Lung cancer diagnosis and mortality beyond 15 years since quit in individuals with a 20+ pack-year history: A systematic review.

Current US lung cancer screening recommendations limit eligibility to adults with a pack-year (PY) history of ≥20 years and the first 15 years since quit (YSQ). The authors conducted a systematic review to better understand lung cancer incidence, risk and mortality among otherwise eligible individuals in this population beyond 15 YSQ. The PubMed and Scopus databases were searched through February 14, 2023, and relevant articles were searched by hand. Included studies examined the relationship between adults with both a ≥20-PY history and ≥15 YSQ and lung cancer diagnosis, mortality, and screening ineligibility. One investigator abstracted data and a second confirmed. Two investigators independently assessed study quality and certainty of evidence (COE) and resolved discordance through consensus. From 2636 titles, 22 studies in 26 articles were included. Three studies provided low COE of elevated lung cancer incidence beyond 15 YSQ, as compared with people who never smoked, and six studies provided moderate COE that the risk of a lung cancer diagnosis after 15 YSQ declines gradually, but with no clinically significant difference just before and after 15 YSQ. Studies examining lung cancer-related disparities suggest that outcomes after 15 YSQ were similar between African American/Black and White participants; increasing YSQ would expand eligibility for African American/Black individuals, but for a significantly larger proportion of White individuals. The authors observed that the risk of lung cancer not only persists beyond 15 YSQ but that, compared with individuals who never smoked, the risk may remain significantly elevated for 2 or 3 decades. Future research of nationally representative samples with consistent reporting across studies is needed, as are better data from which to examine the effects on health disparities across different populations.

A dynamical model of growth and maturation in Drosophila.

The decision to stop growing and mature into an adult is a critical point in development that determines adult body size, impacting multiple aspects of an adult's biology. In many animals, growth cessation is a consequence of hormone release that appears to be tied to the attainment of a particular body size or condition. Nevertheless, the size-sensing mechanism animals use to initiate hormone synthesis is poorly understood. Here, we develop a simple mathematical model of growth cessation in Drosophila melanogaster, which is ostensibly triggered by the attainment of a critical weight (CW) early in the last instar. Attainment of CW is correlated with the synthesis of the steroid hormone ecdysone, which causes a larva to stop growing, pupate, and metamorphose into the adult form. Our model suggests that, contrary to expectation, the size-sensing mechanism that initiates metamorphosis occurs before the larva reaches CW; that is, the critical-weight phenomenon is a downstream consequence of an earlier size-dependent developmental decision, not a decision point itself. Further, this size-sensing mechanism does not require a direct assessment of body size but emerges from the interactions between body size, ecdysone, and nutritional signaling. Because many aspects of our model are evolutionarily conserved among all animals, the model may provide a general framework for understanding how animals commit to maturing from their juvenile to adult form.

2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease" provides recommendations to guide clinicians in the treatment of patients with lower extremity peripheral artery disease across its multiple clinical presentation subsets (ie, asymptomatic, chronic symptomatic, chronic limb-threatening ischemia, and acute limb ischemia). METHODS: A comprehensive literature search was conducted from October 2020 to June 2022, encompassing studies, reviews, and other evidence conducted on human subjects that was published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through May 2023 during the peer review process, were also considered by the writing committee and added to the evidence tables where appropriate. STRUCTURE: Recommendations from the "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with peripheral artery disease have been developed.

Diagnosis and Management of Pancreatic Cysts.

As pancreatic cyst incidence rises, likely due to the ubiquitous increase in cross-sectional imaging, their management presents multiple challenges for both the practitioner and patient. It is critical that all pancreatic cysts are appropriately characterized, as treatment decisions depend on an accurate diagnosis. Diagnostic modalities such as cytology, biopsy, and cyst fluid biomarkers allow for definitive diagnosis of virtually all lesions. Some cysts, such as intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and cystic pancreatic endocrine neoplasms, have malignant potential and must be surveyed. Other cysts, such as serous cystadenomas and pancreatic fluid collections, do not have malignant potential. Surveillance strategies vary widely depending on cyst type and size and while multiple medical societies advocate surveillance, their published surveillance guidelines are heterogenous. Cysts with high-risk stigmata or worrisome features are usually resected, depending on the patient's surgical fitness. In patients unfit for resection, newer endoscopic ablative techniques are advocated. Controversial aspects regarding cyst management include whether surveillance can be stopped, how surveillance should be performed, and the extensive financial burden cyst management places on the health care system. Further study into the natural history of cystic lesions, including definitive determination of the rate of malignant transformation for each cyst type, is essential.

