Encoding and context-dependent control of reward consumption within the central nucleus of the amygdala.

Dysregulation of the central amygdala is thought to underlie aberrant choice in alcohol use disorder, but the role of central amygdala neural activity during reward choice and consumption is unclear. We recorded central amygdala neurons in male rats as they consumed alcohol or sucrose. We observed activity changes at the time of reward approach, as well as lick-entrained activity during ongoing consumption of both rewards. In choice scenarios where rats could drink sucrose, alcohol, or quinine-adulterated alcohol with or without central amygdala optogenetic stimulation, rats drank more of stimulation-paired options when the two bottles contained identical options. Given a choice among different options, central amygdala stimulation usually enhanced consumption of stimulation-paired rewards. However, optogenetic stimulation during consumption of the less-preferred option, alcohol, was unable to enhance alcohol intake while sucrose was available. These findings indicate that the central amygdala contributes to refining motivated pursuit toward the preferred available option.

What can the common fruit fly teach us about stroke?: lessons learned from the hypoxic tolerant Drosophila melanogaster.

Stroke, resulting in hypoxia and glucose deprivation, is a leading cause of death and disability worldwide. Presently, there are no treatments that reduce neuronal damage and preserve function aside from tissue plasminogen activator administration and rehabilitation therapy. Interestingly, Drosophila melanogaster, the common fruit fly, demonstrates robust hypoxic tolerance, characterized by minimal effects on survival and motor function following systemic hypoxia. Due to its organized brain, conserved neurotransmitter systems, and genetic similarity to humans and other mammals, uncovering the mechanisms of Drosophila's tolerance could be a promising approach for the development of new therapeutics. Interestingly, a key facet of hypoxic tolerance in Drosophila is organism-wide metabolic suppression, a response involving multiple genes and pathways. Specifically, studies have demonstrated that pathways associated with oxidative stress, insulin, hypoxia-inducible factors, NFκB, Wnt, Hippo, and Notch, all potentially contribute to Drosophila hypoxic tolerance. While manipulating the oxidative stress response and insulin signaling pathway has similar outcomes in Drosophila hypoxia and the mammalian middle cerebral artery occlusion (MCAO) model of ischemia, effects of Notch pathway manipulation differ between Drosophila and mammals. Additional research is warranted to further explore how other pathways implicated in hypoxic tolerance in Drosophila, such as NFκB, and Hippo, may be utilized to benefit mammalian response to ischemia. Together, these studies demonstrate that exploration of the hypoxic response in Drosophila may lead to new avenues of research for stroke treatment in humans.

Morpho-molecular and environmental evidence of the ocurrence of Karenia longicanalis (Dinophyceae: Kareniaceae) as a bloom former in the Eastern Pacific Ocean.

Karenia longicanalis, an athecate dinoflagellate, was first described during a bloom in Victoria Harbour (Hong Kong, China). This study confirms the presence of K. longicanalis as a bloom former in the eastern Pacific Ocean. Specimens were collected in March 2019 at three sampling stations in Acapulco Bay, Mexico. Water temperature, salinity, dissolved oxygen, and pH were measured in situ at the time of sample collection. Cell morphology was examined by optical and scanning electron microscopy. A molecular analysis based on the amplification of the large subunit (LSU) rDNA region revealed that the LSU sequences formed a monophyletic group with other GenBank sequences belonging to K. longicanalis. The resulting phylogeny demonstrates that Karenia is closely related to Asterodinium, Gertia, and Shimiella. The morphology of the specimens was consistent with previous descriptions.

Cullin-RING ligases employ geometrically optimized catalytic partners for substrate targeting.

