Bone and joint infections due to melioidosis; diagnostic and management strategies to optimise outcomes.

BACKGROUND: Melioidosis, a life-threatening infection caused by the gram negative bacterium Burkholderia pseudomallei, can involve almost any organ. Bone and joint infections (BJI) are a recognised, but incompletely defined, manifestation of melioidosis that are associated with significant morbidity and mortality in resource-limited settings. METHODOLOGY/PRINCIPAL FINDINGS: We identified all individuals with BJI due to B. pseudomallei managed at Cairns Hospital in tropical Australia between January 1998 and June 2023. The patients' demographics, their clinical findings and their treatment were correlated with their subsequent course. Of 477 culture-confirmed cases of melioidosis managed at the hospital during the study period, 39 (8%) had confirmed BJI; predisposing risk factors for melioidosis were present in 37/39 (95%). However, in multivariable analysis only diabetes mellitus was independently associated with the presence of BJI (odds ratio (95% confidence interval): 4.04 (1.81-9.00), p = 0.001). BJI was frequently only one component of multi-organ involvement: 29/39 (74%) had infection involving other organs and bacteraemia was present in 31/39 (79%). Of the 39 individuals with BJI, 14 (36%) had osteomyelitis, 8 (20%) had septic arthritis and 17 (44%) had both osteomyelitis and septic arthritis; in 32/39 (83%) the lower limb was involved. Surgery was performed in 30/39 (77%). Readmission after the initial hospitalisation was necessary in 11/39 (28%), 5/39 (13%) had disease recrudescence and 3/39 (8%) had relapse; 4/39 (10%) developed pathological fractures. ICU admission was necessary in 11/39 (28%) but all 11 of these patients survived. Only 1/39 (3%) died, 138 days after admission, due to his significant underlying comorbidity. CONCLUSIONS: The case-fatality rate from melioidosis BJI in Australia's well-resourced health system is very low. However, recrudescence, relapse and orthopaedic complications are relatively common and emphasise the importance of collaborative multidisciplinary care that includes early surgical review, aggressive source control, prolonged antibiotic therapy, and thorough, extended follow-up.

The effect of electronic cigarette use on peri-implant conditions in men: a systematic review and meta-analysis.

OBJECTIVE: To systematically review the effect of electronic cigarette (e-cigarette) use on clinical, radiographic, and immunologic peri-implant parameters in males. STUDY DESIGN: A comprehensive search of indexed databases was conducted to identify studies reporting data on both e-cigarette users and nonsmokers with implant-supported prosthesis with ≥1-year in function, up to May 2022. Marginal bone loss (MBL), probing depth (PD), plaque index (PI), and bleeding on probing (BOP) were recorded. Peri-implant sulcular fluid volume (PISF), tumor necrosis factor alpha (TNF-α) and interleukin 1ß (IL-ß) levels were also assessed. A meta-analysis was performed using random-effect models to determine the effect of e-cigarette use in primary and secondary outcomes. RESULTS: Four cross-sectional studies were included with a total of 327 participants (165 e-cigarette users and 162 nonsmokers). All studies showed greater MBL, PI, PD, and lower BOP in e-cigarette users compared with never smokers. The meta-analysis indicated significant heterogeneity for all outcomes except MBL for distal implant surfaces, with the mean difference between e-cigarette users and nonsmokers of 0.89 mm (95% CI: 0.67-1.11, P < .01). The PISF volume, TNF-α, and IL-1ß levels were increased in e-cigarette users (P < .01) with no heterogeneity present between studies. CONCLUSIONS: E-cigarette use shows a negative effect on clinical, radiographic, and immunologic parameters of dental implants.

Dual peptide-functionalized hydrogels differentially control periodontal cell function and promote tissue regeneration.

