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  • Age-related changes in Vancomycin protein binding: is it time to take it seriously?

    Gadsby, Jessica; Mulla, Hussain; Stochow, Lucy (2024-03-29)
    Background: Vancomycin (VAN) protein binding in plasma is influenced by illness and age; hence, doses titrated according to total concentrations are fraught. In this study, model-estimated free VAN concentrations (EFVC) were compared with assumed free VAN concentrations (AFVC) in neonates, children, and adults in the intensive care unit and those on dialysis. Methods: Patient cohorts were identified from the hospital database. Demographics, clinical characteristics, total VAN concentrations, and laboratory variables were obtained from electronic health records. EFVC was derived from 6 models identified in the literature. For all models, total VAN concentration was the most important predictor; other predictors included albumin, total protein, and dialysis status. The AFVC was calculated as 50% of the total concentration (ie, assumption of 50% bound). Results: Differences between EFVC and AFVC in adults were insignificant; however, differences in pediatric intensive care unit patients, according to 2 different models, were significant: mean ± SD = 4.1 ± 1.58 mg/L and 4.7 ± 2.46 mg/L (P < 0.001); the percentages within the free VAN trough range = 30.4% versus 55.1% and 30% versus 55.1%; and the supratherapeutic percentages = 65.2% versus 31.9% and 66.7% versus 31.9%, respectively. In neonates, the difference between EFVC and AFVC was mean ± SD = 6.9 ± 1.95 mg/L (P < 0.001); the percentages within the free VAN trough range for continuous and intermediate dosing were 0% versus 81.3% and 14.3% versus 71.4%, and the supratherapeutic percentages were 100% versus 6.25% and 71.4% versus 0%, respectively. Conclusions: The fraction of free unbound VAN is higher in sick children and neonates than in adults. Therefore, total VAN concentrations do not correlate with the pharmacologically active free VAN concentrations in the same manner as in adults. Adjusting VAN doses in neonates and children to target the same total VAN concentration as the recommended therapeutic range for adults may result in toxicfree concentrations.
  • Incidental finding of an undifferentiated sarcoma during lower limb Doppler ultrasound: a case report

    Eteng, Rajuno Ernest (2024-05)
    Introduction: Undifferentiated sarcoma is considered a rare and aggressive type of soft tissue sarcoma with the lower extremity reported as the common site for soft tissue sarcomas. Case presentation: We present a rare incidental finding of undifferentiated sarcoma during lower limb Doppler ultrasound with a presenting symptom of right thrombotic-like calf pain in a 49-year-old female. Discussion: On ultrasound, the presented undifferentiated sarcoma appeared as a large heterogeneous, oval-shaped, soft tissue mass deeply seated in the right calf with involvement of the soleus muscle. The features on ultrasound mimicked those of a hematoma; however, the possibility of the lesion being a haematoma was promptly ruled out with the demonstration of internal vascularity on colour Doppler application. The case was then referred to a sarcoma triage multidisciplinary team for a review. Magnetic resonance imaging, computed tomography and biopsy were parts of the diagnostic workup for this case, histology confirmed the soft tissue lesion to be an undifferentiated sarcoma. Emergency above knee amputation of the right leg was performed as part of the patient's treatment. Conclusion: This case report presents a rare incidental finding of undifferentiated sarcoma encountered during lower limb Doppler ultrasound causing thrombotic-like calf pain. Sonographers are encouraged to pay necessary attention and carefully examine any adjacent and incidental soft tissue lesion during lower limb Doppler ultrasound using compression, two-dimensional imaging and colour imaging, especially those that appear with characteristic features of malignancy; urgent referral should be made of such cases to a tertiary soft tissue sarcoma centre for further evaluation and management.
  • MRI reporting radiographers - has there been a progression or regression in numbers and scope of practice?

