Age- and Sex-Specific Myocardial Blood Flow Values in Patients Without Coronary Atherosclerosis on Rb-82 PET Myocardial Perfusion Imaging.

BACKGROUND: Quantitative myocardial blood flow (MBF) on positron-emission tomography myocardial perfusion imaging is a measure of the overall health of the coronary circulation. The ability to adequately augment blood flow, measured by myocardial blood flow reserve (MBFR), is associated with lower major adverse cardiovascular events and all-cause mortality. The age-specific ranges of MBFR in patients without demonstrable coronary artery disease have not been well established. We aimed to determine the effect of age and sex on MBF in a cohort of patients without demonstrable coronary artery disease. METHODS: Patients who underwent positron-emission tomography myocardial perfusion imaging studies from 2012 to 2022 on positron-emission tomography/computed tomography cameras were included if the summed stress score was 0, the coronary calcium score was 0, and the left ventricular ejection fraction was ≥50%. Those with known coronary artery disease, prior history of coronary intervention, diabetes, heart/kidney/liver transplant, cirrhosis, or chronic kidney disease stage IV+ were excluded. MBF was calculated using a net retention model (ImagenQ, Cardiovascular Imaging Technologies, Kansas City), and quantile regression models were developed to predict MBF. RESULTS: Among 2789 patients (age 59.9±13.0 years, 76.4% females), median rest MBF was 0.73 (0.60-0.91) mL/min·g, stress MBF was 1.72 (1.41-2.10) mL/min·g, and MBFR was 2.31 (1.96-2.74). Across all ages, males augmented MBF in response to vasodilator stress to a greater degree than females but achieved lower absolute stress MBF. Younger males in particular achieved a higher MBFR than their female counterparts, and this gap narrowed with increasing age. Predicted MBFR for a 20-year-old male was 3.18 and female was 2.50, while predicted MBFR for an 80-year-old male was 2.17 and female was 2.02. CONCLUSIONS: In patients without demonstrable coronary artery disease, MBFR is higher in younger males than younger females and decreases with age in both sexes. Age- and sex-specific MBFR may be important in risk prediction and guidance for revascularization and warrant further study.

Synaptic gene expression changes in frontotemporal dementia due to the MAPT 10+16 mutation.

Mutations in the MAPT gene encoding tau protein can cause autosomal dominant neurodegenerative tauopathies including frontotemporal dementia (often with Parkinsonism). In Alzheimer's disease, the most common tauopathy, synapse loss is the strongest pathological correlate of cognitive decline. Recently, PET imaging with synaptic tracers revealed clinically relevant loss of synapses in primary tauopathies; however, the molecular mechanisms leading to synapse degeneration in primary tauopathies remain largely unknown. In this study, we examined post-mortem brain tissue from people who died with frontotemporal dementia with tau pathology (FTDtau) caused by the MAPT intronic exon 10+16 mutation, which increases splice variants containing exon 10 resulting in higher levels of tau with four microtubule binding domains. We used RNA sequencing and histopathology to examine temporal cortex and visual cortex, to look for molecular phenotypes compared to age, sex, and RNA integrity matched participants who died without neurological disease (n=12 per group). Bulk tissue RNA sequencing reveals substantial downregulation of gene expression associated with synaptic function. Upregulated biological pathways in human MAPT 10+16 brain included those involved in transcriptional regulation, DNA damage response, and neuroinflammation. Histopathology confirmed increased pathological tau accumulation in FTDtau cortex as well as a loss of presynaptic protein staining, and region-specific increased colocalization of phospho-tau with synapses in temporal cortex. Our data indicate that synaptic pathology likely contributes to pathogenesis in FTDtau caused by the MAPT 10+16 mutation.

Making clear and effective communication SOuND BETTeR for patients with communication barriers.

