International Panel Research Articles

Developing a Patient and Public Voice/Involvement (PPV/I) program at the Global Brain Health Institute (GBHI) with global impact

AbstractBackgroundGBHI, a brain health leadership program for international fellows from across disciplines, undertook a 24‐month project to develop a PPV/I program aiming to: (1) provide a PPV/I perspective on GBHI activities; (2) introduce fellows to the principles and practice of PPV/I; (3) develop a ‘global PPV/I toolkit’; and (4) develop a PPV/I Special Interest Group to inform Senior Fellows around the world about PPV/I to support their local work in brain health.MethodPhase 1: Recruiting an international panel of people with lived experience of dementia to inform GBHI’s work, called ‘‘Dementia Community Research Advisory Panel’ (DC‐RAP). Phase 2: Educating: We designed and implemented a dementia‐specific PPV/I training curriculum for GBHI fellows & a PPV/I awareness raising program for GBHI faculty & staff; Phase 3: Creating & disseminating: We developed a global resource document (‘toolkit’) to support the introduction of brain health professionals from different disciplines working around the world to PPV/I practice, fostering a global PPV/I dementia network; Phase 4: Evaluation: We tracked learning outcomes of the project at staff/faculty and Fellow level through Kirkpatrick model and overall project success through Kotter’s 7‐step organizational change model.ResultsPhase 1: DC‐RAP formed and solidified within GBHI to inform GBHI activities, provide feedback on research proposals and lay summary writing. Phase 2: We delivered a PPV/I training program for the 2020 and 2021 Fellow cohorts, which is now fully integrated into curriculum. Phase 3: The GBHI ‘Global Public Involvement in Dementia Guidelines’ were launched by a team of Senior Fellows from 10 countries, who have formed a PPV/I Special Interest Group for PPV/I practice beyond the anglosphere. Phase 4: A Kirkpatrick evaluation revealed changes in PPV/I knowledge, attitude and practices for Fellows and staff/faculty. Multiple strategic wins have enabled us to embed a culture of PPV/I at GBHI, evident in mapping against Kotter’s 7‐step organizational change model.ConclusionEmbedding dementia relevant PPV/I in GBHI provides the potential to disseminate PPV/I principles within GBHI and globally, fostering meaningful public engagement in dementia research and projects to advance dementia understanding worldwide.

Delphi consensus project on prostate-specific membrane antigen (PSMA)-targeted surgery-outcomes from an international multidisciplinary panel.

Prostate-specific membrane antigen (PSMA) is increasingly considered as a molecular target to achieve precision surgery for prostate cancer. A Delphi consensus was conducted to explore expert views in this emerging field and to identify knowledge and evidence gaps as well as unmet research needs that may help change practice and improve oncological outcomes for patients. One hundred and five statements (scored by a 9-point Likert scale) were distributed through SurveyMonkey®. Following evaluation, a consecutive second round was performed to evaluate consensus (16 statements; 89% response rate). Consensus was defined using the disagreement index, assessed by the research and development project/University of California, Los Angeles appropriateness method. Eighty-six panel participants (72.1% clinician, 8.1% industry, 15.1% scientists, and 4.7% other) participated, most with a urological background (57.0%), followed by nuclear medicine (22.1%). Consensus was obtained on the following: (1) The diagnostic PSMA-ligand PET/CT should ideally be taken < 1month before surgery, 1-3months is acceptable; (2) a 16-20-h interval between injection of the tracer and surgery seems to be preferred; (3) PSMA targeting is most valuable for identification of nodal metastases; (4) gamma, fluorescence, and hybrid imaging are the preferred guidance technologies; and (5) randomized controlled clinical trials are required to define oncological value. Regarding surgical margin assessment, the view on the value of PSMA-targeted surgery was neutral or inconclusive. A high rate of "cannot answer" responses indicates further study is necessary to address knowledge gaps (e.g., Cerenkov or beta-emissions). This Delphi consensus provides guidance for clinicians and researchers that implement or develop PSMA-targeted surgery technologies. Ultimately, however, the consensus should be backed by randomized clinical trial data before it may be implemented within the guidelines.

Highly Sensitive Chip-Based Digital PCR Platform for Quantitative Detection of BCR::ABL1 Transcripts throughout CML Treatment

