Gut bacteria-derived serotonin promotes immune tolerance in early life.

The gut microbiota promotes immune system development in early life, but the interactions between the gut metabolome and immune cells in the neonatal gut remain largely undefined. Here, we demonstrate that the neonatal gut is uniquely enriched with neurotransmitters, including serotonin, and that specific gut bacteria directly produce serotonin while down-regulating monoamine oxidase A to limit serotonin breakdown. We found that serotonin directly signals to T cells to increase intracellular indole-3-acetaldehdye and inhibit mTOR activation, thereby promoting the differentiation of regulatory T cells, both ex vivo and in vivo in the neonatal intestine. Oral gavage of serotonin into neonatal mice resulted in long-term T cell-mediated antigen-specific immune tolerance toward both dietary antigens and commensal bacteria. Together, our study has uncovered an important role for specific gut bacteria to increase serotonin availability in the neonatal gut and identified a function of gut serotonin in shaping T cell response to dietary antigens and commensal bacteria to promote immune tolerance in early life.

Construction of a Searchable Database for Gene Expression Changes in Spinal Cord Injury Experiments.

Spinal cord injury (SCI) is a debilitating condition with an estimated 18,000 new cases annually in the United States. The field has accepted and adopted standardized databases such as the Open Data Commons for Spinal Cord Injury (ODC-SCI) to aid in broader analyses, but these currently lack high-throughput data despite the availability of nearly 6000 samples from over 90 studies available in the Sequence Read Archive. This limits the potential for large datasets to enhance our understanding of SCI-related mechanisms at the molecular and cellular level. Therefore, we have developed a protocol for processing RNA-Seq samples from high-throughput sequencing experiments related to SCI resulting in both raw and normalized data that can be efficiently mined for comparisons across studies, as well as homologous discovery across species. We have processed 1196 publicly available RNA-Seq samples from 50 bulk RNA-Seq studies across nine different species, resulting in an SQLite database that can be used by the SCI research community for further discovery. We provide both the database as well as a web-based front-end that can be used to query the database for genes of interest, differential gene expression, genes with high variance, and gene set enrichments.

Climate change dynamics and mercury temporal trends in Northeast Arctic cod (Gadus morhua) from the Barents Sea ecosystem.

The Northeast Arctic cod (Gadus morhua) is the world's northernmost stock of Atlantic cod and is of considerable ecological and economic importance. Northeast Arctic cod are widely distributed in the Barents Sea, an environment that supports a high degree of ecosystem resiliency and food web complexity. Here using 121 years of ocean temperature data (1900-2020), 41 years of sea ice extent information (1979-2020) and 27 years of total mercury (Hg) fillet concentration data (1994-2021, n = 1999, ≥71% Methyl Hg, n = 20) from the Barents Sea ecosystem, we evaluate the effects of climate change dynamics on Hg temporal trends in Northeast Arctic cod. We observed low and consistently stable, Hg concentrations (yearly, least-square means range = 0.022-0.037 mg/kg wet wt.) in length-normalized fish, with a slight decline in the most recent sampling periods despite a significant increase in Barents Sea temperature, and a sharp decline in regional sea ice extent. Overall, our data suggest that recent Arctic amplification of ocean temperature, "Atlantification," and other perturbations of the Barents Sea ecosystem, along with rapidly declining sea ice extent over the last ∼30 years did not translate into major increases or decreases in Hg bioaccumulation in Northeast Arctic cod. Our findings are consistent with similar long-term, temporal assessments of Atlantic cod inhabiting Oslofjord, Norway, and with recent investigations and empirical data for other marine apex predators. This demonstrates that Hg bioaccumulation is highly context specific, and some species may not be as sensitive to current climate change-contaminant interactions as currently thought. Fish Hg bioaccumulation-climate change relationships are highly complex and not uniform, and our data suggest that Hg temporal trends in marine apex predators can vary considerably within and among species, and geographically. Hg bioaccumulation regimes in biota are highly nuanced and likely driven by a suite of other factors such as local diets, sources of Hg, bioenergetics, toxicokinetic processing, and growth and metabolic rates of individuals and taxa, and inputs from anthropogenic activities at varying spatiotemporal scales. Collectively, these findings have important policy implications for global food security, the Minamata Convention on Mercury, and several relevant UN Sustainable Development Goals.

