Randomized trial of anetumab ravtansine and pembrolizumab compared to pembrolizumab for mesothelioma.

PURPOSE: The mesothelin-targeting antibody-drug conjugate anetumab ravtansine was evaluated in combination with the programmed cell death-1 (PD-1) inhibitor pembrolizumab based on the common expression of mesothelin and reports of activity in mesothelioma. PATIENTS AND METHODS: A phase 1 safety run-in of the combination of anetumab ravtansine (6.5 mg/kg iv q3weeks) and pembrolizumab (200 mg, IV q3weeks) was conducted, followed by a phase 2 randomization to the combination or pembrolizumab alone at medical centers across the United States and Canada in the National Cancer Institute's Experimental Therapeutics Clinical Trials Network. Patients with pleural mesothelioma that expressed mesothelin and had previously received platinum-based therapy were eligible. RESULTS: In phase 1 (n = 12) only one dose limiting toxicity was observed and the rules for dose reduction were not met. In phase 2, there was no difference in the confirmed response rates between the combination group (n = 18, 2 partial responses [PR], 11 %) and the pembrolizumab group (n = 17, 1 PR, 6 %; z = -0.5523, p = 0.29116). The median PFS was 12.2 months (95 % CI 5.1-not evaluable [NE]) for the combination, and 3.9 months for pembrolizumab (95 % CI 2.1-NE)(HR=0.55, p = 0.20). Patients with high baseline levels of soluble mesothelin who received anetumab ravtansine had a median PFS of 5 months. CONCLUSIONS: The numeric difference in PFS between treatment groups was not statistically significant, likely related to a smaller than planned sample size. High levels of soluble mesothelin should potentially be considered to select against the use of mesothelin-targeting therapies in development that are neutralized by soluble mesothelin.

Genome sequencing and de novo assembly of Trichoderma longibrachiatum isolate collected from Florida agricultural soils.

We report a draft genome assembly of Trichoderma longibrachiatum isolate GEV 3550, obtained from Florida, United States of America.

A phase I oncolytic virus trial with vesicular stomatitis virus expressing human interferon beta and tyrosinase related protein 1 administered intratumorally and intravenously in uveal melanoma: safety, efficacy, and T cell responses.

Introduction: Metastatic uveal melanoma (MUM) has a poor prognosis and treatment options are limited. These patients do not typically experience durable responses to immune checkpoint inhibitors (ICIs). Oncolytic viruses (OV) represent a novel approach to immunotherapy for patients with MUM. Methods: We developed an OV with a Vesicular Stomatitis Virus (VSV) vector modified to express interferon-beta (IFN-ß) and Tyrosinase Related Protein 1 (TYRP1) (VSV-IFNß-TYRP1), and conducted a Phase 1 clinical trial with a 3 + 3 design in patients with MUM. VSV-IFNß-TYRP1 was injected into a liver metastasis, then administered on the same day as a single intravenous (IV) infusion. The primary objective was safety. Efficacy was a secondary objective. Results: 12 patients with previously treated MUM were enrolled. Median follow up was 19.1 months. 4 dose levels (DLs) were evaluated. One patient at DL4 experienced dose limiting toxicities (DLTs), including decreased platelet count (grade 3), increased aspartate aminotransferase (AST), and cytokine release syndrome (CRS). 4 patients had stable disease (SD) and 8 patients had progressive disease (PD). Interferon gamma (IFNγ) ELIspot data showed that more patients developed a T cell response to virus encoded TYRP1 at higher DLs, and a subset of patients also had a response to other melanoma antigens, including gp100, suggesting epitope spreading. 3 of the patients who responded to additional melanoma antigens were next treated with ICIs, and 2 of these patients experienced durable responses. Discussion: Our study found that VSV-IFNß -TYRP1 can be safely administered via intratumoral (IT) and IV routes in a previously treated population of patients with MUM. Although there were no clear objective radiographic responses to VSV-IFNß-TYRP1, dose-dependent immunogenicity to TYRP1 and other melanoma antigens was seen.

What Are the Care Needs of Families Experiencing Sudden Cardiac Arrest? A Survivor- and Family-Performed Systematic Review, Qualitative Meta-Synthesis, and Clinical Practice Recommendations.