Introduction: With various BCR::ABL1 tyrosine kinase inhibitors (TKIs), chronic myeloid leukemia (CML) has become a manageable disease and current therapeutic goal is treatment-free remission (TFR). To achieve a successful TFR in more patients, a precise assessment of minimal residual disease (MRD) is one of the prerequisite requirements. Since undetectable BCR::ABL1 fusion transcripts by conventional Taqman™-based quantitative polymerase chain reaction (qPCR) is not an indicator for complete eradication of the CML clone, it requires the development of more sensitive technologies. Currently, to overcome some limitations of conventional qPCR, such as rigorous standardization process and variations in sensitivity between laboratories, digital quantitative-PCR (dqPCR) methods have been developed for accurate and precise detection and its use in the routine clinical practice is gradually expanding. However, current dqPCR methods require the inclusion of one or more negative partitions to calculate the concentration using Poisson distribution. Consequently, this leads to a more than a 10-fold decrease in the maximum detectable concentration in a single test compared to conventional qPCR. Therefore, we have developed a novel technology, High Dynamic Range Digital Real-time PCR (so called HDR-drPCR) to achieve wider dynamic range, which allows more stable, accurate and sensitive monitoring of BCR::ABL1 in a timely manner. Methods: For linearity assessment, we used BCR::ABL1 positive (e14a2) K562 cell line diluted to 7 points by 10-fold serial dilutions from 25 to 2.5x10 -5 %IS with BCR::ABL1 negative HL60 cells. In HDR-drPCR, the GUSB gene was employed as a control gene to determine %IS values. For this purpose, the 1 st WHO international genetic reference panel was utilized to calculate the correction factor (CF). With the results from cell lines, we also evaluated equivalence between conventional qPCR and HDR-drPCR using 219 clinical specimens. Among them, 100 samples were determined as DMR (&amp;lt;0.01%IS) based on the qPCR test results In detail, conventional qPCR was performed using Transcriptor First Strand cDNA Synthesis Kit (Roche, USA) for cDNA synthesis and Real-Q BCR-ABL Quantification Kit (Biosewoom, South Korea) for qPCR. For HDR-drPCR (1-step reverse transcriptase PCR), 10 6 to 10 7 copies per reaction of GUSB gene were applied to disposable cartridges of Genotizer™ HDR BCR::ABL1 Major IS detection kit (Optolane Technologies, South Korea) with LOAA platform (Optolane Technologies, Korea). Based on the results, correlation analysis between qPCR and HDR-drPCR was performed using correlation graphs and Blend-Altman plots. Results: Linearity was assessed by the dilution of RNA of K562 with RNA of HL60 using 10-fold serial dilution of up to - 7 log. The result showed accurate linearity (R 2 = 0.9972) at the range of BCR::ABL1/GUSB ratio of 10 1 to 10 -5(%). Notably, HDR-drPCR technology allowed to detect the level of BCR::ABL1 transcript of MR 6.34 (0.00005 %IS) (Figure 1A). The correlation analysis for 209 clinical samples showed that measured values from both qPCR and HDR-drPCR were closely correlated with the R 2 of 0.973 1 (Figure 1B) . The Bland-Altman plot showed a mean bias of 0.159, and the limit of agreement at the 95% confidence interval (LOA95) was calculated as -0.387 to 0.705. Furthermore, the concordance rate between the two methods was 96.17%, as measured by the proportion of samples in which the difference between the two methods was within a factor of 5. This indicates a strong concordance between the two methods. HDR-drPCR reliably detected BCR::ABL1 transcripts in all 90 clinical specimens measured below 0.01%IS (DMR) using qPCR. Additionally, HDR-drPCR detected trace amounts of BCR::ABL1 transcripts in 6 out of 10 specimens that were not detected by qPCR, showcasing its improved sensitivity compared to the conventional qPCR method. Conclusion: Taken together, we believe our high dynamic range real-time digital PCR(HDR-drPCR) may minimize false positive results and maximize the analytical sensitivity of detecting BCR::ABL1 fusion transcripts and thus, would be useful for accurately assessing treatment in routine clinical practice and facilitating the application of treatment-free remission (TFR). We will include these results in further intensive studies focusing on DMR clinical specimens Study support: Funded by Korea Research Foundation

Analysis of Treatment Patterns and Outcomes in Patients Ages 60-74 in the Post-Venetoclax Era

