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Journal of the Nuffield Department of Surgical Sciences (JNDS) has published its third issue.
Evaluation of 3D C-Arm Fluoroscopy versus Diagnostic CT for Deep Brain Stimulation Stereotactic Registration and Post-Operative Lead Localization.
INTRODUCTION: DBS efficacy depends on accuracy. CT-MRI fusion is established for both stereotactic registration and electrode placement verification. The desire to streamline DBS workflows, reduce operative time, and minimize patient transfers has increased interest in portable imaging modalities such as the Medtronic O-arm® and mobile CT. However, these remain expensive and bulky. 3D C-arm fluoroscopy (3DXT) units are a smaller and less costly alternative, albeit incompatible with traditional frame-based localization and without useful soft tissue resolution. We aimed to compare fusion of 3DXT and CT with pre-operative MRI to evaluate if 3DXT-MRI fusion alone is sufficient for accurate registration and reliable targeting verification. We further assess DBS targeting accuracy using a 3DXT workflow and compare radiation dosimetry between modalities. METHODS: Patients underwent robot-assisted DBS implantation using a workflow incorporating 3DXT which we describe. Two intra-operative 3DXT spins were performed for registration and accuracy verification followed by conventional CT post-operatively. Post-operative 3DXT and CT images were independently fused to the same pre-operative MRI sequence and co-ordinates generated for comparison. Registration accuracy was compared to 15 consecutive controls who underwent CT-based registration. Radial targeting accuracy was calculated and radiation dosimetry recorded. RESULTS: Data were obtained from 29 leads in 15 consecutive patients. 3DXT registration accuracy was significantly superior to CT with mean error 0.22 ± 0.03 mm (p < 0.0001). Mean Euclidean electrode tip position variation for CT to MRI versus 3DXT to MRI fusion was 0.62 ± 0.40 mm (range 0.0 mm-1.7 mm). In comparison, direct CT to 3DXT fusion showed electrode tip Euclidean variance of 0.23 ± 0.09 mm. Mean radial targeting accuracy assessed on 3DXT was 0.97 ± 0.54 mm versus 1.15 ± 0.55 mm on CT with differences insignificant (p = 0.30). Mean patient radiation doses were around 80% lower with 3DXT versus CT (p < 0.0001). DISCUSSION: Mobile 3D C-arm fluoroscopy can be safely incorporated into DBS workflows for both registration and lead verification. For registration, the limited field of view requires the use of frameless transient fiducials and is highly accurate. For lead position verification based on MRI co-registration, we estimate there is around a 0.4 mm discrepancy between lead position seen on 3DXT versus CT when corrected for brain shift. This is similar to that described in O-arm® or mobile CT series. For units where logistical or financial considerations preclude the acquisition of a cone beam CT or mobile CT scanner, our data support portable 3D C-arm fluoroscopy as an acceptable alternative with significantly lower radiation exposure.
LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells.
Using 13C6 glucose labeling coupled to gas chromatography-mass spectrometry and 2D 1H-13C heteronuclear single quantum coherence NMR spectroscopy, we have obtained a comparative high-resolution map of glucose fate underpinning β cell function. In both mouse and human islets, the contribution of glucose to the tricarboxylic acid (TCA) cycle is similar. Pyruvate fueling of the TCA cycle is primarily mediated by the activity of pyruvate dehydrogenase, with lower flux through pyruvate carboxylase. While the conversion of pyruvate to lactate by lactate dehydrogenase (LDH) can be detected in islets of both species, lactate accumulation is 6-fold higher in human islets. Human islets express LDH, with low-moderate LDHA expression and β cell-specific LDHB expression. LDHB inhibition amplifies LDHA-dependent lactate generation in mouse and human β cells and increases basal insulin release. Lastly, cis-instrument Mendelian randomization shows that low LDHB expression levels correlate with elevated fasting insulin in humans. Thus, LDHB limits lactate generation in β cells to maintain appropriate insulin release.
