Early Alzheimer's disease pathology in human cortex involves transient cell states.

Cellular perturbations underlying Alzheimer's disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the early cortical amyloid response-were prominent in neurons, wherein we identified a transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with ß-amyloid production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.

Acetylation of GhCaM7 enhances cotton resistance to Verticillium dahliae.

Protein lysine acetylation is an important post-translational modification mechanism involved in cellular regulation in eukaryotes. Calmodulin (CaM) is a ubiquitous Ca2+ sensor in eukaryotes and is crucial for plant immunity, but it is so far unclear whether acetylation is involved in CaM-mediated plant immunity. Here, we found that GhCaM7 is acetylated upon Verticillium dahliae (V. dahliae) infection and a positive regulator of V. dahliae resistance. Overexpressing GhCaM7 in cotton and Arabidopsis enhances V. dahliae resistance and knocking-down GhCaM7 makes cotton more susceptible to V. dahliae. Transgenic Arabidopsis plants overexpressing GhCaM7 with mutation at the acetylation site are more susceptible to V. dahliae than transgenics overexpressing the wild-type GhCaM7, implying the importance of the acetylated GhCaM7 in response to V. dahliae infection. Yeast two-hybrid, bimolecular fluorescent complementation, luciferase complementation imaging, and coimmunoprecipitation assays demonstrated interaction between GhCaM7 and an osmotin protein GhOSM34 that was shown to have a positive role in V. dahliae resistance. GhCaM7 and GhOSM34 are co-localized in the cell membrane. Upon V. dahliae infection, the Ca2+ content reduces almost instantly in plants with downregulated GhCaM7 or GhOSM34. Down regulating GhOSM34 enhances accumulation of Na+ and increases cell osmotic pressure. Comparative transcriptomic analyses between cotton plants with an increased or reduced expression level of GhCaM7 and wild-type plants indicate the involvement of jasmonic acid signaling pathways and reactive oxygen species in GhCaM7-enabled disease resistance. Together, these results demonstrate the involvement of CaM protein in the interaction between cotton and V. dahliae, and more importantly, the involvement of the acetylated CaM in the interaction.

A Par3/LIM Kinase/Cofilin Pathway Mediates Human Airway Smooth Muscle Relaxation by TAS2R14.

TAS2Rs (bitter taste receptors) are GPCRs (G protein-coupled receptors) expressed on human airway smooth muscle (HASM) cells; when activated by receptor agonists they evoke marked airway relaxation. In both taste and HASM cells, TAS2Rs activate a canonical Gßγ-mediated stimulation of Ca2+ release from intracellular stores by activation of PLCß (phospholipase Cß). Alone, this [Ca2+]i signaling does not readily account for relaxation, particularly since bronchoconstrictive agonists acting at Gq-coupled receptors also increase [Ca2+]i. We established that TAS2R14 activation in HASM promotes relaxation through F-actin (filamentous actin) severing. This destabilization of actin was from agonist-promoted activation (dephosphorylation) of cofilin, which was pertussis toxin sensitive. Cofilin dephosphorylation was due to TAS2R-mediated deactivation of LIM domain kinase. The link between early receptor action and the distal cofilin dephosphorylation was found to be the polarity protein partitioning defective 3 (Par3), a known binding partner with PLCß that inhibits LIM kinase. The physiologic relevance of this pathway was assessed using knock-downs of cofilin and Par3 in HASM cells and in human precision-cut lung slices. Relaxation by TAS2R14 agonists was ablated with knock-down of either protein as assessed by magnetic twisting cytometry in isolated cells or intact airways in the slices. Blocking [Ca2+]i release by TAS2R14 inhibited agonist-promoted cofilin dephosphorylation, confirming a role for [Ca2+]i in actin-modifying pathways. These results further elucidate the mechanistic basis of TAS2R-mediated HASM relaxation and point toward nodal points that may act as asthma or chronic obstructive pulmonary disease response modifiers or additional targets for novel bronchodilators.

