Natural hazard risk assessments at the global scale

Since 1990, natural hazards have led to over 1.6 million fatalities globally, and economic losses are estimated at an average of around USD 260–310 billion per year. The scientific and policy communities recognise the need to reduce these risks. As a result, the last decade has seen a rapid development of global models for assessing risk from natural hazards at the global scale. In this paper, we review the scientific literature on natural hazard risk assessments at the global scale, and we specifically examine whether and how they have examined future projections of hazard, exposure, and/or vulnerability. In doing so, we examine similarities and differences between the approaches taken across the different hazards, and we identify potential ways in which different hazard communities can learn from each other. For example, there are a number of global risk studies focusing on hydrological, climatological, and meteorological hazards that have included future projections and disaster risk reduction measures (in the case of floods), whereas fewer exist in the peer-reviewed literature for global studies related to geological hazards. On the other hand, studies of earthquake and tsunami risk are now using stochastic modelling approaches to allow for a fully probabilistic assessment of risk, which could benefit the modelling of risk from other hazards. Finally, we discuss opportunities for learning from methods and approaches being developed and applied to assess natural hazard risks at more continental or regional scales. Through this paper, we hope to encourage further dialogue on knowledge sharing between disciplines and communities working on different hazards and risk and at different spatial scales

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy

Background Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1–specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.Method We performed a phase I clinical trial evaluating the safety of NY-ESO-1–specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15.Results Four patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1–specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor–based products at other centers.Conclusions ETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1–specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression

Natural hazard risk assessments at the global scale

Since 1990, natural hazards have led to over 1.6 million fatalities globally, and economic losses are estimated at an average of around USD 260-310 billion per year. The scientific and policy communities recognise the need to reduce these risks. As a result, the last decade has seen a rapid development of global models for assessing risk from natural hazards at the global scale. In this paper, we review the scientific literature on natural hazard risk assessments at the global scale, and we specifically examine whether and how they have examined future projections of hazard, exposure, and/or vulnerability. In doing so, we examine similarities and differences between the approaches taken across the different hazards, and we identify potential ways in which different hazard communities can learn from each other. For example, there are a number of global risk studies focusing on hydrological, climatological, and meteorological hazards that have included future projections and disaster risk reduction measures (in the case of floods), whereas fewer exist in the peer-reviewed literature for global studies related to geological hazards. On the other hand, studies of earthquake and tsunami risk are now using stochastic modelling approaches to allow for a fully probabilistic assessment of risk, which could benefit the modelling of risk from other hazards. Finally, we discuss opportunities for learning from methods and approaches being developed and applied to assess natural hazard risks at more continental or regional scales. Through this paper, we hope to encourage further dialogue on knowledge sharing between disciplines and communities working on different hazards and risk and at different spatial scales.

Review article: Natural hazard risk assessments at the global scale

Since 1990, natural hazards have led to over 1.6 million fatalities globally, and economic losses are estimated at an average of around USD 260–310 billion per year. The scientific and policy communities recognise the need to reduce these risks. As a result, the last decade has seen a rapid development of global models for assessing risk from natural hazards at the global scale. In this paper, we review the scientific literature on natural hazard risk assessments at the global scale, and we specifically examine whether and how they have examined future projections of hazard, exposure, and/or vulnerability. In doing so, we examine similarities and differences between the approaches taken across the different hazards, and we identify potential ways in which different hazard communities can learn from each other. For example, there are a number of global risk studies focusing on hydrological, climatological, and meteorological hazards that have included future projections and disaster risk reduction measures (in the case of floods), whereas fewer exist in the peer-reviewed literature for global studies related to geological hazards. On the other hand, studies of earthquake and tsunami risk are now using stochastic modelling approaches to allow for a fully probabilistic assessment of risk, which could benefit the modelling of risk from other hazards. Finally, we discuss opportunities for learning from methods and approaches being developed and applied to assess natural hazard risks at more continental or regional scales. Through this paper, we hope to encourage further dialogue on knowledge sharing between disciplines and communities working on different hazards and risk and at different spatial scales

IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy.

BackgroundSynovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1-specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.MethodWe performed a phase I clinical trial evaluating the safety of NY-ESO-1-specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15.ResultsFour patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1-specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor-based products at other centers.ConclusionsETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1-specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression