A Systems Map of the Challenges of Climate Communication.

Over the past sixty years, scientists have been warning about climate change and its impacts on human health, but evidence suggests that many may not be heeding these concerns. This raises the question of whether new communication approaches are needed to overcome the unique challenges of communicating what people can do to slow or reverse climate change. To better elucidate the challenges of communicating about the links between human activity, climate change and its effects, and identify potential solutions, we developed a systems map of the factors and processes involved based on systems mapping sessions with climate change and communication experts. The systems map revealed 27 communication challenges such as "Limited information on how individual actions contribute to collective human activity," "Limited information on how present activity leads to long-term effects," and "Difficult to represent and communicate complex relationships." The systems map also revealed several themes among the identified challenges that exist in communicating about climate change, including a lack of available data and integrated databases, climate change disciplines working in silos, a need for a lexicon that is easily understood by the public, and the need for new communication strategies to describe processes that take time to manifest.

What is the economic benefit of annual COVID-19 vaccination from the adult individual perspective?

BACKGROUND: With COVID-19 vaccination no longer mandated by many businesses/organizations, it is now up to individuals to decide whether to get any new boosters/updated vaccines going forward. METHODS: We developed a Markov model representing the potential clinical/economic outcomes from an individual perspective in the United States of getting versus not getting an annual COVID-19 vaccine. RESULTS: For an 18-49-year-old, getting vaccinated at its current price ($60) can save the individual on average $30-$603 if the individual is uninsured and $4-$437 if the individual has private insurance, as long as the starting vaccine efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is ≥50% and the weekly risk of getting infected is ≥0.2%, corresponding to an individual interacting with 9 other people in a day under Winter 2023-2024 Omicron SARS-CoV-2 variant conditions with an average infection prevalence of 10%. For a 50-64-year-old, these cost-savings increase to $111-$1,278 and $119-$1,706, for someone without and with insurance, respectively. The risk threshold increases to ≥0.4% (interacting with 19 people/day), when the individual has 13.4% pre-existing protection against infection (e.g., vaccinated 9 months earlier). CONCLUSION: There is both clinical and economic incentive for the individual to continue to get vaccinated against COVID-19 each year.

How the Timing of Annual COVID-19 Vaccination of Nursing Home Residents and Staff Affects Its Value.

OBJECTIVES: To evaluate the epidemiologic, clinical, and economic value of an annual nursing home (NH) COVID-19 vaccine campaign and the impact of when vaccination starts. DESIGN: Agent-based model representing a typical NH. SETTING AND PARTICIPANTS: NH residents and staff. METHODS: We used the model representing an NH with 100 residents, its staff, their interactions, COVID-19 spread, and its health and economic outcomes to evaluate the epidemiologic, clinical, and economic value of varying schedules of annual COVID-19 vaccine campaigns. RESULTS: Across a range of scenarios with a 60% vaccine efficacy that wanes starting 4 months after protection onset, vaccination was cost saving or cost-effective when initiated in the late summer or early fall. Annual vaccination averted 102 to 105 COVID-19 cases when 30-day vaccination campaigns began between July and October (varying with vaccination start), decreasing to 97 and 85 cases when starting in November and December, respectively. Starting vaccination between July and December saved $3340 to $4363 and $64,375 to $77,548 from the Centers for Medicare & Medicaid Services and societal perspectives, respectively (varying with vaccination start). Vaccination's value did not change when varying the COVID-19 peak between December and February. The ideal vaccine campaign timing was not affected by reducing COVID-19 levels in the community, or varying transmission probability, preexisting immunity, or COVID-19 severity. However, if vaccine efficacy wanes more quickly (over 1 month), earlier vaccination in July resulted in more cases compared with vaccinating later in October. CONCLUSIONS AND IMPLICATIONS: Annual vaccination of NH staff and residents averted the most cases when initiated in the late summer through early fall, at least 2 months before the COVID-19 winter peak but remained cost saving or cost-effective when it starts in the same month as the peak. This supports tethering COVID vaccination to seasonal influenza campaigns (typically in September-October) for providing protection against SARS-CoV-2 winter surges in NHs.