Introduction Clear standards of care exist for patients with AML under the age of 60 who are eligible for intensive chemotherapy (IC), as well as for patients over the age of 75 or who are unfit for IC. Fit patients between the ages of 60-74 have historically been understudied, but have lower rates of remission and increased rates of toxicity with intensive regimens compared to younger individuals with AML. We sought to evaluate treatment patterns and outcomes in this patient group. Methods We performed a single-center, retrospective analysis of consecutive patients ages 60 through 74 years at the time of their AML diagnosis who received frontline therapy between April 2018 and September 2022. Low intensity therapy (LIT) regimens included combinations of a hypomethylating agent, low dose cytarabine, venetoclax, cladribine, and/or targeted agents. IC regimens included an anthracycline and higher-dose cytarabine-based regimens (≥1g/m 2) +/- targeted agents. Clinical and genomic data including patient demographics, laboratory results including bone marrow pathology and mutational data, treatment responses, and allogeneic hematopoietic stem cell transplantation (HCT) data including conditioning regimen and donor type (when applicable) were abstracted from the medical record. Minimal residual disease (MRD) status was assessed by multi-parameter flow cytometry with a sensitivity of 0.02%. The statistical analysis was performed using R 1. Results 143 patients were included in the analysis; 47 (33%) received front line IC, and 96 (67%) received LIT. Baseline characteristics are shown in Table 1. Patients receiving IC were younger, more likely to be female, and more likely to have a favorable ELN risk stratification 2, but otherwise balanced. The percentage of patients receiving IC remained the same in each calendar year. Patients in the IC and LIT groups had similar rates of complete remission (CR; 70% vs 70%, respectively, p = 0.96). Among those achieving CR, 22 (67%) patients in the IC group achieved MRD-negativity vs. 35 (52%) in the LIT group (p = 0.17). The median duration of remission was 9 months in the IC group and 12 months in the LIT group (p = 0.17). The median overall survival (OS) was 17 months for IC and 15 months for LIT (p = 0.16). For patients harboring FLT3-ITD, IDH1, IDH2, or TP53 mutations, there was no difference in OS based on receipt of either IC or LIT, nor was there any difference in OS according to ELN 2022 risk category. A significantly higher proportion of patients who received IC underwent HCT (68% vs 42%, p = 0.003). In both groups, OS was significantly longer for patients who received HCT. Treatment-related mortality (TRM) was comparable in each group, with 5 (11%) and 8 (8%) deaths in IC vs. LIT, respectively. The median number of days hospitalized within the first 60 days after induction therapy was notably different at 32 days for IC and 5.5 days for LIT (p &amp;lt; 0.00001), with 34 (35%) LIT patients who had 0 days of hospitalization post-induction compared to IC patients who universally were hospitalized as part of their induction treatment plan. Conclusion In our cohort, patients with AML between the ages of 60-74 had comparable rates of CR, MRD negativity, duration of response, and overall survival whether treated with IC or LIT, with no difference when stratified by mutational status or ELN risk. Intensively-treated patients were younger and more likely to receive HCT but both groups had an OS benefit from HCT. Our data suggest that in the era of novel agents such as venetoclax, less intensive induction strategies may be appropriate for IC-eligible patients between the ages of 60-74. References 1R Core Team (2021). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/. 2Döhner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, Ebert BL, Fenaux P, Godley LA, Hasserjian RP, Larson RA, Levine RL, Miyazaki Y, Niederwieser D, Ossenkoppele G, Röllig C, Sierra J, Stein EM, Tallman MS, Tien HF, Wang J, Wierzbowska A, Löwenberg B. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022 Sep 22;140(12):1345-1377. doi: 10.1182/blood.2022016867. PMID: 35797463.

Key Prognostic Factors in Patients with Relapsed/Refractory Follicular Lymphoma: An Evidence Based Systematic Literature and Medical Review

Introduction: A multi-center multi-country retrospective cohort study (FLORA [NCT05338879]), using real-world data (RWD) from electronic medical records (EMRs) and research databases, for patients with relapsed/refractory follicular lymphoma grade 1-3a (r/r FL) treated with standard of care is being conducted to contextualize treatment outcomes in a single-arm trial. A systematic literature review (SLR) was carried out to identify baseline prognostic factors that will be evaluated for imbalances between cohorts in the single-arm trial and RWD study. This SLR was followed by an evidence-based clinical expert review and ranking of prognostic variables in order of importance for the FLORA study as described herein. Methods: The approach and methods of the SLR (International Prospective Register of Systematic Reviews [PROSPERO] CRD42022307561) were informed by guidelines set forth by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins et. al. 2021) and PRISMA (Page et. al. BMJ 2021) and described previously (Hampp et. al. ISPOR 2023). Following the conduct of the SLR, the identified potential prognostic variables were evaluated by the FLORA study team to remove treatment-specific and outcome variables, determine their availability in the single-arm trial and FLORA RWD study, and develop a questionnaire. In the questionnaire, prognostic variables were grouped by type of variable - clinical, laboratory data, or treatment characteristic. Each prognostic variable was reviewed by an international panel consisting of 3 clinical experts in the field of lymphoma who categorized the prognostic impact on treatment response and survival on a 5-point scale ranging from “Very high importance” to “Not important”. The clinicians were asked to consider possible correlation among the variables, possible effect modifiers, specific variable definitions (e.g., chemoresistant), and whether there were any other prognostically important variables not captured in the questionnaire. For each variable the clinical experts categorized the availability within routine care on a 3-point scale ranging from “Readily available” to “Limited availability”. The results of the 3 expert completed questionnaires were reviewed and the top 10 highest ranking variables were determined by summing the clinicians' categorization of prognostic impact and considering variable availability in the event of a tie. Individual interviews with each clinical expert were held to clarify variables and definitions, discuss discrepant categorization, and rank the prognostic variables from 1-10. Following the 3 interviews, the ranking of each variable was summed across the 3 experts to determine the final ranking. Results: Across the 13 studies included, the SLR identified 28 prognostic factors, including patient demographics and clinical characteristics, disease and treatment characteristics, and laboratory data. Seven clinical outcomes with statistically significant associations were identified (most commonly, overall survival [OS], progression-free survival [PFS], and relapse/progression). No additional prognostic factors were identified by the clinical experts. The final ranked list of the 10 most important prognostic variables in descending order of importance includes: progression of disease within 2 years (POD24), chemo-immunorefractory/chemoresistant, refractory to last line of therapy (LoT), number of prior LoTs, serum lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group (ECOG) performance status, Follicular Lymphoma International Prognostic Index (FLIPI), age at start of LoT, Ann Arbor disease stage, and refractory to rituximab. Conclusion: SLR-based identification of prognostic factors combined with expert clinical review provides an unbiased evaluation and ranking of the level of evidence to assist in selecting prognostic factors to collect for the FLORA real-world cohort study. The appropriate selection of prognostic factors is critical for valid outcome estimation. These factors will be used for the evaluation of balance with the single-arm trial and for adjustment in a propensity score model. With this approach, the prognostic factors are chosen a priori to enable balancing of baseline covariates prior to outcome estimation.

