ATM/NEMO signaling modulates the expression of PD-L1 following docetaxel chemotherapy in prostate cancer

BackgroundThe efficacy of docetaxel-based chemotherapy is limited by the development of drug resistance. Recent studies demonstrated the efficacy of anti-programmed death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immunotherapies in metastatic prostate cancer. The ataxia telangiectasia mutation (ATM) protein plays a crucial role in maintaining genome stability and function of mitosis. Here, we aimed to determine whether PD-1/PD-L1 signaling contributes to the resistance to DTX and to elucidate the mechanism underlying DTX-induced PD-L1 expression.MethodsIn this retrospective study, PD-L1 expression was analyzed in 33 tumor tissue samples from prostate cancer patients. Prostate cell lines were used to perform functional assays and examine underlying mechanisms in vitro. A fully mouse prostate cancer model and a humanized chimeric mouse bearing human prostate tumors and peripheral blood mononuclear cells were used for in vivo assays.ResultsWe have shown that DTX, a chemotherapeutic drug which causing microtubule interference, could significantly induce the expression of PD-L1 in prostate cancer cells. This effect is blocked by the inhibition of ATM, suggesting that it plays an essential role in PD-L1 expression upregulated by DTX. Mechanistic studies have shown that ATM activity in cancer cells enhances the stability of the NF-κB essential modulator (NEMO), which leading to an increase in the NF-κB activity and PD-L1 expression. Using the mouse model, it was further demonstrated that a combination of ATM and NEMO inhibitors along with DTX augmented the antitumor efficacy of chemotherapy, which are comparable to that of PD-L1 antibody.ConclusionsOur findings have revealed that a previously unrecognized ATM-NEMO signaling which induced by DTX is capable of suppressing tumor immunity by activating the expression of PD-L1, suggesting that the ATM-NEMO-NF-κB axis can be exploited to restore the immune balance and overcome cancer resistance triggered by DTX.Graphic Abstract: supplementary file 1

Accelerated Partner Therapy: optimising an inter-actional contact tracing intervention to reduce chlamydia reinfection

Background: A number of interventions have evolved to assist with contact tracing for sexually transmitted infections (STIs) yet absence of theoretical support, detailed description and specific intervention components result in heterogeneous delivery with ambiguous outcomes. This paper reports a process to optimise Accelerated Partner Therapy (APT), a UK partner notification intervention, to reduce chlamydia reinfection.Method: Varied data sources involved an analysis of behavioural elements of existing contact tracing interventions identified through systematic review, a behavioural analysis of videos of APT, a behaviourally informed analysis of qualitative data from 56 patients/public, 30 healthcare professionals (HCPs) and expert input including the use of the APEASE criteria in specifying content for the intervention manual. This involved the theoretical domains framework (TDF), the Behaviour Change Wheel (BCW) and the Behaviour Change Technique Taxonomy (BCTT) to specify potentially useful ways of optimising APT that would enhance engagementResults: The APT intervention was characterised as interactional; involving HCPs, index patients and sex partners. It involved four main delivery steps and eight behavioural domains. Varied barriers and facilitators to engagement with APT were identified and further analysed to optimise APT content. The APEASE criteria were used to select and prioritise content/intervention functions for inclusion in the intervention manual, training materials and all information material to support the delivery of APT for HCP and index patients (videos, leaflets etc.) Discussion The approach outlined here aimed to behaviourally inform APT in order to provide a transparent way of optimising the intervention by specifying its active components and theorising its key mechanisms. We include a supplementary file with the final intervention manual.

Monomorphic Trypanozoon: towards reconciling phylogeny and pathologies

2.AbstractTrypanosoma brucei evansi and Trypanosoma brucei equiperdum are animal infective trypanosomes conventionally classified by their clinical disease presentation, mode of transmission, host range, kDNA composition and geographic distribution. Unlike other members of the subgenus Trypanozoon, they are non-tsetse transmitted and predominantly morphologically uniform (monomorphic) in their mammalian host. Their classification as independent species or subspecies has been long debated and genomic studies have found that isolates within T. b. evansi and T. b. equiperdum have polyphyletic origins. Since current taxonomy does not fully acknowledge these polyphyletic relationships, we re-analysed publicly available genomic data to carefully define each clade of monomorphic trypanosome. This allowed us to identify, and account for, lineage specific variation. We included a recently published isolate, IVM-t1, which was originally isolated from the genital mucosa of a horse with dourine and typed as T. equiperdum. Our analyses corroborate previous studies in identifying at least four distinct monomorphic T. brucei clades. We also found clear lineage specific variation in the selection efficacy and heterozygosity of the monomorphic lineages, supporting their distinct evolutionary histories. The inferred evolutionary position of IVM-t1 suggests its reassignment to the T. b. evansi type B clade, challenging the relationship between the Trypanozoon species, the infected host, mode of transmission and the associated pathological phenotype. The analysis of IVM-t1 also provides the first evidence of the expansion of T. b. evansi type B, or a 5th monomorphic lineage represented by IVM-t1, outside of Africa, with important possible implications for disease diagnosis.3.Impact statementTrypanosoma brucei are unicellular parasites typically transmitted by tsetse flies. Subspecies of T. brucei cause human African trypanosomiasis and the animal diseases, nagana, surra and dourine. T. b. evansi and T. b. equiperdum have branched from T. brucei and, by foregoing tsetse transmission, expanded their geographic range beyond the sub-Saharan tsetse belt. These species can only reproduce asexually and exhibit morphological uniformity in their host (‘monomorphism’). T. b. evansi and T. b. equiperdum have historically been classified based on fragmentary information on the parasites’ transmission routes, geographic distribution, kDNA composition and disease phenotypes. Our analysis of genome sequencing data from monomorphic T. brucei supports at least four independent origins with distinct evolutionary histories. One isolate, IVM-t1, typed as T. equiperdum, is a closer relative to T. b. evansi, highlighting the risk of using pathognomonic descriptors for subspecies assignment. We show clear lineage specific variation in the selection efficacy in monomorphic T. brucei. Using the evolutionary relationships between lineages, we suggest it would be beneficial to reconcile phylogeny and pathology in monomorphic trypanosomes.4.Data summaryThe data used in this study is available from the Sequence Read Archive or the Wellcome Sanger Institute. The accessions can be found in Supplementary file 1.