Fluctuating Atlantic inflows modulate Arctic atlantification.

Enhanced warm, salty subarctic inflows drive high-latitude atlantification, which weakens oceanic stratification, amplifies heat fluxes, and reduces sea ice. In this work, we show that the atmospheric Arctic Dipole (AD) associated with anticyclonic winds over North America and cyclonic winds over Eurasia modulates inflows from the North Atlantic across the Nordic Seas. The alternating AD phases create a "switchgear mechanism." From 2007 to 2021, this switchgear mechanism weakened northward inflows and enhanced sea-ice export across Fram Strait and increased inflows throughout the Barents Sea. By favoring stronger Arctic Ocean circulation, transferring freshwater into the Amerasian Basin, boosting stratification, and lowering oceanic heat fluxes there after 2007, AD+ contributed to slowing sea-ice loss. A transition to an AD- phase may accelerate the Arctic sea-ice decline, which would further change the Arctic climate system.

Experiences of gender-based violence among Somali refugee women: a socio-ecological model approach.

Gender-based violence (GBV) is an all-encompassing term that speaks to acts or threats that may lead to physical, sexual or emotional harm to an individual based on their gender. This paper provides a scoping review of research on gender-based violence among Somali refugee women in different parts of the world. Using the socio-ecological model as a framework, we reviewed 30 empirical studies focusing on some form of GBV among Somali refugee women. We identified societal, community and individual factors contributing to the experience of GBV. We also discuss how these factors influence women's willingness to access care, especially healthcare and social services. The review reveals that oftentimes, institutions that work closely with this population have a limited understanding of how closely culture affects the willingness and ability to seek help about GBV. Based on our analysis, we suggest ways in which social institutions and healthcare providers can provide culturally-safe support to Somali refugee women who have experienced some form of GBV.

Instrumented Versus Uninstrumented Posterolateral Fusion for Lumbar Spondylolisthesis: A Randomized Controlled Trial.

BACKGROUND: In Scandinavia, spinal fusion is frequently performed without instrumentation, as use of instrumentation in the elderly can be complicated by poor bone quality and the risk of screw pull-out. However, uninstrumented fusion carries the risk of nonunion. We performed a randomized controlled trial in an attempt to determine if use of instrumentation leads to better outcomes and fusion rates when spinal fusion is performed for degenerative spondylolisthesis in the elderly. METHODS: This was a randomized, single-center, open-label trial of patients with symptomatic single-level degenerative spondylolisthesis who were assigned 1:1 to decompression and fusion with or without instrumentation after at least 12 weeks of nonoperative treatment had failed. The primary outcome was the change in the Oswestry Disability Index (ODI), and secondary outcomes included fusion rates within 1 year, reoperation rates within 2 years, and changes in the EuroQol-5 Dimension-3 Level (EQ-5D) score. RESULTS: Fifty-four subjects were randomized to each of the 2 groups, which had similar preoperative demographic and surgical characteristics. We found similar improvements in the ODI (p = 0.791), back pain, leg pain, and quality of life between groups at 1 and 2 years of follow-up. Solid fusion on computed tomography (CT) scans was noted in 94% of the patients in the instrumented group and 31% in the uninstrumented group (p < 0.001). One patient (2%) in the instrumented group and 7 (13%) in the uninstrumented group (p = 0.031) had a reoperation within 2 years after the index surgery. CONCLUSIONS: We found no difference in patient-reported outcomes when we compared instrumented with uninstrumented fusion in patients with degenerative spondylolisthesis. The uninstrumented group had a significantly higher rate of nonunion and reoperations at 2 years. LEVEL OF EVIDENCE: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

The mast cell exosome-fibroblast connection: A novel pro-fibrotic pathway.