Consensus-Based Best Practice Recommendations for Myelofibrosis Management in Routine Clinical Practice with a Focus on Patients with Cytopenias: Systematic Literature Review and Clinical Practice Recommendations from a Global Consensus Group

Background: Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm (MPN) characterized by progressive bone marrow fibrosis, splenomegaly, and cytopenias due to impaired hematopoiesis (Passamonti and Mora. Blood 2022). Despite the availability of comprehensive national and international guidelines for diagnosing and managing MF, gaps remain in translating these guidelines into clinical practice, particularly for patients with cytopenias, non-response or intolerance to Janus kinase (JAK) inhibitor treatment, and those ineligible for clinical trial enrollment. Consequently, an international expert consensus group was established with the objective of augmenting the existing guidance. Objectives: To develop a set of evidence- and consensus-based recommendations for managing MF in routine clinical practice, with a focus on patients with cytopenias, including practical strategies and tools to support clinicians. Methods : Modified Delphi methodology was utilized to achieve consensus (Figure 1). A Steering Committee (SC) of 9 expert hematologists (the authors) was established. During an initial meeting, the SC proposed 25 clinical questions that addressed key issues across 5 consensus themes: 1) Defining the thresholds for anemia and when to initiate/modify treatment; 2) defining the threshold for thrombocytopenia and when to initiate/modify treatment; 3) defining JAK inhibitor failure and what would warrant switching treatment; 4) how and when to determine prognosis in patients with MF; and, 5) unmet needs in MF clinical trials. An extended faculty (EF) was then enlisted, comprising hematologists and patient advocacy groups, who voted on the importance of the questions to address. The 15 highest scoring questions were selected for the consensus program (Table 1). To gather scientific evidence around the questions, a systematic literature review (SLR) was conducted using the PubMed and Embase databases, adhering to a PICO (Population, Intervention, Comparison, Outcome) framework. In a subsequent meeting, recommendations were formulated to address the questions using evidence from the SLR and the expert clinical experience of the SC. An online voting platform was then used for both the SC and EF to provide an agreement score for each recommendation. Consensus was achieved when 75% of the respondents agreed within the range of 7-9 on a 9-point scale (1=strongly disagree, 9=strongly agree). Results: Consensus was achieved among voters (hematologists [n=29] and patients [n=9] from Europe, the United States, Canada, Australia, and Israel) for all 15 recommendations. Recommendations in theme 1 emphasize the importance of comprehensive evaluation, exclusion of other causes of anemia, therapy dose optimization, and consideration of additional treatments for managing anemia in patients with MF. Recommendations in theme 2 highlight the complexity of managing splenomegaly, symptoms, and anemia in patients with low platelet counts, and factors guiding therapy selection for these patients. Theme 3 recommendations discuss criteria used to determine JAK inhibitor failure, including relapse, refractoriness, or intolerance, and guidance for distinguishing between these. In theme 4, recommendations address the use of validated prognostic scores at diagnosis and during the disease course, and transplantation risk assessment. The limitations and appropriate utilization of these scores are emphasized, and the need to develop prognostic scores in pre-primary MF is highlighted. Theme 5 recommendations cover the importance of addressing unmet needs in MF clinical trials, and include striving for inclusivity by removing barriers to the participation of underserved patient populations and focusing efforts on validating additional endpoints beyond traditional measures. Conclusions: An international panel of physicians with expertise in MF, together with a diverse EF, was able to achieve a high level of consensus across a wide range of critical gaps in MF management. These recommendations provide a valuable framework to support clinicians in optimizing care for patients with MF.

Development of an international prehospital CPR-induced consciousness guideline: A Delphi study

Background Improved prehospital systems are contributing to increased presentations of CPR-Induced Consciousness (CPRIC). Data registries do not report CPRIC presentations and thus continued lack of evidence exists, causing a significant variation of prehospital CPRIC management guidelines. The result is variation in recognizing and managing CPRIC. Steps are needed to improve knowledge of CPRIC and model evidence-based guidelines. Objective An international panel of experts was recruited to create CPRIC definitions, guidelines, and a reporting framework which can be used for reporting purposes. Methods A Delphi methodology was used to gain consensus, defined as ≥70% agreement rate, on three domains or areas of interest: Definition, management guideline and data reporting. Participants were invited from the author's professional organizations, as well as social media outlets to recruit as many international clinicians as possible. The study administered four rounds of online surveys. Each round had multiple consensus statements for participants to respond to. Results Eighty-two percent of panelists reported seeing or managing CPRIC suggesting either improved awareness or increased exposure. Consensus was achieved in all three domains. There was agreement on a clear definition of CPRIC. The panel developed two subgroups of CPRIC; interfering and non-interfering CPRIC. Ketamine was the preferred choice to treat CPRIC. Panelists overwhelmingly felt CPRIC needed to be included into the Utstein guidelines. Conclusions This study successfully created definitions of CPRIC, management guidelines, and a data reporting framework. Using this study as a building block, the study team hopes stronger, evidence-based guidelines can now be researched and published.