INTRODUCTION: Cardiac arrest care systems are being designed and implemented to address patients', family members', and survivors' care needs. We conducted a systematic review and a meta-synthesis to understand family experiences and care needs during cardiac arrest care to create treatment recommendations. METHODS: We searched eight electronic databases to identify articles. Study findings were extracted, coded and synthesized. Confidence in the quality, coherence, relevance, and adequacy of data underpinning the resulting findings was assessed using GRADE-CERQual methods. RESULTS: In total 4181 studies were screened, and 39 met our inclusion criteria; these studies enrolled 215 survivors and 418 family participants-which includes both co-survivors and bereaved family members. From these studies findings and participant data we identified 5 major analytical themes: (1) When the crisis begins we must respond; (2) Anguish from uncertainty, we need to understand; (3) Partnering in care, we have much to offer; (4) The crisis surrounding the victim, ignore us, the family, no longer; (5) Our family's emergency is not over, now is when we need help the most. Confidence in the evidence statements are provided along with our review findings. DISCUSSION: The family experience of cardiac arrest care is often chaotic, distressing, complex and the aftereffects are long-lasting. Patient and family experiences could be improved for many people. High certainty family care needs identified in this review include rapid recognition and response, improved information sharing, more effective communication, supported presence and participation, or supported absence, and psychological aftercare.

The Timing, Trajectory, and Incidence of Immune-Related Adverse Events in NSCLC Treated With Atezolizumab.

Introduction: Immune-related adverse events (irAEs) due to immune checkpoint inhibitors can have complicated clinical courses. We comprehensively evaluated the timing, trajectory, and incidence of both single and multiple irAEs for NSCLC treated with atezolizumab. Methods: Data were pooled from 2457 patients who participated in the IMpower130, IMpower132, and IMpower150 clinical trials investigating the use of atezolizumab in metastatic NSCLC as part of a chemoimmunotherapy regimen. Longitudinal irAE data with landmark analysis, time-to-onset, changes in grading severity, and occurrence of multiple events were summarized. Results: In general, 1557 patients were treated with atezolizumab and 900 patients were in the control groups. Median follow-up was 32.3 and 23.5 months, respectively. In the atezolizumab group, 753 patients (48.4%) experienced at least one irAE. In the control group, 289 patients (32.1%) experienced at least one nonimmune adverse event that was attributed to an irAE. In the atezolizumab group, the most common irAEs were rash, hepatitis, and hypothyroidism. Furthermore, 13% of the patients experienced two irAEs and 4% experienced three irAEs. Within 5 months of treatment, the cumulative incidence for any irAE was 39.2%. Median time-to-onset varied from 1 to 10 months based on the specific irAE. Grade 1 to 2 irAEs increased in severity for 33% of the patients. Conclusions: We identified dynamic clinical patterns for irAEs in patients treated with atezolizumab, including variations in time-to-onset, incidence of multiple irAEs, and frequency of irAEs increasing in severity. These results can guide clinical management and future reporting of adverse events to enable comprehensive longitudinal analyses.

Comparative Genomics of Fusarium circinatum Isolates Used to Screen Southern Pines for Pitch Canker Resistance.

Pitch canker, caused by the fungal pathogen Fusarium circinatum, is a global disease affecting many Pinus spp. Often fatal, this disease causes significant mortality in both commercially grown and natural pine forests and is an issue of current and growing concern. F. circinatum isolates collected from three locations in the U.S. state of Florida were shown to be virulent on both slash and loblolly pine, with two of the isolates causing equivalent and significantly larger lesions than those caused by the third isolate during pathogenicity trials. In addition, significant genetic variation in lesion length in the pedigreed slash pine population was evident and rankings of parents for lesion length were similar across isolates. Experimental data demonstrate that both host and pathogen genetics contribute to disease severity. High-quality genomic assemblies of all three isolates were created and compared for structural differences and gene content. No major structural differences were observed among the isolates; however, missing or altered genes do contribute to genomic variation in the pathogen population. This work evaluates in planta virulence among three isolates of F. circinatum, provides genomic resources to facilitate study of this organism, and details comparative genomic methods that may be used to explore the pathogen's contribution to disease development.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

MAP kinases differentially bind and phosphorylate NOS3 via two unique NOS3 sites.

