E-cigarette use and other risk factors associated with tobacco smoking susceptibility among Australian adolescents.

OBJECTIVE: To explore risk factors for smoking susceptibility among Australian adolescents to inform prevention policies and programs. METHODS: Cross-sectional survey of students aged 12-17 years who reported having never smoked (n=4,171). Bivariate associations between smoking susceptibility and a range of factors previously linked to youth smoking and smoking susceptibility were initially examined, with significant factors (p<0.05) included in a final multivariable logistic regression model. RESULTS: Eleven percent of adolescents who had never smoked were susceptible to smoking. Smoking susceptibility was independently associated with ever use of e-cigarettes (adjusted odds ratio [AOR]=3.26, 95% confidence interval [CI]: 1.83-5.81), perceiving those who smoke to be more popular (AOR=2.87, 95% CI: 1.62-5.10), having a close friend/s who smokes (AOR=2.66, 95% CI: 1.61-4.40), not perceiving smoking one or two cigarettes occasionally as personally dangerous (AOR=2.56, 95% CI: 1.61-4.09), and having symptoms of depression (AOR=1.59, 95% CI: 1.06-2.38). CONCLUSIONS: The strongest smoking-initiation risk factor identified was ever use of e-cigarettes, with social norms, harm misperceptions around low-rate tobacco use and mental health also linked to smoking susceptibility. IMPLICATIONS FOR PUBLIC HEALTH: Stronger e-cigarette regulations that reduce promotion to and access by youth, as well as interventions addressing the other identified risk factors, may help prevent future smoking uptake among Australian adolescents.

A systematic review of economic evaluations of preoperative smoking cessation for preventing surgical complications.

BACKGROUND: Whilst there is a substantial body of evidence on the costs and benefits of smoking cessation generally, the benefits of routinely providing smoking cessation for surgical populations are less well known. This review summarises the evidence on the cost-effectiveness of preoperative smoking cessation to prevent surgical complications. MATERIALS AND METHODS: A search of the Cochrane, Econlit, EMBASE, Health Technology Assessment, Medline Complete and Scopus databases was conducted from inception until June 23, 2021. Peer-reviewed, English-language articles describing economic evaluations of preoperative smoking cessation interventions to prevent surgical complications were included. Search results were independently screened for potentially eligible studies. Study characteristics, economic evaluation methods and cost-effectiveness results were extracted by one reviewer and details checked by a second. Two authors independently assessed reporting and methodological quality using the Consolidated Health Economic Evaluation Reporting Standards statement (CHEERS) and the Quality of Health Economic Studies Instrument checklist (QHES) respectively. RESULTS: After removing duplicates, twenty full text articles were screened from 1423 database records, resulting in six included economic evaluations. Studies from the United States (n = 4), France (n = 1) and Spain (n = 1) were reported between 2009 and 2020. Four evaluations were conducted from a payer perspective. Two-thirds of evaluations were well-conducted (mean score 83) and well-reported (on average, 86% items reported). All studies concluded preoperative smoking cessation is cost-effective for preventing surgical complications; results ranged from cost saving to €53,131 per quality adjusted life year gained. CONCLUSIONS: Preoperative smoking cessation is cost-effective for preventing surgical complications from a payer or provider perspective when compared to standard care. There is no evidence from outside the United States and Europe to inform healthcare providers, funders and policy-makers in other jurisdictions and more information is needed to clarify the optimal point of implementation to maximise cost-effectiveness of preoperative smoking cessation intervention. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO 2021 CRD42021257740. RESEARCH REGISTRY REGISTRATION NUMBER: reviewregistry1369.

Spectroscopic and Computational Investigation of the Epoxyqueuosine Reductase QueG Reveals Intriguing Similarities with the Reductive Dehalogenase PceA.

Queuosine (Q) is a highly modified nucleoside of transfer RNA that is formed from guanosine triphosphate over the course of eight steps. The final step in this process, involving the conversion of epoxyqueuosine (oQ) to Q, is catalyzed by the enzyme QueG. A recent X-ray crystallographic study revealed that QueG possesses the same cofactors as reductive dehalogenases, including a base-off Co(II)cobalamin (Co(II)Cbl) species and two [4Fe-4S] clusters. While the initial step in the catalytic cycle of QueG likely involves the formation of a reduced Co(I)Cbl species, the mechanisms employed by this enzyme to accomplish the thermodynamically challenging reduction of base-off Co(II)Cbl to Co(I)Cbl and to convert oQ to Q remain unknown. In this study, we have used electron paramagnetic resonance (EPR) and magnetic circular dichroism (MCD) spectroscopies in conjunction with whole-protein quantum mechanics/molecular mechanics (QM/MM) computations to further characterize wild-type QueG and select variants. Our data indicate that the Co(II)Cbl cofactor remains five-coordinate upon substrate binding to QueG. Notably, during a QM/MM optimization of a putative QueG reaction intermediate featuring an alkyl-Co(III) species, the distance between the Co ion and coordinating C atom of oQ increased to >3.3 Å and the C-O bond of the epoxide reformed to regenerate the oQ-bound Co(I)Cbl reactant state of QueG. Thus, our computations indicate that the QueG mechanism likely involves single-electron transfer from the transient Co(I)Cbl species to oQ rather than direct Co-C bond formation, similar to the mechanism that has recently been proposed for the tetrachloroethylene reductive dehalogenase PceA.