    Estall, Helen (2024-05-03)
    Introduction: The aim of this study was to determine whether there had been a progression or regression in the numbers and scope of practice of reporting radiographers in Magnetic Resonance Imaging (MRI) in the United Kingdom (UK), using data from a previous study conducted by the author in 2019/20 as a comparison. Methods: Data was gathered via a survey sent to multiple users and groups of MRI Radiographers in the UK. The survey consisted of a questionnaire, using both numerical and free text answers to enable the responders to elaborate on their scope of practice whilst also allowing numerical data to be easily analysed. The responses were analysed for patterns and comparison was made with the data from the previous survey. The questionnaire was based on three main themes of those in training, those trained and those in practice. Results: A total of 62 sites had radiographers in training (n =24) or trained (n = 125) in MRI reporting compared to 46 sites in the previous survey. The majority of responders were from England (n = 56/62) with only a few sites in Scotland (n = 4) and Wales (n = 2). There were 24 radiographers in training, a reduction compared to the previous survey and an increase in the number of radiographers trained (n = 80 to n = 125) and in practice (n = 57 to n = 84). Scope of practice had also increased with the addition of MRCPs, orbits and pituitary. Conclusion: This survey provides evidence that the number and scope of practice of MRI reporting radiographers within the UK has progressed when compared to a previous survey from 2019/20. The numbers however are still low and there remain significant geographical variations. The continued predominance of single handed practice is a concern and the reasons behind this and the slow expansion of skill mix reporting in this modality needs further investigation. Implications for practice: This study provides evidence of the number and scope of practice of the radiographer reporting of MRI examinations in the UK. It also demonstrates that there has been an increase in scope and number of radiographers reporting MRI scans, this will provide evidence and proof of concept for departments looking to initiate or increase this practice.
  • Cognitive Functional Therapy compared with usual physiotherapy care in people with persistent low back pain: a mixed methods feasibility randomised controlled trial in the United Kingdom National Health Service

    Newton, Christopher (2024-06)
    Objectives: To determine the feasibility of completing a definitive randomised controlled trial (RCT), evaluating the clinical and cost-effectiveness of Cognitive Functional Therapy (CFT) in comparison to usual physiotherapy care (UPC), for people with persistent low back pain (LBP). Design and setting: A two-arm parallel feasibility RCT completed in a United Kingdom (UK) Secondary Care National Health Service (NHS) physiotherapy service. Participants: Sixty adult participants who reported LBP lasting for more than three months, that was not attributable to a serious (e.g. cancer) or specific (e.g. radiculopathy) underlying cause, were invited to participate. Participants were allocated at random to receive CFT or UPC. Interventions: Cognitive Functional Therapy and Usual Physiotherapy Care for persistent LBP. Main outcome measures: The primary outcome was the feasibility of completing a definitive RCT, defined by recruitment of at least 5 participants per month, delivery of CFT per protocol and securing relevant and acceptable outcome measures. Data concerning study processes, resources, management and participant reported outcome measures were collected at baseline, 3, 6 and 12-month follow-up. Results: Sixty participants (n = 30 CFT and n = 30 UPC) were recruited with 80% (n = 48), 72% (n = 43) and 53% (n = 32) retained at 3, 6 and 12-month follow-up respectively. NHS physiotherapists were trained to competence and delivered CFT with fidelity. CFT was tolerated by participants with no adverse events. Relevant and clinically important outcome data were collected at all time points (0.4%, 3%, 1% and 0.8% of data was missing from the returned outcome measure booklets at baseline and 3, 6 and 12-month follow-up respectively). The Roland-Morris disability questionnaire was considered the most suitable primary outcome measure with a proposed sample size of 540 participants for a definitive cluster RCT. Conclusion: It is feasible to conduct a randomised study of CFT in comparison to UPC for NHS patients. A future study should incorporate an internal pilot to address aspects of feasibility further, including participant retention strategies. Clinical trial registration number: ISRCTN12965286 CONTRIBUTION OF THE PAPER.
  • The paradox of haemodialysis: the lived experience of the clocked treatment of chronic illness

    Burton, James O; Hull, Katherine L (2024-03)
    Studies exploring the relationship between time and chronic illness have generally focused on measurable aspects of time, also known as linear time. Linear time follows a predictable, sequential order of past, present and future; measured using a clock and predicated on normative assumptions. Sociological concepts addressing lifecourse disruption following diagnosis of chronic illness have served to enhance the understanding of lived experience. To understand the nuanced relationship between time and chronic illness, however, requires further exploration. Here, we show how the implicit assumptions of linear time meet in tension with the lived experience of chronic illness. We draw on interviews and photovoice work with people with end-stage kidney disease in receipt of in-centre-daytime haemodialysis to show how the clocked treatment of chronic illness disrupts experiences of time. Drawing on concepts of 'crip' and 'chronic' time we argue that clocked treatment and the lived experience of chronic illness converge at a paradox whereby clocked treatment allows for the continuation of linear time yet limits freedom. We use the concept of 'crip time' to challenge the normative assumptions implicit within linear concepts of time and argue that the understanding of chronic illness and its treatment would benefit from a 'cripped' starting point.
  • The 1000 Mitoses Project: a consensus-based international collaborative study on mitotic figures classification