Cullin-RING ligases (CRLs) ubiquitylate specific substrates selected from other cellular proteins. Substrate discrimination and ubiquitin transferase activity were thought to be strictly separated. Substrates are recognized by substrate receptors, such as Fbox or BCbox proteins. Meanwhile, CRLs employ assorted ubiquitin-carrying enzymes (UCEs, which are a collection of E2 and ARIH-family E3s) specialized for either initial substrate ubiquitylation (priming) or forging poly-ubiquitin chains. We discovered specific human CRL-UCE pairings governing substrate priming. The results reveal pairing of CUL2-based CRLs and UBE2R-family UCEs in cells, essential for efficient PROTAC-induced neo-substrate degradation. Despite UBE2R2's intrinsic programming to catalyze poly-ubiquitylation, CUL2 employs this UCE for geometrically precise PROTAC-dependent ubiquitylation of a neo-substrate and for rapid priming of substrates recruited to diverse receptors. Cryo-EM structures illuminate how CUL2-based CRLs engage UBE2R2 to activate substrate ubiquitylation. Thus, pairing with a specific UCE overcomes E2 catalytic limitations to drive substrate ubiquitylation and targeted protein degradation.

The Impact of Menthol Cigarette Bans: A Systematic Review and Meta-Analysis.

INTRODUCTION: This review investigates the impacts of banning the sale of menthol cigarettes at stores. METHODS: A systematic search of studies published in English up to November 2022 was conducted. The following databases were searched: PubMed/Medline, CINAHL, PsycINFO, Web of Science, and Embase, as well as a non-indexed journal. Studies evaluating either the impact of real-world or hypothesized menthol cigarette bans were included. Primary outcomes include tobacco use behaviors. Secondary outcomes include cigarette sales, retailer compliance, and the tobacco industry's response to a menthol ban. Data on tobacco use behavior after a menthol ban were pooled using random-effects models. Two pairs of reviewers independently extracted data and assessed study quality. RESULTS: Of the 964 articles that were identified during the initial search, 78 were included in the review and 16 were included in the meta-analysis. Cessation rates among menthol cigarette smokers were high after a menthol ban. Pooled results show that 24% (95% confidence interval [95% CI]: 20%, 28%) of menthol cigarette smokers quit smoking after a menthol ban, 50% (95% CI: 31%, 68%) switched to non-menthol cigarettes, 12% (95% CI: 3%, 20%) switched to other flavored tobacco products, and 24% (95% CI: 17%, 31%) continued smoking menthol cigarettes. Hypothesized quitting and switching rates were fairly close to real-world rates. Studies found the tobacco industry attempts to undermine menthol bans. National menthol bans appear more effective than local or state menthol bans. CONCLUSIONS: Menthol cigarette bans promote smoking cessation suggesting their potential to improve public health. IMPLICATIONS: Findings from this review suggest that menthol cigarette bans promote smoking cessation among menthol cigarette smokers and have the potential to improve public health.

Highly active fish in low oxygen environments: vertical movements and behavioural responses of bigeye and yellowfin tunas to oxygen minimum zones in the eastern Pacific Ocean.

Oxygen minimum zones in the open ocean are predicted to significantly increase in volume over the coming decades as a result of anthropogenic climatic warming. The resulting reduction in dissolved oxygen (DO) in the pelagic realm is likely to have detrimental impacts on water-breathing organisms, particularly those with higher metabolic rates, such as billfish, tunas, and sharks. However, little is known about how free-living fish respond to low DO environments, and therefore, the effect increasing OMZs will have cannot be predicted reliably. Here, we compare the responses of two active predators (bigeye tuna Thunnus obesus and yellowfin tuna Thunnus albacares) to DO at depth throughout the eastern Pacific Ocean. Using time-series data from 267 tagged tunas (59,910 days) and 3D maps of modelled DO, we find that yellowfin tuna respond to low DO at depth by spending more time in shallower, more oxygenated waters. By contrast, bigeye tuna, which forage at deeper depths well below the thermocline, show fewer changes in their use of the water column. However, we find that bigeye tuna increased the frequency of brief upward vertical excursions they performed by four times when DO at depth was lower, but with no concomitant significant difference in temperature, suggesting that this behaviour is driven in part by the need to re-oxygenate following time spent in hypoxic waters. These findings suggest that increasing OMZs will impact the behaviour of these commercially important species, and it is therefore likely that other water-breathing predators with higher metabolic rates will face similar pressures. A more comprehensive understanding of the effect of shoaling OMZs on pelagic fish vertical habitat use, which may increase their vulnerability to surface fisheries, will be important to obtain if these effects are to be mitigated by future management actions. Supplementary Information: The online version contains supplementary material available at 10.1007/s00227-023-04366-2.

