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Oxidative-Stress-Mediated Epigenetic Dysregulation in Spermatogenesis: Implications for Male Infertility and Offspring Health
No full textMale reproductive health is governed by an intricate interplay of genetic, epigenetic, and environmental factors. Epigenetic mechanisms-encompassing DNA methylation, histone modifications, and non-coding RNA activity-are crucial both for spermatogenesis and sperm maturation. However, oxidative stress, driven by excessive reactive oxygen species, disrupts these processes, leading to impaired sperm function and male infertility. This disruption extends to epigenetic modifications, resulting in abnormal gene expression and chromatin remodeling that compromise genomic integrity and fertilization potential. Importantly, oxidative-stress-induced epigenetic alterations can be inherited, affecting the health and fertility of offspring and future generations. This review investigates how oxidative stress influences epigenetic regulation in male reproduction by modifying DNA methylation, histone modifications, and non-coding RNAs, ultimately compromising spermatogenesis. Additionally, it discusses the transgenerational implications of these epigenetic disruptions and their potential role in hereditary infertility and disease predisposition. Understanding these mechanisms is vital for developing therapeutic strategies that mitigate oxidative damage and restore epigenetic homeostasis in the male germline. By integrating insights from molecular, clinical, and transgenerational research, this work emphasizes the need for targeted interventions to enhance male reproductive health and prevent adverse outcomes in progeny. Furthermore, elucidating the dose-response relationships between oxidative stress and epigenetic changes remains a critical research priority, informing personalized diagnostics and therapeutic interventions. In this context, future studies should adopt standardized markers of oxidative damage, robust clinical trials, and multi-omic approaches to capture the complexity of epigenetic regulation in spermatogenesis. Such rigorous investigations will ultimately reduce the risk of transgenerational disorders and optimize reproductive health outcomes.Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
A survey of perioperative medicine services with a focus on provision for older surgical patients in the UK and Republic of Ireland: SNAP-3
No full textBACKGROUND: Perioperative medicine aims to improve care for high-risk patients, and is endorsed by national guidelines in the UK and Republic of Ireland (ROI). However, comprehensive perioperative medicine services are not yet uniformly available. This survey addressed the current state of perioperative medicine services for older surgical patients in the UK and ROI and how these services align with current national guidance. METHODS: A survey was distributed electronically to all publicly administered UK and ROI hospitals performing surgical procedures. The survey examined perioperative care against national recommendations regarding service organisation and conduct. RESULTS: Of 339 eligible hospitals, 54.9% (186/339) responded. A hospital frailty lead was appointed in 54% (101/186) of hospitals, and 9% (16/186) had a designated anaesthetist for cognitive impairment. Hospital anaesthetic services outside the theatre were focused on preoperative assessment clinics (146/172), with few reporting routine postoperative involvement (17/166). Nurse-led preoperative assessments of frailty, cognition, and delirium risk were conducted in 49.5% (90/182), 44.3% (78/176), and 13.7% (24/175) of hospitals, respectively. The Clinical Frailty Scale was used in 87.0% (147/169) of hospitals for frailty screening. The 4 'A's Test (45.7% [85/186]) and Abbreviated Mental Test (43.0% [80/186]) were the preferred cognitive assessment tools. CONCLUSIONS: The survey highlights the variation in perioperative medicine services that exist for older surgical patients despite national guidelines advocating their widespread implementation. Opportunity exists to develop interspecialty perioperative services further and promote identification of frailty, cognitive impairment, and delirium, all of which negatively impact postoperative outcomes for older surgical patients.Creative Commons CC BY 4.0 (open access
The Ocular Surface and the Anterior Segment of the Eye in the Pseudoexfoliation Syndrome: A Comprehensive Review
