Prostaglandin E2 stimulates cAMP signaling and resensitizes human leukemia cells to glucocorticoid-induced cell death.

Glucocorticoid (GC) resistance remains a clinical challenge in pediatric acute lymphoblastic leukemia where response to GC is a reliable prognostic indicator. To identify GC resistance pathways, we conducted a genome-wide, survival-based, short hairpin RNA screen in murine T-cell acute lymphoblastic leukemia (T-ALL) cells. Genes identified in the screen interfere with cyclic adenosine monophosphate (cAMP) signaling and are underexpressed in GC-resistant or relapsed ALL patients. Silencing of the cAMP-activating Gnas gene interfered with GC-induced gene expression, resulting in dexamethasone resistance in vitro and in vivo. We demonstrate that cAMP signaling synergizes with dexamethasone to enhance cell death in GC-resistant human T-ALL cells. We find the E prostanoid receptor 4 expressed in T-ALL samples and demonstrate that prostaglandin E2 (PGE2) increases intracellular cAMP, potentiates GC-induced gene expression, and sensitizes human T-ALL samples to dexamethasone in vitro and in vivo. These findings identify PGE2 as a target for GC resensitization in relapsed pediatric T-ALL.

Smartphone-based financial incentives to promote smoking cessation during pregnancy: A pilot study.

Cigarette smoking during pregnancy increases risk for pregnancy complications, growth restriction, and other adverse health outcomes. The most effective intervention for reducing smoking during pregnancy is financial incentives contingent on biochemically-verified smoking abstinence. The present study examined the efficacy of a smartphone-based intervention whereby smoking monitoring and incentive delivery occurred remotely using a mobile app. If efficacious, this remote intervention would allow pregnant women residing in geographically remote areas to benefit from incentives-based cessation interventions. Sixty U.S. pregnant smokers were recruited between May 2018 to May 2019 via obstetrical clinics, Women, Infants, and Children (WIC) offices, and Facebook. Participants were assigned sequentially to one of two treatments: best practices alone (N = 30) or best practices plus financial incentives (N = 30). Outcomes were analyzed using repeated measures analysis based on generalized estimating equations (GEE). Seven-day point prevalence abstinence rates were greater in the incentives versus best practices arms early- (46.7% vs 20.0%, OR = 3.50, 95%CI = 1.11,11.02) and late-antepartum (36.7% vs 13.3%, OR = 3.76, 95%CI = 1.04,13.65), and four- (36.7% vs 10.0%, OR = 5.21, 95%CI = 1.28,21.24) and eight-weeks postpartum (40.0% vs 6.7%, OR = 9.33, 95%CI = 1.87,46.68), although not at the 12- (23.3% vs 10.0%, OR = 2.74, 95%CI = 0.63,11.82) or 24-week (20.0% vs 6.7%, OR = 3.50, 95%CI = 0.65,18.98) postpartum assessments likely due to this pilot study being underpowered for discerning differences at the later assessments, especially 24-weeks postpartum which was three months after treatment completion. These results support the efficacy of this remote, incentives-based intervention for pregnant smokers. Further research evaluating its efficacy and cost-effectiveness in a well-powered, randomized controlled trial appears warranted.

Leveraging technology to address the problem of cigarette smoking among women of reproductive age.

Women of reproductive age and particularly pregnant women underutilize evidence-based smoking cessation services such as counseling and quit lines. Mobile health (mHealth) may constitute an unexplored and innovative avenue for providing smoking cessation support to a population that is otherwise difficult to reach with evidence-based interventions. Female respondents aged 18-44 years (N = 10,023) were drawn from the first wave of the Population Assessment of Tobacco and Health (PATH) study (2013-2014). We examined prevalence of use of various digital forms of communication (e.g., social media, text messaging, smartphone ownership) among non-pregnant women of reproductive age, pregnant women, and among smokers versus non-smokers within these groups. Multiple logistic regression modeling was conducted to identify correlates of using each digital form adjusting for smoking status, pregnancy, and demographic characteristics. Over two thirds of women overall and within subgroups of non-pregnant and pregnant smokers reported using social media, owning a cell phone, owning a smartphone, downloading apps, and sending/receiving text messages. Current smokers and those with lower educational attainment generally had lower odds of using each digital form relative to non-smokers and those with higher educational attainment, the exception being that smokers had higher odds of using social media relative to non-smokers. The high prevalence of using various digital forms among both non-pregnant smokers of reproductive age and pregnant smokers suggests that leveraging technology to expand access to prevention, education, and treatment resources may reduce smoking-attributable adverse health effects among reproductive-aged women and their offspring.

Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates.

Host recognition and immune-mediated foreign body response to biomaterials can compromise the performance of implanted medical devices. To identify key cell and cytokine targets, here we perform in-depth systems analysis of innate and adaptive immune system responses to implanted biomaterials in rodents and non-human primates. While macrophages are indispensable to the fibrotic cascade, surprisingly neutrophils and complement are not. Macrophages, via CXCL13, lead to downstream B cell recruitment, which further potentiated fibrosis, as confirmed by B cell knockout and CXCL13 neutralization. Interestingly, colony stimulating factor-1 receptor (CSF1R) is significantly increased following implantation of multiple biomaterial classes: ceramic, polymer and hydrogel. Its inhibition, like macrophage depletion, leads to complete loss of fibrosis, but spares other macrophage functions such as wound healing, reactive oxygen species production and phagocytosis. Our results indicate that targeting CSF1R may allow for a more selective method of fibrosis inhibition, and improve biomaterial biocompatibility without the need for broad immunosuppression.

Examining the relationship between pregnancy and quitting use of tobacco products in a U.S. national sample of women of reproductive age.

This study examined quit rates longitudinally for cigarettes, e-cigarettes, hookah, cigars, and all tobacco products in a U.S. national sample of women aged 18-44 who completed both Wave 1 (W1) and Wave 2 (W2) of the Population Assessment of Tobacco and Health (PATH, 2013-2014, 2014-2015) study (N = 7814). Quit rates were examined among women who transitioned into pregnancy across survey waves, and among a comparable sample of non-pregnant women to provide contextual information about quitting among the broader population of reproductive-aged women. Multiple logistic regression modeling was used to estimate the associations of pregnancy and quitting adjusting for other demographic and psychosocial characteristics. Quit rates among women who were pregnant in W2 were highest for hookah (98.3%), followed by cigars (88.0%), e-cigarettes (81.3%), and lowest for tobacco cigarettes (53.4%). Slightly more than half (58.7%) of women reported quitting use all tobacco products while pregnant. Pregnancy was independently associated with increased odds of quitting hookah (AOR = 52.9, 95%CI = 3.4, 830.2), e-cigarettes (AOR = 21.0, 95%CI = 2.6, 170.3), all tobacco products (AOR = 9.6, 95%CI = 6.4, 14.5), and cigarettes (AOR = 6.5, 95%CI = 4.2, 10.1), although not cigars. Relative to other demographic and psychosocial characteristics, pregnancy was the strongest predictor of quitting use of each tobacco product. While these data indicate that pregnancy has strong, independent associations with quitting a variety of commercially available tobacco products, the comparatively lower quit rates for cigarettes versus other tobacco products underscores the long-standing need for more intensive, multipronged clinical and regulatory interventions to reduce cigarette use among reproductive-aged women.

Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates.

The efficacy of implanted biomedical devices is often compromised by host recognition and subsequent foreign body responses. Here, we demonstrate the role of the geometry of implanted materials on their biocompatibility in vivo. In rodent and non-human primate animal models, implanted spheres 1.5 mm and above in diameter across a broad spectrum of materials, including hydrogels, ceramics, metals and plastics, significantly abrogated foreign body reactions and fibrosis when compared with smaller spheres. We also show that for encapsulated rat pancreatic islet cells transplanted into streptozotocin-treated diabetic C57BL/6 mice, islets prepared in 1.5-mm alginate capsules were able to restore blood-glucose control for up to 180 days, a period more than five times longer than for transplanted grafts encapsulated within conventionally sized 0.5-mm alginate capsules. Our findings suggest that the in vivo biocompatibility of biomedical devices can be significantly improved simply by tuning their spherical dimensions.

Evolving trends of pharmaceutical poisonings associated with QRS complex prolongation.