Kidney Tissue Proteome Profiles in Short Versus Long Duration of Delayed Graft Function - A Pilot Study in Donation After Circulatory Death Donors
Introduction: Delayed graft function (DGF) is often defined as the need for dialysis treatment in the first week after a kidney transplantation. This definition, though readily applicable, is generic and unable to distinguish between “types” of DGF or time needed to recover function that may also significantly affect longer-term outcomes. We aimed to profile biological pathways in donation after circulatory death (DCD) kidney donors that correlate with DGF and different DGF durations. Methods: A total of N ¼ 30 DCD kidney biopsies were selected from the UK Quality in Organ Donation (QUOD) biobank and stratified according to DGF duration (immediate function, IF n ¼ 10; “short-DGF” (1–6 days), SDGF n ¼ 10; “long-DGF” (7–22 days), LDGF n ¼ 10). Samples were matched for donor and recipient demographics and analyzed by label-free quantitative (LFQ) proteomics, yielding identification of N ¼ 3378 proteins. Results: Ingenuity pathway analysis (IPA) on differentially abundant proteins showed that SDGF kidneys presented upregulation of stress response pathways, whereas LDGF presented impaired response to stress, compared to IF. LDGF showed extensive metabolic deficits compared to IF and SDGF. Conclusion: DCD kidneys requiring dialysis only in the first week posttransplant present acute cellular injury at donation, alongside repair pathways upregulation. In contrast, DCD kidneys requiring prolonged dialysis beyond 7 days present minimal metabolic and antioxidant responses, suggesting that current DGF definitions might not be adequate in distinguishing different patterns of injury in donor kidneys contrib uting to DGF.
Adaptation to chronic hypoxia in triple-negative breast cancer
Low levels of oxygen (i.e. hypoxia) are often observed in solid tumours. Hypoxia is able to drive several of the cancer hallmarks and promotes resistance to both radio and chemotherapy, resulting in its association with poor prognosis. Triple-negative breast cancer has the worst prognosis of all breast cancer subtypes with a 5 year survival rate of only 76.7%, and only 10.8% if the cancer has already metastasised. In line with this, triple-negative tumours often have higher levels of hypoxia than their hormone receptor expressing counterparts. The length and severity of hypoxia is heterogeneous both within and between tumours, meaning cells within the same tumour may experience both acute and chronic hypoxia. Acute hypoxia (⩽ 24 hours) is relatively well studied, whereas research into chronic hypoxia (⩾ 7 days) is lacking. This thesis therefore aimed to characterise the transcriptional response to chronic hypoxia using RNA sequencing. It also aimed to identify proteins or microRNAs which are necessary for adaptation to chronic hypoxia using genome-wide CRISPR screening. This method enables specific vulnerabilities in hypoxic cells to be identified, meaning drugs can be designed to target these “Achilles heels”. The major pathways altered under chronic hypoxia were related to epithelial-mesenchymal transition (EMT) and cell adhesion, with triple-negative breast cancer cells undergoing an atypical form of EMT. However, none of the genes which were upregulated in response to chronic hypoxia were found to be essential for their survival. Instead, hypoxic cells had a greater dependence on general control nonderepressible 2 (GCN2), an instigator of the integrated stress response usually activated under amino acid starvation. GCN2 was found to be active under chronic hypoxia, and chemical inhibition of GCN2 reduced cell growth in vitro. Previous work has shown that GCN2 knockout mice are healthy unless fed a diet restricted in essential amino acids, meaning targeting GCN2 is unlikely to result in severe toxicities. Together, this means GCN2 constitutes a promising therapeutic target for hypoxic tumours. No microRNAs essential for survival under hypoxia were identified in this study.
A Report on the Safety of Acitretin Use in Renal Failure Patients on Hemodialysis
Abstract Acitretin, commonly used for severe psoriasis and keratinocyte carcinoma chemoprevention in high-risk patients, is contraindicated in patients with end stage renal disease on hemodialysis. However, these patients often lack medication choices and in certain clinical scenarios, the benefits of acitretin may outweigh the potential risks. We identified 24 end stage renal disease patients on HD taking acitretin from Duke and Vanderbilt University Medical Centers. While adverse effects were common, patients did not frequently discontinue the medication due to them. We also found no association between acitretin with hospital admissions or mortality. We lastly found statistically significant increases in ALP and total bilirubin when on acitretin and dialysis compared to baseline. However, there was no dose-dependency or temporal association with acitretin or hemodialysis initiation. Based off these preliminary findings, we find that acitretin may safely be used in patients receiving HD with close monitoring of ALP and bilirubin.
Long-term Outcomes With Islet-Alone and Islet-After-Kidney Transplantation for Type 1 Diabetes in the Clinical Islet Transplantation Consortium: The CIT-08 Study.
