Management of glioblastoma: State of the art and future directions.

Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor-treating fields, delivering low-intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood-brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.

Longitudinal molecular trajectories of diffuse glioma in adults.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

Perceptions of a reduced nicotine policy and predictors of policy support: A nationally representative U.S. survey.

BACKGROUND: The U.S. Food and Drug Administration is considering a policy to reduce nicotine in cigarettes to non-addictive levels. Although current evidence supports the public-health benefits of a reduced-nicotine policy, almost half of people who smoke (∼ 40%) do not support the policy. This study estimates the factors most strongly associated with support or opposition toward the policy, including tobacco use status, perceived effects of a reduced nicotine policy, trust in the FDA, and psychological distress. The study aims to inform messaging campaigns and policy makers. METHODS: Data were collected in 2021 with nationally representative samples of U.S. adults (n = 1763). After receiving information about the reduced nicotine policy, participants indicated their beliefs and support for or opposition to the policy, along with other individual difference characteristics. Univariate population parameters and multinomial logistic regression coefficients were estimated. RESULTS: In adjusted models, people who formerly or never smoked were less likely to oppose the policy compared to those who currently smoke; people with higher psychological distress and those who believe the policy will promote switching to e-cigarettes were more likely to oppose the policy. In addition, people were more likely to support the policy if they believed it would make quitting easier or that the FDA is trustworthy. CONCLUSIONS: Educational campaigns about reduced nicotine policy should expect higher impact by targeting prevalent perceptions and those more strongly associated with policy sentiment. In anticipation of the policy rollout, there may be a critical window to shape public opinion.

Tobacco Constituents, Flavorants, and Paper Permeability of Factory-Made and Roll-Your-Own Cigarettes on the Australian Market.

INTRODUCTION: Roll-your-own (RYO) tobacco is a popular choice in Australia, with some people who smoke finding these products more attractive than factory-made cigarettes (FMC). Differences in visual and tactile properties and in the feel and taste of the smoke may contribute to this attractiveness. These differences may be driven by variation in tobacco constituents and wrapping paper permeability. However, to date, there has been no comparison of RYO and FMC products on the Australian market. AIMS AND METHODS: Chemical constituents, pH, flavorants, and paper permeability were compared in unburned RYO tobacco and tobacco from FMC. RYO and FMC products from matched brands were compared, as were products from the most popular FMC and RYO brands on the Australian market in 2018. RESULTS: RYO tobacco had higher moisture and humectant content (glycerol and propylene glycol) than FMC tobacco. RYO tobacco also had higher amounts of total and reducing sugars and lower nicotine when comparing the most popular brands. RYO papers were less permeable than FMC papers. Both RYO and FMC tobacco contained many chemicals identified as flavorants, including fourteen with known potential health risks. For most measured constituents and flavorants, RYO tobaccos had more in common with other RYO than FMC, with the commonalities remaining even when matched brands were compared. CONCLUSIONS: Higher levels of moisture, humectants, and sugars in Australian RYO tobacco compared to FMC may be increasing attractiveness of RYO by reducing the harsh taste of the smoke and increasing the moist feel of the tobacco. IMPLICATIONS: While price is the main factor driving the use of RYO tobacco, some people who smoke find these products more attractive. This study has shown that Australian RYO tobacco contains higher amounts of glycerol, propylene glycol, and sugars than FMC. These chemicals may be improving the taste of the tobacco, as well as creating a moist feel that is falsely perceived as indicating that the tobacco is "fresh" and "less chemically." Ironically, it may be that higher amounts of some added chemicals in RYO contribute to false perceptions of a more natural and less harmful product.

Reactions to Messages About a Nicotine Reduction Policy: A Focus Group Study Among People Who Use Little Cigars and Cigarillos.