INTRODUCTION: Tricyclic antidepressants often cause drug-induced QRS complex prolongation in overdose but are now less commonly prescribed. We sought to determine, among a contemporary cohort of patients, the pharmaceuticals independently associated with QRS complex prolongation in acute overdose. METHODS: We performed secondary analysis of data from the Toxicology Investigators Consortium (ToxIC) Core Registry. We included adult patients presenting from January 2016 through March 2023 with acute or acute-on-chronic pharmaceutical exposures. The primary outcome was QRS complex prolongation >0.12 s. Secondary outcomes included cardiac arrest, death, ventricular dysrhythmia, intensive care unit admission, initiation of vasopressors, and treatment with sodium bicarbonate. We used a multivariable logistic regression model with QRS complex prolongation as the outcome and individual pharmaceuticals of interest as independent variables. We assessed yearly trends of the contribution of relevant pharmaceuticals to QRS complex prolongation since 2016. RESULTS: Of 11,945 patients in the total cohort (median age 37 years, 6,652 [55.7%] female), 366 (3.1%) developed QRS complex prolongation. Of 9,417 patients included in the model, 290 (3.1%) developed QRS complex prolongation. Amitriptyline, nortriptyline, doxepin, imipramine, noxiptiline, bupropion, flecainide, carvedilol, propranolol, diphenhydramine, and lamotrigine poisonings were independent predictors of QRS complex prolongation. Flecainide poisoning conferred the greatest odds of QRS complex prolongation (OR 574.1; 95% CI: 88.3-12,747). The contribution of tricyclic antidepressants to QRS complex prolongation decreased from 38.8% to 17.6% of all patients with QRS complex prolongation from 2016 to 2022. In 2022, the proportion of QRS complex prolongation from diphenhydramine (20.6%) surpassed that of tricyclic antidepressants. DISCUSSION: This study provides insights into contemporary pharmaceutical poisoning associated with QRS complex prolongation. Tricyclic antidepressants remain clinically relevant exposures but are no longer the most common cause of drug-induced QRS complex prolongation. CONCLUSIONS: Bupropion, diphenhydramine, and antidysrhythmics are increasingly common causes of QRS complex prolongation, each associated with numerous severe outcomes in poisoning. Greater safety measures to protect patients from cardiovascular toxicity from these pharmaceuticals are warranted.

Decreasing Prescribing Errors in Antimicrobial Stewardship Program-Restricted Medications.

OBJECTIVES: Antimicrobial stewardship programs (ASPs) restrict prescribing practices to regulate antimicrobial use, increasing the risk of prescribing errors. This quality improvement project aimed to decrease the proportion of prescribing errors in ASP-restricted medications by standardizing workflow. METHODS: The study took place on all inpatient units at a tertiary care children's hospital between January 2020 and February 2022. Patients <22 years old with an order for an ASP-restricted medication course were included. An interprofessional team used the Model for Improvement to design interventions targeted at reducing ASP-restricted medication prescribing errors. Plan-Do-Study-Act cycles included standardizing communication and medication review, implementing protocols, and developing electronic health record safety nets. The primary outcome was the proportion of ASP-restricted medication orders with a prescribing error. The secondary outcome was time between prescribing errors. Outcomes were plotted on control charts and analyzed for special cause variation. Outcomes were monitored for a 3-month sustainability period. RESULTS: Nine-hundred ASP-restricted medication orders were included in the baseline period (January 2020-December 2020) and 1035 orders were included in the intervention period (January 2021-February 2022). The proportion of prescribing errors decreased from 10.9% to 4.6%, and special cause variation was observed in Feb 2021. Mean time between prescribing errors increased from 2.9 days to 8.5 days. These outcomes were sustained. CONCLUSIONS: Quality improvement methods can be used to achieve a sustained reduction in the proportion of ASP-restricted medication orders with a prescribing error throughout an entire children's hospital.

RSV causes more severe respiratory illness than influenza in admitted children under 2-years-old.