OBJECTIVE: To determine long-term outcomes for islet-alone and islet-after-kidney transplantation in adults with type 1 diabetes complicated by impaired awareness of hypoglycemia. RESEARCH DESIGN AND METHODS: This was a prospective interventional and observational cohort study of islet-alone (n = 48) and islet-after-kidney (n = 24) transplant recipients followed for up to 8 years after intraportal infusion of one or more purified human pancreatic islet products under standardized immunosuppression. Outcomes included duration of islet graft survival (stimulated C-peptide ≥0.3 ng/mL), on-target glycemic control (HbA1c <7.0%), freedom from severe hypoglycemia, and insulin independence. RESULTS: Of the 48 islet-alone and 24 islet-after-kidney transplantation recipients, 26 and 8 completed long-term follow-up with islet graft function, 15 and 7 withdrew from follow-up with islet graft function, and 7 and 9 experienced islet graft failure, respectively. Actuarial islet graft survival at median and final follow-up was 84% and 56% for islet-alone and 69% and 49% for islet-after-kidney (P = 0.007) with 77% and 49% of islet-alone and 57% and 35% of islet-after-kidney transplantation recipients maintaining posttransplant HbA1c <7.0% (P = 0.0017); freedom from severe hypoglycemia was maintained at >90% in both cohorts. Insulin independence was achieved by 74% of islet-alone and islet-after-kidney transplantation recipients, with more than one-half maintaining insulin independence during long-term follow-up. Kidney function remained stable during long-term follow-up in both cohorts, and rates of sensitization against HLA were low. Severe adverse events occurred at 0.31 per patient-year for islet-alone and 0.43 per patient-year for islet-after-kidney transplantation. CONCLUSIONS: Islet transplantation results in durable islet graft survival permitting achievement of glycemic targets in the absence of severe hypoglycemia for most appropriately indicated recipients having impaired awareness of hypoglycemia, with acceptable safety of added immunosuppression for both islet-alone and islet-after-kidney transplantation.
Neutrophilia, lymphopenia and myeloid dysfunction: a living review of the quantitative changes to innate and adaptive immune cells which define COVID-19 pathology.
Destabilization of balanced immune cell numbers and frequencies is a common feature of viral infections. This occurs due to, and further enhances, viral immune evasion and survival. Since the discovery of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), which manifests in coronavirus disease 2019 (COVID-19), a great number of studies have described the association between this virus and pathologically increased or decreased immune cell counts. In this review, we consider the absolute and relative changes to innate and adaptive immune cell numbers, in COVID-19. In severe disease particularly, neutrophils are increased, which can lead to inflammation and tissue damage. Dysregulation of other granulocytes, basophils and eosinophils represents an unusual COVID-19 phenomenon. Contrastingly, the impact on the different types of monocytes leans more strongly to an altered phenotype, e.g. HLA-DR expression, rather than numerical changes. However, it is the adaptive immune response that bears the most profound impact of SARS-CoV-2 infection. T cell lymphopenia correlates with increased risk of intensive care unit admission and death; therefore, this parameter is particularly important for clinical decision-making. Mild and severe diseases differ in the rate of immune cell counts returning to normal levels post disease. Tracking the recovery trajectories of various immune cell counts may also have implications for long-term COVID-19 monitoring. This review represents a snapshot of our current knowledge, showing that much has been achieved in a short period of time. Alterations in counts of distinct immune cells represent an accessible metric to inform patient care decisions or predict disease outcomes.
T cell phenotypes in COVID-19 - a living review.
COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients' long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation.
The integrated on-chip isolation and detection of circulating tumour cells
Circulating tumour cells (CTCs) are cancer cells shed from a primary tumour which intravasate into the blood stream and have the potential to extravasate into distant tissues, seeding metastatic lesions. As such, they can offer important insight into cancer progression with their presence generally associated with a poor prognosis. The detection and enumeration of CTCs is, therefore, critical to guiding clinical decisions during treatment and providing information on disease state. CTC isolation has been investigated using a plethora of methodologies, of which immunomagnetic capture and microfluidic size-based filtration are the most impactful to date. However, the isolation and detection of CTCs from whole blood comes with many technical barriers, such as those presented by the phenotypic heterogeneity of cell surface markers, with morphological similarity to healthy blood cells, and their low relative abundance (∼1 CTC/1 billion blood cells). At present, the majority of reported methods dissociate CTC isolation from detection, a workflow which undoubtedly contributes to loss from an already sparse population. This review focuses on developments wherein isolation and detection have been integrated into a single-step, microfluidic configuration, reducing CTC loss, increasing throughput, and enabling an on-chip CTC analysis with minimal operator intervention. Particular attention is given to immune-affinity, microfluidic CTC isolation, coupled to optical, physical, and electrochemical CTC detection (quantitative or otherwise).