Monitoring changes in smoking and quitting behaviours among Australians with and without mental illness over 15 years.

OBJECTIVE: This study examines smoking prevalence and quitting behaviours among Australians with and without mental illness. METHODS: Analysis of data from Australia's triennial National Drug Strategy Household Surveys 2004-2019. The prevalence of regular smokers, never smokers, the quit proportion, cigarette consumption, and use of cessation aids were examined for those with and without mental illness. RESULTS: Among Australians with mental illness, there was a significant decrease in regular smokers and significant increases in never smokers and in the proportion of ever smokers who had quit between 2004 and 2019. Smokers with mental illness were generally as likely to attempt to quit and more likely to use cessation support; however, they were also more likely to report unsuccessful quit attempts. Smokers with mental illness who had quit reported lower levels of psychological distress than those still smoking. CONCLUSION: Since 2004, there have been some encouraging trends in reducing tobacco use among people with mental illness; however, smoking rates remain substantially higher than among those without mental illness. IMPLICATIONS FOR PUBLIC HEALTH: Findings highlight the importance of routinely identifying smokers with mental illness and improving access and adherence to best practice smoking cessation treatment.

A Spectroscopically Validated Computational Investigation of Viable Reaction Intermediates in the Catalytic Cycle of the Reductive Dehalogenase PceA.

Organisms that produce reductive dehalogenases utilize halogenated aromatic and aliphatic substances as terminal electron acceptors in a process termed organohalide respiration. These organisms can couple the reduction of halogenated substances with the production of ATP. Tetrachloroethylene reductive dehalogenase (PceA) catalyzes the reductive dehalogenation of per- and trichloroethylenes (PCE and TCE, respectively) to primarily cis-dichloroethylene (DCE). The enzymatic conversion of PCE to TCE (and subsequently DCE) could potentially proceed via a mechanism in which the first step involves a single-electron transfer, nucleophilic addition followed by chloride elimination or protonation, or direct attack at the halogen. Difficulties with producing adequate quantities of PceA have greatly hampered direct experimental studies of the reaction mechanism. To overcome these challenges, we have generated computational models of resting and TCE-bound PceA using quantum mechanics/molecular mechanics (QM/MM) calculations and validated these models on the basis of experimental data. Notably, the norpseudo-cob(II)alamin [Co(II)Cbl*] cofactor remains five-coordinate upon binding of the substrate to the enzyme, retaining a loosely bound water on the lower face. Thus, the mechanism for the thermodynamically challenging Co(II) → Co(I)Cbl* reduction used by PceA differs fundamentally from that utilized by adenosyltransferases, which generate four-coordinate Co(II)Cbl species to facilitate access to the Co(I) oxidation state. The same QM/MM computational methodology was then applied to viable reaction intermediates in the catalytic cycle of PceA. The intermediate predicted to possess the lowest energy is that resulting from electron transfer from Co(I)Cbl* to the substrate to yield Co(II)Cbl*, a chloride ion, and a vinylic radical.

Chlorocob(II)alamin Formation Which Enhances the Thiol Oxidase Activity of the B12-Trafficking Protein CblC.

CblC is a chaperone that catalyzes removal of the ß-axial ligand of cobalamin (or B12), generating cob(II)alamin in an early step in the cofactor trafficking pathway. Cob(II)alamin is subsequently partitioned to support cellular needs for the synthesis of active cobalamin cofactor derivatives. In addition to the ß-ligand transferase activity, the Caenorhabdiitis elegans CblC (ceCblC) and clinical R161G/Q variants of the human protein exhibit robust thiol oxidase activity, converting glutathione to glutathione disulfide while concomitantly reducing O2 to H2O2. The chemical efficiency of the thiol oxidase side reaction during ceCblC-catalyzed dealkylation of alkylcobalamins is noteworthy in that it effectively scrubs ambient oxygen from the reaction mixture, leading to air stabilization of the highly reactive cob(I)alamin product. In this study, we report that the enhanced thiol oxidase activity of ceCblC requires the presence of KCl, which explains how the wasteful thiol oxidase activity is potentially curtailed inside cells where the chloride concentration is low. We have captured an unusual chlorocob(II)alamin intermediate that is formed in the presence of potassium chloride, a common component of the reaction buffer, and have characterized it by electron paramagnetic resonance, magnetic circular dichroism, and computational analyses. The ability to form a chlorocob(II)alamin intermediate could represent an evolutionary vestige in ceCblC, which is structurally related to bacterial B12-dependent reductive dehalogenases that have been proposed to form halogen cob(II)alamin intermediates in their catalytic cycle.