Restoring the tooth-supporting tissues lost during periodontitis is a significant clinical challenge, despite advances in both biomaterial and cell-based approaches. This study investigated poly(ethylene glycol) (PEG) hydrogels functionalized with integrin-binding peptides RGD and GFOGER for controlling periodontal ligament cell (PDLC) activity and promoting periodontal tissue regeneration. Dual presentation of RGD and GFOGER within PEG hydrogels potentiated two key PDLC functions, alkaline phosphatase (ALP) activity and matrix mineralization, over either peptide alone and could be tuned to differentially promote each function. Hydrogel matrix mineralization, fostered by high concentrations of GFOGER together with RGD, identified a PDLC phenotype with accelerated matrix adhesion formation and expression of cementoblast and osteoblast genes. In contrast, maximizing ALP activity through high RGD and low GFOGER levels resulted in minimal hydrogel mineralization, in part, through altered PDLC pyrophosphate regulation. Transplantation of PDLCs in hydrogels optimized for either outcome promoted cementum formation in rat periodontal defects; however, only hydrogels optimized for in vitro mineralization improved new bone formation. Overall, these results highlight the utility of engineered hydrogel systems for controlling PDLC functions and their promise for promoting periodontal tissue regeneration.

A structurally engineered fatty acid, icosabutate, suppresses liver inflammation and fibrosis in NASH.

BACKGROUND & AIMS: Although long-chain omega-3 fatty acids (LCn-3FAs) regulate inflammatory pathways of relevance to non-alcoholic steatohepatitis (NASH), their susceptibility to peroxidation may limit their therapeutic potential. We compared the metabolism of eicosapentaenoic acid (EPA) with an engineered EPA derivative (icosabutate) in human hepatocytes in vitro and their effects on hepatic glutathione metabolism, oxidised lipids, inflammation, and fibrosis in a dietary mouse model of NASH, and in patients prone to fatty liver disease. METHODS: Oxidation rates and cellular partitioning of EPA and icosabutate were compared in primary human hepatocytes. Comparative effects of delayed treatment with either low- (56 mg/kg) or high-dose (112 mg/kg) icosabutate were compared with EPA (91 mg/kg) or a glucagon-like peptide 1 receptor agonist in a choline-deficient (CD), L-amino acid-defined NASH mouse model. To assess the translational potential of these findings, effects on elevated liver enzymes and fibrosis-4 (FIB-4) score were assessed in overweight, hyperlipidaemic patients at an increased risk of NASH. RESULTS: In contrast to EPA, icosabutate resisted oxidation and incorporation into hepatocytes. Icosabutate also reduced inflammation and fibrosis in conjunction with a reversal of CD diet-induced changes in the hepatic lipidome. EPA had minimal effect on any parameter and even worsened fibrosis in association with depletion of hepatic glutathione. In dyslipidaemic patients at risk of NASH, icosabutate rapidly normalised elevated plasma ALT, GGT and AST and reduced FIB-4 in patients with elevated ALT and/or AST. CONCLUSION: Icosabutate does not accumulate in hepatocytes and confers beneficial effects on hepatic oxidative stress, inflammation and fibrosis in mice. In conjunction with reductions in markers of liver injury in hyperlipidaemic patients, these findings suggest that structural engineering of LCn-3FAs offers a novel approach for the treatment of NASH. LAY SUMMARY: Long-chain omega-3 fatty acids are involved in multiple pathways regulating hepatic inflammation and fibrosis, but their susceptibility to peroxidation and use as an energy source may limit their clinical efficacy. Herein, we show that a structurally modified omega-3 fatty acid, icosabutate, overcame these challenges and had markedly improved antifibrotic efficacy in a mouse model of non-alcoholic steatohepatitis. A hepatoprotective effect of icosabutate was also observed in patients with elevated circulating lipids, in whom it led to rapid reductions in markers of liver injury.

Ligand conjugate SAR and enhanced delivery in NHP.

N-Acetylgalactosamine (GalNAc) conjugated short interfering RNAs (siRNAs) are a leading RNA interference (RNAi) platform allowing targeted inhibition of disease-causing genes in hepatocytes. More than a decade of development has recently resulted in the first approvals for this class of drugs. While substantial effort has been made to improve nucleic acid modification patterns for better payload stability and efficacy, relatively little attention has been given to the GalNAc targeting ligand. In addition, the lack of an intrinsic endosomal release mechanism has limited potency. Here, we report a stepwise analysis of the structure activity relationships (SAR) of the components comprising these targeting ligands. We show that there is relatively little difference in biological performance between bi-, tri-, and tetravalent ligand structures while identifying other features that affect their biological activity more significantly. Further, we demonstrate that subcutaneous co-administration of a GalNAc-functionalized, pH responsive endosomal release agent markedly improved the activity and duration of effect for siRNA conjugates, without compromising tolerability, in non-human primates. These findings could address a significant bottleneck for future siRNA ligand conjugate development.