The potential epidemiologic, clinical, and economic value of a universal coronavirus vaccine: a modelling study.

Background: With efforts underway to develop a universal coronavirus vaccine, otherwise known as a pan-coronavirus vaccine, this is the time to offer potential funders, researchers, and manufacturers guidance on the potential value of such a vaccine and how this value may change with differing vaccine and vaccination characteristics. Methods: Using a computational model representing the United States (U.S.) population, the spread of SARS-CoV-2 and the various clinical and economic outcomes of COVID-19 such as hospitalisations, deaths, quality-adjusted life years (QALYs) lost, productivity losses, direct medical costs, and total societal costs, we explored the impact of a universal vaccine under different circumstances. We developed and populated this model using data reported by the CDC as well as observational studies conducted during the COVID-19 pandemic. Findings: A pan-coronavirus vaccine would be cost saving in the U.S. as a standalone intervention as long as its vaccine efficacy is ≥10% and vaccination coverage is ≥10%. Every 1% increase in efficacy between 10% and 50% could avert an additional 395,000 infections and save $1.0 billion in total societal costs ($45.3 million in productivity losses, $1.1 billion in direct medical costs). It would remain cost saving even when a strain-specific coronavirus vaccine would be subsequently available, as long as it takes at least 2-3 months to develop, test, and bring that more specific vaccine to the market. Interpretation: Our results provide support for the development and stockpiling of a pan-coronavirus vaccine and help delineate the vaccine characteristics to aim for in development of such a vaccine. Funding: The National Science Foundation, the Agency for Healthcare Research and Quality, the National Institute of General Medical Sciences, the National Center for Advancing Translational Sciences, and the City University of New York.

Health and Economic Value of Eliminating Socioeconomic Disparities in US Youth Physical Activity.

Importance: There are considerable socioeconomic status (SES) disparities in youth physical activity (PA) levels. For example, studies show that lower-SES youth are less active, have lower participation in organized sports and physical education classes, and have more limited access to PA equipment. Objective: To determine the potential public health and economic effects of eliminating disparities in PA levels among US youth SES groups. Design and Setting: An agent-based model representing all 6- to 17-year-old children in the US was used to simulate the epidemiological, clinical, and economic effects of disparities in PA levels among different SES groups and the effect of reducing these disparities. Main Outcomes and Measures: Anthropometric measures (eg, body mass index) and the presence and severity of risk factors associated with weight (stroke, coronary heart disease, type 2 diabetes, or cancer), as well as direct and indirect cost savings. Results: This model, representing all 50 million US children and adolescents 6 to 17 years old, found that if the US eliminates the disparity in youth PA levels across SES groups, absolute overweight and obesity prevalence would decrease by 0.826% (95% CI, 0.821%-0.832%), resulting in approximately 383 000 (95% CI, 368 000-399 000) fewer cases of overweight and obesity and 101 000 (95% CI, 98 000-105 000) fewer cases of weight-related diseases (stroke and coronary heart disease events, type 2 diabetes, or cancer). This would result in more than $15.60 (95% CI, $15.01-$16.10) billion in cost savings over the youth cohort's lifetime. There are meaningful benefits even when reducing the disparity by just 25%, which would result in $1.85 (95% CI, $1.70-$2.00) billion in direct medical costs averted and $2.48 (95% CI, $2.04-$2.92) billion in productivity losses averted. For every 1% in disparity reduction, total productivity losses would decrease by about $83.8 million, and total direct medical costs would decrease by about $68.7 million. Conclusions and Relevance: This study quantified the potential savings from eliminating or reducing PA disparities, which can help policymakers, health care systems, schools, funders, sports organizations, and other businesses better prioritize investments toward addressing these disparities.

Cost-effectiveness of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) testing and isolation strategies in nursing homes.