Utility of the 2023 international MOGAD panel proposed criteria in clinical practice: An institutional cohort

BackgroundMyelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently defined demyelinating disorder with a rapidly evolving clinical spectrum. Recently, consensus criteria have been proposed (Banwell et al., 2023) to help with disease diagnosis. However, validation of the proposed criteria in real-life MOGAD patients is lacking. In this study, we applied the proposed criteria to an institutional cohort of MOG antibody-positive patients. MethodsA retrospective study was conducted at a tertiary neuroimmunology clinic from 2018 to 2023. Patients who had at least one core clinical feature of MOGAD and positive serum MOG antibody by cell-based assay were included. Demographics and clinical data were recorded and analyzed. Cases were divided into definite MOGAD, questionable MOGAD, and false-positive MOG antibody as determined by the treating neuroimmunology and/or neuro-ophthalmology specialists prior to applying the new MOGAD criteria by an independent investigator. We then calculated the sensitivity, specificity, positive predictive value, and negative predictive value of the new criteria compared to the treating physicians’ assessment. ResultsA total of 27 patients were included of which, 19 (70.4%) were female, the average age of the sample was 44 +/- 15 years. High titer MOG antibody (≥ 1:100) was found in 11 patients (40.7%); low titer (< 1: 100) in 13 (48.1%), and unreported titer in 3 patients. As determined by expert opinion; 18 (66.7%) were identified as definitive MOGAD, 6 (22.2%) as false-positive MOG antibody, and 3 (11.1%) as questionable MOGAD. All 18 patients identified by clinicians as definite MOGAD met the new 2023 criteria. Of the 9 patients with questionable MOGAD or false-positive MOG antibody, four patients met the 2023 MOGAD criteria. Those four patients had the following final diagnoses: CNS vasculitis, primary progressive MS with activity and progression, pseudotumor cerebri, and bevacizumab-induced anterior ischemic optic neuropathy in the setting of paraneoplastic retinopathy. Compared to clinician assessment, applying the 2023 MOGAD criteria to our institutional cohort yielded a sensitivity of 100%, a specificity of 55.5%, a positive predictive value of 81.5% and a negative predictive value of 100%. ConclusionThese findings suggest that the 2023 MOGAD criteria are highly sensitive for detection of definite MOGAD but has modest specificity. A number of MOGAD mimickers can resemble the core clinical events of MOGAD and share similar supportive clinical and MRI features. Clinicians should practice caution when evaluating patients with low titer MOG antibody even if they meet the additional supportive features proposed by the 2023 criteria. Further studies are needed to evaluate the 2023 criteria in larger cohorts and in the pediatric population.

Robotics: Enabler and inhibitor of the Sustainable Development Goals

Robotics has the power to help our society in managing many current and foreseeable challenges, and contribute to a responsible future, as formally structured in the United Nations' Sustainable Development Goals (SDGs) initiative. Prior work has already investigated the impact of Artificial Intelligence (AI) on the SDGs, using a systematic consensus-based expert elicitation process. However, the existing literature has not focused on the intricacies of robotics and the unique dynamics this domain presents regarding the SDGs. In this vein, this work adapts an established approach, to focus on and dive deeper into the field of robotics and social responsibility. We introduce a multidisciplinary analysis of both the enabling and disabling roles of robotics, in achieving the SDG-presented, major economic, social and environmental priorities. The United Nation's 17 SDG and the 169 Targets, were individually examined within the context of state-of-the-art robotics already documented in scientific literature. The significance and the quality-of-evidence of enabling/inhibiting impacts, were assessed by an international panel of experts, to quantify the positive or negative effect of the applied robotic systems. Results from this study indicate that robotics has the potential to enable 46 % of the Targets, particularly for the industry and environment-related SDGs, forecasting a huge impact on our production systems and thus on our entire society. Inversely, robotics could inhibit 19 % of the SDG Targets, mainly through exacerbation of inequalities and tensions in the SDGs. The objective of this paper is to assess and grade the current impact of the robotics megatrend on the SDGs, provide comparable data, and encourage the robotics community to work on these targets, in a unified way and eventually improve the quality of the related outcomes.

Biomarkers in Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Updated Review of the Literature.

Myocarditis is a disease caused by cardiac inflammation that can progress to dilated cardiomyopathy, heart failure, and eventually death. Several etiologies, including autoimmune, drug-induced, and infectious, lead to inflammation, which causes damage to the myocardium, followed by remodeling and fibrosis. Although there has been an increasing understanding of pathophysiology, early and accurate diagnosis, and effective treatment remain challenging due to the high heterogeneity. As a result, many patients have poor prognosis, with those surviving at risk of long-term sequelae. Current diagnostic methods, including imaging and endomyocardial biopsy, are, at times, expensive, invasive, and not always performed early enough to affect disease progression. Therefore, the identification of accurate, cost-effective, and prognostically informative biomarkers is critical for screening and treatment. The review then focuses on the biomarkers currently associated with these conditions, which have been extensively studied via blood tests and imaging techniques. The information within this review was retrieved through extensive literature research conducted on major publicly accessible databases and has been collated and revised by an international panel of experts. The biomarkers discussed in the article have shown great promise in clinical research studies and provide clinicians with essential tools for early diagnosis and improved outcomes.

