Implementation of low-intensity thrombolysis monitoring care in routine practice: process evaluation of the Optimal Post rtPA-IV Monitoring in Acute Ischemic Stroke (OPTIMISTmain) study in the United States.

INTRODUCTION: The ongoing OPTIMISTmain study, an international, multicenter, stepped-wedge cluster randomized trial, aims to determine effectiveness and safety of low-intensity versus standard monitoring in thrombolysis-treated patients with mild-to-moderate acute ischemic stroke (AIS). An embedded process evaluation explored integration and impact of the intervention on care processes at participating US sites. METHODS: A mixed-methods approach with quantitative and qualitative data were collected between September 2021 and November 2022. Implementer surveys were undertaken at pre- and post-intervention phases to understand the perceptions of low-intensity monitoring strategy. A sample of stroke care nurses were invited to participate in semi-structured interviews at an early stage of post-intervention. Qualitative data were analyzed deductively using the normalization process theory; quantitative data were tabulated. RESULTS: Interviews with 21 nurses at 8 hospitals have shown low-intensity monitoring was well accepted, as there were less time constraints and reduced workload for each patient. There were initial safety concerns over missing deteriorating patients and difficulties in changing established routines. Proper training, education, and communication, and changing the habits and culture of care, were key elements to successfully adopting the new monitoring care into routine practice. Similar results were found in the post-intervention survey (42 nurses from 13 hospitals). Nurses reported time being freed up to provide patient education (56%), daily living care (50%), early mobilization (26%), mood/cognition assessment (44%), and other aspects (i.e. communication, family support). CONCLUSIONS: Low-intensity monitoring for patients with mild-to-moderate acute ischemic stroke, facilitated by appropriate education and organizational support, appears feasible and acceptable at US hospitals.

Clinical Trial Protocol for BEACH: A Phase 2a Study of MW189 in Patients with Acute Nontraumatic Intracerebral Hemorrhage.

Patients with acute spontaneous intracerebral hemorrhage (ICH) develop secondary neuroinflammation and cerebral edema that can further damage the brain and lead to increased risk of neurologic complications. Preclinical studies in animal models of acute brain injury have shown that a novel small-molecule drug candidate, MW01-6-189WH (MW189), decreases neuroinflammation and cerebral edema and improves functional outcomes. MW189 was also safe and well tolerated in phase 1 studies in healthy adults. The proof-of-concept phase 2a Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) clinical trial is a first-in-patient, multicenter, randomized, double-blind, placebo-controlled trial. It is designed to determine the safety and tolerability of MW189 in patients with acute ICH, identify trends in potential mitigation of neuroinflammation and cerebral edema, and assess effects on functional outcomes. A total of 120 participants with nontraumatic ICH will be randomly assigned 1:1 to receive intravenous MW189 (0.25 mg/kg) or placebo (saline) within 24 h of symptom onset and every 12 h for up to 5 days or until hospital discharge. The 120-participant sample size (60 per group) will allow testing of the null hypothesis of noninferiority with a tolerance limit of 12% and assuming a "worst-case" safety assumption of 10% rate of death in each arm with 10% significance and 80% power. The primary outcome is all-cause mortality at 7 days post randomization between treatment arms. Secondary end points include all-cause mortality at 30 days, perihematomal edema volume after symptom onset, adverse events, vital signs, pharmacokinetics of MW189, and inflammatory cytokine concentrations in plasma (and cerebrospinal fluid if available). Other exploratory end points are functional outcomes collected on days 30, 90, and 180. BEACH will provide important information about the utility of targeting neuroinflammation in ICH and will inform the design of future larger trials of acute central nervous system injury.

Cigarette health warning label compliance in Nigeria: A multi-city observational study.