INTRODUCTION: Both respiratory syncytial virus (RSV) and influenza-associated lower respiratory tract infections (LRTI) cause serious respiratory infections in infants and toddlers. We aimed to assess the frequency of complex hospital courses among patients admitted with influenza versus RSV LRTI. METHODS: A retrospective cohort study was performed on admissions of children <2 years who were admitted for LRTI and tested positive for influenza or RSV from 2016 to 2019. The primary outcome, complex hospital course, was a composite including: intensive care unit admission, respiratory support, nasogastric tube feeds, prolonged length of stay, and death. Secondary outcomes included 7-day readmission and time to respiratory support. Differences between RSV and influenza groups were assessed and unadjusted and adjusted regression models and competing risks time to event models were developed. RESULTS: There were 1094 (89%) RSV admissions and 134 (11%) influenza admissions. Children admitted for influenza were significantly older (336 vs. 165 days, p < 0.001), more likely to present with an abnormal heart rate for age (84.3% vs. 73.5%, p < 0.01) and a fever (27.6% vs. 18.9%, p = 0.02). Admissions with RSV were significantly more likely to experience a complex hospital course (ORadj = 3.5, 95% CI: 2.2-5.6). In time to event analysis, RSV admissions had a significantly higher rate of respiratory support (HRadj = 3.2, 95% CI: 2.0, 5.2). Readmission rates were similar. CONCLUSIONS: RSV admissions were associated with a higher risk for a complex hospital course and required higher rates of respiratory support than influenza admissions. This information may help in evaluating hospital resources and admissions.

Household-smoking bans are associated with reduced nicotine exposure, increased smoking abstinence, and improved birth outcomes among pregnant women enrolled in smoking-cessation treatment.

Data indicate household-smoking bans aid cessation and reduce secondhand smoke exposure. This study assessed prevalence of antepartum (AP) and postpartum (PP) household-smoking bans and associations with nicotine exposure, abstinence, and birth weight among pregnant women. The current study is a secondary analysis of clinical trials examining the efficacy of financial incentives for smoking-cessation among pregnant women (N = 284). Participants were current smokers at the start of prenatal care and followed from ∼10 weeks gestational age through 24 weeks PP. Household-smoking rules and biochemically verified urinary cotinine were measured repeatedly. Nicotine exposure and birth weight were analyzed using analysis of covariance. Association with abstinence was analyzed using backward elimination logistic regressions. Prevalence of household-smoking bans increased from ∼ 45% to 55% AP and then increased to ∼80% PP. Women with a ban exhibited lower nicotine exposure in early and late pregnancy compared to smokers without a ban. Women with a ban at baseline or who adopted a ban early in treatment were more likely to be abstinent at late pregnancy and 24 weeks PP compared to women without a ban. There was a dose-response relationship between combined exposure (i.e., smoking and ban status) and infant birth weight, with infants of women who quit and reported a ban having the highest adjusted mean birth weight (3426 ± 63 g), while infants of women who continued smoking without a ban having the lowest (3153 ± 37 g). These results provide an empirical rationale for prospectively investigating whether adopting a household-smoking ban can reduce fetal exposure among pregnant smokers. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Impact of electronic nicotine delivery systems and other respondent characteristics on tobacco use transitions among a U.S. national sample of women of reproductive age.

BACKGROUND: Identifying predictors of tobacco use patterns that differ in harm among reproductive-aged women may inform efforts to protect women and children against adverse health impacts of tobacco use. METHODS: Changes in tobacco use patterns were examined among women (18-49 years) who completed Wave 1 (W1) and Wave 2 (W2), or W2 and Wave 3 (W3) of the U.S. Population Assessment of Tobacco and Health (PATH, 2013-2016) study, and were using cigarettes, filtered cigars and/or cigarillos in the first wave over which data were included for that respondent (Time 1; T1). We examined the proportion of respondents whose tobacco use transitions from T1 to Time 2 (T2) were harm-maintaining (continued using combusted tobacco), harm-reducing (transitioned to electronic nicotine delivery systems (ENDS), or harm-eliminating (quit tobacco). Multinomial logistic regressions (with harm-maintaining as the baseline category) were conducted to examine associations between ENDS use, demographic, and psychosocial characteristics with each transition. RESULTS: A majority of women (83 %) exhibited harm-maintaining transitions, followed by harm-eliminating (14.7 %) and harm-reducing (2.3 %) transitions. Use of ENDS at T1 was associated with increased odds of harm reduction and decreased odds of harm elimination. Younger women were more likely to make both harm-reducing and harm-eliminating transitions. Increased educational attainment, identifying as Black or Hispanic, increased psychiatric symptoms, and pregnancy were associated with harm elimination, whereas living at or above poverty was associated with harm reduction. CONCLUSIONS: Study results contribute new information on the impact of ENDS, sociodemographic characteristics, psychiatric symptoms, and pregnancy on tobacco use transitions among reproductive-aged women.