Dual targeting of hepatic fibrosis and atherogenesis by icosabutate, an engineered eicosapentaenoic acid derivative.

BACKGROUND & AIMS: While fibrosis stage predicts liver-associated mortality, cardiovascular disease (CVD) is still the major overall cause of mortality in patients with NASH. Novel NASH drugs should thus ideally reduce both liver fibrosis and CVD. Icosabutate is a semi-synthetic, liver-targeted eicosapentaenoic acid (EPA) derivative in clinical development for NASH. The primary aims of the current studies were to establish both the anti-fibrotic and anti-atherogenic efficacy of icosabutate in conjunction with changes in lipotoxic and atherogenic lipids in liver and plasma respectively. METHODS: The effects of icosabutate on fibrosis progression and lipotoxicity were investigated in amylin liver NASH (AMLN) diet (high fat, cholesterol and fructose) fed ob/ob mice with biopsy-confirmed steatohepatitis and fibrosis and compared with the activity of obeticholic acid. APOE*3Leiden.CETP mice, a translational model for hyperlipidaemia and atherosclerosis, were used to evaluate the mechanisms underlying the lipid-lowering effect of icosabutate and its effect on atherosclerosis. RESULTS: In AMLN ob/ob mice, icosabutate significantly reduced hepatic fibrosis and myofibroblast content in association with downregulation of the arachidonic acid cascade and a reduction in both hepatic oxidised phospholipids and apoptosis. In APOE*3Leiden.CETP mice, icosabutate reduced plasma cholesterol and TAG levels via increased hepatic uptake, upregulated hepatic lipid metabolism and downregulated inflammation pathways, and effectively decreased atherosclerosis development. CONCLUSIONS: Icosabutate, a structurally engineered EPA derivative, effectively attenuates both hepatic fibrosis and atherogenesis and offers an attractive therapeutic approach to both liver- and CV-related morbidity and mortality in NASH patients.

Peri-Implant Diseases and Biologic Complications at Implant-Supported Fixed Dental Prostheses in Partially Edentulous Patients.

PURPOSE: This is a single center, retrospective study to assess the prevalence of peri-implant disease and biologic complications in a cohort of partially edentulous subjects in relation to selected prosthetic factors. MATERIALS AND METHODS: Subjects previously treated with one or more implant-supported fixed dental prosthesis (ISFDPs) were recalled for a comprehensive examination. Clinical and radiographic records were taken and questionnaires were administered. The prevalence of implant failure, peri-implant disease and other biologic complications were correlated with selected prosthetic, clinical and patient-related factors using chi-square and multiple regression analyses. RESULTS: A convenience sample of 71 subjects with 100 prostheses supported by 222 dental implants were enrolled in the study. The mean follow-up time after prosthesis delivery was 3.3 ± 1.5 years (range of 1-9 years). The cumulative implant survival rate was 99.1%. Peri-implantitis was the most frequent major biologic complication (5% of implants), while the most frequent minor biologic complication was peri-implant mucositis (84.10% of implants). A diagnosis of peri-implant mucositis was more likely associated with cement-retained prostheses compared to screw-retained prostheses (OR 6.8, 95% CI 1.1-78.6, p = 0.045) and for short-span prostheses (≤3 prosthetic units) (OR 2.3, 95% CI 1.1-5.0, p = 0.034). Subject-reported quality of life measures were high regardless of the existence of major and/or minor complications, but decreased with increasing number of minor and total biologic complications. CONCLUSIONS: Peri-implant mucositis and other minor biologic complications were highly prevalent. The distribution of the observed complications differed based on the method of prosthesis retention and the number of prosthetic units replaced.

Is it reasonable to ignore vitamin D status for musculoskeletal health?

