified, 40,462 (46%) had an antibiotic prescription within 5 days of their first CRS diagnosis. Of patients receiving a first line antibiotic within 5 days of CRS diagnosis, over 80%, in each CRS group, received a subsequent prescription for an antibiotic. Within 5 years of diagnosis, 9% are estimated to have had 5 or more antibiotics within 5 days of a CRS-related consultation. With data spanning almost 20 years, it was possible to discern trends in antibiotics prescriptions, with a clear increasing trend towards macrolide and tetracycline prescribing evident. CONCLUSIONS: While antibiotics may have been prescribed for acute exacerbations, we have found high rates of repeated antibiotic prescription in some patients with CRS in primary care. There is a need for stronger evidence on the role of antibiotics in CRS management.
Risk of mortality and cardiovascular events following macrolide prescription in chronic rhinosinusitis patients: a cohort study using linked primary care electronic health records.
BACKGROUND: Macrolide antibiotics have demonstrated important anti-inflammatory and immunomodulatory properties in chronic rhinosinusitis (CRS) patients. However, reports of increased risks of cardiovascular events have led to safety concerns. We investigated the risk of all-cause and cardiac death, and cardiovascular outcomes, associated with macrolide use. METHODOLOGY: Observational cohort (1997-2016) using linked data from the Clinical Practice Research Datalink, Hospital Episodes Statistics, and the Office for National Statistics. Patients aged 16-80 years with CRS prescribed a macrolide antibiotic or penicillin were included, comparing prescriptions for macrolide antibiotics to penicillin. Outcomes were all-cause mortality, cardiac death, myocardial infarction, stroke, diagnosis of peripheral vascular disease, and cardiac arrhythmia. RESULTS: Analysis included 320,798 prescriptions received by 66,331 patients. There were 3,251 deaths, 815 due to cardiovascular causes, 925 incident myocardial infarctions, 859 strokes, 637 diagnoses of peripheral vascular disease, and 1,436 cardiac arrhythmias. A non-statistically significant trend towards increased risk of myocardial infarction during the first 30 days following macrolide prescription was observed. No statistically significant short- or long-term risks were observed for macrolide prescription. No significant risks were identified for clarithromycin in particular. CONCLUSIONS: Although not statistically significant, our best estimates suggest an increased short-term risk of myocardial infarction in patients with CRS following macrolide prescription, supporting previous observational evidence. However, confounding by indication remains a possible explanation for this apparent increased risk. We found no evidence of longer term increased risks.
Cortico-thalamic tremor circuits and their associations with deep brain stimulation effects in essential tremor.
Essential tremor (ET) is one of the most common movement disorders in adults. Deep brain stimulation (DBS) of the ventralis intermediate nucleus (VIM) of the thalamus and/or the posterior subthalamic area (PSA) has been shown to provide significant tremor suppression in patients with ET, but with significant inter-patient variability and habituation to the stimulation. Several non-invasive neuromodulation techniques targeting other parts of the central nervous system, including cerebellar, motor cortex, or peripheral nerves, have also been developed for treating ET, but the clinical outcomes remain inconsistent. Existing studies suggest that pathology in ET may emerge from multiple cortical and subcortical areas, but its exact mechanisms remain unclear. By simultaneously capturing neural activities from motor cortices and thalami, and hand tremor signals recorded via accelerometers in fifteen human subjects who have undergone lead implantations for DBS, we systematically characterized the efferent and afferent cortico-thalamic tremor networks. Through the comparisons of these network characteristics and tremor amplitude between DBS OFF and ON conditions, we further investigated the associations between different tremor network characteristics and the magnitude of DBS effect. Our findings implicate the thalamus, specifically the contralateral hemisphere, as the primary generator of tremor in ET, with a significant contribution of the ipsilateral hemisphere as well. Although there is no direct correlation between the cortico-tremor connectivity and tremor power or reduced tremor by DBS, the strength of connectivity from the motor cortex to the thalamus and vice versa at tremor frequency predicts baseline tremor power and effect of DBS. Interestingly, there is no correlation between these two connectivity pathways themselves, suggesting that, independent of the subcortical pathway, the motor cortex appears to play a relatively distinct role, possibly mediated through an afferent/feedback loop in the propagation of tremor. DBS has a greater clinical effect in those with stronger cortico-thalamo-tremor connectivity involving the contralateral thalamus, which is also associated with bigger and more stable tremor measured with an accelerometer. Interestingly, stronger cross-hemisphere coupling between left and right thalami is associated with more unstable tremor. Together this study provides important insights into a better understanding of the cortico-thalamic tremor generating network and its implication for the development of patient-specific therapeutic approaches for ET.
HDE-Array: Development and Validation of a New Dry Electrode Array Design to Acquire HD-sEMG for Hand Position Estimation.