Nitric oxide synthase 3 (NOS3) is a major vasoprotective enzyme that catalyzes the conversion of l-arginine to nitric oxide (NO) in response to a significant number of signaling pathways. Here, we provide evidence that NOS3 interactions with MAP kinases have physiological relevance. Binding interactions of NOS3 with c-Jun N-terminal kinase (JNK1α1 ), p38α, and ERK2 were characterized using optical biosensing with full-length NOS3 and NOS3 specific peptides and phosphopeptides. Like p38α and ERK2, JNK1α1 exhibited high-affinity binding to full-length NOS3 (KD 15 nm). Rate constants exhibited fast-on, slow-off binding (kon = 4106 m-1 s-1 ; koff = 6.2 × 10-5 s-1 ). Further analysis using synthetic NOS3 peptides revealed two MAP kinase binding sites unique to NOS3. p38α evinced similar affinity with both NOS3 binding sites. For ERK2 and JNK1α1, the affinity at the two sites differed. However, NOS3 peptides with a phosphate at either S114 or S633 did not meaningfully interact with the kinases. Immunoblotting revealed that each kinase phosphorylated NOS3 with a unique pattern. JNK1α1 predominantly phosphorylated NOS3 at S114, ERK2 at S600, and p38α phosphorylated both residues. In vitro production of NO was unchanged by phosphorylation at these sites. In human microvascular endothelial cells, endogenous interactions of all the MAP kinases with NOS3 were captured using proximity ligation assay in resting cells. Our results underscore the importance of MAP kinase interactions, identifying two unique NOS3 interaction sites with potential for modulation by MAP kinase phosphorylation (S114) and other signaling inputs, like protein kinase A (S633).

Understanding commercial actors' engagement in policy debates on proposed e-cigarette regulation in Scotland.

INTRODUCTION: There is growing concern about transnational tobacco corporations' (TTCs) and other commercial actors' involvement in e-cigarette policy development. Previous analyses suggest that TTCs used e-cigarette debates to demonstrate alignment with public health and re-gain policy influence. Less is known about the engagement of other types of commercial actors in e-cigarette policy debates. METHODS: This paper is the first to empirically analyse commercial actors' engagement in an e-cigarette policy consultation process and to examine their views on proposed regulation. It applies mixed methods, drawing on policy consultation submissions (n=32), semi-structured interviews (n=9) and a social network analysis of website links among 32 commercial actors. RESULTS: The results show that commercial actors' positions on e-cigarette regulation aligned with business interests. TTCs, independent e-cigarette manufacturers and other non-licensed commercial actors were opposed to most aspects of potential e-cigarette regulation (except for age of sale restrictions), whereas licensed commercial actors, including pharmaceutical companies, supported more stringent regulation. While collaboration was viewed as strategically important to gain policy influence, distinct commercial interests and concerns about TTC credibility led to strategic distancing and to collaboration being largely confined to sector boundaries. In addition to reiterating arguments employed by TTCs in previous regulatory debates, commercial actors focused on highlighting the technical complexity and harm reduction potential of e-cigarettes. CONCLUSION: Awareness of the various commercial interests and strategic positioning of commercial actors in e-cigarette policy should inform public health advocacy and policy development, including managing conflicts of interest in the context of Framework Convention on Tobacco Control Article 5.3.

NLR diversity and candidate fusiform rust resistance genes in loblolly pine.