Introduction: In addition to the traditional activation of resident receptors by release of local mediators, new evidence favors the existence of exosomes in cell-to-cell communication that mediates delivery of specific cargo to modulate recipient cell function. We report that mast cell exosomes are an additional source of pro-fibrotic substances and constitute a unique pathway for the generation of excess collagen. Methods: We use primary human lung fibroblasts (HLFs) to demonstrate the uptake of labeled exosomes isolated from the human mast cell line HMC-1 (MC-EXOs), previously shown to contain protein cargo in common with human mast cell exosomes. Results: The MC-EXO uptake by HLF is to the cytosol and increases both proline hydroxylation in HLF lysate and secreted collagen, within 24 h, which is sustained over 72 h, the same time required for transforming growth factor-ß (TGF-ß) to activate collagen synthesis in the HLFs. Unlike TGF-ß, MC-EXO uptake does not induce fibrillar gene activation or invoke the Smad-nuclear transcription pathway. We show that MC-EXO uptake and TGF-ß have an additive effect on collagen synthesis in HLF and postulate that MC-EXO uptake by HLFs is a contributing factor to excess collagen synthesis and represents a unique paradigm for understanding fibrosis. Discussion: It is known that, in the lungs, mast cells are more activated and increase in number with inflammation, injury and viral infection associated with fibrosis. With the reported increased incidence of post-COVID-pulmonary fibrosis (PCPF), data from patients with severe COVID-19 are presented that show an increase in the mast cell number in lung parenchyma, the site of PCPF. Our findings provide a rationale for targeting multiple fibrogenic pathways in the management of lung fibrosis and the use of mast cell exosomes as a biomarker for the prognostic and diagnostic management of evolving fibrotic lung disease.

Construction of a searchable database for gene expression changes in spinal cord injury experiments.

Spinal cord injury (SCI) is a debilitating disease resulting in an estimated 18,000 new cases in the United States on an annual basis. Significant behavioral research on animal models has led to a large amount of data, some of which has been catalogued in the Open Data Commons for Spinal Cord Injury (ODC-SCI). More recently, high throughput sequencing experiments have been utilized to understand molecular mechanisms associated with SCI, with nearly 6,000 samples from over 90 studies available in the Sequence Read Archive. However, to date, no resource is available for efficiently mining high throughput sequencing data from SCI experiments. Therefore, we have developed a protocol for processing RNA-Seq samples from high-throughput sequencing experiments related to SCI resulting in both raw and normalized data that can be efficiently mined for comparisons across studies as well as homologous discovery across species. We have processed 1,196 publicly available RNA-seq samples from 50 bulk RNA-Seq studies across nine different species, resulting in an SQLite database that can be used by the SCI research community for further discovery. We provide both the database as well as a web-based front-end that can be used to query the database for genes of interest, differential gene expression, genes with high variance, and gene set enrichments.

Under-ice observations by trawls and multi-frequency acoustics in the Central Arctic Ocean reveals abundance and composition of pelagic fauna.

The rapid ongoing changes in the Central Arctic Ocean call for baseline information on the pelagic fauna. However, sampling for motile organisms which easily escape vertically towed nets is challenging. Here, we report the species composition and catch weight of pelagic fishes and larger zooplankton from 12 trawl hauls conducted in ice covered waters in the Central Arctic Ocean beyond the continental slopes in late summer. Combined trawl catches with acoustics data revealed low amounts of fish and zooplankton from the advective influenced slope region in the Nansen Basin in the south to the ice-covered deep Amundsen Basin in the north. Both arctic and subarctic-boreal species, including the ones considered as Atlantic expatriate species were found all the way to 87.5o N. We found three fish species (Boreogadus saida, Benthosema glaciale and Reinhardtius hippoglossoides), but the catch was limited to only seven individuals. Euphausiids, amphipods and gelatinous zooplankton dominated the catch weight in the Nansen Basin in the mesopelagic communities. Euphausiids were almost absent in the Amundsen Basin with copepods, amphipods, chaetognaths and gelatinous zooplankton dominating. We postulate asymmetric conditions in the pelagic ecosystems of the western and eastern Eurasian Basin caused by ice and ocean circulation regimes.

Barriers to PrEP uptake among Black female adolescents and emerging adults.