Mutational and Functional Analyses of Substrate Binding and Catalysis of the Listeria monocytogenes EutT ATP:Co(I)rrinoid Adenosyltransferase.

ATP:Co(I)rrinoid adenosyltransferases (ACATs) catalyze the transfer of the adenosyl moiety from co-substrate ATP to a corrinoid substrate. ACATs are grouped into three families, namely, CobA, PduO, and EutT. The EutT family of enzymes is further divided into two classes, depending on whether they require a divalent metal ion for activity (class I and class II). To date, a structure has not been elucidated for either class of the EutT family of ACATs. In this work, results of bioinformatics analyses revealed several conserved residues between the C-terminus of EutT homologues and the structurally characterized Lactobacillus reuteri PduO (LrPduO) homologue. In LrPduO, these residues are associated with ATP binding and formation of an intersubunit salt bridge. These residues were substituted, and in vivo and in vitro data support the conclusion that the equivalent residues in the metal-free (i.e., class II) Listeria monocytogenes EutT (LmEutT) enzyme affect ATP binding. Results of in vivo and in vitro analyses of LmEutT variants with substitutions at phenylalanine and tryptophan residues revealed that replacement of the phenylalanine residue at position 72 affected access to the substrate-binding site and replacement of a tryptophan residue at position 238 affected binding of the Cbl substrate to the active site. Unlike the PduO family of ACATs, a single phenylalanine residue is not responsible for displacement of the α-ligand. Together, these data suggest that while EutT enzymes share a conserved ATP-binding motif and an intersubunit salt bridge with PduO family ACATs, class II EutT family ACATs utilize an unidentified mechanism for Cbl lower-ligand displacement and reduction that is different from that of PduO and CobA family ACATs.

Hardening or softening? An observational study of changes to the prevalence of hardening indicators in Victoria, Australia, 2001-2016.

BACKGROUND: The hardening hypothesis predicts that as smoking prevalence declines, remaining smokers will be more heavily addicted to nicotine and/or less interested in quitting. We tested this hypothesis in a population exposed to a comprehensive tobacco control programme over a 16-year period. METHODS: Annual cross-sectional surveys randomly sampled adults (aged 26+) in the state of Victoria, Australia, between 2001 and 2016. Until 2010, participants were recruited through random digit dialling to landline telephones; from 2011, sampling frames also included mobile phones. Logistic regressions assessed changes over time in the prevalence of smoking and each hardening indicator; additional models examined interactions by sex, age, education and socioeconomic status. RESULTS: Smoking prevalence declined significantly between 2001 and 2016 (20.1%-13.0%), as did the prevalence of seven hardening indicators: daily smoking, heavy consumption, no quit attempt in the past 5 years or past 12 months, no intention to quit in the next 6 months or next 30 days, and happiness to keep smoking. In addition, the proportion of smokers defined as 'hardcore' decreased from 17.2% to 9.1%. On the whole, hardening indicators decreased to a similar extent among demographic subgroups. CONCLUSIONS: These results are inconsistent with the hardening hypothesis. Rather, they suggest that a comprehensive tobacco control programme that combines provision of cessation support to individual smokers with implementation of population-level interventions to drive all smokers towards quitting, can successfully reduce both smoking prevalence and levels of dependence and desire to keep smoking among the remaining population of smokers.

Reasons for regular vaping and for its discontinuation among smokers and recent ex-smokers: findings from the 2016 ITC Four Country Smoking and Vaping Survey.