Severe vitamin D deficiency-25-hydroxyvitamin D (25OHD) concentrations below around 25-30 nmol/L-may lead to growth plate disorganization and mineralization abnormalities in children (rickets) and mineralization defects throughout the skeleton (osteomalacia) and proximal muscle weakness. Both problems are reversed with vitamin D treatment. Apart from this musculoskeletal dysfunction at very low vitamin D levels, there is apparent inconsistency in the available data about whether concentrations of 25OHD below around 50 nmol/L cause muscle function impairment and increase the risk of fracture. This narrative review provides evidence to support the contention that improving vitamin D status, up to around 50 nmol/L, plays a small causal role in optimizing bone and muscle function as well as reducing overall mortality.

Financial incentives to Medicaid smokers for engaging tobacco quit line treatment: maximising return on investment.

BACKGROUND: Low-income smokers experience greater difficulty in quitting smoking than do other smokers. Providing financial incentives for treatment engagement increases smoking cessation success. This study models the cost-effectiveness of varying levels of financial incentives to maximise return on investment (ROI) for engaging low-income Medicaid recipients who smoke to take calls from a tobacco quit line. METHODS: Participants (N=1900) were recruited from May 2013 to June 2015 through quit line-based (n=980), clinic-based (n=444) or community-based referrals (n=476) into the Wisconsin Medicaid Quit Line Incentive project. Incentive (n=948) and control group participants (n=952) received $30 versus $0 per call, respectively, for taking up to five Wisconsin Tobacco Quit Line (WTQL) calls. Cost-effectiveness analyses estimated the incremental cost-effectiveness ratio for alternative financial incentives for engagement with WTQL calls. Probabilistic sensitivity analysis was employed to determine an optimal strategy for financial incentives to minimise the cost per individual who quit smoking. RESULTS: Using fixed payments, the incremental cost-effectiveness ratio of $2316 per smoker who quit in the randomised trial decreased to $2150 per smoker who quit when the incentives were modelled at $20 per each of five WTQL calls taken. Using variable payments, the minimal cost per additional smoker who quit was $2125 when incentives for the first four WTQL calls were set at $20, and the financial payment for the fifth WTQL call was set at $70. CONCLUSIONS: Modelling suggests that financial incentives in the amount of $20 per call for taking the first four quit line calls and $70 for taking a fifth quit line call maximise ROI to engage low-income smokers with evidence-based smoking cessation treatment.

Paying Low-Income Smokers to Quit? The Cost-Effectiveness of Incentivizing Tobacco Quit Line Engagement for Medicaid Recipients Who Smoke.

OBJECTIVES: To determine the cost-effectiveness of an incentive-based stop-smoking intervention that paid Medicaid recipients who smoke to take calls from a tobacco quit line. METHODS: A cost-effectiveness analysis was conducted alongside a randomized controlled trial. The analysis was conducted from a health care systems perspective on the basis of costs and effectiveness over a 6-month follow-up. Participants (n = 1900) were recruited from May 2013 to June 2015 through quit line (n = 980), clinic-based (n = 444), or community-based (n = 476) referrals. Incentive group participants (n = 948) received $30 a call for taking up to five tobacco quit line calls and $40 for biochemically verified tobacco abstinence at 6 months. Control group participants (n = 952) did not receive financial incentives for taking quit line calls. Intervention resource costs included incentive payments to participants, counselor and administrative staff time, and smoking cessation medications. Smoking status at baseline and 6 months was determined for all study participants via carbon monoxide (CO) breath tests (abstinence: CO < 7 ppm). Cost-effectiveness analysis calculated the incremental cost-effectiveness ratio (ICER). RESULTS: Incentive treatment produced higher 6-month CO-confirmed 7-day point-prevalence abstinence than did the control treatment (21.6 vs. 13.8%; P < 0.001). The ICER of the financial incentives intervention was $2316 (95% confidence interval $1582-$4270) per additional person who quit. The study ICER compares favorably with other smoking treatments, such as varenicline combined with proactive telephone counseling, whose ICER has been estimated at $2600 per additional smoker who quits. CONCLUSIONS: Use of financial incentives to engage with tobacco quit line treatment is a cost-effective option to enhance smoking cessation rates for low-income smokers.

A Randomized Controlled Trial of an Optimized Smoking Treatment Delivered in Primary Care.

