Quantifying the proportion of different cell types in the human cortex using DNA methylation profiles

BACKGROUND: Due to interindividual variation in the cellular composition of the human cortex, it is essential that covariates that capture these differences are included in epigenome-wide association studies using bulk tissue. As experimentally derived cell counts are often unavailable, computational solutions have been adopted to estimate the proportion of different cell types using DNA methylation data. Here, we validate and profile the use of an expanded reference DNA methylation dataset incorporating two neuronal and three glial cell subtypes for quantifying the cellular composition of the human cortex. RESULTS: We tested eight reference panels containing different combinations of neuronal- and glial cell types and characterised their performance in deconvoluting cell proportions from computationally reconstructed or empirically derived human cortex DNA methylation data. Our analyses demonstrate that while these novel brain deconvolution models produce accurate estimates of cellular proportions from profiles generated on postnatal human cortex samples, they are not appropriate for the use in prenatal cortex or cerebellum tissue samples. Applying our models to an extensive collection of empirical datasets, we show that glial cells are twice as abundant as neuronal cells in the human cortex and identify significant associations between increased Alzheimer's disease neuropathology and the proportion of specific cell types including a decrease in NeuNNeg/SOX10Neg nuclei and an increase of NeuNNeg/SOX10Pos nuclei. CONCLUSIONS: Our novel deconvolution models produce accurate estimates for cell proportions in the human cortex. These models are available as a resource to the community enabling the control of cellular heterogeneity in epigenetic studies of brain disorders performed on bulk cortex tissue.published versionRD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted

PSMF1 variants cause a phenotypic spectrum from early-onset Parkinson's disease to perinatal lethality by disrupting mitochondrial pathways

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a new gene implicated in PD and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD and parkinsonism to perinatal lethality with neurological manifestations across 15 unrelated pedigrees with 22 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants impair mitochondrial membrane potential, dynamics and mitophagy in patient-derived fibroblasts. Additionally, we develop models of psmf1 knockdown Drosophila and Psmf1 conditional knockout mouse exhibiting age-dependent motor impairment, with diffuse gliosis in mice. These findings unequivocally link defective PSMF1 to early-onset PD and neurodegeneration and suggest mitochondrial dysfunction as a mechanistic contributor.UnknownUnpublished eprin

A scoping review of stroke services within the Philippines

BACKGROUND: Stroke is a leading cause of mortality and disability. In higher-income countries, mortality and disability have been reduced with advances in stroke care and early access to rehabilitation services. However, access to such services and the subsequent impact on stroke outcomes in the Philippines, which is a lower- and middle-income countries (LMIC), is unclear. Understanding gaps in service delivery and underpinning research from acute to chronic stages post-stroke will allow future targeting of resources. AIMS: This scoping review aimed to map available literature on stroke services in the Philippines, based on Arksey and O'Malley's five-stage-process. A targeted strategy was used to search relevant databases (Focused: MEDLINE (ovid), EMBASE (ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO (ebsco); broad-based: Scopus; review-based: Cochrane Library, International Prospective Register of Systematic Reviews (PROSPERO), JBI (formerly Joanna Briggs Institute) as well as grey literature (Open Grey, Google scholar). The searches were conducted between 12/2022-01/2023 and repeated 12/2023. Literature describing adults with stroke in the Philippines and stroke services that aimed to maximize well-being, participation and function were searched. Studies were selected if they included one or more of: (a) patient numbers and stroke characteristics (b) staff numbers, qualifications and role (c) service resources (e.g., access to a rehabilitation unit) (d) cost of services and methods of payment) (e) content of stroke care (f) duration of stroke care/rehabilitation and interventions undertaken (g) outcome measures used in clinical practice. A total of 70 papers were included. Articles were assessed, data extracted and classified according to structure, process, or outcome related information. Advances in stroke services, including stroke ready hospitals providing early access to acute care such as thrombectomy and thrombolysis and early referral to rehabilitation coupled with rehabilitation guidelines have been developed. Gaps exist in stroke services structure (e.g., low number of neurologists and neuroimaging, lack of stroke protocols and pathways, inequity of stroke care across urban and rural locations), processes (e.g., delayed arrival to hospital, lack of stroke training among health workers, low awareness of stroke among public and non-stroke care workers, inequitable access to rehabilitation both hospital and community) and outcomes (e.g., low government insurance coverage resulting in high out-of-pocket expenses, limited data on caregiver burden, absence of unified national stroke registry to determine prevalence, incidence and burden of stroke). Potential solutions such as increasing stroke knowledge and awareness, use of mobile stroke units, TeleMedicine, TeleRehab, improving access to rehabilitation, upgrading PhilHealth and a unified national long-term stroke registry representing the real situation across urban and rural were identified. CONCLUSION: This scoping review describes the existing evidence-base relating to structure, processes and outcomes of stroke services for adults within the Philippines. Developments in stroke services have been identified however, a wide gap exists between the availability of stroke services and the high burden of stroke in the Philippines. Strategies are critical to address the identified gaps as a precursor to improving stroke outcomes and reducing burden. Potential solutions identified within the review will require healthcare government and policymakers to focus on stroke awareness programs, primary and secondary stroke prevention, establishing and monitoring of stroke protocols and pathways, sustainable national stroke registry, and improve access to and availability of rehabilitation both hospital and community. WHAT IS ALREADY KNOWN?: Stroke services in the Philippines are inequitable, for example, urban versus rural due to the geography of the Philippines, location of acute stroke ready hospitals and stroke rehabilitation units, limited transport options, and low government healthcare insurance coverage resulting in high out-of-pocket costs for stroke survivors and their families. WHAT ARE THE NEW FINDINGS?: The Philippines have a higher incidence of stroke in younger adults than other LMICs, which impacts the available workforce and the country's economy. There is a lack of data on community stroke rehabilitation provision, the content and intensity of stroke rehabilitation being delivered and the role and knowledge/skills of those delivering stroke rehabilitation, unmet needs of stroke survivors and caregiver burden and strain, WHAT DO THE NEW FINDINGS IMPLY?: A wide gap exists between the availability of stroke services and the high burden of stroke. The impact of this is unclear due to the lack of a compulsory national stroke registry as well as published data on community or home-based stroke services that are not captured/published. WHAT DOES THIS REVIEW OFFER?: This review provides a broad overview of existing evidence-base of stroke services in the Philippines. It provides a catalyst for a) healthcare government to address stroke inequities and burden; b) development of future evidence-based interventions such as community-based rehabilitation; c) task-shifting e.g., training non-neurologists, barangay workers and caregivers; d) use of digital technologies and innovations e.g., stroke TeleRehab, TeleMedicine, mobile stroke units.Published vesionJournal 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