OBJECTIVE: Nursing home residents may be particularly vulnerable to coronavirus disease 2019 (COVID-19). Therefore, a question is when and how often nursing homes should test staff for COVID-19 and how this may change as severe acute respiratory coronavirus virus 2 (SARS-CoV-2) evolves. DESIGN: We developed an agent-based model representing a typical nursing home, COVID-19 spread, and its health and economic outcomes to determine the clinical and economic value of various screening and isolation strategies and how it may change under various circumstances. RESULTS: Under winter 2023-2024 SARS-CoV-2 omicron variant conditions, symptom-based antigen testing averted 4.5 COVID-19 cases compared to no testing, saving $191 in direct medical costs. Testing implementation costs far outweighed these savings, resulting in net costs of $990 from the Centers for Medicare & Medicaid Services perspective, $1,545 from the third-party payer perspective, and $57,155 from the societal perspective. Testing did not return sufficient positive health effects to make it cost-effective [$50,000 per quality-adjusted life-year (QALY) threshold], but it exceeded this threshold in ≥59% of simulation trials. Testing remained cost-ineffective when routinely testing staff and varying face mask compliance, vaccine efficacy, and booster coverage. However, all antigen testing strategies became cost-effective (≤$31,906 per QALY) or cost saving (saving ≤$18,372) when the severe outcome risk was ≥3 times higher than that of current omicron variants. CONCLUSIONS: SARS-CoV-2 testing costs outweighed benefits under winter 2023-2024 conditions; however, testing became cost-effective with increasingly severe clinical outcomes. Cost-effectiveness can change as the epidemic evolves because it depends on clinical severity and other intervention use. Thus, nursing home administrators and policy makers should monitor and evaluate viral virulence and other interventions over time.

Benefits of Meeting the Healthy People 2030 Youth Sports Participation Target.

INTRODUCTION: Healthy People 2030, a U.S. government health initiative, has indicated that increasing youth sports participation to 63.3% is a priority in the U.S. This study quantified the health and economic value of achieving this target. METHODS: An agent-based model developed in 2023 represents each person aged 6-17 years in the U.S. On each simulated day, agents can participate in sports that affect their metabolic and mental health in the model. Each agent can develop different physical and mental health outcomes, associated with direct and indirect costs. RESULTS: Increasing the proportion of youth participating in sports from the most recent participation levels (50.7%) to the Healthy People 2030 target (63.3%) could reduce overweight/obesity prevalence by 3.37% (95% CI=3.35%, 3.39%), resulting in 1.71 million fewer cases of overweight/obesity (95% CI=1.64, 1.77 million). This could avert 352,000 (95% CI=336,200, 367,500) cases of weight-related diseases and gain 1.86 million (95% CI=1.86, 1.87 million) quality-adjusted life years, saving $22.55 billion (95% CI=$22.46, $22.63 billion) in direct medical costs and $25.43 billion (95% CI= $25.25, $25.61 billion) in productivity losses. This would also reduce depression/anxiety symptoms, saving $3.61 billion (95% CI=$3.58, $3.63 billion) in direct medical costs and $28.38 billion (95% CI=$28.20, $28.56 billion) in productivity losses. CONCLUSIONS: This study shows that achieving the Healthy People 2030 objective could save third-party payers, businesses, and society billions of dollars for each cohort of persons aged 6-17 years, savings that would continue to repeat with each new cohort. This suggests that even if a substantial amount is invested toward this objective, such investments could pay for themselves.

The Need for Systems Approaches for Precision Communications in Public Health.

A major challenge in communicating health-related information is the involvement of multiple complex systems from the creation of the information to the sources and channels of dispersion to the information users themselves. To date, public health communications approaches have often not adequately accounted for the complexities of these systems to the degree necessary to have maximum impact. The virality of COVID-19 misinformation and disinformation has brought to light the need to consider these system complexities more extensively. Unaided, it is difficult for humans to see and fully understand complex systems. Luckily, there are a range of systems approaches and methods, such as systems mapping and systems modeling, that can help better elucidate complex systems. Using these methods to better characterize the various systems involved in communicating public health-related information can lead to the development of more tailored, precise, and proactive communications. Proceeding in an iterative manner to help design, implement, and adjust such communications strategies can increase impact and leave less opportunity for misinformation and disinformation to spread.

End-tidal carbon dioxide measured at emergency department triage outperforms standard triage vital signs in predicting in-hospital mortality and intensive care unit admission.

OBJECTIVES: This study assessed the ability of end-tidal carbon dioxide (ETCO2 ) in predicting in-hospital mortality and intensive care unit (ICU) admission compared to standard vital signs at ED triage as well as comparing to measures of metabolic acidosis. METHODS: This prospective study enrolled adult patients presenting to the ED of a tertiary care Level I trauma center over 30 months. Patients had standard vital signs measured along with exhaled ETCO2 at triage. Outcome measures included in-hospital mortality; ICU admission; and correlations with lactate, sodium bicarbonate (HCO3 ), and anion gap. RESULTS: There were 1136 patients enrolled and 1091 patients with outcome data available. There were 26 (2.4%) patients who did not survive to hospital discharge. Mean ETCO2 levels were 34 (33-34) in survivors and 22 (18-26) nonsurvivors (p < 0.001). The area under the curve (AUC) for predicting in-hospital mortality for ETCO2 was 0.82 (0.72-0.91). In comparison the AUC for temperature was 0.55 (0.42-0.68), respiratory rate (RR) 0.59 (0.46-0.73), systolic blood pressure (SBP) 0.77 (0.67-0.86), diastolic blood pressure (DBP) 0.70 (0.59-0.81), heart rate (HR) 0.76 (0.66-0.85), and oxygen saturation (SpO2 ) 0.53 (0.40-0.67). There were 64 (6%) patients admitted to the ICU, and the ETCO2 AUC for predicting ICU admission was 0.75 (0.67-0.80). In comparison the AUC for temperature was 0.51, RR 0.56, SBP 0.64, DBP 0.63, HR 0.66, and SpO2 0.53. Correlations between expired ETCO2 and serum lactate, anion gap, and HCO3 were rho = -0.25 (p < 0.001), rho = -0.20 (p < 0.001), and rho = 0.330 (p < 0.001), respectively. CONCLUSIONS: ETCO2 was a better predictor of in-hospital mortality and ICU admission than the standard vital signs at ED triage. ETCO2 correlated significantly with measures of metabolic acidosis.

Predictability of Endoscopic Success for Foregut and Bariatric Leak in an Experienced Quaternary Center.

BACKGROUND: Leaks of the esophagus and stomach are difficult to manage and associated with significant morbidity and mortality. Endoscopic therapy can manage these leaks without surgical intervention. Our goal is to create a scoring tool to aid in predicting the success of endoscopic therapy in these patients. STUDY DESIGN: An IRB-approved prospectively maintained database was retrospectively reviewed for all patients treated for gastrointestinal leaks from July 2013 to January 2021, including patients treated for esophageal and stomach leaks. Endpoints include success of leak closure for patients treated solely by endoscopic therapy (ET) compared with surgical therapy as failed endoscopic therapy (FET). A multivariable logistic regression model was fitted to identify independent risk factors for predicting success of endoscopic therapy, and a scoring calculator was developed. RESULTS: There were 80 patients (60 females) with a mean age of 50 years. The ET group included 59 patients (74%), whereas the FET group included 21 patients (26%). Patient demographics, comorbidities, surgical history, and timing of leak diagnosis were used. Multivariable analysis resulted in 4 variables associated with higher probability of successful endoscopic leak management without need for additional surgery. These included increased age, lower BMI, lack of previous bariatric surgery, and quicker identification of the leak. Consequently, a scoring nomogram was developed with values from 0 to 22. CONCLUSION: Our data show the development of a scoring calculator capable of quantifying the likelihood of success treating foregut and bariatric leaks with endoscopic therapies. This can be used clinically to guide treatment decisions.

The potential epidemiologic, clinical, and economic impact of requiring schools to offer Physical Education (PE) classes in Mexico City.

BACKGROUND: Many schools have been cutting physical education (PE) classes due to budget constraints, which raises the question of whether policymakers should require schools to offer PE classes. Evidence suggests that PE classes can help address rising physical inactivity and obesity prevalence. However, it would be helpful to determine if requiring PE is cost-effective. METHODS: We developed an agent-based model of youth in Mexico City and the impact of all schools offering PE classes on changes in weight, weight-associated health conditions and the corresponding direct and indirect costs over their lifetime. RESULTS: If schools offer PE without meeting guidelines and instead followed currently observed class length and time active during class, overweight and obesity prevalence decreased by 1.3% (95% CI: 1.0%-1.6%) and was cost-effective from the third-party payer and societal perspectives ($5,058 per disability-adjusted life year [DALY] averted and $5,786/DALY averted, respectively, assuming PE cost $50.3 million). When all schools offered PE classes meeting international guidelines for PE classes, overweight and obesity prevalence decreased by 3.9% (95% CI: 3.7%-4.3%) in the cohort at the end of five years compared to no PE. Long-term, this averted 3,183 and 1,081 obesity-related health conditions and deaths, respectively and averted ≥$31.5 million in direct medical costs and ≥$39.7 million in societal costs, assuming PE classes cost ≤$50.3 million over the five-year period. PE classes could cost up to $185.5 million and $89.9 million over the course of five years and still remain cost-effective and cost saving respectively, from the societal perspective. CONCLUSION: Requiring PE in all schools could be cost-effective when PE class costs, on average, up to $10,340 per school annually. Further, the amount of time students are active during class is a driver of PE classes' value (e.g., it is cost saving when PE classes meet international guidelines) suggesting the need for specific recommendations.

Maintaining face mask use before and after achieving different COVID-19 vaccination coverage levels: a modelling study.

BACKGROUND: Face mask wearing has been an important part of the response to the COVID-19 pandemic. As vaccination coverage progresses in countries, relaxation of such practices is increasing. Subsequent COVID-19 surges have raised the questions of whether face masks should be encouraged or required and for how long. Here, we aim to assess the value of maintaining face masks use indoors according to different COVID-19 vaccination coverage levels in the USA. METHODS: In this computational simulation-model study, we developed and used a Monte Carlo simulation model representing the US population and SARS-CoV-2 spread. Simulation experiments compared what would happen if face masks were used versus not used until given final vaccination coverages were achieved. Different scenarios varied the target vaccination coverage (70-90%), the date these coverages were achieved (Jan 1, 2022, to July 1, 2022), and the date the population discontinued wearing face masks. FINDINGS: Simulation experiments revealed that maintaining face mask use (at the coverage seen in the USA from March, 2020, to July, 2020) until target vaccination coverages were achieved was cost-effective and in many cases cost saving from both the societal and third-party payer perspectives across nearly all scenarios explored. Face mask use was estimated to be cost-effective and usually cost saving when the cost of face masks per person per day was ≤US$1·25. In all scenarios, it was estimated to be cost-effective to maintain face mask use for about 2-10 weeks beyond the date that target vaccination coverage (70-90%) was achieved, with this added duration being longer when the target coverage was achieved during winter versus summer. Factors that might increase the transmissibility of the virus (eg, emergence of the delta [B.1.617.2] and omicron [B.1.1.529] variants), or decrease vaccine effectiveness (eg, waning immunity or escape variants), or increase social interactions among certain segments of the population, only increased the cost savings or cost-effectiveness provided by maintaining face mask use. INTERPRETATION: Our study provides strong support for maintaining face mask use until and a short time after achieving various final vaccination coverage levels, given that maintaining face mask use can be not just cost-effective, but even cost saving. The emergence of the omicron variant and the prospect of future variants that might be more transmissible and reduce vaccine effectiveness only increases the value of face masks. FUNDING: The Agency for Healthcare Research and Quality, the National Institute of General Medical Sciences, the National Science Foundation, the National Center for Advancing Translational Sciences, and the City University of New York.

Phase I/Ib dose-escalation study of avelumab in Chinese patients with advanced solid tumors.

Aim: Data for avelumab (anti-PD-L1 antibody) in Chinese patients are limited. Patients & methods: Phase I/Ib, open-label, dose-escalation study of Chinese patients with advanced solid tumors. Primary study objectives were to evaluate the maximum tolerated dose (MTD) and pharmacokinetics (PK) of avelumab. Results: 24 patients received avelumab 3 mg/kg every 2 weeks (Q2W; n = 3), 10 mg/kg Q2W (n = 7), 20 mg/kg Q2W (n = 6) or 10 mg/kg weekly for 12 weeks and then Q2W thereafter (n = 8). MTD was not reached. Avelumab exposure was increased in higher dose groups. Partial responses occurred in two patients (confirmed in one patient); best overall response was stable disease in nine patients. Conclusion: Data for avelumab in Chinese patients with advanced solid tumors were consistent with previous global studies.

Avelumab is a form of medicine that falls under the category of immunotherapy. This means that it can help the immune system find and destroy cancer cells. In this study, researchers looked at the safety of avelumab in a small group of Chinese people with different types of cancer. Researchers also looked at blood levels of avelumab after treatment. Different doses of avelumab were given to different groups of people. Overall, study results for avelumab in Chinese people were similar to results from earlier studies in other countries.  Clinical trial registration: NCT03523390 (ClinicalTrials.gov).

Can subjective symptoms predict objective findings in gastroesophageal reflux disease patients?

INTRODUCTION: Medical therapy is the first-line treatment for gastroesophageal reflux disease, but surgical options are available and shown to be effective when medical management fails. There is no consensus for when a surgical evaluation is indicated. We set out to determine if the GERD-HRQL questionnaire scores correlate to objective findings found in patients undergoing anti-reflux surgery to predict when surgical consultation could be warranted. METHODS: A prospectively gathered database was used for patients undergoing anti-reflux surgery from January 2014 to September 2020. Inclusion criteria required a diagnosis of GERD and comprehensive esophageal workup with the GERD-HRQL questionnaire, EGD, esophageal manometry, and ambulatory pH monitoring. Analysis of the GERD-HRQL scores was compared to objective endpoints to see correlation and predictability. Logistic regression analysis was used to assess relationship between the presence of objective findings and GERD-HRQL questionnaire scores. RESULTS: There were 246 patients meeting inclusion criteria. There was no significant correlation between GERD-HRQL score and DeMeester score (correlation coefficient = 0.23), or presence of a hiatal hernia, regardless of size (p = 0.89). Patients with esophagitis had significantly higher average GERD-HRQL scores compared to those without esophagitis (40.1 ± 18.9 vs 30.4 ± 19.1, p < 0.0001). Patients with a score of 40 or greater had a 42% to 65% probability of having esophagitis versus a score of 30 or less, lowering the chances of having esophagitis to less than 35%. CONCLUSION: Usage of a GERD-HRQL questionnaire score can potentially show the correlation between subjective and objective findings in the workup of a patient for anti-reflux surgery. Specifically, patients with a GERD-HRQL score of 40 or greater have an increased probability of esophagitis compared to those with a score of 30 or less. Using these scores can help referring clinicians identify those patients failing medical therapy and allow for prompt referral for surgical evaluation.

Pharmacometric modeling and machine learning analyses of prognostic and predictive factors in the JAVELIN Gastric 100 phase III trial of avelumab.