Background: The effectiveness of smoking cessation treatment is limited in real-world use, perhaps because we have not selected the components of such treatments optimally nor have treatments typically been developed for and evaluated in real-world clinical settings. Purpose: To validate an optimized smoking cessation treatment package that comprises intervention components identified as effective in factorial screening experiments conducted as per the Multiphase Optimization Strategy (MOST). Methods: Adult smokers motivated to quit were recruited from primary care clinics (N = 623). Participants were randomized to receive either recommended usual care (R-UC; 10 min of in-person counseling, 8 weeks of nicotine patch, and referral to quitline services) or abstinence-optimized treatment (A-OT; 3 weeks of prequit mini-lozenges, 26 weeks of nicotine patch + mini-lozenges, three in-person and eight phone counseling sessions, and 7-11 automated calls to prompt medication use). The key outcomes were self-reported and biochemically confirmed (carbon monoxide, CO <6 ppm) 7-day point-prevalence abstinence. Results: A-OT participants had significantly higher self-reported abstinence rates than R-UC participants at 4, 8, 16, and 26 weeks (ORs: 1.91-3.05; p <. 001). The biochemically confirmed 26-week abstinence rates were lower than the self-reported 26-week rates, but revealed a similar treatment effect size (OR = 2.94, p < .001). There was no moderation of treatment effects on 26-week abstinence by demographic, psychiatric, or nicotine dependence variables. A-OT had an incremental cost-effectiveness ratio for 26-week CO-confirmed abstinence of $7,800. Conclusions: A smoking cessation treatment that is optimized via MOST development meaningfully enhances cessation rates beyond R-UC smoking treatment in smokers seen in primary care. Clinical Trial Registration: NCT02301403.

PREOPERATIVE MAGNETIC RESONANCE IMAGING DIAGNOSTIC FEATURES OF UTERINE LEIOMYOSARCOMAS: A SYSTEMATIC REVIEW.

OBJECTIVES: There are no current established pathognomonic diagnostic features for uterine leiomyosarcomas in the pre- or perioperative setting. Recent inadvertent upstaging of this rare malignancy during laparoscopic morcellation of a presumed fibroid has prompted widespread debate among clinicians regarding the safety of current surgical techniques for management of fibroids. This study aims to conduct a systematic review investigating significant diagnostic features in magnetic resonance imaging (MRI) of uterine leiomyosarcomas. METHODS: A comprehensive database search was conducted guided by PRISMA recommendations for peer-reviewed publications to November 2017. Parameters available in MRI were compared for reliability and accuracy of diagnosis of leiomyosarcomas. A decision tree algorithm classifier model was constructed to investigate whether T1 and T2 MRI signal intensities are useful indicators. RESULTS: Nine eligible studies were identified for analysis. There appears to be a significant relationship between histopathological type and T1 and T2 intensity signals (p < .05). A decision tree model analyzing T1 and T2 signal intensity readings supports this trend, with a diagnostic specificity of 77.78 percent for uterine leiomyosarcomas. The apparent diffusion coefficient (ADC) values were not observed to have a significant relationship with tumor pathology (p = .18). CONCLUSIONS: Various studies have investigated pre- and perioperative techniques in differentiating uterine leiomyosarcoma from benign fibroids. Given the rarity of the malignancy and lack of pathognomonic diagnostic parameters, there is difficulty in establishing definitive criteria. A decision tree model is proposed to aid diagnosis based on MRI signal intensities.

A randomized controlled trial of financial incentives to low income pregnant women to engage in smoking cessation treatment: Effects on post-birth abstinence.