Trapping of Nicotinic Acetylcholine Receptor Ligands Assayed by In Vitro Cellular Studies and In Vivo PET Imaging.

A question relevant to nicotine addiction is how nicotine and other nicotinic receptor membrane-permeant ligands, such as the anti-smoking drug varenicline (Chantix), distribute in brain. Ligands, like varenicline, with high pKa and high affinity for α4ß2-type nicotinic receptors (α4ß2Rs) are trapped in intracellular acidic vesicles containing α4ß2Rs in vitro Nicotine, with lower pKa and α4ß2R affinity, is not trapped. Here, we extend our results by imaging nicotinic PET ligands in vivo in male and female mouse brain and identifying the trapping brain organelle in vitro as Golgi satellites (GSats). Two PET 18F-labeled imaging ligands were chosen: [18F]2-FA85380 (2-FA) with varenicline-like pKa and affinity and [18F]Nifene with nicotine-like pKa and affinity. [18F]2-FA PET-imaging kinetics were very slow consistent with 2-FA trapping in α4ß2R-containing GSats. In contrast, [18F]Nifene kinetics were rapid, consistent with its binding to α4ß2Rs but no trapping. Specific [18F]2-FA and [18F]Nifene signals were eliminated in ß2 subunit knock-out (KO) mice or by acute nicotine (AN) injections demonstrating binding to sites on ß2-containing receptors. Chloroquine (CQ), which dissipates GSat pH gradients, reduced [18F]2-FA distributions while having little effect on [18F]Nifene distributions in vivo consistent with only [18F]2-FA trapping in GSats. These results are further supported by in vitro findings where dissipation of GSat pH gradients blocks 2-FA trapping in GSats without affecting Nifene. By combining in vitro and in vivo imaging, we mapped both the brain-wide and subcellular distributions of weak-base nicotinic receptor ligands. We conclude that ligands, such as varenicline, are trapped in neurons in α4ß2R-containing GSats, which results in very slow release long after nicotine is gone after smoking.SIGNIFICANCE STATEMENT Mechanisms of nicotine addiction remain poorly understood. An earlier study using in vitro methods found that the anti-smoking nicotinic ligand, varenicline (Chantix) was trapped in α4ß2R-containing acidic vesicles. Using a fluorescent-labeled high-affinity nicotinic ligand, this study provided evidence that these intracellular acidic vesicles were α4ß2R-containing Golgi satellites (GSats). In vivo PET imaging with F-18-labeled nicotinic ligands provided additional evidence that differences in PET ligand trapping in acidic vesicles were the cause of differences in PET ligand kinetics and subcellular distributions. These findings combining in vitro and in vivo imaging revealed new mechanistic insights into the kinetics of weak base PET imaging ligands and the subcellular mechanisms underlying nicotine addiction.

2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

AIM: The "2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease" provides an update to and consolidates new evidence since the "2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease" and the corresponding "2014 ACC/AHA/AATS/PCNA/SCAI/STS Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease." METHODS: A comprehensive literature search was conducted from September 2021 to May 2022. Clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human participants were identified that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. STRUCTURE: This guideline provides an evidenced-based and patient-centered approach to management of patients with chronic coronary disease, considering social determinants of health and incorporating the principles of shared decision-making and team-based care. Relevant topics include general approaches to treatment decisions, guideline-directed management and therapy to reduce symptoms and future cardiovascular events, decision-making pertaining to revascularization in patients with chronic coronary disease, recommendations for management in special populations, patient follow-up and monitoring, evidence gaps, and areas in need of future research. Where applicable, and based on availability of cost-effectiveness data, cost-value recommendations are also provided for clinicians. Many recommendations from previously published guidelines have been updated with new evidence, and new recommendations have been created when supported by published data.

The effect of neighborhood socioeconomic disadvantage on smoking status, quit attempts, and receipt of cessation support among adults with cancer: Results from nine ECOG-ACRIN Cancer Research Group trials.

BACKGROUND: Tobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer. METHODS: A modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) was administered to patients enrolled in nine ECOG-ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression. RESULTS: A total of 740 patients completing the C-TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8 years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR], 3.57; 95% CI, 1.69-7.54; p = .0009), and more likely to report being asked about smoking (OR, 4.24; 95% CI, 1.64-10.98; p = .0029), but less likely to report receiving counseling (OR, 0.11; 95% CI, 0.02-0.58; p = .0086) versus those in the least disadvantaged neighborhoods. CONCLUSIONS: Greater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods.