    Oswald, Nicola K (2024-04-16)
    Introduction. The identification of mitotic figures is essential for the diagnosis, grading, and classification of various different tumors. Despite its importance, there is a paucity of literature reporting the consistency in interpreting mitotic figures among pathologists. This study leverages publicly accessible datasets and social media to recruit an international group of pathologists to score an image database of more than 1000 mitotic figures collectively. Materials and Methods. Pathologists were instructed to randomly select a digital slide from The Cancer Genome Atlas (TCGA) datasets and annotate 10-20 mitotic figures within a 2 mm2 area. The first 1010 submitted mitotic figures were used to create an image dataset, with each figure transformed into an individual tile at 40x magnification. The dataset was redistributed to all pathologists to review and determine whether each tile constituted a mitotic figure. Results. Overall pathologists had a median agreement rate of 80.2% (range 42.0%-95.7%). Individual mitotic figure tiles had a median agreement rate of 87.1% and a fair inter-rater agreement across all tiles (kappa = 0.284). Mitotic figures in prometaphase had lower percentage agreement rates compared to other phases of mitosis. Conclusion. This dataset stands as the largest international consensus study for mitotic figures to date and can be utilized as a training set for future studies. The agreement range reflects a spectrum of criteria that pathologists use to decide what constitutes a mitotic figure, which may have potential implications in tumor diagnostics and clinical management.
  • When will the glomerular filtration rate in former preterm neonates catch up with their term peers?

    Mulla, Hussain (2024-04)
    Aims: Whether and when glomerular filtration rate (GFR) in preterms catches up with term peers is unknown. This study aims to develop a GFR maturation model for (pre)term-born individuals from birth to 18 years of age. Secondarily, the function is applied to data of different renally excreted drugs. Methods: We combined published inulin clearance values and serum creatinine (Scr) concentrations in (pre)term born individuals throughout childhood. Inulin clearance was assumed to be equal to GFR, and Scr to reflect creatinine synthesis rate/GFR. We developed a GFR function consisting of GFRbirth (GFR at birth), and an Emax model dependent on PNA (with GFRmax, PNA50 (PNA at which half of GFR max is reached) and Hill coefficient). The final GFR model was applied to predict gentamicin, tobramycin and vancomycin concentrations. Result: In the GFR model, GFRbirth varied with birthweight linearly while in the PNA-based Emax equation, GA was the best covariate for PNA50, and current weight for GFRmax. The final model showed that for a child born at 26 weeks GA, absolute GFR is 18%, 63%, 80%, 92% and 96% of the GFR of a child born at 40 weeks GA at 1 month, 6 months, 1 year, 3 years and 12 years, respectively. PopPK models with the GFR maturation equations predicted concentrations of renally cleared antibiotics across (pre)term-born neonates until 18 years well. Conclusions: GFR of preterm individuals catches up with term peers at around three years of age, implying reduced dosages of renally cleared drugs should be considered below this age.
  • Broad evidence of xylazine in the UK illicit drug market beyond heroin supplies: Triangulating from toxicology, drug-testing and law enforcement

    Rice, Kathleen (2024-04-09)
    Background and aims: Xylazine is a non-opioid sedative which has spread rapidly throughout the US illicit drug supply. This study aimed to describe the spread of xylazine throughout the UK illicit drug supply. Methods: Xylazine detections in human biological samples were collated from toxicology laboratories operating in the United Kingdom with the date, location, case type, xylazine concentration and co-detected drugs (with quantifications where performed) detailed, where permitted, by the corresponding coroner. Drug-testing cases positive for xylazine were collated from the Welsh Emerging Drugs and Identification of Novel Substances (WEDINOS) drug-testing postal service with the date, location, purchase intent and co-detected drugs detailed. Drug seizures made by UK law enforcement were communicated by the Office for Health Improvement and Disparities with the date and location detailed. Results: By the end of August 2023, xylazine was detected in 35 cases from throughout toxicology, drug-testing and drug seizure sources covering England, Scotland and Wales. There were no cases reported from Northern Ireland. Xylazine was detected in biological samples from 16 people. In most cases where full toxicology results were provided, xylazine was detected with heroin and/or a strong opioid (n = nine of 11), but this polydrug use pattern was not evident in all cases (n = two of 11), suggesting a wider circulation of xylazine in the UK illicit drug market beyond heroin supplies. Evidence from WEDINOS supports this claim, as all 14 drug samples (100%) submitted from across the UK contained xylazine; however, in none of these cases was heroin the purchase intent but rather counterfeit prescription medication tablets (n = 11 of 14), tetrahydrocannabinol (THC) vapes (n = two of 14) or white powder (n = one of 14). Additional evidence for the spread of illicit xylazine comes from five drug seizures made by law enforcement. Conclusions: Xylazine has penetrated the UK illicit drug market and is not limited to heroin supplies.
  • Critical care pharmacy service provision and workforce in adult extracorporeal membrane oxygenation centres: a multicentre cross-sectional survey