OBJECTIVE: Evaluate the effectiveness of monetary incentives for increasing engagement in smoking cessation treatment and improving 6-month abstinence in low-income pregnant smokers. METHOD: Two-group randomized clinical trial recruiting low-income (Medicaid-registered) pregnant smokers receiving assistance through a perinatal support program. Participants were randomized to either an incentive (n = 505) or control condition (n = 509). All participants were offered identical smoking cessation counseling at contacts. Incentive condition participants received incentives for attending pre- and postbirth treatment contacts: $25 for each of 6 prebirth provider visits, $25-40 for each of 4 postbirth home visits at Weeks 1, 2, 4, and 6 (total = $130), $20 for each of 5 postbirth counseling calls and $40 for biochemically verified abstinence at the Week 1 and 6-month visits. Control condition participants received only $40 for attendance at the Week 1 and 6-month postbirth visits ($40 each). MAIN OUTCOMES: Primary outcome was biochemically confirmed 7-day point-prevalence abstinence at 6-month postbirth follow-up. Secondary outcomes included number of home visits and phone calls taken over the first 6 months postbirth; biochemically confirmed abstinence at postbirth Week 1 visit; and self-reported smoking status at 2- and 4-month visits. RESULTS: Incentive condition participants had a higher biochemically confirmed abstinence rate at 6-month postbirth than controls (14.7% vs. 9.2%, respectively: p < .01). This effect was mediated by incentive condition participants' greater acceptance of postbirth home visits and counseling calls. CONCLUSIONS: Moderate incentive payments for smoking treatment engagement (a mean of ≈$214 paid) increased low-income pregnant smokers' engagement and success in smoking cessation treatment. (PsycINFO Database Record

Acute Inflammatory Responses to Exercise in Patients with Abdominal Aortic Aneurysm.

PURPOSE: Inflammation and extracellular matrix degeneration contribute to abdominal aortic aneurysm (AAA) development. We aimed to assess the effect of exercise intensity on circulating biomarkers of inflammation and extracellular matrix degeneration in patients with AAA and healthy older adults. METHODS: Twenty patients with AAA (74 ± 6 yr) and 20 healthy males (72 ± 5 yr) completed moderate-intensity cycling at 40% peak power output, higher-intensity intervals at 70% peak power output, and control (rest) on separate days. Circulating matrix metalloproteinase-9 (MMP-9), transforming growth factor beta 1, interleukin-6 (IL-6), IL-10, and tumor necrosis factor alpha (TNF-α) were analyzed at rest and 0 to 90 min postexercise. RESULTS: Biomarkers at baseline were similar between groups. IL-6 responses to exercise were similar between groups, with a greater increase in ΔIL-6 after moderate-intensity compared with higher-intensity exercise (P < 0.001). Delta MMP-9 showed a 118-ng·mL (95% confidence interval = 23 to 214, P = 0.02) greater increase immediately after higher-intensity exercise compared with changes in control in both groups. Delta MMP-9 then decreased by 114 ng·mL (18 to 211, P = 0.02) 90 min after higher-intensity exercise compared with the changes in control. Delta TNF-α was not different between protocols in healthy adults. In patients with AAA, delta TNF-α showed a greater decrease after higher-intensity compared with moderate-intensity exercise (-6.1 pg·mL, -8.5 to -3.6, P < 0.001) and control (-4.9 pg·mL, -7.4 to -2.4, P < 0.001). IL-10 and transforming growth factor beta 1 did not change in either group. CONCLUSIONS: These findings suggest that a bout of higher-intensity exercise elicits a greater anti-inflammatory response compared with moderate-intensity exercise, which may be further augmented in patients with AAA. Exercise-induced reductions in biomarkers associated with AAA progression may represent a protective effect of exercise in patients with AAA.

A Randomized Trial of Incentives for Smoking Treatment in Medicaid Members.

INTRODUCTION: Low-income populations are especially likely to smoke and have difficulty quitting. This study evaluated a monetary incentive intended to increase smoking treatment engagement and abstinence among Medicaid recipients who smoke. STUDY DESIGN: Two-group randomized clinical trial of Incentive (n=948) and Control interventions (n=952) for smoking. SETTING/PARTICIPANTS: Medicaid recipients recruited from primary care patients (n=920) and callers to the Wisconsin Tobacco Quit Line (n=980). INTERVENTION: Participants were offered five quitline cessation calls and were encouraged to obtain cessation medication (covered by Medicaid). All participants received payment for completing a baseline assessment and a 6-month smoking test. Only Incentive condition participants received compensation for taking counseling calls ($30 per call) and for biochemically verified abstinence at the 6-month visit ($40). MAIN OUTCOME MEASURES: Seven-day point-prevalence smoking abstinence 6-months post study entry and cost/quit. RESULTS: Incentive condition participants had significantly higher biochemically determined 7-day point-prevalence smoking abstinence rates 6 months after study induction than did Controls (21.6% vs 13.8%, respectively, p<0.0001). A positive treatment effect of incentives was present across other abstinence indices, but the size of effects and levels of abstinence varied considerably across indices. Incentive condition participants were also significantly more likely than non-incentivized Control participants to accept Wisconsin Tobacco Quit Line treatment calls and their acceptance of calls mediated their attainment of higher abstinence rates at 6-month follow-up. The cost/quit/participant averaged $4,268.26 for the Control participants and $3,601.37 for the Incentive participants. CONCLUSIONS: This study shows that fairly moderate levels of incentive payments for treatment engagement and abstinence (a total possible payment of $190) increased very low-income smokers' engagement and success in smoking cessation treatment. CLINICAL REGISTRATION: This study is registered at www.clinicaltrials.gov: NCT02713594.