The consequences of ineffective communication between patients and clinicians in the ED range from frustration to significant adverse events. Unfortunately, scenarios where we are unable to understand what our patient is saying to us are common, due to a multitude of factors including acute illness, disability and patient diversity. Current communication aids can be difficult to access and use in the Emergency setting due to lack of physical resources, specific training and time. Our aim was to develop a communication tool which allowed for the rapid identification of urgent patient needs. In order to overcome current challenges, the tool had to be resource-light, quick to use and not reliant on additional staff training or patient education for its effective use. The SOuND BETTeR communication tool is a list of yes/no questions, formatted as a mnemonic, which aims to identify the most common and urgent needs of patients in the ED. As the list of potential needs is not exhaustive, the tool does not purport to replace formal communication aids in the medium and long term, but to bridge the gap often left in the ED where urgent needs must be met and more formal communication aids are not yet available. The tool can effectively and quickly identify important needs in patients with expressive communication barriers such as those with aphasia, facial trauma and on non-invasive ventilation. In addition, the tool can be modified for use in patients with non-English speaking backgrounds. At this stage the tool has not yet been prospectively validated.

Use of Social Media as a Platform for Education and Support for People With Diabetes During a Global Pandemic.

BACKGROUND: Patient education is a fundamental aspect of self-management of diabetes. The aim of this study was to understand whether a social media platform is a viable method to deliver education to people with diabetes and understand if people would engage and interact with it. METHODS: Education sessions were provided via 3 platforms in a variety of formats. "Tweetorials" and quizzes were delivered on the diabetes101 Twitter account, a virtual conference via Zoom and video presentations uploaded to YouTube. Audience engagement during and after the sessions were analyzed using social media metrics including impressions and engagement rate using Twitter analytics, Tweepsmap, and YouTube Studio. RESULTS: A total of 22 "tweetorial" sessions and 5 quizzes with a total of 151 polls (both in tweetorial and quiz sessions) receiving a total of 21,269 votes took place. Overall, the 1-h tweetorial sessions gained 1,821,088 impressions with an engagement rate of 6.3%. The sessions received a total of 2,341 retweets, 2,467 replies and 10,060 likes. The quiz days included 113 polls receiving 16,069 votes. The conference covered 8 topics and was attended live by over 100 people on the day. The video presentations on YouTube have received a total of 2,916 views with a watch time of 281 h and 8,847 impressions. CONCLUSION: Despite the limitations of social media, it can be harnessed to provide relevant reliable information and education about diabetes allowing people the time and space to learn at their own pace.

Successful Thrombectomy for Large Vessel Occlusion after Emergent Transoceanic Patient Transport: An International Hub and Spoke Collaboration.

Mechanical thrombectomy (MT) is the standard of care for the treatment of acute ischemic stroke due to large vessel occlusion, but the capacity to deliver this treatment can be limited in less populous areas and island territories. Here, we describe the case of a man who developed right MCA syndrome while in Bermuda who was successfully diagnosed, transported over 800 miles to the East Coast of the USA, and treated with MT within 24 h. This case underscores the benefits of having organized systems of care and demonstrates the feasibility of urgent transoceanic patient transportation for stroke requiring MT.

Nitrogen and sulfur deposition reductions projected to partially restore forest soil conditions in the US Northeast, while understory composition continues to shift with future climate change.

Human activities have dramatically increased nitrogen (N) and sulfur (S) deposition, altering forest ecosystem function and structure. Anticipating how changes in deposition and climate impact forests can inform decisions regarding these environmental stressors. Here, we used a dynamic soil-vegetation model (ForSAFE-Veg) to simulate responses to future scenarios of atmospheric deposition and climate change across 23 Northeastern hardwood stands. Specifically, we simulated soil percent base saturation, acid neutralizing capacity (ANC), nitrate (NO3 -) leaching, and understory composition under 13 interacting deposition and climate change scenarios to the year 2100, including anticipated deposition reductions under the Clean Air Act (CAA) and Intergovernmental Panel on Climate Change-projected climate futures. Overall, deposition affected soil responses more than climate did. Soils recovered to historic conditions only when future deposition returned to pre-industrial levels, although anticipated CAA deposition reductions led to a partial recovery of percent base saturation (60 to 72%) and ANC (65 to 71%) compared to historic values. CAA reductions also limited NO3 - leaching to 30 to 66% above historic levels, while current levels of deposition resulted in NO3 - leaching 150 to 207% above historic values. In contrast to soils, understory vegetation was affected strongly by both deposition and climate. Vegetation shifted away from historic and current assemblages with increasing deposition and climate change. Anticipated CAA reductions could maintain current assemblages under current climate conditions or slow community shifts under increased future changes in temperature and precipitation. Overall, our results can inform decision makers on how these dual stressors interact to affect forest health, and the efficacy of deposition reductions under a changing climate.