This paper aims to introduce HDE-Array (High-Density Electrode Array), a novel dry electrode array for acquiring High-Density surface electromyography (HD-sEMG) for hand position estimation through RPC-Net (Recursive Prosthetic Control Network), a neural network defined in a previous study. We aim to demonstrate the hypothesis that the position estimates returned by RPC-Net using HD-sEMG signals acquired with HDE-Array are as accurate as those obtained from signals acquired with gel electrodes. We compared the results, in terms of precision of hand position estimation by RPC-Net, using signals acquired by traditional gel electrodes and by HDE-Array. As additional validation, we performed a variance analysis to confirm that the presence of only two rows of electrodes does not result in an excessive loss of information, and we characterized the electrode-skin impedance to assess the effects of the voltage divider effect and power line interference. Performance tests indicated that RPC-Net, used with HDE-Array, achieved comparable or superior results to those observed when used with the gel electrode setup. The dry electrodes demonstrated effective performance even with a simplified setup, highlighting potential cost and usability benefits. These results suggest improvements in the accessibility and user-friendliness of upper-limb rehabilitation devices and underscore the potential of HDE-Array and RPC-Net to revolutionize control for medical and non-medical applications.
Predicting future fallers in Parkinson's disease using kinematic data over a period of 5 years.
Parkinson's disease (PD) increases fall risk, leading to injuries and reduced quality of life. Accurate fall risk assessment is crucial for effective care planning. Traditional assessments are subjective and time-consuming, while recent assessment methods based on wearable sensors have been limited to 1-year follow-ups. This study investigated whether a short sensor-based assessment could predict falls over up to 5 years. Data from 104 people with PD without prior falls were collected using six wearable sensors during a 2-min walk and a 30-s postural sway task. Five machine learning classifiers analysed the data. The Random Forest classifier performed best, achieving 78% accuracy (AUC = 0.85) at 60 months. Most models showed excellent performance at 24 months (AUC > 0.90, accuracy 84-92%). Walking and postural variability measures were key predictors. Adding clinicodemographic data, particularly age, improved model performance. Wearable sensors combined with machine learning can effectively predict fall risk, enhancing PD management and prevention strategies.
The Association between COVID-19 Status and Economic Costs in the Early Stages of the COVID-19 Pandemic: Evidence from a UK Symptom Surveillance Digital Survey.
INTRODUCTION: In the absence of a vaccination programme, the coronavirus disease 2019 (COVID-19) pandemic had substantial impacts on population health and wellbeing and health care services. We explored the association between COVID-19 status, sociodemographic, socioeconomic and clinical factors and economic costs during the second wave of the COVID-19 pandemic. DATA: The study used patient-reported digital survey and symptom surveillance data collected between July and December 2020, in collaboration with a primary care computerised medical record system supplier, EMIS Health, in the UK. The study included 11,534 participants. METHODS: Generalised linear models (GLM) and two-part regression models were used to estimate factors associated with economic costs (£sterling, 2022 prices) estimated from two perspectives: (i) a UK National Health Service (NHS) and personal social services (PSS) perspective and (ii) a societal perspective. RESULTS: Experience of the onset of COVID-19 symptoms started more than 3 months ago was associated with significantly higher NHS and PSS costs (GLM: £319.8, two-part: £171.7) (p < 0.001) and societal costs (GLM: £776.9, two-part: £675.6) (p < 0.001) in both models. A positive test result within the previous 14 days was associated with significantly higher NHS and PSS costs (two-part: £389.1) (p < 0.05) and societal costs (GLM: £470.7, two-part: £439.2) (p < 0.01). Age between 31 and 55 years was associated with significantly higher societal costs than age between 16 and 30 years. CONCLUSION: This study identifies and quantifies factors associated with the economic costs incurred during the second wave of the COVID-19 pandemic in the UK. The results of our study can inform cross-country comparisons and other cost comparisons.
Cognitive-behavioural therapy for a variety of conditions: an overview of systematic reviews and panoramic meta-analysis.
BACKGROUND: Cognitive-behavioural therapy aims to increase quality of life by changing cognitive and behavioural factors that maintain problematic symptoms. A previous overview of cognitive-behavioural therapy systematic reviews suggested that cognitive-behavioural therapy was effective for many conditions. However, few of the included reviews synthesised randomised controlled trials. OBJECTIVES: This project was undertaken to map the quality and gaps in the cognitive-behavioural therapy systematic review of randomised controlled trial evidence base. Panoramic meta-analyses were also conducted to identify any across-condition general effects of cognitive-behavioural therapy. DATA SOURCES: The overview was designed with cognitive-behavioural therapy patients, clinicians and researchers. The Cochrane Library, MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Child Development & Adolescent Studies, Database of Abstracts of Reviews of Effects and OpenGrey databases were searched from 1992 to January 2019. REVIEW METHODS: Study inclusion criteria were as follows: (1) fulfil the Centre for Reviews and Dissemination criteria; (2) intervention reported as cognitive-behavioural therapy or including one cognitive and one behavioural element; (3) include a synthesis of cognitive-behavioural therapy trials; (4) include either health-related quality of life, depression, anxiety or pain outcome; and (5) available in English. Review quality was assessed with A MeaSurement Tool to Assess systematic Reviews (AMSTAR)-2. Reviews were quality assessed and data were extracted in duplicate by two independent researchers, and then mapped according to condition, population, context and quality. The effects from high-quality reviews were pooled within condition groups, using a random-effect panoramic meta-analysis. If the across-condition heterogeneity was I2