Implementation, enrollment, and engagement in an opt-out telehealth pharmacist-assisted tobacco treatment program for patients seen in oncology outpatient clinics.

OBJECTIVE: To describe the workflow, reach, cost, and self-reported quit rates for an opt-out tobacco treatment program (TTP) for patients seen in 43 oncology outpatient clinics. METHODS: Between May 25, 2021, and December 31, 2022, adult patients (≥18 years) visiting clinics affiliated with the Medical University of South Carolina Hollings Cancer Center were screened for smoking status. Those currently smoking were referred to a telehealth pharmacy-assisted TTP. An attempt was made to contact referred patients by phone. Patients reached were offered free smoking cessation counseling and a 2-week starter kit of nicotine replacement medication. A random sample of 420 patients enrolled in the TTP were selected to participate in a telephone survey to assess smoking status 4 to 12 months after enrollment. RESULTS: During the reference period 35,756 patients were screened and 9.3% were identified as currently smoking. Among the 3319 patients referred to the TTP at least once, 2393 (72.1%) were reached by phone, of whom 426 (12.8%) were ineligible for treatment, 458 (13.8%) opted out of treatment, and 1509 (45.5%) received treatment. More than 90% of TTP enrollees smoked daily, with an average of 13.1 cigarettes per day. Follow-up surveys were completed on 167 of 420 patients, of whom 23.4% to 33.5% reported not smoking; if all nonresponders to the survey are counted as smoking, the range of quit rates is 9.3% to 13.3%. CONCLUSION: The findings demonstrate the feasibility of reaching and delivering smoking cessation treatments to patients from a diverse set of geographically dispersed oncology clinics.

PegIFN alpha-2a reduces relapse in HBeAg-negative patients after nucleo(s)tide analogue cessation: A randomized-controlled trial.

BACKGROUND & AIMS: Nucleo(s)tide analogue (NUC) cessation can lead to HBsAg clearance but also a high rate of virological relapse. However, the effect of pegylated interferon alpha-2a (PegIFN-α-2a) on virological relapse after NUC cessation is unknown. Therefore, this study aimed to evaluate the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse until week 96. METHODS: In this multicentre randomized controlled clinical trial, 180 non-cirrhotic HBeAg-negative chronic hepatitis B patients on continuous NUC therapy for ≥ 2.5 years with HBV DNA levels < 60 IU/mL were randomized to discontinue NUC (n=90) or receive 48 weeks of PegIFN-α-2a treatment (n=90) and followed up till 96 weeks. The primary endpoint was the virological relapse rate until week 96. RESULTS: Intention-to-treat analysis revealed patients in the interferon monotherapy group had significantly lower cumulative virological relapse rates than the NUC cessation group until week 96 (20.8% vs. 53.6%, P < 0.0001). Consistently, a significantly lower proportion of patients in the interferon monotherapy group had virological relapse than those in the NUC cessation group at 48 weeks off treatment (17.8% vs. 36.7%, P = 0.007). The virological relapse rate positively correlated with HBsAg levels in the NUC cessation group. The interferon monotherapy group had a lower cumulative clinical relapse rate (7.8% vs. 20.9%, P = 0.008) and a higher HBsAg loss rate (21.5% vs. 9.0%, P = 0.03) than the NUC cessation group. CONCLUSIONS: Switching from NUC to PegIFN-α-2a treatment for 48 weeks significantly reduces virological relapse rates and achieves higher HBsAg loss rates than NUC treatment cessation alone in HBeAg-negative chronic hepatitis B patients. IMPACT AND IMPLICATIONS: Nucleo(s)tide analogue (NUC) cessation can lead to HBsAg clearance but also a high rate of virological relapse, but an optimised scheme to reduce the virological relapse rate after NUC withdrawal is yet to be reported. This randomized controlled trial investigated the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse until week 96 in HBeAg-negative chronic hepatitis B patients. The interferon monotherapy group had a significantly lower cumulative virological relapse rate (20.8% vs. 53.6%, P < 0.0001) and higher HBsAg loss rate (21.5% vs. 9.0%, P= 0.03) than the NUC cessation group until week 96. This provides an optimized strategy for NUC cessation in HBeAg-negative patients. TRIAL REGISTRATION NUMBER: NCT02594293.

