mRNA melanoma vaccine revolution spurred by the COVID-19 pandemic.

The advent of mRNA vaccines represents a significant advance in the field of vaccinology. While several vaccine approaches (mRNA, DNA, recombinant protein, and viral-vectored vaccines) had been investigated at the start of the COVID-19 pandemic, mRNA vaccines quickly gained popularity due to superior immunogenicity at a low dose, strong safety/tolerability profiles, and the possibility of rapid vaccine mass manufacturing and deployment to rural regions. In addition to inducing protective neutralizing antibody responses, mRNA vaccines can also elicit high-magnitude cytotoxic T-cell responses comparable to natural viral infections; thereby, drawing significant interest from cancer immunotherapy experts. This mini-review will highlight key developmental milestones and lessons we have learned from mRNA vaccines during the COVID-19 pandemic, with a specific emphasis on clinical trial data gathered so far for mRNA vaccines against melanoma and other forms of cancer.

Reduction in Long-term Mortality after Sleeve Gastrectomy and Gastric Bypass Compared to Non-surgical Patients with Severe Obesity.

OBJECTIVE: To separately compare the long-term risk of mortality among bariatric surgical patients undergoing either RYGB or SG to large, matched, population-based cohorts of patients with severe obesity who did not undergo surgery. BACKGROUND: Bariatric surgery has been associated with reduced long-term mortality compared to usual care for severe obesity which is particularly relevant in the COVID-19 era. Most prior studies involved the Roux-en-Y gastric bypass (RYGB) operation and there is less long-term data on the sleeve gastrectomy (SG). METHODS: In this retrospective, matched cohort study, patients with a body mass index ≥35 kg/m2 who underwent bariatric surgery from January 2005 to September 2015 in three integrated health systems in the United States were matched to nonsurgical patients on site, age, sex, body mass index, diabetes status, insulin use, race/ethnicity, combined Charlson/Elixhauser comorbidity score, and prior health care utilization, with follow-up through September 2015. Each procedure (RYGB, SG) was compared to its own control group and the two surgical procedures were not directly compared to each other. Multivariable-adjusted Cox regression analysis investigated time to all-cause mortality (primary outcome) comparing each of the bariatric procedures to usual care. Secondary outcomes separately examined the incidence of cardiovascular-related death, cancer related-death, and diabetes related-death. RESULTS: Among 13,900 SG, 17,258 RYGB, and 87,965 nonsurgical patients, the 5-year follow-up rate was 70.9%, 72.0%, and 64.5%, respectively. RYGB and SG were each associated with a significantly lower risk of all-cause mortality compared to nonsurgical patients at 5-years of follow-up (RYGB: HR = 0.43; 95% CI: 0.35,0.54; SG: HR = 0.28; 95% CI: 0.13,0.57) Similarly, RYGB was associated with a significantly lower 5-year risk of cardiovascular- (HR = 0.27; 95% CI: 0.20, 0.37), cancer- (HR = 0.54; 95% CI: 0.39, 0.76), and diabetes-related mortality (HR = 0.23; 95% CI:0.15, 0.36). There was not enough follow-up time to assess 5-year cause-specific mortality in SG patients, but at 3-years follow up, there was significantly lower risk of cardiovascular- (HR = 0.33; 95% CI:0.19, 0.58), cancer- (HR = 0.26; 95% CI:0.11, 0.59), and diabetes-related (HR = 0.15; 95% CI:0.04, 0.53) mortality for SG patients. CONCLUSION: This study confirms and extends prior findings of an association with better survival following bariatric surgery in RYGB patients compared to controls and separately demonstrates that the SG operation also appears to be associated with lower mortality compared to matched control patients with severe obesity that received usual care. These results help to inform the trade-offs between long-term benefits and risks of bariatric surgery.

Association between tocilizumab, sarilumab and all-cause mortality at 28 days in hospitalised patients with COVID-19: A network meta-analysis.