Effects of Nicotine Patch vs Varenicline vs Combination Nicotine Replacement Therapy on Smoking Cessation at 26 Weeks: A Randomized Clinical Trial.

IMPORTANCE: Smoking cessation medications are routinely used in health care; it is vital to identify medications that most effectively treat this leading cause of preventable mortality. OBJECTIVE: To compare the efficacies of varenicline, combination nicotine replacement therapy (C-NRT), and the nicotine patch for 26-week quit rates. DESIGN, SETTING, AND PARTICIPANTS: Three-group randomized intention-to-treat clinical trial occurring from May 2012 to November 2015 among smokers recruited in the Madison, Wisconsin, and Milwaukee, Wisconsin, communities; 65.5% of smokers offered the study (2687/4102) refused participation prior to randomization. INTERVENTIONS: Participants were randomized to one of three 12-week open-label smoking cessation pharmacotherapy groups: (1) nicotine patch only (n = 241); (2) varenicline only (including 1 prequit week; n = 424); and (3) C-NRT (nicotine patch + nicotine lozenge; n = 421). Six counseling sessions were offered. MAIN OUTCOMES AND MEASURES: The primary outcome was carbon monoxide-confirmed self-reported 7-day point-prevalence abstinence at 26 weeks. Secondary outcomes were carbon monoxide-confirmed self-reported initial abstinence, prolonged abstinence at 26 weeks, and point-prevalence abstinence at weeks 4, 12, and 52. RESULTS: Among 1086 smokers randomized (52% women; 67% white; mean age, 48 years; mean of 17 cigarettes smoked per day), 917 (84%) provided 12-month follow-up data. Treatments did not differ on any abstinence outcome measure at 26 or 52 weeks, including point-prevalence abstinence at 26 weeks (nicotine patch, 22.8% [55/241]; varenicline, 23.6% [100/424]; and C-NRT, 26.8% [113/421]) or at 52 weeks (nicotine patch, 20.8% [50/241]; varenicline, 19.1% [81/424]; and C-NRT, 20.2% [85/421]). At 26 weeks, the risk differences for abstinence were, for patch vs varenicline, -0.76% (95% CI, -7.4% to 5.9%); for patch vs C-NRT, -4.0% (95% CI, -10.8% to 2.8%); and for varenicline vs C-NRT, -3.3% (95% CI, -9.1% to 2.6%). All medications were well tolerated, but varenicline produced more frequent adverse events than did the nicotine patch for vivid dreams, insomnia, nausea, constipation, sleepiness, and indigestion. CONCLUSIONS AND RELEVANCE: Among adults motivated to quit smoking, 12 weeks of open-label treatment with nicotine patch, varenicline, or C-NRT produced no significant differences in biochemically confirmed rates of smoking abstinence at 26 weeks. The results raise questions about the relative effectiveness of intense smoking pharmacotherapies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01553084.

Comparative effectiveness of intervention components for producing long-term abstinence from smoking: a factorial screening experiment.