Accounting for Endogeneity in Regression Models Using Copulas: A Step-by-Step Guide for Empirical Studies

We provide a detailed presentation and guide for the use of Copulas in order to account for endogeneity in linear regression models without the need for instrumental variables. We start by developing the model from first principles of likelihood inference, and then focus on the Gaussian Copula. We discuss its merits and propose diagnostics to assess its validity. We analyze in detail and provide solutions to the various issues that may arise in empirical applications for applying the method. We treat the cases of both continuous and discrete endogenous regressors. We present simulation evidence for the performance of the proposed model in finite samples, and we illustrate its application by a short empirical study. A Supplementary File contains additional simulations and another empirical illustration.

Study protocol of the global Effisayil 1 Phase II, multicentre, randomised, double-blind, placebo-controlled trial of spesolimab in patients with generalized pustular psoriasis presenting with an acute flare

IntroductionGeneralized pustular psoriasis (GPP) is a rare, potentially life-threatening disease characterised by recurrent flares of widespread neutrophilic aseptic skin pustular eruption. Despite the availability of approved biologics for GPP in Japan, Taiwan and Thailand, associated evidence is largely based on uncontrolled studies in which acute flares were not directly assessed. Therefore, there is a high unmet need to investigate new rapid-acting effective treatments that resolve symptoms associated with acute GPP flares. A prior Phase I proof-of-concept study showed rapid improvements in skin and pustule clearance with a single intravenous dose of spesolimab, a novel anti-interleukin-36 receptor antibody, in patients presenting with an acute GPP flare. Here, we present the design and rationale of Effisayil 1, a global, Phase II, placebo-controlled study to evaluate the efficacy, safety and tolerability of spesolimab in patients presenting with an acute GPP flare.Methods and analysisAt least 51 patients with an acute GPP flare will be randomised 2:1 to receive a single 900 mg intravenous dose of spesolimab or placebo and followed for up to 28 weeks. The primary endpoint is a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (pustule clearance) at Week 1. The key secondary endpoint is a GPPGA score of 0 or 1 (clear or almost clear) at Week 1. Safety will be assessed over the study duration by the occurrence of treatment-emergent adverse events. Blood and skin biopsies will be collected to assess biomarkers. Superiority of spesolimab over placebo in the proportion of patients achieving the primary and key secondary endpoints will be evaluated.Ethics and disseminationThe study complies with the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation’s Good Clinical Practice and local regulations. Ethics committee approvals have been obtained for each centre from all participating countries and are listed in online supplementary file 1. Primary results will be published in a peer-reviewed journal.Trial registration detailsClinicalTrials.gov identifier: NCT03782792; Pre-results.

Faculty retention in regional medical schools in Iran: a qualitative content analysis

Background and purpose Recruitment and retention of competent faculty members are important in maintaining and improving the quality of education and research performance of universities. The aim of the present study was to find out the faculty members’ views, experiences, and attitudes to identify the reasons for faculty attrition and retention in regional medical schools in Iran. Methods In this qualitative study, we used a content analysis method. The participants included 12 faculty members who had been transferred to type I universities, four faculty members who had applied for transfer, four with more than 10 years of experience and working in the type 3 universities with no intention to be transferred. Data were collected using semi-structured interviews, which were conducted either face-to-face or via phone calls. The interview was developed for this study (Supplementary file). To measure the trustworthiness of the data, we evaluated four components of credibility, transferability, dependability, and conformability, as proposed by Lincoln and Guba. Results The findings were classified into three categories and 14 subcategories. The first category was “retention facilitators” including four subcategories of facilitated communication, proximity to major universities, gaining experience, and support by authorities. The second category was “retention threats” including six subcategories of social infrastructure, individual dimension, occupation dimension, economic dimension, sense of respect, and executive management. The third category was “retention strategies” which included four subcategories of recruitment and promotion processes, inter-university collaboration with type I universities, facilitation of the scientific growth, and fulfilment of the safety needs. Conclusion Several factors play a role in the faculty members’ retention in regional medical schools in Iran. Authorities can create a more positive environment by devising a suitable reward system, supporting academic activities, and increasing the level of faculty autonomy practically to develop a sense of belonging among them and reduce the intention to be transferred among their human resources.

419 What are the priorities for older adults attending the ED? Findings from a multiple stakeholder group consensus meeting

Aims/Objectives/BackgroundPatient Reported Experience & Outcome Measures (PREMs/PROMs) are not yet well established in emergency care. This study aimed to determine priorities for older adults attending the ED, to inform item inclusion for a new PREM/PROM.Methods/DesignOne hundred thirty-five priority statements, linked to suggested PREM/PROM items, were derived from the literature, patient interviews (n=24) and staff focus groups (n=7)(October 2018- April 2019). All statements had a Flesch-Kincaid Reading Ease score >70. A one-day consensus meeting was held, December 2019.Invitations were issued via social media, patient/public involvement groups and charities. Following focus groups to assess interpretability, nominal group technique was used to prioritise statements. Individuals scored statements from 1(least important) to 9(most important). Statements with a median score of >6.5 were ‘critically important’, 3.5 to 6 ‘important, not critical’, and <3 ‘less important’. Inter-rater agreement was assessed using mean absolute deviation from the median (MADM). ‘Critically important’ or ‘less important’ statements with MADM <50% were automatically included or excluded, respectively. Statements deemed ‘important, not critical’, or with MADM >50% underwent further voting.Remaining statements underwent dichotomous voting. A >70% favourable majority was required for inclusion.Results/ConclusionsTwenty-nine participants attended. Average age was 65.6 years (R32—78). Experiences of emergency care were as a patient (n=16(55.2%)), accompanying person (n=11(37.9%)), third-sector representative (n=14(48.2%)) and/or clinician (n=7(27.6%)).Initial prioritisation yielded 71 statements for inclusion. Further voting led to the inclusion of another 31 statements (102 total).Statements relating to care delivery, communication and emotional needs ranked as more important overall. Statements related to waiting were considered less important (seesupplementary file).Participants reported having ‘adequate say’ during the meeting (76.9% Strongly Agree).ConclusionThis meeting established priorities for older adults attending the ED. The low priority assigned to waiting confounds some previous findings. Further item reduction is planned to create a final PREM/PROM for older adults.

Novel metric for hyperbolic phylogenetic tree embeddings

Advances in experimental technologies such as DNA sequencing have opened up new avenues for the applications of phylogenetic methods to various fields beyond their traditional application in evolutionary investigations, extending to the fields of development, differentiation, cancer genomics, and immunogenomics. Thus, the importance of phylogenetic methods is increasingly being recognized, and the development of a novel phylogenetic approach can contribute to several areas of research. Recently, the use of hyperbolic geometry has attracted attention in artificial intelligence research. Hyperbolic space can better represent a hierarchical structure compared to Euclidean space, and can therefore be useful for describing and analyzing a phylogenetic tree. In this study, we developed a novel metric that considers the characteristics of a phylogenetic tree for representation in hyperbolic space. We compared the performance of the proposed hyperbolic embeddings, general hyperbolic embeddings, and Euclidean embeddings, and confirmed that our method could be used to more precisely reconstruct evolutionary distance. We also demonstrate that our approach is useful for predicting the nearest-neighbor node in a partial phylogenetic tree with missing nodes. This study highlights the utility of adopting a geometric approach for further advancing the applications of phylogenetic methods.The demo code is attached as a supplementary file in a compiled jupyter notebook. The code used for analyses is available on GitHub at https://github.com/hmatsu1226/HyPhyTree.

Developing "Code of Ethics for Medical Professionals, Medical Council of Islamic Republic of Iran"

Background: The medical profession has always been an inspiration for human societies throughout its diverse history. This position and historical authority in the field of ethics has had a different and higher status, in such a way that many of the norms of general ethics and professional ethics, especially principles, such as trust, confidentiality and respect for human dignity, have been developed by medical professionals. Developing guidelines of general and professional ethics is one of the inherent duties of the Medical Council of the Islamic Republic of Iran (IRIMC) as a professional organization. In this regard, the Supreme Council of IRIMC has approved the "Code of Ethics for Medical Professionals" and, in accordance with its legal authority, has annexed it to the disciplinary regulations of IRIMC. Methods: A draft document, the result of extensive literature review, was discussed in 27 expert panel meetings and after receiving and endorsing the stakeholders’ point of view, was approved by the IRIMC Supreme Council. Results: The first edition of "Code of Ethics for Medical Professionals, Medical Council of Islamic Republic of Iran" was developed on July 6, 2017 by the Supreme Council of IRIMC. The guideline was set to take effect one year after its enactment. The first edition was revised and completed and final edition was adopted on August 9, 2018 by IRIMC in 13 chapters and 140 articles (original full text is available in the Supplementary file 1). Conclusion: According to the approved decision by the Supreme Council of IRIMC on May 10, 2018, the final edition takes effect as of October 7, 2018.