Inhibition of nonsense-mediated decay rescues p53ß/γ isoform expression and activates the p53 pathway in MDM2-overexpressing and select p53-mutant cancers.

Inactivation of p53 is present in almost every tumor, and hence, p53-reactivation strategies are an important aspect of cancer therapy. Common mechanisms for p53 loss in cancer include expression of p53-negative regulators such as MDM2, which mediate the degradation of wildtype p53 (p53α), and inactivating mutations in the TP53 gene. Currently, approaches to overcome p53 deficiency in these cancers are limited. Here, using non-small cell lung cancer and glioblastoma multiforme cell line models, we show that two alternatively spliced, functional truncated isoforms of p53 (p53ß and p53γ, comprising exons 1 to 9ß or 9γ, respectively) and that lack the C-terminal MDM2-binding domain have markedly reduced susceptibility to MDM2-mediated degradation but are highly susceptible to nonsense-mediated decay (NMD), a regulator of aberrant mRNA stability. In cancer cells harboring MDM2 overexpression or TP53 mutations downstream of exon 9, NMD inhibition markedly upregulates p53ß and p53γ and restores activation of the p53 pathway. Consistent with p53 pathway activation, NMD inhibition induces tumor suppressive activities such as apoptosis, reduced cell viability, and enhanced tumor radiosensitivity, in a relatively p53-dependent manner. In addition, NMD inhibition also inhibits tumor growth in a MDM2-overexpressing xenograft tumor model. These results identify NMD inhibition as a novel therapeutic strategy for restoration of p53 function in p53-deficient tumors bearing MDM2 overexpression or p53 mutations downstream of exon 9, subgroups that comprise approximately 6% of all cancers.

Association of perceived stress with health status outcomes in patients with peripheral artery disease.

OBJECTIVE: To assess association of chronic self-perceived stress with health status outcomes of patients with peripheral artery disease. METHODS: The PORTRAIT study is a prospective registry that enrolled 1275 patients with symptoms of peripheral artery disease across 16-sites in US, Netherlands, and Australia from June 2011 to December 2015. Demographics, comorbidities and diagnostic information was abstracted from chart review. Self-perceived stress was assessed using the 4-item perceived stress scale at baseline, 3- and 6-month follow-up. Scores range from 0 to 16 with higher scores indicating greater stress. Sum scores were calculated at each time point and averaged to quantify average exposure to stress from enrollment through 6 months. Disease-specific health status were assessed at baseline and 12-months using the peripheral artery disease questionnaire summary score. RESULTS: The mean age of the analytical cohort (n = 1060) was 67.7 ± 9.3 years, 37.1% were females, and 82.3% were white. Comorbidities were highly prevalent with 80.9% having hypertension, 32.6% having diabetes, and 36.4% being smokers. In models adjusted for demographics, comorbidities, disease severity and socioeconomic status, having a higher average stress score was associated with poorer recovery (from baseline) in peripheral artery disease questionnaire summary score at 12-months (-1.4 points per +1-point increase in averaged 4-point perceived stress score, 95% CI -2.1, -0.6 p < 0.001). CONCLUSION: In patients with peripheral artery disease, experiencing higher chronic stress throughout the 6-months following their diagnosis, was independently associated with poorer recovery in 12-month disease-specific health status outcomes. (ClinicalTrial.gov identifier: NCT01419080).

Abdominal muscle segmentation from CT using a convolutional neural network.

CT is widely used for diagnosis and treatment of a variety of diseases, including characterization of muscle loss. In many cases, changes in muscle mass, particularly abdominal muscle, indicate how well a patient is responding to treatment. Therefore, physicians use CT to monitor changes in muscle mass throughout the patient's course of treatment. In order to measure the muscle, radiologists must segment and review each CT slice manually, which is a time-consuming task. In this work, we present a fully convolutional neural network (CNN) for the segmentation of abdominal muscle on CT. We achieved a mean Dice similarity coefficient of 0.92, a mean precision of 0.93, and a mean recall of 0.91 in an independent test set. The CNN-based segmentation method can provide an automatic tool for the segmentation of abdominal muscle. As a result, the time required to obtain information about changes in abdominal muscle using the CNN takes a fraction of the time associated with manual segmentation methods and thus can provide a useful tool in the clinical application.