HIV/AIDS disproportionately impacts Black cisgender female adolescents and emerging adults. Pre-Exposure Prophylaxis (PrEP) reduces the risk of HIV infection; however, structural barriers may exacerbate resistance to PrEP in this population. The purpose of this paper is to understand the characteristics of age, race, gender, history, and medical mistrust as barriers to PrEP uptake among Black female adolescents and emerging adults (N = 100 respondents) between the ages of 13-24 years in Chicago. Between January and June of 2019, participants completed the survey. We used directed content analysis to examine reported barriers to PrEP uptake. The most commonly identified barriers to PrEP uptake were side effects (N = 39), financial concerns (N = 15), and medical mistrust (N = 12). Less frequently reported barriers included lack of PrEP knowledge and misconceptions (N = 9), stigma (N = 2), privacy concerns (N = 4). We describe innovative multi-level strategies to provide culturally safe care to improve PrEP acceptability among Black female adolescents and emerging adults in Chicago. These recommendations may help mitigate the effect of medical mistrust, stigma, and misconceptions of PrEP within Black communities.

Turning Community Feedback into a Culturally Responsive Program for American Indian/Alaska Native Commercial Tobacco Users.

BACKGROUND: American Indian/Alaska Native (AI/AN) cigarette smoking prevalence is disproportionately high, especially in the northern United States. Tailored quitlines are needed to support AI/AN commercial tobacco users with quitting. OBJECTIVES: Obtain community feedback by working with trusted AI/AN partners; genuinely incorporate feedback into program design; collaboratively develop and implement culturally relevant quitline services for Minnesota's AI/AN community. METHODS: Working in partnership, AI/AN community input was gathered, and community partners were engaged to inform the development, training, implementation and monitoring of a tailored program within the existing state quitline. RESULTS: Findings suggest focusing on the commercial tobacco user/coach relationship, increased cultural understanding and program content adaptations could make quitlines more acceptable for AI/AN commercial tobacco users. CONCLUSIONS: The development and launch of the AI Quitline demonstrated the feasibility of collaboration among AI/AN organizations and community members, funders and providers to create a culturally relevant cessation service for AI/AN commercial tobacco users.

Successive extreme climatic events lead to immediate, large-scale, and diverse responses from fish in the Arctic.

The warming trend of the Arctic is punctuated by several record-breaking warm years with very low sea ice concentrations. The nature and reversibility of marine ecosystem responses to these multiple extreme climatic events (ECEs) are poorly understood. Here, we investigate the ecological signatures of three successive bottom temperature maxima concomitant with surface ECEs between 2004 and 2017 in the Barents Sea across spatial and organizational scales. We observed community-level redistributions of fish concurrent with ECEs at the scale of the whole Barents Sea. Three groups, characterized by different sets of traits describing their capacity to cope with short-term perturbations, reacted with different timing and intensity to each ECE. Arctic species co-occurred more frequently with large predators and incoming boreal taxa during ECEs, potentially affecting food web structures and functional diversity, accelerating the impacts of long-term climate change. On the species level, responses were highly diversified, with different ECEs impacting different species, and species responses (expansion, geographical shift) varying from one ECE to another, despite the environmental perturbations being similar. Past ECEs impacts, with potential legacy effects, lagged responses, thresholds, and interactions with the underlying warming pressure, could constantly set up new initial conditions that drive the unique ecological signature of each ECE. These results highlight the complexity of ecological reactions to multiple ECEs and give prominence to several sources of process uncertainty in the predictions of climate change impact and risk for ecosystem management. Long-term monitoring and studies to characterize the vertical extent of each ECE are necessary to statistically link demersal species and environmental spatial-temporal patterns. In the future, regular monitoring will be crucial to detect early signals of change and understand the determinism of ECEs, but we need to adapt our models and management to better integrate risk and stochasticity from the complex impacts of global change.

Privacy, or the Lack Thereof, and Its Implications for Dignity in Mobile COVID-19 Testing.

