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Checkpoint inhibition reduces the threshold for drug-specific T-Cell priming and increases the incidence of sulfasalazine hypersensitivity.
No full textAn emerging clinical issue associated with immune-oncology agents is the collateral effects on the tolerability of concomitant medications. One report of this phenomenon was the increased incidence of hypersensitivity reactions observed in patients receiving concurrent immune checkpoint inhibitors and sulfasalazine. Thus, the aim of this study was to characterize the T-cells involved in the pathogenesis of such reactions, and recapitulate the effects of inhibitory checkpoint blockade on de-novo priming responses to compounds within in-vitro platforms. A regulatory competent human dendritic cell/T-cell co-culture assay was used to model the effects of immune checkpoint inhibitors on de-novo nitroso sulfamethoxazole- and sulfapyridine (the sulfonamide component of sulfasalazine) hydroxylamine-specific priming responses. The role of T-cells in the pathogenesis of the observed reactions was explored in three patients through phenotypic characterization of sulfapyridine/sulfapyridine hydroxylamine-responsive T-cell clones, and assessment of cross-reactivity and pathways of T-cell activation. Augmentation of the frequency of responding drug-specific T-cells and intensity of the T-cell response was observed with PD-1/PD-L1 blockade. Monoclonal populations of sulfapyridine- and sulfapyridine hydroxylamine-responsive T-cells were isolated from all three patients. A core secretory effector molecule profile (IFN-γ, IL-13, granzyme B and perforin) was identified for sulfapyridine and sulfapyridine hydroxylamine responsive T-cell clones, which proceeded through Pi and hapten mechanisms, respectively. Data presented herein provides evidence that drug-responsive T-cells are effectors of hypersensitivity reactions observed in oncology patients administered immune checkpoint inhibitors and sulfasalazine. Perturbation of drug-specific T-cell priming is a plausible explanation for clinical observations of how an increased incidence of these adverse events is occurring
Posterior ischemic optic neuropathy following a major burn injury and review of the literature.
No full textPosterior ischemic optic neuropathy following burns is a rare but devastating condition that can result in total bilateral visual loss. Numerous treatment modalities have been trialed, yet there is no effective therapy to delay or reverse the disease. Hence, it is imperative for burns surgeons to be aware of the potential risk factors and have a high index of suspicion right from the outset to prevent this outcome. Here, we discuss the case of a patient that developed posterior ischemic optic neuropathy subsequent to a major burn injury. We also present a literature review on optic neuropathies following burns to describe the etiology, clinical signs, and potential management
Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis.
No full textBACKGROUND & AIMS
Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the biliary tree. The bile acid receptor TGR5 (GPBAR1) is found on biliary epithelial cells (BECs), where it promotes secretion, proliferation and tight junction integrity. Thus, we speculated that changes in TGR5-expression in BECs may contribute to PSC pathogenesis.
METHODS
TGR5-expression and -localization were analyzed in PSC livers and liver tissue, isolated bile ducts and BECs from Abcb4, Abcb4/Tgr5 and ursodeoxycholic acid (UDCA)- or 24-norursodeoxycholic acid (norUDCA)-fed Abcb4 mice. The effects of IL8/IL8 homologues on TGR5 mRNA and protein levels were studied. BEC gene expression was analyzed by single-cell transcriptomics (scRNA-seq) from distinct mouse models.
RESULTS
TGR5 mRNA expression and immunofluorescence staining intensity were reduced in BECs of PSC and Abcb4 livers, in Abcb4 extrahepatic bile ducts, but not in intrahepatic macrophages. No changes in TGR5 BEC fluorescence intensity were detected in liver tissue of other liver diseases, including primary biliary cholangitis. Incubation of BECs with IL8/IL8 homologues, but not with other cytokines, reduced TGR5 mRNA and protein levels. BECs from Abcb4 mice had lower levels of phosphorylated Erk and higher expression levels of Icam1, Vcam1 and Tgfβ2. Overexpression of Tgr5 abolished the activated inflammatory phenotype characteristic of Abcb4 BECs. NorUDCA-feeding restored TGR5-expression levels in BECs in Abcb4 livers.
CONCLUSIONS
Reduced TGR5 levels in BECs from patients with PSC and Abcb4 mice promote development of a reactive BEC phenotype, aggravate biliary injury and thus contribute to the pathogenesis of sclerosing cholangitis. Restoration of biliary TGR5-expression levels represents a previously unknown mechanism of action of norUDCA.
LAY SUMMARY
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease-associated with progressive inflammation of the bile duct, leading to fibrosis and end-stage liver disease. Bile acid (BA) toxicity may contribute to the development and disease progression of PSC. TGR5 is a membrane-bound receptor for BAs, which is found on bile ducts and protects bile ducts from BA toxicity. In this study, we show that TGR5 levels were reduced in bile ducts from PSC livers and in bile ducts from a genetic mouse model of PSC. Our investigations indicate that lower levels of TGR5 in bile ducts may contribute to PSC development and progression. Furthermore, treatment with norUDCA, a drug currently being tested in a phase III trial for PSC, restored TGR5 levels in biliary epithelial cells
Outcomes of Cochlear Implantation in Patients with Temporal Bone Trauma: A Systematic Review and Narrative Synthesis.
No full textEstablish outcomes following cochlear implantation (CI) in patients following temporal bone trauma. Systematic review and narrative synthesis. Medline, Pubmed, Embase, Web of Science, Cochrane Collection, and ClinicalTrials.gov. No limits are placed on language or year of publication. The review conducted in accordance with the PRISMA statement. Searches identified 223 abstracts and 64 full texts. Of these, 23 studies met the inclusion criteria reporting outcomes in 77 patients with at least 96 implants. Hearing outcomes were generally good with most patients demonstrating improved audiological and functional outcomes. Complications were reported in 14 cases with 10 of these being major. The methodological quality of included studies was modest, predominantly consisting of case reports and non-controlled case series with small numbers of patients. All studies were OCEBM grade IV. Hearing outcomes following CI in temporal bone trauma are good with useful functional improvement demonstrated in the majority of patients. It appears to be an effective method of aural rehabilitation and should be considered in selected cases following hearing loss due to temporal bone fracture
Placenta accreta spectrum disorders - detection rate and maternal outcomes following implementation of an institutional protocol.
No full textPlacenta accreta spectrum (PAS) disorders have been on the rise in recent years with increasing caesarean rates. The purpose of this prospective observational study was to describe our detection rates and to review outcomes in PAS after the introduction of an institutional screening and management protocol. Twenty-one patients with suspected PAS over 5 years were identified. 20/21 patients had an accurate determination of placental invasion and positive correlation with surgical and histopathological examination. Early morbidity (massive haemorrhage) was found in 7/21 patients, whilst late morbidity (hospital readmission) was found in 5/21 patients. There were no maternal deaths and admissions to intensive therapy unit (ITU). In summary, our centre demonstrated a high antenatal detection rate for PAS using an evidence-based protocol. This has led to timely intervention by an experienced multidisciplinary team and excellent outcomes. Immediate and delayed postoperative counselling was effective for optimal patient understanding and experience.Impact Statement With rising caesarean section rates, the incidence of placenta accreta spectrum (PAS) disorders is increasing. Despite this, most obstetricians have personally managed only a small number of patients with PAS. Moreover, there appears to be some debate over the optimal diagnostic and management strategy. As the incidence increases, development of institutional screening and management protocol is a necessity for large units. Timely diagnosis, extensive pre and postoperative counselling and multidisciplinary teamwork ensure reduced early and late morbidity. Evidence based screening protocols for PAS disorders reduce the likelihood of undiagnosed cases and should be developed in every unit. Consideration must also be given to standardisation of the diagnostic and management protocols, including contingency plan for emergencies
COSMIC, chemotherapy plus ofatumumab at standard or mega-dose in chronic lymphocytic leukaemia, a phase II randomised study.
No full textUltra-high Magnification Endocytoscopy and Molecular Markers for Defining Endoscopic and Histologic Remission in Ulcerative Colitis-An Exploratory Study to Define Deep Remission.
No full textBACKGROUND
Endoscopic and histological remission are both important treatment goals in patients with ulcerative colitis (UC). We aimed to define cellular architecture, expression of molecular markers, and their correlation with endoscopic scores assessed by ultra-high magnification endocytoscopy (ECS) and histological scores.
METHODS
Patients with UC (n = 29) were prospectively recruited. The correlation among ECS score (ECSS), Mayo endoscopic score (MES), and histological scores were determined. Area under curve were plotted to determine the best thresholds for ECSS that predicted histological remission by Robarts (RHI) and Nancy Histological Index (NHI).Soluble analytes relevant to inflammation were measured in serum and mucosal culture supernatants using ProcartaPlex Luminex assays and studied by partial least square discriminant analysis and logistic model. Mucosal RNA sequencing and bioinformatics analysis were performed to define differentially expressed genes/pathways.
RESULTS
Endocytoscope scoring system correlated strongly with RHI (r = 0.89; 95% CI, 0.51-0.98) and NHI (r = 0.86; 95% CI, 0.42-0.98) but correlated poorly with MES (r = 0.28; 95% CI, 0.27-0.70). We identified soluble brain-derived neurotrophic factors (BDNF), macrophage inflammatory proteins (MIP-1 α) and soluble vascular cell adhesion molecule 1 (sVCAM-1) predicted histological remission. Mucosal biopsy cultures also identified sVCAM-1 associated with healed mucosa. RNA-seq analysis identified gene expressions shared between ECSS, RHI, or NHI defined healing. A number of gene expressions and pathways were identified including inflammation and metabolic and tumor suppressors that discriminated healed from nonhealed mucosa.
CONCLUSIONS
Endocytoscopy represents an interesting tool that may sit between endoscopy and histology-but closer to the latter-identifying gene expression markers and pathways that are also identified by histology
Impacts of the COVID-19 pandemic on training, morale and wellbeing among the UK renal workforce.
No full textRole of liver support systems in the management of post hepatectomy liver failure: A systematic review of the literature.
No full textBackgrounds/Aims
Post-hepatectomy liver failure (PHLF) is a serious complication following liver resection, with limited treatment options, and is associated with high mortality. There is a need to evaluate the role of systems that support the function of the liver after PHLF.
Aims
The aim of this study was to review the literature and summarize the role of liver support systems (LSS) in the management of PHLF. Publications of interest were identified using systematically designed searches. Following screening, data from the relevant publications was extracted, and pooled where possible.
Findings
Systematic review identified nine studies, which used either Plasma Exchange (PE) or Molecular Adsorbent Recirculating System (MARS) as LSS after PHLF. Across all studies, the pooled 90-day mortality rate was 38% (95% CI: 9-70%). However, there was substantial heterogeneity, likely since studies used a variety of definitions for PHLF, and had different selection criteria for patient eligibility for LSS treatment.
Conclusions
The current evidence is insufficient to recommend LSS for the routine management of severe PHLF, with the current literature consisting of only a limited number of studies. There is a definite need for larger, multicenter, prospective studies, evaluating the conventional and newer modalities of support systems, with a view to improve the outcomes in this group of patients