AIMS: To identify promising intervention components that help smokers attain and maintain abstinence during a quit attempt. DESIGN: A 2 × 2 × 2 × 2 × 2 randomized factorial experiment. SETTING: Eleven primary care clinics in Wisconsin, USA. PARTICIPANTS: A total of 544 smokers (59% women, 86% white) recruited during primary care visits and motivated to quit. INTERVENTIONS: Five intervention components designed to help smokers attain and maintain abstinence: (1) extended medication (26 versus 8 weeks of nicotine patch + nicotine gum); (2) maintenance (phone) counseling versus none; (3) medication adherence counseling versus none; (4) automated (medication) adherence calls versus none; and (5) electronic medication monitoring with feedback and counseling versus electronic medication monitoring alone. MEASUREMENTS: The primary outcome was 7-day self-reported point-prevalence abstinence 1 year after the target quit day. FINDINGS: Only extended medication produced a main effect. Twenty-six versus 8 weeks of medication improved point-prevalence abstinence rates (43 versus 34% at 6 months; 34 versus 27% at 1 year; P = 0.01 for both). There were four interaction effects at 1 year, showing that an intervention component's effectiveness depended upon the components with which it was combined. CONCLUSIONS: Twenty-six weeks of nicotine patch + nicotine gum (versus 8 weeks) and maintenance counseling provided by phone are promising intervention components for the cessation and maintenance phases of smoking treatment.

Enhancing the effectiveness of smoking treatment research: conceptual bases and progress.

BACKGROUND AND AIMS: A chronic care strategy could potentially enhance the reach and effectiveness of smoking treatment by providing effective interventions for all smokers, including those who are initially unwilling to quit. This paper describes the conceptual bases of a National Cancer Institute-funded research program designed to develop an optimized, comprehensive, chronic care smoking treatment. METHODS: This research is grounded in three methodological approaches: (1) the Phase-Based Model, which guides the selection of intervention components to be experimentally evaluated for the different phases of smoking treatment (motivation, preparation, cessation, and maintenance); (2) the Multiphase Optimization Strategy (MOST), which guides the screening of intervention components via efficient experimental designs and, ultimately, the assembly of promising components into an optimized treatment package; and (3) pragmatic research methods, such as electronic health record recruitment, that facilitate the efficient translation of research findings into clinical practice. Using this foundation and working in primary care clinics, we conducted three factorial experiments (reported in three accompanying papers) to screen 15 motivation, preparation, cessation and maintenance phase intervention components for possible inclusion in a chronic care smoking treatment program. RESULTS: This research identified intervention components with relatively strong evidence of effectiveness at particular phases of smoking treatment and it demonstrated the efficiency of the MOST approach in terms both of the number of intervention components tested and of the richness of the information yielded. CONCLUSIONS: A new, synthesized research approach efficiently evaluates multiple intervention components to identify promising components for every phase of smoking treatment. Many intervention components interact with one another, supporting the use of factorial experiments in smoking treatment development.

Comparative effectiveness of motivation phase intervention components for use with smokers unwilling to quit: a factorial screening experiment.

AIMS: To screen promising intervention components designed to reduce smoking and promote abstinence in smokers initially unwilling to quit. DESIGN: A balanced, four-factor, randomized factorial experiment. SETTING: Eleven primary care clinics in southern Wisconsin, USA. PARTICIPANTS: A total of 517 adult smokers (63.4% women, 91.1% white) recruited during primary care visits who were willing to reduce their smoking but not quit. INTERVENTIONS: Four factors contrasted intervention components designed to reduce smoking and promote abstinence: (1) nicotine patch versus none; (2) nicotine gum versus none; (3) motivational interviewing (MI) versus none; and (4) behavioral reduction counseling (BR) versus none. Participants could request cessation treatment at any point during the study. MEASUREMENTS: The primary outcome was percentage change in cigarettes smoked per day at 26 weeks post-study enrollment; the secondary outcomes were percentage change at 12 weeks and point-prevalence abstinence at 12 and 26 weeks post-study enrollment. FINDINGS: There were few main effects, but a significant four-way interaction at 26 weeks post-study enrollment (P = 0.01, ß = 0.12) revealed relatively large smoking reductions by two component combinations: nicotine gum combined with BR and BR combined with MI. Further, BR improved 12-week abstinence rates (P = 0.04), and nicotine gum, when used without MI, increased 26-week abstinence after a subsequent aided quit attempt (P = 0.01). CONCLUSIONS: Motivation-phase nicotine gum and behavioral reduction counseling are promising intervention components for smokers who are initially unwilling to quit.