Ambitious near-term decarbonization and direct air capture deployment in Latin America's net-zero goal

The International Panel on Climate Change (IPCC) recommended more stringent climate mitigation strategies compared to the updated nationally determined contributions (NDC) presented by nations at COP27 to keep global warming temperatures below 2 °C. Given the unique geographical, political, and socioeconomic factors in different regions, it is imperative to evaluate diverse mitigation scenarios required to achieve global climate objectives. This study focuses on the Latin America and Caribbean region due to its vulnerability to global climate adversities and deteriorating climate conditions, notwithstanding its minor contribution to global emissions. Despite facing distinct climate changes, Latin America remains significantly understudied in the broader context of global climate research. The deployment of negative emission technology (NET) is crucial for achieving the end-of-century global climate goal of limiting global mean temperature to 1.5 °C and realizing regional net-zero greenhouse gas (GHG) emission targets. Most countries in Latin America have established such targets for 2050. Among various NETs, Direct Air Carbon Capture and Storage (DACCS) has recently gained research interests. This study examines the strategic implementation of NETs across the five socio-economic pathways (SSPs) to provide a comprehensive understanding of the uncertainties in regional mitigation actions and impacts on the intricate climate-energy-land-food-water nexus. In the scenario where emissions decrease by 56 % by 2030 compared to 2020 levels (NDC-56 %) on a net-zero trajectory, energy consumption under DACCS deployment is 13.1–36.2 % higher than without DACCS (between 2040 and 2100, across all SSPs). The energy demands of DACCS, especially in the aggressive NDC-56 % scenario place significant strain on energy resources, which is offset by fossil fuels. Under a globally co-ordinated climate policy and co-deployment of DACCS and Bioenergy with Carbon Capture and Storage (BECCS), the NDC-56 % scenario restricts global warming temperatures to 1.81–1.96 °C by 2100.

2022 Peritoneal Surface Oncology Group International Consensus on HIPEC Regimens for Peritoneal Malignancies: Colorectal Cancer

BackgroundSelected patients with peritoneal metastases of colorectal cancer (PM-CRC) can benefit from potentially curative cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC), with a median overall survival (OS) of more than 40 months.ObjectiveThe aims of this evidence-based consensus were to define the indications for HIPEC, to select the preferred HIPEC regimens, and to define research priorities regarding the use of HIPEC for PM-CRC.MethodsThe consensus steering committee elaborated and formulated pertinent clinical questions according to the PICO (patient, intervention, comparator, outcome) method and assessed the evidence according to the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) framework. Standardized evidence tables were presented to an international expert panel to reach a consensus (4-point, weak and strong positive/negative) on HIPEC regimens and research priorities through a two-round Delphi process. The consensus was defined as ≥ 50% agreement for the 4-point consensus grading or ≥ 70% for either of the two combinations.ResultsEvidence was weak or very weak for 9/10 clinical questions. In total, 70/90 eligible panelists replied to both Delphi rounds (78%), with a consensus for 10/10 questions on HIPEC regimens. There was strong negative consensus concerning the short duration, high-dose oxaliplatin (OX) protocol (55.7%), and a weak positive vote (53.8–64.3%) in favor of mitomycin-C (MMC)-based HIPEC (preferred choice: Dutch protocol: 35 mg/m2, 90 min, three fractions), both for primary cytoreduction and recurrence. Determining the role of HIPEC after CRS was considered the most important research question, regarded as essential by 85.7% of the panelists. Furthermore, over 90% of experts suggest performing HIPEC after primary and secondary CRS for recurrence > 1 year after the index surgery.ConclusionsBased on the available evidence, despite the negative results of PRODIGE 7, HIPEC could be conditionally recommended to patients with PM-CRC after CRS. While more preclinical and clinical data are eagerly awaited to harmonize the procedure further, the MMC-based Dutch protocol remains the preferred regimen after primary and secondary CRS.

Key Prognostic Factors in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma: An Evidence Based Systematic Literature and Medical Review