Acceptability of magnetic resonance imaging for prostate cancer diagnosis with patients and GPs: a qualitative interview study

BACKGROUND: Magnetic resonance imaging (MRI) of the prostate is a new, more accurate, non-invasive test for prostate cancer diagnosis. AIM: To understand the acceptability of MRI for patients and GPs for prostate cancer diagnosis. DESIGN AND SETTING: Qualitative study of men who had undergone a prostate MRI for possible prostate cancer, and GPs who had referred at least one man for possible prostate cancer in the previous 12 months in West London and Devon. METHOD: Semi-structured interviews, conducted in person or via telephone, were audio-recorded and transcribed verbatim. Deductive thematic analysis was undertaken using Sekhon's Theoretical Framework of Acceptability, retrospectively for patients and prospectively for GPs. RESULTS: Twenty-two men (12 from Devon, age range 47-80 years), two patients' partners, and 10 GPs (6 female, age range 36-55 years) were interviewed. Prostate MRI was broadly acceptable for most patient participants, and they reported that it was not a significant undertaking to complete the scan. GPs were more varied in their views on prostate MRI, with a broad spectrum of knowledge and understanding of prostate MRI. Some GPs expressed concerns about additional clinical responsibility and local availability of MRI if direct access to prostate MRI in primary care were to be introduced. CONCLUSION: Prostate MRI appears to be acceptable to patients. Some differences were found between patients in London and Devon, mainly around burden of testing and opportunity costs. Further exploration of GPs' knowledge and understanding of prostate MRI could inform future initiatives to widen access to diagnostic testing in primary care.Not permittedJournal 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

Predictors of appendicectomy one year after antibiotic treatment for acute appendicitis: Insights from a prospective, multicentre, observational study

BACKGROUND: Surgeons are sometimes reluctant to manage uncomplicated appendicitis non-operatively. Reasons cited include the risk of recurrent appendicitis and the risk of missed appendiceal malignancy. The aim of this study was to address these uncertainties and determine the long-term efficacy of antibiotic versus operative management of appendicitis. METHOD: One-year follow-up of patients enrolled in the multicentre, COVID:HAREM cohort study during March-June 2020 was performed. Initial operative or non-operative management was determined on a case-by-case basis by the responsible surgeon. Outcomes were appendicectomy rate at 1-year, histology of removed appendix and predictors of unsuccessful antibiotic treatment. RESULTS: A total of 625 patients who had non-operative management were included. Emergency appendicectomy had been performed by 1-year in 24% (149/625), with a median time to appendicectomy of 12 days [IQR 1-77] from presentation. Thirty-one patients had elective appendicectomy. Normal histology was reported in 6% of emergency procedures and 58% of elective ones. There were 7 malignancies and 3 neuroendocrine tumors identified at histology. All patients with malignant histology had ≥1 risk factors for malignancy at initial presentation. Faecolithiasis (hazard ratios (HR) 2.3, 95% confidence intervals (CI) 1.51-3.49) and a high Adult Appendicitis Score (AAS >16; HR 2.44, 95% CI 1.52-3.92) were independent risk factors for unsuccessful non-operative management. CONCLUSION: At 1 year, 71% of patients managed non-operatively did not undergo an appendicectomy. Recurrence of appendicitis was associated with faecolithiasis and a high AAS. Patients at higher risk for appendiceal malignancy should have targeted follow-up. These factors should be considered when counseling patients on non-operative management.RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted

Emergency umbilical hernia management: scoping review

BACKGROUND: Umbilical hernias, while frequently asymptomatic, may become acutely symptomatic, strangulated or obstructed, and require emergency treatment. Robust evidence is required for high-quality care in this field. This scoping review aims to elucidate evidence gaps regarding emergency care of umbilical hernias. METHODS: EMBASE, MEDLINE and CENTRAL databases were searched using a predefined strategy until November 2023. Primary research studies reporting on any aspect of emergency umbilical hernia care and published in the English language were eligible for inclusion. Studies were excluded where emergency umbilical hernia care was not the primary focus and subsets of relevant data were unable to be extracted. Two independent reviewers screened abstracts and full texts, resolving disagreements by consensus or a third reviewer. Data were charted according to core concepts addressed by each study and a narrative synthesis was performed. RESULTS: Searches generated 534 abstracts, from which 32 full texts were assessed and 14 included in the final review. This encompassed 52 042 patients undergoing emergency umbilical hernia care. Most were retrospective cohort designs (11/14), split between single (6/14) and multicentre (8/14) with only one randomized trial. Most multicentre studies were from national databases (7/8). Themes arising included risk assessment (n = 4), timing of surgery (n = 4), investigations (n = 1), repair method (n = 8, four mesh versus suture; four laparoscopic versus open) and operative outcomes (n = 11). The most commonly reported outcomes were mortality (n = 9) and morbidity (n = 7) rates and length of hospital stay (n = 5). No studies included patient-reported outcomes specific to emergency umbilical hernia repair. CONCLUSION: This scoping review demonstrates the paucity of high-quality data for this condition. There is a need for randomized trials addressing all aspects of emergency umbilical hernia repair, with patient-reported outcomes.Published version, accepted version, submitted versionJournal 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

Investigating the genetic basis of hereditary spastic paraplegia and cerebellar Ataxia in Pakistani families

BACKGROUND: Hereditary Spastic Paraplegias (HSPs) and Hereditary Cerebellar Ataxias (HCAs) are progressive neurodegenerative disorders encompassing a spectrum of neurogenetic conditions with significant overlaps of clinical features. Spastic ataxias are a group of conditions that have features of both cerebellar ataxia and spasticity, and these conditions are frequently clinically challenging to distinguish. Accurate genetic diagnosis is crucial but challenging, particularly in resource-limited settings. This study aims to investigate the genetic basis of HSPs and HCAs in Pakistani families. METHODS: Families from Khyber Pakhtunkhwa with at least two members showing HSP or HCA phenotypes, and who had not previously been analyzed genetically, were included. Families were referred for genetic analysis by local neurologists based on the proband's clinical features and signs of a potential genetic neurodegenerative disorder. Whole Exome Sequencing (WES) and Sanger sequencing were then used to identify and validate genetic variants, and to analyze variant segregation within families to determine inheritance patterns. The mean age of onset and standard deviation were calculated to assess variability among affected individuals, and the success rate was compared with literature reports using differences in proportions and Cohen's h. RESULTS: Pathogenic variants associated with these conditions were identified in five of eight families, segregating according to autosomal recessive inheritance. These variants included previously reported SACS c.2182 C > T, p.(Arg728*), FA2H c.159_176del, p.(Arg53_Ile58del) and SPG11 c.2146 C > T, p.(Gln716*) variants, and two previously unreported variants in SACS c.2229del, p.(Phe743Leufs*8) and ZFYVE26 c.1926_1941del, p.(Tyr643Metfs*2). Additionally, FA2H and SPG11 variants were found to have recurrent occurrences, suggesting a potential founder effect within the Pakistani population. Onset age among affected individuals ranged from 1 to 14 years (M = 6.23, SD = 3.96). The diagnostic success rate was 62.5%, with moderate effect sizes compared to previous studies. CONCLUSIONS: The findings of this study expand the genotypic and phenotypic spectrum of HSPs and HCAs in Pakistan and emphasize the importance of utilizing exome/genome sequencing for accurate diagnosis or support accurate differential diagnosis. This approach can improve genetic counseling and clinical management, addressing the challenges of diagnosing neurodegenerative disorders in resource-limited settings.This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/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