    Cooke, Sarah (2024-03-29)
    Background: There is good evidence describing pharmacy workforce and service provision in general critical care units. However, no data exist from adult extracorporeal membrane oxygenation (ECMO) centres. Aim: To describe workforce characteristics, pharmacy service provision, and pharmaceutical care activities in critical care units (CCUs) providing an adult ECMO service in the United Kingdom (UK) and compare to national staffing standards for CCUs. Method: We conducted a multicentre, cross-sectional electronic survey inviting one pharmacy professional response per UK ECMO centre. We collated information on workforce, service provision, and pharmaceutical care activities provided by pharmacy teams in adult CCUs with an ECMO service. Results: The survey response rate was 90.9%: representatives of 10/11 tertiary hospitals providing ECMO services responded. Median critical care pharmacist to critical care bed was 1:12.1 (IQR: 1:9.4-1:14.9). Most centres (90.0%) did not meet national standards for pharmacy professionals to critical care bed staffing ratios for weekday services. Total critical care beds covered by the critical care pharmacy team varied across the UK: median (IQR) - 45 (37-80) beds. Two centres funded pharmacist time for ECMO activity, and one centre funded a pharmacy technician post. Median peak ECMO activity was 4 ECMO patients in a single day (IQR: 3-5). Most respondents reported reduced pharmacy service at weekends compared to weekday, with limited on-site support. Conclusion: Most responding ECMO centres in the UK reported pharmacy staffing ratios below nationally agreed critical care standards. There was high variability in clinical pharmacy services to ECMO patients over 7 days.
  • Bilateral cubonavicular and synchronous talocalcaneal tarsal coalition with stress response-case report and review of literature

    Hussein, Mohsin (2023-10-27)
    Tarsal coalition occurs in 1% of the population and represents a congenital failure of segmentation in two or more tarsal bones. It most commonly occurs at the talocalcaneal and calcaneonavicular joint. Although commonly asymptomatic, it may present with pain, rigidity, and pes planus. Cubonavicular, multiple synchronous, and bilateral coalitions are rare but an awareness is required to ensure accurate diagnosis and management. In this article, we presented the first reported case (to the best of our knowledge) of bilateral cubonavicular coalition with synchronous talocalcaneal coalition and stress response within the intermediate cuneiform.
  • Popliteal artery-related pathologies in athletes-a primer for musculoskeletal radiologists

    Thaker, Siddharth (2023-11-23)
    Vascular complications in athletes are common and mimic musculoskeletal injuries such as muscle sprains, fractures, and cartilage abnormalities. They include traumatic vascular injuries and more subtle pathologies like entrapment syndromes, pseudoaneurysms, arterial occlusions, and venous thrombosis. Such vascular complications may be occult on imaging and can be difficult for a musculoskeletal radiologist to diagnose, resulting in a lack of timely diagnosis and potentially limb-threatening consequences. Although the final diagnosis may require multidisciplinary input from orthopaedic, sports and exercise medicine, and vascular and interventional radiology inputs, a musculoskeletal radiologist with prior knowledge of such conditions can be the first to diagnose such conditions aiding the athlete's performance. A musculoskeletal radiologist should pay due attention to anatomical courses of vascular channels and look for potential causes of vascular compression, aberrant myotendinous bands, accessory muscles, etc., before concluding a computed tomography (CT) or magnetic resonance imaging (MRI) as normal. Doppler ultrasound, CT, or MR angiography are commonly employed techniques for primary evaluation, whereas digital subtraction angiography is generally reserved for troubleshooting as advanced dynamic imaging.
  • The bright Easter bunny sign: a useful aide-memoire on MRI for costotransverse joint inflammation in axial spondyloarthritis