INTRODUCTION: The U.S. Food and Drug Administration (FDA) has proposed rulemaking to reduce the nicotine content in cigarettes and other combusted tobacco products to non-addictive levels. This qualitative study documents reactions to messages communicating this policy among people who use little cigars and cigarillos (LCCs). AIMS AND METHODS: We conducted eight focus groups with participants from four populations with the highest prevalence of cigar use (African American males and females, white males and females). Participants described their reactions to eight messages about the policy: Three messages about the equal risk of LCCs with regular and low nicotine levels; three quit efficacy messages about low nicotine LCCs being easier to quit; one "compensation" message to correct misperceptions about the policy causing people to smoke more to get desired nicotine; and one message about using alternative nicotine sources (eg, e-cigarettes). RESULTS: Participants perceived risk messages as the most motivating to quit, whereas efficacy messages made some participants feel that the policy would cause former users of LCCs to relapse. Many participants expressed favorable responses to the compensation message. The message about using alternative nicotine sources sparked intense responses, with many participants expressing outrage and mistrust of the message. Participants' beliefs that they were not addicted to LCCs dampened their perceptions of the effectiveness of the policy. CONCLUSIONS: Perceptions of the addictiveness and relative harms of LCCS influenced responses to policy messages. The FDA should consider using different messages to communicate with people who use LCCs because they perceive LCCs as different from cigarettes. IMPLICATIONS: This is the first study to document affective and cognitive responses to the FDA's reduced nicotine policy among people who use LCCs. The false belief that cigar products are less harmful than cigarettes may be influencing people's lack of support for the reduced nicotine policy and difficulty in understanding its potential positive impact. To maximize the public health benefit of the reduced nicotine policy, the FDA should include LCC products in the policy; however, it is crucial that they use educational messaging to clarify misperceptions regarding nicotine and harm as it applies to LCCs.

Independent and combined effects of very low nicotine cigarette messages and e-cigarette messages: a randomised clinical trial.

BACKGROUND: USA is considering reducing nicotine in cigarettes to non-addictive levels, coupled with promoting alternative nicotine delivery products (eg, e-cigarettes). However, effective communication is needed to reduce misperceptions about very low nicotine cigarettes (VLNCs) being less harmful than regular cigarettes. METHODS: In 2022-2023, we conducted a four-group randomised clinical trial with a national probability sample from an online panel (971 adults who smoked cigarettes exclusively, 472 adults who dual used cigarettes and e-cigarettes and 458 adults aged 18-29 who had never smoked). Participants were randomised (parallel assignment) to one message condition: (1) VLNCs as harmful but easier to quit than regular cigarettes (n=468), (2) those who are not ready to quit should consider switching to e-cigarettes as less harmful alternatives (n=484), (3) combined (VLNC and e-cigarette messages; n=476) or (4) control condition (ie, water ads), n=473. The primary outcome was perceived absolute harm of VLNCs. RESULTS: Perceived harm of VLNCs was higher in the VLNC condition compared with the e-cigarette and control conditions, and higher in the combined condition compared with the e-cigarette condition (adjusted p<0.05). Among adults who dual used, intention to switch to e-cigarettes was higher in the VLNC condition than the e-cigarette, combined or control conditions (adjusted p<0.05). CONCLUSIONS: VLNC messages reduced the misperception that VLNCs are less harmful than cigarettes, but adding messages about e-cigarettes did not enhance desired outcomes. These VLNC messages can be considered during the rollout of a reduced nicotine policy. TRIAL REGISTRATION: NCT05506046.

Mouth Level Intake of Nicotine from Three Brands of Little Filtered Cigars with Widely Differing Product Characteristics Among Adult Consumers.

Little filtered cigars are tobacco products with many cigarette-like characteristics. However, despite cigars falling under the U.S. Food and Drug Administration regulatory authority, characterizing flavors, which are still allowed in little filtered cigars, and filter design may influence how people use the products and the resulting exposure to harmful and potentially harmful constituents. We estimated nicotine mouth level intake (MLI) from analyses of little cigar filter butt solanesol levels, brand characteristics, carbon monoxide boost, and puff volume in 48 dual cigarette/cigar users during two repeat bouts of ad lib smoking of three little filtered cigar brands. Mean nicotine MLI for the three brands was significantly different with Swisher Sweets (0.1% ventilation) Cherry at 1.20 mg nicotine, Cheyenne Menthol (1.5%) at 0.63 mg, and Santa Fe unflavored (49%) at 0.94 mg. The association between nicotine MLI and puff volume was the same between Cheyenne Menthol and Santa Fe unflavored. However, these were different from Swisher Sweets Cherry. At least five main factors─flavor, ventilation, filter design, nicotine delivery related to tar, and user puff volume─may directly or indirectly impact MLI and its association with other measures. We found that users of little filtered cigars that have different filter ventilation and flavor draw dissimilar amounts of nicotine from the product, which may be accompanied by differences in exposure to other harmful smoke constituents.