State and rate-of-change encoding in parallel mesoaccumbal dopamine pathways.

The nervous system uses fast- and slow-adapting sensory detectors in parallel to enable neuronal representations of external states and their temporal dynamics. It is unknown whether this dichotomy also applies to internal representations that have no direct correlation in the physical world. Here we find that two distinct dopamine (DA) neuron subtypes encode either a state or its rate-of-change. In mice performing a reward-seeking task, we found that the animal's behavioral state and rate-of-change were encoded by the sustained activity of DA neurons in medial ventral tegmental area (VTA) DA neurons and transient activity in lateral VTA DA neurons, respectively. The neural activity patterns of VTA DA cell bodies matched DA release patterns within anatomically defined mesoaccumbal pathways. Based on these results, we propose a model in which the DA system uses two parallel lines for proportional-differential encoding of a state variable and its temporal dynamics.

Concussion-Related Decision-Making by Certified Athletic Trainers: Implications for Concussion Prevention and Care.

Concussions are a common sport-related injury that require appropriate initial care. Athletic trainers, often a primary source of healthcare for student-athletes, are key individuals involved in initial concussion diagnostic and management decisions. Challenges exist within the athletic environment that may hinder the consistency, efficacy, and/or effectiveness of concussion-related decision-making by athletic trainers, thereby impacting secondary concussion prevention and patient health. The purpose of this study was to identify factors that impact the intentions of athletic trainers to make appropriate concussion-related decisions under various circumstances. Overall, 1029 participants completed a survey examining educational precursors (quantity and quality of healthcare communication educational focus), demographic precursors (age, gender, educational degree, and employment setting), theory-based mediators (attitudes, perceived norms, and personal agency), and external mediators (knowledge, salience, and communication/collaboration practices) on appropriate concussion-related decision-making intentions. Data were analyzed using a two-step structural equation modeling approach. Quality of healthcare communication educational focus indirectly impacted appropriate concussion-related decision-making intentions via perceived behavioral control and communication/collaboration practices. Additionally, several factors impacted intentions to make appropriate concussion-related decisions directly including employment setting, self-efficacy, and general attitudes towards decision-making and concussions. Concussion prevention is aided by the initial and appropriate action taken by a healthcare professional to reduce immediate consequences; however, this action may be influenced by stakeholder relationships. These influential factors of decision-making may place athletes at further injury risk and negatively impact overall athlete health. As such, a sound theoretical framework incorporating the complexity of factors that may influence decision-making is needed.

The Use of Social Media to Express and Manage Medical Uncertainty in Dyskeratosis Congenita: Content Analysis.

BACKGROUND: Social media has the potential to provide social support for rare disease communities; however, little is known about the use of social media for the expression of medical uncertainty, a common feature of rare diseases. OBJECTIVE: This study aims to evaluate the expression of medical uncertainty on social media in the context of dyskeratosis congenita, a rare cancer-prone inherited bone marrow failure and telomere biology disorder (TBD). METHODS: We performed a content analysis of uncertainty-related posts on Facebook and Twitter managed by Team Telomere, a patient advocacy group for this rare disease. We assessed the frequency of uncertainty-related posts, uncertainty sources, issues, and management and associations between uncertainty and social support. RESULTS: Across all TBD social media platforms, 45.98% (1269/2760) of posts were uncertainty related. Uncertainty-related posts authored by Team Telomere on Twitter focused on scientific (306/434, 70.5%) or personal (230/434, 53%) issues and reflected uncertainty arising from probability, ambiguity, or complexity. Uncertainty-related posts in conversations among patients and caregivers in the Facebook community group focused on scientific (429/511, 84%), personal (157/511, 30.7%), and practical (114/511, 22.3%) issues, many of which were related to prognostic unknowns. Both platforms suggested uncertainty management strategies that focused on information sharing and community building. Posts reflecting response-focused uncertainty management strategies (eg, emotional regulation) were more frequent on Twitter compared with the Facebook community group (χ21=3.9; P=.05), whereas posts reflecting uncertainty-focused management strategies (eg, ordering information) were more frequent in the Facebook community group compared with Twitter (χ21=55.1; P<.001). In the Facebook community group, only 36% (184/511) of members created posts during the study period, and those who created posts did so with a low frequency (median 3, IQR 1-7 posts). Analysis of post creator characteristics suggested that most users of TBD social media are White, female, and parents of patients with dyskeratosis congenita. CONCLUSIONS: Although uncertainty is a pervasive and multifactorial issue in TBDs, our findings suggest that the discussion of medical uncertainty on TBD social media is largely limited to brief exchanges about scientific, personal, or practical issues rather than ongoing supportive conversation. The nature of uncertainty-related conversations also varied by user group: patients and caregivers used social media primarily to discuss scientific uncertainties (eg, regarding prognosis), form social connections, or exchange advice on accessing and organizing medical care, whereas Team Telomere used social media to express scientific and personal issues of uncertainty and to address the emotional impact of uncertainty. The higher involvement of female parents on TBD social media suggests a potentially greater burden of uncertainty management among mothers compared with other groups. Further research is needed to understand the dynamics of social media engagement to manage medical uncertainty in the TBD community.