    Bansal, T; Rennie, W J (2024-05)
    Aim: To assess the significance of the "bright Easter bunny" sign on magnetic resonance imaging (MRI) to indicate inflammatory costotransverse joint (CtJ) lesions to diagnose axial spondyloarthritis (ax-SpA). Materials and methods: Consecutive cases of patients with ax-SpA from a specialist rheumatology clinic were analysed retrospectively over two cohorts, between 2012-2014 and 2018-2020, to determine newly diagnosed patients under the Assessment of SpondyloArthritis international Society (ASAS) criteria. Biological naive adult patients who underwent spine MRI and sacroiliac imaging with full immunological work-up and a C-reactive protein reading within 3 months of the scan were included. Blinded images were reviewed by experienced musculoskeletal radiologists. Result: From the 1,284 cases that were identified, 40 cases met the inclusion criteria for this study. Seven out of the 40 cases (17.5%) identified inflammatory lesions at the CtJ with five (70%) showing concordance with the bright Easter bunny sign. Conclusion: The bright Easter bunny sign is concordant with inflammatory costotransverse enthesitis. This aide-memoire radiological sign is often on overlooked edge-of-field sections and this emphasises the need to ensure adequate coverage of the CtJ on spine MRI protocols as an important anatomical site of inflammatory change in ax-SpA assessment.
  • Association of epicardial adipose tissue with early structural and functional cardiac changes in Type 2 diabetes

    Ayton, Sarah; Bilak, Joanna; Brady, Emer; Dattani, Abhishek; Deshpande, Aparna; Graham-Brown, Matthew P M; Moss, Alastair J; McCann, Gerry P; Singh, Anvesha; Yeo, Jian (2024-05)
    Background: Dysregulated epicardial adipose tissue (EAT) may contribute to the development of heart failure in Type 2 diabetes (T2D). This study aimed to evaluate the associations between EAT volume and composition with imaging markers of subclinical cardiac dysfunction in people with T2D and no prevalent cardiovascular disease. Methods: Prospective case-control study enrolling participants with and without T2D and no known cardiovascular disease. Two hundred and fifteen people with T2D (median age 63 years, 60 % male) and thirty-nine non-diabetics (median age 59 years, 62 % male) were included. Using computed tomography (CT), total EAT volume and mean CT attenuation, as well as, low attenuation (Hounsfield unit range -190 to -90) EAT volume were quantified by a deep learning method and volumes indexed to body surface area. Associations with cardiac magnetic resonance-derived left ventricular (LV) volumes and strain indices were assessed using linear regression. Results: T2D participants had higher LV mass/volume ratio (median 0.89 g/mL [0.82-0.99] vs 0.79 g/mL [0.75-0.89]) and lower global longitudinal strain (GLS; 16.1 ± 2.3 % vs 17.2 ± 2.2 %). Total indexed EAT volume correlated inversely with mean CT attenuation. Low attenuation indexed EAT volume was 2-fold higher (18.8 cm3/m2 vs. 9.4 cm3/m2, p < 0.001) in T2D and independently associated with LV mass/volume ratio (ß = 0.002, p = 0.01) and GLS (ß = -0.03, p = 0.03). Conclusions: Higher EAT volumes seen in T2D are associated with a lower mean CT attenuation. Low attenuation indexed EAT volume is independently, but only weakly, associated with markers of subclinical cardiac dysfunction in T2D.
  • A scoping review of artificial intelligence in medical education: BEME Guide No. 84