"I Get the Flavors and It Makes Me Love Vaping More": How and Why Youth Users Modify Electronic Nicotine Delivery Systems.

INTRODUCTION: Youth in the United States are using electronic nicotine delivery systems (ENDS) at a high rate. Modifications to ENDS by youth can introduce additional health hazards which have not been previously considered. To better understand these risks, we need more information on what these modifications are, the motivations behind them, and the sources of information on modifications. AIMS AND METHODS: Utilizing a trained moderator, in 2020-2021, we conducted one-on-one interviews with 19 youth ENDS users aged 16-17 living in the United States and analyzed their responses using a qualitative description approach. RESULTS: The most prominent modification was to the e-liquid; youth indicated they mixed e-juices to create new flavors and added substances not intended for vaping, including illicit drugs such as cannabis and cocaine. Few youths from our sample were interested in achieving a specific nicotine level to vape, and modifications to the battery, coil and wick were less frequently mentioned. Some of these modifications were motivated by a desire to achieve specific experiences with their device. At other times, modifications were made due to necessity because of limited access to ENDS devices and supplies. YouTube and peers were the main sources of information about modifying. CONCLUSIONS: Youth are making modifications that are both intended and unintended by the manufacturer. Adding illicit drugs and other substances not made for vaping is of particular concern. Understanding how youth modify ENDS and how that changes their use is important to guide regulatory policy intended to reduce harm to youth from ENDS use. IMPLICATIONS: Youth from our study indicated that they make modifications to the ENDS devices, specifically to the e-liquid. These modifications are both intended by the manufacturer, such as changing the e-liquid and replacing coils, and unintended, such as adding substances not meant for vaping. Future policies aimed at reducing youth ENDS use should consider mandating better safeguards against modifications that appeal to youth.

"I'm Bored and I'm Stressed": A Qualitative Study of Exclusive Smokers, ENDS Users, and Transitioning Smokers or ENDS Users in the Time of COVID-19.

BACKGROUND: To better understand the various influences of COVID-19 on tobacco use, we examined three different tobacco user groups using qualitative methods. METHODS: Ten online focus groups with 61 adults from the Atlanta, GA area were held in October-November 2020: four with exclusive smokers (n = 16), three with Electronic Nicotine Delivery System (ENDS) users (dual and exclusive, n = 22), and three with transitioning (recently quit or currently quitting) smokers and/or ENDS users (n = 23). RESULTS: Exclusive smokers reported smoking more frequently, driven by COVID-19-related stress, time at home, and boredom. They were not motivated to quit during the pandemic, and some considered smoking to be protective against COVID-19. ENDS users reported vaping less, with dual users often increasing their smoking; many were concerned about health effects of smoking and ENDS use during the pandemic. Transitioning smokers/ENDS users worried about their health and wanted to quit, but many found the stress of COVID-19 unbearable without tobacco use. CONCLUSIONS: There were some similarities among the groups, but also pronounced differences. Educational campaigns should capitalize on the teachable moment of COVID-19 to increase perceived risk of smoking. Smokers need access to more adaptive ways to deal with stress (such as mindfulness training) in lieu of smoking and systems-level approaches should address structural determinants of health that cause high levels of stress. The proposed policy to lower nicotine in combusted tobacco products might help smokers choose other means of coping instead of cigarettes by reducing the stress-relieving properties of smoking particularly salient during the pandemic. IMPLICATIONS: Smokers believe that cigarettes help them deal with the stresses and challenges of the COVID-19 pandemic. This needs to be counteracted by educational campaigns to increase perceived harm of smoking, alternative stress-relief strategies, and mandated changes to the combusted tobacco products to make them less appealing.

The Short-Term and Long-Term Associations Between Receiving Tobacco Discounts or Coupons and Smoking Cessation Among U.S. Adult Cigarette Smokers With Intention to Quit.