No full textPseudoexfoliation syndrome (PXS) is an age-related fibrillopathy where fibrillar exfoliation material accumulates and deposits in ocular and extra-ocular tissue. Within the eye, this substance accumulates on the ocular surface and in the anterior segment of the eye, impacting ocular structures such as the conjunctiva, Tenon's capsule, sclera, cornea, iris, ciliary body, trabecular meshwork, and lens. This review aims to collate the current literature on how each anatomical part of the eye is affected by PXS, with a strong focus on molecular changes. We also summarise the current understanding of the key genetic factors influencing the development of PXS.Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Journal content freely available via Open Access. Some content may be unavailable due to publisher embarg
Postoperative outcomes in older patients living with frailty and multimorbidity in the UK: SNAP-3, a snapshot observational study
No full textBACKGROUND: Older surgical patients experience longer hospital stays and a higher risk of morbidity and mortality than their younger counterparts. Frailty (19.6% of cohort) and multimorbidity (63.1% of cohort) increase these risks. The 3(rd) Sprint National Anaesthesia Project (SNAP-3) describes the impact of frailty and multimorbidity on postoperative outcomes. METHODS: We conducted a prospective observational cohort study over 5 days in 2022 aiming to recruit all UK patients aged ≥60 yr undergoing surgery (excluding minor procedures). Data included patient characteristics, clinical variables, Clinical Frailty Scale (CFS), multimorbidity (two or more comorbidities), length of stay (LOS), postoperative delirium, morbidity, and mortality. Quantile regression and mixed effects logistic regression were used to analyse relationships. RESULTS: We recruited 7129 patients from 214 hospitals. Increasing frailty was associated with longer LOS, higher odds of delirium, morbidity, and mortality ≥1 yr, with a clear increase noted from CFS of 4 (19.0% of cohort). Amongst those without multimorbidity, individuals with CFS score of 4 had longer admissions than non-frail individuals (median LOS 0.75 days longer, 95% confidence interval [CI] 0.34-1.16), increasing to 2.69 days longer for CFS 5 (95% CI 0.76-4.62). Multimorbidity increased the odds of postoperative morbidity by 46% (adjusted odds ratio 1.46, 95% CI 1.24-1.73), but there was no evidence for multimorbidity impacting LOS, delirium, or mortality. CONCLUSIONS: SNAP-3 highlights the impact of frailty on postoperative outcomes. Multimorbidity had less impact, with an effect on postoperative morbidity the only one to have strong statistical evidence. The impact of these conditions must be discussed with older patients considering surgical intervention.CC BY‑NC‑ND 4.0 (open access
A systematic review of the role of quantitative CT in the prognostication and disease monitoring of interstitial lung disease
No full textBACKGROUND: The unpredictable trajectory and heterogeneity of interstitial lung disease (ILDs) make prognostication challenging. Current prognostic indices and outcome measures have several limitations. Quantitative computed tomography (qCT) provides automated numerical assessment of CT imaging and has shown promise when applied to the prognostication and disease monitoring of ILD. This systematic review aims to highlight the current evidence underpinning the prognostic value of qCT in predicting outcomes in ILD. METHODS: A comprehensive search of four databases (Medline, EMCare, Embase and CINAHL (Cumulative Index to Nursing and Allied Health Literature)) was conducted for studies published up to and including 22 November 2024. A modified CHARMS (CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies) checklist was used for data extraction. The risk of bias was assessed using a Quality in Prognostic Studies template. RESULTS: The search identified 1134 unique studies, of which 185 studies met inclusion and exclusion criteria. Commonly studied ILD subtypes included idiopathic pulmonary fibrosis (41%, n=75), mixed subtypes (26%, n=48) and systemic sclerosis ILD (16%, n=30). Numerous studies showed significant prognostic signals, even when adjusted for common covariates and/or significant correlation between serial qCT biomarkers and conventional outcome measures. Heterogenous and nonstandardised reporting methods meant that direct comparison or meta-analysis of studies was not possible. Studies were limited by the use of retrospective methodology without prospective validation and significant study attrition. DISCUSSION: qCT has shown efficacy in the prognostication and disease monitoring of a range of ILDs. Hurdles exist to widespread adoption including governance concerns, appropriate algorithm anchoring and standardisation of image acquisition. International collaboration is underway to address these hurdles, paving the way for regulatory approval and ultimately patient benefit.CC BY 4.0 (Creative Commons Attribution