BACKGROUND: A recent prospective meta-analysis demonstrated that interleukin-6 antagonists are associated with lower all-cause mortality in hospitalised patients with COVID-19, compared with usual care or placebo. However, emerging evidence suggests that clinicians are favouring the use of tocilizumab over sarilumab. A new randomised comparison of these agents from the REMAP-CAP trial shows similar effects on in-hospital mortality. Therefore, we initiated a network meta-analysis, to estimate pairwise associations between tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and ventilation, based on all available direct and indirect evidence. METHODS: Eligible trials randomised hospitalised patients with COVID-19 that compared tocilizumab or sarilumab with usual care or placebo in the prospective meta-analysis or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomisation. Pairwise associations between tocilizumab, sarilumab and usual care or placebo for all-cause mortality 28 days after randomisation were estimated using a frequentist contrast-based network meta-analysis of odds ratios (ORs), implementing multivariate fixed-effects models that assume consistency between the direct and indirect evidence. FINDINGS: One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab [0·82 [0·71-0·95, p = 0·008]] and sarilumab [0·80 [0·61-1·04, p = 0·09]] compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1·03 [95%CI 0·81-1·32, p = 0·80]. The p-value for the global test of inconsistency was 0·28. CONCLUSIONS: Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist.

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Trial Registration: PROSPERO Identifier: CRD42021230155.

The Evidence for High-Titer Convalescent Plasma in SARS-CoV-2.

Convalescent plasma therapy has been used successfully in the past to treat respiratory infections. In SARS-CoV-2, there was initially strong evidence in favor of convalescent plasma therapy from a large observational study but the evidence from recent randomized controlled trials has been mixed. However, two of those studies provided convalescent plasma therapy on average 8 days after diagnosis despite earlier data proving that the therapy is most effective when given within 3 days of diagnosis. Another more recent randomized controlled trial found evidence in support of convalescent plasma therapy and we believe that it is no coincidence that they administered convalescent plasma therapy within 3 days of symptom onset. We call for more robustly planned randomized controlled studies to further reliably determine the efficacy of convalescent plasma therapy against SARS-CoV-2. Progress has been made with developing a vaccine but there is likely to be a substantial lag in widespread administration of the vaccine, especially in poorer countries. We therefore propose that patients with SARS-CoV-2 infection should be considered for early ambulatory administration of high-dose convalescent plasma in order to reduce the burden of severe SARS-CoV-2 disease.

Advancing Sustainable Development and Protected Area Management with Social Media-Based Tourism Data

Sustainable tourism involves increasingly attracting visitors while preserving the natural capital of a destination for future generations. To foster tourism while protecting sensitive environments, coastal managers, tourism operators, and other decision-makers benefit from information about where tourists go and which aspects of the natural and built environment draw them to particular locations. Yet this information is often lacking at management-relevant scales and in remote places. We tested and applied methods using social media as data on tourism in The Bahamas. We found that visitation, as measured by numbers of geolocated photographs, is well correlated with counts of visitors from entrance surveys for islands and parks. Using this relationship, we predicted nearly 4 K visitor-days to the network of Bahamian marine protected areas annually, with visitation varying more than 20-fold between the most and least visited parks. Next, to understand spatial patterns of tourism for sustainable development, we combined social media-based data with entrance surveys for Andros, the largest island in The Bahamas. We estimated that tourists spend 125 K visitor-nights and more than US$45 M in the most highly visited district, five times that of the least visited district. We also found that tourists prefer accessible, natural landscapes—such as reefs near lodges—that can be reached by air, roads, and ferries. The results of our study are being used to inform development and conservation decisions, such as where to invest in infrastructure for visitor access and accommodation, siting new marine protected areas, and management of established protected areas. Our work provides an important example of how to leverage social media as a source of data to inform strategies that encourage tourism, while conserving the environments that draw visitors to a destination in the first place.

The State of Melanoma: Emergent Challenges and Opportunities.

Five years ago, the Melanoma Research Foundation (MRF) conducted an assessment of the challenges and opportunities facing the melanoma research community and patients with melanoma. Since then, remarkable progress has been made on both the basic and clinical research fronts. However, the incidence, recurrence, and death rates for melanoma remain unacceptably high and significant challenges remain. Hence, the MRF Scientific Advisory Council and Breakthrough Consortium, a group that includes clinicians and scientists, reconvened to facilitate intensive discussions on thematic areas essential to melanoma researchers and patients alike, prevention, detection, diagnosis, metastatic dormancy and progression, response and resistance to targeted and immune-based therapy, and the clinical consequences of COVID-19 for patients with melanoma and providers. These extensive discussions helped to crystalize our understanding of the challenges and opportunities facing the broader melanoma community today. In this report, we discuss the progress made since the last MRF assessment, comment on what remains to be overcome, and offer recommendations for the best path forward.

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis.

Importance: Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support. Objective: To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality. Design, Setting, and Participants: Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance-weighted fixed-effect analysis using risk ratios. Exposures: Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients). Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events. Results: A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as "low" for 6 of the 7 mortality results and as "some concerns" in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo. Conclusions and Relevance: In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.