INTRODUCTION: Tobacco remains the world's leading preventable cause of death, with the majority of tobacco-caused deaths occurring in low- and middle-income countries. The first global health treaty, the Framework Convention on Tobacco Control (FCTC), outlines a set of policy initiatives that have been demonstrated as effective in reducing tobacco use. Article 11 of the FCTC focuses on using the tobacco package to communicate tobacco-caused harms; it also seeks to restrict the delivery of misleading information on the pack about the product.The objective of his study is to establish a surveillance system for tobacco packs in Nigeria to assess pack compliance with in-country health warning label requirements. The Tobacco Pack Surveillance System (TPackSS) monitors whether required health warnings on tobacco packages are being implemented as intended and identifies pack designs that might violate the communication of harm-related information and undermine the impact of the country's tobacco packaging laws. METHODS: Tobacco cigarette packs were collected in three cities in 2019-2020. The intention was, to the extent possible, to construct a census of 'unique' pack presentations available for purchase in Nigeria. We implemented the TPackSS standardized Protocol for acquiring packs from 36 diverse neighborhoods across three cities. At the time of purchase, data on the price and place of acquisition of each pack were recorded. We photographed packs, coded, and archived them. Each pack was coded for compliance according to the current health warning label laws. Each pack was coded by two independent coders consistently. We routinely measured intercoder reliability and only retained variables for which a good level of reliability was achieved. RESULTS: Across the three cities in Nigeria, the team collected 90 tobacco packs. Overall, 77% of packs evaluated for HWL compliance complied with all the relevant common indicators of HWL compliance. There was a 92% compliance with the location of the HWL (e.g. top or bottom of pack, front or back panel) with in-country requirements. Of the four compliance indicators, the size of the HWL (the minimum required coverage) showed the lowest compliance (31%) (i.e. the HWL was too small on most of the packs). Label elements (such as color contrast or content of warnings) showed 85% compliance overall. CONCLUSIONS: The analysis of the packs showed various levels of compliance with Health Warning Label provisions for Nigeria. Periodic evaluations are required to ensure that minimum requirements are met.

Beyond Gutka: Evidence of Illegal Smokeless Tobacco in Rural and Semi-urban Areas in India.

INTRODUCTION: Gutka, a popular smokeless tobacco (SLT) product combining chewing tobacco, areca nut, and spices, was banned by states in India beginning in 2012. Gutka can be recreated by the user mixing twin packets of tobacco and spice mixtures. We examine the availability of premixed gutka, the sale of twin packets (chewing tobacco and spice mixture sold together but in separate packets) and whether SLT was sold without legally mandated health warning labels (HWLs), without the printed maximum retail price (MRP), and above the MRP. AIMS AND METHODS: In October/November of 2017, unique SLT packets were purchased using a systematic protocol in 25 localities with populations under 50 000 across five Indian states. Purchase information (location, twin packets, price paid) and packaging information (SLT type, printed MRP, type of HWL) were used to assess legality. RESULTS: Of the 240 purchases of unique SLT packets, three were premade gutka. Twin packets were half of the sample, sold in every state, and illegally sold in Maharashtra where they were banned. Over half (62%) of single packets and 27% of twin packets did not feature a legal HWL. While only 5% of packets did not have a printed MRP, 29% of single packets, and 38% of twin packets were sold illegally for more than the MRP. CONCLUSIONS: SLT without the proper HWL or sold above the MRP were common. Twin packets were widely available. India should consider a country-wide restriction to ban single serving tobacco packets that would decrease affordability. IMPLICATIONS: This study is the earliest and that first outside of Mumbai that we are aware of to present evidence of tobacco products being sold above the MRP in India. While finding little evidence of premade gutka being sold, we found twin packets (chewing tobacco and spice mixture packets sold together) are widely available even in Maharashtra, which has a policy in place to ban twin packets. This study also finds evidence of SLT products sold without the correct HWL and without a MRP listed which shows that implementation and enforcement of regulations are as important as passing regulations.

Health Warning Label Compliance for Smokeless Tobacco Products and Bidis in Five Indian States.

BACKGROUND: The burden of tobacco use In India is very high. To inform users of harm, India has a strong health warning label law that applies to all tobacco products. This study examines the extent of compliance of health warning labels on smokeless tobacco (SLT) and bidi products with the Indian law. METHODS: In 2017, a systematic protocol was used to collect unique SLT and bidi packages from five Indian states. To assess compliance, we used three indicators: location, label elements, and warning size. RESULTS: Only 1% of the 133 SLT products and none of the 32 bidi packs were compliant with all three compliance indicators. Other compliance-related issues included non-standardized packaging, incomplete health warning labels, poor printing quality, and old warning labels. CONCLUSION: There is very poor compliance with the health warning label law on bidi and SLT products. India needs to regularly monitor and address implementation to ensure that warning labels are effective.

