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Medical Sciences Division and John Cairns
A case of disseminated autochthonous Cladophialophora bantiana infection in a renal transplant recipient in the UK.
Disease associated with Cladophialophora bantiana infection is uncommon but can be characterised by severe and life-threatening CNS involvement. Diagnosis is challenging due to both the infection's rarity and non-specific clinical presentation, which can mimic malignancy and infection caused by more common organisms. Transmission can occur via inhalation or inoculation through compromised skin, followed by haematogenous dissemination to the brain and other organs. We report a case of a 42-year-old renal transplant recipient with no travel history presenting with neurological symptoms and skin and lung lesions due to C bantiana infection. An aggressive treatment approach comprising combination antifungal therapy, surgical debridement, and withdrawal of immunosuppression resulted in disease control, although this treatment was complicated by voriconazole-induced skeletal fluorosis. This organism, more commonly encountered in tropical regions, has traditionally been considered imported into the UK by returning travellers, therefore this case of autochthonous infection could reflect an expanding range alongside global climactic shifts.
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 Use of Fluorescent Markers to Detect and Delineate Head and Neck Cancer: A Scoping Review
ABSTRACTObjectivesThe aim of surgery for head and neck squamous cell carcinoma (HNSCC) is to achieve clear resection margins, whilst preserving function and cosmesis. Fluorescent markers have demonstrated potential in the intraoperative visualisation and delineation of tumours, such as glioma, with consequent improvements in resection. The purpose of this scoping review was to identify and compare the fluorescent markers that have been used to detect and delineate HNSCC to date.MethodsA literature search was performed using the Ovid MEDLINE, Ovid Embase, Cochrane CENTRAL, ClinicalTrials.gov and ICTRP databases. Primary human studies published through September 2023 demonstrating the use of fluorescent markers to visualise HNSCC were selected and reviewed independently by two authors.ResultsThe search strategy identified 5776 records. Two hundred and forty‐four full texts were reviewed, and sixty‐five eligible reports were included. The most used fluorescent markers in the included studies were indocyanine green (ICG) (n = 14), toluidine blue (n = 11), antibodies labelled with IRDye800CW (n = 10) and 5‐aminolevulinic acid (5‐ALA) (n = 8). Toluidine blue and ICG both have limited specificity, although novel targeted options derived from ICG may be more effective. 5‐ALA has been demonstrated as a topical marker and, recently, via enteral administration but it is associated with photosensitivity reactions. The fluorescently labelled antibodies cetuximab‐IRDye800CW and panitumumab‐IRDye800CW are promising options being investigated by ongoing trials.ConclusionMultiple safe fluorescent markers have emerged which may aid the surgical resection of HNSCC. Further research in larger cohorts is required to identify which marker should be considered gold standard.
Department Wide Validation in Digital Pathology-Experience from an Academic Teaching Hospital Using the UK Royal College of Pathologists' Guidance.
AIM: we describe our experience of validating departmental pathologists for digital pathology reporting, based on the UK Royal College of Pathologists (RCPath) "Best Practice Recommendations for Implementing Digital Pathology (DP)," at a large academic teaching hospital that scans 100% of its surgical workload. We focus on Stage 2 of validation (prospective experience) prior to full validation sign-off. METHODS AND RESULTS: twenty histopathologists completed Stage 1 of the validation process and subsequently completed Stage 2 validation, prospectively reporting a total of 3777 cases covering eight specialities. All cases were initially viewed on digital whole slide images (WSI) with relevant parameters checked on glass slides, and discordances were reconciled before the case was signed out. Pathologists kept an electronic log of the cases, the preferred reporting modality used, and their experiences. At the end of each validation, a summary was compiled and reviewed with a mentor. This was submitted to the DP Steering Group who assessed the scope of cases and experience before sign-off for full validation. A total of 1.3% (49/3777) of the cases had a discordance between WSI and glass slides. A total of 61% (30/49) of the discordances were categorised as a minor error in a supplementary parameter without clinical impact. The most common reasons for diagnostic discordances across specialities included identification and grading of dysplasia, assessment of tumour invasion, identification of small prognostic or diagnostic objects, interpretation of immunohistochemistry/special stains, and mitotic count assessment. Pathologists showed similar mean diagnostic confidences (on Likert scale from 0 to 7) with a mean of 6.8 on digital and 6.9 on glass slide reporting. CONCLUSION: we describe one of the first real-world experiences of a department-wide effort to implement, validate, and roll out digital pathology reporting by applying the RCPath Recommendations for Implementing DP. We have shown a very low rate of discordance between WSI and glass slides.