INTRODUCTION: To examine the associations between baseline receipt of cigarette and non-cigarette tobacco discounts or coupons and smoking cessation at follow-up among US adult cigarette smokers with the intention to quit at baseline. AIMS AND METHODS: Data were from the Population Assessment of Tobacco and Health (PATH) study wave 3 (October 2015-October 2016), wave 4 (December 2016-January 2018), and wave 5 (December 2018-November 2019) surveys. Two separate sets of analyses were conducted using wave 3-4 data (N = 3707) and wave 4-5 data (N = 6251). Specifically, wave 4 was used as the 1-year follow-up of wave 3 to examine the short-term association, and wave 5 was used as the 2-year follow-up of wave 4 to examine the longer-term association. Study population were current established cigarette smokers with the intention to quit (within 1 year for wave 3-4 data) at baseline. Exposure was self-reported past 12-month receipt of discounts or coupons for cigarettes and non-cigarette tobacco products at baseline, and outcome was self-reported completely quitting cigarette smoking at follow-up. Baseline single-wave weights were applied, and multivariate logistic regressions were used to estimate the adjusted associations. RESULTS: Participants who received cigarette discounts or coupons at baseline were less likely to quit completely for both 1-year follow-up (aOR = 0.66, 95% CI: 0.48 to 0.90) and 2-year follow-up (aOR = 0.74, 95% CI: 0.61 to 0.90). Baseline receipt of discounts or coupons for non-cigarette tobacco products were not consistently associated with cigarette smoking cessation at follow-up. CONCLUSIONS: Receipt of cigarette discounts or coupons was associated with a reduced likelihood of successful quitting among cigarette smokers with intention to quit. Policies restricting cigarette coupons may help them quit completely. IMPLICATIONS: This study found that among baseline current established cigarette smokers with intention to quit in the United States, baseline receipt of cigarette discounts or coupons was negatively associated with cigarette smoking cessation for both 1-year follow-up and 2-year follow-up. Baseline receipt of discounts or coupons for e-cigarettes, cigars, and other tobacco products were not consistently significantly associated with cigarette smoking cessation at follow-up. Our study results indicated that policies restricting cigarette coupons may help increase the likelihood of successful smoking cessation for smokers with intention to quit.

Variability in Urinary Nicotine Exposure Biomarker Levels Between Waves 1 (2013-2014) and 2 (2014-2015) in the Population Assessment of Tobacco and Health Study.

INTRODUCTION: To date, no studies have evaluated the consistency of biomarker levels in people who smoke over a long-time period in real-world conditions with a large number of subjects and included use behavior and measures of nicotine metabolism. We evaluated the variability of biomarkers of nicotine exposure over approximately a 1-year period in people who exclusively smoke cigarettes, including intensity and recency of use and brand switching to assess impact on understanding associations with product characteristics. AIMS AND METHODS: Multivariate regression analysis of longitudinal repeated measures of urinary biomarkers of nicotine exposure from 916 adults in the Population Assessment of Tobacco and Health (PATH) Study with demographic characteristics and use behavior variables. Intraclass correlation coefficients (ICCs) were calculated to examine individual variation of nicotine biomarkers and the uncertainty of repeat measures at two time points (Waves 1 and 2). RESULTS: Age, race, and urinary creatinine were significant covariates of urinary cotinine. When including use behavior, recency, and intensity of use were highly significant and variance decreased to a higher extent between than within subjects. The ICC for urinary cotinine decreased from 0.7530 with no use behavior variables in the model to 0.5763 when included. Similar results were found for total nicotine equivalents. CONCLUSIONS: Urinary nicotine biomarkers in the PATH Study showed good consistency between Waves 1 and 2. Use behavior measures such as time since last smoked a cigarette and number of cigarettes smoked in the past 30 days are important to include when assessing factors that may influence biomarker concentrations. IMPLICATIONS: The results of this study show that the consistency of the nicotine biomarkers cotinine and total nicotine equivalents in spot urine samples from Waves 1 to 2 of the PATH Study is high enough that these data are useful to evaluate the association of cigarette characteristics with biomarkers of exposure under real-world use conditions.

Use of Trametinib in Children and Young Adults With Progressive Low-grade Glioma and Glioneuronal Tumors.