Hypoxia Tolerance Declines with Age in the Absence of Methionine Sulfoxide Reductase (MSR) in Drosophila melanogaster.

Unlike the mammalian brain, Drosophila melanogaster can tolerate several hours of hypoxia without any tissue injury by entering a protective coma known as spreading depression. However, when oxygen is reintroduced, there is an increased production of reactive oxygen species (ROS) that causes oxidative damage. Methionine sulfoxide reductase (MSR) acts to restore functionality to oxidized methionine residues. In the present study, we have characterized in vivo effects of MSR deficiency on hypoxia tolerance throughout the lifespan of Drosophila. Flies subjected to sudden hypoxia that lacked MSR activity exhibited a longer recovery time and a reduced ability to survive hypoxic/re-oxygenation stress as they approached senescence. However, when hypoxia was induced slowly, MSR deficient flies recovered significantly quicker throughout their entire adult lifespan. In addition, the wildtype and MSR deficient flies had nearly 100% survival rates throughout their lifespan. Neuroprotective signaling mediated by decreased apoptotic pathway activation, as well as gene reprogramming and metabolic downregulation are possible reasons for why MSR deficient flies have faster recovery time and a higher survival rate upon slow induction of spreading depression. Our data are the first to suggest important roles of MSR and longevity pathways in hypoxia tolerance exhibited by Drosophila.

The Market for Bidis, Smokeless Tobacco, and Cigarettes in India: Evidence From Semi-Urban and Rural Areas in Five States.

Objectives: Compare the brand availability, pricing and presence of illicit products in semi-urban and rural areas in India across product types and states. Methods: In late 2017, 382 unique tobacco products were purchased from localities with populations under 50,000 in the states of Assam, Karnataka, Maharashtra, Rajasthan, and Uttar Pradesh. Brand, printed maximum retail price, price paid, tax, and health warning labels (HWLs) were used to compare the market for bidis, smokeless tobacco (SLT), and cigarettes. Results: Brand availability and pricing of SLT products was similar to cigarettes. Brand availability and pricing of bidis was consistent with having many small producers. Bidis and single serving SLT with spice mixtures were more affordable than cigarettes and SLT sold alone. 2% of SLT and 10% of cigarettes did not feature an India HWL. Conclusion: The elimination of single serving SLT packets and the removal of tax exemptions for small producers, often exploited by bidi producers, could reduce their respective affordability. State differences in illegal and illicit products could indicate a greater need for enforcement in some states.

Machine-assessed tar yield marketing on cigarette packages from two cities in South Korea.

INTRODUCTION: South Koreans continue to smoke at high rates. Tobacco manufacturers have a history of branding cigarettes with misleading descriptors including the introduction of low or ultra-low tar brand variants. The government bans traditional misleading descriptors (low, mild) but requires the presence of machine-assessed tar yields on cigarette packages. Literature suggests the presence of quantitative constituents can be misleading for smokers. We analyzed the machine-assessed tar value branding and the presence of additional branding that highlight tar levels on South Korean cigarette packs. METHODS: In August 2018, we analyzed 178 unique cigarette packs purchased in Seoul and Busan, South Korea using a systematic protocol. Cigarette packs were coded for tar levels and classified as ultra-low, low, mid, and high tar. The presence of misleading descriptors and any additional branding relating to tar or potentially indicating strength were also coded. RESULTS: Machine-assessed tar yields ranged from 0.1 to 8 mg. Cigarettes with a 1 mg machine-assessed tar yield accounted for 38% of all packs purchased. A majority (80%) of packs with tar values <3 mg had additional marketing present on the pack that highlighted tar yields, compared to 45% for packs with tar values 3 mg or greater. Many (85%) of the 1 mg packs and all of the 0.1 and 0.5 mg packs had additional marketing present that referenced tar levels. CONCLUSIONS: These findings suggest that tobacco manufacturers are highlighting and reinforcing the tar yields of lower tar cigarettes by the deliberate use of tar level branding. These actions have the potential to mislead South Korean consumers that some cigarettes are less harmful than others. Strengthening of tobacco packaging regulations to prohibit references to tar yields on packs are needed to further protect consumers.