The 'vulnerable nerve'; surgically acquired neuropathy in distal humeral surgery patients and the role of a tourniquet

BACKGROUND: The complication of neuropathy is high in patients undergoing distal humerus surgery. Tourniquets (TQs) are typically used but can lead to nerve injury. METHODS: We present a comparative study of a pre-intervention group (n = 38) and a post-intervention group (n = 38) undergoing distal humerus surgery between November 2020 and July 2023. The intervention included TQ discontinuation and the introduction of intravenous tranexamic acid at induction. Our analysis encompasses patient, anaesthetic, and surgical variables, as well as the rates and severity of neuropathy. RESULTS: Post-intervention, the rate of surgically acquired or deterioration in nerve injury improved from 15.8% (n = 6) to 2.6% (n = 1). Pre-intervention, the mean TQ duration was significantly longer for patients with post-operative neuropathy versus those without (120 min, SD = 29 vs. 88 min, SD = 38, p = 0.032). Surgery duration was not significantly longer without a TQ but was associated with a greater reduction in haemoglobin (12.7 g/L, SD = 10.9 vs. 25.2 g/L, SD = 15.5, p = 0.03). DISCUSSION: Trauma patients have a high risk of acquiring a nerve injury following elbow surgery or deterioration of a pre-surgical nerve injury, which emphasises the concept of vulnerable nerves. The cessation of using a TQ was associated with a lower nerve injury rate, with no cases of major nerve injury and no significant increase in surgical time.Full Text unavailable for 1 year from time of publication

The Getting It right First Time (GIRFT) programme in urology; rationale and methodology

The Getting It Right First Time (GIRFT) programme is a quality improvement initiative covering the National Health Service in England. The programme aims to standardise clinical practices and improve patient and system level outcomes by utilising data-driven insights and clinically-led recommendations. There are GIRFT workstreams for every medical and surgical specialty, including urology. Defining features of the GIRFT methodology are that it is clinically led by experienced clinicians, data-driven, and specialty specific. Each specialty workstream conducts deep-dive visits to every hospital, analysing performance data and engaging with clinicians and management to identify and share improvement priorities. For urology, GIRFT has completed deep-dive visits and published reports outlining priority areas for development. Reports include recommendations pertaining to streamlining care pathways, reducing the acuity of care environments, enhancing emergency services, optimising utilisation of outpatient services, and workforce training and utilisation. The GIRFT academy provides guides for implementing best practices specific to priority areas of care. These include important disease pathways, and GIRFT-advocated innovations such as urology investigation units and urology area networks. GIRFT offers clinical transformation, cost reduction, equity in access to care, and leaner models of care that are often more environmentally sustainable. Evaluation efforts of the programme have focussed on assessing the adoption of GIRFT recommendations, understanding barriers to change, and modelling the climate impact of advocated practices.Published version, accepted version (12 month embargo), submitted versionRDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted

Single-shot liposomal bupivacaine in place of rectus sheath catheters to provide non-opiate analgesia after laparotomy: a quality improvement project to reduce the need for ongoing nursing input

Opioid-sparing pain management is an integral component of enhanced recovery after colonic and rectal surgery. In our hospital, rectus sheath catheters (RSCs) are routinely placed during emergency laparotomy for colorectal procedures to allow a postoperative compartmental block of the surgical site with repeated doses of bupivacaine. However, RSCs require a significant amount of clinical nursing time to maintain and 'top-up'. We present a quality improvement project in which we administered single-shot liposomal bupivacaine (LB) intraoperatively as an alternative to bolus doses of conventional bupivacaine delivered through RSCs. Having thereby reduced the demands placed on nursing time through a reduction in the use of RSCs, we sought to establish whether there was any associated change in analgesic efficacy. Patient pain scores, use of patient-controlled analgesia (PCA) and length of stay following surgery were analysed before and after the introduction of LB. No disruption in these outcomes was identified using statistical process control analysis. A direct comparison of results for patients who received LB versus those who received bolus dosing of bupivacaine via RSCs found no significant differences, with a median total PCA dose of 270 mg oral morphine equivalents (OME) for patients who received LB versus 396 mg OME for patients who had RSCs (p=0.54). The median length of stay for patients who received LB was 15.5 days versus 16 days for those who had RSCs (p=0.87). We conclude that LB represents a viable alternative to boluses of conventional bupivacaine via RSCs in promoting enhanced recovery after emergency laparotomy and look to extend its use locally.Published version, accepted version, submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text