Behçet's patients' response to COVID-19 vaccination.

Immune hyperstimulation by SARS-CoV2 results in multi-system involvement with consequent organ damage not dissimilar to Behçet's Disease (BD). Management of BD includes immunosuppressive medication, which led to concerns that; firstly, SARS-CoV-2 would stimulate BD activity, thrombin, clotting times, TPO antibodies, and the effectiveness and duration of the COVID-19 vaccines' response in this potentially vulnerable group. The main objectives of this study were: to assess BD patients' immune response to the COVID-19 vaccines based on age, gender, disease activity, BD phenotype, and immunomodulatory medication compared to healthy control participants by measuring anti-spike IgG levels. Further to evaluate the effect of the COVID-19 vaccines on T and B cells, immunoglobulins, thrombophilia, thyroid function and COVID-19 antibody production. Patients on immunosuppressive medication had a reduced immune response to COVID-19 vaccines. -Also, patients over 40 years and with the neurologic BD phenotype had lower responses. mRNA COVID-19 vaccines were more effective and had fewer side effects compared to conventional COVID-19 vaccines.

Systems analysis of the effects of the 2014-16 Ebola crisis on WHO-reporting nations' policy adaptations and 2020-21 COVID-19 response: a systematized review.

BACKGROUND: Recent case studies indicate that the 2014-2016 Ebola outbreak, one of the worst pre-2020 global biological catastrophes in modern history, helped some nations to better prepared their responses for the COVID-19 pandemic. While such national case studies explore how specific nations applied EVD-related policies in their domestic battle against the COVID-19 pandemic, there is no known study that assesses how many WHO nations learned from the West African crisis and to what scale. OBJECTIVE: Applying the policy legacies analytical framework and a systematized literature review, this research examines how prior policy experiences with the 2014-16 EVD crisis as a large-scale emergent outbreak helped to inform and to condition WHO nations to proactively prepare their national policies and health systems for future threats, including ultimately COVID-19. METHODS: A systematized literature review of 803 evaluated sources assesses to what extent Ebola-affected and non-affected nations directly modified governmental health systems in relation to this warning. The study further evaluates how nations with documented Ebola-related changes fared during COVID-19 compared to nations that did not. We present a categorical theoretical framework that allows for classifying different types of national response activities (termed conditioned learning). RESULTS: Ten (90.9%) of 11 nations that were affected by 2014-16 Ebola crisis have documented evidence of repurposing their EVD-related policies to fight COVID-19. 164 (70.0%) of 234 non-EVD-affected nations had documented evidence of specifically adapting national systems to incorporate policy recommendations developed from the 2014-16 crisis, which informed their COVID-19 responses in 2020. CONCLUSIONS: The shock of 2014-16 EVD outbreak affected most nations around the world, whether they experienced Ebola cases. We further develop a categorical framework that helps characterised nations previous experiences with this biological catastrophe, providing a means to analyse to what extent that individual nations learned and how these EVD-related changes helped inform their COVID-19 response. Nations that demonstrated EVD-related conditioned learning nations tended to have more stringent COVID-19 responses before April 2020 and utilized documented response mechanisms developed out of the West African crisis.

Genes Encoding Structurally Conserved Serpins in the Wheat Genome: Identification and Expression Profiles during Plant Development and Abiotic and Biotic Stress.

Serpins constitute a family of proteins with a very wide distribution in nature. Serpins have a well-conserved tertiary structure enabling irreversible protease inhibition or other specific biochemical functions. We examined the 189 putative wheat serpin genes previously identified by Benbow et al. (2019) via analysis of gene annotations (RefSeq v1.0) and combined our previous examinations of wheat ESTs and the 454 genome assembly. We found that 81 of the 189 putative serpin genes, plus two manually annotated genes, encode full-length, structurally conserved serpins. Expression of these serpin genes during wheat development and disease/abiotic stress responses was analysed using a publicly available RNAseq database. Results showed that the wheat LR serpins, homologous to Arabidopsis AtSerpin1 and barley BSZx, are ubiquitously expressed across all tissues throughout the wheat lifecycle, whereas the expression of other wheat serpin genes is tissue-specific, including expression only in the grain, only in the root, and only in the anther and microspore. Nine serpin genes were upregulated in both biotic and abiotic responses. Two genes in particular were highly expressed during disease and abiotic challenges. Our findings provide valuable information for further functional study of the wheat serpins, which in turn may lead to their application as molecular markers in wheat breeding.