Avelumab (anti-PD-L1) is an approved anticancer treatment for several indications. The JAVELIN Gastric 100 phase III trial did not meet its primary objective of demonstrating superior overall survival (OS) with avelumab maintenance versus continued chemotherapy in patients with advanced gastric cancer/gastroesophageal junction cancer; however, the OS rate was numerically higher with avelumab at timepoints after 12 months. Machine learning (random forests, SIDEScreen, and variable-importance assessments) was used to build models to identify prognostic/predictive factors associated with long-term OS and tumor growth dynamics (TGDs). Baseline, re-baseline, and longitudinal variables were evaluated as covariates in a parametric time-to-event model for OS and Gompertzian population model for TGD. The final OS model incorporated a treatment effect on the log-logistic shape parameter but did not identify a treatment effect on OS or TGD. Variables identified as prognostic for longer OS included older age; higher gamma-glutamyl transferase (GGT) or albumin; absence of peritoneal carcinomatosis; lower neutrophil-lymphocyte ratio, lactate dehydrogenase, or C-reactive protein (CRP); response to induction chemotherapy; and Eastern Cooperative Oncology Group performance status of 0. Among baseline and time-varying covariates, the largest effects were found for GGT and CRP, respectively. Liver metastasis at re-baseline predicted higher tumor growth. Tumor size after induction chemotherapy was associated with number of metastatic sites and stable disease (vs. response). Asian region did not impact OS or TGD. Overall, an innovative workflow supporting pharmacometric modeling of OS and TGD was established. Consistent with the primary trial analysis, no treatment effect was identified. However, potential prognostic factors were identified.

Laparoscopic repair of large diaphragmatic hernia after left ventricular assist device implantation followed by orthotopic heart transplantation.

In patients with advanced heart failure and deteriorating clinical status, a left ventricular assist device (LVAD) can be used as a bridge to transplantation or as an alternative to transplantation. An uncommon complication of orthotopic heart transplant or LVADs is diaphragmatic hernia during implantation or explantation of the device. We describe a patient with a diaphragmatic hernia with incarcerated colon and small bowel treated previously with a HeartMate 3 LVAD and subsequent transplantation. This case highlights the need to consider the diagnosis of diaphragmatic hernia based on symptoms after HeartMate 3 implantation and/or subsequent transplantation, as well as the ability to manage these hernias with a minimally invasive laparoscopic approach to minimize postoperative morbidity and mortality.

HLA-A*03 and response to immune checkpoint blockade in cancer: an epidemiological biomarker study.

BACKGROUND: Predictive biomarkers could allow more precise use of immune checkpoint inhibitors (ICIs) in treating advanced cancers. Given the central role of HLA molecules in immunity, variation at the HLA loci could differentially affect the response to ICIs. The aim of this epidemiological study was to determine the effect of HLA-A*03 as a biomarker for predicting response to immunotherapy. METHODS: In this epidemiological study, we investigated the clinical outcomes (overall survival, progression free survival, and objective response rate) after treatment for advanced cancer in eight cohorts of patients: three observational cohorts of patients with various types of advanced tumours (the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] cohort, the Dana-Farber Cancer Institute [DFCI] Profile cohort, and The Cancer Genome Atlas) and five clinical trials of patients with advanced bladder cancer (JAVELIN Solid Tumour) or renal cell carcinoma (CheckMate-009, CheckMate-010, CheckMate-025, and JAVELIN Renal 101). In total, these cohorts included 3335 patients treated with various ICI agents (anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitors) and 10 917 patients treated with non-ICI cancer-directed therapeutic approaches. We initially modelled the association of HLA amino-acid variation with overall survival in the MSK-IMPACT discovery cohort, followed by a detailed analysis of the association between HLA-A*03 and clinical outcomes in MSK-IMPACT, with replication in the additional cohorts (two further observational cohorts and five clinical trials). FINDINGS: HLA-A*03 was associated in an additive manner with reduced overall survival after ICI treatment in the MSK-IMPACT cohort (HR 1·48 per HLA-A*03 allele [95% CI 1·20-1·82], p=0·00022), the validation DFCI Profile cohort (HR 1·22 per HLA-A*03 allele, 1·05-1·42; p=0·0097), and in the JAVELIN Solid Tumour clinical trial for bladder cancer (HR 1·36 per HLA-A*03 allele, 1·01-1·85; p=0·047). The HLA-A*03 effect was observed across ICI agents and tumour types, but not in patients treated with alternative therapies. Patients with HLA-A*03 had shorter progression-free survival in the pooled patient population from the three CheckMate clinical trials of nivolumab for renal cell carcinoma (HR 1·31, 1·01-1·71; p=0·044), but not in those receiving control (everolimus) therapies. Objective responses were observed in none of eight HLA-A*03 homozygotes in the ICI group (compared with 59 [26·6%] of 222 HLA-A*03 non-carriers and 13 (17·1%) of 76 HLA-A*03 heterozygotes). HLA-A*03 was associated with shorter progression-free survival in patients receiving ICI in the JAVELIN Renal 101 randomised clinical trial for renal cell carcinoma (avelumab plus axitinib; HR 1·59 per HLA-A*03 allele, 1·16-2·16; p=0·0036), but not in those receiving control (sunitinib) therapy. Objective responses were recorded in one (12·5%) of eight HLA-A*03 homozygotes in the ICI group (compared with 162 [63·8%] of 254 HLA-A*03 non-carriers and 40 [55·6%] of 72 HLA-A*03 heterozygotes). HLA-A*03 was associated with impaired outcome in meta-analysis of all 3335 patients treated with ICI at genome-wide significance (p=2·01 × 10-8) with no evidence of heterogeneity in effect (I2 0%, 95% CI 0-0·76) INTERPRETATION: HLA-A*03 is a predictive biomarker of poor response to ICI. Further evaluation of HLA-A*03 is warranted in randomised trials. HLA-A*03 carriage could be considered in decisions to initiate ICI in patients with cancer. FUNDING: National Institutes of Health, Merck KGaA, and Pfizer.

