Perfluorochemical-facilitated plasminogen activator delivery to the airways: A novel treatment for inhalational smoke-induced acute lung injury.

BACKGROUND: Effective clinical management of airway clot and fibrinous cast formation of severe inhalational smoke-induced acute lung injury (ISALI) is lacking. Aerosolized delivery of tissue plasminogen activator (tPA) is confounded by airway bleeding; single-chain urokinase plasminogen activator (scuPA) moderated this adverse effect and supported transient improvement in gas exchange and lung mechanics. However, neither aerosolized plasminogen activator (PA) yielded durable improvements in physiologic responses or reduction in cast burden. Here, we hypothesized that perfluorochemical (PFC) liquids would facilitate PA distribution and sustain improvements in physiologic outcomes in ISALI. METHODS: Spontaneously breathing adult sheep (n = 36) received anesthesia and analgesia and were instrumented, exposed to cotton smoke inhalation, and supported by mechanical ventilation for 48 h. Groups (n = 6/group) were studied without supplemental treatment, or, starting 4 h post injury, they received intratracheal low volume (8 mL) PFC liquid alone or a dose range of tPA/PFC or scuPA/PFC suspensions (4 or 8 mg in 8 mL PFC) every 8 h. Outcomes were evaluated by sequential measurements of cardiopulmonary parameters, lung histomorphology, and biochemical analyses of bronchoalveolar lavage fluid. RESULTS: Dose-response and PA-type comparisons of outcomes demonstrated sustained superiority with low-volume PFC suspensions of scuPA over tPA or PFC alone, favoring the highest dose of scuPA/PFC suspension over lower doses, without airway bleeding. CONCLUSIONS: We propose that this improved profile over previously reported aerosolized delivery is likely related to improved dose distribution. Sustained salutary responses to scuPA/PFC suspension delivery in this translational model are encouraging and support the possibility that the observed outcomes could be of clinical importance.

Financial incentives and proactive calling for reducing barriers to tobacco treatment among socioeconomically disadvantaged women: A factorial randomized trial.

Improved strategies and scalable interventions to engage low-socioeconomic status (SES) smokers in tobacco treatment are needed. We tested an intervention designed to connect low-SES smokers to treatment services, implemented through Minnesota's National Breast and Cervical Cancer Early Detection Program (Sage) in 2017; the trial was designed to last 3 months (July through October). Participants were female smokers who were 250% below the federal poverty level (randomized N = 3723; analyzed N = 3365). Using a factorial design, participants were randomized to six intervention groups consisting of a proactive call (no call vs call) and/or a financial incentive offered for being connected to treatment services ($0 vs $10 vs $20). Simple randomization was conducted using Stata v.13. All individuals received direct mail. Participants and staff were blinded to allocation. The outcome was connection via phone to QUITPLAN Services®, Minnesota's population-based cessation services. Groups that received $10 or $20 incentives had higher odds of treatment engagement compared to the no incentive group [respectively, OR = 1.94; 95% CI (1.19-3.14); OR = 2.18; 95% CI (1.36-3.51)]. Individuals that received proactive calls had higher odds of treatment engagement compared to individuals not called [OR = 1.59; 95% CI (1.11-2.29)]. Economic evaluation revealed that the $10 incentive, no call group had the best cost-benefit ratio compared to the no incentive, no call group. Direct mail with moderate incentives or proactive calling can successfully encourage connections to population-based tobacco treatment services among low-SES smokers. The intervention could be disseminated to similar programs serving low-SES populations. This trial is registered at ClinicalTrials.gov (NCT03760107).

Modulation of Peroxynitrite Reduces Norepinephrine Requirements in Ovine MRSA Septic Shock.

Vascular hypo-responsiveness to vasopressors during septic shock is a challenging problem. This study is to test the hypothesis that reactive nitrogen species (RNS), such as peroxynitrite, are major contributing factors to vascular hypo-responsiveness in septic shock. We hypothesized that adjunct therapy with peroxynitrite decomposition catalyst (PDC) would reduce norepinephrine requirements in sepsis resuscitation. Fourteen female Merino sheep were subjected to a "two-hit" injury (smoke inhalation and endobronchial instillation of live methicillin-resistant Staphylococcus aureus [1.6-2.5 × 10 CFUs]). The animals were randomly allocated to control: injured, fluid resuscitated, and titrated norepinephrine, n = 7; or PDC: injured, fluid resuscitated, titrated norepinephrine, and treated with PDC, n = 7. One-hour postinjury, an intravenous injection of PDC (0.1 mg/kg) was followed by a continuous infusion (0.04 mg/kg/h). Titration of norepinephrine started at 0.05 mcg/kg/min based on their mean arterial pressure. All animals were mechanically ventilated and monitored in the conscious state for 24 h. The mean arterial pressure was well maintained in the PDC with significantly less norepinephrine requirement from 7 to 23 h after injury compared with control. Total norepinephrine dose, the highest norepinephrine rate, and time on norepinephrine support were also significantly lower in PDC. Modified sheep organ failure assessment scores at 6 to 18 h postinjury were significantly lower in PDC compared with control. PDC improved survival rate at 24 h (71.4% vs. 28.6%). PDC treatment had no adverse effects. In conclusion, the modulation of RNS may be considered an effective adjunct therapy for septic shock, in the case of hypo-responsiveness to norepinephrine.

Nebulization of Single-Chain Tissue-Type and Single-Chain Urokinase Plasminogen Activator for Treatment of Inhalational Smoke-Induced Acute Lung Injury.

Single-chain tissue-type plasminogen activator (sctPA) and single-chain urokinase plasminogen activator (scuPA) have attracted interest as enzymes for the treatment of inhalational smoke-induced acute lung injury (ISALI). In this study, the pulmonary delivery of commercial human sctPA and lyophilized scuPA and their reconstituted solution forms were demonstrated using vibrating mesh nebulizers (Aeroneb® Pro (active) and EZ Breathe® (passive)). Both the Aeroneb® Pro and EZ Breathe® vibrating mesh nebulizers produced atomized droplets of protein solution of similar size of less than about 5 µm, which is appropriate for pulmonary delivery. Enzymatic activities of scuPA and of sctPA were determined after nebulization and both remained stable (88.0% and 93.9%). Additionally, the enzymatic activities of sctPA and tcuPA were not significantly affected by excipients, lyophilization or reconstitution conditions. The results of these studies support further development of inhaled formulations of fibrinolysins for delivery to the lungs following smoke-induced acute pulmonary injury.

The Efficacy of Direct Mail, Patient Navigation, and Incentives for Increasing Mammography and Colonoscopy in the Medicaid Population: A Randomized Controlled Trial.

Background: Despite lower cancer screening rates and survival rates in the Medicaid population compared with those with private insurance, there is a dearth of population-based, evidence-based interventions targeting Medicaid clients to address this problem.Methods: This study reports results of a population-based randomized controlled trial (RCT) among all individuals enrolled in Minnesota's Medicaid program who were overdue for breast cancer (n = 22,113) and/or colorectal cancer (n = 94,294) screening. Individuals were randomized to intervention or control groups. The intervention group received persuasive and innovative direct mail materials coupled with a $20 incentive for using their Medicaid benefit to get screened. Direct mail materials provided a phone number to a call center staffed by patient navigators who addressed barriers and scheduled appointments via three-way calls. The control group received the intervention 15 months later. Primary outcomes were completion of mammography or colonoscopy within 12 weeks of the intervention. Billing claims served as evidence of screening.Results: Multivariate logistic regression showed significant differences for both breast cancer (P < 0.001) and colorectal cancer (P < 0.01). The odds of receiving a mammogram for the treatment group were significantly higher than the control group [OR = 1.30; 95% confidence interval (95% CI) = 1.16-1.46], and the treatment group was more likely to receive a colonoscopy than the control group (OR = 1.12; 95% CI = 1.04-1.21).Conclusions: This population-based intervention increased breast cancer and colorectal cancer screening in a Medicaid population overdue for screening.Impact: These findings may have broad application for reaching individuals who generally remain outside the health care system despite having public health insurance. Cancer Epidemiol Biomarkers Prev; 27(9); 1047-56. ©2018 AACR.

Coupling Financial Incentives With Direct Mail in Population-Based Practice.

Financial incentives are being used increasingly to encourage a wide array of health behaviors because of their well-established efficacy. However, little is known about how to translate incentive-based strategies to public health practice geared toward improving population-level health, and a dearth of research exists on how individuals respond to incentives through public health communication strategies such as direct mail. This study reports results of a population-based randomized controlled trial testing a direct mail, incentive-based intervention for promoting mammography uptake. The study population was composed of a random sample of Minnesota women enrolled in Medicare fee-for-service and overdue for breast cancer screening. Participants ( N = 18,939) were randomized into three groups: (1) Direct Mail only, (2) Direct Mail plus Incentive, and (3) Control. Both direct mail groups received two mailers with a message about the importance of mammography; however, Mail plus Incentive mailers also offered a $25 incentive for getting a mammogram. Logistic regression analyses measured intervention effects. Results showed the odds for receiving mammography were significantly higher for the Direct Mail plus Incentive group compared with both Direct Mail only and Control groups. The use of incentives also proved to be cost-effective. Additionally, the Direct Mail only group was more likely to receive mammography than the Control group. Findings offer experimental evidence on how the population-based strategy of direct mail coupled with a financial incentive can encourage healthy behavior, as well as how incentive-based programs can be translated into health promotion practice aimed at achieving population-level impact.

Connecting low-income smokers to tobacco treatment services.