Exposure to Sedation and Analgesia Medications: Short-term Cognitive Outcomes in Pediatric Critical Care Survivors With Acquired Brain Injury.

Background/Objective: Pediatric intensive care unit (PICU) survivors risk significant cognitive morbidity, particularly those with acquired brain injury (ABI) diagnoses. Studies show sedative and analgesic medication may potentiate neurologic injury, but few studies evaluate impact on survivor outcomes. This study aimed to evaluate whether exposures to analgesic and sedative medications are associated with worse neurocognitive outcome. Methods: A retrospective cohort study was conducted of 91 patients aged 8 to 18 years, undergoing clinical neurocognitive evaluation approximately 1 to 3 months after PICU discharge. Electronic health data was queried for sedative and analgesic medication exposures, including opioids, benzodiazepines, propofol, ketamine, and dexmedetomidine. Doses were converted to class equivalents, evaluated by any exposure and cumulative dose exposure per patient weight. Cognitive outcome was derived from 8 objective cognitive assessments with an emphasis on executive function skills using Principal Components Analysis. Then, linear regression was used to control for baseline cognitive function estimates to calculate a standardized residualized neurocognitive index (rNCI) z-score. Multivariable linear regression evaluated the association between rNCI and medication exposure controlling for covariates. Significance was defined as P < .05. Results: Most (n = 80; 88%) patients received 1 or more study medications. Any exposure and higher cumulative doses of benzodiazepine and ketamine were significantly associated with worse rNCI in bivariate analyses. When controlling for Medicaid, preadmission comorbid conditions, length of stay, delirium, and receipt of other medication classes, receipt of benzodiazepine was associated with significantly worse rNCI (ß-coefficient = -0.48, 95% confidence interval = -0.88, -0.08). Conclusions: Exposure to benzodiazepines was independently associated with worse acute phase cognitive outcome using objective assessments focused on executive function skills when controlling for demographic and illness characteristics. Clinician decisions regarding medication regimens in the PICU may serve as a modifiable factor to improve outcomes. Additional inquiry into associations with long-term cognitive outcome and optimal medication regimens is needed.

The power of written word: Reflection reduces errors of omission.

BACKGROUND: Medical trainees are expected to perform complex tasks while experiencing interruptions, which increases susceptibility to errors of omission. In our study, we examine whether documentation of clinical encounters increases reflective thinking and reduces errors of omission among novice learners in a simulated setting. METHODS: In 2021, 56 senior medical students participated in a simulated paging curriculum involving urgent inpatient cross-cover scenarios (sepsis and atrial fibrillation). Students responded to pages from standardized registered nurses (SRNs) via telephone, gathered history, and discussed clinical decision-making. Following the phone encounter, students documented a brief note (documentation encounter). A 'phone' score (number of checklist items completed in the phone encounter) and a 'combined' score (number of checklist items completed in the phone and documentation encounters) were calculated. Data were analyzed for differences between the phone scores (control) and combined scores using T-tests and McNemar test of symmetry. FINDINGS: Fifty-four students (96%) participated. Combined scores were higher than phone scores for sepsis (72.8 ± 11.3% vs. 67.9 ± 11.9%, p < 0.001) and atrial fibrillation (74.0 ± 10.1% vs. 67.6 ± 10.0%, p < 0.001) cases. Important items, such as ordering blood cultures for sepsis (p = 0.023) and placing the patient on telemetry for atrial fibrillation (p = 0.013), were more likely to be present when a note was documented. DISCUSSION: This study suggests that documentation provides a mechanism for learners to reflect, which could increase important diagnostic and therapeutic interventions. CONCLUSION: Documentation by novice medical learners may improve patient care by allowing for reflection and reducing errors of omission.