    Uraiby, Hussein (2024-02-29)
    Background: Artificial Intelligence (AI) is rapidly transforming healthcare, and there is a critical need for a nuanced understanding of how AI is reshaping teaching, learning, and educational practice in medical education. This review aimed to map the literature regarding AI applications in medical education, core areas of findings, potential candidates for formal systematic review and gaps for future research. Methods: This rapid scoping review, conducted over 16 weeks, employed Arksey and O'Malley's framework and adhered to STORIES and BEME guidelines. A systematic and comprehensive search across PubMed/MEDLINE, EMBASE, and MedEdPublish was conducted without date or language restrictions. Publications included in the review spanned undergraduate, graduate, and continuing medical education, encompassing both original studies and perspective pieces. Data were charted by multiple author pairs and synthesized into various thematic maps and charts, ensuring a broad and detailed representation of the current landscape. Results: The review synthesized 278 publications, with a majority (68%) from North American and European regions. The studies covered diverse AI applications in medical education, such as AI for admissions, teaching, assessment, and clinical reasoning. The review highlighted AI's varied roles, from augmenting traditional educational methods to introducing innovative practices, and underscores the urgent need for ethical guidelines in AI's application in medical education. Conclusion: The current literature has been charted. The findings underscore the need for ongoing research to explore uncharted areas and address potential risks associated with AI use in medical education. This work serves as a foundational resource for educators, policymakers, and researchers in navigating AI's evolving role in medical education. A framework to support future high utility reporting is proposed, the FACETS framework.
  • Late-onset mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and the role of serial imaging

    Ambrogetti, Robert (2024-02-27)
    Mitochondria are essential for human metabolic function. Over 350 genetic mutations are associated with mitochondrial diseases, which are inherited in a matrilineal fashion. In mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), defective mitochondrial function and resultant impaired cellular energy production compromise vascular perfusion in affected tissues. Early diagnostic criteria suggested the diagnosis should be considered in those under 40. However, a broader range of phenotypes are now recognised, including those that present for the first time later in life. The primary presenting feature in MELAS is a stroke-like episode invariably resulting in patients undergoing neuroradiological imaging. We present a case of a woman with a first presentation of a stroke-like episode and seizures in her 40s who was eventually diagnosed with MELAS. We detail her clinical presentation, treatment and diagnosis, emphasising the role of serial imaging in her diagnosis.
  • Soft tissue tumor imaging in adults: European Society of Musculoskeletal Radiology-Guidelines 2023-overview, and primary local imaging: how and where?

    Rennie, Winston (2023-12-07)
    Objectives: Early, accurate diagnosis is crucial for the prognosis of patients with soft tissue sarcomas. To this end, standardization of imaging algorithms, technical requirements, and reporting is therefore a prerequisite. Since the first European Society of Musculoskeletal Radiology (ESSR) consensus in 2015, technical achievements, further insights into specific entities, and the revised WHO-classification (2020) and AJCC staging system (2017) made an update necessary. The guidelines are intended to support radiologists in their decision-making and contribute to interdisciplinary tumor board discussions. Materials and methods: A validated Delphi method based on peer-reviewed literature was used to derive consensus among a panel of 46 specialized musculoskeletal radiologists from 12 European countries. Statements were scored online by level of agreement (0 to 10) during two iterative rounds. Either "group consensus," "group agreement," or "lack of agreement" was achieved. Results: Eight sections were defined that finally contained 145 statements with comments. Overall, group consensus was reached in 95.9%, and group agreement in 4.1%. This communication contains the first part consisting of the imaging algorithm for suspected soft tissue tumors, methods for local imaging, and the role of tumor centers. Conclusion: Ultrasound represents the initial triage imaging modality for accessible and small tumors. MRI is the modality of choice for the characterization and local staging of most soft tissue tumors. CT is indicated in special situations. In suspicious or likely malignant tumors, a specialist tumor center should be contacted for referral or teleradiologic second opinion. This should be done before performing a biopsy, without exception. Clinical relevance: The updated ESSR soft tissue tumor imaging guidelines aim to provide best practice expert consensus for standardized imaging, to support radiologists in their decision-making, and to improve examination comparability both in individual patients and in future studies on individualized strategies. Key points: • Ultrasound remains the best initial triage imaging modality for accessible and small suspected soft tissue tumors. • MRI is the modality of choice for the characterization and local staging of soft tissue tumors in most cases; CT is indicated in special situations. Suspicious or likely malignant tumors should undergo biopsy. • In patients with large, indeterminate or suspicious tumors, a tumor reference center should be contacted for referral or teleradiologic second opinion; this must be done before a biopsy.
  • Pharmacological management of fragile X syndrome: a systematic review and narrative summary of the current evidence