INTRODUCTION: Chicago's COVID-19 Rapid Response Team (CRRT) is a decentralized, interprofessional group of nurses, residents, students, and faculty who provide free COVID-19 testing for those living or working in congregate settings (i.e., shelters, long term care facilities, prisons and encampments) due to their increased risk. Individuals within these vulnerable populations regularly experience stigma, a lack of privacy, and healthcare discrimination as they are often in low-income and underserved communities. The CRRT tests in settings that are necessarily large (cafeterias, meeting areas, gymnasiums, recreation rooms), and provide little physical privacy. Regardless of patient circumstances, respecting patient dignity is a professional standard of care, and patient privacy is consistent with that standard. METHODS: Guided by trauma-informed care techniques, emancipatory nursing practice, and cultural safety methodology, student members of the CRRT initiated a project focused on expanding physical privacy protection for those undergoing COVID-19 testing. CONCLUSION: Though the introduction of a portable privacy screen started as an initiative to safeguard the dignity for underserved populations, this call to action implores current and future health care providers to prioritize the ethical treatment of those most vulnerable by advocating for patient dignity and privacy.

Disruption of GPR35 Signaling in Bone Marrow-Derived Cells Does Not Influence Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice.

G-protein-coupled receptor-35 (GPR35) has been identified as a receptor for the tryptophan metabolite kynurenic acid (KynA) and suggested to modulate macrophage polarization in metabolic tissues. Whether GPR35 can influence vascular inflammation and atherosclerosis has however never been tested. Lethally irradiated LdlrKO mice were randomized to receive GPR35KO or wild type (WT) bone marrow transplants and fed a high cholesterol diet for eight weeks to develop atherosclerosis. GPR35KO and WT chimeric mice presented no difference in the size of atherosclerotic lesions in the aortic arch (2.37 ± 0.58% vs. 1.95 ± 0.46%, respectively) or in the aortic roots (14.77 ± 3.33% vs. 11.57 ± 2.49%, respectively). In line with these data, no changes in the percentage of VCAM-1+, IAb + cells, and CD3+ T cells, as well as alpha smooth muscle cell actin expression, was observed between groups. Interestingly, the GPR35KO group presented a small but significant increase in CD68+ macrophage infiltration in the plaque. However, in vitro culture experiments using bone marrow-derived macrophages from both groups indicated that GPR35 plays no role in modulating the secretion of major inflammatory cytokines. Our study indicates that GPR35 expression does not play a direct role in macrophage activation, vascular inflammation, and the development of atherosclerosis.

Sphingosine 1-phosphate-induced nitric oxide production simultaneously controls endothelial barrier function and vascular tone in resistance arteries.

The regulations of endothelial permeability and vascular tone by sphingosine 1-phosphate (S1P) have been well-studied independently. Little is known about whether the effects of S1P on endothelial permeability can directly influence vascular tone in resistance arteries, which impact blood flow. The endothelium forms a partial barrier that regulates access of circulating agonists to underlying vascular smooth muscle cells (VSMCs). We hypothesized that physiological concentrations of circulating S1P simultaneously control endothelial barrier function and vascular tone through endothelial production of nitric oxide (NO). We adapted the pressure myograph system to simultaneously measure both functions in pressurized mesenteric compared to uterine resistance arteries from wild-type and eNOS KO mice. We established that: 1) S1P interacting directly with the endothelium inside pressurized arteries generates NO that limits endothelial permeability; 2) an intact endothelium forms a partial physical barrier that regulates access of intraluminal S1P to the underlying VSMCs and 3) S1P infused lumenally also generates NO through eNOS that counterbalances the constriction induced by S1P that is able to access VSMCs and this is critical to control vascular tone. We conclude that targeting the S1P signaling system, particularly the capacity to produce NO could be clinically important in the treatment of vascular diseases.

Online Versus Telephone Registration: Differences in Quitline Participant Characteristics.

INTRODUCTION: Although 72% of Internet users have searched for health information, online quitline registration is not universally available. In 2014, QUITPLAN Services (Minnesota's quitline) added options (Individual Services: 2-week nicotine-replacement therapy starter kit, text messaging, e-mail messaging, quit guide) to the existing Helpline (telephone counseling, nicotine-replacement therapy, integrated e-mails and texts, quit guide) and online registration for all programs. Demographic and quit outcome differences by registration mode (online versus telephone) and program type (Individual Services versus Helpline) were examined. METHODS: A total of 4 years (March 2014-February 2018) of participants' registration and utilization data (N=55,817) were examined. Data were also studied from subsets of participants who completed the outcome evaluations conducted in 2014 (n=1,127) and 2017 (n=872). Select demographic and program use characteristics and quit outcomes were analyzed by registration method and stratified by program type. Associations between registration mode and quit outcomes were examined within program and adjusted for available covariates using 2017 outcome study data. Data were analyzed in 2019. RESULTS: Overall, 65.8% of participants enrolled online, and 34.2% enrolled by telephone. Helpline participants were more likely to enroll by telephone than Individual Services participants (85.8% vs 25.3%). Younger adults were more likely to enroll online for either program type than older adults (p<0.001). No differences were found in 30-day point prevalence abstinence by registration mode within program after adjusting for covariates. CONCLUSIONS: Online quitline registration has multiple benefits, including engaging younger tobacco users. Moreover, abstinence rates do not differ. Online registration may be particularly appropriate for nontelephone quitline services. Quitlines may wish to add online registration to capitalize on Internet use.