Cohort antler size signals environmental stress in a moderate climate.

Research in northern latitudes confirms that climate teleconnections exert important influences on ungulate fitness, but studies from regions with milder climates are lacking. We explored the influence of the Pacific Decadal Oscillation (PDO), Northern Atlantic Oscillation (NAO), and El Niño-Southern Oscillation (ENSO) on male, 2.5-year-old white-tailed deer (Odocoileus virginianus) antler and body mass in Mississippi, USA, a region with mild winters and warm, humid summers. Explanatory variables were seasonal averages of each climate index extending back to 3 years prior to account for possible maternal and lag effects. Seasonal climate indices from the period of gestation and the first year of life were correlated with deer morphometrics. Reduced antler mass was largely correlated (R2 = 0.52) with PDO values indicating dry conditions during parturition and neonatal development and NAO values indicating warmer than normal winters during gestation and the first year of life. Body mass was less correlated (R2 = 0.16) to climate indices, responding negatively to warmer winter weather during the first winter of life. Climate may promote variable fitness among cohorts through long-term effects on male competition for dominance and breeding access. Because broad-scale climate indices simplify complex weather systems, they may benefit management at larger scales. Although this study compared climate with morphological variables, it is likely that demographic characteristics can likewise be modeled using climate indices. As climate change in this region is projected to include greater variability in summer precipitation, we may see concomitantly greater variability in fitness among cohorts of white-tailed deer.

Individualizing Revascularization Strategy for Diabetic Patients With Multivessel Coronary Disease.

BACKGROUND: In patients with diabetes and multivessel coronary artery disease (CAD), the FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial demonstrated that, on average, coronary artery bypass grafting (CABG) was superior to percutaneous coronary intervention (PCI) for major acute cardiovascular events (MACE) and angina reduction. Nonetheless, multivessel PCI remains a common revascularization strategy in the real world. OBJECTIVES: To translate the results of FREEDOM to individual patients in clinical practice, risk models of the heterogeneity of treatment benefit were built. METHODS: Using patient-level data from 1,900 FREEDOM patients, the authors developed models to predict 5-year MACE (all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke) and 1-year angina after CABG and PCI using baseline covariates and treatment interactions. Parsimonious models were created to support clinical use. The models were internally validated using bootstrap resampling, and the MACE model was externally validated in a large real-world registry. RESULTS: The 5-year MACE occurred in 346 (18.2%) patients, and 310 (16.3%) had angina at 1 year. The MACE model included 8 variables and treatment interactions with smoking status (c = 0.67). External validation in stable CAD (c = 0.65) and ACS (c = 0.68) demonstrated comparable performance. The 6-variable angina model included a treatment interaction with SYNTAX score (c = 0.67). PCI was never superior to CABG, and CABG was superior to PCI for MACE in 54.5% of patients and in 100% of patients with history of smoking. CONCLUSIONS: To help disseminate the results of FREEDOM, the authors created a personalized risk prediction tool for patients with diabetes and multivessel CAD that could be used in shared decision-making for CABG versus PCI by estimating each patient's personal outcomes with both treatments.

Correction to: SGLT2 Inhibitors: Cardiovascular Benefits Beyond HbA1c-Translating Evidence into Practice.

In the original publication, Table 2 note was incorrectly published as "SGLT2i therapies may be initiated in people with eGFR 60 mL/min/1.73 m2. Individuals already treated with canagliflozin or empagliflozin who demonstrate renal decline may continue treatment until eGFR reaches < 45 mL/min/1.73 m2".

SGLT2 Inhibitors: Cardiovascular Benefits Beyond HbA1c-Translating Evidence into Practice.