    Barwell, Julian (2024-02-23)
    Introduction: Fragile X Syndrome (FXS) is the most common inherited cause of Intellectual Disability. There is a broad phenotype that includes deficits in cognition and behavioral changes, alongside physical characteristics. Phenotype depends upon the level of mutation in the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene. The molecular understating of the impact of the FMR1 gene mutation provides an opportunity to target treatment not only at symptoms, but on a molecular level. Methods: We conducted a systematic review to provide an up-to-date narrative summary of the current evidence for pharmacological treatment in FXS. The review was restricted to randomized, blinded, placebo-controlled trials. Results: The outcomes from these studies are discussed and the level of evidence assessed against validated criteria. The initial search identified 2377 articles, of which 16 were included in the final analysis. Conclusion: Based on this review to date there is limited data to support any specific pharmacological treatments, although the data for cannabinoids is encouraging in those with FXS and in future developments in gene therapy may provide the answer to the search for precision medicine. Treatment must be person-centered and consider the combination of medical, genetic, cognitive and emotional challenges.
  • Digital pathology for reporting histopathology samples, including cancer screening samples - definitive evidence from a multisite study

    Hero, Emily (2024-04)
    Aims: To conduct a definitive multicentre comparison of digital pathology (DP) with light microscopy (LM) for reporting histopathology slides including breast and bowel cancer screening samples. Methods: A total of 2024 cases (608 breast, 607 GI, 609 skin, 200 renal) were studied, including 207 breast and 250 bowel cancer screening samples. Cases were examined by four pathologists (16 study pathologists across the four speciality groups), using both LM and DP, with the order randomly assigned and 6 weeks between viewings. Reports were compared for clinical management concordance (CMC), meaning identical diagnoses plus differences which do not affect patient management. Percentage CMCs were computed using logistic regression models with crossed random-effects terms for case and pathologist. The obtained percentage CMCs were referenced to 98.3% calculated from previous studies. Results: For all cases LM versus DP comparisons showed the CMC rates were 99.95% [95% confidence interval (CI) = 99.90-99.97] and 98.96 (95% CI = 98.42-99.32) for cancer screening samples. In speciality groups CMC for LM versus DP showed: breast 99.40% (99.06-99.62) overall and 96.27% (94.63-97.43) for cancer screening samples; [gastrointestinal (GI) = 99.96% (99.89-99.99)] overall and 99.93% (99.68-99.98) for bowel cancer screening samples; skin 99.99% (99.92-100.0); renal 99.99% (99.57-100.0). Analysis of clinically significant differences revealed discrepancies in areas where interobserver variability is known to be high, in reads performed with both modalities and without apparent trends to either. Conclusions: Comparing LM and DP CMC, overall rates exceed the reference 98.3%, providing compelling evidence that pathologists provide equivalent results for both routine and cancer screening samples irrespective of the modality used.
  • Redox modulation of oxidatively-induced DNA damage by ascorbate enhances both in vitro and ex-vivo DNA damage formation and cell death in melanoma cells

    Brown, Karen; Saldanha, Gerald; Sanusi, Timi (2024-03)
    Elevated genomic instability in cancer cells suggests a possible model-scenario for their selective killing via the therapeutic delivery of well-defined levels of further DNA damage. To examine this scenario, this study investigated the potential for redox modulation of oxidatively-induced DNA damage by ascorbate in malignant melanoma (MM) cancer cells, to selectively enhance both DNA damage and MM cell killing. DNA damage was assessed by Comet and ɣH2AX assays, intracellular oxidising species by dichlorofluorescein fluorescence, a key antioxidant enzymatic defence by assessment of catalase activity and cell survival was determined by clonogenic assay. Comet revealed that MM cells had higher endogenous DNA damage levels than normal keratinocytes (HaCaT cells); this correlated MM cells having higher intracellular oxidising species and lower catalase activity, and ranked with MM cell melanin pigmentation. Comet also showed MM cells more sensitive towards the DNA damaging effects of exogenous H2O2, and that ascorbate further enhanced this H2O2-induced damage in MM cells; again, with MM cell sensitivity to induced damage ranking with degree of cell pigmentation. Furthermore, cell survival data indicated that ascorbate enhanced H2O2-induced clonogenic cell death selectively in MM cells whilst protecting HaCaT cells. Finally, we show that ascorbate serves to enhance the oxidising effects of the MM therapeutic drug Elesclomol in both established MM cells in vitro and primary cell cultures ex vivo. Together, these results suggest that ascorbate selectively enhances DNA damage and cell-killing in MM cells. This raises the option of incorporating ascorbate into clinical oxidative therapies to treat MM.

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