Pancreatic Transplantation
The first pancreas transplant was performed in 1966 by Lillehei and Kelly at the University of Minnesota (1). Today, over 50 000 pancreas transplants have been performed globally and transplant is considered the treatment of choice for patients with type 1 diabetes mellitus (T1DM) with hypoglycaemic unawareness. Improvements in patient management has resulted in the expanding indications for both simultaneous pancreas kidney and isolated pancreas transplantation. However, the pancreas remains one of the most challenging organs to successfully transplant and a constant assessment of risks of surgery and immunosuppression needs to be made and weighed against the clinical benefit associated with the long-term tight glycaemic control offered by pancreas transplantation. With an estimated 15% of healthcare costs in the West being diabetes-related and the healthcare costs of a typical patient with T1DM being over $52 000 by the age of 40, pancreas transplantation remains both of significant clinical and economic importance (2).
Using freedom of information requests to access novel data sources in health professions education research.
Educators and researchers are reliant upon access to data to drive teaching methods, curricular improvements, and progress in medical education research. However, data are not always accessible, due to resource constraints, institutional policies, and privacy concerns. Researchers have attempted to access novel data sources through surveys, semistructured interviews, and databases; however, these methodologies are limited. To improve access to data, Freedom of Information (FOI) Acts grant researchers the ability to formally request data that any public institute holds. Researchers have been reluctant to use this tool due to negative perceptions, despite its unique benefits. To increase awareness of this underutilized methodology, we summarize the process of FOI Act requests, its strengths and weaknesses, and the ways in which health professions education can leverage FOI requests within research. We provide examples of the use of FOI requests as a research method within adjacent fields and nascent use within the field of health professions research. In doing so, we hope to highlight how FOI requests can be a useful tool in health professions education researchers and its potential to increase access to unique data sources.
Diagnosis and management of rectal syphilis-case report.
The incidence and prevalence of syphilis are rising worldwide. Rectal syphilis is a rare condition with few reported cases in the literature and therefore often missed from differential diagnosis of atypical anorectal ulceration. We report a case of a 64-year-old male who presented with change in the bowel habit and a palpable rectal mass on examination. Colonoscopy revealed a small, ulcerated lesion in the rectum. However, histopathological analysis and radiological assessments were inconclusive. A cutaneous ulceration prompted a repeat biopsy and staining for spirochaetes, which was diagnostic of syphilitic proctitis. He was successfully treated with first line antibiotics via the Genitourinary Medicine clinic. With its increasing incidence, syphilis should be considered as a potential diagnosis of atypical anorectal ulceration. A complete sexual history including relevant risk factors should be taken and a full clinical examination performed actively looking for signs and symptoms of disease.
A call for objectivity: Radiologists' proposed wishlist for response evaluation in solid tumors (RECIST 1.1).
The Response Evaluation in Solid Tumors (RECIST) 1.1 provides key guidance for performing imaging response assessment and defines image-based outcome metrics in oncology clinical trials, including progression free survival. In this framework, tumors identified on imaging are designated as either target lesions, non-target disease or new lesions and a structured categorical response is assigned at each imaging time point. While RECIST provides definitions for these categories, it specifically and objectively defines only the target disease. Predefined thresholds of size change provide unbiased metrics for determining objective response and disease progression of the target lesions. However, worsening of non-target disease or emergence of new lesions is given the same importance in determining disease progression despite these being qualitatively assessed and less rigorously defined. The subjective assessment of non-target and new disease contributes to reader variability, which can impact the quality of image interpretation and even the determination of progression free survival. The RECIST Working Group has made significant efforts in developing RECIST 1.1 beyond its initial publication, particularly in its application to targeted agents and immunotherapy. A review of the literature highlights that the Working Group has occasionally employed or adopted objective measures for assessing non-target and new lesions in their evaluation of RECIST-based outcome measures. Perhaps a prospective evaluation of these more objective definitions for non-target and new lesions within the framework of RECIST 1.1 might improve reader interpretation. Ideally, these changes could also better align with clinically meaningful outcome measures of patient survival or quality of life.
Expanding Human Breg for Cellular Therapy in Transplantation: Time for Translation.