Using the Cigarette Purchase Task to examine the relative reinforcing value of cigarettes among mothers with versus without opioid dependence.

The Cigarette Purchase Task (CPT), in which participants estimate the number of cigarettes they would smoke across increasing cigarette prices, measures the relative reinforcing value of cigarettes. Although opioid-dependent individuals are particularly vulnerable to tobacco addiction, more research is needed to elucidate whether and to what extent their motivation to smoke differs from not-opioid-dependent smokers controlling for potential sociodemographic differences. Participants were 173 women (65 opioid-dependent) in an ongoing clinical trial for smoking cessation. Baseline CPT responses were compared between opioid-dependent and not-opioid-dependent women using five demand indices: Demand Intensity; Omax; Pmax; Breakpoint (BP); and α, and two latent factors: Amplitude and Persistence. Final regression models adjusted for sociodemographic characteristics differing between the two groups. Opioid-dependent women had greater demand Intensity (i.e., number of cigarettes they would smoke if they were free) than not-opioid dependent women in the adjusted model, F(1, 156) = 6.93, p = .016. No other demand indices differed significantly. Regarding latent factors, demand Amplitude (i.e., volumetric consumption), but not Persistence (i.e., price insensitivity), was greater for opioid-dependent women in the adjusted model, F(1, 146) = 4.04, p = .046. These results further demonstrate that the CPT is a highly sensitive task that can illuminate potentially important individual and population differences in the relative reinforcing value of smoking. Greater demand Intensity and Amplitude differentiated smokers with comorbid opioid dependence; thus, decreasing smoking prevalence among opioid-dependent populations may require policies and interventions that can decrease cigarette demand Intensity and Amplitude. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The pharmacological chaperone 1-deoxynojirimycin increases the activity and lysosomal trafficking of multiple mutant forms of acid alpha-glucosidase.

Pompe disease is a lysosomal storage disorder (LSD) caused by mutations in the gene that encodes acid alpha-glucosidase (GAA). Recently, small molecule pharmacological chaperones have been shown to increase protein stability and cellular levels for mutant lysosomal enzymes and have emerged as a new therapeutic strategy for the treatment of LSDs. In this study, we characterized the pharmacological chaperone 1-deoxynojirimycin (DNJ) on 76 different mutant forms of GAA identified in Pompe disease. DNJ significantly increased enzyme activity and protein levels for 16 different GAA mutants in patient-derived fibroblasts and in transiently transfected COS-7 cells. Additionally, DNJ increased the processing of these GAA mutants to their mature lysosomal forms, suggesting facilitated trafficking through the secretory pathway. Immunofluorescence microscopy studies showed increased colocalization of GAA with the lysosomal marker LAMP2 after incubation with DNJ, confirming increased lysosomal trafficking. Lastly, a GAA structural model was constructed based on the related eukaryotic glucosidase maltase-glucoamylase. The mutated residues identified in responsive forms of GAA are located throughout most of the structural domains, with half of these residues located in two short regions within the catalytic domain. Taken together, these data support further evaluation of DNJ as a potential treatment for Pompe disease in patients that express responsive forms of GAA.

Experimental validation of Monte Carlo (MANTIS) simulated x-ray response of columnar CsI scintillator screens.