Transcriptome and metabolome profiling in different stages of infestation of Eucalyptus urophylla clones by Ralstonia solanacearum.

Eucalyptus urophylla is an economically important tree species that widely planted in tropical and sub-tropical areas around the world, which suffers significant losses due to Ralstonia solanacearum. However, little is known about the molecular mechanism of pathogen-response of Eucalyptus. We collected the vascular tissues of a E. urophylla clone infected by R. solanacearum in the laboratory, and combined transcriptome and metabolome analysis to investigate the defense responses of Eucalyptus. A total of 11 flavonoids that differentially accumulated at the first stage or a later stage after infection. The phenylpropanoid of p-coumaraldehyde, the two alkaloids trigonelline and DL-ephedrine, two types of traditional Chinese medicine with patchouli alcohol and 3-dihydrocadambine, and the amino acid phenylalanine were differentially accumulated after infection, which could be biomarkers indicating a response to R. solanacearum. Differentially expressed genes involved in plant hormone signal transduction, phenylpropanoids, flavonoids, mitogen-activated protein kinase (MAPK) signaling, and amino acid metabolism were activated at the first stage of infection or a later stage, indicating that they may participate in the defense against infection. This study is expected to deliver several insights into the molecular mechanism in response to pathogens in E. urophylla, and the findings have far-reaching implications in the control of E. urophylla pathogens.

Transcriptome and metabolome profiling in naturally infested Casuarina equisetifolia clones by Ralstonia solanacearum.

Casuarina equisetifolia is an important pioneer tree and suffers from bacterial wilt caused by Ralstonia solanacearum. We collected resistant (R) and susceptible (S) C. equisetifolia clones naturally infected by R. solanacearum and compared their transcriptome and metabolome with a clone (CK) from a non-infested forest, in order to study their response and resistance to bacterial wilt. We identified 18 flavonoids differentially accumulated among the three clonal groups as potential selection biomarkers against R. solanacearum. Flavonoid synthesis-related genes were up-regulated in the resistant clones, probably enhancing accumulation of flavonoids and boosting resistance against bacterial wilt. The down-regulation of auxin/indoleacetic acid-related genes and up-regulation of brassinosteroid, salicylic acid and jasmonic acid-related differentially expressed genes in the R vs CK and R vs S clonal groups may have triggered defense signals and increased expression of defense-related genes against R. solanacearum. Overall, this study provides an important insight into pathogen-response and resistance to bacterial wilt in C. equisetifolia.

The Upregulated Expression of the Citrus RIN4 Gene in HLB Diseased Citrus Aids Candidatus Liberibacter Asiaticus Infection.

The citrus industry has been threatened by Huanglongbing (HLB) for over a century. Here, an HLB-induced Arabidopsis RPM1-interacting protein 4 (RIN4) homologous gene was cloned from Citrus clementina, and its characteristics and function were analyzed to determine its role during citrus-Candidatus Liberibacter asiaticus (CLas) interactions. Quantitative real-time PCR showed that RIN4 was expressed in roots, stems, leaves and flowers, with the greatest expression level in leaves. Its expression was suppressed by gibberellic acid, indole-3-acetic acid, salicylic acid and jasmonic acid treatments, but was induced by abscisic acid and salt treatments, as well as wounding. The transient expression of a RIN4-GFP showed that RIN4 was localized in the cell membrane. RIN4-overexpressing transgenic C. maxima cv. 'Shatianyou' plants were obtained, and some transgenic plants showed greater sensitivity to CLas infection and earlier HLB symptoms appearance than non-transgenic controls. Results obtained in this study indicated that the upregulated expression of RIN4 in HLB diseased citrus may aid CLas infection.

Expression Analysis of Moritella viscosa-Challenged Atlantic Salmon Identifies Disease-Responding Genes, MicroRNAs and Their Predicted Target Genes and Pathways.

Moritella viscosa is a bacterial pathogen causing winter-ulcer disease in Atlantic salmon. The lesions on affected fish lead to increased mortality, decreased fish welfare, and inferior meat quality in farmed salmon. MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional regulation by guiding the miRNA-induced silencing complex to specific mRNA transcripts (target genes). The goal of this study was to identify miRNAs responding to Moritella viscosa in salmon by investigating miRNA expression in the head-kidney and the muscle/skin from lesion sites caused by the pathogen. Protein coding gene expression was investigated by microarray analysis in the same materials. Seventeen differentially expressed guide-miRNAs (gDE-miRNAs) were identified in the head-kidney, and thirty-nine in lesion sites, while the microarray analysis reproduced the differential expression signature of several thousand genes known as infection-responsive. In silico target prediction and enrichment analysis suggested that the gDE-miRNAs were predicted to target genes involved in immune responses, hemostasis, angiogenesis, stress responses, metabolism, cell growth, and apoptosis. The majority of the conserved gDE-miRNAs (e.g., miR-125, miR-132, miR-146, miR-152, miR-155, miR-223 and miR-2188) are known as infection-responsive in other vertebrates. Collectively, the findings indicate that gDE-miRNAs are important post-transcriptional gene regulators of the host response to bacterial infection.

PacBio full-length transcriptome of wild apple (Malus sieversii) provides insights into canker disease dynamic response.

BACKGROUND: Valsa canker is a serious disease in the stem of Malus sieversii, caused by Valsa mali. However, little is known about the global response mechanism in M. sieversii to V. mali infection. RESULTS: Phytohormone jasmonic acid (JA) and salicylic acid (SA) profiles and transcriptome analysis were used to elaborate on the dynamic response mechanism. We determined that the JA was initially produced to respond to the necrotrophic pathogen V. mali infection at the early response stage, then get synergistically transduced with SA to respond at the late response stage. Furthermore, we adopted Pacific Biosciences (PacBio) full-length sequencing to identify differentially expressed transcripts (DETs) during the canker response stage. We obtained 52,538 full-length transcripts, of which 8139 were DETs. Total 1336 lncRNAs, 23,737 alternative polyadenylation (APA) sites and 3780 putative transcription factors (TFs) were identified. Additionally, functional annotation analysis of DETs indicated that the wild apple response to the infection of V. mali involves plant-pathogen interaction, plant hormone signal transduction, flavonoid biosynthesis, and phenylpropanoid biosynthesis. The co-expression network of the differentially expressed TFs revealed 264 candidate TF transcripts. Among these candidates, the WRKY family was the most abundant. The MsWRKY7 and MsWRKY33 were highly correlated at the early response stage, and MsWRKY6, MsWRKY7, MsWRKY19, MsWRKY33, MsWRKY40, MsWRKY45, MsWRKY51, MsWRKY61, MsWRKY75 were highly correlated at the late stage. CONCLUSIONS: The full-length transcriptomic analysis revealed a series of immune responsive events in M. sieversii in response to V. mali infection. The phytohormone signal pathway regulatory played an important role in the response stage. Additionally, the enriched disease resistance pathways and differentially expressed TFs dynamics collectively contributed to the immune response. This study provides valuable insights into a dynamic response in M. sieversii upon the necrotrophic pathogen V. mali infection, facilitates understanding of response mechanisms to canker disease for apple, and provides supports in the identification of potential resistance genes in M. sieversii.

The Development and Operation of a Home Management System during the COVID-19 Pandemic: Experience of the Local Government Gyeonggi-do in Korea.

During the three the coronavirus disease 2019 (COVID-19) surges in South Korea, there was a shortage of hospital beds for COVID-19 patients, and as a result, there were cases of death while waiting for hospitalization. To minimize the risk of death and to allow those confirmed with COVID-19 to safely wait for hospitalization at home, the local government of Gyeonggi-do in South Korea developed a novel home management system (HMS). The HMS team, comprised of doctors and nurses, was organized to operate HMS. HMS provided a two-way channel for the taskforce and patients to monitor the severity of patient's condition and to provide healthcare counseling as needed. In addition, the HMS team cooperated with a triage/bed assignment team to expedite the response in case of an emergency, and managed a database of severity for real-time monitoring of patients. The HMS became operational for the first time in August 2020, initially managing only 181 patients; it currently manages a total of 3,707 patients. The HMS supplemented the government's COVID-19 confirmed case management framework by managing patients waiting at home for hospitalization due to lack of hospital and residential treatment center beds. HMS also could contribute a sense of psychological stability in patients and prevented the situation from worsening by efficient management of hospital beds and reduction of workloads on public healthcare centers. To stabilize and improve the management of COVID-19 confirmed cases, governments should organically develop self-treatment and HMS, and implement a decisive division of roles within the local governments.

Characterization of patients with metastatic non-small-cell lung cancer obtaining long-term benefit from immunotherapy.

Aim: A minority of patients gains advantage from immunotherapy (IO). Predictive variables of long-term benefit (LTB) are incompletely understood. Materials & methods: We retrospectively collected data about metastatic non-small-cell lung cancer patients treated with IO from April 2013 to July 2017. We defined LTB to IO as complete response (CR), partial response (PR) or disease stability as best response and maintaining it for ≥12 months. Results: Thirty-five of the 147 patients had LTB. More LTB patients than controls showed CR/PR as first and best response to IO. Only CR/PR as best response to IO retained association to LTB at multivariate analyses. Conclusion: Objective response appears as a central factor for LTB from IO.

Deep, multi-stage transcriptome of the schistosomiasis vector Biomphalaria glabrata provides platform for understanding molluscan disease-related pathways.

BACKGROUND: The gastropod mollusc Biomphalaria glabrata is well known as a vector for the tropical disease schistosomiasis, which affects nearly 200 million people worldwide. Despite intensive study, our understanding of the genetic basis of B. glabrata development, growth and disease resistance is constrained by limited genetic resources, constraints for which next-generation sequencing methods provide a ready solution. METHODS: Illumina sequencing and de novo assembly using the Trinity program was used to generate a high-quality transcriptomic dataset spanning the entirety of in ovo development in schistosomiasis-free B. glabrata. This was subjected to automated (KEGG, BLAST2GO) and manual annotation efforts, allowing insight into the gene complements of this species in a number of contexts. RESULTS: Excellent dataset recovery was observed, with 133,084 contigs produced of mean size 2219.48 bp. 80,952 (60.8 %) returned a BLASTx hit with an E value of less than 10-3, and 74,492 (55.97 %) were either mapped or assigned a GO identity using the BLAST2GO program. The CEGMA set of core eukaryotic genes was found to be 99.6 % present, indicating exceptional transcriptome completeness. We were able to identify a wealth of disease-pathway related genes within our dataset, including the Wnt, apoptosis and Notch pathways. This provides an invaluable reference point for further work into molluscan development and evolution, for studying the impact of schistosomiasis in this species, and perhaps providing targets for the treatment of this widespread disease. CONCLUSIONS: Here we present a deep transcriptome of an embryonic sample of schistosomiasis-free B. glabrata, presenting a comprehensive dataset for comparison to disease-affected specimens and from which conclusions can be drawn about the genetics of this widespread medical model. Furthermore, the dataset provided by this sequencing provides a useful reference point for comparison to other mollusc species, which can be used to better understand the evolution of this commercially, ecologically and medically important phylum.

'Between Combat boots and Birkenstocks'-Lessons from HIV/AIDS, SARS, H1N1 and Ebola.