Low-grade gliomas/glioneuronal tumors comprise one-third of all pediatric-type CNS tumors. These tumors are generally caused by activating mutations in the mitogen-activated protein kinase (MAPK) pathway. Targeted drugs, such as trametinib, have shown promise in other cancers and are being utilized in low-grade gliomas. A retrospective chart review was conducted to evaluate radiographic response, visual outcomes, tolerability, and durability of response in progressive circumscribed low-grade gliomas treated with trametinib. Eleven patients were treated with trametinib. The best radiographic response was 2/11 partial response, 3/11 minor response, 3/11 stable disease, and 3/13 progressive disease. In the patients with partial or minor response, the best response was seen after longer durations of therapy; 4 of 5 best responses occurred after at least 9 months of therapy with a median of 21 months. Patients with optic pathway tumors showed at least stable vision throughout treatment, with 3 having improved vision on treatment. Trametinib is effective and well-tolerated in patients with progressive low-grade glioma. Best responses were seen after a longer duration of therapy in those with a positive response. Patients with optic pathway lesions showed stable to improved vision while on treatment.

Brief report on IQOS point-of-sale marketing, promotion and pricing in IQOS retail partner stores in Atlanta, Georgia, USA.

OBJECTIVES: Philip Morris has a history of aggressive marketing tactics in its global pursuit of IQOS sales, which extant literature suggests may appeal to non-smokers and young adults. This study was the first to examine point-of-sale (POS) marketing and pricing of IQOS after it entered the US market in October 2019. METHODS: Trained field staff assessed 75 retail partner stores selling IQOS/HeatSticks in the Atlanta area in February-November 2020 using an IQOS-tailored, standardised assessment tool. The tool assessed store characteristics, product availability and accessibility, marketing and promotions and pricing for each store. RESULTS: All stores assessed sold HeatSticks in at least one of the three flavours (tobacco, smooth menthol, fresh menthol), but did not sell the IQOS device. IQOS/HeatSticks marketing was present inside 98.5% and outside 17.3% of stores assessed. Marketing for other tobacco products was present inside 98.5% and outside 32% of stores. The average price per HeatSticks pack was US$6.40 compared with US$6.08 for Marlboro Red cigarettes. CONCLUSION: Our study revealed a considerable amount of POS marketing and promotion for IQOS/HeatSticks at retail partner locations, visible to all retail consumers, including youth and non-smokers. This study was the first to examine IQOS POS marketing and promotion in the US context and findings add to the extant literature on IQOS global marketing strategies. As additional novel tobacco/nicotine products continue to enter the market, targeted monitoring of the POS marketing and promotion for these new products is warranted.

Perceptions of Nicotine Reduction Policy in the United States: A Qualitative Study.

INTRODUCTION: Several countries are considering a reduced nicotine policy that would make cigarettes minimally or nonaddictive. This qualitative study documents reactions to the policy that should be addressed by future communication efforts. METHODS: In 2020, we recruited participants in Atlanta, GA and San Francisco, CA (27 people who exclusively smoke, 25 who dual use cigarettes and e-cigarettes, 32 who formerly smoked, and 31 young adults who do not smoke). We held 16 focus groups: 2 focus groups for each smoking status in each city. Participants viewed messages about very low nicotine content cigarettes (VLNCs) and were asked about their reactions to each message and their overall response to the reduced nicotine policy. RESULTS: While responses to the policy were predominantly positive, focus group discussion also revealed concerns, questions, and misunderstandings (referred to here collectively as "perceptions") that may need to be addressed if a reduced nicotine policy is enacted. Participants expressed perceptions related to the policy intent, including that the FDA has ulterior motives, adoption/ implementation, including that nicotine would have to be replaced with other chemicals if removed or that the policy would be unfeasible to implement, and effectiveness, including concern that VLNCs would still be addictive or the policy would backfire. CONCLUSIONS: Addressing perceptions about reduced nicotine policy intent, adoption/implementation, and effectiveness could be key in creating public support and political motivation to move forward with such a policy. Countries contemplating adopting such a policy should consider pairing it with communications that address these perceptions. IMPLICATIONS: This study is one of very few to use qualitative methods to explore potentially problematic perceptions about nicotine reduction policy among US adults. Results illuminated new policy-specific concerns, questions, and misunderstandings about the reduced nicotine policy intent, adoption/implementation, and effectiveness. Identifying, studying, and addressing relevant perceptions may play a key role in generating support in countries contemplating such a policy.

Evolution of tobacco products: recent history and future directions.

Declines in cigarette smoking prevalence in many countries and the consolidation of the tobacco industry have prompted the introduction of other forms of nicotine delivery. These include electronic nicotine delivery systems (ENDS), heated tobacco products (HTPs) and oral nicotine products (ONPs). Evolving over time, some of these products now deliver nicotine at levels comparable to cigarettes and may serve as effective substitutes for smokers. However, certain products, especially ENDS like JUUL, have also appealed to youth and non-smokers, prompting concerns about expanding nicotine use (and potentially nicotine addiction). The tobacco industry could shift away from primarily promoting cigarettes to promoting ENDS, HTPs and/or ONPs, though at this time it continues to heavily promote cigarettes in low and middle-income countries. Differing regulatory regimes may place upward and downward pressures on both cigarettes and these newer products in terms of population use, and may ultimately drive the extent to which cigarettes are or are not displaced by ENDS, HTPs and/or ONPs in the coming decade.

'It brings light to what you really put into your body': a focus group study of reactions to messages about nicotine reduction in cigarettes.

OBJECTIVE: In 2017, the US Food and Drug Administration (FDA) announced a proposed regulation to lower nicotine in cigarettes to minimally addictive levels to help smokers quit. We sought to explore effective message strategies communicating about nicotine reduction in cigarettes across the different key audiences that the regulation is most likely to influence. METHODS: We designed four types of messages: efficacy messages, risk messages, a message about alternative sources of nicotine and a compensation message. Sixteen virtual focus groups were conducted in Atlanta and San Francisco in April-May 2020. Data were analysed in NVivo 12.0 using a thematic analysis approach. FINDINGS: Exclusive smokers were receptive to both efficacy messages and risk messages. Dual users were the only group that was open to resorting to alternative sources of nicotine. Former smokers were critical of these messages as promoting the new kinds of cigarettes and potentially encouraging initiation and relapse of smoking. Non-smokers felt that efficacy messages downplayed the risks of smoking and did not scare people away from smoking. Presenting information that very low nicotine cigarettes (VLNCs) still contain harmful chemicals made smokers question continued smoking in the absence of nicotine and view VLNCs as harmful. CONCLUSIONS: Messages communicating about nicotine reduction in cigarettes might help to motivate smokers to quit and can correct the misperceptions that VLNCs are less harmful. The FDA should consider specific target audiences and use different messages that complement each other in communicating about this regulation.

Messaging about very low nicotine cigarettes (VLNCs) to influence policy attitudes, harm perceptions and smoking motivations: a discrete choice experiment.

BACKGROUND: To reduce smoking and the harms it causes, countries, including the USA, are considering policies to reduce nicotine in combustible tobacco to minimally addictive levels. Effective messages about very low nicotine cigarettes (VLNCs) and this policy are crucial in combating misperceptions threatening the policy's effectiveness. DATA AND METHODS: A discrete choice experiment assessed messages about VLNCs. Participants were 590 adults who smoked exclusively, 379 adults who both smoked and used e-cigarettes, 443 adults who formerly smoked and 351 young adults who never smoked (total n=1763). Seven message attributes were varied systematically (source, harm, chemicals, nicotine, satisfaction, addictiveness and quitting efficacy). Outcomes were selection of messages that generated the most positive attitude towards reduced nicotine policy, the greatest perceived harmfulness of VLNCs, and most strongly motivated quitting and initiating behaviour for VLNCs. RESULTS: Information about specific harms and chemicals of VLNCs had the largest effects on selection of messages as eliciting more negative attitudes towards VLNCs policy, increasing perceived VLNC harmfulness, increasing motivation to quit VLNCs and decreasing motivation to try VLNCs. Messages with information about quitting efficacy were selected as more motivating to quit among those who smoke, but also more motivating to try VLNCs among those who do not smoke. CONCLUSION: Harm and chemical information can be prioritised to ensure VLNCs are not misperceived as less harmful than regular cigarettes. Messages about increased quitting efficacy and reduced addictiveness associated with VLNCs may backfire if presented to those who do not smoke.

Recurrent Glioblastoma Treated with Recombinant Poliovirus.

BACKGROUND: The prognosis of patients with recurrent World Health Organization (WHO) grade IV malignant glioma is dismal, and there is currently no effective therapy. We conducted a dose-finding and toxicity study in this population of patients, evaluating convection-enhanced, intratumoral delivery of the recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment. METHODS: We enrolled consecutive adult patients who had recurrent supratentorial WHO grade IV malignant glioma, confirmed on histopathological testing, with measurable disease (contrast-enhancing tumor of ≥1 cm and ≤5.5 cm in the greatest dimension). The study evaluated seven doses, ranging between 107 and 1010 50% tissue-culture infectious doses (TCID50), first in a dose-escalation phase and then in a dose-expansion phase. RESULTS: From May 2012 through May 2017, a total of 61 patients were enrolled and received a dose of PVSRIPO. Dose level -1 (5.0×107 TCID50) was identified as the phase 2 dose. One dose-limiting toxic effect was observed; a patient in whom dose level 5 (1010 TCID50) was administered had a grade 4 intracranial hemorrhage immediately after the catheter was removed. To mitigate locoregional inflammation of the infused tumor with prolonged glucocorticoid use, dose level 5 was deescalated to reach the phase 2 dose. In the dose-expansion phase, 19% of the patients had a PVSRIPO-related adverse event of grade 3 or higher. Overall survival among the patients who received PVSRIPO reached a plateau of 21% (95% confidence interval, 11 to 33) at 24 months that was sustained at 36 months. CONCLUSIONS: Intratumoral infusion of PVSRIPO in patients with recurrent WHO grade IV malignant glioma confirmed the absence of neurovirulent potential. The survival rate among patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among historical controls. (Funded by the Brain Tumor Research Charity and others; ClinicalTrials.gov number, NCT01491893 .).

Photosynthetic quantum efficiency in south-eastern Amazonian trees may be already affected by climate change.

Tropical forests are experiencing unprecedented high-temperature conditions due to climate change that could limit their photosynthetic functions. We studied the high-temperature sensitivity of photosynthesis in a rainforest site in southern Amazonia, where some of the highest temperatures and most rapid warming in the Tropics have been recorded. The quantum yield (Fv /Fm ) of photosystem II was measured in seven dominant tree species using leaf discs exposed to varying levels of heat stress. T50 was calculated as the temperature at which Fv /Fm was half the maximum value. T5 is defined as the breakpoint temperature, at which Fv /Fm decline was initiated. Leaf thermotolerance in the rapidly warming southern Amazonia was the highest recorded for forest tree species globally. T50 and T5 varied between species, with one mid-storey species, Amaioua guianensis, exhibiting particularly high T50 and T5 values. While the T50 values of the species sampled were several degrees above the maximum air temperatures experienced in southern Amazonia, the T5 values of several species are now exceeded under present-day maximum air temperatures.

Comparability of six different immunoassays measuring SARS-CoV-2 antibodies with neutralizing antibody levels in convalescent plasma: From utility to prediction.

BACKGROUND: Convalescent plasma (CP) therapy for coronavirus disease (COVID-19) provides virus-neutralizing antibodies that may ameliorate the outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. The effectiveness of CP likely depends on its antiviral neutralizing potency and is determined using in vitro neutralizing antibody assays. STUDY DESIGN AND METHODS: We evaluated abilities of three immunoassays for anti-spike antibodies (EUROimmun, Ortho, Roche), a pseudotype-based neutralization assay, and two assays that quantify ACE2 binding of spike protein (GenScript and hemagglutination test [HAT]-based assay) to predict neutralizing antibody titers in 113 CP donations. Assay outputs were analyzed through linear regression and calculation of sensitivities and specificities by receiver operator characteristic (ROC) analysis. RESULTS: Median values of plasma samples containing neutralizing antibodies produced conversion factors for assay unitage of ×6.5 (pseudotype), ×19 (GenScript), ×3.4 (HAT assay), ×0.08 (EUROimmun), ×1.64 (Roche), and ×0.10 (Ortho). All selected assays were sufficient in identifying the high titer donations based on ROC analysis; area over curve ranged from 91.7% for HAT and GenScript assay to 95.6% for pseudotype assay. However, their ability to predict the actual neutralizing antibody levels varied substantially as shown by linear regression correlation values (from 0.27 for Ortho to 0.61 for pseudotype assay). DISCUSSION: Overall, the study data demonstrate that all selected assays were effective in identifying donations with high neutralizing antibody levels and are potentially suitable as surrogate assays for donation selection for CP therapy.