Spatial Clustering of Tobacco Retailers Near US Public Schools.

INTRODUCTION: Previous studies have found that tobacco retailers cluster near schools. However, all retail outlets may be located near each other and near schools due to existing infrastructure and zoning policies. We assessed whether tobacco retailers cluster near schools in the United States more than expected when accounting for existing retail locations. AIMS AND METHODS: We identified 322 056 probable tobacco retailers, 95 110 public schools, and more than 3.8 million businesses comparable to tobacco retailers in land use and business type. We created 500 simulated tobacco retailer datasets by randomly selecting from the larger list of businesses. For each simulated dataset, we calculated the distance from schools to the nearest tobacco retailer (proximity) and the count of tobacco retailers within 800 m of schools (density). Observed proximity and density values were compared to 95% coverage intervals from the 500 simulations. We stratified analyses by urbanicity, percentage of students in the free and reduced-priced lunch program (FRLP), and percentage of Hispanic/Latino, non-Hispanic Black, and non-Hispanic white students. RESULTS: Tobacco retailers were closer to schools in rural areas, cities, and towns and more dense around schools in rural areas, cities, and suburbs compared to random locations in potential retail space. Schools with more students receiving FRLP had higher density than expected while schools with fewer students receiving FRLP had lower density than expected. Within rural areas, clustering did not vary across sociodemographic groups. Within non-rural areas, there were inequities in clustering by racial, ethnic, and socioeconomic school composition. CONCLUSIONS: Tobacco retailers cluster near schools after accounting for existing business patterns. There are inequities in clustering by sociodemographic school composition. IMPLICATIONS: This study provides compelling evidence that tobacco retailers cluster near US public schools and that there are racial, ethnic, and socioeconomic inequities in clustering, even when accounting for overall retail location patterns. Given that public schools tend to reflect neighborhood demographics, policies to limit tobacco retailers near schools may reduce both school-based and neighborhood-based inequities.

Nucleus accumbens and dorsal medial striatal dopamine and neural activity are essential for action sequence performance.

Separable striatal circuits have unique functions in Pavlovian and instrumental behaviors but how these roles relate to performance of sequences of actions with and without associated cues are less clear. Here, we tested whether dopamine transmission and neural activity more generally in three striatal subdomains are necessary for performance of an action chain leading to reward delivery. Male and female Long-Evans rats were trained to press a series of three spatially distinct levers to receive reward. We assessed the contribution of neural activity or dopamine transmission within each striatal subdomain when progression through the action sequence was explicitly cued and in the absence of cues. Behavior in both task variations was substantially impacted following microinfusion of the dopamine antagonist, flupenthixol, into nucleus accumbens core (NAc) or dorsomedial striatum (DMS), with impairments in sequence timing and numbers of rewards earned after NAc flupenthixol. In contrast, after pharmacological inactivation to suppress overall activity, there was minimal impact on total rewards earned. Instead, inactivation of both NAc and DMS impaired sequence timing and led to sequence errors in the uncued, but not cued task. There was no impact of dopamine antagonism or reversible inactivation of dorsolateral striatum on either cued or uncued action sequence completion. These results highlight an essential contribution of NAc and DMS dopamine systems in motivational and performance aspects of chains of actions, whether cued or internally generated, as well as the impact of intact NAc and DMS function for correct sequence performance.

Online Purchase Attempts of Flavored E-Cigarettes to Minors in California Before and After Senate Bill 793.

This survey study assesses whether the online purchase attempt completion rate of e-cigarettes changed after passage of California Senate Bill 793.

Contexts facilitate dynamic value encoding in the mesolimbic dopamine system.