JNJ-73763989 and bersacapavir treatment in nucleos(t)ide analogue-suppressed patients with chronic hepatitis B: REEF-2.

BACKGROUND & AIMS: Functional cure for chronic hepatitis B (CHB) requires finite treatment. Two agents under investigation with the goal of achieving functional cure are the small-interfering RNA JNJ-73763989 (JNJ-3989) and the capsid assembly modulator JNJ-56136379 (JNJ-6379; bersacapavir). METHODS: REEF-2, a phase IIb, double-blind, placebo-controlled, randomized study, enrolled 130 nucleos(t)ide analogue (NA)-suppressed hepatitis B e-antigen (HBeAg)-negative patients with CHB who received JNJ-3989 (200 mg subcutaneously every 4 weeks) + JNJ-6379 (250 mg oral daily) + NA (oral daily; active arm) or placebos for JNJ-3989 and JNJ-6379 +active NA (control arm) for 48 weeks followed by 48 weeks off-treatment follow-up. RESULTS: At follow-up Week 24, no patients achieved the primary endpoint of functional cure (off-treatment hepatitis B surface antigen [HBsAg] seroclearance). No patients achieved functional cure at follow-up Week 48. There was a pronounced on-treatment reduction in mean HBsAg from baseline at Week 48 in the active arm vs. no decline in the control arm (1.89 vs. 0.06 log10 IU/ml; p = 0.001). At follow-up Week 48, reductions from baseline were >1 log10 IU/ml in 81.5% vs. 12.5% of patients in the active and control arms, respectively, and 38/81 (46.9%) patients in the active arm achieved HBsAg <100 IU/ml vs. 6/40 (15.0%) patients in the control arm. Off-treatment HBV DNA relapse and alanine aminotransferase increases were less frequent in the active arm with 7/77 (9.1%) and 11/41 (26.8%) patients in the active and control arms, respectively, restarting NAs during follow-up. CONCLUSIONS: Finite 48-week treatment with JNJ-3989 + JNJ-6379 + NA resulted in fewer and less severe post-treatment HBV DNA increases and alanine aminotransferase flares, and a higher proportion of patients with off-treatment HBV DNA suppression, with or without HBsAg suppression, but did not result in functional cure. IMPACT AND IMPLICATIONS: Achieving a functional cure from chronic hepatitis B (CHB) with finite treatments is a major unmet medical need. The current study assessed the rate of functional cure and clinical outcome after controlled nucleos(t)ide analogue (NA) withdrawal in patients with low levels of HBsAg induced by 48 weeks of treatment with the small-interfering RNA JNJ-3989 and the capsid assembly modulator JNJ-6379 plus NA vs. patients who only received NA treatment. Though functional cure was not achieved by any patient in either arm, the 48-week treatment regimen of JNJ-3989, JNJ-6379, and NA did result in more patients achieving pronounced reductions in HBsAg, with clinically meaningful reductions maintained for up to 48 weeks off all treatments, as well as fewer off-treatment HBV DNA increases and alanine aminotransferase flares. These findings provide valuable insights for future studies investigating potential finite treatment options, while the reported efficacy and safety outcomes may be of interest to healthcare providers making treatment decisions for patients with NA-suppressed HBeAg-negative CHB. GOV IDENTIFIER: NCT04129554.

Calls to action on lung cancer management and research.

Lung cancer, the leading cause of cancer-related deaths globally, remains a pressing health issue despite significant medical advances. The New York Lung Cancer Foundation brought together experts from academia, the pharmaceutical and biotech industries as well as organizational leaders and patient advocates, to thoroughly examine the current state of lung cancer diagnosis, treatment, and research. The goal was to identify areas where our understanding is incomplete and to develop collaborative public health and scientific strategies to generate better patient outcomes, as highlighted in our "Calls to Action." The consortium prioritized 8 different calls to action. These include (1) develop strategies to cure more patients with early-stage lung cancer, (2) investigate carcinogenesis leading to lung cancers in patients without a history of smoking, (3) harness precision medicine for disease interception and prevention, (4) implement solutions to deliver prevention measures and effective therapies to individuals in under-resourced countries, (5) facilitate collaborations with industry to collect and share data and samples, (6) create and maintain open access to big data repositories, (7) develop new immunotherapeutic agents for lung cancer treatment and prevention, and (8) invest in research in both the academic and community settings. These calls to action provide guidance to representatives from academia, the pharmaceutical and biotech industries, organizational and regulatory leaders, and patient advocates to guide ongoing and planned initiatives.

Immediate smoking cessation support during lung cancer screening: long-term outcomes from two randomised controlled trials.

BACKGROUND: Immediate smoking cessation interventions delivered alongside targeted lung health checks (TLHCs) to screen for lung cancer increase self-reported abstinence at 3 months. The impact on longer term, objectively confirmed quit rates remains to be established. METHODS: We followed up participants from two clinical trials in people aged 55-75 years who smoked and took part in a TLHC. These randomised participants in the TLHC by day of attendance to either usual care (UC) (signposting to smoking cessation services) or an offer of immediate smoking cessation support including pharmacotherapy. In the QuLIT1 trial, this was delivered face to face and in QuLIT2, it was delivered remotely. Follow-up was conducted 12 months after the TLHC by telephone interview with subsequent biochemical verification of smoking cessation using exhaled CO. RESULTS: 430 people were enrolled initially (115 in QuLIT1 and 315 in QuLIT2), with 4 deaths before 12 months leaving 426 (62.1±5.27 years old and 48% women) participants for analysis. At 12 months, those randomised to attend on smoking cessation support intervention days had higher quit rates compared with UC adjusted for age, gender, deprivation, and which trial they had been in; self-reported 7-day point prevalence (20.0% vs 12.8%; adjusted OR (AOR)=1.78; 95% CI 1.04 to 2.89) and CO-verified quits (12.1% vs 4.7%; AOR=2.97; 95% CI 1.38 to 6.90). Those in the intervention arm were also more likely to report having made a quit attempt (30.2% vs UC 18.5%; AOR 1.90; 95% CI 1.15 to 3.15). CONCLUSION: Providing immediate smoking cessation support alongside TLHC increases long term, biochemically confirmed smoking abstinence. TRIAL REGISTRATION NUMBER: ISRCTN12455871.

Stopping Nucleos(t)ide Analogues in Chronic Hepatitis B Using HBsAg Thresholds: A Meta-Analysis and Meta-Regression.

BACKGROUND AND AIMS: Recommendations for stopping nucleoside analogue (NA) therapy in hepatitis B e antigen-negative chronic hepatitis B (CHB) are unclear. End-of-treatment quantitative hepatitis B serum antigen (EOTqHBsAg) thresholds <100 IU/mL or <1000 IU/mL have been proposed as stopping criteria, which we assessed by meta-analysis and meta-regression. METHODS: We searched PubMed, EMBASE, and conference abstracts for studies of hepatitis B e antigen-negative CHB NA discontinuation. Extracted studies were analyzed for risk of bias, pooled risk of hepatitis B serum antigen (HBsAg) loss, virological relapse (VR), and biochemical relapse (BR). Significant heterogeneity (I2) was addressed by subgroup analysis and random-effects meta-regression with known important covariates, including EOTqHBsAg thresholds, ethnicity, duration of therapy, and follow-up. RESULTS: We found 24 articles (3732 subjects); 16 had low and 8 had moderate risk of bias. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <100 IU/mL were 41.8%, 33.4%, and 17.3%, respectively, vs 4.6%, 72.1%, and 34.6%, respectively, for EOTqHBsAg ≥100 IU/mL. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <1000 IU/mL were 22.0%, 52.7%, and 15.9%, respectively, vs 3.4%, 63.8%, and 26.4%, respectively, for EOTqHBsAg ≥1000 IU/mL. Multivariable analysis for HBsAg loss showed that ethnicity, follow-up duration, and EOTqHBsAg <100 IU/mL and ≥100 IU/mL explained 85% of the variance in heterogeneity; Asians with EOTqHBsAg <100 IU/mL had 28.2%, while non-Asians with EOTqHBsAg <1000 IU/mL had 38.4% HBsAg loss. Multivariable analysis showed EOTqHBsAg <100 IU/mL and ≥100 IU/mL and other covariates only explained 43% and 63% of the variance in heterogeneity for VR and BR, respectively, suggesting that other factors are also important for relapse. CONCLUSIONS: While EOTqHBsAg thresholds, ethnicity, and follow-up duration strongly predict HBsAg loss, this is not true for VR and BR, hence stopping NA therapy should be considered cautiously.

Does cessation of combustible cigarette and heated tobacco product smoking immediately following a fracture benefit fracture healing? In vivo and in vitro validation.