The Flavor Train: The Nature and Extent of Flavored Cigarettes in Low- and Middle-Income Countries.

INTRODUCTION: Flavors and depictions of flavors are attractive and facilitate initiation and use of tobacco products. However, little is known about the types of flavored products on the market, particularly in low- and middle-income countries. We describe the nature and extent of flavored cigarettes sold in nine low- and middle-income countries from four of the six World Health Organization (WHO) regions. AIMS AND METHODS: We employed a systematic protocol to purchase unique cigarette packs in Bangladesh, Brazil, China, India, Indonesia, Philippines, Russia, Thailand, and Vietnam. Packs were double coded for flavor descriptors and imagery using a standard codebook. Frequencies and crosstabs were conducted to examine the proportion of packs with flavor descriptors and/or flavor imagery, and flavor capsules, by country and by major manufacturer. RESULTS: Overall, 15.4% of the country-unique cigarette packs had flavor descriptors and/or imagery, representing a variety of flavors: menthol or mint (8.2%), "concept" descriptors (3.5%) (eg, Fusion blast), fruit or citrus (3.3%), beverages (1.4%), and others (1.4%). Flavor was mostly communicated using descriptors (15.2%), with flavor imagery being less common (2.2%). Flavor capsules were prevalent (6.2%), with almost half having "concept" descriptors. All major tobacco companies produced cigarettes with flavors, and with capsules. CONCLUSIONS: A range of flavored cigarettes remain on the market in the low- and middle-income countries with the greatest number of smokers. This finding is particularly concerning given the appeal of flavored cigarettes among youth and their potential to circumvent country bans on flavored tobacco products if those laws are not sufficiently comprehensive. Laws addressing flavored tobacco products need to account for flavor capsules and concept descriptors. IMPLICATIONS: While a number of countries have restricted flavors in tobacco products to reduce their appeal and attractiveness, a range of flavors continue to be on the market in low- and middle-income countries, putting people in these countries at increased risk for tobacco use and subsequent tobacco-caused death and disease. The presence of capsules and concept descriptors is particularly concerning given their appeal among youth and their potential to circumvent country bans on flavored tobacco products if those laws are not sufficiently comprehensive.

Global review of tobacco product flavour policies.

OBJECTIVE: We determined which countries prohibit flavoured tobacco products and the details of those restrictions in order to identify possible gaps and opportunities for these and other countries to address. METHODS: We reviewed the grey literature, scanned news articles and consulted with key informants and identified 11 countries and the European Union (EU) that ban or restrict tobacco product flavours. We reviewed policy documents for their stated policy rationale, terms and definitions of flavours, tobacco products covered and restrictions on the use of flavour imagery and terms on tobacco product packaging. RESULTS: Countries with a tobacco product flavour policy include the USA, Canada, Brazil, Ethiopia, Uganda, Senegal, Niger, Mauritania, EU (28 Member States), Moldova, Turkey and Singapore. Most of the countries' policies provide a rationale of dissuading youth from taking up tobacco use. Ten of the 12 policies use the terms 'flavours' (n=6) or 'characterising flavours' (n=4). Six policies cover all products made entirely or partly of tobacco leaf. Countries consistently prohibit flavours associated with fruits, vanilla and spices. The USA and Niger make an exception for menthol, while Mauritania and Uganda do not specify the scope of flavours or ingredients covered by their policies. Eight policies make no specific reference to restricting flavour descriptors on tobacco product packaging. CONCLUSION: Countries looking to implement policies restricting flavours in tobacco products can build on existing comprehensive policies. Future research could examine the implementation and impacts of these policies, to inform other countries interested in acting in this policy domain.