ENAP1 retrains seed germination via H3K9 acetylation mediated positive feedback regulation of ABI5.

Histone acetylation is involved in the regulation of seed germination. The transcription factor ABI5 plays an essential role in ABA- inhibited seed germination. However, the molecular mechanism of how ABI5 and histone acetylation coordinate to regulate gene expression during seed germination is still ambiguous. Here, we show that ENAP1 interacts with ABI5 and they co-bind to ABA responsive genes including ABI5 itself. The hypersensitivity to ABA of ENAP1ox seeds germination is recovered by the abi5 null mutation. ABA enhances H3K9Ac enrichment in the promoter regions as well as the transcription of target genes co-bound by ENAP1 and ABI5, which requires both ENAP1 and ABI5. ABI5 gene is directly regulated by ENAP1 and ABI5. In the enap1 deficient mutant, H3K9Ac enrichment and the binding activity of ABI5 in its own promoter region, along with ABI5 transcription and protein levels are all reduced; while in the abi5-1 mutant, the H3K9Ac enrichment and ENAP1 binding activity in ABI5 promoter are decreased, suggesting that ENAP1 and ABI5 function together to regulate ABI5- mediated positive feedback regulation. Overall, our research reveals a new molecular mechanism by which ENAP1 regulates H3K9 acetylation and mediates the positive feedback regulation of ABI5 to inhibit seed germination.

Real-world treatment patterns and outcomes in PD-L1-positive non-small cell lung cancer.

Aim: We report real-world treatment patterns and outcomes in patients with PD-L1+ non-small-cell lung cancer (NSCLC). Methods: This retrospective, observational study using the ConcertAI Oncology Dataset (Symphony AI, CA, USA), included patients with PD-L1+ (≥1% expression) metastatic NSCLC who began first-line (1L) treatment between 2016 and 2019. Treatment outcomes were assessed by treatment class (immune checkpoint inhibitor [ICI] monotherapy, ICI combinations or chemotherapy). Results: In total, 128 (25.5%), 237 (47.3%) and 136 patients (27.1%) received 1L chemotherapy, 1L ICI monotherapy and 1L ICI combinations, respectively. ICI combinations and monotherapy had improved clinical outcomes versus chemotherapy. Adjusted analyses showed no significant difference in outcome between ICI monotherapy and ICI combinations. Conclusion: ICI-based treatments are being increasingly adopted into clinical practice and were associated with better outcomes versus chemotherapy.