Combustible cigarette and heated tobacco products (HTPs), the two most frequently used tobacco products, negatively affect bone healing. However, whether smoking cessation following fracture benefits bone healing is unclear. Therefore, this study investigated the effect of smoking cessation immediately after surgery on reduced fracture healing induced by smoking. Smoking combustible cigarettes and heated tobacco products generates cigarette smoking extracts (CSE) (extracts from combustible cigarettes [cCSE] and from HTPs [hCSE], respectively). In vivo, CSEs were injected intraperitoneally into rat models for 3 weeks before femoral midshaft osteotomy and fixation. The rats were then divided into CSE continuation and cessation groups postoperatively. Micro-computed tomography (µCT) and biomechanical analyses were performed 6 weeks postoperatively to assess bone union at the fracture site. In vivo study showed µCT assessment also revealed significantly higher cortical bone mineral density (p = 0.013) and content (p = 0.013), and a higher bone union score (p = 0.046) at the fracture site in the cCSE cessation group than in the cCSE continuation group. Biomechanical assessment revealed that elasticity at the fracture site was significantly higher in the cCSE cessation group than in the cCSE continuation group (p = 0.041). These findings provide that smoking cessation, particularly of combustible cigarette, immediately after a fracture accelerates bone fracture healing and increases mechanical strength at the fracture site.

Evaluation of a hospital-initiated tobacco dependence treatment service: uptake, smoking cessation, readmission and mortality.

BACKGROUND: The National Health Service in England aims to implement tobacco dependency treatment services in all hospitals by 2024. We aimed to assess the uptake of a new service, adapted from the Ottawa Model of Smoking Cessation, and its impact on 6-month quit rates and readmission or death at 1-year follow-up. METHODS: We conducted a pragmatic service evaluation of a tobacco dependency service implemented among 2067 patients who smoked who were admitted to 2 acute hospitals in London, England, over a 12-month period from July 2020. The intervention consisted of the systematic identification of smoking status, automatic referral to tobacco dependence specialists, provision of pharmacotherapy and behavioural support throughout the hospital stay, and telephone support for 6 months after discharge. The outcomes were (i) patient acceptance of the intervention during admission, (ii) quit success at 6 months after discharge, (iii) death, or (iv) readmission up to 1 year following discharge. Multivariable logistic regression was used to estimate the impact of a range of clinical and demographic variables on these outcomes. RESULTS: The majority (79.4%) of patients accepted support at the first assessment. Six months after discharge, 35.1% of successfully contacted patients reported having quit smoking. After adjustment, odds of accepting support were 51-61% higher among patients of all non-White ethnicity groups, relative to White patients, but patients of Mixed, Asian, or Other ethnicities had decreased odds of quit success (adjusted odds ratio (AOR) = 0.32, 95%CI = 0.15-0.66). Decreased odds of accepting support were associated with a diagnosis of cardiovascular disease or diabetes; however, diabetes was associated with increased odds of quit success (AOR = 1.88, 95%CI = 1.17-3.04). Intention to make a quit attempt was associated with a threefold increase in odds of quit success, and 60% lower odds of death, compared to patients who did not intend to quit. A mental health diagnosis was associated with an 84% increase in the odds of dying within 12 months. CONCLUSIONS: The overall quit rates were similar to results from Ottawa models implemented elsewhere, although outcomes varied by site. Outcomes also varied according to patient demographics and diagnoses, suggesting personalised and culturally tailored interventions may be needed to optimise quit success.

Short- and long-term impact of aspirin cessation in older adults: a target trial emulation.

BACKGROUND: The net benefit of aspirin cessation in older adults remains uncertain. This study aimed to use observational data to emulate a randomized trial of aspirin cessation versus continuation in older adults without cardiovascular disease (CVD). METHODS: Post hoc analysis using a target trial emulation framework applied to the immediate post-trial period (2017-2021) of a study of low-dose aspirin initiation in adults aged ≥ 70 years (ASPREE; NCT01038583). Participants from Australia and the USA were included if they were free of CVD at the start of the post-trial intervention period (time zero, T0) and had been taking open-label or randomized aspirin immediately before T0. The two groups in the target trial were as follows: aspirin cessation (participants who were taking randomized aspirin immediately before T0; assumed to have stopped at T0 as instructed) versus aspirin continuation (participants on open-label aspirin at T0 regardless of their randomized treatment; assumed to have continued at T0). The outcomes after T0 were incident CVD, major adverse cardiovascular events (MACE), all-cause mortality, and major bleeding during 3, 6, and 12 months (short-term) and 48 months (long-term) follow-up. Hazard ratios (HRs) comparing aspirin cessation to continuation were estimated from propensity-score (PS) adjusted Cox proportional-hazards regression models. RESULTS: We included 6103 CVD-free participants (cessation: 5427, continuation: 676). Over both short- and long-term follow-up, aspirin cessation versus continuation was not associated with elevated risk of CVD, MACE, and all-cause mortality (HRs, at 3 and 48 months respectively, were 1.23 and 0.73 for CVD, 1.11 and 0.84 for MACE, and 0.23 and 0.79 for all-cause mortality, p > 0.05), but cessation had a reduced risk of incident major bleeding events (HRs at 3 and 48 months, 0.16 and 0.63, p < 0.05). Similar findings were seen for all outcomes at 6 and 12 months, except for a lowered risk of all-cause mortality in the cessation group at 12 months. CONCLUSIONS: Our findings suggest that deprescribing prophylactic aspirin might be safe in healthy older adults with no known CVD.

The effectiveness of a standardized tobacco cessation program on psychophysiological parameters in patients with addiction undergoing long-term rehabilitation: a quasi-experimental pilot study.

BACKGROUND: Although there is a very high comorbidity between tobacco dependence and other addictive disorders, there are only few studies examining the implementation and outcomes of a tobacco cessation program in patients with addictive diseases. Therefore, the aim of this study is to investigate to what extent a standardized tobacco cessation program leads to improvements regarding psychological/physical parameters in patients with addiction undergoing therapy and whether there is a reduction in tobacco consumption. METHODS: The study took place in a therapeutic community specialized in addiction therapy. A total sample of 56 participants were non-randomly assigned to an intervention group (IG; n = 31) and a treatment as usual group (TAUG; n = 25). The IG participated in a 6-week tobacco cessation program, while the TAUG received no additional treatment. Both groups were assessed for changes in primary outcomes (tobacco dependence, smoked cigarettes per day (CPD), and general substance-related craving) and secondary outcomes (heart rate variability (HRV): root mean square of successive differences, self-efficacy, and comorbid psychiatric symptoms) at two measurement time points (pre- and post-treatment/6 weeks). RESULTS: We observed significant improvements in self-efficacy (F(1,53) = 5.86; p < .05; ηp2 = .11) and decreased CPD in the IG (ß = 1.16, ρ < .05), while no significant changes were observed in the TAUG. No significant interaction effects were observed in psychiatric symptoms, general substance-related craving, and HRV. CONCLUSIONS: The results highlight the potential benefit of an additional tobacco cessation program as part of a general addiction treatment. Although no improvements in the physiological domain were observed, there were significant improvements regarding self-efficacy and CPD in the IG compared to the TAUG. Randomized controlled trials on larger samples would be an important next step. TRIAL REGISTRATION: ISRCTN15684371.

SPL16 and SPL23 mediate photoperiodic control of seasonal growth in Populus trees.

Perennial trees in boreal and temperate regions undergo growth cessation and bud set under short photoperiods, which are regulated by phytochrome B (phyB) photoreceptors and PHYTOCHROME INTERACTING FACTOR 8 (PIF8) proteins. However, the direct signaling components downstream of the phyB-PIF8 module remain unclear. We found that short photoperiods suppressed the expression of miR156, while upregulated the expression of miR156-targeted SQUAMOSA-PROMOTER BINDING PROTEIN-LIKE 16 (SPL16) and SPL23 in leaves and shoot apices of Populus trees. Accordingly, either overexpression of MIR156a/c or mutagenesis of SPL16/23 resulted in the attenuation of growth cessation and bud set under short days (SD), whereas overexpression of SPL16 and SPL23 conferred early growth cessation. We further showed that SPL16 and SPL23 directly suppressed FLOWERING LOCUS T2 (FT2) expression while promoted BRANCHED1 (BRC1.1 and BRC1.2) expression. Moreover, we revealed that PIF8.1/8.2, positive regulators of growth cessation, directly bound to promoters of MIR156a and MIR156c and inhibited their expression to modulate downstream pathways. Our results reveal a connection between the phyB-PIF8 module-mediated photoperiod perception and the miR156-SPL16/23-FT2/BRC1 regulatory cascades in SD-induced growth cessation. Our study provides insights into the rewiring of a conserved miR156-SPL module in the regulation of seasonal growth in Populus trees.

The comparison of alendronate and raloxifene after denosumab (CARD) study: A comparative efficacy trial.

Denosumab discontinuation results in accelerated bone remodeling, decreased bone mineral density (BMD), and an increased risk of multiple vertebral fractures. Bisphosphonates are at least partially effective at inhibiting these consequences but there have been no randomized clinical trials assessing the efficacy of alternative antiresorptives. PURPOSE: The aim of this study was to evaluate the comparative efficacy of alendronate and the SERM, raloxifene, in preventing the post-denosumab high-turnover bone loss. METHODS: We conducted an open-label randomized controlled trial in which 51 postmenopausal women at increased risk of fracture were randomized with equal probability to receive 12-months of denosumab 60-mg 6-monthly followed by 12-months of either alendronate 70-mg weekly or raloxifene 60-mg daily. Serum bone remodeling markers were measured at 0,6,12,15,18, and 24 and areal BMD of the distal radius, spine, and hip were measured at 0,12,18 and 24 months. RESULTS: After denosumab discontinuation, serum markers of bone remodeling remained suppressed when followed by alendronate, but gradually increased to baseline when followed by raloxifene. In the denosumab-to-alendronate group, denosumab-induced BMD gains were maintained at all sites whereas in the denosumab-to-raloxifene group, BMD decreased at the spine by 2.0% (95% CI -3.2 to -0.8, P = 0.003) and at the total hip by 1.2% (-2.1 to -0.4%, P = 0.008), but remained stable at the femoral neck and distal radius and above the original baseline at all sites. The decreases in spine and total hip BMD in the denosumab-to-raloxifene group (but not the femoral neck or distal radius) were significant when compared to the denosumab-to-alendronate group. CONCLUSIONS: These results suggest that after one year of denosumab, one year of alendronate is better able to maintain the inhibition of bone remodeling and BMD gains than raloxifene.

One versus 2 years of alendronate following denosumab: the CARD extension.

When denosumab is discontinued, antiresorptive therapy is critical to reduce high-turnover bone loss. The ideal duration of antiresorptive therapy after denosumab is uncertain. This study demonstrates that both 1 and 2 years of alendronate maintained bone density gains achieved with 1 year of denosumab. BACKGROUND: When denosumab is discontinued, antiresorptive therapy is critical to attenuate high-turnover bone loss. The ideal choice and duration of antiresorptive therapy are not yet defined, however. In the Comparison of Alendronate or Raloxifene following Denosumab (CARD) study, we demonstrated that 12 months of alendronate was better able to maintain the bone mineral density (BMD) gains achieved with 12 months of denosumab versus 12 months of raloxifene. In this extension, we wished to determine if 12 months of alendronate would be sufficient in maintaining these denosumab-induced BMD gains. METHODS: In the CARD study, postmenopausal osteoporotic women aged 60-79 at high fracture risk received 12 months of denosumab 60-mg SC every 6 months followed by 12 months of either alendronate 70 mg weekly (N = 26) or raloxifene (N = 25). All subjects in the alendronate arm were then offered participation in a 1-year extension in which they were randomized to continue alendronate for an additional 12 months (N = 10) or to receive calcium and vitamin D alone (N = 8). The primary outcome was change in spine BMD between months 24 and 36. Exploratory endpoints included changes in areal BMD (aBMD) at other anatomic sites as well as changes in serum bone turnover markers. RESULTS: The CARD study demonstrated the effectiveness of 12 months alendronate in preserving denosumab-induced BMD gains. In the extension, aBMD was maintained at the spine, total hip, and femoral neck in both those randomized to an additional year of alendronate and those randomized to calcium/vitamin D alone. We did, however, observe a transient comparative decrease between months 24-30 in the calcium/vitamin D group at the total hip (P = 0.008) and femoral neck (P = 0.040). At the end of 24 months of the CARD study, bone turnover markers serum c-telopeptide (CTX) and procollagen N-propeptide of type I collagen (PINP) were suppressed in both groups and then increased more between months 24-36 in the calcium/vitamin D group than the alendronate group (P = 0.051 for CTX, P = 0.030 for P1NP). Both CTX and PINP remained below the month 0 baseline in both groups (P < 0.05 for all comparisons). CONCLUSIONS: With the limitations of our small sample size, these data suggest that both 1 and 2 years of alendronate effectively maintain BMD gains achieved with 1 year of denosumab and prevented any rebound in bone turnover marker levels above pre-denosumab baseline. This is the first randomized trial to assess minimum duration of bisphosphonate after short-term denosumab and may be helpful to guide clinical care. Similar studies performed after longer durations of denosumab would be helpful to further define optimal management. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT03623633.