Regulatory B cells (Breg) are instrumental in protecting allografts in transplantation. Breg signatures are identified in operationally tolerant human kidney transplant recipients and can predict organ survival and acute rejection. Animal models of transplantation and autoimmunity support the use of Breg as an adoptive cellular therapy. Detailed mechanistic studies have identified multiple signaling pathways utilized by Breg in their induction, expansion, and downstream function. These preclinical studies provide the guiding principles, which will inform protocols by which to expand this crucial immunoregulatory population before clinical use. There is an urgent need for novel therapies to improve long-term transplant outcomes and to minimize immunosuppression-related morbidity including life-threatening infection and cancer. Systematic evaluation of the signals, which drive Breg expansion, will be key to transforming the as of yet unharnessed potential of this potent immunoregulatory cell. In this review, we explore the potential avenues of translating Breg subsets from cell culture at the laboratory bench to cell therapy at the patient's bedside. We will discuss the standardization of Breg phenotypes to aid in precursor population selection and quality control of a Breg-cell therapy product. We will evaluate avenues by which to optimize protocols to drive human Breg expansion to levels sufficient for cellular therapy. Finally, we will examine the steps required in process development including scalable culture systems and quality control measures to deliver a viable Breg-cell therapy product for administration to a transplant recipient.
Single cell and spatial transcriptomics highlight the interaction of club-like cells with immunosuppressive myeloid cells in prostate cancer.
Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 120 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells are associated with myeloid inflammation previously linked to androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting.
Improvement of the outcome of the saphenous vein graft when connected to the internal thoracic artery.
BACKGROUND: Since 2000, we have been grafting the right coronary artery system (RCAs) using the proximal portion of the right internal thoracic artery (RITA) as the inflow of the saphenous vein graft (SVG) to increase the number of patients undergoing beating heart complete myocardial revascularization. METHODS: From 2000 to 2022, 928 consecutive patients underwent SVG on the RCAs. In 546 patients (58.8%), the inflow was the RITA (I-graft group), and in 382 patients (41.2%), the inflow was the aorta (Ao-graft group). The inclusion criteria were age ≤75 years, ejection fraction >35%, only one SVG per patient, bilateral internal thoracic arteries as a Y-graft on the left system (three-vessel disease, n = 817, 88.0%) or left internal thoracic artery on the left anterior descending artery and RITA + SVG on the RCAs (two-vessel disease, n = 111, 12.0%). Propensity matching identified 306 patients per group. After a median follow-up of 8 (5-10) years, graft patency was assessed by coronary computed tomographic angiography in 132 patients (64 in the I-graft group and 68 in the Ao-graft group). RESULTS: Early results were similar in both groups. The I-graft group had higher 10-year survival and freedom from main adverse cardiac events (90.0 ± 2.0 vs. 80.6 ± 3.8, p = 0.0162, and 81.3 ± 2.7 vs. 64.7 ± 5.6, p = 0.0206, respectively). When RITA was the inflow, SVG had a higher estimated 10-year patency rate (82.8% ± 6.5 vs. 58.8% ± 7.4, p = 0.0026) and a smaller inner lumen diameter (2.7 ± 0.4 vs. 3.4 ± 0.6 mm, p
Ten years survival benefit and appropriateness of surgical versus percutaneous revascularization in synergy between percutaneous coronary intervention with taxus and cardiac surgery randomized trial.
OBJECTIVES: Average treatment effects from randomized trials do not reflect the heterogeneity of an individual's response to treatment. This study evaluates the appropriate proportions of patients for coronary artery bypass grafting, or percutaneous intervention based on the predicted/observed ratio of 10-year all-cause mortality in the SYNTAX population. METHODS: The study included 1800 randomized patients and 1275 patients in the nested percutaneous (n = 198) or surgical (n = 1077) registries. The primary end-point was 10-year all-cause mortality. The SYNTAX score II-2020 was validated internally in the randomized cohort and externally in the registry cohort. Proportions of patients with survival benefits from coronary artery bypass grafting or percutaneous intervention were determined using SYNTAX score II-2020. RESULTS: Ten-year mortality was 23.8% for coronary artery bypass grafting 28.6% for percutaneous intervention in the randomized cohort, 27.6% for coronary artery bypass grafting, and 55.4% for percutaneous intervention in the registries. In the coronary artery bypass grafting registry, the SYNTAX score II-2020 predicted 10-year mortality with helpful calibration and discrimination (C-index : 0.70, intercept : 0.00, slope : 0.76). The proportion of patients deriving a predicted survival benefit from coronary artery bypass grafting over percutaneous intervention was 82.4% (2143/2602) and 17.7% (459/2602) for the entire SYNTAX trial population; translating into a 4.7 to 1 appropriate ratio of treatment allocation to coronary artery bypass grafting and percutaneous intervention. CONCLUSIONS: Choosing a revascularization modality should depend on an individual's long-term prognosis rather than average treatment effects. Additionally, patients should be informed about their predicted prognosis. TRIAL REGISTRATION: Registered on clinicaltrial.govSYNTAXES: NCT03417050 (https://clinicaltrials.gov/ct2/show/NCT03417050);SYNTAX: NCT00114972 (https://www.clinicaltrials.gov/ct2/show/NCT00114972).