Cardiovascular disease (CVD), including heart failure (HF), is a leading cause of morbidity and mortality in people with type 2 diabetes mellitus (T2DM). CVD and T2DM share common risk factors for development and progression, and there is significant overlap between the conditions in terms of worsening outcomes. In assessing the cardiovascular (CV) safety profiles of anti-diabetic drugs, sodium-glucose co-transporter-2 inhibitor (SGLT2i) therapies have emerged with robust evidence for reducing the risk of adverse CVD outcomes in people with T2DM who have either established CVD or are at risk of developing CVD. A previous consensus document from the Improving Diabetes Steering Committee has examined the potential role of SGLT2is in T2DM management and considered the risk-benefit profile of the class and the appropriate place for these medicines within the T2DM pathway. This paper builds on these findings and presents practical guidance for maximising the pleiotropic benefits of this class of medicines in people with T2DM in terms of reducing adverse CVD outcomes. The Improving Diabetes Steering Committee aims to offer evidence-based practical guidance for the use of SGLT2i therapies in people with T2DM stratified by CVD risk. This is of particular importance currently because some treatment guidelines have not been updated to reflect recent evidence from cardiovascular outcomes trials (CVOTs) and real-world studies that complement the CVOTs. The Improving Diabetes Steering Committee seeks to support healthcare professionals (HCPs) in appropriate treatment selection for people with T2DM who are at risk of developing or have established CVD and examines the role of SGLT2i therapy for these people.Funding: Napp Pharmaceuticals Limited.

Provider-Level Variation in Smoking Cessation Assistance Provided in the Cardiology Clinics: Insights From the NCDR PINNACLE Registry.

Background Studies show suboptimal provision of smoking cessation assistance (counseling or pharmacotherapy) for current smokers attempting to quit. We aimed to identify smoking cessation assistance patterns in US cardiology practices. Methods and Results Among 328 749 current smokers seen between January 1, 2013, and March 31, 2016, in 348 NCDR (National Cardiovascular Data Registry) PINNACLE (Practice Innovation and Clinical Excellence)-affiliated cardiology practices, we measured the rates of cessation assistance. We used multivariable hierarchical logistic regression models to determine provider-, practice-, and patient-level predictors of cessation assistance. We measured provider variation in cessation assistance using median rate ratio (the likelihood that the same patient would receive the same assistance at by any given provider; >1.2 suggests significant variation). Smoking cessation assistance was documented in only 34% of encounters. Despite adjustment of provider, practice, and patient characteristics, there was large provider-level variation in cessation assistance (median rate ratio, 6 [95% CI , 5.76-6.32]). Practice location in the South region (odds ratio [OR], 0.48 [0.37-0.63] versus West region) and rural or suburban location (OR, 0.92 [0.88-0.95] for rural; OR, 0.94 [0.91-0.97] for suburban versus urban) were associated with lower rates of cessation assistance. Similarly, older age (OR, 0.88 [0.88-0.89] per 10-year increase), diabetes mellitus (OR, 0.84 [0.82-0.87]), and atrial fibrillation (OR, 0.93 [0.91-0.96]) were associated with lower odds of receiving cessation assistance. Conclusions In a large contemporary US registry, only 1 in 3 smokers presenting for a cardiology visit received smoking cessation assistance. Our findings suggest the presence of a large deficit and largely idiosyncratic provider-level variation in the provision of smoking cessation assistance.

A synthesis of ecosystem management strategies for forests in the face of chronic nitrogen deposition.

Total nitrogen (N) deposition has declined in many parts of the U.S. and Europe since the 1990s. Even so, it appears that decreased N deposition alone may be insufficient to induce recovery from the impacts of decades of elevated deposition, suggesting that management interventions may be necessary to promote recovery. Here we review the effectiveness of four remediation approaches (prescribed burning, thinning, liming, carbon addition) on three indicators of recovery from N deposition (decreased soil N availability, increased soil alkalinity, increased plant diversity), focusing on literature from the U.S. We reviewed papers indexed in the Web of Science since 1996 using specific key words, extracted data on the responses to treatment along with ancillary data, and conducted a meta-analysis using a three-level variance model structure. We found 69 publications (and 2158 responses) that focused on one of these remediation treatments in the context of N deposition, but only 29 publications (and 408 responses) reported results appropriate for our meta-analysis. We found that carbon addition was the only treatment that decreased N availability (effect size: -1.80 to -1.84 across metrics), while liming, thinning, and prescribed burning all tended to increase N availability (effect sizes: +0.4 to +1.2). Only liming had a significant positive effect on soil alkalinity (+10.5%-82.2% across metrics). Only prescribed burning and thinning affected plant diversity, but with opposing and often statistically marginal effects across metrics (i.e., increased richness, decreased Shannon or Simpson diversity). Thus, it appears that no single treatment is effective in promoting recovery from N deposition, and combinations of treatments should be explored. These conclusions are based on the limited published data available, underscoring the need for more studies in forested areas and more consistent reporting suitable for meta-analyses across studies.