Resistance to fusiform rust disease in loblolly pine (Pinus taeda) is a classic gene-for-gene system. Early resistance gene mapping in the P. taeda family 10-5 identified RAPD markers for a major fusiform rust resistance gene, Fr1. More recently, single nucleotide polymorphism (SNP) markers associated with resistance were mapped to a full-length gene model in the loblolly pine genome encoding for a nucleotide-binding site leucine-rich repeat (NLR) protein. NLR genes are one of the most abundant gene families in plant genomes and are involved in effector-triggered immunity. Inter- and intraspecies studies of NLR gene diversity and expression have resulted in improved disease resistance. To characterize NLR gene diversity and discover potential resistance genes, we assembled de novo transcriptomes from 92 loblolly genotypes from across the natural range of the species. In these transcriptomes, we identified novel NLR transcripts that are not present in the loblolly pine reference genome and found significant geographic diversity of NLR genes providing evidence of gene family evolution. We designed capture probes for these NLRs to identify and map SNPs that stably cosegregate with resistance to the SC20-21 isolate of Cronartium quercuum f.sp. fusiforme (Cqf) in half-sib progeny of the 10-5 family. We identified 10 SNPs and 2 quantitative trait loci associated with resistance to SC20-21 Cqf. The geographic diversity of NLR genes provides evidence of NLR gene family evolution in loblolly pine. The SNPs associated with rust resistance provide a resource to enhance breeding and deployment of resistant pine seedlings.

What are the care needs of families experiencing cardiac arrest?: A survivor and family led scoping review.

AIM: The sudden and unexpected cardiac arrest of a family member can be a grief-filled and life-altering event. Every year many hundreds of thousands of families experience the cardiac arrest of a family member. However, care of the family during the cardiac arrest and afteris poorly understood and incompletely described. This review has been performed with persons with lived experience of cardiac arrest to describe, "What are the needs of families experiencing cardiac arrest?" from the moment of collapse until the outcome is known. METHODS: This review was guided by specific methodological framework and reporting items (PRISMA-ScR) as well as best practices in patient and public involvement in research and reporting (GRIPP2). A search strategy was developed for eight online databases and a grey literature review. Two reviewers independently assessed all articles for inclusion and extracted relevant study information. RESULTS: We included 47 articles examining the experience and care needs of families experiencing cardiac arrest of a family member. Forty one articles were analysed as six represented duplicate data. Ten family care need themes were identified across five domains. The domains and themes transcended cardiac arrest setting, aetiology, family-member age and family composition. The five domains were i) focus on the family member in cardiac arrest, ii) collaboration of the resuscitation team and family, iii) consideration of family context, iv) family post-resuscitation needs, and v) dedicated policies and procedures. We propose a conceptual model of family centred cardiac arrest. CONCLUSION: Our review provides a comprehensive mapping and description of the experience of families and their care needs during the cardiac arrest of a family-member. Furthermore, our review was conducted with co-investigators and collaborators with lived experience of cardiac arrest (survivors and family members of survivors and non-survivors alike). The conceptual framework of family centred cardiac arrest care presented may aid resuscitation scientists and providers in adopting greater family centeredness to their work.

The Needs of Families During Cardiac Arrest Care: A Survivor- and Family-led Scoping Review Protocol.

INTRODUCTION: Sudden cardiac arrest is a leading cause of death. Family members often witness the event and attempt resuscitation. The physiological and psychological impact of a loved one's death, witnessed or unwitnessed, can be significant and long-lasting. However, little is known about the care needs of families during the cardiac arrest care of a loved one. This scoping review protocol was designed with, and will be performed in partnership with, persons with lived experience of sudden cardiac arrest (survivors and family members of survivors and nonsurvivors alike). METHODS: The review will be performed in accordance with accepted methods such as the Arksey and O'Malley methodology framework and the Levac extension. We will search multiple databases, and Google Scholar for both qualitative and quantitative scientific literature. Articles will be screened, extracted, and analyzed by a team with lived experience of cardiac arrest. Two reviewers will conduct all screening and data extraction independently. A descriptive overview, tabular and/or graphical summaries, and a directed content analysis will be carried out on extracted data. DISCUSSION: This protocol outlines a planned literature review to systematically examine the nature of existing evidence to describe what the care needs of families experiencing the cardiac arrest of a loved one are. Such evidence will contribute to the development of strategies to meet identified care needs. Persons with lived experience participated in the creation of this protocol, and they will also participate in the execution of this review as partners and coinvestigators, not as research subjects or participants. The results of the scoping review will be disseminated upon completion of the work described in this protocol.

Knowledge of and Attitudes Toward Perinatal Home Visiting in Women with High-Risk Pregnancies.

INTRODUCTION: Published research indicates that some perinatal home visiting programs are highly effective. However, there is a dearth of information regarding how these services apply to women experiencing a high-risk pregnancy. The aim of this study was to determine the potential acceptability of home visiting services within this vulnerable population and identify what services women want. METHODS: Four focus groups (N = 32) were conducted with a population of low-income, pregnant individuals in medically underserved central Georgia (United States). Participants were evaluated based on their current exposure to home visiting, receptiveness to home visiting, and reasons for apprehension regarding home visiting. RESULTS: The results of this study were mixed, with women expressing both interest in and reluctance about home visiting programs. Themes of distrust and fear of judgment or persecution existed. Women also varied with regard to what home visiting services they would like offered. Those discussed included assistance with maternal or infant medical needs, maternal function tasks, household tasks, and child care. DISCUSSION: Home visiting programs can be effective for improving maternal and child health outcomes. However, not all home visiting programs effectively reach their target population. More research is needed to determine what women who have high-risk conditions during pregnancy want help with and how to increase receptiveness. The results of this study could be informative to health care providers who treat persons with high-risk conditions in identifying adjunctive services for those in need of additional support.

Evidence use in E-cigarettes debates: scientific showdowns in a 'wild west' of research.

BACKGROUND: Against a backdrop of declining tobacco use, e-cigarette markets are growing. The UK now has a higher percentage of e-cigarette users than any other European country. These developments have prompted fierce discussions in scientific, advocacy and policy communities about how best to respond. This article is one of the first to examine the role of evidence in these debates. METHODS: We analysed 121 submissions to two Scottish policy consultations on e-cigarettes (in 2014 and 2015) and undertook interviews with 26 key informants in 2015-2016, following up with a sub-set in 2019-2020. All data were thematically coded, and our analysis was informed by insights from policy studies and the sociology of science. RESULTS: First, we affirm previous research in suggesting that e-cigarettes appeared to have triggered a breakdown of old public health alliances. Second, we demonstrate that, amid concerns about research quality and quantity, actors are guided by normative outlooks (and/or economic interests) in their assessments of evidence. Third, we show that, despite describing e-cigarette debates as contentious and polarised, actors engaging in Scottish policy debates exhibit a spectrum of views, with most interviewees occupying an uncertain 'middle ground' that is responsive to new evidence. Fourth, we suggest that the perceived divisiveness of e-cigarette debates is attributed to recurrent media simplifications and tensions arising from the behaviours of some actors with settled positions working to promote particular policy responses (including by strategically enrolling supportive evidence). Fifth, we argue that the actions of these actors are potentially explained by the prospect that e-cigarettes could usher in a new tobacco 'policy paradigm'. Finally, we show how scientific authority is employed as a tool within these debates. CONCLUSIONS: E-cigarette debates are likely to reconcile only if a clear majority of participants in the uncertain 'middle ground' settle on a more fixed position. Our results suggest that many participants in Scottish e-cigarette debates occupy this 'middle ground' and express concerns that can be empirically assessed, implying evidence has the potential to play a more important role in settling e-cigarette debates than previous research suggests.

An atlas of health inequalities and health disparities research: "How is this all getting done in silos, and why?"

Research on health inequalities and health disparities has grown exponentially since the 1960s, but this expansion has not been matched by an associated sense of progress. Criticisms include claims that too much research addresses well-trodden questions and that the field has failed to gain public and policy traction. Qualitative studies have found researchers partly attribute these challenges to fragmentation resulting from disciplinary and methodological differences. Yet, empirical investigation ('research on research') is limited. This study addresses this gap, employing mixed-methods to examine, at scale, how and why this field is defined by insular research clusters. First, bibliometric analysis identifies and visualizes the 250 most-connected authors. Next, an algorithm was used to identify clustering via citation links between authors. We used researcher profiling to ascertain authors' geographical and institutional locations and disciplinary training, examining how this mapped onto clusters. Finally, causes of siloing were investigated via semi-structured interviews with 45 researchers. The resulting 'atlas' of health inequalities and health disparities research identifies eight clusters of authors with varying degrees of connectedness. No single factor neatly describes observed fragmentation, health equity scholars exhibit a diverse disciplinary backgrounds, and geographical, institutional, and historical factors appear to intersect to explain siloed citation patterns. While the configuration of research activity within clusters potentially helps render questions scientifically manageable, it affirms perceptions of the field as fragmented. We draw on Thomas Kuhn and Sheila Jasanoff to position results within theoretical pictures of scientific progress. Newcomers to the field can use our findings to orient themselves within the many streams of health equity scholarship, and existing health equity scholars can use the atlas to move beyond existing geo-disciplinary networks. However, although stronger cross-cluster engagement would be likely to improve insights, the complex nexus of factors underlying the field's structure will likely make this challenging in practice.

Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer Living With HIV: A Perspective on Recent Progress and Future Needs.

Recent studies have identified durable responses with the use of immune checkpoint inhibitors in patients with mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC). The dramatic improvement in clinical outcomes led to the US Food and Drug Administration approval of pembrolizumab, nivolumab, and nivolumab in combination with ipilimumab in metastatic patients with MSI-H/MMR-D CRC who previously experienced progression on cytotoxic therapies. In the clinical trials investigating these agents, HIV-seropositive patients were not included and therefore the clinical efficacy of these agents in patients with metastatic MSI-H/MMR-D CRC living with HIV is unclear. On the basis of growing evidence, immune checkpoint blockade therapies seem to be a safe approach in patients with well-controlled HIV infection. Research on immunotherapeutic approaches in patients living with HIV and cancer is an area of unmet medical need that can be addressed by clinical trial designs that are inclusive of patients with well-controlled seropositive HIV and trials that specifically evaluate immune therapies in patients living with HIV.

Development of the Inner City attitudinal assessment tool (ICAAT) for learners across Health care professions.

BACKGROUND: Many health professions learners report feeling uncomfortable and underprepared for professional interactions with inner city populations. These learners may hold preconceptions which affect therapeutic relationships and provision of care. Few tools exist to measure learner attitudes towards these populations. This article describes the development and validity evidence behind a new tool measuring health professions learner attitudes toward inner city populations. METHODS: Tool development consisted of four phases: 1) Item identification and generation informed by a scoping review of the literature; 2) Item refinement involving a two stage modified Delphi process with a national multidisciplinary team (n = 8), followed by evaluation of readability and response process validity with a focus group of medical and nursing students (n = 13); 3) Pilot testing with a cohort of medical and nursing students; and 4) Analysis of psychometric properties through factor analysis and reliability. RESULTS: A 36-item online version of the Inner City Attitudinal Assessment Tool (ICAAT) was completed by 214 of 1452 undergraduate students (67.7% from medicine; 32.3% from nursing; response rate 15%). The resulting tool consists of 24 items within a three-factor model - affective, behavioural, and cognitive. Reliability (internal consistency) values using Cronbach alpha were 0.87, 0.82, and 0.82 respectively. The reliability of the whole 24-item ICAAT was 0.90. CONCLUSIONS: The Inner City Attitudinal Assessment Tool (ICAAT) is a novel tool with evidence to support its use in assessing health care learners' attitudes towards caring for inner city populations. This tool has potential to help guide curricula in inner city health.

E-Cigarettes: A Disruptive Technology? An Analysis of Health Actors' Positions on E-Cigarette Regulation in Scotland.

Concerns have been raised that the divisions emerging within public health in response to electronic cigarettes are weakening tobacco control. This paper employed thematic and network analysis to assess 90 policy consultation submissions and 18 interviews with political actors to examine the extent of, and basis for, divisions between health-focused actors with regard to the harms and benefits of e-cigarettes and appropriate approaches to regulation in Scotland. The results demonstrated considerable engagement in e-cigarette policy development by health-focused actors and a widely held perception of strong disagreement. They show that actors agreed on substantive policy issues, such as age-of-sale restrictions and, in part, the regulation of advertising. Points of contestation were related to the harms and benefits of e-cigarettes and the regulation of vaping in public places. The topicality, limitations of the evidence base and underlying values may help explain the heightened sense of division. While suggesting that some opportunities for joint advocacy might have been missed, this analysis shows that debates on e-cigarette regulation cast a light upon differences in thinking about appropriate approaches to health policy development within the public health community. Constructive debates on these divisive issues among health-focused actors will be a crucial step toward advancing public health.