AIMS: To examine current and ex-smokers' reasons for continuing or discontinuing regular use of nicotine vaping products (NVPs). DESIGN AND PARTICIPANTS: Cross-sectional study of 2722 current daily/weekly, and 921 ex-daily/weekly, adult vapers who were either current or ex-cigarette smokers when surveyed. SETTING: 2016 ITC Four Country Smoking and Vaping wave 1 (4CV1) surveys conducted in the United States (n = 1159), England (n = 1269), Canada (n = 964) and Australia (n = 251). MEASUREMENTS: Current vapers were asked about the following reasons for regular NVP use: less harmful to others, social acceptance, enjoyment, use in smoke-free areas, affordability and managing smoking behaviour. Ex-vapers were asked about the following reasons for discontinuing regular NVP use: addiction concerns, affordability, negative experiences, perceived social unacceptability, safety concerns, product dissatisfaction, inconvenience, unhelpfulness for quitting, unhelpfulness for managing cravings and not needed for smoking relapse prevention. Possible correlates of NVP use and discontinuation, including smoking status, smoking/vaping frequency, quit duration (ex-smokers only), country, age and type of NVP device used, were examined using multivariate logistic regression models. FINDINGS: For current smokers, the top three reasons for current regular NVP use were: helpful for cutting down smoking (85.6%), less harmful to others (77.9%) and helpful for quitting smoking (77.4%). The top three reasons for discontinuing vaping were: not being satisfying (77.9%), unhelpfulness for cravings (63.2%), and unhelpfulness for quitting smoking (52.4%). For ex-smokers, the top three reasons for current vaping were: enjoyment (90.6%), less harmful to others (90%) and affordability (89.5%); and for discontinuing were: not needed to stay quit (77.3%), not being satisfying (49.5%) and safety concerns (44%). Reported reasons varied by user characteristics, including age, country and NVP device type. CONCLUSIONS: Regular use of nicotine vaping products is mainly motivated by its perceived benefits, especially for reducing or quitting smoking, whereas its discontinuation is motivated by perceived lack of such benefits, with some variation by user characteristics.

When to Pick the Nose: Out-of-Hospital and Emergency Department Intranasal Administration of Medications.

The intranasal route for medication administration is increasingly popular in the emergency department and out-of-hospital setting because such administration is simple and fast, and can be used for patients without intravenous access and in situations in which obtaining an intravenous line is difficult or time intensive (eg, for patients who are seizing or combative). Several small studies (mostly pediatric) have shown midazolam to be effective for procedural sedation, anxiolysis, and seizures. Intranasal fentanyl demonstrates both safety and efficacy for the management of acute pain. The intranasal route appears to be an effective alternative for naloxone in opioid overdose. The literature is less clear on roles for intranasal ketamine and dexmedetomidine.

Overview of extended release tacrolimus in solid organ transplantation.

Tacrolimus (Prograf(©), Astellas Pharma Europe Ltd, Staines, United Kingdom; referred to as tacrolimus-BID) is an immunosuppressive agent to prevent and treat allograft rejection in kidney transplant recipients in combination with mycophenolate mofetil, corticosteroids, with or without basiliximab induction. The drug has also been studied in liver, heart and lung transplant; however, these are currently off-label indications. An extended release tacrolimus formulation (Advagraf(©), Astagraf XL(©)) allows for once-daily dosing, with the potential to improve adherence. Extended release tacrolimus has similar absorption, distribution, metabolism and excretion to tacrolimus-BID. Phase I pharmacokinetic trials comparing extended release tacrolimus and tacrolimus-BID have demonstrated a decreased maximum concentration (Cmax) and delayed time to maximum concentration (tmax) with the extended release formulation; however, AUC0-24 was comparable between formulations. Overall extended release tacrolimus has a very similar safety and efficacy profile to tacrolimus-BID. It is not recommended in the use of liver transplant patient's due to the increased risk of mortality in female recipients. There has been minimal data regarding the use of extended release tacrolimus in heart and lung transplant recipients. With the current data available for all organ groups the extended release tacrolimus should be dosed in a 1:1 fashion, the exception may be the cystic fibrosis population where their initial dose may need to be higher.

New drugs of abuse.

Drug abuse is a common problem and growing concern in the United States, and over the past decade, novel or atypical drugs have emerged and have become increasingly popular. Recognition and treatment of new drugs of abuse pose many challenges for health care providers due to lack of quantitative reporting and routine surveillance, and the difficulty of detection in routine blood and urine analyses. Furthermore, street manufacturers are able to rapidly adapt and develop new synthetic isolates of older drugs as soon as law enforcement agencies render them illegal. In this article, we describe the clinical and adverse effects and purported pharmacology of several new classes of drugs of abuse including synthetic cannabinoids, synthetic cathinones, salvia, desomorphine, and kratom. Because many of these substances can have severe or life-threatening adverse effects, knowledge of general toxicology is key in recognizing acute intoxication and overdose; however, typical toxidromes (e.g., cholinergic, sympathomimetic, opioid, etc.) are not precipitated by many of these agents. Medical management of patients who abuse or overdose on these drugs largely consists of supportive care, although naloxone may be used as an antidote for desomorphine overdose. Symptoms of aggression and psychosis may be treated with sedation (benzodiazepines, propofol) and antipsychotics (haloperidol or atypical agents such as quetiapine or ziprasidone). Other facets of management to consider include treatment for withdrawal or addiction, nutrition support, and potential for transmission of infectious diseases.