Small Bowel Motility Quantified by Cine MRI to Predict Longer-Term Response in Patients with Crohn's Disease Commencing Biological Therapy: The Motility Study
No full textBACKGROUND: Small bowel Crohn's disease (SBCD) is increasingly treated with biological therapies. Predicting response or remission (RoR) for individual patients is difficult and complicates treatment strategy. We aimed to determine if motility magnetic resonance imaging (mMRI) is superior to CRP and fecal calprotectin (FC) for the prediction of RoR at 1 year in patients commencing biologics for SBCD. METHODS: Prospective, multicenter (n = 13) cohort study of patients with active non-stricturing SBCD requiring anti-TNFα or anti-IL-12/23 treatment. We measured mMRI and CRP at baseline and post-induction (visit 2: 12-30 weeks), and FC in a subset. RoR was assessed at 1 year using clinical and structural magnetic resonance enterography parameters. We compared sensitivity, specificity, and area under the receiver operating characteristic curve (ROC-AUC) of changes in mMRI and CRP to predict RoR at 1 year. Secondary outcomes compared mMRI with FC, and prediction of improved quality of life (QoL). RESULTS: Eighty-six participants completed all assessments. Stable or improved mMRI at visit 2 was more sensitive than normalization of CRP for RoR (mMRI:71.0%, 95%CI 52.0-85.8; CRP:45.2%, 95%CI 27.3-64.0%, P = .008) but less specific (mMRI:30.9%, 95%CI 19.1-44.8; CRP:67.3%, 95%CI 53.3-79.3%, P < .001). There was no significant difference in ROC-AUC (mMRI:0.48; CRP:0.53, P = .65). Similar results were obtained for FC. None of mMRI, CRP, or FC predicted patient QoL at 1 year. CONCLUSIONS: Although improved mMRI is more sensitive than CRP and FC to predict RoR at 1 year, it is less specific. No factor predicted patient QoL. Motility MRI remains a marker of disease activity at given timepoints.
Changes in CRP, fecal calprotectin level, or small bowel motility as quantified by MRI do not reliably predict response or remission to biological therapy at 1 year. Motility MRI is a useful marker of active small bowel inflammation.
engThis article is available under the Creative Commons CC-BY-NC license and permits non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Knowledge translation in Anglo-American paramedicine: a scoping review
No full textOBJECTIVE: To map what is currently known about knowledge translation (KT) in Anglo-American paramedicine. The review focuses on reported barriers and facilitators to the implementation of new knowledge, and the use of models, theories and frameworks to guide implementation practice. DESIGN: Scoping review reported as per both the Joanna Briggs Institute and Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews reporting guidelines. DATA SOURCES: CINAHL (EBSCO Host) and Medline (OVID interface) were searched from January 2000 to May 2023. Reference lists of all included papers were reviewed, and several key professional journals were hand-searched. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Primary sources that focused on KT models, theories or frameworks, or barriers and facilitators to KT implementation, involving paramedics or Emergency Medical Technicians (Paramedic in America) working in an out-of-hospital, Anglo-American Emergency Medical Service (EMS) system were eligible for inclusion. DATA EXTRACTION AND SYNTHESIS: One reviewer used a data extraction template developed for this review and 10% of the papers were checked by the second author. Findings were summarised in tables and synthesised both quantitatively and qualitatively. RESULTS: The search yielded 1268 primary sources, of which 48 were included in the review. Thirty-two papers examining KT interventions and 16 papers examining the barriers and facilitators to KT were found. Only one randomised controlled trial was found, and only one paper made explicit use of any KT framework. Overall, eight themes describing barriers and facilitators to KT arose from the qualitative literature, with clinicians' perception of the evidence being the dominant theme. All 32 papers describing KT interventions included some form of educational intervention. CONCLUSIONS: Overall, there is little depth and breadth in the literature, with many papers focusing on trauma and airway management. There are large gaps in the evidence surrounding the use of KT theories and frameworks in Anglo-American EMS. Further research is needed to identify appropriate KT models and frameworks that are contextualised to EMS to ensure that paramedic-led research finds its way to the clinicians needing to use it.This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial.This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial
Correction: High patient acceptance of immediately sequential bilateral cataract surgery (ISBCS) as part of a one-stop see-and-treat pathway within an innovative NHS cataract unit
No full textCC BY 4.0 (Creative Commons Attribution
Genetic Discovery and Risk Prediction for Type 1 Diabetes in Individuals Without High-Risk HLA-DR3/DR4 Haplotypes
No full textOBJECTIVE: More than 10% of patients with type 1 diabetes (T1D) do not have high-risk HLA-DR3 or -DR4 haplotypes with distinct clinical features, such as later onset and reduced insulin dependence. We aimed to identify genetic drivers of T1D in the absence of DR3/DR4 and improve prediction of T1D risk in these individuals. RESEARCH DESIGN AND METHODS: We performed T1D association and fine-mapping analyses in 12,316 non-DR3/DR4 samples. Next, we performed heterogeneity tests to examine differences in T1D risk variants in individuals without versus those with DR3/DR4 haplotypes. We further assessed genome-wide differences in gene regulatory element and biological pathway enrichments between the non-DR3/DR4 and DR3/DR4 cohorts. Finally, we developed a genetic risk score (GRS) to predict T1D in individuals without DR3/DR4 and compared with an existing T1D GRS. RESULTS: A total of 18 T1D risk variants in non-DR3/DR4 samples were identified. Risk variants at the MHC and multiple other loci genome wide had heterogeneity in effects on T1D dependent on DR3/DR4 status, and non-DR3/DR4 T1D had evidence for a greater polygenic burden. T1D-associated variants in non-DR3/DR4 were more enriched for regulatory elements and pathways involved in antigen presentation, innate immunity, and β-cells and depleted in T cells compared with DR3/DR4. A non-DR3/DR4 GRS outperformed an existing risk score GRS2 in discriminating non-DR3/DR4 T1D from no diabetes (area under the curve 0.867; P = 7.48 × 10-32) and type 2 diabetes (0.907; P = 4.94 × 10-44). CONCLUSIONS: In total, we identified heterogeneity in T1D genetic risk dependent on high-risk HLA-DR3/DR4 haplotype, which uncovers disease mechanisms and enables more accurate prediction of T1D across the HLA background.Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available atJournal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Informant accuracy of IQCODE, AD8 and GPCOGi for diagnosis of dementia: does your friend know best?
No full textBACKGROUND: Increasing numbers of people require evaluation for possible dementia. However, research on the accuracy of informant questionnaires in primary care remains limited. METHODS: This study assessed the diagnostic accuracy of IQCODE, AD8, and GPCOGi based on the informant's relationship to the patient. We recruited 240 participants from 21 general practices in South West England. The reference standard for a diagnosis of dementia was made by a specialist clinician using ICD-10 criteria. A threshold of greater than 3.3 on IQCODE, greater or equal to 2 on AD8 and less than 5 on the informant component of GPCOG was used to indicate an abnormal test. RESULTS: Of 238 participants with informant data, 131 had dementia, 60 had CIND, and 47 had normal cognition. Median informant age was 70 years (IQR 60 years to 78 years). 71% of informants were female and 56% were spouses. On all three questionnaires, compared to spouses, adult descendants tended to score participants more cognitively impaired, whereas friends scored participants less cognitively impaired. However, there was little evidence of difference by informant type once fully adjusted. Sensitivity by informant type ranged from 91 to 100% for IQCODE, 94-100% for AD8 and 99% to100% for GPCOGi. There was no significant difference in sensitivity by informant type. Specificity by informant type ranged from 25 to 79% for IQCODE, 13-75% for AD8 and 17-38% for GPCOGi. Adult descendants tended to have the lowest specificity at 25% (95% CI 10-47%) for IQCODE, 13% (95% CI 3-32%) for AD8 and 17% (95% CI 5-37%) for GPCOGi. Friends tended to have the highest specificity at 79% (95% CI 49-95%) for IQCODE, 75% (95% CI 48-93%) for AD8 and 38% (95% CI 15-64%) for GPCOGi. CONCLUSIONS: An informant of any relationship type, using IQCODE, AD8 or GPCOGi may be useful for ruling out dementia but not for ruling it in. We found no evidence of difference between spouse or adult descendants but friends performed significantly better overall on IQCODE and AD8.CC BY 4.0 (Creative Commons Attribution