Endourethral injection of bulking agents for urinary incontinence in children.
OBJECTIVE: To assess the early and late outcome of endourethral injection with bulking agents in children with urinary incontinence (a neuropathic bladder or exstrophy-epispadias complex), by reviewing our experience over a 5-year period. PATIENTS AND METHODS: The records of 15 children (10 boys) were reviewed retrospectively; 10 had spina bifida and a neurogenic bladder, four had a neurogenic bladder from other causes and one had epispadias. All children had a stable low-pressure detrusor and a compliant bladder with sphincteric weakness on preoperative urodynamic testing. Four children had undergone previous enterocystoplasty with a Mitrofanoff stoma, with concomitant urethral lengthening in two and a Goretex trade mark bladder neck sling in two. Three children voided spontaneously while 12 depended on intermittent catheterization. The agent was injected under general anaesthesia in all patients but one, with an endourethral submucosal injection of the bulking agent into four or more points at the junction of the bladder neck and proximal urethra, aiming to obtain visual occlusion of the urethra. The median (range) number of injections was 2 (1-3); five children had one injection, seven had two and three had three. There were no procedure-related complications and most were day-case procedures. Initially PTFE paste was used as the bulking agent, being replaced by bovine collagen or polydimethylsiloxane in the latter half of the series. RESULTS: At a median (range) follow-up of 28 (11-65) months three children were completely dry after a single injection; there was no change in four and a short-term improvement (median 25 months, range 4 days to 37 months) in eight. After this period all children deteriorated to their original incontinence grade; hence the overall cure rate was three of 15. CONCLUSION: This experience with a long-term follow-up differs from previously reported high success rates for the endourethral injection of bulking agents for urinary incontinence in children. Despite a short-term benefit, in the long-term this technique was unreliable and often ineffective. Patients and their carers should be given a realistic and guarded prognosis.
Ownership and uses of human tissue: does the Nuffield bioethics report accord with opinion of surgical inpatients?
OBJECTIVE: To compare opinion of surgical inpatients with the conclusions of the report of the Nuffield Council on Bioethics regarding the ownership and uses of human tissue. DESIGN: Survey of results of questionnaires completed by patients. SETTING: Large teaching hospital. SUBJECTS: 384 postoperative adult surgical patients. RESULTS: There was strong support among patients for the use of tissues in medical education, research, and science with the exception of those tissues which may transmit disease to others. Few patients (39; 10%) believed that they retained ownership of tissue removed at surgery. Most believed that the tissue belonged to the hospital (103; 27%), to nobody (103; 27%), or to the laboratory (77; 20%). Most patients had not been given any information about the possible uses of their tissues after removal. CONCLUSIONS: Surgical inpatients seem to endorse the conclusions of the Nuffield report regarding the ownership and uses of human tissue. The recommendations regarding patient information and consent procedures should be implemented at the earliest opportunity.
New role of fat-free mass in cancer risk linked with genetic predisposition.
Cancer risk is associated with the widely debated measure body mass index (BMI). Fat mass and fat-free mass measurements from bioelectrical impedance may further clarify this association. The UK Biobank is a rare resource in which bioelectrical impedance and BMI data was collected on ~ 500,000 individuals. Using this dataset, a comprehensive analysis using regression, principal component and genome-wide genetic association, provided multiple levels of evidence that increasing whole body fat (WBFM) and fat-free mass (WBFFM) are both associated with increased post-menopausal breast cancer risk, and colorectal cancer risk in men. WBFM was inversely associated with prostate cancer. We also identified rs615029[T] and rs1485995[G] as associated in independent analyses with both PMBC (p = 1.56E-17 and 1.78E-11) and WBFFM (p = 2.88E-08 and 8.24E-12), highlighting splice variants of the intriguing long non-coding RNA CUPID1 (LINC01488) as a potential link between PMBC risk and fat-free mass.