Increasing Sphingolipid Synthesis Alleviates Airway Hyperreactivity.

Impaired sphingolipid synthesis is linked genetically to childhood asthma and functionally to airway hyperreactivity (AHR). The objective was to investigate whether sphingolipid synthesis could be a target for asthma therapeutics. The effects of GlyH-101 and fenretinide via modulation of de novo sphingolipid synthesis on AHR was evaluated in mice deficient in SPT (serine palmitoyl-CoA transferase), the rate-limiting enzyme of sphingolipid synthesis. The drugs were also used directly in human airway smooth-muscle and epithelial cells to evaluate changes in de novo sphingolipid metabolites and calcium release. GlyH-101 and fenretinide increased sphinganine and dihydroceramides (de novo sphingolipid metabolites) in lung epithelial and airway smooth-muscle cells, decreased the intracellular calcium concentration in airway smooth-muscle cells, and decreased agonist-induced contraction in proximal and peripheral airways. GlyH-101 also decreased AHR in SPT-deficient mice in vivo. This study identifies the manipulation of sphingolipid synthesis as a novel metabolic therapeutic strategy to alleviate AHR.

Replicating state Quitline innovations to increase reach: findings from three states.

BACKGROUND: Reaching tobacco users is a persistent challenge for quitlines. In 2014, ClearWay MinnesotaSM changed its quitline services and media campaign, and observed substantial increases in reach and strong quit outcomes. Oklahoma and Florida implemented the same changes in 2015 and 2016. We examined whether the strategies used in Minnesota could be replicated with similar results. METHODS: We conducted a cross-sectional observational study of Minnesota's QUITPLAN® Services, the Oklahoma Tobacco Helpline, and Florida's Quit Your Way program. Each program offers free quitline services to their state's residents. For each state, data were compared for 1 year prior to service changes to 1 year after services changed and promotions began. Registration and program utilization data from 21,918 (Minnesota); 64,584 (Oklahoma); and 141,209 (Florida) program enrollees were analyzed. Additionally, outcome study data from 1542 (Minnesota); 3377 (Oklahoma); and 3444 (Florida) program enrollees were analyzed. We examined treatment reach, satisfaction, 24-h quit attempts, 30-day point prevalence abstinence rates, select demographic characteristics, registration mode (post period only), and estimated number of quitters. Data were analyzed using χ2 analyses and t-tests. RESULTS: Treatment reach rates increased by 50.62% in Oklahoma, 66.88% in Florida, and 480.56% in Minnesota. Significant increases in the estimated number of quitters were seen, ranging from + 42.75% to + 435.90%. Statistically significant changes in other variables (satisfaction, 24-h quit attempts, 30-day point prevalence abstinence rates, gender, and race) varied by state. During the post period, participants' method of registration differed. Online enrollment percentages ranged from 19.44% (Oklahoma), to 54.34% (Florida), to 70.80% (Minnesota). In Oklahoma, 71.63% of participants enrolled by phone, while 40.71% of Florida participants and 26.98% of Minnesota participants enrolled by phone. Fax or electronic referrals comprised 8.92% (Oklahoma), 4.95% (Florida), and 2.22% (Minnesota) of program enrollees, respectively. CONCLUSIONS: Changing quitline services and implementing a new media campaign increased treatment reach and the estimated number of participants who quit smoking in three states. Quitline funders and tobacco control program managers may wish to consider approaches such as these to increase quitline utilization and population health impact.

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).