Adaptive behavior in a dynamic environment often requires rapid revaluation of stimuli that deviates from well-learned associations. The divergence between stable value-encoding and appropriate behavioral output remains a critical test to theories of dopamine's function in learning, motivation, and motor control. Yet how dopamine neurons are involved in the revaluation of cues when the world changes to alter our behavior remains unclear. Here we make use of pharmacology, in vivo electrophysiology, fiber photometry, and optogenetics to resolve the contributions of the mesolimbic dopamine system to the dynamic reorganization of reward-seeking. Male and female rats were trained to discriminate when a conditioned stimulus would be followed by sucrose reward by exploiting the prior, non-overlapping presentation of a separate discrete cue - an occasion setter. Only when the occasion setter's presentation preceded the conditioned stimulus did the conditioned stimulus predict sucrose delivery. As a result, in this task we were able to dissociate the average value of the conditioned stimulus from its immediate expected value on a trial-to-trial basis. Both the activity of ventral tegmental area dopamine neurons and dopamine signaling in the nucleus accumbens were essential for rats to successfully update behavioral responding in response to the occasion setter. Moreover, dopamine release in the nucleus accumbens following the conditioned stimulus only occurred when the occasion setter indicated it would predict reward. Downstream of dopamine release, we found that single neurons in the nucleus accumbens dynamically tracked the value of the conditioned stimulus. Together these results reveal a novel mechanism within the mesolimbic dopamine system for the rapid revaluation of motivation.

Too big not to fail: Different paths lead to senescence of enlarged cells.

In this issue of Molecular Cell, Crozier et al.,1 Foy et al.,2 Manohar et al.,3 and Wilson et al.4 show how excessive cell growth caused by a temporary G1 arrest leads to permanent cell cycle exit at different stages of the cell cycle.

Patient-to-nurse ratios: Balancing quality, nurse turnover, and cost.

We consider the problem of setting appropriate patient-to-nurse ratios in a hospital, an issue that is both complex and widely debated. There has been only limited effort to take advantage of the extensive empirical results from the medical literature to help construct analytical decision models for developing upper limits on patient-to-nurse ratios that are more patient- and nurse-oriented. For example, empirical studies have shown that each additional patient assigned per nurse in a hospital is associated with increases in mortality rates, length-of-stay, and nurse burnout. Failure to consider these effects leads to disregarded potential cost savings resulting from providing higher quality of care and fewer nurse turnovers. Thus, we present a nurse staffing model that incorporates patient length-of-stay, nurse turnover, and costs related to patient-to-nurse ratios. We present results based on data collected from three participating hospitals, the American Hospital Association (AHA), and the California Office of Statewide Health Planning and Development (OSHPD). By incorporating patient and nurse outcomes, we show that lower patient-to-nurse ratios can potentially provide hospitals with financial benefits in addition to improving the quality of care. Furthermore, our results show that higher policy patient-to-nurse ratio upper limits may not be as harmful in smaller hospitals, but lower policy patient-to-nurse ratios may be necessary for larger hospitals. These results suggest that a "one ratio fits all" patient-to-nurse ratio is not optimal. A preferable policy would be to allow the ratio to be hospital-dependent.

Elimination of Emergency Department Ambulance Divert during the COVID-19 Pandemic Was Not Associated with an Increase in the Average Number of Ambulance Arrivals per Day.