Introduction: A multi-center multi-country retrospective cohort study (ORCHID [NCT05338879]), using real-world data (RWD) from electronic medical records (EMRs) and research databases, for patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) treated with standard of care is being conducted to contextualize treatment outcomes in a single-arm trial. A systematic literature review (SLR) was carried out to identify baseline prognostic factors that will be evaluated for imbalances between cohorts in the single-arm trial and RWD study. This SLR was followed by an evidence-based clinical expert review of prognostic variables and ranking in order of importance for the ORCHID study as described herein. Methods:The approach and methods of the SLR (International Prospective Register of Systematic Reviews [PROSPERO] CRD42022307557) were informed by guidelines set forth by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins et. al. 2021) and PRISMA (Page et. al. BMJ 2021) and described previously (Hampp et. al. ISPOR 2023). Following the conduct of the SLR, the identified potential prognostic variables were evaluated by the ORCHID study team to remove treatment-specific and outcome variables, determine their availability in the single-arm trial and ORCHID RWD study, and develop a questionnaire. In the questionnaire, prognostic variables were grouped by type of variable - clinical, laboratory data, molecular characteristic, or treatment characteristic. Each prognostic variable was reviewed by an international panel consisting of 3 clinical experts in the field of lymphoma who categorized the prognostic impact on treatment response and survival on a 5-point scale ranging from “Very high importance” to “Not important”. The clinicians were asked to consider possible correlation among the variables, possible effect modifiers, specific variable definitions (e.g., early chemoimmunotherapy failure), and whether there were any other prognostically important variables not captured in the questionnaire. For each variable, the clinical experts categorized the availability within routine care on a 3-point scale ranging from “Readily available” to “Limited availability”. The results of the 3 expert completed questionnaires were reviewed and the top 10 highest ranking variables were determined by summing the clinicians' categorization of prognostic impact and considering variable availability in the event of a tie. Individual interviews with each clinical expert were held to clarify variables and definitions, discuss discrepant categorization, and rank the prognostic variables from 1-10. Following the 3 interviews, the ranking of each variable was summed across the 3 experts to determine the final ranking. Results: Across the 46 studies included, the SLR identified 36 prognostic factors, including patient demographics and clinical characteristics, disease and treatment characteristics, and laboratory data. Seven clinical outcomes with statistically significant associations were identified (most commonly, overall survival [OS], progression-free survival [PFS], and overall response rate [ORR]). No additional prognostic factors were identified by the clinical experts. The final ranked list of the 10 most important prognostic variables in descending order of importance includes: early chemoimmunotherapy failure, Eastern Cooperative Oncology Group (ECOG) performance status, refractory to last line of therapy (LoT), number of prior LoTs, double or triple-hit lymphoma, age at start of LoT, Internal Prognostic Index (IPI) risk classification, Ann Arbor disease stage, serum lactate dehydrogenase (LDH), and Deauville score. Conclusion:SLR-based identification of prognostic factors combined with expert clinical review provides an unbiased evaluation and ranking of the level of evidence to assist in selecting prognostic factors to collect for the ORCHID real-world cohort study. The appropriate selection of prognostic factors is critical for valid outcome estimation. These factors will be used for the evaluation of balance with the single-arm trial and for adjustment in a propensity score model. With this approach, the prognostic factors are chosen a priori to enable balancing of baseline covariates prior to outcome estimation.

P082 - Delphi Consensus Project on Prostate-specific Membrane Antigen (PSMA)-Targeted Surgery – outcomes from an international multidisciplinary panel

P082 - Delphi Consensus Project on Prostate-specific Membrane Antigen (PSMA)-Targeted Surgery – outcomes from an international multidisciplinary panel

Postfasciotomy Classification System for Acute Compartment Syndrome of the Leg.

Acute compartment syndrome (ACS) is a true emergency. Even with urgent fasciotomy, there is often muscle damage and need for further surgery. Although ACS is not uncommon, no validated classification system exists to aid in efficient and clear communication. The aim of this study was to establish and validate a classification system for the consequences of ACS treated with fasciotomy. Using a modified Delphi method, an international panel of ACS experts was assembled to establish a grading scheme for the disease and then validate the classification system. The goal was to articulate discrete grades of ACS related to fasciotomy findings and associated costs. A pilot analysis was used to determine questions that were clear to the respondents. Discussion of this analysis resulted in another round of cases used for 24 other raters. The 24 individuals implemented the classification system 2 separate times to compare outcomes for 32 clinical cases. The accuracy and reproducibility of the classification system were subsequently calculated based on the providers' responses. The Fleiss Kappa of all raters was at 0.711, showing a strong agreement between the 24 raters. Secondary validation was performed for paired 276 raters and correlation was tested using the Kendall coefficient. The median correlation coefficient was 0.855. All 276 pairs had statistically significant correlation. Correlation coefficient between the first and second rating sessions was strong with the median pair scoring at 0.867. All surgeons had statistically significant internal consistency. This new ACS classification system may be applied to better understand the impact of ACS on patient outcomes and economic costs for leg ACS.

Consensus goals and standards for specialist cough clinics: the NEUROCOUGH international Delphi study.

Current guidelines on the management of chronic cough do not provide recommendations for the operation of specialist cough clinics. The objective of the present study was to develop expert consensus on goals and standard procedures for specialist cough clinics. We undertook a modified Delphi process, whereby initial statements proposed by experts were categorised and presented back to panellists over two ranking rounds using an 11-point Likert scale to identify consensus. An international panel of 57 experts from 19 countries participated, with consensus reached on 15 out of 16 statements, covering the aims, roles and standard procedures of specialist cough clinics. Panellists agreed that specialist cough clinics offer optimal care for patients with chronic cough. They also agreed that history taking should enquire as to cough triggers, cough severity rating scales should be routinely used, and a minimum of chest radiography, spirometry and measurements of type 2 inflammatory markers should be undertaken in newly referred patients. The importance of specialist cough clinics in promoting clinical research and cough specialty training was acknowledged. Variability in healthcare resources and clinical needs between geographical regions was noted. The Delphi exercise provides a platform and guidance for both established cough clinics and those in planning stages.