The Affordable Care Act calls for using population-level incentive-based interventions, and cigarette smoking is one of the most significant health behaviors driving costs and adverse health in low-income populations. Telehealth offers an opportunity to facilitate delivery of evidence-based smoking cessation services as well as incentive-based interventions to low-income populations. However, research is needed on effective strategies for linking smokers to services, how to couple financial incentives with telehealth, and on how to scale this to population-level practice. The current paper evaluates primary implementation and follow-up results of two strategies for connecting low-income, predominantly female smokers to a telephone tobacco quitline (QL). The population-based program consisted of participant-initiated phone contact and two recruitment strategies: (1) direct mail (DM) and (2) opportunistic telephone referrals with connection (ORC). Both strategies offered financial incentives for being connected to the QL, and all QL connections were made by trained patient navigators through a central call center. QL connections occurred for 97% of DM callers (N=870) and 33% of ORC callers (N=4550). Self-reported continuous smoking abstinence (i.e., 30 smoke-free days at seven-month follow-up) was 20% for the DM group and 16% for ORC. These differences between intervention groups remained in ordered logistic regressions adjusting for smoking history and demographic characteristics. Each recruitment strategy had distinct advantages; both successfully connected low-income smokers to cessation services and encouraged quit attempts and continuous smoking abstinence. Future research and population-based programs can utilize financial incentives and both recruitment strategies, building on their relative strengths.

Interpersonal Communication and Smoking Cessation in the Context of an Incentive-Based Program: Survey Evidence From a Telehealth Intervention in a Low-Income Population.

The tobacco epidemic disproportionately affects low-income populations, and telehealth is an evidence-based strategy for extending tobacco cessation services to underserved populations. A public health priority is to establish incentive-based interventions at the population level in order to promote long-term smoking cessation in low-income populations. Yet randomized clinical trials show that financial incentives tend to encourage only short-term steps of cessation, not continuous smoking abstinence. One potential mechanism for increasing long-term cessation is interpersonal communication (IPC) in response to population-level interventions. However, more research is needed on IPC and its influence on health behavior change, particularly in the context of incentive-based, population-level programs. This study used survey data gathered after a population-level telehealth intervention that offered $20 incentives to low-income smokers for being connected to Minnesota's free quitline in order to examine how perceived incentive importance and IPC about the incentive-based program relate to both short-term and long-term health behavior change. Results showed that IPC was strongly associated with initial quitline utilization and continuous smoking abstinence as measured by 30-day point prevalence rates at 7-month follow-up. Perceived incentive importance had weak associations with both measures of cessation, and all associations were nonsignificant in models adjusting for IPC. These results were found in descriptive analyses, logistic regression models, and Heckman probit models that adjusted for participant recruitment. In sum, a behavioral telehealth intervention targeting low-income smokers that offered a financial incentive inspired IPC, and this social response was strongly related to utilization of intervention services as well as continuous smoking abstinence.

Does it pay to pay people to share information? Using financial incentives to promote peer referral for mammography among the underinsured.

PURPOSE: Efforts to screen underinsured women for breast cancer face challenges in reaching desired audiences. One option is viral marketing through peer referral. We sought the optimal way to solicit nominations of peers. DESIGN: An experiment (N  =  2968) compared impact of incentives on peer nomination. Women were offered a $20 incentive each time someone they referred was screened, a $5 incentive for each name and valid address or phone number (regardless of screening completion), or no financial incentive for nomination. SETTING: Study sample was drawn from free mammography program participants in Minnesota. ANALYSIS: Post hoc Scheffé t-tests compared conditions on nominees per invitation card sent (N  =  2968), mean number of nominees scheduling mammogram per referrer (n  =  107), and proportion of total nominees (N  =  1041) scheduling a mammogram for each incentive condition. RESULTS: Offering $5 per nomination yielded .52 nominations per referral invitation sent, compared to .36 nominations per invitation sent for $20 per completed mammogram and only .17 nominations per invitation in the no incentive group. In the no incentive condition, however, each referrer generated .35 scheduled mammograms on average, which was statistically equivalent to the .16 scheduled mammograms delivered on average by $20 per completed mammogram referrers and statistically superior, p < .05, to the .09 rate produced by $5 per name referrers. CONCLUSION: Programs interested in peer referral could productively pursue the strategy without incurring incentive costs.

The availability of community ties predicts likelihood of peer referral for mammography: geographic constraints on viral marketing.

Engaging social networks to encourage preventive health behavior offers a supplement to conventional mass media campaigns and yet we do not fully understand the conditions that facilitate or hamper such interpersonal diffusion. One set of factors that should affect the diffusion of health campaign information involves a person's community. Variables describing geographic communities should predict the likelihood of residents accepting campaign invitations to pass along information to friends, family, and others. We investigate two aspects of a community--the availability of community ties and residential stability--as potential influences on diffusion of publicly-funded breast cancer screening in the United States in 2008-2009. In a survey study of 1515 participants living in 91 zip codes across the State of Minnesota, USA, we focus on the extent to which women refer others when given the opportunity to nominate family, friends, and peers to receive free mammograms. We predicted nomination tendency for a particular zip code would be a function of available community ties, measured as religious congregation density in that zip code, and also expected the predictive power of available ties would be greatest in communities with relatively high residential stability (meaning lower turnover in home residence). Results support our hypotheses. Congregation density positively predicted nomination tendency both in bivariate analysis and in Tobit regression models, and was most predictive in zip codes above the median in residential stability. We conclude that having a local infrastructure of social ties available in a community predicts the diffusion of available health care services in that community.