INTRODUCTION: During the COVID-19 pandemic, ambulance divert in our EMS system reached critical levels. We hypothesized that eliminating ambulance divert would not be associated with an increase in the average number of daily ambulance arrivals. Our study objective was to quantify the EMS and emergency department (ED) effects of eliminating ambulance divert during the COVID-19 pandemic. METHODS: Regional hospital divert data were obtained for the 10-county Twin Cities metro from MNTrac, a state-supported online system designed to allow hospitals to indicate their divert status to EMS. ED metrics are reported for a single Level I trauma center and were obtained by a deidentified data pull from our electronic medical record covering the 12 months prior to the elimination of divert (2021) and the 12 months after divert elimination (2022). The decision to eliminate divert occurred in November 2021, based on data available through October, with an implementation date of January 2022. The primary study outcome was to quantify the effect of the elimination of divert on the number of ambulances arriving per day at the study hospital. RESULTS: Regional utilization of ambulance divert increased steadily by 859% from January to October 2021 when 355 individual divert events occurred, totaling 809 h (34 days). There was no significant difference in the number of ambulances that arrived to the study hospital in 2021 (30,774) vs 2022 (30,421) p = 0.15. As compared to 2021, in 2022 there was no significant increase in mean ambulance arrivals per day (84/day vs 83/day, p = 0.08), time to room Emergency Severity Index level 2 (ESI) patients (28 min vs 28 min, p = 0.90), or time to obtain emergent head CT in acute "code stroke" patients (12 min vs 12 min, p = 0.15). Ambulance turnaround interval in the ED did not appreciably increase (16 min vs 17 min, p = 0.15). CONCLUSION: Elimination of ambulance divert was not associated with increases in the number of mean daily ambulance arrivals or EMS turnaround intervals, delays in ESI 2 patients being placed in beds, or prolonged time to head CT in stroke code patients.

Effects of Modified Risk Tobacco Product Claims on Consumer Responses.

BACKGROUND: US tobacco manufacturers can seek authorization from FDA to market products using modified risk tobacco product (MRTP) claims. To inform regulatory decisions, we examined the impact of MRTP claim specificity and content, including whether the claims produced halo effects (i.e., inferring health benefits beyond what is stated). METHODS: Participants were 3,161 US adult cigarette smokers. Using a 2 (general vs. specific) × 2 (risk vs. exposure) plus independent control design, we randomized participants to view one message from these conditions: general risk claim (e.g., "tobacco-related diseases"), general exposure claim (e.g., "harmful chemicals"), specific risk claim (e.g., "lung cancer"), specific exposure claim (e.g., "arsenic"), or control. Claims described benefits of completely switching from cigarettes to the heated tobacco product IQOS. RESULTS: MRTP claims of any sort elicited higher willingness to try IQOS relative to control (d=0.09, p=0.043). Claims also elicited lower perceived risk of disease and exposure to harmful chemicals for completely switching from cigarettes to IQOS (d=-0.32 and-0.31) and partially switching (d=-0.25 and=-0.26; all p<0.05). Relative to specific MRTP claims, general MRTP claims led to lower perceived risk and exposure for complete switching (d=-0.13 and d=-0.16) and partial switching (d=-0.14 and d=-0.12; all p<0.05). Risk and exposure MRTP claims had similar effects (all p>0.05). DISCUSSION: MRTP claims led to lower perceived risk and exposure, and higher willingness to try IQOS. General claims elicited larger effects than specific claims. MRTP claims also promoted unintended halo effects (e.g., lower perceived risk of disease and chemical exposure for partial switching). IMPLICATIONS: We found evidence that MRTP claims promoted health halo effects. In light of these findings, FDA should require research on halo effects prior to authorization. Further, if an MRTP claim is authorized, FDA should require tobacco manufacturers to conduct post-market surveillance of how the claim affects consumer understanding, including partial switching perceived risk and exposure beliefs, as well as monitoring of dual-use behaviors.

Regulation with cell size ensures mitochondrial DNA homeostasis during cell growth.

To maintain stable DNA concentrations, proliferating cells need to coordinate DNA replication with cell growth. For nuclear DNA, eukaryotic cells achieve this by coupling DNA replication to cell-cycle progression, ensuring that DNA is doubled exactly once per cell cycle. By contrast, mitochondrial DNA replication is typically not strictly coupled to the cell cycle, leaving the open question of how cells maintain the correct amount of mitochondrial DNA during cell growth. Here, we show that in budding yeast, mitochondrial DNA copy number increases with cell volume, both in asynchronously cycling populations and during G1 arrest. Our findings suggest that cell-volume-dependent mitochondrial DNA maintenance is achieved through nuclear-encoded limiting factors, including the mitochondrial DNA polymerase Mip1 and the packaging factor Abf2, whose amount increases in proportion to cell volume. By directly linking mitochondrial DNA maintenance to nuclear protein synthesis and thus cell growth, constant mitochondrial DNA concentrations can be robustly maintained without a need for cell-cycle-dependent regulation.