PURPOSE: MANTIS is a Monte Carlo code developed for the detailed simulation of columnar CsI scintillator screens in x-ray imaging systems. Validation of this code is needed to provide a reliable and valuable tool for system optimization and accurate reconstructions for a variety of x-ray applications. Whereas previous validation efforts have focused on matching of summary statistics, in this work the authors examine the complete point response function (PRF) of the detector system in addition to relative light output values. METHODS: Relative light output values and high-resolution PRFs have been experimentally measured with a custom setup. A corresponding set of simulated light output values and PRFs have also been produced, where detailed knowledge of the experimental setup and CsI:Tl screen structures are accounted for in the simulations. Four different screens were investigated with different thicknesses, column tilt angles, and substrate types. A quantitative comparison between the experimental and simulated PRFs was performed for four different incidence angles (0 degrees, 15 degrees, 30 degrees, and 45 degrees) and two different x-ray spectra (40 and 70 kVp). The figure of merit (FOM) used measures the normalized differences between the simulated and experimental data averaged over a region of interest. RESULTS: Experimental relative light output values ranged from 1.456 to 1.650 and were in approximate agreement for aluminum substrates, but poor agreement for graphite substrates. The FOMs for all screen types, incidence angles, and energies ranged from 0.1929 to 0.4775. To put these FOMs in context, the same FOM was computed for 2D symmetric Gaussians fit to the same experimental data. These FOMs ranged from 0.2068 to 0.8029. Our analysis demonstrates that MANTIS reproduces experimental PRFs with higher accuracy than a symmetric 2D Gaussian fit to the experimental data in the majority of cases. Examination of the spatial distribution of differences between the PRFs shows that the main reason for errors between MANTIS and the experimental data is that MANTIS-generated PRFs are sharper than the experimental PRFs. CONCLUSIONS: The experimental validation of MANTIS performed in this study demonstrates that MANTIS is able to reliably predict experimental PRFs, especially for thinner screens, and can reproduce the highly asymmetric shape seen in the experimental data. As a result, optimizations and reconstructions carried out using MANTIS should yield results indicative of actual detector performance. Better characterization of screen properties is necessary to reconcile the simulated light output values with experimental data.

Frontline Science: Splenic progenitors aid in maintaining high neutrophil numbers at sites of sterile chronic inflammation.

Neutrophils are constantly generated from hematopoietic stem and progenitor cells in the bone marrow to maintain high numbers in circulation. A considerable number of neutrophils and their progenitors have been shown to be present in the spleen too; however, their exact role in this organ remains unclear. Herein, we sought to study the function of splenic neutrophils and their progenitors using a mouse model for sterile, peritoneal inflammation. In this microcapsule device implantation model, we show chronic neutrophil presence at implant sites, with recruitment from circulation as the primary mechanism for their prevalence in the peritoneal exudate. Furthermore, we demonstrate that progenitor populations in the spleen play a key role in maintaining elevated neutrophil numbers. Our results provide new insight into the role for splenic neutrophils and their progenitors and establish a model to study neutrophil function during sterile inflammation.

Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates.

The foreign body response is an immune-mediated reaction that can lead to the failure of implanted medical devices and discomfort for the recipient. There is a critical need for biomaterials that overcome this key challenge in the development of medical devices. Here we use a combinatorial approach for covalent chemical modification to generate a large library of variants of one of the most widely used hydrogel biomaterials, alginate. We evaluated the materials in vivo and identified three triazole-containing analogs that substantially reduce foreign body reactions in both rodents and, for at least 6 months, in non-human primates. The distribution of the triazole modification creates a unique hydrogel surface that inhibits recognition by macrophages and fibrous deposition. In addition to the utility of the compounds reported here, our approach may enable the discovery of other materials that mitigate the foreign body response.

Neutrophil Responses to Sterile Implant Materials.

In vivo implantation of sterile materials and devices results in a foreign body immune response leading to fibrosis of implanted material. Neutrophils, one of the first immune cells to be recruited to implantation sites, have been suggested to contribute to the establishment of the inflammatory microenvironment that initiates the fibrotic response. However, the precise numbers and roles of neutrophils in response to implanted devices remains unclear. Using a mouse model of peritoneal microcapsule implantation, we show 30-500 fold increased neutrophil presence in the peritoneal exudates in response to implants. We demonstrate that these neutrophils secrete increased amounts of a variety of inflammatory cytokines and chemokines. Further, we observe that they participate in the foreign body response through the formation of neutrophil extracellular traps (NETs) on implant surfaces. Our results provide new insight into neutrophil function during a foreign body response to peritoneal implants which has implications for the development of biologically compatible medical devices.