Northward range expansions are not the full story: A case study of Sabellaria alveolata in Great Britain

Warming oceans are causing changes in the distribution of numerous species. If greenhouse gas production continues to follow current trends, further distribution changes will result. It is often assumed that range shifts into higher latitudes may mitigate threats to susceptible species. Sabellaria alveolata is an important intertidal ecosystem engineer and protected by the UK Biodiversity Action Plan. In this study we created a habitat suitability model for S. alveolata around Great Britain and quantified changes in coastal suitability with increasing sea surface temperatures (SST) using Representative Concentration Pathway (RCP) scenarios modelled by the International Panel on Climate Change. The model included maximum and minimum SST, substrate, slope, kinetic energy due to waves and currents, photosynthetically active radiation, and the coefficient of light attenuation. The model performed very well (AUC = 0.932, 50.2% of deviance explained) and all variables explaining comparable deviance (up to 10%). Recent SST was then combined with predicted SST increases, leading to suitable habitat locations expanding across the southern and western GB coastlines and resulting in larger patches, hence potential for connectivity. Some northern extension was observed; however, this was limited and patchy. The greatest extensions were seen on the south coast, with most of the south coast becoming a continuous network with excellent suitability. With an increase of 1.2 °C, the extent of coast in the excellent suitability class was increased by 5.75% compared to 2020, and by 38.1% with 3.2 °C. Despite the importance of winter temperature in driving S. alveolata distribution, over-riding environmental constraints prevented any major northward migration. The assertion that potential for range shifts to higher latitudes may mitigate the effects of climate change depends on niche availability which may not always be realised.

Aerosol Typology and Trajectories in the Metropolitan Region of Rio De Janeiro, Brazil

Aerosols are liquid or solid particles suspended in the atmosphere. Correct determination of the distribution of aerosol types in the atmosphere is of paramount importance for long-term climate predictions. The latest report of the International Panel on Climate Change (IPCC) addresses aerosols as representing the most significant uncertainties in the context of forcing climate sources. These particles can interfere with the climate directly, indirectly, or semi-directly. Directly, we can highlight the interaction of these particles with solar radiation through their scattering or absorption. Indirectly, the role of these aerosols as nuclei for the condensation of liquid and ice in clouds is significant. Depending on their quantity, these aerosols can form larger or smaller droplets, leading to changes in the cloud's albedo. As for semi-direct effects, we can emphasize the role of aerosols as radiation absorbers within clouds, consequently leading to changes in the stability of the air parcel. As a semi-direct effect, we can highlight changes in the life cycle and the ability to make convective clouds colder and more profound.

Dynamics of Decapoda larvae communities in a southwest Iberian estuary: Understanding the impact of different thermal regimes

Environmental conditions play a pivotal role in shaping the dynamics of meroplanktonic communities, which represent a vital life stage, crucial for successful recruitment. Specifically, temperature can impact the survival and duration of larval development in decapod crustacean species. The objective of this study is to analyze the community of decapod larvae in the Guadiana estuary, located in southwest Iberia. The analysis focuses on the community's taxonomic composition, temporal variability, and the influence of environmental factors. Particularly, the study emphasizes investigating the impacts of different thermal regimes on the abundance of these assemblages. A comprehensive zooplankton sampling program was conducted at a single station in the lower estuary, from 2014 to 2022. The decapod larvae assemblages are dominated by Upogebia spp., followed by Diogenes pugilator, Panopeus africanus, Afropinnotheres monodi, and Polybius henslowii species. The results of structural equation modeling unveiled a strong influence of water temperature and salinity on the community, while chlorophyll-a concentration, river runoff, and the large-scale climatic mode North Atlantic Oscillation (NAO) revealed no impact on the abundance of these assemblages. Overall, the community and the main taxa displayed a positive linear trend in response to increased salinity. However, the effect of increasing temperature varied among species. In the current climatic scenario, water temperature emerges as a critical factor in predicting seasonal variation of the assemblages' abundances, exhibiting a marked seasonality during spring and summer. Predictive models used to investigate future scenarios, Representative Concentration Pathway (RCP) 2.6 and RCP 8.5, defined by the International Panel on Climate Change (IPCC), where the temperature is expected to rise 2 °C and 4.3 °C by 2100, suggest the possibility for an alteration in assemblages' composition, where the abundances of D. pugilator, the second most abundant species, tend to decrease abruptly. Reported evidence, coupled with the typical Mediterranean climate of the region, where extreme climatic events, like marine heatwaves, are becoming more frequent, the high connectivity with the Mediterranean Sea, where invasion by non-indigenous species is increasing, also connected with changes in freshwater discharges, may trigger significant alterations in species dominance and abundance, with ecological and socio-economic implications.

Management of Persistent, Post-adenotonsillectomy Obstructive Sleep Apnea in Children: An Official American Thoracic Society Clinical Practice Guideline.

Background: Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder. Although adenotonsillectomy is first-line management for pediatric OSA, up to 40% of children may have persistent OSA. This document provides an evidence-based clinical practice guideline on the management of children with persistent OSA. The target audience is clinicians, including physicians, dentists, and allied health professionals, caring for children with OSA. Methods: A multidisciplinary international panel of experts was convened to determine key unanswered questions regarding the management of persistent pediatric OSA. We conducted a systematic review of the relevant literature. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of the clinical recommendations. The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Results: Recommendations were developed for six management options for persistent OSA. Conclusions: The panel developed recommendations for the management of persistent pediatric OSA based on limited evidence and expert opinion. Important areas for future research were identified for each recommendation.