Newspaper Reporting on a Cluster of Suicides in the UK.

BACKGROUND: Media reporting may influence suicide clusters through imitation or contagion. In 2008 there was extensive national and international newspaper coverage of a cluster of suicides in young people in the Bridgend area of South Wales, UK. AIMS: To explore the quantity and quality of newspaper reporting during the identified cluster. METHOD: Searches were conducted for articles on suicide in Bridgend for 6 months before and after the defined cluster (June 26, 2007, to September 16, 2008). Frequency, quality (using the PRINTQUAL instrument), and sensationalism were examined. RESULTS: In all, 577 newspaper articles were identified. One in seven articles included the suicide method in the headline, 47.3% referred to earlier suicides, and 44% used phrases that guidelines suggest should be avoided. Only 13% included sources of information or advice. CONCLUSION: A high level of poor-quality and sensationalist reporting was found during an ongoing suicide cluster at the very time when good-quality reporting could be considered important. A broad awareness of media guidelines and expansion and adherence to press codes of practice are required by journalists to ensure ethical reporting.

Constituent components of out-of-field scatter dose for 18-MV intensity modulated radiation therapy versus 3-dimensional conformal radiation therapy: a comparison with 6-MV and implications for carcinogenesis.

PURPOSE: To characterize and compare the components of out-of-field dose for 18-MV intensity modulated radiation therapy (IMRT) versus 3-dimensional conformal radiation therapy (3D-CRT) and their 6-MV counterparts and consider implications for second cancer induction. METHODS AND MATERIALS: Comparable plans for each technique/energy were delivered to a water phantom with a sloping wall; under full scatter conditions; with field edge abutting but outside the bath to prevent internal/phantom scatter; and with shielding below the linear accelerator head to attenuate head leakage. Neutron measurements were obtained from published studies. RESULTS: Eighteen-megavolt IMRT produces 1.7 times more out-of-field scatter than 18-MV 3D-CRT. In absolute terms, however, differences are just approximately 0.1% of central axis dose. Eighteen-megavolt IMRT reduces internal/patient scatter by 13%, but collimator scatter (C) is 2.6 times greater than 18-MV 3D-CRT. Head leakage (L) is minimal. Increased out-of-field photon scatter from 18-MV IMRT carries out-of-field second cancer risks of approximately 0.2% over and above the 0.4% from 18-MV 3D-CRT. Greater photoneutron dose from 18-MV IMRT may result in further maximal, absolute increased risk to peripheral tissue of approximately 1.2% over 18-MV 3D-CRT. Out-of-field photon scatter remains comparable for the same modality irrespective of beam energy. Machine scatter (C+L) from 18 versus 6 MV is 1.2 times higher for IMRT and 1.8 times for 3D-CRT. It is 4 times higher for 6-MV IMRT versus 3D-CRT. Reduction in internal scatter with 18 MV versus 6 MV is 27% for 3D-CRT and 29% for IMRT. Compared with 6-MV 3D-CRT, 18-MV IMRT increases out-of-field second cancer risk by 0.2% from photons and adds 0.28-2.2% from neutrons. CONCLUSIONS: Out-of-field photon dose seems to be independent of beam energy for both techniques. Eighteen-megavolt IMRT increases out-of-field scatter 1.7-fold over 3D-CRT because of greater collimator scatter despite reducing internal/patient scatter. Out-of-field carcinogenic risk is thus increased (but improved in-field dose conformity may offset this). Potentially increased carcinogenic risk should be weighed against any benefit 18-MV IMRT may provide.

Stromal response to Hedgehog signaling restrains pancreatic cancer progression.

Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention.