Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less ...extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Rash and fever in a kidney transplant recipient Todd, Peter J.; Smyth, John S.; Leonard, Niall ...
American journal of transplantation,
March 2020, 2020-Mar, 2020-03-00, 20200301, Volume:
20, Issue:
3
Journal Article
Peer reviewed
Open access
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Aims Galectin-3 plays an important role in adhesion, proliferation, differentiation, angiogenesis and metastasis in multiple tumours. To investigate the role of galectin-3 in melanoma ...pathogenesis we examined the expression of galectin-3 in melanocytic lesions and analysed the correlation between galectin-3 expression and clinicopathologic factors including patient survival and BRAF mutation status. Methods We evaluated the expression of galectin-3 in 53 cases of benign naevi, 31 cases of dysplastic naevi, 59 in-situ melanomas, 314 cases of primary melanoma and 69 metastatic melanomas using tissue microarray and immunohistochemistry. Results Marked differences in expression of galectin-3 were seen between different categories of melanocytic lesions (ANOVA p < 0.0001). An increase in expression of galectin-3 between benign naevi and thin primary melanomas and a progressive decrease in expression between thin primary melanomas and thicker melanomas or metastatic melanomas was seen. Strong galectin-3 expression was associated with improved overall survival ( p = 0.002 and p = 0.0002 for cytoplasmic and nuclear expression, respectively) and melanoma-specific survival ( p = 0.017 and p = 0.003 for cytoplasmic and nuclear expression, respectively). A multifactorial Cox regression analysis suggested that galectin-3 expression was an independent prognostic marker for overall survival in melanoma (risk ratio 0.73, 95% CI 0.547–0.970, p = 0.031 for cytoplasmic expression and risk ratio 0.76, 95% CI 0.587–0.985, p = 0.036 for nuclear expression). No association between galectin-3 expression and BRAF mutation status was observed. Conclusion This study suggests that galectin-3 is a marker of progression in melanocytic lesions and a novel prognostic marker in primary melanoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
This paper describes the process development conducted toward the multi-kilogram synthesis of a hemiadipic acid pro-drug of buprenorphine. The major challenges were to control the levels of the ...dibuprenorphine monoadipate impurity and to improve the robustness of the final recrystallization. Modification of the reaction conditions limited the levels of the impurity formed during the reaction, and an additional point of control was introduced, a reslurry with dichloromethane. The solid-state properties of the pro-drug were fully investigated, and extensive polymorph screening was undertaken. An unusual low-temperature endothermic event was observed in the differential scanning calorimetry thermogram. This low-temperature event was further investigated using variable-temperature X-ray powder diffraction and variable-temperature solid-state nuclear magnetic resonance spectroscopy. It was concluded that this event was likely to be associated with a reversible, minor conformational change of the adipate side chain.
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IJS, KILJ, NUK, PNG, UL, UM
Social media has changed the way surgeons communicate worldwide, particularly in dissemination of trial results. However, it is unclear if social media could be used in recruitment to surgical ...trials. This study aimed to investigate the influence of Twitter in promoting surgical recruitment in The Emergency Laparotomy and Frailty (ELF) Study.
The ELF Study was a UK-based, prospective, observational cohort that aimed to assess the influence of frailty on 90-day mortality in older adults undergoing emergency surgery. A power calculation required 500 patients to be recruited to detect a 10% change in mortality associated with frailty. A 12-week recruitment period was selected, calculated from information submitted by participating hospitals and the numbers of emergency surgeries performed in adults aged > 65 years. A Twitter handle was designed (@ELFStudy) with eye-catching logos to encourage enrolment and inform the public and clinicians involved in the study. Twitter Analytics and Twitonomy (Digonomy Pty Ltd) were used to analyse user engagement in relation to patient recruitment.
After 90 days of data collection, 49 sites from Scotland, England and Wales recruited 952 consecutive patients undergoing emergency laparotomy, with data logged into a database created on REDCap. Target recruitment (n = 500) was achieved by week 11. A total of 591 tweets were published by @ELFStudy since its conception, making 218,136 impressions at time of writing. The number of impressions (number of times users see a particular tweet) prior to March 20th 2017 (study commencement date) was 23,335 (343.2 per tweet), compared to the recruitment period with 114,314 impressions (256.3 per tweet), ending June 20th 2017. Each additional tweet was associated with an increase in recruitment of 1.66 (95%CI 1.36 to 1.97; p < 0.001).
The ELF Study over-recruited by nearly 100%, reaching over 200,000 people across the U.K. Branding enhanced tweet aesthetics and helped increase tweet engagement to stimulate discussion and healthy competition amongst clinicians to aid trial recruitment. Other studies may draw from the social media experiences of the ELF Study to optimise collaboration amongst researchers.
This study is registered online at www.clinicaltrials.gov (registration number NCT02952430 ) and has been approved by the National Health Service Research Ethics Committee.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Crankshaft bearings of an automotive engine require smooth and high reliability performance as they operate in a harsh environment of heat, pressure, abrasion, and chemical attack that may cause ...wear. The bearings are designed to meet high precision tolerances and require high-quality surface finish and surface topography. The journals are first grounded and finally polished to an outstanding surface finish in the order of sub-micrometers. In a mass production process, the tapes that are used for final polish may break without being revealed by the automation. Therefore, it is essential to provide an in-line inspection system for such parts to eliminate manual inspection. In order to achieve this goal, we developed a machine vision technique to validate that all journals were polished and detect the unpolished ones. In utilizing this technique, a full-size prototype go/no-go demonstrator was built to validate the performance and reliability of the method. The sensitivity of the system is high enough to differentiate sub-micron level roughness change of the crankshaft surface.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
Problem alcohol use (PAU) is common and associated with considerable adverse outcomes among patients receiving opioid agonist treatment (OAT). The purpose of this paper is to describe a ...qualitative feasibility assessment of a primary care-based complex intervention to promote screening and brief intervention for PAU, which also aims to examine acceptability and potential effectiveness.
Design/methodology/approach
Semi-structured interviews were conducted with 14 patients and eight general practitioners (GPs) who had been purposively sampled from practices that had participated in the feasibility study. The interviews were transcribed verbatim and analysed thematically.
Findings
Six key themes were identified. While all GPs found the intervention informative and feasible, most considered it challenging to incorporate into practice. Barriers included time constraints, and overlooking and underestimating PAU among this cohort of patients. However, the intervention was considered potentially deliverable and acceptable in practice. Patients reported that (in the absence of the intervention) their use of alcohol was rarely discussed with their GP, and were reticent to initiate conversations on their alcohol use for fear of having their methadone dose reduced.
Research limitations/impelications
Although a complex intervention to enhance alcohol screening and brief intervention among primary care patients attending for OAT is likely to be feasible and acceptable, time constraints and patients’ reticence to discuss alcohol as well as GPs underestimating patients’ alcohol problems is a barrier to consistent, regular and accurate screening by GPs. Future research by way of a definitive efficacy trial informed by the findings of this study and the Psychosocial INTerventions for Alcohol quantitative data is a priority.
Originality/value
To the best of the knowledge, this is the first qualitative study to examine the capability of primary care to address PAU among patients receiving OAT.
Background: The PTCL are a heterogeneous group of non-Hodgkin lymphomas originating from mature T-lymphocytes. They are aggressive diseases, often resistant to conventional chemotherapy. Despite the ...fact that a number of new agents have been approved, treatment paradigms tailored to the biology of the disease have yet to emerge. Tolinapant (ASTX660) is a potent antagonist of both cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), and is presently in phase I/II trials in patients with advanced solid tumors and lymphomas (NCT02503423). IAP antagonists enhance tumor necrosis factor (TNF) receptor superfamily mediated apoptosis (Ward GA, et al. Mol Cancer Ther. 2018), are potent anti-tumor immune enhancers and induce markers of immunogenic cell death such as damage associated molecular patterns (DAMPs; Ye W, et al, Oncoimmunology, 2020). Objectives: We explored the sensitivity of a range of T-cell lymphoma (TCL) cell lines to tolinapant. We establish the synergy coefficient between tolinapant and the HDAC inhibitor, romidepsin, and interrogated the molecular basis of their synergistic interaction. Methods: A panel of human T-cell lymphoma cell lines were tested in proliferation assays (CellTiterGlo) for sensitivity to tolinapant in the presence or absence of 10ng/ml of TNF alpha. For combination studies, with tolinapant and romidepsin, each drug was tested at the IC10 and IC40 concentrations in the presence or absence of TNF alpha. Synergy scores using the Excess over Bliss (EOB) model were calculated using SynergyFinder (Aleksandr Ianevski et al; Nucleic Acids Research, 2020). Additionally, the effects of tolinapant and romidepsin on the IAPs and caspases were analyzed by western blots. TNFR1 receptor expression and induction of DAMPs were also analyzed by flow cytometry. Results: TCL Lines demonstrated varying sensitivities to tolinapant in the presence or absence of TNF alpha. The most sensitive cell lines, ALK+ ALCL and SUP-M2, had IC50 concentrations ranging from 200nM ± 100nM to 20nM ± 1nM in the absence or presence of TNF alpha, respectively, at 24, 48 and 72hrs, while a resistant CTCL cell line HH had an IC50 concentration of over 20mM, even in the presence of TNF alpha. Interestingly, using western blot analysis, we found that the presence of TNF alpha increased the levels of cIAP1 in the tolinapant sensitive SUP-M2 cell line, but not in the resistant HH cell line. However, there was a concentration dependent decrease in cIAP1 but not in XIAP in both cell lines treated with tolinapant. Flow cytometry analysis demonstrated that tolinapant increases the expression of TNFR1 and DAMPs in a dose dependent manner on the sensitive SUP-M2, but not in the resistant HH cells. In combination experiments, using the EOB model, tolinapant plus romidepsin was found to be synergistic in the absence of TNF alpha, at 36hrs, in both the sensitive cell line SUP-M2 and the resistant cell line HH. In the presence of TNF alpha, synergism was seen only in the sensitive cell line SUP-M2 and antagonistic in the HH cell line (Fig. 3). In the tolinapant plus romidepsin treated samples, cIAP1 levels decreased in the SUP-M2 cell line, in the absence of TNF alpha, however, addition of TNF alpha did not alter the levels of cIAP1 in the SUP-M2 cells. The cIAP1 levels decreased in the HH cells treated with the combination, in both the presence or absence of TNF alpha (Figure). Our findings indicate that the synergy of the tolinapant plus romidepsin is not dependent on the presence of TNF alpha. Conclusion: Tolinapant has demonstrated potent cytotoxic effects against a broad range of TCL lines both as a monotherapy and in combination with the HDAC Inhibitor, romidepsin. In in vitro studies, T cell lymphoma cell lines demonstrated varying sensitivity to tolinapant with certain cell lines being more resistant, even in the presence of TNF alpha. Interestingly, the addition of romidepsin appeared to overcome the intrinsic resistance to tolinapant in the absence of TNF alpha. These data provide the rationale to continue to explore the combination of tolinapant and romidepsin in vivo and to investigate additional combinations with T-cell specific agents (e.g. pralatrexate, belinostat, azacitidine and decitabine).
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Smyth: Astex Pharmaceuticals: Current Employment. Sims: Astex Pharmaceuticals: Current Employment. Loughran: Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioniz Therapeutics: Membership on an entity's Board of Directors or advisory committees; Keystone Nano: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Membership on an entity's Board of Directors or advisory committees. Marchi: Kyowa Kirin: Honoraria; Myeloid Therapeutics: Honoraria; Astex: Research Funding; BMS: Research Funding; Merck: Research Funding; Kymera Therapeutics: Other: Scientific Advisor.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Diagnostic testing is fundamental to medicine. However, studies of diagnostic testing in respiratory medicine vary significantly in terms of their methodology, definitions, and reporting of results. ...This has led to often conflicting or ambiguous results. To address this issue, a group of 20 respiratory journal editors worked to develop reporting standards for studies of diagnostic testing based on a rigorous methodology to guide authors, peer reviewers, and researchers when conducting studies of diagnostic testing in respiratory medicine. Four key areas are covered, including defining the reference standard of truth, measures of dichotomous test performance when used for dichotomous outcomes, measures of multichotomous test performance for dichotomous outcomes, and what constitutes a useful definition of diagnostic yield. The importance of using contingency tables for reporting results is addressed with examples from the literature. A practical checklist is provided as well for reporting studies of diagnostic testing.
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