OBJECTIVES: In late 2013, an Ebola outbreak quickly grew into an epidemic of extraordinary magnitude, killing more people than all previous Ebola outbreaks combined. Although the epidemic was unprecedented, the world had previously experienced several acute public health emergencies requiring global coordination. HIV/AIDS, SARS and H1N1 tested global response, and in each case coordination proved problematic, making the 2013-2015 Ebola epidemic no exception. The purpose of this project was to identify persistent vulnerabilities within global public health emergency response and to identify areas for future research and improvement. STUDY DESIGN: Non-systematic review and qualitative interview study. METHODS: Using PubMed and Google, a comprehensive search of articles connected to the HIV/AIDS, SARS, H1N1 and Ebola responses was conducted. Then, 21 key responders involved in those emergencies, primarily from the US Centers for Disease Control and Prevention, participated in in-depth interviews. The content analysis and in-depth interview data were analysed using MAXQDA analysis software. RESULTS: A number of issues emerged, including cultural and political clashes within relevant agencies and a lack of confidence in those agencies, policy barriers that hinder long-term international response, a shortage of personnel and resources, itemized funding streams that limit flexibility to direct resources, and challenges to deploying responders internationally. CONCLUSIONS: The data suggest that the world remains ill prepared to handle sustained responses and global pandemics. The study identified major vulnerabilities persistent within US-led global public health response and offers recommendations for further focused research to fully understand why these challenges persist.

Collaborative wildlife disease outbreak investigation and response at Bells Swamp Victoria, February 2023.

In February 2023, a report of morbidity and mortality in waterbirds triggered a collaborative regional wildlife disease outbreak investigation and response, led by Parks Victoria. Triage, rehabilitation and diagnosis of sick and dead birds were undertaken by Zoos Victoria (ZV), Agriculture Victoria, Vets for Compassion, Wildlife Victoria and Melbourne Veterinary School (MVS). The field response focused on collection of sick and dead birds for wildlife welfare, for diagnosis, and to reduce environmental contamination. Botulism was suspected, based on clinical signs and lack of significant gross pathology, and this diagnosis was confirmed by PCR testing. Low pathogenicity avian influenza (LPAI) viruses non H5 or H7 were detected in two birds and ruled out in all in others tested. These incidental, non-clinical LPAI detections are considered part of the natural wild bird virus community in Australia. A number of elements contributed to the collaborative effort. Regional individuals had the necessary connections for reporting, collecting and transporting birds. There was rapid determination by the Victorian Department of Energy, Environment and Climate Action (DEECA) that Parks Victoria, as the land managers, should lead the response. Zoos Victoria provided capacity and expertise in wildlife triage and rehabilitation, and Agriculture Victoria, ZV and MVS were responsible for veterinary management of the response and diagnosis. Field investigation and response were conducted by Parks Victoria, Agriculture Victoria, MVS and veterinary teams from Vets for Compassion and Wildlife Victoria. Wildlife Health Australia (WHA) provided guidance and information, approved National Significant Disease Investigation Program funding and captured the event in the national wildlife health information database. Communication and media were important for community understanding of the event.

Imaging Response to Treatment in Rheumatology.

This article highlights the crucial role of various imaging techniques in the diagnosis and monitoring of rheumatologic diseases. It provides an overview of the different modalities available for imaging rheumatic diseases, the disease processes they are able to demonstrate, and their utility in the monitoring response to therapy. It emphasizes the need for a multifaceted approach that combines radiography, ultrasound, MR imaging, and PET imaging to gain a comprehensive understanding of disease progression and treatment response. Standardized grading systems along with quantitative imaging techniques are playing an increasing role in monitoring disease activity and assessing response to therapy.

Enfortumab vedotin-related cutaneous toxicity correlates with overall survival in patients with urothelial cancer: a retrospective experience.

Introduction: Enfortumab vedotin (EV) is an antibody drug conjugate approved for advanced urothelial cancer, consisting of a monomethyl auristatin E payload linked to a human monoclonal antibody targeting nectin-4. No validated biomarker predictive of or correlated with response exists for EV. Cutaneous toxicity is among the most common EV-related toxicities and typically emerges in early cycles. This retrospective experience of patients with urothelial cancer treated with EV monotherapy evaluated whether EV-related cutaneous toxicity correlated with improved outcomes including progression-free (PFS) and overall (OS) survival and overall response rate (ORR). Patients and methods: Patients treated with EV monotherapy at Johns Hopkins were identified, and baseline characteristics, treatment, and toxicity details were extracted through chart review. Univariable Cox hazard ratios (HRs) were calculated for assessing the effect of baseline patient characteristics and cutaneous toxicity in PFS and OS. Based on the univariable analysis and known risk factors, all subsequent analyses were adjusted for: Eastern Cooperative Oncology Group performance status, visceral metastases at baseline, gender as well as EV dose, and weight to account for dosing differences. Multivariable Cox proportional HRs were used for comparing PFS and OS between patients with and without cutaneous toxicity, assessing toxicity and EV dose as a time-dependent variables. Adjusted p-values were calculated to compare ORR and disease control rate (DCR) between groups using the Poisson regression model. Results: Of the 78 patients analyzed, 42 (53.8%) experienced EV-related cutaneous toxicity that appeared early during treatment (median time to occurrence 0.5 months from EV initiation). Cutaneous toxicity correlated with significantly improved OS [HR, 0.48; 95% confidence interval (CI), 0.25, 0.9; P = 0.0235], ORR (68.3% vs. 20.7%, P = 0.0033) and DCR (82.9% vs. 48.3%, P = 0.0122). Median PFS was numerically longer in the cutaneous toxicity group (6.3 vs. 1.7 months), although no significance was achieved in the multivariable analysis (HR, 0.62; 95% CI: 0.35, 0.108; P = 0.0925). Conclusion: In this retrospective study, EV-related cutaneous toxicity was associated with improved patient outcomes. Confirming this observation and understanding its mechanism could lead to discovery of a new clinical biomarker of EV response that can emerge in the first cycle.

Phase II randomised, double-blind study of mFOLFIRINOX plus ramucirumab versus mFOLFIRINOX plus placebo in advanced pancreatic cancer patients (HCRN GI14-198).

BACKGROUND: Vascular endothelial growth factor receptor (VEGFR)-mediated signalling contributes to andgiogenesis and therapy resistance in pancreatic ductal adenocarcinoma (PDAC). Ramucirumab (RAM) is a VEGFR2 monoclonal antibody. We conducted a randomised phase II trial to compare progression-free survival (PFS) between mFOLFIRINOX with or without RAM in first line therapy of metastatic PDAC. METHODS: This phase II randomised, multi-centre, placebo controlled, double-blinded, trial randomly assigned to recurrent/metastatic PDAC patients to either mFOLFIRINOX/RAM (Arm A) or mFOLFIRINOX/placebo (Arm B). The primary endpoint is PFS at 9 months, and the secondary endpoints include overall survival (OS), response rate and toxicity evaluation. RESULTS: A total of 86 subjects enrolled, 82 eligible (42 in Arm A versus 40 in Arm B). The mean age was comparable (61.7 versus 63.0, respectively). Majority were White (N = 69) and males (N = 43). The median PFS was 5.6 compared to 6.7 months, for Arm A and B, respectively. At 9 months, the PFS rates were 25.1% and 35.0% for Arms A and B, respectively (p = 0.322). The median OS in Arm A was 10.3 compared to 9.7 months for Arm B (p = 0.094). The disease response rate for Arm A was 17.7% compared to Arm B of 22.6%. FOLFIRINOX/RAM combination was well tolerated. CONCLUSIONS: The addition of RAM to FOLFIRINOX did not significantly impact PFS or OS. The combination was well tolerated (Funded by Eli Lilly; ClinicalTrials.gov number, NCT02581215).

Corrigendum: User perceptions about sharing exposure notification information for communicable diseases.

[This corrects the article DOI: 10.3389/fdgth.2022.926683.].